Δ9-Tetrahydrocannabinol attenuates MDMA-induced hyperthermia in rhesus monkeys

Background: Cannabis is commonly consumed by Ecstasy (3,4-methylenedioxymethamphetamine; MDMA) users, including as an intentional strategy to manipulate the drug experience. The most active psychoactive constituent in cannabis, Δ9-tetrahydrocannabinol (THC), and other drugs with partial or full agonist activity at the CB1 receptor, produces a reduction of body temperature in rodents. Reports show that administration of THC can attenuate temperature increases caused by MDMA in mice or rats; however, a recent study in humans shows that THC potentiates MDMA-induced temperature elevations. Relatively little scientific evidence on the thermoregulatory effects of THC in monkeys is available. Methods: The body temperature of male rhesus macaques was recorded after challenge with THC (0.1–0.3 mg/kg, i.m.) or combined challenge of THC with the CB1 receptor antagonist SR141716 (Rimonabant; 0.3 mg/kg, i.m.) or combined challenge of THC (0.1, 0.3 mg/kg, i.m.) with MDMA (1.78 mg/kg p.o.) using minimally-invasive, implanted radiotelemetry techniques. Results: THC reduced the body temperature of monkeys in a dose-dependent manner with the nadir observed 3–5 h post-injection; however, an attenuation of normal circadian cooling was also produced overnight following dosing. Hypothermia induced by THC (0.3 mg/kg, i.m.) was prevented by Rimonabant (0.3 mg/kg, i.m.). Finally, 0.3 mg/kg THC (i.m.) attenuated the elevation of body temperature produced by MDMA for about 4 h after oral dosing. Conclusions: As with rodents THC produces a robust and lasting decrement in the body temperature of rhesus monkeys; this effect is mediated by the CB1 receptor. THC also protects against the immediate hyperthermic effects of MDMA in monkeys in a dose-dependent manner. Nevertheless, a paradoxical attenuation of circadian cooling overnight after the THC/MDMA combination cautions that longer-term effects may be critical in assessing risks for the recreational user of cannabis in combination with MDMA.

▶Δ9-tetrahydrocannabinol (THC) reduces the temperature of freely moving macaques. ▶Effective at doses (0.1–0.3 mg/kg, i.m.) below those which sedate. ▶THC hypothermia is reversed by the CB1 antagonist SR141716/Rimonabant. ▶MDMA-induced hyperthermia is attenuated by THC.