Modification of MDMA-Induced Hyperthermia by Other Recreational Drugs
Michael A. Taffe
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA
Background: Oral MDMA elevates body
temperature in unrestrained monkeys.
0.0
*
-0.5
-1.0
-1.5
*
*
* *
*
Veh
1.78 mg/kg MDMA
1 mg/kg Caffeine
1.0
*#
0.5
#
*#
*
*
-0.5
-1.0
-1.5
-2.0
Hours Post-Injection
Caffeine enhances the elevation in body temperature
produced by a recreational dose of MDMA.
*#
*
0.0
1.78 mg/kg MDMA + 1 mg/kg Caffeine
-1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
*
*
*
*
*
*
*
THC attenuates elevations in body temperature
produced by a recreational dose of MDMA.
*
Veh
1.78 mg/kg MDMA
5 mg/kg Caffeine
1.78 mg/kg MDMA + 5 mg/kg Caffeine
-1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Hours Post-Injection
Caffeine effects are dose dependent (w/o MDMA)
5 mg/kg Caffeine + MDMA elevates body temperature more than either drug alone
Barrett et al, 2006; 2007; Sumnall et al, 2006; Chinet et al, 2007
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20
Hours Post-Injection
Δ9-tetrahydrocannabinol
(0.1-0.3 mg/kg i.m.; 1:1:18 Emulphor:EtOH:Saline Veh)
Minutes Post-Injection
0.00
-1.0
-1.5
-1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Hours Post-Injection
-0.25
Vehicle
0.3 mg/kg THC
0.3 mg/kg SR
SR + THC
300
270
240
90
60
30
210
* SR and SR+THC differ from THC alone
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-1.00
150
-0.75
120
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0
300
270
240
210
180
150
90
120
(1, 5 mg/kg p.o.; Tang, Kool-Aide Veh)
60
-1.25
-0.5
-2.0
0.25
-30
-1.00
N=6
0.50
-60
-0.75
0.75
-90
Vehicle
0.1 mg/kg THC
0.2 mg/kg THC
0.3 mg/kg THC
Change from Baseline ( C)
-0.50
Body Temperature
-0.25
30
Caffeine
0.00
-90
(1.78 mg/kg, p.o.; Tang, Kool-Aide Veh)
0.25
0
( )3,4-Methylenedioxymethamphetamine HCl
N = 10
0.50
-30
Data Sciences International (Transoma)
0.75
-60
Radiotelemetric monitoring of subcutaneous
temperature and spontaneous locomotor activity.
Change from Baseline ( C)
Male rhesus macaques
Body Temperature
Methods
Open symbols indicate significant difference (p<0.05) from baseline
and vehicle; shaded symbols indicate significant difference from baseline only.
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Minutes Post-Injection
SR141716 blocks THC-induced hypothermia at a dose which
does not affect temperature when administered alone.
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*
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*
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-1.0
-1.5
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#
#
#
*
#
*
#
*#
*
#
*
#
*
MDMA + 0.1 mg/kg METH
*
*
37.0
MDMA + 0.32 mg/kg METH
#
36.5
#
#
36.0
35.5
35.0
-1
#
2
4
6
8
10
12
14
16
18
Hours Post-Administration
20
#
vs MDMA alone
* MDMA/THC
MDMA/THC vs THC alone
# 0.1 vs 0.3 mg/kg THC
-2.0
Veh + 0.32 mg/kg METH
37.5
-1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Skeletal muscle contracture contributes to heat
generation in medical emergency after MDMA.
Hours Post-Injection
0.3 mg/kg THC i.m. attenuates acute oral MDMA-induced hyperthermia.
0.3 mg/kg THC i.m. + 1.78 mg/kg MDMA p.o. also interferes with overnight circadian
cooling more than either drug administered alone.
4.5
2.5
2.0
1.5
10 mg/kg MDMA
1.78 mg/kg MDMA (T1)
Seizure-like behavior
abolished
Diazepam
1.0
0.5
0.0
Seizure-like behavior
-0.5
-1.0
-1.5
M454
Minutes Post-Injection
3.5
1.7 S(+)MDMA
1.7 (+/-)MDMA
2.4 (+/-)MDMA
2.4 S(+)MDMA
2.5
1.5
Recovery
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-0.5
-1.5
Seizure-like behavior
M405
Minutes Post-Injection
180
5
1.78 mg/kg MDMA, p.o. + 0.3 mg/kg THC, i.m.
38.0
165
4
0.3 mg/kgTHC, i.m.
Veh + Veh
Veh + 0.1 mg/kg METH
135
150
3
0.5
38.5
120
2
1.78 mg/kg MDMA, p.o. + 0.1 mg/kg THC, i.m.
Caffeine may be a more
critical contributor than
methamphetamine in
monkeys.
1.78 mg/kg MDMA, p.o.
90
105
-1 1
0.1 mg/kgTHC, i.m.
39.0
N=5
75
35.5
1.78 mg/kg MDMA, p.o.
Veh, p.o.
Oral MDMA + Methamphetamine
45
60
N = 10
0.5
Veh, p.o.
1.0
0.3 mg/kg THC
30
36.0
1.0
0.1 mg/kg THC
0
15
36.5
[Clemens et al., 2004, 2005]
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Does caffeine interact with MDMA to increase skeletal muscle
heat production?
THC significantly reduces body
temperature with maximum effect
observed 3-6 hrs after intramuscular
administration.
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Klingler et al, 2005
37.0
Methamphetamine does not alter MDMA
hyperthermia in rats.
Change from Baseline ( C)
Caffeine contracture test for Malignant Hyperthermia: MDMA
enhances contracture in human muscle.
Vehicle
0.1 mg/kg THC
0.2 mg/kg THC
0.3 mg/kg THC
[Camarasa et al., 2006; McNamara et al.,2006]
Body Temperature
McNamara et al, 2006; Camarasa et al, 2006; McNamara et al, 2007
37.5
Caffeine increases MDMA hyperthermia in rats.
Temperature ( C)
Caffeine increases thermoregulatory, locomotor, cardiac and
lethal responses to MDMA in rats.
THC attenuates
MDMA-induced hyperthermia
Change in
Body Temperature ( C)
Baggott et al., 2000; Cheng et al. 2003; Camilleri and Caldicot, 2005;
Teng et al, 2006; Tanner-Smith, 2006; Giraudon and Bello, 2007
Body Temperature ( C)
Caffeine is a common contaminant of Ecstasy tablets in many
countries (US, Taiwan, Australia, Hong Kong, France).
THC induces hypothermia in monkeys
Change in
Body Temperature ( C)
THC produces hypothermia; is it protective against Ecstasyinduced hyperthermia?
The relative risk associated with co-administered
drugs is a clinically important question and a
necessary preamble to relevant mechanistic questions.
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Cannabis commonly used in combination with Ecstasy.
Discussion
Change from Baseline ( C)
Crean et al., 2007;
Pharmacol Biochem Behav, 87:11-19.
1.78 mg/kg MDMA (p.o.) and 1-5 mg/kg Caffeine (p.o.) elevate body temperature
Body Temperature
Taffe et al., 2006; Crean et al, 2006; VonHuben et al, 2007; Crean et al, 2007
MDMA alone
* vs
vs Caff alone
# 1 vs 5 mg/kg Caff
300
270
240
210
180
Oral administration of MDMA in recreational doses results in significant
elevation of body temperature in unrestrained monkeys. Activity levels
are suppressed by intramuscular, but not by oral, administration of MDMA.
Unrestrained rhesus monkeys exhibit hyperthermia when MDMA
is administered orally or intramuscularly in recreational doses.
Change in
Body Temperature ( C)
300
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90
60
30
0
150
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30
0
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open symbol: significant difference from baseline; * indicates significant difference from vehicle
Gillman, 1997; Greene et al., 2003; Mallick and Bodenham, 1997
5 mg/kg Caffeine
N=5
0.5
MDMA-induced elevations of body temperature are
modified by two drugs commonly used with
MDMA by the recreational user.
Minutes Post-Administration
Minutes Post-Administration
Emergency departments report elevated body temperature
in MDMA-associated mentions and fatalities.
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60
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30
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Vehicle, IM
1.78 mg/kg MDMA, IM
0
Activity Counts
1.0
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300
270
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210
180
150
120
90
60
30
0
Vehicle, IM
1.78 mg/kg MDMA, IM
40
35
30
25
20
15
10
5
0
-30
1.5
-30
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-0.5
-90
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*
1 mg/kg Caffeine
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*
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Vehicle, PO
1.78 mg/kg MDMA, PO
-90
1.0
40
35
30
25
20
15
10
5
0
-90
Activity Counts
Change from Baseline ( C)
Vehicle, PO
1.78 mg/kg MDMA, PO
-90
Introduction
1.5
Change from Baseline ( C)
Temperature
Temperature
Human mortality from exposure to the recreationally abused drug
( )3,4-methelenedioxymethamphetamine (MDMA, Ecstasy ) is typically
associated with acute thermoregulatory distress including malignant
hyperthermia. The Ecstasy user, however, frequently ingests other
psychoactive compounds in combination with MDMA. Studies were
conducted to evaluate the extent to which caffeine, nicotine, delta9tetrahydrocannabinol (THC) and ethanol can modify the hyperthermia
induced by MDMA in a rhesus monkey model. Temperature was assessed
noninvasively and continuously using radiotelemetry. Administration of
MDMA (1.78 mg/kg, p.o.) or caffeine (1, 5 mg/kg, p.o.) elevated body
temperature whereas THC (0.1-0.3 mg/kg, i.m.) decreased body
temperature. Coadministration of 5 mg/kg caffeine (p.o.) increased, while
co-administration of 0.3 mg/kg THC (i.m.) reversed, the hyperthermic
response to 1.78 mg/kg MDMA (p.o.) These data show that at doses
relevant for the recreational consumer, combined exposure to MDMA and
other common recreational psychoactive compounds can produce
interactive effects on body temperature. In particular this study identifies a
potential role of caffeine in MDMA-related medical emergency.
Supported by NIH Grant DA018418.
Summary
Caffeine increases
MDMA-induced hyperthermia
Change in
Body Temperature ( C)
Abstract