Opioid abuse and dependence continues to be a significant problem in the US;in particular, rates of non-medical use of prescription opioids have increased in the past several years. The main treatment approaches include detoxification followed by psychosocial treatment or agonist maintenance. Unfortunately, rates of relapse are high with detoxification only approaches, and agonist-based treatments have several limitations and remain controversial. The alternative pharmacological strategy, naltrexone maintenance, has clear advantages. However, its use has been limited due to difficulties in initiating treatment and poor tolerability during the first weeks of treatment. Pharmacological strategies targeting aversive symptoms associated with opioid withdrawal and naltrexone induction could significantly improve its early tolerability, permit expansion of clinical use, and improve long-term outcome of opioid dependence treatment. There is strong support, from preclinical and preliminary clinical studies suggesting that dronabinol, a cannabinoid receptor agonist, may be effective in improving tolerability of naltrexone induction. Dronabinol may diminish signs and symptoms associated with naltrexone induction consistent with acute and residual opioid withdrawal, such as insomnia, anergia, hyperalgesia, GI distress, lack of appetite, anxiety, irritability, heightened stress reactivity, dysphoria, and anhedonia. Our uncontrolled observations suggest that among naltrexone-treated opioid dependent patients, moderate use of cannabis was associated with improved treatment retention. The goal of this three-year study is to test the efficacy of dronabinol as an adjunct to maintenance treatment with naltrexone in opioid-dependent individuals. We are proposing a randomized, double-blind, placebo controlled, parallel-groups, 8-week study of relapse prevention in opioid-dependent individuals. Participants will be randomized into one of two conditions: (1) Naltrexone + Placebo and (2) Naltrexone + dronabinol 20 mg bid (N=40 per group). Treatment will be delivered in an outpatient setting except for the initial phase of inpatient detoxification, lasting 8 days. A long-acting, injectable form of naltrexone 380 mg (Vivitrol) will be administered once per month (the total of two injections), while dronabinol or placebo will be taken daily. In addition, patients will receive a psychosocial intervention that will include elements of motivational interviewing and cognitive-behavioral relapse prevention therapy. Primary outcome measure will be retention in treatment by the end of the study. The primary aim is to test the efficacy of dronabinol in reducing attrition during detoxification and the first two months of naltrexone treatment. PUBLIC HEALTH RELEVANCE: Rates of opioid dependence have increased steadily over the past several years, mostly due to an increase in illicit use of prescription analgesics. The available treatments (agonist-based or therapy-only approaches) are not suitable for all patients and have limited effectiveness. Development of an improved antagonist based approach would open it up as a viable treatment alternative for a larger population of opioid dependent individuals.