Para-Methoxyamphetamine

para-Methoxyamphetamine
Clinical data
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
  • AU: S9 (Prohibited substance)
  • CA: Schedule I
  • DE: Anlage I (Authorized scientific use only)
  • UK: Class A
  • US: Schedule I
  • UN: Psychotropic Schedule I
Identifiers
IUPAC name
  • 1-(4-methoxyphenyl)propan-2-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.525
Edit this at Wikidata
Chemical and physical data
FormulaC10H15NO
Molar mass165.236 g·mol−1
3D model (JSmol)
SMILES
  • C1=CC(=CC=C1CC(C)N)OC
InChI
  • InChI=1S/C10H15NO/c1-8(11)7-9-3-5-10(12-2)6-4-9/h3-6,8H,7,11H2,1-2H3 checkY
  • Key:NEGYEDYHPHMHGK-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

para-Methoxyamphetamine (PMA), also known as 4-methoxyamphetamine (4-MA), is a designer drug of the amphetamine class with serotonergic effects.[1][2][3] Unlike other similar drugs of this family, PMA does not produce stimulant, euphoriant, or entactogen effects,[4] and behaves more like an antidepressant in comparison, though it does have some psychedelic properties.[5][6]

PMA has been found in tablets touted as MDMA (ecstasy)[7][8][9][10] 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, mainly because the starting material for MDMA, safrole, has become less available due to law enforcement action, causing illicit drug manufacturers to use anethole as an alternative.[11]

Adverse effects

PMA has been associated with numerous adverse reactions including death.[12][13] 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 and vomiting, severe hyperthermia 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.[14] While PMA alone may cause significant toxicity, the combination of PMA with MDMA has a synergistic effect that seems to be particularly hazardous.[15] 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.[16]

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, tachycardia, and hypertension, along with agitation, confusion, and convulsions. PMA overdose also tends to cause hypoglycaemia and hyperkalaemia, 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 or thiopental used if convulsions continue. Blood pressure can be lowered either with a combination of alpha blockers and beta blockers (or a mixed alpha/beta blocker), or with other drugs such as nifedipine or nitroprusside. Serotonin antagonists and dantrolene 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.[17]

Pharmacology

PMA acts as a selective serotonin releasing agent (SSRA) with weak effects on dopamine and norepinephrine transporters.[18][19][20] However, relative to MDMA, it is considerably less effective as a releaser of serotonin with properties more akin to a reuptake inhibitor in comparison.[21] It evokes robust hyperthermia in rodents while producing only modest hyperactivity and serotonergic neurotoxicity, substantially lower than that caused by MDMA, and only at very high doses.[19][20][21] Accordingly, it is not self-administered by rodents unlike amphetamine and MDMA,[4] and anecdotal reports by humans suggest it is not particularly euphoric at all, perhaps even dysphoric in contrast. PMA has also been shown to act as a potent, reversible inhibitor of the enzyme MAO-A with no significant effects on MAO-B,[22][23] and the combination of this property and serotonin release is likely responsible for its high lethality potential.[21]

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.[21][24] Amphetamines, especially serotonergic analogues such as MDMA, are strongly contraindicated to take with MAOIs. 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 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).[25][26][27] 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.[28]

History

PMA first came into circulation in the early 1970s, where it was used intentionally as a substitute for the hallucinogenic properties of LSD.[29] 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.[30] Between 1974 and the mid-1990s, there appear to have been no known fatalities from PMA.[31]

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.[10] There have been a number of PMA-induced deaths around the world since then.[32][33]

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 crown logo on them.[8] Several deaths in Northern Ireland, Particularly East Belfast were also linked to "Green Rolex" pills during that month.[34]

In 2014, 2015 and early 2016, PMA sold as ecstasy was attributed for more deaths in the United States, United Kingdom, Netherlands, and Argentina. The pills containing the drug were reported to be red triangular tablets with a "Superman" logo.[9][35][36][37]

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.[38]

Society and culture

International

PMA is a Schedule I drug under the Convention on Psychotropic Substances.[39]

Australia

PMA is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015).[40] 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.[40]

Germany

PMA is part of the Appendix 1 of the Betäubungsmittelgesetz. Therefore owning and distribution of PMA is illegal.

Netherlands

On 13 June 2012 Edith Schippers, Dutch Minister of Health, Welfare and Sport, revoked the legality of PMA in the Netherlands after five deaths were reported in that year.[41]

United Kingdom

PMA is a Class A drug in the UK.

United States

PMA is classified as a Schedule I hallucinogen under the Controlled Substances Act in the United States.[42]

Economics

Distribution

PMA capsules seized in Maryland, USA

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.[43] 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.[44][45] Notable batches of pills containing PMA have included Louis Vuitton,[46] Mitsubishi Turbo, Blue Transformers, Red/Blue Mitsubishi and Yellow Euro pills. Also PMA has been found in powder form.[47]

Analogues

Four analogues of PMA have been reported to be sold on the black market, including PMMA, PMEA,[48] 4-ETA and 4-MTA. 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.[49] 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

References

  1. ↑ Drug Enforcement Administration October 2000. The Hallucinogen PMA: Dancing With Death
  2. ↑ Ann Shulgin; Alexander Shulgin (1991). Pihkal: A Chemical Love Story. Transform Press. ISBN 978-0-9630096-0-9.
  3. ↑ Salna, Karlis (7 April 2008). "Warning of possible shift to killer drug". Sydney Morning Herald. Fairfax. Retrieved 2008-06-29.
  4. 1 2 Corrigall WA, Robertson JM, Coen KM, Lodge BA (January 1992). "The reinforcing and discriminative stimulus properties of para-ethoxy- and para-methoxyamphetamine". Pharmacology Biochemistry and Behavior. 41 (1): 165–9. CiteSeerX 10.1.1.670.6929. doi:10.1016/0091-3057(92)90077-S. PMID 1539067. S2CID 30080516.
  5. ↑ Hegadoren KM, Martin-Iverson MT, Baker GB (April 1995). "Comparative behavioural and neurochemical studies with a psychomotor stimulant, a hallucinogen and 3,4-methylenedioxy analogues of amphetamine". Psychopharmacology. 118 (3): 295–304. doi:10.1007/BF02245958. PMID 7617822. S2CID 30756295.
  6. ↑ Winter JC (February 1984). "The stimulus properties of para-methoxyamphetamine: a nonessential serotonergic component". Pharmacology Biochemistry and Behavior. 20 (2): 201–3. doi:10.1016/0091-3057(84)90242-9. PMID 6546992. S2CID 9673028.
  7. ↑ EcstasyData.org. "EcstasyData.org: Results : Lab Test Results for Recreational Drugs". www.ecstasydata.org.
  8. 1 2 Davies, Caroline (10 July 2013). "Warning over fake ecstasy tablets after seven people die in Scotland". The Guardian. Retrieved 10 July 2013.
  9. 1 2 "Four Dead Amid Fears Of Dodgy Batch Of 'Superman' Ecstasy Hitting The UK". huffingtonpost.co.uk. 2 January 2015.
  10. 1 2 Byard, RW; Gilbert, J; James, R; Lokan, RJ (1998). "Amphetamine Derivative Fatalities in South Australia-Is "Ecstasy" the Culprit?". The American Journal of Forensic Medicine and Pathology. 19 (3): 261–265. doi:10.1097/00000433-199809000-00013. PMID 9760094. Retrieved 2008-06-29.
  11. ↑ Waumas D, Bruneel N, Tytgat J. Anise oil as para-methoxyamphetamine (PMA) precursor. Forensic Science International. 2003 Apr 23;133(1-2):159-70.
  12. ↑ Martin TL. Three cases of fatal paramethoxyamphetamine overdose. Journal of Analytical Toxicology. 2001 Oct;25(7):649-51.
  13. ↑ Becker J, Neis P, Röhrich J, Zörntlein S. A fatal paramethoxymethamphetamine intoxication. Legal Medicine (Tokyo). 2003 Mar;5 Suppl 1:S138-41.
  14. ↑ Smets G, Bronselaer K, De Munnynck K, De Feyter K, Van de Voorde W, Sabbe M. Amphetamine toxicity in the emergency department. European Journal of Emergency Medicine. 2005 Aug;12(4):193-7.
  15. ↑ Lora-Tamayo C, Tena T, Rodriguez A, Moreno D, Sancho JR, Ensenat P, Muela F. The designer drug situation in Ibiza. Forensic Science International. 2004 Mar 10;140(2-3):195-206.
  16. ↑ Dams R, De Letter EA, Mortier KA, Cordonnier JA, Lambert WE, Piette MH, Van Calenbergh S, De Leenheer AP. Fatality due to combined use of the designer drugs MDMA and PMA: a distribution study. Journal of Analytical Toxicology. 2003 Jul-Aug;27(5):318-22.
  17. ↑ Caldicott DG, Edwards NA, Kruys A, Kirkbride KP, Sims DN, Byard RW, Prior M, Irvine RJ (2003). "Dancing with "death": p-methoxyamphetamine overdose and its acute management". Journal of Toxicology. Clinical Toxicology. 41 (2): 143–54. doi:10.1081/CLT-120019130. PMID 12733852. S2CID 39578828.
  18. ↑ Menon MK, Tseng LF, Loh HH (May 1976). "Pharmacological evidence for the central serotonergic effects of monomethoxyamphetamines". The Journal of Pharmacology and Experimental Therapeutics. 197 (2): 272–9. PMID 946817.
  19. 1 2 Hitzemann RJ, Loh HH, Domino EF (October 1971). "Effect of para-methoxyamphetamine on catecholamine metabolism in the mouse brain". Life Sciences. Pt. 1: Physiology and Pharmacology. 10 (19): 1087–95. doi:10.1016/0024-3205(71)90227-x. PMID 5132700.
  20. 1 2 Tseng LF, Menon MK, Loh HH (May 1976). "Comparative actions of monomethoxyamphetamines on the release and uptake of biogenic amines in brain tissue". The Journal of Pharmacology and Experimental Therapeutics. 197 (2): 263–71. PMID 1271280.
  21. 1 2 3 4 Daws LC, Irvine RJ, Callaghan PD, Toop NP, White JM, Bochner F (August 2000). "Differential behavioural and neurochemical effects of para-methoxyamphetamine and 3,4-methylenedioxymethamphetamine in the rat". Progress in Neuro-psychopharmacology & Biological Psychiatry. 24 (6): 955–77. doi:10.1016/S0278-5846(00)00113-5. PMID 11041537. S2CID 24347904.
  22. ↑ Green AL, El Hait MA (April 1980). "p-Methoxyamphetamine, a potent reversible inhibitor of type-A monoamine oxidase in vitro and in vivo". The Journal of Pharmacy and Pharmacology. 32 (4): 262–6. doi:10.1111/j.2042-7158.1980.tb12909.x. PMID 6103055. S2CID 42213032.
  23. ↑ Ask AL, Fagervall I, Ross SB (September 1983). "Selective inhibition of monoamine oxidase in monoaminergic neurons in the rat brain". Naunyn-Schmiedeberg's Archives of Pharmacology. 324 (2): 79–87. doi:10.1007/BF00497011. PMID 6646243. S2CID 403633.
  24. ↑ Ask, A. L.; Fagervall, I.; Ross, S. B. (1 September 1983). "Selective inhibition of monoamine oxidase in monoaminergic neurons in the rat brain". Naunyn-Schmiedeberg's Archives of Pharmacology. 324 (2): 79–87. doi:10.1007/BF00497011. PMID 6646243. S2CID 403633.
  25. ↑ Jaehne EJ, Salem A, Irvine RJ. Effects of 3,4-methylenedioxymethamphetamine and related amphetamines on autonomic and behavioral thermoregulation. Pharmacology Biochemistry and Behavior. 2005 Jul;81(3):485-96.
  26. ↑ Callaghan PD, Irvine RJ, Daws LC. Differences in the in vivo dynamics of neurotransmitter release and serotonin uptake after acute para-methoxyamphetamine and 3,4-methylenedioxymethamphetamine revealed by chronoamperometry. Neurochemistry International. 2005 Oct;47(5):350-61.
  27. ↑ Jaehne EJ, Salem A, Irvine RJ. Pharmacological and behavioral determinants of cocaine, methamphetamine, 3,4-methylenedioxymethamphetamine, and para-methoxyamphetamine-induced hyperthermia. Psychopharmacology. 2007 May 27
  28. ↑ Refstad S. Paramethoxyamphetamine (PMA) poisoning; a 'party drug' with lethal effects. Acta Anaesthesiologica Scandinavia. 2003 Nov;47(10):1298-9.
  29. ↑ "PiHKAL - #97 4-MA". www.erowid.org. Retrieved 1 September 2009.
  30. ↑ DEA. "The Hallucinogen PMA: Dancing With Death" (PDF). Retrieved 2008-06-29.
  31. ↑ Felgate, Heather E.; Felgate, Peter D.; James, Ross A.; Sims, Noel; Vozzo, Dominic C. (1998). "Recent Paramethoxyamphetamine Deaths". Journal of Analytical Toxicology. 22 (2): 169–172. doi:10.1093/jat/22.2.169. PMID 9547415. Retrieved 2008-06-29. A Canadian report from 1974 is the most recent report of death due to PMA toxicity
  32. ↑ Galloway JH, Forrest AR (September 2002). "Caveat Emptor: Death involving the use of 4-methoxyamphetamine". Journal of Clinical Forensic Medicine. 9 (3): 160. doi:10.1016/S1353-1131(02)00043-3. PMID 15274949.
  33. ↑ Lamberth PG, Ding GK, Nurmi LA (April 2008). "Fatal paramethoxy-amphetamine (PMA) poisoning in the Australian Capital Territory". The Medical Journal of Australia. 188 (7): 426. doi:10.5694/j.1326-5377.2008.tb01695.x. PMID 18393753. S2CID 11987961.
  34. ↑ "Renewed warning over 'Rolex' pills". BBC News. 24 July 2013.
  35. ↑ "WATCH OUT FOR DANGEROUS SUPERMAN PILL - News - Deep House Amsterdam". deephouseamsterdam.com. 30 January 2014.
  36. ↑ ElPais. "¿Qué es Superman, la droga que ya ha cobrado varias vidas en el mundo?". elpais.com.uy.
  37. ↑ "Las claves para entender qué pasó". La Nación. 2016-04-17.
  38. ↑ "Drug Warning – Reagent Tests UK". www.reagent-tests.uk.
  39. ↑ "Annual Estimates Of Requirements Of Narcotic Drugs, Manufacture Of Synthetic Drugs, Opium Production And Cultivation Of The…" (PDF). Retrieved 2008-06-15.
  40. 1 2 Poisons Standard October 2015 https://www.comlaw.gov.au/Details/F2015L01534
  41. ↑ "Doden na gebruik speed met 4-MA" [Deaths after using speed 4-MA] (in Dutch). 13 June 2012.
  42. ↑ 21 CFR 1308.11
  43. ↑ Galloway JH, Forrest AR. Caveat Emptor: Death involving the use of 4-methoxyamphetamine. Journal of Clinical Forensic Medicine. 2002 Sep;9(3):160.
  44. ↑ "Drug Info". Archived from the original on 2008-05-29. Retrieved 2008-06-15.
  45. ↑ "Warning: pills sold as ecstasy found to contain PMA". Retrieved 2008-06-15.
  46. ↑ Chamberlin T, Murray D. NET Syndicated QLD News 'Louis Vuitton' designer death drug hits the streets
  47. ↑ Kraner JC, McCoy DJ, Evans MA, Evans LE, Sweeney BJ. Fatalities caused by the MDMA-related drug paramethoxyamphetamine (PMA). Journal of Analytical Toxicology. 2001 Oct;25(7):645-8.
  48. ↑ John F. Casale, Patrick A. Hays, Trinette K. Spratley, and Pamela R. Smith. The Characterization of 4-Methoxy-N-ethylamphetamine Hydrochloride. DEA Microgram Journal 2006; 4(1-4)
  49. ↑ Alexander & Ann Shulgin, PiHKAL #97
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