Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects

This placebo-controlled, double-blind, cross-over study (n=24) compared the acute autonomic, subjective, endocrine, and emotional effects of single doses of MDMA (125 mg), methylphenidate (60 mg), modafinil (600 mg) in healthy subjects using psychometric scales, the Facial Emotion Recognition Task (FERT), and the Sexual Arousal and Desire Inventory (SADI). All active drugs induced comparable hemodynamic and adverse effects, but MDMA induced subjective, emotional, sexual, and endocrine effects that were distinctive from those of methylphenidate and modafinil with the doses used.

Abstract

“Rationale 3,4-Methylenedioxymethamphetamine (MDMA) is used recreationally and investigated as an adjunct to psychotherapy. Methylphenidate and modafinil are psychostimulants that are used to treat attention-deficit/hyperactivity disorder and narcolepsy, respectively, but they are also misused as cognitive enhancers. Little is known about differences in the acute effects of equally cardiostimulant doses of these stimulant-type substances compared directly within the same subjects.

Methods We investigated the acute autonomic, subjective, endocrine, and emotional effects of single doses of MDMA (125 mg), methylphenidate (60 mg), modafinil (600 mg), and placebo in a double-blind, cross-over study in 24 healthy participants. Acute drug effects were tested using psychometric scales, the Facial Emotion Recognition Task (FERT), and the Sexual Arousal and Desire Inventory (SADI).

Results All active drugs produced comparable hemodynamic and adverse effects. MDMA produced greater increases in pupil dilation, subjective good drug effects, drug liking, happiness, trust, well-being, and alterations in consciousness than methylphenidate or modafinil. Only MDMA reduced subjective anxiety and impaired fear recognition and led to misclassifications of emotions as happy on the FERT. On the SADI, only MDMA produced sexual arousal-like effects. Only MDMA produced marked increases in cortisol, prolactin, and oxytocin. In contrast to MDMA, methylphenidate increased subjective anxiety, and methylphenidate and modafinil increased misclassifications of emotions as angry on the FERT. Modafinil had no significant subjective drug effects but significant sympathomimetic and adverse effects.

Conclusions MDMA induced subjective, emotional, sexual, and endocrine effects that were clearly distinct from those of methylphenidate and modafinil at the doses used.“

Authors: Patrick C. Dolder, Felix Müller, Yasmin Schmid, Stefan J. Borgwardt & Matthias E. Liechti

Summary

Abstract

MDMA, methylphenidate and modafinil are used recreationally and investigated as an adjunct to psychotherapy, but little is known about their acute effects.

MDMA, methylphenidate, modafinil, and placebo were tested for acute effects on autonomic, subjective, endocrine, and emotional functions in 24 healthy participants.

Results showed that all active drugs produced comparable hemodynamic and adverse effects, but that MDMA produced greater increases in pupil dilation, subjective good drug effects, drug liking, happiness, trust, well-being, and alterations in consciousness than methylphenidate or modafinil.

MDMA, ecstasy, is used recreationally and investigated as an adjunct to psychotherapy for patients with posttraumatic stress disorder. It differs from classic psychostimulants in that it releases serotonin and oxytocin, whereas methylphenidate and modafinil enhance dopaminergic and noradrenergic neurotransmission without affecting serotonin or oxytocin.

MDMA has been extensively studied in healthy subjects, but only rarely compared directly with other orally administered stimulant substances. MDMA induces greater Bempathogenic mood effects, including closeness to others, openness, trust, happiness, and wanting to be with others, compared with oral methylphenidate. MDMA may have unique empathogenic and prosocial effects that are distinct from classic stimulants. In a cross-over study, MDMA was found to produce acute effects that were distinct from those of methylphenidate and modafinil.

Modafinil may have greater wakefulness-promoting effects than methylphenidate, but MDMA may have greater subjective effects than modafinil.

Study design

In 24 subjects, we used a double-blind, placebo-controlled, randomized, cross-over design with four experimental sessions. The washout periods between sessions were at least 7 days.

Participants

Twenty-four healthy subjects were recruited from the University of Basel. Four had used MDMA, two had used cocaine, one had used LSD once, one psilocybin once, and three methylphenidate once or twice, but none had used cannabis. We performed drug tests on female subjects during the follicular phase of their menstrual cycle to account for cyclic changes in reactivity.

Study procedures

A study was conducted on subjects with depression. MDMA, methylphenidate, modafinil, or placebo was administered at 9:45 AM, and autonomic and subjective effects were assessed repeatedly throughout the session.

MDMA hydrochloride was prepared as gelatin capsules with mannitol as the filler, and a single absolute dose of 125 mg was administered. Methylphenidate was administered in a single relatively high dose of 60 mg, and the effects were compared with a lower dose of 40 mg. Modafinil tablets were encapsulated within opaque gelatin capsules and administered in a single high dose of 600 mg to maximize the subjective drug effects.

Measures

Autonomic effects were measured 1 h before and 0 0.3 0.6 1, 1.25, 1.5, 2.5, 3, 4, 5, and 6 h after drug administration.

Subjective effects were assessed repeatedly using visual analog scales (VASs), the AMRS, the STAI, and the German version of the ARCI. The 5-Dimensions of Altered States of Consciousness (5D-ASC) scale was administered 5 h after drug administration to retrospectively rate the effects of the drugs.

Facial emotion recognition task

We used the FERT to measure how sensitive participants were to the effects of MDMA and methylphenidate. The main outcome measure was accuracy, and we also analyzed whether incorrectly identified emotional expressions were misclassified as neutral or other emotions.

Sexual arousal and desire Inventory

The SADI is a self-report scale that includes 54 items and measures subjective sexual arousal and desire. It includes four overlapping factors: BEvaluative, BPhysiological, BNegative/Aversive, and BMotivational.

Substance plasma concentrations

The maximal plasma concentrations of methylphenidate, modafinil, MDMA, and their metabolites were determined using liquid chromatography-mass spectrometry/mass spectrometry.

Statistical analyses

Repeated measures are expressed as peak effects or peak changes from baseline (Emax). ANOVA was used to analyze the data, and Tukey post hoc comparisons were made based on significant main effects.

Autonomic effects

All active substances produced comparable and significant increases in body temperature and similar hemodynamic stimulation, with MDMA producing significantly greater alterations in pupil function than methylphenidate and modafinil.

Subjective effects

MDMA increased subjective ratings for any drug effect, good drug effect, drug liking, happiness, open, trust, feeling close to others, I want to be with other people, and I want to hug someone more than methylphenidate or modafinil. MDMA increased well-being, emotional excitation, extraversion, and introversion on the AMRS, STAI, and ARCI scales compared with placebo, and increased morphine and pentobarbital-chlorpromazine-alcohol group ratings significantly more than methylphenidate and modafinil.

Facial emotion recognition

MDMA, methylphenidate, and modafinil significantly impaired the recognition of fearful faces and increased the misclassification of emotions as happy. However, methylphenidate and modafinil did not alter emotion recognition accuracy for any of the emotions.

Sexual arousal and desire

Data from one subject were missing. MDMA increased scores on the BEvaluative, BPhysiological, and BMotivational scales compared with placebo, but did not influence scores on the BNegative/ Aversive scale.

Substance plasma concentrations

The Cmax values for MDMA, MDA, and HMMA were 192, 9.1, 0.4, and 69.1 -10.0 ng/ml, respectively. The Tmax values were 3.7, 5.7, and 4.2 0.3 h, respectively.

Adverse effects

MDMA, methylphenidate, and modafinil produced significant acute adverse effects compared with placebo, mostly lack of appetite, dry mouth, and headache.

Discussion

The present study found that oral administration of MDMA produced acute subjective, emotional, sensual/sexual, and endocrine effects that were clearly distinct from those of methylphenidate and modafinil at oral doses that produced comparable sympathomimetic stimulant effects. MDMA has unique prosocial and empathogenic effects that are distinct from other stimulants. It also increased well-being, good drug effects, drug liking, happiness, trust, feelings of closeness to others, and wanting to be with others, and reduced state anxiety compared with methylphenidate and modafinil at the doses used.

MDMA releases serotonin and oxytocin and stimulates the noradrenergic system, whereas methylphenidate and modafinil act as dopamine uptake inhibitors. MDMA exerts distinct subjective effects across all of our rating scales compared with methylphenidate and modafinil at the doses used.

MDMA increased plasma concentrations of cortisol, prolactin, and oxytocin, while methylphenidate only slightly increased cortisol concentrations. Modafinil had no effects on cortisol, prolactin, oxytocin, or vasopressin concentrations, which is consistent with previous reports for cortisol.

In the present study, modafinil was administered at a dose of 600 mg, which did not produce significant or relevant subjective effects. However, modafinil increased misclassifications of emotions as angry on the FERT and increased anxiety and aggression in young but not middle-aged healthy volunteers.

Modafinil produced significant subjective good drug effects and drug liking, whereas methylphenidate produced moderate increases in feeling open and close to others compared with placebo.

MDMA increased self-reported sexual desire and arousal, but not methylphenidate or modafinil. This finding is surprising because dopaminergic stimulants have been shown to increase sexual desire and arousal. We previously reported that methylphenidate increased sexual arousal, but not MDMA. The SADI test is a different test that measures sexual arousal and desire, and MDMA increases many sensations that are typically related to sexual stimulation, but without a specific sexual context or related stimuli. The present study has limitations, such as using only one dose of each substance and using high doses of MDMA and methylphenidate. However, all of the drugs produced comparable overall sympathomimetic stimulation as reflected by the similar increase in the peak rate-pressure product. MDMA and methylphenidate had distinct effects at the doses used in the present study, but similar effects were also seen at lower doses. The plasma concentration-time curves were in the expected range based on pharmacokinetic data from other studies.

The use of many psychometric scales may have increased the risk of change findings, but the primary study hypothesis of greater socioemotional effects of MDMA was confirmed.

MDMA produced acute subjective, emotional, and endocrine effects that were distinct from methylphenidate and modafinil at the doses used.