PROJECT SUMMARY Despite having distributed thousands of doses of naloxone (NLX) to those at risk of witnessing an opioid- related overdose, deaths in the U.S. remain high. Our research has found that the fear of precipitating withdrawal often makes individuals hesitant to administer NLX, even in life-or-death situations. Meanwhile, once revived, the adverse withdrawal symptoms may lead the overdose victim to seek opioids for relief, putting them again at risk of overdose. The goal of the proposed R21 application is to test the ability of a novel inhaled formulation of the drug dronabinol (synthetic THC), to reduce the severity of NLX-precipitated withdrawal. The endocannabinoid system is a novel target for reducing opioid withdrawal severity. Preclinical studies have demonstrated that THC decreases signs of opioid withdrawal in morphine-dependent rodents. In humans, oral dronabinol and smoked cannabis have been shown to reduce the severity of opioid withdrawal during opioid detoxification and stabilization. Additionally, in the clinical laboratory, cannabinoids have been shown to have analgesics effects that may provide relief from the muscle and joint pain commonly seen during opioid withdrawal. For this randomized, double-blind, placebo-controlled, inpatient, clinical laboratory study, inhaled dronabinol (.00, .35, .70 mg) will be combined with intranasal (IN) NLX (0.0, 0.2 and 0.4 mg). This investigation will recruit healthy participants with Opioid Use Disorder (N=16). Testing will begin following 5-7 days of stabilization on oral morphine (30 mg, QID). During each testing session, a single dronabinol + naloxone dose combination will be assessed with 48 hours between testing sessions (> 5 half-lives via this route). Laboratory testing sessions will consist of a modified naloxone challenge procedure (Wang Test) that our division has used for over 15 years. The challenge begins with baseline assessment of opioid withdrawal, measurements of miosis (pupil diameter; an indicator of mu-opioid receptor activation), and vital signs. Common symptoms of opioid withdrawal will be assessed by a blinded research nurse. Each symptom is coded as either “absent” or “present” points added when a symptom is observed. Following pre-test assessments, the physician will administer the study drug combination. Assessments of withdrawal are made at 10-minute intervals up to 50 minutes after study drug. The total withdrawal score is calculated at the end of the session. The Subjective and Clinical Opioid Withdrawal Scales also be utilized. The primary aim of this project is to assess the ability of dronabinol to alter the severity of NLX-precipitated withdrawal (dependent variable (DV): total withdrawal score). Secondary aims include: the safety of inhaled dronabinol in combination with naloxone (DV: non-withdrawal-related adverse events & physiological parameters), the effects of dronabinol on naloxone’s antagonism of the µ-opioid receptor (DV: pupil diameter), and ...