Oral administration of (+/-)3,4-methylenedioxymethamphetamine and (+)methamphetamine alters temperature and activity in rhesus macaques

Abstract

Rationale: Emergency Department visits and fatalities in which (+/-)3,4-methylenedioxymethamphetamine (MDMA) or (+)methamphetamine (METH) are involved frequently feature unregulated hyperthermia. MDMA and METH significantly elevate body temperature in multiple laboratory species and, most importantly, can also produce unregulated and threatening hyperthermia in nonhuman primates. A majority of prior animal studies have administered drugs by injection whereas human consumption of "Ecstasy" is typically oral, an important difference in route of administration which may complicate the translation of animal data to the human condition.

Objective: To determine if MDMA and METH produce hyperthermia in monkeys following oral administration as they do when administered intramuscularly.

Methods: Adult male rhesus monkeys were challenged intramuscularly (i.m.) and per os (p.o.) with 1.78 or 5 mg/kg (+/-)MDMA and with 0.1 or 0.32 mg/kg (+)METH. Temperature and activity were monitored with a radiotelemetry system.

Results: Oral administration of either MDMA or METH produced significant increases in body temperature. Locomotor activity was suppressed by MDMA and increased by METH following either route of administration.

Conclusions: The data show that the oral route of administration is not likely to qualitatively reduce the temperature increase associated with MDMA or METH although oral administration did slow the rate of temperature increase. It is further established that MDMA reduces activity in monkeys even after relatively high doses and oral administration.

Figure 1

Mean (N=6, bars indicate SEM) temperature for animals treated with 1.78 mg/kg MDMA per os (left panels) or intramuscularly (right panels). Temperature data are represented as changes from the average of three samples prior to administration for each animal to appropriately reflect the repeated measures analysis of the absolute temperature data. The break in each series indicates the time of injection; the slight change in temperature at time “0” in part reflects variation in injecting all 6 subjects relative to the computer sampling schedule and the moving average procedure, see Methods. The intramuscular data were previously reported (Crean et al., 2006) and are reused with permission from Elsevier. The open symbols indicate a significant difference from both baseline (the sample immediately prior to drug administration) and the respective vehicle condition and the * indicates a significant difference from the baseline (only).

Figure 2

Mean (N=6, bars indicate SEM) temperature for animals treated with 5.0 mg/kg MDMA per os or intramuscularly. Temperature data are represented as changes from the average of three samples prior to administration for each animal to appropriately reflect the repeated measures analysis of the absolute temperature data. The open symbols indicate a significant difference from both baseline (the sample immediately prior to drug administration) and the respective vehicle condition and shaded symbols indicate a significant difference from the vehicle condition at a given timepoint (only). A significant difference between MDMA administered i.m. and p.o. is indicated by #.

Figure 3

Mean (N=6, bars indicate SEM) temperature values for animals treated with 0.1 or 0.32 mg/kg METH per os or intramuscularly are presented. Temperature data are represented as changes from the average of three samples prior to administration for each animal to appropriately reflect the repeated measures analysis of the absolute temperature data. The intramuscular data were previously reported (Crean et al., 2006) and are reused with permission from Elsevier. The open symbols indicate a significant difference from both baseline (the sample immediately prior to drug administration) and the respective vehicle condition. The * indicates a significant difference from the baseline (only) and a significant difference between METH administered i.m. and p.o. is indicated by #.

Figure 4

The mean (N=6, bars indicate SEM) of hourly activity counts for animals treated with A) 1.78 mg/kg MDMA; B) 5.0 mg/kg MDMA; or C) METH (0.1, 0.32 mg/kg) by oral or intramuscular routes are presented. The intramuscular data (except 5 mg/kg MDMA) were previously reported (Crean et al., 2006) and are reused with permission from Elsevier. A significant difference from baseline is indicated by *, a significant difference from the respective vehicle timepoint by ‡ and a significant difference between doses administered i.m. and p.o. is indicated by #.

Figure 5

Mean (N=4) and individual temperatures derived from the subcutaneous telemetry implant and with a rectal thermometer are presented in the upper panel. Animals were immobilized with ketamine either without pre-treatment (Baseline) or following administration of 5 mg/kg MDMA. Significant differences between Baseline and MDMA conditions are indicated by *.