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

This double-blind, placebo-controlled, within-subject study (n=17) explored the role of 5-HT₁ and 5-HT₂ receptors in MDMA effects on mood and impulsivity. It found that 5-HT₂ receptors mediate positive moods induced by MDMA but not negative moods or impulsivity. There were no mediating effects of 5-HT₁ receptors.

Abstract

“MDMA induces positive mood and increases impulse control during intoxication, but only a few studies on the neuropharmacological mechanisms underlying these processes have been conducted. It was hypothesized that pretreatment with 5-HT₁ and 5-HT₂ receptor blockers would prevent MDMA effects on mood and impulsivity. Subjects (N = 17) participated in a double-blind, placebo-controlled, within-subject design involving 6 experimental conditions consisting of pretreatment (T1) and treatment (T2). T1 preceded T2 by 30 minutes. 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 g MDMA. Subjects completed a Profile of Mood States (POMS) questionnaire and several impulsivity tasks (Stop signal task, Matching familiar figures task, Cue dependent reversal-learning task) at 1.5 hrs post-treatment. MDMA alone increased both positive (vigour, arousal, friendliness, elation, positive mood) and negative affect (anxiety, confusion) as assessed by the POMS questionnaire. MDMA also increased stop reaction time in the Stop signal task and reaction time in the Matching familiar figures task. Pretreatment with ketanserin blocked MDMA effects on positive affect, but not negative affect. Ketanserin did not influence the effects of MDMA on impulsivity. Pindolol did not interact with MDMA on any of the measures. In conclusion, 5-HT₂ receptors mediate positive moods induced by MDMA but not negative moods or impulsivity. 5-HT₁ receptors do not appear to be involved in MDMA effects on mood and impulse control.”

Authors: Janelle H. P. van Wel, Kim P. C. Kuypers, Eef L. Theunissen, Wendy M. Bosker, Katja Bakker & Johannes G. Ramaekers

Summary

MDMA induces positive mood and increases impulse control during intoxication, but 5-HT1 and 5-HT2 receptor blockers did not prevent these effects. Ketanserin blocked positive moods but not negative moods or impulsivity, and pindolol did not affect any of the measures.

MDMA has been shown to affect mood and impulsivity during intoxication and abstinence, and to increase feelings of openness, enhance mood and well-being and heighten feelings of happiness. However, depressed mood has been reported in MDMA-users following acute administration of the drug.

Low levels of 5-HT have been linked to impulsive, suicidal and aggressive behaviour, and substance abuse, whereas high levels have been linked to increased impulse control.

There is evidence that 5-HT1 and 5-HT2 receptors contribute to the influence of MDMA on mood and impulsivity. 5-HT1 and 5-HT2 antagonists have been shown to decrease impulsivity and anxiety.

The effects of MDMA on mood and impulse control were assessed, and the effects were absent when pre-treated with 5-HT1 and 5-HT2 receptor blockers.

Subjects

Seventeen healthy MDMA-users aged between 19 and 27 took the drug on 1 to 65 separate occasions in the previous year, and on 3 to 780 occasions in their lifetime.

Subjects were recruited through advertisements in local newspapers and by word of mouth. They were examined by a medical supervisor and given an information leaflet before the study explaining the entire study procedure.

This study was conducted according to the code of ethics on human experimentation, and subjects were paid for their participation.

Design, Doses and Administration

Subjects participated in a double-blind, placebo controlled, within-subject design involving 6 experimental conditions consisting of pretreatment (T1) and treatment (T2). MDMA 75 mg was used as the experimental drug, and pindolol 20 mg and ketanserin 50 mg were used as the control drugs.

Procedures

Subjects were trained before the experiment, were asked to refrain from drugs, were not allowed to use alcohol on the day prior to an experimental session, and were tested for drugs, alcohol and pregnancy.

Treatments were administered using a double dummy technique to synchronize time of maximal drug concentrations (Tmax), and subjects’ mood and impulsivity were assessed by means of a number of tasks.

Subjective Measures

The Profile of Mood States is a self-assessment mood questionnaire with 72 items. Eight mood states are classified and quantified, i.e., anxiety, depression, anger, vigor, fatigue, confusion, friendliness and elation.

Impulsivity Tests

The Matching Familiar Figures Task is a measure of reflection impulsivity. Subjects who respond impulsively are faster, but make more errors, while those who pause and think about the alternatives are slower and more accurate.

The computerized MFF20 test format involves simultaneous presentation of a target figure and six alternatives. Subjects are asked to select the figure that exactly matches the target as quickly as possible.

Two dependent measures are automatically recorded: mean latency to first response and total number of errors. An Impulsivity score (Iscore) and an Efficiency score (E-score) can be calculated.

The stop signal task is used to measure motor impulsivity and is sensitive to stimulating as well as sedating drugs.

Subjects are presented with four letters (ABCD) at a time on a computer screen and are required to respond to each letter as quickly as possible. A stop signal occurs in 48 trials during the test and subjects are required to withhold their response in case a stop signal is presented.

The method for calculating stop reaction time was taken from the race model of inhibitory control. It was determined by subtracting the appropriate stop-signal delay from reaction time at the n-th percentile of the RT distribution and averaging the resulting values to yield a single measure of stop reaction time.

In the cue-dependent reversal learning task, subjects are required to respond to target stimuli and to inhibit their response on non-target stimuli. Cues provide preliminary information regarding the type of imperative target stimulus that is likely to follow.

Subjects have to detect a change in a rule and modify their response pattern. More impulsive individuals have more problems inhibiting responses after a change in rule.

Blood Samples

Blood samples were collected at 1.5 hrs post T2 and frozen at 220uC until analyses for pharmacokinetic assessments.

Statistics

MDMA, Ketanserin and MDMA 6 Ketanserin were tested for their interaction with MDMA induced impulsivity and mood in 2 separate General Linear Model (GLM) analyses.

Subjective Measures

MDMA increased feelings of anxiety, confusion, vigor, friendliness, elation, positive mood and arousal, and reduced feelings of fatigue. Ketanserin increased feelings of depression, fatigue and confusion, and decreased feelings of vigor, friendliness, elation, positive mood and arousal.

Impulsivity Tasks

MDMA increased SRT and RT in the stop signal task, but did not affect performance on any other impulsivity parameters. Ketanserin decreased inhibitions in the cue-dependent reversal learning task.

Blood Samples

MDMA concentrations in the serum were 157 (48) ng/mL at 1.5 hours after administration. When combined with ketanserin or pindolol, the concentrations were 164 (62) and 156 (56) ng/mL respectively.

Discussion

The current study investigated the role of 5-HT1 and 5-HT2 receptors in MDMA induced changes in mood and impulsive behavior. Single doses of MDMA increased positive as well as negative moods, while making subjects feel more anxious and confused.

Ketanserin significantly decreased positive mood ratings when combined with MDMA, but did not reverse the negative moods produced by MDMA. This indicates that the 5-HT2 receptor is only involved in mediating positive moods during intoxication.

Pretreatment with pindolol did not affect the effects of MDMA on mood. This is in line with a previous study that showed that the 5-HT1A receptor does not play a role in mediating MDMA induced mood states.

MDMA had no effect on measures of impulsivity, but increased SRT and reaction time in the stop signal task and decreased cue dependent reversal learning in the MFF20. Possibly, the lack of effect on other measures of impulsivity is due to the fact that the measures represent different psychological constructs of impulse control.

Results show that administration of MDMA has both positive and negative influences on mood states, and that treatment with a partial 5-HT1 receptor antagonist did not interfere with MDMA effects on mood.