Background

Phenethylamines refer to a class of substances with documented psychoactive and stimulant effects and include amphetamine, methamphetamine and MDMA, all of which are controlled under the 1971 Convention.[1]The phenethylamines also include ring substituted substances such as the ‘2C series’, ring substituted amphetamines such as the ‘D series’ (e.g.DOI, DOC), benzodifurans (e.g. Bromo-Dragonfly, 2C-B-Fly) and others (e.g. p-methoxymethamphetamine (PMMA)).

Seizures of phenethylamines were first reported from the United States and European countries and since 2009 substances such as 2C-E, 2C-I, 4-FA and PMMA have been commonly reported by several countries in different regions. Other phenethylamines increasingly reported to UNODC since 2011 include 4-FMA, 5-APB, 6-APB and 2C-C-NBOMe.

A number of studies have reported the synthesis of some phenethylamines and amphetamine substitutes. In the 1980s and 1990s, Alexander Shulgin, a biochemist and pharmacologist, reported the synthesis of numerous new psychoactive compounds.[2]This included the ‘D series’ (e.g. DOC, DOI) and the ‘2C series’ (e.g. 2C-T-7, 2C-T-2) of phenethylamines.

Simple variations on the mescaline molecule (a natural phenylethylamine) led to the synthesis of powerful hallucinogenic substances, e.g. 4-bromo-2,5-dimethoxyphenethylamine (2C-B), synthesized by Shulgin in 1974. The ‘2C’ series differs from the ‘D’ series only by a slight modification in the chemical structure, and their psychoactive effects have been reported to be dose dependant, ranging from mere stimulant effect at lower doses, with hallucinogenic and entactogenic effects at higher doses.[3]

Over two decades later, a new generation of phenethylamines was researched by Professor David Nichols and his research team at Purdue University in the United States. The team found the potency of synthetic analogues of mescaline such as 2C-B and DOB, to exceed that of many naturally occurring hallucinogens.[4] Several substances were synthesized, including a wide range of benzodifuranyl substances, later known as the ‘FLY’.[5] Benzodifurans, such as ‘FLY’ (tetrahydrobenzodifuranyl) and ‘Dragonfly’ (benzodifuranyl aminoalkanes) are potent hallucinogens. Bromo-Dragonfly is the most common and potent substance in this sub-group.

Other phenethylamines such as PMMA, first synthesized in 1938,[6] are also sold in the drug market as a substitute for ‘ecstasy’. PMMA, in combination with PMA (a substance listed in Schedule I of the 1971 United Nations Convention on Psychotropic Substances), has been frequently found in tablets that carry a similar logo to ‘ecstasy’.[7]

Whereas some phenethylamines such as 2C-B, brolamphetamine (DOB), STP/DOM, MDE, 4-MTA, are listed in Schedules I and II of the 1971 Convention, most of the new substances such as the 2C series, the D-Series and ‘others’ such as PMMA are not under international control. Some phenethylamine derivatives are controlled in some countries.

Description

Street names for some phenethylamines include ‘Europa’ for 2C-E; ‘4-FMP’, ‘para-fluoroamphetamine’, ‘RDJ’ for 4-FA; and ‘4-MMA’, ‘Methyl-MA’ for PMMA. Phenethylamines are usually available in form of pills, but FLY compounds are commonly sold in powder form, while oral doses (on a slip of blotter paper) are usually available for ‘D substances’. Ingestion is the most common route of administration of phenethylamines.

Most phenethylamines act as either central nervous system stimulants, or as hallucinogens. Stimulants mediate the actions of dopamine, norepinephrine and/or serotonin, mimicking the effects of traditional drugs such as cocaine, amphetamine, methamphetamine, and ecstasy. Classic hallucinogens (psychedelics) mediate specific serotonin-receptor activities and produce hallucinations. Substances in these group mimic the effects of traditional drugs such as 2C-B, LSD and DMT but may also possess residual stimulant activity.

Reported adverse effects

Phenethylamines included in the ‘D series’ are described to be longer lasting, more potent and reportedly more liable to induce vasoconstriction than other members of the phenethylamine family.[8]

Reported adverse effects associated with the use of the ‘D series’ derivatives include agitation, tachycardia, mydriasis, hallucinations, severe limb ischemia, seizures, liver and renal failure.[9]Bromo-Dragonfly has also been associated with a number of deaths in Scandinavia.[10]A case of acute psychosis after ingestion of 2C-T-4 was reported in Japan.[11] Three fatal cases associated with the use of 2C-T-7 have been identified, two of which involved poly-drug use.[12]

PMA, PMMA and 4-methylthioamfetamine have been more often associated with incidental deaths than other phenethylamines. PMA and PMMA are known to have a particularly high toxicity but there is no data available on fatalities associated with their use. Clinical observations

have reported severe hyperthermia following the use of these substances.[13] Studies in animals have suggested that some metabolites may be exposed to increased toxicity from 4-MTA.

 References

[1]Hill, SL., Thomas, S.H., ‘Clinical toxicology of newer recreationaldrugs’, Journal: Clinical Toxicology, 2011, 49(8), 705-19

[2]Alexander Shulgin research institute, ‘Alexander ‘Sasha’ Shulgin’ (http://www.shulginresearch.org/home/about/alexander-sasha-shulgin/)

[3] Huang, H.H. and Bai, Y.M. ‘Persistent psychosis after ingestion of a single tablet of ‘ 2C-B ’’, Journal: Progress in Neuro-Psychopharmacology & Biological Psychiatryis, 2010, 35 (1), 293-4

[4]Monte, A.P., Waldman, S.R.., Marona-Lewicka, D., Wainscott, D.B., Nelson, D.L., Sanders-Bush, E., Nichols, D.E., ‘Dihydrobenzofuran analogues of hallucinogens. 4. Mescaline derivatives’, Journal of Medicinal Chemistry, 1997, 40 (19), 2997–3008

[5]Collins, M., ‘Some new psychoactive substances: precursor chemicals and synthesis-driven end-products’, Drug Testing and Analysis, 2011, 3 (7-8), 404-16

[6]Glennon, R. A., Ismaiel, A. E. M., Martin, B., Poff, D. and Sutton, M., ‘A preliminary behavioral investigation of PMMA, the 4-methoxy analog of methamphetamine’, Pharmacology Biochemistry and Behavior, 1988, 31 (1), 9-13

[7]European Monitoring Centre for Drugs and Drug Addiction, ‘Report on the risk assessment of PMMA in the framework of the joint action on new synthetic drugs’, 2003, 56

[8]Hill, S. and Thomas S. H., ‘Clinical toxicology of newer recreational drugs’, Clinical Toxicology, 2011, 49, 705-19

[9]King’s College London. Institute of psychiatry, Psychonaut Web Mapping Research Group, ‘Bromo-Dragonfly report’, London UK, 2009, (http://194.83.136.209/documents/reports/Bromodragonfly. pdf; accessed in: September 2012); Wood, D.M., Looker, J.J., Shaikh,

[10]Andreasen, M.F., Telving, R., Birkler, R., Schumacher, B. and Johannsen, M., ‘A fatal poisoning involving Bromo-Dragonfly’, Annales de Toxicologie Analitique, 20 (1), 1-55; Personne, M., Hulten, P., ‘Bromo-Dragonfly, a life threatening designer drug’, Journal: Clinical Toxicology, 2008, 46, 379-80

[11]Miyajima, M., Matsumoto, T and Ito, S., ‘2C-T-4 intoxication: acute psychosis caused by a designer drug’, Journal: Psychiatry and Clinical Neurosciences, 2008, 62, 243

[12]Curtis, B., Kemp, P., Harty, L., Choi, C. and Christensen, D., ‘Postmortem identification and quantitation of 2,5-dimethoxy-4-n-propylthiophenethylamine using GC-MSD and GC-NPD’, Journal of Analytical Toxicology, 2003, 27, 493-98

[13]Ling, L.H., Marchant, C., Buckley, N. A., Prior, M., Irvine, R.J., ‘Poisoning with the recreational drug paramethoxyamphetamine (‘ death ’)’, Medical Journal of Australia, 2001, 174, 453-55; De Letter, E.A., Coopman, V.A., Cordonnier, J.A. and Piette, M.H., ‘One fatal and seven non-fatal cases of 4-methylthioamphetamine (4-MTA) intoxication: clinico-pathological findings’, International Journal of Legal Medicine, 2001, 114, 352-56; Elliot, S.P., ‘Fatal poisoning with a new phenethylamine: 4-methylthioamphetamine (4-MTA)’, Journal of Analytical Toxicology, 2000, 24, 85-9; Felgate, H.E., Felgate, P.D., James, R.A., Sims, D.N. and Vozzo, D.C., ‘Recent paramethoxyamphetamine deaths’, Journal of Analytical Toxicology, 1998, 22, 169-72; Lamberth, P.G., Ding, G.K., Nurmi, L.A., ‘Fatal paramethoxy-amphetamine (PMA) poisoning in the Australian Capital Territory’, Medical Journal of Australia, 2008, 188, 426