Clinical EndoCannabinoid Deficiency (CECD) Revisited:

Science & Research

OBJECTIVES: Ethan B. Russo’s paper of December 1, 2003, explored the concept of a clinical endocannabinoid deficiency (CECD) underlying the pathophysiology of a migraine, fibromyalgia, irritable bowel syndrome and other functional conditions alleviated by clinical cannabis.
METHODS: Available literature was reviewed, including literature searches via the National Library of Medicine database and other sources.
RESULTS: A review of the literature indicates that significant progress has been made since Dr. Ethan B. Russo’s landmark paper just ten years ago (February 2, 2004). Investigation at that time suggested that cannabinoids can block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, irritable bowel syndrome and muscle spasm.
CONCLUSION: Subsequent research has confirmed that underlying endocannabinoid deficiencies indeed play a role in migraine, fibromyalgia, irritable bowel syndrome and a growing list of other medical conditions. Clinical experience is bearing this out. Further research and especially, clinical trials, will further demonstrate the usefulness of medical cannabis. As legal barriers fall and scientific bias fades this will become more apparent.

By Dr. Mark Wagner, C3® Medical Director & Steele Clarke Smith, C3® Chairman & CEO
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In 1964, thanks to the groundbreaking work of two Israeli researchers, Drs. Raphael Mechoulan and Yehiel Gaoni, the psychoactive component of marijuana was identified and synthesized at the Hebrew University in Jerusalem. The substance, named THC (tetrahydrocannabinol) turned out to be just one of an entire family of cannabinoid (“cannabis-like”) compounds. However, THC is the only cannabinoid that has psychoactive properties, when decarboxylated with heat.1 Over the decades that followed, the role of cannabinoids in neurological function was teased-out, first by Allyn Howlett, Ph.D., and her graduate student assistant, William Devane, in 1988. They demonstrated how THC binds to receptors in the brain.

This was a breakthrough in our understanding of endogenous receptors – a biologic “signaling system” that indicated that we produce substances similar to cannabis, to act on these receptors, switching them on and off. The first two receptors identified were CB1 and CB2—Cannabinoid #1 and #2. By 1992 the exogenous compounds that fit these receptors like a key in a lock were discovered, again at the Hebrew University. Thus began the nefarious story of cannabis’ ubiquitous role in our bodies. Subsequent research has shown that these endogenous receptors are scattered throughout various organs, CB1 primarily in the brain and CB2 in the GI tract, liver spleen, various endocrine glands and reproductive system. CB2 receptors are also involved in our immune system and peripheral nervous system.2 Thus, is it any surprise to find that cannabis can affect multiple bodily systems and play a role by replenishing these immunodeficiencies in these clinically endocannabinoid deprived systems.

These discoveries and those that followed, have become the scientific basis for debunking the erroneous stigmatization of cannabis that began with a vengeance in 1935. Finally, after more than three-quarters of a century, the mainstream media is finally telling the true story of cannabis and its role in fighting disease.3 Clinical EndoCannabinoid Deficiency Syndrome (CECD) and other Neurological Disorders. In 2003 Ethan Russo, M.D. proposed the concept that a chemical endocannabinoid deficiency could explain the underlying cause of a migraine, fibromyalgia and irritable bowel syndrome (IBS) among other neuro-physiological conditions.4
Can this Concept Explain the Therapeutic Benefits of Cannabis in Migraine, Fibromyalgia, Irritable Bowel Syndrome and other Treatment-Resistant Conditions?
Dr. Russo understood that each neurotransmitter system can develop pathological conditions caused by a deficiency: Alzheimer’s dementia attributed to the loss of acetylcholine activity, parkinsonism due to dopamine deficiency, depression associated with lowered levels of serotonin, etc. Thus he reasoned, should this be any different in the endocannabinoid system, where the endocannabinoid receptors are especially dense? Could an endogenous endocannabinoid deficiency—either congenital or acquired—explain the pathophysiology of these elusive conditions?

Migraine, Fibromyalgia and Irritable Bowel Syndrome

In a migraine, pathways involving serotonin are integral to the condition. THC (tetrahydrocannabinol) inhibits serotonin release from the blood platelets of humans with migraine headaches.5 Through a series of reactions involving ”anandamide” (AEA – the common name for arachidonylethanolamide – with behavioral activity similar to THC) both of these substances partially oppose CB1 receptors which are especially prevalent in the periaquaductal gray matter, the cerebral origin of most migraine headaches. 6 These and other observations suggest the probable efficacy of therapeutic cannabinoid in the treatment of a migraine.


Myofascial pain syndrome – fibromyalgia – is characterized by tender muscle points which tend to cluster in similar anatomical locations from patient-to-patient. Although the veracity of the condition has been questioned by neurologists, studies by J.D. Richardson,, support a relationship of fibromyalgia to a clinical endocannabinoid deficiency, suggesting that the endocannabinoid system regulates the immunodeficiency system and modulates pain thresholds and its absence may underlie the hyperalgesic tender muscle points of this condition.7,8 These and subsequent studies have suggested that cannabinoid agonists would be useful in the treatment of chronic pain conditions such as myofascial pain syndrome, temporomandibular joint pain (TMJ) and reflex sympathetic dystrophy (RSD), a condition which can follow minor trauma, usually to an extremity and is often described as being worse than the original injury.
Irritable bowel syndrome (IBS) can be a recurring nightmare for patients and their physicians. It involves recurrent constipation and/or diarrhea, often associated with painful abdominal spasms and distention. Infection, diet and emotional stress can trigger an attack and the conditions represent the most common cause of referral to gastroenterologists. All of the current treatments are only partially effective. We have previously noted that CB2 receptors are commonly found in the gut and 2-arachidonylglycerol (2-AG) has been identified in dog intestine by Dr. Mechoulam and her associates to bind to these endogenous cannabinoid receptors.9

Pertwee, who has exhaustively studied the relationship of cannabinoids in gastrointestinal function, has demonstrated that mammalian enteric nervous systems contain CB1 receptors and stimulation depresses GI motility.10 These stimuli include delayed gastric emptying, decrease peptic acid production and slowed peristalsis. Furthermore, these effects are also mediated in the brain, confirming the old adage “the brain and gut speak the same language.” Confirming this, it has been shown that chronic intestinal inflammation results in the sensitization of cannabinoid receptors, to the extent that Izzo and DiCarlo suggested the use of cannabinoid drugs to treat IBS.11, 12 Given the above, it is not surprising that co-morbidities of these conditions should exist. Indeed, a high lifetime prevalence of migraine, IBS, depression and panic disorder were found among 33 women meeting the American College of Rheumatology criteria for figromyalgia.13

Autism Spectrum Disorder
The interaction of gastric and environmental factors appear to play a role in the genesis of the constellation of clinical entities known as Autism Spectrum Disorder (ASD). They are recognized by delayed and disordered social and communication skills and frequently with repetitive speech and behavior. Success in treating ASD has been slow due to our poor understanding of its causes. This has resulted in the lack of a single standard approach to treatment. However, in 2008 Agudelo, Newton and associates discovered an immune system dysregulation in autistic children revealing an altered immune response in peripheral blood mononuclear cells (PBMC’s).14

As noted above, there are two known endogenous cannabinoid receptor subtypes: CB1, expressed primarily (but not exclusively) in the brain, and CB2 found primarily in peripheral somatic tissue and to a lesser extent, in the brain. The next exciting revelation came in April 2013, when Dr. Dario Siniscalo and his co-workers discovered that CB2 was significantly increased in the peripheral blood mononuclear cells (PBMCs) of autistic children compared to their age-related normal controls. Variations in cellular biochemical events in ASD have been identified, such as mitochondrial dysfunction, intestinal dysfunction, and immune dysregulation.15 Other immunological dysfunction in ASD demonstrated that PMBCs show increased levels of pro-inflammatory cytokines and interleukins that result in long-term immune system alterations.16

Recently Sinisscalco and co-workers demonstrated that PBMCs in ASD children show altered pleiomorphic enzymes (caspases) that regulate apoptosis and inflammatory signaling pathways. Caspases are pleiomorphic enzymes that function in cell proliferation and differentiation, as well as cellular activation and nuclear re-programming.17, 18

The Future of Endocannabinoids

Endocannabinoids consist of arachidonic acid-derived compounds and their receptors, representing a complex network of lipid signaling pathways. A growing body of evidence is accumulating that pinpoints the endocannabinoid system playing a role in such psychiatric disorders as anxiety, major depression, bipolar disorder and schizophrenia, as well as developmental disorders, including the elusive autism spectrum disorder.19, 20, 21, 22, 23 We can expect that in the near future, our understanding of the role of the endocannabinoid system will grow exponentially.

A study of 17 children with autism was reported in 2013 by Dr’s Dario Siniscalo, Anne Sapone and associates.24 The study children were compared with 22 age and sex-matched healthy children devoid of any neurological or psychiatric disorder. Fresh peripheral blood samples were obtained from each subject and their peripheral blood mononuclear cells (PMBCs) were isolated and the ribonucleic acid (RNA) was extracted. From these samples, the endocannabinoid system gene expression was determined.25 Compared to the controls, the PMBC-extracted RNA levels showed an increase in the CB2 receptor genes of the ASD children. CB2 protein levels are increased in the polymorphonuclear blood cells of ADS children. No differences were noted in the CB1 receptor regulation.

CB2 receptor activation triggers immune suppression26 and after inflammation or tissue injury, there is a local rapid increase in endocannabinoid levels. This appears to mediate immune response through down-regulation of cytokine expression.27 Furthermore, Basu and Dittel demonstrated that CB2 receptors are able to modulate the development, migration, proliferation and effect or function of immune cells.28 Combining these observations with our current understanding suggest that CB2 receptor up-regulation in PMBCs may be related to ASD-immune dysregulation. The CB2 receptor changes, but not CB1 or anandamide enzyme(s). This would indicate that the main function of CB2 endocannabinoids in these cells is to regulate inflammation and immune responses. CB1 receptors do not appear to be involved.

It has been fifty years since Drs. Mechoulan and Gaoni first isolated and named tetrahydrocannabinol. Dr. Russo found that a chemical endocannabinoid deficiency might explain the source of such diverse neurological conditions as a migraine, fibromyalgia and irritable bowel syndrome. With increasing legal tolerance, the pace of research is accelerating with enticing new evidence that a wide variety of neurological disorders may be classified as clinical endocannabinoid deficiencies.

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