Para-Methoxymethamphetamine

para-Methoxymethamphetamine (PMMA), also known as 4-methoxy-N-methylamphetamine (4-MMA), is a serotonergic drug of the amphetamine family related to para-methoxyamphetamine (PMA). It is the 4-methoxy analogue of methamphetamine. Little is known about the pharmacological properties, metabolism, and toxicity of PMMA; because of its structural similarity to PMA, which has known toxicity in humans, it is thought to have considerable potential to cause harmful side effects or death in overdose.^[2] In the early 2010s, a number of deaths in users of the drug MDMA were linked to misrepresented tablets and capsules of PMMA.^[3]

para-Methoxymethamphetamine

Clinical data
Other names	PMMA; p-Methoxymethamphetamine; para-Methoxy-N-methylamphetamine; 4-Methoxy-N-methylamphetamine; 4-MMA; Methyl-MA; 4-PMDA
Drug class	Serotonin–norepinephrine releasing agent; Monoamine oxidase inhibitor
Legal status
Legal status	BR: Class F2 (Prohibited psychotropics)[1] CA: Schedule I DE: Anlage I (Authorized scientific use only) UK: Class A US: Schedule 1
Identifiers
IUPAC name 1-(4-Methoxyphenyl)-N-methylpropan-2-amine
CAS Number	22331-70-0 Y
PubChem CID	90766
ChemSpider	81951
UNII	037U5SR9KL
KEGG	C22810 Y
CompTox Dashboard (EPA)	DTXSID30874251
ECHA InfoCard	100.040.818
Chemical and physical data
Formula	C11H17NO
Molar mass	179.263 g·mol−1
3D model (JSmol)	Interactive image Interactive image
SMILES CC(CC1=CC=C(C=C1)OC)NC C1=CC(=CC=C1CC(C)NC)OC
InChI InChI=1S/C11H17NO/c1-9(12-2)8-10-4-6-11(13-3)7-5-10/h4-7,9,12H,8H2,1-3H3 Key:UGFMBZYKVQSQFX-UHFFFAOYSA-N
(verify)

PMMA is a serotonin–norepinephrine releasing agent (SNRA)^[4][5][6][7] as well as potent monoamine oxidase inhibitor (MAOI).^[8] Its effects in humans are reputedly similar to those of PMA, but slightly more empathogenic in nature.^{[medical citation needed]} It has a reduced tendency to produce severe hyperthermia at low dosages,^[9][10] but at higher dosages side effects and risk of death become similar to those of PMA.^[11]

The synthesis and effects of PMMA were described by American experimental chemist Alexander Shulgin in his book PiHKAL, where it is referred to by the name "methyl-MA", as the N-methylated form of 4-MA (PMA).^[12]

Effects

According to Alexander Shulgin in PiHKAL, the effects of PMMA at 110 mg included tachycardia, compulsive yawning, and nystagmus, among others.^[12] It was said to have some of the physical side effects of the entactogen MDMA but none of its central effects.^[12] No psychedelic-like effects were mentioned.^[12] In rodents, PMMA produces hyperlocomotion, no changes in locomotor activity, and/or catatonia, and has effects that are said to differ from those of amphetamine-like stimulants.^[13][14][4] It has been said not to have amphetamine-like properties in rodents even at high doses.^[13][14][4] Similarly, PMMA did not substitute for the psychedelic DOM.^[14] On the other hand, in contrast to PMA, PMMA fully substituted for MDMA in drug discrimination tests in rodents, despite not having MDMA-like psychoactive effects in humans.^[13][4][12] In any case, PMMA is said to lack the amphetamine- or stimulant-like properties of MDMA.^[14][4]

Pharmacology

Pharmacodynamics

PMMA is a monoamine releasing agent (MRA).^[4][5][6][7] The drug's EC₅₀Tooltip half-maximal effective concentration values for induction of monoamine release in rat brain synaptosomes have been reported for the individual enantiomers of PMMA.^[4][5][6] In the case of (S)-PMMA, they are 41 nM for serotonin, 147 nM for norepinephrine, and 1,000 nM for dopamine, whereas for (R)-PMMA, they are 134 nM for serotonin, >14,000 nM for norepinephrine, and 1,600 nM for dopamine.^[4][5][6] Hence, PMMA appears to be a serotonin–norepinephrine releasing agent (SNRA) with weak effects on dopamine.^[4][5][6][7] The drug has been found to strongly release serotonin and to weakly release dopamine in the brain in rodents in vivo.^[7]

In addition to its MRA activity, PMMA is a potent monoamine oxidase A (MAO-A) inhibitor.^[8] Its IC₅₀Tooltip half-maximal inhibitory concentration for MAO-A inhibition has been reported to be 1,700 nM.^[8] This is several-fold less potent than the related agents para-methoxyamphetamine (PMA) and 4-methylthioamphetamine (4-MTA).^[8]

PMMA is said to lack affinity for the serotonin 5-HT_2A receptor.^[4] In one study, its affinities were >20,000 nM for the serotonin 5-HT_1A receptor, 13,600 nM for the serotonin 5-HT_2A receptor, and >13,000 nM for the serotonin 5-HT_2C receptor.^[15] On the other hand, PMMA shows much higher affinities for the mouse and rat trace amine-associated receptor 1 (TAAR1).^[15]

Monoamine release of PMMATooltip para-methoxymethamphetamine and related agents (EC₅₀Tooltip Half maximal effective concentration, nM)

Compound	5-HTTooltip Serotonin	NETooltip Norepinephrine	DATooltip Dopamine	Ref
d-Amphetamine	698–1,765	6.6–7.2	5.8–24.8	[16][17]
d-Methamphetamine	736–1,292	12.3–13.8	8.5–24.5	[16][18]
2-Methoxyamphetamine	ND	473	1,478	[19]
3-Methoxyamphetamine	ND	58.0	103	[19]
para-Methoxyamphetamine (PMA)	ND	166	867	[19][6]
PMMATooltip para-Methoxymethamphetamine	ND	ND	ND	ND
(S)-PMMA	41	147	1,000	[4][5][6]
(R)-PMMA	134	>14,000	1,600	[4][5][6]
4-Methylamphetamine (4-MA)	53.4	22.2	44.1	[20][21][19]
4-Methylmethamphetamine (4-MMA)	67.4	66.9	41.3	[22][23]
para-Chloroamphetamine (PCA)	28.3	23.5–26.2	42.2–68.5	[21][19][24][25]
para-Chloromethamphetamine (PCMA)	29.9	36.5	54.7	[24][25]
Methedrone (4-MeO-MC)	120–195	111	506–881	[26][27][28][29][30]
Mephedrone (4-MMC)	118.3–122	58–62.7	49.1–51	[18][17][27][29][30]
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs: [31][32]

Recreational use

Tablets of PMMA recovered by the U.S. Drug Enforcement Administration

PMMA has been found in tablets and capsules of the MDMA sold as "ecstasy". A number of deaths have been attributed to tablets sold as ecstasy that contained other substances, such as PMMA's structural analog, PMA.^[33][34] Death can occur when an ecstasy user believes they are consuming recreational doses of MDMA, when they are in fact consuming a lethal dose of another substance with similar effects. PMA is of particular concern because it not only causes a release of serotonin but also acts as a monoamine oxidase inhibitor (MAOI); if it is used in combination with MDMA or another MDMA-like substance, serotonin syndrome can result.^[35]

PMMA can be detected with reagent testing kits.

Deaths

In January 2011, the Norwegian Broadcasting Corporation reported that Norway had seen 12 deaths related to PMMA over the course of six months. In March 2011, Dutch media reported that there had been four deaths in the province of Limburg since November 2010.^[36] In April 2011, Icelandic media reported the death of a young woman that may have been connected to PMMA.^{[citation needed]}

In 2011, four deaths were recorded in Scotland as a result of ecstasy tablets which also contained PMMA.^[37]

In January 2012, a number of ecstasy-related deaths in Canada in the previous year were linked to PMMA overdoses. In the single year, approximately 45 exposures occurred, resulting in 21 deaths. Cases were centred primarily in Calgary and Vancouver.^{[38][39][40][41][42][43]}

In September 2012, the deaths of two men in County Cork, Ireland, have been linked to PMMA overdoses.^[44] In the same month, the death of a man in Queensland, Australia was attributed to PMMA.^[45]

In June 2013 a PMMA-related death occurred in the Dutch city of 's-Hertogenbosch.^[46] Two months later, In August 2013, another possibly PMMA-related death occurred in the nearby town of Sliedrecht.^[47][48][49]

In January 2015 in the UK four people died, suspected of taking ecstasy containing PMMA.^[50] In the same month, in Sweden, another man died from ecstasy laced with PMMA.^[51]

In May 2015 a young woman died in Dublin, Ireland, after taking what is suspected to be PMMA.^[52]

In April 2016 four young Argentines and one Uruguayan died during a massive rave called "Time Warp" in Buenos Aires and five more were hospitalized. PMMA was found in their bodies. ^[53]

Legal status

United States

On June 25, 2021, the DEA finalized a rule placing PMMA on the Controlled Substance Act federal Schedule as a Schedule I substance effective July 26, 2021.^[54]

United Kingdom

PMMA is controlled as a Schedule 1, Class A drug in the UK.^{[citation needed]}

See also

• Substituted methoxyphenethylamine
• 2-Methoxymethamphetamine (methoxyphenamine)
• 3-Methoxymethamphetamine (MMMA)
• 4-Fluoromethamphetamine (4-FMA)
• 4-Methylmethamphetamine (4-MMA)
• 4-Methoxymethcathinone (bk-PMMA)
• 4-Methylthiomethamphetamine (4-MTMA)
• Venlafaxine