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Mescaline, also known as mescalin or mezcalin, and in chemical terms 3,4,5-trimethoxyphenethylamine, is a natural product psychedelic drug alkaloid of the substituted phenethylamine class, found in Cactus like peyote ( Lophophora williamsii) and San Pedro (certain species of the genus Echinopsis) and known for its Serotonin Hallucinogen effects.
Mescaline is typically taken orally and used recreationally, spiritually, and medically, with psychedelic effects occurring at doses from 100 to 1,000mg, including microdosing below 75mg, and it can be consumed in pure form or via mescaline-containing cacti. Mescaline induces a psychedelic experience characterized by vivid visual patterns, altered perception of time and self, synesthesia, and spiritual effects, with an onset of 0.5 to 0.9hours and a duration that increases with dose, ranging from about 6 to 14hours. Mescaline has a high median lethal dose across species, with the human LD50 estimated at approximately 880mg/kg, making it very difficult to consume a fatal amount. Ketanserin blocks mescaline’s psychoactive effects, and while it's unclear if mescaline is metabolized by monoamine oxidase enzymes, but preliminary evidence suggests Harmala alkaloid may potentiate its effects.
Mescaline primarily acts as a partial agonist at serotonin 5-HT2A receptors, with varying affinity and efficacy across multiple serotonin, adrenergic, dopamine, histamine, muscarinic, and trace amine receptors, but shows low affinity for most non-serotonergic targets. It is a relatively Hydrophile psychedelic compound structurally related to Catecholamine but acting on the serotonergic system, first synthesized in 1919, with numerous synthetic methods and potent analogues developed since. Mescaline occurs naturally in various cacti species, with concentrations varying widely, and is Biosynthesis in plants from phenylalanine via catecholamine pathways likely linked to stress responses.
Mescaline-containing cacti use dates back over 6,000 years. Peyote was studied scientifically in the 19th and 20th centuries, culminating in the isolation of mescaline as its primary psychoactive compound, legal recognition of its religious use, and ongoing exploration of its therapeutic potential. Mescaline is largely illegal worldwide, though exceptions exist for religious, scientific, or ornamental use, and it has influenced many notable cultural figures through its psychoactive effects. Very few studies concerning mescaline's activity and potential therapeutic effects in people have been conducted since the early 1970s.
In addition to pure form, mescaline is used in the form of mescaline-containing cactus such as peyote and San Pedro.
Prominence of color is distinctive, appearing brilliant and intense. Recurring visual patterns observed during the mescaline experience include stripes, checkerboards, angular spikes, multicolor dots, and very simple fractals that turn very complex. The English writer Aldous Huxley described these self-transforming amorphous shapes as like animated stained glass illuminated from light coming through the eyelids in his autobiographical book The Doors of Perception (1954). Like LSD, mescaline induces distortions of form and Kaleidoscope experiences but they manifest more clearly with eyes closed and under low lighting conditions. (2025). 9789048124473, Springer Science & Business Media. ISBN 9789048124473
Heinrich Klüver coined the term "cobweb figure" in the 1920s to describe one of the four form constant geometric visual hallucinations experienced in the early stage of a mescaline trip: "Colored threads running together in a revolving center, the whole similar to a cobweb". The other three are the chessboard design, tunnel, and spiral. Klüver wrote that "many 'atypical' visions are upon close inspection nothing but variations of these form-constants."
An unusual but unique characteristic of mescaline use is the "geometrization" of three-dimensional objects. The object can appear flattened and distorted, similar to the presentation of a Cubism painting. (1989). 9780874894998, Medical Economics Books. ISBN 9780874894998
Mescaline elicits a pattern of sympathetic arousal, with the peripheral nervous system being a major target for this substance. (1996). 9780023287640, Prentice Hall. ISBN 9780023287640
According to a research project in the Netherlands, ceremonial San Pedro use seems to be characterized by relatively strong spiritual experiences, and low incidence of challenging experiences.
The duration of mescaline appears to be dose dependence, varying from 6.4hours on average (range 3.0–10hours) at a dose of 100mg, 9.7 to 11hours on average (range 5.6–22hours) at moderate doses of 300 to 500mg, and 14hours on average (range 7.2–22hours) at a dose of 800mg.
It is unclear whether mescaline is drug metabolism by monoamine oxidase (MAO) or whether monoamine oxidase inhibitors (MAOIs) might increase the effects of mescaline. However, there are preliminary reports that , which are reversible inhibitors of monoamine oxidase A (RIMAs), may potentiate the effects of mescaline in humans, and the combination of mescaline or mescaline-containing cacti with harmala alkaloids has been referred to as "peyohuasca". In accordance with these findings, the harmala alkaloid and RIMA harmine has been reported to augment the effects of mescaline in animals.
In humans, mescaline acts similarly to other psychedelic agents. It acts as an agonist, binding to and activating the serotonin 5-HT2A receptor. Its at the serotonin 5-HT2A receptor is approximately 10,000nM and at the serotonin 5-HT2B receptor is greater than 20,000nM. How activating the 5-HT2A receptor leads to psychedelic effects is still unknown, but it is likely that somehow it involves excitation of neurons in the prefrontal cortex. In addition to the serotonin 5-HT2A and 5-HT2B receptors, mescaline is also known to bind to the serotonin 5-HT2C receptor and a number of other targets.
Mescaline lacks affinity for the monoamine transporters, including the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) (Ki > 30,000nM). However, it has been found to increase levels of the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) at high doses in rodents. This finding suggests that mescaline might inhibit the reuptake and/or induce the release of serotonin at such doses. In any case, this possibility has not yet been further assessed or demonstrated. Besides serotonin, mescaline might also weakly induce the release of dopamine, but this is probably of modest significance, if it occurs. In accordance, there is no evidence of the drug showing drug addiction or drug dependence. Mescaline appears to be inactive in terms of norepinephrine release induction and indirect sympathomimetic activity. Other psychedelic phenethylamines, including the closely related 2C, DOx, and TMA drugs, are inactive as monoamine releasing agents and reuptake inhibitors. However, an exception is trimethoxyamphetamine (TMA), the amphetamine analogue of mescaline, which is a very low-potency serotonin releasing agent ( = 16,000nM). The possible monoamine-releasing effects of mescaline would likely be related to its structural similarity to substituted amphetamines and related compounds.
Mescaline is a relatively low-potency psychedelic, with active doses in the hundreds of milligrams and micromolar affinities for the serotonin 5-HT2A receptor. For comparison, psilocybin is approximately 20-fold more potent (doses in the tens of milligrams) and lysergic acid diethylamide (LSD) is approximately 2,000-fold more potent (doses in the tens to hundreds of micrograms). There have been efforts to develop more potent analogues of mescaline. Difluoromescaline and trifluoromescaline are more potent than mescaline, as is its amphetamine homologue TMA. Escaline and proscaline are also both more potent than mescaline, showing the importance of the 4-position substituent with regard to receptor binding.
There is no evidence of acute drug tolerance with mescaline. However, tolerance to mescaline builds with repeated use, lasting for a few days. The drug causes cross-tolerance with other serotonergic psychedelics such as LSD and psilocybin.
The cryo-EM structures of the serotonin 5-HT2A receptor with mescaline, as well as with various other psychedelics and serotonin 5-HT2A receptor agonists, have been solved and published by Bryan L. Roth and colleagues.
Mescaline appears to have relatively poor blood–brain barrier permeability due to its low lipophilicity. However, it is still able to cross into the central nervous system and produce psychoactive effects at sufficiently high doses. The poor central permeability of mescaline appears to be responsible for its delayed onset of effects and is also thought to contribute to its low potency.
The primary metabolic pathway of mescaline is oxidative deamination. The specific mediating the deamination of mescaline are controversial however. Monoamine oxidase (MAO), diamine oxidase (DAO; histamine oxidase), and/or other enzymes may be responsible. Preclinical studies of mescaline given in combination with inhibitors of MAO and/or DAO, such as iproniazid, pargyline, and semicarbazide, have been conducted, but findings have been conflicting. Mescaline has been reported to be a poor or negligible substrate of highly purified human MAO in-vitro.
Mescaline appears not to be subject to metabolism by CYP2D6 based on in-vitro studies with human liver microsomes. Similarly, the in-vitro cytotoxicity of mescaline does not appear to be affected by cytochrome P450 (CYP450) . Conversely, it was potentiated by the MAO-A inhibitor clorgiline but not by the MAO-B inhibitor rasagiline. These findings were in contrast to those with the related compound 2C-B, which was potentiated by rasagiline but not by clorgiline.
Circulating peak and area-under-the-curve concentrations of mescaline and 3,4,5-trimethoxyphenylacetic acid (TMPAA) are similar with oral administration of mescaline. Conversely, levels of N-acetylmescaline (NAM) are far lower than those of mescaline or TMPAA and are thought not to be of clinical relevance. Intravenous injection of mescaline may result in less hepatic deamination than with oral administration.
Active metabolites of mescaline might contribute to its psychoactive effects. However, both TMPAA and NAM have been said to be inactive based on human tests. Similarly, 3,4,5-trimethoxyphenylethanol (TMPE), 3,4,5-trimethoxyphenylacetaldehyde (TMPA), and NAM all failed to produce mescaline-like effects in rodent drug discrimination tests.
3,4,5-Trimethoxyamphetamine (TMA), the α-methyl group analogue of mescaline and an MAO-resistant psychedelic, is only about twice as potent as mescaline as a psychedelic in humans despite having similar serotonin receptor affinity. This suggests that the deamination of mescaline has a relatively limited impact on its potency, compared to for example the 2C series of psychedelics.
Mescaline was originally reported to have an elimination half-life of 6hours based on a study conducted in the 1960s. However, subsequent research published in the 2020s found that its half-life is actually about 3.6hours (range 2.6–5.3hours). The previous higher estimate is believed to have been due to small sample size and collective measurement of mescaline metabolites. The elimination half-life of mescaline does not appear to be dose dependence. TMPAA has a half-life of about 3.7 to 4.1hours, similar to that of mescaline.
Mescaline has a similar half-life as LSD yet has a longer duration. This is due to mescaline having slower absorption and onset rather than a longer half-life.
The drug is relatively hydrophilic with low lipophilicity. Its predicted log P (XLogP3) is 0.7.
The physical properties and general chemistry of mescaline have been reviewed. (1968). 9783034870641 ISBN 9783034870641
As shown in the accompanying table, the concentration of mescaline in different specimens can vary largely within a single species. Moreover, the concentration of mescaline within a single specimen varies as well.
In plants, mescaline may be the end-product of a pathway utilizing catecholamines as a method of stress response, similar to how animals may release such compounds and others such as cortisol when stressed. The in vivo function of catecholamines in plants has not been investigated, but they may function as , as developmental signals, and as integral cell wall components that resist degradation from pathogens. The deactivation of catecholamines via methylation produces alkaloids such as mescaline.
Tyrosine and phenylalanine serve as metabolic precursors towards the synthesis of mescaline. Tyrosine can either undergo a decarboxylation via tyrosine decarboxylase to generate tyramine and subsequently undergo an oxidation at carbon 3 by a monophenol hydroxylase or first be hydroxylated by tyrosine hydroxylase to form L-DOPA and decarboxylated by DOPA decarboxylase. These create dopamine, which then experiences methylation by a catechol-O-methyltransferase (COMT) by an S-adenosyl methionine (SAM)-dependent mechanism. The resulting intermediate is then oxidized again by a hydroxylase enzyme, likely monophenol hydroxylase again, at carbon 5, and methylated by COMT. The product, methylated at the two meta positions with respect to the alkyl substituent, experiences a final methylation at the 4 carbon by a guaiacol-O-methyltransferase, which also operates by a SAM-dependent mechanism. This final methylation step results in the production of mescaline.
Phenylalanine serves as a precursor by first being converted to L-tyrosine by L-amino acid hydroxylase. Once converted, it follows the same pathway as described above.
In traditional peyote preparations, the top of the cactus is cut off, leaving the large tap root along with a ring of green photosynthesizing area to grow new heads. These heads are then dried to make disc-shaped buttons. Buttons are chewed to produce the effects or soaked in water to drink. However, the taste of the cactus is bitter, so modern users will often grind it into a powder and pour it into capsules to avoid having to taste it. The typical dosage is 200–400 milligrams of mescaline sulfate or 178–356 milligrams of mescaline hydrochloride. The average peyote button contains about 25mg mescaline. (1982). 9780874881820, Medical Examination Publishing Company. ISBN 9780874881820 Some analyses of traditional preparations of San Pedro cactus have found doses ranging from 34mg to 159mg of total alkaloids, a relatively low and barely psychoactive amount. It appears that patients who receive traditional treatments with San Pedro ingest sub-psychoactive doses and do not experience psychedelic effects.
Botanical studies of peyote began in the 1840s and the drug was listed in the Mexican pharmacopeia. The first use of mescal buttons was published by John Raleigh Briggs in 1887. In 1887, the German pharmacologist Louis Lewin received his first sample of the peyote cactus, found numerous new alkaloids and later published the first methodical analysis of it. Mescaline was first isolated and identified in 1897 by the German chemist Arthur Heffter. He showed that mescaline was exclusively responsible for the psychoactive or hallucinogenic effects of peyote. However, other components of peyote, such as hordenine, pellotine, and anhalinine, are also active. Mescaline was first synthesized in 1919 by Ernst Späth.
In 1955, English politician Christopher Mayhew took part in an experiment for BBC's Panorama, in which he ingested 400mg of mescaline under the supervision of psychiatrist Humphry Osmond. Though the recording was deemed too controversial and ultimately omitted from the show, Mayhew praised the experience, calling it "the most interesting thing I ever did".
Studies of the potential therapeutic effects of mescaline started in the 1950s.
The mechanism of action of mescaline, activation of the serotonin 5-HT2A receptors, became known in the 1990s.
While mescaline-containing cacti of the genus Echinopsis are technically controlled substances under the Controlled Substances Act, they are commonly sold publicly as . (2025). 9780123704672, Academic Press. ISBN 9780123704672
In Russia mescaline, its derivatives and mescaline-containing plants are banned as narcotic drugs (Schedule I).
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