Mescaline

Peyote has been used for at least 5,700 years by Native Americans in Mexico.[5] Europeans noted use of peyote in Native American religious ceremonies upon early contact, notably by the Huichols in Mexico. 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, has since spread as far as Saskatchewan, Canada.[5]

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 contemporary users will often grind it into a powder and pour it into capsules to avoid having to taste it. The usual human dosage is 200–400 milligrams of mescaline sulfate or 178–356 milligrams of mescaline hydrochloride.[6] The average 76 mm (3.0 in) button contains about 25 mg mescaline.[7]

Mescaline was first isolated and identified in 1897 by the German chemist Arthur Heffter[8] and first synthesized in 1918 by Ernst Späth.[9]

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. 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".[10]

Mescaline is biosynthesized from tyrosine which, in turn, is derived from phenylalanine by the enzyme phenylalanine hydroxylase. In Lophophora williamsii (Peyote), dopamine converts into mescaline in a biosynthetic pathway involving m-O-methylation and aromatic hydroxylation.[14]

Tyrosine and phenylalanine serve as the metabolic precursors to 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.[15][16]

Biosynthesis of mescaline

Laboratory synthetic mescaline. Biosynthesized by peyote, this was the first psychedelic compound to be extracted and isolated.[17]

Mescaline was first synthesized in 1919 by Ernst Späth from 3,4,5-trimethoxybenzoyl chloride.[18] Subsequent to this, numerous approaches utilizing different starting materials have been developed. Notable examples include the following:

• Hofmann rearrangement of 3,4,5-trimethoxyphenylpropionamide.[19]
• Cyanohydrin reaction between potassium cyanide and 3,4,5-Trimethoxybenzaldehyde followed by acetylation and reduction.[20][21]
• Henry reaction of 3,4,5-Trimethoxybenzaldehyde with nitromethane followed by nitro compound reduction of ω-nitrotrimethoxystyrene.[22][23][24][25][26][27][28]
• Ozonolysis of elemicin followed by reductive amination.[29]
• Ester reduction of Eudesmic acid's methyl ester followed by halogenation, Kolbe nitrile synthesis, and nitrile reduction.[30][31][32]
• Amide reduction of 3,4,5-trimethoxyphenylacetamide.[33]
• Reduction of 3,4,5-trimethoxy-(2-nitrovinyl)benzene with lithium aluminum hydride.[34]
• 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. [35]

Tolerance builds with repeated usage, lasting for a few days. Mescaline causes cross-tolerance with other serotonergic psychedelics such as LSD and psilocybin.[36]

About half the initial dosage is excreted after 6 hours, but some studies suggest that it is not metabolized at all before excretion. Mescaline appears not to be subject to metabolism by CYP2D6[37] and between 20% and 50% of mescaline is excreted in the urine unchanged, and the rest being excreted as the carboxylic acid form of mescaline, a likely result of MAO degradation.[38] The LD₅₀ of mescaline has been measured in various animals: 212 mg/kg i.p. (mice), 132 mg/kg i.p. (rats), and 328 mg/kg i.p. (guinea pigs). For humans, the LD₅₀ of mescaline has been reported to be approximately 880 mg/kg.[39]

Mescaline induces a psychedelic state similar to those produced by LSD and psilocybin, but with unique characteristics. Subjective effects may include altered thinking processes, an altered sense of time and self-awareness, and closed- and open-eye visual phenomena.[40]

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. Aldous Huxley described these self-transforming amorphous shapes as like animated stained glass illuminated from light coming through the eyelids. Like LSD, mescaline induces distortions of form and kaleidoscopic experiences but they manifest more clearly with eyes closed and under low lighting conditions.[41]

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."[42]

As with LSD, synesthesia can occur especially with the help of music.[43] An unusual but unique characteristic of mescaline use is the "geometricization" of three-dimensional objects. The object can appear flattened and distorted, similar to the presentation of a Cubist painting.[44]

Mescaline elicits a pattern of sympathetic arousal, with the peripheral nervous system being a major target for this substance.[43]

Mescaline is produced when products of natural mammalian catecholamine-based neuronal signaling such as dopamine and noradrenaline are subjected to additional metabolism via methylation, and mescaline's hallucinogenic properties stem from its structural similarities with these two neurotransmitters. In plants, this compound 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 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.[15]

Mescaline acts similarly to other psychedelic agents.[45] It acts as an agonist,[46] binding to and activating the serotonin 5-HT_2A receptor with a high affinity.[47] How activating the 5-HT_2A receptor leads to psychedelia is still unknown, but it is likely that somehow it involves excitation of neurons in the prefrontal cortex.[48] Mescaline is also known to bind to and activate the serotonin 5-HT_2C receptor.[49]

Difluoromescaline and trifluoromescaline are more potent than mescaline, as is its amphetamine homologue trimethoxyamphetamine.[51][52] Escaline and proscaline are also both more potent than mescaline, showing the importance of the 4-position substituent with regard to receptor binding.[53]

• Jerry Garcia took peyote prior to forming The Grateful Dead but later switched to LSD and DMT since they were easier on the stomach.
• 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).[62][63][64]
• 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.[65]
• 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.
• 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.[66]
• Bryan Wynter produced Mars Ascends after trying the substance his first time.[67]
• According to Paul Strathern's book Sartre in 90 Minutes, Jean-Paul Sartre experimented with mescaline, and his description of ultimate reality (in Nausea) as "viscous and obscene" was written under mescaline's influence.
• George Carlin mentions mescaline use during his youth while being interviewed.[68]
• Carlos Santana told in 1989 about his mescaline use in a Rolling Stone interview.[69]
• Disney animator Ward Kimball described participating in a study of mescaline and peyote conducted by UCLA in the 1960s.[70]
• Michael Cera used real mescaline for the movie Crystal Fairy & the Magical Cactus, as expressed in an interview.[71]
• Philip K. Dick was inspired to write Flow My Tears, The Policeman Said after taking mescaline.[72]

• List of psychedelic plants
• Psychedelic experience
• Psychoactive drug
• Entheogen
• The Doors of Perception
  • Mind at Large (concept in The Doors of Perception)
• The Psychedelic Experience: A Manual Based on the Tibetan Book of the Dead
• 2C-B

• Jay, Mike. 2019. Mescaline: A Global History of the First Psychedelic. Yale University Press

Wikimedia Commons has media related to Mescaline.

• National Institutes of Health – National Institute on Drug Abuse Hallucinogen InfoFacts
• Mescaline at Erowid
• PiHKAL entry
• Mescaline entry in PiHKAL • info
• Film of Christopher Mayhew's mescaline experiment on YouTube
• Mescaline: The Chemistry and Pharmacology of its Analogs, an essay by Alexander Shulgin
• Mescaline on the Mexican Border