Effects of acute MDMA intoxication on mood and impulsivity: role of the 5-HT 2 and 5-HT 1 receptors

Van Wel and colleagues situate their study in a literature showing that MDMA acutely elevates subjective positive mood (openness, friendliness, elation) while sometimes producing negative mood states (anxiety, confusion) after intake, plausibly via effects on the serotonin (5-HT) system. Previous work indicates that overall 5-HT levels influence mood and impulsivity, and that specific 5-HT receptor subtypes—particularly 5-HT1 and 5-HT2—may contribute to MDMA's subjective and cognitive effects. Prior mechanistic studies suggested that 5-HT2 antagonism (ketanserin) attenuates some MDMA-induced perceptual and emotional effects, while partial 5-HT1 antagonism (pindolol) has shown mixed influence on subjective responses, but the receptor-specific contribution to impulsivity had not been examined directly. This study tested whether blockade of 5-HT1 or 5-HT2 receptors prevents MDMA-induced changes in mood and impulse control. The investigators hypothesised that a single acute dose of MDMA would alter mood and increase impulse control, and that these effects would be absent when subjects were pretreated with pindolol (a partial 5-HT1 antagonist) or ketanserin (a 5-HT2 antagonist). The experiment used a within-subject, double-blind design to assess these pharmacological interactions during peak drug concentrations.

Seventeen healthy recreational MDMA users (9 men, 8 women; age 19–27, mean 22.76, SD 2.75) participated in a double-blind, placebo-controlled, within-subject study with six experimental conditions. Each session comprised a pretreatment (T1) followed 30 minutes later by the main treatment (T2); the six T1–T2 combinations were: placebo–placebo, 20 mg pindolol–placebo, 50 mg ketanserin–placebo, placebo–75 mg MDMA, 20 mg pindolol–75 mg MDMA and 50 mg ketanserin–75 mg MDMA. Conditions were separated by a minimum 7-day washout and were counterbalanced across three blocks. The MDMA dose was 75 mg racemate; therapeutic doses of pindolol (20 mg) and ketanserin (50 mg) were chosen to achieve partial 5-HT1A blockade (~40%) and substantial 5-HT2 blockade (~91%), respectively. Inclusion criteria required written informed consent, age 18–35, a history of MDMA use, absence of psychotropic medication, good physical health and BMI 18–28. Exclusion criteria included DSM-IV addiction, psychiatric or neurological disorder, pregnancy or lactation, cardiovascular abnormalities, excessive drinking (>20 standard units/week) or heavy smoking (>10 cigarettes/day), and hypertension. Subjects underwent medical screening, provided informed consent, and were compensated. Drug and alcohol screening (including pregnancy tests for females) were performed on each session and treatments were only administered if tests were negative. Ketanserin, pindolol and MDMA were prepared and randomised by the hospital pharmacy. Testing employed a double-dummy technique to synchronise Tmax and maintain blinding. Outcome assessments occurred at approximately 1.5–2 hours after T2 (around Tmax) and included the 72-item Profile of Mood States (POMS) and three laboratory tasks probing distinct facets of impulsivity: the Matching Familiar Figures Test (MFF20) for reflection impulsivity, a Stop Signal Task (SST) for motor response inhibition (stop reaction time, SRT), and a cue-dependent reversal learning task for adaptive inhibition and discrimination-reversal learning. Blood samples for pharmacokinetics were collected at 1.5 hours post-T2 and analysed by solid-phase extraction followed by gas chromatography–mass spectrometry. Vital signs (blood pressure, temperature) were monitored for safety. Statistical evaluation used two separate General Linear Model (GLM) repeated-measures ANOVAs: one testing MDMA (placebo vs 75 mg) and ketanserin (50 mg vs 50 mg + MDMA) interactions, the other testing MDMA and pindolol (20 mg vs 20 mg + MDMA) interactions. Significant main effects were followed by drug–placebo contrasts. The significance threshold was p = 0.05 and analyses were performed in SPSS v15.0.

Seventeen complete data sets entered analysis; three subjects were excluded from the Stop Signal Task due to technical or performance failures, leaving N = 14 for that task. POMS (subjective mood): MDMA produced significant increases in both positive and negative mood dimensions at the testing point. Specifically, MDMA increased anxiety, confusion, vigour, friendliness, elation, positive mood and the composite arousal score, and it reduced fatigue. In the GLM including pindolol, the MDMA effect on positive mood was highly significant (p < .001); in the GLM including ketanserin the MDMA main effect on positive mood approached significance (p = 0.057). Pindolol given alone increased confusion and decreased positive mood, but it did not significantly interact with MDMA on mood measures. Ketanserin had broad effects when administered alone: it increased depression, fatigue and confusion and decreased vigour, friendliness, elation, arousal and positive mood. Importantly, an interaction between MDMA and ketanserin reached significance on four POMS subscales (depression, friendliness, elation and positive mood). When ketanserin was combined with MDMA, ratings of friendliness, elation and positive mood returned to placebo levels, whereas ratings of depression increased. Impulsivity tasks: MDMA significantly increased stop reaction time (SRT) on the Stop Signal Task and increased reaction time (RT) on the MFF20, indicating slower inhibitory and reflective responding. MDMA did not reliably affect other impulsivity parameters. Pindolol did not affect impulsivity measures. Ketanserin alone increased SRT and RT and reduced the number of correct inhibitions in the cue-dependent reversal learning task. There were no significant interactions between MDMA and ketanserin on impulsivity measures; the only reported MDMA × pindolol interaction was an increase in correct inhibitions in the cue-dependent reversal learning task. Pharmacokinetics: Mean (SD) serum MDMA concentration at 1.5 hours post-administration was 157 (48) ng/mL. MDMA concentrations when combined with ketanserin or pindolol were 164 (62) and 156 (56) ng/mL, respectively. Mean (SD) serum concentrations of ketanserin and pindolol alone were 86 and 133 (80) ng/mL, respectively; when combined with MDMA mean (SD) concentrations were 104 and 130 (53) ng/mL, respectively.

The investigators interpret their findings to indicate that 5-HT2 receptor activity contributes to the positive mood effects of MDMA during acute intoxication, while 5-HT1 receptors do not have a measurable role under the present conditions. Single doses of MDMA produced both positive (vigour, friendliness, elation, arousal) and negative (anxiety, confusion) subjective effects. Pretreatment with ketanserin (a 5-HT2 antagonist) prevented MDMA-induced increases in positive mood subscales—ratings during ketanserin+MDMA approximated placebo—whereas ketanserin did not attenuate MDMA-induced anxiety and in fact increased depression ratings when combined with MDMA. These patterns led the authors to conclude that 5-HT2 receptors mediate MDMA's positive mood elevation but do not underlie some negative mood effects. By contrast, pindolol, a partial 5-HT1 antagonist, did not reliably interact with MDMA-induced mood changes; pindolol alone produced modest increases in confusion and small reductions in positive mood. The authors acknowledge the caveat that pindolol blocks only about 40% of 5-HT1A receptors, so incomplete receptor blockade could have limited the ability to detect a true 5-HT1-mediated contribution. Regarding impulsivity, MDMA effects were limited to slowing on SRT and MFF20 RT, with no broad improvements or impairments across other impulsivity measures. Neither ketanserin nor pindolol pretreatment modified MDMA effects on impulse-control tasks. The discussion emphasises that impulsivity is heterogenous—motor and cognitive impulsivity tap different neuropsychological processes—so MDMA might affect only specific subprocesses or its relationship with impulsivity may be marginal during acute intoxication. The authors position their results as consistent with prior studies showing mixed MDMA effects on impulsivity and prior mechanistic findings on receptor involvement in subjective effects. They note key limitations reported in the paper: the partial blockade achieved with pindolol may not be sufficient to exclude a role for 5-HT1 receptors, the sample comprised mild-to-moderate recreational users which may affect generalisability, and MDMA effects on impulsivity were relatively limited, constraining the capacity to detect interactions. The paper concludes that blockade of 5-HT2 receptors attenuates MDMA-induced positive mood but that neither 5-HT1 nor 5-HT2 blockade altered MDMA effects on the impulsivity measures used.