Comparisons of Δ9-tetrahydrocannabinol and Anandamide on a Battery of Cognition-related Behavior in Nonhuman Primates.

The primary psychoactive ingredient of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC), has medicinal value but also produces unwanted deleterious effects on cognitive function, promoting the search for improved cannabinergic therapeutics. The present studies used a battery of touchscreen procedures in squirrel monkeys to compare the effects of different types of cannabinergic drugs on several measures of performance including learning (repeated acquisition), cognitive flexibility (discrimination reversal), short-term memory (delayed matching-to-sample), attention (psychomotor vigilance), and motivation (progressive ratio). Drugs studied included the cannabinoid agonist Δ9-THC, the FAAH inhibitor URB597, the endocannabinoid anandamide, and its stable synthetic analog methanandamide. The effects of Δ9-THC and anandamide after treatment with, respectively, the CB1 inverse agonist/antagonist rimonabant and the FAAH inhibitor URB597 also were examined. Results show: a) Δ9-THC produced dose-related impairments of discrimination-based cognitive behavior with potency that varied across tasks (discriminative capability<learning<flexibility<short-term memory); b) anandamide alone and URB597 alone were without effect on all endpoints; c) anandamide following URB597 pretreatment and methanandamide had negligible effects on discriminative capability, learning, and reversal, but, following large doses, affected DMTS performance in some subjects; d) all drugs, except anandamide and URB597, disrupted attention; e) progressive ratio breakpoints were generally unaffected by all drugs tested, suggesting little to no effect on motivation. Taken together, these data indicate that metabolically stable forms of anandamide may have lesser adverse effects on cognitive functions than Δ9-THC, possibly offering a therapeutic advantage in clinical settings.
The American Society for Pharmacology and Experimental Therapeutics.