Chemistry:Fenfluramine

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Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome.[1][2][3] It was formerly used as an appetite suppressant in the treatment of obesity, but was discontinued for this use due to cardiovascular toxicity before being repurposed for new indications.[4][5] Fenfluramine was used for weight loss both alone under the brand name Pondimin and in combination with phentermine commonly known as fen-phen.[4][6][7]

Side effects of fenfluramine in people treated for seizures include decreased appetite, somnolence, sedation, lethargy, diarrhea, constipation, abnormal echocardiogram, fatigue, malaise, asthenia, ataxia, balance disorder, gait disturbance, increased blood pressure, drooling, excessive salivation, fever, upper respiratory tract infection, vomiting, appetite loss, weight loss, falls, and status epilepticus.[1] Fenfluramine acts as a serotonin and norepinephrine releasing agent, agonist of the serotonin 5-HT2 receptors, and sigma σ1 receptor positive modulator.[8][9][10] Its mechanism of action in the treatment of seizures is unknown,[1] but may involve increased activation of certain serotonin receptors and the sigma σ1 receptor.[9][5][11] Chemically, fenfluramine is a phenethylamine and amphetamine.[8]

Fenfluramine was developed in the early 1960s and was first introduced for medical use as an appetite suppressant in France in 1963 followed by approval in the United States in 1973.[4] In the 1990s, fenfluramine came to be associated with cardiovascular toxicity, and because of this, was withdrawn from the United States market in 1997.[4][12] Subsequently, it was repurposed for the treatment of seizures and was reintroduced in the United States and the European Union in 2020.[2][3][5] Fenfluramine was previously a schedule IV controlled substance in the United States.[2] However, the substance has since no-longer been subject to control pursuant to rule-making issued on 23 December 2022.[13]

Medical uses

Seizures

Fenfluramine is indicated for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome in people age two and older.[1][2][3]

Dravet syndrome is a life-threatening, rare and chronic form of epilepsy.[2] It is often characterized by severe and unrelenting seizures despite medical treatment.[2]

Research is indicating a potential of fenfluramine to treat those with Sunflower syndrome, a rare form of epilepsy often manifesting in distinct hand waiving in front of the face and a tendency to stare at or face the sun.[14]

Obesity

Fenfluramine was formerly used as an appetite suppressant in the treatment of obesity, but was withdrawn for this use due to cardiovascular toxicity.[4]

Adverse effects

The most common adverse reactions in people with seizures include decreased appetite; drowsiness, sedation and lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue or lack of energy; ataxia (lack of coordination), balance disorder, gait disturbance (trouble with walking); increased blood pressure; drooling, salivary hypersecretion (saliva overproduction); pyrexia (fever); upper respiratory tract infection; vomiting; decreased weight; risk of falls; and status epilepticus.[2]

The U.S. Food and Drug Administration (FDA) fenfluramine labeling includes a boxed warning stating the drug is associated with valvular heart disease (VHD) and pulmonary arterial hypertension (PAH).[2] Because of the risks of VHD and PAH, fenfluramine is available only through a restricted drug distribution program, under a risk evaluation and mitigation strategy (REMS).[2] The fenfluramine REMS requires health care professionals who prescribe fenfluramine and pharmacies that dispense fenfluramine to be specially certified in the fenfluramine REMS and that patients be enrolled in the REMS.[2] As part of the REMS requirements, prescribers and patients must adhere to the required cardiac monitoring with echocardiograms to receive fenfluramine.[2]

At higher therapeutic doses, headache, diarrhea, dizziness, dry mouth, erectile dysfunction, anxiety, insomnia, irritability, lethargy, and CNS stimulation have been reported with fenfluramine.[15]

There have been reports associating chronic fenfluramine treatment with emotional instability, cognitive deficits, depression, psychosis, exacerbation of pre-existing psychosis (schizophrenia), and sleep disturbances.[15][16] It has been suggested that some of these effects may be mediated by serotonergic neurotoxicity/depletion of serotonin with chronic administration or activation of serotonin 5-HT2A receptors.[16][17][18][19]

Heart valve disease

The distinctive valvular abnormality seen with fenfluramine is a thickening of the leaflet and chordae tendineae. One mechanism used to explain this phenomenon involves heart valve serotonin receptors, which are thought to help regulate growth. Since fenfluramine and its active metabolite norfenfluramine stimulate serotonin receptors, this may have led to the valvular abnormalities found in patients using fenfluramine. In particular norfenfluramine is a potent inhibitor of the re-uptake of 5-HT into nerve terminals.[20] Fenfluramine and its active metabolite norfenfluramine affect the 5-HT2B receptors, which are plentiful in human cardiac valves. The suggested mechanism by which fenfluramine causes damage is through over or inappropriate stimulation of these receptors leading to inappropriate valve cell division. Supporting this idea is the fact that this valve abnormality has also occurred in patients using other drugs that act on 5-HT2B receptors.[21][22]

According to a study of 5,743 former users conducted by a plaintiff's expert cardiologist, damage to the heart valve continued long after stopping the medication.[23] Of the users tested, 20% of women, and 12% of men were affected. For all ex-users, there was a 7-fold increase of chances of needing surgery for faulty heart valves caused by the drug.[23]

Overdose

In overdose, fenfluramine can cause serotonin syndrome and rapidly result in death.[4][24]

Pharmacology

Pharmacodynamics

Monoamine release of fenfluramine and related agents (EC50, nM)
Compound NE DA 5-HT Ref
Dextroamphetamine 6.6–7.2 5.8–24.8 698–1,765 [25][26][27][28]
Dextroethylamphetamine 28.8 44.1 333.0 [29][30]
Fenfluramine 739 >10,000 (RI) 79.3–108 [31][32][25][33]
  Dexfenfluramine 302 >10,000 51.7 [31][32][25][33]
  Levfenfluramine >10,000 >10,000 147 [31][32][33][34]
Norfenfluramine 168–170 1,900–1,925 104 [31][32][33]
  Dexnorfenfluramine 72.7 924 59.3 [31][32][33]
  Levnorfenfluramine 474 >10,000 287 [31][32][33]
Phentermine 28.8–39.4 262 2,575–3,511 [25][27][35]
Chlorphentermine >10,000 (RI) 935–2,650 18.2–30.9 [25][35]
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs: [36][31][32]

Fenfluramine acts primarily as a serotonin releasing agent (SRA).[33][37] It increases the level of serotonin, a neurotransmitter that regulates mood, appetite and other functions.[33][37] Fenfluramine causes the release of serotonin by disrupting vesicular storage of the neurotransmitter, and reversing serotonin transporter function.[38] The drug also acts as a norepinephrine releasing agent (NRA) to a lesser extent, particularly via its active metabolite norfenfluramine.[33][37] At high concentrations, norfenfluramine, though not fenfluramine, also acts as a dopamine releasing agent (DRA), and so fenfluramine may do this at very high doses as well.[33][37] In addition to monoamine release, while fenfluramine binds only very weakly to the serotonin 5-HT2 receptors, norfenfluramine binds to and activates the serotonin 5-HT2B and 5-HT2C receptors with high affinity and the serotonin 5-HT2A receptor with moderate affinity.[39][40] The result of the increased serotonergic and noradrenergic neurotransmission is a feeling of fullness and reduced appetite.

In spite of acting as a serotonin 5-HT2A receptor agonist, fenfluramine has been described as non-hallucinogenic.[41] However, psychedelic effects and hallucinations have occasionally been reported when large doses of fenfluramine are taken.[41] Similarly to the psychedelic amphetamine DOI, it is the R-Enatiomer (Levofenfluramine) that is more likely to elicit psychedelia, this also holds true for 3,4-Methylenedioxyamphetamine (MDA)[42][32]

Fenfluramine was identified as a potent positive modulator of the σ1 receptor in 2020 and this action may be involved in its therapeutic benefits in the treatment of seizures.[9][10]

Fenfluramine is inactive as an agonist of the rodent trace amine-associated receptor 1 (TAAR1).[43][44] Norfenfluramine is an agonist of the human TAAR1, with dexnorfenfluramine acting as a very weak agonist of the receptor (43% of maximum at a concentration of 10,000 nM) and levonorfenfluramine being inactive.[45]

The combination of fenfluramine with phentermine, a norepinephrine–dopamine releasing agent (NDRA) acting primarily on norepinephrine, results in a well-balanced serotonin–norepinephrine releasing agent (SNRA) with weaker effects of dopamine release.[33][37]

Fenfluramine and related agents at the serotonin 5-HT2 receptors
Compound 5-HT2A 5-HT2B 5-HT2C
Ki (nM) EC50 (nM) Emax (%) Ki (nM) EC50 (nM) Emax (%) Ki (nM) EC50 (nM) Emax (%)
Fenfluramine 5,216 4,131 15% 4,134 ND ND 3,183 ND ND
  Dexfenfluramine 11,107 >10,000 ND 5,099 379 38% 6,245 362 80%
  Levofenfluramine 5,463 5,279 43% 5,713 1,248 47% 3,415 360 84%
Norfenfluramine 2,316 ND ND 52.1 ND ND 557 ND ND
  Dexnorfenfluramine 1,516 630 88% 11.2 18.4 73% 324 13 100%
  Levonorfenfluramine 3,841 1,565 93% 47.8 357 71% 814 18 80%
Phentermine >10,000 IA or ND IA or ND >10,000 IA or ND IA or ND >10,000 1,394 66%
Chlorphentermine ND >10,000 ND ND 5,370 ND ND 6,456 ND
Notes: (1) The smaller the Ki or EC50 value, the more avidly the drug binds to or activates the receptor. The higher the Emax value, the more effectively the drug activates the receptor. (2) All values are for human receptors except for the 5-HT2A and 5-HT2C Ki values, which are for the rat receptors. Refs: [42][32][31]

Pharmacokinetics

The elimination half-life of fenfluramine has been reported as ranging from 13 to 30 hours.[15] The mean elimination half-lives of its enantiomers have been found to be 19 hours for dexfenfluramine and 25 hours for levfenfluramine.[4] Norfenfluramine, the major active metabolite of fenfluramine, has an elimination half-life that is about 1.5 to 2 times as long as that of fenfluramine, with mean values of 34 hours for dexnorfenfluramine and 50 hours for levnorfenfluramine.[4]

Chemistry

Fenfluramine is a substituted amphetamine and is also known as 3-trifluoromethyl-N-ethylamphetamine.[4] It is a racemic mixture of two enantiomers, dexfenfluramine and levofenfluramine.[4] Some analogues of fenfluramine include norfenfluramine, benfluorex, flucetorex, and fludorex.

History

Fenfluramine was developed in the early 1960s and was introduced in France in 1963.[4] Approximately 50 million Europeans were treated with fenfluramine for appetite suppression between 1963 and 1996.[4] Fenfluramine was approved in the United States in 1973.[4] The combination of fenfluramine and phentermine was proposed in 1984.[4] Approximately 5 million people in the United States were given fenfluramine or dexfenfluramine with or without phentermine between 1996 and 1998.[4]

In the early 1990s, French researchers reported an association of fenfluramine with primary pulmonary hypertension and dyspnea in a small sample of patients.[4] Fenfluramine was withdrawn from the U.S. market in 1997 after reports of heart valve disease[46][12] and continued findings of pulmonary hypertension, including a condition known as cardiac fibrosis.[47] It was subsequently withdrawn from other markets around the world. It was banned in India in 1998.[48]

Fenfluramine was an appetite suppressant which was used to treat obesity.[4] It was used both on its own and, in combination with phentermine, as part of the anti-obesity medication Fen-Phen.[4]

In June 2020, fenfluramine was approved for medical use in the United States with an indication to treat Dravet syndrome.[2][49]

The effectiveness of fenfluramine for the treatment of seizures associated with Dravet syndrome was demonstrated in two clinical studies in 202 subjects between ages two and eighteen.[2] The studies measured the change from baseline in the frequency of convulsive seizures.[2] In both studies, subjects treated with fenfluramine had significantly greater reductions in the frequency of convulsive seizures during the trials than subjects who received placebo (inactive treatment).[2] These reductions were seen within 3–4 weeks, and remained generally consistent over the 14- to 15-week treatment periods.[2]

The U.S. Food and Drug Administration (FDA) granted the application for fenfluramine priority review and orphan drug designations.[2][50][51] The FDA granted approval of Fintepla to Zogenix, Inc.[2]

On 15 October 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Fintepla, intended for the treatment of seizures associated with Dravet syndrome.[52] Fenfluramine was approved for medical use in the European Union in December 2020.[3]

Society and culture

Fenfluramine is a prescription medication in the US. Fenfluramine was removed from Schedule IV of the Controlled Substances Act in December 2022.[53]

Recreational use and effects

Unlike various other amphetamine derivatives, fenfluramine is reported to be dysphoric, "unpleasantly lethargic", and non-addictive at therapeutic doses.[54] However, it has been reported to be used recreationally at high doses ranging between 80 and 400 mg, which have been described as producing euphoria, amphetamine-like effects, sedation, and hallucinogenic effects, along with anxiety, nausea, diarrhea, and sometimes panic attacks, as well as depressive symptoms once the drug had worn off.[54][55][56] At very high doses (e.g., 240 mg, or between 200 and 600 mg), fenfluramine induces a psychedelic state resembling that produced by lysergic acid diethylamide (LSD).[56][57][58][59]

Fenfluramine has been found to produce acute effects in humans including decreased arousal, elation, and positive mood, decreased anxiety at lower doses and increased anxiety at higher doses, drug disliking, confusion, reduced psychomotor performance, reduced impulsivity, and decreased aggression.[60][8][61][62][63] Whereas fenfluramine alone decreases positive mood and phentermine alone increases positive mood similarly to amphetamine, the combination of fenfluramine and phentermine results in a neutral impact on mood.[8][61] Similarly fenfluramine diminishes the subjective effects of phentermine and amphetamine.[64][65] In contrast to other serotonin releasers like MDMA and mephedrone, fenfluramine does not produce euphoria.[60] The differing effects with fenfluramine may be attributable to its lack of concomitant dopamine release and its potent serotonin 5-HT2C receptor agonism via its metabolite norfenfluramine.[60]

Research

Social deficits

Fenfluramine has been reported to improve social deficits in children with autism.[66][67] In addition, it has been found to produce prosocial behavior similarly to the entactogen MDMA in animals.[68][66] However, fenfluramine has shown limited effectiveness in treating the symptoms of autism generally.[69] Moreover, the cardiovascular toxicity and neurotoxicity of fenfluramine[70][71][72][73] make it unsuitable for clinical use in the treatment of social deficits.[66]

References

  1. ↑ 1.0 1.1 1.2 1.3 "FINTEPLA- fenfluramine solution". 14 December 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e88f360e-33ad-4cd6-b2de-5ef885857c5d. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 "FDA Approves New Therapy for Dravet Syndrome". U.S. Food and Drug Administration (FDA) (Press release). 25 June 2020. Archived from the original on 26 June 2020. Retrieved 25 June 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ↑ 3.0 3.1 3.2 3.3 Cite error: Invalid <ref> tag; no text was provided for refs named Fintepla EPAR
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. John Wiley & Sons. 3 February 2012. pp. 255–262. ISBN 978-1-118-10605-1. https://books.google.com/books?id=9JLiJcjdqkcC&pg=PA255. 
  5. ↑ 5.0 5.1 5.2 "Fenfluramine repurposing from weight loss to epilepsy: What we do and do not know". Pharmacol Ther 226. October 2021. doi:10.1016/j.pharmthera.2021.107866. PMID 33895186. 
  6. ↑ Swiss Pharmaceutical Society (2000). Swiss Pharmaceutical Society. ed. Index Nominum 2000: International Drug Directory. Taylor & Francis. pp. 431–432. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA431. 
  7. ↑ "How Fen-Phen, A Diet 'Miracle,' Rose and Fell". New York Times (NY, NY, USA). 23 September 1997. https://www.nytimes.com/1997/09/23/science/how-fen-phen-a-diet-miracle-rose-and-fell.html. 
  8. ↑ 8.0 8.1 8.2 8.3 "Neurochemical mechanisms of phentermine and fenfluramine: Therapeutic and adverse effects". Drug Development Research 51 (2): 52–65. 2000. doi:10.1002/1098-2299(200010)51:2<52::AID-DDR2>3.0.CO;2-H. ISSN 0272-4391. 
  9. ↑ 9.0 9.1 9.2 "An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies". Int J Mol Sci 22 (16): 8416. August 2021. doi:10.3390/ijms22168416. PMID 34445144. 
  10. ↑ 10.0 10.1 "Fenfluramine acts as a positive modulator of sigma-1 receptors". Epilepsy Behav 105. April 2020. doi:10.1016/j.yebeh.2020.106989. PMID 32169824. 
  11. ↑ "Individualized treatment approaches: Fenfluramine, a novel antiepileptic medication for the treatment of seizures in Dravet syndrome". Epilepsy Behav 91: 99–102. February 2019. doi:10.1016/j.yebeh.2018.08.021. PMID 30269941. 
  12. ↑ 12.0 12.1 "Appetite suppressants and valvular heart disease". The American Journal of the Medical Sciences 321 (4): 285–291. April 2001. doi:10.1097/00000441-200104000-00008. PMID 11307869. 
  13. ↑ "Schedules of Controlled Substances: Removal of Fenfluramine From Control". U.S. Federal Register. 23 December 2022. https://www.federalregister.gov/documents/2022/12/23/2022-27400/schedules-of-controlled-substances-removal-of-fenfluramine-from-control. 
  14. ↑ Geenen, K. R., Doshi, S. P., Patel, S., Sourbron, J., Falk, A., Morgan, A., Vu, U., Bruno, P. L., & Thiele, E. A. (2021). Fenfluramine for seizures associated with Sunflower syndrome. Developmental medicine and child neurology, 63(12), 1427–1432. https://doi.org/10.1111/dmcn.14965
  15. ↑ 15.0 15.1 15.2 Medical Toxicology. Lippincott Williams & Wilkins. 2004. pp. 874–. ISBN 978-0-7817-2845-4. https://books.google.com/books?id=BfdighlyGiwC&pg=PA874. 
  16. ↑ 16.0 16.1 Drug Injury: Liability, Analysis, and Prevention. Lawyers & Judges Publishing Company. 2005. pp. 276–. ISBN 978-0-913875-27-8. https://books.google.com/books?id=EB00rD8AqaYC&pg=PA276. 
  17. ↑ Integrating the Neurobiology of Schizophrenia. Academic Press. 27 February 2007. pp. 142–. ISBN 978-0-08-047508-0. https://books.google.com/books?id=mksAKriZXuYC&pg=PA142. 
  18. ↑ The Pharmacology of Corticotropin-releasing Factor (CRF). Effects on Sensorimotor Gating in the Rat. 2006. pp. 12–. ISBN 978-0-549-53661-1. https://books.google.com/books?id=kTADn_LMnZ4C&pg=PA12. 
  19. ↑ Handbook of the Behavioral Neurobiology of Serotonin. Academic Press. 30 December 2009. pp. 630–. ISBN 978-0-08-087817-1. https://books.google.com/books?id=aomaKqIE1jUC&pg=PA630. 
  20. ↑ "Evidence that hypophagia induced by d-fenfluramine and d-norfenfluramine in the rat is mediated by 5-HT2C receptors". Neuropharmacology 41 (2): 200–9. 2001. doi:10.1016/s0028-3908(01)00063-6. PMID 11489456. 
  21. ↑ "Drugs and valvular heart disease". The New England Journal of Medicine 356 (1): 6–9. January 2007. doi:10.1056/NEJMp068265. PMID 17202450. 
  22. ↑ "Serotonergic drugs and valvular heart disease". Expert Opinion on Drug Safety 8 (3): 317–329. May 2009. doi:10.1517/14740330902931524. PMID 19505264. 
  23. ↑ 23.0 23.1 "Valvular regurgitation and surgery associated with fenfluramine use: an analysis of 5743 individuals". BMC Medicine 6. November 2008. doi:10.1186/1741-7015-6-34. PMID 18990200. 
  24. ↑ Neuroleptic Malignant Syndrome and Related Conditions. American Psychiatric Pub. 20 May 2008. pp. 111–. ISBN 978-1-58562-744-8. https://books.google.com/books?id=POjw-pQcvW8C&pg=PA111. 
  25. ↑ 25.0 25.1 25.2 25.3 25.4 "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse 39 (1): 32–41. January 2001. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. 
  26. ↑ "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology 38 (4): 552–562. 2013. doi:10.1038/npp.2012.204. PMID 23072836. 
  27. ↑ 27.0 27.1 "Dopamine-releasing agents". Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. July 2008. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf. 
  28. ↑ Liu, Yi (28 March 2018). Structural Determinants for Inhibitor Recognition by the Dopamine Transporter. https://dsc.duq.edu/etd/829/. Retrieved 11 December 2024. "The most commonly studied DAT substrates are amphetamines, including amphetamine and methamphetamine (Fig. 9). S-(+)-amphetamine releases dopamine with an EC50 of 8.7 nM; the R-(−)-amphetamine is 3-fold weaker, at 27.7 nM (EC50) (Blough, Page et al. 2005). Although weaker, a similar trend is seen for the optical isomers of methamphetamine. S-(+)-methamphetamine releases dopamine with an EC50 of 24.5 nM, while the R-(−)-methamphetamine is 16-fold less active at 416 nM (EC50) (Blough, Page et al. 2005). [...] Blough, B. E., K. M. Page, et al. (2005). "Struture-activity relationship studies of DAT, SERT, and NET releasers." New Perspectives on Neurotransmitter Transporter Pharmacology.". 
  29. ↑ "Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones". Neuropharmacology 245. March 2024. doi:10.1016/j.neuropharm.2023.109827. PMID 38154512. 
  30. ↑ Nicole, Lauren (2022). "In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones". https://www.proquest.com/openview/a207e98868b4a9c5ac9296fb24abbcd8/. "FIGURE 2-6: Release: Effects of the specified test drug on monoamine release by DAT (red circles), NET (blue squares), and SERT (black traingles) in rat brain tissue. [...] EC50 values determined for the drug indicated within the panel. [...]" 
  31. ↑ 31.0 31.1 31.2 31.3 31.4 31.5 31.6 31.7 "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. https://zenodo.org/record/1235860. 
  32. ↑ 32.0 32.1 32.2 32.3 32.4 32.5 32.6 32.7 32.8 "Serotonergic drugs and valvular heart disease". Expert Opin Drug Saf 8 (3): 317–329. May 2009. doi:10.1517/14740330902931524. PMID 19505264. 
  33. ↑ 33.00 33.01 33.02 33.03 33.04 33.05 33.06 33.07 33.08 33.09 33.10 "(+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters". The Journal of Pharmacology and Experimental Therapeutics 305 (3): 1191–1199. June 2003. doi:10.1124/jpet.103.049684. PMID 12649307. 
  34. ↑ "Therapeutic and adverse actions of serotonin transporter substrates". Pharmacology & Therapeutics 95 (1): 73–88. July 2002. doi:10.1016/s0163-7258(02)00234-6. PMID 12163129. 
  35. ↑ 35.0 35.1 "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substractes". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc. NIDA Res Monogr. 180. 1999. pp. 1–476 (252). https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261. "RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). [...]" 
  36. ↑ "Monoamine transporters and psychostimulant drugs". Eur J Pharmacol 479 (1–3): 23–40. October 2003. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135. 
  37. ↑ 37.0 37.1 37.2 37.3 37.4 "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Molecular Pharmacology 63 (6): 1223–1229. June 2003. doi:10.1124/mol.63.6.1223. PMID 12761331. 
  38. ↑ Molecular Neuropharmacology: A Foundation for Clinical Neuroscience. McGraw-Hill. 2001. 
  39. ↑ "Dopamine/serotonin releasers as medications for stimulant addictions". Serotonin-dopamine Interaction: Experimental Evidence and Therapeutic Relevance. Elsevier. 2008. pp. 393–. ISBN 978-0-444-53235-0. https://books.google.com/books?id=mPkKtA15KM8C&pg=PA393. 
  40. ↑ "Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine". Mol. Pharmacol. 57 (1): 75–81. 2000. doi:10.1016/S0026-895X(24)26444-0. PMID 10617681. 
  41. ↑ 41.0 41.1 "Psychedelics: preclinical insights provide directions for future research". Neuropsychopharmacology 49 (1): 119–127. January 2024. doi:10.1038/s41386-023-01567-7. PMID 36932180. 
  42. ↑ 42.0 42.1 "Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications". Circulation 102 (23): 2836–2841. December 2000. doi:10.1161/01.cir.102.23.2836. PMID 11104741. 
  43. ↑ "Trace amine-associated receptors and their ligands". Br J Pharmacol 149 (8): 967–978. December 2006. doi:10.1038/sj.bjp.0706948. PMID 17088868. "[...] Bunzow et al. (2001) tested the hypothesis that amphetamine and its congeners would be potent agonists of heterologously expressed TAAR1s. In HEK293 cells stably expressing rat TAAR1, amphetamine stimulated cAMP production with an EC50 comparable to that of β-phenylethylamine (210 nM for R-amphetamine and 440 nM for S-amphetamine). [...] N-ethylderivatives such as fenfluramine and N-ethylamphetamine were substantially less effective, [...]". 
  44. ↑ "Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor". Mol Pharmacol 60 (6): 1181–1188. December 2001. doi:10.1124/mol.60.6.1181. PMID 11723224. 
  45. ↑ "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorg Med Chem 19 (23): 7044–7048. December 2011. doi:10.1016/j.bmc.2011.10.007. PMID 22037049. 
  46. ↑ "Valvular heart disease associated with fenfluramine-phentermine". The New England Journal of Medicine 337 (9): 581–588. August 1997. doi:10.1056/NEJM199708283370901. PMID 9271479. 
  47. ↑ "FDA Announces Withdrawal Fenfluramine and Dexfenfluramine (Fen-Phen)". U.S. Food and Drug Administration. 15 September 1997. https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm179871.htm. 
  48. ↑ "Drugs banned in India". Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India. http://cdsco.nic.in/html/drugsbanned.html. 
  49. ↑ "FDA Approves FINTEPLA (fenfluramine) for the Treatment of Seizures Associated with Dravet Syndrome" (Press release). Zogenix Inc. 25 June 2020. Retrieved 25 June 2020 – via GlobeNewswire.
  50. ↑ "Fenfluramine Orphan Drug Designations and Approvals". 24 December 1999. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=414613. 
  51. ↑ "Fenfluramine Orphan Drug Designations and Approvals". 24 December 1999. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=584217. 
  52. ↑ "Fintepla: Pending EC decision". 16 October 2020. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/fintepla.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  53. ↑ "Schedules of Controlled Substances: Removal of Fenfluramine from Control". DEA. 23 December 2022. https://www.federalregister.gov/documents/2022/12/23/2022-27400/schedules-of-controlled-substances-removal-of-fenfluramine-from-control. 
  54. ↑ 54.0 54.1 Neurological Aspects of Substance Abuse. Butterworth-Heinemann. 2004. pp. 117–. ISBN 978-0-7506-7313-6. https://books.google.com/books?id=fOfxoQm_a7MC&pg=PA117. 
  55. ↑ Competitive problems in the drug industry: hearings before Subcommittee on Monopoly and Anticompetitive Activities of the Select Committee on Small Business, United States Senate, Ninetieth Congress, first session. U.S. Government Printing Office. 1976. pp. 2–. https://books.google.com/books?id=Rs1GAQAAMAAJ&pg=RA2-PA56. 
  56. ↑ 56.0 56.1 Gunne LM (1977). "Effects of Amphetamines in Humans". Drug Addiction II: Amphetamine, Psychotogen, and Marihuana Dependence. Berlin, Germany; Heidelberg, Germany: Springer. pp. 247–260. ISBN 9783642667091. https://books.google.com/books?id=gb_uCAAAQBAJ&pg=PA247. "However, LEVIN recently (1972, 1974) reported on abuse of fenfluramine among LSD and cannabis abusers in South Africa. This group of abusers seems to have appreciated the hallucinogenic LSD-like effects, which fenfluramine exerts when applied in high doses (200—600 mg). At this dose level, the fenfluramine abusers (a total of 115) experienced euphoria with laughing attacks, followed some hours later by depressive symptoms. They reported visual and olfactory hallucinations, anxiety, sometimes with attacks of panic, nausea, and diarrhea." 
  57. ↑ Connell, P. H. (1979). "Drug dependence liability of anorectic drugs: a clinical viewpoint, with particular reference to fenfluramine". Current Medical Research and Opinion 6 (sup1): 153–159. doi:10.1185/03007997909117502. ISSN 0300-7995. "Griffith et al.6 compared fenfluramine with d-amphetamine and noted that fenfluramine was usually identified as LSD by subjects, and LSD scale scores after fenfluramine were significantly elevated. Three subjects receiving 240 mg fenfluramine experienced a psychedelic state characterized by visual and olfactory hallucination, cyclic alterations of mood, distorted time sense, fleeting paranoia, and sexual ideation. They noted that fenfluramine was a weak hallucinogen and, although sharing some features in common with amphetamine, “its overall profile of effects is quite different”.". 
  58. ↑ Griffith, John D. (1977). "Structure-Activity Relationships of Several Amphetamine Drugs in Man". Cocaine and Other Stimulants. Advances in Behavioral Biology. 21. Boston, MA: Springer US. pp. 705–715. doi:10.1007/978-1-4684-3087-5_36. ISBN 978-1-4684-3089-9. https://archive.org/details/cocaineotherstim0021unse/page/705/. "Fenfluramine (60, 120, 240 mg orally) [...] caused a marked dilation of pupils and elevation of the LSD Scale. [...] Fenfluramine was more often identified as an "LSD" or "barbiturate-like" substance. An unexpected response [...] was observed among 3 subjects who manifested hallucinatory states characterized by visual and olfactory hallucinations, rapid and polar changes of mood, distorted time sense, fleeting paranoia, and sexual hallucinations. [...] The remaining five subjects receiving the largest dose of fenfluramine experienced a chlorpromazine-like sedation without hallucinations or other psychedelic effects (Griffith, Nutt, and Jasinski, 1975). Chlorphentermine (50, 100, 200 mg) was similarly assessed. In certain respects, chlorphentermine resembles fenfluramine (Fig. 4), especially in terms of its mydriatic and sedative effects [...] On the other hand, chlorphentermine [...] is not hallucinogenic. [...] the utility of [amphetamine aromatic ring substitution] may be limited by the emergence of certain side-effects [...] e.g., dysphoria, sedation, and/or psychedelic properties." 
  59. ↑ "A comparison of fenfluramine and amphetamine in man". Clin Pharmacol Ther 18 (5 Pt 1): 563–570. November 1975. doi:10.1002/cpt1975185part1563. PMID 1102234. "dl-Fenfluramine hydrochloride (60, 120, 240 mg), d-amphetamine sulfate (20, 40 mg), and placebo were compared in 8 postaddict volunteers, each dose given orally [...] Fenfluramine [...] caused a marked dilation of pupils [...] While fenfluramine produced euphoria in some subjects, its overall effects were unpleasant, sedative, and qualitatively different from amphetamine. Three subjects given 240 mg of fenfluramine experienced brief but vivid hallucinogenic episodes characterized by olfactory, visual, and somatic hallucinations, abrupt polar changes in mood, time distortion, fleeting paranoia, and sexual ideation. These observations indicate that fenfluramine is a hallucinogenic agent with a pharmacologic profile in man that is not amphetamine-like.". 
  60. ↑ 60.0 60.1 60.2 "Serotonin and brain function: a tale of two receptors". J Psychopharmacol 31 (9): 1091–1120. September 2017. doi:10.1177/0269881117725915. PMID 28858536. 
  61. ↑ 61.0 61.1 "Evaluation of phentermine and fenfluramine, alone and in combination, in normal, healthy volunteers". Neuropsychopharmacology 14 (4): 233–241. April 1996. doi:10.1016/0893-133X(95)00113-R. PMID 8924191. 
  62. ↑ "Acute effects of D-fenfluramine on simultaneous measures of aggressive escape and impulsive responses of adult males with and without a history of conduct disorder". Psychopharmacology (Berl) 157 (3): 221–227. September 2001. doi:10.1007/s002130100812. PMID 11605076. 
  63. ↑ "Effect of d-fenfluramine on human experimental anxiety". Psychopharmacology (Berl) 127 (3): 276–282. October 1996. doi:10.1007/BF02806003. PMID 8912406. 
  64. ↑ "Dual dopamine/serotonin releasers: potential treatment agents for stimulant addiction". Exp Clin Psychopharmacol 16 (6): 458–474. December 2008. doi:10.1037/a0014103. PMID 19086767. 
  65. ↑ "Dual dopamine-5-HT releasers: potential treatment agents for cocaine addiction". Trends Pharmacol Sci 27 (12): 612–618. December 2006. doi:10.1016/j.tips.2006.10.006. PMID 17056126. 
  66. ↑ 66.0 66.1 66.2 "Distinct neural mechanisms for the prosocial and rewarding properties of MDMA". Sci Transl Med 11 (522). December 2019. doi:10.1126/scitranslmed.aaw6435. PMID 31826983. "FEN has been reported to improve social deficits in children with autism (34). However, like MDMA, long-term and/or heavy use of FEN is associated with cardiovascular and neurological toxicity (1, 7, 35).". 
  67. ↑ "Review of fenfluramine in the treatment of the developmental disabilities". J Am Acad Child Adolesc Psychiatry 28 (4): 549–565. July 1989. doi:10.1097/00004583-198907000-00014. PMID 2670881. 
  68. ↑ "Exploring the regulatory framework of psychedelics in the US & Europe". Asian J Psychiatr 102. September 2024. doi:10.1016/j.ajp.2024.104242. PMID 39305768. 
  69. ↑ "Evaluating the Potential Use of Serotonergic Psychedelics in Autism Spectrum Disorder". Front Pharmacol 12. 2021. doi:10.3389/fphar.2021.749068. PMID 35177979. "Fenfluramine, a serotonin-releasing agent, enhances serotonin signaling in the brain. While few small-sample, placebo-controlled studies found moderate efficacy in fenfluramine’s ability to increase IQ in individuals with ASD (Geller et al., 1982; Ritvo et al., 1984), far more have found that this treatment is only effective in mildy reducing some of the motor and attentional atypicalities in people with ASD. This data suggests that increasing brain serotonin levels (and consequently serotonin signaling) is generally ineffective in improving the behavioural condition of individuals with ASD.". 
  70. ↑ "Survey of Selective Monoaminergic Neurotoxins Targeting Dopaminergic, Noradrenergic, and Serotoninergic Neurons". Handbook of Neurotoxicity. Cham: Springer International Publishing. 2022. pp. 159–198. doi:10.1007/978-3-031-15080-7_53. ISBN 978-3-031-15079-1. 
  71. ↑ "Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine. A systematic review of the evidence". JAMA 278 (8): 666–672. August 1997. doi:10.1001/jama.1997.03550080076043. PMID 9272900. 
  72. ↑ "Serotonin releasing agents. Neurochemical, therapeutic and adverse effects". Pharmacol Biochem Behav 71 (4): 825–836. April 2002. doi:10.1016/s0091-3057(01)00669-4. PMID 11888573. 
  73. ↑ "Comparative serotonin neurotoxicity of the stereoisomers of fenfluramine and norfenfluramine". Pharmacol Biochem Behav 36 (1): 105–109. May 1990. doi:10.1016/0091-3057(90)90133-3. PMID 2140899. 

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