May is Mental Health Awareness month, and cannabinoid research might have an important role to play in the development of new psychiatric therapies.  

There is a growing body of evidence that the endocannabinoid system (ECS) plays an essential role in cognitive performance, mood, and stress.^1-3 In preliminary studies, cannabinoids have demonstrated anxiolytic (anti-anxiety), antidepressant, antipsychotic, and neuroprotective properties.

It’s important to note straightaway that most of these results are suggestive, rather than conclusive, of therapeutic utility—that is, there is a great deal of additional research and experimentation that must be performed to draw meaningful conclusions about efficacy and safety to inform the clinical use of cannabinoids.

Some of the initial data are encouraging, though, and continued interrogation of the ECS and its roles in cognitive vitality and pathology is certainly warranted. 

Pharmacologically, the cannabinoid receptor 1 (CB1) appears to be primarily responsible for the observed effects of cannabinoids on mood, anxiety, depression, and stress. In animal studies, low doses of CB1 receptor agonists (activators) reduce anxiety and depressive behaviors. In contrast, CB1 antagonists (deactivators), can produce mood disturbances, depression, and sleep dysfunction. Therapeutic CB1 activation, however, is often part and parcel with the undesirable psychotropic effects associated with cannabis intoxication, so developing CB1 agonists with selective antidepressant activity is a considerable challenge.¹ 

Clinically, some individuals have reported that cannabinoids are preferable to traditional psychiatric drugs because their sedative and anti-anxiety effects are not accompanied by a decrease in cognitive function; though for some patients, cannabinoids seem to induce mental confusion.¹ Both THC and CBD are reported to decrease anxiety symptoms at low doses, but this effect is reversed and even inverted at higher concentrations.²

The use of medicinal cannabinoids as adjuvants, drugs that are administered in conjunction with another medication to enhance the primary medication’s effect, seems promising.³ For example, there is some evidence that cannabis may function as a mood stabilizer in bipolar disorder as an adjuvant to lithium treatment: the addition of cannabis enables reduction in lithium dosage.¹ 

In addition to the challenges common to all drug development efforts (e.g., unknown biological mechanisms, undesirable off-target/side effects, safety), there are several unique difficulties associated with quantifying results in mental health research, including indirectness, inconsistency, and imprecision when reporting outcomes such as changes in anxiety, depression, and total symptoms, global functioning, cognitive performance, and emotional functioning.

Another complicating factor is that mental disorders like anxiety and depression are often secondary to other medical conditions, such as chronic pain and multiple sclerosis. Reliable, robust evidence is lacking in studies where mental disorders are the principal targets of treatment.³

Overall, more extensive pre-clinical research and clinical investigation must be completed so that the promise or peril of cannabinoid-based mental health therapies can be fully uncovered.  

References: 

1. Graczyk, M.; Lukowicz, M.; Dzierzanowski, T. Front. Psychiatry. 2021, 12, 1-9. 

2. Kessler, F. H.; et al. Braz. J. Psychiatry. 2021, 43, 455–457. 

3. Black, N.; et al. Lancet Psychiatry. 2019, 6, 995–1010.