Ketanserin reverses the acute response to LSD in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects
In a randomized, double-blind, placebo-controlled crossover study in 24 healthy subjects, a single 40 mg oral dose of the 5‑HT2A antagonist ketanserin given one hour after 100 µg LSD rapidly reversed the acute psychedelic response—shortening subjective effect duration from 8.5 to 3.5 hours and attenuating visual/auditory alterations, ego dissolution, cardiovascular effects and mydriasis—without altering LSD pharmacokinetics or BDNF elevations. These findings support that LSD’s acute effects depend on 5‑HT2A receptor occupancy and indicate ketanserin can serve as a planned or rescue agent to shorten or mitigate LSD experiences in research and therapy.
Authors
- Matthias Liechti
- Friederike Holze
- Nikhil Varghese
Published
Abstract
Background
Lysergic acid diethylamide (LSD) is currently being investigated in psychedelic-assisted therapy. LSD has a long duration of acute action of 8–11 hours. It produces its acute psychedelic effects via stimulation of the serotonin 5-hydroxytryptamine-2A (HT2A) receptor. Administration of the 5-HT2A antagonist ketanserin before LSD almost fully blocks the acute subjective response to LSD. However, unclear is whether ketanserin can also reverse the effects of LSD when administered after LSD.
Methods
We used a double-blind, randomized, placebo-controlled, crossover design in 24 healthy participants who underwent two 14-hour sessions and received ketanserin (40 mg p.o.) or placebo 1 hour after LSD (100 µg p.o.). Outcome measures included subjective effects, autonomic effects, acute adverse effects, plasma brain-derived neurotrophic factor levels, and pharmacokinetics up to 12 hours.
Results
Ketanserin reversed the acute response to LSD, thereby significantly reducing the duration of subjective effects from 8.5 hours with placebo to 3.5 hours. Ketanserin also reversed LSD-induced alterations of mind, including visual and acoustic alterations and ego dissolution. Ketanserin reduced adverse cardiovascular effects and mydriasis that were associated with LSD but had no effects on elevations of brain-derived neurotrophic factor levels. Ketanserin did not alter the pharmacokinetics of LSD.
Conclusions
These findings are consistent with an interaction between ketanserin and LSD and the view that LSD produces its psychedelic effects only when occupying 5-HT2A receptors. Ketanserin can effectively be used as a planned or rescue option to shorten and attenuate the LSD experience in humans in research and LSD-assisted therapy. Trial registry ClinicalTrials.gov (NCT04558294)
Research Summary of 'Ketanserin reverses the acute response to LSD in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects'
Introduction
Classic serotonergic psychedelics such as lysergic acid diethylamide (LSD) and psilocybin are under investigation as adjuncts to psychotherapy. Both produce their acute subjective effects primarily via activation of the serotonin 5-HT2A receptor, but LSD has a substantially longer acute duration (typically ~8.5–11 h at common doses) than psilocybin. Ketanserin, a 5-HT2A antagonist with additional affinity for adrenergic α1A and histamine H1 receptors, reliably prevents the subjective effects of psychedelics when given before dosing, but it is unknown whether ketanserin can attenuate or shorten an LSD experience once the psychedelic effects are already established. The question is clinically relevant because a safe, effective antagonist could shorten long sessions or serve as an emergency rescue medication for intolerable acute effects. Becker and colleagues therefore tested the predefined hypothesis that oral ketanserin (40 mg) administered 1 hour after oral LSD (100 µg) would shorten the subjective response to LSD. The primary outcome was the duration of the subjective effect as measured by a visual analogue scale (VAS) for “any drug effect.” Secondary measures included other subjective scales, autonomic measures, plasma biomarkers (BDNF), and pharmacokinetic assessments to examine whether ketanserin’s effects occur despite continued systemic presence of LSD.
Expert Research Summaries
Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.
Full Text PDF
Full Paper PDF
Create a free account to open full-text PDFs.
Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Becker, A. M., Klaiber, A., Holze, F., Istampoulouoglou, I., Duthaler, U., Varghese, N., Eckert, A., & Liechti, M. E. (2023). Ketanserin reverses the acute response to LSD in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects. International Journal of Neuropsychopharmacology, 26(2), 97-106. https://doi.org/10.1093/ijnp/pyac075
References (20)
Papers cited by this study that are also in Blossom
Barrett, F. S., Johnson, M. W., Griffiths, R. R. · Journal of Psychopharmacology (2015)
Cao, D., Yu, J., Wang, H. et al. · Science (2022)
Carhart-Harris, R. L., Giribaldi, B., Watts, R. et al. · New England Journal of Medicine (2021)
Grob, C. S., Danforth, A. L., Chopra, G. S. et al. · JAMA Psychiatry (2011)
Hesselgrave, N., Troppoli, T. A., Wulff, A. B. et al. · PNAS (2021)
Holze, F., Duthaler, U., Vizeli, P. et al. · British Journal of Clinical Pharmacology (2019)
Holze, F., Vizeli, P., Müller, F. et al. · Neuropsychopharmacology (2019)
Zhang, D. Z., Holze, F., Liechti, M. E. et al. · Clinical Pharmacology and Therapeutics (2020)
Holze, F., Vizeli, P., Ley, L. et al. · Neuropsychopharmacology (2020)
Hutten, N. R. P. W., Mason, N. L., Dolder, P. C. et al. · ACS Pharmacology and Translational Science (2020)
Show all 20 referencesShow fewer
Ly, C., Greb, A. C., Cameron, L. P. et al. · Cell Reports (2018)
Madsen, M. K., Fisher, P. M., Burmester, D. et al. · Neuropsychopharmacology (2019)
Preller, K. H., Herdener, M., Pokorny, T. et al. · Current Biology (2017)
Rickli, A., Moning, O. D., Hoener, M. C. et al. · European Neuropsychopharmacology (2016)
Ross, S., Bossis, A. P., Guss, J. et al. · Journal of Psychopharmacology (2016)
Schmid, Y., Gasser, P., Oehen, P. et al. · Journal of Psychopharmacology (2020)
Schmid, Y., Enzler, F., Gasser, P. et al. · Biological Psychiatry (2015)
Studerus, E., Gamma, A., Vollenweider, F. X. · PLOS ONE (2010)
Valle, M., Maqueda, A. E., Rabella, M. et al. · European Neuropsychopharmacology (2016)
Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A. et al. · NeuroReport (1998)
Cited By (11)
Papers in Blossom that reference this study
Stocker, K., Hartmann, M., Barrett, F. S. et al. · Religion, Brain & Behavior (2026)
O’Mahony, B., Harrington, C., Harkin, A. et al. · Journal of Psychopharmacology (2026)
Perkins, D., Halman, A., Urokohara, A. et al. · Scientific Reports (2025)
Murnane, K. S., Barnett, B. S., Vest, •. M. F. et al. · Psychopharmacology (2024)
Lyons, T., Spriggs, M. J., Kerkelä, L. et al. · Biorxiv (2024)
Warren, A. L., Lankri, D., Cunningham, M. J. et al. · Nature (2024)
Erritzoe, D., Barba, T., Spriggs, M. J. et al. · Journal of Psychopharmacology (2024)
Jaster, A. M., González-Maeso, J. · Molecular Psychiatry (2023)
Straumann, I., Ley, L., Holze, F. et al. · Neuropsychopharmacology (2023)
Ley, L., Holze, F., Arikci, D. et al. · Neuropsychopharmacology (2023)
Show all 11 papersShow fewer
Olson, R., Bartlett, L., Sonneborn, A. et al. · Biorxiv (2023)
Your Personal Research Library
Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.