Abstract
Growing interest has been seen in using lysergic acid diethylamide (LSD) in psychiatric research and therapy. However, no modern studies have evaluated subjective and autonomic effects of different and pharmaceutically well-defined doses of LSD. We used a double-blind, randomized, placebo-controlled, crossover design in 16 healthy subjects (eight women, eight men) who underwent six 25 h sessions and received placebo, LSD (25, 50, 100, and 200 µg), and 200 µg LSD 1 h after administration of the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor antagonist ketanserin (40 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain-derived neurotrophic factor levels, and pharmacokinetics up to 24 h. The pharmacokinetic-subjective response relationship was evaluated. LSD showed dose-proportional pharmacokinetics and first-order elimination and dose-dependently induced subjective responses starting at the 25 µg dose. A ceiling effect was observed for good drug effects at 100 µg. The 200 µg dose of LSD induced greater ego dissolution than the 100 µg dose and induced significant anxiety. The average duration of subjective effects increased from 6.7 to 11 h with increasing doses of 25–200 µg. LSD moderately increased blood pressure and heart rate. Ketanserin effectively prevented the response to 200 µg LSD. The LSD dose–response curve showed a ceiling effect for subjective good effects, and ego dissolution and anxiety increased further at a dose above 100 µg. These results may assist with dose finding for future LSD research. The full psychedelic effects of LSD are primarily mediated by serotonin 5-HT2A receptor activation.
Highlights
Lysergic acid diethylamide (LSD) is a classic serotonergic psychedelic with a broad history of early psychiatric research and recreational use [1, 2]
Subjective drug effects Subjective effects over time on the visual analog scales (VASs) and Adjective Mood Rating Scale (AMRS) are shown in Fig. 1 and Supplementary Fig. S1, respectively
LSD elicited dose-dependent subjective responses starting at the 25 μg dose, which produced significant “any drug effects” compared with placebo (p < 0.05)
Summary
Lysergic acid diethylamide (LSD) is a classic serotonergic psychedelic with a broad history of early psychiatric research and recreational use [1, 2]. No recent data are available on the acute effects of different well-defined psychoactive doses of LSD in humans and within the same study. The present study evaluated acute subjective and autonomic effects of LSD across a range of relevant doses in healthy subjects. In contrast to previous studies [10,11,12], we used pharmaceutically well-defined doses of LSD. Complex acute subjective effects of LSD were determined using validated psychometric instruments that are used internationally and in trials with patients and have been shown to be useful for predicting therapeutic long-term responses [16,17,18,19]. The present LSD dose–response data may be useful for dose finding in future LSD research in healthy subjects and patients
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