Failure in the Endocannabinoid System: Theory or Reality?

By Raquel Peyraube

Dr. Raquel Peyraube is a doctor in medicine and a specialist in the problematic use of drugs. She has trained in psychiatry, toxicology and psychoanalytical psychotherapy and in subjects such as childhood, adolescence and social exclusion. She has 28 years' experience in the field. Throughout her career, she has made contributions in training, prevention, treatment and damage reduction, including innovating theoretical and methodological developments with emphasis on ethical issues. As a former clinical director of ICEERS, she is now an ad hoc consultant of the Uruguayan National Drugs Secretariat giving advice on reform of the public drugs policy and of the Institute of Cannabis Regulation and Control. She is a clinical researcher and a member of research teams for monitoring the law in Uruguay. She sits on several international scientific committees and is an active member of the IACM (International Association for Cannabinoid Medicines). She currently works on the development of clinical trials, medical education on medicinal cannabis, and dissemination of information and advice for reform of drugs policies in various countries.

The endocannabinoid system (ECS) is a complex system that regulates the homeostasis (balance of the internal medium) of the human body. Its importance has been established in the findings of scientific research into its functions and the physiological systems with which it is related in health and disease. The endocannabinoid system is a system of intercellular communication, which has been characterised, together with all its components: endogenous ligands (AEA and 2-AG), receptors (CB1 and CB2), chemical precursors and degradation enzymes (FAAH and MAGL). In addition to these basic pieces, there are also receptors such as GPR55 and TRPV1, and connected ligands PEA and OEA.

Many diseases are the result of failures in regulatory systems. This is the case, for example, of diseases of the endocrine system, which may be due to excessive or deficient action of the different hormones. Hyper or hypo hormonal functions have also been recognised, such as hyper- and hypothyroidism and diabetes. Such alterations may be genetically determined or acquired. It is therefore easy to postulate that a system as complex as ECS might also present genetic or acquired failures. Given the ubiquity of the system and the great variety of mechanisms and actions it regulates, it is also easy to understand that these failures might be expressed in very varied forms, depending on the organ or system in which they occur.

Given that multiple diseases with very dissimilar and apparently unrelated symptoms have been shown to respond positively to treatment with cannabis, it has been conjectured that many conditions treated with cannabis and cannabinoids might be explained either as structural failures of the system itself or as functional failures, i.e. failures in the regulation or regulatory capacity of the ECS. In theory, this means that there might be reductions and/or increases in the endocannabinoids, their receptors and the enzymes they produce or destroy. Another possibility is that the disease in course creates such an intense or prolonged demand that it exceeds the regulatory capacity of the system. To sum up, there could be genetic failures (errors in the genes encoding the ECS) or they might be acquired as a consequence of the impact of certain conditions on the system.

Much work remains to be conducted in this regard. However, data from the research thus far has led to the formulation of the theory of Clinical Endocannabinoid Deficiency (CECD), at least for diseases that respond to treatment with cannabis. E. Russo and other authors have published a number of studies on the subject. The author's first paper was published in 2001 and he discussed the subject in greater depth in 20041. In his most recent work2, he gives updated evidence for this possibility.

Given the physiological importance of ECS, it is understood that an alteration that determines variations in the levels of endocannabinoids through failures in production or destruction, and/or greater or lesser density of the receptors (sites of action), may influence consequences that are reflected in the primordial functions of this system: regulation of pain, mood, digestive and alimentary functions, immunity and sleep3. Increases or reductions in endocannabinoid tone are associated with various pathological states. In some situations alterations of the ECS are the primary failure and, in others, they are a compensation developed by the ECS to alleviate the symptoms of certain physio-pathological conditions. If the injury is transitory, so too is the compensation.

According to Russo the strongest evidence for the existence of the CECD lies in findings on migraine, fibromyalgia and irritable bowel syndrome, conditions which, as well as being resistant to treatment, share certain clinical characteristics such as:

  • a state of hyperalgesia (abnormal increase in sensitivity to pain)
  • a lack of specific pathological signs at tissue level
  • association with high levels of anxiety and depression
  • they have all been labelled as psychosomatic diseases or wastebasket diagnoses
  • and they frequently present in the same individual simultaneously or at different points in time4.

Beside these three pathologies, which Russo has analysed on the basis of the available evidence, both he and other authors point to many other clinical conditions that might be added to the list, including delay in neonatal development; cystic fibrosis; causalgia; infantile colic; dysmenorrhea; repetitive miscarriages; hyperemesis gravidarum; multiple sclerosis; post-traumatic stress disorder and autism spectrum disorder, among others.

This review of the available studies shows alterations in endocannabinoid levels. For example in migraine the serum levels of AEA, or AEA and 2-AG are significantly reduced, which could be due to an increase in their destruction.5 This would explain the relief that cannabinoids can bring to migraine patients. This effect would not be mediated by CB1 receptors, but by TRPV1, the sites of action of cannabidiol (CBD). One of the most categorical studies is by Sarchielli et al. who show a significant difference in AEA levels between people who do not suffer migraine and those who do, with significantly lower values among the latter group. They conclude that this shows strong evidence of ECS failure6.

My own clinical experience with such patients concurs with these findings and I have seen a very good response to treatment with repeated doses of CBD, requiring very low doses of THC, for which reason its adverse effects are almost entirely absent, and where they do present, they tend to disappear when the dose of THC is reduced. Following treatment with cannabinoids, the frequency of migraine crises tends to diminish considerably. In some cases I have even seen it disappear altogether, at least during the period of clinical monitoring.

In the case of fibromyalgia, the findings of the research back the idea of a hypofunction of the ECS at the central level, with significantly reduced levels of AEA being found in the cerebrospinal fluid (CSF) of patients with this pathology7.

As for irritable bowel syndrome, the ECS is well represented in the gastrointestinal tract, with receptors both in the surface and in the intestinal smooth muscle. To sum up, the most important functions of this system in the digestive apparatus can be said to be a reduction in gastric secretion, regulation of the lower oesophageal sphincter, reduction in motility of the digestive apparatus at all levels (stomach, small intestine and colon), reduction in intestinal secretion and control of visceral sensitivity. In addition, it has been shown that they act in situations involving intestinal inflammation and dysfunction. When one considers the symptoms of irritable bowel syndrome (pain, spasm, digestive discomfort, altered bowel movements with diarrhoea or constipation or an alternation between the two, accompanied by anxiety), it is easy to see that this might be explained by a failure of the ECS. Once again, in this pathology one sees a reduction in AEA, and as shown by a study in intestinal biopsies from IBS sufferers, an increase in TRPV1 receptor fibres, which might explain the hypersensitivity and pain.8

Other pathologies that suggest CECD are:

  • Multiple sclerosis, in which a reduction in the levels of AEA and 2-AG have been demonstrated in the LCR
  • Huntington's disease, which presents a marked reduction in CB1 receptors and thus in ECS activity
  • Parkinson's Disease, with twice the normal AEA values, from which one can assume a compensatory reaction to the progressive loss of dopamine and the consequent reduction in ECS tone
  • Post-traumatic stress syndrome, which coincides with significant reductions in 2-AG and AEA
  • Depression, which now tends to be thought of as a degenerative disease linked to ECS deficiency, like anorexia nervosa and autism spectrum disorder

In all these pathologies, an improvement in the specific symptoms can be observed when treated with cannabinoid. The positive results are also reflected in an improvement in quality of life.

In any medical discussion of treatments, the more these treatments impact the process of disease production, the greater the anticipated effectiveness. These are what we call physio-pathological treatments and would be the case of cannabinoids. As more and more pathologies are confirmed involving a deficiency of the ECS and are added to the list of conditions that can be improved with such treatment, we can answer the sceptics who question the use of cannabinoids as a universal panacea by saying that they simply treat the existing failure. We must again insist on the need, as well as scientific consensus, for randomised placebo-controlled clinical trials and also analytical and genetic studies.

Finally, to return to my initial question –Is CECD theory or reality?– although more evidence is still needed for certain pathologies, I would be surprised if future findings find otherwise. All the evidence appears to point to the real existence of CECD, and I have held this belief ever since, coming from the field of problematic drug use, I first began to get involved in the study and understanding of such diseases and the ECS. For a clinical practitioner, this hypothesis is almost self-evident. It is rational and, in empirical terms, it matches the praxis almost perfectly. Indisputably, final confirmation requires more scientific evidence.

Such studies will also make it possible to raise conceptual differences, such as for example whether all such conditions correspond to defective ECS or whether some might involve definitive or transitory deregulations, and in which cases they are the primary cause and in which they are secondary failures resulting from other causes.

In short, based on all the above, but also on the fact that there are other compounds as well as cannabinoids that might help to tackle these deficiencies, I would like to take this opportunity to make an observation and a proposal. Medical specialities have never been named after the treatments they use. The speciality concerned with neurological diseases, for example is neurology; endocrinology is concerned with endocrines; cardiology with the cardiovascular system, and so on.

And yet, in this field we talk about cannabis medicine. Uniquely, it is a field of medicine that is named after some of the products used in treatment. I would therefore like to formally propose that we stop referring to "cannabis medicine" and speak instead of endocannabinology, a speciality that is concerned with the study and treatment of alterations of the ECS.

1. Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinol Lett. 2004;25:31–39.
2. Russo Ethan B.. Cannabis and Cannabinoid Research. July 2016, 1(1): 154-165. doi:10.1089/can.2016.0009. http://online.liebertpub.com/doi/10.1089/can.2016.0009
3. McPartland JM, Guy GW, Di Marzo V. Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system. PLoS One. 2014;9:e89566.
4. Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinol Lett. 2004;25:31–39.
5. Cupini LM, Bari M, Battista N, et al. Abnormal degradation of endocannabinoids in migrainous women. Cephalalgia. 2003;23:684.
6. Sarchielli P, Pini LA, Coppola F, et al. Endocannabinoids in chronic migraine: CSF findings suggest a system failure. Neuropsychopharmacology. 2007;32:1384–1390.
7. Richardson JD, Aanonsen L, Hargreaves KM. Hypoactivity of the spinal cannabinoid system results in NMDA-dependent hyperalgesia. J Neurosci. 1998;18:451–457.
8. Akbar A, Yiangou Y, Facer P, et al. Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain. Gut. 2008;57:923–929