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

Holze and colleagues situate LSD as a classical serotonergic psychedelic that produces complex alterations of consciousness primarily via serotonin 5-HT2A receptor stimulation. Renewed clinical and research interest in LSD has not been matched by modern within-subject data comparing multiple, pharmaceutically well-characterised acute doses in the same participants. The authors note gaps in dose–response knowledge, the need to document plasma exposure (pharmacokinetics, PK) alongside subjective effects, and interest in potential biomarkers of neuroplasticity such as brain-derived neurotrophic factor (BDNF). The study therefore set out to characterise acute subjective, autonomic and biomarker (plasma BDNF) responses to a range of LSD base doses (25, 50, 100 and 200 µg) in healthy volunteers, to define PK-PD relationships, and to test the role of 5-HT2A receptors by administering ketanserin (40 mg) prior to a 200 µg LSD dose. The investigators hypothesised dose-dependent effects that would be blocked by ketanserin and aimed to provide dose-finding data relevant to future research and therapeutic applications.

This was a double-blind, randomised, placebo-controlled, crossover study in 16 healthy adults (eight men, eight women; mean age 29 ± 6.4 years, range 25–52). Each participant completed six 25 h test sessions separated by at least 10 days, receiving in counterbalanced order: placebo, 25 µg LSD, 50 µg LSD, 100 µg LSD, 200 µg LSD, and 200 µg LSD given 1 h after 40 mg ketanserin. Block randomisation and a double-dummy procedure (two capsules and two solutions per session) were used to preserve blinding. The study adhered to Good Clinical Practice and was registered at ClinicalTrials.gov. Eligible participants were screened for medical and psychiatric illness, medication use, substance-use history and pregnancy; exclusion criteria included major psychiatric disorder, interfering medications, significant physical illness, heavy tobacco use and recent illicit drug use. Six participants had prior LSD exposure (1–3 occasions) and most had some lifetime experience with other recreational drugs; drug screens during the study were negative. The LSD solution formulations were manufactured under good manufacturing practice and analytically confirmed (25 µg formulation 25.7 ± 0.57 µg; 100 µg formulation 98.7 ± 1.6 µg). Ketanserin and placebo capsules were encapsulated to match appearance. Procedures began with baseline measures and drug-administration at 09:00 (ketanserin or its placebo at 08:00). Sessions took place in a calm hospital room with continuous staff presence for the first 16 h. Subjective effects were measured repeatedly with visual analogue scales (VAS) at numerous timepoints up to 24 h and with the Adjective Mood Rating Scale (AMRS). The 5D-ASC and mystical experience questionnaires (MEQ43/MEQ30) were administered 24 h after dosing to retrospectively rate peak effects. Autonomic measures (blood pressure, heart rate, tympanic temperature) and adverse effects (list of complaints) were recorded; plasma BDNF was measured at baseline, 6, 12 and 24 h. Plasma LSD and the main metabolite O-H-LSD were quantified by ultra-high-performance liquid chromatography tandem mass spectrometry with a lower limit of quantification of 5 pg/ml. PK parameters were estimated using a one-compartment model with first-order input and elimination; predicted concentrations were linked to pharmacodynamics via a sigmoid Emax model. Time-to-onset, time-to-peak, time-to-offset and effect duration were derived from modelled VAS "any drug effect" curves using a 10% of maximum individual response threshold. Repeated-measures ANOVA with drug as within-subject factor and Tukey post hoc testing was used for statistical analysis, with p < 0.05 considered significant; no correction for multiple testing was applied.

Sixteen participants completed all sessions. Plasma concentrations of LSD and O-H-LSD were measurable in all subjects at all doses and timepoints. PKs were dose-proportional across the 25–200 µg range and followed first-order elimination; noncompartmental and model parameters were reported, and no sex differences in PKs or effects were observed. Ketanserin had no significant effect on LSD pharmacokinetics. Subjective effects. LSD produced dose-dependent subjective effects beginning at 25 µg, where "any drug effect" on VAS differed significantly from placebo (p < 0.05). Positive subjective effects ("good drug effect" and drug liking) exhibited a ceiling at 100 µg, with typically no significant increase at 200 µg. In contrast, the 200 µg dose produced significantly greater ego dissolution on VAS, greater anxious ego dissolution on the 5D-ASC, and higher negative "nadir" effects than 100 µg (all p < 0.05). Only the 200 µg dose induced significant anxiety on the 5D-ASC and AMRS (both p < 0.01); 100 µg did not. Peak subjective-effect durations lengthened with dose: time-to-onset shortened and time-to-offset increased, giving longer overall effect durations as dose increased. Ketanserin markedly attenuated subjective responses to 200 µg LSD (most comparisons p < 0.001), reducing effects approximately to the levels seen after 25 µg LSD; a small delayed residual VAS "good drug effect" remained after ketanserin. Participants did not show significant differences in subjective responses according to prior LSD experience. Retrospective blinding data showed that 100 and 200 µg were generally recognised as high doses but could not be reliably distinguished from each other; 25 µg was mostly distinguished from placebo. Autonomic and adverse effects. LSD moderately increased blood pressure at doses ≥50 µg and increased heart rate at 100 and 200 µg; body temperature was unaffected. Total acute adverse-effect scores (0–12 h) were higher after 100 and 200 µg versus placebo and other conditions. Ketanserin prevented the LSD-induced heart rate increase and transiently reduced the blood pressure response up to about 6 h. No severe adverse events occurred. BDNF and PK-PD modelling. Plasma BDNF rose significantly after 200 µg compared with placebo, peaking at about 6 h; increases after lower doses or after ketanserin plus LSD were nonsignificant. PK-PD modelling reproduced the dose-proportional PKs and the ceiling in predicted VAS any-drug and good-drug effects at 100 µg, while predicted bad-drug effects and ego dissolution increased further at 200 µg.

Holze and colleagues interpret the findings as demonstrating dose-dependent subjective effects of LSD that begin at 25 µg and reach a plateau for positive subjective effects at about 100 µg, while ego dissolution and anxiety continue to increase at 200 µg. The authors emphasise that plasma-confirmed, pharmaceutically characterised dosing and full PK characterisation strengthen the internal validity of the dose–response data. They report no sex differences in PKs or effects and note that PKs were consistent with prior single-dose studies. The ceiling effect for positive subjective effects at 100 µg is contrasted with earlier reports that suggested greater effects at 200 µg; the investigators attribute those discrepancies to unstable formulations and between-study comparisons in prior work rather than within-subject dosing. They propose that 100 µg may be an appropriate starting dose for therapeutic applications where high positive acute effects (e.g. Oceanic Boundlessness) but lower acute anxiety are desirable, whereas doses above 100 µg could be chosen if ego dissolution is the specific aim but with increased risk of anxiety. The 50 µg dose produced substantial positive mood effects with minimal anxious ego dissolution and is suggested as a possible initial dose for psychedelic-naïve or more sensitive patients. Ketanserin substantially blocked the acute subjective and some autonomic effects of high-dose LSD, supporting the conclusion that 5-HT2A receptor activation mediates the primary psychedelic effects in humans. The authors also report a significant increase in plasma BDNF after 200 µg with a 6 h peak but note that the timing and relationship of BDNF changes to clinical outcomes remain uncertain and warrant further study. Strengths highlighted include within-subject comparison of multiple analytically confirmed doses, randomised double-blind crossover design, equal sex representation, validated psychometric instruments, inclusion of a receptor-blocking condition and comprehensive PK sampling. Limitations acknowledged are the controlled laboratory setting, inclusion only of healthy volunteers (many with some prior drug experience), potential positive expectations among volunteers and the consequent limited generalisability to other environments or patient populations. The authors also propose a practical dosing terminology—"microdose" (1–20 µg), "minidose" (21–30 µg) and "psychedelic dose" (>30 µg)—and suggest subcategories within psychedelic doses (30–100 µg favouring positive effects; >100 µg more associated with ego dissolution and anxiety).

The study characterised acute, dose-dependent subjective, autonomic and biomarker effects of LSD across 25–200 µg in healthy volunteers and linked these effects to plasma-confirmed exposures. LSD showed dose-proportional pharmacokinetics with first-order elimination and produced measurable subjective effects from 25 µg. Positive subjective effects reached a ceiling at about 100 µg, whereas ego dissolution and anxiety increased further at 200 µg. Ketanserin nearly abolished the high-dose subjective response, confirming a primary role for 5-HT2A receptor activation in LSD's acute psychedelic effects. These results are presented as dose-finding data to inform future research and LSD-assisted therapy.