Elsevier

Drug and Alcohol Dependence

Volume 159, 1 February 2016, Pages 53-60
Drug and Alcohol Dependence

Full length article
Dronabinol and lofexidine for cannabis use disorder: A randomized, double-blind, placebo-controlled trial

https://doi.org/10.1016/j.drugalcdep.2015.11.025Get rights and content

Highlights

  • One of the few large placebo-controlled treatment trials for cannabis dependence.

  • Participants were randomized to receive dronabinol plus lofexidine or placebo.

  • There was not a significant effect of treatment on achieving cannabis abstinence.

  • There was not a significant effect of treatment on withdrawal scores across time.

  • The intervention did not show promise as a treatment for cannabis use disorder.

Abstract

Background

Cannabis use disorder is associated with substantial morbidity and, after alcohol, is the most common drug bringing adolescents and adults into treatment. At present, there are no FDA-approved medications for cannabis use disorder. Combined pharmacologic interventions might be particularly useful in mitigating withdrawal symptoms and promoting abstinence.

Objective

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, and lofexidine, an alpha-2 agonist, in treating cannabis dependence.

Methods

One hundred fifty six cannabis-dependent adults were enrolled and following a 1-week placebo lead-in phase 122 were randomized in a double-blind, placebo-controlled, 11-week trial. Participants were randomized to receive dronabinol 20 mg three times a day and lofexidine 0.6 mg three times a day or placebo. Medications were maintained until the end of week eight, were then tapered over two weeks and patients were monitored off medications during the last study week. All participants received weekly motivational enhancement and relapse prevention therapy. Marijuana use was assessed using the timeline follow-back method.

Results

There was no significant difference between treatment groups in the proportion of participants who achieved 3 weeks of abstinence during the maintenance phase of the trial (27.9% for the medication group and 29.5% for the placebo group), although both groups showed a reduction over time.

Conclusions

Based on this treatment study, the combined intervention did not show promise as a treatment for cannabis use disorder.

Introduction

Marijuana use has progressively increased over the past decade, with approximately 19.8 million Americans over the age of 12 estimated to have used marijuana in the past month (SAMHSA, 2014). With the exception of alcohol, marijuana is the primary substance bringing Americans into their most recent substance abuse treatment episode (SAMHSA, 2014). Although there has been substantial work assessing various psychotherapeutic strategies for cannabis use disorders (Budney et al., 2011, Budney et al., 2006, Dennis et al., 2004, McRae et al., 2003) most patients with cannabis use disorder continue to use. Up until this time most of the medication development studies have consisted of laboratory studies (Cooper and Haney, 2010), although the outpatient treatment literature is growing. A recent review looked at 14 pharmacologic treatment studies targeting cannabis use disorder and concluded that there was inadequate evidence to support the utility of any specific medication, perhaps not surprising given the heterogeneity of medications studied, study quality, and variability in study outcomes (Marshall et al., 2014). One of its conclusions was that some agents, such as gabapentin and the glutamatergic modulator, N-acetylcysteine, or combination therapies warrant further investigation.

Dronabinol (delta-9-tetrahydrocannabinol, THC) is a cannabinoid receptor partial agonist, and has been a reasonable choice to test as a treatment for cannabis use disorders since other partial agonists have been found to be effective for other substance use disorders (i.e., buprenorphine for opiate use disorders and varenicline for nicotine use disorder). While dronabinol has shown benefit in reducing some withdrawal symptoms and subjective effects of marijuana (Haney et al., 2004, Hart et al., 2002), it has not been shown to alter smoked marijuana self-administration under laboratory conditions (Haney et al., 2008, Hart et al., 2002). Similarly, dronabinol has been shown to reduce withdrawal symptoms and improve retention in an outpatient treatment trial, but was not superior to placebo in reducing marijuana use or promoting abstinence (Levin et al., 2011).

Because emerging evidence suggests that dronabinol may not treat all aspects of cannabis use disorder, it was hypothesized that augmentation with an agent exhibiting complementary pharmacologic properties would provide added benefit. Lofexidine, an α2 noradrenergic agonist, has been hypothesized to be helpful at dampening cannabis withdrawal and craving given its utility in treating opioid withdrawal and in reducing stress-induced and cue-induced opioid craving (Sinha et al., 2007). Indeed, Haney et al. (2008) found that the combination of lofexidine and dronabinol (Lofex–Dro) was superior to placebo in improving sleep and other cannabis withdrawal symptoms; the combination also outperformed either lofexidine or dronabinol alone in mitigating withdrawal symptoms. Thus, we carried out a double-blind placebo-controlled 11-week trial testing lofexidine and dronabinol for the treatment of cannabis use disorder. We hypothesized that lofexidine and dronabinol (Lofex–Dro) would be superior to placebo in reducing withdrawal and achieving abstinence.

Section snippets

Study participants

As described in our prior marijuana treatment studies (Levin et al., 2011, Levin et al., 2013, Mariani et al., 2011), all participants were seeking outpatient treatment for problems related to marijuana use and were recruited by local advertising. The medical screening included a history and physical examination, an electrocardiogram, and laboratory testing (Levin et al., 2011). The psychiatric evaluation included the Structured Clinical Interview (SCID) for Diagnostic and Statistical Manual of

Participants

The CONSORT diagram shows participant flow through the study (Fig. 1). Screening of 984 individuals yielded 156 participants meeting eligibility criteria who were enrolled in the trial with 122 participants being randomized following the placebo lead-in week. Common reasons for non-randomization included placebo responders and those who were no longer interested in treatment (see Fig. 1). Demographic and baseline clinical characteristics of randomized participants are shown in Table 1. The

Discussion

In contrast to our hypothesis, the concurrent administration of lofexidine and dronabinol was not found to be more effective than placebo for promoting abstinence, reducing withdrawal symptoms, or retaining individuals in treatment. This was surprising given that a prior trial found that dronabinol 40 mg a day, outperformed placebo in reducing withdrawal symptoms and improving retention, albeit not abstinence (Levin et al., 2011).

In the prior trial, when we failed to find a higher abstinence

Conflict of interest statement

Dr. Levin received medication from US WorldMed for this trial and served as a consultant to GW Pharmaceuticals, Eli Lily, and served on an advisory board to Shire in 2006–2007. Dr. Levin also serves as a consultant to Major League Baseball, regarding the diagnosis and treatment of ADHD. Dr. Nunes served on an advisory board for Eli Lily and Company in January 2012. Drs. Nunes, Sullivan and Bisaga receive medication from Alkermes for ongoing studies that are sponsored by the National Institute

Contributors

Author Levin designed the study, wrote the protocol and served as PI of the study. Authors Glass, Pavlicova and Brooks undertook the statistical analysis, and authors Levin, Brooks and Glass wrote the first draft of the manuscript. Author Mahony was responsible for many aspects of study implementation, data collection and organization, IRB coordination and other study features. Authors Mariani, Bisaga and Sullivan served as study physicians. All authors contributed to, edited and have approved

Role of funding source

Funding for this research was provided by NIDA grants P50DA09236, K24 DA029647 and K02 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. US WorldMed supplied lofexidine and matched placebo for this trial but 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

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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