Dr. Ethan Russo ranks among the world’s most prolific researchers of medical cannabis, having published innumerous research and review articles in the field during the last two decades (many related to Sativex and intractable epilepsy). At the turn of the century, he authored three often cited articles in which he elaborated a theory of clinical endocannabinoid deficiency.
Seeing how many brain disorders were associated with neurotransmitter deficiencies—such as dopamine in Parkinson's disease and serotonin and norepinephrine in depression—he suggested that a deficit in endocannabinoid signalling might also explain a set of conditions that had until then evaded a proper understanding.
Among the extensive list of conditions proposed to involve endocannabinoid dysfunction, three have gained a reasonable level of support since the publication of those seminal articles: migraines, fibromyalgia and irritable bowel syndrome. In a review article published recently in the open access journal Cannabis and Cannabinoid Research, Dr. Russo discusses the evidence accumulated in this direction.
Fibromyalgia is a condition characterized by pain in soft tissues, particularly in the regions of the shoulder or neck, which is intense or frequent enough to limit physical activity and affect sleep and long-term well-being. Surprisingly to the medical community, there is an absence of clear biomarkers in this disease, including the usual signs of inflammation that accompany other pain syndromes. This has led to a contentious debate about the validity of the diagnosis, but despite this, fibromyalgia ranks as the most common rheumatology diagnosis in the U.S.
In 1998, a team established a link between hyperalgesia (pain) and endocannabinoid hypofunction in the spinal cord, in line with the endocannabinoid deficiency theory. They further demonstrated that endocannabinoids were able to reduce hyperalgesia.
Instead of discussing any progress (or lack thereof) in understanding this mechanism, Dr. Russo then focuses on a trio of uncontrolled clinical trials of THC and cannabis which suggest modest improvements in the pain and discomfort felt by fibromyalgia patients. One of these was an open label trial in which 28 patients reported improvements in pain and stiffness merely 2 hours after cannabis administration, together with improvements in somnolence and well-being when compared to controls.
"While this degree of benefit is yet to be shown in formal RCTs (randomized controlled trials) in fibromyalgia, the court of public opinion supports its utility" he writes in relation to a survey of 1300 patients who overwhelmingly supported cannabis over other prescription medicines for the alleviation of fibromyalgia. This, he argues, is sufficient to justify more definitive clinical trials.
Migraines are a complex syndrome demarcated by strong headaches as well as other unusual symptoms including nausea and light- and sound-related anxiety (photophobia and sonophobia). It affects around 14% of the U.S. population, and is three times more common in women than men.
The evidence for an involvement of the endocannabinoid system starts with the finding that anandamide (an endogenous cannabinoid) modifies the response of serotonin receptors in a way that is strikingly similar to that of drugs deemed effective in treating migraines. In addition, this compound regulates several brain and nerve structures that are thought to be dysregulated in this condition, possibly even those involved in the strange epiphenomena of photo- and sonophobia.
According to the endocannabinoid deficiency theory, we should observe a change in the levels of endocannabinoids among migraine patients. Indeed, several studies by one Italian team found this to be the case with anandamide. In two studies, the researchers detected respectively higher and lower concentrations of FAAH, the enzyme that breaks down anandamide, among migraine patients compared to controls. In a third, these researchers found a significant reduction in the blood levels of anandamide of migraine patients. The best evidence for impaired anandamide signalling, however, comes from a 2007 study where researchers detected lower levels of anandamide in the cerebrospinal fluid of 15 chronic migraine patients.
Clinical evidence for the therapeutic effects of cannabinoids in treating migraines is not yet up to today's medical standards. According to Dr. Russo, the strongest case was made by a 2016 observational trial (not randomized nor controlled) of 120 patients from a cannabis-oriented clinic in Colorado. Eighty-five percent of these patients reported an improvement in migraine frequency with the mean number of monthly events declining from 10.4 to 4.6 during treatment. Dr. Russo reminds us, however, that cannabis was deemed an effective and recommended treatment for migraines in Europe and in North America for over a century until its banning in the 1940s.
Irritable bowel syndrome
Irritable bowel syndrome is characterized by gastrointestinal pain, discomfort and changed bowel movements (leading to either constipation or diarrhea). Although it is the most common gastrointestinal disorder affecting around 10 to 15% of the Western population at some point, there are no known physical culprits with which to guide a formal diagnosis. The current expert consensus is that it is “a disorder of unknown origin being treated by agents with an unknown mechanism of action.”
Cannabis was known to be effective in controlling diarrhea associated with cholera as early as the 19th century, and today we have considerable preclinical evidence that a link exists between the endocannabinoid system and many of the functions affected in irritable bowel syndrome. This includes a pair of studies showing a modulation of gut muscles by anandamide and a higher predisposition to the disease among patients that carry a genetic variant that affects the metabolism of endocannabinoids.
The clinical evidence is—unsurprisingly—more scarce, and limited mostly to anecdotal reports and patient surveys. There have been three small trials of THC, but among these only one found positive evidence supporting the proposed therapeutic effects. In retrospective, Dr. Russo argues that THC might not have been the best candidate, and that novel trials of CBD and full cannabis extracts are necessary.
The three conditions share two broad similarities: 1) they involve pain and physical discomfort; and 2) they lack clear biological culprits and are often associated with depression and anxiety, leading many doctors to brush them off as being 'psychosomatic'. The endocannabinoid deficiency theory by Dr. Russo suggests a clear and testable biological explanation for them. With the increasing momentum surrounding medical cannabis research we should soon expect a definitive answer to whether or not any of these conditions reflects an underlying dysfunctional endocannabinoid system.
Featured image by Zill Niazi.