Cannabis use has been on the rise globally, and with that, cannabis use disorder, or CUD, has become an increasing public health concern. While treatment options like behavioral therapy exist, pharmacological interventions for CUD remain limited. A recent randomized controlled trial published in Addiction examined whether varenicline, a medication commonly used for smoking cessation, could help individuals reduce cannabis use. The findings provide new insights, particularly regarding sex differences in treatment response, and may inform future strategies for managing CUD.
Cannabis use disorder is characterized by persistent cannabis use despite negative consequences, inability to cut down, and significant interference with daily functioning. Its prevalence is rising due in part to changing legal regulations and social attitudes toward cannabis. While many users may benefit from counseling or behavioral interventions, the search for effective pharmacological options has been slow. Varenicline, which targets nicotinic acetylcholine receptors, is a candidate due to its known effects on the reward system and success in other substance use disorders.
Varenicline is a selective partial agonist of the α4β2 nicotinic acetylcholine receptor and a full agonist of the α7 receptor. By modulating the mesocorticolimbic dopamine system, varenicline reduces the rewarding effects of nicotine and potentially other substances. Research has shown that varenicline can improve outcomes for tobacco users and may also aid in alcohol reduction, prompting investigations into its effect on cannabis use.
Preclinical studies suggest that the α7 receptor may influence the reinforcing effects of cannabinoids, while the α4β2 receptor modulates their sedative and motor effects. A six-week pilot study hinted that varenicline could reduce cannabis use when combined with behavioral therapy, motivating a more extensive trial to confirm these preliminary findings.
The trial was conducted at two outpatient research clinics in South Carolina from February 2020 to February 2023. The study included 174 participants diagnosed with CUD who used cannabis at least three days per week. Participants were randomized into two groups: one receiving varenicline, titrated to 1 mg twice daily, and the other receiving a placebo. Both groups received weekly medical management sessions focused on supporting medication adherence and reducing cannabis use.
Participants were screened rigorously. Women who were pregnant or nursing and individuals with severe psychiatric disorders, certain medication use, or other substance use disorders were excluded to ensure safety and study integrity.
The primary outcome was the reduction in weekly cannabis use sessions between weeks six and twelve. Secondary outcomes included cannabis use days, urine cannabinoid levels, withdrawal symptoms, craving, anxiety, and overall physical and mental health.
Cannabis use was tracked through daily self-reports, weekly time-line follow-back interviews, and urine tests. Cannabis use sessions were defined as use separated by at least one hour to standardize across different consumption methods. Withdrawal was assessed with the Cannabis Withdrawal Scale, and craving was measured with the Marijuana Craving Questionnaire. Medication adherence was monitored via video-confirmed dosing.
The trial did not find a significant overall reduction in cannabis use sessions for the entire cohort when comparing varenicline to placebo during weeks six through twelve. Both groups showed similar average weekly use sessions, indicating that varenicline did not reduce cannabis use across all participants.
A critical observation was the significant sex-specific effect. Men treated with varenicline had lower cannabis use sessions and days compared to men receiving placebo. This reduction persisted even at follow-up, suggesting sustained benefits. In contrast, women did not experience reductions in cannabis use with varenicline and in some measures, including withdrawal and anxiety, experienced worse outcomes than women receiving placebo.
These sex differences are intriguing because varenicline shows similar efficacy in men and women for tobacco cessation. In this study, lower medication adherence among women during the later weeks may have contributed, alongside potential biological or psychological differences in response to varenicline.
Cannabis withdrawal and craving patterns mirrored sex-specific use outcomes. Men receiving varenicline reported similar or lower withdrawal and craving scores compared to placebo. Women, however, experienced higher withdrawal and craving scores on varenicline, which may have contributed to continued cannabis use. Increased anxiety in women during treatment further underscores the complex interaction between medication, sex, and substance use behavior.
Urine cannabinoid tests confirmed the self-reported data. Men on varenicline were more likely to have negative urine screens compared to men on placebo, supporting the observed reductions in cannabis use. Women did not show these patterns, highlighting the importance of considering sex in pharmacological treatment strategies.
Adverse events were more common in the varenicline group but were consistent with known side effects, including nausea and dream disturbances. Men and women reported similar types of adverse events, although women had lower adherence, potentially due to these tolerability issues.
The study has several important implications:
The study’s generalizability is limited by several factors:
This randomized controlled trial indicates that varenicline may be an effective pharmacological option for reducing cannabis use in men with cannabis use disorder when combined with medical management. Women did not benefit in the same way, and in some cases experienced worse withdrawal and anxiety symptoms. These findings suggest the potential for sex-specific approaches in CUD treatment and highlight the need for further research to optimize pharmacotherapy strategies.
While pharmacological interventions for CUD remain limited, this study provides a promising step toward evidence-based treatment options, particularly for male users, and underscores the importance of tailoring interventions to individual characteristics.
This blog is for informational purposes only and should not be considered medical advice. Varenicline is a prescription medication and should only be used under the guidance of a qualified healthcare professional. If you or someone you know struggles with cannabis use disorder, please consult a licensed medical provider for evaluation and treatment.
