Effects of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and THC:CBD mixtures on behavioral and physiological signs of morphine withdrawal in rhesus monkeys.

Abstract

The mu-opioid receptor agonists methadone and buprenorphine are effective for treating opioid use disorder (OUD); however, both drugs are diverted and misused and withdrawal signs can emerge when treatment is tapered or discontinued. Mu-opioid and cannabinoid type 1 receptors are colocalized in several brain regions, and cannabinoids have been proposed as potential treatments for opioid withdrawal. This study tested Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), alone and in mixtures, for treating the behavioral and physiological signs of morphine withdrawal in 3 male rhesus monkeys. The α₂-adrenergic receptor agonist lofexidine was also tested. Monkeys received escalating doses of morphine up to 3.2 mg/kg twice daily. After at least 2 weeks of morphine treatment, saline was substituted for morphine for 2 days. Behavioral and physiological signs of opioid withdrawal, including blood pressure, heart rate, body temperature, and activity were measured before and after administration of THC (0.32-1.0 mg/kg), CBD (10-17.8 mg/kg), mixtures of THC (0.32 mg/kg) and CBD (10-17.8 mg/kg), lofexidine (0.032-0.32 mg/kg), or vehicle. Discontinuing morphine treatment markedly increased unusual tongue movements, a characteristic behavioral sign of opioid withdrawal in monkeys, and all physiological signs. The largest THC dose (1.0 mg/kg) decreased unusual tongue movements and heart rate, and the largest lofexidine dose (0.32 mg/kg) decreased unusual tongue movements, blood pressure, heart rate, and activity. CBD alone or with THC had no significant effect. These data demonstrate that THC attenuates some signs of opioid withdrawal; however, THC was not more effective than the currently available medication lofexidine. SIGNIFICANCE STATEMENT: Δ⁹-Tetrahydrocannabinol (THC) alone, but not cannabidiol either alone or in combination with THC, decreased some behavioral and physiological signs of opioid withdrawal in monkeys. However, those effects of THC were not greater than the effects of the currently available nonopioid medication lofexidine.