Comparison of the effects of ( )3,4-Methylenedioxymethamphetamine (MDMA), ( )3,4Methylenedioxyamphetamine (MDA) and d-Methamphetamine (METH) on
temperature and activity in monkeys
Rebecca D. Crean, Sophia A. Davis, Stefani N. Von Huben, Christopher C. Lay, Simon N. Katner and Michael A. Taffe
Molecular and Integrative Neuroscience Department, The Scripps Research Institute, La Jolla, CA
37.0
37.0
# # #
Vehicle
0.56 mg/kg
1.0 mg/kg
1.78 mg/kg
2.4 mg/kg
35
#
*
Open symbols indicate a significant difference from
the vehicle condition at a given time point.
The * symbol indicates a significant increase from
pre-injection baseline.
Vehicle
0.56 mg/kg
1.0 mg/kg
1.78 mg/kg
2.4 mg/kg
1
2
3
5
6
7
8
9
MDA
37.5
Activity Counts
*
**
*
37.0
36.5
36.0
35.5
Vehicle
0.56 mg/kg
1.0 mg/kg
1.78 mg/kg
2.4 mg/kg
35.0
-1
1
2
3
4
5
6
7
8
9
Thermoregulatory and Activity Recordings
Radio telemetric transmitters were surgically implanted subcutaneously in the flank.
Data (temperature and activity) were recorded by the controlling computer and represented as
a 10-minute average of.
*
*
*
*
**
*
37.5
*
*
*
*
*
*
METH
*
*
*
36.5
36.0
Vehicle
0.1 mg/kg
0.32 mg/kg
0.56 mg/kg
1.0 mg/kg
35.5
35.0
-1
1
2
3
4
5
6
7
8
9
MDMA + 0.32 mg/kg METH
37.5
37.0
36.5
300
270
240
210
180
150
120
300
270
240
210
180
150
300
270
240
210
180
150
120
90
60
0
-30
30
8
9
10 11 12 13 14 15 16 17 18 19 20
The * symbol indicates a significant increase from the
vehicle condition.
MDA
1
2
3
4
5
6
7
8
9
200
METH
*
150
120 150 180 210 240 270 300
100
-1
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
1.78 mg/kg MDMA + 0.32 mg/kg Meth
38.5
Vehicle
MDMA only
MDMA + 0.1 mg/kg METH
0.1 mg/kg METH
37.5
37.0
Vehicle
MDMA only
38.0
MDMA + 0.32 mg/kg METH
0.32 mg/kg METH
37.5
0
30
60
Combining METH with MDMA significantly increased
temperature over MDMA alone.
90 120 150 180 210 240 270 300
METH elevates temperature over a more protracted
time course.
Temperature responses to all three amphetamines
were not strongly dose-dependent across the tested
ranges, except when MDMA and METH were combined.
Temperature responses were not dependent on significant increases in locomotor activity following any of
the compounds.
37.0
36.5
-90 -60 -30
The results of the present study establish that rhesus
monkeys develop elevated body temperature following
an intramuscular injection of a range of doses of each
of three substituted amphetamines.
The immediate temperature response in ~4 hours
after the administration of ( )MDA is similar to the
( )MDMA response at identical doses.
Hours Post-Injection
38.0
Discussion
These data support and extend our initial report
(Taffe et al. 2006) that monkeys hyperthermic
responses to these compounds are similar to humans
and not hypothermic, which contrasts with one prior
report on the effects of (+)MDMA in rhesus monkeys
(Bowyer et al. 2003).
10 11 12 13 14 15 16 17 18 19 20
Vehicle
0.1 mg/kg
0.32 mg/kg
0.56 mg/kg
1.0 mg/kg
36.5
90
7
Body Temperature
MDMA + 0.1 mg/kg METH
60
6
1.78 mg/kg MDMA + 0.1 mg/kg Meth
Body Temperature
Body Temperature
MDMA only
30
5
50
10 11 12 13 14 15 16 17 18 19 20
38.5
0
4
100
0
Vehicle
-90 -60 -30
3
50
1.78 mg/kg MDMA + Meth
38.0
2
Open symbols indicate a significant difference from
the pre-injection baseline.
150
Hours Post-Injection
38.5
1
Vehicle
0.56 mg/kg
1.0 mg/kg
1.78 mg/kg
2.4 mg/kg
-1
37.0
34.5
-1
200
10 11 12 13 14 15 16 17 18 19 20
Activity Counts
Body Temperature ( C)
Body temperature and spontaneous home cage activity were monitored
continuously in six male rhesus monkeys via radiotelemetric devices. Subjects were challenged
intramuscularly with 0.56-2.4 mg/kg MDMA, 0.56-2.4 mg/kg MDA and 0.1-1.0 mg/kg METH.
50
250
38.0
*
*
100
Mean (N=6, bars indicate SEM) activity values in the
20 hours following acute challenge with doses of
( )MDMA, ( )MDA and (+)METH.
0
38.5
Methods
MDMA
150
250
38.0
34.5
Vehicle
0.56 mg/kg
1.0 mg/kg
1.78 mg/kg
2.4 mg/kg
200
10 11 12 13 14 15 16 17 18 19 20
38.5
Significant decreases from baseline are not depicted.
120
15
0
4
90
20
-120
36.5
-1
90
25
300
270
240
210
180
150
120
90
60
30
* *
37.0
34.5
60
30
Minutes Post-Injection
MDMA
35.0
Activity levels were only significantly increased by
0.32 mg/kg METH.
35
250
35.5
0.56 mg/kg
1.0 mg/kg
0
38.5
36.0
A disruption of nighttime circadian cooling was
observed up to 18 hours after 1.0. mg/kg METH and
1.78-2.4 mg/kg MDA, but not after MDMA.
5
Activity Counts
Body Temperature ( C)
Mean (N=6, bars indicate SEM) subcutaneous temperature values in the 20 hours following acute challenge with doses of ( )MDMA, ( )MDA and
(+)METH.
60
40
The acute effect of METH lasted hours longer than
MDA or MDMA.
10
0
-30
-90
-60
Vehicle
0.1 mg/kg
0.32 mg/kg
0.56 mg/kg
1.0 mg/kg
30
-120
Activity Counts
37.0
V ehicle
0.1 mg/kg
0.32 mg/kg
METH
45
Increases were not dose-dependent.
Combining METH with 1.78 mg/kg MDMA significantly
increased temperature over MDMA alone, in a dosedependent fashion.
0
METH
**
**
30
15
5
37.5
37.5
0
20
10
38.0
38.0
-30
25
50
36.5
-60
30
300
270
240
210
180
150
120
90
60
30
0
-30
-60
-90
-120
Significant increase in activity, compared with preinjection baseline, were observed with
0.32 mg/kg METH.
0
36.0
40
Breaks in the series indicate the time of injection.
No significant increases in activity, compared with
pre-injection baseline, were observed with MDMA
or MDA.
MDA
-30
**
Vehicle
0.56 mg/kg
1.0 mg/kg
1.78 mg/kg
2.4 mg/kg
45
-60
#
-120
-90
-120
210
180
150
120
90
60
30
0
-30
0
37.5
36.0
Mean (N=6) activity values following acute challenge with doses of ( )MDMA, ( )MDA and
(+)METH.
Minutes Post-Injection
Objective:
The present study was conducted to determine the relative thermoregulatory disruption produced by
recreational doses of MDMA, MDA and METH in nonhuman primates.
Acute Drug Challenges, administered IM in a volume of 0.1 ml/kg saline
MDMA: 0, 0.56, 1.0, 1.78, 2.4 mg/kg
MDA: 0, 0.56, 1.0, 1.78, 2.4 mg/kg
METH: 0, 0.1, 0.32, 0.56, 1.0 mg/kg
Combination of 1.78 mg/kg MDMA with 0.0, 0.1 or 0.32 METH mg/kg
15
5
38.0
38.5
Body Temperature ( C)
A clear distinction of thermoregulatory risks posed by different amphetamines, individually and
in combination, is critical to understand factors that may produce medical emergencies related
to hyperthermia.
20
35.5
Introduction
In animal studies the degree of (subcritical) hyperthermia is often related to the severity of
amphetamine-induced neurotoxicity, suggesting health risks to the human user even when
emergency medical services are not invoked
25
50
36.5
All three amphetamines significantly elevated
temperature.
30
10
MDA
35.5
Severe and malignant hyperthermia is a frequently reported factor in Emergency Department
visits and fatalities in which use of amphetamine drugs, such as MDMA, MDA and METH, is
confirmed. Individuals who use Ecstasy are also often exposed, intentionally or otherwise, to
several of these structurally-related compounds alone or in combination.
35
-60
38.5
-60
35.5
40
300
36.0
Vehicle
0.56 mg/kg
1.0 mg/kg
1.78 mg/kg
2.4 mg/kg
MDMA
45
-90
The * and # indicate time points in which all four (*)
or three of four (#) active dose conditions differed significantly from the vehicle temperature.
Vehicle
0.56 mg/kg
1.0 mg/kg
1.78 mg/kg
2.4 mg/kg
Activity Counts
Open symbols indicate significant change from
pre-injection baseline
#
270
*
240
36.5
-120
Body Temperature ( C)
Breaks in the series indicate the time of injection.
Activity Counts
37.5
-90
Body Temperature ( C)
Mean (N=6, bars indicate SEM) subcutaneous temperature values following acute challenge with doses
of MDMA, MDA and METH.
Body Temperature ( C)
Rationale: Recreational Ecstasy pills thought to contain ( )3,4methylenedioxymethamphetamine (MDMA) frequently include other substituted amphetamines
such as ( )3,4-methylenedioxyamphetamine (MDA) and d-methamphetamine (METH).
Hyperthermia is a critical factor in Ecstasy-related Emergency Department visits and fatalities,
and the degree of hyperthermia is related to the severity of MDMA-induced neurotoxicity in
animal studies. Given that the majority of Ecstasy pills are contaminated with other
amphetamines, the etiology of thermodysregulation is unclear. Objective: To determine the
relative thermoregulatory disruption produced by recreational doses of MDMA, MDA and METH
in nonhuman primates. Methods: Body temperature and spontaneous home cage activity were
monitored continuously in six male rhesus monkeys via radiotelemetric devices. The subjects
were challenged intramuscularly with 0-2.4 mg/kg ( )MDMA, 0-2.4 mg/kg ( )MDA and 0-1.0
mg/kg METH in a randomized order. Results: Temperature was significantly elevated by all
three substituted amphetamines, and the increase was not dose dependent. A disruption of
nighttime circadian cooling was observed as long as 18 hours after 1.0 mg/kg METH and 1.782.4 mg/kg MDA, but not after MDMA. With the exception of 0.32 mg/kg METH , activity levels
were not increased. Conclusions: All three substituted amphetamines produce hyperthermia in
rhesus monkeys and these effects do not depend on elevated locomotor activity. These studies
establish a novel model of thermoregulatory disruption associated with substituted
amphetamines. The results further our understanding of the risks posed by recreational
Ecstasy exposure, clinical MDMA use, and help to refine preclinical models of exposure to
substituted amphetamines.
Supported by DA018418.
MDMA
38.0
Results
50
-90
ABSTRACT
38.5
-90 -60 -30
0
30
60
90
120 150 180 210 240 270 300