Effects of (+/-)3,4-methylenedioxymethamphetamine, (+/-)3,4-methylenedioxyamphetamine and methamphetamine on temperature and activity in rhesus macaques

Abstract

Severe and malignant hyperthermia is a frequently reported factor in emergency department (ED) visits and fatalities in which use of amphetamine drugs, such as (+/-)3,4-methylenedioxymethamphetamine (MDMA), (+/-)3,4-methylenedioxyamphetamine (MDA) and (+)methamphetamine (METH), is confirmed. Individuals who use "ecstasy" are also often exposed, intentionally or otherwise, to several of these structurally-related compounds alone or in combination. In animal studies the degree of (subcritical) hyperthermia is often related to the severity of amphetamine-induced neurotoxicity, suggesting health risks to the human user even when emergency medical services are not invoked. A clear distinction of thermoregulatory risks posed by different amphetamines is therefore critical to understand factors that may produce medical emergency related to hyperthermia. The objective of this study was therefore to determine the relative thermoregulatory disruption produced by recreational doses of MDMA, MDA and METH in nonhuman primates. Body temperature and spontaneous home cage activity were monitored continuously in six male rhesus monkeys via radiotelemetric devices. The subjects were challenged intramuscularly with 0.56-2.4 mg/kg MDMA, 0.56-2.4 mg/kg MDA and 0.1-1.0 mg/kg METH. All three amphetamines significantly elevated temperature; however the time course of effects differed. The acute effect of METH lasted hours longer than MDA or MDMA and a disruption of nighttime circadian cooling was observed as long as 18 h after 1.0 mg/kg METH and 1.78-2.4 mg/kg MDA, but not after MDMA. Activity levels were only reliably increased by 0.32 mg/kg METH. It is concluded that while all three substituted amphetamines produce hyperthermia in rhesus monkeys, the effects do not depend on elevated locomotor activity and exhibit differences between compounds. The results highlight physiological risks posed both by recreational use of the amphetamines and by current trials for clinical MDMA use.

Figure 1

The mean (N=6, bars indicate SEM) subcutaneous temperature values following acute challenge with doses of (±)3,4-methylenedioxymethamphetamine (MDMA), (±)3,4-methylenedioxyamphetamine (MDA) and (+)methamphetamine (METH) are presented. Breaks in the series indicate the time of injection. The statistical analysis included the interval −10 to 240 minutes after injection and a significant change from the −10 min time point is indicated by the open symbol for each treatment condition. The * and # indicate timepoints in which all four (*) or three of four (#) active dose conditions differed significantly from the vehicle temperature; see text for additional effects determined to be statistically reliable.

Figure 2

The mean (N=6, bars indicate SEM) subcutaneous temperature values in the 20 hours following acute challenge with doses of (±)MDMA, (±)MDA and (+)METH are presented. Error bars (SEM) are selectively presented for visual clarity. The statistical analysis included the interval −1 to 18 hours after injection and the open symbols indicate a significant difference from the vehicle condition at a given timepoint. A significant increase from the time point preceding injection is indicated by *, however significant decreases from baseline are not depicted, see Results.

Figure 3

The mean (N=6) activity values following acute challenge with doses of (±)MDMA, (±)MDA and (+)METH are presented. Breaks in the series indicate the time of injection. Error bars (SEM) are selectively presented for visual clarity. Statistical conventions are as in Figure 1.

Figure 4

The mean (N=6, bars indicate SEM) activity values in the 20 hours following acute challenge with doses of (±)MDMA, (±)MDA and (+)METH are presented. Error bars (SEM) are selectively presented for visual clarity. The statistical analysis included the interval −1 to 18 hours after injection and the open symbols indicate a significant difference from the pre-injection baseline and a significant increase from the vehicle conditions is indicated by *.