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4-Methylthiomethamphetamine (4-MTMA; code name PAL-1063), also known as N-methyl-4-methylthioamphetamine (NMMTA), is a monoamine releasing agent (MRA) of the amphetamine family related to 4-methylthioamphetamine (4-MTA). Much less is known about 4-MTMA compared to 4-MTA.

4-MTMA is known to act as a potent serotonin releasing agent (SRA). Its EC₅₀Tooltip half-maximal effective concentration value for induction of serotonin release in rat brain synaptosomes was 21 nM, whereas norepinephrine and dopamine release were not assessed. In addition to its MRA activity, like 4-MTA, the drug has been found to act as a potent reversible enzyme inhibitor of monoamine oxidase A (MAO-A). However, it is about one-third as potent as 4-MTA as an MAO-A inhibitor. Its IC₅₀Tooltip half-maximal inhibitory concentration value for MAO-A inhibition is 0.89 nM, whereas the values of 4-MTA are 0.13 nM for (+)-4-MTA and 2.04 nM for (–)-4-MTA. Neither 4-MTA nor 4-MTMA inhibited monoamine oxidase B (MAO-B). Potent monoamine oxidase inhibition by amphetamines has been associated with dangerous and sometimes fatal toxicity in humans.

In animal drug discrimination tests, 4-MTA and 4-MTMA were found to generalize to MDMA. 4-MTA substituted for the serotonergic agent PMMA, whereas 4-MTMA did not. 4-MTA did not substitute for the serotonergic psychedelic DOM, whereas 4-MTMA was not assessed in DOM-trained animals. Neither 4-MTA nor 4-MTMA substituted for the psychostimulants dextroamphetamine or cocaine. It was concluded that 4-MTA and 4-MTMA show mainly MDMA-like effects in rodents.

4-MTMA had not been identified as an illicit drug or drug of misuse by 2004. However, it is said to have been encountered as a novel designer drug by 2015.

References

1. ^ Murphy J, Flynn JJ, Cannon DM, Guiry PJ, McCormack P, Baird AW, McBean GJ, Keenan AK (May 2002). "In vitro neuronal and vascular responses to 5-hydroxytryptamine: modulation by 4-methylthioamphetamine, 4-methylthiomethamphetamine and 3,4-methylenedioxymethamphetamine". Eur J Pharmacol. 444 (1–2): 61–67. doi:10.1016/s0014-2999(02)01586-8. PMID 12191583.
2. ^ Khorana N, Pullagurla MR, Dukat M, Young R, Glennon RA (August 2004). "Stimulus effects of three sulfur-containing psychoactive agents". Pharmacol Biochem Behav. 78 (4): 821–826. doi:10.1016/j.pbb.2004.05.021. PMID 15301941. The present investigation examined these agents, and the N-monomethyl analog of 4-MTA (i.e., 4-MTMA), in tests of stimulus generalization (substitution) using a two-lever drug discrimination task with groups of rats trained to discriminate either the hallucinogen DOM , the stimulant cocaine, or the empathogen MDMA from vehicle. 4-MTA and its N-monomethyl analog 4-MTMA (ED50 = 0.8 mg/kg in both cases) substituted only for the MDMA stimulus, whereas 2C-T-7 (ED50 = 0.8 mg/kg) substituted only for the DOM stimulus. Thus, at the doses examined, 4-MTA and 4-MTMA appear to be MDMA-like agents, and 2C-T-7 seems best classified as a DOM-like hallucinogen.
3. ^ Rothman RB, Partilla JS, Baumann MH, Lightfoot-Siordia C, Blough BE (April 2012). "Studies of the biogenic amine transporters. 14. Identification of low-efficacy "partial" substrates for the biogenic amine transporters". The Journal of Pharmacology and Experimental Therapeutics. 341 (1): 251–262. doi:10.1124/jpet.111.188946. PMC 3364510. PMID 22271821.
4. ^ Błachut D, Wojtasiewicz K, Czarnocki Z, Szukalski B (November 2009). "The analytical profile of some 4-methylthioamphetamine (4-MTA) homologues". Forensic Sci Int. 192 (1–3): 98–114. doi:10.1016/j.forsciint.2009.08.009. PMID 19766415. Whereas pharmacological properties of 4-MTA are well described in the literature, much less is known about its N-methylated homologue, 4-methylthiomethamphetamine (4- MTMA). The 4-MTMA has been examined in the test of stimulus generalization using MDMA and PMMA-trained rats . Because the stimulus generalization failed to occur with PMMA and instead the substitution took place upon the administration of 4-MTMA to MDMA-trained animals, the drug was considered to be a MDMA-like agent. Only one study was devoted to the biological activity of N-alkyl derivatives of 4-MTA with substituents other than N-methyl . An important conclusion of this work was that all derivatives investigated, including 4-MTA and its N-methyl, Nethyl, N-propyl and N,N-dimethyl-homologues, acted as selective, reversible inhibitors of MAO-A and their potency decreased with the increasing size of the N-alkyl chain.
5. ^ Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK (2019). "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Front Pharmacol. 10: 1590. doi:10.3389/fphar.2019.01590. PMC 6989591. PMID 32038257. Relatively few amino group substituents have been studied in AMPH derivatives regarding their influence upon MAOI potency. In general terms, any N-substitution leads to a decrease in the activity of the compound as a MAOI-A. Thus, the N-methyl derivatives of AMPH, MTA, p-methoxyAMPH (PMA), and 3,4-methylenedioxyAMPH (MDA)— i.e. methamphetamine, NMMTA, PMMA, and MDMA respectively— have about one-third the inhibitory potency of their corresponding primary amine congeners (Scorza et al., 1997; Hurtado-Guzmán et al., 2003; Matsumoto et al., 2014; Santillo, 2014; Tables 1, 2, 4).{{cite journal}}: CS1 maint: unflagged free DOI (link)
6. ^ Hurtado-Guzmán C, Fierro A, Iturriaga-Vásquez P, Sepúlveda-Boza S, Cassels BK, Reyes-Parada M (August 2003). "Monoamine oxidase inhibitory properties of optical isomers and N-substituted derivatives of 4-methylthioamphetamine" (PDF). J Enzyme Inhib Med Chem. 18 (4): 339–47. doi:10.1080/1475636031000118437. PMID 14567549.
7. ^ Dukat M, Young R, Glennon RA (May 2002). "Effect of PMA optical isomers and 4-MTA in PMMA-trained rats". Pharmacol Biochem Behav. 72 (1–2): 299–305. doi:10.1016/s0091-3057(01)00776-6. PMID 11900800.
8. Houck, M.M. (2015). Forensic Chemistry. Advanced Forensic Science Series. Academic Press. p. 187. ISBN 978-0-12-800624-5. Retrieved 12 January 2025.

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