Wikipedia

Fenfluramine

Fenfluramine,sold under the brand nameFintepla,is aserotonergicmedication used for the treatment ofseizuresassociated withDravet syndromeandLennox–Gastaut syndrome.[3][7][4]It was formerly used as anappetite suppressantin the treatment ofobesity,but was discontinued for this use due tocardiovasculartoxicitybefore being repurposed for new indications.[8][9]Fenfluramine was used forweight lossboth alone under the brand namePondiminandin combinationwithphenterminecommonly known asfen-phen.[8][10][11]

Fenfluramine
Ball-and-stick modelsof fenfluramine, showing thedextroisomerabove and the levo isomer below
Clinical data
Trade namesSeizures:Fintepla
Weight loss:Pondimin, Ponderax, Ponderal, others
Other namesZX008; 3-Trifluoromethyl-N-ethylamphetamine
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa620045
License data
Pregnancy
category
  • AU:B2
Routes of
administration		By mouth
Drug classSerotonin–norepinephrine releasing agent;Serotonin5-HT2A,5-HT2B,and5-HT2Creceptor agonist;Anoretic;Anticonvulsant
ATC code
Legal status
Legal status
Pharmacokineticdata
Eliminationhalf-life13–30hours[6]
Identifiers
  • (RS)-N-Ethyl- 1-[3-(trifluoromethyl)phenyl]propan-2-amine
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.006.616Edit this at Wikidata
Chemical and physical data
FormulaC12H16F3N
Molar mass231.262g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • CCNC(C)Cc1cccc(C(F)(F)F)c1
  • InChI=1S/C12H16F3N/c1-3-16-9(2)7-10-5-4-6-11(8-10)12(13,14)15/h4-6,8-9,16H,3,7H2,1-2H3checkY
  • Key:DBGIVFWFUFKIQN-UHFFFAOYSA-NcheckY
(verify)

Side effectsof fenfluramine in people treated for seizures includedecreased 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,andstatus epilepticus.[3]Fenfluramine acts as aserotonin and norepinephrine releasing agent,agonistof theserotonin5-HT2receptors,andsigmaσ1receptorpositive modulator.[12][13][14]Itsmechanism of actionin the treatment of seizures is unknown,[3]but may involve increased activation of certain serotonin receptors and the sigma σ1receptor.[13][9][15]Chemically, fenfluramine is aphenethylamineandamphetamine.[12]

Fenfluramine was developed in the early 1960s and was first introduced for medical use as an appetite suppressant inFrancein 1963 followed by approval in theUnited Statesin 1973.[8]In the 1990s, fenfluramine came to be associated with cardiovascular toxicity, and because of this, waswithdrawnfrom the United States market in 1997.[8][16]Subsequently, it was repurposed for the treatment of seizures and was reintroduced in the United States and theEuropean Unionin 2020.[7][4][9]Fenfluramine was previously aschedule IVcontrolled substancein the United States.[7]However, the substance has since no-longer been subject to control pursuant to rule-making issued on 23 December 2022.[17]

Medical uses

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Seizures

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Fenfluramine is indicated for the treatment of seizures associated withDravet syndromeandLennox–Gastaut syndromein people age two and older.[3][7][4]

Dravet syndrome is a life-threatening, rare and chronic form ofepilepsy.[7]It is often characterized by severe and unrelenting seizures despite medical treatment.[7]

Obesity

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Fenfluramine was formerly used as anappetite suppressantin the treatment ofobesity,but waswithdrawnfor this use due to cardiovascular toxicity.[8]

Adverse effects

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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.[7]

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).[7]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).[7]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.[7]As part of the REMS requirements, prescribers and patients must adhere to the required cardiac monitoring with echocardiograms to receive fenfluramine.[7]

At higher therapeutic doses,headache,diarrhea,dizziness,dry mouth,erectile dysfunction,anxiety,insomnia,irritability,lethargy,andCNSstimulationhave been reported with fenfluramine.[6]

There have been reports associating chronic fenfluramine treatment withemotional instability,cognitive deficits,depression,psychosis,exacerbation of pre-existing psychosis (schizophrenia), andsleep disturbances.[6][18]It has been suggested that some of these effects may be mediated byserotonergicneurotoxicity/depletion of serotonin with chronic administration and/or activation of serotonin5-HT2Areceptors.[18][19][20][21]

Heart valve disease

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The distinctive valvular abnormality seen with fenfluramine is a thickening of the leaflet andchordae 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 metabolitenorfenfluraminestimulate 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.[22]Fenfluramine and its active metabolite norfenfluramine affect the5-HT2Breceptors,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-HT2Breceptors.[23][24]

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.[25]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.[25]

Overdose

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Inoverdose,fenfluramine can causeserotonin syndromeand rapidly result in death.[8][26]

Pharmacology

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Pharmacodynamics

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Monoamine releaseoffenfluramineand related agents (EC50Tooltip Half maximal effective concentration,nM)
Compound NETooltip Norepinephrine DATooltip Dopamine 5-HTTooltip Serotonin Ref
Dextroamphetamine 6.6–7.2 5.8–24.8 698–1,765 [27][28][29][30]
Dextroethylamphetamine 28.8 44.1 333.0 [31][32]
Fenfluramine 739 >10,000 (RI) 79.3–108 [33][34][27][35]
Dexfenfluramine 302 >10,000 51.7 [33][34][27][35]
Levfenfluramine >10,000 >10,000 147 [33][34][35][36]
Norfenfluramine 168–170 1,900–1,925 104 [33][34][35]
Dexnorfenfluramine 72.7 924 59.3 [33][34][35]
Levnorfenfluramine 474 >10,000 287 [33][34][35]
Phentermine 28.8–39.4 262 2,575–3,511 [27][29][37]
Chlorphentermine >10,000 (RI) 935–2,650 18.2–30.9 [27][37]
Notes:The smaller the value, the more strongly the drug releases the neurotransmitter. Theassayswere done in rat brainsynaptosomesand humanpotenciesmay be different. See alsoMonoamine releasing agent § Activity profilesfor a larger table with more compounds.Refs:[38][33][34]

Fenfluramine acts primarily as aserotonin releasing agent(SRA).[35][39]It increases the level ofserotonin,aneurotransmitterthat regulates mood, appetite and other functions.[35][39]Fenfluraminecauses the releaseof serotonin by disruptingvesicularstorage of the neurotransmitter, and reversing serotonintransporterfunction.[40]The drug also acts as anorepinephrine releasing agent(NRA) to a lesser extent, particularly via itsactive metabolitenorfenfluramine.[35][39]At high concentrations, norfenfluramine, though not fenfluramine, also acts as adopamine releasing agent(DRA), and so fenfluramine may do this at very high doses as well.[35][39]In addition to monoamine release, while fenfluramine binds only very weakly to the serotonin5-HT2receptors,norfenfluramine binds to and activates the serotonin5-HT2Band5-HT2Creceptorswith high affinity and the serotonin5-HT2Areceptorwith moderate affinity.[41][42]The result of the increasedserotonergicandnoradrenergicneurotransmissionis a feeling of fullness and reduced appetite.

In spite of acting as a serotonin 5-HT2Areceptor agonist, fenfluramine has been described as non-hallucinogenic.[43]However,psychedeliceffects andhallucinationshave occasionally been reported when large doses of fenfluramine are taken.[43]

Fenfluramine was identified as apotentpositive modulatorof theσ1receptorin 2020 and this action may be involved in its therapeutic benefits in the treatment of seizures.[13][14]

Fenfluramine is inactive as an agonist of the rodenttrace amine-associated receptor 1(TAAR1).[44][45]Norfenfluramine is an agonist of the human TAAR1, withdexnorfenfluramineacting as a very weak agonist of the receptor (43% of maximum at a concentration of 10,000nM) andlevonorfenfluraminebeing inactive.[46]

The combination of fenfluramine withphentermine,anorepinephrine–dopamine releasing agent(NDRA) acting primarily on norepinephrine, results in a well-balancedserotonin–norepinephrine releasing agent(SNRA) with weaker effects of dopamine release.[35][39]

Fenfluramine and related agents at theserotonin5-HT2receptors
Compound 5-HT2A 5-HT2B 5-HT2C
Ki(nM) EC50Tooltip Half-maximal effective concentration(nM) EmaxTooltip Maximal efficacy(%) Ki(nM) EC50Tooltip Half-maximal effective concentration(nM) EmaxTooltip Maximal efficacy(%) Ki(nM) EC50Tooltip Half-maximal effective concentration(nM) EmaxTooltip Maximal efficacy(%)
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 IAorND IAorND >10,000 IAorND IAorND >10,000 1,394 66%
Chlorphentermine ND >10,000 ND ND 5,370 ND ND 6,456 ND
Notes:(1) The smaller the Kior EC50value, the more avidly the drug binds to or activates the receptor. The higher the Emaxvalue, the more effectively the drug activates the receptor. (2) All values are for human receptors except for the 5-HT2Aand 5-HT2CKivalues, which are for the rat receptors.Refs:[47][34][33]

Pharmacokinetics

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Theelimination half-lifeof fenfluramine has been reported as ranging from 13 to 30 hours.[6]The mean elimination half-lives of its enantiomers have been found to be 19 hours for dexfenfluramine and 25 hours for levfenfluramine.[8]Norfenfluramine, the majoractive metaboliteof 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.[8]

Chemistry

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Fenfluramine is asubstituted amphetamineand is also known as 3-trifluoromethyl-N-ethylamphetamine.[8]It is aracemic mixtureof twoenantiomers,dexfenfluramineandlevofenfluramine.[8]Someanaloguesof fenfluramine includenorfenfluramine,benfluorex,flucetorex,andfludorex.

History

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Fenfluramine was developed in the early 1960s and was introduced inFrancein 1963.[8]Approximately 50 million Europeans were treated with fenfluramine for appetite suppression between 1963 and 1996.[8]Fenfluramine was approved in theUnited Statesin 1973.[8]The combination of fenfluramine and phentermine was proposed in 1984.[8]Approximately 5 million people in the United States were given fenfluramine or dexfenfluramine with or without phentermine between 1996 and 1998.[8]

In the early 1990s, French researchers reported an association of fenfluramine with primarypulmonary hypertensionanddyspneain a small sample of patients.[8]Fenfluramine was withdrawn from the U.S. market in 1997 after reports ofheart valve disease[48][16]and continued findings of pulmonary hypertension, including a condition known ascardiac fibrosis.[49]It was subsequently withdrawn from other markets around the world. It was banned in India in 1998.[50]

Fenfluramine was anappetite suppressantwhich was used to treatobesity.[8]It was used both on its own and,in combination with phentermine,as part of theanti-obesity medicationFen-Phen.[8]

In June 2020, fenfluramine was approved for medical use in the United States with an indication to treat Dravet syndrome.[7][51]

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.[7]The studies measured the change from baseline in the frequency of convulsive seizures.[7]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).[7]These reductions were seen within 3–4 weeks, and remained generally consistent over the 14- to 15-week treatment periods.[7]

The U.S.Food and Drug Administration(FDA) granted the application for fenfluraminepriority reviewandorphan drugdesignations.[7][52][53]The FDA granted approval of Fintepla to Zogenix, Inc.[7]

On 15 October 2020, theCommittee for Medicinal Products for Human Use(CHMP) of theEuropean 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.[54]Fenfluramine was approved for medical use in the European Union in December 2020.[4]

Society and culture

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Fenfluramine is a prescription medication in the US. Fenfluramine was removed from Schedule IV of the Controlled Substances Act in December 2022.[55]

Recreational use and effects

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Unlike various other amphetamine derivatives, fenfluramine is reported to bedysphoric,"unpleasantlylethargic",and non-addictiveat therapeutic doses.[56]However, it has been reported to be used recreationally at high doses ranging between 80 and 400 mg, which have been described as producingeuphoria,amphetamine-like effects,sedation,andhallucinogeniceffects, along withanxiety,nausea,diarrhea,and sometimespanic attacks,as well asdepressivesymptomsonce the drug had worn off.[56][57][58]At very high doses (e.g., 240 mg, or between 200 and 600 mg), fenfluramine induces apsychedelic stateresembling that produced bylysergic acid diethylamide(LSD).[58][59][60][61]

Fenfluramine has been found to produce acute effects in humans including decreasedarousal,elation,andpositive mood,decreased anxiety at lower doses and increased anxiety at higher doses,drug disliking,confusion,reducedpsychomotor performance,reducedimpulsivity,and decreasedaggression.[62][12][63][64][65]Whereas fenfluramine alone decreases positive mood andphenterminealone increases positive mood similarly to amphetamine, thecombinationof fenfluramine and phentermine results in a neutral impact on mood.[12][63]Similarly fenfluramine diminishes the subjective effects of phentermine and amphetamine.[66][67]In contrast to other serotonin releasers likeMDMAandmephedrone,fenfluramine does not produce euphoria.[62]The differing effects with fenfluramine may be attributable to its lack of concomitantdopaminerelease and itspotentserotonin5-HT2Creceptoragonismvia itsmetabolitenorfenfluramine.[62]

Research

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Social deficits

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Fenfluramine has been reported to improvesocial deficitsin children withautism.[68][69]In addition, it has been found to produceprosocialbehavior similarly to theentactogenMDMAin animals.[70][68]However, fenfluramine has shown limited effectiveness in treating the symptoms of autism generally.[71]Moreover, thecardiovascular toxicityandneurotoxicityof fenfluramine[72][73][74][75]make it unsuitable for clinical use in the treatment of social deficits.[68]

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  42. ^Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, et al. (2000). "Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine".Mol. Pharmacol.57(1):75–81.doi:10.1016/S0026-895X(24)26444-0.PMID10617681.
  43. ^abGumpper RH, Roth BL (January 2024)."Psychedelics: preclinical insights provide directions for future research".Neuropsychopharmacology.49(1):119–127.doi:10.1038/s41386-023-01567-7.PMC10700551.PMID36932180.
  44. ^Zucchi R, Chiellini G, Scanlan TS, Grandy DK (December 2006)."Trace amine-associated receptors and their ligands".Br J Pharmacol.149(8):967–978.doi:10.1038/sj.bjp.0706948.PMC2014643.PMID17088868.[...] 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, [...]
  45. ^Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, et al. (December 2001). "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.doi:10.1124/mol.60.6.1181.PMID11723224.
  46. ^Lewin AH, Miller GM, Gilmour B (December 2011)."Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class".Bioorg Med Chem.19(23):7044–7048.doi:10.1016/j.bmc.2011.10.007.PMC3236098.PMID22037049.
  47. ^Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, et al. (December 2000). "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.doi:10.1161/01.cir.102.23.2836.PMID11104741.
  48. ^Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, et al. (August 1997)."Valvular heart disease associated with fenfluramine-phentermine".The New England Journal of Medicine.337(9):581–588.doi:10.1056/NEJM199708283370901.PMID9271479.
  49. ^"FDA Announces Withdrawal Fenfluramine and Dexfenfluramine (Fen-Phen)".U.S. Food and Drug Administration.15 September 1997. Archived fromthe originalon 19 July 2013.
  50. ^"Drugs banned in India".Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India. Archived fromthe originalon 21 February 2015.Retrieved17 September2013.
  51. ^"FDA Approves FINTEPLA (fenfluramine) for the Treatment of Seizures Associated with Dravet Syndrome"(Press release). Zogenix Inc. 25 June 2020.Retrieved25 June2020– via GlobeNewswire.
  52. ^"Fenfluramine Orphan Drug Designations and Approvals".U.S.Food and Drug Administration(FDA).24 December 1999.Retrieved25 June2020.
  53. ^"Fenfluramine Orphan Drug Designations and Approvals".U.S.Food and Drug Administration(FDA).24 December 1999.Retrieved25 June2020.
  54. ^"Fintepla: Pending EC decision".European Medicines Agency(EMA).16 October 2020. Archived fromthe originalon 21 October 2020.Retrieved16 October2020.Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  55. ^"Schedules of Controlled Substances: Removal of Fenfluramine from Control".Federal Register.DEA.23 December 2022.Retrieved14 July2023.
  56. ^abBrust JC (2004).Neurological Aspects of Substance Abuse.Butterworth-Heinemann. pp. 117–.ISBN978-0-7506-7313-6.
  57. ^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–.
  58. ^abGunne LM (1977)."Effects of Amphetamines in Humans".Drug Addiction II: Amphetamine, Psychotogen, and Marihuana Dependence.Berlin, Germany; Heidelberg, Germany: Springer. pp.247–260.ISBN9783642667091.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-Iike 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.
  59. ^Connell PH (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.ISSN0300-7995.Griffith et a1.6 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".
  60. ^Griffith JD (1977)."Structure-Activity Relationships of Several Amphetamine Drugs in Man".Cocaine and Other Stimulants.Advances in Behavioral Biology. Vol. 21. Boston, MA: Springer US. pp.705–715.doi:10.1007/978-1-4684-3087-5_36.ISBN978-1-4684-3089-9.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.
  61. ^Griffith JD, Nutt JG, Jasinski DR (November 1975). "A comparison of fenfluramine and amphetamine in man".Clin Pharmacol Ther.18(5 Pt 1):563–570.doi:10.1002/cpt1975185part1563.PMID1102234.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.
  62. ^abcCarhart-Harris RL, Nutt DJ (September 2017)."Serotonin and brain function: a tale of two receptors".J Psychopharmacol.31(9):1091–1120.doi:10.1177/0269881117725915.PMC5606297.PMID28858536.
  63. ^abBrauer LH, Johanson CE, Schuster CR, Rothman RB, de Wit H (April 1996). "Evaluation of phentermine and fenfluramine, alone and in combination, in normal, healthy volunteers".Neuropsychopharmacology.14(4):233–241.doi:10.1016/0893-133X(95)00113-R.PMID8924191.
  64. ^Cherek DR, Lane SD (September 2001). "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.doi:10.1007/s002130100812.PMID11605076.
  65. ^Hetem LA, de Souza CJ, Guimarães ES, Zuardi AW, Graeff FG (October 1996). "Effect of d-fenfluramine on human experimental anxiety".Psychopharmacology (Berl).127(3):276–282.doi:10.1007/BF02806003.PMID8912406.
  66. ^Rothman RB, Blough BE, Baumann MH (December 2008)."Dual dopamine/serotonin releasers: potential treatment agents for stimulant addiction".Exp Clin Psychopharmacol.16(6):458–474.doi:10.1037/a0014103.PMC2683464.PMID19086767.
  67. ^Rothman RB, Blough BE, Baumann MH (December 2006). "Dual dopamine-5-HT releasers: potential treatment agents for cocaine addiction".Trends Pharmacol Sci.27(12):612–618.doi:10.1016/j.tips.2006.10.006.PMID17056126.
  68. ^abcHeifets BD, Salgado JS, Taylor MD, Hoerbelt P, Cardozo Pinto DF, Steinberg EE, et al. (December 2019)."Distinct neural mechanisms for the prosocial and rewarding properties of MDMA".Sci Transl Med.11(522).doi:10.1126/scitranslmed.aaw6435.PMC7123941.PMID31826983.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).
  69. ^Aman MG, Kern RA (July 1989). "Review of fenfluramine in the treatment of the developmental disabilities".J Am Acad Child Adolesc Psychiatry.28(4):549–565.doi:10.1097/00004583-198907000-00014.PMID2670881.
  70. ^Behera HK, Joga R, Yerram S, Karnati P, Mergu T, Gandhi K, et al. (September 2024). "Exploring the regulatory framework of psychedelics in the US & Europe".Asian J Psychiatr.102:104242.doi:10.1016/j.ajp.2024.104242.PMID39305768.
  71. ^Markopoulos A, Inserra A, De Gregorio D, Gobbi G (2021)."Evaluating the Potential Use of Serotonergic Psychedelics in Autism Spectrum Disorder".Front Pharmacol.12:749068.doi:10.3389/fphar.2021.749068.PMC8846292.PMID35177979.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.
  72. ^Kostrzewa RM (2022). "Survey of Selective Monoaminergic Neurotoxins Targeting Dopaminergic, Noradrenergic, and Serotoninergic Neurons".Handbook of Neurotoxicity.Cham: Springer International Publishing. pp.159–198.doi:10.1007/978-3-031-15080-7_53.ISBN978-3-031-15079-1.
  73. ^McCann UD, Seiden LS, Rubin LJ, Ricaurte GA (August 1997). "Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine. A systematic review of the evidence".JAMA.278(8):666–672.doi:10.1001/jama.1997.03550080076043.PMID9272900.
  74. ^Rothman RB, Baumann MH (April 2002). "Serotonin releasing agents. Neurochemical, therapeutic and adverse effects".Pharmacol Biochem Behav.71(4):825–836.doi:10.1016/s0091-3057(01)00669-4.PMID11888573.
  75. ^Johnson MP, Nichols DE (May 1990). "Comparative serotonin neurotoxicity of the stereoisomers of fenfluramine and norfenfluramine".Pharmacol Biochem Behav.36(1):105–109.doi:10.1016/0091-3057(90)90133-3.PMID2140899.

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