''para''-Methoxyamphetamine (PMA), also known as 4-methoxyamphetamine (4-MA), 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. D ...
of the
amphetamine class with
serotonergic
Serotonergic () or serotoninergic () means "pertaining to or affecting serotonin". Serotonin is a neurotransmitter. A synapse is serotonergic if it uses serotonin as its neurotransmitter. A serotonergic neuron ''produces'' serotonin. A substance is ...
effects.
Unlike other similar drugs of this family, PMA does not produce
stimulant,
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 ...
, or
entactogen effects,
and behaves more like an
antidepressant in comparison, though it does have some
psychedelic properties.
PMA has been found in
tablets touted as
MDMA
3,4-Methylenedioxymethamphetamine (MDMA), commonly seen in tablet form (ecstasy) and crystal form (molly or mandy), is a potent empathogen–entactogen with stimulant properties primarily used for recreational purposes. The desire ...
(ecstasy)
although its effects are markedly different compared to those of MDMA. The consequences of such deception have often included hospitalization and death for unwitting users. PMA is commonly synthesized from
anethole, the flavor compound of
anise and
fennel
Fennel (''Foeniculum vulgare'') is a flowering plant species in the carrot family. It is a hardy, perennial herb with yellow flowers and feathery leaves. It is indigenous to the shores of the Mediterranean but has become widely naturalized ...
, mainly because the starting material for MDMA,
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 ...
, has become less available due to law enforcement action, causing illicit drug manufacturers to use anethole as an alternative.
Adverse effects
PMA has been associated with numerous adverse reactions including death. Effects of PMA ingestion include many effects of the hallucinogenic amphetamines including
accelerated and
irregular heartbeat, blurred vision, and a strong feeling of intoxication that is often unpleasant. At high doses unpleasant effects such as
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
and
vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteri ...
, severe
hyperthermia
Hyperthermia, also known simply 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 ...
and
hallucinations may occur. The effects of PMA also seem to be much more unpredictable and variable between individuals than those of MDMA, and sensitive individuals may die from a dose of PMA by which a less susceptible person might only be mildly affected. While PMA alone may cause significant toxicity, the combination of PMA with MDMA has a synergistic effect that seems to be particularly hazardous. Since PMA has a slow onset of effects, several deaths have occurred where individuals have taken a pill containing PMA, followed by a pill containing MDMA some time afterwards due to thinking that the first pill was not active.
Overdose
PMA overdose can be a serious medical emergency that may occur at only slightly above the usual recreational dose range, especially if PMA is mixed with other stimulant drugs such as cocaine or MDMA. Characteristic symptoms are pronounced
hyperthermia
Hyperthermia, also known simply 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 ...
,
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 ( ...
, and
hypertension, along with agitation, confusion, and
convulsions. PMA overdose also tends to cause
hypoglycaemia
Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...
and
hyperkalaemia
Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occasi ...
, which can help to distinguish it from MDMA overdose. Complications can sometimes include more serious symptoms such as
rhabdomyolysis and
cerebral hemorrhage, requiring emergency surgery. There is no specific antidote, so treatment is symptomatic, and usually includes both external cooling, and internal cooling via IV infusion of cooled saline.
Benzodiazepines are used initially to control convulsions, with stronger anticonvulsants such as
phenytoin
Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The in ...
or
thiopental
Sodium thiopental, also known as Sodium Pentothal (a trademark of Abbott Laboratories), thiopental, thiopentone, or Trapanal (also a trademark), is a rapid-onset short-acting barbiturate general anesthetic. It is the thiobarbiturate analog of p ...
used if convulsions continue. Blood pressure can be lowered either with a combination of
alpha blockers and
beta blocker
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack after a first heart attack ( secondary prevention). They are ...
s (or a mixed alpha/beta blocker), or with other drugs such as
nifedipine
Nifedipine (3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate), sold under the brand name Adalat and Procardia, among others, is a calcium channel blocker medication used to manage angina, high blood pressure, Ra ...
or
nitroprusside
Sodium nitroprusside (SNP), sold under the brand name Nitropress among others, is a medication used to lower blood pressure. This may be done if the blood pressure is very high and resulting in symptoms, in certain types of heart failure, and ...
.
Serotonin antagonist
A serotonin antagonist, or serotonin receptor antagonist, is a drug used to inhibit the action at serotonin (5-HT) receptors.
Types
5-HT2A antagonists
Antagonists of the 5-HT2A receptor are sometimes used as atypical antipsychotics (contrast wi ...
s and
dantrolene
Dantrolene sodium, sold under the brand name Dantrium among others, is a postsynaptic muscle relaxant that lessens excitation-contraction coupling in muscle cells. It achieves this by inhibiting Ca2+ ions release from sarcoplasmic reticulum s ...
may be used as required. Despite the seriousness of the condition, the majority of patients survive if treatment is given in time, however, patients with a core body temperature over 40 °C at presentation tend to have a poor prognosis.
Pharmacology
PMA acts 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 ...
(SSRA) with weak effects on dopamine and norepinephrine transporters.
However, relative to
MDMA
3,4-Methylenedioxymethamphetamine (MDMA), commonly seen in tablet form (ecstasy) and crystal form (molly or mandy), is a potent empathogen–entactogen with stimulant properties primarily used for recreational purposes. The desire ...
, it is considerably less effective as a releaser of serotonin with properties more akin to 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 ...
in comparison.
It evokes robust
hyperthermia
Hyperthermia, also known simply 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 ...
in rodents while producing only modest
hyperactivity
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inappr ...
and
serotonergic
Serotonergic () or serotoninergic () means "pertaining to or affecting serotonin". Serotonin is a neurotransmitter. A synapse is serotonergic if it uses serotonin as its neurotransmitter. A serotonergic neuron ''produces'' serotonin. A substance is ...
neurotoxicity
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 – specificall ...
, substantially lower than that caused by MDMA, and only at very high doses.
Accordingly, it is not
self-administered by rodents unlike
amphetamine and MDMA,
and anecdotal reports by humans suggest it is not particularly
euphoric
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 da ...
at all, perhaps even
dysphoric in contrast. PMA has also been shown to act as a potent,
reversible inhibitor of the
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
MAO-A
Monoamine oxidase A, also known as MAO-A, is an enzyme 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 deamination of amines, s ...
with no significant effects on
MAO-B
Monoamine oxidase B, also known as MAOB, is an enzyme that in humans is encoded by the ''MAOB'' gene.
The protein encoded by this gene belongs to the flavin monoamine oxidase family. It is an enzyme located in the outer mitochondrial membrane. I ...
,
and the combination of this property and serotonin release is likely responsible for its high
lethality
Lethality (also called deadliness or perniciousness) is how capable something is of causing death. Most often it is used when referring to diseases, chemical weapons, biological weapons, or their toxic chemical components. The use of this ter ...
potential.
It appears that PMA elevates body temperatures dramatically; the cause of this property is suspected to be related to its ability to inhibit MAO-A and at the same time releasing large amounts of serotonin, effectively causing
serotonin syndrome
Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain serotonergic medications or drugs. The degree of symptoms can range from mild to severe, including a potentiality of death. Symptoms in mild cases include high ...
.
Amphetamines, especially serotonergic analogues such as MDMA, are strongly
contraindicated
In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...
to take with
MAOI
Monoamine oxidase inhibitors (MAOIs) are a 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 antidepressants, especia ...
s. Many amphetamines and adrenergic compounds raise body temperatures, whereas some tend to produce more euphoric activity or peripheral vasoconstriction, and may tend to favor one effect over another. It appears that PMA activates the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
much more strongly than MDMA and other drugs like ephedrine, thereby causing rapid increases in body temperature (which is the major cause of death in PMA mortalities). Many people taking PMA try to get rid of the heat by taking off their clothes, taking cold showers or wrapping themselves in wet towels, and even sometimes by shaving off their hair.
History
PMA first came into circulation in the early 1970s, where it was used intentionally as a substitute for the hallucinogenic properties of
LSD
Lysergic acid diethylamide (LSD), also known colloquially as acid, is a potent psychedelic drug. Effects typically include intensified thoughts, emotions, and sensory perception. At sufficiently high dosages LSD manifests primarily mental, vi ...
.
It went by the street names of "Chicken Powder" and "Chicken Yellow" and was found to be the cause of a number of drug overdose deaths (the dosages taken being in the range of hundreds of milligrams) in the United States and Canada from that time. Between 1974 and the mid-1990s, there appear to have been no known fatalities from PMA.
Several deaths reported as MDMA-induced in
Australia in the mid-1990s are now considered to have been caused by PMA, the users unaware that they were ingesting PMA and not MDMA as they had intended.
There have been a number of PMA-induced deaths around the world since then.
In July 2013, seven deaths in Scotland were linked to tablets containing PMA that had been mis-sold as ecstasy and which had the
Rolex
Rolex SA () is a British-founded Swiss watch designer and manufacturer based in Geneva, Switzerland. Founded in 1905 as ''Wilsdorf and Davis'' by Hans Wilsdorf and Alfred Davis in London, the company registered ''Rolex'' as the brand name of ...
crown logo on them.
Several deaths in Northern Ireland, Particularly East Belfast were also linked to "Green Rolex" pills during that month.
In 2014, 2015 and early 2016, PMA sold as ecstasy was attributed for more deaths in the United States, United Kingdom,
Netherlands
)
, anthem = ( en, "William of Nassau")
, image_map =
, map_caption =
, subdivision_type = Sovereign state
, subdivision_name = Kingdom of the Netherlands
, established_title = Before independence
, established_date = Spanish Netherl ...
, and Argentina. The pills containing the drug were reported to be red triangular tablets with a "Superman" logo.
[
The Red Ferarri pills are a new press of the ''Superman'' logo tablets that were reported to be found in Germany and Norway from 2016-2017.
]
Society and culture
Legal status
International
PMA is a Schedule I drug under the Convention on Psychotropic Substances.
Australia
PMA is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015).[Poisons Standard October 2015 https://www.comlaw.gov.au/Details/F2015L01534] A Schedule 9 substance is a substance 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.
Germany
PMA is part of the Appendix 1 of the Betäubungsmittelgesetz
The Betäubungsmittelgesetz (BtMG), generally meaning Narcotics Law, is the controlled substances law of Germany. In common with the Misuse of Drugs Act of 1971 of the United Kingdom and Controlled Substances Acts of the US and Canada, it is a c ...
. Therefore owning and distribution of PMA is illegal.
Netherlands
On 13 June 2012 Edith Schippers
Edith Ingeborg Schippers (born 25 August 1964) is a retired Dutch politician of the People's Party for Freedom and Democracy (VVD) and businesswoman serving as President of the DSM Company since 1 February 2019.
Schippers, a political consultan ...
, Dutch Minister of Health, Welfare and Sport, revoked the legality of PMA in the Netherlands
)
, anthem = ( en, "William of Nassau")
, image_map =
, map_caption =
, subdivision_type = Sovereign state
, subdivision_name = Kingdom of the Netherlands
, established_title = Before independence
, established_date = Spanish Netherl ...
after five deaths were reported in that year.
United Kingdom
PMA is a Class A drug in the UK.
United States
PMA is classified as a Schedule I hallucinogen
Hallucinogens are a large, diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mood, and perception as well as other changes. Most hallucinogens can be categorize ...
under the Controlled Substances Act in the United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...
.
Economics
Distribution
Because PMA is given out through the same venues and distribution channels that MDMA tablets are, the risk of being severely injured, hospitalized or even dying from use of ecstasy increases significantly when a batch of ecstasy pills containing PMA starts to be sold in a particular area. PMA pills could be a variety of colours or imprints, and there is no way of knowing just from the appearance of a pill what drug(s) it might contain. Notable batches of pills containing PMA have included Louis Vuitton, Mitsubishi Turbo, Blue Transformers, Red/Blue Mitsubishi and Yellow Euro pills. Also PMA has been found in powder form.
Analogues
Four analogues of PMA have been reported to be sold on the black market, including PMMA PMMA may refer to:
* para-Methoxymethamphetamine, a stimulant drug
* Philippine Merchant Marine Academy
The Philippine Merchant Marine Academy ( fil, Akademiya sa Bapor Pangkalakalan ng Pilipinas) also referred to by its acronym PMMA) is a ma ...
, PMEA, 4-ETA and 4-MTA
4-Methylthioamphetamine (4-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, at Purdue University. It acts as a non-neurotoxic h ...
. These are the N-methyl, N-ethyl, 4-ethoxy and 4-methylthio analogues of PMA, respectively. PMMA and PMEA are anecdotally weaker, more "ecstasy-like" and somewhat less dangerous than PMA itself, but can still produce nausea and hyperthermia similar to that produced by PMA, albeit at slightly higher doses. 4-EtOA was briefly sold in Canada in the 1970s, but little is known about it. 4-MTA, however, is even more dangerous than PMA and produces strong serotonergic effects and intense hyperthermia, but with little to no euphoria, and was implicated in several deaths in the late 1990s.
See also
* 1-Aminomethyl-5-methoxyindane
1-Aminomethyl-5-methoxyindane (AMMI), is a drug developed by a team led by David E. Nichols at Purdue University, which acts as a selective serotonin releasing agent (SSRA) and binds to the serotonin transporter
The serotonin transporter (SER ...
(AMMI)
* 2-Methoxyamphetamine (OMA)
* 3-Methoxyamphetamine
''meta''-Methoxyamphetamine (MMA), also known as 3-methoxyamphetamine (3-MA), is a stimulant drug from the amphetamine family. It has similar effects in animal drug discrimination tests to the more widely known derivative 4-methoxyamphetamine ( ...
(MMA)
* 4-Methylamphetamine
4-Methylamphetamine (4-MA; PAL-313; Aptrol; p-TAP) is a stimulant and anorectic drug of the phenethylamine and amphetamine chemical classes.
In vitro, it acts as a potent and balanced serotonin, norepinephrine, and dopamine releasing agen ...
(4-MA)
* 4-Ethoxyamphetamine (4-ETA)
* 4-Methylthioamphetamine
4-Methylthioamphetamine (4-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, at Purdue University. It acts as a non-neurotoxic ...
(4-MTA)
* 4-Methoxy-''N''-ethylamphetamine (PMEA)
* 4-Methoxy-''N''-methylamphetamine (PMMA)
* 4-Hydroxy-''N''-methylamphetamine (pholedrine)
*Anisomycin
Anisomycin, also known as flagecidin, is an antibiotic produced by '' Streptomyces griseolus'' which inhibits eukaryotic protein synthesis. Partial inhibition of DNA synthesis occurs at anisomycin concentrations that effect 95% inhibition of pro ...
References
External links
PiHKAL PMA entry
PMA entry in PiHKAL • info
*
Death drug may become health crisis
', news.ninemsn.com.au article, Issued 22 February 2007.
{{DEFAULTSORT:Methoxyamphetamine, Para-
Substituted amphetamines
Monoamine oxidase inhibitors
Phenol ethers
Designer drugs
Serotonin releasing agents
Serotonin receptor agonists
Methoxy compounds