Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide (LSD) compared with stimulants and entactogens in healthy subjects

Classic psychedelics such as the semi-synthetic ergoline and serotonin (5-HT)2A receptor
agonist lysergic acid diethylamide (LSD) are back in research as potential treatment for various
psychiatric and somatic disorders, e.g. depression, anxiety disorders and cluster headache.
This thesis includes three clinical trials to add knowledge to the pharmacology of LSD. The
first study investigated the distinction of LSD as prototypical psychedelic from the class of
entactogens represented by 3,4-methylenedioxymethamphetamine (MDMA) and the class of
stimulants represented by d-amphetamine. Twenty-eight healthy participants were included in a
randomized, double-blind, placebo-controlled trial. This study was the first study that used an
oral LSD formulation with an exactly known dose and confirmed stability. The second study
investigated the dose-effect relationship of LSD and the role of the 5-HT2A receptor by adding the
5-HT2A receptor antagonist ketanserin prior to the administration of a high dose of LSD (200 μg).
Sixteen healthy participants were included in a randomized, double-blind, placebo-controlled
trial. Treatment conditions were 25 μg, 50 μg, 100 μg, 200 μg LSD, and 200 μg LSD + ketanserin.
The third study investigated LSD microdoses by performing a study using 5, 10, and 20 μg LSD in
healthy subjects. Twenty-four healthy participants were included in this randomized, placebocontrolled,
double-blind trial.
All studies investigated the pharmacokinetics and pharmacokinetic-pharmacodynamic
relationship of LSD. Classic pharmacokinetic parameters as well as effect durations, onset, and
offset were assessed using modern PK-PD modeling techniques. The first two studies also
investigated subjective effects using well established methods and questionnaires such as the 5-
dimensions of altered states of consciousness (5D-ASC) scale, the mystical effects questionnaire
(MEQ), and visual analogue scales (VASs) to measure subjective effects over time. Furthermore,
autonomic effects were assessed including blood pressure, heart rate, body temperature, and
pupil size. Additionally, acute levels of brain-derived neurotrophic factor (BDNF) were assessed.
Summarized, results from the present thesis show that LSD can clearly be distinguished
from stimulants (e.g. d-amphetamine) and entactogens (e.g. MDMA) in terms of subjective
effects. LSD induced significantly higher changes in the acute state of consciousness and
promoted higher mystical-type experiences compared to MDMA and d-amphetamine. But, all of
the substances produced comparable increases in hemodynamic effects, body temperature, and
pupil size, indicating equivalent autonomic responses at the doses used. Furthermore, LSD
showed a dose-proportional pharmacokinetic profile for doses from 5-200 μg and effects were
closely linked with substance-concentrations in the blood. Subjective effects started at 10 μg LSD
suggesting this to be the cut-off for ‘microdosing’ and the maximum effect was reached at a dose
of 100 μg LSD. In addition, ‘bad drug effects’ seem to be associated with higher doses.
Pretreatment with ketanserin effectively prevented the response to 200 μg LSD. The full
psychedelic effects of LSD are therefore primarily mediated by 5-HT2A receptor activation.
Findings from this thesis are important for dose finding of LSD and the choice of substance
in future research for substance- assisted therapy.