The Lure of Medical Marijuana
There is clinical and anecdotal evidence for using cannabis to treat chronic diseases ... but it may not be the best therapy
Hemp has been cultivated for its fibre since Roman times and used medically for hundreds, possibly thousands, of years. However, global politics and an increase in recreational cannabis use in the 20th century resulted in its criminalisation in most parts of the world, despite being a substance that many respected individuals (including the last three US presidents) admitted using.
Thanks to a mixture of anecdotal evidence and scientific research, the therapeutic potential of cannabis was popularly rediscovered in the 1990s and it is now seen by many as a useful therapeutic agent in its own right, and by others as having potential to yield novel therapeutic molecules. Twenty-three US states and the District of Columbia have decriminalised medical cannabis use and some (Colorado, Alaska, Washington) have decriminalised all possession. In the UK, cannabis use remains illegal, though in reality 'users' are rarely prosecuted for possession of small quantities. In fact, one police force (Durham) recently invited controversy when they stated that they would no longer actively prosecute individuals cultivating small quantities of cannabis for personal use.
Cannabis refers to a range of preparations of the leaves, flowers and resins of Cannabis sativa and Cannabis indica that are smoked, vaporised or ingested to elicit effects. The route of administration affects the pharmacokinetic profile (onset, duration), with euphoric effects typically lasting several hours. Cannabinoids and their metabolites are highly lipophilic or fat soluble. They partition into body fat following administration, and get released back into other compartments for several days. As a result, the detection of cannabinoids in blood is a poor indicator of current cannabis intoxication, but a good indicator of consumption within recent weeks.
Cannabis contains two main pharmacologically active components- Δ9-tetrahydrocannabinol (THC) and Cannabidiol (CBD), along with numerous other cannabinoids such as Cannabigerol (CBG), Cannabichromene (CBC), Cannabinol (CBN), Cannabivarin (CBDV), Tetrahydrocannabivarin (THCV) and Cannabicyclol (CBL). It is thought that these phytocannabinoids are produced by the plants to provide both chemical and physical (stickiness) protection against microbial and insect pests.
The majority of scientific and medical research has focussed on THC and CBD, and the relative abundance of these and other cannabinoids in any given cannabis preparation strongly influences the potential pharmacological effects. The illicit use of cannabis is driven by the euphoric psychoactivity of THC; modern black-market cannabis has been selectively bred for extremely high TCH content, altering the ratio of TCH to other cannabinoids and potentially reducing its medical utility. There have also been suggestions that Cannabis indica is more suited to medical use whereas Cannabis sativa is favoured by recreational users, though in reality many of the 100s of Cannabis strains are cross-breeds of the two. Nonetheless, there are good reasons for arguing that cannabis optimised for therapeutic effects should be made available to patients with a medical requirement for the drug, as street cannabis may have limited utility for these individuals.
Cannabinoids exert their effects through endogenous cannabinoid receptors. These are G-protein coupled receptors (GPCRs) which act through Gi/o proteins to activate MAPK and inhibit adenylyl cyclase. There are (currently) two confirmed human endogenous cannabinoid receptors: CB1, which is mainly expressed in the central and peripheral nervous systems, and CB2, which is mainly expressed in cells with immunological functions (eg B-cells, NK cells, spleen, thymus and tonsil). Current cannabinoid-based therapies, including cannabis itself, purified cannabis components, and synthetic cannabinoids are based around direct interaction (agonism or antagonism) with these receptors. Additional mechanisms of action, for example through allosteric modulation of CB1 and CB2, are also being investigated.
Interaction of THC with the CB1 receptor is responsible for the psychotropic effects of cannabis use, although THC itself has a similar affinity for both CB1 and CB2 receptors. THC actually has a relatively low affinity for both CB1 and CB2 receptors, hence, its activity is sensitive to the presence of other cannabinoid receptor ligands.
The endogenous ligands for cannabinoid receptors are fatty acids with structural similarity to prostaglandin-like eicosanoids. The most important endocannabinoids are arachidonoylethanolamide (Anandamide, AEA) and 2-Arachidonoylglycerol (2-AG). The physiological function of endocannabinoids is not fully elucidated, but they are thought to have roles in eating behaviour and metabolism, fertility and neurological function.
Atypical cannabinoid receptors GPR18, GPR55 and GPR119 have also been suggested as potential drug targets. These receptors possess little structural similarity to the CB1 and CB2 receptors, but do interact with many cannabinoid ligands. It is possible that these and other putative cannabinoid receptors will be classified as a CBn receptor subtypes at some point in the future.
So how medical is medical marijuana?
Activation of CB1 and CB2 by agonists leads to a range of therapeutically useful effects. Cannabinoids are currently believed useful in the treatment of chronic pain in MS, cancer, rheumatism and fibromyalgia, in fighting nausea due to cytostatic chemotherapy, in improving appetite in HIV/AIDS, cancer and Alzheimer's disease patients and reducing muscle spasticity in MS and paraplegia. Antagonism of CB1 has been shown to reduce appetite and have potential utility in obesity treatment. As cannabinoid receptors also involved in reward-driven behaviour, there may also be a therapeutic role for cannabinoid antagonism in the treatment of substance abuse.
Overall, cannabis is believed to have a relatively safe therapeutic profile. Accurate analysis of effects has been hindered by the variability in botanical preparations and the changing cannabinoid composition of cannabis over the years. There are also sex-dependent differences in cannabinoid effects and reported side effects.
The most obvious side effect of therapeutic cannabis use is cannabis intoxication, the effects of which (tiredness, dizziness, relaxation) prevent patients from performing tasks such as driving or operating machinery. Although recreational users embrace these effects, many patients find them unpleasant and this is an important cause of discontinuation of treatment.
More seriously, long-term cannabis use has been linked to mental health effects including psychosis and schizophrenia, possibly by disruption of the endocannabinoid system. These effects have been particularly strongly linked with adolescent use and the use of cannabimimetic novel psychoactive substances (synthetic designer drugs or "legal highs").
Chronic, heavy cannabis use results in impaired mental acuity even when not currently intoxicated, and this impairment can last for weeks or months after discontinuation of cannabis use. Tachycardia and postural hypotention are also established effects and would increase the risk of serious side effects in patients with pre-existing cardiac disease.
Finally, if patients choose to administer cannabis by smoking, then there are additional risks due to this method of administration. The composition of cannabis smoke is similar to tobacco smoke but without any nicotine. Because cannabis is often smoked along with tobacco in cigarette form, but without a filter, the actual exposure to smoke toxins is higher. This is tempered by cannabis users typically smoking fewer cannabis cigarettes than smokers take tobacco cigarettes. However chronic use is nonetheless associated with emphysema and bronchitis.
In writing this article, two things have become clear to me: Firstly, that there is strong clinical and anecdotal support for the efficacy of cannabis in the treatment of a wide range of diseases, and secondly, that cannabis itself may not be the best therapy.
Given wide variation in the relative yields of each phytocannabinoid in cannabis preparations, depending on the Cannabis strain, processing and route of ingestion, along with the importance of these relative abundancies on the effects and pharmacological efficacy of cannabis for any given indication, it is not surprising that efforts have been made to harness the therapeutic potential of cannabinoids in controlled medical formulations. This has taken the form of defined mixtures of purified THC and/or CBD, synthetic cannabinoid receptor agonists, and Cannabis strains bred for low THC content.
These and, by extension, cannabinoids and endocannabinoid modulating therapies, hold the greatest potential for establishing successful and socially acceptable therapies from what has, until recently, been a historically useful herb stigmatised by illicit recreational misuse and shunned by recent generations of doctors and politicians alike.
It will be interesting to see how high a place cannabis reaches in the medical marketplace.
How to cite:
Welch, Jonathan. The Lure of Medical Marijuana. Eureka blog. August 25, 2015. Available: https://eureka.criver.com/the-lure-of-medical-marijuana/