Molecular Targets of Cannabidiol in Neurological Disorders

Abstract

Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection

“…Results were obtained using the keywords “CB1R,” “CB2R,” “cannabinoid”, “cannabidiol”, “THC”/“Tetrahydrocannabinol”, “anandamide”, “2-AG”, “FAAH”/“Fatty acid amide hydrolase”, and “MAG lipase” plus the terms “seizures,” “epilepsy,” “epileptogenesis,” and “neuroprotection.” We excluded primarily in vitro studies and clinical studies in humans (clinical trials, case reports, observational studies). Studies were evaluated based on their scientific rigor and use of physiologically relevant drug concentrations to in vivo studies [13]. Summary details of all studies examined in the present review are presented in Supplemental Table 1.…”

Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence

“…Furthermore, it has been suggested that cannabidiol targets GPR55 and GPR18 receptors, further subtypes of transient receptor potential receptors (TRPV2, TRPM8, TRPA1), α3 glycine receptors, adenosine receptors, μ and δ opioid receptors, nicotinic acetylcholine receptors, enzymes of the arachidonic acid cascade, ion channels like voltage-gated calcium channels or mitochondrial Na + /Ca 2+ exchange, nitric oxide signaling and inflammatory cytokines (McPartland et al, 2014; Ibeas Bih et al, 2015). To date, the antipsychotic properties of cannabidiol cannot be directly linked to these possible targets.…”

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

“…One particular area of recent interest to researchers and clinicians has been the potential use of non‐psychoactive phytocannabinoids such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4150) or its analogue cannabidivarin, also known as GWP42006 (Hill et al, 2012a; Bialer et al, 2015), in the treatment of epilepsy, particularly the more refractory, drug‐resistant forms (Ibeas Bih et al, 2015; Devinsky et al, 2017; Gaston and Friedman, 2017). …”