Download MDMA and temperature: A review of the thermal effects of `Ecstasy

Drug and Alcohol Dependence 121 (2012) 1–9
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Drug and Alcohol Dependence
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Review
MDMA and temperature: A review of the thermal effects of ‘Ecstasy’ in humans
A.C. Parrott ∗
Department of Psychology, Swansea University, Swansea SA2 8PP, United Kingdom
a r t i c l e
i n f o
Article history:
Received 9 June 2011
Received in revised form 20 July 2011
Accepted 12 August 2011
Available online 15 September 2011
Keywords:
Ecstasy
Mdma
Serotonin
Dopamine
Heat
Stress
Temperature
Thermal
Neurotoxicity
a b s t r a c t
Aims: To review the thermal effects of MDMA in humans, and discuss the practical implications.
Methods: The literature on Ecstasy/MDMA, body temperature, and subjective thermal self-ratings was
reviewed, and explanatory models for the changes in thermal homeostasis were examined and debated.
Results: In human placebo-controlled laboratory studies, the effects of MDMA were dose related. Low
doses had little effect, moderate doses increased body temperature by around +0.4 ◦ C, and higher doses
caused a mean increase of +0.7 ◦ C. With Ecstasy/MDMA using dance clubbers, the findings showed greater
variation, due possibly to uncontrolled factors such as physical activity, ambient temperature, and overcrowding. Some real world studies found average body temperature increases of over +1.0 ◦ C. Thermal
homeostasis involves a balance between heat production and heat dissipation, and MDMA affects both
aspects of this homeostatic equation. Cellular metabolic heat output is increased, and heat dissipation
mechanisms are stressed, with the onset of sweating delayed. Subjective responses of ‘feeling hot’ or
‘hot-cold flushes’ are frequent, but can show individual variation. Some recreational users report that
heat increases or reinstates the positive mood effects of Ecstasy/MDMA. The dangers of acute hyperthermia can include rare fatalities. It is unclear why moderate hyperthermia can occasionally progress to
severe hyperpyrexia, although it may reflect a combination or cascade of events. In chronic terms, the
bioenergetic stress model notes that the adverse psychobiological effects of MDMA are heightened by
various co-stimulatory factors, including heat stress.
Conclusions: MDMA increases core body temperature and thermal stress in humans.
© 2011 Elsevier Ireland Ltd. All rights reserved.
Contents
1.
2.
3.
4.
5.
6.
7.
8.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Body temperature in laboratory studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Body temperature in dance club studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Clinical hyperthermia and its treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Thermal self-ratings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Thermoregulation mechanisms: heat production and dissipation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Behavioural and environmental co-stressors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
The
methamphetamine
derivative
3,4(MDMA)
impairs
methlenedioxymethamphetamine
thermoregulation in laboratory animals. Gordon et al. (1991) found
that: ‘MDMA exerted profound effects on the thermoregulatory
∗ Corresponding author. Tel.: +44 1792 295271; fax: +44 1792 295679.
E-mail address: [email protected]
0376-8716/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.drugalcdep.2011.08.012
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system of the rat with many of the effects being highly dependent
on ambient temperature (Ta ). MDMA elicited a massive increase
in metabolism in the rat maintained at a Ta of 30 ◦ C which is
undoubtedly responsible for the extreme hyperthermia’. Subsequent animal research has investigated the factors influencing the
temperature changes. Rats become hyperthermic when MDMA is
administered in hot thermal environments, and the combination of
drug and heat can prove fatal (Brown and Kiyatkin, 2004). Ambient
thermal stress also heightens serotonergic neurotoxicity, with
each 2 ◦ C increase in ambient temperature adding further neural
2
A.C. Parrott / Drug and Alcohol Dependence 121 (2012) 1–9
damage (Malberg and Seiden, 1998). The animal research has been
described in a number of articles (Green et al., 2003, 2004; Mills
et al., 2004; Sprague et al., 2003, 2007). These animal findings
have direct implications for humans, since many of the underlying psychophysiological mechanisms will be near-identical. For
instance, the cellular-metabolic processes underlying increased
heat production will be very similar. However, since the human
species is a ‘naked ape’ (Morris, 1967), some of the mechanisms
involved in heat dissipation, such as piloerection and sweating,
may differ between humans and the hairy mammals (Rusniak and
Sprague, 2005). Gordon (2007), in analysis of the implications of
animal thermal MDMA data for humans, similarly noted that there
can be uncertainty in the extrapolation process. This review will
focus on the human findings.
In historical terms, MDMA was first used as a recreational drug
in the early 1980s (Shulgin, 1986; Parrott, 2004a), and as it became
more widely used, the first reports of hyperthermia emerged. The
first fatalities with recreational MDMA involved overheating, with
core body temperatures over 40 ◦ C (Chadwick et al., 1991; Henry
et al., 1992), although these extreme thermal reactions were noted
to be rare. Since then hyperthermic adverse reactions have continued, although hospitals now follow optimal treatment packages,
so that fatalities remain very unusual (Hall and Henry, 2005; Patel
et al., 2005; Greene et al., 2009; Halpern et al., 2011; Grunau et al.,
2010). The effects of MDMA on body temperature in humans have
been investigated in various laboratory studies, and while low
dose studies generate non-significant changes, higher dose studies have found significant increases (Mas et al., 1999; Liechti and
Vollenweider, 2000; Liechti et al., 2001; Freedman et al., 2005).
Body temperature has also been monitored in real world studies of
dance clubbers, but here a range of non-significant and significant
effects have been reported, possibly due to the range of contributory factors (Irvine et al., 2006; Morefield et al., 2009; Parrott et al.,
2008). Subjective thermal responses, such as ‘feeling hot’ or ‘hot
and cold flushes,’ have also been frequently noted (Cohen, 1995;
Davison and Parrott, 1997; Topp et al., 1999; Parrott et al., 2006;
Kish et al., 2010).
The aim of this paper is to review the empirical data on
thermal responses to MDMA/Ecstasy in humans, and debate
the factors influencing these changes. One core question was
whether increased body temperature comprises a typical response
to MDMA, or represents a more unusual reaction. In terms of
methodology, an extensive personal collection of MDMA research
papers was initially scrutinized, followed by a computerized
PubMed search using a range of thermal key words. Laboratory
studies and real world investigations were grouped separately,
in order to gauge whether the temperature reactions to MDMA
differed between the laboratory and club/party environment
(Tables 1 and 2). Clinical cases of extreme hyperthermia were
then reviewed, and the optimal medical treatment packages
outlined. Subjective thermal responses were also covered, and
the underlying mechanisms for the thermoregulatory changes
debated (Table 3).
2. Body temperature in laboratory studies
The first published study to assess the effects of MDMA on body
temperature in humans was a ‘phase-1 pilot study’ by Grob et al.
(1996). Four low dose levels of oral MDMA (0.25, 0.5, 0.75 and
1.00 mg/kg) were administered to six subjects. Oral temperatures
were recorded at four baseline sessions, and 12 post-drug sessions
up to 6 h. The mean baseline and average post-drug temperature
were reported. There were no significant changes in body temperature, although in the 0.50 mg/kg and 0.75 mg/kg MDMA conditions
there were trends for increased temperature (+0.49◦ F; +0.41◦ F),
whereas after 1.00 mg/kg MDMA there was no change (Table 1).
The other physiological effects of these low MDMA doses were also
mild, with slight-to-moderate increases in blood pressure and heart
rate. The authors concluded that: ‘Although our findings of the first
six subjects are intriguing, definitive conclusion must await further
controlled inquiry of the effects of higher dose administration in the
1.0 mg–1.75 mg/kg range.’
Vollenweider et al. (1998) administered the larger dose of
1.7 mg/kg oral MDMA: ‘a typical dose taken for recreational use’,
to 13 volunteers. Under placebo, core body temperature remained
almost constant over the 6 h of testing. Following oral MDMA, temperature was unchanged for the first 75 min post-drug, increased by
+0.2 ◦ C after 75–150 min, then increased further to +0.5 ◦ C between
150 and 300 min post-MDMA. None of the group comparisons was
significant (Table 1), and the authors concluded: ‘MDMA seemed to
produce a discrete increase in body temperature of about 0.2–0.5 ◦ C
which, however, did not reach statistical significance.’ Physiological stimulation was apparent in the increased blood pressure and
heart rate, and in one participant experiencing a brief hypertensive crisis (240/145 mmHg) for 20 min. In a follow-up study (Liechti
and Vollenweider, 2000), 1.5 mg/kg oral MDMA was administered
to 16 healthy volunteers, and with this slightly larger sample, the
increase in body temperature was statistically significant (Table 1).
The mean temperature increase was +0.3 ◦ C after 60 min (p < 0.008),
and + 0.3 ◦ C after 120 min (p < 0.001). In a third study involving 14
volunteers (Liechti et al., 2000), 1.5 mg/kg oral MDMA again led to
a significant increase in body temperature compared to placebo
(p < 0.01), with the mean difference peaking at +0.4 ◦ C after 2 h.
The Swiss group then published an overview of the three studies,
focusing on gender differences (Liechti et al., 2001). Body temperature was increased in both males and females (mean changes:
+0.4 ◦ C, +0.3 ◦ C, respectively), but was only significant for the 44
males (p < 0.001). The mean change was non-significant for the 14
females, although the smaller sample size and reduced statistical
power should be noted.
Mas et al. (1999) assessed 8 males with a previous history of Ecstasy/MDMA, following oral doses of 75 mg MDMA,
125 mg MDMA, 40 mg amphetamine, and placebo. Under placebo,
body temperature remained fairly constant over time. With
amphetamine, temperatures remained constant for around 1.5 h
then increased progressively over time. Following 125 mg MDMA,
during the first hour body temperatures were reduced by around
−0.2 ◦ C, then returned to baseline after 1.5 h, peaked at +0.4 ◦ C after
2 h and remained high after 4 h. The 75 mg MDMA dose showed
a broadly similar pattern to the higher dose, with a similar peak
increase of +0.4 ◦ C, but a slightly more rapid recovery (see Fig. 1 in
Mas et al., 1999). In terms of statistical analyses, all the post-drug
data points were combined, which meant that the initial temperature decreases between 0 and 60 min (recorded every 15 min), were
averaged with the later temperature increases (recorded hourly).
Hence, it is not clear whether the peak thermal increase at 2 h was
statistically significant (Table 1). Farre et al. (2007) administered a
100 mg oral MDMA challenge to 12 volunteers, after they had been
on paroxetine (a potent inhibitor of 4-hydroxutryptamine reuptake
and CYP2D6 activity), or placebo, for three days. In the placebomaintained group, MDMA led to a peak increase of +0.7 ◦ C from
baseline, whereas in the paroxetine-maintained group, the MDMA
challenge led to a significantly reduced temperature increase of
+0.4 ◦ C. However, since there was no acute placebo challenge (i.e.,
no double-placebo or ‘true’ control group) the magnitude of the
temperature rise following MDMA cannot be determined. Hence,
this study was not presented in Table 1.
Tancer et al. (2003) tested four volunteers following 2.0 mg/kg
oral MDMA and placebo, under two ambient temperature conditions (18 ◦ C and 30 ◦ C). Core body temperature was assessed via
rectal probes, and skin temperature was recorded from four sites
and averaged. Core body temperature was minimally affected by
A.C. Parrott / Drug and Alcohol Dependence 121 (2012) 1–9
3
Table 1
MDMA effects on core body temperature and skin temperature: overview of placebo-controlled laboratory studies.
Reference
Sample size
MDMA oral dose
Body site
Peak temperature change
Core body temperature: low dose
Grob et al. (1996)
Grob et al. (1996)
Grob et al. (1996)
Grob et al. (1996)
Kolbrich et al. (2008)
Overall Mean:
n=6
n=6
n=6
n=6
n=8
Low doses up to 1.0 mg/kg
0.25 mg/kg
0.5 mg/kg
0.75 mg/kg
1.0 mg/kg
1.0 mg/kg
Oral
Oral
Oral
Oral
Tympanic
–0.1 ◦ C
+0.3 ◦ C
+0.2 ◦ C
0.0 ◦ C
+0.3 ◦ C
+0.1 ◦ C
Core body temperature: medium dose
Mas et al. (1999)
Liechti et al. (2000a)
Liechti et al. (2000b)
Mas et al. (1999)
Kolbrich et al. (2008)
Vollenweider et al. (1998)
Overall Mean:
n=8
n = 16
n = 16
n=8
n=8
n = 13
Medium doses between 1.1-1.9 mg/kg
75 mg
1.5 mg/kg
1.5 mg/kg
125 mg
1.6 mg/kg
1.7 mg/kg
Oral
Axillary
Axillary
Oral
Tympanic
Axillary
+ 0.4 ◦ C
+0.3 ◦ C
+0.4 ◦ C
+0.4 ◦ C
+0.4 ◦ C
+0.5 ◦ C
+0.4 ◦ C
Core body temperature: higher dose
Tancer et al. (2003)a
Freedman et al. (2005)a
Tancer et al. (2003)b
Freedman et al. (2005)b
Overall Mean:
n=4
n = 10
n=4
n = 10
Higher doses of 2.0 mg/kg
2.0 mg/kg
2.0 mg/kg
2.0 mg/kg
2.0 mg/kg
Tympanic
Ingested
Tympanic
Ingested
+1.0 ◦ C
+0.4 ◦ C
+0.8 ◦ C
+0.6 ◦ C
+0.7 ◦ C
Skin temperature:
Tancer et al. (2003)a
Freedman et al. (2005)a
Tancer et al. (2003)b
Freedman et al. (2005)b
Overall Mean:
n=4
n = 10
n=4
n = 10
Dose of 2.0 mg/kg
2.0 mg/kg
2.0 mg/kg
2.0 mg/kg
2.0 mg/kg
Skin surface
Skin surface
Skin surface
Skin surface
+2.0 ◦ C
+1.0 ◦ C
+0.7 ◦ C
+0.4 ◦ C
+1.0 ◦ C
The procedures for statistical analyses varied across studies. See text for details.
a
low ambient temperature environment = 18 ◦ C.
b
high ambient temperature environment = 30 ◦ C.
the environmental conditions, with nearly identical values under
the low and high ambient conditions. Core body temperature was,
however, significantly affected by drug, being +1.0 ◦ C higher postMDMA than placebo under the low ambient temperature condition
(p < 0.01), and +0.8 ◦ C higher after MDMA compared to placebo
under the high ambient temperature condition (p < 0.05). Skin temperature was strongly affected by the ambient temperature, being
considerably lower in the cooler environment (−3.7 ◦ C lower in the
placebo condition). The effects of drug on skin temperature were
pronounced, with significantly higher values following MDMA than
placebo, under both low ambient temperature condition (+2.0 ◦ C,
p < 0.005), and the higher ambient temperature condition (+0.7 ◦ C,
p < 0.02). Metabolic rate was significantly raised post-MDMA –
again under both ambient temperature conditions. The authors
concluded: ‘In humans, unlike rats, MDMA produces hyperthermia
in cold and warm conditions by raising metabolic rate.’
The next study comprised the most comprehensive laboratory study to date (Freedman et al., 2005). Ten healthy volunteers
(6 males, 4 females) were assessed after placebo and 2.0 mg/kg
oral MDMA under two ambient temperature conditions (18 ◦ C and
30 ◦ C), using a 2 × 2 crossover ANOVA design. Core body temperature was assessed with an ingested radio-telemetry device,
while skin temperature was recorded from 4 sites and averaged.
Shivering, sweating, and subjective thermal responses were also
recorded. All measures were monitored for 4 h and split into 10min blocks (Freedman et al., 2005). MDMA led to a peak increase in
core body temperature of +0.4 ◦ C under the low ambient thermal
condition (p < 0.02), and +0.6 ◦ C under the high ambient temperature (p < 0.001); these temperature increases under MDMA were
significantly higher than under placebo (Table 1). There was a
slight increase in core body temperature post-placebo in the warm
thermal environment, so that the overall effects of MDMA were
broadly similar under both ambient conditions. Skin temperature
Table 2
MDMA/ecstasy effects on body temperature: overview of real-world studies at
dance clubs and parties.
Reference
Sample
size
Measurement
site
Peak temperature
change
Irvine et al. (2006)
Parrott and Young (2005)
Parrott et al. (2008)
Parrott et al. (2007b)
Morefield et al. (2009)
Morefield et al. (2009)
n = 27
n = 32
n = 12
n = 11
n = 41
n = 41
Tympanic
Tympanic
Tympanic
Tympanic
Oral
Skin
+0.2 ◦ C
+1.2 ◦ C
+0.3 ◦ C
+1.6 ◦ C
+1.1 ◦ C
+1.8 ◦ C
The control conditions and procedures for statistical analyses varied across studies.
See text for details.
decreased in the cool ambient environment, and increased in the
hot thermal environment, with non-significant trends for higher
skin temperatures after MDMA. The ANOVA drug effect was statistically borderline in the cooler thermal environment (p = 0.062,
two-tailed), and was non-significant in the hot ambient thermal
environment (p = 0.104, two-tailed). The ANOVA drug × time interaction was, however, significant (p < 0.02), showing that the effect
of drug on skin temperature was dependent on the post-drug
timing. Fig. 2 in Freedman et al. (2005) shows that in the hot
thermal environment, for the first 60 min skin temperatures under
MDMA were slightly lower than under placebo, then became nearidentical 60–100 min post-drug, and then became +0.4 ◦ C higher
post-MDMA until the end of the session after 240 min. The similar
time profile to Mas et al. (1999) may be noted (see earlier). This
complex time course, and inclusion of the pre-drug baseline values, may help to explain why the main ANOVA drug effects for skin
temperature were non-significant (see Figs. 1 and 2 in Freedman
et al., 2005).
Kolbrich et al. (2008) administered oral doses of 1.0 mg/kg and
1.6 mg/kg MDMA (range: 44–150 mg) to 8 volunteers. Tympanic
4
A.C. Parrott / Drug and Alcohol Dependence 121 (2012) 1–9
Table 3
Factors associated with the thermal effects of Ecstasy/MDMA: overview and key references.
MDMA dosage
MDMA plasma level
Metabolic activity
Sweating/perspiration
Ambient temperature
Positive/mood effects
Dance clubs: core body temperature
Dance clubs: prolonged dancing
Dance clubs: hyperthermic factors
Dance clubs: hypothermic factors
Thermal awareness
Polydrug aspects
Regular hyperthermia
Severe hyperthermia: possible causes
Severe hyperthermia: medical treatment
Other factors
Laboratory: dose-related increases in core body temperature (Liechti et al., 2001; Freedman et al., 2005; see Table 1).
Laboratory: significant correlation (p < 0.0001) with core body temperature increase (Kolbrich et al., 2008).
Recreational: borderline correlation (p = 0.058) with core body temperature increase (Irvine et al., 2006).
Laboratory: significant increase, which generates more cellular heat output (Tancer et al., 2003); oxygen consumption
also increased.
Recreational users: increased sweating (Davison and Parrott, 1997; Kish et al., 2010). Skin can feel hot-to-touch (see
text).
Laboratory: onset of sweating significantly delayed (Freedman et al., 2005).
Laboratory: high ambient temperature associated with higher core body temperature, with complex combined effects
(Freedman et al., 2005).
Laboratory animals: MDMA more reinforcing in the heat (Cornish et al., 2003; Banks et al., 2008).
Recreational users: positive moods enhanced or reinstated by heat (Bedi and Redman, 2006).
Range of changes, from slight to pronounced changes, with some group mean increases of over +1.0 ◦ C (Morefield
et al., 2009; Table 2). This variation may reflect a wide range of contributory co-factors (see text).
May exacerbate the thermal/psychobiological effects of Ecstasy/MDMA, although data is very limited (Parrott et al.,
2006).
Social crowding and loud music may act as co-stimulatory factors, although effects have not been empirically
investigated (Parrott, 2004b).
Chill out rooms and rest periods may facilitate cooling, although they have not been empirically investigated (Suy
et al., 1999).
Can be variable, with some recreational users feeling very hot, and others not feeling hot (Parrott et al., 2006; Kish
et al., 2010).
May be related to reduced SERT levels in the insular cortex (Olausson et al., 2005; Kish et al., 2010).
Stimulant co-drugs such as cocaine/amphetamine may increase body temperature, whereas sedatives such as
cannabis may reduce body temperature. However empirical data very limited (Parrott et al., 2007a,b)
May contribute to psychobiological distress also memory/cognitive problems, although more empirical data needed
(Parrott et al., 2006)
Comparatively unusual but medically dangerous, and can prove fatal (Patel et al., 2005). May follow a combination of
susceptibility factors, or cascade of events (debated more in text).
Rapid and aggressive physical cooling with air fans or ice baths (Hall and Henry, 2005), and dantrolene in severe cases
(Grunau et al., 2010). Hyponatraemia requires electrolyte replacement (Halpern et al., 2011).
Age, gender, genetics, hydration and personality, may have contributory roles, and need to be empirically investigated.
membrane (ear) temperature was measured at regular intervals
over an extended time frame, with the overall group mean from
the first 4 h being reported. These values were increased in all
three conditions, although the mean increase was comparatively
higher following MDMA compared to placebo (+0.3 ◦ C after the
lower MDMA dose, and +0.4 ◦ C after higher MDMA dose). The
drug/placebo comparisons were not significant, and the authors
concluded that: ‘Methylenedioxymethamphetamine had no significant effects overall on tympanic temperature.’ There was, however,
a significant correlation between plasma MDMA and increased
body temperature (p < 0.0001).
3. Body temperature in dance club studies
Irvine et al. (2006) prospectively monitored psychophysiological functioning in 27 recreational Ecstasy/MDMA users, before,
during, and after a dance party. Blood tests the following morning
revealed that 100% of the group had taken MDMA, although there
was marked variation in plasma concentrations, with 5 participants
displaying particularly high MDMA levels. Methamphetamine and
cannabis were present in 41% and 33% of the sample respectively.
Tympanic membrane temperature was recorded using a clinical
infrared thermometer, at baseline (evening prior to party), 4 am
(while partying), and 10 am (post-party). The authors reported:
‘There was a small progressive increase in temperature during
and after drug use, which did not reach statistical significance.’
The maximal group temperature change from baseline was around
+0.2 ◦ C (from Fig. 1c in Irvine et al., 2006). However, there was no
control condition, so that circadian factors were uncontrolled. This
is potentially important, since body temperature falls during the
night (Folkard, 1983). Hence the temperature change under MDMA
would probably have been greater if compared with a control condition (see below). The correlation between blood plasma MDMA
and increased temperature was borderline (r = +0.38, p = 0.058,
two-tail). One of their participants had an extremely high methamphetamine level (0.94 mg/l) but normal body temperature; the
two participants with the highest MDMA levels (0.77 mg/l and
0.84 mg/l) showed the largest individual increases in body temperature (+1.0 ◦ C and +1.6 ◦ C respectively).
Parrott and Young (2005) assessed a cohort of 68 Saturday night dance clubbers. They comprised 32 current users
who had taken Ecstasy/MDMA that evening, 10 abstinent/former
Ecstasy users who had not taken any Ecstasy that evening, and
26 non-user controls. Tympanic membrane temperature was
recorded in a relatively quiet area of the dance club, where
subjective thermal self-ratings were also completed. Body temperature was significantly affected by drug status (ANOVA group
effect: p < 0.001), with ecstasy users +1.2 ◦ C higher than controls
(p < 0.001), and abstinent Ecstasy users +0.6 ◦ C higher than controls (p < 0.05). In a subsequent study, Parrott et al. (2008) assessed
12 light/moderate Ecstasy/MDMA users who went dance clubbing
on successive weekends. On one occasion they went clubbing as
usual (with moderate MDMA usage), while on the other weekend they abstained from MDMA or any other stimulant. Saliva
samples confirmed MDMA presence and absence respectively.
Body temperature decreased by 0.2 ◦ C in the abstinence weekend (p < 0.05), and increased by 0.15 ◦ C post-MDMA (non-sig),
with the MDMA-abstinence difference being statistically borderline (p = 0.08, two-tailed). In a third study (Parrott et al., 2007b), 11
experienced Ecstasy polydrug users were assessed at house parties on different weekends. Again, they abstained from stimulant
drug use on one weekend, and took Ecstasy as normal on the other.
Their mean Ecstasy/MDMA usage for their on-drug weekend was
6 tablets, taken at intervals over the night, and they reported not
taking other stimulants. Group mean body temperature (tympanic
membrane) peaked at 1.6 ◦ C after 6 h on-MDMA (Table 2). Cortisol
levels were increased by around 800% in both studies (Parrott et al.,
2007b, 2008).
Morefield et al. (2009) collected data from 41experienced
Ecstasy/MDMA at various dance parties in Australia. Blood samples and a range of psychophysiolgical indices were recorded prior
to ecstasy consumption, and at hourly intervals following drug
A.C. Parrott / Drug and Alcohol Dependence 121 (2012) 1–9
usage. The number of Ecstasy tablets ranged from 1 to 5, with
other drugs occasionally taken. Plasma analyses confirmed MDMA
in every participant, with 25% displaying blood levels in the ‘toxic
to lethal range, according to forensic guidelines’ (Morefield et al.,
2009). The group mean increase in oral temperature peaked at
+1.1 ◦ C, while the group mean increase in skin temperature peaked
at +1.8 ◦ C (Table 2). Heart rate and other psychophysiolgical measures were also markedly increased. The authors concluded that
some recreational ecstasy users were consuming very high doses of
MDMA, which generated strong psychophysiological arousal. They
also noted that these high doses were generally well tolerated, with
predominant feelings of enjoyment and elation.
These recent findings with dance clubbers may be contrasted
with the first published empirical survey of recreational users.
Peroutka et al. (1988) interviewed 100 MDMA users at a California college campus. A typical dose was then a single 125 mg
MDMA tablet, with physiological reactions such as tachycardia
(racing heart), trismus (jaw clenching), and bruxism (tooth grinding), reported by 65–75% of the sample. Peroutka asked his student
researcher how an MDMA user might be identified on their campus:
‘The individual replied stating that if I saw a group of students walking together, holding hands, and laughing or singing, then they may
have ingested MDMA’. There was no mention of dancing or partying. In relation to its thermal effects, ‘hot and cold flushes’ were
reported by 31%, ‘increased sensitivity to cold’ was noted by 27%,
but ‘feeling hot’ was not questioned.
4. Clinical hyperthermia and its treatment
Cases of severe acute hyperthermia are comparatively unusual,
but they do necessitate urgent medical intervention, since
untreated they can prove fatal. Brown and Osterloh (1987)
described the case of a young woman who was admitted to hospital
2 h after taking 100–150 mg of MDMA powders, with a body temperature of 41.6 ◦ C. Intensive care involved multiple interventions,
with the hyperthermia being reduced by ice packs. In succeeding
days, rhabdomyolysis, coagulopathy, toxic hepatitis, a herpes-like
skin rash, and visual hallucinations, all occurred. With intensive
care they were successfully controlled, and eventually she was discharged. Chromatography of the powders revealed high MDMA
purity, while toxicological screening revealed no other substances.
Her friend who had taken her into hospital had taken the same
MDMA without a thermal adverse reaction, and both had taken
MDMA previously. Chadwick et al. (1991) described the first documented hyperthermia fatality. A previously fit 16 year old girl was
admitted to hospital feeling unwell. The provisional diagnosis was
amphetamine overdose, with an axillary temperature of 40 ◦ C. Two
hours later the axillary temperature was 42 ◦ C, and with fresh oral
bleeding, she was moved to the intensive care unit. Intubation and
ventilation were accompanied by invasive haemodynamic monitoring. Multiple medical interventions were attempted, including
35 units of blood and 21 units of platelets, but despite these intensive efforts she died after 36 h. Toxicological analysis revealed
0.424 mg/l MDMA on admission, with no other drugs. Subsequent
police enquires revealed she had taken one tablet of Ecstasy, and
that this was her second experience on the drug.
Henry et al. (1992) analyzed the Ecstasy-related enquiries to the
United Kingdom National Poisons Unit, for 1990 and 1991. Seven
were fatalities with hyperthermia (note: one of these cases was
described by Chadwick in the previous paragraph). Body temperatures on admission ranged between 40 ◦ C and 43 ◦ C. The authors
noted: ‘There was a clear pattern of toxicity in the most severe
cases, which were characterized by hyperthermia, disseminated
intravascular coagulation, rhabdomyolysis, and acute renal failure.’ They noted that these severe adverse reactions did not reflect
high dose levels, with plasma MDMA levels varying from 0.11 mg/l
5
to 1.26 mg/l. In only one case were other drugs reported, with
low levels of amphetamine and MDA. Four further severe cases
were non-fatal, all with body temperatures around 40 ◦ C, and with
intensive medical intervention, which was successful. A fifth case
involved a one year old boy who had accidentally ingested one of
his parents’ tablets, and was admitted to hospital within 30 min;
his body temperature was slightly raised at 38.5 ◦ C. With rapid
medical intervention he became symptom-free after 6 h. The other
acute Ecstasy adverse reactions reported to the Poisons Unit generally involved less severe adverse reactions: ‘agitation, tachycardia,
hypertension, widely dilated pupils, trismus and sweating’ (Henry
et al., 1992). A related medical condition is hyponatraemia, where
excessive water intake leads to a dangerous dilution of sodium and
potassium electrolyte levels in the blood (Halpern et al., 2011). Typically, this occurs when the individual drinks too much water, as
a reaction against feeling too hot. Hyponatraemia can prove fatal
if untreated, but is rapidly reversed by electrolyte replacement
(Table 3).
Following the early case studies, hyperthermic reactions to
Ecstasy have been regularly described. In 48 consecutive emergency admissions at one London hospital, around half had taken
MDMA, while the others had also taken other drugs such as cocaine
or amphetamine (Williams et al., 1998). The majority of admissions
are successfully treated, although a minority can prove fatal (Corre,
1996; Schifano et al., 2006; Grunau et al., 2010). This variation in
outcome can be illustrated by the six case studies described in Patel
et al. (2005). The first three had all attended the same rave party.
One was a 20 year old woman found unresponsive at the party. The
medical personnel noted that her skin felt ‘very hot’ to the touch,
but intensive resuscitation attempts proved unsuccessful. Toxicology revealed 1.21 mg/l MDMA, 0.40 mg/l methamphetamine, with
traces of MDA and amphetamine. The second was a 20 year old
male admitted to hospital in a comatose state, with an oral temperature of 41.5 ◦ C and hot dry skin. Intensive medical intervention,
with rapid physical cooling in an ice bath, reduced his temperature to 38.1 ◦ C within 50 min. He was discharged 2 days later. Urine
toxicology revealed MDMA but no other drugs. He had previously
taken similar amounts of Ecstasy from the same source, without
apparent adverse effects. The third case was mentally agitated and
needed to be physically restrained by the police. His temperature on admission was 40.7 ◦ C, but this was reduced to 38 ◦ C by
cooling blankets, ice baths and isotonic intravenous liquids; symptomatic improvement soon followed. Laboratory analysis revealed
that the Ecstasy pills contained pure MDMA. Two further case
studies involved adults presenting with body temperatures of
40.6 ◦ C and 41.3 ◦ C, although neither had been at dances/raves.
Again aggressive cooling led to reduced temperatures and rapid
recovery. Urine toxicology revealed MDMA alone, and MDMA
with cannabis respectively; again there was evidence of previous Ecstasy/MDMA use (Patel et al., 2005). The sixth case involved
accidental Ecstasy/MDMA ingestion by a 2 year old boy. The body
temperature on admission was 39.4 ◦ C, but this was rapidly corrected by water and fanning, with symptomatic improvement and
discharge.
The optimal medical treatments for MDMA-induced hyperthermia have been outlined elsewhere (White, 2002; Hall and Henry,
2005; Rusniak and Sprague, 2005; Grunau et al., 2010). Hall and
Henry (2005) summarized the physiological adverse reactions to
MDMA and the various treatment options. They noted: Hyperpyrexia and multi-organ failure are now relatively well-known,
other serious effects have become apparent more recently. Patients
with acute MDMA toxicity may present to doctors working in
Anaesthesia, Intensive Care and Emergency Medicine. A broad
knowledge of these pathologies and their treatment is necessary for those working in an acute medicine speciality. Halpern
et al. (2011) described the medical profiles of MDMA-related
6
A.C. Parrott / Drug and Alcohol Dependence 121 (2012) 1–9
admissions to Hospital Emergency Departments in Israel. They
noted that: ‘The most common manifestations were restlessness,
agitation, disorientation, shaking, high blood pressure, headache,
and loss of consciousness. More serious complications were hyperthermia, hyponatraemia, rhabdomyolysis, brain edema, and coma.
The image of ecstasy as a safe party drug is spurious.’ Greene et al.
(2009) reviewed 332 MDMA-related admissions to the Emergency
Department of one London Hospital, over a 3-year period. The core
body temperatures on admission ranged from very low (34.1 ◦ C) to
very high (41.6 ◦ C). Drug treatments for hyperthermia have been
debated, although this is complicated by the diagnostic similarity
between hyperthermia induced by serotonergic and dopaminergic agents (Hall and Henry, 2005). Grunau et al. (2010) reviewed
53 articles on emergency hospital treatments for MDMA-related
hyperthermia, and found that dantrolene was associated with a significantly better outcome. This was particularly when the increased
body temperature was coded as severe (<40.0 ◦ C), or extreme
(<42.0 ◦ C); under these hyperpyrexic conditions dantrolene helped
to reduce the number of fatalities. For moderate hyperthermia the
main approach should however be rapid and aggressive physical
cooling, with air fans or ice baths (Table 3).
5. Thermal self-ratings
In a laboratory study with sedentary volunteers, Harris et al.
(2002) noted subjective reports of ‘hot or cold sensations’ and
‘sweating,’ especially after the higher dose of 1.5 mg/kg MDMA.
In their overview of three laboratory studies, Liechti et al. (2001)
found that ‘sensitivity to cold’ and ‘sweating/sweaty palms’ were
reported by around a third of their sedentary volunteers. Freedman
et al. (2005) reported feelings of warmth in the hot environment,
and feelings of cold in the cool environment. There were no significant overall ANOVA drug effect for the thermal self-ratings, but
they did vary over time. In particular, ‘feeling warm’ scores in the
high ambient temperature condition were similar for MDMA and
placebo over the first 2 h, but then increased 2–4 h after-MDMA,
whereas placebo values remained constant. This period of subjective warmth coincided with time of body temperature increases
(Fig. 4 in Freedman et al., 2005).
In recreational Ecstasy/MDMA users, Davison and Parrott (1997)
reported that ‘increased body temperature’ was noted by 90%,
‘increased sweating’ by 85%, and ‘dehydration’ by 85% of the sample. Topp et al. (1999) found that ‘hot and cold flushes’ and ‘profuse
sweating’ were reported by 39% of their far larger sample. They
were amongst the four most common subjective complaints of
recreational Ecstasy users, although ‘feeling hot’ was not included
in the list of questions. In a neuroimaging study, Kish et al.
(2010) reported that +60% of their volunteers reported ‘overheating/sweating’ when on recreational Ecstasy. Parrott et al. (2006)
undertook an Internet survey of over 200 recreational users; 16%
reported that they did not-feel-hot, 41% felt slightly hot, 31% felt
moderately hot, and 12% reported feeling strongly or extremely hot,
when on-MDMA. This illustrates the wide variation in subjective
thermal responses to Ecstasy/MDMA (Table 3). Parrott and Young
(2005) found that subjective feelings of ‘feeling hot’ and ‘thirsty’
were significantly higher amongst dance clubbers who had taken
ecstasy that evening, compared to dance clubbers who had never
used Ecstasy. Hence the stronger thermal reactions of the Ecstasy
users were not an artifact of being at a dance club. Parrott et al.
(2008) similarly reported significantly higher self-ratings for ‘feeling hot’ and ‘hot-and-cold flushes’ in dance clubbers when they
were on-MDMA, compared both with pre-MDMA baseline, and
with dance clubbing during abstinence.
In a neuroimaging study, Kish et al. (2010) found significantly
lower serotonin transporter (SERT) levels in every region of the
cerebral cortex. One area particularly affected was the Insular Cortex, since 51% of the Ecstasy user group displayed SERT levels
below the lowest value of the control group. Kish et al. (2010)
noted that the Insular Cortex was involved in a various higher
cognitive activities, including ‘self-awareness and insightful cognition.’ Another function subserved by the Insular Cortex is thermal
awareness (Olausson et al., 2005), and this may help explain why
recreational users can experience such a range of thermal reactions.
For instance, dance clubbers can report ‘feeling hot,’ ‘feeling cold,’
and ‘hot-and-cold flushes’ over the same evening (Parrott et al.,
2008). It suggests a partial uncoupling of body temperature from
thermal awareness. It may also help explain how some recreational
Ecstasy users become dangerously hyperthermic (Patel et al., 2005;
Henry et al., 1992; Halpern et al., 2011). Future neuroimaging investigations into the thermal correlates of the SERT reductions in the
Insula Cortex seem warranted.
6. Thermoregulation mechanisms: heat production and
dissipation
This section will briefly review the thermoregulatory mechanisms revealed by animal MDMA research, before debating the
equivalent mechanisms for humans. Sprague et al. (2003, 2007)
noted that the thermogenesis induced by MDMA in laboratory
animals was complex, and involved molecular mediators in the
hypothalamic-pituitary-thyroid axis, sympathetic nervous system,
and uncoupling proteins. Rusniak and Sprague (2005) similarly
noted that: ‘Body temperature regulation is complex and requires
a balance between heat production and dissipation.’ In terms of
heat production, all stimulant drugs increase CNS metabolic activity
and are therefore potentially hyperthermic. Rusniak and Sprague
(2005) noted that increased heat production was an aspect of the
acute serotonin syndrome induced by MDMA. Elsewhere I have
noted that most recreational Ecstasy users display elements of
the serotonin syndrome, although its severity can vary between
individuals (Parrott, 2002). In the laboratory (Tancer et al., 2003),
acute MDMA significantly increased metabolic activity and core
body temperature in humans. Freedman et al. (2005) confirmed
that oxygen consumption and core body temperature were significantly raised by MDMA in humans, under both cool and hot thermal
environments (Table 3).
The other side of thermal homeostasis is heat dissipation (Mills
et al., 2004). In animals this involves increasing the blood supply to
the tail in rats, ears in rabbits, and piloerection in all hairy mammals
to facilitate heat loss; however, these mechanism are less relevant
for the ‘naked ape’ (Morris, 1967). In humans the main physiological route is peripheral vasodilatation, with more warm blood
to the skin, increased skin temperature, and heightened sweating
to facilitate heat loss (Fig. 2 in Gordon, 2007). Skin temperature
shows greater variability than core body temperature, due to the
homeostatic mechanisms of peripheral vasodilatation in the heat
and vasoconstriction in the cold. This has been confirmed with
MDMA in the laboratory, where skin temperature fluctuates more
than core body temperature (Tancer et al., 2003; Freedman et al.,
2005). This has also been found in party-goers on MDMA (Table 2),
with skin temperature increasing more than core body temperature
(Morefield et al., 2009). There are also subjective reports of the skin
‘feeling hot to the touch’ in some recreational users (Parrott, 2004b;
Patel et al., 2005).
Increased sweating or profuse sweating is also noted by some
recreational users (Davison and Parrott, 1997; Topp et al., 1999).
In the laboratory, Freedman et al. (2005) found that acute MDMA
delayed the initiation of sweating; hence the ‘thermoneutral zone’
(Gordon, 2007) was extended by MDMA, with body temperature increasing more than normal before sweating commenced.
A.C. Parrott / Drug and Alcohol Dependence 121 (2012) 1–9
Leon (2008) noted that sweating increased the permeability of the
skin, which ‘facilitates the cutaneous absorption of environmental
toxicants.’ Whether this also occurs in recreational MDMA users
could be an interesting research topic. Perspiration or sweating is
also facilitated by air conditioning, which cools and dehumidifies
the air, and facilitates heat release. Heat loss is also facilitated by
heat uncoupling proteins (UCP’s). During normal cellular activity,
the mitochondrial use of oxygen and oxidative phosphorylation are
closely controlled and remain fairly constant, a physiological process termed respiratory control. Under energetic stressors or toxins,
this can be uncoupled, with ‘potential energy being released as
heat, a process known as uncoupling’ (Rusniak and Sprague, 2005;
Sprague et al., 2007). Three heat uncoupling proteins are currently
known: UCP-1 in brown fat of rodents, UCP-2 in the liver, and
UCP-3 in human skeletal muscles. The effects of MDMA on UCPs
in animals have been reviewed by Rusniak and Sprague (2005);
however equivalent human research is not known. In laboratory
animals, the main neurotransmitters involved in thermal MDMA
changes are dopamine, noradrenaline and serotonin (Green et al.,
2003, 2004; Mills et al., 2004; Gordon, 2007). There is also evidence
that the preoptic anterior hypothalamus, ‘the main area responsible for control of body temperature’ is affected by MDMA in animals
(Benemar et al., 2008). Some of the thermal reactions may reflect
neurohormonal changes. Cortisol levels are increased by MDMA in
the laboratory (Harris et al., 2002), while MDMA-using dance clubbers show an 800% increase in cortisol (Parrott et al., 2008; Parrott,
2009).
7. Behavioural and environmental co-stressors
When thermally stressed, humans generally compensate by
modifying the behaviour. They cease physical activity and move
into a cooler environment, as in the midday ‘siesta’ of tropical
countries. Yet MDMA is typically taken at hot and crowded dance
clubs (Winstock et al., 2001; Suy et al., 1999; Parrott, 2004b). This
raises the intriguing question of why a hyperthermic drug is taken
in thermally stressful environments. Laboratory animal research
has shown that MDMA is more positively reinforcing in the heat,
with both rats (Cornish et al., 2003), and monkeys (Banks et al.,
2008). Hence MDMA may be more reinforcing to humans in the
heat, although it is not clear whether this is increasing its general
stimulant properties, or its more unique mood-enhancing qualities. Controlled empirical studies on this topic are not known,
although there is some supportive qualitative data (Table 3). In an
interview study, Bedi and Redman (2006) reported the following
quotations from recreational Ecstasy users: ‘The hotter it is, the
more pronounced the effects. . .’; ‘Taking a hot shower, bath or spa
could give you the feeling of bringing you back up again. . .’; ‘Dancing or moving around makes it come on a bit faster. . .; ‘A large
part of the ecstasy effect stops when you stop dancing.’ In another
interview study, Rodgers (cited in Parrott, 2004b) noted that some
recreational users wore woolly hats, or sat on radiators, in order to
prolong the on-drug experience.
Behavioural compensation is evident when dancers take rest
periods. Raves have ‘chill out’ rooms, with quieter music, which
allow for physical recovery and fluid replacement. There are also
reports of water being sprayed over dancer clubbers to cool them
down (Parrott, 2004b). The typical behavioural pattern is of energetic dancing, alternating with rest periods, although some dance
until they are exhausted. At one large Belgian rave 198 dancers were
treated in the paramedic help area (Suy et al., 1999). The majority
were treated for physical exhaustion by rest and cooling, although
a minority needed further medical treatment. Those treated for
exhaustion generally returned to the dance floor after resting. Some
Ecstasy users report dancing continuously (Parrott et al., 2006),
7
while bingeing on MDMA for +48 h without sleep has also been
noted, especially in experienced users with greater tolerance (Topp
et al., 1999; Parrott, 2005). The effects of these prolonged periods
of bio-energetic stress are currently unknown.
An important question is how a moderate increase in core body
temperature might develop into severe hyperthermia. This probably reflects a cascade of inter-related events, some of which will
increase thermal stress, while others might decrease it. Factors
which increase thermal stress would include higher single dose
levels or successive ‘binge’ doses (Topp et al., 1999), also prolonged
dancing (Parrott et al., 2006), especially in crowded clubs with high
ambient temperatures (Suy et al., 1999; Winstock et al., 2001).
Hydration is a contributory factor in laboratory animals (Dafters,
1995), and needs to be empirically investigated in humans. Factors which would reduce overheating include taking rest periods,
and moving into cooler environments. Individual difference factors, including personality, gender, and genetic profiles, may also
be important. For instance, impulsivity is associated with illicit
drug usage, and this personality trait might also be associated with
continued dancing despite feeling hot. This leads to the question
of thermal awareness, and potential differences between ‘feeling
hot’ and actual body temperature (Parrott, 2004a,b). One crucial
hypothesis for future study is that those with low thermal awareness might be most at risk from developing severe hyperthermia,
since they may then fail to take the necessary compensatory actions
for cooling down. Related to this is the Kish et al. (2010) finding
that 50% of abstinent MDMA users had significantly reduced serotonin levels in the insula cortex. As noted elsewhere, this region of
the cerebral cortex is involved with thermal awareness (Olausson
et al., 2005), and hence any serotonergic loss may heighten the risk
of developing hyperthermia.
8. Overview
MDMA is clearly a thermal stressor. Its hyperthermic properties are well established in laboratory animal studies (Gordon,
2007; Green et al., 2003; Mills et al., 2004; Sprague et al.,
2003, 2007), and this review has confirmed its hyperthermic
actions in humans. In placebo-controlled laboratory studies, the
increase in core body temperature was related to dosage, with
low doses having minimal effects, moderate doses leading to temperature increases of around +0.4 ◦ C, and higher doses causing
mean peak increase of +0.7 ◦ C (Table 1). In real world studies of
dance clubbers, some have found slight thermal changes, whereas
others have shown more pronounced increases in core body temperature (Table 2). This variation in thermal reactions may be
similar to the variation in other psychobiological responses to
ecstasy/MDMA (Parrott, 2006). It may be associated with factors
such as acute dosage/bingeing, cumulative lifetime usage, extent of
dancing/exercise, and environmental stimulation (Parrott, 2004a,b,
2005). It is also probably related to polydrug usage, since other CNS
stimulants would contribute to the temperature increases, whereas
sedative-hypothermic drugs such as cannabis might decrease thermal stress (Kiyatkin, 2004; Parrott et al., 2007a; Patel et al., 2005;
Greene et al., 2009; Table 3). A degree of variation in thermal reactions to MDMA hasalso been noted in the laboratory. Kolbrich et al.
(2008) administered a weight-controlled dose of 1.6 mg/kg MDMA,
and found a group mean increase of +0.4 ◦ C in core body temperature, although one sedentary volunteer developed a peak increase
of +1.9 ◦ C. Hence, individual difference factors also need to be elucidated.
Thermoregulation involves a subtle balance between heat production and dissipation, and MDMA affects both sides of this
homeostatic equation (Table 3). Acute MDMA increases cellular metabolic activity and heat output, while heat dissipation
8
A.C. Parrott / Drug and Alcohol Dependence 121 (2012) 1–9
mechanisms may become stressed, with delayed sweating and an
extended ‘thermoneutral zone’ (Freedman et al., 2005; Gordon,
2007). The subjective thermal response also shows considerable
variation, although it remains unclear why some recreational
Ecstasy/MDMA users report feeling very-hot, other feel slightly
moderately hot, while a minority do not feel hot (Parrott et al.,
2006). Some of this variation may reflect genetic factors, or endogenous variation in homeostatic control mechanisms. The role of the
insula cortex in relation to thermal awareness (Kish et al., 2010)
is also a key topic for future research. MDMA may be disrupting
normal thermoregulatory integration – so that the different thermal control mechanisms become dissociated. One female MDMA
user at a dance club reported feeling cold, wore extra clothes, and
displayed pronounced shivering, yet her body temperature was
unchanged from baseline (Parrott et al., 2008). In hospital Emergency Department admissions, the MDMA related casualties can
present with both low and high body temperatures (Greene et al.,
2009), although hyperpyrexic reactions provide the main focus for
medical attention (Patel et al., 2005).
Another health issue is the neuropsychobiological effects of
cumulative thermal stress. Indeed, this may be a more important issue for most users. The bio-energetic stress model notes
that MDMA is a powerful CNS stimulant and metabolic stressor,
and this is often heightened by co-factors including thermal stress
(Huether et al., 1997; Parrott, 2001, 2004b, 2006, 2009). In a neuroimaging study, Kish et al. (2010) noted that SERT reductions were
unrelated to subjective report of being-hot or not-being-hot on
MDMA, but subjective feelings may diverge from actual body temperatures. Hence, a key methodological topic is how to measure
and quantify cumulative thermal stress in regular users. The final
question relates to temperature levels within the brain. Kiyatkin
(2004) noted that only indirect indices of brain temperature could
be used with humans. Furthermore, tympanic membrane indices of
core body temperature often diverged from more direct measures
of brain temperature (in animals), with: ‘measurements of tympanic temperatures. . . consistently lower than and independent of
arterial and venous temperatures.’ This suggests that the brains of
Ecstasy users may be heating-up even more than current (indirect)
evidence suggests.
Role of funding source
Nothing declared.
Conflict of interest
No conflict declared.
References
Banks, M.L., Sprague, J.E., Czoty, P.W., Nader, M.A., 2008. Effects of ambient temperature on the relative reinforcing strength of MDMA using a choice procedure in
monkeys. Psychopharmacology 196, 63–70.
Bedi, G., Redman, J., 2006. Recreational ecstasy use: acute effects potentiated by
ambient conditions? Neuropsychobiology 53, 113.
Benemar, K., Geller, E.B., Adler, M.W., 2008. A new brain area affected by 3,4methylenedioxymethamphetamine: a microdialysis-biotelemetry study. Eur. J.
Pharmacol. 596, 84–88.
Brown, P.L., Kiyatkin, E.A., 2004. Brain hyperthermia induced by MDMA (‘ecstasy’):
modulation by environmental conditions. Eur. J. Neurosci. 20, 51–58.
Brown, C., Osterloh, J., 1987. Multiple severe complications from recreational ingestion of MDMA (’Ecstasy’). JAMA 258, 780–781.
Chadwick, I.S., Curry, P.D., Linsley, A., Freemont, A.J., Doran, B., 1991. Ecstasy,
3,4-methylenedioxymethamphetamine (MDMA), a fatality associated with
coagulopathy and hyperthermia. J. Royal Soc. Med. 84, 371.
Cohen, R.S., 1995. Subjective reports on the effects of the MDMA (Ecstasy) experience
in humans. Prog. Neuropsychopharmacol. Biol. Psychiatry 19, 1137–1145.
Cornish, J.L., Schahnawaz, Z., Thompson, M.R., Wong, S., Morley, K.C., Hunt, G.E.,
McGregor, I.S., 2003. Heat increases 3,4-methylenedioxymethamphetamine
administration and social effects in rats. Eur. J. Pharmacol. 482, 339–341.
Corre, J.R., 1996. A fatal trip with ecstasy: a case of 3,4methylenedioxymethamphetamine toxicity. J. Royal Soc. Med. 89, 51–52.
Dafters, R., 1995. Hyperthermia following MDMA administration in rats: effects of
ambient temperature, water consumption, and chronic dosing. Physiol. Behav.
58, 877–882.
Davison, D., Parrott, A.C., 1997. Ecstasy in recreational users: self-reported psychological and physiological effects. Hum. Psychopharmacol. 12, 91–97.
Farre, M., Abanades, S., Roset, P.N., Peiro, A.M., Torrens, M., O’Mathuna, B.,
Segura, M., de la Torre, R., 2007. Pharmacological interactions between 3,4methylenedioxymethamphetamine (ecstasy) and paroxetine: pharmacological
effects and pharmacodynamics. J. Pharmacol. Exp. Ther. 323, 954–962.
Folkard, S., 1983. Diurnal Variation. Stress and Fatigue in Human Performance. Wiley,
Chichester and New York.
Freedman, R.R., Johanson, C.E., Tancer, M.E., 2005. Thermoregulatory effects of 3,4methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology
183, 248–256.
Gordon, C.J., 2007. Thermophysiological response to hyperthermic drugs: extrapolating from rodent to human. Prog. Brain Res. 162, 63–79.
Gordon, C.J., Watkinson, W.P., O’Callaghan, J.P., Miller, D.B., 1991. Effects of 3,4methylenedioxymethamphetamine on thermoregulatory responses in the rat.
Pharmacol. Biochem. Behav. 38, 339–344.
Green, A.R., Mechan, A.O., Elliott, J.M., O’Shea, E., Colado, M.I., 2003. The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine
(MDMA, “ecstasy”). Pharmacol. Rev. 55, 463–508.
Green, A.R., Sanchez, V., O’Shea, E., Saadat, K.S., Elliott, J.M., Colado, M.I.,
2004. Effect of ambient temperature and a prior neurotoxic dose of 3,4methylenedioxymethamphetamine (MDMA) on the hyperthermic response of
rats to a single or repeated (‘binge’ ingestion) low dose of MDMA. Psychopharmacology 173, 264–269.
Greene, S.L., Wood, D.M., Dargan, P.I., 2009. Epidemiological and clinical characteristics of acute MDMA related presentations to an inner city London Emergency
Department. Neuropsychobiology 60, 214.
Grob, C.S., Poland, R.E., Chang, L., Ernst, T., 1996. Psychobiologic effects of 3,4methylenedioxymethamphetamine in humans: methodological considerations
and preliminary observations. Behav. Brain. Res. 73, 103–107.
Grunau, B.E., Wiens, M.O., Brubacher, J.R., 2010. Dantrolene in the treatment of
MDMA-related hyperpyrexia: a systematic review. CJEM 12, 435–442.
Hall, A.P., Henry, J.A., 2005. Acute toxicity of ‘Ecstasy’ (MDMA) and related compounds: overview of pathophysiology and clinical management. Br. J. Anaesth.
96, 678–685.
Halpern, P., Moskovich, J., Avrahami, B., Bentur, Y., Soffer, D., Peleg, K., 2011. Morbidity associated with MDMA (ecstasy) abuse—a survey of emergency department
admissions. Hum. Exp. Toxicol. 30, 259–266.
Harris, D.S., Baggott, M., Mendelson, J.H., Mendelson, J.E., Jones, R.T., 2002. Subjective and hormonal effects of 3,4-methylenedioxymethamphetamine (MDMA)
in humans. Psychopharmacology 162, 396–405.
Henry, J.A., Jeffries, K.J., Dawling, S., 1992. Toxicity and deaths from 3,4methylenedioxymethamphetamine (“Ecstasy”). Lancet 340, 384–387.
Huether, G., Zhou, D., Ryuther, E., 1997. Causes and consequences of the
loss of serotonergic presynapses elicited by the consumption of 3,4methylenedioxymethamphetamine (MDMA, “ecstasy”) and its congeners. J.
Neural Transm. 104, 771–794.
Irvine, R.J., Keane, M., Felgate, P., Mc Cann, U.D., Callaghan, P.D., White, J.M., 2006.
Plasma drug concentrations and physiological measures in dance party participants. Neuropsychopharmacology 31, 424–430.
Kish, S.J., Lerch, J., Furukawa, Y., Tong, J., Mc Cluskey, T., Wilkins, D., Houle, S.,
Meyer, J., Mundo, E., Wilson, A.A., Rusjan, P.M., Saint-Cyr, J.A., Guttman, M.,
Collins, D.L., Shapiro, C., Warsh, J.J., Boileau, I., 2010. Decreased cerebral cortical
serotonin transporter binding in ecstasy users: a positron emission tomography/[(11)C]DASB and structural brain imaging study. Brain 133, 1779–1797.
Kiyatkin, E.A., 2004. Brian hyperthermia during physiological and pathological conditions: causes, mechanisms, and functional implications. Curr. Neurovasc. Res.
1, 77–90.
Kolbrich, E.A., Goodwin, R.S., Gorelick, D.A., Hayes, R.J., Stein, E.A.,
Huetis, M.A., 2008. Physiological and subjective responses to 3,4methylenedioxymethamphetamine administration. J. Clin. Psychopharmacol.
28, 432–440.
Leon, L.R., 2008. Thermoregulatory responses to environmental toxicants: the interactions of thermal stress and toxicant exposure. Toxicol. App. Pharmacol. 233,
146–161.
Liechti, M.E., Vollenweider, F.X., 2000. The serotonin uptake inhibitor
citalopram reduces cardiovascular and vegetative effects of 3,4methylenedioxymethamphetamine (ecstasy) in human volunteers. J.
Psychopharmacol. 14, 269–274.
Liechti, M.E., Saur, W.R., Gamma, A., Hell, D., Vollenweider, F.X., 2000. Psychological and physiological effects of MDMA (ecstasy) after pretreatment with the
5-HT2 antagonist ketanserin in healthy humans. Neuropsychopharmacology 23,
396–404.
Liechti, M.E., Gamma, A., Vollenweider, F.X., 2001. Gender differences in the subjective effects of MDMA. Psychopharmacology 154, 161–168.
Malberg, J.E., Seiden, L.S., 1998. Small changes in ambient temperature cause large
changes in 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin neurotoxicity and core body temperature in the rat. J. Neurosci. 18,
5086–5094.
Mas, M., Farre, M., de la Torre, R., Roset, P.N., Ortuno, J., Segura, J., Cami, J.,
1999. Cardiovascular and neuroendocrine effects and pharmacokinetics of 3,4-
A.C. Parrott / Drug and Alcohol Dependence 121 (2012) 1–9
methylenedioxymethamphetamine in humans. J. Pharmacol. Exp. Ther. 290,
136–145.
Mills, E.M., Rusyniak, D.E., Sprague, J.E., 2004. The role of the sympathetic
nervous system and uncoupling proteins in the thermogenesis induced by 3,4methylenedioxymethamphetamine. J. Mol. Med. 82, 787–799.
Morefield, K.M., Keane, M., Felgate, P., White, J.M., Irvine, R.J., 2009. The acute psychobiological impacts of ilicit 3,4-methylenedioxymethamphetamine (MDMA,
‘Ecstasy’) consumption in recreational environments. Neuropsychobiology 60,
216.
Morris, D., 1967. The Naked Ape. Corgi Press, London.
Olausson, H., Charron, J., Marchand, S., Villemure, C., Strigo, I.A., Bushnell, M.C., 2005.
Feelings of warmth correlate with neural activity in right anterior insular cortex.
Neurosci. Lett. 389, 1–5.
Parrott, A.C., 2001. Human psychopharmacology of ecstasy (MDMA): a review of
fifteen years of empirical research. Hum. Psychopharmacol. 16, 557–577.
Parrott, A.C., 2002. Recreational ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity. Pharmacol. Biochem. Behav. 71, 837–844.
Parrott, A.C., 2004a. Is ecstasy MDMA? A review of the proportion of ecstasy tablets
containing MDMA, dosage levels, and the changing perceptions of purity. Psychopharmacology 173, 234–241.
Parrott, A.C., 2004b. MDMA (3,4-methylenedioxymethamphetamine) or Ecstasy: the
neuropsychobiological implications of taking it at dances and raves. Neuropsychobiology 50, 329–335.
Parrott, A.C., 2005. Chronic tolerance to recreational MDMA (3,4methylenedioxymethamphetamine) or Ecstasy. J. Psychopharmacol. 19,
71–83.
Parrott, A.C., 2006. MDMA in humans: factors which affect the neuropsychobiological profiles of recreational Ecstasy users, the integrative role of bio-energetic
stress. J. Psychopharmacol. 20, 147–163.
Parrott, A.C., 2009. Cortisol and MDMA (3,4-methylenedioxymethamphetamine):
neurohormonal aspects of bioenergetic-stress in Ecstasy users. Neuropsychobiology 60, 148–158.
Parrott, A.C., Young, L., 2005. Increased body temperature in recreational
Ecstasy/MDMA users out clubbing and dancing. J. Psychopharmacol. 19, a26.
Parrott, A.C., Rodgers, J., Buchanan, T., Ling, J., Heffernan, T., Scholey, A.B., 2006. Dancing hot on ecstasy: physical activity and thermal comfort ratings are associated
with the memory and other psychobiological problems of recreational MDMA
users. Hum. Psychopharmacol. 21, 285–298.
Parrott, A.C., Milani, R.M., Gouzoulis-Mayfrank, E., Daumann, J., 2007a. Cannabis and
Ecstasy/MDMA (3,4-methylenedioxymethamphetamine): an analysis of their
neuropsychobiological interactions in recreational users. J. Neural Transm. 114,
959–968.
Parrott, A.C., Adnum, L., Evans, A., Kissling, C., Thome, J., 2007b. Heavy Ecstasy/MDMA
use at cool house parties: substantial cortisol release and increased body temperature. J. Psychopharmacol. 21, a35.
9
Parrott, A.C., Lock, J., Conner, A.C., Kissling, C., Thome, J., 2008. Dance
clubbing on MDMA and during abstinence from Ecstasy/MDMA: prospective neuroendocrine and psychobiological changes. Neuropsychobiology 57,
165–180.
Patel, M.M., Belson, M.G., Longwater, A.B., Olson, K.R., Miller, M.A., 2005. Methylenedioxymethamphetamine (ecstasy)-related hyperthermia. J. Emerg. Med. 29,
451–454.
Peroutka, S.J., Newman, H., Harris, H., 1988. Subjective effects of 3,4methylenedioxymethamphetamine in recreational users. Neuropsychopharmacology 1, 273–277.
Rusniak, D.E., Sprague, J.E., 2005. Toxin-induced hyperthermic syndromes. Med. Clin.
North Am. 89, 1277–1296.
Schifano, F., Corkery, J., Deluca, P., Oyefeso, A., Ghodse, A.H., 2006. Ecstasy
(MDMA, MDA, MDEA, MBDB) consumption, seizures, related offences, prices,
dosage levels and deaths in the UK (1994–2003). J. Psychopharmacol. 20,
456–463.
Shulgin, A.T., 1986. The background and chemistry of MDMA. J. Psychoactive Drugs
18, 291–304.
Sprague, J.E., Mallett, N.M., Rusniak, D.E., Mills, E., 2003. Hypothalamic-pituitarythyroid axis and sympathetic nervous system involvement in hyperthermia
induced by 3,4-methylenedioxymethamphetamine (Ecstasy). J. Pharmacol. Exp.
Ther. 305, 159–166.
Sprague, J.E., Yang, X., Sommers, J., Gilman, T.L., Mills, E.M., 2007. Roles of norepinephrine, free fatty acids, thyroid status, and skeletal muscle uncoupling
protein 3 expression in sympathomimetic-induced thermogenesis. J. Pharmacol.
Exp. Ther. 320, 274–280.
Suy, K., Gijsenbergh, F., Baute, L., 1999. Emergency medical assistance during a mass
gathering. Eur. J. Emerg. Med. 6, 249–254.
Tancer, M.E., Johanson, C.E., Freedman, R.R., 2003. MDMA elevates core temperature in warm and cold conditions in man. In: College on Problems of Drug
Dependence Annual Conference, Florida, USA, June 2003, Conference Abstract,
p. 169.
Topp, L., Hando, J., Dillon, P., Roche, A., Solowij, N., 1999. Ecstasy use in Australia:
patterns of use and associated harm. Drug Alcohol Depend. 55, 105–115.
Vollenweider, F.X., Gamma, A., Liechti, M., Huber, T., 1998. Psychological and cardiovascular effects and short-term sequelae of MDMA (“ecstasy”) in MDMA-naive
healthy volunteers. Neuropsychopharmacology 19, 241–251.
White, S.R., 2002. Amphetamine toxicity. Semin. Respir. Crit. Care Med. 23,
27–36.
Williams, H., Dratcu, L., Taylor, R., Roberts, M., Oyefeso, A., 1998. Saturday night fever:
ecstasy related problems in a London accident and emergency department. J.
Acc. Emerg. Med. 15, 322–326.
Winstock, A.R., Griffiths, P., Stewart, D., 2001. Drugs and the dance music scene: a
survey of current drug use patterns among a sample of dance music enthusiasts
in the UK. Drug Alcohol Depend. 64, 9–17.