Lysergic acid diethylamide (LSD) and psilocybin are classic serotonergic psychedelics used recreationally and showing promise in treating various psychiatric and neurological disorders. Both substances alter consciousness via serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor stimulation. LSD additionally affects dopamine D1-3 receptors, while psilocin (psilocybin's active metabolite) inhibits the serotonin transporter. However, whether these receptor binding differences lead to varying subjective effects in humans remains unstudied. Prior research investigated either psilocybin or LSD individually, leaving their acute effects, similarities, and dose equivalence unclear. This study directly compared the acute subjective, autonomic, and endocrine effects of LSD and psilocybin using two doses of each substance and placebo in the same subjects. Validated psychometric instruments assessed acute subjective effects, using tools employed internationally in both healthy subjects and therapeutic patient studies. Plasma LSD and psilocin concentrations were measured over 24 hours to provide pharmacokinetic parameters, crucial for potential medicinal development given the strong link between plasma concentrations and subjective effects. Prior research indicated dose-dependent cardiovascular stimulation and endocrine influence from both substances; however, potential differences between them were uninvestigated. Therefore, blood pressure, heart rate, body temperature, and endocrine effects (cortisol, prolactin, oxytocin) were assessed. Plasma levels of brain-derived neurotrophic factor (BDNF), a potential neurogenesis marker, were also measured, given previous studies showing BDNF increases following psychedelic administration.

The introduction section cites numerous studies exploring the therapeutic potential of LSD and psilocybin for various conditions, including anxiety disorders, major depressive disorder, cluster headaches, and migraines. These studies mostly focused on either LSD or psilocybin alone, lacking direct comparisons of their effects. The introduction highlights the need for a study directly comparing the acute effects of these two substances to understand potential differences and similarities, including the issue of dose equivalence. Several cited studies investigated the pharmacological mechanisms of action for LSD and psilocybin, including their interactions with the 5-HT2A receptor, other serotonin receptors, and dopamine receptors. Additionally, relevant pharmacokinetic studies were mentioned, establishing a foundation for understanding drug absorption, distribution, metabolism, and excretion.

This study employed a double-blind, placebo-controlled, crossover design with five experimental sessions (placebo, 100 µg LSD, 200 µg LSD, 15 mg psilocybin, 30 mg psilocybin). The order of administration was randomized and counterbalanced, with at least 10 days between sessions. 28 healthy participants (14 men, 14 women, mean age 35 ± 9.4 years) were recruited. Exclusion criteria included age outside 25–65 years, pregnancy, personal/family history of major psychiatric disorders, use of interfering medications, chronic/acute illness, heavy smoking, substantial illicit drug use (except cannabis), and recent drug use. Participants were instructed to limit alcohol intake. LSD was administered orally (100 µg/mL in 96% ethanol), with placebo consisting of ethanol alone. Psilocybin was given in capsules (15mg or 30mg), with mannitol as a placebo. A double-dummy method was used to maintain blinding. Sessions were conducted in a quiet hospital room with a single investigator present. Urine tests were conducted to confirm drug abstinence. Baseline measurements were taken before the 9:00 AM administration of the drug. Outcome measures were repeatedly assessed for 24 hours, with standardized meals provided. Subjective effects were measured using visual analog scales (VAS), Adjective Mood Rating Scale (AMRS), 5 Dimensions of Altered States of Consciousness (5D-ASC) scale, and States of Consciousness Questionnaire (including MEQ43 and MEQ30). Onset, maximal effect, offset, and duration of subjective effects were analyzed using a PK-PD link model. Autonomic effects (blood pressure, heart rate, body temperature, pupil size) were repeatedly measured. Adverse effects were tracked using a List of Complaints (LC). Endocrine effects (cortisol, prolactin, oxytocin, BDNF) were assessed via plasma level measurements. Plasma LSD and psilocin concentrations were determined by ultra-high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated non-compartmentally using Phoenix WinNonlin. Data analysis involved repeated-measures ANOVA with Tukey post hoc tests.

Comparable subjective effects were observed with 100 and 200 µg LSD and 30 mg psilocybin. The 15 mg psilocybin dose produced significantly weaker effects. 200 µg LSD increased ego-dissolution, impaired control, and anxiety more than 100 µg LSD, but only ineffability significantly more than 30 mg psilocybin. LSD's effects lasted significantly longer than psilocybin's. Psilocybin increased blood pressure more, while LSD increased heart rate more; however, rate-pressure product showed comparable cardiostimulant effects for high doses. Both substances showed dose-proportional pharmacokinetics and first-order elimination. Both LSD doses and the high psilocybin dose produced very similar subjective effects, with differences primarily related to dose rather than substance. Autonomically, psilocybin raised blood pressure more and caused greater pupil dilation impairment than LSD, although LSD elicited a more pronounced heart rate increase. Both substances increased cortisol, prolactin, and oxytocin levels but did not impact BDNF levels. The study showed good blinding, with placebo being easily identified but active substances often confused with each other, suggesting the quality of subjective effects is dose-dependent rather than substance-dependent.

This study provided a direct comparison of LSD and psilocybin, contrasting with previous research that focused on each substance individually. The findings suggest that the subjective effects of high doses of LSD and psilocybin are remarkably similar qualitatively, differing primarily in the duration of action due to pharmacokinetic differences in elimination half-life. The dose-response relationship for LSD appeared to plateau at 100 µg for positive effects, with negative effects increasing at 200 µg. Psilocybin showed a clearer dose-response relationship within the tested range. The relatively short duration of psilocybin's effects might have therapeutic advantages by limiting potential adverse experiences, while LSD's longer duration could be beneficial for some applications. The observed autonomic differences warrant further investigation, especially concerning the differential effects on blood pressure and heart rate. The study suggests an approximate dose equivalence of 100 µg LSD to 20 mg psilocybin and 150 µg LSD to 30 mg psilocybin. The good blinding success further supports the conclusion that subjective experiences are more dose-dependent than substance-specific, at least within the dose ranges tested.

This study provides valuable data for dose-finding in future research and psychedelic-assisted therapies, estimating a dose equivalence of approximately 100 µg LSD to 20 mg psilocybin and 150 µg LSD to 30 mg psilocybin. While no significant qualitative differences were found in the altered states of consciousness induced by either substance, psilocybin showed a shorter duration of action. Further research is needed to explore these findings in various settings and patient populations.

This study was conducted in a highly controlled laboratory setting with only healthy participants, limiting the generalizability of the findings to real-world settings and patient populations with psychiatric disorders. The specific formulations of LSD and psilocybin used may also influence the results. The relatively small sample size may also impact the statistical power of the study.