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Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Accordingly, in the first of two separate studies, these variables were investigated in three groups: 1 MDMA group—recreational ecstasy users who also used other illicit substances ; 2 polydrug controls—who had never taken ecstasy, but otherwise had drug histories and personal characteristics similar to the ecstasy users; and 3 nondrug controls—who had never used illicit drugs, but had similar personal characteristics. Although there were no group differences in TOL performance, ecstasy users were again found to commit more errors in the MFF20 than polydrug users. Furthermore, the GHQ and IVE scores of the ecstasy users in the second study indicated, respectively, that they were more psychologically disturbed and impulsive than nondrug controls. The combined data from the two studies indicated that ecstasy users exhibited elevated impulsivity on both self-report and behavioral measures and that those who had taken the most ecstasy had the most elevated trait impulsiveness scores. These findings are consistent with previous evidence that elevated levels of impulsivity in humans are associated with reduced levels of serotonergic function. Recent evidence from studies with human participants is consistent with these findings. Serotonin has been implicated in the regulation of mood, anxiety, aggression, and impulsivity. Transient reductions in 5-HT activity, induced by tryptophan depletion, have been reported to produce a rapid lowering of mood in normal males Young et al. Furthermore, there is evidence that disorders of central serotonergic neurotransmission, as reflected by low levels of 5-HIAA, are associated with anxiety e. It has also been proposed that 5-HT may play an orchestrating role in cognition, and that extreme deviations of 5-HT activity can result in biases in cognitive processing Spoont and impairments in learning and memory e. Despite this evidence, the possible long-term psychological sequelae of ecstasy use in humans has received relatively little attention from researchers, partly because most controlled laboratory studies of the effects of repeated administration of ecstasy are precluded for legal and ethical reasons. Nevertheless, preliminary evidence has emerged that recreational use of ecstasy may, indeed, be associated with differences in psychological measures. There are also reports that recreational ecstasy users exhibited significant decrements in working memory in ecstasy users, as compared with alcohol users Curran and Travill , and were impaired on tests of immediate and delayed recall, as compared to nonusers, although they were unimpaired on other neuropsychological tests Krystal and Price ; Parrott One of the problems encountered with investigation of the potential effects of MDMA in humans, however, is that the majority of recreational ecstasy users also use many other illicit drugs. All previous investigations of the psychological sequelae of recreational ecstasy use have failed to control adequately for the possible long-term influence of other illicit, and legal e. A strategy that can be adopted to identify the psychological sequelae associated with ecstasy use specifically, as distinct from those associated with the use of illicit drugs generally, is to compare the performance of ecstasy users not only with that of participants who have never taken any illicit drugs, but also with a group of polydrug users, who have used similar amounts of other illicit drugs, but have never taken ecstasy. The results of the first study indicated that ecstasy-users committed significantly more errors in a behavioral test of impulsivity, but there were few other significant differences between the ecstasy users and participants in the other two groups. In light of the potential theoretical implications of the evidence for elevated behavioral impulsivity in the first study, another, larger, sample of participants was recruited, and a second study was conducted to determine the reliability of this finding. Finally, because both studies employed the same design, the data from measures that were common to both were combined for further analysis. Forty-four participants participated in the first study: 16 recreational ecstasy users MDMA group , 12 polydrug controls, and 16 nondrug controls. The demographics of the study groups are shown in Table 1. All participants were university students or graduates who were recruited by poster advertisements and word of mouth and were first screened for eligibility by interviews. For inclusion in the MDMA group, individuals had to be in good health, to have used ecstasy on at least 20 occasions, and could not have any of the exclusionary criteria see below. To be admitted to the polydrug control group, participants had to meet all of these criteria, and have a drug-use history that was similar to that of the MDMA participants, with the exception being that they must have no history of ecstasy exposure. To be in the nondrug control group, participants had to meet the same personal characteristics criteria, and have no history of use of illicit drugs. Information about past use of ecstasy was obtained in several ways: 1 a preliminary telephone or face-to-face interview; 2 a general drug-use questionnaire; and 3 a specific ecstasy-use questionnaire that requested information on the duration of usage, the last time used, the amount number of tablets used in the last month, the frequency of use per month, the average amount taken per session, the maximum amount taken per session, and the total amount taken in the participant's lifetime. Exclusionary criteria for all groups included past or present major illnesses, pregnancy, history of psychosis, current major depressive disorder, and alcohol or opiate dependence. Participants who passed the initial screening were administered the National Adult Reading Test NART Nelson to ensure an adequate knowledge of English they were required to score fewer than 25 incorrect answers to participate , and to provide an estimate of premorbid IQ. The study was approved by the local health authority ethics committee. The IVE yields three independent scores for impulsiveness, venturesomeness, and empathy, which range from 0 to 19 for impulsiveness and empathy, and from 0 to 16 for venturesomeness. High scores indicated high levels of these personality characteristics. The STAI produces a score for state and trait anxiety levels, which ranges from 20 to 80 in both cases. Low scores indicated low anxiety levels. Cognitive functioning was investigated with the use of the Cambridge Neuropsychological Test Automated Battery CANTAB , Working Memory and Planning Battery: a suite of computerized tests, employing a touch-sensitive screen, which has been used to examine differential patterns of cognitive deficits in frontal lobe patients e. After six practice trials, there were 2, 3, 4, and 5 move problems, which demanded that participants plan the solution to the problem prior to the first move. The number of moves required by the participant to rearrange the balls correctly and the selection and movement latencies for both the first and subsequent moves were recorded. In this condition, the solutions the participant had generated previously, for the 2, 3, 4, and 5 move problems, were played back, one move at a time, and the participant simply had to follow these movements. For both initial and subsequent thinking times, simple movement times, derived from the yoked control condition, were subtracted from the total thinking times to provide an accurate estimate of pure planning time, unconfounded by any motor deficits. A pattern of white squares was shown on the touch-screen. Some of the squares changed color, one-by-one, in a variable sequence. At the end of the presentation, a tone indicated that the participant should touch each of the squares that changed color in the same sequence as they were presented. The task became progressively more difficult, as the number of squares in the sequence was increased from two, at the start of the test, to a maximum of nine. There were three sequences at each level of difficulty. If the participant was unable to repeat all sequences at any one level, the three sequences at the next level were presented, but then the test was terminated. Participants were given one practice trial before commencing at the two-square level. The sequence of administration of the TOL and Span tests were counterbalanced to avoid order effects. The test format of the MFF20, involves simultaneous presentation of a stimulus figure and an array of six alternatives, all except one of which differ one or more details. The subject was then asked to select from the alternatives the figure that exactly matched the standard. Each subject was given two practice items followed by 20 test items. If their initial selection was incorrect, they were told that they were wrong and were asked to try again. For each subject, the 20 items were scored according to the time to first response, the first position indicated, and the number of errors made before the correct match. The data were analysed using multivariate analysis of variance, and Duncan's multiple range test was employed for post hoc analyses. Multivariate analysis of variance MANOVA of the personal characteristics of participants in the three experimental groups MDMA, polydrug control, and nondrug control indicated that they were not significantly different in terms of their age, gender ratio, education level achieved, height, weight, or estimated premorbid IQ see Table 1. Furthermore, analysis of self-reported drug use histories of participants in the two polydrug-using groups MDMA and polydrug controls showed that their duration of use of alcohol, cannabis, and amphetamine was not significantly different, nor was their consumption of cigarettes in the week prior to testing, alcohol and cannabis in the previous month, or amphetamine in the previous year see Table 2. Self-reported use of other classes of illicit drugs was not sufficiently frequent for comparison with parametric statistics. However, the drug histories of the two groups seemed similar in terms of use of LSD, pscilocybin mushrooms, and benzodiazepines. Six of the MDMA participants and seven of the polydrug control participants reported occasional use of psilocybin mushrooms. Three of MDMA participants and two of the polydrug control participants reported occasional use of benzodiazepines. The groups did differ with respect to their infrequent use of cocaine, amylnitrite, and barbiturates. Six of the MDMA participants reported having used cocaine but only on one occasion, and more than a month prior to testing, in all cases. One polydrug control subject reported once having used an unknown barbiturate. Finally, one of the nondrug control participants admitted to having used cannabis on one occasion several years before testing. Seven of these participants reported that they had taken ecstasy within the week before to testing, although none had taken it for at least 3 days prior to testing. The number of participants who reported long-term psychological problems they attributed to their use of ecstasy is summarized in Table 4. Finally, analysis of the scores on the impulsiveness, and empathy, subscales of the IVE, indicated that there were no significant differences between the groups in terms of these trait measures. Post hoc analysis with Duncan's test indicated that this difference was attributable to the elevated levels of trait venturesomeness of participants in the two illicit drug-using groups, as compared to those in the nondrug using control group see Table 5. Multivariate analysis of variance of spatial span, total number of sequence errors made, and total number of usage errors made the number of times a box was pressed that was not illuminated during the spatial span task indicated that participants in the three experimental groups MDMA, polydrug control, and nondrug control were not significantly different in terms of any of these measures of spatial span performance. Post hoc analysis with Duncan's test indicated that this effect was attributable to the fact that participants in the MDMA group committed more than twice as many errors in the MFF20 task than participants in the other two control groups see Table 6. Limitations with the previous study included: small sample sizes, lack of information about the type of ecstasy tablets taken, and the fact that seven of the 16 participants in the MDMA group reported that they had taken ecstasy within the week prior to testing, although none reported having had taken any for at least 3 days prior to testing. The present study sought to address these limitations by recruiting a larger sample of participants for each group, with more MDMA participants who had not taken ecstasy for several weeks, and asking participants to identify the total number of each type of ecstasy tablet that they had taken. The IVE was retained, because it had diffferentiated between groups in both the previous study and an earlier investigation Callow. A similar policy was adopted toward the behavioral measures employed in the previous study. The CANTAB spatial span test was dispensed with, and the TOL was retained and repeated on two successive occasions to explore the possibility that it might differentiate between groups more effectively once participants had become familiar with the task. There was one other innovation in the present study. Before the administration of the first TOL test, participants were presented with a brief audiotaped news story taken from the Rivermead Behavioral Memory Test Wilson et al. They were subsequently tested for delayed recall after completion of the second TOL test. The results of the latter test have been submitted for publication elsewhere. Sixty-four participants participated in the second study: 25 ecstasy users MDMA group , 20 polydrug controls; and 19 nondrug controls. The demographics of the study groups are shown in Table 4. Again, all participants were university students or graduates who were recruited by poster advertisements and word of mouth. All participants were first screened for eligibility by interviews using the criteria employed in the first study. They were then instructed to listen to a brief audiotaped news story taken from the Rivermead Behavioral Memory Test RBMT and were tested for immediate recall. After they had completed these tests, 40—50 min after the story had been presented, subjects were tested for delayed recall. Again, MANOVA was used to compare the data from the three experimental groups, and Duncan's multiple range test was employed for post hoc analyses. The Pearson product-moment correlation coefficient was used as a measure of correlation. Multivariate analysis of variance of the personal characteristics of participants in the three experimental groups MDMA, polydrug control, and nondrug control indicated that they were not significantly different in terms of their age, gender ratio, education level achieved, height, weight, or estimated premorbid IQ see Table 7. Furthermore, analysis of self-reported drug use histories of participants in the two polydrug-using groups MDMA and polydrug controls showed that they were not significantly different in terms of their duration of use of alcohol, cigarettes, cannabis, amphetamine, and LSD. In the MDMA group, however, eight participants reported occasional use of benzodiazepines, three reported having used barbiturates, and two reported having taken ketamine; whereas, none of the participants in the polydrug control group reported having used these drugs. Five of these participants reported that they had last taken ecstasy within the week prior to testing, although none had taken it for at least 3 days prior to testing. The number of participants who reported long-term psychological problems which they attributed to their use of ecstasy is summarized in Table 4. Post hoc analysis with Duncan's test indicated that participants in the MDMA group exhibited significantly higher levels of trait impulsiveness and venturesomeness and significantly lower GHQ scores than participants in the nondrug control group. However, MDMA users did not differ significantly from polydrug controls on any of these measures see Table 7. Post hoc analysis indicated that the initial thinking times for participants in the nondrug control group were significantly longer than those of participants in both of the other two groups see Table 9. Furthermore, the difference in the total number errors committed by the polydrug and MDMA groups was significant at the. Post hoc analysis with Duncan's test indicated that participants in the MDMA group committed significantly more errors than participants in the polydrug control group, although they did not differ significantly from participants in the nondrug control group see Table 9. In light of the similarity of the design employed in both studies, the data for psychological measures that were common to both studies were reanalyzed using multivariate analysis with two independent factors: 1 group; and 2 study. Reanalysis of the data from both studies indicated that there were no significant group by study interactions for any of the measures recorded in both studies i. There was, however, a significant difference between the number of MFF20 errors committed in Study 1 and Study 2. Participants in the two control groups in the second study committed more errors than their counterparts in the first study see Table Post hoc analysis indicated that participants in the combined MDMA group exhibited significantly higher levels of trait impulsiveness, and participants in both of the combined groups of illicit drug-users exhibited significantly higher levels of trait venturesomeness than participants in the combined nondrug control group See Table Finally, the number of ecstasy tablets consumed by participants in the MDMA group ranged from the minimum entry requirement of 20 tablets to more than To explore the possibility of a dose-response effect on IVE and MFF20 measures of impulsivity, the MDMA group was divided into three categories: those who had taken 20 to 30 tablets of ecstasy 15 participants ; those who had taken between 30 and 60 tablets 10 participants ; and those who had taken more than 60 tablets 16 participants. Post-hoc analysis indicated that participants in the combined MDMA group who had taken more than 30 ecstasy tablets had significantly elevated impulsiveness scores compared to participants who had only taken between 20 and 30 tablets. Combined data from the present studies indicated that recreational ecstasy users committed significantly more errors in the MFF20 Cairns and Cammock than polydrug control subjects, who had similar drug histories but had never taken ecstasy, and nondrug control subjects who had never taken illicit drugs, all of whom were of similar age, height, gender, education, and estimated premorbid IQ. In both studies, the results of the IVE Eysenck and Eysenck questionnaire indicated that, although there were no group differences in trait empathy scores, there were significant differences between groups in terms of venturesomeness. These differences are to be expected, however, because both groups that reported having used illicit drugs which can be viewed as an example of venturesome behavior reported themselves to be more venturesome than participants who reported that they had never used illicit drugs. The combined IVE data from the present studies also indicated that recreational ecstasy users exhibited elevated trait impulsiveness, as compared to participants who had never taken illicit drugs and that the recreational users who had consumed the most ecstasy exhibited the most impulsiveness. Otherwise, the results of the present studies indicated that mood and personality measures of participants in the three groups were generally similar. In the first study, there were no significant group differences in subjective mood state at the outset of the study, state and trait anxiety measures from the STAI Spielberger et al. These results replicate the findings of previous studies in which we employed a similar design, Callow ; Davies The cognitive performance of the three groups was also generally similar. In the first study, participants in all three groups performed equally well in the CANTAB spatial span task, and there were no group differences in either study in performance of the CANTAB TOL test, despite the fact that this test was repeated twice in the second study. This may simply be attributable to the use of different measures, because Ricaurte et al. It is arguable, however, that more credence should be given to the present results. First, it should be noted that the reduction in impulsivity and indirect hostility in recreational ecstasy users reported by Ricaurte et al. Reduced levels of serotonergic function, as indicated by low levels of 5-HIAA, have previously been found to be consistently associated with elevated levels of hostility and impulsivity e. Second, we have used a design that allowed ecstasy users to be compared to a polydrug control group who had used similar quantities of other drugs and a conventional control group that had not used illicit drugs. The exact relationship between self-report measures of trait impulsiveness and behavioral measures of impulsivity is unclear, however, because further analysis showed that performance on these two measures was not correlated. This was not particularly surprising, however, because low correlations between self-report and behavioral measures of impulsivity have been reported by a number of previous investigators e. The lack of correlation does suggest, however, that the scores provided by these different types of measures are probably estimates of different constructs. Furthermore, Block et al. Because accuracy clearly differentiated groups in the present studies, and latency did not, if high error rates on the MFF20 reflect the same personality concomitants in adults, perhaps the present results suggest that ecstasy users are more emotionally reactive and less capable of coping with high levels of cognitive demand than are individuals who have taken other illicit drugs. The latter interpretation is consistent with some of the descriptions of psychological problems that were attributed to the use of ecstasy by participants in the MDMA group in the present studies. If high error rates on the MFF20 reflect reduced ability to cope with high levels of cognitive demand, and ecstasy causes reductions in brain serotonergic activity, the present results are also consistent with the view that 5-HT plays an orchestrating role in cognition, and that extreme deviations of 5-HT activity can result in biases in cognitive processing, which can predispose individuals to pathological conditions such as impulsive behavior, violent suicide, and aggression Spoont There were a number of unavoidable methodological limitations with the present studies. One was that the period of time elapsed since last use an average of 20 days in the first study and 65 days in the second prohibited biochemical assays of MDMA consumption. As a result, there was no objective confirmation of the dose or purity of MDMA taken. Another limitation was that, for legal and ethical reasons, there was no control over drug administration. Instead, drug consumption data had to be collected retrospectively, which inevitably created interpretative difficulties concerning the etiology of the behavioral and personality differences in recreational ecstasy users. By definition, some of the elevated trait impulsiveness, observed in both groups of participants who had used illicit drugs, probably reflects a pre-existing predisposition that may have led to subsequent use of illicit drugs. However, it is also possible that some of the elevation of trait impulsiveness, particularly the additional elevation associated with heavy past consumption of ecstasy, may be attributable to the neurotoxic effects of ecstasy on brain 5-HT systems, because, as noted above, reductions in serotonergic function have consistently been associated with elevated levels of impulsive behavior. It is more difficult to conceive of the group difference in the MFF20 error rate as being attributable to a pre-existing trait, because this measure was markedly elevated in ecstasy-users, as compared to polydrug control subjects, and it seems implausible that only individuals with high levels of behavioral impulsivity of this type would be especially predisposed to taking ecstasy, rather than other illicit drugs. This argument is supported by the reports of the ecstasy users themselves. Clearly, however, further research, perhaps including the use of longditudinal studies, is needed to clarify this issue. Finally, a striking feature of the present results was the selectivity of the psychological sequelae of chronic exposure to ecstasy. This is consistent with previous reports that, although the recall performance of ecstasy users was impaired, their cognitive performance was not impaired on other a variety of other neuropsychological measures Krystal and Price ; Parrott It has been suggested that more general cognitive impairments associated with serotonergic denervation of the neocortex may not be evident under usual circumstances because of sufficient neural reserve Hunter If, however, 5-HT function declines with age, ecstasy-exposed individuals could be at increased risk for developing other age-related, cognitive, and affective deficits. Further research with older ecstasy users and young participants who have not used ecstasy for more extended periods of time, is needed to clarify the longer-term clinical implications of the present findings. Baddeley A. Child Devel 47 : — Google Scholar. Callow N. Cairns E, Cammock T. Dev Psychol 13 : — Article Google Scholar. Addiction 92 : — Davies G. Arch Gen Psychiat 47 : — Frederick D, Paule M. Neurosci Biobehav Rev 21 : 67— Psychiat Res 57 : 1—5. Multivariate Behav Res 22 : — Goldberg D. Psychopharmacology : — Hunter A. Biochem Soc Trans 17 : 79— Psychol Mono 78 1, Whole No. J Drug Alcohol Abuse 18 : — Int Clin Psychopharm 8 : 53— Neuropsychopharmacology 10 : — J Neurochemistry 54 : 14— Dev Psychol 17 : — Nelson H. Neuropsychologia 28 : — Parrott AC. Brit Psych Soc Proc 5 : Ann NY Ac Sci : — Salkind NJ, Wright J. Human Dev 20 : — Saunders N. Shallice T. Psychopharmacology 91 : — Spielberger CD. Spoont MR. Psych Bull : — Addiction 89 : — Soc Neurosci Abstr : 2— Psychopharmacology 87 : — Download references. Wales, UK. You can also search for this author in PubMed Google Scholar. Reprints and permissions. Morgan, M. Neuropsychopharmacol 19 , — Download citation. Received : 31 December Revised : 22 December Accepted : 21 January Issue Date : 01 October Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. International Journal of Mental Health and Addiction Skip to main content Thank you for visiting nature. Download PDF. STUDY 2 Limitations with the previous study included: small sample sizes, lack of information about the type of ecstasy tablets taken, and the fact that seven of the 16 participants in the MDMA group reported that they had taken ecstasy within the week prior to testing, although none reported having had taken any for at least 3 days prior to testing. References Baddeley A. D View author publications. Rights and permissions Reprints and permissions. About this article Cite this article Morgan, M. Copy to clipboard. Colzato Experimental Brain Research Are executive function and impulsivity antipodes? A conceptual reconstruction with special reference to addiction Warren K. Bickel David P. Jarmolowicz Samuel M. 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Possession of MDMA (Ecstasy)

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Official websites use. Share sensitive information only on official, secure websites. Correspondence should be addressed to Eugene A. Psychomotor stimulants are frequently used by humans to intensify subjective experience of different types of social interactions. Since psychomotor stimulants enhance metabolism and increase body temperatures, their use under conditions of psychophysiological activation and often in warm, humid environments that prevent normal heat loss could result in pathological hyperthermia, a life-threatening symptom of acute drug intoxication. Here, we will describe the brain hyperthermic effects of MDMA, MDPV and methylone, three structurally-similar recreational drugs commonly used by young adults during raves and other forms of social gatherings. After a short introduction on brain temperature and basic mechanisms underlying its physiological fluctuations, we will consider how the hyperthermic effects of these drugs are modulated in rats under conditions of social interaction and at warm ambient temperature. We will also discuss the mechanisms underlying hyperthermic effects of these drugs, particularly the roles of intra-brain heat production due to metabolic brain activation and peripheral vasoconstriction. Finally, we will present our recent data, which compared the efficacy of different pharmacological strategies for reversing MDMA-induced brain and body hyperthermia. These data could be important not only for understanding the potential dangers of each drug, but also the development of a pharmacotherapy to alleviate drug-induced hyperthermia and potentially save the lives of highly-intoxicated individuals. In contrast to therapeutic psychoactive drugs, which are taken voluntarily or given by medical professionals to alleviate specific pathological symptoms, individuals take drugs recreationally to induce pleasurable, novel, or unusual psycho-emotional effects. At low doses, the physiological effects of such drugs may mimic physiological responses induced by naturally arousing stimuli. However, at higher doses, these drug-induced responses may reach pathological levels, resulting in acute drug-induced intoxication and posing a significant risk to human health. Drug dose is an obvious critical parameter in predicting acute intoxication; however, many other factors play important roles in determining the severity of drug-induced responses, including individual responsiveness, previous drug experience, simultaneous multi-drug use, silent pre-existing pathologies, as well as the specific conditions under which the drug is taken. As such, our focus here will be on drug-induced perturbations in temperature homeostasis, with a special emphasis on brain temperature as an important parameter that not only reflects the metabolic aspects of brain activity, but also affects neural activity and neural functioning Kiyatkin While the direct monitoring of brain temperature in rats is a relatively simple procedure, human data are limited and often restricted to neurological patients Mariak et al. Therefore, it has not been definitely proven that similar, relatively large brain temperature fluctuations could occur in healthy humans. However, several observations suggest that this could be the case. First, monkeys show robust physiological changes in brain temperature within a range comparable to that observed in rats Baker et al. Finally, direct measurements of venous outflow from healthy human volunteers wearing water-impermeable clothing which impaired normal heat dissipation to the external environment revealed that brain temperatures could reach Importantly, even at such high brain temperatures, the physical and mental states of these volunteers remained normal, suggesting that the brain can tolerate relatively large, but transient temperature increases. Brain temperature is determined by the balance of two opposing forces: metabolism-related intra-brain heat production and heat loss via cerebral blood outflow to the rest of the body and then to the external environment. This heat is removed from brain tissue by the cerebral circulation due to arrival from the lings of cooler arterial blood Feitelberg et al. Although mechanistic, the cooling of an internal combustion engine is a good analogy when considering brain temperature exchange. Similar to circulating coolant that continuously removes heat from a working engine, cool, oxygenated arterial blood removes heat from the brain via heat exchange. The now warmed venous blood then returns to the heart to be cooled and re-oxygenated in the lungs. Such an arrangement determines the critical role of cerebral blood flow in brain temperature homeostasis and the essential inter-dependence between temperature in the brain and the rest of the body. While brain temperature tends to increase due to metabolism-related intra-brain heat production, it also rises when brain-generated heat cannot be properly dissipated to the body and then to the external environment. Similarly, a decrease in cerebral metabolism tends to lower brain temperature; however this effect could be strongly enhanced by a peripheral vasodilatation that promotes heat loss to a cooler environment Kiyatkin and Brown Since most psychoactive drugs affect metabolism as well as the state of peripheral and cerebral blood vessels, drug-induced brain temperature responses should depend significantly upon the ongoing state of the organism and the environmental conditions of drug-use. A drug at a certain dose could induce minimal temperature effects in an environment where the adaptive mechanisms of heat loss are fully effective, but the same drug at the exact same dose could induce very powerful hyperthermic effects in an environment where heat dissipation mechanisms are significantly impaired. Since peripheral vasodilatation and perspiration are powerful means for heat loss in humans, drug-induced impairment of these adaptive mechanisms may be a very important determinant of drug-induced increases in brain and body temperatures. Similar to other psychostimulants, MDMA increases metabolism and induces hyperactivity coupled with hyperthermia Gordon ; Alberts and Sonsalla ; Mechan et al. The influence of environmental conditions and specific activity states could be especially important for MDMA because, in addition to metabolic activation, it also induces peripheral vasoconstriction Gordon ; Pederson and Blessing , thus diminishing heat dissipation from body surfaces and enhancing heat accumulation in the brain and body. Such products were designed to circumvent regulations controlling the sale and use of psychoactive substances. Two very popular synthetic cathinones are 3,4-methylenedioxymethcathinone methylone and 3,4-methylenedioxypyrovalerone MDPV Spiller et al. While low recreational doses of synthetic cathinones enhance mood and increase energy, high doses or chronic use can cause serious medical complications, including agitation, psychosis, tachycardia, hyperthermia, and even death Prosser and Nelson ; Ross et al. Methylone is a non-selective transporter substrate that evokes the release of dopamine, norepinephrine and serotonin, analogous to the effects of MDMA Baumann et al. By contrast, MDPV is a potent transporter blocker that inhibits the uptake of dopamine and norepinephrine, with minimal effects on serotonin uptake Baumann et al. Although robust increases in body temperature have been reported in humans as the result of acute intoxication with both methylone Pearson et al. In rats, MDPV 1. Since these drugs are structurally similar to MDMA, we compared the thermogenic effects of MDPV and methylone with those induced by MDMA and assessed whether and how these thermogenic effects are modulated by social interaction and moderately warm environments. By using this three-point recording procedure we were able to assess how these drugs affect intra-brain heat production NAc-muscle differential and skin vascular tone i. Figure 1 shows that MDMA, MDPV and methylone each increased brain and muscle temperatures, rapidly decreased skin temperature, and induced locomotor activation. These changes differed from a transient temperature increase induced by the saline injection, which did not result in an evident motor response a-c. While brain temperature increases induced by all three drugs were approximately equal in its magnitude 1. Injections of each drug induced rapid increases in NAc-Muscle differentials, but this effect, suggesting metabolic brain activation and enhanced intra-brain heat production, was clearly larger vs. Each drug also rapidly decreased Skin-Muscle differential, suggesting cutaneous vasoconstriction; this effect was about the same for each drug. Finally, all three drugs induced locomotor activation; this effect was clearly the greatest for MDPV. Filled symbols mark values significantly different from pre-injection baselines. Bold arrows mark the moment of injection. Original data shown in this graph were reported in Kiyatkin et al. To examine how the temperature effects of drugs are affected by associated physiological activation, we examined temperature dynamics during social interaction between two rats. While the changes in NAc and muscle temperatures were generally parallel, the rise was stronger and more rapid in the brain. This resulted in a significant increase in NAc-Muscle differentials that indicated metabolic brain activation. Social interaction was also accompanied by a strong decrease in Skin-Muscle temperature differentials, indicating stimulus-induced cutaneous vasoconstriction. While NAc-Muscle differentials rapidly returned to baseline after the end of the social interaction period, Skin-Muscle differentials increased above baseline, suggesting a rebound vasodilation. These physiological parameters and locomotion showed consistent changes at the start and end of the social interaction. Filled symbols mark values significantly different from the pre-injection baseline. The first and third vertical hatched lines in each graph show onset and offset of social interaction 60 min and black arrows at the second hatched lines mark the moment of drug administration. When rats received methylene instead of saline, temperature differences were minimal, but the decreases in NAcc and muscle temperatures and Skin-Muscle differentials after the end of social interaction were more prolonged Fig. Mean values of all parameters did not differ statistically vs. The mean increase in NAc temperature calculated for the entire 5-hour post-drug interval as the area under the curve was maximal with methylone used under quiet resting conditions 1. Similar to methylone, injection of MDPV delayed brain and muscle temperature decreases after social interaction Fig. MDPV, quiet-resting conditions 0. When taken in an activated physiological state, MDPV also enhanced both increases in NAc-Muscle differentials and decreases in skin-muscle differentials, suggesting a weak potentiation of MDPV-induced metabolic and vasoconstrictive effects. The most robust potentiation of hyperthermic effects was found with MDMA used during social interaction Fig. These changes, however, were highly variable in individual rats, with peak brain temperatures ranging from The mean temperature elevations were maximal in this case 2. The pure effects of MDMA on brain temperature were also significantly stronger during social interaction than in quiet resting conditions 1. Social interaction likewise potentiated metabolic brain activation as well as vasoconstriction, two major physiological mechanisms underlying MDMA-induced hyperthermia. Rats exposed to a warm ambient temperatures maintained stable but slightly higher internal temperatures mean: Saline injections under these conditions induced weak, transient injection-related temperature responses similar to that seen with saline injection at standard room temperature Fig. Black arrows at the hatched lines mark the moment of drug administration. Since all rats exposed to MDMA died within 6 hrs post-injection, MDMA data are shown as individual changes j and mean values of NAc-Muscle, Skin-Muscle differentials and locomotion k and l for the first 80 min post-injection when all rats were still alive. The potentiation of these hyperthermic effects was coupled with stronger and more prolonged increases in NAc-Muscle differentials and stronger decreases in Skin-Muscle differentials. However, these changes were not significant vs. When calculated as the pre-lethality temperature peak, the mean increase in NAc temperature was 2. Drug-specific differences in the pattern of modulation are especially evident when we compare the brain hyperthermic effects of each drug administered under different experimental conditions Fig. As can be seen, each of the three drugs induced an approximately equal brain hyperthermic effect when tested at standard laboratory conditions. However, the effects of these drugs showed distinct differences when they were administered during social interaction and at warm ambient temperatures. This pattern of interaction suggests that methylone and social interaction share common effector mechanisms e. When these mechanisms are naturally activated during social interaction i. Horizontal hatched line in A show values in control saline group. Horizontal hatched lines in B show values induced by each drug under quiet resting conditions. While the mechanisms underlying this potentiation remain unclear, it is likely that MDPV, in addition to its central action, acts directly on the vessels potentiating skin vasoconstriction and increasing intra-brain heat accumulation. A powerful enhancement of the hyperthermic effects of MDMA by environmental conditions seen in rats may help to explain the exceptionally strong, sometimes fatal, responses of some individuals induced by this drug under rave party conditions. However, some caution should be taken in extrapolating these findings to human conditions because humans have much more sophisticated mechanisms of heat loss from the body than do rats Gordon , thus making them more resistant to high environmental temperatures and thermogenic effects of psychomotor stimulants. In contrast to rats, humans have a well-developed ability to sweat and have a very high dynamic range of flow rates in the skin, thus allowing them to lose more metabolic heat 1 kW than could be maximally produced in the body Rowell These differences in the effector mechanisms of heat loss could explain weaker MDMA-induced body temperature increases and their lesser dependence on ambient temperatures found in monkeys Taffe et al. Despite their high efficiency, the compensatory mechanisms of heat loss in humans could be greatly impaired under specific conditions, resulting in progressive heat accumulation in the organism. Therefore, pathological brain hyperthermia induced by overdose of psychomotor stimulants under rave conditions results not only from excessive heat production due to drug-induced and associated psycho-physiological activation, but also from the powerful drug-induced peripheral vasoconstriction and impaired ability to dissipate metabolic heat due to warm, humid environment. Since our previous work established a critical role of peripheral vasoconstriction in potentiating brain and body hyperthermic effects of MDMA, we explored two alternative pharmacological strategies for possible reversal of this effect in order to decrease brain and body temperature Kiyatkin et al. We assessed the effects of clozapine, an atypical neuroleptic, and carvedilol and labetalol, mixed alpha and beta adrenoceptor blockers. These medications are routinely used to treat chronic health problems in humans, and were chosen because of their preclinical success in attenuating MDMA-induced body hyperthermia Blessing et al. Clozapine acts on multiple neural receptors and glial cells in the brain, presumably inhibiting MDMA-induced metabolic neural activation, sympathetic tone, and centrally-mediated vasoconstriction Baldessarini and Frankenburg ; Breier et al. Carvedilol and labetalol act peripherally to dilate skin vessels by blocking alpha and beta adrenoceptors Sponer et al. Similar to our previous studies, brain temperature was our primary focus, but we also simultaneously recorded temperatures from the temporal muscle and facial skin to determine the basic physiological mechanisms underlying brain temperature responses. This three-point recording technique allowed us to evaluate the effects of the drugs on intra-brain heat production due to metabolic neural activation and heat loss due to changes in peripheral vascular tone Kiyatkin Our experimental protocol has three important features. This protocol is more relevant for human conditions because MDMA is recreationally used in social settings associated with high arousal e. Third, in contrast to most studies, where a treatment drug was administered before or at the same time as MDMA Yeh ; Sprague et al. This dosing regimen closely mimics the clinical situation, in which MDMA-intoxicated patients are treated for pathological hyperthermia in hospital emergency rooms. Although we strived for a fully factorial, within-subjects design, the variability associated with MDMA temperature response made this difficult. In rats from the first two groups, we injected MDMA 10 min after the onset of the 1-h social interaction followed by a counterbalanced injection of either a treatment drug clozapine, carvedilol, and labetalol or saline. In rats from two other groups, we injected either a treatment drugs clozapine, carvedilol, and labetalol or saline under quiet resting conditions. Each rat received only two MDMA injections, either alone or with a treatment drug. As shown in Figure 5e-f , after clozapine injection, NAc temperature rapidly decreased, resulting in a large difference vs. The clozapine-induced temperature decrease was rapid and profound; the final temperature values in the clozapine treatment group were lower than the initial baseline and significantly lower than in the control group that received MDMA with saline. These post-treatment temperature values, however, remain within the physiological range; similarly low or even lower values occur in well-habituated rats during day-time recording Kiyatkin Muscle and skin temperatures also decreased after clozapine injection, and the difference vs. The effects of clozapine, carvedilol and labetalol on MDMA-induced temperature and locomotor responses. The graphs show changes in different parameters before and after administration of each testing drug and saline 0 min. Filled symbols show values significantly different from the last pre-treatment value; the absence of filled symbols indicates the absence of a significant effect on a specified parameter evaluated with one-way ANOVA, n: number of rats original data of this study were published in Kiyatkin et al. In contrast to the stable increase in NAc-Muscle differentials present in the control group Fig. However, the most rapid and strong effects of clozapine were found for the Skin-Muscle differentials, which reflect the vasomotor tone of skin vessels. While this parameter further decreased after saline injection Fig. The difference between clozapine and saline appeared from the second data point 3—6 min and this difference continued to increase throughout the entire post-treatment interval. Carvedilol also had a strong attenuating effect on MDMA-induced increases in NAc, temporal muscle, and skin temperatures, returning these parameters to near-baseline levels by the end of the session Fig. Carvedilol minimally affected NAc-Muscle differential Fig. Lastly, carvedilol inhibited MDMA-induced locomotor activation, although locomotor activity was maintained at normal levels throughout the recording session Fig. Labetalol had no evident effects on any of the temperature responses caused by MDMA plus social interaction Fig. Additionally, we approximated temperature change, as analyzed by the integral of the difference between saline and drug treatment groups i. Comparative effectiveness of different drugs in reversing MDMA-induced temperature responses. Left panel shows the time-course of the effects of each drug difference vs. Right panel shows the mean effects area under curve for 80 min post-injection for each testing drug E-H. As can be seen in Fig. Clozapine also has the greatest attenuating effects on MDMA-induced intra-brain heat production and skin vasoconstriction, showing the largest decrease in NAc-Muscle differential and a strong, sustained increase in Skin-Muscle differential, respectively. In contrast, carvedilol had a much weaker effect on NAc-Muscle differentials and a less pronounced, short-lived effect on Skin-Muscle differentials. Finally, labetalol had minimal effects on MDMA-induced changes in all temperature measures. The downstream pharmacological and biochemical mechanisms underlying MDMA-induced hyperthermia are complex and involve multiple factors, including excessive sympathetic activation, dopamine hyperactivity, decoupling of mitochondrial ATP and heat production in both the brain and periphery are currently being explored see Dao et al. As such, rather than focusing on the specific downstream neurotransmitter, receptor, or signaling mechanisms, we chose to focus on the basic physiological mechanisms underlying MDMA-induced hyperthermia and its reversal by the treatment drugs. Consistent with its central, antipsychotic action, clozapine strongly reduced MDMA-induced increases in NAc-Muscle temperature differentials, suggesting a gradual decrease in intra-brain heat production due to blockade of drug-induced metabolic brain activation. Within the first 3 min post-treatment, clozapine also reversed the decreases in Skin-Muscle temperature differentials, suggesting a rapid blockade of skin vasoconstriction. In addition, clozapine decreased MDMA-induced locomotor activation while maintaining normal activity levels and showing no evident signs of sedation. Carvedilol and labetalol are mixed alpha-beta adrenoceptor blockers that directly dilate blood vessels Sponer et al. In contrast to the strong effects of clozapine on MDMA-induced increases in NAc-Muscle differentials, peripherally acting carvedilol had virtually no effects on this metabolism-related parameter. Surprisingly, the effects of carvedilol on MDMA-induced changes in Skin-Muscle differentials, an index of cutaneous vascular tone, were weaker and incomplete compared to the effects of clozapine. Although human reports suggest that labetalol taken before MDMA exposure decrease MDMA-induced hyperthermia Liechti , in our hands this drug was ineffective and had minimal, if any, effects on all temperature parameters. The reasons for the differences between carvedilol and labetalol are unclear and may be due to their different affinities for the various subgroups of alpha- and beta-adrenoceptors Ruffolo et al. As a vasodilator, labetalol also appears to be less potent than carvedilol Tomlinson et al. Current emergency therapeutic options to counteract MDMA-induced pathological hyperthermia mainly focus on whole body cooling, water substitution, and sedative therapy. Indeed, body cooling should have a hypothermic effect, but the effectiveness of this treatment is limited due to strong, sustained MDMA-induced vasoconstriction and the natural vasoconstrictive effect of skin cooling. To the best of our knowledge, our study is the first to compare the effectiveness of clozapine and carvedilol in alleviating MDMA-induced hyperthermia under conditions that mimic recreational drug use. Using our three-point thermorecording procedure, we were able to clarify the basic physiological mechanisms underlying the therapeutic actions of these drugs. In conclusion, the data indicate that carvedilol, by acting directly on blood vessels, is modestly effective in attenuating MDMA-induced brain and body hyperthermia. In contrast, clozapine induces much more rapid and powerful hypothermic effects by both decreasing MDMA-induced brain activation and diminishing the sympathetic outflow to peripheral vessels. A therapeutic agent such as clozapine that not only mitigates, but reverses, MDMA-induced hyperthermia could be indispensable for emergency situations and could save the lives of highly-intoxicated individuals. As a library, NLM provides access to scientific literature. Curr Top Behav Neurosci. Published in final edited form as: Curr Top Behav Neurosci. Find articles by Eugene A Kiyatkin. Find articles by Suelynn E Ren. PMC Copyright notice. The publisher's version of this article is available at Curr Top Behav Neurosci. Open in a new tab. Disclosure of Potential Conflicts of Interest No potential conflicts of interest are disclosed. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. 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