Absolute Oral Bioavailability and Bioequivalence of LSD Base and Tartrate in a Double-Blind, Placebo-Controlled, Crossover Study

Arikci and colleagues situate their work in the context of renewed clinical interest in lysergic acid diethylamide (LSD) as a potential treatment for psychiatric and neurological disorders and note that both freebase and tartrate salt formulations are used in research and recreational settings. They identify two gaps: whether LSD base and tartrate formulations are pharmacokinetically and pharmacodynamically equivalent when dosed by freebase content, and the lack of a direct determination of LSD's absolute oral bioavailability in humans. To address these gaps, the investigators conducted a randomized, double-blind, placebo-controlled, five-period crossover study in healthy volunteers. The study compared three oral formulations (an ethanolic freebase drinking solution, an aqueous tartrate drinking solution, and a rapid dissolvable tablet [RDT] containing freebase) and an intravenous tartrate formulation, with the primary aims of testing bioequivalence among oral formulations and determining absolute oral bioavailability at approximately 80 μg freebase equivalent. The design also enabled comparison of pharmacodynamic and safety outcomes between routes and formulations.

The trial used a double-blind, double-dummy, placebo-controlled, five-period crossover design with randomized, counterbalanced order and washouts of at least 10 days. Twenty healthy participants (10 men, 10 women; mean age 37 ± 11 years; mean body weight 70 ± 12 kg) completed all sessions. Exclusion criteria included age < 25 or > 65 years, pregnancy/breastfeeding, personal or first-degree family history of major psychiatric disorders, interfering medications, significant medical illness, heavy tobacco use, recent illicit drug use, or lifetime psychedelic use > 20 times. Recruitment was from volunteers and word of mouth; all provided informed consent. The study was approved by relevant Swiss ethics and regulatory bodies and registered on ClinicalTrials.gov. The five test conditions were: (i) oral ethanolic LSD freebase solution (nominal 80 μg freebase in 1 mL 96% ethanol), (ii) oral aqueous LSD tartrate solution (117 μg tartrate yielding ~81 μg freebase in 1 mL water for injection), (iii) an RDT containing LSD freebase (initial content measured and adjusted for stability), (iv) intravenous LSD tartrate (diluted to 2 mL saline and infused over 9 minutes as four aliquots), and (v) matching placebos using a double-dummy approach. Measured analytical contents were reported (ethanolic solution mean 83.1 ± 1.59 μg; tartrate aqueous solution mean 81.0 ± 1.43 μg). Because RDT content declined over time, the investigators estimated individual RDT doses based on measured stability data and dosing date, yielding an estimated mean RDT dose of 80.5 ± 4.1 μg. Sessions began at 08:00; doses were given at 09:00 after a standardised light breakfast. Blood for pharmacokinetic (PK) analysis was sampled pre-dose and repeatedly up to 24 hours (multiple early timepoints up to 12 h and later at 14, 16, and 24 h). Plasma LSD and the main metabolite 2-oxo-3-hydroxy-LSD (O‑H‑LSD) were quantified by validated HPLC–tandem mass spectrometry with a lower limit of quantification of 10 pg/mL. Pharmacokinetic analyses used non-compartmental methods in Phoenix WinNonlin 8.4, with dosing-time adjustments (intravenous dosing time set to the mean of the infusion) and use of the analytically confirmed dose for dose-corrected parameters. Bioequivalence testing followed European Medicines Agency guidelines using the ethanolic LSD base solution as reference and predefined acceptance limits of 90% confidence intervals (CI) of 80.00–125.00% for log-transformed Cmax and AUC∞. Additional analyses included a one-compartment compartmental model for oral formulations and a two-compartment micro model for the intravenous formulation, plus a formal PK–PD analysis using predicted individual concentrations as input to sigmoid Emax models. Subjective effects were repeatedly assessed with Visual Analog Scales (VAS) at numerous timepoints up to 24 h, with additional questionnaires including the Adjective Mood Rating Scale (AMRS), the 5D-ASC, the Psychedelic Experience Scale (PES), and the MEQ (administered at 24 h). Autonomic measures (blood pressure, heart rate, tympanic temperature) were recorded at the same timepoints as PK sampling. Adverse effects were captured by the List of Complaints at 12 and 24 h and by spontaneous reports. Statistical analyses for repeated measures used repeated-measures ANOVA with formulation as the within-subject factor and Tukey post hoc tests; significance threshold was p < 0.05.

All 20 participants completed the five sessions and were included in the primary analyses; three participants dropped out after the first visit (two withdrew after experiencing challenging effects following intravenous LSD; one was excluded due to inadequate venous access for PK sampling). Plasma LSD and O‑H‑LSD were quantifiable at all scheduled timepoints. The oral formulations produced broadly similar concentration–time curves and comparable non-compartmental PK parameters: similar Cmax, tmax, elimination half-life (t1/2), and AUC∞. The intravenous tartrate formulation produced higher Cmax and AUC∞ values than the oral administrations. Formal bioequivalence testing using the ethanolic LSD base solution as reference met regulatory criteria for all oral formulations. Reported 90% CIs were: for the RDT, 93–111% (AUC∞) and 94–114% (Cmax); for oral LSD tartrate, 92–111% (AUC∞) and 99–120% (Cmax). Absolute oral bioavailability (F), calculated as AUC∞ oral / AUC∞ intravenous, was approximately 80–81% for all oral formulations. Compartmental modelling results and PK–PD model outputs were reported but specific EC50 or Emax values are not clearly provided in the extracted text. Subjective pharmacodynamics were similar across the three oral formulations. All oral forms produced comparable onset, time to peak, peak intensity, duration, and total effect (AUEC) on the primary VAS item “any drug effect,” and they elicited similar scores on the 5D-ASC, PES/MEQ, and AMRS. Intravenous LSD produced a significantly faster onset and earlier peak, although effect duration was similar to oral dosing. Compared with oral tartrate, intravenous LSD yielded greater ratings of “any drug effect” (p < 0.01), “good drug effect” (p < 0.05), “stimulated” (p < 0.05), and “ego dissolution” (p < 0.05). Intravenous LSD also produced higher ratings of anxiety: on the VAS, anxiety was higher versus all oral formulations (p < 0.01 vs oral base; p < 0.001 vs RDT and tartrate). Additional comparisons showed greater “bad drug effect” and “nausea” after intravenous dosing compared with oral base and tartrate, and higher 5D-ASC and 3D-ASC total scores versus oral tartrate (p < 0.01) and versus RDT (p < 0.05), but not versus oral base. Autonomic effects were modest: all LSD formulations produced moderate increases in blood pressure, while only intravenous LSD significantly increased heart rate versus placebo and versus oral formulations. Adverse events were generally transient and included nausea, headache, loss of appetite, concentration difficulties, inner tension, tremor (acute), and tiredness, headache and insomnia (subacute). Three flashback phenomena were reported (two after oral base, one after oral tartrate). No serious adverse events occurred. Blinding was maintained between oral formulations, but intravenous LSD was identified correctly by 80% of participants at the end of the session and by 95% at study end.

Arikci and colleagues interpret their findings as demonstrating that the crystal form—freebase versus tartrate salt—does not meaningfully alter LSD absorption or distribution when dosing is expressed in freebase equivalents, and that a rapid dissolving tablet formulation with comparable freebase content behaves pharmacokinetically and pharmacodynamically like liquid oral formulations. All oral formulations satisfied regulatory bioequivalence criteria for Cmax and AUC∞ (90% CI within 80–125%), supporting interchangeable use of these formulations in research and clinical contexts when dosed by freebase content. The investigators report an absolute oral bioavailability of approximately 80–81%, a direct estimate that is slightly higher than an earlier indirect estimate of ~71%. They highlight that intravenous administration produced faster onset and larger early subjective effects, including more anxiety, nausea, and “bad drug effect,” which the authors attribute plausibly to the more rapid onset of action with bolus intravenous dosing and reduced time to accommodate the experience. A notable observation was a lag of roughly 1 hour between plasma peak and subjective effect peak after intravenous dosing, a phenomenon the authors note is unexplained and contrasts with findings for some other psychedelics. Strengths listed by the investigators include use of a validated analytical assay, dense PK sampling to 24 h covering ~96–98% of AUC, a within-subject design of 20 participants (exceeding common regulatory minima), and balanced sex representation. Limitations they acknowledge include the risk of contamination when using the same intravenous catheter for dosing and sampling (though the team reports measures to minimise and no indication of contamination in the data), and a gradual decline of LSD content in the RDT over 18 months that required dose estimation and correction. The authors conclude that the demonstrated bioequivalence of common oral LSD formulations and the measured high oral bioavailability are important for interpreting prior and future LSD research and for selecting formulations in clinical trials.