Naltrexone Maintenance Decreases Cannabis Self-Administration and Subjective Effects in Daily Cannabis Smokers

Abstract

Given that cannabis use is increasing in the United States, pharmacological treatment options to treat cannabis use disorder are needed. Opioid antagonists modulate cannabinoid effects and may offer a potential approach to reducing cannabis use. In this double-blind, placebo-controlled human laboratory study, we assessed the effects of naltrexone maintenance on the reinforcing, subjective, psychomotor, and cardiovascular effects of active and inactive cannabis. Nontreatment-seeking, daily cannabis smokers were randomized to receive naltrexone (50 mg: n=18 M and 5 F) or placebo (0 mg; n=26 M and 2 F) capsules for 16 days. Before, during, and after medication maintenance, participants completed 10 laboratory sessions over 4-6 weeks, assessing cannabis' behavioral and cardiovascular effects. Medication compliance was verified by observed capsule administration, plasma naltrexone, and urinary riboflavin. Relative to placebo, maintenance on naltrexone significantly reduced both active cannabis self-administration and its positive subjective effects ('good effect'). Participants in the placebo group had 7.6 times (95% CI: 1.1-51.8) the odds of self-administering active cannabis compared with the naltrexone group. This attenuation of reinforcing and positive subjective effects also influenced cannabis use in the natural ecology. Naltrexone had intrinsic effects: decreasing ratings of friendliness, food intake, and systolic blood pressure, and increasing spontaneous reports of stomach upset and headache, yet dropout rates were comparable between groups. In summary, we show for the first time that maintenance on naltrexone decreased cannabis self-administration and ratings of 'good effect' in nontreatment-seeking daily cannabis smokers. Clinical studies in patients motivated to reduce their cannabis use are warranted to evaluate naltrexone's efficacy as a treatment for cannabis use disorder.

Figure 1

Percentage of participants self-administering inactive (0.0% THC) or active (5.5% THC) cannabis, that is, purchasing at least 1 puff of cannabis available for self-administration (max=3 puffs) as a function of time and naltrexone dose. Baseline refers to the session before naltrexone administration commenced. Post-NTX refers to the session that occurred at least 1 week following termination of naltrexone administration. All participants received placebo capsules during baseline and post-NTX sessions. *P<0.05, significant difference between the naltrexone and placebo groups. Error bars represent ±SEM.

Figure 2

Mean effects of inactive (0.0% THC) and active cannabis (5.5% THC) on ratings of ‘Good Effect' as a function of naltrexone condition and time. Note the data were statistically analyzed including baseline measures as a covariate. Data collected for 2 h after cannabis administration were averaged. See Figure 1 for details.

Figure 3

Number of participants reporting peak cannabis use in their natural environment as a function of time. Participants were asked to describe the amount of cannabis smoked since their last laboratory visit. Pre-NTX refers to cannabis smoked outside the laboratory on the day before the first session and on the two baseline sessions. Days 1–15 are portrayed; data were not collected for days 16–20. Post-NTX refers to cannabis smoked outside the laboratory on the days 21 and 22; data were not collected for day 23. *P<0.05, significant difference between the distribution of peak cannabis use in the naltrexone and placebo groups.