This review (2018) looks at the history, pharmacology, metabolism, and psychological effects of mescaline.

Abstract

“Archeological studies in the United States, Mexico, and Peru suggest that mescaline, as a cactus constituent, has been used for more than 6000 years. Although it is a widespread cactus alkaloid, it is present in high concentrations in few species, notably the North American peyote (Lophophora williamsii) and the South American wachuma (Trichocereus pachanoi, T. peruvianus, and T. bridgesii). Spanish 16th century chroniclers considered these cacti “diabolic”, leading to their prohibition, but their use persisted to our days and has been spreading for the last 150 years. In the late 1800s, peyote attracted scientific attention; mescaline was isolated, and its role in the psychedelic effects of peyote tops or “mescal buttons” was demonstrated. Its structure was established by synthesis in 1929, and alternative routes were developed, providing larger amounts for pharmacological and biosynthetic research. Although its effects are attributed mainly to its action as a 5-HT2A serotonin receptor agonist, mescaline binds in a similar concentration range to 5-HT1A and α2A receptors. It is largely excreted unchanged in human urine, and its metabolic products are apparently unrelated to its psychedelic properties. Its low potency is probably responsible for its relative neglect by recreational substance users, as the successful search for structure–activity relationships in the hallucinogen field focused largely on finding more potent analogues. Renewed interest in the possible therapeutic applications of psychedelic drugs may hopefully lead to novel insights regarding the commonalities and differences between the actions of individual classic hallucinogens.“

Authors: Bruce K. Cassels & Patricio Sáez-Briones

Summary

Mescaline is an exceptional hallucinogen because of its outstandingly long record of use. Peyote and wachuma cacti were used by ancient cultures as psychedelics and are depicted on steles and ceramic vessels from at least 2500 YBP.

Current use of mescaline, either isolated from natural sources or synthesized in the laboratory, seems to be infrequent, possibly due to the relatively high doses required to attain a full psychedelic experience. However, use of peyote buttons and wachuma brews is common in some cultures and subcultures and is growing in geographic range and popularity.

Scientific interest in peyote exploded in the second half of the 19th century, after press reports described its use by Native American tribes.

A German toxicologist named Louis Lewin obtained a crude alkaloid extract of a cactus from Mexico and named it Anhalonium lewinii. Heffter isolated pellotine from the cactus and recommended pellotine as a sleep inducer, and most significantly showed that mescaline was responsible for the remarkable effects of peyote buttons.

Although the presence of mescaline in wachuma had been suspected for years, its definitive identification as mescaline was only confirmed in 1960 in two different laboratories.

Mescaline is found in many plants, but is rarely abundant and has a low psychedelic potency. T. pachanoi, L. williamsii, and T. peruvianus are the only widely consumed botanical sources.

The genus Lophophora was only segregated from Anhalonium by Coulter in 1894, explaining why peyote was called Anhalonium williamsii or A. lewinii in the early literature. Today, there are only two generally recognized Lophophora species, L. williamsii and L. diffusa.

Trichocereus is a South American genus of about 45 species. It has been proposed that Trichocereus be included in the related Echinopsis, but DNA analysis does not support this change.

In 1898, Heffter remarked that the upper chlorophyll containing part of what he called Anhalonium williamsii is very bitter, while the roots are hardly bitter at all. A recent paper reported that the crown and the root of a single L. williamsii plant have similar total alkaloid contents but with radically different compositions.

Peyote plants from the Chihuahuan desert and Tamaulipan thornscrub populations in Texas were analyzed for mescaline content. The average concentrations varied within a narrow range.

A study of interindividual variation in T. pachanoi was published in 2010. The results showed that the cacti vary widely in their mescaline content, and more work is needed to better characterize mescaline-rich accessions.

Heffter began his study of mescaline by preparing and analyzing salts, including the neutral sulfate dihydrate (C11H17NO3)2 H2SO42H2O, but did not analyze the free base. It was later shown to be a carbonate, and the correct structure was finally demonstrated by synthesis from 3,4,5-trimethoxybenzal-dehyde.

Slotta and Heller developed an improved method for the synthesis of mescaline, which required the synthesis of isomers and of mono- and dimethoxyphenethylamines. Kindler and Peschke used a transfer hydrogenation method to obtain N-benzoyl-benzoyloxymescaline, which was then improved upon by Slotta.

In 1950 Erne and Ramirez used lithium aluminum hydride to reduce 3,4,5-trimethoxy-nitrostyrene, and the following year Benington and Morin performed the same synthesis. Dornow and Petsch used LAH to prepare radioactive mescaline, and in spite of its poor overall yield, obtained N-methylmescaline and N,Ndimethylmescaline (trichocereine).

In the late 1960s, the biosynthesis of mescaline in L. williamsii and T. pachanoi was studied. The general and still accepted scheme is that put forth by Lundstrom and Agurell (Scheme 3), but there was little interest or technical expertise to study the enzymes involved or the relative importance of alternative pathways.

RELATIONSHIPS

Peyote contains at least 15 different phenethylamine and isoquinoline alkaloids that may all be bioactive, but mescaline is the main psychedelic compound found in this cactus. Recently, there has been renewed interest in exploring possible uses of psychedelics in biomedicine.

Lewin’s original “Anhalonin” was a potent “reflex tetanus-producing” poison with no indication of any psychotropic activity. Heffter isolated anhaline and pellotine from two frog species and studied their pharmacology in live animals, confirming their narcotic effect in frogs and lack of obvious toxicity in mammals.

A dog that received 200 mg subcutaneously began to whine and bark, not at the observer but toward the opposite side of his cage, a peculiar behavior that lasted “for a long while”. Heffter himself experienced the effects of mescaline after swallowing 1.0 g of crude alkaloid sulfates extracted from a similar amount of cactus.

Prentiss and Morgan performed medical observations with peyote, and noted that the effects were generally pleasant visions and a loss of the sense of time, but also reported a case of paranoid ideation, an out-of-body experience and at least temporary relief from the symptoms of “neurasthenia”, “nervous prostration” and “softening of the brain”.

Havelock Ellis consumed three mescal buttons and wrote a particularly beautiful account of his experience. Samuel Fernberger chewed and swallowed six mescal buttons and reported increased and distorted visual, tactile, and auditory sensations and his sense of time, which he was still able to judge in its real dimension.

Mescaline intoxication can be experienced by humans after ingesting mescal buttons, and can include cardiac arrest and respiratory failure, combined with psychotropic effects, including diffuse anxiety, hallucinations with closed eyes, motor dysfunction, intensification of color patterns, and spatial distortion.

After the first synthesis of mescaline, experimentation with mescal buttons or their extracts effectively ended, and the pure drug became available in any desired amount. Clinical studies with mescaline were subsequently carried out, prompting the controversial idea of using this drug to study psychosis. Early experimental evidence demonstrated that mescaline possesses a mixed serotonergic and dopaminergic mechanism of action, although it also binds to 5-HT1A, 5-HT2A, and 2A receptors with little to no other receptor/transporter interactions.

Despite its relevance as a naturally occurring psychotropic alkaloid, mescaline has only been the subject of fragmentary, nonsystematic research. This may be because slight structural modifications provided more potent and therefore more attractive 4-substituted 2,5-dimethoxyphenylisopropylamines.

Early evidence suggested that mescaline hallucinations resembled those achieved by hypnosis, and that mescaline may either activate or depress cortical serotonergic and noradrenergic neurons in a different “mode” compared to typical excitatory effects elicited by glutamate or acetylcholine and inhibitory effects induced by glycine or GABA.

Psychedelic effects might involve functional selectivity in 5-HT2A/2C receptors that could generate differential activation of signal transduction pathways to achieve their characteristic central effects.

Mescaline has been shown to have behavioral effects in animal models, including hypolocomotion, increases of acoustic and tactile startle reactions, and disruption of the temporal distribution of investigatory responses. It has also been shown to increase the head-shake response, a distinctive behavioral hallmark of serotonergic psychedelics.

Mescaline is eliminated almost completely from the human body within 48 h, mostly unchanged, and has a half-life of about 6 h. Oxidative modifications predominate, and the most important process is oxidative deamination to 3,4,5-trimethoxyphenylacetaldehyde.

Mescaline is oxidized little if at all by the amine oxidase of rat brain, liver, or kidney, and is methylated to 3,5-dimethoxy-4-hydroxyphenethylamine by catecholamine O-methyl transferase (COMT) in rabbit liver and lung homogenate.

Investigation into the human pharmacokinetics and metabolism of mescaline seems to have come to a standstill after 1978. One line of research is still untouched, and may be relevant to the effects of peyote and wachuma.

The mescaline structure was used to design a large number of analogues tested in humans, of which the racemic -methylmesca- line (TMA, 3,4,5-trimethoxyamphetamine) was found to be somewhat more potent in a visual test. The emotional responses were quite different and devoid of mescaline’s “enhanced capacity for empathy”.

The difficulty of defining psychotomimetic or hallucinogenic compounds in animal models is illustrated by the use of stimulus generalization, head shakes or twitches, or a panel of several different behavioral responses.

Early studies showed that an isopropyl side chain and triple methoxy substitution provide optimum activity, and an ortho methoxy group usually enhances the compounds’ potency. Cyclization of the side chain gave a derivative that was 3 times as potent as mescaline.

The tethering of the C-3 methoxyl group to the C-3 and C-5 groups of the isopropylamine analogue of mescaline resulted in more potent derivatives, but lower efficacies than serotonin and the full agonist mescaline in phosphoinositide hydrolysis assays.

Mescaline elicits an altered state of consciousness in nonschizophrenic subjects that may be comparable to schizophrenic psychosis. Its potential receptor interaction profile and behavioral profile in rodents suggest a more complex mechanism of action that is still not fully understood.