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Cannabinoids: Plants are medicine and as research continues with these alternative medicines then more information is available when it comes to medical options for various ailments, conditions, diseases, disorders etc… Chiropractor, Dr. Alex Jimenez investigates and brings insight to these developing medicines. How they can help patients, what they can do and what they cannot do.

The marijuana plant are how most know about cannabinoids. It is the most recognized cannabinoid tetrahydrocannabinol (THC), which is the compound that causes feelings of euphoria.

Scientists identified cannabinoids only in cannabis. However, new research has found these same medicinal qualities in many plants, including black pepper, broccoli, carrots, clove, echinacea and ginseng.

These vegetables or spices won’t get you high, but having an understanding of how these different plants affect the human body can lead to vital health discoveries.

For more information, or if you have any questions please feel free to contact us at (915) 850-0900

CBD – Cannabidiol’s Life Changing Properties

CBD – Cannabidiol’s Life Changing Properties

CBD research currently being conducted is showing its medical potential. This has opened doors for antipsychotic, anticancer and anti-inflammatory treatment options among a variety of others. Scientists from all over are publishing studies that are proving CBD is one of the most effective and favorable cannabinoids that promotes proper function of the body’s systems.

Five Properties Of CBD

CBD Medical Benefits

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1. Inhibits Cancer Cell Growth

Studies have supported this claim. By way of Proapoptotic action or apoptosis, Cannabidiol, Tetrahydrocannabinol, Cannabigerol and Cannabichromene in this order are extremely effective in tumor growth reduction in rats and cancerous human prostate cells. Research is still ongoing, but understanding that these cannabinoids stimulate the body’s process of killing cells that no longer function properly or at their optimal level. In traditional chemotherapy both healthy and cancerous cells are destroyed and only works when the cancer cells are replicating more frequently than healthy cells. CBD treatment promotes the body’s natural immune response to cells that are not functioning properly, which eradicates tumors.

2. Pain Reducer

The most common reason people start using marijuana despite its psychoactive affects, is that it also functions, as a pain reliever! People with chronic pain that are tired of taking pain killing opiates, rely on cannabinoid products to deal with pain and eliminate its source, commonly inflammation. Inflammation is the body’s natural response to injury, which floods the injured area with blood and nutrients to aid in rehabilitation. But inflammation creates secondary problems, among them pain and discomfort. Through stimulation of nutrients in the area that is injured, CBD creates negative feedback to inflammatory reactions, as the nutrients that came with the inflammation are already there.

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3. Treats Anxiety

Anxiety along with PTSD affects over 40 million adults in the U.S. Valium and Xanax is what is normally used to treat these conditions. However, CBD products are becoming the preferred treatment, as they have none of the side effects or dependency issues. The effects of CBD have been observed thoroughly by experts and studies have proved its effectiveness, as a dependable alternative for mental disorders. Two receptors in the human brain responsible for sending out Adrenaline and Serotonin are the α2-adrenergic receptor agonist and 5-HT1A receptor antagonist. These receptors both are related to anxiety, depression, insomnia, and other mental disorders when imbalanced.

4. Strengthens The Immune System

Phytocannabinoids are able to balance, reinforce and strengthen the immune system. Cannabinoid products taken daily, work in regulating the immune system. This increases the body’s detection of foreign and potentially dangerous organisms, which include cancer cells.

5. Prevents Muscle Spasms

CBD contains chemically antispasmodic properties. Athletes from all sports love CBD and what it can do. It is a preferred supplement and these oils have proven to prevent muscle spasms and soreness. This is done through lubricating the potassium and calcium pumps within the muscle tissue.

CBD is finding its place, slowly, but surely. It is one of natures own medicines and it is our job to discover and figure how to utilize these properties. Consult a doctor before beginning any treatment of diagnosed or undiagnosed diseases with CBD. For the more severe diseases like diabetes, schizophrenia, epilepsy, which, CBD can treat, but only when used properly.

Medical Benefits

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Endocannabinoid System And The Human Body

Endocannabinoid System And The Human Body

The endocannabinoid system’s discovery has created debate on its conclusions on human health. Because of its capability to target various therapeutic agents that are in different states of disease has piqued interest for researchers.

Some researchers suggest the endocannabinoid system plays a vital role in cellular homeostasis. This could mean that the health of this system could affect the health of the whole body.

What is the endocannabinoid system and why is it important?

This article reviews the basics of the endocannabinoid system and its role in cardiovascular and neurological health and specifically, endocannabinoid system deficiency and the adverse effects on the other body’s systems.

Endocannabinoid System & What It Consists Of

The endocannabinoid system is comprised of two receptors and a series of internally produced compounds. The two main receptors in the endocannabinoid system are the CB1 and CB2 receptors.

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endocannabinoid el paso tx.

Endocannabinoid comes from the fact that cannabinoids from the cannabis plant interact with receptors in the endocannabinoid system. There are many endocannabinoids, the most widely known and studied is;

N-arachidonoylethanolamine (AEA).

AEA increases in times of oxidative stress, inflammation or cell death. Researchers believe that it may be produced as a response to injury when counteracting inflammatory activity. This activity could be the evidence of the systems role in cellular homeostasis.

CB1 and CB2 receptors are found throughout the body. CB1 receptors are primarily found in the nervous system, while CB2 receptors are primarily found in intestinal epithelium cells and immune system cells.

CB1 receptors predominantly interact with THC and other psychoactive compounds from the cannabis plant. This is a logical find because the CB1 receptors are found primarily in the nervous system. This interaction of CB1 receptors and THC could cause certain changes in brain chemistry, which leads to the euphoric feeling produced from cannabis use.

CB2 receptors interact with cannabidiol (CBD) which is a secondary major compound in cannabis. This does not mean that CBD does not interact with CB1 receptors ever, but because these interactions are quite uncommon they are considered unimportant. Because CBD does not have compelling interaction with CB1 receptors, the psychoactive effects from THC are not present.

Both cannabinoid compounds have therapeutic potential. Studies have found these compounds help control chronic inflammation in conditions like IBS (irritable bowel syndrome).

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THC use in modulating endocannabinoid system deficiency has been very limited because of its psychoactive properties. Because of this, THC has become rejected in many U.S. states, the U.S federal government, and in conservative countries around the world. Researchers refrain from investigating its therapeutic properties or recommending it, as an alternative medicine.

Cannabinoid Research Marches On Despite THC Affects

CBD contains the same therapeutic properties as THC, without the psychoactive effects. CBD is under extensive research, as a compound that can help with various diseases and their progression. This has led researchers to create synthetic compounds that mimic CBD and its interaction with CB2 receptors.

The endocannabinoid systems role in cardiovascular health and disease.

Depending on the receptors involved cardiovascular health, and the endocannabinoid system’s activation could lead to beneficial or conflicting effects.

CB1 receptors have been linked to an increase of cardiovascular disease or cardiovascular incidents.  Incidents include heart attack, atherosclerosis (plaque inside the blood vessels ), stroke, kidney dysfunction and liver problems. Animal models and epidemiological studies have shown these findings.

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However, activation of the endocannabinoid system’s CB2 receptors may have cardioprotective properties. Certain animal studies show how the use of synthetic cannabinoids interacting with CB2 receptors could beneficial for heart attacks. This comes from their ability to limit infiltration of cells that cause inflammation by CB2 activation.

The Clinical Significance

The difference between CBD and THC:

THC use, as a therapeutic agent could increase risk of cardiovascular incidents from interaction with CB1 receptors. But CBD also interacts with CB2 receptors and is possible that administration of CBD could lead to cardioprotective effects.

Adult neurogenesis, brain health and the endocannabinoid system

Various research reports show neural-progenitor cells produce endocannabinoids in time of injury and stress. This stimulates cell division in the brain, especially in areas like the hippocampus and sub-ventricles. This division is believed to be produced through interaction of endocannabinoids and CB1 receptors.

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Other reports have shown CB1 deficient mice have a decreased ability in neural progenitor cell division when a nervous system injury occurs. This could mean CB1 deficient mice have less of a chance to recover from stroke or other type of brain injury compared to mice with CB1 at normal levels.

AEA, for example, induces astroglial proliferation in mice. Astroglia are star-shaped neurons thought to be extremely important for brain structure and protection. These are found in various areas like the blood brain barrier. Pharmacological stimulation of CB1 using synthetic cannabinoids has lead to neurogenesis or new growth of nervous tissue.

Can Synthetic Cannabinoids Be Beneficial For Brain Health

Synthetic cannabinoids could be beneficial not just for brain injuries, but could also be utilized as an antidepressant. The synthetic cannabinoid HU210 has been used for this purpose from its ability to modulate the endocannabinoid system and increase neural growth.

Recent studies show that CB1-deficient mice tend to suffer from early age related cognitive impairment or a noticeable and measurable decline in cognitive abilities, which include memory and thinking skills. This could be because CB1 deficient mice cannot regenerate cells in the nervous system, making them succumb faster to age related cellular death. But this is a perfect example of endocannabinoid system deficiencies, which could lead to detrimental effects in humans.

Injury Medical Clinic: Stress Management Care & Treatments

Hemp, What Is It Exactly?

Hemp, What Is It Exactly?

Hemp, is one of the oldest cultivated crops, which was grown thousands of years ago in Asia as a food source. Ancient civilizations wove the strong and durable fibers into clothing and rope.1

It helped Christopher Columbus with the ships he sailed, both the sails and ropes were made of hemp and it was also placed between the planks to help the ships remain watertight.2

Two Plants With Completely Different Uses

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Hemp (Cannabis Sativa)

In this form is cultivated outside the United States (however, the U.S. Government has allowed it to be grown for research purposes) for clothing, paper, dietary supplements, cosmetics, foods, biofuels, and bioplastics. European hemp has less than 0.3% of the psychoactive compound tetrahydrocannabinol (THC), as measured in dried flower tops.3

Marijuana (Cannabis Sativa)

This cannabis sativa is cultivated to maximize the THC content, which is focused in the United States, and used exclusively for recreational and medicinal purposes.

How Hemp Helps The Body

Foods made from the plant are processed from the plant’s seeds and are quite common. Common foods include granola, roasted seeds, milk, and butter. These foods do not appear on drug tests when consumed.

The European strain offers a variety of health benefits without the side effects of the THC.


Powder is made from the oil the of the seeds and then processed into powder. The result is a complete protein that contains all nine essential amino acids plus omega fatty acids and fiber4. When compared to whey or animal protein, hemp powder is low in lysine and leucine.

Can’t Stand Fish?

For essential fatty acids, seeds are rich in healthy fats, which include omega-3,6, and 9 fatty acids. It also contains linoleic acid, and gamma-linolenic acid (GLA).5

Health Benefits Of Phytocannabinoids

The stalk of the plant contains natural compounds called phytocannabinoids. When eaten, they interact with the body’s endocannabinoid system (ECS) and help with stress, as well as, relieve aches, pains, and discomfort. Phytocannabinoids also support brain, bone, digestive health, and promote immune and metabolic function.

The plant contains over 80 different phytocannabinoids that help supplement the cannabinoids in your body makes naturally and support the ECS.6 Legally stalk extracts that are imported from outside of the United States must have less than 0.3% THC.

hemp el paso, tx.


Since 1970, cultivation of cannabis sativa from both the hemp and marijuana plants have been illegal in the U.S. under the federal Controlled Substances Act. Even though some States have legalized marijuana and the federal Farm Bill of 2014 allows States to issue licenses for limited and experimental growth, federal law still prohibits the domestic cultivation, sale, and distribution.8

Hemp products such as, paper, rope, clothing, and bioplastics, have always been available in the United States. Federal law never banned the importation of these products, as long as, the THC content is less than or equal to 0.3 percent.8

Now with people interested in plant nutrition there is a larger availability of hemp-derived foods. These foods are made from sources outside of the U.S. These sources only contain a minimal amount of THC, and are completely legal.

When Buying Hemp Products

When buying a hemp products, make sure that it is made from imported industrial hemp. Buy brands that manufacture with Good Manufacturing Practice (GMP) standards and test their products purity and quality.

  • Food purchases should be from major brands and reputable sources. It’s best to go with organic products, which do not contain pesticides.
  • Hemp oil products should be organic and cold processed. These oils should be refrigerated to avoid rancidity.
  • When buying hemp protein, find brands, which list amino acid content. There should be no additives, i.e. a lot of sugar.

Cannabidiol (CBD) & Phytocannabinoids


  1. [Accessed March 19, 2018]
  2. [Accessed March 19, 2018]
  3. Johnson R. Hemp as an agricultural commodity. Washington, D.C. Library of Congress Congressional Research Service, 2014.
  4. Callaway J. Hempseed as a nutritional resource: An overview. Euphytica 2004;140(1-2):65-72.
  5. Leizer C, Ribnicky D, Poulev A, et al. The composition of hemp seed oil and its potential as an important source of nutrition. J Nutraceut Func Med Foods 2002;2(4):35-53.
  6. Borgelt L, Franson K, Nussbaum A, Wang G. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 2013;33(2):195-209.
  7. Cherney J, Small E. Industrial hemp in North America: production, politics and potential. Agronomy 2016;6(4):58.
  8. Mead A. The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. law. Epilepsy Behav 2017;70(Pt B):149-153.
Cannabidiol for Neurodegenerative Disorders

Cannabidiol for Neurodegenerative Disorders

Neurodegenerative disorders are on the rise worldwide. In the USA alone nearly 5.4 million individuals suffer from Alzheimer’s disease, while roughly 500,000 suffer from Parkinson’s disease. As the American population ages, these numbers are just likely to increase. A large proportion of individuals have direct experience with neurodegenerative disorders either on their own or through their loved ones. Brain disorders like Parkinson’s, Huntington’s or Alzheimer’s, have some of the maximum disease burdens.


Illness burden, according to the World Health Organization, or WHO, characterizes the amount of healthy years that are influenced by disability. Neurodegenerative disorders are more burdensome because they not only affect the person, but also have an enormous financial, emotional and physical effect on households. The disease burden for neurodegenerative disorders has been calculated to be more significant than that of cancers. As scientific research expands into the realm of medical marijuana, and its various beneficial elements, there’s beginning to be significant excitement surrounding the treatment possibilities for neurodegenerative ailments with CBD, or cannabidiol, oil.


Research studies into CBD for neurodegenerative diseases, including Huntington’s, Parkinson’s and Alzheimer’s, appears to be overwhelmingly positive. Not only does CBD, or cannabidiol, treatment target some of the most painful symptoms of these diseases but CBD also seems to indicate little to no side effect risk. For a lot of people managing their symptoms, CBD is offering a ray of hope for an assortment of progressively severe neurological diseases. The purpose of the following article is to demonstrate as well as discuss the effects of cannabidiol for the treatment and prevention of neurodegenerative disorders.


Cannabidiol for Neurodegenerative Disorders: Important New Clinical Applications for this Phytocannabinoid?




Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and anti-oxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ9-tetrahydrocannabinol is already under clinical evaluation in patients with Huntington’s disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ9-tetrahydrocannabinol, i.e. CB1 and CB2 receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB2 receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels.


Keywords: cannabidiol, cannabinoid signalling system, Huntington’s disease, neonatal ischaemia, neuroprotection, Parkinson’s disease


Overview on the Therapeutic Properties of CBD


Cannabidiol (CBD) is one of the key cannabinoid constituents in the plant Cannabis sativa in which it may represent up to 40% of cannabis extracts [1]. However, contrarily to Δ9-tetrahydrocannabinol (Δ9-THC), the major psychoactive plant-derived cannabinoid, which combines therapeutic properties with some important adverse effects, CBD is not psychoactive (it does not activate CB1 receptors [2]), it is well-tolerated and exhibits a broad spectrum of therapeutic properties [3]. Even, combined with Δ9-THC in the cannabis-based medicine Sativex® (GW Pharmaceuticals Ltd, Kent, UK), CBD is able to enhance the beneficial properties of Δ9-THC while reducing its negative effects [4]. Based on this relatively low toxicity, CBD has been studied, even at the clinical level, alone or combined with other phytocannabinoids, to determine its therapeutic efficacy in different central nervous system (CNS) and peripheral disorders [3]. In the CNS, CBD has been reported to have anti-inflammatory properties, thus being useful for neuroinflammatory disorders [5], including multiple sclerosis for which CBD combined with Δ9-THC (Sativex®) has been recently licenced as a symptom-relieving agent for the treatment of spasticity and pain [6]. Based on its anticonvulsant properties, CBD has been proposed for the treatment of epilepsy [7–9], and also for the treatment of sleep disorders based on its capability to induce sleep [10]. CBD is also anti-emetic, as are most of the cannabinoid agonists, but its effects are independent of CB1 receptors and are possibly related to its capability to modulate serotonin transmission (see [11] and below). CBD has antitumoural properties that explain its potential against various types of cancer [12, 13]. Moreover, CBD has recently shown an interesting profile for psychiatric disorders, for example, it may serve as an antipsychotic and be a promising compound for the treatment of schizophrenia [14–17], but it also has potential as an anxiolytic [18] and antidepressant [19], thus being also effective for other psychiatric disorders. Lastly, based on the combination of its anti-inflammatory and anti-oxidant properties, CBD has been demonstrated to have an interesting neuroprotective profile as indicated by results obtained through intense preclinical research into numerous neurodegenerative disorders, in particular the three disorders addressed in this review, neonatal ischaemia (CBD alone) [20], Huntington’s disease (HD) (CBD combined with Δ9-THC as in Sativex®) [21–23] or Parkinson’s disease (PD) (CBD probably combined with the phytocannabinoid Δ9-tetrahydrocannabivarin, Δ9-THCV) [24, 25], work that has recently progressed to the clinical area in some specific cases [26]. The neuroprotective potential of CBD for the management of certain other neurodegenerative disorders, e.g. Alzheimer’s disease, stroke and multiple sclerosis, has also been investigated in studies that have yielded some positive results [27–33]. However, these data will be considered here only very briefly.


Overview on the Mechanisms of Action of CBD


The therapeutic properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ9-THC, i.e. CB1 and CB2 receptors. CBD has in general negligible activity at these cannabinoid receptors [2], so it has been generally assumed that most of its pharmacological effects are not a priori pharmacodynamic in nature and related to the activation of specific signalling pathways, but related to its innate chemical properties, in particular with the presence of two hydroxyl groups (see below) that enables CBD to have an important anti-oxidant action [2]. However, in certain pathological conditions (i.e. damage of immature brain), CBD has shown some activity at the CB2 receptor exerted directly ([20], see also Table 1) or indirectly through an inhibitory effect on the mechanisms of inactivation (i.e. transporter, FAAH enzyme) of endocannabinoids [34, 35], enhancing the action of these endogenous molecules at the CB2 receptor but also at the CB1 and at other receptors for endocannabinoids, i.e. TRPV1 [35] and TRPV2 [36] receptors.


Table 1 CBD Reported Functions


However, the anti-oxidant profile of CBD, as well as the few effects it exerts through targets within the endocannabinoid system in certain pathophysiological conditions, cannot completely explain all of the many pharmacological effects of CBD, prompting a need to seek out possible targets for this phytocannabinoid outside the endocannabinoid system. There is, indeed, already evidence that CBD can affect serotonin receptors (i.e. 5HT1A) [18, 19, 28], adenosine uptake [37], nuclear receptors of the PPAR family (i.e. PPAR-γ) [38, 39] and many other pharmacological targets (see Table 1 including references [40–56]). In part, this information derives from numerous studies directed at identifying the pharmacological actions that CBD produces in vitro. This phytocannabinoid has been found to display a wide range of actions in vitro some at concentrations in the submicromolar range, and others at concentrations between 1 and 10 µm or above 10 µm. Its pharmacological targets include a number of receptors, ion channels, enzymes and cellular uptake processes (summarized in Table 1). There is evidence too that CBD can inhibit delayed rectifier K+ and L-type Ca2+ currents and evoked human neutrophil migration, activate basal microglial cell migration, and increase membrane fluidity, all at submicromolar concentrations, and that at concentrations between 1 and 10 µm it can inhibit the proliferation of human keratinocytes and of certain cancer cells (reviewed in [44]). At concentrations between 1 and 10 µm, CBD has also been reported to be neuroprotective, to reduce signs of oxidative stress, to modulate cytokine release and to increase calcium release from neuronal and glial intracellular stores (reviewed in [44]), and at 15 µM to induce mRNA expression of several phosphatases in prostate and colon cancer cells [57].


As will be discussed in the following section, the question of which of these many actions contributes most towards the beneficial effects that CBD displays in vivo in animal models of neurodegenerative disorders such as PD and HD remains to be fully investigated. Also still to be explored is the possibility that CBD may ameliorate signs and symptoms of such disorders and others (i.e. psychiatric disorders), at least in part, by potentiating activation of 5-HT1A receptors by endogenously released serotonin. Thus, although CBD only activates the 5-HT1A receptor at concentrations above 10 µm (Table 1), it can, at the much lower concentration of 100 nm enhance the ability of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin to stimulate [35S]-GTPγS binding to rat brainstem membranes [58]. Furthermore, there is evidence first, that activation of 5-HT1A receptors can ameliorate specific symptoms in PD [59, 60] and second, that beneficial effects displayed by CBD in vivo in animal models of ischaemic injury [27, 28], hepatic encephalopathy [61], anxiety, stress and panic [18, 62–64], depression [19], pain [65] and nausea and vomiting [66] are all mediated by increased activation of the 5-HT1A receptor. Importantly, the dose–response curve of CBD for the production of its effects in several of these models has been found to be bell-shaped [19, 28, 62, 65, 67, 68]. This is a significant observation since it strengthens the hypothesis that CBD can act in vivo to potentiate 5-HT-induced activation of 5-HT1A receptors. Thus, the concentration–response curve of CBD for its enhancement of 8-hydroxy-2-(di-n-propylamino)tetralin-induced stimulation of [35S]-GTPγS binding to rat brainstem membranes is also bell-shaped [58].


CBD as a Neuroprotective Agent


In contrast to the neuroprotective properties of cannabinoid receptor agonists [69, 70], those of CBD do not seem to be attributable to the control of excitotoxicity via the activation of CB1 receptors and/or to the control of microglial toxicity via the activation of CB2 receptors. Thus, except in preclinical models of neonatal ischaemia (see below and [20]), CBD has been found not to display any signs of CB1 or CB2 receptor activation, and yet is no less active than cannabinoid receptor agonists against the brain damage produced by different types of cytotoxic insults ([71–75], reviewed in [76]). What then are the cannabinoid receptor-independent mechanisms by which CBD acts as a neuroprotective agent? Finding the correct answer to this question is not easy, although data obtained in numerous investigations into different pathological conditions associated with brain damage indicate that CBD does normalize glutamate homeostasis [71, 72], reduce oxidative stress [73, 77] and attenuate glial activation and the occurrence of local inflammatory events [74, 78]. Furthermore, a recent study by Juknat et al. [79] has strongly demonstrated the existence of notable differences in the genes that were altered by CBD (not active at CB1 or CB2 receptors) and those altered by Δ9-THC (active at both these receptors) in inflammatory conditions in an in vitro model. These authors found a greater influence of CBD on genes controlled by nuclear factors known to be involved in the regulation of stress responses (including oxidative stress) and inflammation [79]. This agrees with the idea that there may be two key processes underlying the neuroprotective effects of CBD. The first and the most classic mechanism is the capability of CBD to restore the normal balance between oxidative events and anti-oxidant endogenous mechanisms [69] that is frequently disrupted in neurodegenerative disorders, thereby enhancing neuronal survival. As has been mentioned above [73, 77], this capability seems to be inherent to CBD and structurally-similar compounds, i.e. Δ9-THC, cannabinol, nabilone, levonantradol and dexanabinol, as it would depend on the innate anti-oxidant properties of these compounds and be cannabinoid receptor-independent. Alternatively, or in addition, the anti-oxidant effect of CBD may involve intracellular mechanisms that enhance the ability of endogenous anti-oxidant enzymes to control oxidative stress, in particular the signaling triggered by the transcription factor nuclear factor-erythroid 2-related Factor 2 (nrf-2), as has been found in the case of other classic anti-oxidants. According to this idea, CBD may bind to an intracellular target capable of regulating this transcription factor which plays a major role in the control of anti-oxidant-response elements located in genes encoding for different anti-oxidant enzymes of the so-called phase II-anti-oxidant response (see proposed mechanism in Figure 1). This possibility is presently under investigation (reviewed in [69]).


Figure 1 Mechanisms Exerted by CBD


The second key mechanism for CBD as a neuroprotective compound involves its anti-inflammatory activity that is exerted by mechanisms other than the activation of CB2 receptors, the canonic pathway for the anti-inflammatory effects of most of cannabinoid agonists [70]. Anti-inflammatory effects of CBD have been related to the control of microglial cell migration [80] and the toxicity exerted by these cells, i.e. production of pro-inflammatory mediators [81], similarly with the case of cannabinoid compounds targeting the CB2 receptor [70]. However, a key element in this CBD effect is the inhibitory control of NFκB signalling activity and the control of those genes regulated by this transcription factor (i.e. iNOS) [31, 81]. This inhibitory control of NFκB signalling may be exerted by reducing the phosphorylation of specific kinases (i.e. p38 MAP kinase) involved in the control of this transcription factor and by preventing its translocation to the nucleus to induce the expression of pro-inflammatory genes [31]. However, it has been recently proposed that CBD may bind the nuclear receptors of the PPAR family, in particular the PPAR-γ[38, 39] (Table 1) and it is well known that these receptors antagonize the action of NFκB, reducing the expression of pro-inflammatory enzymes (i.e. iNOS, COX-2), pro-inflammatory cytokines and metalloproteases, effects that are elicited by different cannabinoids including CBD (reviewed in [9, 39]). Therefore, it could well be that CBD may produce its anti-inflammatory effects by the activation of these nuclear receptors and the regulation of their downstream signals although various aspects of this mechanism are pending further research and confirmation (see proposed mechanism in Figure 1).


Other mechanisms proposed for the neuroprotective effects of CBD include: (i) the contribution of 5HT1A receptors, e.g. in stroke [27, 28], (ii) the inhibition of adenosine uptake [37], e.g. in neonatal ischaemia ([20], see below) and (iii) specific signalling pathways (e.g. WNT/β-catenin signaling) that play a role in β-amyloid-induced GSK-3β activation and tau hyperphosphorylation in Alzheimer’s disease [82].


CBD in Specific Neurodegenerative Disorders: from Basic to Clinical Studies


Although the neuroprotective properties of CBD have been already examined in numerous acute or chronic neurodegenerative disorders, we will address here only three disorders, i.e. neonatal ischaemia, HD and PD, in which a clinical evaluation of CBD, as monotherapy or in combination with other phytocannabinoids, is already in progress or may be developed soon. CBD has demonstrated significant effects in preclinical models of these three disorders, but, in some cases, its combination with other phytocannabinoids (i.e. Δ9-THC for HD, Δ9-THCV for PD) revealed some interesting synergies that may be extremely useful at the clinical level.


CBD and Neonatal Ischaemia


Brain damage by hypoxia-ischaemia (HI) affects 0.3% subjects over 65 years old in developed countries leading to more than 150 000 deaths per year in the USA (for review see [83]). Although less prevalent, newborn hypoxic-ischaemic brain damage (NHIBD) is of great importance too. Approximately 0.1–0.2% live term births experience perinatal asphyxia with one third of them developing a severe neurological syndrome. About 25% of severe NHIBD leads to lasting sequelae and about 20% to death. Energy failure during ischaemia provokes the dysfunction of ionic pumps in neurons, leading to accumulation of ions and excitotoxic substances such as glutamate. The consequent increase in intracellular calcium content aggravates the neuron dysfunction and activates different enzymes, starting different processes of immediate and programmed cell death. During post ischaemic reperfusion, inflammation and oxidative stress aggravate and amplify such responses, increasing and spreading neuron and glial cell damage. Excitotoxicity, inflammation and oxidative stress play, therefore, a particularly relevant role in HI-induced brain cell death in newborns [83].


Unfortunately, the therapeutic outcome in NHIBD is still very limited and there is a strong need for novel strategies. We have solid evidence that CBD may be a good candidate to be tested in NHIBD at the clinical level. Using forebrain slices from newborn mice subjected to glucose-oxygen deprivation, a well-known in vitro model of NHIBD, we have already reported that CBD is able to reduce necrotic and apoptotic damage [20]. This neuroprotective effect is related to the modulation of excitotoxicity, oxidative stress and inflammation, as CBD normalizes the release of glutamate and cytokines as well as the induction of iNOS and COX-2 [20]. Surprisingly, we found that co-incubation of CBD with the CB2 receptor antagonist AM-630 abolished all these protective effects, suggesting that CB2 receptors are somehow involved in neuroprotective effects of CBD in immature brain [20]. In addition, adenosine receptors, in particular A2A receptors, seem to be also involved in these neuroprotective effects of CBD in the immature brain as revealed by the fact that the effect of CBD in this model was abolished by co-incubation with the A2A receptor antagonist SCH58261 [20]. CBD has been tested further in an in vivo model of NHIBD in newborn pigs, which closely resembles the actual human condition. In this model, the administration of CBD after the HI insult also reduces immediate brain damage by modulating cerebral haemodynamic impairment and brain metabolic derangement, and preventing the appearance of brain oedema and seizures. These neuroprotective effects are not only free from side effects but also associated with some beneficial cardiac, haemodynamic and ventilatory effects [84]. These protective effects restore neurobehavioural performance in the following 72 h post HI [85].


CBD and Huntington’s Disease


HD is an inherited neurodegenerative disorder caused by a mutation in the gene encoding the protein huntingtin. The mutation consists of a CAG triplet repeat expansion translated into an abnormal polyglutamine tract in the amino-terminal portion of huntingtin, which due to a gain of function becomes toxic for specific striatal and cortical neuronal subpopulations, although a loss of function in mutant huntingtin has been also related to HD pathogenesis (see [86] for review). Major symptoms include hyperkinesia (chorea) and cognitive deficits (see [87] for review). At present, there is no specific pharmacotherapy to alleviate motor and cognitive symptoms and/or to arrest/delay disease progression in HD. Thus, even though a few compounds have produced encouraging effects in preclinical studies (i.e. minocycline, coenzyme Q10, unsaturated fatty acids, inhibitors of histone deacetylases) none of the findings obtained in these studies have yet led on to the development of an effective medicine [88]. Importantly, therefore, following on from an extensive preclinical evaluation using different experimental models of HD, clinical tests are now being performed with cannabinoids, and this includes the use of CBD combined with Δ9-THC [26]. To get here, CBD was first studied in rats lesioned with 3-nitropropionic acid, a mitochondrial toxin that replicates the complex II deficiency characteristic of HD patients and that provokes striatal injury by mechanisms that mainly involve the Ca++-regulated protein calpain and generation of ROS. Neuroprotective effects in this experimental model were found with CBD alone [21] or combined with Δ9-THC as in Sativex®[22], and in both cases, these effects were not blocked by selective antagonists of either CB1 or CB2 receptors, thus supporting the idea that these effects are caused by the anti-oxidant and cannabinoid receptor-independent properties of these phytocannabinoids. It is possible, however, that this anti-oxidant/neuroprotective effect of phytocannabinoids involves the activation of signalling pathways implicated in the control of redox balance (i.e. nrf-2/ARE), as mentioned before. CBD has also been studied in rats lesioned with malonate, a model of striatal atrophy that involves mainly glial activation, inflammatory events and activation of apoptotic machinery. CBD alone did not provide protection in this model as only CB2 receptor agonists were effective [89], but the combination of CBD with Δ9-THC used in Sativex® was highly effective in this model, by preserving striatal neurons, and this protective effect involved both CB1 and CB2 receptors [23]. It is interesting to note that Δ9-THC alone produced biphasic effects in this model whereas CB1 receptor blockade aggravated the striatal damage [90]. We are presently studying the efficacy of this phytocannabinoid combination in a transgenic murine model of HD, i.e. R6/2 mice, in which the activation of both CB1 and CB2 receptors has already been found to induce beneficial effects [91, 92]. This solid preclinical evidence has provided substantial support for the evaluation of Sativex®, or equivalent cannabinoid-based medicines, as a new disease-modifying therapy in HD patients. Previous clinical studies had already used CBD, but they concentrated on symptom relief (i.e. chorea) rather than on disease progression and they did not show any significant improvement [93, 94]. We are presently engaged in a novel phase II-clinical trial with Sativex® as a disease-modifying agent in presymptomatic and early symptomatic patients [26], the outcome of which will be known soon.


CBD and Parkinson’s Disease


PD is also a progressive neurodegenerative disorder whose aetiology has been, however, associated with environmental insults, genetic susceptibility or interactions between both causes [95]. The major clinical symptoms in PD are tremor, bradykinesia, postural instability and rigidity, symptoms that result from the severe dopaminergic denervation of the striatum caused by the progressive death of dopaminergic neurons of the substantia nigra pars compacta[96]. CBD has also been found to be highly effective as a neuroprotective compound in experimental models of parkinsonism, i.e. 6-hydroxydopamine-lesioned rats, by acting through anti-oxidant mechanisms that seem to be independent of CB1 or CB2 receptors [24, 25, 97]. This observation is particularly important in the case of PD due to the relevance of oxidative injury to this disease, and because the hypokinetic profile of cannabinoids that activate CB1 receptors represents a disadvantage for this disease because such compounds can acutely enhance rather than reduce motor disability, as a few clinical data have already revealed (reviewed in [98]). Therefore, major efforts are being directed at finding cannabinoid molecules that may provide neuroprotection through their anti-oxidant properties and that may also activate CB2 receptors, but not CB1 receptors, or that may even block CB1 receptors, actions which may provide additional benefits, for example by relieving symptoms such as bradykinesia. One interesting example of a compound with this profile is the phytocannabinoid Δ9-THCV, which is presently under investigation in preclinical models of PD [25]. Thus, there could well be clinical advantages to administering Δ9-THCV together with CBD as this might induce symptomatic relief (due to the blockade of CB1 by Δ9-THCV) and neuroprotection (due to the anti-oxidant and anti-inflammatory properties of both CBD and Δ9-THCV). The combination of CBD with Δ9-THCV (rather than with Δ9-THC) would merit investigation in parkinsonian patients (reviewed in [9, 99]), as previous data obtained in clinical studies have indicated that CBD was effective in the relief of some PD-related symptoms such as dystonia, although not in others like tremor [100], but its combination with Δ9-THC, which can activate CB1 receptors, failed to improve parkinsoniam symptoms or to attenuate levodopa-induced dyskinesias [101].



Dr. Alex Jimenez’s Insight

Because the number of neurodegenerative diseases are likely to continue to grow as time passes, the race is on to discover effective treatment options for these debilitating conditions. The choices available today are restricted in scope, and therefore are typically costly. They also have side effects which should be carefully considered. Many of the most common drugs and/or medications used for Parkinson’s disease and Alzheimer’s disease cause nausea, vomiting, digestive issues, and decreased appetite, just to mention a couple. However, the use of cannabidiol, or CBD, is demonstrated to provide many health benefits without the harmful side-effects of many of these drugs and/or medications. It’s essential for healthcare professionals and researchers to continue in the search for evidence regarding the use of CBD for neurodegenerative diseases.


Concluding Remarks and Futures Perspectives


The experimental evidence presented in this review supports the idea that, from a pharmaceutical point of view, CBD is an unusually interesting molecule. As presented above, its actions are channeled through several biochemical mechanisms and yet it causes essentially no undesirable side effects and its toxicity is negligible [2]. It has shown valuable activities in numerous pharmaceutically important areas: (i) it is a potent anti-oxidant [73], which may partly explain its neuroprotective effects in PD [24, 25], and possibly in cerebral ischaemia-reperfusion (reviewed in [83]), (ii) it has been evaluated in human epileptic patients with very positive results [7–9], (iii) it has shown activity in mice with several autoimmune diseases, i.e. type-1 diabetes [102] and rheumatoid arthritis [103], (iv) it lowers the effects of myocardial ischaemic-reperfusion injury in mice [104], (v) it reduces microglial activation in mice and hence may slow the progression of Alzheimer’s disease [78], (vi) it protects against hepatic ischaemia/reperfusion injury in animals [105] and has shown considerable activity in an animal model of hepatic encephalopathy [106], (vii) it even lowers anxiety (in humans) [107] and (viii) it is already in use, together with Δ9-THC, in a buccal spray (Sativex®) to lower symptoms of multiple sclerosis [6]. The presence of CBD in Sativex® enhances the positive effects of Δ9-THC whilst reducing its adverse effects, in concordance with previous data that indicated that CBD alters some of the effects of Δ9-THC, i.e. it lowers the acute memory-impairing effects and anxiety produced by Δ9-THC [108]. In addition, cannabis with high CBD content presumably leads to fewer psychotic experiences than cannabis with a highest proportion of Δ9-THC [17].


It is possible that CBD has not become a licensed medicine (except in Sativex®) because of patenting problems. However, commercial issues apart, CBD has tremendous potential as a new medicine. Thus, because the mechanisms that underlie its anti-inflammatory effects are different from those of prescribed drugs, it could well prove to be of considerable benefit to a large number of patients, who for various reasons are not sufficiently helped by existing drugs. In type 1-diabetes, we have shown that in mice CBD very significantly lowers the number of insulin-producing cells that are affected even after the disease has advanced [102]. Its neuroprotective effects are extremely valuable as no drugs exist that have similar properties. Surprisingly very few CBD derivatives have been evaluated and compared with CBD. At least one of them, CBD-dimethylheptyl-7-oic acid, is more potent than CBD as an anti-inflammatory agent [109]. Aren’t we missing a valuable new pathway to a family of very promising new therapeutic agents?




The experimental work carried out by our group and that has been mentioned in this review article, has been supported during the last years by grants from CIBERNED (CB06/05/0089), MICINN (SAF2009-11847), CAM (S2011/BMD-2308) and GW Pharmaceuticals Ltd. The authors are indebted to all colleagues who contributed in this experimental work and to Yolanda García-Movellán for administrative support.


Competing Interests


JFR, OS and CG are supported by GW Pharma for research on phytocannabinoids and motor disorders. JMO and MRP have received funds for research from GW Pharma, Ltd. RP’s research is supported in part by funding from GW Pharmaceuticals. RM is a consultant of GW Pharma.


Cannabis, the Endocannabinoid System and Good Health


As healthcare professionals continue to sort through the emerging research studies of cannabis and cannabinoids, one thing remains clear: a more functional endocannabinoid system is fundamental for overall health and wellness. From embryonic implantation on the walls of our mother’s uterus, to nursing and growth, to reacting to injuries, endocannabinoids help us survive in a quickly changing and increasingly hostile atmosphere. As a result, many researchers began to wonder, can an individual enrich their endocannabinoid system by taking supplemental cannabis? Beyond treating symptoms, beyond even curing disease, can cannabis help us prevent disease and promote health by sparking a system that is hard-wired into most people?


Research studies have demonstrated that small doses of cannabinoids from cannabis can indicate the body to create more endocannabinoids and construct more cannabinoid receptors. That is why many first-time cannabis users do not feel a consequence, but by their second or third time working with the herb they have assembled more cannabinoid receptors and are ready to respond. More receptors raise a person’s sensitivity to cannabinoids; smaller doses have bigger impacts, and the patient has an enhanced baseline of endocannabinoid activity. Healthcare professionals believe that small, regular doses of cannabis may function as a tonic to our most central physiologic therapeutic system.


Unlike artificial derivatives, herbal cannabis may contain over one hundred distinct cannabinoids, including THC, which all work synergistically to produce better medical effects and less side effects than THC alone. While cannabis is safe and works well when smoked, most patients prefer to avoid respiratory irritation and instead use a vaporizer, cannabis tincture, or topical salve. Scientific inquiry and patient testimonials indicate that herbal cannabis has superior medical qualities to synthetic cannabinoids. Of course, we want more human-based research analyzing the effectiveness of cannabis, but the evidence base is currently large and growing continuously, despite the DEA’s best efforts to dissuade cannabis-related research.


People today need safe, natural and inexpensive remedies that stimulate our bodies’ ability to self-heal and assist our population to enhance the quality of life. Medical cannabis is just one such option. The purpose of this article has been to spread the knowledge and assist to educate patients and healthcare professionals around the evidence behind the medical use of cannabis and cannabinoids and its health benefits, including its effects on neurodegenerative disorders. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


Curated by Dr. Alex Jimenez


Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.


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EXTRA IMPORTANT TOPIC: Low Back Pain Management


MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments


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Cannabidiol for Treatment and Prevention of Movement Disorders

Cannabidiol for Treatment and Prevention of Movement Disorders

An astonishing one million Americans have Parkinson’s disease, making it the second most common neurodegenerative disorder after Alzheimer’s. This impacts more people than those influenced with other movement disorders like ALS, muscular dystrophy or multiple sclerosis, combined. Characterized by involuntary tremors and debilitating chronic pain, movement disorders are incredibly painful. They impact an individual’s well-being, which makes it hard to interact socially, and the expensive drugs and/or medications can often plummet the patient’s circumstance.


The problem is, there’s no known cure for movement disorders. Worse, no one yet knows how to prevent them. Not only do people suffer from them, they also have to rely on treatment approaches with harsh side effects for the remainder of their lives. However, there’s a new treatment in the forefront of movement disorder research, CBD oil. The results are nothing short of miraculous, reducing tremors and lessening pain. CBD is a abbreviation for cannabidiol oil. Created with an extraction process utilizing either the marijuana or hemp plant. Extracting the CBD provides the consumer the amazing medical benefits without the effects of THC. Because there are no psychedelic properties in CBD, studies have demonstrated it is completely safe for consumption. The purpose of the article below is to demonstrate as well as discuss cannabidiol as a promising strategy to treat and prevent movement disorders.


Cannabidiol as a Promising Strategy to Treat and Prevent Movement Disorders?




Movement disorders such as Parkinson’s disease and dyskinesia are highly debilitating conditions linked to oxidative stress and neurodegeneration. When available, the pharmacological therapies for these disorders are still mainly symptomatic, do not benefit all patients and induce severe side effects. Cannabidiol is a non-psychotomimetic compound from Cannabis sativa that presents antipsychotic, anxiolytic, anti-inflammatory, and neuroprotective effects. Although the studies that investigate the effects of this compound on movement disorders are surprisingly few, cannabidiol emerges as a promising compound to treat and/or prevent them. Here, we review these clinical and pre-clinical studies and draw attention to the potential of cannabidiol in this field.


Keywords: cannabidiol, movement disorders, Parkinson’s disease, Huntington’s disease, dystonic disorders, cannabinoids


Cannabidiol (CBD)


Cannabidiol (CBD) is one of the over 100 phytocannabinoids identified in Cannabis sativa (ElSohly and Gul, 2014), and constitutes up to 40% of the plant’s extract, being the second most abundant component (Grlic, 1976). CBD was first isolated from marijuana in 1940 by Adams et al. (1940) and its structure was elucidated in 1963 by Mechoulam and Shvo (1963). Ten years later, Perez-Reyes et al. (1973) reported that, unlike the main constituent of cannabis Δ9-tetrahydrocannabinol (Δ9-THC), CBD does not induce psychological effects, leading to the suggestion that CBD was an inactive drug. Nonetheless, subsequent studies demonstrated that CBD modulates the effects of Δ9-THC and displays multiple actions in the central nervous system, including antiepileptic, anxiolytic and antipsychotic effects (Zuardi, 2008).


Interestingly, CBD does not induce the cannabinoid tetrad, namely hypomotility, catalepsy, hypothermia, and antinociception. In fact, CBD mitigates the cataleptic effect of Δ9-THC (El-Alfy et al., 2010). Clinical and pre-clinical studies have pointed to beneficial effects of CBD on the treatment of movement disorders. The first studies investigated CBD’s actions on dystonia, with encouraging results. More recently, the studies have been focusing on Parkinson’s (PD) and Huntington’s (HD) diseases. The mechanisms whereby CBD exerts its effects are still not completely understood, mainly because several targets have been identified. Of note, CBD displays anti-inflammatory and antioxidant actions (Campos et al., 2016), and both inflammation and oxidative stress are linked to the pathogenesis of various movement disorders, such as PD (Farooqui and Farooqui, 2011; Niranjan, 2014), HD (Sánchez-López et al., 2012), and tardive dyskinesia (Zhang et al., 2007).


It is noteworthy that, when available, the pharmacological treatments for these movement disorders are mainly symptomatic and induce significant side effects (Connolly and Lang, 2014; Lerner et al., 2015; Dickey and La Spada, 2017). Nonetheless, despite its great clinical relevance, the studies evaluating CBD’s role on the pharmacotherapy of movement disorders are surprisingly few. Here, we will review the clinical and pre-clinical evidence and draw attention to the potential of CBD in this field.


CBD’s Mechanisms of Action


CBD has several molecular targets, and new ones are currently being uncovered. CBD antagonizes the action of CB1 and CB2 receptors agonists, and is suggested to act as an inverse agonist of these receptors (Pertwee, 2008). Moreover, recent evidence point to CBD as a non-competitive negative allosteric modulator of CB1 and CB2 (Laprairie et al., 2015; Martínez-Pinilla et al., 2017). CBD is also an agonist of the vanilloid receptor TRPV1 (Bisogno et al., 2001), and the previous administration of a TRPV1 antagonist blocks some of CBD effects (Long et al., 2006; Hassan et al., 2014). In parallel, CBD inhibits the enzymatic hydrolysis and the uptake of the main endocannabinoid anandamide (Bisogno et al., 2001), an agonist of CB1, CB2 and TRPV1 receptors (Pertwee and Ross, 2002; Ross, 2003). The increase in anandamide levels induced by CBD seems to mediate some of its effects (Leweke et al., 2012). Moreover, in some behavioral paradigms the administration of an inhibitor of anandamide metabolism promotes effects similar to CBD (Pedrazzi et al., 2015; Stern et al., 2017).


CBD has also been shown to facilitate the neurotransmission mediated by the serotonin receptor 5-HT1A. It was initially suggested that CBD would act as an agonist of 5-HT1A (Russo et al., 2005), but the latest reports propose that this interaction might be allosteric or through an indirect mechanism (Rock et al., 2012). Although this interaction is not fully elucidated, multiple CBD’s effects were reported to depend on 5-HT1A activation (Espejo-Porras et al., 2013; Gomes et al., 2013; Pazos et al., 2013; Hind et al., 2016; Sartim et al., 2016; Lee et al., 2017).


The peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor involved in glucose metabolism and lipid storage, and PPARγ ligands have been reported to display anti-inflammatory actions (O’Sullivan et al., 2009). Data show that CBD can activate this receptor (O’Sullivan et al., 2009), and some of CBD effects are blocked by PPARγ antagonists (Esposito et al., 2011; Dos-Santos-Pereira et al., 2016; Hind et al., 2016). CBD also up-regulates PPARγ in a mice model of multiple sclerosis, an effect suggested to mediate the CBD’s anti-inflammatory actions (Giacoppo et al., 2017b). In a rat model of Alzheimer’s disease, CBD, through interaction with PPARγ, stimulates hippocampal neurogenesis, inhibits reactive gliosis, induces a decline in pro-inflammatory molecules, and consequently inhibits neurodegeneration (Esposito et al., 2011). Moreover, in an in vitro model of the blood-brain barrier, CBD reduces the ischemia-induced increased permeability and VCAM-1 levels—both effects are attenuated by PPARγ antagonism (Hind et al., 2016).


CBD also antagonizes the G-protein-coupled receptor GPR55 (Ryberg et al., 2007). GPR55 has been suggested as a novel cannabinoid receptor (Ryberg et al., 2007), but this classification is controversial (Ross, 2009). Currently, the phospholipid lysophosphatidylinositol (LPI) is considered the GPR55 endogenous ligand (Morales and Reggio, 2017). Although only few studies link the CBD effect to its action on GPR55 (Kaplan et al., 2017), it is noteworthy that GPR55 has been associated with PD in an animal model (Celorrio et al., 2017) and with axon growth in vitro (Cherif et al., 2015).


More recently, CBD was reported to act as inverse agonist of the G-protein-coupled orphan receptors GPR3, GPR6, and GPR12 (Brown et al., 2017; Laun and Song, 2017). GPR6 has been implicated in both HD and PD. Concerning animal models of PD, GPR6 deficiency was related to both diminished dyskinesia after 6-OHDA lesion (Oeckl et al., 2014), and increased sensitivity to MPTP neurotoxicity (Oeckl and Ferger, 2016). Moreover, Hodges et al. (2006) described decreased expression of GPR6 in brain of HD patients, compared to control. GPR3 is suggested as a biomarker for the prognosis of multiple sclerosis (Hecker et al., 2011). In addition, GPR3, GPR6, and GPR12 have been implicated in cell survival and neurite outgrow (Morales et al., 2018).


CBD has also been reported to act on mitochondria. Chronic and acute CBD administration increases the activity of mitochondrial complexes (I, II, II-III, and IV), and of creatine kinase in the brain of rats (Valvassori et al., 2013). In a rodent model of iron overload—that induces pathological changes that resemble neurodegenerative disorders—CBD reverses the iron-induced epigenetic modification of mitochondrial DNA and the reduction of succinate dehydrogenase’s activity (da Silva et al., 2018). Of note, multiple studies associate mitochondrial dysfunctions with the pathophysiology of PD (Ammal Kaidery and Thomas, 2018).


In parallel, several studies show anti-inflammatory and antioxidant actions of CBD (Campos et al., 2016). CBD treatment decreases the levels of the pro-inflammatory cytokines IL-1β, TNF-α, IFN-β, IFN-γ, IL-17, and IL-6 (Watzl et al., 1991; Weiss et al., 2006; Esposito et al., 2007, 2011; Kozela et al., 2010; Chen et al., 2016; Rajan et al., 2016; Giacoppo et al., 2017b), and increases the levels of the anti-inflammatory cytokines IL-4 and IL-10 (Weiss et al., 2006; Rajan et al., 2016). In addition, it inhibits the expression of iNOS (Esposito et al., 2007; Pan et al., 2009; Chen et al., 2016; Rajan et al., 2016) and COX-2 (Chen et al., 2016) induced by distinct mechanisms. CBD also displays antioxidant properties, being able to donate electrons under a variable voltage potential and to prevent the hydroperoxide-induced oxidative damage (Hampson et al., 1998). In rodent models of PD and HD, CBD up-regulates the mRNA levels of the antioxidant enzyme superoxide dismutase (Garcia-Arencibia et al., 2007; Sagredo et al., 2007). In accordance, CBD decreases oxidative parameters in in vitro models of neurotoxicity (Hampson et al., 1998; Iuvone et al., 2004; Mecha et al., 2012). Of note, the anti-inflammatory and antioxidant effects of CBD on lipopolysaccharide-stimulated murine macrophages are suppressed by a TRPV1 antagonist (Rajan et al., 2016). It has also been shown that CBD can affect the expression of several genes involved in zinc homeostasis, which is suggested to be linked to its anti-inflammatory and antioxidant actions (Juknat et al., 2012).


CBD’s mechanisms of action are summarized in Figure ​1.


Figure 1 CBD's Mechanism of Action


Parkinson’s Disease (PD)


PD is among the most common neurodegenerative disorders, with a prevalence that increases with age, affecting 1% of the population over 60 years old (Tysnes and Storstein, 2017). The disease is characterized by motor impairment (hypokinesia, tremors, muscle rigidity) and non-motor symptoms (e.g., sleep disturbances, cognitive deficits, anxiety, depression, psychotic symptoms) (Klockgether, 2004).


The pathophysiology of PD is mainly associated with the loss of midbrain dopaminergic neurons in the substantia nigra pars compacta (SNpc), with consequent reduced levels of dopamine in the striatum (Dauer and Przedborski, 2003). When the motor symptoms appear, about 60% of dopaminergic neurons is already lost (Dauer and Przedborski, 2003), hindering a possible early diagnosis. The most effective and used treatment for PD is L-DOPA, a precursor of dopamine that promotes an increase in the level of dopamine in the striatum, improving the motor symptoms (Connolly and Lang, 2014). However, after a long-term treatment the effect of L-DOPA can be unstable, presenting fluctuations in symptoms improvement (on / off effect) (Jankovic, 2005; Connolly and Lang, 2014). In addition, involuntary movements (namely L-DOPA-induced dyskinesia) appear in approximately 50% of the patients (Jankovic, 2005).


The first study with CBD on PD patients aimed to verify CBD’s effects on the psychotic symptoms. Treatment with CBD for 4 weeks decreased the psychotic symptoms, evaluated by the Brief Psychiatric Rating Scale and the Parkinson Psychosis Questionnaire, without worsening the motor function or inducing adverse effects (Zuardi et al., 2009). Later, in a case series with four PD patients, it was verified that CBD is able to reduce the frequency of the events related to REM sleep behavior disorder (Chagas et al., 2014a). In addition, although not ameliorating PD patients’ motor function or their general symptoms score, treatment with CBD for 6 weeks improves PD’s patients quality of life (Chagas et al., 2014b). The authors suggest that this effect might be related to CBD’s anxiolytic, antidepressant and antipsychotic properties (Chagas et al., 2014b).


Although the studies with patients with PD report beneficial effects of CBD only on the non-motor symptoms, CBD has been shown to prevent and/or reverse increased catalepsy behavior in rodents. When administered before the cataleptic agents haloperidol (antipsychotic drug), L-nitro-N-arginine (non-selective inhibitor of nitric oxide synthase) or WIN 55-212,2 (agonist of cannabinoid receptors), CBD hinders the cataleptic behavior in a dose-dependent manner (Gomes et al., 2013). A possible role of the activation of serotonin receptors 5-HT1A in this action has been proposed, because this effect of CBD is blocked by the pre-treatment with the 5-HT1A antagonist WAY100635 (Gomes et al., 2013). In accordance, Sonego et al. (2016) showed that CBD diminishes the haloperidol-induced catalepsy and c-Fos protein expression in the dorsal striatum, also by a mechanism dependent on 5-HT1A activation. Moreover, CBD prevents the increased catalepsy behavior induced by repeated administration of reserpine (Peres et al., 2016).


In addition, pre-clinical studies in animal models of PD have shown neuroprotective effects of CBD. The unilateral injection of the toxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle promotes neurodegeneration of nigrostriatal dopaminergic neurons, being used to model PD (Bové et al., 2005). When inside the cell, the neurotoxin 6-OHDA oxidizes in hydrogen peroxide and paraquinone, causing death mainly of catecolaminergic neurons (Breese and Traylor, 1971; Bové et al., 2005). This neurodegeneration leads to depletion of dopamine and decrease in tyrosine hydroxylase activity in caudate-putamen (Bové et al., 2005; Lastres-Becker et al., 2005). Treatment with CBD during the 2 weeks following 6-OHDA administration prevents these effects (Lastres-Becker et al., 2005). In another study, it was observed that CBD’s protective effects after 6-OHDA injury are accompanied by elevation of mRNA levels of the antioxidant enzyme Cu,Zn-superoxide dismutase in substantia nigra (Garcia-Arencibia et al., 2007). The protective effects of CBD in this model do not seem to depend on the activation of CB1 receptors (Garcia-Arencibia et al., 2007). In addition to preventing the loss of dopaminergic neurons—assessed by tyrosine hydroxylase immunostaining –, the administration of CBD after 6-OHDA injury attenuates the activation of microglia in substantia nigra (Garcia et al., 2011).


In an in vitro study, CBD increased the viability of cells treated with the neurotoxin N-methyl-4-phenylpyrimidine (MPP+), and prevented the MPP+-induced increase in caspase-3 activation and decrease in levels of nerve growth factor (NGF) (Santos et al., 2015). CBD treatment was also able to induce cell differentiation even in the presence of MPP+, an effect that depends on trkA receptors (Santos et al., 2015). MPP+ is a product of oxidation of MPTP that inhibits complex I of the respiratory chain in dopaminergic neurons, causing a rapid neuronal death (Schapira et al., 1990; Meredith et al., 2008).


Data from clinical and pre-clinical studies are summarized in Tables ​1, ​2, respectively.


Table 1 Effects of CBD on Movement Disorders


Table 2 Pre-Clinical Studies of CBD


Huntington’s Disease (HD)


HD is a fatal progressive neurodegenerative disease characterized by motor dysfunctions, cognitive loss and psychiatric manifestations (McColgan and Tabrizi, 2018). HD is caused by the inclusion of trinucleotides (CAG) in the exons of the huntingtin gene, on chromosome 4 (MacDonald et al., 1993; McColgan and Tabrizi, 2018), and its prevalence is 1–10,000 (McColgan and Tabrizi, 2018). Neurodegeneration in HD affects mainly the striatal region (caudate and putamen) and this neuronal loss is responsible for the motor symptoms (McColgan and Tabrizi, 2018). Cortical degeneration is seen in later stages, and huntingtin inclusions are seen in few cells, but in all patients with HD (Crook and Housman, 2011). The diagnosis of HD is based on motor signs accompanied by genetic evidence, which is positive genetic test for the expansion of the huntingtin gene or family history (Mason and Barker, 2016; McColgan and Tabrizi, 2018).


The pharmacotherapy of HD is still directed toward the symptomatic relief of the disease, i.e., the motor disorders believed to be due to dopaminergic hyperactivity. This treatment is often conducted with typical and atypical antipsychotics, but in some cases the use of dopaminergic agonists is needed (Mason and Barker, 2016; McColgan and Tabrizi, 2018). Indeed, the role of dopamine in HD is not fully elucidated yet. Regarding the cognitive deficits, none of the investigated drugs was able to promote improvements (Mason and Barker, 2016; McColgan and Tabrizi, 2018).


Recently, there has been a growing number of studies aiming to verify the therapeutic potential of cannabinoid compounds in the treatment of HD, mainly because some cannabinoids present hypokinetic characteristics (Lastres-Becker et al., 2002). In a controlled clinical trial, patients with HD were treated with CBD for 6 weeks. There was no significant reduction in the chorea indicators, but no toxicity was observed (Consroe et al., 1991).


The protective effects of CBD and other cannabinoids were also evaluated in a cell culture model of HD, with cells expressing mutated huntingtin. In this model, the induction of huntingtin promotes rapid and extensive cell death (Aiken et al., 2004). CBD and the other three cannabinoid compounds tested—Δ8-THC, Δ9-THC, and cannabinol—show 51–84% protection against the huntingtin-induced cell death (Aiken et al., 2004). These effects seem to be independent of CB1 activation, since absence of CB1 receptors has been reported in PC12, the cell line used (Molderings et al., 2002). The authors suggest that the cannabinoids exert this protective effect by antioxidant mechanisms (Aiken et al., 2004).


Regarding studies with animal models, treatment with 3-nitropropionic acid (3-NP), an inhibitor of complex II of the respiratory chain, induces striatal damage—mainly by calpain activation and oxidative injury –, being suggested as relevant to study HD (Brouillet et al., 2005). Sub-chronic administration of 3-NP in rats reduces GABA contents and the levels of mRNA for several markers of striatal GABAergic neurons projections (Sagredo et al., 2007). In addition, 3-NP diminishes the levels of mRNA for the antioxidant enzymes superoxide dismutase-1 (SOD-1) and -2 (SOD-2) (Sagredo et al., 2007). The administration of CBD reverses or attenuates these 3-NP-induced alterations (Sagredo et al., 2007). CBD’s neuroprotective effects are not blocked by the administration of antagonists of the CB1, TRPV1 or A2A receptors (Sagredo et al., 2007).


More recently, clinical and pre-clinical HD studies started to investigate the effects of Sativex® (CBD in combination with Δ9-THC in an approximately 1:1 ratio). In accordance with what previously seen with CBD alone, Sativex administration attenuates all the 3-NP induced neurochemical, histological and molecular alterations (Sagredo et al., 2011). These effects do not seem to be linked to activation of CB1 or CB2 receptors (Sagredo et al., 2011). Authors also observed a protective effect of Sativex in reducing the increased expression of iNOS gene induced by malonate (Sagredo et al., 2011). Malonate administration leads to striatal damage by apoptosis and inflammatory events related to glial activation, being used as an acute model for HD (Sagredo et al., 2011; Valdeolivas et al., 2012).


In a subsequent study, it was observed that the administration of a Sativex-like combination attenuates all the malonate-induced alterations, namely: increased edema, decreased number of surviving cells, enhanced number of degenerating cells, strong glial activation, and increased expression of inflammatory markers (iNOS and IGF-1) (Valdeolivas et al., 2012). Although the beneficial effects of Sativex on cell survival are blocked by both CB1 or CB2 antagonists, CB2 receptors seem to have a greater role in the protective effect observed (Valdeolivas et al., 2012).


The beneficial effects of Sativex have also been described in the R6/2 mice, a transgenic model of HD. Treatment with a Sativex-like combination, although not reversing animal’s deterioration in rotarod performance, attenuates the elevated clasping behavior, that reflects dystonia (Valdeolivas et al., 2017). Moreover, treatment mitigates R6/2 mice reduced metabolic activity in basal ganglia and some of the alterations in markers of brain integrity (Valdeolivas et al., 2017).


In spite of the pre-clinical encouraging results with Sativex, a pilot trial with 25 HD patients treated with Sativex for 12 weeks failed to detect improvement in symptoms or molecular changes on biomarkers (López-Sendón Moreno et al., 2016). Nonetheless, Sativex did not induce severe adverse effects or clinical worsening (López-Sendón Moreno et al., 2016). The authors suggest that future studies, with higher doses and/or longer treatment periods, are in need. More recently, one study described the results of administering cannabinoid drugs to 7 patients (2 of them were treated with Sativex; the others received dronabinol or nabilone, agonists of the cannabinoid receptors): patients displayed improvement on UHDRS motor score and dystonia subscore (Saft et al., 2018).


Tables ​1, ​2 summarize data from clinical and pre-clinical studies, respectively.



Dr. Alex Jimenez’s Insight

Involuntary muscle spasms, tremors and jerking are all uncontrollable movements known as dyskinesia, which are the most common symptoms of a variety of movement disorders. Movement disorders often have no known cause and these are considered to have no cure. As a result, individuals with these debilitating conditions have to turn to drugs and/or medications to keep their symptoms under control for the rest of their lives. However, several research studies have been conducted to determine the effectiveness of CBD, or cannabidiol, for the treatment and prevention of movement disorders. In one study, CBD was found to decrease pain and reduce inflammation in patients with Parkinson’s disease without the psychoactive effects of THC. Moreover, healthcare professionals and researchers alike are trying to demonstrate further health benefits of CBD on movement disorders.


Other Movement Disorders


Dystonias are the result of abnormal muscles tone, causing involuntary muscle contraction, and resulting in repetitive movements or abnormal posture (Breakefield et al., 2008). Dystonias can be primary, for instance paroxysmal dyskinesia, or secondary to other conditions or drug use, such as tardive dyskinesia after prolonged treatment with antipsychotic drugs (Breakefield et al., 2008).


Consroe et al. (1986) were the first to evaluate the effects of CBD alone in movement disorders. In this open label study, the five patients with dystonic movement disorders displayed 20–50% improvement of dystonic symptoms when treated with CBD for 6 weeks. Of note, two patients with simultaneous PD’s signs showed worsening of their hypokinesia and/or resting tremor when receiving the higher doses of CBD. However, it should be noted that in two more recent studies with PD patients no worsening of motor function was seen (Zuardi et al., 2009; Chagas et al., 2014b). In accordance, Sandyk et al. (1986) reported improvement of dystonic symptoms in two patients—one with idiopathic spasmodic torticollis and one with generalized torsion dystonia—after acute treatment with CBD.


The effects of CBD on dystonic movements were also evaluated in pre-clinical studies. In a hamster model of idiopathic paroxysmal dystonia, the higher dose of CBD showed a trend to delay the progression of dystonia (Richter and Loscher, 2002). In addition, CBD prevents the increase in vacuous chewing movements, i.e., dyskinesia, promoted by repeated administration of reserpine (Peres et al., 2016). CBD’s beneficial effects are also seen in L-DOPA-induced dyskinesia in rodents, but only when CBD is administered with capsazepine, an antagonist of TRPV1 receptors (Dos-Santos-Pereira et al., 2016). These effects seem to depend on CB1 and PPARγ receptors (Dos-Santos-Pereira et al., 2016). In addition, treatment with capsazepine and CBD decreases the expression of inflammatory markers, reinforcing the suggestion that the anti-inflammatory actions of CBD may be beneficial to the treatment of dyskinesia (Dos-Santos-Pereira et al., 2016).


Moreover, Sativex has been used in the treatment of spasticity in multiple sclerosis. Spasticity is a symptom that affects up to 80% of patients with multiple sclerosis and is associated with poorer quality of life (Flachenecker et al., 2014). A significant portion of patients does not respond to the conventional anti-spasmodic therapies, and some strategies are invasive, posing risks of complications (Flachenecker et al., 2014; Crabtree-Hartman, 2018). Recent data point to Sativex as a valid and well-tolerated therapeutic option. Sativex is able to treat the spasms, improving the quality of life, and displays a low incidence of adverse effects (Giacoppo et al., 2017a).


Data from clinical and pre-clinical studies are summarized in Tables ​1, 2, respectively.


Safety and Side Effects


One important concern is whether CBD is a safe therapeutic strategy. Several preclinical and clinical reports show that CBD does not alter metabolic and physiological parameters, such as glycemia, prolactin levels, blood pressure, and heart rate. In addition, CBD does not modify hematocrit, leukocyte and erythrocyte counts, and blood levels of bilirubin and creatinine in humans. CBD also does not affect urine osmolarity, pH, albumin levels, and leukocyte and erythrocyte counts. Moreover, in vitro studies demonstrate that CBD does not alter embryonic development nor the vitality of non-tumor cell lines. The most reported side effects of CBD are tiredness, diarrhea, and changes on appetite. CBD does not seem to induce tolerance. For a broad review of CBD’s side effects, see Bergamaschi et al. (2011) and Iffland and Grotenhermen (2017).


In the context of movement disorders with concomitant cognitive symptoms, as the ones discussed here, it is crucial to evaluate the potential motor and cognitive side effects of CBD. CBD does not induce catalepsy behavior in rodents—being even able to attenuate the effects of several cataleptic agents, as discussed above (El-Alfy et al., 2010; Gomes et al., 2013; Peres et al., 2016; Sonego et al., 2016). In accordance, CBD does not induce extrapyramidal effects in humans (Leweke et al., 2012).


With respect to cognitive effects, studies report that CBD does not impair cognition, being even able to improve it in some conditions. Pre-clinical data show that CBD restores the deficit in the novel object recognition task in mice treated with MK-801 (a protocol used to model schizophrenia) (Gomes et al., 2015), in rats submitted to neonatal iron overload (Fagherazzi et al., 2012), in a transgenic mice model for Alzheimer’s disease (Cheng et al., 2014), and in a mice model for cerebral malaria (Campos et al., 2015). CBD also reverses impaired social recognition in a murine model for Alzheimer’s disease (Cheng et al., 2014) and restores the deficits in the Morris water maze—a task that evaluates spatial learning—in rodent models for Alzheimer’s disease (Martín-Moreno et al., 2011), brain ischemia (Schiavon et al., 2014) and cerebral malaria (Campos et al., 2015). In addition, studies demonstrate that CBD per se does not modify animals’ performance in cognitive tasks (Osborne et al., 2017; Myers et al., 2018) and does not induce withdrawal after prolonged treatment (Myers et al., 2018). In accordance, in one recent clinical trial using CBD as an adjunctive therapy for schizophrenia, CBD group displayed greater cognitive improvement (assessed by BACS—Brief Assessment of Cognition in Schizophrenia), although it fell short of significance (McGuire et al., 2018). CBD also improves facial emotion recognition in cannabis users (Hindocha et al., 2015).


It is noteworthy that in some cases, particularly concerning multiple sclerosis and HD clinical studies, CBD per se does not seem to be beneficial. However, when CBD is administered with Δ9-THC in a 1:1 ratio, therapeutic effects are observed. Therefore, it is also important to evaluate the interactions between CBD and Δ9-THC as well as the adverse effects of this mixture. Multiple reports point to deleterious effects of Δ9-THC on human cognition, mainly on memory and emotional processing (Colizzi and Bhattacharyya, 2017). On the other hand, studies reveal that CBD can counteract Δ9-THC detrimental cognitive effects in rodents and monkeys (Wright et al., 2013; Jacobs et al., 2016; Murphy et al., 2017). Nonetheless, this protective effect depends on the doses, on the interval between CBD and Δ9-THC administration, as well as on the behavioral paradigm used. In fact, some pre-clinical studies do not observe the protective effect of CBD against the Δ9-THC cognitive effects (Wright et al., 2013; Jacobs et al., 2016) or even show that CBD may potentiate them (Hayakawa et al., 2008). Limited clinical evidence indicate that CBD does not worse Δ9-THC cognitive effects and, depending on the dose, may protect against them (Colizzi and Bhattacharyya, 2017; Englund et al., 2017; Osborne et al., 2017). Multiple clinical studies with Sativex have not observed motor or cognitive adverse effects (Aragona et al., 2009; Rekand, 2014; López-Sendón Moreno et al., 2016; Russo et al., 2016). Nevertheless, one recent open-label study compared multiple sclerosis patients who continued the treatment with Sativex to those who quitted and reported worse balance and decrease in cognitive performance in the continuers (Castelli et al., 2018). In line with these findings, in an observational study with a large population of Italian patients with multiple sclerosis, cognitive/psychiatric disturbances were seen in 3.9% of the cases (Patti et al., 2016).




The data reviewed here point to a protective role of CBD in the treatment and/or prevention of some movement disorders. Although the studies are scarce, CBD seems to be effective on treating dystonic movements, both primary and secondary. It is noteworthy that in some cases, particularly concerning multiple sclerosis and HD, the clinical beneficial effects are observed only when CBD is combined with Δ9-THC in a 1:1 ratio (Sativex). In fact, these therapeutic effects are probably due to Δ9-THC, since they are also seen with other cannabinoid agonists (Curtis et al., 2009; Nielsen et al., 2018; Saft et al., 2018). Nonetheless, CBD is shown to diminish the Δ9-THC unwanted effects, such as sedation, memory impairments, and psychosis (Russo and Guy, 2006). Data regarding HD are scarce, but the results of using Sativex in multiple sclerosis are encouraging. Reviews of the clinical use of this compound in the last decade point to effectiveness in the treatment of spasticity as well as improvement in quality of life, with low incidence of adverse effects (Giacoppo et al., 2017a).


In respect to PD, although the pre-clinical studies are promising, the few studies with patients failed to detect improvement of the motor symptoms after treatment with CBD. There is a significant difference between the clinical and pre-clinical PD studies. In animals, the beneficial effects are seen when CBD is administered prior to or immediately after the manipulation that induces the PD-like symptoms. Of note, when treatment with CBD commences 1 week after the lesion with 6-OHDA, the protective effects are not seen (Garcia-Arencibia et al., 2007). These data suggest that CBD’s might have a preventive role rather than a therapeutic one in PD. In clinical practice, PD is diagnosed subsequently to the emergence of motor symptoms—that appear up to 10 years after the beginning of neurodegeneration and the onset of non-motor symptoms (Schrag et al., 2015). When the diagnosis occur, approximately 60% of the dopaminergic neurons has already been lost (Dauer and Przedborski, 2003). The fact that in clinical trials CBD is administered only after this substantial progression of the disease might explain the conflicting results. Unfortunately, the early diagnosis of PD remains a challenge, posing difficulty to the implementation of preventive strategies. The development of diagnosis criteria able to detect PD in early stages would probably expand the CBD’s applications in this disease.


The molecular mechanisms associated with CBD’s improvement of motor disorders are likely multifaceted. Data show that it might depend on CBD’s actions on 5-HT1A, CB1, CB2, and/or PPARγ receptors. Moreover, all movement disorders are in some extent linked to oxidative stress and inflammation, and CBD has been reported to display an antioxidant and anti-inflammatory profile, in vitro and in animal models for movement abnormalities.


The studies investigating the role of CBD on the treatment of movement disorders are few. Furthermore, differences in the dose and duration of treatment as well as in the stage of the disease (for instance, PD patients are treated only in an advanced stage of the disease) among these studies (shown in detail in Table ​Table1)1) limit the generalization of the positive effect of CBD and might explain the conflicting results. Notwithstanding, the beneficial neuroprotective profile of CBD added to the preliminary results described here are encouraging. Undoubtedly, future investigations are needed to endorse these initial data and to elucidate the mechanisms involved in the preventive and/or therapeutic potential of CBD on movement disorders.


Introduction to the Endocannabinoid System


Since you read the article concerning the effects of cannabidiol on movement disorders, one thing will become quickly evident: cannabis has a profound influence on the human body. This one herb and its own variety of therapeutic chemicals seem to impact every aspect of the brain and body. However, how is this possible? There’s a system in the human body which many individuals are not aware of nor do they known how important it’s functions are: the endocannabinoid system.


What Is The Endocannabinoid System?


The endogenous cannabinoid system, or the cannabinoid system, named after the plant that resulted in its discovery, is possibly the most important physiologic system involved in establishing and maintaining human health. Endocannabinoids and their receptors are found throughout the body: in the brain, organs, connective tissues, glands, and immune cells. In each tissue, the endocannabinoid system performs various tasks, but the goal is always the same: homeostasis, the maintenance of a stable internal environment despite changes in the external environment.


Cannabinoids promote homeostasis at every level of biological lifetime, from the sub-cellular, into the organism, and possibly into the community and more. Here is one instance: autophagy, a process where a cell sequesters part of its contents to be self-digested and recycled, is mediated by the endocannabinoid system. While this procedure keeps normal cells alive, permitting them to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products, it has a fatal effect on cancerous tumor cells, causing them to consume themselves at a programmed cellular suicide. The death of cancer cells, of course, promotes homeostasis and survival in the level of the whole organism.


Endocannabinoids and cannabinoids are also found at the intersection of the body’s various systems, enabling communication and coordination between distinct cell types. In the case of an injury, for instance, cannabinoids are available diminishing the discharge of activators and sensitizers in the injured tissue, stabilizing the nerve cell to stop excessive firing, and calming nearby immune cells to prevent discharge of pro-inflammatory substances. Three different mechanisms of action on three distinct cell types for one purpose: minimize the pain and damage caused by the injury.


The endocannabinoid system, using its complicated activities in our immune system, nervous system, and all of the body’s organs, is literally a bridge between the brain and the body. By understanding this system we begin to observe a mechanism that explains the way the states of awareness can promote disease or health.


Along with regulating the human body’s internal and cellular homeostasis, cannabinoids affect an individual’s connection with the external environment. Socially, the management of cannabinoids clearly changes human behavior, frequently promoting sharing, comedy, and imagination. By mediating neurogenesis, neuronal plasticity, and learning, cannabinoids may directly affect a person’s open-mindedness and capability to move beyond limiting patterns of thought and behaviour from past scenarios. Reformatting these older patterns is an essential part of health in our quickly changing environment. Furthermore, the article above found that CBD appears to be an effective treatment option for dystonic movements, both primary and secondary, although further reasearch studies are required. The research of CBD has been controversial, however, more and more studies are starting to demonstrate the health benefits of cannabidiol. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


Curated by Dr. Alex Jimenez


Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




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EXTRA IMPORTANT TOPIC: Low Back Pain Management


MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments


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Safety and Side Effects of Cannabidiol

Safety and Side Effects of Cannabidiol

Cannabidiol is a compound in the Cannabis sativa plant, also known as marijuana. More than 80 chemicals, called cannabinoids, have been identified in the Cannabis sativa plant. Even though delta-9-tetrahydrocannabinol, or THC, is the major active ingredient, cannabidiol constitutes about 40 percent of cannabis extracts and has been analyzed for many distinct uses. According to the U.S. Food and Drug Administration, or the FDA, because cannabidiol was analyzed as a new drug, products containing cannabidiol are not defined as dietary supplements. But there are still products labeled as dietary supplements available on the marketplace which contain cannabidiol.


Cannabidiol has antipsychotic results. The exact cause for these effects isn’t clear. However, cannabidiol appears to protect against the breakdown of a chemical in the brain that affects pain, mood, and mental function. Preventing the breakdown of this compound and raising its levels in the blood seems to decrease psychotic symptoms related to conditions such as schizophrenia. Cannabidiol may also block some of the untoward effects of delta-9-tetrahydrocannabinol, or THC. Additionally, cannabidiol appears to decrease pain and anxiety. The purpose of the following article is to demonstrate an update on the safety and side effects of cannabidiol involving clinical data and relevant animal studies.


An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies




  • Introduction: This literature survey aims to extend the comprehensive survey performed by Bergamaschi et al. in 2011 on cannabidiol (CBD) safety and side effects. Apart from updating the literature, this article focuses on clinical studies and CBD potential interactions with other drugs.
  • Results: In general, the often described favorable safety profile of CBD in humans was confirmed and extended by the reviewed research. The majority of studies were performed for treatment of epilepsy and psychotic disorders. Here, the most commonly reported side effects were tiredness, diarrhea, and changes of appetite/weight. In comparison with other drugs, used for the treatment of these medical conditions, CBD has a better side effect profile. This could improve patients’ compliance and adherence to treatment. CBD is often used as adjunct therapy. Therefore, more clinical research is warranted on CBD action on hepatic enzymes, drug transporters, and interactions with other drugs and to see if this mainly leads to positive or negative effects, for example, reducing the needed clobazam doses in epilepsy and therefore clobazam’s side effects.
  • Conclusion: This review also illustrates that some important toxicological parameters are yet to be studied, for example, if CBD has an effect on hormones. Additionally, more clinical trials with a greater number of participants and longer chronic CBD administration are still lacking.
  • Keywords: cannabidiol, cannabinoids, medical uses, safety, side effects, toxicity




Since several years, other pharmacologically relevant constituents of the Cannabis plant, apart from Δ9-THC, have come into the focus of research and legislation. The most prominent of those is cannabidiol (CBD). In contrast to Δ9-THC, it is nonintoxicating, but exerts a number of beneficial pharmacological effects. For instance, it is anxiolytic, anti-inflammatory, antiemetic, and antipsychotic. Moreover, neuroprotective properties have been shown.1,2 Consequently, it could be used at high doses for the treatment of a variety of conditions ranging in psychiatric disorders such as schizophrenia and dementia, as well as diabetes and nausea.1,2


At lower doses, it has physiological effects that promote and maintain health, including antioxidative, anti-inflammatory, and neuroprotection effects. For instance, CBD is more effective than vitamin C and E as a neuroprotective antioxidant and can ameliorate skin conditions such as acne.3,4


The comprehensive review of 132 original studies by Bergamaschi et al. describes the safety profile of CBD, mentioning several properties: catalepsy is not induced and physiological parameters are not altered (heart rate, blood pressure, and body temperature). Moreover, psychological and psychomotor functions are not adversely affected. The same holds true for gastrointestinal transit, food intake, and absence of toxicity for nontransformed cells. Chronic use and high doses of up to 1500 mg per day have been repeatedly shown to be well tolerated by humans.1


Nonetheless, some side effects have been reported for CBD, but mainly in vitro or in animal studies. They include alterations of cell viability, reduced fertilization capacity, and inhibition of hepatic drug metabolism and drug transporters (e.g., p-glycoprotein).1 Consequently, more human studies have to be conducted to see if these effects also occur in humans. In these studies, a large enough number of subjects have to be enrolled to analyze long-term safety aspects and CBD possible interactions with other substances.


This review will build on the clinical studies mentioned by Bergamaschi et al. and will update their survey with new studies published until September 2016.



Dr. Alex Jimenez’s Insight

Cannabidiol, or CBD, is a cannabis compound which is believed to have significant health benefits and can counteract the psychoactivity of THC. Because CBD is non-psychoactive or less psychoactive than THC-dominant strains, it has become an appealing treatment option for patients experiencing chronic pain, inflammation, anxiety, seizures, psychosis and other conditions without the common side effects. associated with THC. Numerous research studies have been conducted to demonstrate evidence on the health benefits of cannabidiol, or CBD, on the human body.


Relevant Preclinical Studies


Before we discuss relevant animal research on CBD possible effects on various parameters, several important differences between route of administration and pharmacokinetics between human and animal studies have to be mentioned. First, CBD has been studied in humans using oral administration or inhalation. Administration in rodents often occures either via intraperitoneal injection or via the oral route. Second, the plasma levels reached via oral administration in rodents and humans can differ. Both these observations can lead to differing active blood concentrations of CBD.1,5,6


In addition, it is possible that CBD targets differ between humans and animals. Therefore, the same blood concentration might still lead to different effects. Even if the targets, to which CBD binds, are the same in both studied animals and humans, for example, the affinity or duration of CBD binding to its targets might differ and consequently alter its effects.


The following study, which showed a positive effect of CBD on obsessive compulsive behavior in mice and reported no side effects, exemplifies the existing pharmacokinetic differences.5 When mice and humans are given the same CBD dose, more of the compound becomes available in the mouse organism. This higher bioavailability, in turn, can cause larger CBD effects.


Deiana et al. administered 120 mg/kg CBD either orally or intraperitoneally and measured peak plasma levels.5 The group of mice, which received oral CBD, had plasma levels of 2.2 μg/ml CBD. In contrast, i.p. injections resulted in peak plasma levels of 14.3 μg/ml. Administering 10 mg/kg oral CBD to humans leads to blood levels of 0.01 μg/ml.6 This corresponds to human blood levels of 0.12 μg/ml, when 120 mg/kg CBD was given to humans. This calculation was performed assuming the pharmacokinetics of a hydrophilic compound, for simplicity’s sake. We are aware that the actual levels of the lipophilic CBD will vary.


A second caveat of preclinical studies is that supraphysiological concentrations of compounds are often used. This means that the observed effects, for instance, are not caused by a specific binding of CBD to one of its receptors but are due to unspecific binding following the high compound concentration, which can inactivate the receptor or transporter.


The following example and calculations will demonstrate this. In vitro studies have shown that CBD inhibits the ABC transporters P-gp (P glycoprotein also referred to as ATP-binding cassette subfamily B member 1=ABCB1; 3–100 μM CBD) and Bcrp (Breast Cancer Resistance Protein; also referred to as ABCG2=ATP-binding cassette subfamily G member 2).7 After 3 days, the P-gp protein expression was altered in leukemia cells. This can have several implications because various anticancer drugs also bind to these membrane-bound, energy-dependent efflux transporters.1 The used CBD concentrations are supraphysiological, however, 3 μM CBD approximately corresponds to plasma concentrations of 1 μg/ml. On the contrary, a 700 mg CBD oral dose reached a plasma level of 10 ng/ml.6 This means that to reach a 1 μg/ml plasma concentration, one would need to administer considerably higher doses of oral CBD. The highest ever applied CBD dose was 1500 mg.1 Consequently, more research is warranted, where the CBD effect on ABC transporters is analyzed using CBD concentrations of, for example, 0.03–0.06 μM. The rationale behind suggesting these concentrations is that studies summarized by Bih et al. on CBD effect on ABCC1 and ABCG2 in SF9 human cells showed that a CBD concentration of 0.08 μM elicited the first effect.7


Using the pharmacokinetic relationships mentioned above, one would need to administer an oral CBD dose of 2100 mg CBD to affect ABCC1 and ABCG2. We used 10 ng/ml for these calculations and the ones in Table 1,6,8 based on a 6-week trial using a daily oral administration of 700 mg CBD, leading to mean plasma levels of 6–11 ng/ml, which reflects the most realistic scenario of CBD administration in patients.6 That these levels seem to be reproducible, and that chronic CBD administration does not lead to elevated mean blood concentrations, was shown by another study. A single dose of 600 mg led to reduced anxiety and mean CBD blood concentrations of 4.7–17 ng/ml.9


Table 1 Inhibition of Human Metabolic Enzymes


It also seems warranted to assume that the mean plasma concentration exerts the total of observed CBD effects, compared to using peak plasma levels, which only prevail for a short amount of time. This is not withstanding, that a recent study measured Cmax values for CBD of 221 ng/ml, 3 h after administration of 1 mg/kg fentanyl concomitantly with a single oral dose of 800 mg CBD.10


CBD-Drug Interactions


Cytochrome P450-complex enzymes. This paragraph describes CBD interaction with general (drug)-metabolizing enzymes, such as those belonging to the cytochrome P450 family. This might have an effect for coadministration of CBD with other drugs.7 For instance, CBD is metabolized, among others, via the CYP3A4 enzyme. Various drugs such as ketoconazol, itraconazol, ritonavir, and clarithromycin inhibit this enzyme.11 This leads to slower CBD degradation and can consequently lead to higher CBD doses that are longer pharmaceutically active. In contrast, phenobarbital, rifampicin, carbamazepine, and phenytoin induce CYP3A4, causing reduced CBD bioavailability.11 Approximately 60% of clinically prescribed drugs are metabolized via CYP3A4.1 Table 1 shows an overview of the cytochrome inhibiting potential of CBD. It has to be pointed out though, that the in vitro studies used supraphysiological CBD concentrations.


Studies in mice have shown that CBD inactivates cytochrome P450 isozymes in the short term, but can induce them after repeated administration. This is similar to their induction by phenobarbital, thereby implying the 2b subfamily of isozymes.1 Another study showed this effect to be mediated by upregulation of mRNA for CYP3A, 2C, and 2B10, after repeated CBD administration.1


Hexobarbital is a CYP2C19 substrate, which is an enzyme that can be inhibited by CBD and can consequently increase hexobarbital availability in the organism.12,13 Studies also propose that this effect might be caused in vivo by one of CBD metabolites.14,15 Generally, the metabolite 6a-OH-CBD was already demonstrated to be an inducer of CYP2B10. Recorcinol was also found to be involved in CYP450 induction. The enzymes CYP3A and CYP2B10 were induced after prolonged CBD administration in mice livers, as well as for human CYP1A1 in vitro.14,15 On the contrary, CBD induces CYP1A1, which is responsible for degradation of cancerogenic substances such as benzopyrene. CYP1A1 can be found in the intestine and CBD-induced higher activity could therefore prevent absorption of cancerogenic substances into the bloodstream and thereby help to protect DNA.2


Effects on P-glycoprotein activity and other drug transporters. A recent study with P-gp, Bcrp, and P-gp/Bcrp knockout mice, where 10 mg/kg was injected subcutaneously, showed that CBD is not a substrate of these transporters itself. This means that they do not reduce CBD transport to the brain.16 This phenomenon also occurs with paracetamol and haloperidol, which both inhibit P-gp, but are not actively transported substrates. The same goes for gefitinib inhibition of Bcrp.


These proteins are also expressed at the blood–brain barrier, where they can pump out drugs such as risperidone. This is hypothesized to be a cause of treatment resistance.16 In addition, polymorphisms in these genes, making transport more efficient, have been implied in interindividual differences in pharmacoresistance.10 Moreover, the CBD metabolite 7-COOH CBD might be a potent anticonvulsant itself.14 It will be interesting to see whether it is a P-gp substrate and alters pharmacokinetics of coadministered P-gp-substrate drugs.


An in vitro study using three types of trophoblast cell lines and ex vivo placenta, perfused with 15 μM CBD, found BCRP inhibition leading to accumulation of xenobiotics in the fetal compartment.17 BCRP is expressed at the apical side of the syncytiotrophoblast and removes a wide variety of compounds forming a part of the placental barrier. Seventy-two hours of chronic incubation with 25 μM CBD also led to morphological changes in the cell lines, but not to a direct cytotoxic effect. In contrast, 1 μM CBD did not affect cell and placenta viability.17 The authors consider this effect cytostatic. Nicardipine was used as the BCRP substrate in the in vitro studies, where the Jar cell line showed the largest increase in BCRP expression correlating with the highest level of transport.17,and references therein


The ex vivo study used the antidiabetic drug and BCRP substrate glyburide.17 After 2 h of CBD perfusion, the largest difference between the CBD and the placebo placentas (n=8 each) was observed. CBD inhibition of the BCRP efflux function in the placental cotyledon warrants further research of coadministration of CBD with known BCRP substrates such as nitrofurantoin, cimetidine, and sulfasalazine. In this study, a dose–response curve should be established in male and female subjects (CBD absorption was shown to be higher in women) because the concentrations used here are usually not reached by oral or inhaled CBD administration. Nonetheless, CBD could accumulate in organs physiologically restricted via a blood barrier.17


Physiological Effects


CBD treatment of up to 14 days (3–30 mg/kg b.w. i.p.) did not affect blood pressure, heart rate, body temperature, glucose levels, pH, pCO2, pO2, hematocrit, K+ or Na+ levels, gastrointestinal transit, emesis, or rectal temperature in a study with rodents.1


Mice treated with 60 mg/kg b.w. CBD i.p. for 12 weeks (three times per week) did not show ataxia, kyphosis, generalized tremor, swaying gait, tail stiffness, changes in vocalization behavior or open-field physiological activity (urination, defecation).1


Neurological and Neurospychiatric Effects


Anxiety and depression. Some studies indicate that under certain circumstances, CBD acute anxiolytic effects in rats were reversed after repeated 14-day administration of CBD.2 However, this finding might depend on the used animal model of anxiety or depression. This is supported by a study, where CBD was administered in an acute and “chronic” (2 weeks) regimen, which measured anxiolytic/antidepressant effects, using behavioral and operative models (OBX=olfactory bulbectomy as model for depression).18 The only observed side effects were reduced sucrose preference, reduced food consumption and body weight in the nonoperated animals treated with CBD (50 mg/kg). Nonetheless, the behavioral tests (for OBX-induced hyperactivity and anhedonia related to depression and open field test for anxiety) in the CBD-treated OBX animals showed an improved emotional response. Using microdialysis, the researchers could also show elevated 5-HT and glutamate levels in the prefrontal cortex of OBX animals only. This area was previously described to be involved in maladaptive behavioral regulation in depressed patients and is a feature of the OBX animal model of depression. The fact that serotonin levels were only elevated in the OBX mice is similar to CBD differential action under physiological and pathological conditions.


A similar effect was previously described in anxiety experiments, where CBD proved to be only anxiolytic in subjects where stress had been induced before CBD administration. Elevated glutamate levels have been proposed to be responsible for ketamine’s fast antidepressant function and its dysregulation has been described in OBX mice and depressed patients. Chronic CBD treatment did not elicit behavioral changes in the nonoperated mice. In contrast, CBD was able to alleviate the affected functionality of 5HT1A receptors in limbic brain areas of OBX mice.18 and references therein.


Schiavon et al. cite three studies that used chronic CBD administration to demonstrate its anxiolytic effects in chronically stressed rats, which were mostly mediated via hippocampal neurogenesis.19 and references therein For instance, animals received daily i.p. injections of 5 mg/kg CBD. Applying a 5HT1A receptor antagonist in the DPAG (dorsal periaqueductal gray area), it was implied that CBD exerts its antipanic effects via these serotonin receptors. No adverse effects were reported in this study.


Psychosis and bipolar disorder. Various studies on CBD and psychosis have been conducted.20 For instance, an animal model of psychosis can be created in mice by using the NMDAR antagonist MK-801. The behavioral changes (tested with the prepulse inhibition [PPI] test) were concomitant with decreased mRNA expression of the NMDAR GluN1 subunit gene (GRN1) in the hippocampus, decreased parvalbumin expression (=a calcium-binding protein expressed in a subclass of GABAergic interneurons), and higher FosB/ΔFosB expression (=markers for neuronal activity). After 6 days of MK-801 treatment, various CBD doses were injected intraperitoneally (15, 30, 60 mg/kg) for 22 days. The two higher CBD doses had beneficial effects comparable to the atypical antipsychotic drug clozapine and also attenuated the MK-801 effects on the three markers mentioned above. The publication did not record any side effects.21


One of the theories trying to explain the etiology of bipolar disorder (BD) is that oxidative stress is crucial in its development. Valvassori et al. therefore used an animal model of amphetamine-induced hyperactivity to model one of the symptoms of mania. Rats were treated for 14 days with various CBD concentrations (15, 30, 60 mg/kg daily i.p.). Whereas CBD did not have an effect on locomotion, it did increase brain-derived neurotrophic factor (BDNF) levels and could protect against amphetamine-induced oxidative damage in proteins of the hippocampus and striatum. No adverse effects were recorded in this study.22


Another model for BD and schizophrenia is PPI of the startle reflex both in humans and animals, which is disrupted in these diseases. Peres et al., list five animal studies, where mostly 30 mg/kg CBD was administered and had a positive effect on PPI.20 Nonetheless, some inconsistencies in explaining CBD effects on PPI as model for BD exist. For example, CBD sometimes did not alter MK-801-induced PPI disruption, but disrupted PPI on its own.20 If this effect can be observed in future experiments, it could be considered to be a possible side effect.


Addiction. CBD, which is nonhedonic, can reduce heroin-seeking behavior after, for example, cue-induced reinstatement. This was shown in an animal heroin self-administration study, where mice received 5 mg/kg CBD i.p. injections. The observed effect lasted for 2 weeks after CBD administration and could normalize the changes seen after stimulus cue-induced heroin seeking (expression of AMPA, GluR1, and CB1R). In addition, the described study was able to replicate previous findings showing no CBD side effects on locomotor behavior.23


Neuroprotection and neurogenesis. There are various mechanisms underlying neuroprotection, for example, energy metabolism (whose alteration has been implied in several psychiatric disorders) and proper mitochondrial functioning.24 An early study from 1976 found no side effects and no effect of 0.3–300 μg/mg protein CBD after 1 h of incubation on mitochondrial monoamine oxidase activity in porcine brains.25 In hypoischemic newborn pigs, CBD elicited a neuroprotective effect, caused no side effects, and even led to beneficial effects on ventilatory, cardiac, and hemodynamic functions.26


A study comparing acute and chronic CBD administration in rats suggests an additional mechanism of CBD neuroprotection: Animals received i.p. CBD (15, 30, 60 mg/kg b.w.) or vehicle daily, for 14 days. Mitochondrial activity was measured in the striatum, hippocampus, and the prefrontal cortex.27 Acute and chronic CBD injections led to increased mitochondrial activity (complexes I-V) and creatine kinase, whereas no side effects were documented. Chronic CBD treatment and the higher CBD doses tended to affect more brain regions. The authors hypothesized that CBD changed the intracellular Ca2+ flux to cause these effects. Since the mitochondrial complexes I and II have been implied in various neurodegenerative diseases and also altered ROS (reactive oxygen species) levels, which have also been shown to be altered by CBD, this might be an additional mechanism of CBD-mediated neuroprotection.1,27


Interestingly, it has recently been shown that the higher ROS levels observed after CBD treatment were concomitant with higher mRNA and protein levels of heat shock proteins (HSPs). In healthy cells, this can be interpreted as a way to protect against the higher ROS levels resulting from more mitochondrial activity. In addition, it was shown that HSP inhibitors increase the CBD anticancer effect in vitro.28 This is in line with the studies described by Bergamaschi et al., which also imply ROS in CBD effect on (cancer) cell viability in addition to, for example, proapoptotic pathways such as via caspase-8/9 and inhibition of the procarcinogenic lipoxygenase pathway.1


Another publication studied the difference of acute and chronic administration of two doses of CBD in nonstressed mice on anxiety. Already an acute i.p. administration of 3 mg/kg was anxiolytic to a degree comparable to 20 mg/kg imipramine (an selective serotonin reuptake inhibitor [SSRI] commonly prescribed for anxiety and depression). Fifteen days of repeated i.p. administration of 3 mg/kg CBD also increased cell proliferation and neurogenesis (using three different markers) in the subventricular zone and the hippocampal dentate gyrus. Interestingly, the repeated administration of 30 mg/kg also led to anxiolytic effects. However, the higher dose caused a decrease in neurogenesis and cell proliferation, indicating dissociation of behavioral and proliferative effects of chronic CBD treatment. The study does not mention adverse effects.19


Immune System


Numerous studies show the CBD immunomodulatory role in various diseases such as multiple sclerosis, arthritis, and diabetes. These animal and human ex vivo studies have been reviewed extensively elsewhere, but studies with pure CBD are still lacking. Often combinations of THC and CBD were used. It would be especially interesting to study when CBD is proinflammatory and under which circumstances it is anti-inflammatory and whether this leads to side effects (Burstein, 2015: Table 1 shows a summary of its anti-inflammatory actions; McAllister et al. give an extensive overview in Table 1 of the interplay between CBD anticancer effects and inflammation signaling).29,30


In case of Alzheimer’s disease (AD), studies in mice and rats showed reduced amyloid beta neuroinflammation (linked to reduced interleukin [IL]-6 and microglial activation) after CBD treatment. This led to amelioration of learning effects in a pharmacological model of AD. The chronic study we want to describe in more detail here used a transgenic mouse model of AD, where 2.5-month-old mice were treated with either placebo or daily oral CBD doses of 20 mg/kg for 8 months (mice are relatively old at this point). CBD was able to prevent the development of a social recognition deficit in the AD transgenic mice.


Moreover, the elevated IL-1 beta and TNF alpha levels observed in the transgenic mice could be reduced to WT (wild-type) levels with CBD treatment. Using statistical analysis by analysis of variance, this was shown to be only a trend. This might have been caused by the high variation in the transgenic mouse group, though. Also, CBD increased cholesterol levels in WT mice but not in CBD-treated transgenic mice. This was probably due to already elevated cholesterol in the transgenic mice. The study observed no side effects.31 and references within


In nonobese diabetes-prone female mice (NOD), CBD was administered i.p. for 4 weeks (5 days a week) at a dose of 5 mg/kg per day. After CBD treatment was stopped, observation continued until the mice were 24 weeks old. CBD treatment lead to considerable reduction of diabetes development (32% developed glucosuria in the CBD group compared to 100% in untreated controls) and to more intact islet of Langerhans cells. CBD increased IL-10 levels, which is thought to act as an anti-inflammatory cytokine in this context. The IL-12 production of splenocytes was reduced in the CBD group and no side effects were recorded.32


After inducing arthritis in rats using Freund’s adjuvant, various CBD doses (0.6, 3.1, 6.2, or 62.3 mg/day) were applied daily in a gel for transdermal administration for 4 days. CBD reduced joint swelling, immune cell infiltration. thickening of the synovial membrane, and nociceptive sensitization/spontaneous pain in a dose-dependent manner, after four consecutive days of CBD treatment. Proinflammatory biomarkers were also reduced in a dose-dependent manner in the dorsal root ganglia (TNF alpha) and spinal cord (CGRP, OX42). No side effects were evident and exploratory behavior was not altered (in contrast to Δ9-THC, which caused hypolocomotion).33


Cell Migration


Embryogenesis. CBD was shown to be able to influence migratory behavior in cancer, which is also an important aspect of embryogenesis.1 For instance, it was recently shown that CBD inhibits Id-1. Helix-loop-helix Id proteins play a role in embryogenesis and normal development via regulation of cell differentiation. High Id1-levels were also found in breast, prostate, brain, and head and neck tumor cells, which were highly aggressive. In contrast, Id1 expression was low in noninvasive tumor cells. Id1 seems to influence the tumor cell phenotype by regulation of invasion, epithelial to mesenchymal transition, angiogenesis, and cell proliferation.34


There only seems to exist one study that could not show an adverse CBD effect on embryogenesis. An in vitro study could show that the development of two-cell embryos was not arrested at CBD concentrations of 6.4, 32, and 160 nM.35


Cancer. Various studies have been performed to study CBD anticancer effects. CBD anti-invasive actions seem to be mediated by its TRPV1 stimulation and its action on the CB receptors. Intraperitoneal application of 5 mg/kg b.w. CBD every 3 days for a total of 28 weeks, almost completely reduced the development of metastatic nodules caused by injection of human lung carcinoma cells (A549) in nude mice.36 This effect was mediated by upregulation of ICAM1 and TIMP1. This, in turn, was caused by upstream regulation of p38 and p42/44 MAPK pathways. The typical side effects of traditional anticancer medication, emesis, and collateral toxicity were not described in these studies. Consequently, CBD could be an alternative to other MMP1 inhibitors such as marimastat and prinomastat, which have shown disappointing clinical results due to these drugs’ adverse muscoskeletal effects.37,38


Two studies showed in various cell lines and in tumor-bearing mice that CBD was able to reduce tumor metastasis.34,39 Unfortunately, the in vivo study was only described in a conference abstract and no route of administration or CBD doses were mentioned.36 However, an earlier study used 0.1, 1.0, or 1.5 μmol/L CBD for 3 days in the aggressive breast cancer cells MDA-MB231. CBD downregulated Id1 at promoter level and reduced tumor aggressiveness.40


Another study used xenografts to study the proapoptotic effect of CBD, this time in LNCaP prostate carcinoma cells.36 In this 5-week study, 100 mg/kg CBD was administered daily i.p. Tumor volume was reduced by 60% and no adverse effects of treatment were described in the study. The authors assumed that the observed antitumor effects were mediated via TRPM8 together with ROS release and p53 activation.41 It has to be pointed out though, that xenograft studies only have limited predictive validity to results with humans. Moreover, to carry out these experiments, animals are often immunologically compromised, to avoid immunogenic reactions as a result to implantation of human cells into the animals, which in turn can also affect the results.42


Another approach was chosen by Aviello et al.43 They used the carcinogen azoxymethane to induce colon cancer in mice. Treatment occurred using IP injections of 1 or 5 mg/kg CBD, three times a week for 3 weeks (including 1 week before carcinogen administration). After 3 months, the number of aberrant crypt foci, polyps, and tumors was analyzed. The high CBD concentration led to a significant decrease in polyps and a return to near-normal levels of phosphorylated Akt (elevation caused by the carcinogen).42 No adverse effects were mentioned in the described study.43


Food Intake and Glycemic Effects


Animal studies summarized by Bergamaschi et al. showed inconclusive effects of CBD on food intake1: i.p. administration of 3–100 mg/kg b.w. had no effect on food intake in mice and rats. On the contrary, the induction of hyperphagia by CB1 and 5HT1A agonists in rats could be decreased with CBD (20 mg/kg b.w. i.p.). Chronic administration (14 days, 2.5 or 5 mg/kg i.p.) reduced the weight gain in rats. This effect could be inhibited by coadministration of a CB2R antagonist.1


The positive effects of CBD on hyperglycemia seem to be mainly mediated via CBD anti-inflammatory and antioxidant effects. For instance, in ob/ob mice (an animal model of obesity), 4-week treatment with 3 mg/kg (route of administration was not mentioned) increased the HDL-C concentration by 55% and reduced total cholesterol levels by more than 25%. In addition, treatment increased adiponectin and liver glycogen concentrations.44 and references therein.


Endocrine Effects


High CBD concentrations (1 mM) inhibited progesterone 17-hydroxylase, which creates precursors for sex steroid and glucocorticoid synthesis, whereas 100 μM CBD did not in an in vitro experiment with primary testis microsomes.45 Rats treated with 10 mg/kg i.p. b.w. CBD showed inhibition of testosterone oxidation in the liver.46


Genotoxicity and Mutagenicity


Jones et al. mention that 120 mg/kg CBD delivered intraperetonially to Wistar Kyoto rats showed no mutagenicity and genotoxicity based on personal communication with GW Pharmaceuticals47,48 These data are yet to be published. The 2012 study with an epilepsy mouse model could also show that CBD did not influence grip strength, which the study describes as a “putative test for functional neurotoxicity.”48


Motor function was also tested on a rotarod, which was also not affected by CBD administration. Static beam performance, as an indicator of sensorimotor coordination, showed more footslips in the CBD group, but CBD treatment did not interfere with the animals’ speed and ability to complete the test. Compared to other anticonvulsant drugs, this effect was minimal.48 Unfortunately, we could not find more studies solely focusing on genotoxicity by other research groups neither in animals nor in humans.



Dr. Alex Jimenez’s Insight

Clinical and scientific research has attempted to show the effects of cannabidiol, or CBD, for the treatment of a wide range of conditions, including arthritis, diabetes, multiple sclerosis, chronic pain, schizophrenia, PTSD, depression, anxiety, infections, epilepsy, and many other neurological disorders. Evidence has also found that cannabidiol has neuroprotective and neurogenic effects and its anti-cancer properties are currently being investigated in many research studies. Further evidence has suggested that CBD can also be safe and effective even in higher doses, as recommended by a healthcare professional.


Acute Clinical Data


Bergamaschi et al. list an impressive number of acute and chronic studies in humans, showing CBD safety for a wide array of side effects.1 They also conclude from their survey, that none of the studies reported tolerance to CBD. Already in the 1970s, it was shown that oral CBD (15–160 mg), iv injection (5–30 mg), and inhalation of 0.15 mg/kg b.w. CBD did not lead to adverse effects. In addition, psychomotor function and psychological functions were not disturbed. Treatment with up to 600 mg CBD neither influenced physiological parameters (blood pressure, heart rate) nor performance on a verbal paired-associate learning test.1


Fasinu et al. created a table with an overview of clinical studies currently underway, registered in Clinical Trials. gov.49 In the following chapter, we highlight recent, acute clinical studies with CBD.


CBD-Drug Interactions


CBD can inhibit CYP2D6, which is also targeted by omeprazole and risperidone.2,14 There are also indications that CBD inhibits the hepatic enzyme CYP2C9, reducing the metabolization of warfarin and diclofenac.2,14 More clinical studies are needed, to check whether this interaction warrants an adaption of the used doses of the coadministered drugs.


The antibiotic rifampicin induces CYP3A4, leading to reduced CBD peak plasma concentrations.14 In contrast, the CYP3A4 inhibitor ketoconazole, an antifungal drug, almost doubles CBD peak plasma concentration. Interestingly, the CYP2C19 inhibitor omeprazole, used to treat gastroesophageal reflux, could not significantly affect the pharmacokinetics of CBD.14


A study, where a regimen of 6×100 mg CBD daily was coadministered with hexobarbital in 10 subjects, found that CBD increased the bioavailability and elimination half-time of the latter. Unfortunately, it was not mentioned whether this effect was mediated via the cytochrome P450 complex.16


Another aspect, which has not been thoroughly looked at, to our knowledge, is that several cytochrome isozymes are not only expressed in the liver but also in the brain. It might be interesting to research organ-specific differences in the level of CBD inhibition of various isozymes. Apart from altering the bioavailability in the overall plasma of the patient, this interaction might alter therapeutic outcomes on another level. Dopamine and tyramine are metabolized by CYP2D6, and neurosteroid metabolism also occurs via the isozymes of the CYP3A subgroup.50,51 Studying CBD interaction with neurovascular cytochrome P450 enzymes might also offer new mechanisms of action. It could be possible that CBD-mediated CYP2D6 inhibition increases dopamine levels in the brain, which could help to explain the positive CBD effects in addiction/withdrawal scenarios and might support its 5HT (=serotonin) elevating effect in depression.


Also, CBD can be a substrate of UDP glucuronosyltransferase.14 Whether this enzyme is indeed involved in the glucuronidation of CBD and also causes clinically relevant drug interactions in humans is yet to be determined in clinical studies. Generally, more human studies, which monitor CBD-drug interactions, are needed.


Physiological Effects


In a double-blind, placebo-controlled crossover study, CBD was coadministered with intravenous fentanyl to a total of 17 subjects.10 Blood samples were obtained before and after 400 mg CBD (previously demonstrated to decrease blood flow to (para)limbic areas related to drug craving) or 800 mg CBD pretreatment. This was followed by a single 0.5 (Session 1) or 1.0μg/kg (Session 2, after 1 week of first administration to allow for sufficient drug washout) intravenous fentanyl dose. Adverse effects and safety were evaluated with both forms of the Systematic Assessment for Treatment Emergent Events (SAFTEE). This extensive tool tests, for example, 78 adverse effects divided into 23 categories corresponding to organ systems or body parts. The SAFTEE outcomes were similar between groups. No respiratory depression or cardiovascular complications were recorded during any test session.


The results of the evaluation of pharmacokinetics, to see if interaction between the drugs occurred, were as follows. Peak CBD plasma concentrations of the 400 and 800 mg group were measured after 4 h in the first session (CBD administration 2 h after light breakfast). Peak urinary CBD and its metabolite concentrations occurred after 6 h in the low CBD group and after 4 h in the high CBD group. No effect was evident for urinary CBD and metabolite excretion except at the higher fentanyl dose, in which CBD clearance was reduced. Importantly, fentanyl coadministration did not produce respiratory depression or cardiovascular complications during the test sessions and CBD did not potentiate fentanyl’s effects. No correlation was found between CBD dose and plasma cortisol levels.


Various vital signs were also measured (blood pressure, respiratory/heart rate, oxygen saturation, EKG, respiratory function): CBD did not worsen the adverse effects (e.g., cardiovascular compromise, respiratory depression) of iv fentanyl. Coadministration was safe and well tolerated, paving the way to use CBD as a potential treatment for opioid addiction. The validated subjective measures scales Anxiety (visual analog scale [VAS]), PANAS (positive and negative subscores), and OVAS (specific opiate VAS) were administered across eight time points for each session without any significant main effects for CBD for any of the subjective effects on mood.10


A Dutch study compared subjective adverse effects of three different strains of medicinal cannabis, distributed via pharmacies, using VAS. “Visual analog scale is one of the most frequently used psychometric instruments to measure the extent and nature of subjective effects and adverse effects. The 12 adjectives used for this study were as follows: alertness, tranquility, confidence, dejection, dizziness, confusion/disorientation, fatigue, anxiety, irritability, appetite, creative stimulation, and sociability.” The high CBD strain contained the following concentrations: 6% Δ9-THC/7.5% CBD (n=25). This strain showed significantly lower levels of anxiety and dejection. Moreover, appetite increased less in the high CBD strain. The biggest observed adverse effect was “fatigue” with a score of 7 (out of 10), which did not differ between the three strains.52


Neurological and Neurospychiatric Effects


Anxiety. Forty-eight participants received subanxiolytic levels (32 mg) of CBD, either before or after the extinction phase in a double-blind, placebo-controlled design of a Pavlovian fear-conditioning experiment (recall with conditioned stimulus and context after 48 h and exposure to unconditioned stimulus after reinstatement). Skin conductance (=autonomic response to conditioning) and shock expectancy measures (=explicit aspects) of conditioned responding were recorded throughout. Among other scales, the Mood Rating Scale (MRS) and the Bond and Bodily Symptoms Scale were used to assess anxiety, current mood, and physical symptoms. “CBD given postextinction (active after consolidation phase) enhanced consolidation of extinction learning as assessed by shock expectancy.” Apart from the extinction-enhancing effects of CBD in human aversive conditioned memory, CBD showed a trend toward some protection against reinstatement of contextual memory. No side/adverse effects were reported.53


Psychosis. The review by Bergamaschi et al. mentions three acute human studies that have demonstrated the CBD antipsychotic effect without any adverse effects being observed. This holds especially true for the extrapyramidal motor side effects elicited by classical antipsychotic medication.1


Fifteen male, healthy subjects with minimal prior Δ9-THC exposure (<15 times) were tested for CBD affecting Δ9-THC propsychotic effects using functional magnetic resonance imaging (fMRI) and various questionnaires on three occasions, at 1-month intervals, following administration of 10 mg delta-9-Δ9-THC, 600 mg CBD, or placebo. Order of drug administration was pseudorandomized across subjects, so that an equal number of subjects received any of the drugs during the first, second, or third session in a double-blind, repeated-measures, within-subject design.54 No CBD effect on psychotic symptoms as measured with PANSS positive symptoms subscale, anxiety as indexed by the State Trait Anxiety Inventory (STAI) state, and Visual Analogue Mood Scale (VAMS) tranquilization or calming subscale, compared to the placebo group, was observed. The same is true for a verbal learning task (=behavioral performance of the verbal memory).


Moreover, pretreatment with CBD and subsequent Δ9-THC administration could reduce the latter’s psychotic and anxiety symptoms, as measured using a standardized scale. This effect was caused by opposite neural activation of relevant brain areas. In addition, no effects on peripheral cardiovascular measures such as heart rate and blood pressure were measured.54


A randomized, double-blind, crossover, placebo-controlled trial was conducted in 16 healthy nonanxious subjects using a within-subject design. Oral Δ9-THC=10 mg, CBD=600 mg, or placebo was administered in three consecutive sessions at 1-month intervals. The doses were selected to only evoke neurocognitive effects without causing severe toxic, physical, or psychiatric reactions. The 600 mg CBD corresponded to mean (standard deviation) whole blood levels of 0.36 (0.64), 1.62 (2.98), and 3.4 (6.42) ng/mL, 1, 2, and 3 h after administration, respectively.


Physiological measures and symptomatic effects were assessed before, and at 1, 2, and 3 h postdrug administration using PANSS (a 30-item rating instrument used to assess psychotic symptoms, with ratings based on a semistructured clinical interview yielding subscores for positive, negative, and general psychopathology domains), the self-administered VAMS with 16 items (e.g., mental sedation or intellectual impairment, physical sedation or bodily impairments, anxiety effects and other types of feelings or attitudes), the ARCI (Addiction Research Center Inventory; containing empirically derived drug-induced euphoria; stimulant-like effects; intellectual efficiency and energy; sedation; dysphoria; and somatic effects) to assess drug effects and the STAI-T/S, where subjects were evaluated on their current mood and their feelings in general.


There were no significant differences between the effects of CBD and placebo on positive and negative psychotic symptoms, general psychopathology (PANSS), anxiety (STAI-S), dysphoria (ARCI), sedation (VAMS, ARCI), and the level of subjective intoxication (ASI, ARCI), where Δ9-THC did have a pronounced effect. The physiological parameters, heart rate and blood pressure, were also monitored and no significant difference between the placebo and the CBD group was observed.55


Addiction. A case study describes a patient treated for cannabis withdrawal according to the following CBD regimen: “treated with oral 300 mg on Day 1; CBD 600 mg on Days 2–10 (divided into two doses of 300 mg), and CBD 300 mg on Day 11.” CBD treatment resulted in a fast and progressive reduction in withdrawal, dissociative and anxiety symptoms, as measured with the Withdrawal Discomfort Score, the Marijuana Withdrawal Symptom Checklist, Beck Anxiety Inventory, and Beck Depression Inventory (BDI). Hepatic enzymes were also measured daily, but no effect was reported.56


Naturalistic studies with smokers inhaling cannabis with varying amounts of CBD showed that the CBD levels were not altering psychomimetic symptoms.1 Interestingly, CBD was able to reduce the “wanting/liking”=implicit attentional bias caused by exposure to cannabis and food-related stimuli. CBD might work to alleviate disorders of addiction, by altering the attentive salience of drug cues. The study did not further measure side effects.57


CBD can also reduce heroin-seeking behaviors (e.g., induced by a conditioned cue). This was shown in the preclinical data mentioned earlier and was also replicated in a small double-blind pilot study with individuals addicted to opioids, who have been abstinent for 7 days.52,53 They either received placebo or 400 or 800 mg oral CBD on three consecutive days. Craving was induced with a cue-induced reinstatement paradigm (1 h after CBD administration). One hour after the video session, subjective craving was already reduced after a single CBD administration. The effect persisted for 7 days after the last CBD treatment. Interestingly, anxiety measures were also reduced after treatment, whereas no adverse effects were described.23,58


A pilot study with 24 subjects was conducted in a randomized, double-blind, placebo-controlled design to evaluate the impact of the ad hoc use of CBD in smokers, who wished to stop smoking. Pre- and post-testing for mood and craving of the participants was executed. These tests included the Behaviour Impulsivity Scale, BDI, STAI, and the Severity of Dependence Scale. During the week of CBD inhalator use, subjects used a diary to log their craving (on a scale from 1 to 100=VAS measuring momentary subjective craving), the cigarettes smoked, and the number of times they used the inhaler. Craving was assessed using the Tiffany Craving Questionnaire (11). On day 1 and 7, exhaled CO was measured to test smoking status. Sedation, depression, and anxiety were evaluated with the MRS.


Over the course of 1 week, participants used the inhaler when they felt the urge to smoke and received a dose of 400 μg CBD via the inhaler (leading to >65% bioavailability); this significantly reduced the number of cigarettes smoked by ca. 40%, while craving was not significantly different in the groups post-test. At day 7, the anxiety levels for placebo and CBD group did not differ. CBD did not increase depression (in contract to the selective CB1 antagonist rimonabant). CBD might weaken the attentional bias to smoking cues or could have disrupted reconsolidation, thereby destabilizing drug-related memories.59


Cell Migration


According to our literature survey, there currently are no studies about CBD role in embryogenesis/cell migration in humans, even though cell migration does play a role in embryogenesis and CBD was shown to be able to at least influence migratory behavior in cancer.1


Endocrine Effects and Glycemic (Including Appetite) Effects


To the best of our knowledge, no acute studies were performed that solely concentrated on CBD glycemic effects. Moreover, the only acute study that also measured CBD effect on appetite was the study we described above, comparing different cannabis strains. In this study, the strain high in CBD elicited less appetite increase compared to the THC-only strain.52


Eleven healthy volunteers were treated with 300 mg (seven patients) and 600 mg (four patients) oral CBD in a double-blind, placebo-controlled study. Growth hormone and prolactin levels were unchanged. In contrast, the normal decrease of cortisol levels in the morning (basal measurement=11.0±3.7 μg/dl; 120 min after placebo=7.1±3.9 μg/dl) was inhibited by CBD treatment (basal measurement=10.5±4.9 μg/dl; 120 min after 300 mg CBD=9.9±6.2 μg/dl; 120 min after 600 mg CBD=11.6±11.6 μg/dl).60


A more recent study also used 600 mg oral CBD for a week and compared 24 healthy subjects to people at risk for psychosis (n=32; 16 received placebo and 16 CBD). Serum cortisol levels were taken before the TSST (Trier Social Stress Test), immediately after, as well as 10 and 20 min after the test. Compared to the healthy individuals, the cortisol levels increased less after TSST in the 32 at-risk individuals. The CBD group showed less reduced cortisol levels but differences were not significant.61 It has to be mentioned that these data were presented at a conference and are not yet published (to our knowledge) in a peer-reviewed journal.


Chronic CBD Studies in Humans


Truly chronic studies with CBD are still scarce. One can often argue that what the studies call “chronic” CBD administration only differs to acute treatment, because of repeated administration of CBD. Nonetheless, we also included these studies with repeated CBD treatment, because we think that compared to a one-time dose of CBD, repeated CBD regimens add value and knowledge to the field and therefore should be mentioned here.


CBD-Drug Interactions


An 8-week-long clinical study, including 13 children who were treated for epilepsy with clobazam (initial average dose of 1 mg/kg b.w.) and CBD (oral; starting dose of 5 mg/kg b.w. raised to maximum of 25 mg/kg b.w.), showed the following. The CBD interaction with isozymes CYP3A4 and CYP2C19 caused increased clobazam bioavailability, making it possible to reduce the dose of the antiepileptic drug, which in turn reduced its side effects.62


These results are supported by another study described in the review by Grotenhermen et al.63 In this study, 33 children were treated with a daily dose of 5 mg/kg CBD, which was increased every week by 5 mg/kg increments, up to a maximum level of 25 mg/kg. CBD was administered on average with three other drugs, including clobazam (54.5%), valproic acid (36.4%), levetiracetam (30.3%), felbamate (21.2%), lamotrigine (18.2%), and zonisamide (18.2%). The coadministration led to an alteration of blood levels of several antiepileptic drugs. In the case of clobazam this led to sedation, and its levels were subsequently lowered in the course of the study.


Physiological Effects


A first pilot study in healthy volunteers in 1973 by Mincis et al. administering 10 mg oral CBD for 21 days did not find any neurological and clinical changes (EEG; EKG).64 The same holds true for psychiatry and blood and urine examinations. A similar testing battery was performed in 1980, at weekly intervals for 30 days with daily oral CBD administration of 3 mg/kg b.w., which had the same result.65


Neurological and Neuropsychiatric Effects


Anxiety. Clinical chronic (lasting longer than a couple of weeks) studies in humans are crucial here but were mostly still lacking at the time of writing this review. They hopefully will shed light on the inconsistencies observerd in animal studies. Chronic studies in humans may, for instance, help to test whether, for example, an anxiolytic effect always prevails after chronic CBD treatment or whether this was an artifact of using different animal models of anxiety or depression.2,18


Psychosis and bipolar disorder. In a 4-week open trial, CBD was tested on Parkinson’s patients with psychotic symptoms. Oral doses of 150–400 mg/day CBD (in the last week) were administered. This led to a reduction of their psychotic symptoms. Moreover, no serious side effects or cognitive and motor symptoms were reported.66


Bergamaschi et al. describe a chronic study, where a teenager with severe side effects of traditional antipsychotics was treated with up to 1500 mg/day of CBD for 4 weeks. No adverse effects were observed and her symptoms improved. The same positive outcome was registered in another study described by Bergamaschi et al., where three patients were treated with a starting dose of CBD of 40 mg, which was ramped up to 1280 mg/day for 4 weeks.1 A double-blind, randomized clinical trial of CBD versus amisulpride, a potent antipsychotic in acute schizophrenia, was performed on a total of 42 subjects, who were treated for 28 days starting with 200 mg CBD per day each.67 The dose was increased stepwise by 200 mg per day to 4×200 mg CBD daily (total 800 mg per day) within the first week. The respective treatment was maintained for three additional weeks. A reduction of each treatment to 600 mg per day was allowed for clinical reasons, such as unwanted side effects after week 2. This was the case for three patients in the CBD group and five patients in the amisulpride group. While both treatments were effective (no significant difference in PANSS total score), CBD showed the better side effect profile. Amisulpride, working as a dopamine D2/D3-receptor antagonist, is one of the most effective treatment options for schizophrenia. CBD treatment was accompanied by a substantial increase in serum anandamide levels, which was significantly associated with clinical improvement, suggesting inhibition of anandamide deactivation via reduced FAAH activity.


In addition, the FAAH substrates palmitoylethanolamide and linoleoyl-ethanolamide (both lipid mediators) were also elevated in the CBD group. CBD showed less serum prolactin increase (predictor of galactorrhoea and sexual dysfunction), fewer extrapyramidal symptoms measured with the Extrapyramidal Symptom Scale, and less weight gain. Moreover, electrocardiograms as well as routine blood parameters were other parameters whose effects were measured but not reported in the study. CBD better safety profile might improve acute compliance and long-term treatment adherence.67,68


A press release by GW Pharmaceuticals of September 15th, 2015, described 88 patients with treatment-resistant schizophrenic psychosis, treated either with CBD (in addition to their regular medication) or placebo. Important clinical parameters improved in the CBD group and the number of mild side effects was comparable to the placebo group.2 Table 2 shows an overview of studies with CBD for the treatment of psychotic symptoms and its positive effect on symptomatology and the absence of side effects.69


Table 2 Studies with CBD


Treatment of two patients for 24 days with 600–1200 mg/day CBD, who were suffering from BD, did not lead to side effects.70 Apart from the study with two patients mentioned above, CBD has not been tested systematically in acute or chronic administration scenarios in humans for BD according to our own literature search.71


Epilepsy. Epileptic patients were treated for 135 days with 200–300 mg oral CBD daily and evaluated every week for changes in urine and blood. Moreover, neurological and physiological examinations were performed, which neither showed signs of CBD toxicity nor severe side effects. The study also illustrated that CBD was well tolerated.65


A review by Grotenhermen and Müller-Vahl describes several clinical studies with CBD2: 23 patients with therapy-resistant epilepsy (e.g., Dravet syndrome) were treated for 3 months with increasing doses of up to 25 mg/kg b.w. CBD in addition to their regular epilepsy medication. Apart from reducing the seizure frequency in 39% of the patients, the side effects were only mild to moderate and included reduced/increased appetite, weight gain/loss, and tiredness.


Another clinical study lasting at least 3 months with 137 children and young adults with various forms of epilepsy, who were treated with the CBD drug Epidiolex, was presented at the American Academy for Neurology in 2015. The patients were suffering from Dravet syndrome (16%), Lennox–Gastaut syndrome (16%), and 10 other forms of epilepsy (some among them were very rare conditions). In this study, almost 50% of the patients experienced a reduction of seizure frequency. The reported side effects were 21% experienced tiredness, 17% diarrhea, and 16% reduced appetite. In a few cases, severe side effects occurred, but it is not clear, if these were caused by Epidiolex. These were status epilepticus (n=10), diarrhea (n=3), weight loss (n=2), and liver damage in one case.


The largest CBD study conducted thus far was an open-label study with Epidiolex in 261 patients (mainly children, the average age of the participants was 11) suffering from severe epilepsy, who could not be treated sufficiently with standard medication. After 3 months of treatment, where patients received CBD together with their regular medication, a median reduction of seizure frequency of 45% was observed. Ten percent of the patients reported side effects (tiredness, diarrhea, and exhaustion).2


After extensive literature study of the available trials performed until September 2016, CBD side effects were generally mild and infrequent. The only exception seems to be a multicenter open-label study with a total of 162 patients aged 1–30 years, with treatment-resistant epilepsy. Subjects were treated for 1 year with a maximum of 25 mg/kg (in some clinics 50 mg/kg) oral CBD, in addition to their standard medication.


This led to a reduction in seizure frequency. In this study, 79% of the cohort experienced side effects. The three most common adverse effects were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), and diarrhea (n=31 [19%]).72 It has to be pointed out that no control group existed in this study (e.g., placebo or another drug). It is therefore difficult to put the side effect frequency into perspective. Attributing the side effects to CBD is also not straightforward in severely sick patients. Thus, it is not possible to draw reliable conclusions on the causation of the observed side effects in this study.


Parkinson’s disease. In a study with a total of 21 Parkinson’s patients (without comorbid psychiatric conditions or dementia) who were treated with either placebo, 75 mg/day CBD or 300 mg/day CBD in an exploratory double-blind trial for 6 weeks, the higher CBD dose showed significant improvement of quality of life, as measured with PDQ-39. This rating instrument comprised the following factors: mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort. For the factor, “activities of daily living,” a possible dose-dependent relationship could exist between the low and high CBD group—the two CBD groups scored significantly different here. Side effects were evaluated with the UKU (Udvalg for Kliniske Undersøgelser). This assessment instrument analyzes adverse medication effects, including psychic, neurologic, autonomic, and other manifestations. Using the UKU and verbal reports, no significant side effects were recognized in any of the CBD groups.73


Huntington’s disease. Fifteen neuroleptic-free patients with Huntington’s disease were treated with either placebo or oral CBD (10 mg/kg b.w. per day) for 6 weeks in a double-blind, randomized, crossover study design. Using various safety outcome variables, clinical tests, and the cannabis side effect inventory, it was shown that there were no differences between the placebo group and the CBD group in the observed side effects.6


Immune System


Forty-eight patients were treated with 300 mg/kg oral CBD, 7 days before and until 30 days after the transplantation of allogeneic hematopoietic cells from an unrelated donor to treat acute leukemia or myelodysplastic syndrome in combination with standard measures to avoid GVHD (graft vs. host disease; cyclosporine and short course of MTX). The occurrence of various degrees of GVHD was compared with historical data from 108 patients, who had only received the standard treatment. Patients treated with CBD did not develop acute GVHD. In the 16 months after transplantation, the incidence of GHVD was significantly reduced in the CBD group. Side effects were graded using the Common Terminology Criteria for Adverse Events (CTCAE v4.0) classification, which did not detect severe adverse effects.74


Endocrine and Glycemic (Including Appetite, Weight Gain) Effects


In a placebo-controlled, randomized, double-blind study with 62 subjects with noninsulin-treated type 2 diabetes, 13 patients were treated with twice-daily oral doses of 100 mg CBD for 13 weeks. This resulted in lower resistin levels compared to baseline. The hormone resistin is associated with obesity and insulin resistance. Compared to baseline, glucose-dependent insulinotropic peptide levels were elevated after CBD treatment. This incretin hormone is produced in the proximal duodenum by K cells and has insulinotropic and pancreatic b cell preserving effects. CBD was well tolerated in the patients. However, with the comparatively low CBD concentrations used in this phase-2-trial, no overall improvement of glycemic control was observed.40


When weight and appetite were measured as part of a measurement battery for side effects, results were inconclusive. For instance, the study mentioned above, where 23 children with Dravet syndrome were treated, increases as well as decreases in appetite and weight were observed as side effects.2 An open-label trial with 214 patients suffering from treatment-resistant epilepsy showed decreased appetite in 32 cases. However, in the safety analysis group, consisting of 162 subjects, 10 showed decreased weight and 12 had gained weight.52 This could be either due to the fact that CBD only has a small effect on these factors, or appetite and weight are complex endpoints influenced by multiple factors such as diet and genetic predisposition. Both these factors were not controlled for in the reviewed studies.



Dr. Alex Jimenez’s Insight

One of the most crucially important qualities of cannabidiol, or CBD, is its lack of psychoactivity. When taken on its own, consumers can experience the many health benefits of CBD without experiencing the euphoric sensations commonly known to be caused by THC. Cannabidiol acts directly with the endocannabinoid system, an essential system in the human body which many individuals may not be particularly familiar with. When CBD binds to the endocannabinoid system’s receptors, it can stimulate all kinds of changes in the human body. Most of those changes are beneficial, and research studies keep uncovering real and potential medical uses for them.




This review could substantiate and expand the findings of Bergamaschi et al. about CBD favorable safety profile.1 Nonetheless, various areas of CBD research should be extended. First, more studies researching CBD side effects after real chronic administration need to be conducted. Many so-called chronic administration studies, cited here were only a couple of weeks long. Second, many trials were conducted with a small number of individuals only. To perform a throrough general safety evaluation, more individuals have to be recruited into future clinical trials. Third, several aspects of a toxicological evaluation of a compound such as genotoxicity studies and research evaluating CBD effect on hormones are still scarce. Especially, chronic studies on CBD effect on, for example, genotoxicity and the immune system are still missing. Last, studies that evaluate whether CBD-drug interactions occur in clinical trials have to be performed.


In conclusion, CBD safety profile is already established in a plethora of ways. However, some knowledge gaps detailed above should be closed by additional clinical trials to have a completely well-tested pharmaceutical compound.


Abbreviations Used


  • AD – Alzheimer’s disease
  • ARCI – Addiction Research Center Inventory
  • BD – bipolar disorder
  • BDI – Beck Depression Inventory
  • CBD – cannabidiol
  • HSP – heat shock protein
  • IL – interleukin
  • MRS – Mood Rating Scale
  • PPI – prepulse inhibition
  • ROS – reactive oxygen species
  • SAFTEE – Systematic Assessment for Treatment Emergent Events
  • STAI – State Trait Anxiety Inventory
  • TSST – Trier Social Stress Test
  • UKU – Udvalg for Kliniske Undersøgelser
  • VAMS – Visual Analogue Mood Scale
  • VAS – Visual Analog Scales




The study was commissioned by the European Industrial Hemp Association. The authors thank Michal Carus, Executive Director of the EIHA, for making this review possible, for his encouragement, and helpful hints.


Author Disclosure Statement


EIHA paid nova-Institute for the review. F.G. is Executive Director of IACM.


Chiropractic Care Guide to CBD


Chiropractors and health professionals everywhere have become increasingly curious about the health benefits of CBD, or cannabidiol. Below, we will summarize what CBD oil is and we will also discuss its benefits to help guide consumers regarding the use of CBD oil. Incorporating CBD oil into chiropractic care with patients who can benefit from it’s various advantages, may be an innovative approach to help effectively treat a variety of health issues.


What is CBD Oil?


Cannabidiol, or CBD, is one of the compounds available today with the most growing interest behind its use but it is also one of the most controversial, and consumers worldwide are discovering its own health benefits. CBD is a cannabinoid, a type of over 100 chemical compounds found in the cannabis plant, such as marijuana and hemp. Found in the cannabis plant’s flowers, seeds, and stalks, CBD could be extracted from the plant as part of its cannabis oil. This oil can then be processed into many CBD supplements which can be used to boost well-being and the human body’s ability to keep equilibrium. When CBD oil has been extracted from low-THC hemp, the resulting products are non-psychoactive and safe to use by anyone.


How is CBD Used on Patients?


These CBD oil products can be given to patients to assist them attain health and wellness by promoting proper sleep, appetite, metabolism, immune reaction, and much more.


When CBD petroleum goods are utilized, plant-based cannabinoids or phytocannabinoids such as CBD are consumed by the body in the place where they make their way to the bloodstream and are transported through the body to interact with specific cannabinoid receptors in both peripheral and central nervous systems.


The neural communication network that employs these cannabinoid neurotransmitters, known as the endocannabinoid system, plays a fundamental role in the nervous system’s normal functioning. Endocannabinoids, such as anandamide and 2-AG, function as neurotransmitters, delivering chemical messages between nerve cells throughout the nervous system.


Phytocannabinoids mimic the functions of the body’s endogenous, or naturally-occurring, cannabinoids like anandamide and 2-AG. CBD and THC’s chemical structures are similar to those of 2-AG and anandamide, letting us use them to control the endocannabinoid system to achieve beneficial effects in the body.


CBD oil products come in many different consumption forms, such as capsules, tinctures, topical salves, vaporizers, pure hemp oil oral applicators, and more. These daily use products supply all the benefits of CBD with none of the worry over THC from other medical marijuana solutions.


But is CBD Legal?


Hemp products, such as nutritional supplements, are lawful in the U.S. provided that they’re manufactured using imported hemp. Hemp is defined at the U.S. as any cannabis plant containing 0.3 percent THC per dry weight or less. At those levels, the THC in hemp-derived CBD petroleum merchandise is far too low to produce psychoactive effects in people. Because our products are derived from low-THC hemp, they’re legal from the U.S. and in over 40 countries globally. However, we suggest you check your regional laws to find out if CBD oil products possess some particular restrictions.



Dr. Alex Jimenez’s Insight

Cannabidiol, or CBD, is a phytocannabinoid which is devoid of psychoactive activity which is why it has been used to provide its many benefits to patients without the side effects commonly associated with THC, or marijuana. Many healthcare professionals, including chiropractors, have started utilizing CBD as a part of their treatment program. Numerous research studies have demonstrated the many health benefits of cannabidiol, or CBD. According to the article above, the favorable safety profile of CBD in humans was confirmed and extended by the reviewed research. Cannabidiol, or CBD, is most often utilized as an adjunct therapy, therefore, it’s interaction with other drugs and/or medications requires further research.


Is CBD Safe to Use on Patients?


CBD is regarded as safe and nontoxic for humans, even at large quantities. Researchers have conducted numerous studies regarding the use of cannabidiol, or CBD, for its health benefits.


In conclusion, the use of cannabidiol, or CBD, has been a controversial topic for many years. However, due to it’s reported health benefits, more and more research studies regarding its advantages in the human body have been conducted in attempts to shine light on the safety and efficiency of this compound as well as thoroughly discussing its side effects. Furthermore, the use of CBD by healthcare professionals, including chiropractors, has become a new treatment approach for a variety of underlying health issues. Further research studies are still required to conclude the health benefits of cannabidiol, or CBD.Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


Curated by Dr. Alex Jimenez


Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




blog picture of cartoon paperboy big news


EXTRA IMPORTANT TOPIC: Low Back Pain Management


MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments


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Understanding Phytocannabinoids

Understanding Phytocannabinoids

Phytocannabinoids: With the discovery of the endocannabinoid system (ECS) during the 1980s provided researchers a new perspective on the compounds in hemp and marijuana identified 40 years before. And one of the new perspectives was how these compounds interacted with the human body.

Phytocannabinoids: (Phyto) – For Plant Was The Name Given To These Compounds

Over 80 phytocannabinoids have been identified in marijuana and hemp. The psychoactive phytocannabinoid in marijuana  known as tetrahydrocannabinol (THC) represents only one of the many phytocannabinoids being studied for its health benefits.1

The more science learns about the effects of the ECS in supporting brain health, enhancing immune function, maintaining a healthy inflammatory response, and promoting GI health, fertility, bone health, etc. Now there is more interest in finding phytocannabinoids in nature and learning how they affect human health.

Because of this interest, phytocannabinoids have now been identified in many plants outside of the Cannabis species. An example is in plants like clove, black pepper, echinacea, broccoli, ginseng, and carrots.2

Phytocannabinoids In Hemp

Most people have heard of cannabadiol (CBD), but this is only one of many components in hemp that interacts with the ECS.

phytocannabinoids el paso tx.

Two other phytocannabinoids include:

Cannabichromene (CBC)

  • CBC research began in the 1980’s when it was found that it would act upon a normal inflammatory response in rats.3 Recently CBC has shown to promote brain health,4 skin health,5 and keep normal movement in the digestive system.6

Cannabigerol (CBG)

  • CBG research focuses on how it supports nervous system health. CBG has multiple jobs in the ECS. These include inhibiting the re-uptake of anandamide. Although still unknown, but CBG could possibly provide support for immune function, skin health, and being in a good mood. And CBG is found in much higher levels in industrial hemp than in marijuana.7

Phytocannabinoids In Other Plants

Current research has found phytocannabionids in many other plants. Some of these include:

Beta-caryophyllene (BCP)

  • BCP is found in the flowers and leaves of hemp, and since only the hemp stalk is used in supplements, BCP content gets lost. But, BCP is contained in many other plants, i.e. cloves and black pepper. BCP joins itself to the CB2 cannabinoid receptor. This helps maintain a healthy inflammatory response while at the same time promoting health to the digestive system, skin, and liver.8,9

Diindolylmethane (DIM)

  • DIM is a compound that is produced in our bodies when consuming vegetables like broccoli, cauliflower and cabbage. DIM is a readily available dietary supplement. Just like beta-caryophyllene, DIM binds to the CB2 cannabinoid receptor.10 The immune system is abundant in CB2 receptors, this could explain benefits of these foods especially in immune system health.


  • Alkylamides also play a role in the ECS, that is generating interest. It is found in the herb Echinacea, These compounds act on the CB2 receptor for regulation of cytokine synthes is and immune function support.11 This helps explain the common uses of Echinacea.


  • Falcarinol is found in carrots, celery, parsley, and Panax or Asian ginseng. Falcarinol compound binds to the CB1 cannabinoid receptor but has the opposite effect of anandamide. Because of this, falcarinol can cause allergic skin reactions due to the blocking of our own ECS from regulating local inflammation.12


  • This phytocannabinoid is found in the Kava plant (Piper methysticum). This compound binds to CB1 receptors and acts on GABA receptors in the nervous system. Yangonin has shown to promote relaxation and regulate responses to stress, however, it could be unhealthy for the liver.13

Information and knowledge of the endocannabinoid system is growing at a rapid rate. Science and scientists continue their research in order to find more phytocannabinoids in foods/plants that will benefit human health.


  1. Borgelt L, Franson K, Nussbaum A, Wang G. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 2013;33(2):195-209.
  2. Gertsch J, Roger G, Vincenzo D. Phytocannabinoids beyond the cannabis plant – do they exist? Br J Pharmacol 2010;160(3):523-529.
  3. Wirth P, Watson E, ElSohly M, et al. Anti-inflammatory properties of cannabichromene. Life Sci 1980;26(23):1991-1995.
  4. Shinjyo N, Di Marzo V. The effect of cannabichromene on adult neural stem/progenitor cells. Neurochem Int 2013;63(5):432-437.
  5. Izzo A, Capasso R, Aviello G, et al. Inhibitory effect of cannabichromene, a major non?psychotropic cannabinoid extracted from Cannabis sativa, on inflammation?induced hypermotility in mice. Br J Pharmacol 2012;166(4):1444-1460.
  6. Oláh A, Markovics A, Szabó?Papp J, et al. Differential effectiveness of selected non?psychotropic phytocannabinoids on human sebocyte functions implicates their introduction in dry/seborrheic skin and acne treatment. Exp Dermatol 2016;25(9):701-707.
  7. De Meijer E, Hammond K. The inheritance of chemical phenotype in Cannabis sativa L.(II): cannabigerol predominant plants. Euphytica 2005;145(1-2):189-198.
  8. Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci 2008;105(26):9099-9104.
  9. Klauke A, Racz I, Pradier B, et al. The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. Eur Neuropsychopharmacol 2014;24(4):608-620.
  10. Yin H, Chu A, Li W, et al. Lipid G protein-coupled receptor ligand identification using β-arrestin PathHunter™ assay. J Biol Chem 2009;284(18):12328-12338.
  11. Raduner S, Majewska A, Chen J, et al. Alkylamides from Echinacea are a new class of cannabinomimetics Cannabinoid type 2 receptor-dependent and-independent immunomodulatory effects. J Biol Chem 2006;281(20):14192-14206.
  12. Leonti M, Casu L, Raduner S, et al. Falcarinol is a covalent cannabinoid CB1 receptor antagonist and induces pro-allergic effects in skin. Biochem Pharmacol 2010;79(12):1815-1826.
  13. Tang J, Dunlop R, Rowe A, et al. Kavalactones Yangonin and Methysticin induce apoptosis in human hepatocytes (HepG2) in vitro. Phytother Res 2011;25(3):417-423.
Cannabidiol (CBD) For Migraines And Headaches?

Cannabidiol (CBD) For Migraines And Headaches?

The therapeutic effects of Cannabidiol or CBD, is often the cannabinoid’s pain soothing effect that gets talked about. Headaches are the most common source of pain for the general population. Therefore, it makes sense that CBD use for migraines and headaches is an obvious.

Migraines and headaches can be a medical mystery, but usually their causes are brought on by problems with brain stem centers. The only treatments thus far, has been painkillers i.e. paracetamol or ibuprofen. Triptan medications, which constricts the blood vessels in order to block pain pathways in the brain are used as well. But is there a better more natural way to treat headaches and migraines?

cannabidiol el paso, tx.

Cannabis Has Been Treating Headaches For Quite Awhile

CBD oil for headaches is not a new therapy. Cannabis is mentioned as treatment for headaches in ancient texts that go back thousands of years. However, its use didn’t become familiar in the west until the 19th century when it would be prescribed by doctors as a tincture.

Today conclusive clinical evidence is incomplete, as far as, medical cannabis and hemp oil use for headaches. But scientists do know when it comes to CBD oil use for headaches and migraines, that the endocannabinoid system is working in conjunction with the compounds.

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The Endocannabinoid System & Migraines

A theory brought about a possible contributing cause of migraines is dysfunction in the endocannabinoid system or (ECS). This is the body’s network of receptors and cannabis-like chemicals that respond and regulate:

  • Pain
  • Immune system
  • Mood
  • Sleep
  • Appetite
  • Memory

Researchers have noted ECS mechanisms that could have a connection to migraine attacks.

Anandamide (AEA) is one of the prime endocannabinoids in the body. It is both a painkiller and has been found to power the serotonin 5-HT1A receptors.

The clearest record of endocannabinoid dysfunction that contributes to migraines is from a study in 2007 at the University of Perugia and published in the Journal of Neuropsychopharmacology. Researchers measured endocannabinoid levels in the cerebrospinal fluid of patients with chronic migraines and found significantly lower amounts of Anandamide. These findings, could “reflect an impairment of the endocannabinoid system in these patients, which may contribute to chronic head pain.”

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Clinical Endocannabinoid Deficiency? Migraines Could Be A Sign

The link between lower levels of endocannabinoids in migraine patients has contributed to the formulation of what has been termed Clinical Endocannabinoid Deficiency. This theory was developed by Neurologist and Cannabinoid Researcher Dr. Ethan Russo.

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The theory comes from how many brain disorders are inadequate or missing neurotransmitters like acetylcholine. Russo has suggested “a comparable deficiency in endocannabinoid levels might manifest similarly in certain disorders that display predictable clinical features as sequelae of this deficiency.”

In an interview he describes how, “If you don’t have enough endocannabinoids you have pain where there shouldn’t be pain. You would be sick, meaning nauseated. You would have a lowered seizure threshold. And just a whole litany of other problems.”

Russo relates these deficiencies can be addressed through introduction to plant cannabinoids, which act almost like those found in the body, by stimulating the endocannabinoid receptors. There is CB1 agonists such as Marinol and Nabilone have been tested for migraines, Russo suggests that the ECS needs a “gentle nudge” rather than a “forceful shove” given by these synthetic alternatives. He suggests small doses of whole plant cannabis, which contain “additional synergistic and buffering components, such as CBD and cannabis terpenoids.” 

Cannabidiol CBD Oil: Migraines

Russo in particular singles out CBD (Cannabidiol) in that it brings balance to the endocannabinoid system. In his interview with Martin Lee from Project CBD he says, “cannabidiol is an endocannabinoid modulator, in other words, when given chronically it actually increases the gain of the system…. So, if there’s too much activity in a system, homeostasis requires that it be brought back down. If there’s too little, it’s got to come up. And that’s what cannabidiol can do as a promoter of endocannabinoid tone.”

Scientists still are not exactly sure of how CBD interacts with the endocannabinoid system. Unlike psychoactive THC, CBD does not bind with any of the endocannabinoid receptors. Instead it activates a host of other non-endocannabinoid receptors, which work in the development and treatment of migraines, i.e. the 5-HT1A serotonin and TRPV-1 receptors.

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Another possible explanation is CBD’s role as a fatty acid amide hydrolase (FAAH) inhibitor, which breaks down anandamide in the body. By inhibiting its production the theory is that it might lead to higher levels of pain relieving endocannabinoid. This is something that would benefit migraine sufferers.

Lack Of Clinical Evidence

Currently there are no gold standard, double blind, placebo clinical studies published to back up any accounts that suggest CBD or cannabis is an effective treatment for headaches and migraines.

One placebo controlled study has been conducted, documenting the safety and efficacy of synthetic THC medication Dronabinol for migraines. However, the results are still pending.

The largest study to take place was done from a retrospective basis. It was published in 2016 and found that out of 121 participants that suffer from migraines and were prescribed medical cannabis by a doctor; 103 participants found their migraine frequency reduced by half.

Can Cannabidiol Cause A Headache?

There are those who tried CBD and noted persistent headaches and even migraines. Does CBD cause headaches, even though the research suggests the contrary.

Those who reported getting headaches after taking CBD oil noted that the oil they bought was low quality, and the ingredients used included ethanol, various alcohols, preservatives and harsh chemicals.

When purchasing CBD oil for migraines or other conditions, get the best quality, not the cheapest!

How To Use CBD For Head Pain

There are different ways to apply CBD oil for headaches. If taking CBD for tension headaches, migraines or general headaches, there are many way to administer. Probably the simplest and most effective ways of using CBD is the sublingual method.

With this method one places a few drops of oil underneath the tongue. There it permeates through the membrane and makes its way to where it needs to go.

This isn’t the only method and many others can be just as effective. Make sure to do research when looking for CBD products online and the methods of administering these products.

Just like the nature of migraines, CBD for headaches and migraines is still not completely and scientifically understood. But with continued research of CBD and Cannabinoid based medicine, the future of sufferers of headaches and migraines will get better.

Injury Medical Clinic: Migraine Treatment & Recovery

Mechanisms of Acute Pain vs Chronic Pain

Mechanisms of Acute Pain vs Chronic Pain

Pain is a very important function of the human body, including the involvement of nociceptors and the central nervous system, or CNS, to transmit messages from noxious stimulation to the brain. Nociceptors are adrenal glands which are responsible for detecting hazardous or harmful stimuli and transmitting electrical signals into the nervous system. The receptors are present in skin, viscera, muscles, joints and meninges to discover a range of stimulation, which might be mechanical, thermal or chemical.


There are two types of nociceptors:


  • C-fibres would be the most common type and are slow to conduct and respond to stimuli. As the proteins in the membrane of the receptor convert the stimulation into electrical impulses that can be taken through the nervous system.
  • A-delta fibers are known to conduct more rapidly and convey messages of sharp, momentary pain.


Additionally, there are silent nociceptors which are usually restricted to stimuli but can be “awoken” with high-intensity mechanical stimulation in response to chemical mediators from the body. Nociceptors may have many different voltage-gated stations for transduction that cause a set of action potentials to commence the electric signaling to the nervous system. The excitability and behavior of the cell are based on the types of channels within the nociceptor.


It is important to differentiate between nociception and pain when considering the mechanism of the pain. Nociception is the normal response of the body to noxious stimuli, including reflexes below the suprathreshold that protect the human body from injury. Pain is just perceived when superthreshold for those nociceptors to reach an action possible and initiate the pain pathway is attained, which is comparatively high. The purpose of the article below is to demonstrate the cellular and molecular mechanisms of pain, including acute pain and chronic pain, or persistent pain, as referred to below.


Cellular and Molecular Mechanisms of Pain




The nervous system detects and interprets a wide range of thermal and mechanical stimuli as well as environmental and endogenous chemical irritants. When intense, these stimuli generate acute pain, and in the setting of persistent injury, both peripheral and central nervous system components of the pain transmission pathway exhibit tremendous plasticity, enhancing pain signals and producing hypersensitivity. When plasticity facilitates protective reflexes, it can be beneficial, but when the changes persist, a chronic pain condition may result. Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain.


Introduction: Acute Versus Persistent Pain


The ability to detect noxious stimuli is essential to an organism’s survival and wellbeing. This is dramatically illustrated by examination of individuals who suffer from congenital abnormalities that render them incapable of detecting painful stimuli. These people cannot feel piercing pain from a sharp object, heat of an open flame, or even discomfort associated with internal injuries, such as a broken bone. As a result, they do not engage appropriate protective behaviors against these conditions, many of which can be life threatening.


More commonly, alterations of the pain pathway lead to hypersensitivity, such that pain outlives its usefulness as an acute warning system and instead becomes chronic and debilitating. This may be seen, at some level, as an extension of the normal healing process, whereby tissue or nerve damage elicits hyperactivity to promote guarding of the injured area. For example, sunburn produces temporary sensitization of the affected area. As a result normally innocuous stimuli, such as light touch or warmth, are perceived as painful (a phenomenon referred to as allodynia), or normally painful stimuli elicit pain of greater intensity (referred to as hyperalgesia). At its extreme, the sensitization does not resolve. Indeed, individuals who suffer from arthritis, post-herpetic neuralgia (following a bout of shingles), or bone cancer, experience intense and often unremitting pain that is not only physiologically and psychologically debilitating, but may also hamper recovery. Chronic pain may even persist long after an acute injury, perhaps most commonly experienced as lower back pain or sciatica.


Persistent or chronic pain syndromes can be initiated or maintained at peripheral and/or central loci. In either case, the elucidation of molecules and cell types that underlie normal (acute) pain sensation is key to understanding the mechanisms underlying pain hypersensitivity. In the present review we highlight the molecular complexity of the primary afferent nerve fibers that detect noxious stimuli. We not only summarize the processing of acute pain, but also describe how changes in pain processing occur in the setting of tissue or nerve injury.


The profound differences between acute and chronic pain emphasize the fact that pain is not generated by an immutable, hard-wired system, but rather results from the engagement of highly plastic molecules and circuits, the molecular biochemical and neuroanatomical basis of which are the focus of current studies. Importantly, this new information has identified a host of potential therapeutic targets for the treatment of pain. We focus here on the peripheral and second order neurons in the spinal cord; the reader is referred to some excellent reviews of supraspinal pain processing mechanisms, which include remarkable insights that imaging studies have brought to the field (Apkarian et al., 2005).


Anatomical Overview


Nociception is the process by which intense thermal, mechanical or chemical stimuli are detected by a subpopulation of peripheral nerve fibers, called nociceptors (Basbaum and Jessell, 2000). The cell bodies of nociceptors are located in the dorsal root ganglia (DRG) for the body and the trigeminal ganglion for the face, and have both a peripheral and central axonal branch that innervates their target organ and the spinal cord, respectively. Nociceptors are excited only when stimulus intensities reach the noxious range, suggesting that they possess biophysical and molecular properties that enable them to selectively detect and respond to potentially injurious stimuli. There are two major classes of nociceptors. The first includes medium diameter myelinated (Aδ) afferents that mediate acute, well-localized “first” or fast pain. These myelinated afferents differ considerably from the larger diameter and rapidly conducting Aβ fibers that respond to innocuous mechanical stimulation (i.e. light touch). The second class of nociceptor includes small diameter unmyelinated “C” fibers that convey poorly localized, “second” or slow pain.


Electrophysiological studies have further subdivided Aδ nociceptors into two main classes. Type I (HTM: high threshold mechanical nociceptors) respond to both mechanical and chemical stimuli, but have relatively high heat thresholds (>50C). If, however, the heat stimulus is maintained, these afferents will respond at lower temperatures. And most importantly, they will sensitize (i.e. the heat or mechanical threshold will drop) in the setting of tissue injury. Type II Aδ nociceptors have a much lower heat threshold, but a very high mechanical threshold. Activity of this afferent almost certainly mediates the “first” acute pain response to noxious heat. Indeed, compression block of myelinated peripheral nerve fibers eliminates first, but not second, pain. By contrast, the Type I fiber likely mediates the first pain provoked by pinprick and other intense mechanical stimuli.


The unmyelinated C fibers are also heterogeneous. Like the myelinated afferents, most C fibers are polymodal, that is, they include a population that is both heat and mechanically sensitive (CMHs) (Perl, 2007). Of particular interest are the heat responsive, but mechanically insensitive unmyelinated afferents (so-called silent nociceptors) that develop mechanical sensitivity only in the setting of injury (Schmidt et al., 1995). These afferents are more responsive to chemical stimuli (capsaicin or histamine) compared to the CMHs, and likely come into play when the chemical milieu of inflammation alters their properties. Subsets of these afferents are also responsive to a variety of itch-producing pruritogens. It is worth noting that not all C fibers are nociceptors. Some respond to cooling, and a particularly interesting population of unmyelinated afferents responds to innocuous stroking of the hairy skin, but not to heat or chemical stimulation. These latter fibers appear to mediate pleasant touch (Olausson et al., 2008).


Neuroanatomical and molecular characterization of nociceptors has further demonstrated their heterogeneity, particularly for the C fibers (Snider and McMahon, 1998). For example, the so-called ‘peptidergic’ population of C nociceptors releases the neuropeptides, substance P, and calcitonin-gene related peptide (CGRP); they also express the TrkA neurotrophin receptor, which responds to nerve growth factor (NGF). The non-peptidergic population of C nociceptors expresses the c-Ret neurotrophin receptor that is targeted by glial-derived neurotrophic factor (GDNF), as well as neurturin and artemin. A large percentage of the c-Ret-positive population also binds the IB4 isolectin, and expresses G protein-coupled receptors of the Mrg family (Dong et al., 2001), as well as specific purinergic receptor subtypes, notably P2X3. Nociceptors can also be distinguished according to their differential expression of channels that confer sensitivity to heat (TRPV1), cold (TRPM8), acidic milieu (ASICs), and a host of chemical irritants (TRPA1) (Julius and Basbaum, 2001). As noted below, these functionally and molecularly heterogeneous classes of nociceptors associate with specific function in the detection of distinct pain modalities.


The Nociceptor: a Bidirectional Signaling Machine


One generally thinks of the nociceptor as carrying information in one direction, transmitting noxious stimuli from the periphery to the spinal cord. However, primary afferent fibers have a unique morphology, called pseudo-unipolar, wherein both central and peripheral terminals emanate from a common axonal stalk. The majority of proteins synthesized by the DRG or trigeminal ganglion cell are distributed to both central and peripheral terminals. This distinguishes the primary afferent neuron from the prototypical neuron, where the recipient branch of the neuron (the dendrite) is biochemically distinct from the transmission branch (the axon). The biochemical equivalency of central and peripheral terminals means that the nociceptor can send and receive messages from either end. For example, just as the central terminal is the locus of Ca2+-dependent neurotransmitter release, so the peripheral terminal releases a variety of molecules that influence the local tissue environment. Neurogenic inflammation, in fact, refers to the process whereby peripheral release of the neuropeptides, CGRP and substance P, induces vasodilation and extravasation of plasma proteins, respectively (Basbaum and Jessell, 2000). Furthermore, whereas only the peripheral terminal of the nociceptor will respond to environmental stimuli (painful heat, cold and mechanical stimulation), both the peripheral and central terminals can be targeted by a host of endogenous molecules (such as pH, lipids, and neurotransmitters) that regulate its sensitivity. It follows that therapeutics directed at both terminals can be developed to influence the transmission of pain messages. For example, spinal (intrathecal) delivery of morphine targets opioid receptors expressed by the central terminal of nociceptors, whereas topically applied drugs (such as local anesthetics or capsaicin) regulate pain via an action at the peripheral terminal.


Central Projections of the Nociceptor


Primary afferent nerve fibers project to the dorsal horn of the spinal cord, which is organized into anatomically and electrophysiological distinct laminae (Basbaum and Jessell, 2000) (Figure 1). For example, Aδ nociceptors project to lamina I as well as to deeper dorsal horn (lamina V). The low threshold, rapidly conducting Aβ afferents, which respond to light touch, project to deep laminae (III, IV, and V). By contrast, C nociceptors project more superficially to laminae I and II.


Figure 1 Anatomy of the Pain Pathway


This remarkable stratification of afferent subtypes within the superficial dorsal horn is further highlighted by the distinct projection patterns of C nociceptors (Snider and McMahon, 1998). For example, most peptidergic C fibers terminate within lamina I and the most dorsal part of lamina II. By contrast, the nonpeptidergic afferents, including the Mrg-expressing subset, terminate in the mid-region of lamina II. The most ventral part of lamina II is characterized by the presence of excitatory interneurons that express the gamma isoform of protein kinase C (PKC), which has been implicated in injury-induced persistent pain (Malmberg et al., 1997). Recent studies indicate that this PKCγ layer is targeted predominantly by myelinated non-nociceptive afferents (Neumann et al., 2008). Consistent with these anatomical studies, electrophysiological analyses demonstrate that spinal cord neurons within lamina I are generally responsive to noxious stimulation (via Aδ and C fibers), neurons in laminae III and IV are primarily responsive to innocuous stimulation (via Aβ), and neurons in lamina V receive a convergent non-noxious and noxious input via direct (monosynaptic) Aδ and Aβ inputs and indirect (polysynaptic) C fiber inputs. The latter are called wide dynamic range (WDR) neurons, in that they respond to a broad range of stimulus intensities. There is also commonly a visceral input to these WDR neurons, such that the resultant convergence of somatic and visceral likely contributes to the phenomenon of referred pain, whereby pain secondary to an injury affecting a visceral tissue (for example, the heart in angina) is referred to a somatic structure (for example, the shoulder).


Ascending Pathways and the Supraspinal Processing of Pain


Projection neurons within laminae I and V constitute the major output from the dorsal horn to the brain (Basbaum and Jessell, 2000). These neurons are at the origin of multiple ascending pathways, including the spinothalamic and spinoreticulothalamic tracts, which carry pain messages to the thalamus and brainstem, respectively (Figure 2). The former is particularly relevant to the sensory-discriminative aspects of the pain experience (that is, where is the stimulus and how intense is it?), whereas the latter may be more relevant to poorly localized pains. More recently, attention has focused on spinal cord projections to the parabrachial region of the dorsolateral pons, because the output of this region provides for a very rapid connection with the amygdala, a region generally considered to process information relevant to the aversive properties of the pain experience.


Figure 2 Primary Afferent Fibers and Spinal Cord


From these brainstem and thalamic loci, information reaches cortical structures. There is no single brain area essential for pain (Apkarian et al., 2005). Rather, pain results from activation of a distributed group of structures, some of which are more associated with the sensory-discriminative properties (such as the somatosensory cortex) and others with the emotional aspects (such as the anterior cingulate gyrus and insular cortex). More recently, imaging studies demonstrate activation of prefrontal cortical areas, as well as regions not generally associated with pain processing (such as the basal ganglia and cerebellum). Whether and to what extent activation of these regions is more related to the response of the individual to the stimulus, or to the perception of the pain is not clear. Finally, Figure 2 illustrates the powerful descending controls that influence (both positive and negatively) the transmission of pain messages at the level of the spinal cord.


Acute Pain


The primary afferent nerve fiber detects environmental stimuli (of a thermal, mechanical, or chemical nature) and transduces this information into the language of the nervous system, namely electrical current. First, we review progress in understanding the molecular basis of signal detection, and follow this with a brief overview of recent genetic studies that highlight the contribution of voltage-gated channels to pain transmission (Figure 3).


Figure 3 Nociceptor Diversity


Activating the Nociceptor: Heat


Human psychophysical studies have shown that there is a clear and reproducible demarcation between the perception of innocuous warmth and noxious heat, which enables us to recognize and avoid temperatures capable of causing tissue damage. This pain threshold, which typically rests around 43°C, parallels the heat sensitivity of C and Type II Aδ nociceptors described earlier. Indeed, cultured neurons from dissociated dorsal root ganglia show similar heat sensitivity. The majority display a threshold of 43°C, with a smaller cohort activated by more intense heat (threshold >50°C) (Cesare and McNaughton, 1996; Kirschstein et al., 1997; Leffler et al., 2007; Nagy and Rang, 1999). Molecular insights into the process of heat sensation came from the cloning and functional characterization of the receptor for capsaicin, the main pungent ingredient in ‘hot’ chili peppers. Capsaicin and related vanilloid compounds produce burning pain by depolarizing specific subsets of C and Aδ nociceptors through activation of the capsaicin (or vanilloid) receptor, TRPV1, one of approximately 30 members of the greater transient receptor potential (TRP) ion channel family (Caterina et al., 1997). The cloned TRPV1 channel is also gated by increases in ambient temperature, with a thermal activation threshold (∼43°C).


Several lines of evidence support the hypothesis that TRPV1 an endogenous transducer of noxious heat. First, TRPV1 is expressed in the majority of heat-sensitive nociceptors (Caterina et al., 1997). Second, capsaicin- and heat-evoked currents are similar, if not identical, in regard to their pharmacological and biophysical properties, as are those of heterologously expressed TRPV1 channels. Third, and as described in greater detail below, TRPV1-evoked responses are markedly enhanced by pro-algesic or pro-inflammatory agents (such as extracellular protons, neurotrophins, or bradykinin), all of which produce hypersensitivity to heat in vivo (Tominaga et al., 1998)). Fourth, analysis of mice lacking this ion channel not only revealed a complete loss of capsaicin sensitivity, but these animals also exhibit significant impairment in their ability to detect and respond to noxious heat (Caterina et al., 2000; Davis et al., 2000). These studies also demonstrated an essential role for this channel in the process whereby tissue injury and inflammation leads to heat hypersensitivity, reflecting the ability of TRPV1 to serve as a molecular integrator of thermal and chemical stimuli (Caterina et al., 2000; Davis et al., 2000).


The contribution of TRPV1 to acute heat sensation, however, has been challenged by data collected from an ex vivo preparation in which recordings are obtained from the soma of DRG neurons with intact central and peripheral fibers. In one study, no differences were observed in heat-evoked responses from wild type and TRPV1-deficient animals (Woodbury et al., 2004), but a more recent analysis from this group found that TRPV1-deficient mice do, indeed, lack a cohort of neurons robustly activated by noxious heat (Lawson et al., 2008). Taken together with the results described above we conclude that TRPV1 unquestionably contributes to acute heat sensation, but agree that TRPV1 is not solely responsible for heat transduction.


In this regard, whereas TRPV1-deficient mice lack a component of behavioral heat sensitivity, the use of high dose capsaicin to ablate the central terminals of TRPV1-expressing primary afferent fibers results in a more profound, if not complete loss of acute heat pain sensitivity (Cavanaugh et al., 2009). As for the TRPV1 mutant, there is also a loss of tissue injury-evoked heat hyperalgesia. Taken together these results indicate that both the TRPV1-dependent and TRPV1-independent component of noxious heat sensitivity is mediated via TRPV1-expressing nociceptors.


What accounts for the TRPV1-independent component of heat sensation? A number of other TRPV channel subtypes, including TRPV2, 3 and 4, have emerged as candidate heat transducers that could potentially cover detection of stimulus intensities flanking that of TRPV1, including both very hot (>50°C) and warm (mid-30°Cs) temperatures (Lumpkin and Caterina, 2007). Heterologously expressed TRPV2 channels display a temperature activation threshold of ∼52°C, whereas TRPV3 and TRPV4 are activated between 25 – 35°C. TRPV2 is expressed in a subpopulation of Aδ neurons that respond to high threshold noxious heat and its biophysical properties resemble those of native high threshold heat-evoked currents (Leffler et al., 2007; Rau et al., 2007). As yet, there are no published reports describing either physiological or behavioral tests of TRPV2 knockout mice. On the other hand, TRPV3- and TRPV4-deficient mice do display altered thermal preference when placed on a surface of graded temperatures, suggesting that these channels contribute in some way to temperature detection in vivo (Guler et al., 2002). Interestingly, both TRPV3 and TRPV4 show substantially greater expression in keratinocytes and epithelial cells compared to sensory neurons, raising the possibility that detection of innocuous heat stimuli involves a functional interplay between skin and the underlying primary afferent fibers (Chung et al., 2003; Peier et al., 2002b).


Activating the Nociceptor: Cold


As for capsaicin and TRPV1, natural cooling agents, such as menthol and eucalyptol, have been exploited as pharmacological probes to identify and characterize cold-sensitive fibers and cells (Hensel and Zotterman, 1951; Reid and Flonta, 2001) and the molecules that underlie their behavior. Indeed, most cold-sensitive neurons respond to menthol and display a thermal activation threshold of ∼25°C. TRPM8 is a cold and menthol-sen sitive channel whose physiological characteristics match those of native cold currents and TRPM8-deficient mice show a very substantial loss of menthol and cold-evoked responses at the cellular or nerve fiber level. Likewise, these animals display severe deficits in cold-evoked behavioral responses (Bautista et al., 2007; Colburn et al., 2007; Dhaka et al., 2007) over a wide range of temperatures spanning 30 to 10°C. As in the case of TRPV1 and he at, TRPM8-deficient mice are not completely insensitive to cold. For example, there remains a small (∼4%) cohort of cold-sensitive, menthol-insensitive neurons that have a low threshold of activation, of approximately 12°C. These may account for the residual cold sensitivity seen in behavioral tests, wherein TRPM8-deficient animals can still avoid extremely cold surfaces below 10°C. Importantly, TRPM8-deficient mice show normal sensitivity to noxious heat. Indeed, TRPV1 and TRPM8 are expressed in largely non-overlapping neuronal populations, consistent with the notion that hot and cold detection mechanisms are organized into anatomically and functionally distinct ‘labeled lines.’


Based on heterologous expression systems, TRPA1 has also been suggested to detect cold, specifically within the noxious (<15°C) range. Moreover TRPA1 is activated by the cooling compounds icilin and menthol (Bandell et al., 2004; Karashima et al., 2007; Story et al., 2003), albeit at relatively high concentrations compared to their actions at TRPM8. However, there continues to be disagreement as to whether native or recombinant TRPA1 are intrinsically cold sensitive (Bandell et al., 2004; Jordt et al., 2004; Karashima et al., 2009; Nagata et al., 2005; Zurborg et al., 2007). This controversy has not been resolved by the analysis of two independent TRPA1-deficient mouse lines. At the cellular level, one study showed normal cold-evoked responses in TRPA1-deficient neurons following a 30 second drop in temperature from 22°C to 4 °C (Bautista et al., 2006); a more recent study has shown a decrease in cold sensitive neurons from 26% (WT) to 10% (TRPA1-/-), when tested after a 200 sec drop in temperature, from 30°C to 10°C (Karashima et al., 2009). In behavioral studies, TRPA1-deficient mice display responses similar to wild-type littermates in the cold-plate and acetone-evoked evaporative cooling assays (Bautista et al., 2006). A second study using the same assays showed that female, but not male, TRPA1 knockout animals displayed attenuated cold sensitivity compared to wild type littermates (Kwan et al., 2006). Karashima et al found no difference in shivering or paw withdrawal latencies in male or female TRPA1-deficient mice on the cold plate test, but observed that prolonged exposure to the cold surface elicited jumping in wild type, but not TRPA1-deficient animals (Karashima et al., 2009). Conceivably, the latter phenotype reflects a contribution of TRPA1 to cold sensitivity in the setting of tissue injury, but not to acute cold pain. Consistent with the latter hypothesis, single nerve fiber recordings show no decrement in acute cold sensitivity in TRPA1-deficient mice (Cavanaugh et al., 2009; Kwan et al., 2009). Finally, it is noteworthy that capsaicin-treated mice lacking the central terminals of TRPV1-expressing fibers show intact behavioral responses to cool and noxious cold stimuli (Cavanaugh et al., 2009). Because TRPA1 is expressed in a subset of TRPV1-positive neurons, it follows that TRPA1 is not required for normal acute cold sensitivity. Future studies using mice deficient for both TRPM8 and TRPA1 will help to resolve these issues and to identify the molecules and cell types that underlie the residual TRPM8-independent component of cold sensitivity.


Additional molecules, including voltage-gated sodium channels (discussed below), voltage-gated potassium channels, and two-pore background KCNK potassium channels, coordinate with TRPM8 to fine tune cold thresholds or to propagate cold-evoked action potentials (Viana et al., 2002; Zimmermann et al., 2007; Noel et al., 2009). For example, specific Kv1 inhibitors increase the temperature threshold of cold-sensitive neurons and injection of these inhibitors into the rodent hindpaw reduces behavioral responses to cold, but not to heat or mechanical stimuli (Madrid et al., 2009). Two members of the KCNK channel family, KCNK2 (TREK-1) and KCNK4 (TRAAK) are expressed in a subset of C-fiber nociceptors (Noel et al., 2009) and can be modulated by numerous physiological and pharmacological stimuli, including pressure and temperature. Furthermore, mice lacking these channels display abnormalities in sensitivity to pressure, heat, and cold (Noel et al., 2009). Although these findings suggest that TREK-1 and TRAAK channels modulate nociceptor excitability, it remains unclear how their intrinsic sensitivity to physical stimuli relates to their in vivo contribution to thermal or mechanical transduction.


Activating the Nociceptor: Mechanical


The somatosensory system detects quantitatively and qualitatively diverse mechanical stimuli, ranging from light brush of the skin to distension of the bladder wall. A variety of mechanosensitive neuronal subtypes are specialized to detect this diverse array of mechanical stimuli and can be categorized according to threshold sensitivity. High threshold mechanoreceptors include C fibers and slowly adapting Aδ mechanoreceptor (AM) fibers, both of which terminate as free nerve endings in the skin. Low threshold mechanoreceptors include Aδ D-hair fibers that terminate on down hairs in the skin and detect light touch. Finally, Aβ fibers that innervate Merkel cells, Pacinian corpuscles and hair follicles detect texture, vibration, and light pressure.


As in the case of thermal stimuli, mechanical sensitivity has been probed at a number of levels, including dissociated sensory neurons in culture, ex-vivo fiber recordings, as well as recordings from central (i.e. dorsal horn neurons) and measurements of behavioral output. Ex-vivo skin-nerve recordings have been most informative in matching stimulus properties (such as intensity, frequency, speed, and adaptation) to specific fiber subtypes. For example, Aβ fibers are primarily associated with sensitivity to light touch, whereas C and Aδ fibers are primarily responsive to noxious mechanical insults. At the behavioral level, mechanical sensitivity is typically assessed using two techniques. The most common involves measuring reflex responses to constant force applied to the rodent hind paw by calibrated filaments (Von Frey hairs). The second applies increasing pressure to the paw or tail via a clamp system. In either case, information about mechanical thresholds is obtained under normal (acute) or injury (hypersensitivity) situations. One of the challenges in this area has been to develop additional behavioral assays that measure different aspects of mechanosensation, such as texture discrimination and vibration, which will facilitate the study of both noxious and non-noxious touch (Wetzel et al., 2007).


At the cellular level, pressure can be applied to the cell bodies of cultured somatosensory neurons (or to their neurites) using a glass probe, changes in osmotic strength, or stretch via distension of an elastic culture surface, though it is unclear which stimulus best mimics physiological pressure (Bhattacharya et al., 2008; Cho et al., 2006; Cho et al., 2002; Drew et al., 2002; Hu and Lewin, 2006; Lin et al., 2009; Takahashi and Gotoh, 2000). Responses can be assessed using electrophysiological or live cell imaging methods. The consensus from such studies is that that pressure opens a mechanosensitive cation channel to elicit rapid depolarization. However, a dearth of specific pharmacological probes and molecular markers with which to characterize these responses or to label relevant neuronal subtypes has hampered attempts to match cellular activities with anatomically or functionally defined nerve fiber subclasses. These limitations have also impeded the molecular analysis of mechansosensation and the identification of molecules that constitute the mechanotransduction machinery. Nonetheless, a number of candidates have emerged, based largely on studies of mechanosensation in model genetic organisms. Mammalian orthologues of these proteins have been examined using gene targeting approaches in mice, in which the techniques mentioned above can be used to assess deficits in mechanosensation at all levels. Below we briefly summarize some of the candidates revealed in these studies.


Candidate Mechanotransducers: DEG/ENaC Channels


Studies in the nematode Caenorhabditis elegans (C. elegans) have identified mec-4 and mec-10, members of the degenerin/epithelial Na+ channel (DEG/ENaC) families, as mechanotransducers in body touch neurons (Chalfie, 2009). Based on these studies, the mammalian orthologues ASIC 1, 2 and 3 have been proposed as mechanotransduction channels. ASICs are acid-sensitive ion channels that serve as receptors for extracellular protons (tissue acidosis) produced during ischemia (see below). Although these channels are expressed by both low and high threshold mechanosensitive neurons, genetic studies do not uniformly support an essential role in mechanotransduction. Mice lacking functional ASIC1 channels display normal behavioral responses to cutaneous touch, and little or no change in mechanical sensitivity when assessed by single fiber recording (Page et al., 2004; Price et al., 2000). Likewise, peripheral nerve fibers from ASIC2-deficient mice display only a slight decrease in action potential firing to mechanical stimuli, whereas ASIC3-deficient fibers display a slight increase (no change in mechanical thresholds or baseline behavioral mechanical sensitivity was observed in these animals) (Price et al., 2001; Roza et al., 2004). Analysis of mice deficient for both ASIC2 and ASIC3 also fails to support a role for these channels in cutaneous mechanotransduction (Drew et al., 2004). Thus, although these channels appear to play a role in musculoskeletal and ischemic pain (see below), their contribution to mechanosensation remains unresolved.


Genetic studies suggest that C. elegans mec-4/mec-10 channels exist in a complex with the stomatin-like protein MEC-2 (Chalfie, 2009). Mice lacking the MEC-2 orthologue, SLP3, display a loss of mechanosensitivity in low-threshold Aβ and Aδ fibers, but not in C fibers (Wetzel et al., 2007). These mice exhibit altered tactile acuity, but display normal responses to noxious pressure, suggesting that SLP3 contributes to the detection of innocuous, but not noxious mechanical stimuli. Whether SLP3 functions in a mechanotransduction complex or interacts with ASICs in mammalian sensory neurons is unknown.


Candidate Mechanotransducers: TRP Channels


As noted above, when expressed heterologously, TRPV2 not only responds to noxious heat, but also to osmotic stretch. Additionally, native TRPV2 channels in vascular smooth muscle cells are activated by direct suction and osmotic stimuli (Muraki et al., 2003). A role for TRPV2 for somatosensory mechanotransduction in vivo has not yet been tested.


TRPV2 is robustly expressed in medium and large diameter, Aδ fibers that respond to both mechanical and thermal stimuli (Caterina et al., 1999; Muraki et al., 2003). TRPV4 shows modest expression in sensory ganglia, but is more abundantly expressed in the kidney and stretch-sensitive urothelial cells of the bladder (Gevaert et al., 2007; Mochizuki et al., 2009). When heterologously expressed, both TRPV2 and TRPV4 have been shown to respond to changes in osmotic pressure (Guler et al., 2002; Liedtke et al., 2000; Mochizuki et al., 2009; Strotmann et al., 2000). Analysis of TRPV4-deficient animals suggests a role in osmosensation as knockout animals display defects in blood pressure, water balance, and bladder voiding (Gevaert et al., 2007; Liedtke and Friedman, 2003). These animals exhibit normal acute cutaneous mechanosensation, but show deficits in models of mechanical and thermal hyperalgesia (Alessandri-Haber et al., 2006; Chen et al., 2007; Grant et al., 2007; Suzuki et al., 2003). Thus, TRPV4 is unlikely to serve as a primary mechanotransducer in sensory neurons, but may contribute to injury-evoked pain hypersensitivity.


TRPA1 has also been proposed to serve as a detector of mechanical stimuli. Heterologously expressed mammalian TRPA1 is activated by membrane crenators (Hill and Schaefer, 2007) and the worm orthologue is sensitive to mechanical pressure applied via a suction pipette (Kindt et al., 2007). However, TRPA1-deficient mice display only weak defects in mechanosensory behavior and the results are inconsistent. Two studies reported no change in mechanical thresholds in TRPA1-deficient animals (Bautista et al., 2006; Petrus et al., 2007), whereas a third study reported deficits (Kwan et al., 2006). A more recent study shows that C and Aβ mechanosensitive fibers in TRPA1 knockout animals have altered responses to mechanical stimulation (some increased and others decreased) (Kwan et al., 2009). Whether and how these differential physiological effects are manifest at the level of behavior is unclear. Taken together, TRPA1 does not appear to function as a primary detector of acute mechanical stimuli, but perhaps modulates excitability of mechanosensitive afferents.


Candidate Mechanotransducers: KCNK Channels


In addition to the potential mechanotransducer role of KCNK2 and 4 (see above), KCNK18 has been discussed for its possible contribution to mechanosensation. Thus, KCNK18 is targeted by hydroxy-a-sanshool, the pungent ingredient in Szechuan peppercorns that produces tingling and numbing sensations, suggestive of an interaction with touch-sensitive neurons (Bautista et al., 2008; Bryant and Mezine, 1999; Sugai et al., 2005). KCNK18 is expressed in a subset of presumptive peptidergic C fibers and low threshold (Aβ) mechanoreceptors, where it serves as a major regulator of action potential duration and excitability (Bautista et al., 2008; Dobler et al., 2007). Moreover, sanshool depolarizes osmo- and mechanosensitive large diameter sensory neurons, as well as a subset of nociceptors (Bautista et al., 2008; Bhattacharya et al., 2008). Although it is not known if KCNK18 is directly sensitive to mechanical stimulation, it may be a critical regulator of the excitability of neurons involved in innocuous or noxious touch sensation.


In summary, the molecular basis of mammalian mechanotransduction is far from clarified. Mechanical hypersensitivity in response to tissue or nerve injury represents a major clinical problem and thus elucidating the biological basis of touch under normal and pathophysiological conditions remains one of the main challenges in somatosensory and pain research.


Activating the Nociceptor: Chemical


Chemo-nociception is the process by which primary afferent neurons detect environmental irritants and endogenous factors produced by physiological stress. In the context of acute pain, chemo-nociceptive mechanisms trigger aversive responses to a variety of environmental irritants. Here, again, TRP channels have prominent roles, which is perhaps not surprising given that they function as receptors for plant-derived irritants, including capsaicin (TRPV1), menthol (TRPM8), as well as the pungent ingredients in mustard and garlic plants, isothiocyanates and thiosulfinates (TRPA1) (Bandell et al., 2004; Caterina et al., 1997; Jordt et al., 2004; McKemy et al., 2002; Peier et al., 2002a).


With respect to environmental irritants, TRPA1 has emerged as a particularly interesting member of this group. This is because TRPA1 responds to compounds that are structurally diverse but unified in their ability to form covalent adducts with thiol groups. For example, allyl isothiocyanate (from wasabi) or allicin (from garlic) are membrane permeable electrophiles that activate TRPA1 by covalently modifying cysteine residues within the amino-terminal cytoplasmic domain of the channel (Hinman et al., 2006; Macpherson et al., 2007). How this promotes channel gating is currently unknown. Nevertheless, simply establishing the importance of thiol reactivity in this process has implicated TRPA1 as a key physiological target for a wide and chemically diverse group of environmental toxicants. One notable example is acrolein (2-propenal), a highly reactive α,β-unsaturated aldehyde present in tear gas, vehicle exhaust, or smoke from burning vegetation (i.e. forest fires and cigarettes). Acrolein and other volatile irritants (such as hypochlorite, hydrogen peroxide, formalin, and isocyanates) activate sensory neurons that innervate the eyes and airways, producing pain and inflammation (Bautista et al., 2006; Bessac and Jordt, 2008; Caceres et al., 2009). This action can have especially dire consequences for those suffering from asthma, chronic cough, or other pulmonary disorders. Mice lacking TRPA1 show greatly reduced sensitivity to such agents, underscoring the critical nature of this channel as a sensory detector of reactive environmental irritants (Caceres et al., 2009). In addition to these environmental toxins, TRPA1 is targeted by some general anesthetics (such as isofluorane) or metabolic byproducts of chemotherapeutic agents (such as cyclophosphamide), which likely underlies some of the adverse side effects of these drugs, including acute pain and robust neuroinflammation (Bautista et al., 2006; Matta et al., 2008).


Finally, chemical irritants and other pro-algesic agents are also produced endogenously in response to tissue damage or physiological stress, including oxidative stress. Such factors can act alone, or in combination, to sensitize nociceptors to thermal and/or mechanical stimuli, thereby lowering pain thresholds. The result of this action is to enhance guarding and protective reflexes in the aftermath of injury. Thus, chemo-nociception represents an important interface between acute and persistent pain, especially in the context of peripheral tissue injury and inflammation, as discussed in greater detail below.


Acute Pain: Conducting the Pain Signal


Once thermal and mechanical signals are transduced by the primary afferent terminal, the receptor potential activates a variety of voltage-gated ion channels. Voltage-gated sodium and potassium channels are critical to the generation of action potentials that convey nociceptor signals to synapses in the dorsal horn. Voltage-gated calcium channels play a key role in neurotransmitter release from central or peripheral nociceptor terminals to generate pain or neurogenic inflammation, respectively. We restrict our discussion to members of the sodium and calcium channel families that serve as targets of currently used analgesic drugs, or for which human genetics support a role in pain transmission. A recent review has discussed the important contribution of KCNQ potassium channels, including the therapeutic benefit of increasing K+ channel activity for the treatment of persistent pain (Brown and Passmore, 2009).


Voltage-Gated Sodium Channels


A variety of sodium channels are expressed in somatosensory neurons, including the tetrodotoxin (TTX)-sensitive channels Nav1.1, 1.6 and 1.7, and the TTX-insensitive channels, Nav1.8 and 1.9. In recent years, the contribution of Nav1.7 has received much attention, as altered activity of this channel leads to a variety of human pain disorders (Cox et al., 2006; Dib-Hajj et al., 2008). Patients with loss-of-function mutations within this gene are unable to detect noxious stimuli, and as a result suffer injuries due to lack of protective reflexes. In contrast, a number of gain-of-function mutations in Nav1.7 leads to hyperexcitability of the channel and are associated with two distinct pain disorders in humans, erythromelalgia, and paroxysmal extreme pain disorder, both of which cause intense burning sensations (Estacion et al., 2008; Fertleman et al., 2006; Yang et al., 2004). Animal studies have demonstrated that Nav1.7 is highly upregulated in a variety of inflammatory pain models. Indeed, analysis of mice lacking Nav1.7 in C nociceptors supports a key role for this channel in mechanical and thermal hypersensitivity following inflammation, and in acute responses to noxious mechanical stimuli (Nassar et al., 2004). Somewhat surprisingly, pain induced by nerve injury is unaltered, suggesting that distinct sodium channel subtypes, or another population of Nav1.7-expressing afferents, contribute to neuropathic pain (Nassar et al., 2005).


The Nav1.8 sodium channel is also highly expressed by most C nociceptors. As with Nav1.7 knockout animals, those lacking Nav1.8 display modest deficits in sensitivity to innocuous or noxious heat, or innocuous pressure; however, they display attenuated responses to noxious mechanical stimuli (Akopian et al., 1999). Nav1.8 is also required for the transmission of cold stimuli, as mice lacking this channel are insensitive to cold over a wide range of temperatures (Zimmermann et al., 2007). This is because Nav1.8 is unique among voltage-sensitive sodium channels in that it does not inactivate at low temperature, making it the predominant action potential generator under cold conditions.


Interestingly, transgenic mice lacking the Nav1.8 expressing subset of sensory neurons, which were deleted by targeted expression of diphtheria toxin A (Abrahamsen et al., 2008), display attenuated responses to both low and high threshold mechanical stimuli and cold. In addition, mechanical and thermal hypersensitivity in inflammatory pain models is severely attenuated. The differential phenotypes of mice lacking Nav1.8 channels versus deletion of the Nav1.8-expressing neurons presumably reflects the contribution of multiple voltage-gated sodium channel subtypes to transmission of pain messages.


Voltage-gated sodium channels are targets of local anesthetic drugs, highlighting the potential for the development of subtype-specific analgesics. Nav1.7 is a particularly interesting target for treating inflammatory pain syndromes, in part, because the human genetic studies suggest that Nav1.7 inhibitors should reduce pain without altering other essential physiological processes (see above). Another potential application of sodium channel blockers may be to treat extreme hypersensitivity to cold, a particularly troublesome adverse side effect of platinum-based chemotherapeutics, such as oxaliplatin (Attal et al., 2009). Nav1.8 (or TRPM8) antagonists may alleviate this, or other forms of cold allodynia. Finally, the great utility of the antidepressant serotonin and norepinephrine reuptake inhibitors for the treatment of neuropathic pain may, in fact, result from their ability to block voltage gated sodium channels (Dick et al., 2007).


Voltage-Gated Calcium Channels


A variety of voltage-gated calcium channels are expressed in nociceptors. N-, P/Q- and T-type calcium channels have received the most attention. P/Q-type channels are expressed at synaptic terminals in laminae II-IV of the dorsal horn. Their exact role in nociception is not completely resolved. However, mutations in these channels have been linked to familial hemiplegic migraine (de Vries et al., 2009). N- and T-type calcium channels are also expressed by C-fibers and are upregulated under pathophysiological states, as in models of diabetic neuropathy or after other forms of nerve injury. Animals lacking Cav2.2 or 3.2 show reduced sensitization to mechanical or thermal stimuli following inflammation or nerve injury, respectively (Cao, 2006; Swayne and Bourinet, 2008; Zamponi et al., 2009; Messinger et al., 2009). Moreover, ω-conotoxin GVIA, which blocks N-type channels, is administered intrathecally (as ziconotide) to provide relief for intractable cancer pain (Rauck et al., 2009).


All calcium channels are heteromeric proteins composed of α1 pore forming subunits and the modulatory subunits α2δ, α2β or α2γ. The α2δ subunit regulates current density and kinetics of activation and inactivation. In C nociceptors, the α2δ subunit is dramatically upregulated following nerve injury and plays a key role in injury-evoked hypersensitivity and allodynia (Luo et al., 2001). Indeed, this subunit is the target of gabapentinoid class of anticonvulsants, which are now widely used to treat neuropathic pain (Davies et al., 2007).


Persistent Pain: Peripheral Mechanisms


Persistent pain associated with injury or diseases (such as diabetes, arthritis, or tumor growth) can result from alterations in the properties of peripheral nerves. This can occur as a consequence of damage to nerve fibers, leading to increased spontaneous firing or alterations in their conduction or neurotransmitter properties. In fact, the utility of topical and even systemic local anesthetics for the treatment of different neuropathic pain conditions (such as postherpetic neuralgia) likely reflects their action on sodium channels that accumulate in injured nerve fibers.


The Chemical Milieu of Inflammation


Peripheral sensitization more commonly results from inflammation-associated changes in the chemical environment of the nerve fiber (McMahon et al., 2008). Thus, tissue damage is often accompanied by the accumulation of endogenous factors released from activated nociceptors or non-neural cells that reside within or infiltrate into the injured area (including mast cells, basophils, platelets, macrophages, neutrophils, endothelial cells, keratinocytes, and fibroblasts). Collectively. these factors, referred to as the ‘inflammatory soup’, represent a wide array of signaling molecules, including neurotransmitters, peptides (substance P, CGRP, bradykinin), eicosinoids and related lipids (prostaglandins, thromboxanes, leukotrienes, endocannabinoids), neurotrophins, cytokines, and chemokines, as well as extracellular proteases and protons. Remarkably, nociceptors express one or more cell surface receptors capable of recognizing and responding to each of these pro-inflammatory or pro-algesic agents (Figure 4). Such interactions enhance excitability of the nerve fiber, thereby heightening its sensitivity to temperature or touch.


Figure 4 Peripheral Mediators of Inflammation


Unquestionably the most common approach to reducing inflammatory pain involves inhibiting the synthesis or accumulation of components of the inflammatory soup. This is best exemplified by non-steroidal anti-inflammatory drugs, such as aspirin or ibuprofen, which reduce inflammatory pain and hyperalgesia by inhibiting cyclooxygenases (Cox-1 and Cox-2) involved in prostaglandin synthesis. A second approach is to block the actions of inflammatory agents at the nociceptor. Here, we highlight examples that provide new insight into cellular mechanisms of peripheral sensitization, or which form the basis of new therapeutic strategies for treating inflammatory pain.


NGF is perhaps best known for its role as a neurotrophic factor required for survival and development of sensory neurons during embryogenesis, but in the adult, NGF is also produced in the setting of tissue injury and constitutes an important component of the inflammatory soup (Ritner et al., 2009). Among its many cellular targets, NGF acts directly on peptidergic C fiber nociceptors, which express the high affinity NGF receptor tyrosine kinase, TrkA, as well as the low affinity neurotrophin receptor, p75 (Chao, 2003; Snider and McMahon, 1998). NGF produces profound hypersensitivity to heat and mechanical stimuli through two temporally distinct mechanisms. At first, a NGF-TrkA interaction activates downstream signaling pathways, including phospholipase C (PLC), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K). This results in functional potentiation of target proteins at the peripheral nociceptor terminal, most notably TRPV1, leading to a rapid change in cellular and behavioral heat sensitivity (Chuang et al., 2001). In addition to these rapid actions, NGF is also retrogradely transported to the nucleus of the nociceptor, where it promotes increased expression of pro-nociceptive proteins, including substance P, TRPV1, and the Nav1.8 voltage-gated sodium channel subunit (Chao, 2003; Ji et al., 2002). Together, these changes in gene expression enhance excitability of the nociceptor and amplify the neurogenic inflammatory response.


In addition to neurotrophins, injury promotes the release of numerous cytokines, chief among them interleukin 1β (IL-1β) and IL-6, and tumor necrosis factor α (TNF-α) (Ritner et al., 2009). Although there is evidence to support a direct action of these cytokines on nociceptors, their primary contribution to pain hypersensitivity results from potentiation of the inflammatory response and increased production of pro-algesic agents (such as prostaglandins, NGF, bradykinin, and extracellular protons).


Irrespective of their pro-nociceptive mechanisms, interfering with neurotrophin or cytokine signaling has become a major strategy for controlling inflammatory disease or resulting pain. The main approach involves blocking NGF or TNF-α action with a neutralizing antibody. In the case of TNF-α, this has been remarkably effective in the treatment of numerous autoimmune diseases, including rheumatoid arthritis, leading to dramatic reduction in both tissue destruction and accompanying hyperalgesia (Atzeni et al., 2005). Because the main actions of NGF on the adult nociceptor occur in the setting of inflammation, the advantage of this approach is that hyperalgesia will decrease without affecting normal pain perception. Indeed, anti-NGF antibodies are currently in clinical trials for treatment of inflammatory pain syndromes (Hefti et al., 2006).


Targets of the Inflammatory Soup


TRPV1. Robust hypersensitivity to heat can develop with inflammation or after injection of specific components of the inflammatory soup (such as bradykinin or NGF). Lack of such sensitization in TRPV1-deficient mice provides genetic support for the idea that TRPV1 is a key component of the mechanism through which inflammation produces thermal hyperalgesia (Caterina et al., 2000; Davis et al., 2000). Indeed, in vitro studies have shown that TRPV1 functions as a polymodal signal integrator whose thermal sensitivity can be profoundly modulated by components of the inflammatory soup (Tominaga et al., 1998). Some of these inflammatory agents (for example, extracellular protons and lipids) function as direct positive allosteric modulators of the channel, whereas others (bradykinin, ATP, and NGF) bind to their own receptors on primary afferents and modulate TRPV1 through activation of downstream intracellular signaling pathways. In either case, these interactions result in a profound decrease in the channel’s thermal activation threshold, as well as an increase in the magnitude of responses at supra-threshold temperatures—the biophysical equivalents of allodynia and hyperalgesia, respectively.


However, there remains controversy concerning the intracellular signaling mechanisms most responsible for TRPV1 modulation (Lumpkin and Caterina, 2007). Reminiscent of ancestral TRP channels in the fly eye, many mammalian TRP channels are activated or positively modulated by phospholipase C-mediated cleavage of plasma membrane phosphatidyl inositol 4,5 bisphosphate (PIP2). Of course, there are many downstream consequences of this action, including a decrease in membrane PIP2, increase levels of diacylglycerol and its metabolites, increased cytoplasmic calcium, as well as consequent activation of protein kinases. In the case of TRPV1, most, if not all, of these pathways have been implicated in the sensitization process and it remains to be seen which are most relevant to behavioral thermal hypersensitivity. Nevertheless, there is broad agreement that TRPV1 modulation is relevant to tissue injury-evoked pain hypersensitivity, particularly in the setting of inflammation. This would include conditions such as sunburn, infection, rheumatoid or osteoarthritis, and inflammatory bowl disease. Another interesting example includes pain from bone cancer (Honore et al., 2009), where tumor growth and bone destruction are accompanied by extremely robust tissue acidosis, as well as production of cytokines, neurotrophins, and prostaglandins.


TRPA1. As described above, TRPA1 is activated by compounds that form covalent adducts with cysteine residues. In addition to environmental toxins, this includes endogenous thiol reactive electrophiles that are produced during tissue injury and inflammation, or as a consequence of oxidative or nitrative stress. Chief among such agents are 4-hydroxy-2-nonenal and 15-deoxy-Δ12,14-prostaglandin J2, which are both α,β unsaturated aldehydes generated through peroxidation or spontaneous dehydration of lipid second messengers (Andersson et al., 2008; Cruz-Orengo et al., 2008; Materazzi et al., 2008; Trevisani et al., 2007). Other endogenous TRPA1 agonists include nitrooleic acid, hydrogen peroxide, and hydrogen sulfide. In addition to these directly acting agents, TRPA1 is also modulated indirectly by pro-algesic agents, such as bradykinin, which act via PLC-coupled receptors. Indeed, TRPA1-deficient mice show dramatically reduced cellular and behavioral responses to all of these agents, as well as a reduction in tissue injury-evoked thermal and mechanical hypersensitivity (Bautista et al., 2006; Kwan et al., 2006). Finally, because TRPA1 plays a key role in neurogenic and other inflammatory responses to both endogenous agents and volatile environmental toxins, its contribution to airway inflammation, such as occurs in asthma, is of particular interest. Indeed, genetic or pharmacological blockade of TRPA1 reduces airway inflammation in a rodent model of allergen-evoked asthma (Caceres et al., 2009).


ASICs. As noted above, ASIC channels are members of the DEG/ENaC family that are activated by acidification, and thus represent another important site for the action of extracellular protons produced as a consequence of tissue injury or metabolic stress. ASIC subtypes can form a variety of homomeric or heteromeric channels, each having distinct pH sensitivity and expression profile. Channels containing the ASIC3 subtype are specifically expressed by nociceptors and especially well represented in fibers that innervate skeletal and cardiac muscle. In these tissues, anaerobic metabolism leads to buildup of lactic acid and protons, which activate nociceptors to generate musculoskeletal or cardiac pain (Immke and McCleskey, 2001). Interestingly, ASIC3-containing channels open in response to the modest decrease in pH (e.g. 7.4 to 7.0) that occurs with cardiac ischemia (Yagi et al., 2006). Lactic acid also significantly potentiates proton-evoked gating through a mechanism involving calcium chelation (Immke and McCleskey, 2003). Thus, ASIC3-containing channels detect and integrate signals specifically associated with muscle ischemia and, in this way, are functionally distinct from other acid sensors on the primary afferent, such as TRPV1 or other ASIC channel subtypes.


Persistent Pain: Central Mechanisms


Central sensitization refers to the process through which a state of hyperexcitability is established in the central nervous system, leading to enhanced processing of nociceptive (pain) messages (Woolf, 1983). Although numerous mechanisms have been implicated in central sensitization here we focus on three: alteration in glutamatergic neurotransmission/NMDA receptor-mediated hypersensitivity, loss of tonic inhibitory controls (disinhibition) and glial-neuronal interactions (Figure 5).


Figure 5 Spinal Cord Central Sensitization


Glutamate/NMDA Receptor-Mediated Sensitization


Acute pain is signaled by the release of glutamate from the central terminals of nociceptors, generating excitatory post-synaptic currents (EPSCs) in second order dorsal horn neurons. This occurs primarily through activation of postsynaptic AMPA and kainate subtypes of ionotropic glutamate receptors. Summation of sub-threshold EPSCs in the postsynaptic neuron will eventually result in action potential firing and transmission of the pain message to higher order neurons. Under these conditions, the NMDA subtype of glutamate channel is silent, but in the setting of injury, increased release of neurotransmitters from nociceptors will sufficiently depolarize postsynaptic neurons to activate quiescent NMDA receptors. The consequent increase in calcium influx can strengthen synaptic connections between nociceptors and dorsal horn pain transmission neurons, which in turn will exacerbate responses to noxious stimuli (that is, generate hyperalgesia).


In many ways, this processes is comparable to that implicated in the plastic changes associated with hippocampal long-term potentiation (LTP) (for a review on LTP in the pain pathway, see Drdla and Sandkuhler, 2008). Indeed, drugs that block spinal LTP reduce tissue injury-induced hyperalgesia. As in the case of hippocampal LTP, spinal cord central sensitization is dependent on NMDA-mediated elevations of cytosolic Ca2+ in the postsynaptic neuron. Concurrent activation of metabotropic glutamate and substance P receptors on the postsynaptic neuron may also contribute to sensitization by augmenting cytosolic calcium. Downstream activation of a host of signaling pathways and second messenger systems, notably kinases (such as MAPK, PKA, PKC, PI3K, Src), further increases excitability of these neurons, in part by modulating NMDA receptor function (Latremoliere and Woolf, 2009). Illustrative of this model is the demonstration that spinal injections of a nine amino acid peptide fragment of Src not only disrupts an NMDA receptor–Src interaction but also markedly decreases the hypersensitivity produced by peripheral injury, without changing acute pain. Src null mutant mice also display reduced mechanical allodynia after nerve injury (Liu et al., 2008).


In addition to enhancing inputs from the site of injury (primary hyperalgesia), central sensitization contributes to the condition in which innocuous stimulation of areas surrounding the injury site can produce pain. This secondary hyperalgesia involves heterosynaptic facilitation, wherein inputs from Aβ afferents, which normally respond to light touch, now engage pain transmission circuits, resulting in profound mechanical allodynia. The fact that compression block of peripheral nerve fibers concurrently interrupts conduction in Aβ afferents and eliminates secondary hyperalgesia indicates that these abnormal circuits are established in clinical settings as well as in animal models (Campbell et al., 1988).


Loss of GABAergic and Glycinergic Controls: Disinhibition


GABAergic or glycinergic inhibitory interneurons are densely distributed in the superficial dorsal horn and are at the basis of the longstanding gate control theory of pain, which postulates that loss of function of these inhibitory interneurons (disinhibition) would result in increased pain (Melzack and Wall, 1965). Indeed, in rodents, spinal administration of GABA (bicuculline) or glycine (strychnine) receptor antagonists (Malan et al., 2002; Sivilotti and Woolf, 1994; Yaksh, 1989) produces behavioral hypersensitivity resembling that observed after peripheral injury. Consistent with these observations, peripheral injury leads to a decrease in inhibitory postsynaptic currents in superficial dorsal horn neurons. Although Moore et al. (2002) suggested that the disinhibition results from peripheral nerve injury-induced death of GABAergic interneurons, this claim has been contested (Polgar et al., 2005). Regardless of the etiology, the resulting decreased tonic inhibition enhances depolarization and excitation of projection neurons. As for NMDA-mediated central sensitization, disinhibition enhances spinal cord output in response to painful and non-painful stimulation, contributing to mechanical allodynia (Keller et al., 2007; Torsney and MacDermott, 2006).


Following upon an earlier report that deletion of the gene encoding PKCγ in the mouse leads to a marked decrease in nerve injury-evoked mechanical hypersensitivity (Malmberg et al., 1997), recent studies address the involvement of these neurons in the disinhibitory process. Thus, after blockade of glycinergic inhibition with strychnine, innocuous brushing of the hindpaw activates PKCγ-positive interneurons in lamina II (Miraucourt et al., 2007), as well as projection neurons in lamina I. Because PKCγ-positive neurons in the spinal cord are located only in the innermost part of lamina II (Figure 1), it follows that these neurons are essential for the expression of nerve injury-evoked persistent pain, and that disinhibitory mechanisms lead to their hyperactivation.


Other studies indicate that changes in the projection neuron, itself, contribute to the dis-inhibitory process. For example, peripheral nerve injury profoundly down-regulates the K+-Cl- co-transporter KCC2, which is essential for maintaining normal K+ and Cl- gradients across the plasma membrane (Coull et al., 2003). Downregulating KCC2, which is expressed in lamina I projection neurons, results in a shift in the Cl- gradient, such that activation of GABA-A receptors depolarize, rather than hyperpolarize the lamina I projection neurons. This would, in turn, enhance excitability and increase pain transmission. Indeed, pharmacological blockade or siRNA-mediated downregulation of KCC2 in the rat induces mechanical allodynia. Nonetheless, Zeilhofer and colleagues suggest that, even after injury, sufficient inhibitory tone remains such that enhancement of spinal GABAergic neurotransmission might be a valuable approach to reduce pain hypersensitivity induced by peripheral nerve injury (Knabl et al., 2008). In fact, studies in mice suggest that drugs specifically targeting GABAA complexes containing α2 and/or α3 subunits reduce inflammatory and neuropathic pain without producing sedative-hypnotic side effects typically associated with benzodiazepines, which enhance activity of α1-containing channels.


Disinhibition can also occur through modulation of glycinergic signaling. In this case the mechanism involves a spinal cord action of prostaglandins (Harvey et al., 2004). Specifically, tissue injury induces spinal release of the prostaglandin, PGE2, which acts on EP2 receptors expressed by excitatory interneurons and projection neurons in the superficial dorsal horn. Resultant stimulation of the cAMP-PKA pathway phosphorylates GlyRa3 glycine receptor subunits, rendering the neurons unresponsive to the inhibitory effects of glycine. Accordingly, mice lacking the GlyRa3 gene have decreased heat and mechanical hypersensitivity in models of tissue injury.


Glial-Neuronal Interactions


Finally, glial cells, notably microglia and astrocytes, also contribute to the central sensitization process that occurs in the setting of injury. Under normal conditions, microglia function as resident macrophages of the central nervous system. They are homogeneously distributed within the grey matter of the spinal cord and are presumed to function as sentinels of injury or infection. Within hours of peripheral nerve injury, however, microglia accumulate in the superficial dorsal horn within the termination zone of injured peripheral nerve fibers. Microglia also surround the cell bodies of ventral horn motoneurons, whose peripheral axons are concurrently damaged. The activated microglia release a panoply of signaling molecules, including cytokines (such as TNF-α, interleukin-1β and 6), which enhance neuronal central sensitization and nerve injury-induced persistent pain (DeLeo et al., 2007). Indeed, injection of activated brain microglia into the cerebral spinal fluid at the level of the spinal cord can reproduce the behavioral changes observed after nerve injury (Coull et al., 2005). Thus, it appears that microglial activation is sufficient to trigger the persistent pain condition (Tsuda et al., 2003).


As microglia are activated following nerve, but not inflammatory tissue injury, it follows that activation of the afferent fiber, which occurs under both injury conditions, is not the critical trigger for microglial activation. Rather, physical damage of the peripheral afferent must induce the release of specific signals that are detected by microglia. Chief among these is ATP, which targets microglial P2-type purinergic receptors. Of particular interest are P2X4 (Tsuda et al., 2003), P2X7 (Chessell et al., 2005) and P2Y12 (Haynes et al., 2006; Kobayashi et al., 2008) receptor subtypes. Indeed, ATP was used to activate brain microglia in the spinal cord transplant studies referred to above (Tsuda et al., 2003). Furthermore, genetic or pharmacological blockade of purinergic receptor function (Chessell et al., 2005; Tozaki-Saitoh et al., 2008; Ulmann et al., 2008) prevents or reverses nerve injury-induced mechanical allodynia (Honore et al., 2006; Kobayashi et al., 2008; Tozaki-Saitoh et al., 2008; Tsuda et al., 2003).


Coull and colleagues proposed a model in which ATP/P2X4-mediated activation of microglia triggers a mechanism of disinhibition (Coull et al., 2005). Specifically, they demonstrated that ATP-evoked activation of P2X4 receptors induces release of the brain-derived neurotrophic factor (BDNF) from microglia. The BDNF, in turn, acts upon TrkB receptors on lamina I projection neurons, to generate a change in the Cl- gradient, which as described above, would shift the action of GABA from hyperpolarization to depolarization. Whether the BDNF-induced effect involves KCC2 expression, as occurs after nerve injury, is not known. Regardless of the mechanism, the net result is that activation of microglia will sensitize lamina I neurons such that their response to monosynaptic inputs from nociceptors, or indirect inputs from Aβ afferents, is enhanced.


In addition to BDNF, activated microglia, like peripheral macrophages, release and respond to numerous chemokines and cytokines, and these also contribute to central sensitization. For example, in the uninjured (normal) animal, the chemokine fractalkine (CXCL1) is expressed by both primary afferents and spinal cord neurons (Lindia et al., 2005; Verge et al., 2004; Zhuang et al., 2007). In contrast, the fractalkine receptor (CX3CR1) is expressed on microglial cells and importantly, is upregulated after peripheral nerve injury (Lindia et al., 2005; Zhuang et al., 2007). Because spinal delivery of fractalkine can activate microglia, it appears that nerve injury-induced release of fractalkine provides yet another route through which microglia can be engaged in the process of central sensitization. Indeed blockade of CX3CR1 with a neutralizing antibody prevents both the development and maintenance of injury-induced persistent pain (Milligan et al., 2004; Zhuang et al., 2007). This pathway may also be part of a positive feedback loop through which injured nerve fibers and microglial cells interact in a reciprocal and recurrent fashion to amplify pain signals. This point is underscored by the fact that fractalkine must be cleaved from the neuronal surface prior to signaling, an action that is carried out by the microglial-derived protease, cathepsin S, inhibitors of which reduce nerve injury-induced allodynia and hyperalgesia (Clark et al., 2007). Importantly, spinal administration of cathepsin S generates behavioral hypersensitivity in wild type, but not in CX3CX1 knockout mice, linking cathepsin S to fractalkine signaling (Clark et al., 2007; Zhuang et al., 2007). Although the factor(s) that initiates release of cathepsin S from microglia remains to be determined,. ATP seems a reasonable possibility.


Very recently, several members of the Toll-like receptors (TLRs) family have also been implicated in the activation of microglia following nerve injury. TLRs are transmembrane signaling proteins expressed in peripheral immune cells and glia. As part of the innate immune system, they recognize molecules that are broadly shared by pathogens. Genetic or pharmacological inhibition of TLR2, TLR3 or TLR4 function in mice results not only in decreased microglial activation, but also reduces the hypersensitivity triggered by peripheral nerve injury (Kim et al., 2007; Obata et al., 2008; Tanga et al., 2005). Unknown are the endogenous ligands that activate TLR2-4 after nerve-injury. Among the candidates are mRNAs or heat shock proteins that could leak from the damaged primary afferent neurons and diffuse into the extracellular milieu of the spinal cord.


The contribution of astrocytes to central sensitization is less clear. Astrocytes are unquestionably induced in the spinal cord after injury to either tissue or nerve (for a review, see Ren and Dubner, 2008). But, in contrast to microglia, astrocyte activation is generally delayed and persists much longer, up to several months. One interesting possibility is that astrocytes are more critical to the maintenance, rather than to the induction of central sensitization and persistent pain.


Finally, it is worth noting that peripheral injury not only activates glia in the spinal cord, but also in the brainstem, where glia contribute to supraspinal facilitatory influences on the processing of pain messages in the spinal cord (see Figure 2), a phenomenon named descending facilitation (for a review, see Ren and Dubner, 2008). Such facilitation is especially prominent in the setting of injury, and appears to counteract the feedback inhibitory controls that concurrently arise from various brainstem loci (Porreca et al., 2002).



Dr. Alex Jimenez’s Insight

As established by the International Association for the Study of Pain, or the IASP, pain is “an unpleasant sensory and emotional experience associated with acutal or potential tissue damage, or described in terms of tissue damage or both. Numerous research studies have been proposed to demonstrate the physiological basis of pain, however, none has been able to include the entire aspects associated with pain perception. Understanding the pain mechanisms of acute pain versus chronic pain is fundamental during clinical evaluations as this can help determine the best treatment approach for patients with underlying health issues.


Specificity in the Transmission and Control of Pain Messages


Understanding how stimuli are encoded by the nervous system to elicit appropriate behaviors is of fundamental importance to the study of all sensory systems. In the simplest form, a sensory system uses labeled lines to transduce stimuli and elicit behaviors through strictly segregated circuits. This is perhaps best exemplified by the taste system, where exchanging a sweet receptor for a bitter one in a population of “sweet taste afferents” does not alter the behavior provoked by activity in that labeled line; under these conditions, a bitter tastant stimulates these afferents to elicit a perception of sweetness (Mueller et al., 2005).


In the pain pathway, there is also evidence to support the existence of labeled lines. As mentioned above, heat and cold are detected by largely distinct subsets of primary afferent fibers. Moreover, elimination of subsets of nociceptors can produce selective deficits in the behavioral response to a particular noxious modality. For example, destruction of TRPV1-expressing nociceptors produces a profound loss of heat pain (including heat hyperalgesia), with no change in sensitivity to painful mechanical or cold stimuli. Conversely, deletion of the MrgprD subset of nociceptors results in a highly selective deficit in mechanical responsiveness, with no change in heat sensitivity (Cavanaugh et al., 2009). Further evidence for functional segregation at the level of the nociceptor comes from the analysis of two different opioid receptor subtypes (Scherrer et al., 2009). Specifically, the mu opioid receptor (MOR) predominates in the peptidergic population, whereas the delta opioid receptor (DOR) is expressed in non-peptidergic nociceptors. MOR-selective agonists block heat pain, whereas DOR selective agonists block mechanical pain, again illustrating functional separation of molecularly distinct nociceptor populations.


These observations argue for behaviorally-relevant specificity at the level of the nociceptor. However, this is likely to be an oversimplification for at least two reasons. First, many nociceptors are polymodal and can therefore be activated by thermal, mechanical, or chemical stimuli, leaving one to wonder how elimination of large cohorts of nociceptors can have modality-specific effects. This argues for a substantial contribution of spinal circuits to the process whereby nociceptive signals are encoded into distinct pain modalities. Indeed, an important future goal is to better delineate neuronal subtypes within the dorsal horn and characterize their synaptic interactions with functionally or molecularly defined subpopulations of nociceptors. Second, the pain system shows a tremendous capacity for change, particularly in the setting of injury, raising questions about whether and how a labeled line system might accommodate such plasticity, and how alterations in such mechanisms underlie maladaptive changes that produce chronic pain. Indeed, we know that substance P-saporin-mediated deletion of a discrete population of lamina I dorsal horn neurons, which express the substance P receptor, can reduce both the thermal and mechanical pain hypersensitivity that occurs after tissue or nerve injury (Nichols et al., 1999). Such observations suggest that in the setting of injury specificity of the labeled line is not strictly maintained as information is transmitted to higher levels of the neuraxis.


Clearly, answers to these questions will require the combined use of anatomical, electrophysiological, and behavioral methods to map the physical and functional circuitry that underlies nociception and pain. The ongoing identification of molecules and genes that mark specific neuronal cell types (both peripheral and central) provides essential tools with which to manipulate genetically or pharmacologically these neurons and to link their activities to specific components of pain behavior under normal and pathophysiological circumstances. Doing so should bring us closer to understanding how acute pain gives way to the maladaptive changes that produce chronic pain, and how this switch can be prevented or reversed.


Hemp vs Marijuana - What's the Difference? | El Paso, TX Chiropractor


Hemp vs Marijuana: What’s the Difference?


With approximately half of U.S. states now permitting the sale of medical marijuana, and a few even allowing the sale of marijuana for recreational use, more and more people are becoming interested in the possible health benefits of this controversial plant.


Whilst science on its medical use continues to advance, many people these days are considering how they could access the plant’s health benefits without experiencing its well-known unwanted psychoactive effect. This is completely possible with marijuana’s close relative, hemp but it is essential that you be aware of the difference so that you may be a smart consumer.


One Cultivars of the Exact Same Plant


Fundamentally, both hemp and marijuana are the exact same plant: Cannabis sativa. There is evidence that Cannabis sativa L has been grown in Asia thousands of years back for its fiber as well as a food supply. Humans eventually realized that the flowering tops of the plant had psychoactive properties. With time, as humans have done so with many other plants, Cannabis farmers began cultivating specific plants to enhance specific properties.


Nowadays, though some might argue the true number of plant types, there are really two simple distinctions,


Hemp – A plant primarily cultivated outside the United States, although a few U.S. countries let it be grown for study purposes) for use in clothes, paper, biofuels, bioplastics, dietary supplements, cosmetics, and foods. Hemp is cultivated outdoors as a large crop with both male and female plants being present to boost pollination and improve seed production. Legally imported industrial hemp contains less than 0.3 percent of its carcinogenic chemical tetrahydrocannabinol, or THC, content. In reality, legally imported hemp will usually specifically eliminate any extracts in the plant’s dried flowering tops.


Marijuana (Marihuana) – Cannabis sativa especially cultivated to enhance its THC content to be used for medicinal or recreational purposes. Marijuana plants are typically grown indoors, under controlled conditions, and growers eliminate all of the male plants from the harvest to prevent fertilization because fertilization lowers the plant’s THC degree.


Legality of Medical Marijuana


The medical use of marijuana is an increased area of controversy for researchers and consumers alike. Although maybe not quite half of U.S. states have legalized the medical use of this plant, it remains illegal under federal law, and consequently its use remains controversial regardless of the fact that there does seem to be real health benefits for various serious health issues.


Those that are looking to use marijuana for medical use should talk about its benefits versus its dangers with a skilled health-care professional before using it. In addition, many consumers who have an interest in its health benefits do not need the psychoactive side effects of THC or the danger of a positive drug test.


Hemp: Health Benefits without the Risks


Imported hemp, that has a very low, almost absent, level of THC, can be a solution for consumers that are looking for the plant’s health benefits minus the effects of THC.


Though THC has some health benefits, hemp comprises more than 80 bioactive compounds that could provide excellent support for a range of health issues, such as stress response, positive mood, and physical discomfort or pain. Hemp can also benefit gastrointestinal health, help keep a healthy inflammatory response throughout the entire body, and support normal immune function.


If you are considering the use of a nutritional supplement product which includes hemp, then it’s ideal to buy a product from a trusted source.


In conclusion, both the peripheral and central nervous system detect, interpret and regulate a wide range of thermal and mechanical stimulation as well as environmental and endogenous chemical irritants. If the stimuli is too intense, it can generate acute pain where in the instance of persistent or chronic pain, pain transmission can be tremendously affected. The article above describes the cellular and molecular mechanisms of pain for guidance in clinical assessments. Furthermore, the use of hemp can have many health benefits in comparison to the controversial effects of marijuana. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


Curated by Dr. Alex Jimenez


Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




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EXTRA IMPORTANT TOPIC: Low Back Pain Management


MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments


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Cannabinoids And Plant Medicine

Cannabinoids And Plant Medicine

Cannabinoids: Plants and medicine have come around like never before. With more research taking place and more information coming to the medical field, there are now more options for ailments, conditions, diseases and disorders. Chiropractor, Dr. Alex Jimenez analyzes the data and brings insight to these developing medicines and treatments. How they can help patients, what can they do and what can’t they do?

Most associate cannabinoids with the marijuana plant. This is the most recognized cannabinoid compound – tetrahydrocannabinol (THC), which is what causes feelings of euphoria.

However, scientists have identified cannabinoids in many plants, which include black pepper, broccoli, carrots, clove, echinacea, and ginseng. None of these will get you high. But with an understanding of how the cannabinoids in these various plants affect the human body can create a path to important health discoveries.

Plants Are Medicine

Many modern drugs were developed through plant research. Researching compounds in these plants led to discovering life saving drugs and furthered the knowledge of how the human body functions. An example is the foxglove plant, which gave us digoxin and digitoxin. Two very important heart medications.1

Humans have been especially resourceful when finding plants for pleasure or to decrease pain.

Caffeine provides energy, while nicotine from tobacco stimulates and relaxes. This explains why tobacco is still popular even though we know the health risks of smoking.2

Pain-Relieving Drugs & Their Origin


In ancient times, medical practitioners drank tea made from willow tree, in order to reduce fever and pain. It took hundreds of years for scientists to find and isolate the active compound, which is salicylic acid. This led to the discovery of aspirin and from there, it evolved into inflammation reduction.4


Coca plant leaves were used by the Incan’s in South America. It was used to treat headaches, wounds, and fractures. However, the coca plant also brought about cocaine. But is an effective anesthetic. To have an understanding of how cocaine blocks pain has created common anesthetics like lidocaine, which is used in dental procedures.5


Scientists studying opium from the poppy plant, have discovered opiate receptors in the human body and how they manage pain. This led to morphine, codeine, and other opiate based medications.3

Human Health & Cannabis

Cannabis has been used for centuries. Chinese text from the year A.D. 1 has recorded the use of hemp in treating over 100 ailments, which date back to 2737 B.C.6 After this, the tops of the cannabis plant were cultivated for their psychoactive attributes. While this was happening a different strain of the plant was grown for industrial hemp use, in making clothing, paper, biofuels, foods, and other products.

cannabinoids plant medicine el paso, tx.

Based on the controversy surrounding marijuana, it has not been easy for researchers to study the effects of the non-THC components in cannabis. THC was identified in the 1940’s, but it was not until 50 years later that research revealed humans (and almost all animals) have a system of cannabinoid receptors.

Humans make cannabinoids (endocannabinoids) and they act on these receptors.7

This system is called the endocannabinoid system (ECS). The ECS is involved in multiple processes, which include:

  • Pain Sensation
  • Appetite
  • Memory
  • Mood

Ever hit your toe, digest a piece of fruit or forget a password? Then the ECS was involved.

Discovery of the ECS along with the natural compounds identified in cannabis helped science and medicine. Researchers called these compounds phytocannabinoids, from the prefix “phyto” for plant. Over 80 phytocannabinoids have now been discovered in marijuana and hemp. THC is just one of the many compounds being studied for their health benefits.8

Cannabis & THC Moving Forward

Now that many plants are known to contain these compounds, phytocannabinoids are no longer just associated with cannabis.9 Chances are you have some source of phytocannabinoids in your diet right now.

Remember it could be just a small amount, and not all phytocannabinoids interact strongly with the ECS.

How Far Has This Research Developed?

Current research shows that some of the phytocannabinoids in hemp, clove, and black pepper can support the ECS to promote relaxation, decrease nerve discomfort, and improve digestive health. And as these compounds do not contain THC there is no mind-altering effects. Therefore, the option of using phytocannabinoids for health benefits, without feeling the psychoactive effects is definitely something to look forward to.10


  1. Gurib-Fakim A. Medicinal plants: traditions of yesterday and drugs of tomorrow. Mol Aspects Med 2006;27(1):1-93.
  2. Singh Y, Blumenthal M. Kava: an overview. Distribution, mythology, botany, culture, chemistry and pharmacology of the South Pacific’s most revered herb. Herbalgram 1997;39(suppl):34-56.
  3. Brownstein M. A brief history of opiates, opioid peptides, and opioid receptors. Proc Natl Acad Sci U S A 1993;90(12):5391-5393.
  4. Vainio H, Gareth M. Aspirin for the second hundred years: new uses for an old drug. Pharmacol Toxicol 1997;81(4):151-152.
  5. Ruetsch Y, Thomas B, Alain B. From cocaine to ropivacaine: the history of local anesthetic drugs. Curr Top Med Chem 2001;1(3):175-182.
  6. [Accessed April 16, 2018].
  7. Pertwee R. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol 2006;147(Supp 1):163-171.
  8. Borgelt L, Franson K, Nussbaum A, Wang G. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 2013;33(2):195-209.
  9. Gertsch J, Roger G, Vincenzo D. Phytocannabinoids beyond the Cannabis plant – do they exist? Br J Pharmacol 2010;160(3):523-529.
  10. Russo E. Taming THC: potential cannabis synergy and phytocannabinoid?terpenoid entourage effects. Br J Pharmacol 2011;163(7):1344-1364.
Brain Changes Associated with Chronic Pain

Brain Changes Associated with Chronic Pain

Pain is the human body’s natural response to injury or illness, and it is often a warning that something is wrong. Once the problem is healed, we generally stop experiencing this painful symptoms, however, what happens when the pain continues long after the cause is gone? Chronic pain is medically defined as persistent pain that lasts 3 to 6 months or more. Chronic pain is certainly a challenging condition to live with, affecting everything from the individual’s activity levels and their ability to work as well as their personal relationships and psychological conditions. But, are you aware that chronic pain may also be affecting the structure and function of your brain? It turns out these brain changes may lead to both cognitive and psychological impairment.


Chronic pain doesn’t just influence a singular region of the mind, as a matter of fact, it can result in changes to numerous essential areas of the brain, most of which are involved in many fundamental processes and functions. Various research studies over the years have found alterations to the hippocampus, along with reduction in grey matter from the dorsolateral prefrontal cortex, amygdala, brainstem and right insular cortex, to name a few, associated with chronic pain. A breakdown of a few of the structure of these regions and their related functions might help to put these brain changes into context, for a lot of individuals with chronic pain. The purpose of the following article is to demonstrate as well as discuss the structural and functional brain changes associated with chronic pain, particularly in the case where those reflect probably neither damage nor atrophy.


Structural Brain Changes in Chronic Pain Reflect Probably Neither Damage Nor Atrophy




Chronic pain appears to be associated with brain gray matter reduction in areas ascribable to the transmission of pain. The morphological processes underlying these structural changes, probably following functional reorganisation and central plasticity in the brain, remain unclear. The pain in hip osteoarthritis is one of the few chronic pain syndromes which are principally curable. We investigated 20 patients with chronic pain due to unilateral coxarthrosis (mean age 63.25±9.46 (SD) years, 10 female) before hip joint endoprosthetic surgery (pain state) and monitored brain structural changes up to 1 year after surgery: 6–8 weeks, 12–18 weeks and 10–14 month when completely pain free. Patients with chronic pain due to unilateral coxarthrosis had significantly less gray matter compared to controls in the anterior cingulate cortex (ACC), insular cortex and operculum, dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex. These regions function as multi-integrative structures during the experience and the anticipation of pain. When the patients were pain free after recovery from endoprosthetic surgery, a gray matter increase in nearly the same areas was found. We also found a progressive increase of brain gray matter in the premotor cortex and the supplementary motor area (SMA). We conclude that gray matter abnormalities in chronic pain are not the cause, but secondary to the disease and are at least in part due to changes in motor function and bodily integration.




Evidence of functional and structural reorganization in chronic pain patients support the idea that chronic pain should not only be conceptualized as an altered functional state, but also as a consequence of functional and structural brain plasticity [1], [2], [3], [4], [5], [6]. In the last six years, more than 20 studies were published demonstrating structural brain changes in 14 chronic pain syndromes. A striking feature of all of these studies is the fact that the gray matter changes were not randomly distributed, but occur in defined and functionally highly specific brain areas – namely, involvement in supraspinal nociceptive processing. The most prominent findings were different for each pain syndrome, but overlapped in the cingulate cortex, the orbitofrontal cortex, the insula and dorsal pons [4]. Further structures comprise the thalamus, dorsolateral prefrontal cortex, basal ganglia and hippocampal area. These findings are often discussed as cellular atrophy, reinforcing the idea of damage or loss of brain gray matter [7], [8], [9]. In fact, researchers found a correlation between brain gray matter decreases and duration of pain [6], [10]. But the duration of pain is also linked to the patient’s age, and the age dependent global, but also regionally specific decline of gray matter is well documented [11]. On the other hand, these structural changes could also be a decrease in cell size, extracellular fluids, synaptogenesis, angiogenesis or even due to blood volume changes [4], [12], [13]. Whatever the source is, for our interpretation of such findings it is important to see these morphometric findings in the light of a wealth of morphometric studies in exercise dependant plasticity, given that regionally specific structural brain changes have been repeatedly shown following cognitive and physical exercise [14].


It is not understood why only a relatively small proportion of humans develop a chronic pain syndrome, considering that pain is a universal experience. The question arises whether in some humans a structural difference in central pain transmitting systems may act as a diathesis for chronic pain. Gray matter changes in phantom pain due to amputation [15] and spinal cord injury [3] indicate that the morphological changes of the brain are, at least in part, a consequence of chronic pain. However, the pain in hip osteoarthritis (OA) is one of the few chronic pain syndrome which is principally curable, as 88% of these patients are regularly free of pain following total hip replacement (THR) surgery [16]. In a pilot study we have analysed ten patients with hip OA before and shortly after surgery. We found decreases of gray matter in the anterior cingulated cortex (ACC) and insula during chronic pain before THR surgery and found increases of gray matter in the corresponding brain areas in the pain free condition after surgery [17]. Focussing on this result, we now expanded our studies investigating more patients (n = 20) after successful THR and monitored structural brain changes in four time intervals, up to one year following surgery. To control for gray matter changes due to motor improvement or depression we also administered questionnaires targeting improvement of motor function and mental health.


Materials and Methods




The patients reported here are a subgroup of 20 patients out of 32 patients published recently who were compared to an age- and gender-matched healthy control group [17] but participated in an additional one year follow-up investigation. After surgery 12 patients dropped out because of a second endoprosthetic surgery (n = 2), severe illness (n = 2) and withdrawal of consent (n = 8). This left a group of twenty patients with unilateral primary hip OA (mean age 63.25±9.46 (SD) years, 10 female) who were investigated four times: before surgery (pain state) and again 6–8 and 12–18 weeks and 10–14 months after endoprosthetic surgery, when completely pain free. All patients with primary hip OA had a pain history longer than 12 months, ranging from 1 to 33 years (mean 7.35 years) and a mean pain score of 65.5 (ranging from 40 to 90) on a visual analogue scale (VAS) ranging from 0 (no pain) to 100 (worst imaginable pain). We assessed any occurrence of minor pain events, including tooth-, ear- and headache up to 4 weeks prior to the study. We also randomly selected the data from 20 sex- and age matched healthy controls (mean age 60,95±8,52 (SD) years, 10 female) of the 32 of the above mentioned pilot study [17]. None of the 20 patients or of the 20 sex- and age matched healthy volunteers had any neurological or internal medical history. The study was given ethical approval by the local Ethics committee and written informed consent was obtained from all study participants prior to examination.


Behavioural Data


We collected data on depression, somatization, anxiety, pain and physical and mental health in all patients and all four time points using the following standardized questionnaires: Beck Depression Inventory (BDI) [18], Brief Symptom Inventory (BSI) [19], Schmerzempfindungs-Skala (SES = pain unpleasantness scale) [20] and Health Survey 36-Item Short Form (SF-36) [21] and the Nottingham Health Profile (NHP). We conducted repeated measures ANOVA and paired two-tailed t-Tests to analyse the longitudinal behavioural data using SPSS 13.0 for Windows (SPSS Inc., Chicago, IL), and used Greenhouse Geisser correction if the assumption for sphericity was violated. The significance level was set at p<0.05.


VBM – Data Acquisition


Image acquisition. High-resolution MR scanning was performed on a 3T MRI system (Siemens Trio) with a standard 12-channel head coil. For each of the four time points, scan I (between 1 day and 3 month before endoprosthetic surgery), scan II (6 to 8 weeks after surgery), scan III (12 to 18 weeks after surgery) and scan IV (10–14 months after surgery), a T1 weighted structural MRI was acquired for each patient using a 3D-FLASH sequence (TR 15 ms, TE 4.9 ms, flip angle 25°, 1 mm slices, FOV 256×256, voxel size 1×1×1 mm).


Image Processing and Statistical Analysis


Data pre-processing and analysis were performed with SPM2 (Wellcome Department of Cognitive Neurology, London, UK) running under Matlab (Mathworks, Sherborn, MA, USA) and containing a voxel-based morphometry (VBM)-toolbox for longitudinal data, that is based on high resolution structural 3D MR images and allows for applying voxel-wise statistics to detect regional differences in gray matter density or volumes [22], [23]. In summary, pre-processing involved spatial normalization, gray matter segmentation and 10 mm spatial smoothing with a Gaussian kernel. For the pre-processing steps, we used an optimized protocol [22], [23] and a scanner- and study-specific gray matter template [17]. We used SPM2 rather than SPM5 or SPM8 to make this analysis comparable to our pilot study [17]. as it allows an excellent normalisation and segmentation of longitudinal data. However, as a more recent update of VBM (VBM8) became available recently (, we also used VBM8.


Cross-Sectional Analysis


We used a two-sample t-test in order to detect regional differences in brain gray matter between groups (patients at time point scan I (chronic pain) and healthy controls). We applied a threshold of p<0.001 (uncorrected) across the whole brain because of our strong a priory hypothesis, which is based on 9 independent studies and cohorts showing decreases in gray matter in chronic pain patients [7], [8], [9], [15], [24], [25], [26], [27], [28], that gray matter increases will appear in the same (for pain processing relevant) regions as in our pilot study (17). The groups were matched for age and sex with no significant differences between the groups. To investigate whether the differences between groups changed after one year, we also compared patients at time point scan IV (pain free, one year follow-up) to our healthy control group.


Longitudinal Analysis


To detect differences between time points (Scan I–IV) we compared the scans before surgery (pain state) and again 6–8 and 12–18 weeks and 10–14 months after endoprosthetic surgery (pain free) as repeated measure ANOVA. Because any brain changes due to chronic pain may need some time to recede following operation and cessation of pain and because of the post surgery pain the patients reported, we compared in the longitudinal analysis scan I and II with scan III and IV. For detecting changes that are not closely linked to pain, we also looked for progressive changes over all time intervals. We flipped the brains of patients with OA of the left hip (n = 7) in order to normalize for the side of the pain for both, the group comparison and the longitudinal analysis, but primarily analysed the unflipped data. We used the BDI score as a covariate in the model.




Behavioral Data


All patients reported chronic hip pain before surgery and were pain free (regarding this chronic pain) immediately after surgery, but reported rather acute post-surgery pain on scan II which was different from the pain due to osteoarthritis. The mental health score of the SF-36 (F(1.925/17.322) = 0.352, p = 0.7) and the BSI global score GSI (F(1.706/27.302) = 3.189, p = 0.064) showed no changes over the time course and no mental co-morbidity. None of the controls reported any acute or chronic pain and none showed any symptoms of depression or physical/mental disability.


Before surgery, some patients showed mild to moderate depressive symptoms in BDI scores that significantly decreased on scan III (t(17) = 2.317, p = 0.033) and IV (t(16) = 2.132, p = 0.049). Additionally, the SES scores (pain unpleasantness) of all patients improved significantly from scan I (before the surgery) to scan II (t(16) = 4.676, p<0.001), scan III (t(14) = 4.760, p<0.001) and scan IV (t(14) = 4.981, p<0.001, 1 year after surgery) as pain unpleasantness decreased with pain intensity. The pain rating on scan 1 and 2 were positive, the same rating on day 3 and 4 negative. The SES only describes the quality of perceived pain. It was therefore positive on day 1 and 2 (mean 19.6 on day 1 and 13.5 on day 2) and negative (n.a.) on day 3 & 4. However, some patients did not understand this procedure and used the SES as a global “quality of life” measure. This is why all patients were asked on the same day individually and by the same person regarding pain occurrence.


In the short form health survey (SF-36), which consists of the summary measures of a Physical Health Score and a Mental Health Score [29], the patients improved significantly in the Physical Health score from scan I to scan II (t(17) = −4.266, p = 0.001), scan III (t(16) = −8.584, p<0.001) and IV (t(12) = −7.148, p<0.001), but not in the Mental Health Score. The results of the NHP were similar, in the subscale “pain” (reversed polarity) we observed a significant change from scan I to scan II (t(14) = −5.674, p<0.001, scan III (t(12) = −7.040, p<0.001 and scan IV (t(10) = −3.258, p = 0.009). We also found a significant increase in the subscale “physical mobility” from scan I to scan III (t(12) = −3.974, p = 0.002) and scan IV (t(10) = −2.511, p = 0.031). There was no significant change between scan I and scan II (six weeks after surgery).


Structural Data


Cross-sectional analysis. We included age as a covariate in the general linear model and found no age confounds. Compared to sex and age matched controls, patients with primary hip OA (n = 20) showed pre-operatively (Scan I) reduced gray matter in the anterior cingulate cortex (ACC), the insular cortex, operculum, dorsolateral prefrontal cortex (DLPFC), right temporal pole and cerebellum (Table 1 and Figure 1). Except for the right putamen (x = 31, y = −14, z = −1; p<0.001, t = 3.32) no significant increase in gray matter density was found in patients with OA compared to healthy controls. Comparing patients at time point scan IV with matched controls, the same results were found as in the cross-sectional analysis using scan I compared to controls.


Figure 1 Statistical Parametric Maps

Figure 1: Statistical parametric maps demonstrating the structural differences in gray matter in patients with chronic pain due to primary hip OA compared to controls and longitudinally compared to themselves over time. Significant gray matter changes are shown superimposed in color, cross-sectional data is depicted in red and longitudinal data in yellow. Axial plane: the left side of the picture is the left side of the brain. top: Areas of significant decrease of gray matter between patients with chronic pain due to primary hip OA and unaffected control subjects. p<0.001 uncorrected bottom: Gray matter increase in 20 pain free patients at the third and fourth scanning period after total hip replacement surgery, as compared to the first (preoperative) and second (6–8 weeks post surgery) scan. p<0.001 uncorrected Plots: Contrast estimates and 90% Confidence interval, effects of interest, arbitrary units. x-axis: contrasts for the 4 timepoints, y-axis: contrast estimate at −3, 50, 2 for ACC and contrast estimate at 36, 39, 3 for insula.


Table 1 Cross-Sectional Data


Flipping the data of patients with left hip OA (n = 7) and comparing them with healthy controls did not change the results significantly, but for a decrease in the thalamus (x = 10, y = −20, z = 3, p<0.001, t = 3.44) and an increase in the right cerebellum (x = 25, y = −37, z = −50, p<0.001, t = 5.12) that did not reach significance in the unflipped data of the patients compared to controls.


Longitudinal analysis. In the longitudinal analysis, a significant increase (p<.001 uncorrected) of gray matter was detected by comparing the first and second scan (chronic pain/post-surgery pain) with the third and fourth scan (pain free) in the ACC, insular cortex, cerebellum and pars orbitalis in the patients with OA (Table 2 and Figure 1). Gray matter decreased over time (p<.001 whole brain analysis uncorrected) in the secondary somatosensory cortex, hippocampus, midcingulate cortex, thalamus and caudate nucleus in patients with OA (Figure 2).


Figure 2 Increases in Brain Gray Matter

Figure 2: a) Significant increases in brain gray matter following successful operation. Axial view of significant decrease of gray matter in patients with chronic pain due to primary hip OA compared to control subjects. p<0.001 uncorrected (cross-sectional analysis), b) Longitudinal increase of gray matter over time in yellow comparing scan I&IIscan III>scan IV) in patients with OA. p<0.001 uncorrected (longitudinal analysis). The left side of the picture is the left side of the brain.


Table 2 Longitudinal Data


Flipping the data of patients with left hip OA (n = 7) did not change the results significantly, but for a decrease of brain gray matter in the Heschl’s Gyrus (x = −41, y = −21, z = 10, p<0.001, t = 3.69) and Precuneus (x = 15, y = −36, z = 3, p<0.001, t = 4.60).


By contrasting the first scan (presurgery) with scans 3+4 (postsurgery), we found an increase of gray matter in the frontal cortex and motor cortex (p<0.001 uncorrected). We note that this contrast is less stringent as we have now less scans per condition (pain vs. non-pain). When we lower the threshold we repeat what we have found using contrast of 1+2 vs. 3+4.


By looking for areas that increase over all time intervals, we found changes of brain gray matter in motor areas (area 6) in patients with coxarthrosis following total hip replacement (scan I<scan II<scan III<scan IV)). Adding the BDI scores as a covariate did not change the results. Using the recently available software tool VBM8 including DARTEL normalisation ( we could replicate this finding in the anterior and mid-cingulate cortex and both anterior insulae.


We calculated the effect sizes and the cross-sectional analysis (patients vs. controls) yielded a Cohen’s d of 1.78751 in the peak voxel of the ACC (x = −12, y = 25, z = −16). We also calculated Cohen’s d for the longitudinal analysis (contrasting scan 1+2 vs. scan 3+4). This resulted in a Cohen’s d of 1.1158 in the ACC (x = −3, y = 50, z = 2). Regarding the insula (x = −33, y = 21, z = 13) and related to the same contrast, Cohen’s d is 1.0949. Additionally, we calculated the mean of the non-zero voxel values of the Cohen’s d map within the ROI (comprised of the anterior division of the cingulate gyrus and the subcallosal cortex, derived from the Harvard-Oxford Cortical Structural Atlas): 1.251223.



Dr. Alex Jimenez’s Insight

Chronic pain patients can experience a variety of health issues over time, aside from their already debilitating symptoms. For instance, many individuals will experience sleeping problems as a result of their pain, but most importantly, chronic pain can lead to various mental health issues as well, including anxiety and depression. The effects that pain can have on the brain may seem all too overwhelming but growing evidence suggests that these brain changes are not permanent and can be reversed when chronic pain patients receive the proper treatment for their underlying health issues. According to the article, gray matter abnormalities found in chronic pain do not reflect brain damage, but rather, they are a reversible consequence which normalizes when the pain is adequately treated. Fortunately, a variety of treatment approaches are available to help ease chronic pain symptoms and restore the structure and function of the brain.




Monitoring whole brain structure over time, we confirm and expand our pilot data published recently [17]. We found changes in brain gray matter in patients with primary hip osteoarthritis in the chronic pain state, which reverse partly when these patients are pain free, following hip joint endoprosthetic surgery. The partial increase in gray matter after surgery is nearly in the same areas where a decrease of gray matter has been seen before surgery. Flipping the data of patients with left hip OA (and therefore normalizing for the side of the pain) had only little impact on the results but additionally showed a decrease of gray matter in the Heschl’s gyrus and Precuneus that we cannot easily explain and, as no a priori hypothesis exists, regard with great caution. However, the difference seen between patients and healthy controls at scan I was still observable in the cross-sectional analysis at scan IV. The relative increase of gray matter over time is therefore subtle, i.e. not sufficiently distinct to have an effect on the cross sectional analysis, a finding that has already been shown in studies investigating experience dependant plasticity [30], [31]. We note that the fact that we show some parts of brain-changes due to chronic pain to be reversible does not exclude that some other parts of these changes are irreversible.


Interestingly, we observed that the gray matter decrease in the ACC in chronic pain patients before surgery seems to continue 6 weeks after surgery (scan II) and only increases towards scan III and IV, possibly due to post-surgery pain, or decrease in motor function. This is in line with the behavioural data of the physical mobility score included in the NHP, which post-operatively did not show any significant change at time point II but significantly increased towards scan III and IV. Of note, our patients reported no pain in the hip after surgery, but experienced post-surgery pain in surrounding muscles and skin which was perceived very differently by patients. However, as patients still reported some pain at scan II, we also contrasted the first scan (pre-surgery) with scans III+IV (post-surgery), revealing an increase of gray matter in the frontal cortex and motor cortex. We note that this contrast is less stringent because of less scans per condition (pain vs. non-pain). When we lowered the threshold we repeat what we have found using contrast of I+II vs. III+IV.


Our data strongly suggest that gray matter alterations in chronic pain patients, which are usually found in areas involved in supraspinal nociceptive processing [4] are neither due to neuronal atrophy nor brain damage. The fact that these changes seen in the chronic pain state do not reverse completely could be explained with the relatively short period of observation (one year after operation versus a mean of seven years of chronic pain before the operation). Neuroplastic brain changes that may have developed over several years (as a consequence of constant nociceptive input) need probably more time to reverse completely. Another possibility why the increase of gray matter can only be detected in the longitudinal data but not in the cross-sectional data (i.e. between cohorts at time point IV) is that the number of patients (n = 20) is too small. It needs to be pointed out that the variance between brains of several individuals is quite large and that longitudinal data have the advantage that the variance is relatively small as the same brains are scanned several times. Consequently, subtle changes will only be detectable in longitudinal data [30], [31], [32]. Of course we cannot exclude that these changes are at least partly irreversible although that is unlikely, given the findings of exercise specific structural plasticity and reorganisation [4], [12], [30], [33], [34]. To answer this question, future studies need to investigate patients repeatedly over longer time frames, possibly years.


We note that we can only make limited conclusions regarding the dynamics of morphological brain changes over time. The reason is that when we designed this study in 2007 and scanned in 2008 and 2009, it was not known whether structural changes would occur at all and for reasons of feasibility we chose the scan dates and time frames as described here. One could argue that the gray matter changes in time, which we describe for the patient group, might have happened in the control group as well (time effect). However, any changes due to aging, if at all, would be expected to be a decrease in volume. Given our a priori hypothesis, based on 9 independent studies and cohorts showing decreases in gray matter in chronic pain patients [7], [8], [9], [15], [24], [25], [26], [27], [28], we focussed on regional increases over time and therefore believe our finding not to be a simple time effect. Of note, we cannot rule out that the gray matter decrease over time that we found in our patient group could be due to a time effect, as we have not scanned our control group in the same time frame. Given the findings, future studies should aim at more and shorter time intervals, given that exercise dependant morphometric brain changes may occur as fast as after 1 week [32], [33].


In addition to the impact of the nociceptive aspect of pain on brain gray matter [17], [34] we observed that changes in motor function probably also contribute to the structural changes. We found motor and premotor areas (area 6) to increase over all time intervals (Figure 3). Intuitively this may be due to improvement of motor function over time as the patients were no more restricted in living a normal life. Notably we did not focus on motor function but an improvement in pain experience, given our original quest to investigate whether the well-known reduction in brain gray matter in chronic pain patients is in principle reversible. Consequently, we did not use specific instruments to investigate motor function. Nevertheless, (functional) motor cortex reorganization in patients with pain syndromes is well documented [35], [36], [37], [38]. Moreover, the motor cortex is one target in therapeutic approaches in medically intractable chronic pain patients using direct brain stimulation [39], [40], transcranial direct current stimulation [41], and repetitive transcranial magnetic stimulation [42], [43]. The exact mechanisms of such modulation (facilitation vs. inhibition, or simply interference in the pain-related networks) are not yet elucidated [40]. A recent study demonstrated that a specific motor experience can alter the structure of the brain [13]. Synaptogenesis, reorganisation of movement representations and angiogenesis in motor cortex may occur with special demands of a motor task. Tsao et al. showed reorganisation in the motor cortex of patients with chronic low back pain that seem to be back pain-specific [44] and Puri et al. observed a reduction in left supplemental motor area gray matter in fibromyalgia sufferers [45]. Our study was not designed to disentangle the different factors that may change the brain in chronic pain but we interpret our data concerning the gray matter changes that they do not exclusively mirror the consequences of constant nociceptive input. In fact, a recent study in neuropathic pain patients pointed out abnormalities in brain regions that encompass emotional, autonomic, and pain perception, implying that they play a critical role in the global clinical picture of chronic pain [28].


Figure 3 Statistical Parametric Maps

Figure 3: Statistical parametric maps demonstrating a significant increase of brain gray matter in motor areas (area 6) in patients with coxarthrosis before compared to after THR (longitudinal analysis, scan I<scan II<scan III<scan IV). Contrast estimates at x = 19, y = −12, z = 70.


Two recent pilot studies focussed on hip replacement therapy in osteoarthritis patients, the only chronic pain syndrome which is principally curable with total hip replacement [17], [46] and these data are flanked by a very recent study in chronic low back pain patients [47]. These studies need to be seen in the light of several longitudinal studies investigating experience-dependent neuronal plasticity in humans on a structural level [30], [31] and a recent study on structural brain changes in healthy volunteers experiencing repeated painful stimulation [34]. The key message of all these studies is that the main difference in the brain structure between pain patients and controls may recede when the pain is cured. However, it must be taken into account that it is simply not clear whether the changes in chronic pain patients are solely due to nociceptive input or due to the consequences of pain or both. It is more than likely that behavioural changes, such as deprivation or enhancement of social contacts, agility, physical training and life style changes are sufficient to shape the brain [6], [12], [28], [48]. Particularly depression as a co-morbidity or consequence of pain is a key candidate to explain the differences between patients and controls. A small group of our patients with OA showed mild to moderate depressive symptoms that changed with time. We did not find the structural alterations to covary significantly with the BDI-score but the question arises how many other behavioural changes due to the absence of pain and motor improvement may contribute to the results and to what extent they do. These behavioural changes can possibly influence a gray matter decrease in chronic pain as well as a gray matter increase when pain is gone.


Another important factor which may bias our interpretation of the results is the fact that nearly all patients with chronic pain took medications against pain, which they stopped when they were pain free. One could argue that NSAIDs such as diclofenac or ibuprofen have some effects on neural systems and the same holds true for opioids, antiepileptics and antidepressants, medications which are frequently used in chronic pain therapy. The impact of pain killers and other medications on morphometric findings may well be important (48). No study so far has shown effects of pain medication on brain morphology but several papers found that changes in brain structure in chronic pain patients are neither solely explained by pain related inactivity [15], nor by pain medication [7], [9], [49]. However, specific studies are lacking. Further research should focus the experience-dependent changes in cortical plasticity, which may have vast clinical implications for the treatment of chronic pain.


We also found decreases of gray matter in the longitudinal analysis, possibly due to reorganisation processes that accompany changes in motor function and pain perception. There is little information available about longitudinal changes in brain gray matter in pain conditions, for this reason we have no hypothesis for a gray matter decrease in these areas after the operation. Teutsch et al. [25] found an increase of brain gray matter in the somatosensory and midcingulate cortex in healthy volunteers that experienced painful stimulation in a daily protocol for eight consecutive days. The finding of gray matter increase following experimental nociceptive input overlapped anatomically to some degree with the decrease of brain gray matter in this study in patients that were cured of long-lasting chronic pain. This implies that nociceptive input in healthy volunteers leads to exercise dependant structural changes, as it possibly does in patients with chronic pain, and that these changes reverse in healthy volunteers when nociceptive input stops. Consequently, the decrease of gray matter in these areas seen in patients with OA could be interpreted to follow the same fundamental process: exercise dependant changes brain changes [50]. As a non-invasive procedure, MR Morphometry is the ideal tool for the quest to find the morphological substrates of diseases, deepening our understanding of the relationship between brain structure and function, and even to monitor therapeutic interventions. One of the great challenges in the future is to adapt this powerful tool for multicentre and therapeutic trials of chronic pain.


Limitations of this Study


Although this study is an extension of our previous study expanding the follow-up data to 12 months and investigating more patients, our principle finding that morphometric brain changes in chronic pain are reversible is rather subtle. The effect sizes are small (see above) and the effects are partly driven by a further reduction of regional brain gray matter volume at the time-point of scan 2. When we exclude the data from scan 2 (directly after the operation) only significant increases in brain gray matter for motor cortex and frontal cortex survive a threshold of p<0.001 uncorrected (Table 3).


Table 3 Longitudinal Data




It is not possible to distinguish to what extent the structural alterations we observed are due to changes in nociceptive input, changes in motor function or medication consumption or changes in well-being as such. Masking the group contrasts of the first and last scan with each other revealed much less differences than expected. Presumably, brain alterations due to chronic pain with all consequences are developing over quite a long time course and may also need some time to revert. Nevertheless, these results reveal processes of reorganisation, strongly suggesting that chronic nociceptive input and motor impairment in these patients leads to altered processing in cortical regions and consequently structural brain changes which are in principle reversible.




We thank all volunteers for the participation in this study and the Physics and Methods group at NeuroImage Nord in Hamburg. The study was given ethical approval by the local Ethics committee and written informed consent was obtained from all study participants prior to examination.


Funding Statement


This work was supported by grants from the DFG (German Research Foundation) (MA 1862/2-3) and BMBF (The Federal Ministry of Education and Research) (371 57 01 and NeuroImage Nord). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Endocannabinoid System | El Paso, TX Chiropractor


The Endocannabinoid System: The Essential System You’ve Never Heard Of


In case you haven’t heard of the endocannabinoid system, or ECS, there’s no need to feel embarrassed. Back in the 1960’s, the investigators that became interested in the bioactivity of Cannabis eventually isolated many of its active chemicals. It took another 30 years, however, for researchers studying animal models to find a receptor for these ECS chemicals in the brains of rodents, a discovery which opened a whole world of inquiry into the ECS receptors existence and what their physiological purpose is.


We now know that most animals, from fish to birds to mammals, possess an endocannabinoid, and we know that humans not only make their own cannabinoids that interact with this particular system, but we also produce other compounds that interact with the ECS, those of which are observed in many different plants and foods, well beyond the Cannabis species.


As a system of the human body, the ECS isn’t an isolated structural platform like the nervous system or cardiovascular system. Instead, the ECS is a set of receptors widely distributed throughout the body which are activated through a set of ligands we collectively know as endocannabinoids, or endogenous cannabinoids. Both verified receptors are just called CB1 and CB2, although there are others which were proposed. PPAR and TRP channels also mediate some functions. Likewise, you will find just two well-documented endocannabinoids: anadamide and 2-arachidonoyl glycerol, or 2-AG.


Moreover, fundamental to the endocannabinoid system are the enzymes that synthesize and break down the endocannabinoids. Endocannabinoids are believed to be synthesized in an as-needed foundation. The primary enzymes involved are diacylglycerol lipase and N-acyl-phosphatidylethanolamine-phospholipase D, which respectively synthesize 2-AG and anandamide. The two main degrading enzymes are fatty acid amide hydrolase, or FAAH, which breaks down anandamide, and monoacylglycerol lipase, or MAGL, which breaks down 2-AG. The regulation of these two enzymes may increase or decrease the modulation of the ECS.


What is the Function of the ECS?


The ECS is the principal homeostatic regulatory system of the body. It may readily be viewed as the body’s internal adaptogenic system, always working to maintain the balance of a variety of function. Endocannabinoids broadly work as neuromodulators and, as such, they regulate a broad range of bodily processes, from fertility to pain. Some of those better-known functions from the ECS are as follows:


Nervous System


From the central nervous system, or the CNS, general stimulation of the CB1 receptors will inhibit the release of glutamate and GABA. In the CNS, the ECS plays a role in memory formation and learning, promotes neurogenesis in the hippocampus, also regulates neuronal excitability. The ECS also plays a part in the way the brain will react to injury and inflammation. From the spinal cord, the ECS modulates pain signaling and boosts natural analgesia. In the peripheral nervous system, in which CB2 receptors control, the ECS acts primarily in the sympathetic nervous system to regulate functions of the intestinal, urinary, and reproductive tracts.


Stress and Mood


The ECS has multiple impacts on stress reactions and emotional regulation, such as initiation of this bodily response to acute stress and adaptation over time to more long-term emotions, such as fear and anxiety. A healthy working endocannabinoid system is critical to how humans modulate between a satisfying degree of arousal compared to a level that is excessive and unpleasant. The ECS also plays a role in memory formation and possibly especially in the way in which the brain imprints memories from stress or injury. Because the ECS modulates the release of dopamine, noradrenaline, serotonin, and cortisol, it can also widely influence emotional response and behaviors.


Digestive System


The digestive tract is populated with both CB1 and CB2 receptors that regulate several important aspects of GI health. It’s thought that the ECS might be the “missing link” in describing the gut-brain-immune link that plays a significant role in the functional health of the digestive tract. The ECS is a regulator of gut immunity, perhaps by limiting the immune system from destroying healthy flora, and also through the modulation of cytokine signaling. The ECS modulates the natural inflammatory response in the digestive tract, which has important implications for a wide range of health issues. Gastric and general GI motility also appears to be partially governed by the ECS.


Appetite and Metabolism


The ECS, particularly the CB1 receptors, plays a part in appetite, metabolism, and regulation of body fat. Stimulation of the CB1 receptors raises food-seeking behaviour, enhances awareness of smell, also regulates energy balance. Both animals and humans that are overweight have ECS dysregulation that may lead this system to become hyperactive, which contributes to both overeating and reduced energy expenditure. Circulating levels of anandamide and 2-AG have been shown to be elevated in obesity, which might be in part due to decreased production of the FAAH degrading enzyme.


Immune Health and Inflammatory Response


The cells and organs of the immune system are rich with endocannabinoid receptors. Cannabinoid receptors are expressed in the thymus gland, spleen, tonsils, and bone marrow, as well as on T- and B-lymphocytes, macrophages, mast cells, neutrophils, and natural killer cells. The ECS is regarded as the primary driver of immune system balance and homeostasis. Though not all the functions of the ECS from the immune system are understood, the ECS appears to regulate cytokine production and also to have a role in preventing overactivity in the immune system. Inflammation is a natural part of the immune response, and it plays a very normal role in acute insults to the body, including injury and disease ; nonetheless, when it isn’t kept in check it can become chronic and contribute to a cascade of adverse health problems, such as chronic pain. By keeping the immune response in check, the ECS helps to maintain a more balanced inflammatory response through the body.


Other areas of health regulated by the ECS:


  • Bone health
  • Fertility
  • Skin health
  • Arterial and respiratory health
  • Sleep and circadian rhythm


How to best support a healthy ECS is a question many researchers are now trying to answer. Stay tuned for more information on this emerging topic.


In conclusion, chronic pain has been associated with brain changes, including the reduction of gray matter. However, the article above demonstrated that chronic pain can alter the overall structure and function of the brain. Although chronic pain may lead to these, among other health issues, the proper treatment of the patient’s underlying symptoms can reverse brain changes and regulate gray matter. Furthermore, more and more research studies have emerged behind the importance of the endocannabinoid system and it’s function in controlling as well as managing chronic pain and other health issues. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


Curated by Dr. Alex Jimenez


Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




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EXTRA IMPORTANT TOPIC: Low Back Pain Management


MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments


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The Connection Between Anxiety and Inflammation

The Connection Between Anxiety and Inflammation

Anxiety is the most common mental health disorder in the United States, impacting more than 40 million adults. Though some instances can be moderate and short-lived, others may be painfully debilitating, lasting for years, or becoming a chronic problem. While almost anyone can experience temporary anxiety before a variety of events, anxiety is regarded as problematic when it starts to interfere in one way or another with regular, everyday function, including sleep disturbances, social stress, or self-care. Anxiety is connected to a number of lifestyle, health, and nutritional aspects, but understanding the triggers and root causes can result in a more effective treatment approach.


The thought of the existence of an interaction between the immune system and the central nervous system, or CNS, has prompted extensive research attention into the subject of “psychoneuroimmunology”, carrying the area to an intriguing level where new hypotheses are being increasingly tested. So far, the presence of inflammatory reactions and the crucial effects of depression have received most attention. But considering a large socioeconomic impact due to an alarming increase in anxiety disorder patients, there is an urgent research need for better comprehension of the role of inflammation in anxiety and how this relationship can influence one another. The purpose of the article below is to demonstrate the results as well as discuss the outcome measures of a large cohort study conducted in order to determine the possible connection between anxiety disorders and brain inflammation.


Anxiety Disorders and Inflammation in a Large Adult Cohort




Although anxiety disorders, like depression, are increasingly being associated with metabolic and cardiovascular burden, in contrast with depression, the role of inflammation in anxiety has sparsely been examined. This large cohort study examines the association between anxiety disorders and anxiety characteristics with several inflammatory markers. For this purpose, persons (18–65 years) with a current (N=1273) or remitted (N=459) anxiety disorder (generalized anxiety disorder, social phobia, panic disorder, agoraphobia) according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and healthy controls (N=556) were selected from the Netherlands Study of Depression and Anxiety. In addition, severity, duration, age of onset, anxiety subtype and co-morbid depression were assessed. Inflammatory markers included C-reactive protein (CRP), interleukin (IL)-6 and tumor-necrosis factor (TNF)-α. Results show that after adjustment for sociodemographics, lifestyle and disease, elevated levels of CRP were found in men, but not in women, with a current anxiety disorder compared with controls (1.18 (s.e.=1.05) versus 0.98 (s.e.=1.07) mg l−1, P=0.04, Cohen’s d=0.18). No associations were found with IL-6 or TNF-α. Among persons with a current anxiety disorder, those with social phobia, in particular women, had lower levels of CRP and IL-6, whereas highest CRP levels were found in those with an older age of anxiety disorder onset. Especially in persons with an age of onset after 50 years, CRP levels were increased compared with controls (1.95 (s.e.=1.18) versus 1.27 (s.e.=1.05) mg l−1, P=0.01, Cohen’s d=0.37). In conclusion, elevated inflammation is present in men with current anxiety disorders. Immune dysregulation is especially found in persons with a late-onset anxiety disorder, suggesting the existence of a specific late-onset anxiety subtype with a distinct etiology, which could possibly benefit from alternative treatments.


Keywords: anxiety disorder, anxiety characteristics, cohort study, inflammation




Anxiety disorders are among the most prevalent and disabling mental disorders.1, 2 Increasing evidence links anxiety to cardiovascular risk factors and diseases such as atherosclerosis,3 metabolic syndrome,4 and coronary heart disease.5, 6 As low-grade systemic inflammation is clearly involved in the etiology of these somatic conditions,7, 8, 9 it has been hypothesized that inflammation has a role in anxiety disorders and may form the link between anxiety disorders and cardiovascular burden.10 Anxiety disorders are also highly co-morbid with depression,11 which has recurrently been associated with immune dysregulation.12, 13 However, unlike depression, very few studies have investigated the relationship between anxiety disorders and inflammation. Two recent studies have correlated anxiety symptoms with increased cytokine levels, in particular C-reactive protein (CRP).14, 15 With regard to anxiety disorders, research has mainly focused on posttraumatic stress disorder, in which high levels of inflammatory markers have been found.16, 17 Sparse evidence from relatively small clinical studies (n≈100) suggests increased inflammatory activation in patients with panic disorder18 and generalized anxiety disorder,19 which seems to be independent of co-morbid depression.


As there is yet limited research on immune dysregulation and anxiety, one can only speculate on the mechanisms linking these two conditions. Experimentally induced stress has been shown to produce an inflammatory reaction,20 which has led researchers to suggest that it is in particular the experience of acute stress, such as present in panic disorders, causing the high levels of inflammation in anxiety.18 On the other hand, chronic stress may initiate changes in the hypothalamic–pituitary–adrenal (HPA) axis and the immune system, which in turn can trigger depression as well as anxiety.21 These pathways are not independent as the HPA-axis and the immune system are closely linked. Although the HPA axis in normal situations should temper inflammatory reactions, prolonged hyperactivity of the HPA axis could result in blunted anti-inflammatory responses to glucocorticoids resulting in increased inflammation.22, 23 Likewise, it can be hypothesized that immune changes associated with chronic disease and aging,24 could induce similar anxiety-enhancing effects. Although several mechanisms might explain an association between inflammation and anxiety disorders, it can be expected that immune dysregulation is not a general phenomenon in anxiety disorders, but might be restricted to specific subgroups. Whether this anxiety subgroup is defined by the type of disorder, the severity or duration of the disorder, the co-morbidity with depression, or its age of onset, is yet to be examined.


The present study investigates the association between several common anxiety disorders (generalized anxiety disorder, social phobia, panic disorder, agoraphobia) and heightened inflammation (CRP, interleukin (IL)-6, tumor necrosis factor (TNF)-α) in a large sample of persons with current and remitted anxiety disorders and healthy controls. In addition, it will be examined whether specific anxiety characteristics (severity, duration, age of onset, subtype, depression co-morbidity) further discriminate those anxiety patients with elevated inflammation.


Subjects and Methods




The Netherlands Study of Depression and Anxiety (NESDA) includes 2981 persons with and without depressive and anxiety disorders, aged 18–65 years at the baseline assessment in 2004–2007. Participants were recruited from the community (19%), general practice (54%) and secondary mental health care (27%) in order to reflect the broad range and developmental trajectory of psychopathology. Persons with insufficient command of the Dutch language or a primary clinical diagnosis of bipolar disorder, obsessive compulsive disorder, severe substance use disorder, psychotic disorder or organic psychiatric disorder, as reported by themselves or their mental health practitioner, were excluded. A detailed description of the NESDA study design and sampling procedures can be found elsewhere.25 The research protocol was approved by the ethics committee of participating universities and after complete description of the study all respondents provided written informed consent.


During the baseline interview, the presence of anxiety disorder (generalized anxiety disorder, social phobia, panic disorder, agoraphobia) and depressive disorder (major depressive disorder, dysthymia) was established using the Composite Interview Diagnostic Instrument (CIDI) according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria.26 The CIDI is a highly reliable and valid instrument for assessing depressive and anxiety disorders27 and was administered by specially trained research staff. In addition, the severity of anxiety was measured in all participants using the 21-item self-report Beck Anxiety Inventory.28 For the present analyses, we selected persons with a current (that is, past 6 months) or remitted (lifetime, but not current) anxiety disorder and healthy controls. Healthy controls had no lifetime anxiety or depressive disorder and a Beck Anxiety Inventory score below 10, as a score of 10 or above indicates mild anxiety.29 Persons with anxiety disorders were allowed to have a co-morbid depression. Of these 2342 persons, 54 were excluded due to missing information on inflammatory markers, leaving a sample of 2288 persons for the present study. Persons with missing data on inflammation were less often female (55.6 versus 66.9%, P=0.08), but did not differ from included persons in terms of age, years of education and the presence of anxiety disorder.


Anxiety Characteristics


Next to subtype of CIDI anxiety disorder diagnosis (generalized anxiety disorder, social phobia, panic disorder, agoraphobia), anxiety characteristics included anxiety symptoms severity as measured by the Beck Anxiety Inventory, and anxiety symptoms duration, using the Life Chart Interview (LCI).30 The LCI uses a calendar method to determine life events during the past 4 years to refresh memory after which the presence of anxiety and avoidance symptoms during that period is assessed. From this, the per cent of time patients reported anxiety symptoms was computed. The LCI has been used by other large cohort studies31 and event history calendars such as the LCI have been suggested a natural method of choice for retrospective data collection.32 To be able to test whether inflammation was in particular associated with anxiety disorders with a later onset, as we had found for depression,33 age of anxiety onset was derived from the CIDI interview. Last, the presence of a current co-morbid depressive disorder (major depressive disorder, dysthymia) was taken from the CIDI to check whether a possible inflammation–anxiety association was independent of co-morbid depression.


Inflammatory Markers


Markers of inflammation were assessed at the baseline NESDA measurement and included CRP, IL-6 and TNF-α. Fasting blood samples of NESDA participants were obtained in the morning between 0800 and 0900 hours and kept frozen at −80 °C. CRP and IL-6 were assayed at the Clinical Chemistry Department of the VU University Medical Center. High-sensitivity plasma levels of CRP were measured in duplicate by an in-house ELISA based on purified protein and polyclonal anti-CRP antibodies (Dako, Glostrup, Denmark). Intra- and inter-assay coefficients of variation were 5% and 10%, respectively. Plasma IL-6 levels were measured in duplicate by a high sensitivity ELISA (PeliKine CompactTM ELISA, Sanquin, Amsterdam, The Netherlands). Intra- and inter-assay coefficients of variation were 8% and 12%, respectively. Plasma TNF-α levels were assayed in duplicate at Good Biomarker Science, Leiden, The Netherlands, using a high-sensitivity solid phase ELISA (Quantikine® HS Human TNF-α Immunoassay, R&D systems, Minneapolis, MN, USA). Intra- and inter-assay coefficients of variation were 10% and 15%, respectively.




Sociodemographic characteristics included sex, age and years of education. As lifestyle characteristics can be associated with both anxiety and inflammation, smoking status (never, former, current), alcohol intake (<1, 1–14 (women)/1–21 (men), >14 (women)/>21 (men) drinks per week), physical activity (measured with the International Physical Activity Questionnaire34 in MET-minutes (ratio of energy expenditure during activity compared with rest times the number of minutes performing the activity) per week) and body mass index (weight in kilograms divided by height in meters squared) were assessed. In addition, several disease-related covariates were taken into account including the presence of cardiovascular disease (assessed by self-report supported by appropriate medication use (see Vogelzangs et al.6 for detailed description)), the presence of diabetes (fasting plasma glucose level ⩾7.0 mmol l−1 or use of anti-diabetic medication (ATC code A10)) and the number of other self-reported chronic diseases for which persons received treatment (including lung disease, osteoarthritis or rheumatic disease, cancer, ulcer, intestinal problem, liver disease, epilepsy and thyroid gland disease). Medication use was assessed based on drug container inspection of all drugs used in the past month and classified according to the World Health Organization Anatomical Therapeutic Chemical classification.35 Statin use (C10AA, C10B) and use of systemic anti-inflammatory medication (M01A, M01B, A07EB, A07EC) were assessed. Antidepressant medication included regular use (>50% of the time) of selective serotonin reuptake inhibitors (SSRI; N06AB), serotonin-norepinephrine reuptake inhibitors (SNRI; N06AX16, N06AX21), tricyclic antidepressants (TCA; N06AA) and tetracyclic antidepressants (TeCA; N06AX03, N06AX05, N06AX11).


Statistical Analyses


Baseline characteristics were compared between men and women using χ2 test for dichotomous and categorical variables, independent samples t-test for continuous variables, and Mann–Whitney U-test for inflammatory markers. For subsequent analyses, CRP, IL-6 and TNF-α were ln-transformed to normalize distributions, but back-transformed values are presented to enhance interpretation. Associations between anxiety disorders and inflammatory markers were examined using analyses of (co)variance, and (adjusted) means across anxiety groups (no, remitted, current) are presented. To take the effects of potential confounding factors into account, three different models were tested: unadjusted, adjusted for sociodemographics (sex, age, education) and additionally adjusted for lifestyle and disease (smoking status, alcohol intake, physical activity, body mass index, cardiovascular disease, diabetes, number of other chronic diseases, statins, anti-inflammatory medication). As depression has been reported to differentially affect inflammation in men and women,33 a sex-interaction for anxiety disorders is plausible. Therefore, we tested sex-interactions by including a sex × anxiety disorder status interaction term. When present, analyses were repeated sex stratified.


To test whether specific anxiety characteristics were related to elevated inflammation levels, we performed linear regression analyses with inflammatory markers as the outcome for each anxiety characteristic (severity, duration, age of onset, subtype, depression co-morbidity) within the sample of persons with a current anxiety disorder.



Dr. Alex Jimenez’s Insight

Anxiety is a common term which is often used to refer to situational stress or to describe momentary tenseness, however, for individuals living with an anxiety disorder, the symptoms associated with this mental health issue can be debilitating. Anxiety can be caused by a wide variety of factors, including depression and chronic pain, however, research studies have started to hypothesize that another common factor may be the true source as to why some people develop anxiety while other don’t: inflammation. The connection between anxiety and inflammation, as well as depression and inflammation, is becoming increasingly understood. Anxiety isn’t likely caused by inflammation alone, but, measuring inflammatory levels in the body could help determine the best treatment approach for a variety of anxiety disorders and for underlying health issues most commonly associated with inflammation, such as chronic pain.




Mean age of the study sample was 41.8 (s.d.=13.1) years and 66.9% were women. Baseline characteristics of the total sample and for men and women separately are shown in Table 1. Women were younger, more often non-drinkers, had a lower body mass index, less often cardiovascular disease or diabetes and less often used statins than men. In addition, women had higher levels of CRP than men. All covariates were associated with at least one of the inflammation markers, which has been presented elsewhere.33 Pearson’s correlations between inflammatory markers were modest (CRP–IL-6: r=0.31; CRP–TNF-α: r=0.13; IL-6–TNF-α: r=0.12; all P<0.001).


Table 1 Baseline Characteristics


Table 2 shows (adjusted) mean inflammation levels across anxiety groups (controls, remitted, current) based on analyses of (co)variance. In the total sample, higher CRP levels were found in persons with a current anxiety disorder compared with controls in unadjusted analyses (1.36 (s.e.=1.04) versus 1.11 (s.e.=1.05) mg l−1, P=0.001), but after adjustment, there were no associations between anxiety disorders and any of the inflammation markers. However, a significant sex × anxiety disorder interaction was found for CRP (remitted: P=0.57; current: P=0.002). Stratified analyses for CRP showed that even after full adjustment for lifestyle and disease, men with current anxiety disorders had higher levels of CRP compared with controls (1.18 (s.e.=1.05) versus 0.98 (s.e.=1.07) mg l−1, P=0.04, Cohen’s d=0.18). In women, anxiety disorders were not significantly associated with CRP. No sex interactions were found for IL-6 (remitted: P=0.47; current: P=0.40) or TNF-α (remitted: P=0.92; current: P=0.87). As we have previously reported associations between inflammatory levels and antidepressant use within currently depressed persons,33 we checked the influence of antidepressant use on our current results. Higher levels of CRP were found in TCA/TeCA users within our present sample of persons with current anxiety disorders (N=1273; P=0.001). To examine whether the finding of elevated CRP in currently anxious men was independent of TCA/TeCA use, we excluded all men using TCA/TeCA (N=36). Results remained similar, although no longer significant (men with current anxiety disorders versus controls: 1.13 (s.e.=1.05) versus 0.97 (s.e.=1.07) mg l−1, P=0.08, Cohen’s d=0.15). In addition, to reduce the possible confounding effects of acute illness on inflammatory levels at the time of blood draw, all persons who reported having had a cold or fever in the week before blood draw were excluded (N=645), but findings remained alike (men with current anxiety disorders versus controls: 1.09 (s.e.=1.06) versus 0.91 (s.e.=1.07) mg l−1, P=0.06, Cohen’s d=0.19).


Table 2 Adjusted Mean Marker Levels


To investigate whether specific anxiety characteristics (severity, duration, age of onset, subtype, depression co-morbidity) were associated with inflammation, linear regression analyses were performed within the subgroup of persons with current anxiety disorders (N=1273; Table 3). Anxiety severity and duration did not correlate with inflammation. Later age of anxiety disorder onset was associated with elevated CRP levels (β=0.053, P=0.05), even after additional adjustment for TCA/TeCA use (β=0.053, P=0.05). Persons with social phobia had lower levels of CRP (β=−0.053, P=0.04) and IL-6 (β=−0.052, P=0.05) compared with persons with other types of anxiety disorders. The association between social phobia and IL-6 appeared to be specific for women (β=−0.089, P=0.007), but not men (β=0.025, P=0.61; P sex-interaction=0.05). Co-morbid depressive disorder did not further differentiate anxious persons with elevated inflammation.


Table 3 Association of Characteristics


To further illustrate the findings with regard to age of onset, we constructed five age of anxiety disorder onset groups (<20, 20–30, 30–40, 40–50, ⩾50). Figure 1 presents adjusted means of back-transformed CRP levels across controls and age of onset groups based on analysis of covariance. CRP levels were only increased in persons with an age of onset after 50 years (1.95 (s.e.=1.18) versus 1.27 (s.e.=1.05) mg l−1 in controls, P=0.01, Cohen’s d=0.37). For comparison, adjusted mean CRP levels for persons with cardiovascular disease were 1.62 (s.e=1.11), illustrating the clinical relevance of this finding. Excluding persons reporting having had a cold or fever in the week before blood draw (N=513), yielded similar findings (age of onset after 50 years versus controls: 1.73 (s.e.=1.20) versus 1.18 (s.e.=1.05) mg l−1, P=0.04, Cohen’s d=0.35). Results were also similar when the analysis of Figure 1 was restricted to the sample of persons aged 50 years or above (N=589; age of onset after 50 years versus controls: 2.05 (s.e.=1.16) versus 1.35 (s.e.=1.08) mg l−1, P=0.01, Cohen’s d=0.40), underlining that higher CRP in those with an age of onset of 50 years or above was not due to the higher age itself in these persons. Last, in a post-hoc analysis, we directly compared CRP levels between persons with a late versus early onset of anxiety disorder at a cutoff of 50 years, and found significantly higher CRP levels in the late onset group (1.91 (s.e.=1.19) versus 1.35 (s.e.=1.03) mg l−1, P=0.05, Cohen’s d=0.30).


Figure 1 Adjusted Mean CRP Levels




The current study is one of the first and the largest to date to examine the association between anxiety disorders and inflammation. The results show that men with a current anxiety disorder have somewhat increased levels of CRP, even after taking a large set of lifestyle and disease factors into account. Elevated levels of CRP were in particular found in those persons with a late onset of the anxiety disorder.


Our results are in line with the few previous studies examining the relationship between anxiety symptoms or disorders with inflammation. Available evidence until now was limited to assessing anxiety symptoms in the general population,14, 15 confined to specific anxiety disorders in small clinical samples16, 17, 18 or in a heart disease population.19 Our study adds to the literature by showing that elevated CRP levels can be found among several common anxiety disorders in a relatively large cohort of anxious persons and controls, specifically in those with a later onset of the anxiety disorder. CRP levels were in particular elevated among men with anxiety disorders, which is in line with the large-scale study by Liukkonen et al.,15 which showed an association between anxiety symptoms and CRP only in men. In contrast, Pitsavos et al.14 found associations between an anxiety symptoms score and CRP levels in both men and women. Persons included in the study by Pitsavos et al. were much older (18–89 years; mean age 45 years) than those in the study by Liukkonen et al. (all 31 years old), and slightly older than those in the present study (18–65 years; mean age 42 years). Perhaps sex differences become less clear with increasing age, as a result of hormonal changes across the lifespan of women, which affect inflammation levels.36 This could be in line with our finding that CRP levels were elevated in both men and women with a late onset of anxiety disorders.


Our findings with respect to anxiety disorders are also very comparable to our earlier findings regarding depressive disorders and inflammation.33 In that study, we found elevated inflammation, specifically CRP, in depressed men, especially among those with a later depression onset. The effect sizes for CRP in men with a current disorder are also comparable for anxiety (Cohen’s d=0.18) and depressive (Cohen’s d=0.21) disorders. A trend for association with IL-6, which was found for current depressive disorders in men, was not found for current anxiety disorders. Of note is that in persons with an anxiety disorder, a co-morbid depressive disorder was not associated with higher inflammation levels, suggesting that the effects found for anxiety disorders are independent of depression.


In line with our previous findings for current depressive disorders,33 CRP levels were in particular elevated among persons with a later onset of anxiety disorders. In contrast, characteristics that are more often associated with an early age of onset, such as higher severity and longer duration were not associated with increased inflammation. Also, in our sample, women had an earlier age of anxiety disorder onset than men, possibly contributing to the lack of an overall association between anxiety disorders and inflammation in women. Furthermore, we found that CRP levels were lowest among persons with social phobia when compared with other anxiety disorders, in particular in women. Social phobia has been reported to have a much earlier age of onset compared with generalized anxiety disorder or panic disorder,37 which was confirmed in our sample (16.6 versus 25.9 years, P<0.001). To our knowledge, no other study has yet examined the association between social phobia and inflammation. In our study, only nine persons with social phobia had an disorder onset at or after 50 years. Therefore, low inflammation levels in persons with social phobia cannot explain our findings for elevated CRP levels in persons with an age of anxiety disorder onset after 50 years. A recent study by Copeland et al.38 showed that, after taking health-related behaviors into account, generalized anxiety disorder was not associated with elevated CRP levels among children and adolescents. These findings argue against the idea that the inflammation–anxiety association is merely a result of acute stress experienced in anxiety disorders. Although we cannot make inferences about etiology based on our cross-sectional analyses, our current findings are in line with the growing evidence suggesting a distinct etiology involving vascular/metabolic/inflammatory factors in depression or anxiety disorders with an onset later in life.39, 40, 41, 42 Possibly, accumulating psychological and physical stress across the life-span might induce immunological changes24 that eventually results in depression and anxiety.


In our previous report,33 we had found differences in inflammation levels among different classes of antidepressant medication use, which was confirmed for higher CRP in TCA/TeCA users within our present sample of persons with current anxiety disorders. Excluding persons using TCA or TeCA, resulted in a slightly weaker effect size for the association between current anxiety disorder and CRP in men. This might suggest that the elevated CRP levels in men with current anxiety disorders are for some part due to use of TCA/TeCA. On the other hand, persons using TCA/TeCA might represent the more severe cases of anxiety disorders, in which case exclusion of these persons leads to an underestimation of the association. Adjustment for TCA/TeCA use had no effect on our findings for age of anxiety disorder onset, suggesting that late-onset anxiety disorders are independently associated with higher levels of CRP.


What are the clinical implications of our findings? First, our finding of increased CRP levels in particularly those with a late onset of the anxiety disorder might implicate the existence of a specific late-onset anxiety subtype with a distinct etiology. As we have found similar results for depression33 and because depression and anxiety are highly co-morbid disorders,11 this might suggest that depression and anxiety with a late onset share a similar etiology and represent one particular group of disorders, which might be more distinct from other depressive or anxiety disorders, which present earlier in life. As we can only speculate on etiology based on our cross-sectional research, longitudinal research is needed to validate the existence of an etiologically distinct late-onset subtype. Second, if confirmed, a distinct etiology for late-onset disorders implicates different treatment strategies for this subgroup. Perhaps anti-inflammatory medication or lifestyle interventions, such as exercise, for which (some) evidence exists that they normalize immune and metabolic dysregulation,43 as well as improve depressive symptoms to some degree,44, 45 could be beneficial in persons with late onset anxiety disorders as well.


Our study has some important strengths such as a large sample size, assessment of multiple inflammatory markers, clinical diagnoses of several anxiety disorders, adequate adjustment for potential confounders and the ability to examine the role of anxiety characteristics. However, some limitations need to be acknowledged. As our data are cross-sectional, we cannot make any inferences about the direction of the association. Also, although we adjusted for a large set of possible confounding factors, unmeasured poor lifestyle behaviors or health factors may be the explaining link between inflammation and anxiety disorders. For instance, subclinical cardiovascular disease could possibly precede both inflammation and anxiety. On the other hand, subclinical disease may be one pathway of how inflammation leads to anxiety in later life. Longitudinal studies are needed to investigate whether immune dysregulation is a precursor or the result of anxiety, or whether this relationship is bidirectional. Further, like most other studies, we assessed circulating levels of inflammatory markers, which show a high degree of intra-individual variation that could explain the rather modest overall associations between anxiety disorders and inflammation in our study.


In conclusion, our results show that low-grade systemic inflammation is present in men with anxiety disorders. Elevated inflammation is in particular found in both men and women with the onset of anxiety disorder later in life. Longitudinal studies are needed to confirm inflammation as an etiological factor in anxiety disorders with a late-life onset, followed by intervention trials investigating new treatment strategies (for example, anti-inflammatory medication, lifestyle interventions) for this subset of persons with late-onset anxiety.




The infrastructure for the NESDA study ( is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Institute for Quality of Health Care (IQ Healthcare), the Netherlands Institute for Health Services Research (NIVEL) and the Netherlands Institute of Mental Health and Addiction (Trimbos)). NV was supported through a fellowship from the EMGO Institute for Health and Care Research and BP through a VICI grant (NWO grant g1811602). Assaying of inflammatory markers was supported by the Neuroscience Campus Amsterdam.




The authors declare no conflict of interest.


Supporting the Endocannabinoid System | El Paso, TX Chiropractor


Beyond CBD – Supporting the Entire Endocannabinoid System


Every day, more and more health-conscious consumers are starting to take great interest in nutritional supplements that encourage the proper function of the endocannabinoid system, or ECS. Although marijuana and substances derived from or related to marijuana were believed to be the only options to achieve this effect, the focus in the consumer market has largely shifted to a single chemical: cannabidiol.


What’s CBD?


Cannabidiol, commonly known as CBD, is a chemical found in marijuana and in hemp which does interact with the ECS. CBD is just one of a wide group of chemicals known as phytocannabinoids. Cannabidiol has turned into a well-known phytocannabinoid because it is being researched to turn into a new medication and also the benefits demonstrated by CBD have created a lot of attention in this compound.


What Can CBD Do?


Although CBD does perform multiple actions within the human body, its own best-known function in the ECS, or endocannabinoid system, is in its potential to inhibit the activity of the enzyme called fatty acid amide hydrolase, or FAAH. FAAH breaks down anandamide, among the body’s endogenous cannabinoids, which is known to bind to the ECS’s CB1 receptor. The ECS’s CB1 receptor, primarily found in the brain, is the exact same receptor which THC, or tetrahydrocannabinol, binds to. In other words, anandamide, often referred to as “the bliss molecule”, is the human body’s natural THC.


Significantly, however, whereas THC could have negative effects, such as triggering feelings of anxiety, mild hallucinations, dizziness, rapid heart rate, slowed reaction times, and food cravings, the anandamide made naturally by the body appears to exert positive effects on mood, memory, brain function and pain. Because anandamide is normally rapidly broken up by FAAH and because CBD modulates FAAH, Cannabidiol’s primary importance is in the way it can maintain anandamide levels, thus enhancing anandamide’s beneficial impact in the ECS. CBD also binds directly to CB1 and CB2 receptors and has a selection of activity outside of the ECS which can result in its many health benefits.


CBD is a Drug According to the FDA


Because CBD is comparatively safe, lacks the unwanted side effects of THC, and may be easily derived from hemp instead of marijuana, the natural products industry was flooded with products labeled as CBD. However, before this recent phenomenon, a British pharmaceutical company began studying the merits of CBD as an alternate to the drugs and/or medications being utilized to treat resistant childhood epilepsy.


This company, GW Pharmaceuticals (dba Greenwich Biosciences) began pre-clinical operations on CBD in 2007 and contains an investigational new drug called Epidiolex® in late stage clinical trials.


In multiple warning letters in 2017 sent to a number of businesses, the FDA noted ,”If an article, such as CBD, has been approved for investigation as a new drug and/or medication for which substantial clinical investigations have been instituted and for which the existence of such investigations have been made public, then products containing that chemical are outside the definition of a dietary supplement” Since the investigational work completed on CBD as a drug predates the promotion of CBD as a dietary supplement, products containing purified CBD or enriched with CBD are considered by the FDA to be medication and not dietary supplements.


Why Support the Entire ECS?


The ECS is not just a bodily system which completes a single function, as a matter of fact it’s far from it. ECS receptors are widely dispersed throughout the entire body. CBD is an isolated molecule which acts primarily on just a single component of the ECS; i.e., it inhibits the degrading enzyme FAAH, thus allowing the anandamide naturally produced by your endocannabinoid system to possess higher action. But what about the rest of the ECS?


The ECS has at least two major receptors, CB1 and CB2 receptors. And along with anandamide, humans also produce an endocannabinoid called 2-archidonoyl glycerol, or 2-AG, which can be degraded by the enzyme monoacylglycerol lipase, or MAGL. If our intention is to support and nourish the whole ECS, then focusing on a single molecule like CBD that only works on one portion of the ECS might not be the best approach.


Hemp includes heaps of active molecules, including a range of phytocannabinoids. Some such as cannabigerol, or CBG, bind weakly to the CB1 and CB2 receptors. Both CBG and cannabichromene, or CBC, may also help maintain wholesome anandamide levels. The phytocannabinoid beta-caryophyllene, or BCP, that is found in plants like black pepper and clove, binds to the CB2 receptor, which supports the actions of 2AG. Other natural plant compounds, particularly specific terpenoids, have functions which are complementary to that of phytocannabinoids.


The “Entourage” Impact


Although isolated CBD does have a part in overall health and wellness, cannabidiol is not anywhere near the entire process for encouraging the ECS. By using a whole hemp stalk infusion combined with hops, pepper, clove and rosemary that include naturally occurring complementary compounds, hemp oil nourishes the whole ECS, giving a holistic approach to a system that’s often neglected and out of equilibrium in today’s stressful world.


Hemp oil nourishes the entire ECS, giving a holistic approach to a system that’s frequently ignored and out of equilibrium in today’s stressful world. Scientists who research the ECS refer to the approach as the”entourage” effect, and several top researchers believe this approach to be extremely effective in keeping the health and tone of the valuable endocannabinoid system as well as controlling the symptoms of inflammation and anxiety in the human body.


In conclusion, anxiety is one of the most common mental health disorders in the United States. This debilitating health issue can be caused by a variety of factors, however, many research studies have started to demonstrate a connection between anxiety disorders and brain inflammation. According to the article above, stress has been shown to produce an inflammatory reaction, which has led researchers to suggest that anxiety may be causing high levels of inflammation. The outcome measures of te cohort study found that low-grade inflammation is present in individuals with anxiety disorders. Further research studies are still required to confirm the connection between anxiety and inflammation. Furthermore, supporting the function of the endocannabinoid system, or ECS, with the use of CBD or cannabidiol, has been found to have many health benefits, including helping with inflammation and anxiety.  Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


Curated by Dr. Alex Jimenez


Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




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EXTRA IMPORTANT TOPIC: Low Back Pain Management


MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments


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  37. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593–602. [PubMed]
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The Connection Between Inflammation and Depression

The Connection Between Inflammation and Depression

One standard hypothesis of depression is that individuals who are depressed have a lack in monoamine receptors within the body, which in turn leads to reduced levels of neurotransmitters, such as serotonin and norephinephrine, in the brain. But growing evidence supports that at least some kinds of depression might also be linked to continuing low-grade inflammation in the body.

Previous research studies have linked depression with higher level of inflammatory markers when compared with people who aren’t depressed. When individuals are given pro-inflammatory cytokines, they report experiencing more symptoms of depression and anxiety. Chronically high levels of inflammation due to health issues, including chronic pain conditions, are also associated with high rates of depression. Even brain imaging of patients with depression show their brain scans have improved neuroinflammation. If your body is in an inflammatory state, fighting off the common cold or influenza, you can experience symptoms overlapping with depression, including, interrupted sleep, depressed mood, fatigue, foggy-headedness and impaired concentration.

A new study published in The Journal of Clinical Psychiatry supports the assumption that an increase in inflammation might play a role in depression. The huge study analyzed data from 14,275 people who have been interviewed between 2007 and 2012 using the Patient Health Questionnaire, or PHQ-9, to screen for depression and had blood samples drawn. They found that people who had depression had 46 percent greater levels of C-reactive protein, or CRP, a marker of inflammatory disease, in their own blood samples. The research study was just able to establish an association between inflammation and depression but not causation, even though it confirms the association of depression with high levels of inflammation as measured through CRP.

The theory that depression might be viewed as a psychoneuroimmunological disorder may also help explain why attempts to reduce chronic inflammation in the body also enhances and helps prevent depression. The purpose of the article below is to demonstrate as well as thoroughly discuss the role of inflammation in depression. Furthermore, the article will describe the evolutionary imperative to the modern treatment target, including a discussion of phytocannabinoids and their association with the treatment of a variety of health issues, including chronic pain symptoms.

The Role of Inflammation in Depression: from Evolutionary Imperative to Modern Treatment Target


Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.


Depression is a devastating disorder, afflicting up to 10% of the adult population in the United States and representing one of the leading causes of disability worldwide1. Although effective treatments are available, approximately one third of all patients with depression fail to respond to conventional antidepressant therapies2, further contributing to the global burden of the disease. Accordingly, there is a pressing need for new conceptual frameworks for understanding the development of depression to develop better treatments. In this Review, we outline emerging data that point to the immune system — and, in particular, the inflammatory response — as a potentially important contributor to the pathophysiology of depression. We first consider the origins of this notion from an evolutionary perspective, examining the advantages of depressive behaviours in the context of host immune responses to pathogens, predators and conspecifics in ancestral environments. The pivotal role of psychosocial stress in the modern world are then examined, highlighting inflammasome activation and immune cell trafficking as novel mechanisms by which stress-induced inflammatory signals can be transmitted to the brain. Neurotransmitters and neurocircuits that are targets of the inflammatory response are also explored followed by an examination of brain–immune interactions as risk and resilience factors for depression. Finally, these interactions are discussed as a foundation for a new era of therapeutics that target the immune system to treat depression, with a focus on how immunological biomarkers can be used to personalize care.

An Evolutionary Perspective

Data from humans and laboratory animals provide compelling evidence that stress-relevant neurocircuitry and immunity form an integrated system that evolved to protect organisms from a wide range of environmental threats. For example, in the context of a laboratory stressor that entails delivering a speech to a judgmental panel of supposed ‘behavioural experts’, subjects experience a classic ‘fight or flight’ response characterized by increases in heart rate and blood pressure as well as in cortisol and catecholamines. But something else happens within the body that demands a deeper explanation. The stressor activates key inflammatory pathways in peripheral blood mononuclear cells, including activation of the transcription factor nuclear factor–κB (NF-κB), and leads to marked increases in circulating levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6)3,4. In essence, the body mounts an immune response not against a pathogen, but against a threat to the subject’s self-esteem. Moreover, individuals at high risk of developing depression (for example, those who have experienced early-life trauma) show increased inflammatory responses to such laboratory stressors compared with low-risk individuals3. Furthermore, the greater the inflammatory response to a psychosocial stressor, the more probable the subject is to develop depression over the ensuing months5. Two questions immediately present themselves: why should a stimulus devoid of any pathogen induce an inflammatory response, and why should this response promote the development of depression?

Pathogen Host Defense and Depression

No coherent answer to these questions is apparent if immunity is viewed as merely another physiological system within the body. However, when seen against the back-drop of millions of years of co-evolution between mammals and the world of microorganisms and parasites, the human inflammatory bias exposed by laboratory stressors and reflected in the association between immune activation and depression not only makes imminent adaptive sense but also provides insight into a paradox deep within the heart of depression itself; namely, why are the genetic alleles that are most frequently associated with depression so common in the modern gene pool6 (FIG. 1)

Figure 1 Evolutionary Legacy of an Inflammatory Bias | El Paso, TX Chiropractor

Figure 1: Evolutionary legacy of an inflammatory bias. Early evolutionary pressures derived from human interactions with pathogens, predators and human conspecifics (such as rivals) resulted in an inflammatory bias that included an integrated suite of immunological and behavioural responses that conserved energy for fighting infection and healing wounds, while maintaining vigilance against attack. This inflammatory bias is believed to have been held in check during much of human evolution by exposure to minimally pathogenic, tolerogenic organisms in traditional (that is, rural) environments that engendered immunological responses characterized by the induction of regulatory T (TReg) cells, regulatory B (BReg) cells and immunoregulatory M2 macrophages as well as the production of the anti-inflammatory cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGFβ). In modern times, sanitized urban environments of more developed societies are rife with psychological challenges but generally lacking in the types of infectious challenges that were primary sources of morbidity and mortality across most of human evolution. In the absence of traditional immunological checks and balances, the psychological challenges of the modern world instigate ancestral immunological and behavioural repertoires that represent a decided liability, such as high rates of various inflammation-related disorders including depression.

Most adaptive theories of depression have focused on the potential benefits of depressive symptoms for relationships with other humans7. However, recent models have shifted the focus away from relationships with people, to relationships — both detrimental and beneficial — with pathogens6,8. These theories, which are supported by converging evidence (BOX 1), posit that modern humans have inherited a genomic bias towards inflammation because this response — and the depressive symptoms it promotes — enhanced host survival and reproduction in the highly pathogenic environments in which humans evolved6. From this theoretical perspective, at least some of the human vulnerability to depression evolved out of a behavioural repertoire — often referred to as ‘sickness behaviour’ — which promoted host survival in the face of infection. Indeed, it has been hypothesized that the social avoidance and anhedonia characteristic of depression serve to shunt energy resources to fighting infection and wound healing, whereas the hypervigilance characteristic of anxiety disorders, commonly comorbid with depression, subserves protection from attack and subsequent pathogen exposure6,9. Even psychological stress can be understood from this theoretical perspective, given that the vast majority of stressors faced by mammals over evolutionary time boiled down to risks inherent in hunting, being hunted or competing for reproductive access or status. In all of these circumstances, the risk of pathogen invasion — and subsequent death from infection — was greatly increased as a result of wounding. In ancestral environments, the association between stress perception and risk of subsequent wounding was reliable enough that evolution favoured organisms that prepotently activated inflammatory systems in response to a wide array of environmental threats and challenges (including psychosocial stressors), even if this activation was often a ‘false alarm’ (REF. 6).

Pathogen Host Defense Hypothesis of Depression

Several lines of evidence support the notion that the evolution and persistence of depression risk alleles and depressive symptoms in human populations are based on their relevance to ‘pathogen host defence’. This evidence includes:

  • Until recently, approximately 50% of humans died from infectious causes before adulthood, thereby providing strong selective pressure for genetic alleles that enhance host defence124.
  • As a result of strong selective pressure, microbial interactions have been a primary driver of human evolution125.
  • Patterns of inflammatory activation associated with depression promote survival in highly pathogenic environments while increasing mortality in sanitary conditions common in the developed world126.
  • The best replicated risk alleles for depression have pro-inflammatory and/or anti-pathogen protective effects or have been implicated in social behaviours that are likely to reduce pathogen exposure6.
  • Environmental risk factors for the development of depression (that is, psychosocial stress, early life adversity, obesity and processed-food diet) are uniformly pro-inflammatory13.
  • Exposure to pro-inflammatory cytokines produces a sickness syndrome with symptoms that overlap considerably with those seen in depression and that can be ameliorated by treatment with antidepressants23. In addition, the onset of depression is often mistaken with development of sickness, and symptoms
  • associated with infections are often mistaken with the onset of depression127.
  • Chronic cytokine exposure produces a combination of withdrawal and/or energy conservation, anxiety and/or hypervigilance behaviours and emotions that commonly coexist in depression6,9.
  • Symptoms shared by depression and sickness behaviour — such as hyperthermia and reduced iron availability — that lack any conceivable social value have potent anti-pathogen effects6.

The ‘pathogen host defence’ hypothesis of depression may also provide insight into the twofold increase in depression in women compared to men, especially during the reproductive years10. Recent data indicate that women are more sensitive to the behavioural effects of inflammation, demonstrating greater increases in depressed mood than men following endotoxin exposure despite a similar magnitude in cytokine (IL-6 and tumour necrosis factor (TNF)) responses11. Women also exhibit a greater likelihood than men to develop depression in response to standardized doses of interferon-α (IFNα)12. By being more sensitive to inflammation-induced depressive symptoms, women may have benefited more from the protection provided by these symptoms in terms of fighting infection, healing wounds and avoiding subsequent pathogen exposure. Given the potentially negative impact of inflammation on reproductive success (for example, by reducing fertility and impairing lactation), the increase of depressive symptoms in women across evolutionary time may have given women of reproductive age an advantage in coping with and avoiding pathogens and the related inflammation, with increased depressive disorders being the ultimate trade-off in modern times.

Modern Exaggeration of the Inflammatory Bias

The prevalence of autoimmune, allergic and inflammatory diseases has markedly increased in the past 100 years, and rates of these conditions follow a similar upward trajectory in societies transitioning from traditional (that is, rural) to modern (that is, urban) ways of life13. Increasing evidence suggests that this pattern of widespread immune dysregulation may result from disruptions in our relationship and/or contact with a variety of co-evolved, non-lethal immunoregulatory microorganisms and parasites, especially commensals and symbiotes in the microbiotas of the gut, skin and nasal and oral cavities, that were ubiquitous in the natural environments in which humans evolved14. Although widely disparate, these organisms (often referred to as ‘old friends’) share a tendency to reduce inflammation and suppress effector immune cells through the induction of IL-10 and transforming growth factor-β (TGFβ) while promoting the development of anti-inflammatory immune cell populations, such as alternatively activated (also referred to as ‘M2’) macrophages and regulatory T (TReg) cells and regulatory B cells13,14 (FIG. 1). Owing to various cultural changes, including the loss of exposure to microbial diversity with the advent of sanitation practices, modern humans now lack this immunoregulatory input — especially during infancy and childhood. Consequently, we find ourselves in a condition of an exacerbated inflammatory bias, with the particular conditions afflicting any given individual largely the result of genetic predisposition and environmental (for example, psychosocial) exposures13,14, ultimately accounting for the high co-morbidity between depression and autoimmune, allergic and inflammatory disorders13,15.

Inflammation and Depression

Data supporting the role of inflammation in depression are extensive and include findings that span experimental paradigms. Patients with major depressive disorder exhibit all of the cardinal features of an inflammatory response, including increased expression of pro-inflammatory cytokines and their receptors and increased levels of acute-phase reactants, chemokines and soluble adhesion molecules in peripheral blood and cerebrospinal fluid (CSF)16,17. Peripheral blood gene expression profiles consistent with a pro-inflammatory ‘M1’ macrophage phenotype and an over-representation of IL-6, IL-8 and type I IFN-induced signalling pathways have also been described18–20. In addition, increased expression of a variety of innate immune genes and proteins, including IL-1β, IL-6, TNF, Toll-like receptor 3 (TLR3) and TLR4, has been found in post-mortem brain samples from suicide victims that had depression16,18,19,21. Meta-analyses of the literature conclude that peripheral blood IL-1β, IL-6, TNF and C-reactive protein (CRP) are the most reliable biomarkers of inflammation in patients with depression16. Polymorphisms in inflammatory cytokine genes, including those encoding IL-1β, TNF and CRP, have also been associated with depression and its response to treatment22. Moreover, other genes implicated in depression derived from meta-analyses of genome-wide association studies have been linked to the immune response and the response to pathogens including TNF6 (BOX 1). Administration of inflammatory cytokines (for example, IFNα) or their inducers (for example, endotoxin or typhoid vaccination) to otherwise non-depressed individuals causes symptoms of depression23–26. Furthermore, blockade of cytokines, such as TNF, or of inflammatory signalling pathway components, such as cyclooxygenase 2, has been shown to reduce depressive symptoms in patients with medical illnesses, including rheumatoid arthritis, psoriasis and cancer, as well as in patients with major depressive disorder27–29.

As the field has matured, it has become increasingly apparent that inflammatory markers are elevated not only in a subgroup of patients with depression30,31 but also in patients with other neuropsychiatric disorders including anxiety disorders and schizophrenia32,33. Moreover, as described below, it may be more accurate to characterize the impact of inflammation on behaviour as being associated not wholly with depression but with specific symptom dimensions across diagnoses that align with the Research Domain Criteria framework put forth by the National Institute of Mental Health (US Department of Health and Human Services). These symptoms, including positive and negative valence systems, relate to altered motivation and motor activity (anhedonia, fatigue and psychomotor impairment) and increased threat sensitivity (anxiety, arousal and alarm)34. Finally, inflammation has been associated with antidepressant treatment non-responsiveness9,32,35–37. For example, in a recent study, 45% of patients with non-response to conventional antidepressants exhibited a CRP >3 mg L−1 (REF. 30), which is considered indicative of a high level of inflammation on the basis of widely accepted cut-off points38. Of note, however, the percentage of patients with high CRP levels can vary as a function of the population being studied, with higher percentages in patients with depression and treatment resistance, childhood maltreatment, medical illnesses and metabolic syndrome.

Immune Pathways Involved in Depression

Inflammasomes: Stress in Translation

Exposure to psychosocial stress is one of the most robust and reproducible predictors of developing depression in humans and is the primary experimental pathway to depressive-like behaviour in laboratory animals. Thus, the observation that exposure to a psychosocial laboratory stressor can activate an inflammatory response in humans was a major breakthrough in linking inflammation to depression3,4. An important question for the field, however, is by what mechanism is stress translated into inflammation? Although considerable attention has been paid to stress-induced neuroendocrine pathways, including the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS), both of which have immunomodulatory functions39, recent focus has been shifted towards inflammasomes, which may represent a crucial immunological interface between stress and inflammation40 (FIG. 2). Inflammasomes are cytosolic protein complexes that form in myeloid cells in response to pathogenic microorganisms and non-pathogenic or ‘sterile’ stressors. Assembly of the inflammasome leads to activation of caspase 1, which then cleaves the precursor forms of IL-1β and IL-18 into the active cytokines41. Given the relatively sterile nature of psychosocial stress, primary interest has been directed towards understanding how inflammasome activation in depression may be triggered by endogenous damage-associated molecular patterns (DAMPs), including ATP, heat shock proteins (HSPs), uric acid, high mobility group box 1 (HMGB1) and a variety of molecules linked with oxidative stress. Indeed, all of these DAMPs are induced by the psychological and mixed (that is, psychological and physiological) stressors used in animal models of depression42; an effect that is in part mediated by stress-induced release of catecholamines43. Moreover, studies in laboratory animals indicate that chronic mild-stress activates the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, which is well-known to respond to DAMPs44,45. Blockade of NLRP3 reverses stress-induced increases in IL-1β in the peripheral blood and brain, while also abrogating depressive-like behaviour in mice45. Interestingly, NLRP3 inflammasome upregulation and caspase-mediated cleavage of the glucocorticoid receptor can cause resistance to the effects of glucocorticoids, which are among the most potent anti-inflammatory hormones in the body46,47. Stress-induced glucocorticoid resistance is a well-characterized biological abnormality in patients with major depressive disorder and has been associated with increased inflammation48,49.

Figure 2 Transmitting Stress Induced Inflammatory Signals | El Paso, TX Chiropractor

Figure 2: Transmitting stress-induced inflammatory signals to the brain. In the context of psychosocial stress, catecholamines (such as noradrenaline) released by activated sympathetic nervous system fibres stimulate bone marrow production and the release of myeloid cells (for example, monocytes) that enter the periphery where they encounter stress-induced damage-associated molecular patterns (DAMPs), bacteria and bacterial products such as microbial-associated molecular patterns (MAMPs) leaked from the gut. These DAMPs and MAMPs subsequently activate inflammatory signalling pathways such as nuclear factor-κB (NF-κB) and the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. Stimulation of NLRP3 in turn activates caspase 1, which leads to the production of mature interleukin-1β (IL-1β) and IL-18 while also cleaving the glucocorticoid receptor contributing to glucocorticoid resistance. Activation of NF-κB stimulates the release of other pro-inflammatory cytokines including tumour necrosis factor (TNF) and IL-6, which together with IL-1β and IL-18 can access the brain through humoral and neural routes. Psychosocial stress can also lead to the activation of microglia to a M1 pro-inflammatory phenotype, which release CC-chemokine ligand 2 (CCL2) that in turn attracts activated myeloid cells to the brain via a cellular route. Once in the brain, activated macrophages can perpetuate central inflammatory responses. ASC, apoptosis-associated speck-like protein containing a CARD; HMGB1, high mobility group box 1; HSP, heat shock protein; LPS, lipopolysaccharide; TLR, Toll-like receptor.

Supporting the potential role of the NLRP3 inflammasome in human depression are data demonstrating that increased expression of NLRP3 and caspase 1 in peripheral blood mononuclear cells of patients with depression is associated with increased blood concentrations of IL-1β and IL-18, which in turn correlate with depression severity19,50. In addition, DAMPs that are known to activate NLRP3 are increased in patients with mood disorders, with examples including HSPs, reactive oxygen species and other markers of oxidative stress such as xanthine oxidase, peroxides and F2-isoprostanes51–53. Finally, there is increasing interest in the potential role of the gut microbiome in mood regulation, which may be mediated in part by the inflammasomes54. Indeed, non-pathogenic commensal bacteria and derived microbial-associated molecular patterns (MAMPs) in the gut can leak into the peripheral circulation during stress and activate the inflammasomes55, a process mediated by the SNS and catecholamines56 (FIG. 2). Of note, stress-induced increases in IL-1β and IL-18 were attenuated by treating animals with antibiotics or neutralizing lipopolysaccharide (LPS), demonstrating the importance of the composition of the gut microbiome and gut permeability in stress-induced inflammatory responses55. Taken together, these data support the notion that the inflammasome may be a key immunological point of integration of stress-induced danger signals that ultimately drive inflammatory responses relevant to depression.

Transmitting Inflammatory Signals to the Brain

In addition to increased expression of innate immune cytokines and TLRs in post-mortem brain samples from suicide victims with depression, evidence of microglial and astroglial activation in several brain regions including frontal cortex, anterior cingulate cortex (ACC) and thalamus in post-mortem studies of patients with depression have been described57–59,60. Moreover, a well-controlled neuroimaging study using positron emission tomography (PET) and a radiolabelled tracer for the translocator protein (TSPO) — which is overexpressed in activated microglia, macrophages and astrocytes — revealed increased immune activation in the brains of patients with major depressive disorder compared with control subjects61. Of note, not all studies have revealed increased TSPO binding in patients with depression, possibly owing to effects of medication and/or a paucity of subjects with increased inflammation61,62. However, data from endotoxin administration to healthy volunteers indicates that radiolabelled TSPO ligands can readily identify cellular activation in several regions of the brain following a potent peripheral immune stimulus63.

Work from laboratory animal studies has elucidated several pathways through which inflammatory signals can be transmitted from the periphery to the brain (FIG. 2). These data support the idea that inflammatory responses in peripheral tissues may drive inflammation in the brain leading to depression. Much of the early work focused on how inflammatory cytokines, which are relatively large molecules, could cross the blood–brain barrier (BBB) and influence brain function64. Two major pathways have been described: the ‘humoral pathway’, which involves cytokine passage through leaky regions in the BBB, such as the circumventricular organs, and the binding of cytokines to saturable transport molecules on the BBB; and the ‘neural pathway’, which involves the binding of cytokines to peripheral afferent nerve fibres, such as the vagus nerve, that in turn stimulate ascending catecholaminergic fibres in the brain and/or are translated back into central cytokine signals16. More recently, however, attention has shifted to a third pathway referred to as the ‘cellular pathway’, which involves the trafficking of activated immune cells, typically monocytes, to the brain vasculature and parenchyma. The details of this pathway have been elegantly dissected in the context of behavioural changes in mice that are associated with peripherally induced inflammation in the liver65. In these studies, the release of TNF from inflamed liver was found to stimulate microglial cell production of CC-chemokine ligand 2 (CCL2; also known as MCP1) that then attracted monocytes to the brain65. Blockade of monocyte infiltration to the brain using antibodies specific for the adhesion molecules P-selectin and α4 integrin abrogated depressive-like behaviour in this animal model65. Of note, cytokine-stimulated astrocytes also may be major producers of chemokines, such as CCL2 and CXC-chemokine ligand 1 (CXCL1), that attract immune cells to the brain66. The cellular pathway additionally has been elucidated in the context of social defeat stress, whereby GFP-labelled monocytes coalesced in several regions of the brain associated with the detection of threat (for example, amygdala) — an effect that was dependent on CCL2 and was facilitated by mobilization of monocytes from the bone marrow as a result of stress-induced release of catecholamines67,68 (FIG. 2). Of note, initial microglial activation during social defeat stress appeared to be a result of neuronal activation by catecholamines and decreased neuronal production of CX3C-chemokine ligand 1 (CX3CL1; also known as fractalkine), which maintains microglia in a quiescent state67,68. Interestingly, this cellular pathway has received intriguing support from post-mortem analyses of brain tissue from patients with depression who committed suicide that showed increased numbers of perivascular macrophages in association with increased gene expression of allograft inflammatory factor 1 (AIF1, also known as IBA1) and CCL2, which are associated with macrophage activation and cellular trafficking59.

This evidence of peripheral myeloid cells trafficking to the brain during depression constitutes some of the first data supporting the existence of a central inflammatory response in human depression that is primarily driven by peripheral inflammatory events. Moreover, data demonstrate that antibodies that are specific for TNF but which do not cross the BBB, can block stress-induced depression in mice69. These findings indicate that peripheral inflammatory responses not only can provide important clues to the immunological mechanisms of inflammation in depression but also may serve as biomarkers and targets of immune-based therapies for depression. Protein biomarkers such as plasma CRP and TNF as well as immunotherapies targeting individual cytokines such as TNF, IL-1 and IL-6 may be most relevant in this regard. Of note, plasma CRP is a strong response predictor in anti-cytokine therapy70.

Cytokines and Neurotransmitters

Given the pivotal importance of neurotransmission to mood regulation, attention has been paid to the impact of inflammation and inflammatory cytokines on the monoamines serotonin, noradrenaline and dopamine, as well as on the excitatory amino acid glutamate (FIG. 3). There are several pathways through which inflammatory cytokines can lead to reduced synaptic availability of the monoamines, which is believed to be a fundamental mechanism in the pathophysiology of depression71. For example, IL-1β and TNF induction of p38 mitogen-activated protein kinase (MAPK) has been shown to increase the expression and function of the reuptake pumps for serotonin, leading to decreased synaptic availability of serotonin and depressive-like behaviour in laboratory animals72. Through the generation of reactive oxygen and nitrogen species, inflammatory cytokines have also been found to decrease the availability of tetrahydrobiopterin (BH4), a key enzyme co-factor in the synthesis of all monoamines that is highly sensitive to oxidative stress73. Indeed, CSF concentrations of BH4 have been shown to be negatively correlated with CSF levels of IL-6 in patients treated with the inflammatory cytokine IFNα74. In addition, the plasma phenylalanine to tyrosine ratio, an indirect measure of BH4 activity, was shown to correlate with CSF concentrations of dopamine as well as symptoms of depression in IFNα-treated patients74. Activation of the enzyme indoleamine 2,3-dioxygenase (IDO) is also believed to be involved in cytokine-induced neurotransmitter alterations, in part by diverting the metabolism of tryptophan (the primary amino acid precursor of serotonin) into kynurenine, a compound that can be converted into the neurotoxic metabolite quinolinic acid by activated microglia and infiltrating monocytes and macrophages in the brain75,76. Of note, increased levels of quinolinic acid have been found in microglia in the ACC of suicide victims who suffered from depression77. Quinolinic acid directly activates receptors for glutamate (that is, N-methyl-D-aspartate (NMDA) receptors) while also stimulating glutamate release and blocking glutamate reuptake by astrocytes78. The effects of quinolinic acid on glutamate converge with the direct effects of pro-inflammatory cytokines on glutamate metabolism that include decreasing the expression of astrocyte glutamate reuptake pumps and stimulating astrocytic glutamate release79, ultimately contributing to excessive glutamate both within and outside the synapse. The binding of glutamate to extrasynaptic NMDA receptors leads to increased excitotoxicity and decreased production of brain-derived neurotrophic factor (BDNF)80. BDNF fosters neurogenesis, an important prerequisite for an antidepressant response, and has been shown to be reduced by IL-1β and TNF and their downstream signalling pathways including NF-κB in stress-induced animal models of depression81,82. Increased levels of glutamate in the basal ganglia and dorsal ACC (dACC) — as measured by magnetic resonance spectroscopy (MRS) — have been described in patients receiving IFNα, and higher levels of glutamate correlated with an increase in depressive symptoms83. More recent data indicate that in patients with depression, increased inflammation as reflected by a CRP >3 mg L−1 is also associated with increased basal ganglia glutamate (compared with patients with a CRP <1 mg L−1) that correlated with anhedonia and decreased psychomotor speed84. Interestingly, blocking glutamate receptors with ketamine or inhibiting IDO activity protects mice from LPS- or stress-induced depressive-like behaviour but leaves the inflammatory response intact85,86. These results indicate that increased activation of glutamate receptors by glutamate and/or quinolinic acid may be a common pathway through which inflammation causes depressive-like behaviour, suggesting that drugs that block glutamate receptor signalling and/or activation of the IDO pathway and its downstream metabolites might have unique applicability to patients with depression and increased inflammation. Importantly, conventional antidepressant medications act by increasing synaptic availability of monoamines and increasing neurogenesis through induction of BDNF87. Therefore, cytokines such as IL-1β and TNF serve to undermine these activities as they decrease the synaptic availability of monoamines while also decreasing BDNF and increasing extracellular glutamate, which is not a target of conventional antidepressant therapy. These cytokine-driven effects may explain the observations that increased inflammation is associated with less robust antidepressant treatment responses and that treatment-resistant patients exhibit increased inflammatory markers88.

Figure 3 Cytokine Targets in the Brain | El Paso, TX Chiropractor

Figure 3: Cytokine targets in the brain: neurotransmitters and neurocircuits. Once in the brain, the inflammatory response can affect metabolic and molecular pathways influencing neurotransmitter systems that can ultimately affect neurocircuits that regulate behaviour, especially behaviours relevant to decreased motivation (anhedonia), avoidance and alarm (anxiety), which characterize several neuropsychiatric disorders including depression. On a molecular level, pro-inflammatory cytokines including type I and II interferons (IFNs), interleukin-1β (IL-1β) and tumour necrosis factor (TNF) can reduce the availability of monoamines — serotonin (5-HT), dopamine (DA) and noradrenaline (NE) — by increasing the expression and function of the presynaptic reuptake pumps (transporters) for 5-HT, DA and NE through activation of mitogen-activated protein kinase (MAPK) pathways and by reducing monoamine synthesis through decreasing enzymatic co-factors such as tetrahydrobiopterin (BH4), which is highly sensitive to cytokine-induced oxidative stress and is involved in the production of nitric oxide (NO) by NO synthase (NOS). Many cytokines, including IFNγ, IL-1β and TNF, can also decrease relevant monoamine precursors by activating the enzyme indoleamine 2,3-dioxygenase (IDO), which breaks down tryptophan, the primary precursor for serotonin, into kynurenine. Activated microglia can convert kynurenine into quinolinic acid (QUIN), which binds to the N-methyl-D-aspartate receptor (NMDAR), a glutamate (Glu) receptor, and together with cytokine-induced reduction in astrocytic Glu reuptake and stimulation of astrocyte Glu release, in part by induction of reactive oxygen species (ROS) and reactive nitrogen species (RNS), can lead to excessive Glu, an excitatory amino acid neurotransmitter. Excessive Glu, especially when binding to extrasynaptic NMDARs, can in turn lead to decreased brain-derived neurotrophic factor (BDNF) and excitotoxicity. Inflammation effects on growth factors such as BDNF in the dentate gyrus of the hippocampus can also affect fundamental aspects of neuronal integrity including neurogenesis, long-term potentiation and dendritic sprouting, ultimately affecting learning and memory. Cytokine effects on neurotransmitter systems, especially DA, can inhibit several aspects of reward motivation and anhedonia in corticostriatal circuits involving the basal ganglia, ventromedial prefrontal cortex (vmPFC) and subgenual and dorsal anterior cingulate cortex (sgACC and dACC, respectively), while also activating circuits regulating anxiety, arousal, alarm and fear including the amygdala, hippocampus, dACC and insula. BH2, dihydrobiopterin; DAT, dopamine transporter; EAAT2, excitatory amino acid transporter 2; NET, noradrenaline transporter; NF-κB, nuclear factor-κB; SERT, serotonin transporter; TH, tyrosine hydroxylase; TPH, tryptophan hydroxylase. Copyrighted 2015. Advanstar. 120580:1115BN.

Effects of Inflammation on Neurocircuitry

Given the impact of cytokines on neurotransmitter systems that regulate the functional activity of neurocircuits throughout the brain, it is no surprise that neuroimaging studies have revealed cytokine-induced alterations in regional brain activity. Consistent with the evolutionary advantages of the partnership between the brain and the immune system, primary cytokine targets in the CNS involve those brain regions that regulate motivation and motor activity (promoting social avoidance and energy conservation) as well as arousal, anxiety and alarm (promoting hypervigilance and protection against attack) (FIG. 3).

Dopamine has a fundamental role in motivation and motor activity, and cytokines have been shown to decrease the release of dopamine in the basal ganglia in association with decreased effort-based motivation as well as reduced activation of reward circuitry in the basal ganglia, in particular the ventral striatum89–91. Inflammatory stimuli have been associated with reductions in reward responsiveness in the striatum across many neuroimaging platforms, demonstrating the validity and reproducibility of these cytokine-mediated effects on the brain in otherwise non-depressed individuals peripherally administered IFNα, endotoxin or typhoid vaccination and imaged by PET, functional magnetic resonance imaging (fMRI), MRS and quantitative magnetization transfer imaging83,89,90,92,93. Interestingly, recent fMRI studies suggest that inflammation-induced decreases in responsiveness to positive reward are also associated with increased sensitivity to aversive stimuli (that is, negative reinforcement) and reduced responsiveness to novelty in the substantia nigra (which is another dopamine-rich structure in the basal ganglia)93,94. Typhoid vaccination has also been shown to activate the subgenual ACC (sgACC), a brain region implicated in depression, and to decrease connectivity of the sgACC with the ventral striatum, an effect modulated by plasma IL-6 (REF. 26). These fMRI findings have recently been extended to patients with depression whose increased plasma CRP level is associated with decreased functional connectivity within reward-related circuits including the ventral striatum and the ventromedial prefrontal cortex that, in turn, mediates the relationship between CRP and anhedonia95. Indeed, patients with depression with a CRP >3 mg L−1 had little, if any, connectivity within reward-related circuits as measured by fMRI, whereas connectivity in patients with depression with a CRP <1 mg L−1 was similar to healthy controls95. Taken together, these data support the notion that the effect of cytokines on the brain in general and dopaminergic pathways in particular lead to a state of decreased motivation or anhedonia, which is a core symptom of depression.

fMRI studies have demonstrated that increased inflammation is also associated with increased activation of threat- and anxiety-related neurocircuitry, including the dACC as well as the insula and amygdala26,96,97. Of note, the dACC and amygdala are regions that exhibit increased activity in patients with high-trait anxiety and neuroticism98, conditions that often accompany depression and are associated with increased inflammation. For example, increased concentrations of oral IL-6 and soluble TNF receptor 2 (also known as TNFRSF1B) in response to a public speaking stressor was significantly correlated with the response of the dACC to a social rejection task97. In addition, increased oral IL-6 expression in response to a social evaluation stressor was significantly correlated with activation of the amygdala, with subjects who exhibited the highest IL-6 responses to stress demonstrating the greatest connectivity within threat circuitry, including the amygdala and the dorsomedial prefrontal cortex, as measured by fMRI99. Interestingly, these data are consistent with the trafficking of monocytes to the amygdala during social defeat stress in mice68.

Risk and Resilience

Increased Inflammation and the Risk for Depression

Consistent with the emerging recognition that inflammation may cause depression in certain subgroups of individuals, epidemiological studies on large community samples — as well as smaller samples of medically ill individuals — have demonstrated that increased inflammation serves as a risk factor for the future development of depression. For example, increased peripheral blood CRP and IL-6 concentrations were found to significantly predict depressive symptoms after 12 years of follow up in the Whitehall II study of over 3,000 individuals, whereas no association was found between the presence of depressive symptoms and subsequent blood CRP and IL-6 levels100. Similar findings were reported in the English Longitudinal Study of Ageing in which a CRP >3 mg L−1 predicted depressive symptoms and not vice versa101. Of note, however, some studies have found no longitudinal relationship between depression and inflammation, and others have found that depression leads to increased inflammation102. Other factors known to be associated with increased peripheral inflammation, including childhood and adult trauma, have also been shown to be predictive of a greater risk of developing depression103,104.

Both genetic and epigenetic mechanisms may explain why childhood or adult traumas can contribute to exaggerated or persistent inflammation and, ultimately, depression. For example, polymorphisms in CRP were associated not only with increased peripheral blood concentrations of CRP but also with symptoms of post-traumatic stress disorder, especially heightened arousal, in individuals exposed to civilian trauma32. Moreover, gene–environment interactions have been found to influence depression severity in response to chronic interpersonal stress: individuals carrying polymorphisms in IL1B that are associated with higher expression of peripheral IL-1β exhibited more severe depressive symptoms in the context of interpersonal stress than individuals without the IL1B risk allele105. Similarly, mice in which peripheral blood leukocytes produced high concentrations of LPS-induced IL-6 ex vivo before stress exposure showed decreased social exploration after social defeat stress, whereas mice that produced low levels of IL-6 before stress exposure exhibited no behavioural effects in response to social defeat88. Of note, adoptive transfer of bone marrow progenitor cells from mice producing high levels of IL-6 ex vivo to mice that produced low levels of IL-6 made these formerly stress-resilient animals sensitive to the depressive effects of social defeat88.

Epigenetic changes in genes related to inflammation may also affect the risk for depression and anxiety in the context of psychosocial stress. Indeed, the well-documented association of childhood trauma with increased inflammation is linked to stress-induced epigenetic changes in FKBP5, a gene implicated in the development of depression and anxiety as well as in the sensitivity to glucocorticoids106. Allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements of FKBP5 were found to be associated with decreased sensitivity of peripheral blood immune cells to the inhibitory effects of the synthetic glucocorticoid dexamethasone on LPS-induced production of IL-6 in vitro106. Of note, decreased activation of glucocorticoid receptor-responsive genes in association with increased activation of genes regulated by NF-κB has been found to be a ‘fingerprint’ of the effects of chronic stress in several studies examining a variety of psychosocial stressors39,107.

T Cells and Resilience to Depression

Some of the most intriguing data regarding the role of the immune system in depression come from studies showing that T cells may protect against stress and depression in laboratory animals. For example, the adoptive transfer of T cells from animals exposed to chronic social defeat stress led to an antidepressant behavioural phenotype in stress-naive mice, which was associated with decreased pro-inflammatory cytokines in serum, a shift towards a neuroprotective M2 phenotype in microglia and increased neurogenesis in the hippocampus108. Similar results have been reported following acute stress in mice, in which effector T cell migration to the choroid plexus as a result of glucocorticoid induction of intercellular adhesion molecule 1 (ICAM1) expression in the choroid plexus was associated with reduced anxiety-like behaviour109. Mice with impaired release of glucocorticoids in response to stress were anxiety prone109. Immunization of anxiety-prone animals with a CNS-specific antigen restored T cell trafficking to the brain during stress and reversed anxiety-like behaviour in association with increased neurogenesis109. Immunization with a CNS-specific antigen also blocked stress-induced depression in mice110. The mechanism by which T cells influence resilience is believed to be related to their production of IL-4 within the meningeal space. Through as yet uncharacterized pathways, IL-4 then stimulates astrocytes to produce BDNF, and also promotes the conversion of meningeal monocytes and macrophages from a pro-inflammatory M1 phenotype to a less inflammatory M2 phenotype111. The movement of T cells throughout the brain, including the meningeal space, has become an area of special interest with the recent description of a brain lymphatic system that heretofore had gone unrecognized112. Data also indicate that TReg cells may have a role in reducing inflammation and supporting neuronal integrity during stress113. Similar reports have characterized T cells that are activated by vagal nerve stimulation to produce acetylcholine, which can inhibit NF-κB activation by binding to the α7 subunit of the nicotinic acetylcholine receptor114.

Relevant to depression, however, peripheral T cell trafficking in response to glucocorticoids has been shown to be impaired in patients with depression, possibly owing to glucocorticoid resistance as a result of genetically mediated (for example, FKBP5) or inflammasome-mediated mechanisms targeting the glucocorticoid receptor46,115. In addition, inflammatory cytokines and their signalling pathways, including p38 MAPK, have direct inhibitory effects on glucocorticoid receptor function116. Moreover, patients with depression have been shown to have increased numbers of peripheral blood myeloid-derived suppressor cells, which inhibit T cell function117. Of note, activation of the NLRP3 inflammasome leads to increased accumulation of myeloid-derived suppressor cells118. Decreased numbers of peripheral blood TReg cells and reduced concentrations of anti-inflammatory cytokines in the blood, including TGFβ and IL-10, have also been reported in depression119. Thus, it appears that patients with depression may have impairments in neuroprotective and anti-inflammatory T cell responses.

These findings suggest that therapies that boost such T cell responses could be used in patients with depression. Examples include immunization strategies (with CNS antigens as discussed above) that attract T cells to the brain or administration of bacteria, such as Mycobacterium vaccae, or parasites that stimulate TReg cell responses or T cell production of IL-4 (REFS 14,109,110,120). Indeed, colonization of pregnant dams with helminths attenuated the increase of hippocampal IL-1β in neonatal rats infected with bacteria and protected these animals from the subsequent development of microglial sensitization and cognitive dysfunction in adulthood. This effect was associated with increased ex vivo production of IL-4 and decreased production of IL-1β and TNF by splenic macrophages in response to LPS stimulation120. Finally, vagus nerve stimulation could be used to induce anti-inflammatory acetylcholine-producing T cells121. Although many strategies exist to activate anti-inflammatory T cell responses including the induction of TReg cells by administration of mesenchymal stem cells122, the majority of the approaches discussed above have proof-of-concept data in animal models of depression. Nevertheless, the clinical relevance of these approaches has yet to be determined by randomized clinical trials in patients with depression.

Translational Considerations

Our increasing understanding of how inflammatory processes contribute to depression, combined with the growing frustration over the lack of discovery of new antidepressants, have stimulated interest in the possibility that various classes of anti-inflammatory medications or other anti-inflammatory strategies (as discussed above) may hold promise as novel ‘all-purpose’ antidepressants. Unfortunately, it appears that anti-inflammatory agents may only demonstrate effective antidepressant activity in subgroups of patients who show evidence of increased peripheral inflammation, for example individuals with medical conditions including osteoarthritis and psoriasis that are characterized by increased levels of peripheral inflammation and patients with depression with increased inflammatory markers29,30. Moreover, in patients with depression who do not show elevated peripheral levels of inflammation, anti-inflammatory treatments may actually impair placebo responses that contribute to the effectiveness of all known antidepressant modalities123. In the only study to date examining the antidepressant effect of a cytokine antagonist in medically healthy adults with treatment-resistant depression, post hoc analysis revealed a dose-response relationship between baseline levels of peripheral inflammation and subsequent antidepressant response to the TNF inhibitor infliximab30. In patients with baseline plasma CRP concentrations ≥5 mg L−1, infliximab outperformed placebo with an effect size similar to that observed in studies of standard antidepressants. Patients with a CRP >3 mg L−1, the standard cut-off for high inflammation, also exhibited separation from placebo. Of note, this latter finding along with data demonstrating the relevance of a CRP >3 mg L−1 to altered reward circuitry and glutamate metabolism in depression as well as the prediction of subsequent depressive episodes (described above) aligns well with other diseases in which a CRP >3 mg L−1 is relevant to prediction and pathology including cardiovascular disease and diabetes. These data suggest that the cut-off for high inflammation in depression may be consistent with other disorders (BOX 2). Importantly, however, in patients with lower levels of inflammation, blockade of TNF with infliximab actually impaired the placebo response30, suggesting that anti-inflammatory treatments in patients without inflammation may be detrimental, highlighting the growing recognition that the immune system has an important role in several processes central to neuronal integrity.

Guidelines for Anti-Inflammatory Clinical Trials in Depression

Based on the animal and human literature on the effects of cytokines on the brain, the following guidelines can inform clinical trials designed to test the cytokine hypothesis of depression.

  • Inflammation only occurs in subgroups of patients with depression30. Clinical trials should enrich for patient populations with evidence of increased inflammation, particularly those identified by a C-reactive protein (CRP) >3 mg L−1, which has been shown to characterize patients with depression with altered reward circuitry and increased basal ganglia glutamate, as well as those who have shown a response to anti-cytokine therapy30,84,95.
  • Anti-inflammatory drugs may harm patients without increased inflammation. Inflammatory cytokines and the innate immune response have pivotal roles in synaptic plasticity, neurogenesis, long-term potentiation (which is a fundamental process in learning and memory) and possibly antidepressant response123,128.
  • Primary behavioural outcome variables should include measures of anhedonia and anxiety. Neuroimaging studies coupled with studies administering a variety of inflammatory stimuli, including the inflammatory cytokine interferon-α, endotoxin and typhoid vaccination, have revealed that inflammation targets neurocircuits in the brain that regulate motivation and reward as well as anxiety, arousal and alarm35. In addition, these symptoms have been shown to respond to anti-cytokine therapy in limited studies.
  • Drugs that specifically target inflammatory cytokines and/or their signalling pathways are preferable. The majority of clinical trials to date have used anti-inflammatory drugs (non-steroidal anti-inflammatory agents and minocycline, a tetracycline antibiotic) that have several off-target effects making the extant data relevant to testing the cytokine hypothesis of depression difficult to interpret31.
  • Target engagement must be established in the periphery and ultimately the brain. Protein and gene expression markers of inflammation in the peripheral blood can serve as relevant proxies for inflammation in the brain129, especially given evidence of trafficking of activated peripheral immune cells to the brain in stress-induced animal models of depression. Relevant therapeutic interventions should decrease peripheral inflammatory markers in concert with improvement of specific depressive symptoms. Translocator protein neuroimaging ligands may ultimately serve as direct measures of neuroinflammation and its inhibition by anti-inflammatory therapies in future clinical trials61.

We conclude by offering the balanced perspective that anti-inflammatory therapies are unlikely to be all-purpose antidepressants. Perhaps we only think of standard antidepressants as all-purpose agents because we have never succeeded in developing predictive biomarkers that would reliably inform us of who will respond to any given agent. If so, then we view these agents as all-purpose, not because it is true but out of hope and ignorance. Thus, instead of being a negative, perhaps the finding that baseline inflammatory biomarkers such as CRP can predict subsequent symptomatic response to anti-inflammatory strategies is, in fact, the most positive development thus far in our quest to understand how the immune system might be harnessed to improve the treatment of depression.


Dr. Alex Jimenez’s Insight

When you catch a cold, certain symptoms are triggered by inflammatory markers released in response to illness. While sneezing, coughing and a sore throat serve as the most “obvious” signs you may be sick, what truly keeps you in bed when you have a cold is the accompanying fatigue, inattentiveness, loss of appetite, change in sleep pattern, heightened perception of pain and apathetic withdrawal. These symptoms are similar to the wide array of symptoms that define depression. Many research studies have demonstrated that depression may occur due to an inflammatory response to illness, just as in the case of a common cold. The connection between inflammation and depression has long been argued among healthcare professionals and researchers, where new evidence could open the doors to additional treatment approaches which could help better manage this debilitation health issue.


In ancestral times, integration of inflammatory responses and behaviours of avoidance and alarm provided an evolutionary advantage in managing the microbial world. In the absence of the temporizing influence of commensal organisms that were rife in environments in which humans evolved, the inflammatory bias of the human species in the civilized world has been increasingly engaged in the complex world of psychosocial interactions and the inevitable stress it engenders. Responding to these sterile insults with activation of the inflammasome and mobilization of myeloid cells to the brain, the resultant release of inflammatory cytokines impinges on neurotransmitters and neurocircuits to lead to behaviours that are poorly suited for functioning in modern society. This inevitability of our evolutionary past is apparent in the high rates of depression that are seen in society today. There is also an increasing recognition of mechanisms of resilience that derive from our emerging understanding of the neuroprotective effects of a variety of T cell responses ranging from effector T cells that produce IL-4 to TReg cells with anti-inflammatory properties. A better understanding of these neuroprotective pathways and of the inflammatory mechanisms — from inflammasome activation to cell trafficking to the brain — that operate in patients with depression may lead to the development of novel anti-depressant therapies.

For glossary and footnotes visit:

Understanding the Phytocannabinoids

The discovery of the body’s endocannabinoid system, or ECS, in the 1980s provided researchers a totally new outlook on the chemicals in marijuana and hemp that had formerly been identified 40 years earlier, including how these chemicals interacted with and acted on a prevalent regulatory system in the human body. The title given to those chemicals was phytocannabinoids, meaning “phyto” for plantlife. Over 80 phytocannabinoids are identified in marijuana and hemp. The psychoactive phytocannabinoid in marijuana, tetrahydrocannabinol, or THC, represents only one of many phytocannabinoids now being extensively studied for its numerous health benefits. The more science learns about the far-reaching effects of the ECS in encouraging brain health, in improving immune function, in keeping a healthy inflammatory response, and in promoting GI health, fertility, bone health, and much more, the more interest there is in locating these phytocannabinoids in nature and learning how they affect human health. Due to this widespread interest, phytocannabinoids have been identified in many plants outside the Cannabis species; for instance, plants such as clove, black pepper, Echinacea, ginseng, broccoli, and carrots, all contain phytocannabinoids.

Phytocannabinoids in Hemp

Although the majority of people have now heard of cannabadiol (CBD), it’s only one of lots of the constituents in hemp which interact with the ECS. Two other notable phytocannabinoids include:

Cannabichromene (CBC)

CBC was first analyzed in the 1980s as it was found to modulate a normal inflammatory response in a rat model. More recently CBC has been shown to promote brain health, skin health, and preserve normal motility in the digestive tract.

Cannabigerol (CBG)

CBG has been increasingly studied for its capacity to support nervous system health. CBG has multiple roles from the ECS, such as inhibiting the reuptake of anandamide, an extremely beneficial endocannabinoid we make within our own bodies. CBG might also provide help for immune function, skin health, and a positive disposition. CBG is typically found in much higher concentrations in industrial hemp than in marijuana.

Phytocannabinoids in Other Crops

There is also ongoing research in discovering phytocannabionids in many other plants. Some of them include:

Beta-Caryophyllene (BCP)

Although BCP is located from the flowers and leaves of hemp, since just the hemp stalk is used in nutritional supplements, even BCP content is lost. But, BCP is contained in many other plants, like cloves and black pepper. BCP binds to the CB2 cannabinoid receptor in the body, and by doing so it helps maintain a healthy inflammatory reaction and promotes the overall health of the digestive tract, skin, and liver disease.

Diindolylmethane (DIM)

DIM is a compound we create in our bodies when we eat cruciferous vegetables like broccoli, cauliflower, cabbage, and Brussels sprouts. DIM is also a readily available nutritional supplement. Much like beta-caryophyllene, DIM binds to the CB2 cannabinoid receptor. Since the immune system is rich with CB2 receptors, this may clarify the immune-supportive health benefits of the foods.


Located in the familiar herb Echinacea, alkylamides are also drawing interest for their part in the ECS. These unique compounds act on the CB2 cannabinoid receptor to regulate cytokine synthesis and also to support immune function. This activity probably helps clarify some of the common uses of Echinacea.


Found in carrots, celery, parsley, and Panax ginseng, this interesting compound may not be one need to touch. Falcarinol binds to the CB1 cannabinoid receptor which also has the reverse effect of anandamide, that the cannabinoid our bodies make that binds to the receptor. Because of this trend, falcarinol can cause an allergic skin reaction that’s regarded because it prevents our very own ECS from modulating local inflammation.


This phytocannabinoid, found from the Kava plant (Piper methysticum), binds to CB1 cannabinoid receptors and also acts on GABA receptors in the nervous system. Although yangonin appears to promote relaxation and modulate responses to stress, it might also be bad for the liver.

Understanding of the endocannabinoid system is growing quickly. As this knowledge does enlarge, science will continue to find more phytocannabinoids in plants and foods that are useful in supporting health in many ways.

In conclusion, many research studies have found a connection between inflammatory pathways and neurocircuits in the brain which can lead to a variety of behavioral responses, such as avoidance and alarm, however, growing evidence has demonstrated that chronic inflammation can lead to depression. Depression is a debilitating disorder which amounts to one of the leading causes of disability worldwide. The article above describes the connection between inflammation and depression. New insights on the results of the research studies could open the possibilities for new treatments to treat depression, among other associated health issues. Moreover, understanding the role of phytocannabinoids in the human body can function as another treatment approach for inflammation associated with depression.  Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .

Curated by Dr. Alex Jimenez


Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.

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EXTRA IMPORTANT TOPIC: Low Back Pain Management

MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments


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How the Nervous System Processes Chronic Pain

How the Nervous System Processes Chronic Pain

How does your brain know when you are experiencing pain? How does it know the difference between the soft touch of a feather and a needle prick? And, how does that information get to your body in time to respond? How can acute pain become chronic pain? These aren’t simple answers, but with a small explanation about how the nervous system works, you need to have the ability to comprehend the basics before considering any type of treatment approach for chronic pain.


Your nervous system is made up of 2 main parts: the brain and the spinal cord, which unite to form the central nervous system; and both sensory and motor nerves, that form the peripheral nervous system. The names make it easy to picture: the brain and spinal cord are the hubs, whereas the sensory and motor nerves stretch out to provide access to all areas of the body. Put simply, sensory nerves send impulses about what is going on in our environment to the brain through the spinal cord. The brain sends data back into the motor nerves, which help us execute tasks. It is like using an extremely complicated inbox and outbox for everything. The purpose of the article below is to demonstrate the process by which the human nervous system processes chronic pain.


Pain Processing in the Human Nervous System: A Selective Review of Nociceptive and Biobehavioral Pathways




This selective review discusses the psychobiological mediation of nociception and pain. Summarizing literature from physiology and neuroscience, first an overview of the neuroanatomic and neurochemical systems underpinning pain perception and modulation is provided. Second, findings from psychological science are used to elucidate cognitive, emotional, and behavioral factors central to the pain experience. This review has implications for clinical practice with patients suffering from chronic pain, and provides strong rationale for assessing and treating pain from a biopsychosocial perspective.


Keywords: pain, nociception, neurobiology, autonomic, cognitive, affective




Pain is a complex, biopsychosocial phenomenon that arises from the interaction of multiple neuroanatomic and neurochemical systems with a number of cognitive and affective processes. The International Association for the Study of Pain has offered the following definition of pain: “Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”[1] (p210) Thus, pain has sensory and affective components, as well as a cognitive component reflected in the anticipation of future harm. The purpose of the following review is to integrate the literature on the neurobiological pathways within the central, autonomic, and peripheral nervous systems that mediate pain processing, and discuss how psychological factors interact with physiology to modulate the experience of pain.


Functional Neuroanatomy and Neurochemistry of Pain


Pain Processing in the Nervous System


When noxious stimuli impinge upon the body from external or internal sources, information regarding the damaging impact of these stimuli on bodily tissues is transduced through neural pathways and transmitted through the peripheral nervous system to the central and autonomic nervous systems. This form of information processing is known as nociception. Nociception is the process by which information about actual tissue damage (or the potential for such damage, should the noxious stimulus continue to be applied) is relayed to the brain. Nociception is mediated by specialized receptors known as nociceptors that are attached to thin myelinated Aδ and unmyelinated C fibers, which terminate in the dorsal horn of the spine. Sufficiently intense mechanical stimulation (such as stretching, cutting, or pinching), intense warming of the skin, or exposure to noxious chemicals can activate nociceptors.[2] In turn, activation of nociceptors is modulated by inflammatory and bio-molecular influences in the local extracellular environment.[3] Although under most circumstances transmission of nociceptive information results in pain perception, many physicians and patients are unaware that nociception is dissociable from the experience of pain. In other words, nociception can occur in the absence of awareness of pain, and pain can occur in the absence of measurably noxious stimuli. This phenomenon is observable in instances of massive trauma (such as that which might be incurred by a motor vehicle accident) when victims exhibit a stoic painless state despite severe injury, and conversely, when individuals with functional pain syndromes report considerable anguish in spite of having no observable tissue damage.


In contrast, perception of pain occurs when stimulation of nociceptors is intense enough to activate Aδ fibers, resulting in a subjective experience of a sharp, prickling pain.[4] As stimulus strength increases, C fibers are recruited, and the individual experiences an intense, burning pain that continues after the cessation of the stimulus. These types of experiences occur during the two phases of pain perception that occur following an acute injury.[2] The first phase, which is not particularly intense, comes immediately after the painful stimulus and is known as fast pain. The second phase, known as slow pain, is more unpleasant, less discretely localized, and occurs after a longer delay.


Activation of nociceptors is transduced along the axons of peripheral nerves which terminate in the dorsal horn of the spine. There, messages are relayed up the spinal cord and through the spinothalamic tract to output on the thalamus. In turn, the thalamus serves as the major “relay station” for sensory information to the cerebral cortex.[5] Nociceptive pathways terminate in discrete subdivisions of thalamic nuclei known as the ventral posterior lateral nucleus and the ventromedial nucleus.[6] From these nuclei, nociceptive information is relayed to various cortical and subcortical regions, including the amygdala, hypothalamus, periaqueductal grey, basal ganglia, and regions of cerebral cortex. Most notably, the insula and anterior cingulate cortex are consistently activated when nociceptors are stimulated by noxious stimuli, and activation in these brain regions is associated with the subjective experience of pain.[7] In turn, these integrated thalamocortical and corticolimbic structures, which collectively have been termed the pain “neuromatrix,” process somatosensory input and output neural impulses which influence nociception and pain perception.[8]


Neurochemistry of Pain


Nociception is mediated by the function of numerous intra- and extra-cellular molecular messengers involved in signal transduction in the peripheral and central nervous systems. All nociceptors, when activated by the requisite mechanical, thermal, or chemical stimulus, transmit information via the excitatory neurotransmitter glutamate.[9] In addition, inflammatory mediators are secreted at site of the original injury to stimulate nociceptor activation. This “inflammatory soup” is comprised of chemicals such as peptides (e.g., bradykinin), neurotransmitters (e.g., serotonin), lipids (e.g., prostaglandins), and neurotrophins (e.g., NGF). The presence of these molecules excites nociceptors or lowers their activation threshold, resulting in the transmission of afferent signals to the dorsal horn of the spinal cord as well as initiating neurogenic inflammation.[3] Neurogenic inflammation is the process by which active nociceptors release neurotransmitters such as substance P from the peripheral terminal to induce vasodilation, leak proteins and fluids into the extracellular space near the terminal end of the nociceptor, and stimulate immune cells which contribute to the inflammatory soup. As a result of these neurochemical changes in the local environment of nociceptors, the activation of Aδ and C fibers increases, and peripheral sensitization occurs.[10]


In turn, nociceptive signal transduction up the spinothalamic tract results in elevated release of norepinephrine from the locus coeruleus neurons projecting to thalamus, which in turn relays nociceptive information to somatosensory cortex, hypothalamus, and hippocampus.[11,12] As such, norepinephrine modulates the “gain” of nociceptive information as it is relayed for processing in other cortical and subcortical brain regions. Concomitantly, opioid receptors in the peripheral and central nervous systems (e.g., those in neurons of the dorsal horn of the spine and the periaqueductal grey in the brain) result in inhibition of pain processing and analgesia when stimulated by opiates or endogenous opioids like endorphin, enkephalin, or dynorphin.[13] The secretion of endogenous opioids is largely governed by the descending modulatory pain system.[14] The neurotransmitter GABA is also involved in the central modulation of pain processing, by augmenting descending inhibition of spinal nociceptive neurons.[15] A host of other neurochemicals are also involved in pain perception; the neurochemistry of nociception and central-peripheral pain modulation is extremely complex.


Descending Central Modulation of Pain


The brain does not passively receive pain information from the body, but instead actively regulates sensory transmission by exerting influences on the spinal dorsal horn via descending projections from the medulla.[16] In their seminal Gate Control theory of pain, Melzack and Wall proposed that the substantia gelatinosa of the dorsal horn gates the perception of noxious stimuli by integrating upstream afferent signals from the peripheral nervous system with downstream modulation from the brain.[17] Interneurons in the dorsal horn can inhibit and potentiate impulses ascending to higher brain centers, and thus they provide a site where the central nervous system controls impulse transmission into consciousness.


The descending pain modulatory system exerts influences on nociceptive input from the spinal cord. This network of cortical, subcortical, and brainstem structures includes prefrontal cortex, anterior cingulate cortex, insula, amygdala, hypothalamus, periaqueductal grey, rostral ventromedial medulla, and dorsolateral pons/tegmentum.7 The coordinated activity of these brain structures modulates nociceptive signals via descending projections to the spinal dorsal horn. By virtue of the somatotopic organization of these descending connections, the central nervous system can selectively control signal transmission from specific parts of the body.


The descending pain modulatory system has both anti- and pro-nociceptive effects. Classically, the descending pain modulatory system has been construed as the means by which the central nervous system inhibits nociceptive signals at the spinal outputs.[16] In a crucial early demonstration, Reynolds observed that direct electrical stimulation of the periaqueductal grey could produce dramatic analgesic effects as evidenced by the ability to undergo major surgery without pain.[18] Yet, this brain system can also facilitate nociception. For instance, projections from the periaqueductal grey to the rostral ventromedial medulla have been shown to enhance spinal transmission of nociceptive information from peripheral nociceptors.[19]


Central modulation of pain may have been a conserved across human evolution due to its potentially adaptive effects on survival. For instance, in situations of serious mortal threat (for example, in the face of war and civil accidents, or more primordially, when being attacked by a vicious animal), suppression of pain might enable a severely-injured individual to continue intense physical activity such as fleeing from danger or fighting a deadly opponent. Yet, the neurobiological linkages between the brain, the spinothalamic tract, the dorsal horn, and the peripheral nerves also provide a physiological pathway by which negative emotions and stress can amplify and prolong pain, causing functional interference and considerable suffering.


Cognitive, Affective, Psychophysiological, and Behavioral Processes in Pain Perception and Regulation


In addition to the somatosensory elements of pain-processing described above, cognitive and emotional factors are implicit within the definition of pain offered by the International Association for the Study of Pain. Pain perception involves a number of psychological processes, including attentional orienting to the painful sensation and its source, cognitive appraisal of the meaning of the sensation, and the subsequent emotional, psychophysiological, and behavioral reaction, which then feedback to influence pain perception (see Figure 1). Each of these processes will be detailed below.


Schematic of the Human Nervous System Diagram 1 | El Paso, TX Chiropractor

Figure 1: A schematic of nociception, pain perception and the biobehavioral response to pain in the human nervous system.


Attention to Chronic Pain


In the brain, attention allows salient subsets of data to gain preeminence in the competitive processing of neural networks at the expense of other subsets of data.[20] The goal-relevance of a stimulus guides attention to select and distinguish it from the environmental matrix in which it is embedded.[21] Thus, attended stimuli receive preferential information processing and are likely to govern behavior. In this sense, attention allows for the evaluation of salient stimuli, and facilitates execution of approach behaviors in response to appetitive stimuli or avoidance behaviors in response to aversive ones. Thus, depending on its salience to the survival of the organism, the object of attention elicits the motivation to approach or avoid, while the resultant emotional state, as the manifestation of approach or avoidance motivations, tunes and directs attention.[22,23] By virtue of its significance for health and well-being, pain automatically and involuntarily attracts attention.[24,25] Yet pain experience varies according to the locus of attention; when attention is focused on pain, it is perceived as more intense,[26] and whereas when attention is distracted from pain, it is perceived as less intense.[27]


Attentional modulation of pain experience correlates with changes in activation of the pain neuromatrix; for instance, attentional distraction reduces pain-related activations in somatosensory cortices, thalamus, and insula, among other brain regions.[7] Concomitantly, distraction results in strong brain activations in prefrontal cortex, anterior cingulate cortex, and periaqueductal grey, suggesting an overlap and interaction between brain systems involved in attentional modulation of pain and the descending pain modulatory system.[28] In contrast, attentional hypervigilance for pain, a high degree of monitoring internal and external stimuli that is often observed among persons with chronic pain,[29] amplifies pain intensity and is associated with the interpretation of harmless sensations (like moderate levels of pressure) as painfully unpleasant.[30,31]


Cognitive Appraisal of Pain


Pain involves a process of cognitive appraisal, whereby the individual consciously or unconsciously evaluates the meaning of sensory signals emanating from the body to determine the extent to which they signify the presence of an actual or potential harm. This evaluation is decidedly subjective. For instance, experienced weightlifters or runners typically construe the “burn” they feels in their muscles as pleasurable and indicative of increasing strength and endurance; in contrast, a novice might view the same sensation as signaling that damage had occurred. The inherent variability of cognitive appraisal of pain may stem from the neurobiological dissociation between the sensory and affective aspects of the pain experience; change in pain intensity results in altered activation of somatosensory cortex, whereas change in pain unpleasantness results in altered activation of the anterior cingulate cortex.[32,33] Thus, a sensory signal originating from the muscles of lower back might be perceived as a warmth and tightness, or viewed as a terrible agony, in spite of the stimulus intensity being held constant. The manner in which the bodily sensation is appraised may in turn influence whether it is experienced as unpleasant pain or not.[34]


The extent to which a given bodily sensation is interpreted as threatening is in part dependent on whether or not the individual believes he or she is able to cope with that sensation. If, during this complex cognitive process of appraisal, available coping resources are deemed sufficient to deal with the sensation, then pain can be perceived as controllable. Pain intensity is reduced when pain is perceived to be controllable, whether or not the individual acts to control the pain. Ventrolateral prefrontal cortex activation is positively associated with the extent to which pain is viewed as controllable and negatively correlated with subjective pain intensity. This brain region is implicated in emotion regulation efforts, such as when threatening stimuli are reappraised to be benign.[35,36] Concomitantly, reinterpreting pain as a harmless sensation (e.g., warmth or tightness) predicts higher perceived control over pain,[37] and psychological interventions have been shown to reduce pain severity by increasing reinterpretation of pain sensations as innocuous sensory information.[38] In contrast, pain catastrophizing (i.e., viewing pain as overwhelming and uncontrollable) is associated with greater pain intensity irrespective of the extent of physical impairment[39] and prospectively predicts the development of low back pain.[40]


Emotional and Psychophysiological Reactions to Chronic Pain


The aversive nature of pain elicits a powerful emotional reaction that feeds back to modulate pain perception. Pain often results in feelings of anger, sadness, and fear depending on the how the pain is cognitively appraised. For instance, the belief “It’s not fair that I have to live with this pain” is likely to lead to anger, whereas the belief “My life is hopeless now that I have this pain” will likely result in sadness. Fear is a common reaction to pain when individuals interpret the sensations from the body as indicating the presence of serious threat.


These emotions are coupled with autonomic, endocrine, and immune responses which may amplify pain through a number of psychophysiological pathways. For example, pain induction significantly elevates sympathetic nervous system activity, marked by increased anxiety, heart rate, and galvanic skin response.[41] Furthermore, negative emotions and stress increase contraction of muscle tissue; elevated electromyographic activity occurs in the muscles of the back and neck under conditions of stress and negative affect and is perceived as painful spasms.[42,43] This sympathoexcitatory reaction coupled with emotions like anger and fear may reflect an evolutionarily conserved, active coping response to escape the painful stimulus. Yet negative emotional states intensify pain intensity, pain unpleasantness, and pain-induced cardiovascular autonomic responses, while reducing the sense of perceived control over pain.[44] Stress and negative emotions like anger and fear may temporarily dampen pain via norepinephrine release, but when the sympathetic “fight or flight” response is prolonged it can increase blood flow to the muscle and increase muscle tension which may aggravate the original injury.[45] Alternatively, pain inputs from the viscera and muscles may stimulate cardiac vagal premotor neurons, leading to hypotension, bradycardia, and hyporeactivity to the environment – a pattern of autonomic response that corresponds with passive pain coping and depressed affect.[46] In addition to autonomic reactivity, pro-inflammatory cytokines and the stress hormone cortisol are released during the experience of negative emotion; these bio-molecular factors enhance nociception, facilitate processing of aversive information in the brain, and when their release is chronic or recurrent, may cause or exacerbate tissue damage.[8,47,48]


Moreover, negative emotions are associated with increased activation in the amygdala, anterior cingulate cortex, and anterior insula – these brain structures not only mediate the processing of emotions, but are also important nodes of the pain neuromatrix that tune attention toward pain, intensify pain unpleasantness, and amplify interoception (the sense of the physical condition of the body).[49,50] Thus, when individuals experience negative emotions like anger or fear as a result of pain or other emotionally salient stimuli, the heightened neural processing of threat in affective brain circuits primes the subsequent perception of pain[51,52] and increases the likelihood that sensations from within the body will be interpreted as painful.[53–55] The fear of pain, a clinical feature of chronic pain patients, is associated with hypervigilance for and sustained attention to pain-related stimuli.[56] Thus, negative emotions bias attention toward pain, which then increase its unpleasantness. In addition, negative emotions and stress impair prefrontal cortex function, which may reduce the ability to regulate pain using higher order cognitive strategies like reappraisal or viewing the pain as controllable and surmountable.[57,58] Thus, anger, sadness, and fear may result from acute or chronic pain and in turn feedback into the bio-behavioral processes that influence pain perception to exacerbate anguish and suffering.


Behavioral Reactions to Pain


Pain is not only a sensory, cognitive, and emotional experience, but also involves behavioral reactions that may alleviate, exacerbate, or prolong pain experience. Typical pain behaviors in low back pain include grimacing, rubbing, bracing, guarded movement, and sighing.[59] These behaviors facilitate the communication of pain and exert social influences that may have vicarious gain for the individual suffering from pain; such benefits include sympathy, acts of kindness and generosity, tolerance, lowered expectations, and social bonding, among others.[60] In addition, guarding or avoidance of activities associated with pain may be negatively reinforcing by virtue of the temporary alleviation of pain experience.[61] The fact that these avoidant behaviors decrease the occurrence of pain results in increasing use of avoidance as a coping strategy. Yet, greater use of avoidance as a result of fear of pain predicts higher levels of functional disability.[62] It is not merely that persons with greater pain-related disability engage in more avoidant behaviors, but rather studies indicate that avoidant behavior and beliefs are a precursor to disability.[63–65] Avoidance contributes to negative clinical outcomes in patients with chronic low back pain. Fear-avoidance of pain influences physical impairment and is more strongly associated with functional disability than pain severity.[66–68] In contrast, progressive increase in activity through exercise has been shown to result in significant benefits in pain, disability, physical impairment, and psychological distress for low back pain patients.[69] In light of the robust relation between coping behaviors and pain, behavioral and psychosocial interventions hold great promise in reducing pain intensity and pain-related functional disability in chronic pain conditions such as low back pain.[70]



Dr. Alex Jimenez’s Insight

Different sensory nerve fibers respond to different stimulations and produce different chemical reactions which determine how different sensations are interpreted. Special pain receptors, known as nociceptors, activate when there has been trauma from an injury or even through potential damage to the human body. This impulse, immediately sends a signal through the nerve and into the spinal cord, eventually reaching all the way to the brain. The role of the spinal cord in pain perception is also to simultaneously direct impulses to the brain and back down the spinal cord to the region of the injury. These are referred to as reflexes. However, the pain signal still needs to continue to the brain so it can respond accordingly. The brain will assess the type of pain and where it came from, triggering a healing response as well as a variety of other bodily responses to address the pain signal effectively. In the case of chronic pain, pain perception may not be working accordingly along any of the pathways mentioned above. Treatment can help improve chronic pain as well as manage the painful symptoms.




The foregoing review attests to the multidimensionality of pain. Pain is a biopsychosocial experience that goes well beyond mere nociception. In this regard, identification of the physical pathology at the site of injury is necessary but not sufficient to explicate the complex process by which somatosensory information is transformed into the physiological, cognitive, affective, and behavioral response labeled as pain. Indeed, in the case of chronic low back pain, the magnitude of tissue damage may be out of proportion to the reported pain experience, there may be no remaining structural impairment, and physical signs that have a predominantly nonorganic basis are likely to be present.[71,72] In this and other chronic conditions, to consider such pain as malingering or somatization would be to grossly oversimplify the matter. Pain, whether linked with injured tissue, inflammation, or functional impairment, is mediated by processing in the nervous system. In this sense, all pain is physical. Yet, regardless of its source, pain may result in hypervigilance, threat appraisals, emotional reactions, and avoidant behavior. So in this sense, all pain is psychological. Our nomenclature and nosology struggle to categorize the pain experience, but in the brain, all such categories are moot. Pain is fundamentally and quintessentially a psychophysiological phenomenon.


Key Points


  • Pain is a biopsychosocial experience that goes well beyond mere nociception. In this regard, identification of the physical pathology at the site of injury is necessary but not sufficient to explicate the complex process by which somatosensory information is transformed into the physiological, cognitive, affective, and behavioral response labeled as pain
  • In the case of chronic low back pain, the magnitude of tissue damage may be out of proportion to the reported pain experience, there may be no remaining structural impairment, and physical signs that have a predominantly nonorganic basis are likely to be present.
  • Pain, whether linked with injured tissue, inflammation, or functional impairment, is mediated by processing in the nervous system. In this sense, all pain is physical. Yet, regardless of its source, pain may result in hypervigilance, threat appraisals, emotional reactions, and avoidant behavior. So in this sense, all pain is psychological.
  • Our nomenclature and nosology struggle to categorize the pain experience, but in the brain, all such categories are moot. Pain is fundamentally and quintessentially a psychophysiological phenomenon.




ELG was supported by grant DA032517 from the National Institute on Drug Abuse in the preparation of this manuscript.




Plants as Medicine: Are Cannabinoids the Next Breakthrough in Plant Medicine?


If you’ve ever eaten a carrot, then you have consumed a cannabinoid. Most people associate cannabinoids with marijuana. The most commonly recognized cannabinoid is tetrahydrocannabinol, or THC, the chemical in marijuana that causes feelings of euphoria. Until recently, scientists had identified cannabinoids just in the cannabis plant, commonly called hemp or marijuana. Current research, however, has found cannabinoids in several plants, including clove, black pepper, Echinacea, ginseng and broccoli as well as carrots. No matter how many carrots you crunch, however, they will not get you too high. But understanding how the cannabinoids in different plants affect the human body may contribute to important health discoveries.


Plants as Medicine


Some of the most appreciated modern drugs were developed by analyzing plants used in conventional medicine. Researching the chemicals in these plants led to the discovery of life-saving drugs and furthered our knowledge of how the human body works. For instance, the foxglove plant introduced us to digoxin and digitoxin, two important heart medications.[1] As well as the Pacific yew contains paclitaxel, which can be used in the treatment of many cancers.[1] Throughout history, people have been especially adept at finding plants which either increase pleasure or reduce pain. Caffeine from tea and tea provides energy and keeps us awake, while smoking from tobacco is believed to be concurrently stimulating and relaxing, likely explaining why tobacco remains popular despite the known health risks of smoking.[2]


Several sorts of pain-relieving drugs originated with plants:




By analyzing opium from the poppy plant, scientists discovered opiate receptors in the human body and their role in pain control, which led to the development of morphine, codeine, and other opiate drugs and/or medications.[3]




As far back as ancient Egypt, health practitioners used tea made from the willow tree to decrease pain and fever. It took tens of thousands of years for scientists to find and isolate the active chemical, or the fatty acid, which led to the discovery of aspirin and from there, finding insights into the processes involved with inflammation.[4]




The leaves of the coca plant were used from the ancient Incan Empire from South America to deal with headaches, wounds and fractures. Coca eventually yielded the drug cocaine, which is a drug of misuse and abuse, but also an effective anesthetic. Recognizing how cocaine blocked pain led to the development of common anesthetics such as lidocaine, famous for making invasive dental procedures more comfortable.[5]


Cannabis and Human Health


Such as other medicinal plants, the cannabis species has been used for centuries. A Chinese text from the year AD 1 records the usage of hemp to treat more than 100 ailments dating back to 2737 BC.[6] Afterwards, the flowering tops of the Cannabis plant began to be cultivated for their psychoactive properties, while a different selection of the plant was increased as industrial hemp to be used in producing garments, paper, biofuels, foods, and other products.


Because of the controversy surrounding marijuana as a recreational drug, researchers have not been able to readily study the effects of the many non-THC ingredients in Cannabis. Although THC was identified from the 1940s, it was not until 50 years after that studies demonstrated that individuals, and nearly all animals,  have an inner system of cannabinoid receptors. What is more, we really make cannabinoids in our bodies, known as endocannabinoids, that act on these receptors.[7]


This physiological system is called the endocannabinoid system, or ECS, and new science appears almost daily about its function in human health. The ECS is involved in multiple functions, such as pain feeling, hunger, memory, and disposition. If you’ve ever stubbed your toe, digested an apple, then forgotten a password, or happily smile, then your ECS was involved, little did you know.


The discovery of the ECS gave science and medicine a whole new outlook about the organic compounds being identified in Cannabis. Researchers started referring to these chemicals as phytocannabinoids, from the work “phyto” for plant. More than 80 phytocannabinoids have been found in hemp and marijuana. THC is only one of many compounds being studied for the advantages they can provide.[8]


Past Cannabis and THC


Now that many different crops are known to contain chemicals that influence the ECS, phytocannabinoids are no longer just associated with the cannabis plant.[9] Chances are you have some source of phytocannabinoids in your diet right now. But it might be a small quantity, rather than all of phytocannabinoids interact strongly with the ECS.


What exactly do we know up to now? Current research shows that a number of the phytocannabinoids in hemp, clove, and black pepper can encourage the ECS to promote relaxation, decrease nerve distress, and improve digestive health. As these compounds don’t possess the mind-altering effects of THC, more individuals are likely to flip to phytocannabinoids to acquire their health benefits without having high.[10] Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


Curated by Dr. Alex Jimenez




Additional Topics: Back Pain


Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




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EXTRA IMPORTANT TOPIC: Low Back Pain Management


MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments


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Depression and Anxiety in Chronic Pain

Depression and Anxiety in Chronic Pain

Everyone will experience some type of pain throughout their lifetime, however, for those people who have anxiety or depression, pain can become especially intense and it can be challenging to treat. Individuals experiencing depression, for instance, often experience more severe and long-term pain than other individuals. The overlap of anxiety, depression, and pain is very evident in chronic pain and sometimes debilitating syndromes, such as fibromyalgia, irritable bowel syndrome, low back pain, headaches, and nerve pain. Psychiatric disorders not only bring about pain intensity but also contribute to increased risk of disability.


Researchers once believed that the connection between pain, anxiety, and depression resulted mostly from psychological rather than biological factors. Chronic pain can lead to depression, and also, major depression may feel emotionally painful. But as researchers have learned more about how the brain works, and how the nervous system interacts with other areas of the body, they’ve found that pain shares some biological mechanisms with depression and anxiety. Therapy is challenging when pain overlaps with anxiety or depression. Focus on pain can conceal both the clinician’s and patient’s awareness that a psychiatric disorder is also present. Even when the two types of problems are properly diagnosed, they can be difficult to treat.


Depression and Anxiety in Pain




  • Mood disorders, especially depression and anxiety, play an important role in the exacerbation of pain perception in all clinical settings.
  • Depression commonly occurs as a result of chronic pain and needs treating to improve outcome measures and quality of life.
  • Anxiety negatively affects thoughts and behaviours which hinders rehabilitation.
  • Anxiety and depression in acute hospital settings also negatively affect pain experience and should be considered in both adults and children.
  • Poor pain control and significant mood disorders perioperatively contribute to the development of chronic postoperative pain.




Pain concepts have moved radically away from the early nociceptive Cartesian principle, where a specific lesion in the body is experienced as pain by the brain. This has been replaced by the widely accepted biopsychosocial model, where tissue damage, psychology and environmental factors all interact to determine pain experience. The IASP’s definition of pain as “an unpleasant sensory or emotional experience associated with tissue damage…” further emphasises the significant role of mood and emotions for pain perception. Among these, depression and anxiety have been implicated as important contributors to the experience of pain, and have been extensively studied.




Depression is characterised by a pervasive low mood, loss of interest in usual activities and diminished ability to experience pleasure. Within this definition there exists a whole spectrum of severity, symptoms and signs together with their classifications. The DSM-IV (Diagnostic and Statistical Manual) is a common diagnostic classification system for psychiatric conditions and is also used for research, insurance and administration[1]. A common prerequisite for diagnosis of depression or other psychiatric disorders is that any symptoms experienced should result in clinically significant distress or impairment of social, occupational, or other important areas of functioning.


The Scale of the Problem


The association of chronic pain with depression has been of great interest in the past few decades. Chronic musculoskeletal pain patients have higher depression than individuals without pain in a general population study[2]. A third of patients in a pain clinic population had ‘major depression’ according to the criteria of the Diagnostic and Statistical Manual (DSM IV) following structured interviews[3]. The presence of pain can make recognition of depression more difficult, even though increased severity of pain worsens depressive symptoms[4].


Diagnostic and Assessment Issues


The association between depression and chronic pain, though widely accepted, is marred by diagnostic difficulties. In research for ‘depression’ various definitions exist in studies, leading to a variety of assessment methods, including self report instruments, chart reviews and structured or unstructured clinical interviews. Many studies relating to depression and chronic pain include heterogenous groups of patients with different chronic pain conditions and unspecified diagnostic criteria for depression. This clearly questions the validity of studies.


In the clinical setting many tools exist for the assessment of the severity and nature of depression. In chronic pain, the Zung Self-Rating Depression Scale (SDS), Beck’s Depression Inventory (BDI) and Depression, Anxiety and Stress Scale (DASS) are commonly used. The SDS and DASS in particular, have shown high internal consistency and validity in chronic pain patients. However many criteria for depression, like fatigue, insomnia and weight change, are symptoms attributable to chronic pain itself. The DSM-IV places emphasis on weight loss, appetite change and fatigue on diagnosis, and the Beck’s Depression Inventory and Zung Self-Rating Depression Scales also include a substantial number of such somatic items. Such ‘criterion contamination’ may lead to overestimation of depression. The DASS excludes such somatic items and is thought to provide a more accurate assessment of depression, especially in chronic pain patients[5]. Another questionnaire designed specifically for chronic pain patients is the Depression, Anxiety and Positive Outlook Scale (DAPOS). This also contains no somatic items and includes measures of optimism[6].


These points illustrate the unique difficulty present in the study of depression in chronic pain patients. It is not surprising that meta-analyses or systematic reviews in this area are relatively scarce. Just as depression is not a single entity but a spectrum, chronic pain patients are also a very heterogenous group of patients. All these have to be borne in mind when reviewing papers and studies of depression in chronic pain.


Depression and Pain: Chicken and Egg?


Physiological similarities exist between chronic pain and depression. For example, noradrenaline and serotonin involved in the pathophysiology of depression also coincide with the anatomical ‘descending inhibition’ of pain perception. These two neurotransmitters act in the limbic system and periaqueductal areas to modulate incoming pain stimuli. Antidepressants working through these neurotransmitters are also analgesic regardless of the presence of depression.


This leads to the question of whether depression follows the establishment of chronic pain or whether chronic pain is a manifestation of a form of depression or a spectrum thereof. Some evidence exists for both views. For example, patients with preexisting depression were found to be more likely to develop chest pain and headaches in a three year period[7]. Conversely a review of forty studies supported the notion that depression is a consequence of protracted pain[8]. The ‘diathesis-stress’ model for this conundrum is now growing in acceptance which supports that depression is a sequalae of chronic pain. Accordingly people with a psychological predisposition (diathesis), superimposed with the stresses of chronic pain go on to develop clinical depression.


Chronic pain is also associated with anxiety disorders (discussed below), somatoform disorders, substance use disorders, and personality disorders. As with depression, pre-existing, semidormant characteristics of the individual before the onset of chronic pain are activated and exacerbated by the stress of chronic pain, eventually resulting in diagnosable psychopathology[9]. Psychosocial elements which predict chronic pain and disability (yellow flags) used in clinical practice may well fit into this construct.


Yellow Flags are psychosocial factors that increase the risk of developing or perpetuating long-term disability and work loss associated with low back pain. Such include:


  • Attitudes and Beliefs about back pain. The belief that pain is harmful or disabling resulting in fear-avoidance behaviour.
  • Behaviours. Use of extended rest, disproportionate ‘downtime’.
  • Compensation Issues. Lack of financial incentive to return to work.
  • Diagnosis and Treatment. Health professional sanctioning disability, not providing interventions that will improve function.
  • Emotions. Fear of increased pain with activity or work.
  • Family and Work. Over-protective partner/spouse, emphasising fear of harm or encouraging catastrophising. Manual work and job dissatisfaction.


The Costs of Depression in Pain


Social functioning, work and physical activities are all decreased whilst utilisation of medical services increases if depression coexists with pain[10]. Motivation and compliance with treatment is also affected[11]. Such negative outcomes leave little doubt as to the quality of life of such patients. Clearly pain and depression should not be seen as separate dimensions but as interactive in nature. Attempting to treat pain without considering depression is likely to be a futile venture.


Anxiety in Chronic Pain


Anxiety is a physiological state characterized by cognitive, somatic, emotional, and behavioral components producing fear and worry. Anxiety is often accompanied by physical sensations such as heart palpitations and shortness of breath whilst the cognitive component entails expectation of a diffuse and certain danger. As with depression, anxiety disorders are categorised in the DSM-IV, with subtypes including generalised anxiety disorder (GAD), panic disorder and phobias. GAD is the most commonly diagnosed anxiety disorder in chronic pain populations. The coexistence of pain and anxiety is perhaps not surprising: Both signal impending danger and the necessity for action which confer survival value to the individual.


Anxiety disorders are second only to depression in psychological comorbidity in chronic pain populations. Whilst anxiety is a normal response in everyone, clinical anxiety results in increased intensity and prolongation of the feelings of dread that interfere with normal functioning. Measurements of anxiety with chronic pain also show a strong association: as with depression. One such study showed a doubling in the prevalence of anxiety disorders compared to the general population[12]. Anxiety is thought to be an important mediator in the cognitive constructs of catastrophising, hypervigilance and fear avoidance in the exacerbation of pain experiences.


  • Catastfophising is ‘dwelling on the worst possible outcomes’. It is associated with higher disability and pain severity and is an important cognitive measure and prognostic indicator in chronic pain patients.
  • Hypervigilance in pain is the increased attendance to pain and decreased ability to distract oneself from pain-related stimuli.
  • Fear avoidance is the avoidance of movement or activities based on fear of pain or re-injury. This is especially counterproductive for physical rehabilitation and is termed ‘kinesophobia’.


Measurement of Anxiety in Pain


As with depression many measures of anxiety states exist. The State-Trait Anxiety Inventory questionnaire is a well-validated tool used in general psychology but has also been used in pain clinics. For chronic pain, more specific measures of anxiety-related to cognitive and behavioural variables have been designed. Such an instrument is the Pain Anxiety Symptoms Scale (PASS) which measures behavioural responses to pain[13]. The Fear of Pain Inventory measures degree of fear in hypothetical pain inducing situations[14]. These are more useful than general anxiety measurements and give more specific information in relation to the pain experienced. The DASS and DAPOS used for depression also measure anxiety.


Anxiety and Depression Coexist


Despite their differences in symptoms and classification, depression and anxiety seem to exist concurrently to a surprisingly frequent extent. In psychiatry, terms like ‘agitated depression’ have been coined for a state of depression that presents as anxiety which includes restlessness, insomnia and nonspecific panic.


Even mild anxiety symptoms can have a major impact on the course of a depressive illness. Depressed or bipolar patients with lifetime panic symptoms have significant delays in remission for depression[15]. To this end, the presence of both depression and anxiety make treatment of pain more challenging but the presence of one should alert rather than deter the diagnosis of the other.


Treatment of Depression and Anxiety


Mainstays of treatment of depression and anxiety are psychological and pharmacological. Whilst the scope of these is well beyond this article, it is worth noting that cognitive behavioural therapy, which addresses depression and anxiety, has very good evidence for efficacy in chronic pain patients[16]. Important concepts of CBT are also incorporated into Pain Management Programs for delivery to patients with different types of pain.


Depression and Anxiety in Acute Pain


Hitherto depression and anxiety have only been discussed in a chronic setting. Current multidimensional concepts of pain are equally important in the acute setting. Apart from the degree of surgical insult to tissue, psychological and environmental factors influence acute pain experience to a high degree[17].


Preoperative anxiety is correlated with higher pain intensity postoperatively for a variety of operations. In the hospital setting, anxiety is worsened by sleep deprivation in the postoperative period due to interruptions in the wards for observations, other patients and medications. This vicious circle is exacerbated by fear of complications, loss of control and helplessness. Admission to hospital and having an operation is a highly stressful event for most and that is often forgotten by professionals who are frequently involved in perioperative care. Preoperative depression also increases pain intensity, opioid requirements by any route and number of demands from the PCAS (Patient controlled analgesia system) in the postoperative period. Higher levels of dissatisfaction with analgesia also occur if depression coexists[18].



Dr. Alex Jimenez’s Insight

From headaches to muscle tension and body soreness, pain may be all too familiar for individuals who suffer from anxiety and depression. However, many research studies have demonstrated that chronic pain, such as that resulting from conditions like arthritis or fibromyalgia, may in turn lead to a variety of mental health issues. Both anxiety and depression have been implicated to be fundamental contributors in the exacerbation of as well as in the perception of pain. As a result, many healthcare professionals have developed a treatment approach based on therapeutic strategies to help manage symptoms of anxiety and depression. By first controlling these symptoms, many doctors can safely and ef