Δ9-Tetrahydrocannabinol attenuates MDMA-induced hyperthermia in rhesus monkeys

Abstract

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, Δ(9)-tetrahydrocannabinol (THC), and other drugs with partial or full agonist activity at the CB(1) 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 CB(1) 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 CB(1) 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.

Figure 1

Mean (N=10, bars indicate SEM) change in body temperature in the initial 300 minutes (upper panel) and 18 hrs (lower panel) after administration of THC (0.1, 0.2 0.3 mg/kg, i.m.). Shaded symbols indicate a significant difference from the baseline (10 min prior to dosing in 300 min analysis; first hour post-dosing in the 18 hr analysis) at a given timepoint. Open symbols indicate significant differences from the baseline within condition and from the vehicle condition at the respective timepoint. A statistically reliable difference from the vehicle condition and 0.1 mg/kg THC conditions at a given timepoint is indicated by * and a difference from all other conditions by #. The bar in the lower panel indicates the dark period (18:30-06:30 in real time), including the 150 min overlap in which animals treated at 10:30 and 13:00 were offset.

Figure 2

Mean (N=6, bars indicate SEM) change in body temperature in the initial 300 minutes (upper panel) and 18 hrs (lower panel) after administration of THC (0.3 mg/kg, i.m.), SR141716 (0.3 mg/kg, i.m.) or the combination. Shaded symbols indicate a significant difference from the baseline (10 min prior to dosing in 300 min analysis; first hour post-dosing in the 18 hr analysis) at a given timepoint. Open symbols indicate significant differences from the baseline within condition and from the vehicle condition at the respective timepoint. A statistically reliable difference from the vehicle condition and 0.3 mg/kg SR141716 conditions at a given timepoint is indicated by * and a difference from all other conditions by #. The bar in the lower panel indicates the dark period (18:30-06:30 in real time), including the 150 min overlap in which animals treated at 10:30 and 13:00 were offset.

Figure 3

Mean (N=5, bars indicate SEM) change in body temperature associated with 1.78 mg/kg MDMA (p.o.) in combination with 0.3 mg/kg THC (i.m.) in the initial 300 minutes after administration. The Vehicle and MDMA conditions have been duplicated on upper and lower panels to depict the relative effect of the two THC doses more clearly. Shaded symbols indicate a significant difference from the baseline (10 min prior to dosing) at a given timepoint. Open symbols indicate significant differences from the baseline within condition and from the vehicle condition at the respective timepoint. A statistically reliable difference from the vehicle condition at a given timepoint is indicated by *, between vehicle and both MDMA conditions by &, between MDMA and the MDMA+THC conditions by †, and a difference from MDMA+THC conditions is indicated by §.

Figure 4

Mean (N=5, bars indicate SEM) change in body temperature associated with 1.78 mg/kg MDMA (p.o.) in combination with 0.1 and 0.3 mg/kg THC i.m. in the 18 hrs after administration. The Vehicle and MDMA conditions have been duplicated on upper and lower panels to depict the relative effect of the two THC doses more clearly. Shaded symbols indicate a significant difference from the first hour post-dosing at a given timepoint. Open symbols indicate significant differences from the first hour within condition and from the vehicle condition at the respective timepoint. A difference between 0.1 and 0.3 mg/kg THC conditions (either alone or in combination with MDMA) is indicated by #. All other statistical conventions are as in Figure 3. The bar in the upper panel (omitted in the lower panel for clarity) indicates the dark period (18:30-06:30 in real time), including the 150 min overlap in which animals treated at 10:30 and 13:00 were offset.