Mu opioid receptor gene variant modulates subjective response to smoked cannabis

The mu-opioid receptor (MOR) mediates the rewarding properties of many psychoactive drugs and is an important target in the treatment of addictions. Functional interactions between the opioid and endocannabinoid systems are established and have been hypothesized to contribute to the effects of cannabis. We investigated associations between three single nucleotide polymorphisms in the MOR gene OPRM1 (rs1799971, rs2281617, and rs510769) and subjective responses to smoked cannabis. Fifty-two regular cannabis users (1-4 days/week) were given a cannabis cigarette (12.5% THC) and rated their subjective responses on visual analog scales at baseline and at multiple time points after smoking. Blood samples were collected for THC quantification. There was a significant impact of the intronic variant rs510769 on subjective cannabis effects and THC blood levels. The influence of this gene variant may thus be mediated by pharmacodynamics and/or pharmacokinetic factors. We provide novel evidence that variability in OPRM1 contributes to individual responses to cannabis and may affect risk of cannabis use disorder. Our findings add to the growing body of literature on the genetic basis of individual responses to cannabis and may have implications for targeting the endogenous opioid system in the treatment of cannabis use disorder.