N-Methylmescaline
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| Other names | NMM; Methylmescaline; M-M; N-Methyl-3,4,5-trimethoxyphenethylamine |
| Drug class | Serotonin receptor modulator and possible serotonergic psychedelic or hallucinogen |
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| ECHA InfoCard | 100.161.443 |
| Chemical and physical data | |
| Formula | C12H19NO3 |
| Molar mass | 225.288 g·mol−1 |
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N-Methylmescaline (NMM), also known as methylmescaline (M-M), is an alkaloid and serotonin receptor modulator of the phenethylamine family related to mescaline that occurs naturally in cacti including Lophophora williamsii (peyote), Pelecyphora aselliformis, and Pachycereus pringlei, among others.[1][2][3][4][5]
Use and effects
[edit]According to Alexander Shulgin, N-methylmescaline shows no central or peripheral effects at doses of up to 24 or 25 mg, which is many times the minor or trace amounts present in peyote.[6][7][2][8][9][10][11] Nonetheless, according to Shulgin, N-methylmescaline, in combination with potent isoquinoline monoamine oxidase inhibitors (MAOIs) that are also present in the cactus, might be the active psychedelic constituent of Pachycereus pringlei, which notably does not contain mescaline.[3][4][12]
Pharmacology
[edit]N-Methylmescaline shows weak affinity for serotonin receptors similarly to mescaline.[1][13] It was found to have about half the serotonin receptor affinity as mescaline (A2 = 5,250 nM vs. 2,240 nM, respectively).[13]
N-Methylmescaline failed to significantly substitute for mescaline (25 mg/kg) in rodent drug discrimination tests either with intraperitoneal or intracerebroventricular injection.[1][14] In contrast to N-methylmescaline however, trichocereine (N,N-dimethylmescaline) produced similar effects to mescaline at a dose of 50 mg/kg intraperitoneally, whereas it only transiently substituted for mescaline when given intracerebroventricularly.[14] Trichocereine has also been reported to be psychedelic in humans, although findings in this area are controversial and conflicting.[7][2][8] It has been noted that N-methylation of psychedelic phenethylamines, for instance Beatrice (N-methyl-DOM), has invariably eliminated their hallucinogenic activity.[15][4]
N-Methylmescaline is less toxic than mescaline in terms of lethal doses in animals.[16]
Chemistry
[edit]N-Methylmescaline, also known as N-methyl-3,4,5-trimethoxyphenethylamine, is a substituted phenethylamine and scaline (substituted mescaline analogue).[1][9] It is specifically the N-methyl analogue of mescaline (3,4,5-trimethoxyphenethylamine).[1][9]
Notable analogues of N-methylmescaline, besides mescaline, include trichocereine (N,N-dimethylmescaline) and N-acetylmescaline.[1][9] Other psychedelic-related N-methylphenethylamines include Beatrice (N-methyl-DOM), N-methyl-DOB, N-methyl-2C-I, N-methyl-DMA, N-methyl-MMDA-2, and MDMA (N-methyl-MDA).[1][9][15]
History
[edit]N-Methylmescaline was first described in the scientific literature by Ernst Späth and Johann Bruck in 1937.[4][17] It was isolated from Lophophora williamsii (peyote) by the researchers and was also synthesized.[4][4]
Society and culture
[edit]Legal status
[edit]United States
[edit]N-Methylmescaline is not an explicitly controlled substance in the United States.[1] However, it may be considered controlled in this country as it is a positional isomer of 3,4,5-trimethoxyamphetamine (TMA), which is a specifically regulated substance.[18]
See also
[edit]References
[edit]- ^ a b c d e f g h Shulgin A, Manning T, Daley PF (2011). "#95. M-M". The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Berkeley, CA: Transform Press. pp. 233–234. ISBN 978-0-9630096-3-0. OCLC 709667010.
- ^ a b c Shulgin AT (1979). "Chemistry of phenethylamines related to mescaline". Journal of Psychedelic Drugs. 11 (1–2): 41–52. doi:10.1080/02791072.1979.10472091. PMID 522167.
A recent report of the presence of N-methyl mescaline [in peyote] could not be confirmed. [...] N-methylmescaline, which may or may not be in Peyote, has been found to be without any pharmacological effects at dosages of up to 25 mg, a level that far exceeds its possible presence in reasonable amounts of the cactus. It cannot thus be a primary contributing factor to the action of Peyote.
- ^ a b Keeper Trout & friends (2014). Cactus Chemistry By Species (Sacred Cacti 4th edition Part C Cactus Chemistry: Section 2) (PDF). Mydriatic Productions/Better Days Publishing.
Pachycereus pringlei (S.Wats) Br. & R.: AKA "saguesa" or the "elephant cactus" This species is most commonly called "cardon" (a name that is also used for many other Cereoids) [...] Pachycereus pringlei: One of the three cactus that the Seri believe used to be human. Felger & Moser 1985 [...] Following his adventure Earl sought out Sasha Shulgin in an attempt to stimulate more research into the plant's bioactivity. A nice account of the next part of the story appears at: mdma.net/alexander-shu...ofessor-x.html [...] In a series of personal conversation between 2001-2005 Shulgin commented on his observation of N-Methylmescaline in the plant and its possible significance. He mentioned that, despite its established lack of interesting properties, he then suspected that was probably the active compound, enabled to be active orally by due to the presence of one or more MAOIs. Sasha referred to the combination as cactihuasca. He also lamented about the difficulty of finding bioassayists for completing this research. Apparently this was due to a heavy body load for both the plant and pure compound combinations. This is essentially where the matter still stands today, a decade later.
- ^ a b c d e f Keeper Trout & friends (2013). Trout’s Notes on The Cactus Alkaloids Nomenclature, Physical properties, Pharmacology & Occurrences (Sacred Cacti Fourth Edition, Part C: Cactus Chemistry: Section 1) (PDF). Mydriatic Productions/Better Days Publishing. pp. 149–150, 159, 161, 163, 170, 174, 187, 204.
N-Methylmescaline: Human studies show no effects at levels of 25 mg. Shulgin 1973 cited Shulgin, 1967 (Unpublished data) No effects in man. Shulgin 1976 cited Shulgin 1973 N-Methylmescaline has decreased potency. [Ed.: This is true, but more than a little misleading.] Hardman et al. 1973 Shulgin suspected this alkaloid to be the active component in the cactus Pachycereus pringlei. He suspected that it was only enabled to be active due to the co-presence of an MAOI.
- ^ Helmlin HJ, Bourquin D, Brenneisen R (1992). "Determination of phenylethylamines in hallucinogenic cactus species by high-performance liquid chromatography with photodiode-array detection". Journal of Chromatography A. 623 (2): 381. doi:10.1016/0021-9673(92)80380-D.
- ^ Shulgin AT (1976). "Psychotomimetic Agents". In Gordon M (ed.). Psychopharmacological Agents: Use, Misuse and Abuse. Medicinal Chemistry: A Series of Monographs. Vol. 4. Academic Press. pp. 59–146. doi:10.1016/b978-0-12-290559-9.50011-9. ISBN 978-0-12-290559-9.
Two simple homologs of mescaline present in L. williamsii have also been shown to occur in other cacti. N-Methylmescaline (L), present in peyote (Spath and Bruck, 1937), has been reported as a component of Pelecyphora aselliformis (Neal et al., 1972). [...] Of the simpler mescaline substitution products, N-methylmescaline (L) shows no effects either peripherally or centrally at levels that represent many times that which would be encountered in a nominal dose of peyote (A. T. Shulgin, unpublished data, 1973). [...] N-Acetylmescaline (LVII), a trace component in the peyote plant, has been identified as a metabolite of mescaline in man (Charalampous et al., 1966). It has been explored in acute trials in human subjects at levels between 300 and 750 mg total dosage. Only at the highest levels were any effects noticed, and they were summed up as being merely a mild degree of drowsiness.
- ^ a b Shulgin AT (1978). "Psychotomimetic Drugs: Structure-Activity Relationships". In Iversen LL, Iversen SD, Snyder SH (eds.). Stimulants. Boston, MA: Springer US. pp. 243–333. doi:10.1007/978-1-4757-0510-2_6. ISBN 978-1-4757-0512-6.
2.2.1. N-Methylmescaline: N-Methylmescaline (23) has been detected as a minor component in peyote (Spath and Bruck, 1937), but human trials of the compound at levels in excess of those conceivably encountered in peyote consumption (i.e., 25 mg) have produced neither central nor peripheral effects (Shulgin, 1967, unpublished data). This suggests that (23) does not contribute to the plant's overall pharmacological toxicity.
- ^ a b Shulgin AT (March 1973). "Mescaline: the chemistry and pharmacology of its analogs". Lloydia. 36 (1): 46–58. PMID 4576313.
N-methylmescaline (7) similarly is a trace component of peyote (17). Human studies have shown no effects either peripheral or central at levels of 25 mg (18) but even this level represents many times that which would be encountered in a nominal dose of peyote.
- ^ a b c d e Shulgin AT, Shulgin A (1991). "#96 M; MESCALINE; 3,4,5-TRIMETHOXYPHENETHYLAMINE". PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. pp. 702–707. ISBN 978-0-9630096-0-9. OCLC 25627628.
If free base mescaline is brought into reaction with ethyl formate (to produce the amide, N-formylmescaline) and subsequently reduced (with lithium aluminum hydride) it is converted to the N-methyl homologue. This base has also been found as a trace component in the Peyote cactus. And the effects of N-methylation of other psychedelic drugs have been commented upon elsewhere in these recipes, all with consistently negative results (with the noteworthy exception of the conversion of MDA to MDMA). Here, too, there is no obvious activity in man, although the levels assayed were only up to 25 milligrams.
- ^ Mangner TJ (1978). Potential Psychotomimetic Antagonists. N,n -diethyl-1-methyl-3-aryl-1, 2, 5, 6-tetrahydropyridine-5-carboxamides (Ph.D. thesis). University of Michigan. doi:10.7302/11268. Archived from the original on 30 March 2025.
Two N-substituted mescaline analogs isolated from L. williamsii are N-methylmescaline (62a) and N-acetylmescaline (62b).95 N-Methylmescaline shows no central effects at a dose which would represent many times the level that would be encountered in a normal dose of peyote.67 N-Acetylmescaline, which has been identified as a metabolite of mescaline in man, is centrally inactive to 750 mg.96 [...] 67. A. T. Shulgin in "Psychopharmacological Agents," M. Gordon, Ed., Academic Press, New York, 1976, p. 59. [...] 96. K. D. Charalampus, K. E. Walker and V. J. Kinross-Wright, Psychopharm., 9, 48 (1966).
- ^ Alexander Shulgin (1967). Pharmacology Lab Notes #1. https://isomerdesign.com/pihkal/notebooks/transcripts/p1/p1.142.pdf
- ^ "Future Psychedelics". Ask Dr. Shulgin Online. 12 June 2002. Retrieved 20 May 2025.
Another continuing source of new things will be from our plant teachers in nature. We are continuously being made aware of new, active plants about which we know very little. My present pursuits are the psychoactive cacti. A good example is a relatively unexplored columnar giant called Pachycereus pringlei. In the published literature, there have been five compounds reported as being present. I have seen four of these, and have obtained mass spectra of 18 additional compounds. Some of these new components I have already identified, but none of these is known to be active in man. And yet I know that the cactus is active as I have actually eaten it and have gotten real effects. Could this be an example of a plant that contains two compounds that are active in combination whereas neither one is active as an isolated chemical? Such things are known in nature.
- ^ a b Glennon RA, Liebowitz SM, Anderson GM (March 1980). "Serotonin receptor affinities of psychoactive phenalkylamine analogues". Journal of Medicinal Chemistry. 23 (3): 294–299. doi:10.1021/jm00177a017. PMID 7365744.
As we have previously reported, N,N-dimethylation of the terminal amine group halves affinity;6 for the one compound examined (comparing 32 with 34), N-methylation also halves affinity.
- ^ a b Browne RG, Harris RT, Ho BT (1974). "Stimulus properties of mescaline and N-methylated derivatives: difference in peripheral and direct central administration". Psychopharmacologia. 39 (1): 43–56. doi:10.1007/BF00421457. PMID 4425137.
- ^ a b Nichols DE (2018). "Chemistry and Structure-Activity Relationships of Psychedelics". Current Topics in Behavioral Neurosciences. 36: 1–43. doi:10.1007/7854_2017_475. ISBN 978-3-662-55878-2. PMID 28401524.
Although the most active tryptamine hallucinogens are N,N-dialkylated, the phenethylamines generally cannot tolerate even a single N-substitution. Even small groups such as methyl or ethyl (see Table 2) abolish their hallucinogenic activity.
- ^ Hardman HF, Haavik CO, Seevers MH (June 1973). "Relationship of the structure of mescaline and seven analogs to toxicity and behavior in five species of laboratory animals". Toxicology and Applied Pharmacology. 25 (2): 299–309. doi:10.1016/s0041-008x(73)80016-x. PMID 4197635.
2. N-methylation of mescaline decreases central nervous system potency. The N,N-dimethyl analog of mescaline has been found to be less potent than mescaline in man (Luduena, 1936) and in rats (Smythies and Sykes, 1966). The studies reported here, in which the N-monomethyl analog of mescaline was employed, support this conclusion. A comparison of the LD50 values (mmol/kg) for compounds IV and VIII shows that in each species the N-methyl analog (VIII) is less toxic.
- ^ Späth E, Bruck J (1937). "Über ein neues Alkaloid aus den Mezcal buttons (XVII. Mitteil. über Kakteen‐Alkaloide)". Berichte der Deutschen Chemischen Gesellschaft. 70 (12). A and B Series: 2446–2450. doi:10.1002/cber.19370701218. ISSN 0365-9488. Retrieved 3 July 2025.
- ^ "Controlled Substance Schedules". www.deadiversion.usdoj.gov. Retrieved 2023-09-14.
External links
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