Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide microdoses in healthy participants
In a double‑blind, placebo‑controlled crossover study in 23 healthy participants, LSD 5–20 µg produced dose‑proportional plasma concentrations (Cmax ≈151, 279, 500 pg/mL), Tmax ≈1.1 h and an elimination half‑life of ≈2.7–3 h. Psychotropic effects were absent at 5 µg, appeared about 1.1 h and peaked at 2.5 h after 10 µg (identified as the threshold dose), while 20 µg elicited both positive and some negative subjective effects.
Authors
- Patrick Dolder
- Matthias Liechti
- Kim Kuypers
Published
Abstract
“Microdoses” of lysergic acid diethylamide (LSD) are used recreationally to enhance mood and cognition. Increasing interest has also been seen in developing LSD into a medication. Therefore, we performed a pharmacokinetic‐pharmacodynamic study using very low doses of LSD. Single doses of LSD base (5, 10, and 20 µg) and placebo were administered in a double‐blind, randomized, placebo‐controlled crossover study in 23 healthy participants. Test days were separated by at least 5 days. Plasma levels of LSD and subjective effects were assessed up to 6 hours after administration. Pharmacokinetic parameters were determined using compartmental modeling. Concentration‐subjective effect relationships were described using pharmacokinetic‐pharmacodynamic modeling. Mean (95% confidence interval) maximal LSD concentrations were 151 pg/mL (127–181), 279 pg/mL (243–320), and 500 pg/mL (413–607) after 5, 10, and 20 µg LSD administration, respectively. Maximal concentrations were reached after 1.1 hours. The mean elimination half‐life was 2.7 hours (1.5–6.2). The 5 µg dose of LSD elicited no significant acute subjective effects. The 10 µg dose of LSD significantly increased ratings of “under the influence” and “good drug effect” compared with placebo. These effects began an average of 1.1 hours after 10 µg LSD administration, peaked at 2.5 hours, and ended at 5.1 hours. The 20 µg dose of LSD significantly increased ratings of “under the influence,” “good drug effects,” and “bad drug effects.” LSD concentrations dose‐proportionally increased at doses as low as 5–20 µg and decreased with a half‐life of 3 hours. The threshold dose of LSD base for psychotropic effects was 10 µg.
Research Summary of 'Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide microdoses in healthy participants'
Introduction
LSD (lysergic acid diethylamide) is a classic serotonergic psychedelic that is well absorbed orally and has been investigated for potential therapeutic uses including mood disorders, substance use disorders and cluster headache. A recent trend in recreational and investigational use is ‘‘microdosing’’, defined as repeated administration of very low doses of LSD (typically every 2–5 days) to enhance mood and cognition. However, pharmacokinetic data for very low single doses are sparse, and previous controlled studies either lacked sensitive assays to quantify plasma LSD at the lowest doses or did not collect pharmacokinetic samples, leaving gaps in knowledge about dose–concentration relationships, pharmacokinetic parameters and the threshold for subjective effects. Zhang and colleagues set out to characterise the pharmacokinetics, acute subjective effects, and pharmacokinetic–pharmacodynamic relationships of single very low oral doses of LSD base (5, 10 and 20 µg) compared with placebo in healthy volunteers. The primary aims were to obtain full concentration–time curves using a sensitive analytical method, model concentration–effect relationships, and determine the threshold dose for perceivable psychotropic effects. The study uses a double-blind, randomized, placebo-controlled crossover design to provide within-subject comparisons across doses.
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
Holze, F., Liechti, M. E., Hutten, N. R., Mason, N. L., Dolder, P. C., Theunissen, E. L., Duthaler, U., Feilding, A., Ramaekers, J. G., & Kuypers, K. P. (2021). Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide microdoses in healthy participants. Clinical Pharmacology & Therapeutics, 109(3), 658-666. https://doi.org/10.1002/cpt.2057
References (18)
Papers cited by this study that are also in Blossom
Dolder, P. C., Schmid, Y., Haschke, M. et al. · International Journal of Neuropsychopharmacology (2015)
Holze, F., Duthaler, U., Vizeli, P. et al. · British Journal of Clinical Pharmacology (2019)
Gasser, P., Holstein, D., Michel, Y. et al. · Journal of Nervous and Mental Disease (2014)
Sewell, R. A. · Neurology (2006)
Liechti, M. E. · Neuropsychopharmacology (2017)
Fadiman, J., Korb, S. · Journal of Psychoactive Drugs (2019)
Lea, T., Amada, N., Jungaberle, H. et al. · International Journal of Drug Policy (2020)
Hutten, N. P. W., Mason, N. L., Dolder, P. C. et al. · International Journal of Neuropsychopharmacology (2019)
Hutten, N. P. W., Mason, N. L., Dolder, P. C. et al. · Frontiers in Psychiatry (2019)
Kuypers, K. P. C., Erritzoe, D., Knudsen, G. M. et al. · Journal of Psychopharmacology (2019)
Show all 18 referencesShow fewer
Family, N., Maillet, E. L., Williams, L. T. J. et al. · Psychopharmacology (2019)
Bershad, A. K., Schepers, S. T., Bremmer, M. P. et al. · Biological Psychiatry (2019)
Bershad, A. K., Preller, K. H., Lee, R. et al. · Biological Psychiatry (2020)
Dolder, P. C., Schmid, Y., Müller, F. et al. · Neuropsychopharmacology (2016)
Schmid, Y., Enzler, F., Gasser, P. et al. · Biological Psychiatry (2015)
Dolder, P. C., Schmid, Y., Steuer, A. E. et al. · Clinical Pharmacokinetics (2017)
Holze, F., Vizeli, P., Müller, F. et al. · Neuropsychopharmacology (2019)
Dolder, P. C., Müller, F., Schmid, Y. et al. · Psychopharmacology (2017)
Cited By (30)
Papers in Blossom that reference this study
Daldegan-Bueno, D., Donegan, C. J., Sumner, R. et al. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2026)
Daldegan-Bueno, D., Donegan, C. J., Sumner, R. L. et al. · Neuropharmacology (2026)
Cavarra, M., Hutten, N. R. P. W., Schepers, J. et al. · British Journal of Pain (2025)
Mueller, L., Klaiber, A., Ley, L. et al. · Clinical Pharmacokinetics (2025)
Mueller, L., de Jesus, N. M. S., Schmid, Y. et al. · JAMA Psychiatry (2025)
Arikci, D., Holze, F., Mueller, L. et al. · Clinical Pharmacology and Therapeutics (2025)
Morse, D. J., Jeong, S. H., Murphy, R. J. et al. · Journal of Psychopharmacology (2025)
Effinger, D. P., Schalk, S. S., King, J. L. et al. · ACS Pharmacology and Translational Science (2025)
Mueller, J., Mueller, M. J., Aicher, H. D. et al. · International Journal of Neuropsychopharmacology (2025)
Haggarty, C. J., Molla, H. M., Glazer, J. et al. · Psychedelic Medicine (2024)
Show all 30 papersShow fewer
Murphy, R. J. · Psychopharmacology (2024)
Vizeli, P., Studerus, E., Holze, F. et al. · Translational Psychiatry (2024)
Hutten, N. R. P. W., Quaedflieg, C. W. E. M., Mason, N. L. et al. · Translational Psychiatry (2024)
Polito, V., Liknaitzky, P. · Journal of Psychopharmacology (2024)
Murphy, R., Muthukumaraswamy, S., De Wit, H. · Biological Psychiatry (2024)
Molla, H. M., Lee, R., Tare, I. et al. · Neuropsychopharmacology (2023)
Friederike, H., Liechti, M. E., Holze, F. et al. · British Journal of Clinical Pharmacology (2023)
Murphy, R., Sumner, R. L., Evans, W. J. et al. · Biological Psychiatry (2023)
Tagen, M., Mantuani, D., Van Heerden, L. et al. · Journal of Psychopharmacology (2023)
Holze, F., Becker, A. M., Kolaczynska, K. E. et al. · Clinical Pharmacology and Therapeutics (2022)
Becker, A. M., Klaiber, A., Holze, F. et al. · International Journal of Neuropsychopharmacology (2022)
Hartong, V., van Emmerik, A. · Journal of Psychoactive Drugs (2022)
de Wit, H., Molla, H. M., Bershad, A. K. et al. · Addiction Biology (2022)
Strickland, J. C., Johnson, M. W. · Advances in Pharmacology (2022)
Polito, V., Liknaitzky, P. · Psyarxiv (2021)
Holze, F., Caluori, T. V., Vizeli, P. et al. · Psychopharmacology (2021)
Vizeli, P., Straumann, I., Holze, F. et al. · Scientific Reports (2021)
Dressler, H. M., Bright, S. J., Polito, V. · Journal of Psychedelic Studies (2021)
Van Elk, M., Fejer, G., Lempe, P. et al. · Psychopharmacology (2021)
Hutten, N. R. P. W., Mason, N. L., Dolder, P. C. et al. · European Neuropsychopharmacology (2020)
Your Personal Research Library
Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.