Combining Synthetic THC With an Alpha-2 Agonist Did Not Help People Quit Cannabis in a Large Trial
A rigorous 11-week trial of 122 cannabis-dependent adults found that combining dronabinol (synthetic THC) with lofexidine (an alpha-2 agonist) was no better than placebo at achieving cannabis abstinence.
Quick Facts
What This Study Found
With no approved medications for cannabis use disorder, researchers tested a combination approach: dronabinol (synthetic THC, to ease withdrawal by providing cannabinoid receptor stimulation) plus lofexidine (an alpha-2 agonist, to reduce noradrenergic symptoms of withdrawal).
One hundred fifty-six cannabis-dependent adults were enrolled, with 122 randomized after a placebo lead-in week. Participants received either dronabinol 20 mg three times daily plus lofexidine 0.6 mg three times daily, or matching placebos, for 8 weeks with a 2-week taper and 1-week monitoring.
The result was clearly negative. The proportion achieving 3 weeks of abstinence during the maintenance phase was virtually identical: 27.9% for the medication group versus 29.5% for placebo. Both groups showed reduction in cannabis use over time, suggesting the behavioral therapy component (weekly motivational enhancement and relapse prevention) was driving improvement, not the medications.
Key Numbers
156 enrolled, 122 randomized. 3-week abstinence: 27.9% medication vs. 29.5% placebo. Dronabinol 20 mg TID + lofexidine 0.6 mg TID for 8 weeks. Both groups showed reduction in use over time. Weekly behavioral therapy provided to all.
How They Did This
Randomized, double-blind, placebo-controlled, 11-week trial. 156 enrolled, 122 randomized after 1-week placebo lead-in. Dronabinol 20 mg TID plus lofexidine 0.6 mg TID versus matched placebo. All participants received weekly motivational enhancement and relapse prevention therapy. Primary outcome: 3 weeks abstinence during maintenance phase.
Why This Research Matters
This well-designed negative result is important because it eliminates a promising pharmacotherapy approach and redirects research efforts. The fact that both groups improved equally underscores the value of behavioral interventions for cannabis use disorder even in the absence of effective medication.
The Bigger Picture
Cannabis use disorder is the second most common drug use disorder bringing people into treatment after alcohol. The continued failure to find effective medications highlights both the complexity of cannabis dependence and the importance of behavioral treatments.
What This Study Doesn't Tell Us
The dronabinol dose may not have been high enough to fully replace the cannabinoid stimulation from heavy cannabis use. Lofexidine targets only the noradrenergic component of withdrawal. The placebo lead-in may have selected for participants less likely to respond to medication.
Questions This Raises
- ?Would higher doses of dronabinol alone perform differently?
- ?Is the agonist replacement strategy (like methadone for opioids) fundamentally different for cannabis?
- ?What alternative pharmacological approaches might be more effective?
Trust & Context
- Key Stat:
- 27.9% medication vs. 29.5% placebo achieved 3 weeks abstinence (no difference)
- Evidence Grade:
- Well-designed randomized double-blind placebo-controlled trial with adequate sample size. Strong methodology producing a clear negative result.
- Study Age:
- Published in 2016. Research on cannabis use disorder pharmacotherapy continues, with no FDA-approved medications as of this review.
- Original Title:
- Dronabinol and lofexidine for cannabis use disorder: A randomized, double-blind, placebo-controlled trial.
- Published In:
- Drug and alcohol dependence, 159, 53-60 (2016)
- Authors:
- Levin, Frances R(18), Mariani, John J(7), Pavlicova, Martina(8), Brooks, Daniel, Glass, Andrew, Mahony, Amy, Nunes, Edward V, Bisaga, Adam, Dakwar, Elias, Carpenter, Kenneth M, Sullivan, Maria A, Choi, Jean C
- Database ID:
- RTHC-01208
Evidence Hierarchy
Participants are randomly assigned to treatment or placebo groups to test cause and effect.
What do these levels mean? →Frequently Asked Questions
Is there a medication to help quit cannabis?
Not yet. This trial tested a promising combination of synthetic THC and lofexidine but found it no better than placebo. Behavioral therapy (motivational interviewing and relapse prevention) helped both groups improve.
Why is it so hard to find a medication for cannabis dependence?
Cannabis affects the brain differently than opioids or nicotine, and the withdrawal syndrome may be less amenable to agonist replacement strategies. The search continues for medications targeting different aspects of cannabis dependence.
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Cite This Study
https://rethinkthc.com/research/RTHC-01208APA
Levin, Frances R; Mariani, John J; Pavlicova, Martina; Brooks, Daniel; Glass, Andrew; Mahony, Amy; Nunes, Edward V; Bisaga, Adam; Dakwar, Elias; Carpenter, Kenneth M; Sullivan, Maria A; Choi, Jean C. (2016). Dronabinol and lofexidine for cannabis use disorder: A randomized, double-blind, placebo-controlled trial.. Drug and alcohol dependence, 159, 53-60. https://doi.org/10.1016/j.drugalcdep.2015.11.025
MLA
Levin, Frances R, et al. "Dronabinol and lofexidine for cannabis use disorder: A randomized, double-blind, placebo-controlled trial.." Drug and alcohol dependence, 2016. https://doi.org/10.1016/j.drugalcdep.2015.11.025
RethinkTHC
RethinkTHC Research Database. "Dronabinol and lofexidine for cannabis use disorder: A rando..." RTHC-01208. Retrieved from https://rethinkthc.com/research/levin-2016-dronabinol-and-lofexidine-for
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.