Clin Pharmacokinet DOI 10.1007/s40262-017-0513-9 ORIGINAL RESEARCH ARTICLE Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide in Healthy Subjects 1,3 1 2 2 Patrick C. Dolder • Yasmin Schmid • Andrea E. Steuer • Thomas Kraemer • 3 1 1 Katharina M. Rentsch • Felix Hammann • Matthias E. Liechti Ó The Author(s) 2017. This article is published with open access at Springerlink.com Abstract repeatedly assessed. Pharmacokinetic parameters were Background and Objective Lysergic acid diethylamide determined using compartmental modeling. Concentration- (LSD) is used recreationally and in clinical research. The effect relationships were described using pharmacokinetic- aim of the present study was to characterize the pharma- pharmacodynamic modeling. cokinetics and exposure–response relationship of oral LSD. Results Geometric mean (95% confidence interval) maxi- Methods We analyzed pharmacokinetic data from two mum plasma concentration values of 1.3 (1.2–1.9) and 3.1 published placebo-controlled, double-blind, cross-over (2.6–4.0) ng/mL were reached 1.4 and 1.5 h after admin- studies using oral administration of LSD 100 and 200 lgin istration of 100 and 200 lg LSD, respectively. The plasma 24 and 16 subjects, respectively. The pharmacokinetics of half-life was 2.6 h (2.2–3.4 h). The subjective effects las- the 100-lg dose is shown for the first time and data for the ted (mean ± standard deviation) 8.2 ± 2.1 and 200-lg dose were reanalyzed and included. Plasma con- 11.6 ± 1.7 h for the 100- and 200-lg LSD doses, respec- centrations of LSD, subjective effects, and vital signs were tively. Subjective peak effects were reached 2.8 and 2.5 h after administration of LSD 100 and 200 lg, respectively. A close relationship was observed between the LSD con- centration 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. Electronic supplementary material The online version of this Conclusions The present pharmacokinetic data are article (doi:10.1007/s40262-017-0513-9) contains supplementary important for the evaluation of clinical study findings (e.g., material, which is available to authorized users. functional magnetic resonance imaging studies) and the interpretation of LSD intoxication. Oral LSD presented & Matthias E. Liechti [email protected] dose-proportional pharmacokinetics and first-order elimi- nation up to 12 h. The effects of LSD were related to 1 Division of Clinical Pharmacology and Toxicology, changes in plasma concentrations over time, with no evi- Department of Biomedicine and Department of Clinical dence of acute tolerance. Research, University Hospital Basel, Hebelstrasse 2, 4031 Basel, Switzerland Trial registration: NCT02308969, NCT01878942. 2 Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland 3 Laboratory Medicine, University Hospital Basel, Basel, Switzerland P. C. Dolder et al. second goal was to link the plasma concentration changes Key Points over time within subjects to the acute subjective and autonomic effects of LSD to derive half-maximal effective The pharmacokinetics of lysergic acid diethylamide concentration (EC50) values using standard pharmacoki- was dose proportional and the subjective effects netic-pharmacodynamic modeling. were related to the time course of plasma Researchers have correlated subjective drug effects with concentrations within subjects, with no evidence of brain functional magnetic resonance imaging (fMRI) data acute tolerance. [12, 13, 16, 17]. This approach likely detects significant correlations for subjective effects that show large between- Between-subject differences in plasma subject variance but not for subjective effects of the sub- concentrations of lysergic acid diethylamide did not stance that are consistently present in all subjects. Plasma predict the subjective response within a dose group concentrations of LSD have not been determined in any of and when plasma concentrations were above the the published LSD fMRI studies to date; therefore, it is half-maximal effective concentration of the response unclear how LSD exposure in the body is linked to sub- measures. jective effects in these studies. Therefore, a further goal of the present study was to assess associations across subjects between plasma exposure to LSD and the pharmacody- namic effects at corresponding times. 1 Introduction The present study combined data from two similar clinical studies that tested 100- and 200-lg doses of LSD in Lysergic acid diethylamide (LSD) is the prototypical hal- 24 and 16 healthy subjects, respectively. The pharma- lucinogen [1, 2]. Lysergic acid diethylamide has seen cokinetic data and concentration–effect relationship of worldwide interest with regard to pharmacology, psychia- 100 lg LSD are presented. Similar data on 200 lg LSD try, and society at large. Lysergic acid diethylamide con- have been previously reported [23]. In the present study, tinues to be used for recreational and personal purposes [3]. plasma concentrations after 200 lg LSD administration Additionally, considerable interest has been seen in its were newly measured using a more sensitive and specific therapeutic potential [4–9], and experimental clinical analytical method. The results were included for compar- research with LSD has recently been reinitiated [10–23]. isons with the 100-lg data and to newly evaluate However, basic pharmacokinetic information on LSD is dose/concentration–response effects. The subjective effects largely missing. A small study in five male subjects of LSD have been reported for both doses, but relationships reported a mean plasma elimination half-life of LSD of to plasma exposure were not evaluated [21]. 175 min after intravenous administration (2 lg/kg) [24]. Another non-systematic study sampled blood after admin- istration of LSD 160 lg in 13 subjects up to 2.5–5 h but 2 Methods because of sparse and short sampling could not derive pharmacokinetic parameters [25]. We recently reported the 2.1 Study Design first pharmacokinetic data for orally administered LSD (200 lg) in 16 male and female subjects [23]. The con- We performed the pharmacokinetic data analysis on two centrations of LSD were maximal after 1.5 h (median) and similar previously performed studies [21–23] using double- gradually declined to very low levels by 12 h, with an blind, placebo-controlled, cross-over designs with two elimination half-life of 3.6 h [23]. experimental test sessions (LSD and placebo) in a balanced Recent studies have reported the effects of LSD on order. Study 1 used a dose of LSD 100 lg and placebo in various neuronal correlates of brain activation 24 subjects. Study 2 used LSD 200 lg and placebo in 16 [12, 13, 16, 17]. However, plasma exposure and thus the subjects. The washout periods between sessions were at actual presence of LSD in the body have not been docu- least 7 days. The studies were registered at ClinicalTri- mented in any of these studies to date. Unknown are the als.gov (NCT02308969, NCT01878942). time point at which peak concentrations are reached and the actual or predicted concentrations of LSD at the time 2.2 Participants point at which pharmacodynamic outcomes were collected. Therefore, the primary goal of the present study was to Forty healthy participants were recruited from the describe the pharmacokinetics of a controlled administra- University of Basel campus via an online advertisement. tion of oral LSD by assessing the plasma concentration- Twenty-four subjects [12 men, 12 women; age time profile of two doses of LSD (100 and 200 lg). A 33 ± 11 years (mean ± standard deviation); range Pharmacokinetics-Pharmacodynamics of LSD 25–60 years; body weight: 68 ± 8 kg, 55–85 kg) partici- 2.4 Study Drug pated in Study 1 (100 lg), and 16 subjects (eight men, eight women; age 29 ± 6 years; range 25–51 years; body Lysergic acid diethylamide (d-lysergic acid diethylamide weight: 72 ± 12 kg, 52–98 kg) participated in Study 2 hydrate, high-performance liquid chromatography pur- (200 lg). The inclusion and exclusion criteria were iden- ity [99%; Lipomed AG, Arlesheim, Switzerland) was tical for both studies. The exclusion criteria were administered in a single oral dose of 100 or 200 lgasa age \25 years or [65 years, pregnancy (urine pregnancy capsule (Bichsel Laboratories, Interlaken, Switzerland). test at screening and before each test session), personal or Both doses were within the range of doses that are taken for family (first-degree relative) history of major psychiatric recreational purposes [1]. The 200-lg dose (the same disorders (assessed by the semi-structured clinical inter- capsules) was also used in LSD-assisted psychotherapy in view for Diagnostic and Statistical Manual of Mental patients [6], and intravenous doses of 75–100 lg have been Disorders, 4th edition, Axis I disorders by the study used in fMRI studies in healthy subjects [13]. physician and an additional interview by a trained psy- chiatrist), use of medications that may interfere with the 2.5 Measures study drug, chronic or acute physical illness (abnormal physical examination, electrocardiogram, or hematological 2.5.1 Blood Sampling and chemical blood analyses), tobacco smoking (more than ten cigarettes/day), lifetime prevalence of illicit drug use Blood was collected into lithium heparin tubes before and more than ten times (except for tetrahydrocannabinol), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 h after LSD illicit drug use within the previous 2 months, and illicit drug administration. The 0.5-, 1.5-, and 2.5-h samples were not use during the study. We performed urine drug tests at collected in Study 1 (100 lg). The blood samples were screening and before each test session, and no substances immediately centrifuged, and the plasma was rapidly stored were detected during the study.