Pharmacokinetics, pharmacodynamics and urinary recovery of oral lysergic acid diethylamide (LSD) administration in healthy participants

Lysergic acid diethylamide (LSD) is a classical psychedelic whose principal pharmacology involves partial agonism at serotonin 5-HT2A receptors. Earlier human studies of oral LSD across a wide dose range (5–200 µg) have generally shown dose-proportional increases in plasma concentrations, peak levels around 1.5 hours, and first-order elimination with reported half-lives of about 2.7–4.1 hours. Subjective effects such as "any drug effect" also rose dose-proportionally up to about 100 µg, with some ceilinging at higher doses, while unpleasant effects and ego dissolution increased at higher doses. Prior work also reported that LSD is extensively metabolised and that only small fractions of an administered dose appear unchanged in urine, but those urinary data derive from a single-dose study with potential formulation stability concerns and therefore leave uncertainty about urinary recovery across doses within the same participants. This analysis aimed to fill that gap by describing urinary recovery of LSD and its primary metabolite O‑H‑LSD after two analytically confirmed oral doses (85 µg and 170 µg LSD base) administered within the same healthy participants, and to replicate and confirm prior pharmacokinetic and pharmacokinetic–pharmacodynamic (PK–PD) findings for these doses. The objective was both to characterise plasma PK and PD relationships and to quantify urinary excretion and renal clearance for each dose, providing data relevant to dosing, metabolism, and potential dose adjustments in clinical settings.

The study used a double-blind, randomised, placebo-controlled, crossover design with five treatment conditions overall; for this analysis only the two LSD dose conditions and placebo were analysed. Washout intervals between sessions were at least 10 days. Test sessions lasted 25 hours, began at 09:00 with drug administration, and included supervised overnight stays. Participants received a standardised breakfast about 30 minutes before dosing and standard lunch and dinner later in the day. Outcome measures were collected for 24 hours after dosing. Twenty-eight healthy participants were enrolled. The extracted text reports typical exclusion criteria including current use of medications that could interact with the study drugs (for example antidepressants, antipsychotics, sedatives), significant acute or chronic physical illness (abnormal findings on physical examination, ECG, or laboratory tests), heavy smoking (>10 cigarettes/day), substantial lifetime illicit drug use (>10 times, excluding THC), recent/ongoing illicit drug use (within 2 months) and positive urine drug tests during the study. Participants were asked to limit alcohol intake in the days prior to sessions. LSD was administered as an ethanolic oral solution of LSD freebase (Lipomed AG), prepared to good manufacturing practice standards. Each dosing unit contained 85 µg LSD in 1 mL of 96% ethanol; the analytically measured content was 84.5 ± 0.98 µg LSD base. The 85 µg base dose corresponds to approximately 124 µg LSD tartrate. Placebo solution consisted of ethanol alone and was matched in appearance and taste. Pharmacokinetic sampling included blood draws pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours post-dose. Urine was collected in intervals 0–8, 8–16 and 16–24 hours. Plasma and urine samples were stored frozen and analysed using a validated ultra-high-performance liquid chromatography tandem mass spectrometry method. Lower limits of quantification (LLOQ) were 10 pg/mL for plasma LSD and O‑H‑LSD, and 10 pg/mL (LSD) and 50 pg/mL (O‑H‑LSD) for urine. Pharmacokinetic analyses used Phoenix WinNonlin. Non‑compartmental analyses yielded Cmax and Tmax directly; terminal elimination rate (λz), AUC0–24 and AUC∞ were calculated in standard fashion. A one‑compartment model with first‑order input and elimination (no lag time) was applied for compartmental modelling after non‑compartmental assessment; visual inspection and Akaike information criterion values did not justify a two‑compartment model. The PK model produced individual predicted concentrations which were then used as fixed inputs to PK–PD modelling. A first‑order effect‑site equilibration rate constant (ke0) linked effect‑site concentrations to plasma, and a sigmoidal Emax model (EC50, Emax, γ) was used to describe subjective VAS outcomes. Emax was bounded between 0% and 100% and a 10% of individual maximal response threshold defined onset/offset and duration. Renal clearance was calculated as urinary recovery (ng) divided by AUC24 (ng·h/mL).

Plasma pharmacokinetics followed the expected one‑compartment, first‑order profile and were dose‑proportional between the two LSD doses. Mean peak plasma concentrations (Cmax) of LSD were 1.8 ng/mL after 85 µg and 3.4 ng/mL after 170 µg. Reported terminal half‑lives averaged about 3.7–4.0 hours; half‑lives derived from non‑compartmental analysis were slightly longer than those from the compartmental model, but differences were small. Interindividual variability for Cmax was moderate, with coefficients of variation around 32%. Urinary recovery data indicate extensive metabolism and limited renal excretion of unchanged parent drug. On average, 1% of the administered oral LSD dose was recovered unchanged in urine within 24 hours, while approximately 16% of the dose was recovered as O‑H‑LSD over the same interval. Most of the urinary recovery occurred within the first 8 hours after ingestion, and amounts recovered in the 0–8 h and 8–16 h urine intervals were approximately similar for O‑H‑LSD. Calculated renal clearance of LSD averaged 56 ± 37 mL/h. Subjective effects tracked plasma concentrations closely and were well described by the PK–PD model. For the "any drug effect" VAS, reported onsets averaged 0.6 ± 0.2 h (85 µg) and 0.4 ± 0.2 h (170 µg), peaks at 2.5 ± 0.5 h and 2.2 ± 0.6 h, and offsets at 10 ± 3.1 h and 11 ± 3.6 h, yielding mean effect durations of 9.3 ± 3.2 h (range 5.7–17 h) and 11 ± 3.7 h (range 5.8–20 h) for 85 µg and 170 µg, respectively. The higher dose produced earlier onset, longer duration and greater intensity. Modelled maximal responses (Emax, mean ± SD) for "any drug effect" were 70 ± 24% (85 µg) and 78 ± 21% (170 µg). For "good drug effect" Emax values matched those for "any drug effect"; "bad drug effect" Emax values were much lower (12 ± 16% and 17 ± 21%), and "ego dissolution" Emax values were 56 ± 31% and 74 ± 25% for the lower and higher doses respectively. EC50 estimates fell in a similar range across the different subjective measures. Counter‑clockwise hysteresis was observed in concentration–effect plots for all subjective qualities and both doses, consistent with no evidence of acute pharmacodynamic tolerance over the 24‑hour observation period.

Friederike and colleagues interpret their findings as a replication and confirmation of earlier human LSD pharmacokinetic studies, demonstrating dose‑proportional plasma concentrations and metabolite profiles across the two tested doses and validating the one‑compartment, first‑order elimination model. The reported mean Cmax values (1.8 and 3.4 ng/mL for 85 and 170 µg) and mean half‑life around 3.7–4.0 hours are consistent with prior work. The PK–PD analysis similarly reproduced previously observed timing and magnitude of subjective effects and showed no acute tolerance. A novel contribution is the within‑subject characterisation of urinary recovery for two analytically confirmed doses. The authors report that only about 1% of an oral LSD dose is excreted unchanged in urine within 24 hours while roughly 16% appears as O‑H‑LSD, and that urinary recovery is dose‑proportional. They argue that this linear relationship between administered dose and urinary recovery enhances understanding of LSD metabolism and clearance and may assist in clinical pharmacology tasks such as dose adjustment for populations with altered metabolism (for example CYP2D6 slow metabolizers) and in anticipating drug–drug interactions. The investigators note several limitations and uncertainties. Pharmacokinetic measurements were conducted in the fed state, which could affect absorption and bioavailability, so the influence of food warrants further study. Comparison with an earlier single‑dose urinary study is complicated by differences in assay sensitivity (previous LLOQ was 100 pg/mL versus 10 pg/mL here) and possible instability of the formulation used in that prior work. The authors also highlight that most contemporary studies have used an ethanolic LSD freebase formulation and that pharmacokinetics of LSD tartrate—commonly encountered in non‑clinical settings—remain largely uncharacterised; they recommend head‑to‑head comparisons of freebase, tartrate and stable intravenous formulations to define bioavailability and formulation effects. Interindividual variability in plasma concentrations may be partially explained by genetic polymorphisms such as CYP2D6, a point the authors raise as relevant to personalised dosing considerations. In terms of clinical dosing implications, the authors suggest that doses tested here are representative of clinical practice and note that 200 µg has been used in patient studies but sits at the higher end of well‑tolerated dosing; they propose that approximately 150 µg might be an appropriate high dose for future clinical trials. Overall, the study is presented as methodological validation and as providing new, directly comparable urinary recovery data across two doses within the same participants.