By Sophie Blagg
The Cannabis sativa plant has been used for medicinal and recreational purposes for many centuries, with the first evidence of use dating back to around 4,000 B.C. (Zuardi, 2006). During the 20th century the use of cannabis drastically reduced when many countries illegalised cannabinoid substances (Zuardi, 2006), likely due to research into the plant’s psychoactive effects and addictive potential. However, in recent years, there has been a growing interest in the use of compounds from the C. sativa plant for medicinal purposes (Amin & Ali, 2019), as well as a relaxation of the rules around recreational use of certain, non-psychoactive, cannabinoid compounds.
There are two main cannabinoids in the C. sativa plant: ∆9-tetrahydrocannabinol (∆9-THC), which is psychoactive; and cannabidiol (CBD), which is not (Lucas, Galettis & Schneider, 2018). Altered cognitive functions seen with cannabis use are mostly due to the psychoactive ∆9-THC (Kogan, 2007). There are two main endogenous cannabinoids – anandamide (AEA) and 2-arachydonoilglycerol (2-AG) – and two cannabinoid receptors; CB1 and CB2 (Fraguas-Sanchez, 2018). Together, these endocannabinoids and their receptors comprise the endogenous cannabinoid system (ECS), which is involved in many bodily systems including inflammation, pain, and neural pathways (Fraguas-Sanchez, 2018).
With the extensive role of the ECS in maintaining homeostasis (Cristino, Bisogno & Di Marzo, 2020), there is potential for therapeutic benefit from using cannabinoids in drug design. However, through research and observations of recreational use of the drug, adverse effects and addictive properties have lead to hesitancy around administration and use of cannabinoids. The National Academies Report (2017) thoroughly details the various health effects of cannabinoids, and the challenges to researching these issues. A brief outline of some of the conclusions drawn from this report include that there is “conclusive or substantial evidence” that cannabinoids are effective in chronic pain treatment, treating nausea in chemotherapy patients and improving symptoms in multiple-sclerosis (MS) patients. However there is also suggestion of an association between cannabis use and respiratory problems, increased motor crashes, and impaired cognitive functions. The report combines a multitude of research, which gives confidence to the efficacy of cannabinoids in pain management, but the adverse effects and psychoactive properties of the compounds are still a concern.
With many adverse effects reported and various unknowns and gaps in research, why are cannabinoids attracting so much attention into their uses in modern medicine? The answer is that there is a growing socio-economic burden on healthcare systems, particularly in countries with ageing populations, and more treatment options are needed. Diseases such as MS, epilepsy, and neurological disorders that largely affect ageing populations – such as Alzheimer’s Disease and Parkinson’s – are still without effective treatment, or preventative measures. Cannabinoids could be the solution to such diseases.
Research into the use of cannabinoids to treat epilepsy has yielded interesting results and lead to the approval of a CBD-based drug. Epilepsy is a disease involving seizures, in various regions of the brain, caused by hyper-excitable neurons (Amin & Ali, 2019). Animal models of this disease first showed that ∆9-THC, CBD, and AEA, have anticonvulsant effects (Amin & Ali, 2019). This research prompted further pre-clinical and clinical trials, which also gave convincing results: early trials showed improvements in seizure frequency after daily administration of CBD (Huestis et al, 2019). Further trials using CBD and ∆9-THC in a 20:1 ratio show anti-epileptic seizure results with concurrent improved sleep and mood (Amin & Ali, 2019). The benefit of this treatment is that the drug is based on the non-psychoactive CBD, thus reducing adverse cognitive effects.
Another promising use of cannabinoids is in pain management, where its use has been recorded for several centuries (Kogan et al, 2007). The results from clinical trials, however, have been varied. One trial showed ∆9-THC to have no significant effect on pain and the impact of pain (Kogan et al, 2007), but in studies comparing inhaled cannabis against a placebo, moderate pain relief was reported (Amin & Ali, 2019). Cannabinoids taken together with other analgesics, and cannabinoids taken in combination, seem to be more effective in reducing neuropathic pain (Fraguas-Sanchez, 2018), (Kogan & Mechoulam, 2007). An example of this is the drug Sativex (Nabiximols) which has been approved in Canada, the UK, and other European countries to treat pain in cancer patients and neuropathic pain in MS patients (Cristino, 2020).
As well as prescribed uses of cannabinoids, many high street health shops can now sell CBD-based products, provided that the ∆9-THC content is below 0.3% (VanDolah et al, 2019). As CBD oil with <0.3% ∆9-THC is not psychoactive, it can be sold over the counter without prescription (VanDolah et al, 2019). These high-street type products are marketed for various uses, including help sleeping, pain relief, anxiety and digestion. Although CBD products are sold commercially and are marketed as ‘safe’, the novelty of these products means that there has been little research into their long-term safety or their efficacy (Fraguas-Sanchez, 2018). Reports of side-effects of CBD oil use include; diarrhoea, fatigue and weight loss (Huestis et al, 2019). Whilst these side-effects alone may not appear severe, it is not known how CBD oil interacts with other drugs that an individual may be taking, and if the product contains quantities of ∆9-THC above the legal limit, the adverse effects could be more severe.
Though the potential of cannabinoid use in treating life-debilitating conditions is exciting and promising, it remains that the pharmacodynamics of these compounds, and their adverse effects, are still largely unknown. With ongoing research and clinical trials assessing cannabinoid effects on MS, epilepsy, cancer and neurological pathways, the future of patients with these diseases is opening up. Nevertheless, there needs to be sufficient evidence that cannabinoid drugs are better than the current standard of care before prescribing them to patients, and the intake of such drugs should be strictly monitored by health professionals.
References:
Amin M.R., Ali D.W. (2019) Pharmacology of Medical Cannabis. In: Bukiya A. (eds) Recent Advances in Cannabinoid Physiology and Pathology. Advances in Experimental Medicine and Biology, vol: 1162. Springer, Cham. https://doi.org/10.1007/978-3-030-21737-2_8
Cristino, L., Bisogno, T., Di Marzo, V. (2019) Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nature Reviews Neurology. 16, 9-29. https://doi.org/10.1038/s41582-019-0284-z
Fraguas-Sanchez, A. (2018) Medical Use of Cannabis. Springer Nature Switzerland. 78, 1665-1703. https://doi.org/10.1007/s40265-018-0996-1.
Huestis, M., Solimini, R., Pichini, S., Pacifici, R., et al. (2019) Cannabidiol Adverse Effects and Toxicity. Current Neuropharmacology. 17 (10), 974-989. DOI: 10.2174/1570159X17666190603171901.
Kogan, N., Mechoulam R. (2007) Cannabinoids in Health and Disease. Dialogues in Clinical Neuroscience. 9 (4), 413-423.
Lucas, C., Galettis, P., Schneider, J. (2018) The pharmacokinetics and the pharmacodynamics of cannabinoids. British Journal of Clinical Pharmacology. 84, 2477-2482. DOI: 10.1111/bcp.13710.
National Academies of Sciences, Engineering and Medicine. (2017) The Health Effects of Cannabis and Cannabinoids. The National Academies Press. DOI: 10.17226/24625.
VanDolah, H., Bauer, B., Mauck, K. (2019) Clinicians‘ Guide to Cannabidiol and Hemp Oils. Mayo Clinic Proc. 94 (9), 1840-1851. https://doi.org/10.1016/j.mayocp.2019.01.003 .
Zuardi, A. (2006) History of cannabis as a medicine: a review. Rev Bras Psiquiatr. 28 (2), 153-157.
Imperial Bioscience Review 