Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide in healthy subjects

This analysis of data from two double-blind, placebo-controlled studies (n=40) on the pharmacokinetics of LSD (100 and 200µg) found dose-proportional effects. The effects lasted on average 8.2 and 11.6 hours, there was a strong correlation between the blood-plasma level of LSD and subjective effects, but this was only found within-subjects (over time), not between subjects.

Abstract

“Background and Objective: Lysergic 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.

Methods: We 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.

Results: Geometric 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.

Conclusions: The 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.”

Authors: Patrick C. Dolder, Yasmin Schmid, Andrea E. Steuer, Thomas Kraemer, Katharina M. Rentsch, Felix Hammann & Matthias E. Liechti

Notes

This study analysis data from Schmid and colleagues (2015) and Dolder and colleagues (2015).

Summary

Abstract

LSD was administered orally to 24 and 16 subjects in placebo-controlled, double-blind, cross-over studies. Pharmacokinetic parameters were determined using compartmental modeling, and concentration-effect relationships were described using pharmacokinetic-pharmacodynamic modeling.

Results: Maximum plasma concentrations of LSD were reached 1.4 and 1.5 h after administration, respectively, and the plasma half-life was 2.6 h. Subjective peak effects were reached 2.8 and 2.5 h after administration, respectively.

The pharmacokinetics of oral LSD was dose proportional and first-order elimination up to 12 h. The effects of lysergic acid diethylamide were related to changes in plasma concentrations over time, with no evidence of acute tolerance.

1 Introduction

Lysergic acid diethylamide (LSD) is a prototypical hallucinogen that has seen worldwide interest with regard to pharmacology, psychiatry, and society at large. However, basic pharmacokinetic information on LSD is largely missing, and we recently reported the first pharmacokinetic data for orally administered LSD (200 lg) in 16 male and female subjects.

LSD has been shown to affect various neuronal correlates of brain activation, but the time point at which peak concentrations are reached and the actual or predicted concentrations of LSD at the time point at which pharmacodynamic outcomes were collected are unknown.

Researchers have correlated subjective drug effects with brain functional magnetic resonance imaging (fMRI) data, but it is unclear how LSD exposure in the body is linked to subjective effects in these studies.

A study was conducted to evaluate the effects of 100 and 200 mg LSD on healthy subjects. The results were compared with the effects of 100 mg LSD.

2.1 Study Design

We performed pharmacokinetic data analysis on two similar previously performed studies using double-blind, placebo-controlled, cross-over designs with at least 7 days between experimental test sessions.

2.2 Participants

Forty healthy participants were recruited from the University of Basel campus via an online advertisement. Twenty-four subjects participated in Study 1 (100 lg) and 16 subjects participated in Study 2 (200 lg). No substances were detected during the study. The participants were asked to abstain from excessive alcohol consumption and not use medications that could potentially interact with the study drug.

2.3 Study Procedures

Each study included a screening visit, psychiatric interview, two 25-h experimental sessions, and an end-of-study visit. The participants were resting in hospital beds except when going to the restroom, and were given LSD or placebo at 9:00 A.M.

2.4 Study Drug

Lysergic acid diethylamide was administered in a single oral dose of 100 or 200 lgasa capsule, and the 200-lg dose was also used in LSD-assisted psychotherapy in patients.

2.5.1 Blood Sampling

Blood samples were collected before and after LSD administration. The plasma was stored at -20 °C and later at -80 °C until analysis within 12 months.

2.5.3 Subjective Mood

Visual analog scales were used to assess subjective effects over time, including 1 h before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16 and 24 h after drug administration.

2.5.4 Vital Signs

Blood pressure, heart rate, and body temperature were measured repeatedly 1 h before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 24 h after drug administration.

2.6 Pharmacokinetic Analyses and Pharmacokinetic-Pharmacodynamic Modeling

The model fit was not improved by a two-compartment model based on visual inspection of the plots. A sigmoidal maximum effect (Emax) model was selected for all pharmacodynamic effects, and the best Akaike information criterion values were obtained using the classic pharmacokinetic/pharmacodynamic link model module in WinNonlin.

2.7 Statistical Analyses

The subjective and autonomic effects of LSD were determined as a difference from placebo in the same subject at the corresponding time point. The associations between concentrations and effects were assessed using Pearson correlations and multiple regression analysis.

3.1 Pharmacokinetics

The plasma concentration-time curves for LSD show that it can be quantified up to 16 h in all 16 subjects and up to 24 h in 15 subjects. The Tmax and plasma half-lives are also similar for both doses, consistent with dose-proportional pharmacokinetics.

3.2 Pharmacodynamics

Lysergic acid diethylamide produced robust increases in ”any drug effect” and ”good drug effect” ratings, and transient ”bad drug effect” was reported in some subjects. After administration of 100 lg of LSD, the subjective response was onset in 0.8 h and offset in 9.0 h. The time to peak drug effect was 2.8 h and the time to peak effect was 0.4 h. LSD increased blood pressure, heart rate, and body temperature.

3.3 Pharmacokinetic-Pharmacodynamic Modeling

Figures 1 and 2 show the relationship between LSD concentrations and LSD effects over time, and Table 2 shows the predicted concentrations of LSD at the effect site that produced half-maximal effects. The EC50 and keo values could not be determined in some subjects.

LSD concentration did not correlate with the predicted maximal response on the ”any drug effect” VAS, and there were no significant associations between plasma LSD concentrations and different pharmacodynamic effects for matched time points across subjects within dose groups.

Plasma concentrations of LSD did not predict the effects of LSD in all subjects, but a close relationship was found over time within subjects.

4 Discussion

The pharmacokinetics and concentration-effect relationship of LSD after oral administration of 100 lg were studied. Compartmental modeling predicted geometric mean peak plasma concentrations of 1.3 ng/mL, 1.4 h after administration of the 100-lg dose, and mean Cmax values of 3.1 ng/mL, 1.5 h after administration of the 200-lg dose.

The present data on the plasma concentration-time curves of LSD are important because they provide detailed information on the presence of LSD in the human body. Additionally, the present study provides estimates of LSD concentrations in plasma over time for studies that did not perform blood sampling.

The time-concentration curve for 75-lg LSD intravenous preparation remains unknown. However, early studies reported rapid onset and peak effects approximately 30 min after administration.

In the recent studies that used the 75-lg dose administered as the base, subjective effects began within 5 – 15 min and peaked 45 – 90 min after intravenous dosing. In the present study, the effect began and peaked 48 and 170 min later, respectively, after oral administration of LSD 100 lg.

After intravenous administration, a drug is rapidly diluted and distributed within the blood, peak plasma concentrations are reached rapidly, and elimination begins immediately. The Tmax for ”any drug effect” after intravenous administration can be predicted to occur at approximately 70 and 50 min.

LSD produced robust and high subjective ”any drug effect” and ”good drug effect” in almost all of the subjects. The subjective and autonomic effects established themselves relatively slowly, with lag times of 2.8 and 2.5 h, respectively, and 1.1 and 0.6 h, respectively, after the peak LSD concentrations were reached.

No evidence of acute tolerance was found for the pharmacodynamic outcome measures of LSD, and the subjective effects lasted 8 and 11 h, respectively, after administration of the 100- and 200-lg doses.

The present analyses typically found no correlations between LSD concentrations and the effects of LSD across subjects within dose groups. This is likely because the effects of LSD are close to maximal in most subjects and the variability in LSD plasma concentrations is small.

5 Conclusion

Pharmacokinetic data for oral LSD showed that it had dose-proportional pharmacokinetics and first-order elimination up to 12 h, and a close plasma concentration – effect relationship within subjects over time.