Safety pharmacology of acute LSD administration in healthy subjects

LSD (lysergic acid diethylamide) is used recreationally and is being investigated experimentally as an adjunct to psychotherapy for conditions such as depression, anxiety and cluster headache. Although small modern trials and historical reports exist, comprehensive safety data from larger, systematically collected samples are limited, and psychological safety concerns (for example, acute anxiety, suicidality, and persisting perceptual changes sometimes called "flashbacks" or HPPD) and physiological effects (notably cardiovascular stimulation) remain important considerations for potential medical use. The relevance of "set and setting" for psychological risk mitigation is highlighted alongside the need for more robust physiological safety data. Holze and colleagues therefore conducted a pooled safety pharmacology analysis of single-dose LSD administrations in healthy, psychiatrically screened adults. The analysis combined data from four randomized, double-blind, placebo-controlled, crossover Phase I studies performed in the same laboratory to characterise acute subjective, physiological and adverse effects up to 24 hours after dosing, to report any adverse events occurring later during study participation, and to examine basic liver and kidney laboratory markers before and after the studies. Dose exposure was analysed across a range of single LSD doses (nominally 25, 50, 100 and 200 µg of LSD base), with actual grouping adjusted using measured peak plasma LSD concentrations to address formulation uncertainties in two contributing studies.

The study is a pooled analysis of four double-blind, placebo-controlled, random-order, crossover Phase I trials conducted at the University Hospital Basel. Together the studies contributed 83 psychiatrically screened, physically healthy European/Caucasian participants (41 men, 42 women; mean age ~30 years) and a total of 131 single-dose LSD administrations. Washout periods between sessions were at least 10 days. Study protocols and conduct complied with ethical approvals and national authorisations, and participants provided informed consent. Dose administration differed between studies: Study 4 used well‑defined LSD formulations (25, 50, 100, 200 µg), whereas Studies 1 and 2 used gelatin capsules whose stability was uncertain; Study 3 used an ethanolic solution with analytically confirmed content. Because of formulation variability, the investigators reassigned dose groups for Studies 1–3 by using individual peak plasma LSD concentrations, with Study 4 serving as the reference for grouping. Full concentration–time profiles were available for all participants. Outcomes assessed included repeated Visual Analog Scales (VASs) for "any drug effect", "good drug effect", "bad drug effect" and "anxiety"; the 5 Dimensions of Altered States of Consciousness (5D-ASC) administered once after peak effects (reported here as Oceanic Boundlessness (OB) and Anxious Ego-Dissolution (AED)); physiological measures (systolic/diastolic blood pressure, heart rate, tympanic temperature) taken in duplicate after resting; and acute (10–12 h) and subacute (24 h) adverse effects measured with the List of Complaints (a 66-item scale). Severe anxiety was predefined as > 75% on the anxiety VAS. Onset, offset and duration of the subjective response were derived from the "any drug effect" VAS using 10% of individual maximal response as threshold. Blood chemistry and haematology were measured at screening and at an end-of-study visit (mean ~28 days after last LSD dose) to assess kidney and liver function; glomerular filtration rate was estimated by Cockcroft–Gault. Participants were also asked at study end about retrospective experience valence, the influence of setting, willingness to take LSD again, and any flashbacks; flashbacks were defined as transient reoccurrences of the altered state and were assessed only up to the end-of-study visit. For statistical analyses the investigators used ANOVAs with drug as a within-subject factor and dose as a between-subject factor, followed by Tukey post hoc tests for significant effects. Fisher's exact tests compared proportions. Paired t-tests compared laboratory measures between screening and end-of-study visits. The significance threshold was p < 0.05.

Re-grouping by measured peak plasma concentrations yielded four exposure groups corresponding approximately to 25, 50, 100 and 200 µg LSD base; the pooled dataset comprised 131 LSD administrations across 83 participants. Subjective effects on the VASs and 5D-ASC increased with dose. Positive acute effects rose steeply and reached a ceiling around 100 µg, whereas negative effects continued to increase up to 200 µg. Using maximal VAS ratings, proportions of administrations with > 50% "good drug effect" were 37%, 91%, 96% and 91% at the 25, 50, 100 and 200 µg exposure groups, respectively. In contrast, maximal ratings of > 50% for "bad drug effect" occurred in 0%, 9%, 27% and 31% at the same dose levels. Mean OB (Oceanic Boundlessness) ratings on the 5D-ASC were reported as approximately 10%, 25%, 41% and 44% at 25, 50, 100 and 200 µg, respectively; mean AED (Anxious Ego-Dissolution) ratings were about 3.4%, 13%, 20% and 22% for the same doses. Time-course metrics were dose dependent: mean effect durations (based on the "any drug effect" VAS and a 10% threshold) were 4.5 ± 2.4 h, 7.2 ± 2.5 h, 8.5 ± 3.2 h and 11 ± 4.6 h for the 25, 50, 100 and 200 µg groups, respectively. Time to onset and time to peak both shortened as dose increased (onset roughly 1.2 h at 25 µg down to 0.4 h at 200 µg; time to peak roughly 2.9 h at 25 µg down to 2.0 h at 200 µg). Physiological effects were generally moderate and dose dependent for heart rate and temperature; blood pressure increases were observed but without clear dose linearity. No participant reached systolic blood pressure > 180 mmHg. Tachycardia (> 100 beats/min) occurred in 0%, 6%, 20% and 25% of administrations at the 25, 50, 100 and 200 µg groups, respectively; single participants reached maximal heart rates of 129 and 121 beats/min at the 50 µg and 200 µg exposures. Peak tympanic temperature > 38 °C was observed in 0%, 11%, 7% and 34% of administrations across the 25, 50, 100 and 200 µg groups, respectively. Adverse effects measured by the List of Complaints increased versus placebo: mean acute LC scores were 5.6, 9.2, 12 and 13 at the 25, 50, 100 and 200 µg exposure levels. Common acute complaints included lack of concentration, lack of appetite, physical or emotional weakness, restlessness, impaired balance, headache, forgetfulness, dizziness, brooding and hypersensitivity to smells. Subacute complaints (24 h) frequently included tiredness, headache and reduced concentration. Between-session adverse events reported within 48 h included headache, migraine, common cold, gastroenteritis and gastrointestinal symptoms; frequencies were low and in some cases similar to placebo. Six subjects (7% of participants) reported transient flashback phenomena occurring 24–86 h after administration (mean ~43 ± 11 h); no persistent perceptual changes consistent with HPPD were reported up to the end-of-study visit. Laboratory markers of kidney and liver function (creatinine, estimated GFR, alanine aminotransferase, γ‑glutamyl transpeptidase) were unchanged at the end-of-study visit (mean ~28 days after last LSD). Haematology showed decreases in red blood cell counts and haemoglobin and increases in thrombocyte counts, changes attributed by the investigators to cumulative blood loss from repeated sampling rather than to LSD. White blood cell counts were stable. Participant experience metrics indicated that 75% were LSD-naïve; of 83 respondents about 69% stated they would consider taking LSD again, 35% said they might consider it, and small proportions would not take it again or would only consider it under controlled conditions. Overall retrospective valence was positive in 72%, neutral in 19% and negative in 8% of respondents. Most participants (80%) reported that the controlled setting was important and reassuring.

Holze and colleagues interpret the pooled data as indicating that single-dose LSD up to 200 µg produces dose-dependent subjective and physiological effects that are generally well tolerated in psychiatrically healthy adults when administered in a controlled clinical setting. Positive subjective effects (for example, "good drug effect" and Oceanic Boundlessness) emerged at lower exposures and reached a ceiling around 100 µg, while negative subjective effects (for example, anxiety and Anxious Ego-Dissolution) increased with dose up to 200 µg. The investigators therefore describe a therapeutic dose window in which positive acute responses predominate over negative ones for most participants. Cardiovascular and thermoregulatory effects were described as mild to moderate: mild hypertension occurred in roughly half of LSD administrations, moderate hypertension in ~5% and tachycardia in ~15% overall, with no instances of severe hypertension (systolic > 180 mmHg) observed. Peak temperatures did not exceed the maximum measured under placebo and remained well below hyperpyrexia thresholds. The authors position these findings as consistent with prior, smaller studies and with the notion that dose or plasma concentration is the primary determinant of acute response magnitude; they note that plasma LSD concentrations correlate strongly with subjective effects. Comparisons with other psychoactive agents are made empirically: psilocybin produced comparable sympathomimetic activation at clinical doses, whereas MDMA produced larger blood pressure increases and more frequent tachycardia in some comparisons, a difference the investigators ascribe to MDMA's adrenergic actions in addition to serotonergic effects. Several limitations are acknowledged. First, two pooled studies used formulations of uncertain stability, necessitating reassignment of dose groups by peak plasma concentration; while this improves exposure classification, it does not eliminate interindividual pharmacokinetic variability or potential misclassification related to metabolic differences (for example, CYP2D6 polymorphisms). Second, study designs varied (single- versus multiple-dose sessions for some participants), prior substance exposure differed across individuals, participants were psychiatrically healthy and mostly young which limits generalisability to patient populations and to older or medically comorbid patients, and the pooled sample size (83 participants, 131 administrations) is insufficient to detect rare adverse events. Long-term follow-up was also not available. Strengths include randomised, double-blind, placebo-controlled designs conducted in a single laboratory, standardised data collection, and availability of full plasma concentration–time profiles across participants. In terms of implications, the investigators conclude that the principal risks of single-dose LSD administration in controlled settings are psychological rather than physiological, that negative acute experiences were generally transient and manageable with verbal support (benzodiazepines were not required in these studies), and that no evidence of persisting perceptual disturbance was found within the follow-up window. They stress that safety in therapeutic populations and with different administration regimens (for example, microdosing or repeated frequent dosing) remains to be investigated further.

Single-dose administrations of LSD up to 200 µg, given infrequently in a controlled clinical setting to psychiatrically healthy adults, were not associated with serious acute psychological or physical harm in this pooled analysis. LSD produced dose-dependent but generally moderate cardiovascular stimulation and predominantly positive subjective effects, although transient anxiety and other unpleasant experiences occurred in a minority of participants. The investigators conclude that these safety data do not raise concerns about single, infrequent clinical use of LSD in controlled settings, but they emphasise that risks and benefits of LSD in therapeutic populations and with different dosing regimens require further study.