For such an important body system and one that, in evolutionary terms, has been around for so long, why is it that we know so little about the endocannabinoid system (ECS)? And, why do we so rarely utilise the potential benefits of agonists and antagonists of the ECS? The answers are complex but interference by (misinformed) politicians and the influence of societal cultural beliefs are likely culprits rather than lack of inquisitiveness/failure of scientists and medical researchers.
This article will provide an introduction to cannabinoids in general and to ECS specifically and will touch on our current understanding of cannabinoids in neurological disease. There will be no attempt to discuss the importance of ECS in other fields (e.g. metabolic medicine, psychiatry or oncology) nor to discuss medicolegal issues such as medical prescribing in Australia or cannabinoids and driving. Recreational use of cannabinoids is also outside scope of article.
Humans have been aware of marijuana since at least 3000-4000 BC with initial use of marijuana originating from Central Asia. Chinese Emperor Shen Nung (2700 BC) described treatment of beriberi, malaria and forgetfulness and was recorded as stating "if taken over a long-term it makes one communicate with spirits and lighten one's body"! Despite this long history, it was not until 1964 that tetrahydrocannabinol (THC) was first isolated and then in the late 1980s, cannabinoid receptors in the rat brain, followed in 1991 in the human brain, were identified. In the 25 years since, endocannabinoid receptors (CB1 and CB2) have been identified and cloned throughout the CNS/PNS and other body tissues. A variety of endocannabinoids (e.g. anandamide and 2-AG), that act upon these receptors, have also been identified.
So what do we mean when the use the word cannabinoids? It is easiest to think of 3 different groups. Firstly, phytocannabinoids which come from plants e.g. the marijuana plant. Secondly, endocannabinoids, which we all produce in our various bodily systems. Thirdly, synthetic cannabinoids are made in laboratories by scientists in great numbers and varieties. To conceptualise cannabinoids, it is helpful to construct a chart, comparing cannabinoids and opiates (see below).
- ENDOCANNABINOID SYSTEM
ECS is old! Truly old in evolutionary terms! ECS has been identified in the invertebrate “sea squirt” which has been around for about 600 million years. All vertebrates and many invertebrates have an ECS.
Interestingly, in humans, the density and number of cannabinoid receptors (CB1 and CB2) is greater than the aggregate of dopamine and serotonin receptors. Which makes one suspicious that the ECS is likely to be a “significant player”, not mere “bystander” in humans, especially in homeostasis.
Cannabinoid receptors are typically G protein–coupled receptors. CB1 receptors are among the most abundant receptors in the brain, present in almost every brain region and also located in a variety of peripheral tissues, including adipose tissue, liver, muscle, the GI tract, and pancreas. CB2 are present in greater numbers outside CNS, including spleen, bones and skin. Several other endocannabinoid receptors are now being identified e.g. intracellular receptors such as PPARs.
The race is on to identify more endocannabinoids, some of which are listed below.
ECS functions through many mechanisms. In the CNS, ECS activity is mediated through post-synaptic release of endocannabinoids acting upon pre-synaptic endocannabinoid receptors e.g. CB1 which can then modulate neurotransmitter (e.g. GABA or glutamate) release.
- USE IN NEUROLOGY - SOME OF THE EVIDENCE
The evidence for efficacy of cannabinoids, specifically CBD (cannabidinol) in childhood epilepsy, is compelling. This has been particularly demonstrated in Dravet’s syndrome and Lennox-Gastaut syndrome with recent trials in the NEJM leading to approval from the FDA. There is a lesser body of work in adult epilepsy but plenty of promising trials are being conducted around the world.
4.2 PARKINSONS DISEASE
There are several small trials demonstrating symptom improvement with cannabinoids in the motor symptoms of Parkinson disease, particularly rigidity and dyskinesia. This not surprising given evidence of ECS involvement at several levels of motor control. However, there does not seem to be much benefit in tremor. Significantly, there is possibly most benefit in management of non-motor symptoms including anxiety, depression, disturbed sleep and pain.
4.3 MULTIPLE SCLEROSIS
There are five random control trials utilising nabiximols (50% THC / 50% CBD) in management of MS, demonstrating overall benefit.
A review, Cannabinoids for Treatment of MS Symptoms: State of the Evidence by Rice et al in June 2018, concluded “the best evidence is for spasticity and neuropathic pain”.
Given the restrictive and onerous prescribing restrictions of cannabinoids in Australia, it is noteworthy that in December 2017, the Australian Government Department of Health released a publication “Guidance for the use of medicinal cannabis in the treatment of multiple sclerosis in Australia”. This is a wonderful review of the subject, for both clinicians and patients. The recommendations within were supported by 145 references!
There are endocannabinoid receptors throughout the length of pain transmission, commencing at peripheral nerve terminals and involving peripheral nerves, dorsal root ganglia, dorsal horns and the brain. (Both CB1 and CB2 are found at all sites except for the brain, which is mostly CB1).
We may be starting to understand how paracetamol works as there is good evidence that paracetamol, in part, works through “facilitation of endogenous cannabinoids signalling via one of its metabolites”.
Systematic review of 15 RCTs of cannabinoids in chronic non-cancer pain, published in British Journal of Clinical Pharmacology in 2010, concluded “evidence that cannabinoids are safe and modestly effective in neuropathic pain with preliminary evidence of efficacy in fibromyalgia and rheumatoid arthritis”. A more recent systematic review of cannabinoids in chronic pain, published in the JAMA by Whiting et al in June 2015, revealed an overall 40% improvement in pain versus placebo.
- SAFETY OF CANNABINOIDS
In 2014, a systematic review of safety of medical marijuana conducted by Academy American Academy of Neurology and reported in journal Neurology stated “Risk of serious adverse psychopathologic effects was nearly 1%”. My response to that review was “medical marijuana” was safer than expected!
Indeed, a discussion about the safety of cannabinoids needs to be held within the context of the epidemic of opiate abuse and mortality. For better or for worse, there are no recorded cases of fatality with CBD. An explanation for this is the scarcity of CB1 receptors in brainstem compared to the high concentration of opiate receptors.
- FUTURE OF MEDICAL USE OF CANNABINOIDS
The future is today! Already, around the world, medicinal cannabis is accepted as a therapeutic option for a long and varied list of conditions. This has been true for 20-25 years, particularly in countries such as Canada, Israel, Germany, Denmark and UK. We are so far behind here. As a recent attendee at CanneX 2018, an international conference on medicinal cannabis, one felt like a pariah to have AUSTRALIA, on one’s name badge. It is instructive to note that 33 of 50 US States have enacted medicinal cannabis laws.
In a world of increasingly expensive medications, it does seem appropriate that we hone in on one of the body’s homeostatic systems and find appropriate agonists and antagonists that may potentially aid in management of symptoms and pathological processes.
Dr Lodge's also spoke on cannabinoids at the Nordocs meeting in June.