Cross-national reflections on medicinal cannabis and depression

Major Depressive disorder (MDD) manifests by dysphoria, anhedonia, sleep disturbances, poor concentration, fatigue, hopelessness, and suicidality [1]. MDD is highly prevalent worldwide and a major cause of disease burden [1]. Antidepressants are helpful, but many individuals do not respond optimally to these medications [2]. Seeking relief, patients have been utilizing cannabis for thousands of years [3], and more recently have been increasingly turning to medical cannabis (MC). Persons with MDD are more inclined to use marijuana [4,5] and a cross-national meta-analysis identified that pain (64%), anxiety (50%), and depression (34%) were among the major reasons for the use of MC [6]. Several countries including the UK, Canada, Israel, Australia, and the US have approved MC registries, providing convenient samples to help understand the effects of MC in naturalistic settings. Many of these studies examine whether MC alters the course of pain, depression, insomnia and generally include measures of tolerability and safety. Although such studies cannot establish causality, they may help clarify MC safety in real world clinical settings. In one such study, Mangoo et al. (2023) [7] examined changes in depression scores in 129 UK patients who received MC for depression. These patients were moderately depressed as measured by the Patient Health Questionnaire (PHQ-9) and unresponsive to antidepressants. PHQ-9 is a nine-question validated tool that screens for the presence and severity of depressive symptoms. MC was administered via sublingual, vaporized or oral routes. The median daily cannabidiol dose was 100 mg from oil and 0.5 mg from dry flower. This study found that MC treatment was associated with reductions in depression severity at 1, 3, and 6 months [7]. Improvements in PHQ-9 were larger in patients with anxiety, illicit cannabis users and those with severe depression. MC was also associated with decrease in anxiety symptoms as well as sleep and health-related quality of life after 1, 3, and 6 months [7]. 14% reported adverse effects such as fatigue and insomnia, mostly of mild to moderate degree with no disabling adverse events [7]. While this study suggests potential benefits of MC, a Canadian study [8] casts doubt on some of these findings. Round et al. 2020 conducted an observational cohort study (N = 5103) examining the effect of MC on the PHQ-9 in adults receiving MC for any reason up to 3.2 years [8]. These patients had mild depression with the average PHQ-9 score at baseline of 10.5. Of interest, 3.4% of the sample reported improvement and 1.5% reported worsening of their depression [8]. Overall, most MC users showed no clinically significant changes in PHQ-9 scores following MC use [8]. Of note, the patients in the UK sample who exhibited improvements had moderate depressive symptoms relative to the Canadian sample which had mild symptoms. This may have influenced the results. Also noteworthy, are the possible contribution of pharmacological variables, as the mood effects of MC may depend on THC content, frequency, and quantity of use. MC formulations in Canada and the UK may vary in their THC/CBD concentrations, which may account for the variability of clinical effects. While both studies included various MC formulations such as smoking, vaporized or sublingual they did not report on THC/CBD dose ratios. Finally, patients were free to consume illicit cannabis, which can further confound the findings. In both studies, MC was relatively well-tolerated and when it did not help, it apparently did not worsen outcomes.

In contrast to the Canadian study, an observational study from Australia by Vickery et al. (2022) [9] on the use of oral MC in a cohort of 3,961 cannabis-naïve patients with diverse symptoms (e.g. pain, depression, anxiety) showed significant improvements in pain, depression, anxiety, stress, insomnia as well as the clinical global impression [9], similar to results of the UK study [7]. The median total oral daily dose was 10 mg for THC and 22.5 mg for CBD [9]. These doses were generally well-tolerated and remained stable (a surrogate measure for tolerance/addiction) over a two-year period [9].

Together, these cross-national observations seem to suggest that MC may help pain, insomnia, depression, and anxiety in convenience samples with adequate tolerability. However, most studies used measures that captured patient spontaneous side effects reporting and did not explicitly look for addiction as a possible adverse outcome. Cannabis use disorder (CUD) refers to compulsive use of cannabis and impaired control over cannabis use, regardless of consequences [8]. CUD is an important outcome as it has its own sets of risks such as adverse social and health consequences as well as prognostic implications [9]. Currently the risk of CUD in observational studies remains incompletely understood.

In the US Gilman et al. 2022 examined the effects of acquiring a MC card in patients with depression, anxiety, insomnia or pain and the emergence of CUD in a single blind trial. Participants (N- = 186) were randomized either to an immediate card acquisition group or a delayed card acquisition group [10]. The immediate marijuana card group significantly improved their insomnia relative to the 12-week waiting group. There were no significant changes in pain, anxiety, or depression. While only randomized controlled trials can establish efficacy/safety of an intervention, the immediate marijuana card group had more symptoms of CUD [10]. The investigators had concerns about the development of CUD particularly among individuals who sought a marijuana card for depressive symptoms. To the degree that observational studies reflect real world safety data, the development of CUD has clinical and epidemiological implications and merits further examination.

Overall, the use and acceptance of MC appears to be on the rise. As more and more countries adopt this treatment, increased efforts need to be made to understand the harms and benefits of MC in naturalistic settings.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

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

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Funding

This article was funded by departmental resources from the University of Connecticut, the University of Pennsylvania-Perelman School of Medicine and Hartford Behavioral Health, Connecticut.