Mescaline

Mescaline is used recreationally, spiritually, and medically.^[8][1] It is typically taken orally.^[2] The drug is used as a psychedelic at doses of 100 to 1,000 mg orally.^{[10][17][29][22]} Low doses are 100 to 200 mg, an intermediate or "good effect" dose is 500 mg, and a high (ego-dissolution) dose is 1,000 mg.^[10][17] In his book PiHKAL (Phenethylamines I Have Known and Loved), Alexander Shulgin listed a dose range of 200 to 400 mg as the sulfate salt and 178 to 356 mg as the hydrochloride salt.^[20][30] Microdosing involves the use of daily mescaline doses of less than 75 mg.^[10][17] In addition to pure form, mescaline is used in the form of cacti such as peyote and the San Pedro cactus.^[8][18][9] Doses when mescaline is used in the form of fresh or dried cacti have also been described.^{[31][32][2][18]}

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 average 76 mm (3.0 in) peyote button contains about 25 mg mescaline.^{[citation needed]} Some analyses of traditional preparations of San Pedro cactus have found doses ranging from 34 mg to 159 mg 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.^[33]

The onset of the effects of mescaline given orally is 0.5 to 0.9 hours on average with a range of 0.1 to 2.7 hours.^{[10][11][1][2]} Its effects peak after 1.9 to 4.0 hours with a range of 0.5 to 8.0 hours.^{[10][34][15][11]} The duration of mescaline appears to be dose-dependent, varying from 6.4 hours on average (range 3.0–10 hours) at a dose of 100 mg, 9.7 to 11 hours on average (range 5.6–22 hours) at moderate doses of 300 to 500 mg, and 14 hours on average (range 7.2–22 hours) at a dose of 800 mg.^[10][11] Cases of mescaline having unusually prolonged or delayed effects have also been described.^[35]

Mescaline induces a psychedelic state comparable to those produced by LSD and psilocybin, but with unique characteristics.^[27] Subjective effects may include altered thinking processes, an altered sense of time and self-awareness, and closed- and open-eye visual phenomena.^[36] In PiHKAL, Shulgin described the effects of mescaline based on a collection of experience reports.^[20] The effects included brightened colors, increased visual contrast, open-eye visuals like colors and patterns, pareidolia, increased significance of objects, enhanced music appreciation, feeling intoxicated, self-analysis, insights, increased body awareness, feelings of joy, happiness, and peacefulness, feeling hyper and energized, feelings of empathy, things feeling ridiculous, humor and laughter, religious feelings, restlessness, social discomfort and avoidance, and nausea, among others.^[20] Mescaline was one of Shulgin's "magical half-dozen" psychedelic drugs in PiHKAL.^[20]

Prominence of color with mescaline is distinctive, appearing brilliant and intense.^[8] Recurring visual patterns observed during the mescaline experience include stripes, checkerboards, angular spikes, multicolor dots, and very simple fractals that can turn very complex.^[37] 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).^[26] Like LSD, mescaline induces distortions of form and kaleidoscopic experiences but they manifest more clearly with eyes closed and under low lighting conditions.^[37] 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".^[38] The other three are the chessboard design, tunnel, and spiral.^[38] Klüver wrote that "many 'atypical' visions are upon close inspection nothing but variations of these form-constants."^[38] An unusual but unique characteristic of mescaline use is the "geometrization" of three-dimensional objects.^[37][39] The object can appear flattened and distorted, similar to the presentation of a Cubist painting.^[37][39] Detailed descriptions of the psychedelic experience induced by mescaline have been given by many authors.^{[13][22][40][41][42][43][26][20]}

The subjective effects of mescaline are qualitatively similar to those of LSD and psilocybin.^{[10][44][15][12][13]} Based on anecdotal evidence however, mescaline is said to be less threatening and to produce less ego dissolution than other psychedelics like LSD.^[27][25] This may in part be due its slow onset allowing for a more comfortable ease-in of effects.^[27] In addition, mescaline is typically dosed at lower doses than LSD or psilocybin in terms of doses with equivalent or comparable strength.^[11][15][10] According to a study in the Netherlands, ceremonial San Pedro use seems to be characterized by relatively strong spiritual experiences, and low incidence of challenging experiences.^[45] Mescaline, LSD, and psilocybin appear to produce similar color enhancement in clinical studies, though more research is needed.^{[46][47][48][49]}

Contraindications of psychedelic drugs like mescaline include severe cardiovascular disease, epilepsy or seizures, schizophrenia and other psychotic disorders, bipolar disorder, and pregnancy, among others.^[50][51] Serotonin 5-HT_2A receptor antagonists such as atypical antipsychotics and certain antidepressants may block psilocybin's hallucinogenic effects and hence may be considered contraindicated in this sense.^[52][53]

Side effects of mescaline include fatigue, weakness, impaired concentration, restlessness, tension, anxiety, panic, and social discomfort and avoidance, headache, pupil dilation, nausea, vomiting, sweating, trembling, discomfort, feeling hot or cold, palpitations, chest and neck pains, shortness of breath, increased heart rate and blood pressure, and increased body temperature, among others.^{[20][1][10][54]} Nausea and vomiting are important dose-limiting side effects of mescaline and occur at greater rates than with other psychedelics like LSD and psilocybin.^[54][11][15] High doses of mescaline, such as 800 mg and above, are not well-tolerated due to substantial nausea and vomiting.^[44][11][54] On the other hand, mescaline appears to induce less fear and anxiety than LSD and psilocybin even at equivalent doses.^[10][44][54] Rarely, in susceptible individuals such as people with a family history of schizophrenia, mescaline may cause psychosis.^[55]

Only a single case of death due to mescaline, as peyote, has been described, and was likely due to asphyxiation by vomit rather than overdose or toxicity.^{[56][57][6][58][22]} However, there is also a case report of death due to jumping off a cliff while on a high dose of mescaline.^[18][59] In terms of extrapolated human lethal dose based on animal studies, the lethal dose of mescaline relative to a typical recreational dose has been estimated to be 24-fold or around 8,400 mg.^[56][57][58] However, mescaline has reportedly been taken by humans at doses of up to 8,000 mg without apparent toxic reactions.^{[18][22][60][61]} On the other hand, there is one unverified reported case of death due to 15,000 mg intravenously, which would equate to about 150 to 200 mg/kg.^[22] The median lethal dose (LD₅₀) of mescaline has been determined in various animal species, with the values including 212 to 315 mg/kg i.p. in mice, 132 to 410 mg/kg i.p. in rats, 328 mg/kg i.p. in guinea pigs, 54 mg/kg in dogs, and 130 mg/kg i.v. in rhesus macaques, among others.^{[2][22][12][62]} It has been said that it would be difficult to take enough mescaline to cause death in humans.^[2][22] No deaths due to peyote use have been reported aside from the asphyxiation case.^[63][22][58] The highest known dose of peyote taken is 90 dried buttons.^[64][22][65]

The serotonin 5-HT_2A receptor antagonist ketanserin has been found to block the psychoactive effects of mescaline.^[19][11][66] Similarly, the antipsychotic chlorpromazine, which acts as both a dopamine D₂ receptor antagonist and to a lesser extent as a serotonin 5-HT_2A receptor antagonist, has been reported to reverse the psychoactive effects of mescaline.^{[19][67][68][69]} Other phenothiazines, such as promethazine and diethazine, have also been reported to antagonize the effects of mescaline in humans, whereas prochlorperazine was much less effective and promazine was ineffective.^[12][14] Barbiturates, which are GABA_A receptor positive allosteric modulators, have been found to abolish the anxiety induced by mescaline.^[12]

It is unclear whether mescaline is metabolized by monoamine oxidase (MAO) enzymes^[70][2][13] or whether monoamine oxidase inhibitors (MAOIs) might increase the effects of mescaline.^[70][71] No clinical studies of mescaline in combination with MAOIs are known to have been published.^[70] However, there are preliminary reports that harmala alkaloids, 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".^[71][22][70] In accordance with these findings, the harmala alkaloid and RIMA harmine has been reported to augment the effects of mescaline in animals.^[22][13] On the other hand, Daniel Trachsel has stated that mescaline is not metabolized by MAO, instead being metabolized by semicarbazide-sensitive amine oxidase (SSAO), and hence that MAOIs that do not also inhibit SSAO should have no effect on the metabolism of mescaline.^[23] Accordingly, the MAOI iproniazid did not potentiate the behavioral effects of mescaline in rats.^[23][12][72]

Mescaline, also known as 3,4,5-trimethoxyphenethylamine (3,4,5-TMPEA), is a substituted phenethylamine derivative.^[116][9] It is closely structurally related to the dopamine (3,4-dihydroxyphenethylamine), norepinephrine (3,4,β-trihydroxyphenethylamine), and epinephrine (3,4,β-trihydroxy-N-methylphenethylamine).^[116] In contrast to the catecholamine neurotransmitters however, mescaline acts primarily on the serotonergic system rather than on the dopaminergic or adrenergic systems.^[8]

Properties

The physical properties and general chemistry of mescaline have been reviewed.^[12] The compound is relatively hydrophilic with low fat solubility.^[9] Its predicted log P (XLogP3) is 0.7.^[116]

Mescaline has been isolated from numerous cactus species, including Echinopsis (Trichocereus), Gymnocalycium, Lophophora, Opuntia, Stenocereus, and Turbinicarpus species, among others.^[22] It occurs at the highest known concentrations in Lophophora williamsii (peyote), where it is highly variable but makes up 0.1 to 0.255% fresh weight and 0.9 to 6.3% of dry weight.^[22] Levels of mescaline are much lower in other Lophophora species.^[22] The compound also occurs in relatively high concentrations in various Echinopsis species, for instance Echinopsis pachanoi (San Pedro cactus), ranging from 0.02 to 0.12% fresh weight and 0.331 to 2.0% dry weight in this species.^[22] Mescaline occurs in only small or trace amounts in most other cactus species in which it has been detected.^[22]

As shown in the accompanying table, the concentration of mescaline in different specimens can vary largely within a single species.^[22] Moreover, the concentration of mescaline within a single specimen varies as well.^[141]

In peyote, mescaline constitutes about 30% of total alkaloid content.^{[142][143][9][144]} For comparison, the alkaloid contents of other major constituents include pellotine 17%, anhalonidine 14%, anhalamine 8%, hordenine 8%, and lophophorine 5%.^{[142][143][9][144]}

It has also reported to be found in small amounts in certain members of the bean family, Fabaceae, including Senegalia berlandieri (syn. Acacia berlandieri),^[145] although these reports have been challenged and have been unsupported in any additional analyses.^[22][146]

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 antioxidants, 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.^[147]

Biosynthesis

Mescaline is biosynthesized from tyrosine, which, in turn, is derived from phenylalanine by the enzyme phenylalanine hydroxylase.^[8][24][22] In Lophophora williamsii (peyote), dopamine converts into mescaline in a biosynthetic pathway involving m-O-methylation and aromatic hydroxylation.^[148]

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.^[147][149]

Archaeological evidence from sites in the United States, Mexico, and Peru indicates that mescaline-containing cacti have been used for over 6,000 years.^[8] Europeans recorded use of peyote in Native American religious ceremonies upon early contact with the Huichol people in Mexico.^[150] Other mescaline-containing cacti such as the San Pedro cactus have a long history of use in South America, from Peru to Ecuador.^{[151][152][153][154]} While religious and ceremonial peyote use was widespread in the Aztec Empire and northern Mexico at the time of the Spanish conquest, religious persecution confined it to areas near the Pacific coast and up to southwest Texas. However, by 1880, peyote use began to spread north of South-Central America with "a new kind of peyote ceremony" inaugurated by the Kiowa and Comanche people. These religious practices, incorporated legally in the United States in 1920 as the Native American Church, have since spread as far as Saskatchewan, Canada.^[155]

Peyote was first described by Bernardino de Sahagún in 1560.^[12][13] It was first scientifically named as Peyotl zacatensis by Francisco Hernández in 1638.^[13] Botanical studies of peyote began in the 1840s and the drug was listed in the Mexican pharmacopeia.^[9] The first use of mescal buttons was published by John Raleigh Briggs in 1887.^{[9][143][156]} However, he took a very low dose of the drug, and in the modern literature, the symptoms he experienced have been attributed to a severe panic attack in response to the drug.^[157][156] 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.^[18] The effects of mescaline in humans were first properly described by D. W. Prentiss and Francis P. Morgan in 1895.^[143][40] Mescaline was first isolated and identified in 1897 by the German chemist Arthur Heffter.^[9][2][158] He showed that mescaline was exclusively responsible for the psychoactive or hallucinogenic effects of peyote.^[9] However, other components of peyote, such as hordenine, pellotine, and anhalinine, are also active.^[9] Mescaline was first synthesized in 1919 by Ernst Späth.^[2][117]

Three major books on mescaline and/or peyote were published in the mid-to-late 1920s.^[21][159] These included French pharmacist Alexandre Rouhier's Le Peyotl: La Plante Qui Fait les Yeux Émerveillés (Peyote: The Plant That Fills the Eyes with Marvels) in 1927,^{[21][160][157][43]} the German psychiatrist Kurt Beringer's Der Meskalinrausch, seine Geschichte und Erscheinungsweise (Mescaline Intoxication, its History and Manifestation) in 1927,^{[21][159][41]} and German–American psychologist Heinrich Klüver's Mescal: The Divine Plant and Its Psychological Effects in 1928.^{[21][159][42]}

Studies of the potential therapeutic effects of mescaline started in the 1950s.^[9] It was studied as part of psychedelic-assisted psychotherapy by Walter Frederking by 1953.^{[12][13][161][162]} Aldous Huxley's book The Doors of Perception, about his experience with mescaline, was published in 1954.^[163] In 1955, English politician Christopher Mayhew took part in an experiment for BBC's Panorama, in which he ingested 400 mg of mescaline under the supervision of psychiatrist Humphry Osmond.^{[21][164][165][166]} 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" and saying that it was "profoundly thought-provoking".^{[21][164][165][166]}

The mechanism of action of mescaline, activation of the serotonin 5-HT_2A receptors, became fully known in the 1990s.^[9] A serotonin 5-HT_2A receptor antagonist, specifically ketanserin, was first clearly shown to block the psychedelic effects of mescaline in humans by Matthias Liechti and colleagues in 2024.^[11]

The history of mescaline was reviewed in the 2019 book Mescaline: A Global History of the First Psychedelic by cultural historian Mike Jay.^[167][21]

Mescaline has a wide array of suggested medical usage, including treatment of depression, anxiety, PTSD,^[203] nicotine dependence, and alcoholism.^[204][205] However, its status as a Schedule I controlled substance in the Convention on Psychotropic Substances limits availability of the drug to researchers. Because of this, very few studies concerning mescaline's activity and potential therapeutic effects in people have been conducted since the early 1970s.^{[206][203][27]} However, the drug is under development by Journey Colab under the code name JOUR-5700 and by Biomind Labs under the code names BMND04, BMND06, and BMND09 for various medical applications, such as treatment of alcoholism.^{[27][207][208][209][210][211][28][212]}

• Scaline