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

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.

Using a double-blind, randomised, placebo-controlled, within-subject crossover design, 28 healthy volunteers (14 men, 14 women; mean age 35 ± 9.4 years, range 25–52) completed five 25 h experimental sessions separated by at least 10 days. Each participant received, in random counterbalanced order, placebo, LSD 100 µg, LSD 200 µg, psilocybin 15 mg, and psilocybin 30 mg. A double-dummy approach was used so subjects received both oral solutions and capsules each session to preserve blinding. Participants underwent screening including structured psychiatric interview and laboratory testing; exclusion criteria included age <25 or >65 years, pregnancy, personal or first-degree family history of major psychiatric disorders, interfering medications, significant medical illness, heavy tobacco use (>10 cigarettes/day), and substantial recent illicit drug use. Fourteen participants had prior psychedelic experience; ten were drug-naïve apart from cannabis. Test sessions were conducted in a calm hospital room with one investigator present. Baseline measures were taken before dosing at 09:00. Subjective effects were repeatedly assessed using visual analogue scales (VASs) from 1 h before to 24 h after dosing, the Adjective Mood Rating Scale (AMRS) at selected time points, and the 5-Dimensions of Altered States of Consciousness (5D-ASC) administered 24 h post-dose as the primary outcome to retrospectively rate peak effects. Mystical-type experiences were assessed with the States of Consciousness Questionnaire (MEQ30/MEQ43). Effect onset, peak and offset times and duration were estimated using a PK-PD link model (onset/offset threshold 10% of individual maximum). Autonomic measures (blood pressure, heart rate, tympanic temperature, pupil size) were recorded repeatedly up to 24 h. Endocrine measures (cortisol, prolactin, oxytocin) were sampled at baseline and 2.5 h post-dose; BDNF was measured at baseline and 4, 6 and 12 h. Plasma LSD and psilocin concentrations were determined by validated UHPLC–MS/MS methods with sampling up to 24 h. Pharmacokinetic parameters were estimated non-compartmentally. Repeated-measures ANOVA with drug as the within-subject factor and Tukey post hoc tests were used for statistical comparisons; significance was set at p < 0.05.

Twenty-eight participants completed the five-session protocol. On subjective measures, LSD 100 µg, LSD 200 µg and psilocybin 30 mg produced broadly comparable peak subjective effects on multiple VAS items (including "any drug effect," "good drug effect," "feeling high," and "fear") and on 5D-ASC subscales. Psilocybin 15 mg produced clearly weaker subjective responses than both LSD doses and psilocybin 30 mg across VASs and 5D-ASC total and main dimensions (all reported p-values < 0.001 for many comparisons). Compared with 100 µg, 200 µg LSD produced greater ratings of ego-dissolution (p < 0.05) and a trend for increased anxiety (p = 0.054). The only consistent difference between 200 µg LSD and 30 mg psilocybin was higher ratings of "ineffability" on the MEQ for 200 µg LSD. Effect timing and duration differed by substance and dose. Both LSD doses had significantly earlier onsets and longer durations than both psilocybin doses (summary PK-PD parameters reported). Pharmacokinetics supported these findings: geometric mean Cmax for LSD were 1.9 ng/ml (100 µg) and 3.4 ng/ml (200 µg) with median Tmax ~1.6 h and elimination half-lives ~4 h. For psilocin, Cmax for 15 and 30 mg were 13 ng/ml and 25 ng/ml, respectively, with Tmax ~2.3–2.5 h and half-lives ~2.4–2.7 h. Both drugs showed approximately linear, dose-proportional pharmacokinetics and body weight did not influence exposure. The authors noted the faster onset for LSD may reflect its liquid formulation versus psilocybin capsules. Autonomic effects were present for both substances. Both LSD and psilocybin significantly increased systolic and diastolic blood pressure, body temperature and pupil size versus placebo. Psilocybin 30 mg produced larger increases in blood pressure and body temperature than LSD, whereas both LSD doses produced greater increases in heart rate than either psilocybin dose. When combined as rate-pressure product (a common index of cardiac workload combining heart rate and systolic pressure), LSD (both doses) and psilocybin 30 mg produced broadly similar cardiostimulant effects, while psilocybin 15 mg showed weaker overall cardiovascular stimulation. Pupillary light reflex was more impaired after 200 µg LSD and 30 mg psilocybin compared with placebo, with psilocybin producing greater impairment overall. Acute (0–12 h) adverse-effect scores increased for both substances versus placebo; subacute (12–24 h) adverse-effect scores were higher after the high doses (200 µg LSD and 30 mg psilocybin). Reported post-treatment adverse events included headaches (four after psilocybin, three after LSD), one migraine after LSD, nosebleed (one after psilocybin), low mood (two after each substance), nausea (two after psilocybin, one after LSD), nightmares, restlessness, vivid dreams, insomnia, and one involuntary lower-extremity movement. Nine transient "flashback" episodes occurred in five subjects within 72 h (five after LSD, four after psilocybin). No severe adverse events were observed, and the overall types and counts of adverse events were comparable between substances. Endocrine measures: both LSD and psilocybin increased plasma cortisol, prolactin and oxytocin at 2.5 h versus baseline; neither substance significantly altered plasma BDNF at the sampled time points. Blinding: placebo was correctly identified in 96% of sessions. Participants often confused active conditions with other active doses or substances; overall the blinding between LSD and psilocybin remained reasonably effective, with no clear subject ability to distinguish the two drugs consistently.

Holze and colleagues interpret their findings as evidence that, at the doses studied, LSD and psilocybin produce qualitatively similar acute subjective alterations of consciousness, with differences dominated by dose and pharmacokinetic profile rather than fundamentally different subjective phenomenology. The 100 µg and 200 µg LSD doses and psilocybin 30 mg yielded comparable peak subjective effects, whereas psilocybin 15 mg was substantially weaker. The authors note a ceiling effect for positive subjective effects with LSD at about 100 µg, with only ego dissolution and some negative effects increasing at 200 µg, while psilocybin showed a clearer dose–response within the dose range tested. The longer duration and faster apparent onset of LSD effects are explained by pharmacokinetics: LSD had an elimination half-life of ~4 h versus ~2.5 h for psilocin, and the liquid LSD formulation likely produced a faster Tmax than psilocybin capsules. Autonomic differences were substance-specific in pattern: psilocybin elevated arterial blood pressure and body temperature more, whereas LSD increased heart rate more; however, combined cardiac workload (rate-pressure product) was similar for LSD (both doses) and psilocybin 30 mg. The authors consider these autonomic effects moderate and transient, not posing major safety concerns in this controlled setting. Regarding mechanisms, the lack of qualitative differences supports a shared 5-HT2A-mediated action as the dominant driver of subjective effects, despite pharmacological distinctions (dopaminergic activity of LSD, psilocin's serotonin transporter inhibition). The authors also report serotonergic activation as reflected in cortisol and prolactin increases and newly document oxytocin increases after psilocybin. No changes in peripheral BDNF were detected in this study. Strengths cited include the within-subject, double-blind design, two well-characterised doses of each drug, validated psychometrics, balanced sex representation and full pharmacokinetic sampling to 24 h. Limitations acknowledged are the highly controlled laboratory environment and the exclusive recruitment of healthy volunteers, which may limit generalisability to patients or other settings. The authors derive practical dose-equivalence guidance from their data, proposing approximate conversions to assist future clinical dosing and interpretation.

The study characterised acute subjective, autonomic, endocrine and pharmacokinetic effects of two doses each of LSD and psilocybin in healthy subjects. Holze and colleagues conclude there is no evidence for qualitatively different altered states of consciousness between LSD and psilocybin at equipotent levels, aside from a shorter duration of action for psilocybin. They propose an approximate dose equivalence of ~1:200 (LSD base to psilocybin), suggesting that ~20 mg psilocybin corresponds to 100 µg LSD, a finding intended to aid dose finding in future research and therapeutic trials.