Received for publication April 12, 2007.
Revised July 16, 2007.
Accepted for publication July 17, 2007.

Ambient Temperature Effects on 3,4-methylenedioxymethamphetamine (MDMA)-induced Thermodysregulation and Pharmacokinetics in Male Monkeys

Abstract

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, while 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, IV) 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 (HHA), 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 (t1/2) of MDMA at 18°C (136 min) and 31°C (144 min) was increased compared to 24°C (90 min) and is most likely due to 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 to 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.

Key words: cytochrome P450, cytochrome P450 function, drug disposition, GC/MS, gene/environment interactions, mass spectrometry, metabolite kinetics, pharmacokinetics