A Phase II Double-Blind Placebo-Controlled Trial of Dronabinol and BRENDA for the Treatment of Cannabis Withdrawal

1. Background: Cannabis is the most widely used illicit drug in the U.S. According to the 2004 U.S. The 2004 NSDUH estimates there are 3.2 million daily or almost daily marijuana smokers in the United States. Recent reports have estimated that 1.5% of the US population meets DSM-IV diagnostic criteria for cannabis abuse or dependence, with the sharpest increases among young black men and women and young Hispanic men (2). Cannabis users commonly endorse adverse psychosocial and medical effects from their cannabis use, which include dysphoria, loss of control over use, cognitive impairment, and strained social relationships.

In humans, the cannabis withdrawal syndrome is a constellation of affective and behavioral symptoms that occur within 24 to 48 hours after abrupt cessation of marijuana use with a gradual return to baseline after 1-2 weeks. A recent review of the literature on cannabis withdrawal identified consistent reports of anxiety, irritability, physical discomfort, insomnia, and appetite suppression to be associated with abrupt cessation of cannabis use in heavy users across controlled inpatient and outpatient trials.

The agonist dronabinol (Marinol) has shown promise in the prevention of cannabis withdrawal in human lab studies and its reported amelioration of anxiety, misery, insomnia, drug craving and appetite suppression from abrupt cannabis cessation provides the rationale for its use as an agent to prevent cannabis withdrawal in an outpatient, treatment seeking population(9). Dronabinol has also been used as a brief "maintenance" treatment in a cannabis self-administration study in humans. Currently, dronabinol is indicated for treatment of AIDS-related anorexia and nausea associated with cancer chemotherapy. Two principle aims of our proposal are therefore to gain familiarity with cannabis withdrawal in a naturalistic outpatient treatment setting and compare an agonist therapy to placebo to attenuate cannabis withdrawal and enhance treatment outcome.

The general pattern of low rates of total abstinence and lack of significant differences between high intensity psychotherapy treatment vs. low intensity and voucher-based treatment holds across all psychosocial treatment studies. In keeping with prior evidence supporting the relative efficacy of brief interventions for cannabis dependence, the current proposal will apply a well-established brief medicalized psychotherapy known as B.R.E.N.D.A. for the treatment of cannabis dependence.

To date, studies evaluating cannabis patients have primarily focused on identifying neurotoxic drug effects such as impaired learning, memory, attention and executive function. We propose to more fully examine the behaviors with relevance to addiction vulnerability and relapse. Such behaviors include but are not limited to poor inhibition, high risk-taking, positive affective bias toward drug stimuli, poor affect regulation, and poor decision-making. We plan to utilize standardized tasks and questionnaires to objectively characterize dimensions of these addiction relevant behaviors in cannabis patients and to examine the effect of cannabis withdrawal and dronabinol treatment on these behavioral measures. We will also correlate brain differences (structural and functional) with behavioral measures in cannabis dependent patients before and after treatment with dronabinol as compared to placebo.