Medically, you might be interested in…

This month’s column is different from the usual. I have had a look around the literature for the last few years in an effort to look at the evidence for the medicinal use of cannabis – compiled and written by Clare GP Dr Ray O’Connor

Background
Firstly, a little background. Cannabis, or marijuana, was first used for medicinal purposes in 2737 BC.1 The Cannabis plant, (Cannabis Sativa as described by Linnaeus in 1753), has been used for many years as a medicinal agent in the relief of pain and seizures.2 It contains approximately 540 natural compounds including more than 100 that have been identified as phytocannabinoids due to their shared chemical structure.2

The predominant psychotropic component is Δ9-tetrahydrocannabinol (Δ9-THC, also called THC), while the major non-psychoactive ingredient is cannabidiol (CBD). These compounds have been shown to be partial agonists or antagonists at the prototypical cannabinoid receptors, CB1 and CB2, and the therapeutic actions of Δ9-THC and CBD include an ability to act as analgesics, anti-emetics, anti-inflammatory agents, anti-seizure compounds and as protective agents in neurodegeneration.2

Legal status
Under the Misuse of Drugs legislation, products containing THC are strictly controlled; possession is unlawful under the Misuse of Drugs Act, 1977/1984, and is illegal except under licence.3 CBD is not psychoactive, and so it is not controlled under the Misuse of Drugs legislation and does not require a Ministerial Licence.

There are also the warnings from medical quarters. The most recent comes from the incoming president of the Royal College of Psychiatrists in the UK, who has called for a public information campaign to be launched about the consequences to British teenagers of regularly smoking cannabis, including increased risk of developing psychosis in later life.4

Medical evidence
So, what is the evidence of benefit, or otherwise, for cannabis-containing products?

A World Health Organisation paper5 on the topic from 2015 concludes that ‘the medical benefits of cannabis continue to be debated globally, as they have been for nearly 150 years’. Also, ‘with the discovery of the endocannabinoids and their receptors in the brain and other tissues, the rationale for, and research of medicinal effects of cannabis or isolated cannabinoids has entered a modern context.

In the brain endocannabinoids and their receptors play a fundamental role in regulating pleasure, memory, thinking, concentration, body movement, awareness of time, appetite, pain, sensory processing (taste, touch, smell, hearing, and sight), and brain development. In peripheral tissues, the widespread distribution of endocannabinoid signaling systems conceivably account for the myriad effects and therapeutic potential of cannabinoids.

Especially for psychoactive drugs such as cannabis, rigorous criteria for its approval as a safe and effective medicine need to be fulfilled, along with a meticulous cost-benefit analysis to weigh its therapeutic potential, alongside its detrimental effects to individuals and to society’.5

Unfortunately, cannabis trials to date are almost universally small and/or open to bias. For example, one randomised trial recently conducted testing THC and CBD had only 18 participants.6 Another randomised placebo-controlled trial on the use of smoked cannabis for spasticity in multiple sclerosis had only 30 participants.7 Both studies concluded, unsurprisingly, that more research was needed.

Thus, the recurring theme that shows up clearly in the systematic review papers published on the topic of medicinal cannabis is one of small, and often poorly-conducted studies. These reviews include a Cochrane Systematic Review on the medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS.8

The authors’ conclusions were that despite dronabinol (a synthetic delta-9-THC) being registered by at least some medicines regulatory authorities for the treatment of AIDS-associated anorexia, and some jurisdictions making allowances for the ‘medical’ use of marijuana by patients with HIV/AIDS, evidence for the efficacy and safety of cannabis and cannabinoids in this setting is lacking.

Such studies as have been performed have been of short duration, in small numbers of patients, and have focused on short-term measures of efficacy. Long-term data, showing a sustained effect on AIDS-related morbidity, mortality and safety in patients on effective antiretroviral therapy, has yet to be presented. Whether the available evidence is sufficient to justify a wide-ranging revisiting of medicines regulatory practice remains unclear.8

A Canadian review paper on the use of cannabis for more generalised medical indications also concluded that while significant preclinical data have demonstrated the potential therapeutic benefits of cannabis for treating pain in osteoarthritis, rheumatoid arthritis, fibromyalgia and cancer, further studies are needed with randomized controlled trials and larger study populations to identify the specific strains and concentrations that will work best with selected cohorts.9

Another systematic review and meta-analysis of randomised controlled trials (RCTs) published in 2017 looked at the efficacy of cannabis-based medicines (CBM) for pain management.10

The results of 43 RCTs (a total of 2,437 patients) were included in this review, of which only 24 RCTs (a total of 1,334 patients) were eligible for meta-analysis. This analysis showed limited evidence of reduction in chronic pain, especially by inhalation, compared to placebo. Moreover, even though this review consisted of some RCTs that showed a clinically significant improvement with a decrease of pain scores of two points or more, the majority of the studies did not show an effect.

Consequently, although the primary analysis showed that the results were favourable to CBM over placebo, the clinical significance of these findings is uncertain. The most prominent adverse effects (AEs) were related to the central nervous and the gastrointestinal (GI) systems.

Publication limitation could have been present due to the inclusion of English-only published studies. Additionally, the authors remarked that the included studies were extremely heterogeneous.

Only seven studies reported on the patients’ history of prior consumption of CBMs. Furthermore, since cannabinoids are surrounded by considerable controversy in the media and society, and have marked effects, inadequate blinding of the placebo could constitute an important source of limitation in these types of studies.

The authors concluded that CBMs might be effective for chronic pain treatment, based on limited evidence, primarily for neuropathic pain patients. Additionally, GI AEs occurred more frequently when CBMs were administered via oral/oromucosal routes than by inhalation.10

Another review paper published in 2019 also found that the quality of the evidence supporting the use of cannabinoids was suboptimal.11 The following points were made regarding the evidence that was found.

First, studies assessing pain and spasticity are difficult to conduct, in part because of heterogeneity of the outcome measures used in these studies. Second, most RCTs that have evaluated cannabinoid clinical outcomes were small, with fewer than100 participants in each, and small trials may overestimate treatment effects. Third, the timeframe for most studies was too short to assess the long-term effects of these medications. Fourth, tolerance, withdrawal, and potential for drug-drug interactions may affect the usefulness of cannabis, and these phenomena are not well understood for cannabinoids.

The lack of high-quality evidence result in outsized claims of the efficacy of cannabinoids for numerous medical conditions. The author concluded that there is a need for well-designed, large, multisite RCTs of cannabis or cannabinoids to resolve claims of efficacy for conditions for which the claims are not supported by high-quality evidence, such as pain and spasticity.11

The most recent systematic review that I could find on the topic was published in 2021. It looked at cannabinoids, cannabis, and CBM for pain management.12 The authors included 36 studies (7,217 participants) delivering cannabinoids (eight studies), cannabis (six studies), and CBM (22 studies); all had high and/or uncertain risk of bias. Very low-quality evidence of benefit was found for cannabis and nabiximols (a THC plus CBD oral spray).

No other beneficial effects were found for other types of cannabinoids, cannabis, or CBM in the primary analyses. Cannabis, nabiximols, and delta-9-THC had more adverse effects than control. The authors remarked that studies in this field have unclear or high risk of bias, and outcomes had GRADE rating of low- or very low-quality evidence. The authors further stated that they had little confidence in the estimates of effect. The evidence neither supports nor refutes claims of efficacy and safety for cannabinoids, cannabis, or CBM in the management of pain.12

Conclusion
The whole topic of medicinal cannabis is a highly emotive one. There are definitely patients who benefit from its use. However, the drugs have a potential for abuse and are not without significant adverse effects.

For example, a report from the US-based National Institute of Health states that marijuana smoking is associated with large airway inflammation, increased airway resistance, and lung hyperinflation, and those who smoke marijuana regularly report more symptoms of chronic bronchitis than those who do not smoke.13

The obvious conclusion from the available data is that well-conducted controlled clinical trials are needed to establish in what form, and for which patients suffering from which conditions medical cannabinoids are effective for. Can it be shown that they do more good than harm? For example, recently cannabidiol has been shown to reduce seizure frequency in Dravet syndrome.14

Based on current evidence, it is difficult to recommend the use of medical cannabis outside of well-designed adequately powered double blind randomised controlled clinical trials.

In that case, we repeat our call15 that cannabinoids which are thought to have therapeutic efficacy should be made available, subject to legislation such as such as the Misuse of Drugs Act, 1977/1984, if appropriate.

These could then be tested scientifically under controlled conditions and their risk/benefit balance defined rigorously. Funding from a neutral source such as the Health Research Board would help ensure the rigour of this research, and the acceptability of the findings internationally. Only then can the true place of cannabinoids in medical therapeutics be determined.

References:

1. 1. 1. Borgelt L et al. The Pharmacologic and Clinical Effects of Medical Cannabis. Pharmacotherapy 2013;33(2):195–209.
      2. 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.
      3. Garda Press Office. https://www.garda.ie/en/crime/drugs/is-cannabis-legal-html#:~:text=No.,been%20issued%20for%20this%20activity.
      4. Waters A. Cannabis consumption by UK teens is a ticking time bomb, warns president elect BMJ 2023; 380. DOI: https://doi.org/10.1136/bmj.p407. (Published February 22, 2023).
      5. Madras B et al. Update of Cannabis and its medical use. 37th ECDD (2015) Agenda item 6.2. https://www.ncsbn.org/public-files/WHO_Cannabis_and_its_medical_use.pdf.
      6. Zamarripa C et al. Assessment of Orally Administered Δ9-Tetrahydrocannabinol When Coadministered With Cannabidiol on Δ9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics in Healthy Adults: A Randomized Clinical Trial. JAMA Network Open. 2023;6(2):e2254752. DOI:10.1001/jamanetworkopen.2022.54752.
      7. Corey-Bloom J et al. Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ 2012. July 10, 2012, 184(10) DOI:10.1503/cmaj.110837.
      8. Lutge EE et al. The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS (Review). Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD005175. DOI: 10.1002/14651858.CD005175.pub3.
      9. Ko GD et al. Medical cannabis – the Canadian perspective. Journal of Pain Research 2016:9 735–744. DOI: 10.2147/JPR.S98182. eCollection 2016.
      10. Aviram J et al. Efficacy of Cannabis-Based Medicines for Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Pain Physician: September/October 2017: 20:E755-E796.
      11. Hill KP. Medical Use of Cannabis in 2019. JAMA September 10, 2019 Volume 322, Number 10. Published Online: August 9, 2019. DOI:10.1001/jama.2019.11868.
      12. Fisher E et al. Cannabinoids, cannabis, and cannabis-based medicine for pain management: a systematic review of randomised controlled trials. PAIN 162 (2021) S45–S66. DOI: 10.1097/j.pain.0000000000001929.
      13. NIDA. 2021, April 13. What are marijuana’s effects on lung health?. Retrieved from https://nida.nih.gov/publications/research-reports/marijuana/what-are-marijuanas-effects-lung-health on March 6, 2023.
      14. Devinsky O, Cross JH,Wright S, Cannabidiol in Dravet Syndrome Study Group (2017) Trial of cannabidiol for drug-resistant seizures. in the Dravet syndrome. N Engl J Med 376(21):2011–2020. https://doi.org/10.1056/NEJMoa1611618.
      15. O’Doherty J. O’Connor R. The case for medicinal cannabis. Irish Journal of Medical Science (1971–) https://doi.org/10.1007/s11845-018-1770-9.