A Drug Designed to Boost Natural Endocannabinoids Was Itself Addictive in Monkeys

Squirrel monkey intravenous self-administration study using fixed-ratio schedules. Monkeys with prior experience self-administering anandamide or cocaine were tested with AM404 substitution. Reinstatement experiments tested whether AM404 could trigger relapse to previously extinguished drug-seeking. Pharmacological antagonism with rimonabant confirmed mechanism. The FAAH inhibitor URB597 was used to test whether enhancing anandamide levels potentiated the effects.

Endocannabinoid-boosting compounds are being explored as potential treatments for various conditions including addiction and pain. This study raises an important safety flag: compounds that increase brain endocannabinoid levels may themselves carry abuse potential, because the endocannabinoid system is part of the brain's reward circuitry.

The drug development strategy of boosting natural endocannabinoids (rather than using direct cannabinoid agonists like THC) was seen as a potentially safer therapeutic approach. This study complicates that narrative by showing that indirectly increasing endocannabinoid levels can still activate the reward system enough to produce self-administration in primates.

Primate self-administration does not necessarily predict human abuse patterns. The monkeys had prior experience with other drugs, which could sensitize them to reward from AM404. The clinical relevance depends on whether therapeutic doses in humans would reach reinforcing levels. AM404 also has some direct activity at other targets (TRPV1 receptors).