Cannabidiol for Mood Disorders: A Call for More Research

The link between cannabis use disorders and poor outcomes in major affective disorders has been studied for several years. ^1,2 However, there is an increasing interest on the possible role of cannabidiol (CBD), that is, the nonpsychoactive compound of cannabis, for the treatment of mood disorders. In particular, due to its complex pharmacological properties, it seems that CBD may interact with several neurotransmitter systems, including the serotonergic, glutamatergic, and endocannabinoid ones, and may induce neurobiological changes associated with depression. ³ In a work recently published in The Canadian Journal of Psychiatry, ⁴ the current evidence on CBD as a potential therapeutic approach for mood disorders was reviewed. The authors highlighted that clinical trials testing CBD in individuals with mood disorders as a primary condition were not available. Thus, results of this systematic review were based just on clinical studies evaluating mood symptoms as secondary outcomes in different health conditions such as chronic pain and multiple sclerosis. This confirms what emerged from another recent systematic review emphasizing that, since there are no randomized controlled trials (RCTs) based on depression as a primary health condition, the evidence on the role of cannabinoids for the improvement of mood disorders is scarce. ⁵ Consistently, taking into account also other sources of heterogeneity from the literature in terms of eligible individuals, tested compounds (pure CBD or mixed CBD and Δ-9-tetrahydrocannabinol [THC]), CBD target doses, methods to assess depressive symptoms, study design, and mixed results from available studies, the review could not draw clear conclusions on the efficacy of CBD for mood disorders. ⁴ Nonetheless, based on the possible biological rationale mainly deriving from preclinical studies, the authors suggest that the potential role of CBD in the treatment of mood disorders cannot be ruled out and emphasize the urgent need for well-conducted RCTs on CBD as an add-on treatment for acute episodes of major depressive disorder and/or bipolar depression. However, the current state of research in this field does not seem reassuring. According to main clinical trial registers (clinicaltrial.gov, the EU Clinical Trials Register, and the Australian New Zealand Clinical Trial Registry), only two active trials on bipolar disorder are available, that is, one testing CBD as an adjunctive treatment for bipolar depression (clinicaltrials.gov Identifier: NCT03310593) and another assessing effects of CBD and THC on cognition, without considering outcomes related to mood (clinicaltrials.gov Identifier: NCT04231643). Moreover, only one trial, based on 16- to 25-year-old cannabis users, was supposed to test CBD for depression (Trial ID: ACTRN12616001001482p), but no update on recruitment status is provided so far. Two additional trials testing, respectively, a mixed compound of THC and CBD (clinicaltrials.gov Identifier: NCT00397605) and pure CBD (EudraCT Number: 2015-000465-31) for bipolar disorder, were withdrawn or prematurely ended. We are afraid there is no evidence for CBD use for mood disorders so far, and it is unlikely that this scenario will change in the near future, considering the paucity of ongoing trials. We thus call for more research on CBD for the treatment of mood disorders in order to warrant adequate and advance evidence.