3,4-Methylenedioxyamphetamine (also known as MDA and sass) is an
empathogen-entactogen,
psychostimulant, 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. 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 ...
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,
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,
convulsions, 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, epinephri ...
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 ex ...
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 transmi ...
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 ...
of
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'', ...
, and
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 ...
(that is, it is an ).
It is also an
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 ...
of the serotonin
5-HT2A,
5-HT2B,
and
5-HT2C 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 Par ...
for the
α2A-,
α2B-, and
α2C-adrenergic receptors and serotonin
5-HT1A 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'')-
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 ...
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 fo ...
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 danci ...
(
rewarding and
addictive) 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 methylenedioxylated phenethylamine and
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 ...
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
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 ...
, 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 ...
or
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 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 ...
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 ...
by
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 '' ...
. 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 ...
by
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 '' ...
in 1960, and as an
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 ...
under the trade name "Amphedoxamine" in 1961. MDA began to appear on the
recreational drug scene around 1963 to 1964. It was then inexpensive and readily available as a
research chemical 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