Care and concern with cannabinoids used therapeutically

The last few years have witnessed a remarkable academic journey for cannabis with a ten‐fold increase in annual publications from 1990 to 2017 and clinical trials now underway to understand its potential role in clinical practice. This humble plant, thought to have originated in Asia, has been used for around 3000 years for spiritual, industrial and medicinal purposes. It spread widely throughout the world as its psychoactive and medicinal properties were sought after. In the nineteenth and twentieth centuries, like heroin and cocaine, cannabis was publicly vilified as an illicit poison, made illegal in many countries. However, many people continued to use it particularly for recreational use and as an anxiolytic, despite known detrimental effects on brain development and function 1. Now, in the twenty‐first century, cannabis has re‐arrived, the latest ‘super‐therapy’ in popular media 2, yet evidence to date suggests that for most symptoms, the data are mostly low quality and showing little benefit (evidence meta‐analysed in 3). However, like benzodiazepines before it, and alcohol even earlier, it is touted as treatment for maladies of a wide range of chronic symptoms and diseases – ranging from anxiety, cancer treatment symptoms, post‐traumatic stress disorder, seizures, spasticity to chronic pain syndromes and cachexia. Further, standard drug discovery and development for this experimental therapy, and clinical research to understand benefits and harms have lagged well behind the pressure from advocates and the political framework 4.

The reviews in this issue of BJCP summarize what is known about the properties and clinical applications of cannabis, exploring its history, chemistry, pharmacology and several common clinical applications and where the current limitations are, from a clinical pharmacology perspective.

The history of cannabis as a modern medicine can be traced back to 1843 where W. B. O'Shaughnessy reported on the use of Cannabis indica for the treatment of convulsive disorders 5. The respected neurologist, W. R. Gowers, raised the potential of cannabis as a therapy when he included for the treatment of seizure disorders in his famous 1881 treatise ‘Epilepsy and other chronic convulsive diseases’ 6. The use of plant‐based treatments generally, but including cannabis, fell into disuse in the twentieth century with the development of purified specific pharmacological molecules and extracts.

In the twenty‐first century, the resurgence of cannabis as a potential medical treatment appears to be driven as strongly by popular opinion and political interests more than by genuine scientific discovery. It also clearly negates comparison with current medicines that have scientifically had their efficacy and toxicity quantified, and their place in therapy validated 7. In fact, the biological basis underpinning the potential therapeutic efficacy of cannabis has lagged well behind its use. For example, a comprehensive exploration of the effect of CBD and dosing in rodent seizure models was published as recently as 2017 8 just as an open label but randomized controlled trial in a rare paediatric epilepsy syndrome was being reported 9.

Use of cannabis medically has additional issues to other experimental therapies, including the fact that the appropriate components of the cannabis plant must be extracted and purified, and for many of the dozens of cannabinoids known, only a few are so far known to be responsible for toxicity and efficacy. These include the two principle components of cannabis, tetrahydrocannabinol (THC) and cannabidiol (CBD). Bar‐Lev Schleider et al. 10 describe the rapidly increasing number and variable quality of studies examining these components and cautions the need for an evidence‐based focus in interpretation of some of this information. This caution is supported by the recently published position statement from the Royal Australasian College of Physicians 7 and Australasian Faculty of Pain Medicine 11.

A commonly overlooked aspect for patients requesting access to cannabis products is an understanding of the complexity and variation of extraction for clinical use, and knowledge of potentially inconsistent interplay of environment and plant factors. Grof 12 provides an insight into the complex plant biology, extraction and storage of these compounds, and how these can affect expression of cannabinoids. Cannabis uses quite a different process to the development of other medicines derived from plants such as morphine, yet in many jurisdictions requiring the same regulatory controls for safety and efficacy, e.g., quality control, pesticide, microbiological and other aspects around quality and consistency 13.

As with other pharmacological data in special groups, there is a paucity of underlying pharmacological data with cannabinoids. Specifically, there are limited pharmaceutic, pharmacokinetic and pharmacodynamic data to support the currently proposed combination and dosing regimens. Lucas et al. 14 have summarized the current data and limitations for clinical interpretation and therefore planning for definitive studies, supported by Liu and Martin 15 who give advice to pharmacokinetic modellers on research gaps to consider to support the limited data available to inform dosing in special groups.

Despite the lack of knowledge around choice of drug, dose and dosing regimen for the many diseases and symptoms in which it is used, there is now RCT information for use of CBD in at least two rare childhood epileptic syndromes, although there is ongoing controversy as to whether the primary endpoint are due to CBD directly or its impact upon co‐administered anticonvulsants 16. In this issue, Lawson and Scheffer 17 discuss these trials and the current approach to the use of CBD in the clinical management of drug resistant epilepsy, particularly focussing on children.

There has been much interest and use of cannabinoids in the treatment of palliative care patients, fuelled particularly by consumer demand 18. There had been reports of early success in case reports and small clinical trials. However, as Agar demonstrates 19, larger clinical trials address issues such as nausea and vomiting, pain and cachexia have so far failed to demonstrate a significant improvement in outcome when compared with other available treatments. The latest published meta‐analysis for pain similarly shows that comparative advantage of these products is likely to be small 20, with event rates for a 30% reduction in pain intensity of 29.0% (cannabinoids) vs. 25.9% (placebo), and a number needed to treat to benefit of 24 (95% CI 15‐61); for 50% reduction in pain, event rates differences were not significant. In this meta‐analysis, the number needed to treat to harm was 6 (95% CI 5‐8), with no significant impact upon physical or emotional functioning, and low‐quality evidence of improved sleep and patient global impression of change. There are few if any other symptomatic therapies supported for routine use in clinical practice in this setting with such a therapeutic ratio.

As highlighted by the clinical reviews in this issue, the use of cannabis, either medically or recreationally, is not without risks. The long‐term use of recreational smoked cannabis has been associated with severe effects such as the emergence of psychosis, particularly in adolescents and young adults. Bonomo 21 and colleagues explore whether these concerns extend to the use of the medicinal components of cannabis taken via non‐smoking routes while Newton‐Howes 22 considers the specific risks on an individual patient's mental health, particularly those who have underlying disorders including depression, anxiety and addiction. Currently, whether these effects on addiction and mental health are increased or decreased when given to children compared to adults is unknown 23.

In summary, cannabis has a profile in the public eye for the treatment of a significant number of medical ailments. This may be based on previous recreational use, the push for more patient autonomy in health, the clinically unsound perception that in the end of life setting, there is nothing to lose, a potential for benefit together with a desirer in some settings to more ‘natural’ therapies. As demonstrated in this issue, the science lags behind the proposed uses. Thus at this stage, the risks and benefits are uncertain, inconsistent and complicated in terms of many patients, many disease states, and many cannabis components. As several of the articles in this issue warn, additional plant, clinical pharmacology and clinical research are needed before cannabis components such as CBD and THC can be considered routinely as medical treatments. Additional work on pharmacology and dose–response of particular components is also strongly encouraged.

Competing Interests

J.H.M. is the Director of the NHMRC funded Australian Centre for Cannabinoid Research Excellence and is a member of a number of State and Federal Advisory Committees regarding medicinal cannabis.

Martin, J. H. , and Cranswick, N. (2018) Care and concern with cannabinoids used therapeutically. Br J Clin Pharmacol, 84: 2455–2457. 10.1111/bcp.13724.