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The complexity of pharmacology of cannabidiol (CBD) and its implications in the treatment of brain disorders

Cannabidiol (CBD) is one of the major cannabinoid constituents of the Cannabis plant. Recently, CBD has sparked the interest of medical researchers because of its more than 65 identified molecular targets. Of those, mostly studied in brain disorders are cannabinoid, 5HT1A receptors, G-protein receptor protein 55 (GPR55), transient receptor potential (TRP) channels, and cytochrome P450s [1]. Here we discuss possible mechanisms of actions of CBD in several brain disorders.

The evidence suggests that the antiepileptic potential of CBD may be via its modulation of TRP (vanilloid 1 and TRPA), potassium channels, NMDA receptors, and more recently by the interaction with GPR55 to reduce neuronal excitability [1, 2]. Although in the US, CBD is currently prescribed as an adjuvant treatment for seizures in Lennox-Gastaut and Dravet syndromes, as well as tuberous sclerosis complex, it is still unknown if CBD’s antiepileptic properties are due to its direct interaction with the molecular targets, or possibly through potentiating effects of antiepileptic treatments by modulation of cytochrome P450s [1, 3].

CBD exhibited anxiolytic properties by acting on the 5HT1A receptors in animal models [1]. Most recently, an in vitro study showed that CBD might also elicit anxiolytic effects by allosterically modulating GABAA receptors [4]. Human studies using CBD were limited to assessing the short-term effects of CBD on social anxiety disorder (SAD) [1].

By the mechanism of action on the CB1 receptor, CBD attenuated behavioral responses to different forms of aversive memories in rodent PTSD models [5]. Although in human studies, CBD was associated with reduced PTSD symptomatology, the evidence is only limited to case studies, while possibly being confounded by the co-administration of other psychiatric treatments [6].

The antidepressant properties of CBD by activation of 5HT1A receptors were revealed in animal models of depression [1]. However, to date, CBD’s effects on clinical depression have not been studied.

CBD has been proposed to have anti-psychotic effects by modulating dopamine D2, cannabinoid receptors, and TRPV1 channels; however, these mechanisms are somewhat speculative, given the lack of reproducibility of findings. In human studies, CBD produced conflicting evidence to either augment or improve the symptoms of schizophrenia [1].

The anti-addictive potential of CBD was demonstrated in animal models of cannabis, opioid, alcohol, methamphetamine, and cocaine use disorders. Although CBD’s molecular pathways are still poorly understood, they may include neuronal excitability, 5HT1A receptors and possibly cannabinoid and opioid systems. In small-scale clinical trials, CBD reduced cigarette consumption and heroin cue-induced craving. The anecdotal evidence also shows the positive effects of CBD on reducing symptoms of cannabis and alcohol use disorders, yet these effects need further investigation in larger trials [1].

In summary, the complexity of CBD pharmacology is due to CBD’s ability to interact with several molecular targets, making it a good candidate for further therapeutic investigation. Currently, in the US, CBD is only prescribed for treatment of childhood epilepsies, while other indications are still under exploration. To fully elucidate its true therapeutic potential in other brain disorders, CBD needs to be tested in larger-scale randomized, placebo-controlled trials.

Funding and disclosure

BLF has received in-kind donation of cannabis products from Canopy Innovations Inc. and Aurora Cannabis and medication donation from Pfizer and Bioprojet. He was provided a coil for the TMS study from Brainsway. BLF will conduct research with funding obtained from Canopy Innovations Inc. and Aphria (through research grants handled by CAMH and University of Toronto), Bioprojet, ACS and Alkermes. BLF has received in kind donations of nabiximols from GW Pharma for studies funded by CIHR and NIH. The authors declare no competing interests.

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Correspondence to Bernard Le Foll.

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Elsaid, S., Le Foll, B. The complexity of pharmacology of cannabidiol (CBD) and its implications in the treatment of brain disorders. Neuropsychopharmacol. 45, 229–230 (2020). https://doi.org/10.1038/s41386-019-0518-1

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