Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers

Classic serotonergic psychedelics such as lysergic acid diethylamide (LSD) act primarily via the serotonin 2A (5-HT2A) receptor and have been implicated in modulation of cognition, mood, and immune function. Converging preclinical and clinical evidence suggests 5-HT2A receptor agonism can produce anti-inflammatory and neuroprotective effects, reduce soluble amyloid-beta species in animal models, and relate to cognitive and affective processes that are relevant to Alzheimer's disease (AD). However, the psychoactive and behavioural effects of high doses of psychedelics pose therapeutic limitations; some preclinical data indicate that anti-inflammatory effects may occur at sub-perceptual doses, prompting interest in assessing safety and pharmacology at very low doses in humans. Family and colleagues designed the present study to evaluate whether periodic, low oral doses of LSD (5 μg, 10 μg, and 20 μg) could be administered to older healthy volunteers without causing cognitive or functional impairment, and to characterise pharmacokinetics (PK) and selected pharmacodynamic (PD) dose–response relationships. The primary aims were safety, tolerability, and PK; secondary objectives included selected validated cognitive, sensory, and motor measures and subjective drug-effect assessments. The regimen tested six doses given every fourth day over 21 days, a schedule informed by anecdotal microdosing patterns and prior dose-threshold data.

This was a Phase I, double-blind, randomized, placebo-controlled study of repeat dosing of LSD in healthy older adults. Forty-eight volunteers aged 55–75 years were enrolled and randomised within four cohorts to one of four groups (5 μg, 10 μg, 20 μg LSD, or placebo) in a 1:1:1:1 ratio. Each subject received the same assigned oral dose on six occasions spaced 96 hours apart (six doses over 21 days) and remained at the clinical site for approximately 8–12 hours after each dose for testing, blood sampling, and safety monitoring. A follow-up visit occurred about 4 weeks after the last dose. Key eligibility criteria included no LSD use in the past 5 years and absence of lifetime psychotic disorders, bipolar disorder, major depressive episode, recent substance abuse/dependence, and several current psychiatric diagnoses; current smokers and those with elevated blood pressure above specified thresholds were excluded. Safety monitoring included adverse event (AE) collection, Columbia-Suicide Severity Rating Scale (C-SSRS), vital signs, clinical laboratory tests (hematology, chemistry, urinalysis), ECG, and physical examinations. Pharmacokinetic sampling was performed pre-dose and at 30 min, 1, 2, 4, 8, and 12 h post-dose; LSD plasma was quantified by validated LC-MS/MS with a lower limit of quantification (LLOQ) of 200 pg/mL. Non-compartmental methods were used to derive PK parameters including Cmax (maximum measured concentration), Tmax (time to Cmax), AUC (area under the concentration–time curve), and terminal half-life (t1/2). Pharmacodynamic assessments included the CANTAB neuropsychological battery (reaction time, paired associates learning, rapid visual information processing, spatial working memory) administered at baseline and on doses 3 and 6, balance and proprioception testing (BTrackS™ and a proprioception protocol), and subjective drug-effect measures: a 22-item visual analogue scale (VAS) administered repeatedly during dose days and the retrospective 5D-ASC completed ~7 h post-dose. Statistical analyses reported include one-way ANOVA with Bonferroni post hoc tests for CANTAB endpoints, repeated-measures mixed-models for balance and proprioception (baseline as covariate), and polynomial regression for dose–response relationships of subjective measures. No formal sample size calculation was performed.

Forty-eight volunteers (27 male, 21 female; mean age 62.9 years; mean BMI 27.3) were randomised evenly across four dose groups. Safety data showed that low-dose LSD was generally well tolerated over the 21-day dosing period. The overall rate of treatment-emergent adverse events (TEAEs) was relatively high across groups (66.7% to 83.3%) but there were no severe AEs, no unexpected AEs, and no discontinuations due to AEs. Clinical assessments (vital signs, laboratory tests, ECG, physical exams) revealed no clinically significant abnormalities, and daily C-SSRS plus psychiatrist interviews identified no suicidal ideation. Headaches were more frequently reported in active treatment groups than placebo: 16.7% (5 μg), 50.0% (10 μg), and 25.0% (20 μg) versus 8.3% for placebo; reported headaches were mild or moderate. The placebo group had a notable number of nervous system and psychiatric TEAEs; the investigators suggest expectancy effects may have contributed. Plasma pharmacokinetics showed that LSD levels were below the LLOQ (200 pg/mL) at all sampled time points for the 5 μg group and in one participant in the 10 μg group. For the 10 μg and 20 μg groups, measurable plasma concentrations were observed up to about 4 h post-dose for both dose 1 and dose 6. Mean Cmax for the 10 μg group was 305 ± 68 pg/mL at dose 1 and 309 ± 48 pg/mL at dose 6, with Tmax around 0.5 h. For the 20 μg group mean Cmax was 440 ± 79 pg/mL at dose 1 and 504 ± 200 pg/mL at dose 6, with Tmax ~0.5–0.7 h. AUC and Cmax were reproducible between dose 1 and dose 6, and the ratio of Cmax and AUC0-4 between 10 μg and 20 μg groups averaged ~1.5–1.7, indicating a positive but not strictly linear dose–plasma relationship at these low doses. Estimation of t1/2 was limited by low concentrations beyond 4 h; the average terminal half-life across the dataset was 8.25 ± 7.5 h. On selected pharmacodynamic endpoints, one-way ANOVA (with Bonferroni correction) found no significant differences between groups on CANTAB measures at baseline, dose 3, dose 6, or follow-up, indicating no detectable impairment of reaction time, visual memory/learning, visual attention, or spatial working memory. Repeated-measures mixed-model analyses showed no treatment effects on balance or proprioception. Subjective-effect analyses found that peak VAS values (Emax) were stable across repeated measures; however, one 5D-ASC dimension (“vigilance reduction”) and three VAS items showed a statistically significant positive linear relationship with dose. No linear dose–response was detected for “drug liking,” but positive linear relationships were observed for “bad drug effects,” “feeling dizzy,” and “feeling like the body is different or changed.”

Family and colleagues interpret these data as indicating that periodic administration of low oral doses of LSD up to 20 μg every fourth day for three weeks was feasible and carried no major safety signal in healthy older volunteers. Clinical and laboratory safety assessments, together with the absence of severe AEs or trial withdrawals, support tolerability in this limited-duration Phase I context. The investigators note that the only notable clinical difference was an increased frequency of mostly mild-to-moderate headaches in active dose groups, and that some nervous system and psychiatric TEAEs in the placebo arm may reflect expectancy or suggestibility effects in this experimental setting. Pharmacokinetic findings are positioned as consistent with dose-dependent absorption for 10 μg and 20 μg doses while showing that 5 μg produced plasma levels below the assay LLOQ (200 pg/mL). The authors caution that low measured concentrations and truncated profiles limited precise estimation of terminal elimination parameters, though the observed mean terminal half-life approximated values reported for much higher oral doses in prior work. They also highlight that repeated dosing did not produce sustained circulating LSD levels above 200 pg/mL across the dosing interval. Regarding pharmacodynamics, the absence of group differences on objective cognitive, balance, and proprioceptive tests leads the investigators to conclude that these low doses did not impair tested cognitive faculties in a healthy, likely high-performing population; they note this may reflect either insufficient dose to elicit effects or ceiling effects in healthy participants. Subjective reports of reduced vigilance and modest increases in “bad drug effects,” dizziness and altered body perception were dose-related; the authors suggest these may reflect setting-dependent factors (participants confined to bed during testing) and heightened suggestibility under LSD. They acknowledge limits to generalisability: the short (21-day) dosing window, assay sensitivity constraints, the psychedelic-naïve sample, and the need for longer-term monitoring of 5-HT2B receptor engagement given potential risk of drug-induced heart valve disease with chronic 5-HT2B agonism. The investigators recommend further trials to examine vigilance/alertness effects, explore intermittent low-dose regimens over longer periods, and to test efficacy outcomes (anxiolytic, antidepressant, pro-cognitive, anti-inflammatory) in clinical populations including Alzheimer’s disease.

This Phase I double-blind, placebo-controlled, randomised study provides preliminary evidence that intermittent low doses of LSD (5 μg, 10 μg, 20 μg) administered every fourth day for 21 days are generally safe and well tolerated in healthy older adults. No impairment on objective cognitive, balance, or proprioceptive measures was detected, though dose-related increases in subjective vigilance reduction, reports of adverse subjective effects, dizziness, and altered body perception were observed and warrant further study. The authors conclude that these findings support the feasibility of intermittent low-dose LSD regimens and justify larger, longer-duration trials to evaluate potential therapeutic effects, including as a disease-modifying approach for Alzheimer’s disease.