Single and combined effects of plant-derived (THC, CBD) and synthetic (WIN-55,212) cannabinoids on cognition and cannabinoid-associated withdrawal signs in mice.

Background and PurposeIt has been suggested that the non-euphorogenic phytocannabinoid cannabidiol (CBD) can ameliorate adverse effects of (9)-tetrahydrocannabinol (THC). We determined whether CBD ameliorates cognitive deficits and withdrawal signs induced by cannabinoid CB1/CB2 receptor agonists or produces these pharmacological effects on its own. Experimental ApproachThe effects of THC or the CB1/CB2 receptor full agonist WIN55212 alone, CBD alone or their combination were tested across a range of doses. Cognitive effects were assessed in C57BL/6 mice in a conditional discrimination task and in the Barnes maze. Cannabinoid withdrawal signs were assessed following precipitated withdrawal by acute administration of the CB1 receptor antagonist SR141716, the 5-HT1A receptor antagonist WAY100635, the TRPV1 receptor antagonist capsazepine or the adenosine A(2A) receptor antagonist SCH58261. Key ResultsTHC produced significant motor and cognitive impairment in the Barnes maze task, none of which were attenuated by the addition of CBD. CBD alone did not affect cognitive performance. Precipitation of withdrawal signs by SR141716 occurred in mice chronically treated with THC or WIN55,212. These withdrawal signs were not attenuated by addition of chronic CBD. Chronic treatment with CBD alone did not induce withdrawal signs precipitated by SR141716 or WAY100635. Chronic CBD treatment also produced anxiolysis, which was not altered by attempting to precipitate withdrawal-induced anxiety with a range of antagonists. Conclusions and ImplicationsCBD as a monotherapy may prove to be a safer pharmacological agent, than CB1 receptor agonists alone or in combination with CBD, for the treatment of several disorders.