Mescaline

Mescaline is used recreationally, spiritually, and medically. Low doses are 100 to 200mg, an intermediate or "good effect" dose is 500mg, and a high (ego-dissolution) dose is 1,000mg. In his book PiHKAL (Phenethylamines I Have Known and Loved), Alexander Shulgin comprehensively described the effects of mescaline based on a collection of experience reports. Mescaline was one of Shulgin's "magical half-dozen" psychedelic compounds in PiHKAL. Like LSD, mescaline induces distortions of form and kaleidoscopic experiences but they manifest more clearly with eyes closed and under low lighting conditions. 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". An unusual but unique characteristic of mescaline use is the "geometrization" of three-dimensional objects. 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. ==Contraindications==

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. Rarely, in susceptible individuals such as people with a family history of schizophrenia, mescaline may cause psychosis. Tolerance Mescaline is associated with rapid tolerance development, including cross-tolerance with other psychedelics like LSD and psilocybin. This tolerance is apparent within a few days and resets after 3 or 4days of abstinence. ==Overdose==

In terms of extrapolated human lethal dose based on animal studies and human case reports, the lethal dose of mescaline relative to a typical recreational dose is estimated to be 24-fold. The LD50 of mescaline has also been determined in various animal species, with the values including 212 to 315mg/kg i.p. in mice, 132 to 410mg/kg i.p. in rats, 328mg/kg i.p. in guinea pigs, 54mg/kg in dogs, and 130mg/kg i.v. in rhesus macaques. It has been said based on the animal data that it would be very difficult to consume enough mescaline to cause death in humans. ==Interactions==

The serotonin 5-HT2A receptor antagonist ketanserin has been found to block the psychoactive effects of mescaline. It is unclear whether mescaline is metabolized by monoamine oxidase (MAO) enzymes No clinical studies of mescaline in combination with MAOIs are known to have been published. In accordance with these findings, the harmala alkaloid and RIMA harmine has been reported to augment the effects of mescaline in animals. ==Pharmacology==

Pharmacodynamics 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. 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. The drug shows pronounced biased agonism at the serotonin 5-HT2C receptor. Mescaline lacks affinity for the monoamine transporters, including the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) (Ki > 30,000nM). 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. In accordance, there is no evidence of the drug showing addiction or dependence. 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). 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 tolerance with mescaline. 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. Pharmacokinetics Absorption Mescaline is usually taken orally, although it may also be insufflated, smoked, or given intravenously. However, it is still able to cross into the central nervous system and produce psychoactive effects at sufficiently high doses. Metabolism of mescaline in humans and/or animals. The specific enzymes mediating the deamination of mescaline are controversial however. 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 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) enzyme inhibitors. Conversely, it was potentiated by the MAO-A inhibitor clorgiline but not by the MAO-B inhibitor rasagiline. 3,4,5-Trimethoxyamphetamine (TMA), the α-methyl 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. During the first hour after administration, 81.4% of mescaline is excreted unchanged while 13.2% is excreted as its deaminated metabolite 3,4,5-trimethoxyphenylacetic acid (TMPAA). The previous higher estimate is believed to have been due to small sample numbers and collective measurement of mescaline metabolites. The elimination half-life of mescaline does not appear to be dose-dependent. 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. ==Chemistry==

Mescaline, also known as 3,4,5-trimethoxyphenethylamine (3,4,5-TMPEA), is a substituted phenethylamine derivative. The compound is relatively hydrophilic with low fat solubility. • Cyanohydrin reaction between potassium cyanide and 3,4,5-trimethoxybenzaldehyde followed by acetylation and reduction. • Henry reaction of 3,4,5-trimethoxybenzaldehyde with nitromethane followed by nitro compound reduction of ω-nitrotrimethoxystyrene. This was the method used by Alexander Shulgin in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved). • Ester reduction of Eudesmic acid's methyl ester followed by halogenation, Kolbe nitrile synthesis, and nitrile reduction. • Amide reduction of 3,4,5-trimethoxyphenylacetamide. • Reduction of 3,4,5-trimethoxy(2-nitrovinyl)benzene with lithium aluminum hydride. • Treatment of tricarbonyl-(η6-1,2,3-trimethoxybenzene) chromium complex with acetonitrile carbanion in THF and iodine, followed by reduction of the nitrile with lithium aluminum hydride. Analogues A large number of structural analogues of mescaline that act as psychedelics have been developed. These drugs often have far greater potency than mescaline itself. Examples include scalines like escaline, 3Cs like 3,4,5-trimethoxyamphetamine (TMA or TMA-1; α-methylmescaline), 2Cs like 2C-B, and DOx drugs like DOM, among others. Other notable analogues of mescaline include N-methylmescaline (found in Pachycereus pringlei), trichocereine (N,N-dimethylmescaline), mescaline-FLY, and NBOMe-mescaline, among others. Deuterated isotopologues of mescaline include α-D (α,α-dideuteromescaline), β-D (β,β-dideuteromescaline), and 4-D (4-trideuteromescaline), among others. ==Natural occurrence==

It occurs naturally in several species of cacti. It is also reported to be found in small amounts in certain members of the bean family, Fabaceae, including Senegalia berlandieri (syn. Acacia berlandieri), although these reports have been challenged and have been unsupported in any additional analyses. 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 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. 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. ==History==

Archaeological evidence from sites in the United States, Mexico, and Peru indicates that mescaline-containing cacti have been used for over 6,000 years. Other mescaline-containing cacti such as the San Pedro have a long history of use in South America, from Peru to Ecuador. 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. 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 dose is 200 to 400mg of mescaline sulfate or 178 to 356mg of mescaline hydrochloride. The average peyote button contains about 25mg mescaline. 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. 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. 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. ==Society and culture==

Legal status United States In the United States, mescaline was made illegal in 1970 by the Comprehensive Drug Abuse Prevention and Control Act, categorized as a Schedule I hallucinogen. The drug is prohibited internationally by the 1971 Convention on Psychotropic Substances. Mescaline is legal only for certain religious groups (such as the Native American Church by the American Indian Religious Freedom Act of 1978) and in scientific and medical research. In 1990, the Supreme Court ruled that the state of Oregon could ban the use of mescaline in Native American religious ceremonies. The Religious Freedom Restoration Act (RFRA) in 1993 allowed the use of peyote in religious ceremony, but in 1997, the Supreme Court ruled that the RFRA is unconstitutional when applied against states. Many states, including the state of Utah, have legalized peyote usage with "sincere religious intent", or within a religious organization, regardless of race. Synthetic mescaline, but not mescaline derived from cacti, was officially decriminalized in the state of Colorado by ballot measure Proposition 122 in November 2022. While mescaline-containing cacti of the genus Echinopsis are technically controlled substances under the Controlled Substances Act, they are commonly sold publicly as ornamental plants. United Kingdom In the United Kingdom, mescaline in purified powder form is a Class A drug. However, dried cactus can be bought and sold legally. Australia Mescaline is considered a schedule 9 substance in Australia under the Poisons Standard (February 2020). A schedule 9 substance is classified as "Substances with a high potential for causing harm at low exposure and which require special precautions during manufacture, handling or use. These poisons should be available only to specialised or authorised users who have the skills necessary to handle them safely. Special regulations restricting their availability, possession, storage or use may apply." In Russia mescaline, its derivatives and mescaline-containing plants are banned as narcotic drugs (Schedule I). Notable individuals • Salvador Dalí experimented with mescaline believing it would enable him to use his subconscious to further his art potential. • Antonin Artaud wrote 1947's The Peyote Dance, where he describes his peyote experiences in Mexico a decade earlier. • Allen Ginsberg took peyote. Part II of his poem "Howl" was inspired by a peyote vision that he had in San Francisco. • Ken Kesey took peyote prior to writing ''One Flew Over the Cuckoo's Nest''. • Jean-Paul Sartre took mescaline shortly before the publication of his first book, ''L'Imaginaire; he had a bad trip during which he imagined that he was menaced by sea creatures. For many years following this, he persistently thought that he was being followed by lobsters, and became a patient of Jacques Lacan in hopes of being rid of them. Lobsters and crabs figure in his novel Nausea''. • Havelock Ellis was the author of one of the first written reports to the public about an experience with mescaline (1898). • Stanisław Ignacy Witkiewicz, Polish writer, artist and philosopher, experimented with mescaline and described his experience in a 1932 book Nikotyna Alkohol Kokaina Peyotl Morfina Eter. • Aldous Huxley described his experience with mescaline in the essay "The Doors of Perception" (1954). • Jim Carroll in The Basketball Diaries described using peyote that a friend smuggled from Mexico. • Quanah Parker, appointed by the federal government as principal chief of the entire Comanche Nation, advocated the syncretic Native American Church alternative, and fought for the legal use of peyote in the movement's religious practices. • Hunter S. Thompson wrote an extremely detailed account of his first use of mescaline in "First Visit with Mescalito", and it appeared in his book Songs of the Doomed, as well as featuring heavily in his novel Fear and Loathing in Las Vegas. • Psychedelic research pioneer Alexander Shulgin said he was first inspired to explore psychedelic compounds by a mescaline experience. In 1974, Shulgin synthesized 2C-B, a psychedelic phenylethylamine derivative, structurally similar to mescaline, and one of Shulgin's self-rated most important phenethylamine compounds together with Mescaline, 2C-E, 2C-T-7, and 2C-T-2. • Bryan Wynter produced Mars Ascends after trying the substance for the first time. • George Carlin mentioned mescaline use during his youth while being interviewed in 2008. • Carlos Santana told about his mescaline use in a 1989 Rolling Stone interview. • Disney animator Ward Kimball described participating in a study of mescaline and peyote conducted by UCLA in the 1960s. • Michael Cera used real mescaline for the movie Crystal Fairy & the Magical Cactus, as expressed in an interview. • Philip K. Dick was inspired to write Flow My Tears, the Policeman Said after taking mescaline. • Arthur Kleps, a psychologist turned drug legalization advocate and writer whose Neo-American Church defended use of marijuana and hallucinogens such as LSD and peyote for spiritual enlightenment and exploration, bought, in 1960, by mail from Delta Chemical Company in New York 1 g of mescaline sulfate and took 500mg. He experienced a psychedelic trip that caused profound changes in his life and outlook. ==Research==

Mescaline has a wide array of suggested medical usage, including treatment of depression, anxiety, PTSD, and alcoholism. 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. ==See also==