TL neuro

June 13, 2014

Fatal Brain Hyperthermia Induced by MDMA

Filed under: MDMA — mtaffe @ 11:07 am

There is a new paper out at Journal of Neuroscience that addresses physiological mechanisms by which 3,4-methylenedioxymethamphetamine, otherwise known as MDMA or Ecstasy (and more recently Molly), kills people. This is a preclinical study by a group of investigators who work in the Intramural Research Program of the National Institute on Drug Abuse.

Eugene A. Kiyatkin, Albert H. Kim,Ken T. Wakabayashi,Michael H. Baumann, and Yavin Shaham. Critical Role of Peripheral Vasoconstriction in Fatal Brain Hyperthermia Induced by MDMA (Ecstasy) under Conditions That Mimic Human Drug Use, J Neurosci. 2014 Jun 4;34(23):7754-62. doi: 10.1523/JNEUROSCI.0506-14.2014.[PubMed; JNeuro]

The first author, Kiyatkin, has a neat little preparation for the simultaneous monitoring of body temperature in brain, muscle and skin. He has been working away over the years reporting brain/peripheral differentials in the temperature response to drugs, including MDMA.

Mean (±SEM) changes in NAc, muscle, and skin temperatures induced by injection of 9 mg/kg MDMA (C). Mean (±SEM) MDMA-induced changes in temperature relative to saline injection (G), temperature differentials (K), and locomotion (O).

from Fig 1: Mean (±SEM) changes in NAc, muscle, and skin temperatures induced by injection of 9 mg/kg MDMA (C). Mean (±SEM) MDMA-induced changes in temperature relative to saline injection (G), temperature differentials (K), and locomotion (O).

This new paper first shows that brain (probes inserted into the nucleus accumbens) temperature; muscle temperature; skin temperature and that MDMA (1, 3, 9 mg/kg, s.c.) induces a dose-related increase in brain and muscle temperature in Long-Evans rats (the sex wasn’t specified in the methods, one brief mention of males in the Abstract) under 22.5 °Celsius ambient temperature conditions. See the excerpt from Fig 1 as a visual reference. The brain/muscle temperature differential (~1 °C) didn’t change across time after MDMA but of course since skin temperature didn’t increase, the brain/skin differential (~2.5 °C at baseline) became larger. So far so good, but Kiyatkin has shown similar effects before. Also, the demonstration that experimental animals’ temperature goes up after MDMA is hardly novel. It occurs in mouse, rat, guinea pig, swine, monkey and quietly resting humans.

The next major point of this paper is that under warmer (29 °C) ambient temperature conditions, all of the animals (6/6) died after the 9 mg/kg dose. Now, it is true that most laboratory papers on the thermoregulatory response to MDMA do not emphasize the lethality rate. But many of them do report it. Malberg and Seiden, 1998 and Gordon et al, 1991 are cases in point. Those studies featured relatively high MDMA doses, true, but they were doses that were not lethal at lower ambient temperature conditions. Gilpin and colleagues (2011) reported ~30% mortality at normal ambient temperature after a 10 mg/kg dose (i.e., closer to the 9 mg/kg used in Kiyatkin et al) when animals were provided access to a running wheel, possibly addressing an issue of excess heat generation, rather than heat dissipation, but the concept is related. Finally, Brown and Kiyatkin showed 9 mg/kg MDMA under high ambient temperature leads to lethality in a 2004 paper. There are other mentions in the literature that make it very clear that rodents are at increased risk of an unregulated hypothermia and death under high ambient temperature conditions, given an identical dose of MDMA.

There is one important procedural note at this point in the story. A single group of 12 animals participated in all of the studies. The original challenges of 1, 3 and 9 mg/kg were conducted on three sequential days. Subsequent experiments involved another 9 mg/kg dose under normal ambient (in the context of a cage mate) and then the final lethal experiment. The paper doesn’t appear to specify the testing order beyond this and yet the listed subject numbers of 12 for saline, 11 for 9 mg/kg, 9 for 1 mg/kg and 7 for 3 mg/kg implies perhaps that was the test order. If doses were mixed order then the N in each condition doesn’t make any sense at all. Either way, the subject drop-out is nowhere explained that I can locate. The final two experiments were down to N=6. One has to assume that they had some subject mortality after MDMA dosing (but not saline) even under lower ambient temperature. The design also raises a question about the effects of repeated intermittent dosing on the animals that survived until the last experiment. This is probably a good feature in making this model consistent with the human user, but really complicates things in terms of knowing whether the present results were a result of the conditions or of the prior history of the animals.

The second, social interaction experiment is strange in design. It featured the introduction of a new male rat into the experimental animal’s home cage which might be viewed in the light of an Resident-Intruder paradigm, generally used as a stressor. This lacks the setup of including a female with the original male but the point is that “social” conditions need a good deal of explication. This is lacking in the present paper. Acclimated social groups will huddle together under some conditions- this is clearly of great interest when the study concerns body heat – but we are uncertain if that happened here. Certainly an examination of the temperature curves under saline conditions with and without the “social” interaction do not suggest any huddling or even any interaction after the first hour of acclimation. It is even more pertinent to describe the mode when the implicit translational goal is to model humans using ecstasy. Do humans “huddle”? Do humans interact like the animals in the Kiyatkin model do? This is not addressed. Interestingly, Brown and Kiyatkin already showed hyperthermia after 9 mg/kg MDMA is increased by social interaction with a female rat in their 2004 paper. Of greater interest to the point Kiyatkin and colleagues appear to be pursuing with this manipulation, Fantegrossi and colleagues (2003) showed that mice who are socially acclimated in housing groups of 6 or 12 are at increased risk of mortality (versus single housing) across a range of MDMA doses (and isomers).

I am not entirely sure why*, but the paper essentially ignores any discussion (and in some cases citation) of prior work that is highly relevant to the central claims of the paper. When prior related work is cited, it is mentioned in a way that minimizes the direct applicability to the present study. Dafters identifed the relationship between the temperature response to MDMA and the ambient temperature under which rats were examined in 1994 and 1995. Malberg and Seiden (1998; Journal of Neuroscience, no less) used radiotelemetry and an exacting range of ambient temperature conditions to show this relationship in unrestrained, freely moving animals. The ambient temperature/body temperature relationship may be a bit more uncertain in human and non-human primates, this would appear central to the discussion but is not really addressed. Blessing and colleagues showed that peripheral vasoconstriction following MDMA contributes to the increase in body temperature in rabbit and rat (also in J. Neuroscience) models.

As a final point, this paper makes a huge deal out of the role of vasoconstriction as an explanatory mechanism. As mentioned above, Blessing and colleagues already demonstrated this in the context of hyperthermia, if not lethality. Still, I expected that this paper would have directly either measured or manipulated vasoconstriction. The experiments did not. Instead, “vasoconstriction” is merely inferred from the muscle/skin temperature differential. This is disappointing.

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*Given the realities of publishing in the Journal of Neuroscience, one presumes the authors were highly motivated to write this paper in a way that claimed novelty. Proper reference to, and discussion of, the relevant literature as per this blog post would have undoubtedly undercut an impression of novelty.

Disclaimer: I work on this topic and am also professionally acquainted with two of the authors. These may constitute conflicts of interest.

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