Dronabinol for the treatment of cannabis dependence: A randomized, double-blind, placebo-controlled trial

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Abstract

Cannabis dependence is a substantial public health problem. Behavioral treatments have shown promise, but there are no effective medications for cannabis dependence. The purpose of this study was to evaluate the safety and efficacy of dronabinol, a synthetic form of delta-9-tetrahydrocannabinol, a naturally occurring pharmacologically active component of marijuana, in treating cannabis dependence. 156 cannabis-dependent adults were enrolled in a randomized, double-blind, placebo-controlled, 12-week trial. After a 1-week placebo lead-in phase, participants were randomized to receive dronabinol 20 mg twice a day or placebo. Doses were maintained until the end of week 8 and then tapered off over 2 weeks. All participants received weekly motivational enhancement and relapse prevention therapy. Marijuana use was assessed using the timeline followback method. There was no significant difference between treatment groups in the proportion of participants who achieved 2 weeks of abstinence at the end of the maintenance phase (dronabinol: 17.7%; placebo: 15.6%). Although both groups showed a reduction in marijuana use over time, there were no differences between the groups. Treatment retention was significantly higher at the end of the maintenance phase on dronabinol (77%), compared to placebo (61%) (P = .02), and withdrawal symptoms were significantly lower on dronabinol than placebo (P = .02). This is the first trial using an agonist substitution strategy for treatment of cannabis dependence. Dronabinol showed promise, it was well-tolerated, and improved treatment retention and withdrawal symptoms. Future trials might test higher doses, combinations of dronabinol with other medications with complementary mechanisms, or with more potent behavioral interventions.

Introduction

Marijuana is the most commonly used illicit drug in the United States (National Survey on Drug Use and Health, NSDUH, 2008). More that 95 million Americans 12 years or older have tried marijuana at least once and almost 25 million have used it in the past year (NSDUH, 2008). Most marijuana users discontinue use by their mid-20s, but a subset maintains daily, long-term use (Compton et al., 2004, SAMHSA, 2009). After nicotine and alcohol, cannabis dependence is the most prevalent substance dependence syndrome in the general population (NSDUH, 2009, SAMHSA, 2009). Marijuana has surpassed heroin and cocaine as the most common illicit drug listed as the primary problem among patients seeking substance abuse treatment, with nearly 300,000 marijuana-related treatment admissions per year (Treatment Episode Data Set, 2007).

Despite considerable progress in the development of cannabis-dependence-specific psychotherapy interventions, the results of several psychotherapy trials indicate that most dependent patients in treatment do not achieve abstinence (Copeland et al., 2001, Dennis et al., 2004, MTPRG, 2004, Stephens et al., 2000). To date, most of the work conducted evaluating pharmacotherapies for cannabis dependence have been carried out with non-treatment seeking marijuana users in laboratory settings. Several medications have shown potential benefit in reducing some withdrawal symptoms (e.g., mitrazapine, nefazadone) whereas other medications have not shown any clear benefit in mitigating withdrawal symptoms (e.g., bupropion, divalproex) or in reducing the likelihood of relapse (e.g., baclofen) in the laboratory setting (Haney et al., 2001, Haney et al., 2003, Haney et al., 2004, Haney et al., 2010). Unexpectedly, naltrexone increased, rather than decreased, the intoxicating effects of smoked marijuana when administered to non-treatment seekers (Cooper and Haney, 2010). Similarly, outpatient double-blind, randomized treatment trials evaluating nefazadone, bupropion, or divalproex sodium have not shown superiority over placebo in reducing marijuana use (Carpenter et al., 2009, Levin et al., 2004). Compared to other addictive substances, the investigation of pharmacotherapies for cannabis dependence remains limited and no effective medication has yet been identified (McRae-Clark et al., 2009, Nordstrom and Levin, 2007, Vandrey and Haney, 2009).

The agonist substitution strategy has been effective for other substance use disorders, mainly nicotine (nicotine patch, other nicotine replacement products, varenicline) and opioid dependence (methadone, buprenorphine). Therefore, dronabinol, an orally bioavailable synthetic form of delta-9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana acting at the cannabinoid 1 (CB1) receptor, seems a logical candidate medication for cannabis dependence. An ideal agonist medication has low abuse potential, reduces withdrawal symptoms and craving, and decreases the reinforcing effects of the target drug, thereby facilitating abstinence. Dronabinol has been shown to reduce cannabis withdrawal symptoms in laboratory settings among non-treatment seeking cannabis users (Budney et al., 2007, Haney et al., 2004). Although dronabinol produced modest positive subjective effects among cannabis users in the laboratory (Hart et al., 2005), there is little evidence of abuse or diversion of dronabinol in community settings (Calhoun et al., 1998). We conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of dronabinol for patients seeking treatment for cannabis dependence. This is, to our knowledge, the largest clinical trial to date to evaluate a pharmacologic intervention for cannabis dependence, and the first to attempt agonist substitution.

Section snippets

Study participants

All participants were seeking outpatient treatment for problems related to marijuana use and were recruited by local advertising (print, radio, television, and subway) or by clinical referrals in the New York City metropolitan area. The advertisements asked “Is Marijuana a Problem for You?” and informed potential participants that they might qualify for a free and confidential research treatment study at Columbia University Medical Center. The medical screening included a complete history and

Participant progress in study and demographics

The CONSORT diagram showing participant flow through the study is provided in Fig. 1. 709 participants were screened and a total of 156 participants were randomized between DRO (n = 79; 50.6%) and PBO (n = 77; 49.4%). The most common reason for screen failure was that the person was no longer interested in screening or was lost to follow-up (n = 188). The other two most common reasons for screen failure were participation in another clinical trial (n = 92) and exclusionary psychiatric diagnoses (n = 90).

Discussion

To our knowledge, this is the first controlled clinical trial to evaluate agonist substitution pharmacotherapy for cannabis dependence. Dronabinol was superior to placebo in promoting retention in treatment and reducing withdrawal symptoms. However, the overall proportion of patients achieving sustained abstinence was low, and there was no evidence for an advantage of dronabinol over placebo on the outcome of marijuana use. The low overall abstinence rate is similar to low rates found in other

Role of funding source

Funding for this research was provided by NIDA grants P50DA09236 and KO2 000465. NIDA had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Contributors

Author Frances Levin, MD designed the study and wrote the protocol. Authors Frances Levin, MD, John Mariani, MD and Edward Nunes, MD managed the literature searches and summaries of previous related work. Authors Wendy Cheng, MPH, Martina Pavlicova, Ph.D. and Daniel Brooks, MA undertook the statistical analysis, and authors Frances Levin, MD, Daniel Brooks, MA, Wendy Cheng, MPH, and Martina Pavlicova, Ph.D. wrote the first draft of the manuscript. All authors contributed to and have approved

Conflict of interest

Dr. Levin is a past consultant for Shire Pharmaceuticals, OrthoMcNeil Pharmaceuticals and Eli Lily & Co. and has received grant support from UCB Pharma (not current), OrthoMcNeil (not current), Eli Lilly & Company (not current). She currently receives medication from WorldMed for an ongoing study that is sponsored by the National Institute on Drug Abuse. All other authors declare that they have no conflicts of interest.

Acknowledgements

We want to thank the staff of the Substance Treatment and Research Service (STARS) of the New York State Psychiatric Institute for their clinical support.

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