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

This placebo-controlled, double-blind, cross-over case study (n=27) investigated the pharmacokinetics and subjective effects under controlled administration of a known oral LSD (100 μg) in healthy subjects (13 males and 14 females). The study showed that LSD produced high subjective “good drug effect” in almost all of the participants as compared to “bad drug effects” which were not found in every participant, confirming that anxiety is associated with higher LSD concentrations. Contrary to previous findings, the current study showed the close association of LSD concentrations and LSD response over time within each subject as demonstrated in the PK/PD testing. This testing is useful in finding the presence and concentration of LSD in the body.

Abstract

“Aims The aim of the present study was to characterize the pharmacokinetics and exposure–subjective response relationship of a novel oral solution of lysergic acid diethylamide (LSD) that was developed for clinical use in research and patients.

Method LSD (100 μg) was administered in 27 healthy subjects using a placebo-controlled, double-blind, cross-over design. Plasma levels of LSD, nor-LSD, and 2-oxo-3-hydroxy-LSD (O-H-LSD) and subjective drug effects were assessed up to 11.5 hours.

Results First-order elimination kinetics were observed for LSD. Geometric mean maximum concentration (C_max) values (range) of 1.7 (1.0–2.9) ng/mL were reached at a t_max (range) of 1.7 (1.0–3.4) hours after drug administration. The plasma half-life (t_1/2) was 3.6 (2.4–7.3) hours. The AUC_∞ was 13 (7.1–28) ng·h/mL. No differences in these pharmacokinetic parameters were found between male and female subjects. Plasma O-H-LSD but not nor-LSD (< 0.01 ng/mL) concentrations could be quantified in all subjects. Geometric mean O-H-LSD C_max values (range) of 0.11 (0.07–0.19) ng/mL were reached at a t_max (range) of 5 (3.2–8) hours. The t_1/2 and AUC_∞ values of O-H-LSD were 5.2 (2.6–21) hours and 1.7 (0.85–4.3) ng·h/mL, respectively. The subjective effects of LSD lasted (mean ± SD) for 8.5 ± 2.0 hours (range: 5.3–12.8 h), and peak effects were reached 2.5 ± 0.6 hours (range 1.6–4.3 h) after drug administration. EC₅₀ values were 1.0 ± 0.5 ng/mL and 1.9 ± 1.0 ng/mL for “good” and “bad” subjective drug effects, respectively.

Conclusion The present study characterized the pharmacokinetics of LSD and its main metabolite O-H-LSD. The subjective effects of LSD were closely associated with changes in plasma concentrations over time.”

Authors: Friederike Holze, Urs Duthaler, Patrick Vizeli, Felix Müller, Stefan Borgwardt & Matthias E. Liechti

Summary

1 | INTRODUCTION

Lysergic acid diethylamide (LSD) is a prototypical hallucinogen that is increasingly used in experimental research and for the treatment of psychiatric patients.

PD outcomes were collected, but PK parameters could not be derived. A mean plasma elimination halflife of 175 minutes was reported after intravenous administration (2 g/kg9). We recently reported the first comprehensive PK data for orally administered LSD. In this study, we used a novel oral LSD formulation with documented longterm stability (single dose units) and higher content uniformity than is currently being used in experimental studies in healthy subjects, clinical trials in patients, and compassionate use in Switzerland.

2.1 | Study design

We performed a doubleblind, placebocontrolled, crossover study with four experimental 12hour test sessions. Only the novel LSD and placebo data are presented because the sampling time was too short to provide full concentration time curves.

The study was approved by the local ethics committee and was conducted in accordance with the Declaration of Helsinki. All subjects provided written consent before participating.

2.2 | Participants

Twentynine healthy participants were recruited from the University of Basel campus via online advertisement. Of these, 27 completed the study, 13 males and 14 females. We excluded all subjects with the following criteria: pregnancy, personal or family history of major psychiatric disorders, use of medications that may interfere with the study drug, chronic or acute physical illness, tobacco smoking, illicit drug use within the last 2 months, and illicit drug use during the study.

What is already known about this subject

There is very limited data on the human pharmacokinetics of LSD. The data presented here relate plasma concentrations of LSD with its effects in clinical studies and intoxications.

The participants were not allowed to drink xanthine-containing liquids after midnight before the study day, and did not regularly use medications that could potentially interact with the study drug. Five participants had previously used a hallucinogen, including LSD, one to four times during their lives.

2.3 | Study procedures

The study included a screening visit, psychiatric interview, four 12 hour experimental sessions and an endofstudy visit. The participants rested in hospital beds, could interact with the investigator, and listened to music via headphones.

2.4 | Study drug

LSD was administered as a single oral dose in a solution to be administered orally in 1 mL of 96% ethanol according to GMP. The LSD content was 96.2 0.3 g(n = 6) after production and the solution was stable for longer than the study period.

2.5.1 | Blood sampling

Blood samples were collected before and after LSD administration. The plasma was stored at -20°C for longterm storage.

2.5.2 | Analysis of LSD and metabolite concentrations

LSD, OHLSD, norLSD and isoLSD levels were analysed in human plasma by ultrahighperformance liquid chromatography tandem mass spectrometry (UHPLC – MS/MS).

A sample of 50 liters of plasma was extracted with 150 liters of acetonitrile that contained 0.1 ng/mL LSDd3 and 0.25 ng/mL OHLSDd10 of the internal standards (ISs). The sample was loaded on the analytical column using a third pump and a flow rate of 0.1 to 0.6 mL/min within the first 0.5 minutes.

The flow rate of the analytical column was linearly decreased from 0.5 to 0 mL/min in the first 0.5 minutes of each run, and the mobile phase B concentration was increased from 10% to 95% between 0.5 and 2.75 minutes to elute the three analytes.

The analytes were detected by MRM in the positive mode with the interface temperature set at 500°C. The pharmacokinetic data were quantified using MultiQuant 3.0.1 software.

2.5.3 | Subjective mood

Subjective effects were assessed using Visual Analog Scales before, 1.5, 2, 3, 3.5, 4.5, 5.5, 6.5, 7.5, 9.5 and 11.5 hours after LSD administration.

pharmacokinetic‐pharmacodynamic modelling

All analyses were performed using Phoenix WinNonlin 6.4 (Certara, Princeton, NJ, USA). A onecompartment model with firstorder input, firstorder elimination, and no lag time was used to determine the pharmacokinetic parameters. The PK model was fitted and evaluated, and the predicted concentrations were then used as an input to the PD model. A sigmoid maximum effect (Emax) model was selected for all PD effects, and the relationship between estimated effectsite concentrations and LSD effects was best described by a sigmoid model.

2.7 | Statistical analyses

Comparisons of PK parameters between the solution and capsule were made using ttests. Associations between peak concentrations and peak effects across subjects were assessed using Pearson correlations.

3.1 | Pharmacokinetics

LSD and OHLSD concentrations could be quantified in all subjects and at all time points. There were no sex differences in the PK parameters, and no differences in the PK of LSD between tobacco smokers and nonsmokers.

pharmacokinetic‐pharmacodynamic modelling

LSD produced robust increases in “any drug effect” and “good drug effect” VAS ratings, as well as “ego dissolution” (Figure S3). The variability in intensity in subjective drug effects is illustrated in the “any drug effect,””good drug effect” and “bad drug effect” curves, respectively.

LSD had EC50 values of 1.1 0.4 ng/mL and Emax values of 1.0 0.5 ng/mL for “any drug effect”, “good drug effect”, and “ego dissolution”, respectively.

The Cmax of LSD did not correlate with the subjective effects of LSD across subjects after the use of the same dose in all participants.

3.3 | Pharmacokinetic and pharmacokinetic‐pharmacodynamic comparison with LSD capsules

The modelpredicted geometric mean (CV%, 95% confidence interval [CI]) Cmax of the LSD solution was higher compared with the LSD capsule, and the modelpredicted LSD AUC values were higher compared with the LSD capsule. Additional analyses were performed to explore differences in absorption between the two formulations. The onset time needed to reach a minimum plasma LSD concentration of 0.3 ng/mL was significantly shorter and also less variable after administration of the solution compared with the capsule.

The PK of the two formulations were similar, with the exception that the EC50 value for “any drug effect” was lower for the capsule compared with the solution.

4 | DISCUSSION

The present study characterized the PK and subjective effects of a novel LSD solution that is intended for clinical research and use. The results are generally similar to those in previous studies, with the exception of higher Cmax and AUC values.

We expected a faster onset of action and more rapid absorption with the oral solution compared with the capsules, but the absorption coefficients and tmax values were not significantly different between the two formulations. Additionally, a threshold plasma LSD level was reached significantly faster with the solution.

The terminal t1/2 value of LSD should not depend on the type of formulation that is used.

The average AUC value for LSD was 13.3 and 8.1 ngh/mL in the present study and previous study, respectively. Although the oral drinking solution of LSD had higher oral bioavailability than the capsule formulation of LSD, the true LSD content of the previously used LSD capsules may have been lower than reported. Analytical tests on unused old LSD capsules performed years after study completion indicated a marked reduction of LSD content, suggesting that the actual LSD doses used were likely already lower than indicated during the studies.

Based on the results of different qualitycontrol measures, analytical findings, and clinical effects, we surmise that the previous studies actually used less LSD than reported. Although we cannot exclude possible differences in bioavailability, previous studies may have used lower doses of LSD than the present study, and the clinical response to 75 g of intravenous LSD was not significantly different from the oral 100 g dose.

In the present study, LSD produced high subjective “good drug effects” in almost all of the subjects, and low subjective “bad drug effects” in only a few subjects. The subjective LSD response was similar in intensity, onset and duration in both the novel LSD solution and the previously used capsule formulation.

The present study confirmed the previous finding11 that LSD concentrations do not predict the effects of LSD over time within each subject, but rather there is a close relationship over time withinsubjects.

The present study has limitations, such as using data from different studies that included different subjects, and it was not able to characterize the absorption and early distribution phase of LSD. However, it has notable strengths, such as including both male and female subjects and providing quality assurance data.