Thermoregulatory effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans

Rationale Although 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) has been reported to cause fatal hyperthermia, few studies of the effects of MDMA on core body temperature in humans have been conducted demonstrating increased body temperature. In rats, MDMA causes hyperthermia at warm ambient temperatures but hypothermia at cold ones.Objectives In this study, the physiological and subjective effects of MDMA in humans were determined at cold (18°C) and warm (30°C) ambient temperatures in a temperature and humidity-controlled laboratory.Methods Ten healthy volunteers who were recreational users of MDMA were recruited. Four laboratory sessions were conducted in a 2×2 design [i.e., two sessions at 30°C and two at 18°C, two during MDMA (2 mg/kg, p.o.) and two during placebo, in double-blind fashion]. Core body temperature (ingested radiotelemetry pill), skin temperature (four weighted sites), heart rate, blood pressure, metabolic rate (indirect calorimetry), shivering (electromyogram levels), and sweat rate (capacitance hygrometry) were measured as well as subjective effects for several time periods following capsule ingestion.Results MDMA produced significant elevations in core body temperature and metabolic rate in both warm and cold conditions. MDMA also produced significant elevations in blood pressure and heart rate and significantly increased several ratings of subjective effects similar to those previously reported. There were no differences related to ambient temperature for any of the subjective effects, except that ratings of cold and warm were appropriate to the ambient temperature and were not influenced by MDMA.Conclusions Unlike findings in rats, MDMA increased core body temperature regardless of ambient temperature in humans. These increases appeared related to increases in metabolic rate, which were substantial. These findings warrant further investigations on the role of MDMA and other stimulants in altering metabolism and thermogenesis.     

Subjective and hormonal effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) is a widely used phenethylamine. Reports have described the effects of MDMA in a controlled laboratory setting, but the full range of effects of MDMA in humans is still not completely characterized. OBJECTIVES: To describe the physiological, subjective, and hormonal changes after single doses of MDMA in a laboratory setting and examine relationships between these effects. METHODS: Eight MDMA-experienced volunteers each received placebo, 0.5 mg/kg, and 1.5 mg/kg oral doses of MDMA in a double-blind crossover study. RESULTS: The 1.5 mg/kg dose (comparable to that typically used by most participants) produced significant subjective effects, peaking at about 2 h after dosing, including some effects commonly associated with stimulant drugs, hallucinogens, and entactogens. MDMA significantly increased plasma cortisol, prolactin, and dehydroepiandrosterone (DHEA) levels. Increase in plasma cortisol after the 1.5 mg/kg dose correlated with increased heart rate, rate-pressure product, and drug liking. Rise in DHEA correlated with euphoria. CONCLUSIONS: A typically used dose of MDMA produced effects commonly associated with stimulants and hallucinogens. Subjects liked MDMA. Correlations between cortisol and DHEA levels and some physiological and psychological effects are consistent with animal data suggesting that hormones modulate some responses to drugs of abuse.     

Chronic tolerance to recreational MDMA (3,4-methylenedioxymethamphetamine) or Ecstasy

This review of chronic tolerance to MDMA (3,4-methylenedioxymetamphetamine) covers the empirical data on dosage escalation, reduced subjective efficacy and bingeing in recreational Ecstasy users. Novice users generally take a single Ecstasy tablet, regular users typically take 2-3 tablets, whereas the most experienced users may take 10-25 tablets in a single session. Reduced subjective efficacy following repeated usage is typically described, with many users subjectively reporting the development of tolerance. Intensive self-administration or bingeing is often noted by experienced users. This can comprise 'stacking' on several tablets together, and 'boosting' on successive doses over an extended period. Some experienced users snort Ecstasy powder nasally, whereas a small minority inject MDMA. Chronic tolerance and bingeing are statistically linked to higher rates of drug-related psychobiological problems. In terms of underlying mechanisms, neuroadaptive processes are certainly involved, but there is a paucity of evidence on hepatic and behavioural mechanisms. Further studies specifically designed to investigate chronic tolerance, involving low intermittent dose regimens, are required. Most animal research has involved intensive MDMA dosing regimens designed to engender serotonergic neurotoxicity, and this may comprise another underlying mechanism. If distal serotonin axon terminal loss was also developing in recreational users, it may help to explain why reducing subjective efficacy, dosage escalation and increasing psychobiological problems often develop in parallel. In conclusion, there is extensive evidence for chronic pharmacodynamic tolerance to recreational Ecstasy/MDMA, but the underlying mechanisms are currently unclear. Several traditional processes are probably involved, but one of the possible causes is a novel mechanism largely unique to the ring substituted amphetamine derivatives, namely serotonergic neurotoxicity.     

Persistent loss of thermoregulation in the rat induced by 3,4-methylenedioxymethamphetamine (MDMA or “Ecstasy”) but not by fenfluramine

Using radio-biotelemetry, the timecourse of recovery and sensitivity to ambient temperature (Ta) of the thermogenic response of methylenedioxymethamphetamine (MDMA or “Ecstasy”) was examined. Ambient temperatures of 17 and 22°C produced very different response profiles, with the lower temperature producing a hypothermic response to 10 and 15 mg/kg doses of MDMA, and the higher temperature producing a profound hyperthermia to the same doses. Although the peak responses to the drug had subsided within 5 h of administration, residual effects, in the form of an elevation of body temperature during the “low” phase of the diurnal cycle, were present for a further 48 h. Long-lasting disruption of the thermoregulatory system following a short series of MDMA administrations (10 mg/kg once per day for 4 days) was shown by exposing the rats in the undrugged state to a thermoregulatory challenge, consisting of 60-min exposure to a Ta of 30°C, at 1 week before, and at 4 weeks and 14 weeks after the drug administration. MDMA-treated rats showed a prolonged hyperthermic response to the challenge at both post-drug intervals compared with fenfluramine-treated rats and saline-treated controls. Thus, the results indicate both that MDMA’s thermogenic effects are more sensitive to Ta than previously demonstrated, and that the serotonergic neurotoxicity of the drug may produce long-lasting changes in thermoregulatory mechanisms. Received: 7 December 1997/Final version: 23 January 1998     

Opposite effects of 3,4-methylenedioxymethamphetamine (MDMA) on sensorimotor gating in rats versus healthy humans

Rationale: Prepulse inhibition of acoustic startle refers to the reduction in the startle response when the startling stimulus is preceded by a weak prepulse stimulus. This phenomenon provides an operational measure of sensorimotor gating that has been found to be reduced in patients with schizophrenia and rats treated with serotonin agonists or serotonin releasers. Objective: In this study, we compared the effects of a serotonin releaser, MDMA, on prepulse inhibition in laboratory rats and healthy human volunteers. In particular, we investigated whether MDMA disrupts PPI in humans as observed in animal studies. Methods: Rats were tested after placebo and MDMA in a counterbalanced order at an interval of 1 week, with separate groups of rats being used for each dose of MDMA (1.7, 5.4 and 17.0 mg/kg). On each test day, rats were first tested after no injections and retested 2 h later, 10 min after a subcutaneous injection of placebo or MDMA. For the human study, a placebo-controlled within-subject design and double-blind procedures were used. Subjects were examined twice at a 2 to 4 week interval after either placebo or drug administration (order being counterbalanced). On each test day, subjects underwent baseline testing including psychological and PPI measures. Ninety minutes later, subjects received placebo or MDMA (1.7 mg/kg PO) and were retested after 75 min during the peak of behavioral effects of MDMA. Results: As expected, MDMA decreased prepulse inhibition in a dose-related fashion in rats. In contrast, a typical recreational dose of MDMA (1.7 mg/kg, orally) increased prepulse inhibition in subjects experiencing robust psychological effects. Conclusions: This surprising disparity between the effects of the drug in rats and humans may reflect a species-specific difference in the mechanism of action of MDMA or in the behavioral expression of a similar pharmacological effect, or both. Received: 3 April 1998/Final version: 5 November 1998     

Ecstasy (MDMA): a review of its possible persistent psychological effects

RATIONALE: Recreational use of "ecstasy" (3,4-methylenedioxymethamphetamine; MDMA) has become increasingly widespread. Until recently, however, little was known about the possible persistent psychological effects of extensive use of this drug. OBJECTIVE: The aim of the present review is to evaluate recent empirical evidence concerning the persistent psychological sequelae of recreational ecstasy use. METHODS: The methodologies of open trial studies of recreational ecstasy users are evaluated and reports of the presence or absence of persistent psychological problems are related to the extent of past exposure to ecstasy. RESULTS: There is growing evidence that chronic, heavy, recreational use of ecstasy is associated with sleep disorders, depressed mood, persistent elevation of anxiety, impulsiveness and hostility, and selective impairment of episodic memory, working memory and attention. There is tentative evidence that these cognitive deficits persist for at least 6 months after abstinence, whereas anxiety and hostility remit after a year of abstinence. The possibility that some of these psychological problems are caused by ecstasy-induced neurotoxicity is supported by preclinical evidence of MDMA-induced neurotoxicity and behavioural deficits, evidence of depleted serotonin in heavy ecstasy users, and by dose-response relationships between the extent of exposure to ecstasy and the severity of cognitive impairments. CONCLUSIONS: An increasing number of young, heavy ecstasy users are at significant risk of persistent cognitive impairments and disturbances of affect and personality. Some of these problems may remit after abstinence, but residual neurotoxicity and decline of serotonergic function with age may result in recurrent psychopathology and premature cognitive decline.     

A neurotoxic dose of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) to rats results in a long term defect in thermoregulation

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") administration to rats produces damage to cerebral 5-HT nerve endings; however, the long-term functional consequences of this damage are poorly understood. OBJECTIVE: To confirm that MDMA administration produces a long-term effect on thermoregulation and investigate the mechanisms involved. METHODS: Male Dark Agouti rats were injected with a neurotoxic dose of MDMA (12.5 mg/kg i.p.). Five to 6 weeks later, they were exposed to high ambient temp (30 degrees C) for 60 min followed by a return to normal temp (20 degrees C), with rectal temperature being measured under both conditions. Further groups of MDMA-pretreated rats were challenged with 8-OH-DPAT and their temperature response measured. RESULTS: MDMA administration produced acute hyperthermia. Rectal temperature had normalised 24 h later and was similar to saline-injected controls over the following 15 days. MDMA administration produced a 37% loss in hypothalamic 5-HT content 18 days later. When MDMA-pretreated rats were subjected to high ambient temperature 33 days posttreatment, they displayed both a faster rise in rectal temperature and sustained hyperthermia when returned to normal conditions. There was no difference in their hypothermic response to the 5-HT1A agonist 8-OH-DPAT. CONCLUSIONS: A neurotoxic dose of MDMA resulted in impaired thermoregulation when rats were exposed to high ambient temperature. 5-HT1A receptor mechanisms were unaltered. Impaired serotonergic function following MDMA presumably alters the neurotransmitter balance, thereby compromising thermoregulation. Heavy recreational users of MDMA may also have impaired thermoregulation and thus be at greater risk of an acute adverse response to MDMA in a hot crowded dance environment.     

Chronic MDMA (ecstasy) use, cognition and mood

Rationale It has been suggested that 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) causes damage to the serotonergic system, and that this damage results in cognitive and mood impairments.Objectives To examine the effect of chronic MDMA usage on a wide battery of cognitive tests and psychological abilities and processes.Methods In the present study, the performance of 17 participants with a history of MDMA use was compared to the performance of 15 control subjects on a battery of neuropsychological tests. This battery included tests for depression, immediate word recall, delayed recall, attention and working memory.Results Results indicated that the MDMA group had significantly higher scores for depression than the control group, and displayed poorer delayed recall and verbal learning than controls after accounting statistically for the effects of cannabis and depression.Conclusions These results suggest that MDMA users exhibit difficulties in coding information into long-term memory, display impaired verbal learning, are more easily distracted, and are less efficient at focusing attention on complex tasks.     

Ecstasy (MDMA) in Recreational Users: Self-Reported Psychological and Physiological Effects

Twenty recreational drug users were asked to describe the psychological and physiological effects they experienced under MDMA (3,4-methylenedioxymethamphetamine). The subjects comprised 11 males and nine females, in the age range 18–31 years. Five subjects had taken MDMA once, nine had taken it 2–9 times, while six subjects had taken it +10 times. Each subject completed a modified Profile of Mood States Questionnaire (POMS), an Ecstasy Effect Questionnaire, and a structured interview, covering past experience with MDMA. Increased feelings of elation, agreeableness, energy, and mental confusion were reported on-drug (p < 0·001), together with faster heart rate, feeling hot, increased sweating and dehydration, dilated pupils, and tight jaw (trismus). Coming off-Ecstasy led to feelings of lethargy, moodiness, insomnia, depression, irritability, and paranoia. Bad MDMA trips were reported by 25 per cent of the sample, following a variety of unpleasant experiences. Chronic pharmacodynamic tolerance was not apparent, since although regular users all described their first MDMA experience as ‘the most intense’, later trips were affected by knowledge and expectancy, rather than any diminution in drug response. Acute pharmacodynamic tolerance was, however, evident, with a period between drugs being described as necessary in order to maintain drug effectiveness. This may help explain the low addiction potential of MDMA. © 1997 John Wiley & Sons, Ltd.     

Increased cortisol levels in hair of recent Ecstasy/MDMA users

Previous research has revealed an acute 8-fold increase in salivary cortisol following self-administrated Ecstasy/MDMA in dance clubbers. It is currently not known to what extent repeated usage impacts upon activity of the hypothalamic–pituitary–adrenal axis over a more prolonged period of time. This study investigated the integrated cortisol levels in 3-month hair samples from recent Ecstasy/MDMA users and non-user controls. One hundred and one unpaid participants (53 males, 48 females; mean age 21.75 years) completed the University of East London recreational drug use questionnaire, modified to cover the past 3-months of usage. They comprised 32 light recent Ecstasy/MDMA users (1–4 times in last 3 months), 23 recent heavy MDMA users (+5 times in last 3 months), and 54 non-user controls. Volunteers provided 3 cm hair samples for cortisol analysis. Hair cortisol levels were observed to be significantly higher in recent heavy MDMA users (mean= 55.0±80.1 pg/mg), compared to recent light MDMA users (19.4±16.0 pg/mg; p=0.015), and to non-users (13.8±6.1 pg/mg; p<0.001). Hence the regular use of Ecstasy/MDMA was associated with almost 4-fold raised hair cortisol levels, in comparison with non-user controls. The present results are consistent with the bio-energetic stress model for Ecstasy/MDMA, which predicts that repeated stimulant drug use may increase cortisol production acutely, and result in greater deposits of the hormone in hair. These data may also help explain the neurocognitive, psychiatric, and other psychobiological problems of some abstinent users. Future study design and directions for research concerning the psychoneuroendocrinological impact of MDMA are also discussed.     

p-Chloroamphetamine (PCA), 3,4-methylenedioxymethamphetamine (MDMA) andd-fenfluramine pretreatment attenuatesd-fenfluramine-evoked release of 5-HT in vivo

Previous work has suggested that repeated treatment with substituted amphetamines including PCA, MDMA andd-fenfluramine produces a persistent neurodegeneration which is relatively selective for the fine serotoninergic terminals arising from the dorsal raphe nucleus. The aim of the present study was to investigate whether the acute releasing effect ofd-fenfluramine might also be sensitive to lesions produced by PCA, MDMA andd-fenfluramine itself. Basal and 5-HT release evoked byd-fenfluramine or 100 mM KCl was measured by microdialysis in frontal or parietal cortex of rats 2 weeks after they had been treated with a neurodegenerative regime of PCA, MDMA,d-fenfluramine, or vehicle. In frontal cortex of vehicle controls,d-fenfluramine (10 mg/kg IP) and KCl (100 mM via microdialysis probe) evoked an increase in 5-HT of 1740% and 779% of basal, respectively. PCA pretreatment reducedd-fenfluramine-evoked 5-HT release by 90.9% while potassium-evoked release was reduced by only 66.8%. Similar results were obtained in parietal cortex. MDMA (20 mg/kg×8) andd-fenfluramine (12.5 mg/kg×8) pretreatment reducedd-fenfluramine-evoked release of 5-HT in frontal cortex by 45.2% and 72.0%, respectively. Overall, the present data are consistent with the hypothesis that the acute release of 5-HT evoked byd-fenfluramine occurs via those terminals destroyed by pretreatment with PCA, MDMA andd-fenfluramine, while KCl evokes release from both PCA-sensitive and PCA-insensitive terminals. The significance of these results for the interpretation of neuroendocrine data fromd-fenfluramine challenge tests is discussed.     

Reinforcement schedule effects in rats trained to discriminate 3,4-methylenedioxymethamphetamine (MDMA) or cocaine

Rationale Relatively few studies have compared the discriminative stimulus effects of 3,4-methylenedioxymethamphetamine (MDMA) and cocaine, and findings from different laboratories are somewhat inconsistent. One possible reason for discrepant results may be the use of different reinforcement schedules during discrimination training.Objective The present study compared fixed ratio (FR) 20 and variable interval (VI) 15-s reinforcement schedules to determine their influence on discrimination acquisition, response rates, frequency of reinforcements, and stimulus generalization in rats trained to discriminate cocaine or MDMA.Materials and methods Thirty-two male Sprague–Dawley rats were trained to discriminate cocaine (10 mg/kg; n=16) or MDMA (1.5 mg/kg; n=16) from saline under either a FR 20 or a VI 15-s schedule of food reinforcement. Stimulus generalization tests were conducted with a range of doses of cocaine, MDMA, d-amphetamine, and lysergic acid diethylamide in all four training groups.Results The FR 20 schedule facilitated more rapid discrimination acquisition compared to the VI 15-s schedule and established differential response rates and frequency of reinforcement under drug and vehicle conditions. However, reinforcement schedule had little influence on stimulus generalization between MDMA and cocaine. Cocaine produced partial substitution for MDMA in both training groups (FR 20, 51%; VI 15-s, 58%). Likewise, MDMA produced only partial substitution for cocaine in both training groups (FR 20, 40%; VI 15-s, 72%).Conclusions The present findings suggest that the number of sessions required to establish discriminative stimulus control varies with different reinforcement schedules. Nevertheless, training schedules alone do not appear to have significant effects on stimulus generalization between MDMA and cocaine.     

Effect of ambient temperature on hyperthermia and hyperkinesis induced by 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”) in rats

A stress-free, biotelemetric monitoring technique was used to investigate the effects of ambient temperature (T _a) on the hyperthermic and hyperkinetic effects of 3,4-methylenedioxymethamphetamine. In the first experiment a single injection of 5.0 or 7.5 mg/kg MDMA produced hyperthermia in rats maintained at aT _a of 24°C but hypothermia in rats maintained at aT _a of 11°C for 24 h prior to the injection. In contrast, hyperkinesis was induced at bothT _as. In the second experiment, the effects of acute MDMA administration was compared in rats maintained at a standardT _a of 24°C and in rats which were placed in a cool (11°C) room for a brief (90-min) period commencing 30 min after the injection. The brief exposure to the cool environment produced significant attenuation of MDMA-induced hyperthermia but did not affect the magnitude of hyperkinesis. The implications of the results for the understanding of the thermotoxic effects of MDMA in human drug users are discussed.     

Preprotachykinin A gene expression after administration of 3,4-methylene dioxymethamphetamine (Ecstasy)

This study tested the effects of 8 days of subchronic administration of 3,4-methylene dioxymethamphetamine (MDMA) (5 mg/kg b.w.) on preprotachykinin A mRNA levels in discrete rat brain regions. In situ hybridization examined preprotachykinin A mRNA levels in the core and shell of the nucleus accumbens, the islands of Calleja, the olfactory tubercle, the dorsal and ventral caudate–putamen, the bed nucleus of the stria terminalis, the medial preoptic area, the medial habenular nucleus and in the postero-dorsal part of the medial amygdala. Higher levels of preprotachykinin A mRNA were found in the core and shell of the nucleus accumbens, in the islands of calleja, in the olfactory tubercle, in the bed nucleus of the stria terminalis, in the medial habenular nucleus and the postero-dorsal part of the medial amygdala, compared to control animals. Conversely, increased preprotachykinin A mRNA levels were observed in the dorsal and ventral caudate–putamen in MDMA treated when compared to control rats. In the social memory test, MDMA significantly impaired rats' short-term working memory. These results show that chronic exposure to MDMA strongly affects preprotachykinin A mRNA levels in discrete rat brain regions. These changes occur in experimental conditions in which working memory is markedly reduced, suggesting that changes in gene expression of tachykinin mechanisms may contribute to the effects of MDMA on memory function.     

3,4‐methylenedioxymethamphetamine (MDMA; Ecstasy) administration produces dose‐dependent neurochemical,endocrine and immune changes in the rat

3,4‐methylenedioxymethamphetamine (MDMA, Ecstasy) is a widely abused drug that is structurally related to both amphetamines and hallucinogens. In addition to the behavioural and neurochemical effects of MDMA, we recently reported that an acute administration of this drug produces a profound suppression of mitogen‐stimulated lymphocyte proliferation and reduction in the number of circulating white blood cells, which was accompanied by elevated circulating corticosterone concentrations. In the present study, the effect of acute MDMA administration on PHA‐induced lymphocyte proliferation, leucocyte subpopulations, HPA‐axis activity and cortical serotonin utilization were examined in a dose‐dependent manner in female Sprague‐Dawley rats. The results of this study demonstrate that MDMA induces a suppression of lymphocyte function even at doses that fail to provoke any significant alteration in central 5‐HT utilization and plasma corticosterone concentrations, thereby suggesting that the reduced functional responsiveness of lymphocytes to mitogenic stimulation after MDMA administration may be mediated by glucocorticoid independent mechanisms. In contrast, the MDMA‐induced reduction in the number of circulating blood lymphocytes was evident only at doses of MDMA which elevated circulating corticosterone concentrations, suggesting that the observed reduction in circulating lymphocytes may be at least partly a glucocorticoid‐mediated event. Copyright © 1999 John Wiley & Sons, Ltd.     

The hyperthermia mediated by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) is sensitive to sex differences

Female subjects have been reported to be less sensitive to the hyperthermic effects of 3,4-methylenedioxymethamine (MDMA) than males. Studies were designed to examine the cellular mechanisms involved in these sex sensitive differences. Gonadectomized female and male rats were treated with a 200 μg 100 μL^− 1 of estrogen or 100 μg 100 μL^− 1 of testosterone respectively every 5 days for a total of three doses. Rats were then challenged with either saline or MDMA (20 mg kg^− 1, sc). Rats were then euthanized and aortas were constricted, in vitro, by serial phenylephrine (Phe) addition with or without the inhibitor of nitric oxide (NO) synthase, g-nitro-l-Arginine-Methyl Ester (L-NAME). Skeletal muscle uncoupling protein-3 (UCP3) expression was measured as well as plasma norepinephrine (NE) levels. All males but no females developed hyperthermia following MDMA treatment. The EC₅₀ for Phe dose response curves increased only in the females treated with MDMA and T_max for Phe increased following L-NAME only in the females. Both males and females demonstrated an increase in plasma NE following MDMA treatment; however, males displayed a significantly greater NE concentration. Skeletal muscle UCP3 expression was 80% less in females than in males. These results suggest that the inability of MDMA to induce a thermogenic response in the female subjects may be due to four sex-specific mechanisms: 1) Female subjects have reduced sympathetic activation following MDMA challenge; 2) Female vasculature is less sensitive to α₁-AR stimulation following MDMA challenge; 3) Female vasculature has an increased sensitivity to NO; 4) UCP3 expression in skeletal muscle is less in females.     

Effects of MDMA (ecstasy), and multiple drugs use on (simulated) driving performance and traffic safety

Rationale The effects of MDMA on driving behaviour are not clear, since the direct effects of MDMA on cognitive performance are reported as not generally negative.Objectives To assess in an advanced driving simulator acute effects on simulated driving behaviour and heart rate of MDMA, and effects of polydrug use.Methods A group of young participants who had indicated that they regularly used MDMA were asked to complete test rides in an advanced driving simulator, shortly after the use of MDMA, just before going to a party. They were tested again after having visited the rave, while they were under the influence of MDMA and a number of different other active drugs. Participants were also tested sober, at a comparable time at night. Separately, a control group of participants was included in the experiment.Results Driving performance in the sense of lateral and longitudinal vehicle control was not greatly affected after MDMA, but deteriorated after multiple drug use. The most striking result was the apparent decreased sense for risk taking, both after MDMA and after multiple drug use. This was clear from gap acceptance data, while the ultimate indicator of unsafe driving, accident involvement or even causation, was increased by 100% and 150%, respectively.Conclusions Driving under the influence of MDMA alone is certainly not safe; however, driving back (home) after a dance party (rave) where MDMA users regularly combine MDMA with a host of other drugs can be described as extremely dangerous.