Letter to the editor: reflections on the future of medical cannabis research for depression

1.

We read with great interest the recently published letter, entitled ‘Cross-National Reflections on Medicinal Cannabis and Depression,’ which succinctly outlines the current observational evidence available on this topic from different jurisdictions [1]. This evidence builds upon pre-clinical research which has demonstrated the effects of cannabinoids on depressive symptoms through both direct and indirect activation of type 1 cannabinoid receptors [2]. Cannabidiol (CBD), which activates 5-hydroxytryptamine 1A receptors, has also demonstrated direct serotoninergic effects, similar to antidepressants [3]. This research also supplements real-world evidence from common psychiatric comorbidities with overlapping symptoms and pathophysiology with depression, such as anxiety and post-traumatic stress disorder [4–7]. Observational evidence is of the utmost importance as a pharmacovigilance measure for patients prescribed medical cannabis, monitoring the long-term safety of these medications, which appear to be well-tolerated in the medium term [4,6,8]. This real-world data can similarly be utilized to inform physician practice, as well as future randomized controlled trials [8]. Most medical cannabis patients are also engaged in taking part in such studies to better understand its effects on symptoms, as well as the potential to impact the care of other patients [9].

To date, there has been a paucity of randomized controlled trials on the effects of medical cannabis on depression, which has led to limited prescribing in this setting [10,11]. There are inherent challenges with conducting randomized controlled trials of medical cannabis products [8]. Notably, medical cannabis products may contain a broad spectrum of over 500 active pharmaceutical ingredients present within cannabis flower or be limited to isolated preparations of the major cannabinoids (CBD) and/or (−)-trans-Δ⁹-tetrahydrocannabinol (THC). Moreover, these may be manufactured into preparations which can be administered via inhalation, sublingually, orally, topically, or rectally [8]. This heterogeneity makes it challenging to identify the ideal product to study within trials, especially considering the associated financial cost associated with this research [8]. In addition, due to the psychoactive and vasoactive properties of THC and the associated aroma of cannabis it can be difficult to create a placebo and adequately blind participants as to which therapy they are assigned to [8]. In contrast, it has been suggested that there is an expectancy bias due to positive perceptions of the effects of medical cannabis, such that participants receiving a placebo in trials where medical cannabis is a treatment arm have better outcomes compared to those enrolled in studies with other active comparators [12].

With respect to current pharmacotherapies for depression, antidepressants are proven to be efficacious [13]. However, their effect size is typically modest, with variability between individuals, with approximately only 30% of individuals experiencing remission [13–15]. This is why it is important to develop novel treatments, such as medical cannabis, for depression. To determine the true efficacy of medical cannabis and integrate it within clinical practice guidelines it will be important to compare it against placebo and currently available antidepressants within randomized controlled trials. The associated challenges and costs of conducting these present barriers, but the advances in real-world evidence provide insights to help improve the likelihood of their success. Patients with co-morbid anxiety have demonstrated greater improvements in depression compared to those without anxiety, which is concordant with the anxiolytic properties of medical cannabis [1,6]. Moreover, those with more severe depression have demonstrated a greater response rate to medical cannabis compared to those with mild to moderate depressive symptoms [6]. Utilizing this, can help guide inclusion criteria for future studies. Information of relative CBD and THC dosing from currently available observational studies can also help guide appropriate product selection, however data relating to specific products, as shown in chronic pain, can help further inform the ideal products to take forward to clinical trials [16]. The evidence on the efficacy and safety of medical cannabis for depression from pre-clinical and observational studies is promising, but through using these to inform randomized controlled trials over the next 5–10 years will provide immeasurable benefits for advancement of this nascent field.

Declaration of interest

S. Erridge is the Head of Research at Sapphire Medical Clinics and an honorary clinical research fellow at Imperial College London.

S. Mangoo is a medical student at Imperial College London. He has no conflicts of interest to declare.

M.H. Sodergren is Chief Medical Officer at Curaleaf International, a consultant hepatopancreatobiliary surgeon at Imperial College NHS Trust, and a senior clinical lecturer at Imperial College London.

Notes on contribution

Drafting of manuscript: S Erridge, S Mangoo, MH Sodergren. Critical revision: S Erridge, S Mangoo, MH Sodergren. All authors agree to be accountable for all aspects of the work.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.