Chemistry:Phentermine

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Phentermine, sold under the brand name Adipex-P among others, is a medication used together with diet and exercise to treat obesity.[1] It is available by itself or as the combination phentermine/topiramate.[2] Phentermine is taken by mouth.[1]

Common side effects include a fast heart beat, high blood pressure, trouble sleeping, dizziness, and restlessness.[1] Serious side effects may include abuse, but do not include pulmonary hypertension or valvular heart disease, as the latter complications were caused by the fenfluramine component of the "fen-phen" combination.[1] Phentermine is a norepinephrine and dopamine releasing agent (NDRA) and produces stimulant, rewarding, and appetite suppressant effects.[3][4][5] Chemically, it is a substituted amphetamine.[6]

Phentermine was approved for medical use in the United States in 1959.[1] It is available as a generic medication.[1] In 2023, it was the 168th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[7][8] Phentermine was withdrawn from the market in the United Kingdom in 2000, while the combination medication fen-phen, of which it was a part, was withdrawn from the market in 1997 due to side effects of fenfluramine.[9]

Medical uses

Phentermine is used for a short period of time to promote weight loss, if exercise and calorie reduction are not sufficient, and in addition to exercise and calorie reduction.[10][11]

Phentermine is approved for up to 12 weeks of use and most weight loss occurs in the first weeks.[11] However, significant loss continues through the sixth month and has been shown to continue at a slower rate through the ninth month.[12]

Contraindications

Use is not recommended during pregnancy or breastfeeding,[13] or with selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors (MAOIs).[1]

Phentermine is contraindicated for users who:[10][11]

Adverse effects

Tolerance usually occurs; however, risks of dependence and addiction are considered negligible.[12][14] People taking phentermine may be impaired when driving or operating machinery.[11] Consumption of alcohol with phentermine may produce adverse effects.[11]

There is currently no evidence regarding whether or not phentermine is safe for pregnant women.[10][11]

Other adverse effects include:[10][11]

  • Cardiovascular effects like palpitations, tachycardia, high blood pressure, precordial pain; rare cases of stroke, angina, myocardial infarction, cardiac failure and cardiac arrest have been reported.
  • Central nervous system effects like overstimulation, restlessness, nervousness, insomnia, tremor, dizziness and headache; there are rare reports of euphoria followed by fatigue and depression, and very rarely, psychotic episodes and hallucinations.
  • Gastrointestinal effects include nausea, vomiting, dry mouth, cramps, unpleasant taste, diarrhea, and constipation.
  • Other adverse effects include trouble urinating, rash, impotence, changes in libido, and facial swelling.

Interactions

Phentermine may decrease the effect of drugs like clonidine, methyldopa, and guanethidine. Drugs to treat hypothyroidism may increase the effect of phentermine.[11]

Pharmacology

Pharmacodynamics

Monoamine releasing agent

Monoamine release of phentermine and related agents (EC50, nM)
Compound NE DA 5-HT Ref
Phenethylamine 10.9 39.5 >10,000 [15][16][17]
Dextroamphetamine 6.6–7.2 5.8–24.8 698–1,765 [18][19]
Dextromethamphetamine 12.3–13.8 8.5–24.5 736–1,292 [18][20]
Phentermine 28.8–39.4 262 2,575–3,511 [18][17][21]
Chlorphentermine >10,000 (RI) 935–2,650 18.2–30.9 [18][21]
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:[3][4]

Phentermine is a substrate of the monoamine transporters (MATs) and acts as a monoamine releasing agent (MRA), specifically as a norepinephrine–dopamine releasing agent (NDRA).[3][4][5] It also acts as a norepinephrine–dopamine reuptake inhibitor (NDRI) to a lesser extent.[3][5] The drug robustly and dose-dependently elevates brain norepinephrine and dopamine levels in animals.[3] Phentermine is more potent in its effects on norepinephrine than on dopamine and the drug shows only weak effects on serotonin.[3][4][5] Unlike many other amphetamines and MRAs, phentermine is completely inactive at the vesicular monoamine transporter 2 (VMAT2).[15][22] Due to its actions on the catecholamines, phentermine produces effects including stimulation, rewarding effects, appetite suppression, and sympathomimetic effects in animals and humans.[3][23]

In terms of monoamine release in vitro using rat brain synaptosomes, phentermine is about 6-fold less potent than dextroamphetamine in the case of norepinephrine release, 11-fold less potent than dextroamphetamine in the case of dopamine release, and has a ratio of norepinephrine release versus dopamine release of about 6.6:1 compared to dextroamphetamine's ratio of about 3.5:1.[3][4][5] It is more than 3-fold less potent than amphetamine in elevating brain dopamine and serotonin levels in rodents in vivo, is about 10-fold less potent than amphetamine in terms of self-administration in monkeys, and is a relatively weak reinforcer in rodents.[5][24] Although phentermine induces the release of dopamine at sufficiently high concentrations in vitro and at sufficiently high doses in rodents and monkeys in vivo, it may result in only weak or negligible brain dopamine release in humans at typical clinical doses.[4] This may be due to its selectivity for induction of norepinephrine over dopamine release and may be analogous to the case of ephedrine (which is at least 10-fold selective for induction of norepinephrine over dopamine release).[4] The effects of phentermine may be more related to noradrenergic activation rather than dopaminergic activity.[4] However, more research is needed to assess the preceding notions.[4]

As with other MRAs, phentermine produces dopaminergic neurotoxicity in rodents at high doses.[5] It can also produce serotonergic neurotoxicity at very high doses in rodents.[5] The clinical significance of these findings for humans, in which employed doses may be much lower, are unclear.[5]

The combination of phentermine with a serotonin releasing agent (SRA) like fenfluramine results in suppression of brain dopamine release by phentermine and marked attenuation or abolition of phentermine's stimulant and rewarding effects in animals and humans.[3][5][24][25][26][27][28] Conversely, combined phentermine and fenfluramine administration synergistically enhances the appetite suppression of these drugs in animals and results in greater weight loss than either drug alone in humans.[5] Fenfluramine produces serotonergic neurotoxicity in animals and addition of phentermine results in either no change or augmentation of this neurotoxicity.[5]

Other actions

Phentermine has been found to be completely inactive as a ligand or agonist of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors.[4][5][24] This is in contrast to the serotonin releasing agents (SRAs) fenfluramine, norfenfluramine, and to a lesser extent chlorphentermine.[4][24] However, another study found that phentermine was a weak human serotonin 5-HT2C receptor partial agonist (EC50 = 1,394 nM, Vmax = 66%).[24] In accordance with its lack of serotonin release and serotonin 5-HT2B receptor agonism, phentermine appears to show no risk of primary pulmonary hypertension (PPH) or valvular heart disease (VHD) in humans.[29][5][24]

Phentermine has been found to be active as an agonist of the rat and human trace amine-associated receptor 1 (TAAR1).[30][31][32][33] It appears to be a weak human TAAR1 partial agonist (EC50 = 5,470 nM and Emax = 68% in one study).[31] The drug shows reduced activity as a TAAR1 agonist compared to amphetamine.[31][33] TAAR1 agonism by amphetamines that possess this action may serve to auto-inhibit and constrain their effects.[34][35][36][37]

Phentermine is a very weak monoamine oxidase inhibitor (MAOI) in vitro.[38][5][39] It specifically inhibits monoamine oxidase A (MAO-A) (IC50 = 85,000–143,000 nM) and monoamine oxidase B (MAO-B) (IC50 = 285,000 nM).[38][5][39] However, its potency as a MAOI is far below its potency as a monoamine releasing agent.[5] Relatedly, phentermine does not show neurochemical signs of MAOI activity in rodents in vivo.[5] As such, the significance of phentermine as an MAOI in humans is questionable.[5]

Pharmacokinetics

Absorption

The pharmacokinetics of phentermine are dose-dependent.[23] Peak concentrations of phentermine are reached 6 hours following oral administration of a dose of 15 mg.[23] The steady-state levels of phentermine with continuous administration have been found to be around 200 ng/mL in clinical studies.[23] The oral bioavailability of phentermine is not affected by intake of a high-fat meal.[23]

Phentermine is a lipophilic amine that is rapidly absorbed through the gastrointestinal tract following oral ingestion[40]. Its weakly basic nature facilitates absorption in the small intestine, where it exists primarily in a non-ionized form at physiological pH. Peak plasma concentrations can vary slightly based on formulation (immediate vs. extended-release) and gastric motility.[41] The drug’s predictable absorption profile supports once-daily dosing in most therapeutic regimens.

Distribution

The volume of distribution of phentermine is 5 L/kg.[23] Its plasma protein binding is approximately 17.5%.[23] This percentage of 17.5 suggests that a substantial portion of the drug remains unbound and pharmacologically active. Because of its lipophilicity and amphetamine-like structure[42], phentermine readily crosses the blood–brain barrier, contributing to its central nervous system stimulant effects, such as increased alertness and appetite suppression. Distribution into fatty tissues may contribute to a moderate duration of action despite limited metabolism.

Metabolism

Phentermine undergoes minimal metabolism.[23] Only about 6% of an administered dose of phentermine is metabolized.[23] It is metabolized to a minor extent by para-hydroxylation, N-oxidation, and N-hydroxylation, followed by conjugation.[23]

Because phentermine’s metabolism is relatively minor, most of its pharmacologic activity is attributable to the parent compound rather than metabolites. The drug is not known to significantly induce or inhibit CYP450 enzymes,[43] suggesting a low potential for clinically meaningful drug–drug interactions. Variations in metabolic rate due to hepatic function generally have less effect on overall clearance compared to renal factors.

Elimination

The drug is eliminated mainly in urine.[23] It is excreted 62 to 85% unchanged in urine.[23] The elimination half-life of phentermine is 20 to 25 hours.[23][10] The elimination of phentermine is modified by urine acidicity or pH.[23][10] In the case of acidic urine (pH < 5), the elimination half-life of phentermine has been found to be 7 to 8 hours.[23] The clearance of phentermine is 8.79 L/h.[23]

History

frame

In 1959, phentermine first received approval from the US Food and Drug Administration (FDA) as an appetite suppressant.[44] Eventually a hydrochloride salt and a resin form became available.[44]

Phentermine was marketed with fenfluramine or dexfenfluramine as a combination appetite suppressant and fat burning agent under the popular name fen-phen.[45] In 1997, after 24 cases of heart valve disease in fen-phen users, fenfluramine and dexfenfluramine were voluntarily taken off the market at the request of the FDA.[46] Studies later showed nearly 30% of people taking fenfluramine or dexfenfluramine for up to 24 months had abnormal valve findings.[47]

Phentermine is still available by itself in most countries, including the US.[44] However, because it is similar to amphetamine, it is classified as a controlled substance in many countries. Internationally, phentermine is a schedule IV drug under the Convention on Psychotropic Substances.[48] In the United States, it is classified as a Schedule IV controlled substance under the Controlled Substances Act. In contrast, amphetamine preparations are classified as Schedule II controlled substances.[49]

A company called Vivus developed a combination drug, phentermine/topiramate that it originally called Qnexa and then called Qsymia, which was invented and used off-label by Thomas Najarian, who opened a weight-clinic in Los Osos, California in 2001; Najarian had previously worked at Interneuron Pharmaceuticals, which had developed one of the fen-phen drugs previously withdrawn from the market.[50] The FDA rejected the combination drug in 2010 due to concerns over its safety.[50] In 2012 the FDA approved it after Vivus re-applied with further safety data.[51] At the time, one obesity specialist estimated that around 70% of his colleagues were already prescribing the combination off-label.[50]

Chemistry

Phentermine, also known as α,α-dimethylphenethylamine or as α-methylamphetamine, is a substituted phenethylamine and amphetamine.[52][53][54] It is the derivative of amphetamine in which a second methyl group is present at the alpha carbon.[6][52][53][54] The drug is a positional isomer of methamphetamine (N-methylamphetamine) and of other methylamphetamines such as 4-methylamphetamine.[52][53][54]

Derivatives

A number of derivatives of phentermine exist, including cericlamine, chlorphentermine, cloforex, clortermine, etolorex, mephentermine, 3,4-methylenedioxyphentermine (MDPH), 3,4-methylenedioxy-N-methylphentermine (MDMP or MDMPH), and pentorex, among others.[53][54] Some of these drugs, including chlorphentermine, cloforex, clortermine, and mephentermine, have been marketed as pharmaceutical drugs similarly to phentermine, for instance as appetite suppressants.[53][54]

Society and culture

Etymology

The term phentermine is contracted from phenyl-tertiary-butyl amine.

Brand names

Phentermine is marketed under many brand names and formulations worldwide, including Acxion, Adipex, Adipex-P, Duromine, Elvenir, Fastin, Ionamin, Lomaira (phentermine hydrochloride), Panbesy, Qsymia (phentermine and topiramate), Razin, Redusa, Sentis, Suprenza, and Terfamex.[55]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Phentermine Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/phentermine.html. 
  2. ↑ "Phentermine and topiramate Uses, Side Effects & Warnings". https://www.drugs.com/mtm/phentermine-and-topiramate.html. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 "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. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 "Therapeutic potential of monoamine transporter substrates". Curr Top Med Chem 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. 
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 5.15 5.16 5.17 5.18 "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. 
  6. ↑ 6.0 6.1 "Biosynthesis of amphetamine analogs in plants". Trends in Plant Science 17 (7): 404–412. July 2012. doi:10.1016/j.tplants.2012.03.004. PMID 22502775. Bibcode: 2012TPS....17..404H. 
  7. ↑ "Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  8. ↑ "Phentermine Drug Usage Statistics, United States, 2013 - 2023". https://clincalc.com/DrugStats/Drugs/Phentermine. 
  9. ↑ Obesity: Epidemiology, Pathophysiology, and Prevention (Second ed.). CRC Press. 2012. p. 314. ISBN 9781439854259. https://books.google.com/books?id=pvE3I22KhNoC&pg=PA314. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 "METERMINE (Phentermine)" (PDF). TGA eBusiness Services. iNova Pharmaceuticals (Australia) Pty Limited. 22 July 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06558-3. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 11.7 "Phentermine label at FDA" (Last updated: January 2012). FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/085128s065lbl.pdf. 
  12. ↑ 12.0 12.1 "Long-term pharmacotherapy of obesity 2000: a review of efficacy and safety". Archives of Internal Medicine 161 (15): 1814–1824. August 2001. doi:10.1001/archinte.161.15.1814. PMID 11493122. 
  13. ↑ "Phentermine Use During Pregnancy". https://www.drugs.com/pregnancy/phentermine.html. 
  14. ↑ "Weight management in obesity - past and present". International Journal of Clinical Practice 70 (3): 206–217. March 2016. doi:10.1111/ijcp.12771. PMID 26811245. 
  15. ↑ 15.0 15.1 "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug Alcohol Depend 147: 1–19. February 2015. doi:10.1016/j.drugalcdep.2014.12.005. PMID 25548026. 
  16. ↑ Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines. 22 May 2012. https://scholarworks.uno.edu/td/1436/. Retrieved 4 November 2024. 
  17. ↑ 17.0 17.1 "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. 
  18. ↑ 18.0 18.1 18.2 18.3 "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. 
  19. ↑ "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. 
  20. ↑ "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology 37 (5): 1192–1203. 2012. doi:10.1038/npp.2011.304. PMID 22169943. 
  21. ↑ 21.0 21.1 "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). [...]" 
  22. ↑ "Interaction of amphetamines and related compounds at the vesicular monoamine transporter". J Pharmacol Exp Ther 319 (1): 237–246. October 2006. doi:10.1124/jpet.106.103622. PMID 16835371. 
  23. ↑ 23.00 23.01 23.02 23.03 23.04 23.05 23.06 23.07 23.08 23.09 23.10 23.11 23.12 23.13 23.14 23.15 "Phentermine: Uses, Interactions, Mechanism of Action". 4 May 1959. https://go.drugbank.com/drugs/DB00191. 
  24. ↑ 24.0 24.1 24.2 24.3 24.4 24.5 "Dopamine/serotonin releasers as medications for stimulant addictions". Progress in Brain Research. 172. 2008. pp. 385–406. doi:10.1016/S0079-6123(08)00919-9. ISBN 978-0-444-53235-0. 
  25. ↑ "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. 
  26. ↑ "Balance between dopamine and serotonin release modulates behavioral effects of amphetamine-type drugs". Ann N Y Acad Sci 1074 (1): 245–260. August 2006. doi:10.1196/annals.1369.064. PMID 17105921. Bibcode: 2006NYASA1074..245R. 
  27. ↑ "Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions". AAPS J 9 (1): E1–10. January 2007. doi:10.1208/aapsj0901001. PMID 17408232. 
  28. ↑ "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. 
  29. ↑ "Therapeutic and adverse actions of serotonin transporter substrates". Pharmacol Ther 95 (1): 73–88. July 2002. doi:10.1016/s0163-7258(02)00234-6. PMID 12163129. https://www.researchgate.net/publication/11223882. 
  30. ↑ "Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor". Molecular Pharmacology 74 (3): 585–594. September 2008. doi:10.1124/mol.108.048884. PMID 18524885. "we confirmed agonistic activity at human TAAR1 of several other compounds, including the trace amines octopamine and tryptamine, the amphetamine derivatives l-amphetamine, d-methamphetamine, (+)-MDMA, and phentermine, and the catecholamine metabolites 3-MT and 4-MT (Bunzow et al., 2001; Lindemann and Hoener, 2005; Reese et al., 2007; Wainscott et al., 2007; Wolinsky et al., 2007; Xie and Miller, 2007; Xie et al., 2007).". 
  31. ↑ 31.0 31.1 31.2 "Structure-activity correlations for beta-phenethylamines at human trace amine receptor 1". Bioorg Med Chem 16 (15): 7415–7423. August 2008. doi:10.1016/j.bmc.2008.06.009. PMID 18602830. 
  32. ↑ "cAMP Biosensors Based on Genetically Encoded Fluorescent/Luminescent Proteins". Biosensors 11 (2): 39. January 2021. doi:10.3390/bios11020039. PMID 33572585. 
  33. ↑ 33.0 33.1 "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. 
  34. ↑ "Neuronal Functions and Emerging Pharmacology of TAAR1". Taste and Smell. Topics in Medicinal Chemistry. 23. Cham: Springer International Publishing. 2014. pp. 175–194. doi:10.1007/7355_2014_78. ISBN 978-3-319-48925-4. "Interestingly, the concentrations of amphetamine found to be necessary to activate TAAR1 are in line with what was found in drug abusers [3, 51, 52]. Thus, it is likely that some of the effects produced by amphetamines could be mediated by TAAR1. Indeed, in a study in mice, MDMA effects were found to be mediated in part by TAAR1, in a sense that MDMA auto-inhibits its neurochemical and functional actions [46]. Based on this and other studies (see other section), it has been suggested that TAAR1 could play a role in reward mechanisms and that amphetamine activity on TAAR1 counteracts their known behavioral and neurochemical effects mediated via dopamine neurotransmission." 
  35. ↑ "A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse". Hum Psychopharmacol 38 (3). May 2023. doi:10.1002/hup.2866. PMID 36866677. "Another feature that distinguishes [synthetic cathinones (SCs)] from amphetamines is their negligible interaction with the trace amine associated receptor 1 (TAAR1). Activation of this receptor reduces the activity of dopaminergic neurones, thereby reducing psychostimulatory effects and addictive potential (Miller, 2011; Simmler et al., 2016). Amphetamines are potent agonists of this receptor, making them likely to self‐inhibit their stimulating effects. In contrast, SCs show negligible activity towards TAAR1 (Kolaczynska et al., 2021; Rickli et al., 2015; Simmler et al., 2014, 2016). [...] It is worth noting, however, that for TAAR1 there is considerable species variability in its interaction with ligands, and it is possible that the in vitro activity of [rodent TAAR1 agonists] may not translate into activity in the human body (Simmler et al., 2016). The lack of self‐regulation by TAAR1 may partly explain the higher addictive potential of SCs compared to amphetamines (Miller, 2011; Simmler et al., 2013).". 
  36. ↑ "Pharmacological characterization of designer cathinones in vitro". Br J Pharmacol 168 (2): 458–470. January 2013. doi:10.1111/j.1476-5381.2012.02145.x. PMID 22897747. "β-Keto-analogue cathinones also exhibited approximately 10-fold lower affinity for the TA1 receptor compared with their respective non-β-keto amphetamines. [...] Activation of TA1 receptors negatively modulates dopaminergic neurotransmission. Importantly, methamphetamine decreased DAT surface expression via a TA1 receptor-mediated mechanism and thereby reduced the presence of its own pharmacological target (Xie and Miller, 2009). MDMA and amphetamine have been shown to produce enhanced DA and 5-HT release and locomotor activity in TA1 receptor knockout mice compared with wild-type mice (Lindemann et al., 2008; Di Cara et al., 2011). Because methamphetamine and MDMA auto-inhibit their neurochemical and functional effects via TA1 receptors, low affinity for these receptors may result in stronger effects on monoamine systems by cathinones compared with the classic amphetamines.". 
  37. ↑ "Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA)". J Neurosci 31 (47): 16928–16940. November 2011. doi:10.1523/JNEUROSCI.2502-11.2011. PMID 22114263. 
  38. ↑ 38.0 38.1 "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Front Pharmacol 10. 2019. doi:10.3389/fphar.2019.01590. PMID 32038257. 
  39. ↑ 39.0 39.1 "Characterization of phentermine and related compounds as monoamine oxidase (MAO) inhibitors". Biochem Pharmacol 59 (12): 1611–1621. June 2000. doi:10.1016/s0006-2952(00)00306-3. PMID 10799660. 
  40. ↑ "Phentermine" (in en). https://go.drugbank.com/drugs/DB00191. 
  41. ↑ "Phentermine" (in en). https://go.drugbank.com/drugs/DB00191. 
  42. ↑ "Phentermine" (in en). https://go.drugbank.com/drugs/DB00191. 
  43. ↑ "Topiramate and Phentermine". StatPearls. Treasure Island (FL): StatPearls Publishing. 2025. http://www.ncbi.nlm.nih.gov/books/NBK482165/. Retrieved 2025-10-11. 
  44. ↑ 44.0 44.1 44.2 "Sibutramine, Phentermine, and Diethylproprion: Sympathomimetic Drugs in the Management of Obesity". Handbook of Obesity - Volume 2 Clinical Applications (Fourth ed.). Hoboken: Taylor and Francis. 2014. p. 234. ISBN 9781841849829. https://books.google.com/books?id=64XOBQAAQBAJ&pg=PA234. 
  45. ↑ "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. 
  46. ↑ "FDA Announces Withdrawal Fenfluramine and Dexfenfluramine (Fen-Phen)". Fda.gov. https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm179871.htm. 
  47. ↑ "Pharmacological therapy of obesity: past, present, and future". The Journal of Clinical Endocrinology and Metabolism 88 (6): 2462–2469. June 2003. doi:10.1210/jc.2003-030151. PMID 12788841. 
  48. ↑ Convention on Psychotropic Substances
  49. ↑ "New pharmacological approaches for obesity management". Nature Reviews. Endocrinology 9 (8): 467–478. August 2013. doi:10.1038/nrendo.2013.113. PMID 23752772. https://zenodo.org/record/997601. 
  50. ↑ 50.0 50.1 50.2 "Diet Treatment, Already in Use, to Get F.D.A. Review". The New York Times. 16 February 2012. https://www.nytimes.com/2012/02/17/business/diet-treatment-already-in-use-to-get-fda-review.html. 
  51. ↑ "FDA approves weight-management drug Qsymia". FDA. 17 July 2012. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312468.htm. 
  52. ↑ 52.0 52.1 52.2 "Phentermine". https://pubchem.ncbi.nlm.nih.gov/compound/4771. 
  53. ↑ 53.0 53.1 53.2 53.3 53.4 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. 2014. p. 968. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA968. Retrieved 9 January 2025. 
  54. ↑ 54.0 54.1 54.2 54.3 54.4 Schweizerischer Apotheker-Verein (2000). Index Nominum 2000: International Drug Directory. Medpharm Scientific Publishers. p. 824. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA824. Retrieved 9 January 2025. 
  55. ↑ "International brands for phentermine". Drugs.com. https://www.drugs.com/international/phentermine.html. 

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