Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide microdoses in healthy participants

Friederike Holze, Matthias E. Liechti, Nadia R.P.W. Hutten, Natasha L. Mason, Patrick C. Dolder, Eef L. Theunissen, Urs Duthaler, Amanda Feilding, Johannes G. Ramaekers, Kim P.C. Kuypers

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 h 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 h. The mean elimination half‐life was 2.7 h (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 h after 10 µg LSD administration, peaked at 2.5 h, and ended at 5.1 h. 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 h. The threshold dose of LSD base for psychotropic effects was 10 µg.