4-Methylthioamphetamine (4-MTA), also known as ''para''-methylthioamphetamine (MTA), is a
designer drug
A designer drug is a structural or functional analog of a controlled substance that has been designed to mimic the pharmacological effects of the original drug, while avoiding classification as illegal and/or detection in standard drug tests. ...
of the
substituted amphetamine
Substituted amphetamines, or simply amphetamines, are a chemical class, class of compounds based upon the amphetamine structure; it includes all derivative (chemistry), derivative compounds which are formed by replacing, or substitution reacti ...
class developed in the 1990s by a team led by
David E. Nichols, an American pharmacologist and medical chemist, at
Purdue University
Purdue University is a Public university#United States, public Land-grant university, land-grant research university in West Lafayette, Indiana, United States, and the flagship campus of the Purdue University system. The university was founded ...
. It acts as a non-
neurotoxic
Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...
highly
selective serotonin releasing agent
A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter ...
(SSRA) in animals.
4-MTA is the methylthio
derivative
In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...
of
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 ...
.
History
First appearance
In 1997, the
Forensic Science Laboratory of the Netherlands received reports of three unrelated drug deaths. The substance in question was a new ring-substituted amphetamine derivative. In 1998 two additional cases of this still unknown compound were added to the list, and the incidents were reported to the IPSC (Institut de Police Scientifique et de Criminologie, University of Lausanne, Switzerland). In both the Netherlands and Switzerland, the unknown compound was encountered in the
hydrochloride salt form, and pictures of the different tablets were compared to each other. After an investigation, it appeared that in other European countries such as the United Kingdom and Germany the derivative was also encountered. The new drug even got as far as Australia. After analytical research, the compound was identified as 4-methylthioamphetamine (4-MTA). This was an already known compound originally only intended for pharmacological studies on animals. The studies of 4-MTA by David Nichols were then linked to the tablets found in all the different countries.
Development

4-MTA was developed by the research team led by David Nichols
but was intended to be used only as an agent for laboratory research into the serotonin transporter protein. Nichols was reportedly sad to see 4-MTA appear as a drug of abuse on the street. He said after finding out his research was used as a dangerous serotonin releasing drugs, "I was stunned. I had published information ultimately led to human death."
Nichols intentions were to discover how
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 ...
worked in the brain to eventually find a positive use for it in psychotherapy. Nichols studied thereby molecules with similar structure, including 4-MTA. Between 1992 and 1997 they published three papers on the effects of this drug in rats and the idea that it could potentially be used in the treatment of depression and be a potential replacement for
Prozac
Fluoxetine, sold under the brand name Prozac, among others, is an antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used for the treatment of major depressive disorder, anxiety, obsessive–compulsive disor ...
. Without the knowledge of Nichols and his team, others synthesized the drugs into a tablet. These tablets were known by their street name, 'flatliners'. Nichols' laboratory had published that the rats perceived the effects of 4-MTA to be like those of
ecstasy, which was probably the motivation for its production and distribution to humans.
Nichols also said, "I have never considered my research to be dangerous, and in fact hoped one day to develop medicines to help people."
Because of the 4-MTA relating death, Nichols' laboratory was asked to study the human effects of other materials they have studied, to avoid likewise situation as with 4-MTA. Most of the molecules the laboratory further had published could not kill in reasonable dosages.
Use and availability
The typical tablets sold on the street contained approximately between 100–140 mg 4-MTA. 4-MTA was briefly sold in
smart shops in the Netherlands, though was soon banned by the Dutch government after serious side-effects started to emerge. The Union of Smartshop Owners decided to leave it out of their assortment after they discovered the drug had only been tested on rats. It was also briefly sold on the black market as MDMA during the late 1990s, mainly in the US, but proved unpopular due to its high risk of severe side effects (several deaths were reported) and relative lack of positive euphoria.
Effects
4-MTA is a strong serotonin releaser similar to
''para''-methoxyamphetamine (PMA), which can cause pronounced
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 ...
potentially resulting in organ failure and death. Therefore, the major neuropharmacological effect is an increased release of serotonin, and the inhibition of serotonin uptake of mono oxidase A (MAO-A). The combination of the releasing of serotonin from neurons, but the prevention of breaking this neurotransmitter down again, leads to dangerous
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 ...
. The serotonin syndrome is a hyper serotonergic state, which can become fatal and is a side effect of serotonergic enhancing drugs. The symptoms of serotonin syndrome caused by 4-MTA are described in the Report on the Risk Assessment of 4-MTA
Symptoms of the serotonin syndrome caused by 4-MTA
* Euphoria
* Drowsiness
* Sustained rapid eye movement
*
Hyperreflexia
Hyperreflexia is overactive or overresponsive bodily reflexes. Examples of this include twitching and spastic tendencies, which indicate disease of the upper motor neurons and the lessening or loss of control ordinarily exerted by higher brain ...
– overreaction of the reflexes
* Agitation
* Restlessness
*
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 ...
– fast heart rate
* Headache
* Clumsiness
* Disorientation
* Intoxication – feeling drunk and dizzy
* Rigidity
* Rapid muscle contraction and relaxation in the ankle causing abnormal movements of the foot
* Muscle contraction and relaxation in the jaw
* Muscle twitching leading to hyperthermia
* Shivering
* High body temperature
* Sweating
* Altered mental status (including confusion and hypomania – a 'happy drunk state')
Another effect is the increase of the secretion of several hormones, like
adrenocorticotropic hormone
Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...
(ACTH),
corticosterone
Corticosterone, also known as 17-deoxycortisol and 11β,21-dihydroxyprogesterone, is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands. In the very rare case of congenital adrenal hyperplasia due ...
,
prolactin
Prolactin (PRL), also known as lactotropin and mammotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secr ...
,
oxytocin
Oxytocin is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. Present in animals since early stages of evolution, in humans it plays roles in behavior that include Human bonding, ...
, and
renin
Renin ( etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin-angiotensin-aldosterone system (RAAS)—also known as the reni ...
induced by 4-MTA through stimulation of serotonergic neurotransmission.
There has been suggested that 4-MTA because of its slow
onset of action
Onset of action is the duration of time it takes for a drug's effects to come to prominence upon administration. With oral administration, it typically ranges anywhere from 20 minutes to over an hour, depending on the drug in question. Other meth ...
, is more dangerous than other designer drugs. Users of the drug rapidly take another dose because they assume the first was inadequate; thus increasing the possibility of an overdose. (EMCDDA, 1999)
Today the knowledge about the effects of 4-MTA is narrow, because of very limited research and experimental data. The only four studies that are conducted show a weak effect on dopamine and noradrenaline. This study was executed with a single dose of 4-MTA, no study where the effect of multiple doses 4-MTA where researched exist up to date.
Pharmacology
Pharmacodynamics
4-MTA 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).
It was originally characterized as a
selective serotonin releasing agent
A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter ...
(SRA).
However, the drug was subsequently found to more weakly induce the release of
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 ...
as well.
4-MTA shows a similar balance of
monoamine reuptake inhibition as
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 ...
.
In addition to its MRA activity, 4-MTA 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 250nM.
The combination of serotonin release induction and MAOI activity is likely responsible for the severe
serotonergic toxicity and
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 ...
that has occurred with 4-MTA.
4-MTA shows significant
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
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, ...
5-HT2A and
5-HT2C receptors, but not for the serotonin
5-HT1A receptor.
Its affinities for these receptors have been reported to be 1,500nM, 1,800nM, and >18,000nM, respectively.
4-MTA is also a potent
agonist
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
of 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).
However, it is inactive at the human TAAR1 ( > 10,000nM).
In animal
drug discrimination tests, 4-MTA substitutes for MDMA but does not substitute for
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 ...
, suggesting that it has
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 ...
-like but no
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, ...
-like effects.
Similarly, 4-MTA does not substitute for
DOM in drug discrimination tests, suggesting that it lacks
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.
Pharmacokinetics
Metabolism

4-MTA undergoes limited biotransformation, the metabolic pathways of the metabolites in humans is postulated in the following steps:
# β-Hydroxylation of the side chain to 4-hydroxy-4-methylthioamphetamine (step I).
# Ring hydroxylation to a phenolic structure (step II).
# Oxidative deamination to form an oxo metabolite, followed by (step III):
#* reduction into the corresponding alcohol (step IIIa),
#* degradation of the side chain to 4-methylthiobenzoic acid (step IIIb).
The main metabolite was identified as 4-methylthiobenzoic acid. This compound leads to
bioactivation
In chemistry and biology, activation is the process whereby something is prepared or excited for a subsequent reaction.
Chemistry
In chemistry, "activation" refers to the reversible transition of a molecule into a nearly identical chemical or ...
(
toxification), since the metabolite increases dramatically the sensitivity to the reduction in ATP content.
The biotransformation shows great similarities to the metabolic pathway of the structurally related 4-methoxyamphetamine
Chemistry
In a procedure analogous to the production of other amphetamines, 4-MTA has been prepared from 4-(methylthio)phenylacetone by the
Leuckart reaction
The Leuckart reaction is the chemical reaction that converts aldehydes or ketones to amines. The reaction is an example of reductive amination. The reaction, named after Rudolf Leuckart (chemist), Rudolf Leuckart, uses either ammonium formate or ...
and the reaction byproducts have been characterized.
See also
*
4-Methylthiomethamphetamine
*
''N'',''N''-Dimethyl-4-methylthioamphetamine
*
Aleph (psychedelic)
*
''para''-Methoxyamphetamine
*
4-Fluoroamphetamine
4-Fluoroamphetamine (4-FA; 4-FMP; PAL-303; "Flux"), also known as ''para''-fluoroamphetamine (PFA) is a psychoactive drug, psychoactive research chemical of the phenethylamine and substituted amphetamine chemical classes. It produces stimulant a ...
*
''para''-Chloroamphetamine
References
External links
*
Erowid 4-MTA vault
{{DEFAULTSORT:Methylthioamphetamine, 4-
Designer drugs
Monoamine oxidase inhibitors
Serotonin receptor modulators
Serotonin releasing agents
Substituted amphetamines
TAAR1 agonists
Thioethers