Methallylescaline

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Methallylescaline
Methallylescaline.svg
Methallylescaline 3D.png
Clinical data
Other namesMAL; 4-Methylallyloxy-3,5-dimethoxyphenethylamine; 3,5-Dimethoxy-4-methylallyloxyphenethylamine; 4-Methylallyl-desmethylmescaline; MAD
Routes of
administration 		Oral [1]
Drug class Serotonin receptor modulator; Serotonin 5-HT2A receptor agonist; Serotonergic psychedelic; Hallucinogen
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Onset of action ≤1 hour [1]
Duration of action 12–16 hours [1]
Identifiers
  • 2-{3,5-Dimethoxy-4-[(2-methylprop-2-en-1-yl)oxy]phenyl}ethan-1-amine
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C14H21NO3
Molar mass 251.326 g·mol−1
3D model (JSmol)
  • CC(=C)COc1c(cc(cc1OC)CCN)OC
  • InChI=1S/C14H21NO3/c1-10(2)9-18-14-12(16-3)7-11(5-6-15)8-13(14)17-4/h7-8H,1,5-6,9,15H2,2-4H3 Yes check.svgY
  • Key:FOXJFBFFGULACD-UHFFFAOYSA-N Yes check.svgY
   (verify)

Methallylescaline (MAL), also known as 4-methylallyloxy-3,5-dimethoxyphenethylamine, is a psychedelic drug of the phenethylamine and scaline families related to mescaline. [1] [3] It is taken orally. [1] [3]

Contents

The drug acts as a serotonin 5-HT2 receptor agonist, including of the serotonin 5-HT2A receptor. [4] [5] It is closely structurally related to mescaline and to other scalines like escaline and allylescaline. [5]

Methallylescaline was first described by Alexander Shulgin in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved). [3] [1] It was encountered as a novel designer drug by 2013. [6] [7] [8]

Use and effects

In his book PiHKAL (Phenethylamines I Have Known and Loved), Alexander Shulgin lists the dose range of methallylescaline as 40 to 65 mg and its duration as 12 to 16 hours. [1] [9] [10] As such, its dose range is relatively narrow. [1] [9] [10] Moreover, the drug has been reported to have an unusually steep dose–response curve, such that a small increase in dose can result in an unexpectedly large increase in effects. [11] [12] Methallylescaline has about 6 times the potency of mescaline, which has a much higher listed dose range of 200 to 400 mg. [9] [10] [1] Its onset is within 1 hour and peak effects occur within 2 hours. [1]

Shulgin has described methallylescaline as a "mixed bag" in terms of experience reports. [1] Its effects have been reported to include closed-eye visuals, "visual theater", open-eye visuals including visual distortions, visual depth and movement effects, kaleidoscopic neon colors, watercolors, fantasy, mental imagery, feelings of unreality, easy childhood memory recall, self-connectedness, eroticism, initial discomfort, overload, feeling overwhelmed, shades of possible amnesia, loss of contact, extreme restlessness, trouble sleeping, and enhanced dreams. [1] It was also reported to produce quite strong body effects, diuretic effects, and slightly reduced heart rate. [1] Some found it unpleasant and said that they would not repeat the experience, whereas others were impressed by it, found it enjoyable, and called it "beautiful". [1] Many expressed that the dose they tried was too strong for them and that a lower dose would be better. [1] Methallylescaline has been described as having relatively more visual imagery than other scalines like cyclopropylmescaline and allylescaline. [1]

Others have noted that methallylescaline has strong visual effects, as well as prominent nausea, vomiting, and body load, including feeling "overstimulated. [11] The drug is frequently compared to mescaline. [11]

Interactions

Pharmacology

Pharmacodynamics

Methallylescaline activities
Target Affinity (Ki, nM)
5-HT1A 5,100–>10,000
5-HT1B >10,000
5-HT1D 2,754
5-HT1E >10,000
5-HT1F ND
5-HT2A 72–955 (Ki)
8.5–891 (EC50 Tooltip half-maximal effective concentration)
19–110% (Emax Tooltip maximal efficacy)
5-HT2B 110 (Ki)
4.9–>10,000 (EC50)
32–103% (Emax)
5-HT2C 5.1–520 (Ki)
1.8–331 (EC50)
75–102% (Emax)
5-HT3 >10,000
5-HT4 ND
5-HT5A >10,000
5-HT6 >10,000
5-HT7 >10,000
α1A–α1D >10,000
α2A 550–1,500
α2B, α2C >10,000
β1–β3 >10,000
D1–D5 >10,000
H1–H4 >10,000
M1–M5 >10,000
TAAR1 1,000 (Ki) (rat)
3,900 (Ki) (mouse)
(EC50) (rodent)
>10,000 (EC50) (human)
I1 ND
σ1 >10,000
σ2 5,248
SERT Tooltip Serotonin transporter>10,000 (Ki)
ND (IC50 Tooltip half-maximal inhibitory concentration)
NET Tooltip Norepinephrine transporter>10,000 (Ki)
ND (IC50)
DAT Tooltip Dopamine transporter>10,000 (Ki)
ND (IC50)
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [4] [5] [13] [14]

Methallylescaline acts as a potent agonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors, among other actions. [4] [5] [13] [14] It was inactive serotonin 5-HT2B receptor agonist in one study, [5] but was a potent agonist in another study. [4] The comprehensive receptor interactions of methallylescaline have been studied. [4]

The drug produces the head-twitch response (HTR), a behavioral proxy of psychedelic effects, in rodents. [14] Surprisingly, the HTR induced by methallylescaline was blocked by the selective serotonin 5-HT2C receptor antagonist SB-242084 but not by the serotonin 5-HT2A receptor antagonist ketanserin. [14]

In addition to its psychedelic-like effects, methallylescaline produces hyperlocomotion (a stimulant-like effect), conditioned place preference (CPP; a rewarding effect), and modest self-administration (a reinforcing effect) in rodents, among other effects. [15]

Methallylescaline, along with BOD and DOI, has been reported to produce serotonergic neurotoxicity in rodents at high doses given repeatedly. [14] Other psychedelics have also been found to produce neurotoxicity in preclinical research. [16] [17] [18]

Pharmacokinetics

The metabolism of methallylescaline has been studied. [19] [20]

Chemistry

Methallylescaline, also known as 4-methylallyloxy-3,5-dimethoxyphenethylamine, is a substituted phenethylamine and scaline. [1] [3] [9] [10] It is a synthetic derivative of mescaline (3,4,5-trimethoxyphenethylamine) with a meth allyl oxy group instead of methoxy group at the 4 position. [1] [3] [9] [10]

Synthesis

The chemical synthesis of methallylescaline has been described. [1]

Analogues

Analogues of methallylescaline include mescaline, escaline, allylescaline, and cyclopropylmescaline, among others. [1] [3] [9] [10] [21] Some other analogues include 3C-MAL, 2C-T-3, 2C-O-3, and MMALM. [1] [3] [21]

History

Methallylescaline was first described in the literature by Alexander Shulgin in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved). [3] [1] [9] It was first tried by Shulgin in 1981 and its hallucinogenic effects were discovered by him in 1982. [22] [10] The drug has an entry in PiHKAL, but not in Shulgin's 2011 book The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds . [3] It was encountered as a novel designer drug in Europe by 2013. [6] [7] [8] Methallylescaline's pharmacology was described by Matthias Liechti and Daniel Trachsel and colleagues in 2021. [5] Discussion of methallylescaline online began increasing in late 2023. [11]

Society and culture

Names

Alexander Shulgin described the name of methallylescaline (MAL) as "completely unsound". [1] This was because there was no union of a meth allyl group with escaline. [1] Instead, methallylescaline is mescaline with a 2-propene group attached to the methyl of the methoxy group at the 4 position. [1] However, Shulgin expressed that there is no way of naming the compound in that manner. [1] The only corresponding proper name would be 4-methylallyldesmethylmescaline (MAD). [1] However, Shulgin found the acronym MAD to be disagreeable and ultimately preferred MAL. [1]

Sweden

Methallylescaline is illegal in Sweden as of 26 January 2016. [23]

United States

Methallylescaline is not directly scheduled under the Controlled Substances Act. However, due to its structural similarities with mescaline, it could potentially be prosecuted under the Federal Analogue Act if sold for human consumption.

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 "Methallylescaline". PiHKAL.
  2. ↑ Anvisa (2023-07-24). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  3. 1 2 3 4 5 6 7 8 9 Shulgin A, Manning T, Daley PF (2011). "#91. Mescaline". The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds . Vol. 1. Berkeley, CA: Transform Press. pp. 212–225 (217). ISBN   978-0-9630096-3-0. OCLC   709667010. [...] Homologues and Analogues [...] Name: MAL. CAS #: [207740-41-8]. Ref: (30,31). [...] (30) Synthesis (Shulgin and Shulgin, 1991). (31) Orally active in humans at 40-65 mg; duration 12-16 hours (Shulgin and Shulgin, 1991).
  4. 1 2 3 4 5 Jain MK, Gumpper RH, Slocum ST, Schmitz GP, Madsen JS, Tummino TA, Suomivuori CM, Huang XP, Shub L, DiBerto JF, Kim K, DeLeon C, Krumm BE, Fay JF, Keiser M, Hauser AS, Dror RO, Shoichet B, Gloriam DE, Nichols DE, Roth BL (October 2025). "The polypharmacology of psychedelics reveals multiple targets for potential therapeutics" (PDF). Neuron. 113 (19): 3129–3142.e9. doi:10.1016/j.neuron.2025.06.012. PMID   40683247.
  5. 1 2 3 4 5 6 Kolaczynska KE, Luethi D, Trachsel D, Hoener MC, Liechti ME (2021). "Receptor Interaction Profiles of 4-Alkoxy-3,5-Dimethoxy-Phenethylamines (Mescaline Derivatives) and Related Amphetamines". Front Pharmacol. 12 794254. doi: 10.3389/fphar.2021.794254 . PMC   8865417 . PMID   35222010.
  6. 1 2 King LA (2014). "New phenethylamines in Europe". Drug Test Anal. 6 (7–8): 808–818. doi:10.1002/dta.1570. PMID   24574327.
  7. 1 2 "EMCDDA–Europol 2013 Annual Report on the implementation of Council Decision 2005/387/JHA". www.euda.europa.eu. 2 July 2024. Retrieved 9 October 2025.
  8. 1 2 Coelho Neto J (July 2015). "Rapid detection of NBOME's and other NPS on blotter papers by direct ATR-FTIR spectrometry". Forensic Science International. 252: 87–92. doi:10.1016/j.forsciint.2015.04.025. PMID   25965305.
  9. 1 2 3 4 5 6 7 Jacob P, Shulgin AT (1994). "Structure-activity relationships of the classic hallucinogens and their analogs" (PDF). NIDA Res Monogr. 146: 74–91. PMID   8742795. Archived from the original (PDF) on August 5, 2023.
  10. 1 2 3 4 5 6 7 Shulgin AT (2003). "Basic Pharmacology and Effects". In Laing RR (ed.). Hallucinogens: A Forensic Drug Handbook. Forensic Drug Handbook Series. Elsevier Science. pp. 67–137. ISBN   978-0-12-433951-4 . Retrieved 1 February 2025.
  11. 1 2 3 4 "Weekly Briefing Issue 181". National Drug Early Warning System (NDEWS). 10 May 2024. Retrieved 5 January 2026.
  12. ↑ "SATA Early Warning System of the Americas". Archived from the original on 2025-06-19. [United States National Drug Early Warning System (NDEWS)] issued an alert about the substance methallylescaline, a synthetic analog of mescaline and a 5-HT receptor agonist. Discussions in online forums often warn of methallylescaline's steep dose-response curve, where small dosage changes can dramatically alter the experience. Some of the effects discussed are nausea and "body load". Those who experiment with polysubstance use, combine methallylescaline with other substances, such as etizolam.
  13. 1 2 Wang S, Zhu A, Paudel S, Jang CG, Lee YS, Kim KM (March 2023). "Structure-Activity Relationship and Evaluation of Phenethylamine and Tryptamine Derivatives for Affinity towards 5-Hydroxytryptamine Type 2A Receptor". Biomol Ther (Seoul). 31 (2): 176–182. doi:10.4062/biomolther.2022.096. PMC   9970836 . PMID   36224112.
  14. 1 2 3 4 5 Custodio RJ, Ortiz DM, Lee HJ, Sayson LV, Kim M, Lee YS, Kim KM, Cheong JH, Kim HJ (July 2025). "Serotonin 2C receptors are also important in head-twitch responses in male mice". Psychopharmacology (Berl). 242 (7): 1585–1605. doi:10.1007/s00213-023-06482-9. PMID   37882810.
  15. ↑ Custodio RJ, Sayson LV, Botanas CJ, Abiero A, Kim M, Lee HJ, Ryu HW, Lee YS, Kim HJ, Cheong JH (September 2020). "Two newly-emerging substituted phenethylamines MAL and BOD induce differential psychopharmacological effects in rodents". J Psychopharmacol. 34 (9): 1056–1067. doi:10.1177/0269881120936458. PMID   32648801.
  16. ↑ Rudin D, Liechti ME, Luethi D (September 2021). "Molecular and clinical aspects of potential neurotoxicity induced by new psychoactive stimulants and psychedelics". Exp Neurol. 343: 113778. doi:10.1016/j.expneurol.2021.113778. PMID   34090893.{{cite journal}}: CS1 maint: article number as page number (link)
  17. ↑ Capela JP, Ruscher K, Lautenschlager M, Freyer D, Dirnagl U, Gaio AR, Bastos ML, Meisel A, Carvalho F (2006). "Ecstasy-induced cell death in cortical neuronal cultures is serotonin 2A-receptor-dependent and potentiated under hyperthermia". Neuroscience. 139 (3): 1069–1081. doi:10.1016/j.neuroscience.2006.01.007. PMID   16504407.
  18. ↑ Capela JP, Carmo H, Remião F, Bastos ML, Meisel A, Carvalho F (June 2009). "Molecular and cellular mechanisms of ecstasy-induced neurotoxicity: an overview". Mol Neurobiol. 39 (3): 210–271. doi:10.1007/s12035-009-8064-1. PMID   19373443. To further corroborate the fact that MDMA agonistic properties at the 5-HT2A receptor could produce neuronal death, DOI, a prototypical agonist of that receptor was added to cortical neurons [289]. DOI (10 to 100 μM for 24 or 48 h) also induced a dose- and time-dependent apoptotic cortical neuronal apoptosis, which was attenuated by ketanserin and R-96544 [289]. Ketanserin and R-96544 are competitive selective 5-HT2A receptor antagonists and only attenuated MDMA-induced cortical neurodegeneration. However, an antibody raised against the 5-HT2A-receptor, an "irreversible" non-competitive 5-HT2A receptor blocker, prevented almost completely MDMA- and DOI-induced cortical neurotoxicity [289, 290]. Neuronal apoptosis mediated by MDMA is accompanied by activation of caspase 3, which could be blocked by the antibody raised against the 5-HT2A receptor [290]. Therefore, it is likely that DOI- and MDMA-induced neuronal apoptosis arises from direct stimulation of the 5-HT2A receptor [289, 290].
  19. ↑ Tang Y, Xu L, Guo Z, Zhao J, Xiao Y, Xiang P, Xu L, Yan H (June 2025). "Metabolism study of two phenethylamine - derived new psychoactive substances using in silico, in vivo, and in vitro approaches". Arch Toxicol. 99 (6): 2367–2378. doi:10.1007/s00204-025-04010-6. PMID   40064698.
  20. ↑ Kim, Sunjoo; Kim, Ju-Hyun; Kim, Dong Kyun; Lee, Jaesin; In, Sangwhan; Lee, Hye Suk (30 September 2018). "In vitro Metabolism of Methallylescaline in Human Hepatocytes Using Liquid Chromatography-High Resolution Mass Spectrometry". Mass Spectrometry Letters. 9 (3): 86–90. doi:10.5478/MSL.2018.9.3.86.
  21. 1 2 Trachsel, D.; Lehmann, D.; Enzensperger, C. (2013). Phenethylamine: von der Struktur zur Funktion [Phenethylamines: From Structure to Function]. Nachtschatten-Science (in German) (1 ed.). Solothurn: Nachtschatten-Verlag. ISBN   978-3-03788-700-4. OCLC   858805226. Archived from the original on 21 August 2025.
  22. ↑ Alexander Shulgin (1981), Pharmacology Lab Notes #4 (PDF)
  23. ↑ "31 nya ämnen kan klassas som narkotika eller hälsofarlig vara" (in Swedish). Folkhälsomyndigheten. November 2015.
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