Effects of oral cannabidiol (CBD) on spontaneous opioid withdrawal in male and female rats

Opioid use disorder (OUD) remains a public health crisis in the United States. A key factor in continued use, relapse risk, and overdose is the severe withdrawal syndrome that accompanies abstinence. Observational studies suggest cannabis may improve outcomes for patients with OUD. Cannabidiol (CBD), a non-intoxicating compound found in cannabis, is being investigated as a potential treatment for OUD. This study investigated whether CBD alleviated withdrawal symptoms in a rat model of opioid dependence. Sprague Dawley rats (N = 100, 50% female) were administered escalating doses of morphine across 10 days (10–50 mg/kg, s.c., twice daily). Following abrupt discontinuation, withdrawal outcomes were evaluated across acute (38-hr) and protracted (up to day 7) timepoints. Rats were treated with pure CBD (10 or 30 mg/kg, p.o.) or vehicle (sesame oil; 1 mg/ml) daily, beginning 14-hrs after their final morphine or saline injection (n = 8-9 per sex/group). Withdrawal severity was assessed through physical measurements of body weight, food intake, and somatic signs (e.g., body shakes, diarrhea), and pain sensitivity, as well as measurements of anxiety-like behaviors in the protracted phase. Compared to non-dependent controls, morphine-dependent rats had decreased body weight and food intake, showed greater somatic signs, and had increased pain sensitivity that peaked in acute withdrawal (38-hr). Oral CBD did not affect physical symptoms of opioid withdrawal nor protracted anxiety-like behaviors. These data indicate that CBD alone may have limited effectiveness for treating opioid withdrawal. Reports of improved withdrawal symptoms after cannabis use may be attributed to other compounds in cannabis.