3,4-Methylenedioxyamphetamine (also known as MDA and sass) is an empathogen-entactogen,

psychostimulant Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...

, and

psychedelic drug Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary states of consciousness (known as psychedelic experiences or "trips").Pollan, Michael (2018). ''How to Change Your Mind: What the New Science o ...

of the

amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...

family that is encountered mainly as a

recreational drug Recreational drug use indicates the use of one or more psychoactive drugs to induce an altered state of consciousness either for pleasure or for some other casual purpose or pastime by modifying the perceptions and emotions of the user. When a ...

. In terms of

pharmacology Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemica ...

, MDA acts most importantly as a

serotonin–norepinephrine–dopamine releasing agent A serotonin–norepinephrine–dopamine releasing agent (SNDRA), also known as a triple releasing agent (TRA), is a type of drug which induces the release of serotonin, norepinephrine/epinephrine, and dopamine in the brain and body. SNDRAs produc ...

(SNDRA). In most countries, the drug is a

controlled substance A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Single C ...

and its

possession Possession may refer to: Law * Dependent territory, an area of land over which another country exercises sovereignty, but which does not have the full right of participation in that country's governance * Drug possession, a crime * Ownership * ...

and sale are illegal. MDA is rarely sought after as a recreational drug compared to other drugs in the amphetamine family; however, it remains an important and widely used drug due to it being a primary metabolite, the product of hepatic N-dealkylation, of

MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly seen in Tablet (pharmacy), tablet form (ecstasy) and crystal form (molly or mandy), is a potent empathogen–entactogen with stimulant properties primarily used for Recreational dru ...

(ecstasy). In addition, it is common to find MDA as an

adulterant An adulterant is caused by the act of adulteration, a practice of secretly mixing a substance with another. Typical substances that are adulterated include but are not limited to food, cosmetics, pharmaceuticals, fuel, or other chemicals, that ...

of illicitly produced MDMA.

Uses

Medical

MDA currently has no accepted medical use.

Recreational

MDA is bought, sold, and used as a recreational 'love drug', due to its enhancement of mood and

empathy Empathy is the capacity to understand or feel what another person is experiencing from within their frame of reference, that is, the capacity to place oneself in another's position. Definitions of empathy encompass a broad range of social, co ...

. A recreational dose of MDA is sometimes cited as being between 100 and 160 mg.

Adverse effects

MDA produces serotonergic neurotoxic effects, thought to be activated by initial metabolism of MDA. In addition, MDA activates a response of the

neuroglia Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form mye ...

, though this subsides after use.

Overdose

Symptoms of

acute toxicity Acute toxicity describes the adverse effects of a substance that result either from a single exposure or from multiple exposures in a short period of time (usually less than 24 hours). To be described as ''acute'' toxicity, the adverse effect ...

may include agitation,

sweating Perspiration, also known as sweating, is the production of fluids secreted by the sweat glands in the skin of mammals. Two types of sweat glands can be found in humans: eccrine glands and apocrine glands. The eccrine sweat glands are distr ...

increased blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

and

heart rate Heart rate (or pulse rate) is the frequency of the heartbeat measured by the number of contractions (beats) of the heart per minute (bpm). The heart rate can vary according to the body's physical needs, including the need to absorb oxygen and excr ...

, dramatic increase in body temperature,

convulsion A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a s ...

s, and

death Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...

. Death is usually caused by cardiac effects and subsequent hemorrhaging in the brain (

stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...

Pharmacology

Pharmacodynamics

MDA is a substrate of the

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...

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

, and

vesicular monoamine transporter The vesicular monoamine transporter (VMAT) is a transport protein integrated into the membranes of synaptic vesicles of presynaptic neurons. It transports monoamine neurotransmitters – such as dopamine, serotonin, norepinephrine, epinephrine, ...

s, as well as a

TAAR1 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 an intracellular amine-activated and G protein-coupled receptor (GPCR) that is primarily exp ...

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

, and for these reasons acts as a

reuptake inhibitor Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of transmit ...

and

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

, and

(that is, it is an ). It is also an

of the serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors and shows

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 Partn ...

for the α_2A-, α_2B-, and α_2C-adrenergic receptors and serotonin 5-HT_1A and 5-HT₇ receptors. The (''S'')-

optical isomer In chemistry, a molecule or ion is called chiral () if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes. This geometric property is called chirality (). The terms are d ...

of MDA is more potent than the (''R'')-

as a psychostimulant, possessing greater affinity for the three

monoamine transporter Monoamine transporters (MATs) are protein structures that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs (SERT, DAT, NET) are responsible for ...

s. In terms of the subjective and behavioral effects of MDA, it is thought that serotonin release is required for its empathogen-entactogen effects, release of dopamine and norepinephrine is responsible for its psychostimulant effects, dopamine release is necessary for its

euphoriant Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and danc ...

( rewarding and

addictive Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use oft ...

) effects, and direct agonism of the serotonin 5-HT_2A receptor is causative of its psychedelic effects.

Pharmacokinetics

The duration of the drug has been reported as about 6 to 8 hours.

Chemistry

MDA is a

substituted A substitution reaction (also known as single displacement reaction or single substitution reaction) is a chemical reaction during which one functional group in a chemical compound is replaced by another functional group. Substitution reactions ar ...

methylenedioxylated

phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amin ...

and

derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. F ...

. In relation to other phenethylamines and amphetamines, it is the 3,4-methylenedioxy, α-methyl derivative of β-phenylethylamine, the 3,4-methylenedioxy derivative of

, and the ''N''-

desmethyl In chemical nomenclature, nor- is a prefix to name a structural analog that can be derived from a parent compound by the removal of one carbon atom along with the accompanying hydrogen atoms. The nor-compound can be derived by removal of a , , or ...

derivative of MDMA.

Synonyms

In addition to ''3,4-methylenedioxyamphetamine'', MDA is also known by other chemical synonyms such as the following: * α-Methyl-3,4-methylenedioxy-β-phenylethylamine * 1-(3,4-Methylenedioxyphenyl)-2-propanamine * 1-(1,3-Benzodioxol-5-yl)-2-propanamine

Synthesis

MDA is typically synthesized from

essential oil An essential oil is a concentrated hydrophobic liquid containing volatile (easily evaporated at normal temperatures) chemical compounds from plants. Essential oils are also known as volatile oils, ethereal oils, aetheroleum, or simply as the o ...

s such as

safrole Safrole is an organic compound with the formula CH2O2C6H3CH2CH=CH2. It is a colorless oily liquid, although impure samples can appear yellow. A member of the phenylpropanoid family of natural products, it is found in sassafras plants, among oth ...

piperonal Piperonal, also known as heliotropin, is an organic compound which is commonly found in fragrances and flavors.Karl-Georg Fahlbusch, Franz-Josef Hammerschmidt, Johannes Panten, Wilhelm Pickenhagen, Dietmar Schatkowski, Kurt Bauer, Dorothea Garbe a ...

. Common approaches from these

precursors Precursor or Precursors may refer to: * Precursor (religion), a forerunner, predecessor ** The Precursor, John the Baptist Science and technology * Precursor (bird), a hypothesized genus of fossil birds that was composed of fossilized parts of un ...

include: * Reaction of safrole's

alkene In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...

functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...

with a

halogen The halogens () are a group in the periodic table consisting of five or six chemically related elements: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), and tennessine (Ts). In the modern IUPAC nomenclature, this group is ...

containing

mineral acid A mineral acid (or inorganic acid) is an acid derived from one or more inorganic compounds, as opposed to organic acids which are acidic, organic compounds. All mineral acids form hydrogen ions and the conjugate base when dissolved in water. Cha ...

followed by amine alkylation. *

Wacker oxidation The Wacker process or the Hoechst-Wacker process (named after the chemical companies of the same name) refers to the oxidation of ethylene to acetaldehyde in the presence of palladium(II) chloride as the catalyst. This chemical reaction was one of ...

of safrole to yield 3,4-methylenedioxyphenylpropan-2-one (MDP2P) followed by

reductive amination Reductive amination (also known as reductive alkylation) is a form of amination that involves the conversion of a carbonyl group to an amine via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde. It is considered ...

or via reduction of its

oxime In organic chemistry, an oxime is a organic compound belonging to the imines, with the general formula , where R is an organic side-chain and R’ may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted ...

. *

Henry reaction The Henry reaction is a classic carbon–carbon bond formation reaction in organic chemistry. Discovered in 1895 by the Belgian chemist Louis Henry (1834–1913), it is the combination of a nitroalkane and an aldehyde or ketone in the presence o ...

of piperonal with

nitroethane Nitroethane is an organic compound having the chemical formula C2H5NO2. Similar in many regards to nitromethane, nitroethane is an oily liquid at standard temperature and pressure. Pure nitroethane is colorless and has a fruity odor. Preparati ...

followed by nitro compound reduction. *

Darzens reaction The Darzens reaction (also known as the Darzens condensation or glycidic ester condensation) is the chemical reaction of a ketone or aldehyde with an α- haloester in the presence of a base to form an α,β-epoxy ester, also called a "glycidic es ...

on heliotropin was also done by J. Elks, et al. This gives

MDP2P 3,4-Methylenedioxyphenylpropan-2-one or piperonyl methyl ketone (MDP2P or PMK) is a chemical compound consisting of a phenylacetone moiety substituted with a methylenedioxy functional group. It is commonly synthesized from either safrole (which, ...

, which was then subjected to a Leuckart reaction.

Detection in body fluids

MDA may be quantitated in blood, plasma or urine to monitor for use, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or a sudden death. Some drug abuse screening programs rely on hair, saliva, or sweat as specimens. Most commercial amphetamine immunoassay screening tests cross-react significantly with MDA and major metabolites of MDMA, but chromatographic techniques can easily distinguish and separately measure each of these substances. The concentrations of MDA in the blood or urine of a person who has taken only MDMA are, in general, less than 10% those of the parent drug.

Derivatives

MDA constitutes part of the core structure of the β-adrenergic receptor agonist protokylol.

History

MDA was first synthesized by C. Mannich and W. Jacobsohn in 1910. It was first ingested in July 1930 by

Gordon Alles Gordon A. Alles (November 26, 1901 – January 21, 1963), was an American chemist and pharmacologist who did extensive research on the isolation and properties of insulin for the treatment of diabetics. He is also credited with discovering and pub ...

who later licensed the drug to

Smith, Kline & French Smith, Kline & French (SKF) was an American pharmaceutical company. History In 1830, John K. Smith opened a drugstore in Philadelphia, and his younger brother, George, joined him in 1841 to form John K Smith & Co. In 1865, Mahlon Kline joined ...

. MDA was first used in animal tests in 1939, and human trials began in 1941 in the exploration of possible therapies for

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

. From 1949 to 1957, more than 500 human subjects were given MDA in an investigation of its potential use as an

antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...

and/or

anorectic An anorectic or anorexic is a drug which reduces appetite, resulting in lower food consumption, leading to weight loss. By contrast, an appetite stimulant is referred to as orexigenic. The term is (from the Greek ''ἀν-'' (an-) = "without" a ...

. The

United States Army The United States Army (USA) is the land service branch of the United States Armed Forces. It is one of the eight U.S. uniformed services, and is designated as the Army of the United States in the U.S. Constitution.Article II, section 2, cla ...

also experimented with the drug, code named EA-1298, while working to develop a

truth drug Truth is the property of being in accord with fact or reality.Merriam-Webster's Online Dictionarytruth 2005 In everyday language, truth is typically ascribed to things that aim to represent reality or otherwise correspond to it, such as beliefs, ...

or incapacitating agent.

Harold Blauer Harold Blauer (1910 – January 8, 1953) was an American tennis player who died as a result of injections of 450 mg 3,4-methylenedioxyamphetamine (code-named EA-1298) as part of Project MKUltra, a covert CIA mind-control and chemical interro ...

died in January 1953 after being intravenously injected, without his knowledge or consent, with 450 mg of the drug as part of

Project MKUltra Project MKUltra (or MK-Ultra) was an illegal human experimentation program designed and undertaken by the U.S. Central Intelligence Agency (CIA), intended to develop procedures and identify drugs that could be used in interrogations to weak ...

. MDA was patented as an

ataractic A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but th ...

in 1960, and as an

under the trade name "Amphedoxamine" in 1961. MDA began to appear on the

scene around 1963 to 1964. It was then inexpensive and readily available as a

research chemical Research chemicals are chemical substances used by scientists for medical and scientific research purposes. One characteristic of a research chemical is that it is for laboratory research use only; a research chemical is not intended for human o ...

from several scientific supply houses. Several researchers, including

Claudio Naranjo Claudio Benjamín Naranjo Cohen (24 November 1932 – 12 July 2019) was a Chilean-born psychiatrist who is considered a pioneer in integrating psychotherapy and the spiritual traditions. He was one of the three successors named by Fritz Perls ( ...

and Richard Yensen, have explored MDA in the field of

psychotherapy Psychotherapy (also psychological therapy, talk therapy, or talking therapy) is the use of psychological methods, particularly when based on regular personal interaction, to help a person change behavior, increase happiness, and overcome pro ...

Society and culture

Name

When MDA was under development as a potential pharmaceutical drug, it was given the international nonproprietary name (INN) of ''tenamfetamine''.

Legal status

Australia

MDA is schedule 9 prohibited substance under the Poisons Standards.Poisons Standard (October 2015
comlaw.gov.au
/ref> A schedule 9 substance is listed as a "Substances which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities."

United States

MDA is a

Schedule I controlled substance This is the list of Schedule I drugs as defined by the United States Controlled Substances Act. 21 CFRbr>1308.11(CSA Sched I) with changes through (Oct 18, 2012). Retrieved September 6, 2013. The following findings are required for drugs to be pl ...

in the US.

Research

In 2010, the ability of MDA to invoke mystical experiences and alter vision in healthy volunteers was studied. The study concluded that MDA is a "potential tool to investigate mystical experiences and visual perception".

References

External links

Erowid MDA Vault

MDA entry in PiHKAL

MDA entry in PiHKAL • info
{{DEFAULTSORT:Methylenedioxeamphetamine, 3, 4- 5-HT2A agonists 5-HT2B agonists 5-HT2C agonists Benzodioxoles Entactogens and empathogens Euphoriants Psychedelic drugs Serotonin-norepinephrine-dopamine releasing agents Serotonin receptor agonists Stimulants Substituted amphetamines TAAR1 agonists VMAT inhibitors