Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide in Healthy Subjects

Abstract

Background and ObjectiveLysergic acid diethylamide (LSD) is used recreationally and in clinical research. The aim of the present study was to characterize the pharmacokinetics and exposure–response relationship of oral LSD.MethodsWe analyzed pharmacokinetic data from two published placebo-controlled, double-blind, cross-over studies using oral administration of LSD 100 and 200 µg in 24 and 16 subjects, respectively. The pharmacokinetics of the 100-µg dose is shown for the first time and data for the 200-µg dose were reanalyzed and included. Plasma concentrations of LSD, subjective effects, and vital signs were repeatedly assessed. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-effect relationships were described using pharmacokinetic-pharmacodynamic modeling.ResultsGeometric mean (95% confidence interval) maximum plasma concentration values of 1.3 (1.2–1.9) and 3.1 (2.6–4.0) ng/mL were reached 1.4 and 1.5 h after administration of 100 and 200 µg LSD, respectively. The plasma half-life was 2.6 h (2.2–3.4 h). The subjective effects lasted (mean ± standard deviation) 8.2 ± 2.1 and 11.6 ± 1.7 h for the 100- and 200-µg LSD doses, respectively. Subjective peak effects were reached 2.8 and 2.5 h after administration of LSD 100 and 200 µg, respectively. A close relationship was observed between the LSD concentration and subjective response within subjects, with moderate counterclockwise hysteresis. Half-maximal effective concentration values were in the range of 1 ng/mL. No correlations were found between plasma LSD concentrations and the effects of LSD across subjects at or near maximum plasma concentration and within dose groups.ConclusionsThe present pharmacokinetic data are important for the evaluation of clinical study findings (e.g., functional magnetic resonance imaging studies) and the interpretation of LSD intoxication. Oral LSD presented dose-proportional pharmacokinetics and first-order elimination up to 12 h. The effects of LSD were related to changes in plasma concentrations over time, with no evidence of acute tolerance.Trial registration: NCT02308969, NCT01878942.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0513-9) contains supplementary material, which is available to authorized users.

A Single Dose of LSD Does Not Alter Gene Expression of the Serotonin 2A Receptor Gene (HTR2A) or Early Growth Response Genes (EGR1-3) in Healthy Subjects

“…In the present study, we found no evidence of acute pharmacological tolerance within 12 h of acute LSD administration at a dose of 100 μg as documented in detail elsewhere (Dolder et al, 2017). Similarly, no acute tolerance was observed after single-dose administration of 200 μg LSD in humans within 24 h (Dolder et al, 2015b, 2017).…”

Pharmacokinetics and subjective effects of a novel oral LSD formulation in healthy subjects

“…Visual Analog Scales (VASs) were repeatedly used to assess subjective effects over time . The VASs included separate measures for “any drug effect,” “good drug effect,” “bad drug effect”, and “the boundaries between myself and my surroundings seemed to blur” (ego dissolution) and were presented as 100 mm horizontal lines (0–100%) marked from “not at all” on the left to “extremely” on the right.…”

“…The predicted concentrations were then used as an input to the PD model by treating the PK parameters as fixed and using the classic PK/PD link model module in WinNonlin. The model used a first‐order equilibrium rate constant ( k eo ) that related the observed PD effects of LSD to the estimated LSD concentrations at the effect site and accounted for the lag between the plasma and effect site concentration curves . A sigmoid maximum effect ( E max ) model (EC 50 , E max , γ) was selected for all PD effects: E = ( E max × C p h )/( C p h + EC 50 h ), in which E is the observed effect, C p is the plasma LSD concentration, E max is the maximal effect and h is the Hill slope using WinNonlin.…”

“…We recently reported the first comprehensive PK data for orally administered LSD. In two studies, the PK of LSD were determined after the administration of 100 and 200 μg LSD in 24 and 16 healthy subjects, respectively . However, the formulation that was used in these studies did not have long‐term stability.…”

Effects of psilocybin therapy on personality structure

“…Recent pilot studies point to the potential of psychedelic‐assisted therapy to treat conditions including tobacco and alcohol addiction, obsessive‐compulsive disorder , end of life anxiety/depression , major depression , and TRD – (see Carhart‐Harris & Goodwin, 2017 for a review ). Intriguingly, the treatment effect in these trials appears to last for several months – much longer than the pharmacological presence of the actual compounds .…”