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.

Mechanisms Underlying Sex Differences in Cannabis Use

“…However, no consistently significant relationship between menstrual cycle phase and modulation of cannabis self-administration has been observed [116, 117]. Gender-inclusive studies report similar findings, and additionally demonstrate modulation of self-administration by treatment with oral THC [118, 119], oral cannabidiol [120], and an opioid receptor antagonist [121]. These studies, however, either lack adequate power to test for gender differences, or do not report analyses of gender differences.…”

The cannabis withdrawal syndrome: current insights

“…Cannabis users with opioid dependence are less likely to experience CWS,64 which may indicate the contribution of the endogenous opioid system. In a laboratory study, the µ-opioid receptor antagonist naltrexone was recently shown to reduce self-administration of active cannabis and its related subjective positive effects on heavy cannabis users 65. The authors are unaware of any study having directly examined the effect of naltrexone on the CWS under naturalistic conditions.…”

Screening Medications for the Treatment of Cannabis Use Disorder

“…However, the drug history of the person might be an important determinant of the effects of naltrexone, as THC intoxication was blunted by naltrexone in marijuana users but not in naïve subjects (Haney, 2007). A recent human laboratory study showed that chronic administration of naltrexone attenuates reinforcing and positive subjective effects in daily cannabis smokers (Haney, Ramesh, et al, 2015), which is encouraging for further testing in clinical trials (Figure 4). In fact, a clinical trial studying effectiveness of long-acting injectable naltrexone (Vivitrol) in patients with cannabis dependence is currently recruiting participants (ClinicalTrials.gov).…”

“…Self-administration procedures have been used to study preferences for different concentrations of addictive substances (e.g. nicotine or THC), or whether certain treatments are able to modify drug self-administration (Haney, Ramesh, et al, 2015; Hart, Haney, Ward, Fischman, & Foltin, 2002). Drug self-administration studies have been also useful for evaluating motivation for different types of reinforcers (i.e.…”