4-Fluoroamphetamine

4-Fluoroamphetamine (4-FA; 4-FMP; PAL-303; "Flux"), also known as para-fluoroamphetamine (PFA) is a psychoactive research chemical of the phenethylamine and substituted amphetamine chemical classes. It produces stimulant and entactogenic effects. As a recreational drug, 4-FA is sometimes sold along with related compounds such as 2-fluoroamphetamine and 4-fluoromethamphetamine.[1][2]

4-Fluoroamphetamine
Ball-and-stick model of the 4-fluoroamphetamine molecule
Clinical data
Pregnancy
category
  • N
Routes of
administration		By mouth
Legal status
Legal status
Identifiers
  • (RS)-1-(4-Fluorophenyl)propan-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC9H12FN
Molar mass153.200 g·mol−1
3D model (JSmol)
  • Fc1ccc(cc1)CC(N)C
  • InChI=1S/C9H12FN/c1-7(11)6-8-2-4-9(10)5-3-8/h2-5,7H,6,11H2,1H3 checkY
  • Key:DGXWNDGLEOIEGT-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Usage
4-Fluoroamphetamine

4-FA is popular in the Netherlands where it is predominantly used for its specific effects (77% of users) rather than its legal status (18%).[3] 4-FA has become illegal since May 2017.[4]

Effects

The subjective effects of 4-fluoroamphetamine include euphoria which some find similar to the effects of MDMA and amphetamine,[3] increased energy (stimulation), mood elevation, feelings of warmth and empathy, excessive talking, bruxism, and suppressed appetite (anorexic). The general course of effects involves primarily empathogenic effects for the first few hours, which fades out as increased stimulation develops over the next several hours.

The dopamine reuptake inhibition produced by 4-FA is stronger than that of either 4-CA or 4-IA.[5] 4-FA also produces less hyperthermia than similar compounds such as PMA, 3-MTA and 4-methylamphetamine.

Common acute side effects are nausea, headaches, increased heart rate and insomnia.

Chemistry

4-FA reacts with reagent testing to give a semi-unique array of colors which can be used to aid its identification.

Final colors produced by reagent tests
Reagent Reaction color
Marquis No reaction[6]
Mandelin Pale Blue[6][7]
Liebermann Orange[6][7]
Froehde Faint purple/brown[6] or no reaction.

Pharmacology

4-Fluoroamphetamine is a releasing agent and reuptake inhibitor of dopamine, serotonin, and norepinephrine.[8] The respective EC50 values are 2.0 x 10−7 M, 7.3 x 10−7 M, and 0.37 x 10−7 M, while the IC50 values are 7.7 x 10−7 M, 68 x 10−7 M, and 4.2 x 10−7 M.[2]

Regarding the metabolic fate of 4-FA, the C-F bond at the 4-position on the phenyl ring likely resists deactivation in the liver by cytochrome P450 oxidase.[9] [10]

Neurotoxicity

4-FA does not cause long-lasting depletion of brain serotonin, unlike its analogs 4-CA and 4-BA.[11] This is thought to "reflect the inability of the fluoro-compound to be metabolized in the same way as the other haloamphetamines."[12]

Neurotoxicity does not increase down the series of para-halogenated amphetamine derivatives, even though serotonin releasing potency does follow this trend. For example, 4-iodoamphetamine is less toxic than is 4-chloroamphetamine.[5][13] Hence, this property is not related to serotonin releasing potency as such, since PAL-287 was reported to be not at all neurotoxic even though it is a powerful 5-HT releasing agent.[14] It is unclear where 4-methylamphetamine fits in on the neurotoxicity scale. The extensive serotonergic neurotoxicity of 4-chloroamphetamine (and its brominated derivative), and the increased serotonergic toxicity of 4-methylamphetamine[15] suggest that para-substitution seems to increase overall serotonergic (neuro)toxicity, compared to amphetamine. Exceptions include 4-MTA, a para-substituted, non-neurotoxic amphetamine.[16][17][18]

Toxicology

The LD50 (mouse; i.p.) of 4-FA is 46 mg/kg.[19]

Fluoroamphetamine (isomer not determined) in a capsule mixed with 25C-NBOMe was associated with three deaths in Melbourne in 2017.[20]

As of October 2015, 4-FA is a controlled substance in China.[21] 4-FA is banned in the Czech Republic.[22] As of 25 May 2017 4-FA is a controlled substance in the Netherlands.[23] 4-FA is also controlled in Australia, Belgium, UK, Germany, Israel, Slovakia, Bulgaria, Chile, Brazil, Canada, Croatia, Sweden, New Zealand and France.

See also

References
  1. Rösner P, Quednow B, Girreser U, Junge T (March 2005). "Isomeric fluoro-methoxy-phenylalkylamines: a new series of controlled-substance analogues (designer drugs)". Forensic Science International. 148 (2–3): 143–156. CiteSeerX 10.1.1.670.7372. doi:10.1016/j.forsciint.2004.05.003. PMID 15639609.
  2. Nagai F, Nonaka R, Satoh Hisashi Kamimura K (March 2007). "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain". European Journal of Pharmacology. 559 (2–3): 132–137. doi:10.1016/j.ejphar.2006.11.075. PMID 17223101.
  3. Linsen F, Koning RP, van Laar M, Niesink RJ, Koeter MW, Brunt TM (July 2015). "4-Fluoroamphetamine in the Netherlands: more than a one-night stand". Addiction. 110 (7): 1138–1143. doi:10.1111/add.12932. PMID 25808511.
  4. "Het is nu officieel: de partydrug 4-FA is verboden". nos.nl. 25 May 2017. Archived from the original on 24 August 2017.
  5. Marona-Lewicka D, Rhee GS, Sprague JE, Nichols DE (December 1995). "Psychostimulant-like effects of p-fluoroamphetamine in the rat". European Journal of Pharmacology. 287 (2): 105–113. doi:10.1016/0014-2999(95)00478-5. PMID 8749023.
  6. "4-FA reaction colour results with liebermann and froehde reagent test kits". Reagent Tests UK. 3 January 2016. Archived from the original on 14 February 2016. Retrieved 14 February 2016.
  7. Uchiyama N, Kawamura M, Kamakura H, Kikura-Hanajiri R, Goda Y (June 2008). "[Analytical data of designated substances (Shitei-Yakubutsu) controlled by the Pharmaceutical Affairs Law in Japan, part II: Color test and TLC]". Yakugaku Zasshi. 128 (6): 981–987. doi:10.1248/yakushi.128.981. PMID 18520145. Archived from the original on 5 March 2016.
  8. Toennes SW, Schneider D, Pogoda W, Paulke A, Wunder C, Theunissen EL, et al. (July 2019). "Pharmacokinetic properties of 4-fluoroamphetamine in serum and oral fluid after oral ingestion". Drug Testing and Analysis. 11 (7): 1028–1034. doi:10.1002/dta.2595. PMID 30912312. S2CID 85518011.
  9. Fisher MB, Henne KR, Boer J (January 2006). "The complexities inherent in attempts to decrease drug clearance by blocking sites of CYP-mediated metabolism". Current Opinion in Drug Discovery & Development. 9 (1): 101–109. PMID 16445122.
  10. Toennes SW, Schneider D, Pogoda W, Paulke A, Wunder C, Theunissen EL, et al. (July 2019). "Pharmacokinetic properties of 4-fluoroamphetamine in serum and oral fluid after oral ingestion". Drug Testing and Analysis. 11 (7): 1028–1034. doi:10.1002/dta.2595. PMID 30912312. S2CID 85518011.
  11. Harvey JA (June 1978). "Neurotoxic action of halogenated amphetamines". Annals of the New York Academy of Sciences. 305 (1): 289–304. Bibcode:1978NYASA.305..289H. doi:10.1111/j.1749-6632.1978.tb31530.x. PMID 81648. S2CID 38386908.
  12. Fuller RW, Baker JC, Perry KW, Molloy BB (October 1975). "Comparison of 4-chloro-, 4-bromo- and 4-fluoroamphetamine in rats: drug levels in brain and effects on brain serotonin metabolism". Neuropharmacology. 14 (10): 739–746. doi:10.1016/0028-3908(75)90099-4. PMID 1196472. S2CID 9620299.
  13. Nichols DE, Johnson MP, Oberlender R (January 1991). "5-Iodo-2-aminoindan, a nonneurotoxic analogue of p-iodoamphetamine". Pharmacology, Biochemistry, and Behavior. 38 (1): 135–139. CiteSeerX 10.1.1.670.504. doi:10.1016/0091-3057(91)90601-W. PMID 1826785. S2CID 20485505.
  14. Rothman RB, Blough BE, Woolverton WL, Anderson KG, Negus SS, Mello NK, et al. (June 2005). "Development of a rationally designed, low abuse potential, biogenic amine releaser that suppresses cocaine self-administration". The Journal of Pharmacology and Experimental Therapeutics. 313 (3): 1361–1369. doi:10.1124/jpet.104.082503. PMID 15761112. S2CID 19802702.
  15. Blanckaert P, van Amsterdam J, Brunt T, van den Berg J, Van Durme F, Maudens K, van Bussel J (September 2013). "4-Methyl-amphetamine: a health threat for recreational amphetamine users". Journal of Psychopharmacology. 27 (9): 817–822. doi:10.1177/0269881113487950. PMID 23784740. S2CID 35436194.
  16. Huang X, Marona-Lewicka D, Nichols DE (December 1992). "p-methylthioamphetamine is a potent new non-neurotoxic serotonin-releasing agent". European Journal of Pharmacology. 229 (1): 31–38. doi:10.1016/0014-2999(92)90282-9. PMID 1473561.
  17. Li Q, Murakami I, Stall S, Levy AD, Brownfield MS, Nichols DE, Van de Kar LD (December 1996). "Neuroendocrine pharmacology of three serotonin releasers: 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butane (MBDB), 5-methoxy-6-methyl-2-aminoindan (MMAi) and p-methylthioamphetamine (MTA)". The Journal of Pharmacology and Experimental Therapeutics. 279 (3): 1261–1267. PMID 8968349.
  18. Murphy J, Flynn JJ, Cannon DM, Guiry PJ, McCormack P, Baird AW, et al. (May 2002). "In vitro neuronal and vascular responses to 5-hydroxytryptamine: modulation by 4-methylthioamphetamine, 4-methylthiomethamphetamine and 3,4-methylenedioxymethamphetamine". European Journal of Pharmacology. 444 (1–2): 61–67. doi:10.1016/S0014-2999(02)01586-8. PMID 12191583.
  19. Costa E, Garattini S (1970). Amphetamines and Related Compounds. New York: Raven Press. p. 28.
  20. "News: March 2017 – Australia: "Ecstasy" capsules containing NPS are related to several deaths and severe intoxications in Melbourne". www.unodc.org. Retrieved 27 February 2022.
  21. "关于印发《非药用类麻醉药品和精神药品列管办法》的通知" (in Chinese). China Food and Drug Administration. 27 September 2015. Archived from the original on 1 October 2015. Retrieved 1 October 2015.
  22. "Látky, o které byl doplněn seznam č. 4 psychotropních látek (příloha č. 4 k nařízení vlády č. 463/2013 Sb.)" (PDF) (in Czech). Ministerstvo zdravotnictví. Archived (PDF) from the original on 9 March 2016.
  23. Van der Velden L (25 May 2017). "Vanaf vandaag is partydrug 4-FA officieel verboden - maar of dat helpt?" (in Dutch). de Volkskrant. Archived from the original on 25 May 2017. Retrieved 25 May 2017.
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