Pharmacokinetics and concentration-effect relationship of oral LSD in humans

This double-blind, placebo-controlled, within-subjects study (n=16) evaluated the pharmacokinetic profile of oral LSD (200 μg) in humans. The analysis found that the acute subjective and sympathomimetic effects of LSD lasted for up to 12 hours and were closely linked to the plasma concentrations over time and showed no acute tolerance. This is the first such study and can act as a potential reference for the assessment of intoxication with LSD.

Abstract

“Background: The pharmacokinetics of oral lysergic acid diethylamide are unknown despite its common recreational use and renewed interest in its use in psychiatric research and practice.

Methods: We characterized the pharmacokinetic profile, pharmacokinetic-pharmacodynamic relationship, and urine recovery of lysergic acid diethylamide and its main metabolite after administration of a single oral dose of lysergic acid diethylamide (200 μg) in 8 male and 8 female healthy subjects.

Results: Plasma lysergic acid diethylamide concentrations were quantifiable (>0.1ng/mL) in all the subjects up to 12 hours after administration. Maximal concentrations of lysergic acid diethylamide (mean±SD: 4.5±1.4ng/mL) were reached (median, range) 1.5 (0.5–4) hours after administration. Concentrations then decreased following first-order kinetics with a half-life of 3.6±0.9 hours up to 12 hours and slower elimination thereafter with a terminal half-life of 8.9±5.9 hours. One percent of the orally administered lysergic acid diethylamide was eliminated in urine as lysergic acid diethylamide, and 13% was eliminated as 2-oxo-3-hydroxy-lysergic acid diethylamide within 24 hours. No sex differences were observed in the pharmacokinetic profiles of lysergic acid diethylamide. The acute subjective and sympathomimetic responses to lysergic acid diethylamide lasted up to 12 hours and were closely associated with the concentrations in plasma over time and exhibited no acute tolerance.

Conclusions: These first data on the pharmacokinetics and concentration-effect relationship of oral lysergic acid diethylamide are relevant for further clinical studies and serve as a reference for the assessment of intoxication with lysergic acid diethylamide.”

Authors: Patrick C. Dolder, Yasmin Schmid, Manuel Haschke, Katharina M. Rentsch & Matthias E. Liechti

Summary

Introduction

The pharmacokinetics of oral LSD in humans are unknown. A small PK study administered single intravenous doses of 2 g/kg in 5 healthy male human subjects and blood samples were taken up to 8 hours after administration.

The present study aimed to characterize the single-dose kinetics and PK-pharmacodynamic relationships of LSD in healthy male and female subjects.

LSD was administered in a single oral dose of 200 g. The pharmacokinetics are reported in detail elsewhere, but the acute subjective, autonomic, and endocrine effects are presented herein.

Study Design

The study used a double-blind, placebo-controlled, cross-over design and was approved by the Ethics Committee of the Canton of Basel, Switzerland and the Swiss Agency for Therapeutic Products. All subjects provided written informed consent.

Participants

Sixteen healthy subjects were included in the study, 8 men and 8 women; mean age SD: 28.6 6.2 years; range: 25 – 51 years. They were asked to abstain from excessive alcohol consumption between test sessions and particularly limit their use to 1 drink on the day before the test sessions.

Study Outline

The test sessions began at 8:15 AM with a urine sample, a pregnancy test, and baseline measurements. LSD or placebo was administered at 9:00 AM, and 24-hour blood samples were collected the following day.

Drugs

LSD was administered in gelatin capsules containing 100 g and corresponding placebo capsules. The dose was 2.84 g/kg body weight.

Blood and Urine Sampling

LSD and 2-oxo-3-hydroxy-LSD (O-H-LSD) were measured in blood and urine samples 1 hour before and 0.5, 1, 1.5, 2.5, 3, 4, 6, 8, 10, 12, 16 and 24 hours after LSD administration.

Analysis of LSD and O-H-LSD

LSD and O-H-LSD concentrations were determined in plasma and urine using a validated liquid-chromatography-tandem mass-spectrometry method.

The plasma concentration data were analyzed using noncompartmental methods using Phoenix WinNonlin 6.4 (Certara, Princeton, NJ). The terminal elimination rate constant and half-life were calculated using log-linear regression and extrapolation of the AUC 24 using z . We determined a half-life for LSD from T max to 12 hours using at least 3 data points from the concentration-time curve. This half-life does not describe the slower decrease in concentration of LSD observed in a subset of subjects beyond 12 hours or 16 hours.

Statistical Analyses

The pharmacokinetic parameters of LSD were described for 8 subjects of each sex, but the study was not sufficiently powered to exclude sex differences.

The primary pharmacodynamic study results were reported elsewhere. The pharmacodynamic effects of LSD were assessed as a difference from placebo in the same subject at the corresponding time point, and the area within the hysteresis was calculated using the trapezoidal rule.

A sigmoidal concentration-response model was fitted to the plasma concentration-effect data, and the equilibration half-life between plasma and the effect compartment was estimated using NCSS 2004 software.

Pharmacodynamic Measurements

Subjective effects were assessed repeatedly over time using visual analog scales, and vital signs were assessed repeatedly 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, and 24 hours after drug administration.

Results

LSD and O-H-LSD decreased in plasma concentrations following first-order kinetics up to 12 hours, with a half-life of 3.6 0.9 hours. In some subjects, a slower decrease in plasma concentrations was observed late in time between 12 and 24 hours.

We could not determine the pharmacokinetic profiles of LSD in male and female subjects. LSD and O-H-LSD were found in high concentrations in the urine of healthy volunteers. O-H-LSD was found to be 8-14 times more potent than LSD and appeared in the urine within the first 8 hours after administration.

PK-Pharmacodynamic Relationship

Figure 2 shows that there was a close relationship between the LSD concentration and its dynamic effects overt time. No hysteresis was found for heart rate, blood pressure, or bad drug effect, and counterclockwise hysteresis was observed for body temperature, pupil size, any drug effect, and good drug effect. The response to LSD was sigmoidal, with an E max dose-response curve for any drug effect and good drug effect, and no clockwise hysteresis for any concentration-effect curve.

Discussion

The present study determined the single-dose PK of oral LSD in humans. The half-life of 3.6 hours is close to the 3 hours previously observed in a small study that used intravenous LSD administration. In humans, O-H-LSD is the major metabolite of LSD detectable in urine, and O-H-LSD can be detected for a longer time than LSD after LSD administration. O-H-LSD is metabolized by cytochrome P450 enzymes, but the specific enzymes and mechanisms are unknown.

LSD has an oral bioavailability of 71%, which is similar to that of intravenous administration. The PK profiles were similar in male and female subjects, but sex differences in the PK of LSD need to be tested.

We found a close relationship between the plasma concentrations of LSD and the physiologic response or psychotropic effects of LSD over time. The unbound fraction of LSD in human plasma is unknown, but the concentrations in cerebrospinal fluid are similar to free LSD plasma concentrations. Pupil size was strongly increased at low concentrations of LSD, and the increase in pupil diameter was significant until 11 hours after LSD administration. The increase in blood pressure, heart rate, body temperature, and bad drug effects were only significant up to 5 hours after LSD administration.

No evidence of acute tolerance was observed, and counterclockwise hysteresis was observed early in time until the end of the assumed drug absorption phase. Only one other small study measured plasma LSD concentrations and concomitant pharmacodynamic effects. In contrast to repeated daily administration of LSD, tolerance to the subjective effects of MDMA was observed up to 4 days after continuous administration of MDMA. As a result, the pharmacodynamic effects of MDMA last significantly shorter than would be expected based on plasma levels.

MDMA produces acute tolerance through the release of endogenous serotonin and norepinephrine, whereas LSD produces acute tolerance through a direct interaction with the 5-HT 2A receptor.

We show that oral LSD has first-order kinetics and produces physiological and psychotropic effects lasting up to 12 hours.