Mescaline: The forgotten psychedelic

Psychedelics have a long history of ritual and therapeutic use, and classical serotonergic psychedelics are now being reconsidered for psychiatric disorders. Vamvakopoulou and colleagues note that mescaline (a naturally occurring phenylalkylamine found mainly in peyote and several Echinopsis species) is one of the oldest known hallucinogens, with archaeological evidence of use dating back thousands of years. However, research on mescaline has been limited since the international prohibition of psychedelics in the early 1970s, and clinical data are sparse relative to substances such as psilocybin, LSD and DMT. Indigenous and ceremonial use of mescaline-containing cacti has continued and is cited as a source of observational evidence about possible therapeutic benefits. This review sets out to summarise the pharmacology and behavioural effects of mescaline, encompassing preclinical receptor and animal studies, pharmacokinetics and toxicology, human physiological and psychological effects, neuroimaging work, and historical and contemporary therapeutic observations. The authors aim to collate what is known about mescaline’s mechanisms and effects and to identify gaps where modern controlled research is needed to assess clinical utility.

The extracted text presents the paper as a narrative review of preclinical and clinical literature rather than a primary experimental study. It compiles data from receptor-binding and activation studies, animal behavioural experiments (zebrafish, rodents, cats), pharmacokinetic and toxicology reports across species, human psychophysiology and neuroimaging studies, and historical and contemporary clinical or naturalistic observations. The extraction does not clearly report a formal methods section: there is no detailed description of search strategy, databases, date ranges, explicit inclusion/exclusion criteria, or a risk-of-bias or quality-assessment procedure for included studies. The authors organise findings into thematic sections (Receptors, Pharmacology, Animal behaviour, Kinetics, Physiological and psychological effects, Modern neuroscience, Therapeutic studies) and refer to summary tables for preclinical and clinical studies, but the prose does not specify systematic review methods or meta-analytic statistical approaches. Where numerical or experimental details are cited (for example, receptor EC50s, LD50s, pharmacokinetic parameters, and behavioural metrics), these are drawn from small single-laboratory studies or older reports. The review therefore appears to be a synthesis of available experimental and observational findings rather than a quantitative meta-analysis based on a prespecified protocol.

Receptor pharmacology: Across limited in vitro work, mescaline is described primarily as a serotonin 5HT2A/2C receptor agonist, with greater affinity for 5HT2A (reported 5HT2A EC50 ≈ 10 μM; EC50 is the concentration producing half-maximal activation). Activation potency for 5HT2B was reported as >20 μM. Mescaline also shows lower-affinity interactions with serotonin 5HT1A/2B, adrenergic α1A/α2A, dopaminergic D1/D2/D3 receptors, TAAR1, and with monoamine transporters DAT, NET and SERT. The authors note that receptor-screen data are sparse and derived from small studies that seldom used direct psychedelic comparators. Preclinical and behavioural findings: Animal studies report a range of dose-dependent behavioural effects. In rodents and zebrafish, mescaline produced anxiolytic-like effects, increases in locomotion and prosocial behaviours (e.g. enhanced shoaling in zebrafish), and increased investigatory behaviours in familiar settings. Mescaline induces the head-twitch response (HTR) in rodents—a behaviour correlated with 5HT2A agonism—with peak effects around 1 hour after dosing at certain doses; in mice an ED50 for HTR of 6.51 mg/kg was reported (ED50 denotes the dose producing half the maximal behavioural response). Dose–response patterns vary by species and measure, with some inverted-U relations (hyperlocomotion at moderate doses, hypolocomotion at high doses). Mescaline increased acoustic startle and reduced prepulse inhibition (PPI) in rats, effects that were blocked by 5HT2A/2C antagonists and absent in 5HT2A knock-out mice for locomotion, supporting a key role for 5HT2A signalling. In anaesthetised rats, mescaline dose-dependently suppressed spontaneous locus coeruleus firing (ED50 ≈ 0.85 mg/kg) while enhancing evoked reactivity, suggesting complex noradrenergic modulation. Some cat studies suggested dopaminergic contributions, since pre-treatment with serotonin or dopamine antagonists reduced mescaline’s characteristic behaviours. Pharmacokinetics and toxicology: Reported kinetics vary by species. In cats an IV half-life of about 2 hours was reported; in humans an average half-life of ≈ 6 hours is cited (half-life = time for blood concentration to fall by half). Tissue autoradiography in marmosets showed prolonged mescaline presence in hippocampus, amygdala and certain cortical areas up to 18 hours post-injection. Metabolism includes oxidative deamination to 3,4,5-trimethoxyphenylacetic acid (TMPA) via intermediates; CYP2C29 (in mice) and hepatic organic cation transporter OCT1 (in vitro data from HEK293 cells) are implicated in hepatic handling. Reported urinary excretion figures differ across reports in the text (one section cites 28–46% excreted unmodified; another cites ≈ 81.4% of an oral dose excreted unchanged), and the authors do not reconcile this discrepancy in the extracted material. Species LD50 (dose lethal to 50% of subjects) values vary markedly: rhesus macaques ≈ 30 mg/kg (IV), dogs 54 mg/kg (IV), rats 132–534 mg/kg (route-dependent), mice 157–880 mg/kg (route-dependent). In humans, only one death attributed to mescaline is noted in the extracted text. Cell-level assays (HEK293) reported no cytotoxicity for mescaline-like phenethylamines in an adenylate-kinase release assay. Human physiological, psychological and imaging findings: Acute physiological effects reported include mydriasis, transient increases in temperature, pulse rate and blood pressure, and at higher doses nausea and vomiting. Psychologically, mescaline commonly produces vivid visual alterations, synaesthesia, intensified colour perception and kaleidoscopic geometric hallucinations; at very high doses (e.g. 300 mg) users report altered time/space/personality perception. While euphoria and wellbeing are common, infrequent adverse psychological reactions (anxiety, panic, transient psychotomimetic symptoms or ego dissolution) are described, with emergency interventions in extreme cases including benzodiazepines, activated charcoal and other supportive measures. Neuroimaging: Early SPECT studies in small samples report increased regional cerebral blood flow (rCBF) in striato-limbic regions of the right hemisphere and a pattern described as 'hyperfrontal' during acute mescaline effects; investigators historically compared these patterns to those seen in experimental psychosis. Therapeutic observations: Historical clinical trials in schizophrenia (mid-20th century, IV mescaline 500–750 mg) largely failed to demonstrate sustained therapeutic benefit and often produced reactivation or worsening of psychosis. Observational and naturalistic data suggest potential benefits in alcohol-use disorders and general psychological wellbeing: ethnographic reports and ceremonial peyote use within the Native American Church were associated with reductions in alcoholism in some historical reports, and a study comparing frequent peyote users, recovered alcoholics and abstainers found better psychological wellbeing metrics among peyote users. A 2021 international self-report survey (n = 452) of non-clinical mescaline users found self-reported improvements in symptoms: 86% of respondents with depression (n = 184) reported improvement, 80% with anxiety (n = 167), 76% with PTSD (n = 55), 76% with alcohol misuse (n = 48) and 68% with drug misuse (n = 58); these improvements correlated with measures of mystical experience, psychological insight and ego dissolution. The extracted text emphasises that these therapeutic data are observational, often uncontrolled, and not derived from modern randomised double-blind trials.

The authors interpret the assembled evidence as indicating that mescaline shares a core mechanism with other classical psychedelics: agonism at the 5HT2A receptor is central to its hallucinogenic effects. They argue that additional activity at adrenergic α1A/α2A and dopaminergic D1/D2/D3 receptors likely contributes to mescaline’s distinctive behavioural profile relative to other serotonergic psychedelics. Mescaline’s pharmacokinetic features — including a relatively long human half-life reported in the review — and its tissue distribution patterns are highlighted as distinguishing characteristics. Vamvakopoulou and colleagues position the human data as suggestive but limited: early neuroimaging and experimental psychosis models showed changes in right-hemisphere limbic and frontal blood flow, while historical therapeutic trials in schizophrenia did not demonstrate benefit and sometimes produced harm. Conversely, ethnographic and survey-based reports indicate possible benefits for alcoholism and broader mental wellbeing when mescaline is used in ceremonial or naturalistic settings. The authors stress that these positive signals derive from non-randomised, uncontrolled contexts and self-report, limiting causal inference. Key limitations acknowledged in the extracted text include sparse and inconsistent receptor-screening data, reliance on small and sometimes single-laboratory studies, species differences in pharmacology and toxicology, and the absence of modern randomised double-blind clinical trials. The authors therefore call for contemporary, rigorously designed preclinical and clinical research to clarify mescaline’s safety profile, mechanisms of action, dose–response relationships, and therapeutic potential. They also note gaps in translational understanding — for example, inconsistencies in reported urinary excretion percentages and limited in vivo corroboration of in vitro transporter findings — that need resolution before clinical application can be responsibly considered.

The authors conclude that mescaline is pharmacologically and phenomenologically similar to other classical serotonergic psychedelics but is less potent. Its principal action as a 5HT2A receptor agonist is likely responsible for its hallmark perceptual effects, while additional adrenergic and dopaminergic receptor interactions may account for its distinct behavioural features. Mescaline can produce intense altered states of consciousness including visual geometrical hallucinations and, in rare cases, psychotomimetic reactions. Although ethnographic reports and self-reported naturalistic data suggest possible benefits for alcoholism and mental wellbeing, the evidence base is insufficient for clinical recommendations. The authors state that modern, well-controlled studies are required to define mescaline’s therapeutic utility and safety profile before it can be considered for clinical use.