This double-blind, placebo-controlled, crossover study (n=18) of MDMA (75-100mg) and alcohol (very low dose) finds that: acute doses of MDMA enhanced impulse control in the stop-signal task; a moderate dose of alcohol negatively impacted participants' ability to inhibit responses in the stop-signal and go/no-go paradigms; and MDMA didn't influence the alcohol-induced impairment in response inhibition tasks.
The use of 3,4-methylenedioxymethamphetamine (MDMA) has frequently been associated with increased levels of impulsivity during abstinence. The effects of MDMA on measures of impulsivity, however, have not yet been studied during intoxication. The present study was designed to assess the acute effects of MDMA and alcohol, alone and in combination, on behavioral measures of impulsivity and risk-taking behavior. A total of 18 recreational users of MDMA entered a double-blind placebo-controlled six-way crossover study. The treatments consisted of MDMA 0, 75, and 100 mg with and without alcohol. Alcohol dosing was designed to achieve a peak blood alcohol concentration (BAC) of about 0.06 g/dl during laboratory testing. Laboratory tests of impulsivity were conducted between 1.5 and 2 h post-MDMA and included a stop-signal task, a go/no-go task, and the Iowa gambling task. MDMA decreased stop reaction time in the stop-signal task indicating increased impulse control. Alcohol increased the proportion of commission errors in the stop-signal task and the go/no-go task. Signal detection analyses of alcohol-induced commission errors indicated that this effect may reflect impairment of perceptual or attentive processing rather than an increase of motor impulsivity per se. Performance in the Iowa gambling task was not affected by MDMA and alcohol, but there was a nonsignificant tendency towards improvement following alcohol intake. None of the behavioral measures of impulsivity showed an MDMA × alcohol interaction effect. The lack of interaction indicated that the CNS stimulant effects of MDMA were never sufficient to overcome alcohol-induced impairment of impulse control or risk-taking behavior.
Papers in Blossom that reference this study
Ramaekers, J. G., Kuypers, K. P. C., Vollenweider, F. X. · Molecular Psychiatry (2026)
Poyatos, L., Pérez-Mañá, C., Hladun, O. et al. · Frontiers in Pharmacology (2023)
Papaseit, E., Torrens, M., Pérez-Mañá, C. et al. · Expert Opinion on Drug Metabolism and Toxicology (2018)
Carhart-Harris, R. L., Nutt, D. J. · Journal of Psychopharmacology (2017)
Ramaekers and colleagues situate their study in the context of mixed findings about impulsivity among MDMA users. Earlier research described both decreased and increased impulsivity in abstinent MDMA users depending on the measures used, and biological work has linked elevated impulsiveness to low serotonin (5-HT) markers and to dopaminergic activation in prefrontal regions. The authors note that most prior MDMA research used self-report instruments and studies in abstinent users, and argue that acute, placebo-controlled studies using behavioural tasks are needed to establish a direct pharmacological relation between MDMA intoxication and impulse control. The present study therefore set out to assess the acute effects of MDMA, and of MDMA combined with alcohol, on behavioural measures of impulsivity and risk-taking. Using a double-blind, placebo-controlled within-subject design, the investigators tested rapid motor inhibition (stop-signal and go/no-go tasks) and decision-making under uncertainty (Iowa gambling task). They hypothesised that acute increases in brain serotonin after a single MDMA dose would improve impulse control, and included alcohol both as an active control (given its known impairing effects on inhibition) and to test for MDMA by alcohol interactions.
The study used a double-blind, placebo-controlled six-way crossover design. Eighteen recreational MDMA users (nine males, nine females), aged 20–37 years, participated; they reported light-to-moderate recent MDMA use (2–25 occasions in the previous year, mean about 9 occasions). Inclusion criteria included prior MDMA experience, absence of psychotropic medication and major medical or neurological disorders, normal weight/BMI reported between 18 and 28 kg/m2, and written informed consent. Exclusion criteria included a history of drug abuse (other than MDMA), pregnancy or lactation, cardiovascular abnormalities on ECG, excessive drinking (the extracted text gives a threshold but it is not clearly reported), hypertension (thresholds are reported in the extracted text but not clearly readable), and psychiatric or neurological disorder. Screening included medical history, vitals, blood and urine drug screens and standard blood chemistry. Subjects received a training session on the tasks before experimental sessions. Each participant completed six treatment sessions in randomised order with a minimum 1-week washout. Treatments were oral MDMA at 0, 75 and 100 mg, each given with and without alcohol. MDMA was administered as a 25 ml solution in bitter orange peel syrup. Alcohol was dosed to target a peak blood alcohol concentration (BAC) of about 0.06 g/dl, administered 45 min after MDMA and consumed within 15 min. Laboratory testing occurred between 1.5 and 2 h after MDMA administration (that is, approximately 0.5–1 h after alcohol). BAC was monitored every 15 min for 30–90 min after drinking using a Lion SD-4 Breath Alcohol Analyser. Blood for MDMA and MDA quantification was taken at 1.5 h post drug and stored for gas chromatography–mass spectrometry analysis. Behavioural endpoints comprised three established tasks. The stop-signal task measured ability to inhibit an initiated motor response; dependent variables were proportion of commission errors on stop trials and stop reaction time (an estimate of the time required to inhibit a response, calculated using the race model). The go/no-go task measured suppression of a habitual response, with dependent variables of mean reaction time on go trials and commission errors on no-go trials; signal detection theory was applied to derive sensitivity (d') and response criterion (b). The Iowa gambling task assessed decision-making under uncertainty, with net score (cards chosen from advantageous minus disadvantageous decks) as the outcome. Pharmacokinetic measures included plasma MDMA and MDA concentrations and serial BACs. Statistical analyses used repeated measures MANOVA with factors MDMA (three levels) and alcohol (two levels) and their interaction; drug–placebo contrasts were performed after overall effects. The alpha level was set at p = 0.05.
Eighteen complete data sets were available for the Iowa gambling and go/no-go tasks; one stop-signal data set was incomplete due to technical problems and excluded. On the stop-signal task, repeated measures MANOVA showed a significant overall main effect of MDMA on stop reaction time (F2,15 = 4.62; p = 0.027), reflecting shorter stop reaction times (improved inhibitory speed) under MDMA relative to placebo. The MDMA 75 mg dose produced a particularly notable effect in drug–placebo contrasts (p = 0.008). MDMA did not significantly change the proportion of commission errors in the stop-signal task. Alcohol produced significant impairments on motor inhibition measures. MANOVA indicated main effects of alcohol on the percentage of commission errors in the stop-signal task (F1,16 = 7.06; p = 0.017) and in the go/no-go task (F1,17 = 7.84; p = 0.012), with higher proportions of commission errors during alcohol treatments. Signal detection analysis of the go/no-go task showed that alcohol reduced sensitivity (d') to discriminate go from no-go signals (F1,17 = 18.25; p = 0.001) but did not alter response criterion (b), suggesting impaired perceptual or attentive processing rather than a liberal shift in response bias. Reaction times on go and no-go trials were not significantly affected by alcohol. In the Iowa gambling task, MDMA did not affect performance. Alcohol showed a trend toward improved performance (higher net scores), with a near-significant main effect (F1,17 = 3.14; p = 0.09), indicating a tendency to select more advantageous cards under alcohol, although this did not reach the study's significance threshold. No significant MDMA × alcohol interactions were found for any behavioural measure. Pharmacokinetic data reported that mean BACs did not significantly differ between treatments. The extracted values for mean (SE) BACs at the onset of laboratory testing (30 min post drinking) were 0.65 (0.19), 0.56 (0.12), and 0.57 (0.16) mg/ml following placebo, MDMA 75 mg and MDMA 100 mg, respectively; at the end of testing (60 min post drinking) the values were 0.64 (0.16), 0.59 (0.11) and 0.59 (0.12) mg/ml for the same conditions. Plasma MDMA concentrations at 1.5 h post drug averaged 137.4 (31.9) ng/ml and 191.8 (49.1) ng/ml after 75 and 100 mg doses, respectively; combinations with alcohol produced similar or slightly higher concentrations. MDA concentrations were low and comparable across conditions.
Ramaekers and colleagues interpret their findings as showing that a single acute dose of MDMA can improve inhibitory motor control, as evidenced by reduced stop reaction time in the stop-signal task, while a moderate dose of alcohol impairs the ability to inhibit responses in rapid-response paradigms. They emphasise that this is the first controlled study to assess acute MDMA effects on behavioural measures of impulsivity. The investigators propose two plausible pharmacological mechanisms for the MDMA effect: acute serotonergic ‘‘suppletion’’ (MDMA increases 5-HT release and blocks reuptake) and augmented dopaminergic neurotransmission, either of which could plausibly speed inhibitory processing. They place this acute improvement in the context of studies showing low serotonergic markers and impaired impulse control in abstinent MDMA users, suggesting that impulsivity may decrease during acute MDMA intoxication but increase during abstinence when serotonin markers are diminished. The authors also note that the study sample (light-to-moderate recreational users) may respond more like healthy volunteers than long-term stimulant abusers, and they reference prior work showing that chronic stimulant exposure can alter responses to acute dopaminergic stimulation. A central interpretive point concerns the dissociation between motor and cognitive impulsivity: MDMA selectively improved motor inhibition (stop-signal) while leaving cognitive decision-making (Iowa gambling task) unchanged. The authors link this to the notion that impulsivity is multi-dimensional and mediated by distinct neural substrates (for example, anterior cingulate involvement in motor inhibition versus ventromedial prefrontal cortex in decision-making). Regarding alcohol, the team argues that increased commission errors under alcohol reflected reduced sensory/attentional sensitivity rather than a shift toward riskier response bias, because d' decreased while response criterion did not change and reaction times were unaffected. They acknowledge that the go/no-go task was relatively easy for participants and recommend increasing task difficulty in future work to probe sensitivity and criterion effects further. No MDMA by alcohol interactions were observed, leading the authors to conclude that MDMA's central stimulating effects do not overcome alcohol-induced impairment of motor control. They note that this aligns with earlier work showing that MDMA reverses alcohol-induced subjective sedation but does not mitigate alcohol-related psychomotor impairment. As an applied implication, the investigators highlight road-safety concerns: users combining MDMA and alcohol may experience alcohol-induced loss of motor control despite subjective stimulation from MDMA. The authors discuss sample characteristics and task-specific considerations as relevant limitations, and they frame the results as prompting further research into distinct impulsivity domains and the acute versus chronic effects of MDMA on inhibitory control.
Data were analyzed by means of repeated measures MANOVA with alcohol (two levels) and MDMA (three levels) and their interaction as main factors. Separate drugplacebo contrasts were conducted following an overall effect of MDMA or the interaction between MDMA and alcohol. The alpha criterion level of significance was set at p ¼ 0.05.
The main findings of this study on impulsivity were (1) that acute doses of MDMA improved impulse control in the stop-signal task; (2) that a moderate dose of alcohol impaired the subjects' ability to inhibit responses in the stop signal and go/no-go paradigms; and (3) that MDMA did not affect alcohol-induced impairment in response inhibition tasks. The present study has been the first to assess the acute effects of MDMA on behavioral measures of impulsivity. In two tasks, ie the stop-signal task and the go/no-go task, impulsivity was defined as the inability to inhibit an activated or pre-cued response leading to errors of commission. In the third task, ie the Iowa gambling task, impulsivity was defined as the inability to anticipate and reflect on the consequences of decision making. In both response inhibition tasks, MDMA did not affect the proportion of commission errors but significantly improved stop reaction time in the stop-signal task. These data indicate that a single dose of MDMA has the potential to stimulate inhibitory motor control in a stop-signal task during intoxication. The pharmacological mechanism underlying improvement in impulse control may be related to acute serotonergic or dopaminergic suppletion following a single dose of MDMA. MDMA is believed to increase 5HT levels during intoxication by stimulating the acute release of 5HT and by blocking the presynaptic reuptake of 5HT (. Improved impulse control during serotonergic suppletion seems in line with reports on impaired impulse control in heavy users of MDMA during periods of abstinence. Studies on serotonergic function in recreational MDMA users have repeatedly shown low levels of 5HIAA in CSF, reduced density of 5-HT transportersand blunted neuro-endocrine responses in serotonergic challenge testswhen compared to nondrug using controls. In addition, serotonergic depletion has been linked to behaviors characterized by impaired impulse control. Thus, acute improvement of inhibitory control in the stop-signal task following MDMA administration can be interpreted as supportive evidence for current notions on the link between serotonin and impulsivity. Impulsivity levels may drop following serotonin suppletion during acute MDMA intoxication but rise during periods of abstinence when serotonin levels are low. Alternatively, the reduction in stop reaction time during MDMA intoxication may have also resulted from increased dopaminergic neurotransmission. MDMA is known to also stimulate the release of dopamine and to bind to the presynaptic dopamine reuptake transporters, albeit with less affinity then for the 5HT transporter. Studies on the effects of dopamine agonists on behavioral measures of impulsivity have shown patterns of improvement in impulse control that are similar to the one presented here, following MDMA. D-amphetamine for example, was shown to decrease stop reaction time of healthy volunteers in a stop-signal paradigm without affecting reaction time to go trials. However, opposite effects of amphetamine on behavioral tests of impulsivity have also been found when tested in long-term stimulant abusers.reported that an acute dose of d-amphetamine produced a dose-dependent increase in inhibition failures in longterm stimulant abusers performing a cued go/no-go task. Similarly, single doses of cocaine reduced the ability to inhibit responses of cocaine abusers in a stop-signal task. It has been suggested that repeated dopaminergic stimulation of prefrontal pathways leads to impairment of inhibitory functionsand that neural changes following chronic stimulant use may alter the behavioral response to acute dopaminergic stimulation. In the present study, the subjects can be best qualified as light-to-moderate MDMA users. Therefore, subject characteristics in the present study would seem more comparable to those in healthy volunteer studies than to those in studies employing long-term drug abusers. MDMA did not affect measures of impulsivity in every behavioral task employed in the present study. Decisionmaking processes in the Iowa gambling task were not affected by MDMA, which seems to indicate that its effect on stop reaction time in the stop-signal task is rather selective. It has been argued before that impulsivity is a broad conceptual construct that encompasses multiple mechanisms of behavioral control that may be linked to different regions of the brain. Two types of impulsivity that can be distinguished are cognitive impulsivity and motor impulsivity. Cognitive impulsivity as measured by the Iowa gambling task is believed to reflect complex processes involved in the control of several cognitive, behavioral and effective processes. More in particular, it assesses the ability to think and reflect on the consequences of a choice prior to making a decision. The ventromedial section in the prefrontal cortex has been indicated as the most critical neural structure underlying these processes. Motor impulsivity or response inhibition as measured in the stop-signal task or go/no-go task, on the other hand, is believed to relate to the control of motor processes that are subserved by the anterior cingulate. Thus, it is entirely possible that a pharmacological manipulation can affect these control systems independently and selectively. The present study thus suggests that MDMA selectively improves control over motor impulsivity, while leaving cognitive impulsivity intact. It is interesting to note that selectivity of MDMA effects have been reported in other psychological domains as well.demonstrated that a single dose of MDMA produced dissociable effects on psychomotor skills and attention. The effects of alcohol on measures of behavioral impulsivity were intriguing. Alcohol reduced performance in the stop-signal and go/no-go tasks but almost significantly improved performance in the Iowa gambling task. Similar findings have been reported in the scientific literature. Previous studies employing stop-signal paradigms have reported that alcohol increased stop reaction timeor increased the number of commission errors, suggesting increased impulsivity. Application of signal detection theory to data from the go/ no-go task in the present study indicated that the increase in commission errors during alcohol intoxication did not result from a change in response bias toward more liberal or risky decisions, but from a reduced ability to discriminate go from no-go signals. Or in terms of signal detection parameters: sensitivity (d 0 ) significantly decreased following alcohol treatment, whereas the response criterion (b) was unaffected. Sensitivity is a measure of sensory capabilities of the observer or of the effective signal strength, whereas response criterion is a measure of cautiousness and reflects such things as motives and attitudes. The present data thus suggest that the increase in commission errors may reflect impairment of perceptual or attentive processing rather than an increase of motor impulsivity. The absence of an alcohol effect on reaction time in go and no-go trials in the stop-signal task as well as the go/no-go task further supports this notion. It should be noted, however, that overall mean values for sensitivity and response criterion were rather high in the present experiment, which indicates that the go/no-go task was rather easy to perform by the subjects. It would be preferable to increase task difficulty in future studies to further assess the contribution of alcohol-induced changes in sensitivity and response criterion to performance under more compelling laboratory circumstances. Performance on the Iowa gambling task tended to improve following alcohol treatment but this effect only approached statistical significance. It is still noteworthy, however, since similar effects have been reported in models, where cognitive impulsivity is defined as the inability to wait for a larger reward.employed a delay-discounting task, where healthy volunteers made a series of hypothetical choices between a small, immediate reward and a large, delayed reward. In the alcohol condition, subjects tended to discount delayed reward at lower rates than during the sober condition. This difference was not statistically significant, but suggested that alcohol led to more cautious decision making. Performance stimulating effects were not found bybut they did show that alcohol did not detrimentally affect discounting of delayed monetary reward. Although conceptual differences between tasks measuring cognitive impulsivity do exist, it has been shown that performance on delay-discounting tasks is significantly correlated to performance on the Iowa gambling task. Together these results indicate that alcohol does not increase cognitive impulsivity in this type of decisionmaking tasks. The absence of an alcohol effect on decisionmaking tasks vs the presence of a detrimental effect of alcohol on motor inhibition tasks demonstrates once more that impulsivity is not a unitary concept or brain structure but is comprised of several independent psychological domains or brain regions that can respond very selectively to a pharmacological manipulation. None of the behavioral parameters showed any significant MDMA by alcohol interaction effect. This suggests that MDMA does not alter the effects of alcohol on behavioral measures of impulsivity. This notion seems in line with conclusions from a previous study that assessed combined effects of alcohol and MDMA on psychomotor function during intoxication in humans. These investigators reported that MDMA reversed the subjective sedation induced by alcohol but did not change the impairing effect of alcohol on measures of psychomotor function such as simple reaction time and digit symbol substitution. The lack of mitigating effects of MDMA on alcohol-induced impairment on measures of impulsivity or risk tasking may be of particular importance in terms of road safety issues. Most of the MDMA-impaired driving cases that have been reported in the scientific literature consist of drivers who have taken multiple drugs and/or alcohol. The present data indicates that the CNS-stimulating effects of MDMA do not suffice to overcome alcohol-induced impairment of motor control, which is one of the most common causal factors in vehicle crashes.
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Van Wel, J. H. P., Kuypers, K. P. C., Theunissen, E. L. et al. · PLOS ONE (2012)