Investigation of serotonin-1A receptor function in the human psychopharmacology of MDMA

This double-blind, placebo-controlled, within-subjects-design study (n=15) investigated the role of 5-HT_1A receptors on the cognitive and subjective effects of MDMA. Blocking 5-HT_1A receptors had minor effects, which suggests that MDMA effects are not mediated through the 5-HT_1A receptor system.

Abstract

“Serotonin (5-HT) release is the primary pharmacological mechanism of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) action in the primate brain. Dopamine release and direct stimulation of dopamine D2 and serotonin 5-HT_2A receptors also contributes to the overall action of MDMA. The role of 5-HT_1A receptors in the human psychopharmacology of MDMA, however, has not yet been elucidated. In order to reveal the consequences of manipulation at the 5-HT_1A receptor system on cognitive and subjective effects of MDMA, a receptor blocking study using the mixed beta-adrenoreceptor blocker/5-HT_1A antagonist pindolol was performed. Using a double-blind, placebo-controlled within-subject design, 15 healthy male subjects were examined under placebo (PL), 20 mg pindolol (PIN), MDMA (1.6 mg/kg b.wt.), MDMA following pre-treatment with pindolol (PIN-MDMA). Tasks from the Cambridge Neuropsychological Test Automated Battery were used for the assessment of cognitive performance. Psychometric questionnaires were applied to measure effects of treatment on core dimensions of Altered States of Consciousness, mood and state anxiety. Compared with PL, MDMA significantly impaired sustained attention and visual-spatial memory, but did not affect executive functions. Pre-treatment with PIN did not significantly alter MDMA-induced impairment of cognitive performance and only exerted a minor modulating effect on two psychometric scales affected by MDMA treatment (‘positive derealization’ and ‘dreaminess’). Our findings suggest that MDMA differentially affects higher cognitive functions, but does not support the hypothesis from animal studies, that some of the MDMA effects are causally mediated through action at the 5-HT_1A receptor system.”

Authors: Felix Hasler, Erich Studerus, Karl H. Lindner, Stephan Ludewig & Franz X. Vollenweider

Summary

15 healthy male subjects were examined under placebo, 20 mg pindolol, MDMA (1.6 mg/kg b.wt. ), and MDMA following pre-treatment with pindolol (PIN-MDMA). They completed psychometric questionnaires to measure effects of treatment.

Introduction

MDMA causes an increase of extracellular levels of brain serotonin (5-HT), dopamine (DA) and norepinephrine (NE) by promoting non-exocytotic release of these neurotransmitters from storage vesicles. The increase of extracellular 5-HT concentration is blocked by pretreatment with Selective Serotonin Reuptake Inhibitors.

MDMA slows down the metabolic degradation of 5-HT and decelerates the formation of 5-HT in serotonergic nerve cells. Moreover, MDMA may also act through 5-HT2A receptors.

In vitro studies have demonstrated that MDMA increases extracellular 5-HT concentrations in the region of somatodendritic 5-HT1A autoreceptors leading to an inhibition of firing of 5-HT neurons in the dorsal raphe nucleus (DRN). This inhibition can be reversed by the selective 5-HT1A receptor antagonist WAY 100635 in rats. This study investigated the effects of MDMA on cognition, mood and anxiety in healthy human subjects. The results indicated that pretreatment with pindolol might attenuate/modulate MDMA-induced effects.

Subjects

Fifteen healthy male volunteers were recruited from University Hospital staff or were students at the Medical School of the University of Zurich. They completed a structured psychiatric interview and were given the Freiburg Personality Inventory, the State-Trait Anxiety Inventory and the Hopkins Symptom Checklist.

The personality trait factors ‘rigidity’ and ’emotional ability’ were identified as predictors of negative experiences during altered states of consciousness. Therefore, subjects with scores exceeding two SD from the mean value of normative data were excluded.

MDMA and pindolol capsules

Pharmaceutically pure racemic MDMA HCl was prepared as gelatin capsules and administered in a dosage of 1.6 mg/kg b.wt. to induce distinct subjective effects.

Pindolol, a mixed 5-HT1A receptor antagonist/beta-adrenoreceptor blocker, exhibits no in vivo selectivity for the DRN 5-HT1A autoreceptors over postsynaptic 5-HT1A binding sites.

Study design

We conducted a repeated-measures within subject design study with a counter-balanced succession of experimental conditions to avoid time order effects. We administered placebo, pindolol, placebo-MDMA and pindolol-MDMA to healthy subjects at the beginning of each study day.

The AMRS, STAI, neuropsychological testing, 5DASC questionnaire and blood pressure, heart rate and body temperature were measured every 30 min throughout the study day.

Psychometric scales

The 5D-ASC questionnaire measures five dimensions of altered states of consciousness: oceanic boundlessness, anxious ego dissolution, changed percept of time, positive basic mood and mania-like experience.

The 5D-ASC scale contains 18 items and measures ego-disintegration, loss of self-control, negative derealization and delusions. It is constructed by adding the scores from the OB, AED and VR scales and retrospectively rating the experience.

The AMRS is a multidimensional psychometric test developed for repeated measurement of mood states. It consists of 60 adjectives depicting mood states and can be subsumed interpretatively to seven domains of affective states.

The STAI consists of two independent scales: a state anxiety scale (STAI X1) and a trait anxiety scale (STAI X2). The STAI X1 was used to assess state anxiety and the STAI X2 was used to assess trait anxiety.

The CANTAB battery is a set of neuropsychological tests used to measure attention, vigilance, associative learning, (visual) working memory and planning. It was used in this study to assess acute effects of pharmacological manipulation on cognitive functions. The RVP task measures sustained visual attention and vigilance, and also involves components of working memory for its successful execution. Predominantly fronto-parietal networks seem to underlie RVP. The PAL test measures recognition of visual patterns under activation of visual-spatial memory functions. It involves conditioned learning and requires both the elaboration of frontal strategies and mnemonic processes. The CANTAB ID/ED test assesses the cognitive capacity to selectively focus attention and the ability to flexibly shift attention to a previously irrelevant stimulus dimension.

Statistics

Statistical calculations were performed using the STATISTICA® for windows computer software version 6.0 (StatSoft, 1995). The 5D-ASC, AMRS and CANTAB data were analysed using univariate repeated measures ANOVA.

Dimensions of altered states of consciousness

Figure 2 shows that pre-treatment with PLA or PIN and treatment with MDMA affected all five dimensions of the 5D-ASC rating scale.

MDMA treatment caused the most pronounced increase of scores in the scales ‘OB’, ‘VR’, ‘AED’, ‘AA’ and ‘RV’. The increase of scores in the 5D-ASC scale ‘Positive Basic Mood’ was primarily based on enhanced scores in the OB-item-cluster ‘Positive Derealization’.

Significant main effects of pre-treatment were found for the 5D-ASC dimensions ‘OB’ and ‘RV’, but not for other 5D-ASC dimensions. Pre-treatment with PIN attenuated score reductions in the OB item-clusters ‘Positive Derealization’, ‘Positive Basic Mood’ and ‘Mania-like Experience’.

Profiles of affective states

After 5 min and 24 h of exposure, neither significant main effects of treatment nor significant main effects of pre-treatment were apparent. However, administration of MDMA alone led to a significant increase of score-sums of the scales ‘excitability’, ‘heightened mood’, ‘sensitivity’ and ‘dreaminess’.

Pre-treatment with pindolol attenuated MDMA-induced ‘dreaminess’ and heightened mood, increased excitability, decreased sensitivity and decreased introversion, but not at t0 + 135 min. A significant treatment x pre-treatment interaction was found for the AMRS scale ‘dreaminess’.

State anxiety

Two-way ANOVAs revealed that medication had a significant effect on state anxiety, but Tukey HSD post hoc tests revealed no significant effect.

Neuropsychological testings

Treatment with MDMA or placebo had no effect on cognitive performance in the RVP task, but pretreatment with pindolol had an effect.

Post hoc analysis revealed that the acute influence of MDMA reduced RVP performance for both the RVP-TH and RVP-A’ test scores, and that the RVP-TH test score was significantly lowered following pre-treatment with pindolol. However, neither the RVP-TE nor RVP-TT test scores differed statistically from the placebo condition.

Acute effects of MDMA on subjective experience, mood and state anxiety

Administration of 1.6 mg MDMA/kg body weight reliably induced alterations of conscious experience in all study subjects. These effects were in good agreement with previous observations. MDMA induces strong affective changes in terms of heightened mood, increased self-awareness and intense feelings of happiness, a profound state of relaxation and an intensified sense of empathy and closeness to others. This is likely due to a role for 5-HT2A receptors in the pharmacodynamic mode of action of MDMA.

In none of our study subjects was anxiety, panic or paranoid thought content acutely seen, nor was state anxiety under MDMA significantly different from placebo levels. A minority of subjects reported temporary tenseness and thought disturbances as well as transient fears of losing control.

Acute effects of MDMA on cognition

Under the acute influence of MDMA, diverse aspects of cognitive function are affected to varying degrees. MDMA induced a pronounced impairment of visual-spatial memory, a marked decline of the ability to maintain sustained attention, and no measurable impact on the more complex executive functions.

Studies have shown that alterations of the serotonergic system cause malfunctions in all aspects of learning involving several types of memory. The cognitive deficits caused by MDMA in humans are in line with these findings, but in some aspects they are in contrast to previous findings.

Selective serotonin reuptake inhibitors have been shown to impair vigilance performance in sustained attention tasks. MDMA-induced elevated serotonergic neurotransmission was found to impair sustained attention, but not short-term selective attention capacity. MDMA-induced facilitation of memory recollection may be responsible for the increased distractability in the RVP task, and the negative correlation between the 5D-ASC subscales ‘facilitated imagination’ and ‘facilitated recollection’ and RVP performance. Pre-treatment with PIN does not significantly improve MDMA-induced deterioration in the PAL task performance, which is in line with results from a recent mechanistic human study investigating the effect of manipulation at the 5-HT1A and 5-HT2A system on vigilance performance.

Contribution of 5-HT1A receptors to the human psychopharmacology of MDMA

Pre-treatment with PIN only had a minor modulating effect on psychometric scales affected by MDMA treatment. It caused a decrease of MDMA-induced positive derealization and a decrease of AMRS scale ‘dreaminess’, but no significant change in cognitive performance.

The 5-HT1A receptor system is known to play an important role in cognitive processing, modulation of mood, and motor behaviour, and it was investigated whether this system contributes to MDMA effects. The influence of the selective 5-HT1A receptor antagonists BMY 7378 and NAN-190 upon MDMA-induced spontaneous tail-flicks in the rat was strictly dose-dependent. The 20 mg pindolol dose we administered might have been too low to sufficiently occupy the targeted receptor sites. MDMA administration likely induced a negative feedback on 5-HT synthesis and release, and pindolol may have masked subtle modulating effects on postsynaptic 5-HT1A receptors.

Animal data on the role of 5-HT1A receptors in the profile of action of MDMA is inconclusive. Further mechanistic receptor blocking studies should be carried out to better understand this issue.