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Kiyatkin EA, Kim AH, Wakabayashi KT, Baumann MH, Shaham Y. 
“Critical Role of Peripheral Vasoconstriction in Fatal Brain Hyperthermia Induced by MDMA (Ecstasy) under Conditions That Mimic Human Drug Use”. 
J Neurosci. 2014 Jun 06;34(23):7754-62.
MDMA (Ecstasy) is an illicit drug used by young adults at hot, crowed rave parties, yet the data on potential health hazards of its abuse remain controversial. Here, we examined the effect of MDMA on temperature homeostasis in male rats under standard laboratory conditions and under conditions that simulate drug use in humans. We chronically implanted thermocouple microsensors in the nucleus accumbens (a brain reward area), temporal muscle, and facial skin to measure temperature continuously from freely moving rats. While focusing on brain hyperthermia, temperature monitoring from the two peripheral locations allowed us to evaluate the physiological mechanisms (i.e., intracerebral heat production and heat loss via skin surfaces) that underlie MDMA-induced brain temperature responses. Our data confirm previous reports on high individual variability and relatively weak brain hyperthermic effects of MDMA under standard control conditions (quiet rest, 22-23°C), but demonstrate dramatic enhancements of drug-induced brain hyperthermia during social interaction (exposure to male conspecific) and in warm environments (29°C). Importantly, we identified peripheral vasoconstriction as a critical mechanism underlying the activity- and state-dependent potentiation of MDMA-induced brain hyperthermia. Through this mechanism, which prevents proper heat dissipation to the external environment, MDMA at a moderate nontoxic dose (9 mg/kg or ∼1/5 of LD50 in rats) can cause fatal hyperthermia under environmental conditions commonly encountered by humans. Our results demonstrate that doses of MDMA that are nontoxic under cool, quiet conditions can become highly dangerous under conditions that mimic recreational use of MDMA at rave parties or other hot, crowded venues.
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Jun 9, 2014 4:17
Not New: MDMA Becomes More Dangerous with Motor Activity and Environmental Heat #

A number of previous previous studies and user experience have shown that locomotor activity (moving around) and hot environments increase risks associated with MDMA, including hyperthermia, organ damage, and potential neurotoxicity.

Fantegrossi et al. showed in 2003 that racemic MDMA given at a dose of 56 mg/kg kills no mice when they are housed alone, but kills fully 75 percent of them when they are housed 12 per cage. Summarizing Fantegrossi:

Twelve mice per cage isn't even terribly crowded, but increases motor activity and heat.

The paper also has some data on lethality when the experiments are repeated in a 4C (40F) cold room. The results are complex, but decreasing the ambient temperature is protective against lethal effects of racemic MDMA whether mice are alone or crowded, but crowding interacts with temperature for the S(+)-enantiomer, and a cool temperature is not protective at all against the lethal effects of the R(-)-enantiomer. This is expected since the R(-)-enantiomer does not induce hyperthermia, so there's probably no reason to think cooling animals off would be protective.

Fantegrossi WE, Godlewski T, Karabenick RL, Stephens JM, Ullrich T, Rice KC, Woods JH. "Pharmacological characterization of the effects of 3,4-methylenedioxymethamphetamine ("ecstasy") and its enantiomers on lethality, core temperature, and locomotor activity in singly housed and crowded mice" Psychopharmacology (Berl). 2003 Mar 13;166(3):202-11.
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Jun 7, 2014 17:23
NIDA Press Release about Study #

NIH preclinical study suggests higher risk of death is associated with warmer brain temperature

June 03, 2014

A moderate dose of MDMA, commonly known as Ecstasy or Molly, that is typically nonfatal in cool, quiet environments can be lethal in rats exposed to conditions that mimic the hot, crowded, social settings where the drug is often used by people, a study finds. Scientists have identified the therapeutically-relevant cooling mechanism to enable effective interventions when faced with MDMA-induced hyperthermia. The study, publishing tomorrow in the Journal of Neuroscience, was conducted by researchers at the National Institute on Drug Abuses Intramural Research Program (NIDA IRP). NIDA is a part of the National Institutes of Health.

While MDMA can have a range of adverse health effects, previous studies have shown that high doses of MDMA increase body temperature, while results with moderate doses were inconsistent. This has led some people to assume that the drug is harmless if taken in moderation. However, this study shows that in rats even moderate doses of MDMA in certain environments can be dangerous because it interferes with the bodys ability to regulate temperature.

We know that high doses of MDMA can sharply increase body temperature to potentially lead to organ failure or even death, said NIDA Director Dr. Nora D. Volkow. However, this current study opens the possibility that even moderate doses could be deadly in certain conditions.

It is impossible to predict who will have an adverse reaction even to a low dose of MDMA. However, in this study scientists gave the rats low to moderate doses that have been shown in past studies to not be fatal. They monitored the rats to determine drug-induced changes in brain and body temperature and in the bodys ability to cool itself through blood vessel dilation. When rats were alone and in a room-temperature environment, a moderate dose of MDMA modestly increased brain and body temperature and moderately diminished the rats ability to eliminate excessive heat. However, when researchers injected the same dose in rats that were either in a warmer environment or in the presence of another rat in the cage, brain temperature increased, causing death in some rats. These fatal temperature increases were because the drug interfered with the bodys ability to eliminate heat.

These results demonstrate that the use of MDMA in certain warm, social settings could be more dangerous than commonly believed, said Dr. Eugene Kiyatkin, first author on the study and NIDA IRP scientist. Even with moderate doses, we saw drug-induced, fatal brain hyperthermia during conditions of social interaction and in warm environments.

These findings further suggest that medical interventions aimed at increasing the efficiency of whole-body cooling by targeting blood vessel constriction in the skin could be therapeutically relevant for counteracting the development of MDMA-induced hyperthermia.
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