Hyperthermia induced by ( )3,4-methylenedioxymethamphetamine in monkeys:
Impact of ambient temperature
M. A. Taffe, S. N. Von Huben, C. C. Lay, R. D. Crean, S. A. Davis and S. N. Katner
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA
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[N=6 (SEM); 8-9 yr olds]
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Change from Baseline ( C)
Temperature
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open symbol: significant difference from baseline and veh
* indicates significant difference from baseline
# indicates significant difference between IM and PO
open symbol: significant difference from baseline
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MDMA effects on core vs. skin temperature and core vs. muscle temperature can
vary in rodents and rabbits. [Brown and Kiyatkin, 2004; Pedersen and Blessing, 2001; Blessing et al., 2003]
Freedman et al. 2005 found approximately equivalent changes in skin and gastric
temperature after MDMA, p.o., in humans.
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Rectal vs Telemetered
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Animals were immobilized with ketamine 60 min after
receiving 5 mg/kg MDMA, i.m.
MDMA vs Baseline
Significant effects of drug condition and location of temperature measurement were
confirmed. No interaction of factors was observed.
Minutes Post-Injection
MDMA produces an equivalent magnitude hyperthermia in rhesus macaques under
ambient temperature conditions from 18 C to 30 C. Ambient conditions which appear
neuroprotective in the rodent are unlikely to have similar effects in monkeys or
humans (Freedman et al, 2005).
Individual variation in thermoregulatory disruption is consistent within individual and appears
to be of significant magnitude. The monkey may be useful for investigating factors which
determine which human individuals are at risk.
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Body temperature increases with locomotor activity; however, MDMA suppresses
activity in monkeys. Interpretation of drug effects on temperature requires
consideration of activity patterns.
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Discussion
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[N=6 (SEM); 8-9 yr olds]
24 C Ambient Temperature
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Role of Locomotor Activity
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The body temperature response to MDMA was equivalent across the
three ambient temperature conditions. Monkeys are more similar to
humans (Freedman et al. 2005) and less similar to rodents.
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Data Sciences International (Transoma)
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Vehicle, PO
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Change in Temp ( C)
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[N=6 (SEM); 5 yr olds]
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Radiotelemetric monitoring of subcutaneous
temperature and spontaneous locomotor activity.
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Temperature ( Celsius)
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Racemic 3,4-Methylenedioxymethamphetamine HCl
24 C
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5 mg/kg MDMA, IM
5 mg/kg MDMA, PO
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Ambient Temperature: 18 C, 24 C, 30 C
18 C
2.4 mg/kg ( )MDMA
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5-9 year old, 8-13 kg (2 yr range per expt.)
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17 (4-6 per expt) male rhesus macaques
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0.56 mg/kg ( )MDMA
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Methods
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Activity Counts
Freedman et al., 2005
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Activity Counts
Hyperthermia produced by MDMA in humans is of similar
magnitude under ambient temperature from 18 to 30 C.
24 C
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Individual Differences
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Taffe et al., 2006
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Body Temperature ( C)
Unrestrained rhesus monkeys exhibit hyperthermia following
1.78 mg/kg MDMA under ambient of 23.5 C.
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Bowyer et al. (2003) reported hypothermia in chaired rhesus
monkeys following 10 mg/kg MDMA under ambient of ~21 C.
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Dafters, 1994; Malberg and Seiden, 1998
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Oral administration in flavored solutions results in significant
hyperthermia. Activity levels are suppressed by intramuscular,
but not by oral, administration of MDMA.
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Body Temperature Change ( C)
0.56 mg/kg, i.m.
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Body Temperature ( C)
Hyperthermia is positively associated with the ambient
temperature and with the severity of serotonin depletions
produced by repeated MDMA in rats.
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Gillman, 1997; Greene et al., 2003; Mallick and Bodenham, 1997
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Emergency departments report elevated body temperature
in MDMA-associated mentions and fatalities.
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Oral Administration
Activity Counts
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Temperature
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Introduction
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Activity Counts
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Body Temperature ( C)
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Change in Body Temperature ( C)
Ambient temperature (TA) has a significant effect on the direction and
magnitude of the body temperature response to ( )3,4methylenedioxymethamphetamine (MDMA) exposure in rodents. The
degree of hypo/hyperthermia observed also modulates the severity of
lasting brain changes in neurotoxicity models. The effect of TA following
MDMA may differ between species thereby affecting translation of
preclinical results to the human situation. For example, humans exhibit
elevations of temperature after MDMA under (low) TA conditions which
result in hypothermia in rats. The thermoregulatory effects of MDMA have
not been well described in nonhuman primates and it is unknown if, or to
what degree, TA has the potential to affect lasting brain damage. This study
was conducted to determine the effect of T A on body temperature
alterations produced by MDMA 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 under each of
three TA conditions (18 C, 24 C, 30 C) in a randomized order. Temperature
was significantly elevated following injection with all doses of MDMA under
each ambient temperature condition. The magnitude of mean temperature
change was ~1 C in most conditions suggesting a narrowly controlled
thermoregulatory range in monkeys across a range of doses and ambient
temperatures. No elevations of locomotor activity were observed in any
condition. The finding of MDMA-induced hyperthermia in rhesus monkeys
under the low T A condition is consistent with human studies, but is
inconsistent with rodent studies. Therefore thermoregulatory responses to
MDMA in the nonhuman primate may reflect the human condition more
accurately than rodent models.
Supported by NIH Grant DA018418.
Role of Ambient Temperature
Average: 2 Hours Post-Injection
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Abstract
Hyperthermia is produced by oral administration of MDMA in monkeys and the magnitude of
effect is only modestly attenuated relative to i.m. administration. It is unlikely that route of
administration issues seriously question the translation of animal studies to the human
Ecstasy consumer.