Pharmacokinetics and subjective effects of a novel oral LSD formulation in healthy subjects
Friederike Holze, Urs Duthaler, Patrick Vizeli, Felix Müller, Stefan Borgwardt, Matthias E. Liechti
British Journal of Clinical Pharmacology, March 2019
Doi : 10.1111/bcp.13918
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 placebocontrolled, 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 (Cmax) values (range) of 1.7 (1.0–2.9) ng/mL were reached at a tmax (range) of 1.7 (1.0–3.4) hours after drug administration. The plasma halflife (t1/2) 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 Cmax values (range) of 0.11 (0.07–0.19) ng/mL were reached at a tmax (range) of 5 (3.2–8) hours. The t1/2 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.
KEYWORDS : concentration–effect relationship, LSD, metabolism, O‐H‐LSD, pharmacodynamics,
What is already known about this subject
• There is an increasing number of clinical studies using LSD in humans.
• There is very limited data on the human pharmacokinetics of LSD.
• There are no controlled pharmacokinetic studies with validly defined doses of LSD.
What this study adds
• Subjective responses and pharmacokinetics of LSD and its metabolites are described after controlled administration of a known oral dose of LSD.
• The data serves as a reference to relate plasma concentrations of LSD with its effects in clinical studies and intoxications.
1 | INTRODUCTION
Lysergic acid diethylamide (LSD) is a prototypical hallucinogen that has been widely used for recreational and personal purposes.1 Additionally, LSD is increasingly used in experimental research2-6 and for the treatment of psychiatric patients.7,8 However, blood plasma concentrations were not measured in most LSD studies.3,6 Thus, unknown are the concentrations of LSD at the time points at which pharmacodynamic (PD) outcomes were collected. Only limited data are available on the pharmacokinetics (PK) of LSD. A study in five male subjects reported a mean plasma elimination half‐life of LSD of 175 minutes after intravenous administration (2 μg/kg9). Another study used non‐systematic blood sampling after the administration of 160 μg LSD in 13 subjects up to 2.5–5 hours; however, because of the sparse and short sampling, PK parameters could not be derived.10 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.11-13 However, the formulation that was used in these studies did not have long‐term stability.
Therefore, we produced a novel oral LSD solution with documented long‐term stability (single dose units) and higher content uniformity than is currently being used in experimental studies in healthy subjects (ClinicalTrials.gov no. NCT03604744, NCT03321136, and planned studies), clinical trials in patients (ClinicalTrials.gov no. NCT03153579), and in the context of individually authorized patient treatments (compassionate use in Switzerland). The primary aim of the present study was to describe the PK of this LSD formulation in healthy subjects. A second goal was to describe subjective drug effects of LSD and to link these effects to changes in plasma concentrations over time within‐subjects to derive EC50 values using PK/PD modelling. We also analysed concentrations of the LSD metabolites 2‐ oxo‐3‐hydroxy LSD (O‐H‐LSD) and N‐desmethyl‐LSD (nor‐LSD) in plasma. O‐H‐LSD and nor‐LSD are the main metabolites of LSD that are detected in urine.12,14-17 However, only one previous study quantified these metabolites in human plasma.13 Finally, we compared LSD exposure in plasma between the novel solution and previous capsule formulation. The present study is different from our previous PK studies mainly because it used a novel oral formulation with documented content stability.