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

This placebo-controlled, randomized, double-blind, cross-over study (n=28) investigated distinct acute autonomic, subjective, and endocrine effects of single doses of LSD (0.1 mg), MDMA (125 mg), D-amphetamine (40 mg) in healthy subjects. The results show that LSD, MDMA and D-amphetamine had different ratings on the 5 Dimensions of Altered States of Consciousness scale (5DASC) and Mystical Experience Questionnaire (MEQ). It also clearly indicates the distinct neurological and behavioural profiles of LSD, MDMA and D-amphetamine.

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.

Authors: Friederike Holze, Patrick Vizeli, Felix Müller, Laura Ley, Raoul Duerig, Nimmy Varghese, Anne Eckert, Stefan Borgwardt & Matthias E. Liechti

Summary

INTRODUCTION

LSD is a serotonergic hallucinogen that has been used recreationally and to a limited extent in psychiatric research. Recent clinical trials indicate that the quality of the acute psychedelic experience predicts long-term changes in mental health and well-being in patients and healthy persons.

MDMA is a psychostimulant that induces feelings of well-being, love, empathy, and prosociality, and mild perceptual alterations. It is often classified as a psychedelic substance, but produces less profound changes in perception compared with classic hallucinogens.

MDMA may be used to assist psychotherapy, but it has not been studied under double-blind conditions in the same study as D-amphetamine and LSD. This study compared the acute effects of these substances in healthy subjects. LSD was used at 0.1 mg, MDMA at 125 mg, and D-Amphetamine at 40 mg. These doses are representative of doses that are used recreationally and in research, and are expected to produce largely similar subjective positive responses, but considerably more adverse effects.

The present study compared the subjective and autonomic effects of three substances over time and determined plasma concentration – time profiles (pharmacokinetics). It also explored the effects of psychedelics on brain-derived neurotrophic factor (BDNF), a biomarker that is linked to neurogenesis.

MATERIALS AND METHODS Study design

In a double-blind, placebo-controlled, cross-over design, 28 healthy participants were exposed to 0.1 mg LSD, 125 mg MDMA, 40 mg D-amphetamine, and placebo. They provided written consent before participating in the study.

Twenty-eight healthy subjects were recruited from the University of Basel. They were excluded if they were younger than 25 years old, pregnant, used medications that may interfere with the study medications, smoked more than 10 cigarettes a day, or used illicit drugs during the study. Previous studies have found no difference in the response to LSD between hallucinogen naive and moderately experienced subjects. However, we excluded frequent substance users because extensive previous uncontrolled experiences may influence/ condition new substance experiences.

Five participants had previously used a hallucinogen, eight had used MDMA, 13 had previously used a stimulant, and eight had never used any illicit drugs with the exception of cannabis.

A psychiatric interview, four 12-h experimental sessions, and an end-of-study visit were conducted. Autonomic and subjective effects were assessed repeatedly throughout the session, and blood was collected to determine endocrine effects and substance concentrations.

LSD, D-Amphetamine sulfate and MDMA hydrochloride were administered as single oral doses in a double-blind study. The participants were asked to retrospectively guess their treatment assignment at the end of each session and at the end of the study.

Subjective effects were assessed repeatedly using visual analog scales (0 – 100%), and were presented as 100-mm horizontal lines (0 – 100%), marked from “not at all” on the left to “extremely” on the right. A 60-item Adjective Mood Rating Scale, a 5D-ASC scale, a 100-item States of Consciousness Questionnaire, and a 49-item Addiction Research Center Inventory were administered to participants before, 1.5, 4, and 11 h after drug administration.

Autonomic effects and adverse effects were measured 1 and 0.5 h before and 11 h after drug administration. Pupil function was assessed under standardized dark-light conditions and a total adverse effects score was calculated.

Oxytocin and BDNF levels were measured at baseline, 1.5, 2.5, 3, and 5 h after MDMA administration. Analyses were performed at the end of the study in one batch.

Plasma drug concentrations were measured at baseline, 1, 1.5, 2, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 9.5, and 11.5 h after drug administration using liquid chromatography-tandem mass spectrometry.

We used repeated measures analysis of variance to determine the peak effects and peak changes from baseline, and then performed Tukey’s post hoc comparisons.

RESULTS

Subjective mood effects were measured over time using VASs. LSD produced a greater overall response than both MDMA and D-amphetamine, reflected by significantly higher increases in ratings of “any drug effect,””good drug effect,””bad drug effect,” and “ego dissolution” compared with MDMA and D-amphetamine.

LSD was the only drug that significantly increased ratings of “blissful state” compared with placebo, MDMA, and D-amphetamine.

LSD increased ratings on all scales of the MEQ43 and MEQ30 compared with MDMA, D-amphetamine, and placebo, with the exception of a decrease on the benzedrine group scale. MDMA and D-amphetamine increased ratings on the benzedrine group scale.

All active substances increased blood pressure, heart rate, and body temperature compared with placebo, but D-amphetamine produced a significantly higher increase in blood pressure compared with LSD and MDMA, and LSD and MDMA produced lower heart rate increases than D-amphetamine over the first 4 h.

The geometric mean maximum concentrations of LSD, O-H-LSD, D-amphetamine, MDMA, MDA, and HMMA were 1.8, 0.12, 1.6, 5.2, and 10.9 ng/ml, respectively, and the corresponding Tmax values were 3.0, 7.0, and 2.8 h, respectively.

The participants correctly identified placebo, LSD, MDMA, and D-amphetamine. MDMA was misclassified as D-amphetamine and vice versa (21%), and LSD was well distinguished from MDMA and D-amphetamine.

DISCUSSION

LSD produced stronger and more distinct subjective effects compared with MDMA and D-amphetamine, including significant alterations of consciousness on all 5D-ASC and MEQ subscales and greater overall subjective effects on the VAS compared with both MDMA and D-amphetamine.

The present study compared the subjective responses to LSD, MDMA, and D-amphetamine using a within-subjects design. The results showed that all drugs produced comparable ratings of “open” and “talkative” on the VAS, and ratings of “drug high,” “drug liking,” and “stimulated” did not differ between LSD and MDMA.

The present findings have clinical implications, as stronger acute responses to LSD on the 5D-ASC scale and MEQ in healthy subjects may predict better therapeutic outcomes in studies of LSD-assisted psychotherapy in patients with anxiety and depression. In the present study, MDMA produced qualitatively similar positive effects compared with LSD, but with lower associated “bad drug effects” and anxiety. Thus, MDMA may favor its use in patients afraid to take LSD or at risk of adverse reaction.

In the present study, MDMA produced distinct subjective emotional effects compared with D-amphetamine, including greater ratings of “any drug effect”, “good drug effect”, “drug high” and “drug liking”, and smaller “benzedrine group” effects on the ARCI.

MDMA increased plasma oxytocin concentrations, but not D-amphetamine, and LSD did not, in contrast to a higher dose of LSD and inactive placebo in a previous study. MDMA and D-amphetamine both produced similar effects, including similar increases in “open” and “talkative” on the VAS, “well-being” and “extraversion” on the AMRS, and a lack of significant “bad drug effects” or “anxiety” compared with placebo and in contrast to LSD.

In the present study, LSD, MDMA, and D-amphetamine produced comparable sympathomimetic activation, body temperature, and pupil size, and similar amounts of total adverse effects. LSD produced greater acute psychological effects than MDMA and D-amphetamine at doses producing comparable somatic adverse responses.

In the present study, plasma drug concentrations were determined for MDMA, D-amphetamine and LSD. LSD concentrations were higher in the present study compared to a previous study that reportedly used the same dose.

The present study had several strengths, including a double-blind, placebo-controlled, within-subjects design, valid pharmacodynamic and substance concentration measurements, and a relatively low dose of LSD compared to MDMA and D-amphetamine. However, the present study also had limitations, including only using one dose level of each substance. Future studies with multiple dose levels and additional outcomes such as imaging are needed to further define ideal dose ranges for LSD, MDMA, and other psychoactive drugs.

The present study found that LSD induces more pronounced alterations of waking consciousness compared with MDMA and D-amphetamine, and that MDMA also shows partly distinct effects compared with D-amphetamine.

Study details

Compounds studied
LSD MDMA

Topics studied
Neuroscience

Study characteristics
Original Placebo-Controlled Active Placebo Double-Blind Within-Subject Randomized

Participants
28 Humans

Authors

Authors associated with this publication with profiles on Blossom

Matthias Liechti
Matthias Emanuel Liechti is the research group leader at the Liechti Lab at the University of Basel.

Felix Müller
Felix Müller is a researcher at the University of Basel. He is leading the research project on psychedelics at the Department of Psychiatry.

Institutes

Institutes associated with this publication

University of Basel
The University of Basel Department of Biomedicine hosts the Liechti Lab research group, headed by Matthias Liechti.

Compound Details

The psychedelics given at which dose and how many times

LSD 100 μg | 1x MDMA 125 mg | 1x

Linked Research Papers

Notable research papers that build on or are influenced by this paper

Effective-connectivity of thalamocortical interactions following d-amphetamine, LSD, and MDMA administration
This re-analysis of a double-blind, placebo-controlled, crossover study (n=25) investigated the effects of LSD, MDMA and dextroamphetamine on brain measures (thalamocortical and corticothalamic interactions in resting-state fMRI data). Compared to placebo, all three substances increased the effective-connectivity from the thalamus to specific unimodal cortices while reducing their influence on the thalamus, revealing increased bottom-up and decreased top-down information flow; LSD uniquely increased effective-connectivity to both unimodal and transmodal cortices.

The effect of lysergic acid diethylamide (LSD) on whole-brain functional and effective connectivity
This brain modelling study used data from two double-blind, randomized controlled trials to model whole-brain effective connectivity (EC) data and compare it to the previously reported functional connectivity (FC) data gathered following LSD administration. LSD decreased brain connectivity and increased self-inhibition in certain brain regions. EC and FC offer promise as clinically-relevant biomarkers for LSD effects.

Characterizing thalamocortical (dys)connectivity following d-amphetamine, LSD, and MDMA administration
This neuroimaging study (n=28) investigated the effects of LSD, d-amphetamine and MDMA on thalamocortical intrinsic functional connectivity (iFC). Each substance elicited auditory-sensorimotor-thalamic-hyperconnectivity compared to placebo, despite predominantly distinct pharmacological actions and subjective effects. LSD produced salience (SAL) hyperactivity whereas MDMA and amphetamine produced hypoconnectivity with SAL. This range of activity is similar to that seen in patients with psychotic disorders.

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

Linked Clinical Trial

Role of Dopamine, Serotonin and 5-HT2A Receptors in Emotion Processing
The study will test the effect of dopamine, serotonin, and direct 5-HT2A receptor stimulation on empathy, mood perception, and amygdala activity to fearful stimuli.