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

Opioid use disorder 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 opioid use disorder and cannabidiol (CBD), a nonintoxicating compound found in cannabis, is being investigated as a potential treatment. 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, twice daily). Following abrupt discontinuation, withdrawal outcomes were evaluated across acute (38-hr) and protracted (up to Day 7) timepoints. Rats were treated daily with oral CBD (10 or 30 mg/kg, p.o.) or sesame oil vehicle, beginning 14-hr after their final morphine or saline injection. Withdrawal severity was assessed through physical measurements of body weight, food intake, and somatic signs (e.g., body shakes, diarrhea), pain sensitivity, and measurements of anxiety-like behaviors in the protracted phase. Compared to nondependent 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). In the protracted phase, limited withdrawal signs and no anxiety-like behaviors were detected. Oral CBD did not affect symptoms of opioid withdrawal. 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. (PsycInfo Database Record (c) 2026 APA, all rights reserved).