Anxiety DisordersHealthy VolunteersNeurocognitive DisordersMedicinal Chemistry & Drug DevelopmentLSDMDMA

Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects.

In a randomised, double-blind, cross-over study in 28 healthy subjects, single doses of LSD (0.1 mg), MDMA (125 mg) and d-amphetamine (40 mg) produced similar autonomic responses but clearly distinct subjective and endocrine profiles. LSD caused the strongest alterations of consciousness, ego dissolution, cognitive impairment and anxiety; MDMA produced the most positive/empathetic effects and increased plasma oxytocin; d-amphetamine primarily raised blood pressure and enhanced activity and concentration, while none of the drugs altered plasma BDNF — results that can inform dose-finding in substance-assisted psychotherapy.

Authors

  • Patrick Vizeli
  • Stefan Borgwardt
  • Felix Müller

Published

Neuropsychopharmacology
individual Study

Abstract

Lysergic acid diethylamide (LSD) is a classic psychedelic, 3,4-methylenedioxymethamphetamine (MDMA) is an empathogen, and d-amphetamine is a classic stimulant. All three substances are used recreationally. LSD and MDMA are being investigated as medications to assist psychotherapy, and d-amphetamine is used for the treatment of attention-deficit/hyperactivity disorder. All three substances induce distinct acute subjective effects. However, differences in acute responses to these prototypical psychoactive substances have not been characterized in a controlled study. We investigated the acute autonomic, subjective, and endocrine effects of single doses of LSD (0.1 mg), MDMA (125 mg), d-amphetamine (40 mg), and placebo in a randomized, double-blind, cross-over study in 28 healthy subjects. All of the substances produced comparable increases in hemodynamic effects, body temperature, and pupil size, indicating equivalent autonomic responses at the doses used. LSD and MDMA increased heart rate more than d-amphetamine, and d-amphetamine increased blood pressure more than LSD and MDMA. LSD induced significantly higher ratings on the 5 Dimensions of Altered States of Consciousness scale and Mystical Experience Questionnaire than MDMA and d-amphetamine. LSD also produced greater subjective drug effects, ego dissolution, introversion, emotional excitation, anxiety, and inactivity than MDMA and d-amphetamine. LSD also induced greater impairments in subjective ratings of concentration, sense of time, and speed of thinking compared with MDMA and d-amphetamine. MDMA produced greater ratings of good drug effects, liking, high, and ego dissolution compared with d-amphetamine. d-Amphetamine increased ratings of activity and concentration compared with LSD. MDMA but not LSD or d-amphetamine increased plasma concentrations of oxytocin. None of the substances altered plasma concentrations of brain-derived neurotrophic factor. These results indicate clearly distinct acute effects of LSD, MDMA, and d-amphetamine and may assist the dose-finding in substance-assisted psychotherapy research.

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Research Summary of 'Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects.'

Introduction

Holze and colleagues situate LSD, MDMA, and D-amphetamine as representative compounds of three pharmacological classes that are both used recreationally and being investigated clinically: LSD as a classic serotonergic hallucinogen acting principally at 5-HT2A receptors, MDMA as an empathogen/entactogen with serotonergic and noradrenergic effects and oxytocin release, and D-amphetamine as a prototypical psychostimulant acting primarily via dopamine and norepinephrine. The authors note that acute subjective experiences differ between these substances and that the magnitude and quality of psychedelic experiences (for example on measures of mystical-type experiences) have been linked in prior work with longer-term therapeutic outcomes, but that direct head-to-head, double-blind comparisons of their acute autonomic, subjective, and endocrine effects within the same participants are lacking. The primary aim of the study was to characterise and compare the acute autonomic, subjective, endocrine, and pharmacokinetic profiles of single oral doses of LSD (0.1 mg), MDMA (125 mg), and D-amphetamine (40 mg) versus placebo in a within-subject, double-blind, placebo-controlled crossover design. The investigators hypothesised that LSD would produce stronger and qualitatively different alterations of waking consciousness (measured by the 5D-ASC scale and MEQ) than MDMA and D-amphetamine, that MDMA would produce distinct emotional effects and increase plasma oxytocin more than the other drugs, and that none of the drugs would necessarily alter plasma brain-derived neurotrophic factor (BDNF) at the tested doses. The authors framed the head-to-head approach as also improving blinding compared with prior studies that used inactive placebo comparators.

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Study Details

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