''para''-Methoxymethamphetamine (PMMA), also known as 4-methoxy-''N''-methylamphetamine (4-MMA), is a

serotonergic A serotonergic substance, medication, or receptor protein is one that affects neurotransmission pathways that involve serotonin, as follows: * Serotonergic drugs ** Serotonin receptor agonists ** Serotonin receptor antagonists ** Serotonin reupta ...

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

of the

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

family related to ''para''-methoxyamphetamine (PMA). It is the 4-

methoxy In organic chemistry, a methoxy group is the functional group consisting of a methyl group bound to oxygen. This alkoxy group has the formula . On a benzene ring, the Hammett equation classifies a methoxy substituent at the ''para'' position a ...

analogue of

methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...

. Little is known about the

pharmacological Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between ...

properties,

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

, and

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacteria, bacterium, or plant, as well as the effect o ...

of PMMA; because of its structural similarity to PMA, which has known

in humans, it is thought to have considerable potential to cause harmful

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s or death in

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

. In the early 2010s, a number of deaths in users of the drug

MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (tablet form), and molly (crystal form), is an empathogen–entactogenic drug with stimulant and minor Psychedelic drug, psychedelic properties. In studies, it has been used ...

were linked to misrepresented tablets and capsules of PMMA. PMMA is a

serotonin–norepinephrine releasing agent A serotonin–norepinephrine releasing agent (SNRA) is a type of drug which induces the release of serotonin and norepinephrine (and epinephrine) in the body and/or brain. Only a few SNRAs are known, examples of which include norfenfluramine ...

(SNRA) as well as potent

monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a drug class, class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressa ...

(MAOI). Its effects in humans are reputedly similar to those of PMA, but slightly more

empathogenic Entactogens, also known as empathogens or connectogens, are a class of psychoactive drugs that induce the production of experiences of emotional communion, oneness, connectedness, emotional openness—that is, empathy—as particularly observe ...

in nature. It has a reduced tendency to produce severe

hyperthermia Hyperthermia, also known as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme te ...

at low dosages, but at higher dosages side effects and risk of death become similar to those of PMA. The synthesis and effects of PMMA were described by American experimental chemist

Alexander Shulgin Alexander Theodore "Sasha" Shulgin (June 17, 1925 – June 2, 2014) was an American biochemist, broad researcher of synthetic psychoactive compounds, and author of works regarding these, who independently explored the organic chemistry and ph ...

in his book ''

PiHKAL ''PiHKAL: A Chemical Love Story'' is a book by Alexander Shulgin and Ann Shulgin published in 1991. The subject of the work is Psychoactive drug, psychoactive phenethylamine Derivative (chemistry), chemical derivatives, notably those that act ...

'', where it is referred to by the name "methyl-MA", as the ''N''-methylated form of 4-MA (PMA).

Effects

According to

in ''

'', the effects of PMMA at 110mg included

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...

, compulsive

yawning A yawn is a reflex in vertebrate animals characterized by a long inspiratory phase with gradual mouth gaping, followed by a brief climax (or acme) with muscle stretching, and a rapid expiratory phase with muscle relaxation, which typically last ...

, and

nystagmus Nystagmus is a condition of involuntary (or voluntary, in some cases) Eye movement (sensory), eye movement. People can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in visual impairment, re ...

, among others. It was said to have some of the physical

s of the

entactogen Entactogens, also known as empathogens or connectogens, are a class of psychoactive drugs that induce the production of experiences of emotional communion, oneness, connectedness, emotional openness—that is, empathy—as particularly observe ...

but none of its central effects. No

psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

-like effects were mentioned. In rodents, PMMA produces

hyperlocomotion Locomotor activity is a measure of animal behavior which is employed in scientific research. Hyperlocomotion, also known as locomotor hyperactivity, hyperactivity, or increased locomotor activity, is an effect of certain drugs in animals in whi ...

, no changes in

locomotor activity Locomotor activity is a measure of animal behavior which is employed in scientific research. Hyperlocomotion, also known as locomotor hyperactivity, hyperactivity, or increased locomotor activity, is an effect of certain drugs in animals in whi ...

, and/or

catatonia Catatonia is a complex syndrome most commonly seen in people with underlying mood disorders, such as major depressive disorder, or psychotic disorders, such as schizophrenia. People with catatonia exhibit abnormal movement and behaviors, wh ...

, and has effects that are said to differ from those of

-like

stimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...

s. It has been said not to have amphetamine-like properties in rodents even at high doses. Similarly, PMMA did not substitute for the

DOM. On the other hand, in contrast to PMA, PMMA fully substituted for MDMA in

drug discrimination Drug discrimination (DD) is a technique in behavioral neuroscience used to evaluate the discriminative stimulus properties or interoceptive cues of psychoactive drugs. In drug discrimination, a subject is trained on a training drug, and then i ...

tests in rodents, despite not having MDMA-like

psychoactive A psychoactive drug, psychopharmaceutical, mind-altering drug, consciousness-altering drug, psychoactive substance, or psychotropic substance is a chemical substance that alters psychological functioning by modulating central nervous system acti ...

effects in humans. In any case, PMMA is said to lack the amphetamine- or stimulant-like properties of MDMA.

Pharmacology

Pharmacodynamics

PMMA is a

monoamine releasing agent A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrati ...

(MRA). The drug's values for induction of monoamine release in rat brain

synaptosome A synaptosome is an isolated synaptic terminal from a neuron. Synaptosomes are obtained by mild homogenization of nervous tissue under isotonic conditions and subsequent fractionation using differential and density gradient centrifugation. Liquid ...

s have been reported for the individual

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

s of PMMA. In the case of (''S'')-PMMA, they are 41nM for

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

, 147nM for

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

, and 1,000nM for

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

, whereas for (''R'')-PMMA, they are 134nM for serotonin, >14,000nM for norepinephrine, and 1,600nM for dopamine. Hence, PMMA appears to be a

(SNRA) with weak effects on dopamine. The drug has been found to strongly release serotonin and to weakly release dopamine in the brain in rodents ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

''. In addition to its MRA activity, PMMA is a potent

monoamine oxidase A Monoamine oxidase A, also known as MAO-A, is an enzyme ( E.C. 1.4.3.4) that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative dea ...

(MAO-A)

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

. Its for MAO-A inhibition has been reported to be 1,700nM. This is several-fold less potent than the related agents ''para''-methoxyamphetamine (PMA) and

4-methylthioamphetamine 4-Methylthioamphetamine (4-MTA), also known as ''para''-methylthioamphetamine (MTA), is a designer drug of the substituted amphetamine class developed in the 1990s by a team led by David E. Nichols, an American pharmacologist and medical chemist ...

(4-MTA). PMMA is said to lack

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the

5-HT_2A receptor. In one study, its affinities were >20,000nM for the serotonin 5-HT_1A receptor, 13,600nM for the serotonin 5-HT_2A receptor, and >13,000nM for the serotonin 5-HT_2C receptor. On the other hand, PMMA shows much higher affinities for the mouse and rat

trace amine-associated receptor 1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is a primarily intracellular amine-activated and G protein-coupled receptor (GPCR) that is p ...

(TAAR1).

Recreational use

PMMA has been found in tablets and capsules of the

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. 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 Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain Serotonin, serotonergic medications or Recreational drug use, drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild c ...

can result. PMMA can be detected with

reagent testing Reagent testing is one of the processes used to identify substances contained within a pill, usually illicit substances. With the increased prevalence of drugs being available in their pure forms, the terms "drug checking" or "pill testing" may a ...

kits.

Deaths

In January 2011, the

Norwegian Broadcasting Corporation The Norwegian Broadcasting Corporation (), commonly known by its initialism NRK, is a Norwegian state-run, government-influenced radio and television public broadcasting company. The NRK broadcasts three national TV channels and thirteen nat ...

reported that Norway had seen 12 deaths related to PMMA over the course of six months. In March 2011,

Dutch Dutch or Nederlands commonly refers to: * Something of, from, or related to the Netherlands ** Dutch people as an ethnic group () ** Dutch nationality law, history and regulations of Dutch citizenship () ** Dutch language () * In specific terms, i ...

media reported that there had been four deaths in the province of

Limburg Limburg or Limbourg may refer to: Regions * Limburg (Belgium), a province since 1839 in the Flanders region of Belgium * Limburg (Netherlands), a province since 1839 in the south of the Netherlands * Diocese of Limburg, Roman Catholic Diocese in ...

since November 2010. In April 2011,

Iceland Iceland is a Nordic countries, Nordic island country between the Atlantic Ocean, North Atlantic and Arctic Oceans, on the Mid-Atlantic Ridge between North America and Europe. It is culturally and politically linked with Europe and is the regi ...

ic media reported the death of a young woman that may have been connected to PMMA. In 2011, four deaths were recorded in Scotland as a result of ecstasy tablets which also contained PMMA. In January 2012, a number of ecstasy-related deaths in

Canada Canada is a country in North America. Its Provinces and territories of Canada, ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, making it the world's List of coun ...

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. In September 2012, the deaths of two men in

County Cork County Cork () is the largest and the southernmost Counties of Ireland, county of Republic of Ireland, Ireland, named after the city of Cork (city), Cork, the state's second-largest city. It is in the Provinces of Ireland, province of Munster ...

Ireland Ireland (, ; ; Ulster Scots dialect, Ulster-Scots: ) is an island in the North Atlantic Ocean, in Northwestern Europe. Geopolitically, the island is divided between the Republic of Ireland (officially Names of the Irish state, named Irelan ...

, have been linked to PMMA overdoses. In the same month, the death of a man in Queensland, Australia was attributed to PMMA. In June 2013 a PMMA-related death occurred in the Dutch city of

's-Hertogenbosch s-Hertogenbosch (), colloquially known as Den Bosch (), is a List of cities in the Netherlands by province, city and List of municipalities of the Netherlands, municipality in the Netherlands with a population of 160,783. It is the capital of ...

. Two months later, In August 2013, another possibly PMMA-related death occurred in the nearby town of

Sliedrecht Sliedrecht () is a town and municipality in the western Netherlands, in the province of South Holland. The municipality covers an area of of which is covered by water. Sliedrecht is known for the many large dredging companies (including Boskal ...

. In January 2015 in the UK four people died, suspected of taking ecstasy containing PMMA. In the same month, in Sweden, another man died from ecstasy laced with PMMA. In May 2015 a young woman died in

Dublin Dublin is the capital and largest city of Republic of Ireland, Ireland. Situated on Dublin Bay at the mouth of the River Liffey, it is in the Provinces of Ireland, province of Leinster, and is bordered on the south by the Dublin Mountains, pa ...

, Ireland, after taking what is suspected to be PMMA. In April 2016 four young

Argentines Argentines, Argentinians or Argentineans are people from Argentina. This connection may be residential, legal, historical, or cultural. For most Argentines, several (or all) of these connections exist and are collectively the source of their ...

and one

Uruguay Uruguay, officially the Oriental Republic of Uruguay, is a country in South America. It shares borders with Argentina to its west and southwest and Brazil to its north and northeast, while bordering the Río de la Plata to the south and the A ...

an died during a massive rave called "Time Warp" in

Buenos Aires Buenos Aires, controlled by the government of the Autonomous City of Buenos Aires, is the Capital city, capital and largest city of Argentina. It is located on the southwest of the Río de la Plata. Buenos Aires is classified as an Alpha− glob ...

and five more were hospitalized. PMMA was found in their bodies.

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.

United Kingdom

PMMA is controlled as a Schedule 1,

Class A drug The Misuse of Drugs Act 1971 (c. 38) is an act of the Parliament of the United Kingdom. It represents action in line with treaty commitments under the Single Convention on Narcotic Drugs, the Convention on Psychotropic Substances, and the ...

in the UK.

References

{{DEFAULTSORT:Methoxy-N-methylamphetamine, para- Designer drugs Methamphetamines 4-Methoxyphenyl compounds Methoxyphenethylamines Monoamine oxidase inhibitors Serotonin-norepinephrine releasing agents TAAR1 modulators