MDMA-induced indifference to negative sounds is mediated by the 5-HT2A receptor

This placebo-controlled study (n=20) found that individuals under the acute influence of MDMA (75mg) were less sensitive to negative sounds. The authors also found evidence that this may be related to the 5-HT2A receptor.

Abstract

“Background: MDMA has been shown to induce feelings of sociability, a positive emotional bias and enhanced empathy. While previous research has used only visual emotional stimuli, communication entails more than that single dimension and it is known that auditory information is also crucial in this process. In addition, it is, however, unclear what the neurobiological mechanism underlying these MDMA effects on social behaviour is. Previously, studies have shown that MDMA-induced emotional excitability and positive mood are linked to the action on the serotonin (5-HT) 2A receptor.

Aim: The present study aimed at investigating the effect of MDMA on processing of sounds (Processing of Affective Sounds Task (PAST)) and cognitive biases (Approach-Avoidance Task (AAT)) towards emotional and social stimuli and the role of 5-HT_2A receptor in these effects.

Methods: Twenty healthy recreational users entered a 2 × 2, placebo-controlled, within-subject study with ketanserin (40 mg) as pre-treatment and MDMA (75 mg) as treatment. Behavioural (PAST, AAT) measures were conducted 90 min after treatment with MDMA, respectively, 120 min after ketanserin. Self-report mood measures and oxytocin concentrations were taken at baseline and before and after behavioural tests.

Results: Findings showed that MDMA reduced arousal elicited by negative sounds. This effect was counteracted by ketanserin pre-treatment, indicating involvement of the 5-HT₂ receptor in this process. MDMA did not seem to induce a bias towards emotional and social stimuli. It increased positive and negative mood ratings and elevated oxytocin plasma concentrations. The reduction in arousal levels when listening to negative sounds was not related to the elevated subjective arousal.

Conclusion: It is suggested that this decrease in arousal to negative stimuli reflects potentially a lowering of defences, a process that might play a role in the therapeutic process.”

Authors: Kim P. C. Kuypers, R. de la Torre, M. Farre, N. Pizarro, L. Xicota & Johannes G. Ramaekers

Summary

Abstract

MDMA has been shown to induce feelings of sociability, a positive emotional bias and enhanced empathy. The present study aimed to investigate the effect of MDMA on processing of sounds and cognitive biases towards emotional and social stimuli.

Twenty healthy recreational users received ketanserin as pre-treatment and MDMA as treatment. Behavioural measures were conducted 90 min after treatment with MDMA.

MDMA reduced arousal induced by negative sounds, but this effect was counteracted by ketanserin pre-treatment. It also increased positive and negative mood ratings and elevated oxytocin plasma concentrations.

Introduction

MDMA increases emotional empathy in people. However, the effect of MDMA on the processing of auditory stimuli is not known, so a paradigm was used to assess the cognitive aspect of stimulus recognition and the emotional aspects linked to sound processing.

MDMA decreases amygdala activity, induces a positive emotional bias, and reduces avoidance behaviour. This may explain why MDMA increases sociability and empathy.

Serotonin (5-HT) and oxytocin systems are known to be involved in approach-avoidance behaviour. MDMA has been shown to induce an elevation in peripheral oxytocin concentrations, which might be a mechanism by which cognitive biases are induced by MDMA.

Pre-clinical evidence showed that the 5-HT2A receptor was involved in MDMA-induced sociality, and that blockade of the 5-HT2A receptor could prevent or even counteract MDMA-induced behavioural responses to emotional stimuli.

Design and treatments

The study was conducted according to a 2 x 2 double-blind, placebo-controlled, within-subject design including a pretreatment and a treatment. Ketanserin 40 mg was administered orally with water, and all capsules were identically appearing.

Procedures

All participants were medically assessed by a physician, and were familiarized with the procedures, tests and questionnaires on a training day. They were asked to abstain from any drug use 1 week before the medical examination.

Participants were screened for drugs of abuse, had breakfast, filled out a questionnaire, and a blood sample was taken to assess baseline oxytocin concentrations. After the test battery, participants had another questionnaire and blood sample taken.

The study was approved by the Medical Ethics Committee and participants were paid upon completion of the testing periods.

Processing of Affective Sounds Task

MDMA affects how we process affective sounds. We used a database of 111 standardized, emotionally evocative sounds and selected the 30 most positive/pleasant (happy) and 30 most negative/unpleasant (sad (4), fear (19), anger (1), disgust (6)) non-verbal sounds.

Participants had to type in what they thought they heard, categorize the sound as pleasant, neutral, or unpleasant, and rate how aroused the perception of this sound made them.

Implicit attitude tests

Three versions of the Approach-Avoidance Task were used to test automatic action tendency towards presented stimuli. The participants had to push or pull a joystick as fast as possible upon appearance of the stimuli, according to the rules, independently of the content of the stimulus.

The automatic action tendency towards or away from a scene (Social AAT) or an emotion (Threat AAT/Trust) was calculated after removing outliers.

For the Threat AAT and Trust AAT, 24 pictures were selected (12 neutral + 12 high threat; 12 neutral + 12 high trustworthy). This resulted in 96 trials for each task.

The Profile of Mood States

The POMS is a self-assessment mood questionnaire with 72 items, representing eight mood states, and two extra scales, Arousal and Positive mood.

Pharmacokinetics

MDMA and ketanserin were determined by gas chromatography coupled to mass spectrometry and pirenperone by liquid chromatography coupled to mass spectrometry, respectively. The analytes were identified using the multiple reaction mode mass/charge (M +1/z) and fragmentor (F) 200 V, collision energy (CE).

Oxytocin concentrations

A 2-mL sample was drawn and centrifuged, and the serum was removed and frozen at 80 °C until analysis. The oxytocin concentration was determined by a fluorescent immunoassay kit.

Statistical analyses

Data were entered into a general linear model (GLM) repeated measures analysis of variance (RM ANOVA) procedure and paired t tests were conducted to test for interaction effects.

Three measures were collected including baseline, and a GLM RM ANOVA was conducted to test for baseline differences. A paired sample t test was conducted to test for differences between conditions.

Processing of Affective Sounds Task

Analyses revealed that positive sounds were rated as more positive compared to negative sounds, and negative sounds produced more arousal compared to positive sounds. Furthermore, there was a three-way interaction of Pre-treatment valence on arousal.

Threat AAT

Analyses revealed no main effect of Pre-treatment or Treatment on Threat Bias, and no significant difference between Threat neutral faces and Threat-High faces in approach tendency.

Trust AAT

Analysis revealed a Pre-treatment by Treatment interaction, which was due to significant differences between the ketanserin and the placebo condition and ketanserin and the combined condition. When ketanserin was combined with MDMA, the approaching effects were eliminated and even reversed.

Social AAT

Analyses revealed that participants under influence of ketanserin had an avoidance bias (9.5) irrespective of stimulus content, and that the pre-treatment by treatment interaction approached significance (F 1, 19 = 4.16, p =0.056, p2 = 0.18)

Profile of Mood States

There were no baseline differences in POMS scores over the four test days. Ketanserin and MDMA had opposite effects on vigour, elation, arousal, positive mood and fatigue, and the effects of ketanserin and MDMA were similar on anxiety and confusion.

Pharmacokinetics

Paired sample t tests showed that MDMA and ketanserin plasma concentrations did not differ between the MDMA alone and ketanserin combined conditions.

Oxytocin concentrations

Analyses revealed no baseline differences in oxytocin serum concentrations between treatment conditions, and a main effect of MDMA on oxytocin concentrations 90 min after administration.

Analyses revealed that pre-treatment with ketanserin decreased oxytocin concentrations 150′ after MDMA administration, and that pre-treatment by treatment interaction effect decreased oxytocin concentrations.

Post hoc correlations

MDMA effects on arousal, anxiety and oxytocin were explored by calculating correlations between arousal, anxiety and oxytocin levels, and arousal, elation and oxytocin concentrations. These correlations were not statistically significant.

Discussion

The effect of MDMA (75 mg) on processing of auditory stimuli, implicit attitudes towards social and emotional stimuli, mood and oxytocin concentrations was investigated. Ketanserin counteracted a selection of MDMA-induced mood effects 150 min after MDMA intake.

In the Processing of Affective Sounds task, MDMA reduced arousal induced by negative sounds, but pretreatment with ketanserin increased arousal, thereby returning the arousal levels to a placebo-like response. This suggests that MDMA induces an indifference to negative sounds, or an inhibition of fear induced by negative sounds.

The results show that the effects of MDMA on arousal levels are stimulus dependent. When confronted with negative sounds, participants felt less discomfort or more at ease, which could contribute to the therapeutic process.

MDMA did not induce any cognitive bias in the approach-avoidance tasks, but counterintuitively decreased the ketanserin-induced stimulus-intensity-independent approach behaviour. This could be explained by its effect on both positive and negative mood states, which could be blocked by using verbal support during an MDMA session.