Safety, tolerability, pharmacokinetics, and subjective effects of 50, 75, and 100 µg LSD in healthy participants within a novel intervention paradigm: A proof-of-concept study

Classic psychedelics such as lysergic acid diethylamide (LSD) have re‑emerged as potential therapeutics for psychiatric disorders, but many contemporary clinical protocols are resource intensive and may limit population‑level access. Earlier work suggests LSD has a favourable safety profile across a range of doses and can produce transcendent, mystical‑type experiences that are thought to mediate therapeutic effects, yet conventional trials typically use substantial preparatory and integration contact, two on‑site attendants during acute drug action, and multi‑week interventions that are expensive and time consuming. Family and colleagues set out to evaluate a more scalable intervention paradigm by conducting a Phase I proof‑of‑concept, single‑centre, dose‑escalation study of low‑to‑moderate LSD doses (50, 75 and 100 µg) in healthy adults. The paper reports safety, tolerability, pharmacokinetics (PK) and subjective effects within a protocol that used abbreviated preparation/integration, a single attendant per participant, remote monitoring, group interactions and the option to dose up to three participants on the same day. The investigators hypothesised these doses would be safe and tolerable, produce blood plasma exposures congruent with previous studies, and generate mystical‑type subjective experiences relevant to potential therapeutic mechanisms.

This Phase I, single‑centre study combined an open‑label dose‑escalation phase (part 1) and a double‑blind, placebo‑controlled, randomised phase (part 2). Part 1 enrolled psychedelic non‑naive participants (prior use >3 lifetime occasions) in small cohorts (maximum three participants per cohort) who each received a single dose of LSD (50, 75 or 100 µg). Part 2 enrolled predominantly psychedelic‑naive participants and randomised cohorts to either receive 50 µg LSD followed 7 days later by 75 µg (experimental group) or placebo followed 7 days later by 75 µg LSD (placebo‑controlled group). Only part 1 participants provided pharmacokinetic samples. The investigation was performed at an Early Phase Clinical Unit in the UK under Good Clinical Practice and ethics approval. Participants arrived the evening before dosing for a preparatory day that combined group and individual elements (brief introduction to attendant, computer assessments, communal meals, individual problem‑solving discussion, breathing exercises and rapport building). On dosing day the study drug was administered at 09:00, each attendant remained with their participant until 18:30 with remote video/audio monitoring of rooms, and participants had two overnight stays surrounding the drug day. Follow‑up visits occurred at approximately 1 week and 1 month post dosing. Safety and tolerability assessments included adverse event (AE) recording, vital signs, ECGs, clinical laboratory tests, the Columbia‑Suicide Severity Rating Scale (C‑SSRS) and clinical interviews. Blood for PK analysis (part 1 only) was sampled pre‑dose and at 0.5, 1, 2, 4, 8, 12 and 24 h; assay lower limit of quantification (LLOQ) was 200 pg/mL and PK parameters were derived with non‑compartmental methods (Cmax, Tmax, AUC0‑t, λz and apparent half‑life). Subjective effects were measured with repeated visual analogue scales on dosing day (part 1) and with the five‑dimensional Altered States of Consciousness (ASC) scale, the Ego Dissolution Inventory (EDI) and the Mystical Experience Questionnaire (MEQ) administered after the dosing day (both parts). Statistical approaches included ANOVAs (Welch’s or Fisher’s as appropriate), mixed‑effects ANOVA for within‑subject comparisons in part 2, chi‑square tests for categorical outcomes, and Kendall’s tau for small‑sample correlations. Inclusion/exclusion criteria screened for medical and psychiatric disorders and restricted medications likely to interact with LSD.

Thirty‑three participants were determined eligible; 13 were enrolled in part 1 and received a single dose of LSD (50 µg, n = 3; 75 µg, n = 7; 100 µg, n = 3). In part 2 the experimental group received 50 µg then 75 µg (n = 9) and the placebo/75 µg group comprised 10 participants. Overall completion was high: 30 of 33 participants (91%) completed all study procedures. One participant withdrew prior to dosing and two did not receive a planned second dose (one due to nicotine use, one withdrew after an adverse event). Safety and tolerability: No serious adverse events occurred. Twenty‑eight percent of participants (n = 9) experienced at least one treatment‑emergent adverse event (TEAE). The most commonly reported expected AEs were nausea, vomiting and headache (two participants each). All expected AEs were mild except a single moderate expected TEAE recorded as 'Euphoric Mood' in an LSD‑naive participant after 50 µg; that participant withdrew prior to the planned second dose but completed follow‑up with normal clinical assessments. No clinically significant abnormalities were identified in vital signs, ECGs, laboratory tests or clinical review. Pharmacokinetics: For part 1 participants, drug concentrations were quantifiable through approximately 8 h for the 50‑ and 75‑µg conditions and to 12 h for 100 µg; levels were below the LLOQ (200 pg/mL) at 24 h for all doses. Mean Cmax (±SD) and Tmax were: 50 µg, 1088 ± 219 pg/mL at 2.0 h; 75 µg, 1712 ± 417 pg/mL at 1.2 h; 100 µg, 3034 ± 664 pg/mL at 1.7 h. Apparent terminal half‑lives averaged 2.8, 3.2 and 4.3 h for the 50‑, 75‑ and 100‑µg groups, respectively. Ratios of Cmax and AUC0‑24 between doses suggested a positive relationship between dose and plasma exposure but deviated from strict linearity (50→75 ratios ≈1.6–1.7; 50→100 ratios ≈2.8–4.0). The authors note small sample sizes and limited sampling between 4 and 8 h restrict precise elimination‑phase estimation. Subjective effects: Comparing first (or only) doses across placebo, 50, 75 and 100 µg showed significant condition effects on multiple ASC, EDI and MEQ scales. On the ASC, oceanic boundlessness was higher for 50 (p = 0.00009), 75 (p = 0.049) and 100 µg (p = 0.006) versus placebo; visionary restructuralization was higher for 50 (p < 10−7), 75 (p = 0.0002) and 100 µg (p = 0.001) versus placebo; dread of ego dissolution and auditory alterations were elevated for 50 µg versus placebo; vigilance reduction was higher for 50 and 100 µg versus placebo. The EDI was greater for 50 µg versus placebo (p = 0.001). On the MEQ, mystical scores were higher for 50 (p = 0.0004) and 75 µg (p = 0.02) versus placebo (100 µg p = 0.10), positive mood and transcendence of time and space were higher for all doses versus placebo, and ineffability was higher for 50 and 75 µg versus placebo (100 µg p = 0.08). Percentages meeting the MEQ 'complete mystical experience' criterion were placebo 0%, 50 µg 25%, 75 µg 0%, and 100 µg 33.3% (χ2(3, N = 32) = 6.79, p = 0.07). Part 2 within‑ and between‑day analyses: Mixed‑effects ANOVA revealed significant interactions between experimental condition (50/75 µg vs placebo/75 µg) and day of administration for nearly all ASC, EDI and MEQ scales. Participants in the 50/75 µg condition reported greater scores than those in the placebo/75 µg condition on day 1 across ASC, EDI and MEQ scales, while no significant differences were detected on day 8. Within‑subject comparisons found no significant differences between 50 and 75 µg. In the 50/75 µg subgroup the proportion meeting the complete mystical‑experience criterion rose from 33.3% on day 1 to 50% on day 8 (McNemar p = 0.62); in the placebo/75 µg group it rose from 0% to 55% (McNemar p = 0.06, approaching significance). Exploratory comparisons separating part 1 and part 2 data did not reveal significant differences between study parts for the same nominal doses.

Family and colleagues interpret the findings as indicating that single doses of 50, 75 and 100 µg LSD were tolerable in this sample of healthy adults within a novel, resource‑efficient intervention paradigm: no serious adverse events were observed, completion was high (91%), and physiological safety assessments showed no clinically significant abnormalities. The investigators highlight that subjective effects consistent with mystical‑type experiences occurred even at the 50 µg dose and that PK parameters (Tmax ≈1.2–2 h and apparent half‑life ≈2.8–4.3 h) were broadly similar to prior reports, though mean exposure measures in this study were somewhat higher than some earlier estimates. The authors attribute possible exposure differences to small sample size and to formulation/bioavailability differences associated with the aqueous ethanol solution used. The study team positions the tested intervention paradigm—abbreviated non‑drug sessions, a single attendant with remote support, group interaction and dosing multiple participants the same day—as potentially more scalable than conventional high‑contact models, noting that these changes did not appear to compromise acute safety or the capacity to induce transcendent subjective effects in healthy volunteers. The authors also discuss the therapeutic relevance of post‑acute elevated mood ('afterglow') as both a potential window for intervention and a signal that could pose risks (for example, impulsive decision‑making or mania in vulnerable patients), emphasising the need to mitigate such risks in patient populations. Limitations acknowledged by the investigators include the enrolment of only healthy volunteers, small sample sizes—particularly for the 100 µg group (n = 3)—and the potential influence of expectancy because some participants were informed of the drug identity. They also note that components of the novel paradigm (full‑day attendance, meals) may have hidden costs and that no cost‑effectiveness analysis or provider acceptability data were collected. Finally, the low proportion of female participants limits generalisability. The authors recommend larger studies and explicit testing of the paradigm in clinical populations before implementation, and suggest economic evaluations and further refinement of preparatory and integration elements tailored to patient groups.

In conclusion, this Phase I proof‑of‑concept study found that 50–100 µg LSD administered within an abbreviated, single‑attendant, remotely monitored intervention paradigm was generally safe, well tolerated and produced measurable pharmacokinetic exposure and mystical‑type subjective effects in healthy adults. Family and colleagues conclude these data support the feasibility of more resource‑efficient delivery models for classic psychedelic administration, but they call for larger trials, economic evaluation and confirmatory testing in patient populations before clinical implementation.