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Mescaline (3,4,5-trimethoxyphenethylamine) is a naturally occurring psychedelic alkaloid and the prototypical phenethylamine hallucinogen, isolated in 1897 from the peyote cactus (Lophophora williamsii) and also present in South American columnar cacti such as the San Pedro or wachuma (Trichocereus species). Archaeological evidence indicates ritual use of mescaline-bearing cacti for more than 6000 years, making it one of the oldest documented psychoactive substances. Its characteristic alterations of perception, mood, and cognition are attributed principally to agonist activity at the serotonin 5-HT2A receptor, though it binds within a similar concentration range to 5-HT2C and 5-HT1A sites. Compared with other classic psychedelics it has notably low potency, requiring gram-scale oral doses, and it is largely excreted unchanged in the urine. Renewed scientific interest in psychedelic therapeutics has returned mescaline to controlled human study after decades of neglect.
- Long-acting classic psychedelic with a distinctive phenethylamine character
- Low addictive potential and low physiological toxicity
- One of the oldest ritual psychedelics, used for over 6000 years
- Effects trace to selective agonism at the serotonin 5-HT2A receptor
- Nausea and vomiting, especially with crude cactus material
- Pupil dilation, raised heart rate and blood pressure
- Anxiety, fear, or dysphoria during difficult experiences
- Sympathomimetic load unsuitable for significant heart disease
Mechanism
Mescaline is a serotonergic psychedelic whose acute psychoactive effects are mediated chiefly through agonism at the receptor, a Gq-coupled receptor densely expressed on layer V cortical pyramidal neurons. Activation of this receptor by classic hallucinogens recruits specific cortical signaling cascades that increase drive and alter the balance of cortical excitation, producing the perceptual and cognitive changes shared across the psychedelic class. Consistent with the wider hallucinogen literature, mescaline also binds the closely related 5-HT2C receptor and the inhibitory receptor, and it has measurable affinity at alpha- sites; this broader receptor engagement contributes to its distinctive subjective and physiological profile. As a phenethylamine rather than a tryptamine or ergoline, mescaline occupies the 5-HT2A orthosteric pocket through a somewhat different set of contacts than psilocin or LSD, which helps explain its comparatively low potency and long duration.
Pharmacologically, mescaline is slowly absorbed after oral ingestion, with subjective effects emerging over roughly one to two hours and persisting for approximately ten to twelve hours. It undergoes limited metabolism in humans and is largely excreted unchanged in the urine, with its oxidative metabolites appearing unrelated to its psychedelic activity. Controlled double-blind studies in healthy volunteers have characterized its dose-dependent acute effects and directly compared it with lysergic acid diethylamide and psilocybin, finding a broadly comparable qualitative experience at equivalent effect levels but a slower onset and longer duration. Its low potency is thought to explain why medicinal chemistry historically favored more potent analogues, and why mescaline itself has attracted relatively little recreational or research attention until the current resurgence of psychedelic science.
receptor fingerprint
receptoragonist
5-HT2C receptoragonist
Alpha- receptorsweak binding
receptoragonist
Safetyrisks and cautions, not medical advice
Mescaline is generally regarded as one of the more physiologically benign classic psychedelics, with low toxicity and low addictive potential, and controlled trials in screened healthy volunteers have reported an acceptable acute safety profile. Common acute effects include nausea and vomiting (particularly with crude cactus preparations), pupil dilation, elevated blood pressure and heart rate, headache, and marked anxiety or dysphoria during challenging experiences.
As a 5-HT2A and 5-HT2B agonist it carries the sympathomimetic and theoretical cardiovascular cautions common to serotonergic hallucinogens, so it is not appropriate for people with significant cardiovascular disease, and its capacity to precipitate distressing psychological reactions means it should be avoided by individuals with personal or family histories of psychosis. It can produce prolonged and intense states that require a safe setting and support, and it should not be combined with monoamine oxidase inhibitors or other serotonergic drugs. It remains a controlled substance in most jurisdictions. Not medical advice.
Subjective profileweighing the evidence above
Among the gentlest of the classic psychedelics on the body, with low toxicity, low addictive potential and a character worth the very long day it costs. The nausea is real, especially from crude cactus, and the sympathomimetic load makes it a poor fit with significant heart disease.
Resources
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Research
- 2007first citedHallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect…
- 2023controlled trialComparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomi…
- 2025most recentThe polypharmacology of psychedelics reveals multiple targets for potential therapeutics
- 1.Dark Classics in Chemical Neuroscience: Mescaline
- 2.Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects
- 3.Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants
- 4.Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways
- 5.The polypharmacology of psychedelics reveals multiple targets for potential therapeutics
- 6.Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior
- 7.Animal models of serotonergic psychedelics
- 8.Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species
- 9.Cardiovascular safety of psychedelic medicine: current status and future directions
- 10.Psychedelics as Medicines: An Emerging New Paradigm
- 11.5-HT2A receptors: Pharmacology and functional selectivity
11 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
How is mescaline different from LSD or psilocybin?
All three act primarily as 5-HT2A receptor agonists and produce qualitatively similar experiences at equivalent intensity, but mescaline is a phenethylamine rather than a tryptamine or ergoline. In practice it is far less potent (dosed in hundreds of milligrams to grams), comes on more slowly, and lasts longer, often ten to twelve hours.
Why does mescaline often cause nausea?
Nausea and vomiting are common early effects, especially with whole-cactus preparations such as peyote buttons or San Pedro, and reflect both the bitter plant material and serotonergic stimulation of the gut. The effect usually eases as the experience develops.
Is mescaline addictive?
Like other classic serotonergic psychedelics, mescaline has low addictive potential and does not produce compulsive drug-seeking. Tolerance builds quickly with repeated dosing, which further discourages frequent use. It remains a controlled substance in most countries.
Adverse effects
- Nausea and vomiting, especially with crude cactus material
- Pupil dilation, raised heart rate and blood pressure
- Anxiety, fear, or dysphoria during difficult experiences
- Sympathomimetic load unsuitable for significant heart disease
Notes and cautions
- Long duration requiring a safe, supported setting