N-Ethylhexedrone was first synthesized by Boehringer Ingelheim in 1964.[11] It appears to have emerged on the onlineresearch chemical market in late 2015.[12] It is an example of a novel psychoactive substance specifically chosen to mimic the features of prohibited substances and bypass drug laws. It is one of a number of substances collectively referred to as "bath salts".[13]
User reports characterizeN-ethylhexedrone as having euphoric stimulant effects comparable to those ofcrack cocaine andα-PVP-type compounds, particularly when they areinsufflated orvaporized. Like othersubstituted cathinones, N-ethylhexedrone has gained notoriety for its association withcompulsive redosing and addictive behaviors when abused.
N-Ethylhexedrone was patented by the German pharmaceutical company Boehringer Ingelheim in 1964 as a potential anorexigenic agent. The patent describes its synthesis together with other derivatives of aminoketone.[11]
The substance spread remarkably quickly in the NPS market in different European countries.[11] It was first identified in a sample from the Belgian Customs laboratory which was received at theJRC in November 2015. In January 2016, it was identified at the JRC in a sample provided by French Customs. Subsequently, in February 2016, theEMCDDA received notifications of the identification of this substance from other countries, such as Sweden, The Netherlands, France, Belgium and Slovenia.[14]
In 2017 it was the most frequent seized cathinone in the EU, Norway and Turkey.[15] In 2018, it was the most commonly identified cathinone afterpentylone in Drug Enforcement Administration seizures.[13]
N-Ethylhexedrone is a derivative ofhexedrone, in which the methyl group attached to the nitrogen atom is substituted by an ethyl group. It is structurally similar topentedrone, and also α-pyrrolidinohexiophenone (A-PHP), from which it differs by the substitution of a pyrrolidine group with anN-ethyl group.[11]
The compound is a molecule of thecathinone chemical class. The term "substituted cathinone" refers to a broad array of substances based oncathinone, the principally active constituent of thekhat plant. Cathinone is principally constituted of aamphetamine core (aphenethylamine core with an alkyl group attached to the alpha carbon) and an oxygen group attached to the beta carbon. Cathinones are also known as the beta-ketone (βk) (double-bonded oxygen to the β-carbon) analogs ofamphetamines. Notably, the cathinone backbone can be modified in three different places to create hundreds of possible compounds, which include substituents on the aromatic ring (R2-R5), the alpha carbon (Rα), or the amine group (RN1, RN2).[16]
Relative to cathinone,N-ethylhexedrone consists of two added substitutions. At the Rα position, an-butyl substitution forms a hexan chain. The second substitution is an ethyl group, that's attached to the amine group at RN2, thus formingN-ethyl.
Very little data exists on the human pharmacokinetics and pharmacodynamics ofN-ethylhexedrone and many other recently introduced substituted cathinones, aside from post-mortem results in overdose cases.[17][18][19] Like amphetamines, synthetic cathinones exert their stimulating and sympathomimetic effects via increasing synaptic concentration ofcatecholamines such asdopamine,serotonin andnorepinephrine.[20] These molecules are able to inhibitmonoaminereuptake transporters producing a decreased clearance of theneurotransmitters from the synapse. Furthermore, they may cause release of biogenic amines from intracellular stores.[21] It appears thatN-ethylhexedrone has high preference for the dopamine transporter.[11]
Based on the structure and assuming thatN-ethylhexedrone is metabolized similarly to other cathinones, this compound is likely metabolized throughN-dealkylation and/or reduction of the carbonyl group followed byN-dealkylation.[11]
Synthetic cathinones are generally less able than amphetamines to cross the blood–brain barrier because the beta-keto group causes an increase in polarity. Unlike other synthetic cathinones, pyrrolidine derivatives have a higher ability to cross the blood–brain barrier because the pyrrolidine ring confers a low polarity to these molecules. The studies on the metabolism of synthetic cathinones have shown that they areN-demethylated, the keto group is reduced to hydroxyl and ring alkyl groups are oxidised.[22]
Internationally,N-ethylhexedrone was added to the UN Convention on Psychotropic Substances as a Schedule II controlled substance in March 2020.[23][24]
Brazil: Possession, production and sale is illegal as it is listed on Portaria SVS/MS nº 344 since June 5, 2017.[25]
Canada:N-Ethylhexedrone is a Schedule I controlled substance.[11]
Germany:N-Ethylhexedrone is controlled under the NpSG[26] (New Psychoactive Substances Act) as of November 26, 2016.[27] Production and import with the aim to place it on the market, administration to another person, placing it on the market and trading is punishable. Possession is illegal but not punishable.[28][29] The legislator considers it possible that orders ofN-ethylhexedrone are punishable as an incitement to place it on the market.[30]
Hungary:N-Ethylhexedrone is controlled as a new psychoactive substance.[11]
Ireland:N-Ethylhexedrone is controlled under SI 173/2017 under Schedule 1, paragraph 1(b) (page 35) as the substance is structurally derived from 2-amino-1-phenyl-1-propanone and is I the 3-position of the propanone side-chain with an alkyl substituent in this case, an ethyl group (subparagraph iii).[31]
Japan:N-Ethylhexedrone is a controlled substance.[32]
Sweden:N-Ethylhexedrone was classified as a potentially dangerous substance in Sweden on June 21, 2016, and is thus a controlled substance but neither narcotics-classified or fully outlawed.[33]
Switzerland:N-Ethylhexedrone can be considered a controlled substance as a defined derivative of Cathinone under Verzeichnis E point 1. It is legal when used for scientific or industrial use.[34]
United Kingdom:N-Ethylhexedrone is a Class B drug in the United Kingdom as a result of the cathinone catch-all clause.[35]
United States:N-Ethylhexedrone was placed in Schedule I by a DEA temporary scheduling order effective July 2019[36] and was permanently placed in Schedule I effective June 2022.[37]
^DE 1545591, Herbert K, Karl Z, Gerhard L, "Verfahren zur Herstellung von α-Aminoketonen mit heterocyclischer Aminogruppe", published 28 May 1965, assigned to Boehringer Ingelheim
^Liu C, Jia W, Li T, Hua Z, Qian Z (August 2017). "Identification and analytical characterization of nine synthetic cathinone derivatives N-ethylhexedrone, 4-Cl-pentedrone, 4-Cl-α-EAPP, propylone, N-ethylnorpentylone, 6-MeO-bk-MDMA, α-PiHP, 4-Cl-α-PHP, and 4-F-α-PHP".Drug Testing and Analysis.9 (8):1162–1171.doi:10.1002/dta.2136.PMID27863142.
^European Monitoring Centre for Drugs Drug Addiction; European Union Agency for Law Enforcement Cooperation (2019).EU Drug Markets Report 2019(PDF). European Monitoring Centre for Drugs and Drug Addiction (EMCDDA); Europol. p. 185.doi:10.2810/796253.ISBN978-92-9497-459-4.
^Liu C, Jia W, Li T, Hua Z, Qian Z (August 2017). "Identification and analytical characterization of nine synthetic cathinone derivatives N-ethylhexedrone, 4-Cl-pentedrone, 4-Cl-α-EAPP, propylone, N-ethylnorpentylone, 6-MeO-bk-MDMA, α-PiHP, 4-Cl-α-PHP, and 4-F-α-PHP".Drug Testing and Analysis.9 (8):1162–1171.doi:10.1002/dta.2136.eISSN1942-7611.OCLC231680670.PMID27863142.
^La Maida N, Di Trana A, Giorgetti R, Tagliabracci A, Busardò FP, Huestis MA (February 2021). "A Review of Synthetic Cathinone-Related Fatalities From 2017 to 2020".Therapeutic Drug Monitoring.43 (1):52–68.doi:10.1097/FTD.0000000000000808.PMID32881779.S2CID221496238.
^Pieprzyca E, Skowronek R, Czekaj P (January 2023). "Toxicological Analysis of Cases of Mixed Poisonings with Synthetic Cathinones and Other Drugs of Abuse".Journal of Analytical Toxicology.46 (9):1008–1015.doi:10.1093/jat/bkab119.PMID34849994.
