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| Clinical data | |
|---|---|
| Synonyms | 3,4,5-Trimethoxyphenethylamine |
| AHFS/Drugs.com | mescaline |
| Pregnancy category |
US: C (Risk not ruled out)
|
| Routes of administration | Oral, intravenous |
| ATC code |
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| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Elimination half-life | 6 hours |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.000.174  |
| Chemical and physical data | |
| Formula | C11H17NO3 |
| Molar mass | 211.261 g·mol−1 |
| Melting point | 35 to 36 °C (95 to 97 °F) |
| Boiling point | 180 °C (356 °F) at 12 mmHg |
Mescaline (3,4,5-trimethoxyphenethylamine) is a naturally occurring psychedelic alkaloid of the phenethylamine class, known for its hallucinogenic effects comparable to those of LSD and psilocybin.
It occurs naturally in the peyote cactus (Lophophora williamsii), the San Pedro cactus (Echinopsis pachanoi), the Peruvian torch (Echinopsis peruviana), and other members of the Cactaceae plant family. It is also found in small amounts in certain members of the Fabaceae (bean) family, including Acacia berlandieri. However those claims concerning Acacia species have been challenged and have been unsupported in additional analysis.
History and use
Peyote has been used for at least 5,700 years by Native Americans in Mexico. 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.
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 in
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. The average 76 mm (3.0 in) button contains about 25 mg mescaline.
Mescaline was first isolated and identified in 1897 by the German chemist Arthur Heffter and first synthesized in 1918 by Ernst Späth.
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".
Potential medical usage
Mescaline has a wide array of suggested medical usage, including treatment of alcoholism and depression. 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 humans have been conducted since the early 1970s.
Biosynthesis
Mescaline is biosynthesized from tyrosine or a hydroxylated phenylalanine. In Lophophora williamsii (Peyote), dopamine converts into mescaline in a biosynthetic pathway involving m-O-methylation and aromatic hydroxylation.
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.
- Biosynthesis of mescaline
Laboratory synthesis
Laboratory synthetic mescaline. Biosynthesized by peyote, this was the first psychedelic compound to be extracted and isolated.
Mescaline was first synthesized in 1919 by Ernst Späth from 3,4,5-trimethoxybenzoyl chloride.
Subsequent to this, numerous approaches utilizing different starting
materials have been developed. Notable examples include the following:
- Hofmann rearrangement of 3,4,5-trimethoxyphenylpropionamide.
- 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.
- Ozonolysis of elemicin followed by reductive amination.
- Ester reduction of Eudesmic acid's methyl ester followed by halogenation, Kolbe nitrile synthesis, and nitrile reduction.
- Amide reduction of 3,4,5-trimethoxyphenylacetamide.
Pharmacokinetics
Tolerance builds with repeated usage, lasting for a few days. Mescaline causes cross-tolerance with other serotonergic psychedelics such as LSD and psilocybin.
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 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. 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).
Behavioral and non-behavioral effects
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.
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. Mescaline may cause Hallucinogen persisting perception disorder.
As with LSD, synesthesia can occur especially with the help of music.
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.
Mescaline elicits a pattern of sympathetic arousal, with the peripheral nervous system being a major target for this substance.
Mechanism of action
Mescaline is produced when products of natural mammalian catecholamine-based neuronal signalling 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 compounds 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.
Mescaline acts similarly to other psychedelic agents. It binds to and activates the serotonin 5-HT2A receptor with a high affinity.
How activating the 5-HT2A receptor leads to psychedelia is still unknown, but it is likely that somehow it involves excitation of neurons in the prefrontal cortex. Mescaline is also known to bind to and activate the serotonin 5-HT2C receptor.
| Binding Sites | Binding Affinity Ki (µM) |
|---|---|
| 5-HT1A | 4.6 |
| 5-HT2A | 6.3 |
| 5-HT2C | 17 |
| α1A | >15 |
| α2A | 1.4 |
| TAAR1 | 3.3 |
Difluoromescaline and trifluoromescaline are more potent than mescaline, as is its amphetamine homologue trimethoxyamphetamine.
Legality
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 was prohibited internationally by the 1971 Convention on Psychotropic Substances. Mescaline is legal only for certain religious groups (such as the Native American Church)
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.
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.
Other countries
Mescaline is considered a schedule 9 substance in Australia under the Poisons Standard (October 2015).
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."
The peyote cacti and other mescaline-containing plants such as San Pedro are illegal in Western Australia, Queensland, and the Northern Territory, whilst in other states such as Tasmania, Victoria and New South Wales, they are legal for ornamental and gardening purposes.
In Canada, France, The Netherlands and Germany, mescaline in raw
form and dried mescaline-containing cacti are considered an illegal
drug. However, anyone may grow and use peyote, or Lophophora williamsii, as well as Echinopsis pachanoi and Echinopsis peruviana without restriction, as it is specifically exempt from legislation. In Canada, mescaline is classified as a schedule III drug under the Controlled Drugs and Substances Act, whereas peyote is exempt.
In Russia mescaline, its derivatives and mescaline-containing plants are banned as narcotic drugs (Schedule I).
Notable users
- 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).
- Martin Kemp, English actor and former Spandau Ballet bassist, described in an interview experiencing mescaline at a late-night party during the height of his musical career in the 1980s: "Mescaline is the drug The Beatles wrote Rubber Soul about. It turns everything to rubber. Every step you take feels like rubber. It is a lot of fun, I have to say. But it goes on for hours – like eight hours".
- 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.
- Bryan Wynter produced Mars Ascends after trying the substance his first time.
- 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.
- Carlos Santana told in 1989 about his mescaline use in a 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.
