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

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.

Fig. 1

Subjective effects of LSD, MDMA, and d-amphetamine over time on the VASs. The data are expressed as mean ± SEM. LSD produced significantly greater ratings of “any drug effect,” “good drug effect,” “bad drug effect,” and “ego dissolution” compared with MDMA and d-amphetamine. In contrast, LSD reduced ratings of “talkative,” “concentration,” “sense of time,” and “speed of thinking” compared with MDMA and d-amphetamine. MDMA produced greater ratings of “any drug effect,” “good drug effect,” “liking,” “high,” and “ego dissolution” compared with d-amphetamine. The corresponding maximal responses and statistics are shown in Table 1.

Fig. 2

Subjective effects of LSD, MDMA, and d-amphetamine over time on the AMRS. The data are expressed as mean ± SEM changes from baseline. d-Amphetamine increased ratings of activity and concentration compared with LSD. LSD increased ratings of inactivity compared with MDMA and d-amphetamine. LSD increased introversion and reduced extraversion compared with MDMA and d-amphetamine. MDMA and d-amphetamine increased ratings of well-being compared with placebo, whereas LSD produced no significant effect compared with placebo, and its effects did not differ from MDMA or d-amphetamine. LSD significantly increased emotional excitation and anxiety compared with MDMA and D-amphetamine. The corresponding maximal effects and statistics are shown in Table 1.

Fig. 3

Subjective effects of LSD, MDMA, and d-amphetamine on the 5D-ASC scale and MEQ. The data are expressed as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001, vs. placebo. a LSD produced significantly greater ratings on all dimensions and subscales of the 5D-ASC scale compared with MDMA, d-amphetamine, and placebo. The effects of MDMA tended to be greater than d-amphetamine, but these differences were not statistically significant. MDMA produced significant increases only on the blissful state subscale compared with placebo. The effects of d-amphetamine did not differ significantly from placebo on any of the scales. The corresponding maximal effects and statistics are shown in Table S1. b LSD produced significantly higher ratings on all scales of the MEQ43 and MEQ30 compared with MDMA, d-amphetamine, and placebo, with the exception of nonsignificantly different positive mood ratings for LSD and MDMA on the MEQ43. MDMA significantly increased positive mood and ineffability ratings on the MEQ43 and MEQ30 compared with placebo. d-Amphetamine significantly increased positive mood ratings on the MEQ43 and MEQ30, but these effects were significantly lower than MDMA. The corresponding maximal effects and statistics are shown in Table S1.

Fig. 4

Autonomic responses to LSD, MDMA, d-amphetamine, and placebo. The data are expressed as mean ± SEM. All of the active substances produced significant sympathomimetic stimulation, reflected by increases in systolic and diastolic blood pressure, heart rate, body temperature, and pupil size. Importantly, the overall hemodynamic response, expressed as the rate–pressure product, was similarly increased by all of the active substances compared with placebo. However, d-amphetamine produced significantly higher increases in blood pressure than LSD and MDMA. Conversely, LSD and MDMA produced greater increases in heart rate than d-amphetamine during the first 4 h. The corresponding maximal effects and statistics are shown in Table 1.