Anxiety DisordersHealthy VolunteersNeurocognitive DisordersMedicinal Chemistry & Drug DevelopmentLSDPsilocybin

Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects

In a double‑blind crossover study in 28 healthy participants, high‑dose LSD (100–200 µg) and 30 mg psilocybin produced qualitatively and quantitatively similar acute subjective effects, with LSD showing longer duration and the 200 µg dose causing greater ego‑dissolution, cognitive impairment and anxiety. Cardiovascular responses differed (psilocybin raised blood pressure more, LSD increased heart rate more) but overall cardiostimulant load was comparable, indicating differences are dose‑dependent rather than substance‑specific and guiding dose selection for future research.

Authors

  • Patrick Vizeli
  • Felix Müller
  • Matthias Liechti

Published

Neuropsychopharmacology
individual Study

Abstract

Growing interest has been seen in using lysergic acid diethylamide (LSD) and psilocybin in psychiatric research and therapy. However, no modern studies have evaluated differences in subjective and autonomic effects of LSD and psilocybin or their similarities and dose equivalence. We used a double-blind, randomized, placebo-controlled, crossover design in 28 healthy subjects (14 women, 14 men) who underwent five 25 h sessions and received placebo, LSD (100 and 200 µg), and psilocybin (15 and 30 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales for subjective effects, autonomic effects, adverse effects, effect durations, plasma levels of brain-derived neurotrophic factor (BDNF), prolactin, cortisol, and oxytocin, and pharmacokinetics. The doses of 100 and 200 µg LSD and 30 mg psilocybin produced comparable subjective effects. The 15 mg psilocybin dose produced clearly weaker subjective effects compared with both doses of LSD and 30 mg psilocybin. The 200 µg dose of LSD induced higher ratings of ego-dissolution, impairments in control and cognition, and anxiety than the 100 µg dose. The 200 µg dose of LSD increased only ratings of ineffability significantly more than 30 mg psilocybin. LSD at both doses had clearly longer effect durations than psilocybin. Psilocybin increased blood pressure more than LSD, whereas LSD increased heart rate more than psilocybin. However, both LSD and psilocybin showed comparable cardiostimulant properties, assessed by the rate-pressure product. Both LSD and psilocybin had dose-proportional pharmacokinetics and first-order elimination. Both doses of LSD and the high dose of psilocybin produced qualitatively and quantitatively very similar subjective effects, indicating that alterations of mind that are induced by LSD and psilocybin do not differ beyond the effect duration. Any differences between LSD and psilocybin are dose-dependent rather than substance-dependent. However, LSD and psilocybin differentially increased heart rate and blood pressure. These results may assist with dose finding for future psychedelic research.

Available with Blossom Pro

Research Summary of 'Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects'

Introduction

Both lysergic acid diethylamide (LSD) and psilocybin are classical serotonergic psychedelics under renewed investigation for psychiatric and neurologic indications. Previous human research has typically examined either LSD or psilocybin in isolation; differences in their acute subjective, autonomic and endocrine effects, and their dose equivalence, remain unclear. Pharmacologically, both act via 5-HT2A receptor agonism, but LSD has additional dopaminergic activity and psilocin (the active metabolite of psilocybin) inhibits the serotonin transporter, raising the question of whether these receptor-profile differences translate into distinct human effects. Holze and colleagues set out to directly compare acute effects of LSD and psilocybin within the same subjects. Using two doses of each substance and placebo, the study aimed to characterise subjective altered states (with validated psychometric instruments), autonomic and endocrine responses, adverse effects, pharmacokinetics (plasma LSD and psilocin up to 24 h), and effect durations, thereby informing dose-finding and safety considerations for future clinical research.

Expert Research Summaries

Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.

See Pro PlansAlready have an account? Sign in

Study Details

References (30)

Papers cited by this study that are also in Blossom

Trial of Psilocybin versus Escitalopram for Depression

Carhart-Harris, R. L., Giribaldi, B., Watts, R. et al. · New England Journal of Medicine (2021)

927 cited
LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects

Kirchner, K. · Journal of Psychopharmacology (2014)

389 cited
Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin

Schindler, E. A. D., Sewell, R. A., Gottschalk, C. H. et al. · Neurotherapeutics (2021)

Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects

Holze, F., Vizeli, P., Ley, L. et al. · Neuropsychopharmacology (2020)

192 cited
Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action

Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A. et al. · NeuroReport (1998)

The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation

Preller, K. H., Herdener, M., Pokorny, T. et al. · Current Biology (2017)

Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens

Rickli, A., Moning, O. D., Hoener, M. C. et al. · European Neuropsychopharmacology (2016)

Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: similarities and differences in subjective experiences

Carbonaro, T. M., Hurwitz, E., Johnson, M. W. · Psychopharmacology (2017)

102 cited
Modern clinical research on LSD

Liechti, M. E. · Neuropsychopharmacology (2017)

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults

Brown, R. T., Nicholas, C. R., Cozzi, N. V. et al. · Clinical Pharmacokinetics (2017)

Show all 30 references
High dose psilocybin is associated with positive subjective effects in healthy volunteers

Nicholas, C. R., Henriquez, K. M., Gassman, M. C. et al. · Journal of Psychopharmacology (2018)

61 cited
Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study

Hasler, F., Grimberg, U., Benz, M. A. et al. · Psychopharmacology (2004)

181 cited
Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression

Roseman, L., Nutt, D. J., Carhart-Harris, R. L. · Frontiers in Pharmacology (2018)

Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial

Ross, S., Bossis, A. P., Guss, J. et al. · Journal of Psychopharmacology (2016)

Psilocybin-occasioned mystical experiences in the treatment of tobacco addiction

Garcia-Romeu, A., Griffiths, R. R., Johnson, M. W. · Current Drug Abuse Reviews (2015)

Pharmacokinetics and subjective effects of a novel oral LSD formulation in healthy subjects

Holze, F., Duthaler, U., Vizeli, P. et al. · British Journal of Clinical Pharmacology (2019)

Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels

Madsen, M. K., Fisher, P. M., Burmester, D. et al. · Neuropsychopharmacology (2019)

Acute effects of lysergic acid diethylamide in healthy subjects

Schmid, Y., Enzler, F., Gasser, P. et al. · Biological Psychiatry (2015)

Psychedelics promote structural and functional neural plasticity

Ly, C., Greb, A. C., Cameron, L. P. et al. · Cell Reports (2018)

Modulation of Serum Brain-Derived Neurotrophic Factor by a Single Dose of Ayahuasca: Observation From a Randomized Controlled Trial

Galvão-Coelho, N. L., de Almeida, R. N., de Menezes Galvão, A. C. et al. · Frontiers in Psychology (2019)

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

Holze, F., Vizeli, P., Müller, F. et al. · Neuropsychopharmacology (2019)

214 cited
Psychometric evaluation of the altered states of consciousness rating scale (OAV)

Studerus, E., Gamma, A., Vollenweider, F. X. · PLOS ONE (2010)

Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin

Barrett, F. S., Johnson, M. W., Griffiths, R. R. · Journal of Psychopharmacology (2015)

Effects of a β-blocker on the cardiovascular response to MDMA (Ecstasy)

Hysek, C. M., Vollenweider, F. X., Liechti, M. E. · BMJ Open (2010)

47 cited
Acute effects of psilocybin after escitalopram or placebo pretreatment in a randomized, double-blind, placebo-controlled, cross-over study in healthy subjects

Becker, A. M., Holze, F., Grandinett, T. et al. · Clinical Pharmacology and Therapeutics (2021)

Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies

Studerus, E., Kometer, M., Hasler, F. et al. · Journal of Psychopharmacology (2010)

423 cited
Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study

Carhart-Harris, R. L., Bolstridge, M., Rucker, J. et al. · Lancet Psychiatry (2016)

1174 cited
Optimal dosing for psilocybin pharmacotherapy: Considering weight-adjusted and fixed dosing approaches

Garcia-Romeu, A., Barrett, F. S., Carbonaro, T. M. et al. · Journal of Psychopharmacology (2021)

Safety pharmacology of acute LSD administration in healthy subjects

Holze, F., Caluori, T. V., Vizeli, P. et al. · Psychopharmacology (2021)

Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide in healthy subjects

Dolder, P. C., Schmid, Y., Steuer, A. E. et al. · Clinical Pharmacokinetics (2017)

Cited By (65)

Papers in Blossom that reference this study

Mystical Experience Induced by Esketamine Treatment: A Real-World Observational Study

Mallevays, M., Fuet, L., Danon, M. et al. · MedRvix (2026)

Mystical dynamics: renewal, luminous light, and ego disintegration as key features associated with mystical oneness—a psychometric analysis using the PES100 in controlled psychedelic studies

Stocker, K., Hartmann, M., Barrett, F. S. et al. · Religion, Brain & Behavior (2026)

Mixed-methods analysis on psychedelic-augmented meditation experiences from a randomized controlled mindfulness retreat

Schlomberg, J. T. T., Meling, D., Grylka, R. et al. · Scientific Reports (2026)

Psychedelic therapy and postpartum depression: priorities and prospects

Thuery, G., Crossen, F., Mc Loone, D. et al. · Therapeutic Advances in Psychopharmacology (2026)

Trip sitting or just sitting? Session facilitators substantially influence psychedelic experiences in clinical trials but not in healthy ones

Goldy, S. P., Sepeda, N. D., Hilbert, S. N. et al. · Psychiatry Research (2026)

1 cited
Effects of LSD and Psilocybin on Heart Rate in Patients Receiving Psychedelic Treatment for Depressive and Anxiety Disorders: A Retrospective Observational Study

Cheng, M., Aboulafia-Brakha, T., Buchard, A. et al. · Psychology International (2025)

Acute experiences and persisting psychological effects associated with an encapsulated DMT-harmala alkaloid combination: results of a phase 1 study

Perkins, D., Halman, A., Urokohara, A. et al. · Scientific Reports (2025)

A novel psychedelic 5-HT2A receptor agonist GM-2505: The pharmacokinetic, safety, and pharmacodynamic profile from a randomized trial healthy volunteer

Marek, G. J., Makai-Bölöni, S., Umbricht, D. et al. · Journal of Psychopharmacology (2025)

Efficacy and safety of low- versus high-dose-LSD-assisted therapy in patients with major depression: A randomized trial

Mu, F., Zaczek, H., Becker, A. M. et al. · Med (2025)

7 cited
Molecular, haemodynamic, and functional effects of LSD in the human brain

McCulloch, D. E-W., Larsen, K., Johansen, A. et al. · MedRvix (2025)

Show all 65 papers
Pilot Data on Salivary Oxytocin as a Biomarker of LSD Response in Patients with Major Depressive Disorder

Cazorla, L., Alaux, S., Amberger, C. et al. · Preprints (2025)

Absolute Oral Bioavailability and Bioequivalence of LSD Base and Tartrate in a Double-Blind, Placebo-Controlled, Crossover Study

Arikci, D., Holze, F., Mueller, L. et al. · Clinical Pharmacology and Therapeutics (2025)

1 cited
Rapid and sustained antidepressant effects of vaporized N,N-dimethyltryptamine: a phase 2a clinical trial in treatment-resistant depression

Falchi-Carvalho, M., Palhano-Fontes, F., Wießner, I. et al. · Neuropsychopharmacology (2025)

Pharmacokinetics and pharmacodynamics of sublingual microdosed lysergic acid diethylamide in healthy adult volunteers

Morse, D. J., Jeong, S. H., Murphy, R. J. et al. · Journal of Psychopharmacology (2025)

The Role of the Dorsolateral Prefrontal Cortex in Ego Dissolution and Emotional Arousal During the Psychedelic State

Coleman, J. A., Shinozuka, K., Tromm, R. et al. · Human Brain Mapping (2025)

Insights on Psychedelics: A Systematic Review of Therapeutic Effects

Kugel, J., Laukkonen, R., Yaden, D. B. et al. · Neuroscience and Biobehavioral Reviews (2025)

Acute Effects and Pharmacokinetics of LSD after Paroxetine or Placebo Pre-Administration in a Randomized, Double-Blind, Cross-Over Phase I Trial

Becker, A. M., Humbert-Droz, M., Mueller, L. et al. · Clinical Pharmacology and Therapeutics (2025)

Single-dose psilocybin therapy for alcohol use disorder: Pharmacokinetics, feasibility, safety and efficacy in an open-label study

Fink-Jensen, A., Jensen, M. E., Stenbæk, D. S. et al. · Journal of Psychopharmacology (2025)

Acute psilocybin and ketanserin effects on cerebral blood flow: 5-HT2AR neuromodulation in healthy humans

Larsen, K., Lindberg, U., Ozenne, B. et al. · Journal of Cerebral Blood Flow and Metabolism (2025)

Acute dose-dependent effects and self-guided titration of continuous N,N-dimethyltryptamine infusions in a double-blind placebo-controlled study in healthy participants

Erne, L., Vogt, S. B., Müller, L. et al. · Neuropsychopharmacology (2024)

9 cited
Synergistic, multi-level understanding of psychedelics: three systematic reviews and meta-analyses of their pharmacology, neuroimaging and phenomenology

Shinozuka, K., Jerotic, K., Mediano, P. A. M. et al. · Translational Psychiatry (2024)

Effects of psychoplastogens on blood levels of brain-derived neurotrophic factor (BDNF) in humans: a systematic review and meta-analysis

Calder, A. E., Hase, A., Hasler, G. · Molecular Psychiatry (2024)

Neuroplasticity and Psychedelics: a comprehensive examination of classic and non-classic compounds in pre and clinical models

Agnorelli, C., Spriggs, M. J., Godfrey, K. et al. · Preprints (2024)

Safety pharmacology of acute mescaline administration in healthy participants

Klaiber, A., Humbert‐Droz, M., Ley, L. et al. · British Journal of Clinical Pharmacology (2024)

4 cited
Enhanced visual contrast suppression during peak psilocybin effects: Psychophysical results from a pilot randomized controlled trial

Swanson, L. R., Jungers, S., Varghese, R. et al. · Journal of Vision (2024)

Psilocybin-assisted neurofeedback for the improvement of executive functions: a randomized semi-naturalistic-lab feasibility study

Enriquez-Geppert, S,, Lietz, M. P., O'Higgins, F. · Philosophical Transactions of the Royal Society B (2024)

Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects

Klaiber, A., Schmid, Y., Becker, A. M. et al. · Translational Psychiatry (2024)

13 cited
Naturalistic psychedelic therapy: The role of relaxation and subjective drug effects in antidepressant response

Calder, A. E., Rausch, B., Liechti, M. E. et al. · Journal of Psychopharmacology (2024)

Co-administration of midazolam and psilocybin: Differential effects on subjective quality versus memory of the psychedelic experience

Nicholas, C. R., Banks, M. I., Lennertz, R. L. et al. · Translational Psychiatry (2024)

Pharmacological and non-pharmacological predictors of the LSD experience in healthy participants

Vizeli, P., Studerus, E., Holze, F. et al. · Translational Psychiatry (2024)

Acute effects of R-MDMA, S-MDMA, and racemic MDMA in a randomized double-blind cross-over trial in healthy participants

Straumann, I., Avedisian, I., Klaiber, A. et al. · Neuropsychopharmacology (2024)

11 cited
Ketamine induces multiple individually distinct whole-brain functional connectivity signatures

Moujaes, F., Lisa, J., Rahmati, M. et al. · eLife (2024)

The potential of 5-methoxy-N,N-dimethyltryptamine in the treatment of alcohol use disorder: A first look at therapeutic mechanisms of action

Tap, S. C. · Addiction Biology (2024)

Salience, Sensemaking, and Setting in Psilocybin Microdosing: Methodological Lessons and Preliminary Findings of a Mixed Method Qualitative Study

Oblak, A., Korošec Hudnikr, L., Levačić, A. et al. · OSF Preprints (2024)

Safety and tolerability of inhaled N,N-Dimethyltryptamine (BMND01 candidate): A phase I clinical trial

Falchi, M., Wießner, I., Silva, S. R. B. et al. · European Neuropsychopharmacology (2024)

18 cited
Effects of hallucinogenic drugs on the human heart

Neumann, J., Dhein, S., Kirchhefer, U. et al. · Frontiers in Pharmacology (2024)

Synthetic surprise as the foundation of the psychedelic experience

De Filippo, R., Schmitz, D. · Neuroscience and Biobehavioral Reviews (2024)

Neural complexity is increased after low doses of LSD, but not moderate to high doses of oral THC or methamphetamine

Murray, C., Frohlich, J, Haggarty, C. J., Tare, I. et al. · Neuropsychopharmacology (2024)

Potential therapeutic effects of an ayahuasca-inspired N,N-DMT and harmine formulation: a controlled trial in healthy subjects

Aicher, H. D., Mueller, M. J., Dornbierer, D. A. et al. · Frontiers in Psychiatry (2024)

24 cited
Safety pharmacology of acute psilocybin administration in healthy participants

Straumann, I., Holze, F., Becker, A. M. et al. · Neuroscience Applied (2024)

15 cited
Perceptions of psychedelic personality change, determinants of use, setting and drug moderation: Toward a holistic model

Weiss, B., Sleep, C., Beller, N. et al. · Journal of Psychedelic Studies (2023)

10 cited
5-MeO-DMT: An atypical psychedelic with unique pharmacology, phenomenology & risk?

Dourron, H. M., Nichols, C. D., Simonsson, O. et al. · Psychopharmacology (2023)

18 cited
Psilocybin-assisted neurofeedback for the improvement of executive functions: a semi-naturalistic-lab feasibility study

Enriquez-Geppert, S,, Krc, J., O'Higgins, F., Lietz, M. P. · OSF Preprints (2023)

Pharmacokinetics, pharmacodynamics and urinary recovery of oral lysergic acid diethylamide (LSD) administration in healthy participants

Friederike, H., Liechti, M. E., Holze, F. et al. · British Journal of Clinical Pharmacology (2023)

The risk of chronic psychedelic and MDMA microdosing for valvular heart disease

Tagen, M., Mantuani, D., Van Heerden, L. et al. · Journal of Psychopharmacology (2023)

Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication

Goodwin, G. M., Croal, M., Feifel, D. et al. · Neuropharmacology (2023)

Interactive Effects of Ayahuasca and Cannabidiol in Social Cognition in Healthy Volunteers: A Pilot, Proof-of-Concept, Feasibility, Randomized-Controlled Trial

Rossi, G. N., Rocha, J. M., Osório, F. L. et al. · Journal of Clinical Psychopharmacology (2023)

Assessment of the acute effects of 2C-B vs psilocybin on subjective experience, mood and cognition

Mallaroni, P., Mason, N. L., Reckweg, J. T. et al. · Clinical Pharmacology and Therapeutics (2023)

39 cited
Acute effects of MDMA and LSD co-administration in a double-blind placebo-controlled study in healthy participants

Straumann, I., Ley, L., Holze, F. et al. · Neuropsychopharmacology (2023)

27 cited
Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants

Ley, L., Holze, F., Arikci, D. et al. · Neuropsychopharmacology (2023)

138 cited
Acute effects of intravenous DMT in a randomized placebo-controlled study in healthy participants

Vogt, S. B., Ley, L., Erne, L. et al. · Translational Psychiatry (2023)

64 cited
Dose-response relationships of LSD-induced subjective experiences in humans

Prugger, J., Hirschfeld, T., Majic, T. et al. · Neuropsychopharmacology (2023)

19 cited
Investigation of self-treatment with lysergic acid diethylamide and psilocybin mushrooms: Findings from the Global Drug Survey 2020

Kopra, E., Ferris, J. A., Winstock, A. R. et al. · Journal of Psychopharmacology (2023)

Can psychedelics enhance group psychotherapy? A discussion on the therapeutic factors

Ponomarenko, P., Seragnoli, F., Calder, A. et al. · Journal of Psychopharmacology (2023)

Therapeutic effect of psilocybin in addiction: A systematic review

van der Meer, P. B., Fuentes, J. J., Kaptein, A. A. et al. · Frontiers in Psychiatry (2023)

Lysergic acid diethylamide-assisted therapy in patients with anxiety with and without a life-threatening illness A randomized, double-blind, placebo-controlled Phase II study

Holze, F., Gasser, P., Müller, F. et al. · Biological Psychiatry (2023)

Classic psychedelics do not affect T cell and monocyte immune responses

Rudin, D., Areesanan, A., Liechti, M. E. et al. · Frontiers in Psychiatry (2023)

Among psychedelic-experienced users, only past use of psilocybin reliably predicts nature relatedness

Forstmann, M., Kettner, H. S., Sagioglou, C. et al. · Journal of Psychopharmacology (2023)

Pharmacokinetics and pharmacodynamics of oral psilocybin administration in healthy participants

Holze, F., Becker, A. M., Kolaczynska, K. E. et al. · Clinical Pharmacology and Therapeutics (2022)

Altered States of Consciousness During Ceremonial San Pedro Use

Bohn, A., Kiggen, M. H. H., Uthaug, M. V. et al. · International Journal for the Psychology of Religion (2022)

Evidence for tolerance in psychedelic microdosing from the self-blinding microdose trial

Baumann, S., Carhart-Harris, R. L., Nutt, D. J. et al. · Psyarxiv (2022)

Scoping Review of Experiential Measures from Psychedelic Research and Clinical Trials

Herrmann, Z., Earleywine, M., De Leo, J. et al. · Journal of Psychoactive Drugs (2022)

Towards an understanding of psychedelic-induced neuroplasticity

Calder, A. E., Hasler, G. · Neuropsychopharmacology (2022)

Psychedelic drug abuse potential assessment research for new drug applications and Controlled Substances Act scheduling

Henningfield, J. E., Coe, M. A., Griffiths, R. R. et al. · Neuropharmacology (2022)

Pharmacological, Neural, and Psychological Mechanisms underlying Psychedelics: A Critical Review

van Elk, M., Yaden, D. B. · Neuroscience and Biobehavioral Reviews (2022)

Your Personal Research Library

Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.

See Pro PlansSign in