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Ambient Temperature Effects on 3,4-Methylenedioxymethamphetamine-Induced Thermodysregulation and Pharmacokinetics in Male Monkeys

Departments of Physiology and Pharmacology (M.L.B., P.W.C., M.A.N.) and Radiology (M.A.N.), Wake Forest University School of Medicine, Winston-Salem, North Carolina; Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio (J.E.S., D.F.K.); and Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana (D.E.N.)

Changes in ambient temperature are known to alter both the hyperthermic and the serotonergic consequences of 3,4-methylenedioxymethamphetamine (MDMA). Metabolism of MDMA has been suggested to be a requisite for these neurotoxic effects, whereas the hyperthermic response is an important contributing variable. The aim of the present study was to investigate the interaction between ambient temperature, MDMA-induced thermodysregulation, and its metabolic disposition in monkeys. MDMA (1.5 mg/kg i.v.) was administered noncontingently at cool (18°C; n = 5), room (24°C; n = 7), and warm (31°C; n = 7) ambient temperatures. For 240 min following MDMA administration, core temperature was recorded and blood samples were collected for analysis of MDMA and its metabolites 3,4-dihydroxymethamphetamine (HHMA), 3,4-dihydroxyamphetamine, and 3,4-methylenedioxyamphetamine (MDA). A dose of 1.5 mg/kg MDMA induced a hypothermic response at 18°C, a hyperthermic response at 31°C, and did not significantly change core temperature at 24°C. Regardless of ambient temperature, plasma MDMA concentrations reached maximum within 5 min, and HHMA was a major metabolite. Curiously, the approximate elimination half-life (t) of MDMA at 18°C (136 min) and 31°C (144 min) was increased compared with 24°C (90 min) and is most likely because of volume of distribution changes induced by core temperature alterations. At 18°C, there was a significantly higher MDA area under the concentration-time curve (AUC) and a trend for a lower HHMA AUC compared with 24°C and 31°C, suggesting that MDMA disposition was altered. Overall, induction of hypothermia in a cool environment by MDMA may alter its disposition. These results could have implications for MDMA-induced serotonergic consequences.

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