Distinct acute effects of LSD, MDMA, and d-amphetamine in healthy subjects
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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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MDMA does not produce mystical-type experiences as measured using a variety of scales related to altered states of consciousness.
“it does not produce mystical-type experiences as measured using a variety of scales related to altered states of consciousness”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [241]
The Discussion reports that MDMA produced only minimal alterations of consciousness compared with LSD, supporting the claim’s general contrast. But the Results report significant increases in positive mood and ineffability on the Mystical Experience Questionnaires and in blissful state on the 5D-ASC. The categorical statement that MDMA does not produce mystical-type experiences overstates these findings. Page numbers were not provided in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMDMA's ability to enhance social bonding is thought to be driven by its stimulation of oxytocin release, which increases prosocial feelings, greater trust in interpersonal interactions, and openness to social reward and connectedness.
“MDMA’s ability to enhance social bonding is thought to be driven by its stimulation of oxytocin release (84), which increases prosocial feelings (85), greater trust in interpersonal interactions (86), and openness to social reward and connectedness (87).”
From Psychoanalytically informed MDMA-assisted therapy for pathological narcissism: a novel theoretical approach (2025) · cites this paper as [84]
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de Deus Pontual, A. A., Senhorini, H. G., Corradi-Webster, C. M., Tófoli, L. F., & Daldegan-Bueno, D. (2023) · Journal of Psychoactive Drugs · doi:10.1080/02791072.2022.2079108 · Cited by 36 · see citing works
Okano, L., Jones, G., Deyo, B., Brandenburg, A., & Hale, W. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.965641 · Cited by 24 · see citing works
Stocker, K., & Liechti, M. E. (2024) · Journal of Psychopharmacology · doi:10.1177/02698811241265352 · Cited by 19 · see citing works
Self-citationJian-min, C., Zhi-yuan, W., Shi-xuan, W., Rui, S., Ning, W., & Jin, L. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.885574 · Cited by 7 · see citing works
“Lisdexamfetamine, the first prodrug approved for ADHD (16, 17) and binge eating disorder (18) treatment, is synthesized by covalently linking d-amphetamine to the amino acid l-lysine (19).”
BackgroundMethodAlbert, A. E., & Back, A. L. (2025) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1529427 · Cited by 6 · see citing works
- Authors
- Holze, F., Vizeli, P., Müller, F., Ley, L., Duerig, R., Varghese, N., Eckert, A., Borgwardt, S., & Liechti, M. E.
- Affiliations
- University of Basel (CH)
- Corresponding author
- Liechti, Matthias E.
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2019-11-16
- Volume
- 45
- Issue
- 3
- Pages
- 462-471
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC6969135
- OpenAlex
- W2983486486
- Cited by
- 247
- References
- 71
- Citations by year
- 2026: 21 · 2025: 43 · 2024: 45 · 2023: 37 · 2022: 51 · 2021: 29 · 2020: 20
- FWCI
- 28.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Neuropsychopharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- edoc (University of Basel) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (320030_170249)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
- Keywords
- lysergic acid diethylamide, MDMA, d-amphetamine, psychedelics, stimulants, autonomic responses, heart rate, blood pressure, pupil size, body temperature, altered states of consciousness, mystical experience, ego dissolution, concentration difficulties, oxytocin, brain-derived neurotrophic factor, dose-finding
- MeSH terms
- Adult, Affect, Central Nervous System Stimulants, Consciousness, Dextroamphetamine, Double-Blind Method, Female, Hallucinogens, Humans, Lysergic Acid Diethylamide, Male, Middle Aged, Retrospective Studies, Time Factors, Cross-Over Studies, N-Methyl-3,4-methylenedioxyamphetamine, Healthy Volunteers
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