Classic serotonergic psychedelics, including mescaline, lysergic acid diethylamide (LSD), and psilocybin, induce profound alterations in consciousness. While all three primarily act via 5-HT2A receptor stimulation, they differ in their pharmacological profiles and pharmacokinetic properties. Mescaline's potency is significantly lower than LSD and psilocybin, requiring higher doses. It also exhibits a slower onset of action. Previous studies comparing these substances have been limited by methodological shortcomings. This study aimed to directly compare the acute subjective, autonomic, and pharmacokinetic effects of psychoactive-equivalent doses of mescaline, LSD, and psilocybin in a rigorous, controlled setting. The researchers hypothesized that the subjective effects would be comparable across substances due to their shared 5-HT2A agonism, but that mescaline might exhibit greater acrodiniotropic properties due to its activity at other receptors. The study also explored the role of oxytocin and brain-derived neurotrophic factor (BDNF) in the psychedelic experience, given their potential involvement in therapeutic mechanisms.

The introduction extensively reviews existing literature on the three psychedelics, highlighting their historical and cultural uses (mescaline and psilocybin in ethnomedical and spiritual contexts, LSD's use in research and recreation), their current investigation as therapeutic tools for psychiatric disorders, and their recreational use. The review discusses the substances' varying receptor binding profiles (mescaline's affinity for 5-HT2A, 5-HT1A, and adrenergic α2 receptors; LSD's potent 5-HT2A agonism and additional interactions with 5-HT2B, 5-HT1A, and dopamine receptors; psilocin's 5-HT2A agonism and SERT inhibition) and differences in their reported potencies. It also cites the limited number of direct comparisons between these psychedelics in previous research, particularly the lack of robust studies on mescaline in recent decades. This lack of comparative data is presented as the primary motivation for the current study.

The study employed a randomized, double-blind, placebo-controlled, crossover design. Thirty-two healthy participants (16 men, 16 women; mean age 29 ± 4 years) were recruited, with exclusion criteria including a history of major psychiatric disorders, certain medications, excessive substance use, and various health conditions. Participants underwent four experimental sessions, receiving one of four conditions: 300 mg or 500 mg mescaline, 100 µg LSD, 20 mg psilocybin, or placebo. The mescaline dose was escalated from 300 mg to 500 mg for the second half of participants due to initial observations suggesting 300 mg was sub-threshold compared to the LSD and psilocybin doses. The allocation to the substance conditions was randomized and blinded, but not the mescaline dose. Subjective effects were measured using visual analog scales (VAS), the Drug Rating Scale (DRS), the States of Consciousness Questionnaire (SD-ASC), and the Mystical Experience Questionnaire (MEQ). Autonomic effects were assessed through repeated measurements of blood pressure, heart rate, body temperature, and pupil diameter. Adverse effects were recorded using a List of Complaints (LC). Plasma concentrations of mescaline, LSD, and psilocybin were determined by high-performance liquid chromatography. Pharmacokinetic parameters were estimated using non-compartmental methods. Statistical analyses involved repeated measures analysis of variance (ANOVA) with Tukey's post-hoc tests.

The 500 mg mescaline dose, LSD, and psilocybin produced comparable subjective effects across various psychometric scales. The 300 mg mescaline dose showed weaker effects. Autonomic effects were moderate across all three active substances, with psilocybin inducing a significantly higher increase in diastolic blood pressure compared to LSD. LSD showed a trend towards increased heart rate compared to psilocybin. Mescaline had a significantly longer duration of action than LSD and psilocybin, primarily due to a slower onset and longer time to reach maximal effect, despite similar elimination half-lives. Plasma oxytocin levels were significantly increased after mescaline and LSD, but not psilocybin. No significant changes in plasma BDNF levels were observed for any substance. Pharmacokinetic parameters for all substances were determined, revealing a dose-proportional relationship and close relationship between mescaline plasma concentrations and subjective effects. Participants did not reliably distinguish between the active substances during or after the sessions, indicating that subjective experiences were primarily driven by dose rather than specific substance.

The study's findings support the hypothesis that at equivalent psychoactive doses, mescaline, LSD, and psilocybin induce largely similar subjective effects, likely mediated by their shared 5-HT2A agonism. The differences in duration of action are attributable to pharmacokinetic properties rather than fundamentally different qualitative effects. The comparable autonomic responses and tolerability profiles suggest that clinical safety considerations are similar across these substances. The study's dose equivalence findings—500 mg mescaline hydrochloride = 100 µg LSD base = 20 mg psilocybin dihydro—provide valuable information for future research and clinical trials using these psychedelics. The lack of BDNF alteration differs from some previous studies and warrants further investigation.

This study demonstrated that, at equivalent psychoactive doses, mescaline, LSD, and psilocybin produce largely similar subjective effects, with differences primarily in their durations of action. These findings have implications for dose-finding in future research and for psychedelic-assisted therapy. Further research is needed to explore subtle qualitative differences and to investigate the effects of these substances in patient populations.

The study did not perfectly achieve dose equivalence at baseline, necessitating the dose escalation of mescaline midway through. The mescaline dose comparison was not blinded or randomized. The sample was limited to healthy, mostly experienced psychedelic users, potentially limiting the generalizability of results to treatment-naive patients. The psychometric tools may not have been sufficiently sensitive to detect subtle qualitative differences in subjective experiences. Finally, the study used plasma samples for BDNF, which may be a less reliable approach compared to serum samples.