Bupropion: Difference between revisions

{{Short description|Medication mainly used for depression and smoking cessation}}

{{Distinguish|Buprenorphine|Buspirone}}

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{{Use dmy dates|date=August 2024}}

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{{Featured article}}

| verifiedrevid = 852547309

| width = 250

| image2 = Bupropion molecule ball.png

| width2 = 250

| pronounce ={{IPAc-en|b|j|uː|ˈ|p|r|oʊ|p|i|ɒ|n}}<br />{{respell|bew|PROH|pee|on}} <br />{{respell|am|fa|BEW|teh|moan}}

| Drugs.com = {{drugs.com|monograph|bupropion}}

| DailyMedID = Bupropion

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web |title=Bupropion Use During Pregnancy |url=https://www.drugs.com/pregnancy/bupropion.html |website=Drugs.com |access-date=24 December 2018 |archive-date=24 December 2018 |archive-url=https://web.archive.org/web/20181224074103/https://www.drugs.com/pregnancy/bupropion.html |url-status=live }}</ref>

| pregnancy_category =

| routes_of_administration = [[Oral administration|Oral]] (swallowed by mouth)<ref name="pmid31124380" /><ref name="pmid16027765" />

| class = [[Norepinephrine–dopamine reuptake inhibitor|NDRI]] [[antidepressant]]s

| ATC_prefix = N06

| ATC_suffix = AX12

<!-- Legal status -->

| legal_AU_comment = <ref>{{cite web | url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2013-PI-01138-1 | title=TGA eBS – Product and Consumer Medicine Information Licence | access-date=9 January 2023 | archive-date=7 December 2016 | archive-url=https://web.archive.org/web/20161207175501/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2013-PI-01138-1 | url-status=live }}</ref>

| legal_BR = C1

| legal_BR_comment = <ref>{{cite web |author=Brazilian Health Regulatory Agency (Anvisa) |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 – Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 – Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=3 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>

| legal_CA_comment = <ref>{{cite web | title=Wellbutrin Product information | website=[[Health Canada]] | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=61183 | access-date=9 January 2023 | archive-date=9 January 2023 | archive-url=https://web.archive.org/web/20230109064924/https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=61183 | url-status=live }}</ref><ref name="Zyban CA PI">{{cite web | title=Zyban Product information | website=[[Health Canada]] | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=61860 | access-date=9 January 2023 | archive-date=9 January 2023 | archive-url=https://web.archive.org/web/20230109064925/https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=61860 | url-status=live }}</ref>

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK_comment = <ref name="Zyban SmPC">{{cite web | title=Zyban 150 mg prolonged release tablets – Summary of Product Characteristics (SmPC) | website=(emc) | date=21 April 2022 | url=https://www.medicines.org.uk/emc/product/3827/smpc | access-date=9 January 2023 | archive-date=9 January 2023 | archive-url=https://web.archive.org/web/20230109065252/https://www.medicines.org.uk/emc/product/3827/smpc | url-status=live }}</ref>

| legal_US_comment = <ref name="Wellbutrin SR FDA label" /><ref name="Wellbutrin XL FDA label">{{cite web | title=Wellbutrin XL- bupropion hydrochloride tablet, extended release | website=DailyMed | date=4 March 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a435da9d-f6e8-4ddc-897d-8cd2bf777b21 | access-date=9 January 2023 | archive-date=9 January 2023 | archive-url=https://web.archive.org/web/20230109064927/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a435da9d-f6e8-4ddc-897d-8cd2bf777b21 | url-status=live }}</ref><ref name="Aplenzin FDA label" />

| legal_EU = Rx-only

| legal_EU_comment = <ref>{{cite web | title=Bupropion hydrochloride EPAR | website=European Medicines Agency | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/referrals/bupropion-hydrochloride | access-date=7 March 2023 | archive-date=18 August 2022 | archive-url=https://web.archive.org/web/20220818213955/https://www.ema.europa.eu/en/medicines/human/referrals/bupropion-hydrochloride | url-status=live }}</ref>

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = Rx-only

| bioavailability = Unknown<ref name="pmid31124380" />

| protein_bound = Bupropion: 84%<ref name="EMCsustained">{{cite web |title=Zyban 150 mg prolonged release film-coated tablets – Summary of Product Characteristics (SPC) |work=electronic Medicines Compendium |publisher=GlaxoSmithKline UK |date=1 August 2013 |access-date=22 October 2013 |url=http://www.medicines.org.uk/emc/medicine/2948/SPC/Zyban+150+mg+prolonged+release+film-coated+tablets/ |archive-date=20 July 2017 |archive-url=https://web.archive.org/web/20170720170035/http://www.medicines.org.uk/emc/medicine/2948/SPC/Zyban+150+mg+prolonged+release+film-coated+tablets |url-status=live }}</ref><br />Hydroxybupropion: 77%<ref name="EMCsustained" /><br />Threohydrobupropion: 42%<ref name="EMCsustained" />

| metabolism = [[Liver]], [[intestine]]s ([[CYP2B6]], others)<ref name="pmid31124380" />

| metabolites = •{{nbsp}}[[Hydroxybupropion]]<br />•{{nbsp}}[[Threohydrobupropion]]<br />•{{nbsp}}[[Erythrohydrobupropion]]<br />•{{nbsp}}Others

| onset =

| elimination_half-life = Bupropion:{{nbsp}}11–21{{nbsp}}h<ref name="pmid27255113" /><ref name="pmid31124380" /><br />Hydroxybupropion:{{nbsp}}20{{nbsp}}h<ref name="pmid31124380" /><br />Threohydrobupropion:{{nbsp}}37{{nbsp}}h<ref name="pmid31124380" /><br />Erythrohydrobupropion:{{nbsp}}33{{nbsp}}h<ref name="pmid31124380" />

| duration_of_action =

| excretion = [[Urine]]:{{nbsp}}87%{{nbsp}}(0.5%{{nbsp}}unchanged)<ref name="pmid31124380" /><br />[[Feces]]: 10%<ref name="pmid31124380" />

| index2_label = as HCl

| CAS_supplemental = <br />31677-93-7 ([[hydrochloride|HCl]])<br />905818-69-1 [[hydrobromide|HBr]])

| IUPHAR_ligand = 7135

| KEGG2_Ref = {{keggcite|correct|kegg}}

| KEGG2 = D00817

| NIAID_ChemDB =

| PDB_ligand =

| synonyms = Amfebutamone; 3-Chloro-''N''-''tert''-butyl-β-keto-α-methylphenethylamine;<br />3-Chloro-''N''-''tert''-butyl-β-ketoamphetamine;<br />3-Chloro-''N''-''tert''-butylcathinone

| IUPAC_name = (''RS'')-2-(''tert''-Butylamino)-1-(3-chlorophenyl)propan-1-one

| SMILES = O=C(C(C)NC(C)(C)C)C1=CC=CC(Cl)=C1

<!-- Definition and symptoms -->

'''Bupropion''', formerly called '''amfebutamone''',<ref name=Names /> and sold under the brand name '''Wellbutrin''' among others, is an [[atypical antidepressant]] primarily used to treat [[major depressive disorder]], [[seasonal affective disorder]] and to support [[smoking cessation]].<ref name=MD37th>{{cite book | vauthors = Sweetman S |title=Martindale: The Complete Drug Reference |date=2011 |isbn=978-0-85369-982-8 |page=402 |publisher=Pharmaceutical Press |edition=37th}}</ref><ref name="pmid27141292" /> It is also popular as an [[adjunct therapy|add-on]] medication in the cases of "incomplete response" to the first-line [[selective serotonin reuptake inhibitor]] (SSRI) antidepressant.<ref name="pmid27141292" /><ref name="pmid27591914" /> Bupropion has several features that distinguish it from other antidepressants: it does not usually cause sexual dysfunction,<ref name="pmid27141292" /> it is not associated with weight gain<ref name="pmid27141292" /> and [[somnolence|sleepiness]],<ref name="Dhillon" /> and it is more effective than SSRIs at improving symptoms of [[hypersomnia]] and fatigue.<ref name="pmid16848671" /> Bupropion, particularly the immediate release formulation, carries a higher risk of seizure than many other antidepressants, hence caution is recommended in patients with a history of seizure disorder.<ref>{{cite journal | vauthors = Steinert T, Fröscher W | title = Epileptic Seizures Under Antidepressive Drug Treatment: Systematic Review | journal = Pharmacopsychiatry | volume = 51 | issue = 4 | pages = 121–135 | date = July 2018 | pmid = 28850959 | doi = 10.1055/s-0043-117962 | s2cid = 22436728 }}</ref> The medication is taken [[oral administration|by mouth]].<ref name="pmid31124380" /><ref name="pmid16027765" />

Common [[adverse effect]]s of bupropion with the greatest difference from [[placebo]] are [[dry mouth]], [[nausea]], [[constipation]], [[insomnia]], [[anxiety]], [[tremor]], and [[excessive sweating]].<ref name="Wellbutrin SR FDA label" /><ref name="Wellbutrin XL FDA label" /> Raised [[blood pressure]] is notable.<ref name="pmid15705013" /> Rare but serious side effects include [[seizure]]s,<ref name="Wellbutrin SR FDA label" /><ref name="Wellbutrin XL FDA label" /> [[Hepatotoxicity|liver toxicity]],<ref name="pmid24362450" /> [[psychosis]],<ref name="Buproprion-induced psychosis" /> and risk of [[overdose]].<ref name="pmid28135844" /> Bupropion use during [[pregnancy]] may be associated with increased likelihood of [[congenital heart defect]]s.<ref name="pmid33354752" />

Bupropion acts as a [[norepinephrine–dopamine reuptake inhibitor]] (NDRI) and a [[nicotinic receptor antagonist]].<ref name="pmid31124380" /> However, its effects on [[dopamine]] are weak and clinical significance is contentious.<ref name="pmid33977870" /><ref name="pmid24484978" /><ref name="pmid28965364" /><ref name="DeBattista2022" /><ref name="pmid35068363" /> Chemically, bupropion is an [[Aminoaldehydes and aminoketones|aminoketone]] that belongs to the [[chemical classification|class]] of [[substituted cathinone]]s and more generally that of [[substituted amphetamine]]s and [[substituted phenethylamine]]s.<ref name=PubChem2018>{{cite web | title=Bupropion | url=https://pubchem.ncbi.nlm.nih.gov/compound/444 | work=PubChem | publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | access-date=29 July 2018 | date=28 July 2018 | archive-date=29 July 2018 | archive-url=https://web.archive.org/web/20180729081639/https://pubchem.ncbi.nlm.nih.gov/compound/444 | url-status=live }}</ref><ref name=Dye2017>{{cite book |vauthors=Dye LR, Murphy C, Calello DP, Levine MD, Skolnik A |title=Case Studies in Medical Toxicology: From the American College of Medical Toxicology |date=2017 |publisher=Springer |isbn=978-3-319-56449-4 |page=85 |url=https://books.google.com/books?id=cEFEDwAAQBAJ&pg=PA85 |access-date=5 June 2020 |archive-date=29 August 2021 |archive-url=https://web.archive.org/web/20210829111839/https://books.google.com/books?id=cEFEDwAAQBAJ&pg=PA85 |url-status=live }}</ref>

Bupropion was invented by [[Nariman Mehta]], who worked at [[Burroughs Wellcome]], in 1969.<ref name=USPatent>{{cite web |url=http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=3819706.PN.&OS=PN/3819706&RS=PN/3819706 |title=United States Patent 3,819,706: Meta-chloro substituted α-butylamino-propiophenones |vauthors=Mehta NB |date=25 June 1974 |publisher=USPTO |access-date=2 June 2008 |archive-date=7 November 2017 |archive-url=https://web.archive.org/web/20171107011305/http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=3819706.PN.&OS=PN%2F3819706&RS=PN%2F3819706 |url-status=live }}</ref> It was first approved for medical use in the United States in 1985.<ref name="approvals" /> Bupropion was originally called by the generic name amfebutamone, before being renamed in 2000.<ref name=Names>{{cite journal | vauthors = ((World Health Organization)) | title = International nonproprietary names for pharmaceutical substances (INN) : proposed international nonproprietary names : list 83 | journal = WHO Drug Information | volume = 14 | issue = 2 | year = 2000 | author-link = World Health Organization | hdl = 10665/58135 | hdl-access = free }}</ref> In 2022, it was the 21st most commonly prescribed medication in the United States, with more than 25{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Bupropion Drug Usage Statistics, United States, 2013–2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Bupropion | access-date = 30 August 2024 }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref>

{{TOC limit}}

== Medical uses ==

[[File:Wellbutrin.jpg|thumb|250px|A bottle of brand-name Wellbutrin XL 300 mg]]

=== Depression ===

The evidence overall supports the [[effectiveness]] of bupropion over [[placebo]] for the treatment of depression.<ref name="pmid19185342">{{cite journal | vauthors = Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C | title = Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis | journal = Lancet | volume = 373 | issue = 9665 | pages = 746–758 | date = February 2009 | pmid = 19185342 | doi = 10.1016/S0140-6736(09)60046-5 | s2cid = 35858125 }}</ref><ref name="pmid27141292">{{cite journal | vauthors = Patel K, Allen S, Haque MN, Angelescu I, Baumeister D, Tracy DK | title = Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant | journal = Therapeutic Advances in Psychopharmacology | volume = 6 | issue = 2 | pages = 99–144 | date = April 2016 | pmid = 27141292 | pmc = 4837968 | doi = 10.1177/2045125316629071 }}</ref><ref name="pmid29677603">{{cite journal | vauthors = Monden R, Roest AM, van Ravenzwaaij D, Wagenmakers EJ, Morey R, Wardenaar KJ, de Jonge P | title = The comparative evidence basis for the efficacy of second-generation antidepressants in the treatment of depression in the US: A Bayesian meta-analysis of Food and Drug Administration reviews | journal = Journal of Affective Disorders | volume = 235 | issue = | pages = 393–398 | date = August 2018 | pmid = 29677603 | doi = 10.1016/j.jad.2018.04.040 | hdl-access = free | s2cid = 5011570 | hdl = 11370/842b1441-d0f3-4797-b95b-3a6a72262150 | url = https://orca.cardiff.ac.uk/110777/1/Morey.%20The%20comparative.pdf | access-date = 13 December 2021 | archive-date = 27 February 2022 | archive-url = https://web.archive.org/web/20220227080923/https://orca.cardiff.ac.uk/110777/1/Morey.%20The%20comparative.pdf | url-status = live }}</ref> Some peer-reviewed studies suggest the [[quality of evidence]] is low.<ref name="pmid29677603" /><ref name="pmid27141292" /> Some [[meta-analysis|meta-analyses]] report that bupropion has an at-most small [[effect size]] for depression.<ref name="pmid29477251">{{cite journal | vauthors = Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JP, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JP, Geddes JR | title = Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis | journal = Lancet | volume = 391 | issue = 10128 | pages = 1357–1366 | date = April 2018 | pmid = 29477251 | pmc = 5889788 | doi = 10.1016/S0140-6736(17)32802-7 | url = }}</ref><ref name="pmid32101579">{{cite journal | vauthors = Hengartner MP, Jakobsen JC, Sørensen A, Plöderl M | title = Efficacy of new-generation antidepressants assessed with the Montgomery-Asberg Depression Rating Scale, the gold standard clinician rating scale: A meta-analysis of randomised placebo-controlled trials | journal = PLOS ONE | volume = 15 | issue = 2 | pages = e0229381 | date = 2020 | pmid = 32101579 | pmc = 7043778 | doi = 10.1371/journal.pone.0229381 | bibcode = 2020PLoSO..1529381H | url = | doi-access = free }}</ref><ref name="pmid29677603" /><ref name="pmid35918097">{{cite journal | vauthors = Stone MB, Yaseen ZS, Miller BJ, Richardville K, Kalaria SN, Kirsch I | title = Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis | journal = BMJ | volume = 378 | issue = | pages = e067606 | date = August 2022 | pmid = 35918097 | pmc = 9344377 | doi = 10.1136/bmj-2021-067606 | url = }}</ref> One meta-analysis reported a large effect size.<ref name="pmid27141292" /> However, there were methodological limitations with this meta-analysis, including using a subset of only five trials for the effect size calculation, substantial [[heterogeneity|variability]] in effect sizes between the selected trials—which led the authors to state that their findings in this area should be interpreted with "extreme caution"—and general lack of inclusion of [[publication bias|unpublished]] trials in the meta-analysis.<ref name="pmid27141292" /> Unpublished trials are more likely to be negative in findings,<ref name="pmid35045113">{{cite journal | vauthors = Turner EH, Cipriani A, Furukawa TA, Salanti G, de Vries YA | title = Selective publication of antidepressant trials and its influence on apparent efficacy: Updated comparisons and meta-analyses of newer versus older trials | journal = PLOS Med | volume = 19 | issue = 1 | pages = e1003886 | date = January 2022 | pmid = 35045113 | pmc = 8769343 | doi = 10.1371/journal.pmed.1003886 | doi-access = free }}</ref><ref name="pmid18199864">{{cite journal | vauthors = Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R | title = Selective publication of antidepressant trials and its influence on apparent efficacy | journal = N Engl J Med | volume = 358 | issue = 3 | pages = 252–60 | date = January 2008 | pmid = 18199864 | doi = 10.1056/NEJMsa065779 | url = | doi-access = free }}</ref> and other meta-analyses have included unpublished trials.<ref name="pmid29477251" /><ref name="pmid32101579" /><ref name="pmid29677603" /><ref name="pmid35918097" /> Evidence suggests that the effectiveness of bupropion for depression is similar to that of other antidepressants.<ref name="pmid29477251" /><ref name="pmid32101579" /><ref name="pmid27141292" />

Over the autumn and winter months, bupropion prevents development of depression in those who have recurring [[seasonal affective disorder]]: 15% of participants on bupropion experienced a major depressive episode vs. 27% of those on placebo.<ref name="pmid30883669">{{cite journal | vauthors = Gartlehner G, Nussbaumer-Streit B, Gaynes BN, Forneris CA, Morgan LC, Greenblatt A, Wipplinger J, Lux LJ, Van Noord MG, Winkler D | title = Second-generation antidepressants for preventing seasonal affective disorder in adults | journal = The Cochrane Database of Systematic Reviews | volume = 3 | issue = 4| pages = CD011268 | date = March 2019 | pmid = 30883669 | pmc = 6422318 | doi = 10.1002/14651858.CD011268.pub3 }}</ref> Bupropion also improves depression in [[bipolar disorder]], with the efficacy and risk of affective switch being similar to other antidepressants.<ref name="pmid27043678">{{cite journal | vauthors = Li DJ, Tseng PT, Chen YW, Wu CK, Lin PY | title = Significant Treatment Effect of Bupropion in Patients With Bipolar Disorder but Similar Phase-Shifting Rate as Other Antidepressants: A Meta-Analysis Following the PRISMA Guidelines | journal = Medicine | volume = 95 | issue = 13 | pages = e3165 | date = March 2016 | pmid = 27043678 | pmc = 4998539 | doi = 10.1097/MD.0000000000003165 }}</ref>

Bupropion has several features that distinguish it from other antidepressants: for instance, unlike the majority of antidepressants, it does not usually cause sexual dysfunction, and the occurrence of sexual side effects is not different from placebo.<ref name="pmid27141292" /><ref>{{cite journal | vauthors = Clayton AH | title = Antidepressant-Associated Sexual Dysfunction: A Potentially Avoidable Therapeutic Challenge | journal = Primary Psychiatry | volume = 10 | issue = 1 | pages = 55–61 | year = 2003 | url = http://www.primarypsychiatry.com/aspx/articledetail.aspx?articleid=1362 | access-date = 21 March 2013 | archive-date = 4 June 2020 | archive-url = https://web.archive.org/web/20200604183420/http://primarypsychiatry.com/antidepressant-associated-sexual-dysfunction-a-potentially-avoidable-therapeutic-challenge/ | url-status = dead }}</ref> Bupropion treatment is not associated with weight gain; on the contrary, the majority of studies observed significant weight loss in bupropion-treated participants.<ref name="pmid27141292" /> Bupropion treatment also is not associated with the [[somnolence|sleepiness]] that may be produced by other antidepressants.<ref name=Dhillon>{{cite journal | vauthors = Dhillon S, Yang LP, Curran MP | title = Bupropion: a review of its use in the management of major depressive disorder | journal = Drugs | volume = 68 | issue = 5 | pages = 653–689 | year = 2008 | pmid = 18370448 | doi = 10.2165/00003495-200868050-00011 | s2cid = 195687060 }}</ref> Bupropion is more effective than [[selective serotonin reuptake inhibitor]]s (SSRIs) at improving symptoms of [[hypersomnia]] and fatigue in depressed patients.<ref name="pmid16848671">{{cite journal | vauthors = Baldwin DS, Papakostas GI | title = Symptoms of fatigue and sleepiness in major depressive disorder | journal = The Journal of Clinical Psychiatry | volume = 67 | issue = Suppl 6 | pages = 9–15 | year = 2006 | pmid = 16848671 }}</ref> Bupropion is effective in the treatment of anxious depression and, contrary to common belief, does not exacerbate anxiety in this context.<ref name="pmid18605812">{{cite journal | vauthors = Papakostas GI, Stahl SM, Krishen A, Seifert CA, Tucker VL, Goodale EP, Fava M | title = Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of major depressive disorder with high levels of anxiety (anxious depression): a pooled analysis of 10 studies | journal = The Journal of Clinical Psychiatry | volume = 69 | issue = 8 | pages = 1287–1292 | date = August 2008 | pmid = 18605812 | doi = 10.4088/JCP.v69n0812 | s2cid = 25267685 }}</ref><ref name="pmid33843549">{{cite journal | vauthors = Naguy A, ((Badr BHM)) | title = Bupropion-myth-busting! | journal = CNS Spectr | volume = 27 | issue = 5 | pages = 545–546 | date = October 2022 | pmid = 33843549 | doi = 10.1017/S1092852921000365 | s2cid = 233212535 | url = | doi-access = free }}</ref> The effectiveness of bupropion for anxious depression is equivalent to that of SSRIs in the case of depression with low or moderate anxiety, whereas SSRIs show a modest effectiveness advantage in terms of response rates for depression with high anxiety.<ref name="pmid18605812" />

The addition of bupropion to a prescribed SSRI is a common strategy when people do not respond to the SSRI,<ref name="pmid27591914">{{cite journal | vauthors = Arandjelovic K, Eyre HA, Lavretsky H | title = Clinicians' Views on Treatment-Resistant Depression: 2016 Survey Reports | journal = The American Journal of Geriatric Psychiatry | volume = 24 | issue = 10 | pages = 913–917 | date = October 2016 | pmid = 27591914 | pmc = 5540329 | doi = 10.1016/j.jagp.2016.05.010 }}</ref> and it is supported by clinical trials;<ref name="pmid27141292" /> however, it appears to be inferior to the addition of atypical antipsychotic [[aripiprazole]].<ref name="pmid32512768">{{cite journal | vauthors = Ruberto VL, Jha MK, Murrough JW | title = Pharmacological Treatments for Patients with Treatment-Resistant Depression | journal = Pharmaceuticals | volume = 13 | issue = 6 | page = 116 | date = June 2020 | pmid = 32512768 | pmc = 7345023 | doi = 10.3390/ph13060116 | doi-access = free }}</ref>{{Explain|date=May 2023|reason=Per the cited source, while the statistically significant differences in response rate did indeed demonstrate that aripiprazole augmentation produced a somewhat higher ''response'' rate (which the percentages should probably be mentioned inline here), there was no statistically significant difference between them in the ''remission'' rate (!!). Simplifying this result to (effectively) "bupropion augmentation is inferior to aripiprazole augmentation" as was done here is an incredibly misleading oversimplification of the actual results of the scientific research being cited to support this assertion.}}

=== Smoking cessation ===

Prescribed as an aid for smoking cessation, bupropion reduces the severity of [[Craving (withdrawal)|craving]] for nicotine and [[Drug withdrawal|withdrawal]] symptoms<ref>{{cite journal | vauthors = Wilkes S | title = The use of bupropion SR in cigarette smoking cessation | journal = International Journal of Chronic Obstructive Pulmonary Disease | volume = 3 | issue = 1 | pages = 45–53 | date = 2008 | pmid = 18488428 | pmc = 2528204 | doi = 10.2147/copd.s1121 | doi-access = free }}</ref><ref name="Hajizadeh_2023">{{cite journal | vauthors = Hajizadeh A, Howes S, Theodoulou A, Klemperer E, Hartmann-Boyce J, Livingstone-Banks J, Lindson N | title = Antidepressants for smoking cessation | journal = The Cochrane Database of Systematic Reviews | volume = 2023 | issue = 5 | pages = CD000031 | date = May 2023 | pmid = 37230961 | pmc = 10207863 | doi = 10.1002/14651858.CD000031.pub6 }}</ref><ref name="pmid17156479">{{cite journal | vauthors = Wu P, Wilson K, Dimoulas P, Mills EJ | title = Effectiveness of smoking cessation therapies: a systematic review and meta-analysis | journal = BMC Public Health | volume = 6 | pages = 300 | date = December 2006 | pmid = 17156479 | pmc = 1764891 | doi = 10.1186/1471-2458-6-300 | doi-access = free }}</ref> such as depressed

mood, irritability, difficulty concentrating, and increased appetite.<ref name="pmid16831112">{{cite journal | vauthors = Mooney ME, Sofuoglu M | title = Bupropion for the treatment of nicotine withdrawal and craving | journal = Expert Review of Neurotherapeutics | volume = 6 | issue = 7 | pages = 965–981 | date = July 2006 | pmid = 16831112 | doi = 10.1586/14737175.6.7.965 | s2cid = 19195413 }}</ref> Initially, bupropion slows the weight gain that often occurs in the first weeks after quitting smoking. With time, however, this effect becomes negligible.<ref name="pmid16831112" />

The bupropion treatment course lasts for seven to twelve weeks, with the patient halting the use of tobacco about ten days into the course.<ref name="pmid16831112" /><ref name="Wellbutrin SR FDA label" /> After the course, the effectiveness of bupropion for maintaining abstinence from smoking declines over time, from 37% of tobacco abstinence at 3 months to 20% at one year.<ref name="Rosen2018">{{cite journal | vauthors = Rosen LJ, Galili T, Kott J, Goodman M, Freedman LS | title = Diminishing benefit of smoking cessation medications during the first year: a meta-analysis of randomized controlled trials | journal = Addiction | volume = 113 | issue = 5 | pages = 805–816 | date = May 2018 | pmid = 29377409 | pmc = 5947828 | doi = 10.1111/add.14134 }}</ref> It is unclear whether extending bupropion treatment helps to prevent relapse of smoking.<ref>{{cite journal | vauthors = Livingstone-Banks J, Norris E, Hartmann-Boyce J, West R, Jarvis M, Chubb E, Hajek P | title = Relapse prevention interventions for smoking cessation | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 10 | date = October 2019 | pmid = 31684681 | pmc = 6816175 | doi = 10.1002/14651858.CD003999.pub6 }}</ref>

Overall, six months after the therapy, bupropion increases the likelihood of quitting smoking by approximately 1.6 fold as compared to placebo. In this respect, bupropion is as effective as [[nicotine replacement therapy]] but inferior to [[varenicline]]. Combining bupropion and nicotine replacement therapy does not improve the quitting rate.<ref name="pmid33464342">{{cite journal | vauthors = Patnode CD, Henderson JT, Coppola EL, Melnikow J, Durbin S, Thomas RG | title = Interventions for Tobacco Cessation in Adults, Including Pregnant Persons: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force | journal = JAMA | volume = 325 | issue = 3 | pages = 280–298 | date = January 2021 | pmid = 33464342 | doi = 10.1001/jama.2020.23541 | doi-access = free }}</ref>

In children and adolescents, the use of bupropion for smoking cessation does not appear to offer any significant benefits.<ref name="pmid32343335">{{cite journal | vauthors = Selph S, Patnode C, Bailey SR, Pappas M, Stoner R, Chou R | title = Primary Care-Relevant Interventions for Tobacco and Nicotine Use Prevention and Cessation in Children and Adolescents: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force | journal = JAMA | volume = 323 | issue = 16 | pages = 1599–1608 | date = April 2020 | pmid = 32343335 | doi = 10.1001/jama.2020.3332 | doi-access = free }}</ref> The evidence for its use to aid smoking cessation in pregnant women is insufficient.<ref name="pmid32129504">{{cite journal | vauthors = Claire R, Chamberlain C, Davey MA, Cooper SE, Berlin I, Leonardi-Bee J, Coleman T | title = Pharmacological interventions for promoting smoking cessation during pregnancy | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | issue = 3 | pages = CD010078 | date = March 2020 | pmid = 32129504 | pmc = 7059898 | doi = 10.1002/14651858.CD010078.pub3 }}</ref>

=== Attention deficit hyperactivity disorder ===

In the United States, the treatment of [[attention deficit hyperactivity disorder]] (ADHD) is not an approved indication of bupropion, and it is not mentioned in the 2019 guideline on ADHD treatment from the [[American Academy of Pediatrics]].<ref name="pmid31570648">{{cite journal | vauthors = Wolraich ML, Hagan JF, Allan C, Chan E, Davison D, Earls M, Evans SW, Flinn SK, Froehlich T, Frost J, Holbrook JR, Lehmann CU, Lessin HR, Okechukwu K, Pierce KL, Winner JD, Zurhellen W | title = Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents | journal = Pediatrics | volume = 144 | issue = 4 | pages = e20192528 | date = October 2019 | pmid = 31570648 | pmc = 7067282 | doi = 10.1542/peds.2019-2528 }}</ref> Systematic reviews of bupropion for the treatment of ADHD in both adults and children note that bupropion may be effective for ADHD but warn that this conclusion has to be interpreted with caution, because clinical trials were of low quality due to small sizes and risk of bias.<ref name="pmid28965364">{{cite journal | vauthors = Verbeeck W, Bekkering GE, Van den Noortgate W, Kramers C | title = Bupropion for attention deficit hyperactivity disorder (ADHD) in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | issue = 10 | pages = CD009504 | date = October 2017 | pmid = 28965364 | pmc = 6485546 | doi = 10.1002/14651858.CD009504.pub2 }}</ref><ref name="pmid33085721">{{cite journal | vauthors = Elliott J, Johnston A, Husereau D, Kelly SE, Eagles C, Charach A, Hsieh SC, Bai Z, Hossain A, Skidmore B, Tsakonas E, Chojecki D, Mamdani M, Wells GA | title = Pharmacologic treatment of attention deficit hyperactivity disorder in adults: A systematic review and network meta-analysis | journal = PLOS ONE | volume = 15 | issue = 10 | pages = e0240584 | date = 2020 | pmid = 33085721 | pmc = 7577505 | doi = 10.1371/journal.pone.0240584 | doi-access = free | bibcode = 2020PLoSO..1540584E }}</ref><ref name="pmid30097390">{{cite journal | vauthors = Cortese S, Adamo N, Del Giovane C, Mohr-Jensen C, Hayes AJ, Carucci S, Atkinson LZ, Tessari L, Banaschewski T, Coghill D, Hollis C, Simonoff E, Zuddas A, Barbui C, Purgato M, Steinhausen HC, Shokraneh F, Xia J, Cipriani A | title = Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis | journal = The Lancet. Psychiatry | volume = 5 | issue = 9 | pages = 727–738 | date = September 2018 | pmid = 30097390 | pmc = 6109107 | doi = 10.1016/S2215-0366(18)30269-4 }}</ref><ref name="pmid27813651">{{cite journal | vauthors = Ng QX | title = A Systematic Review of the Use of Bupropion for Attention-Deficit/Hyperactivity Disorder in Children and Adolescents | journal = Journal of Child and Adolescent Psychopharmacology | volume = 27 | issue = 2 | pages = 112–116 | date = March 2017 | pmid = 27813651 | doi = 10.1089/cap.2016.0124 }}</ref> Similarly to [[atomoxetine]], bupropion has a delayed [[onset of action]] for ADHD, and several weeks of treatment are required for therapeutic effects.<ref name="pmid28965364" /><ref name="pmid21955201">{{cite journal | vauthors = Wilens TE, Morrison NR, Prince J | title = An update on the pharmacotherapy of attention-deficit/hyperactivity disorder in adults | journal = Expert Review of Neurotherapeutics | volume = 11 | issue = 10 | pages = 1443–1465 | date = October 2011 | pmid = 21955201 | pmc = 3229037 | doi = 10.1586/ern.11.137 }}</ref> This is in contrast to [[stimulant]]s, such as [[amphetamine]] and [[methylphenidate]], which have an immediate onset of effect in the condition.<ref name="pmid21955201" />

=== Sexual dysfunction ===

Bupropion is less likely than other antidepressants to cause [[sexual dysfunction]].<ref name="pmid19440080">{{cite journal | vauthors = Serretti A, Chiesa A | title = Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis | journal = Journal of Clinical Psychopharmacology | volume = 29 | issue = 3 | pages = 259–266 | date = June 2009 | pmid = 19440080 | doi = 10.1097/JCP.0b013e3181a5233f | s2cid = 1663570 }}</ref> A range of studies indicate that bupropion not only produces fewer sexual side effects than other antidepressants but can actually help to alleviate sexual dysfunction<ref name="pmid15361919">{{cite journal | vauthors = Stahl SM, Pradko JF, Haight BR, Modell JG, Rockett CB, Learned-Coughlin S | title = A Review of the Neuropharmacology of Bupropion, a Dual Norepinephrine and Dopamine Reuptake Inhibitor | journal = Primary Care Companion to the Journal of Clinical Psychiatry | volume = 6 | issue = 4 | pages = 159–166 | year = 2004 | pmid = 15361919 | pmc = 514842 | doi = 10.4088/PCC.v06n0403 }}</ref> including sexual dysfunction induced by [[SSRI]] antidepressants.<ref name="pmid29649948">{{cite journal | vauthors = Basson R, Gilks T | title = Women's sexual dysfunction associated with psychiatric disorders and their treatment | journal = Women's Health | volume = 14 | issue = | pages = 1745506518762664 | date = 2018 | pmid = 29649948 | pmc = 5900810 | doi = 10.1177/1745506518762664 }}</ref> There have also been small studies suggesting that bupropion or a bupropion/[[trazodone]] combination may improve some measures of sexual function in women who have [[hypoactive sexual desire disorder]] (HSDD) and are not depressed.<ref name="pmid29523488">{{cite journal | vauthors = Clayton AH, Kingsberg SA, Goldstein I | title = Evaluation and Management of Hypoactive Sexual Desire Disorder | journal = Sexual Medicine | volume = 6 | issue = 2 | pages = 59–74 | date = June 2018 | pmid = 29523488 | pmc = 5960024 | doi = 10.1016/j.esxm.2018.01.004 }}</ref> According to an expert consensus recommendation from the International Society for the Study of Women's Sexual Health, bupropion can be considered as an off-label treatment for HSDD despite limited safety and efficacy data.<ref name="pmid27916394">{{cite journal | vauthors = Goldstein I, Kim NN, Clayton AH, DeRogatis LR, Giraldi A, Parish SJ, Pfaus J, Simon JA, Kingsberg SA, Meston C, Stahl SM, Wallen K, Worsley R | title = Hypoactive Sexual Desire Disorder: International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel Review | journal = Mayo Clinic Proceedings | volume = 92 | issue = 1 | pages = 114–128 | date = January 2017 | pmid = 27916394 | doi = 10.1016/j.mayocp.2016.09.018 | doi-access = free }}</ref> Likewise, a 2022 [[systematic review]] and [[meta-analysis]] of bupropion for sexual desire disorder in women reported that although data were limited, bupropion appeared to be dose-dependently effective for the condition.<ref name="pmid35193485">{{cite journal | vauthors = Razali NA, Sidi H, Choy CL, Ross NA, Baharudin A, Das S | title = The Role of Bupropion in the Treatment of Women with Sexual Desire Disorder: A Systematic Review and Meta-Analysis | journal = Curr Neuropharmacol | volume = 20| issue = 10| pages = 1941–1955| date = February 2022 | pmid = 35193485 | doi = 10.2174/1570159X20666220222145735 | pmc = 9886814 | s2cid = 247057961 | url = }}</ref>

=== Weight gain ===

Bupropion, when used for treating long term weight gain over a period of six to twelve months, results in an average weight loss of {{convert|2.7|kg|lb|sigfig=2}} over placebo.<ref name="pmid15809465" /> This is not much different from the weight loss produced by several other weight-loss medications such as [[sibutramine]] or [[orlistat]].<ref name="pmid15809465">{{cite journal | vauthors = Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR, Hilton L, Suttorp M, Solomon V, Shekelle PG, Morton SC | title = Meta-analysis: pharmacologic treatment of obesity | journal = Annals of Internal Medicine | volume = 142 | issue = 7 | pages = 532–546 | date = April 2005 | pmid = 15809465 | doi = 10.7326/0003-4819-142-7-200504050-00012 | doi-access = free }}</ref> The combination drug [[naltrexone/bupropion]] has been approved by the US [[Food and Drug Administration]] (FDA) for the treatment of obesity.<ref name="Contrave FDA approval package">{{cite web | title=Drug Approval Package: Contrave (naltrexone hydrochloride/bupropion hydrochloride) Extended-Release Tablets NDA #200063 | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/200063Orig1s000TOC.cfm | access-date=5 May 2020 | archive-date=4 June 2020 | archive-url=https://web.archive.org/web/20200604184413/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/200063Orig1s000TOC.cfm | url-status=live }}</ref><ref name="Contrave FDA label">{{cite web | title=Contrave Extended-Release – naltrexone hydrochloride and bupropion hydrochloride tablet, extended release | website=DailyMed | date=26 April 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=485ff360-32c8-11df-928b-0002a5d5c51b | access-date=5 May 2020 | archive-date=4 June 2020 | archive-url=https://web.archive.org/web/20200604190921/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=485ff360-32c8-11df-928b-0002a5d5c51b | url-status=live }}</ref>

=== Other uses ===

Bupropion is not effective in the treatment of [[cocaine dependence]],<ref name="Kampman_2008">{{cite journal | vauthors = Kampman KM | title = The search for medications to treat stimulant dependence | journal = Addiction Science & Clinical Practice | volume = 4 | issue = 2 | pages = 28–35 | date = June 2008 | pmid = 18497715 | pmc = 2797110 | doi = 10.1151/ascp084228 }}</ref> but it is showing promise in reducing drug use in treating amphetamine-type stimulant use and cravings.<ref name="pmid27018393">{{cite journal | vauthors = Cao DN, Shi JJ, Hao W, Wu N, Li J | title = Advances and challenges in pharmacotherapeutics for amphetamine-type stimulants addiction | journal = European Journal of Pharmacology | volume = 780 | issue = | pages = 129–135 | date = June 2016 | pmid = 27018393 | doi = 10.1016/j.ejphar.2016.03.040 }}</ref><ref>{{cite journal | vauthors = Akbar D, Rhee TG, Ceban F, Ho R, Teopiz KM, Cao B, Subramaniapillai M, Kwan AT, Rosenblat JD, McIntyre RS | title = Dextromethorphan-Bupropion for the Treatment of Depression: A Systematic Review of Efficacy and Safety in Clinical Trials | journal = CNS Drugs | volume = 37 | issue = 10 | pages = 867–881 | date = October 2023 | pmid = 37792265 | doi = 10.1007/s40263-023-01032-5 }}</ref> Based on studies indicating that bupropion lowers the level of the inflammatory mediator [[Tumor necrosis factor-alpha|TNF-alpha]], there have been suggestions that it might be useful in treating [[inflammatory bowel disease]], [[psoriasis]], and other autoimmune conditions, but very little clinical evidence is available.<ref name="pmid16984660">{{cite journal | vauthors = Mikocka-Walus AA, Turnbull DA, Moulding NT, Wilson IG, Andrews JM, Holtmann GJ | title = Antidepressants and inflammatory bowel disease: a systematic review | journal = Clinical Practice and Epidemiology in Mental Health | volume = 2 | pages = 24 | date = September 2006 | pmid = 16984660 | pmc = 1599716 | doi = 10.1186/1745-0179-2-24 | doi-access = free }}</ref><ref name="pmid27167571">{{cite journal | vauthors = Thorkelson G, Bielefeldt K, Szigethy E | title = Empirically Supported Use of Psychiatric Medications in Adolescents and Adults with IBD | journal = Inflammatory Bowel Diseases | volume = 22 | issue = 6 | pages = 1509–1522 | date = June 2016 | pmid = 27167571 | doi = 10.1097/MIB.0000000000000734 | doi-access = free }}</ref><ref name="pmid28512664">{{cite journal | vauthors = Eskeland S, Halvorsen JA, Tanum L | title = Antidepressants have Anti-inflammatory Effects that may be Relevant to Dermatology: A Systematic Review | journal = Acta Dermato-Venereologica | volume = 97 | issue = 8 | pages = 897–905 | date = August 2017 | pmid = 28512664 | doi = 10.2340/00015555-2702 | doi-access = free | hdl = 10852/63759 | hdl-access = free }}</ref> Bupropion is not effective in treating chronic low back pain.<ref name="pmid18253994">{{cite journal | vauthors = Urquhart DM, Hoving JL, Assendelft WW, Roland M, van Tulder MW | title = Antidepressants for non-specific low back pain | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD001703 | date = January 2008 | volume = 2008 | pmid = 18253994 | pmc = 7025781 | doi = 10.1002/14651858.CD001703.pub3 | veditors = Urquhart DM }}</ref> The drug may be useful in the treatment of [[excessive daytime sleepiness]] (EDS) and [[narcolepsy]].<ref name="OnoTakenoshitaNishino2022">{{cite journal | vauthors = Ono T, Takenoshita S, Nishino S | title = Pharmacologic Management of Excessive Daytime Sleepiness | journal = Sleep Med Clin | volume = 17 | issue = 3 | pages = 485–503 | date = September 2022 | pmid = 36150809 | doi = 10.1016/j.jsmc.2022.06.012 | url = }}</ref><ref name="NishinoKotorii2016">{{cite book | vauthors = Nishino S, Kotorii N | title=Narcolepsy | chapter=Overview of Management of Narcolepsy | publisher=Springer International Publishing | publication-place=Cham | date=2016 | isbn=978-3-319-23738-1 | doi=10.1007/978-3-319-23739-8_21 | pages=285–305}}</ref><ref name="RyeDiheniaBliwise1998">{{cite journal | vauthors = Rye DB, Dihenia B, Bliwise DL | title = Reversal of atypical depression, sleepiness, and REM-sleep propensity in narcolepsy with bupropion | journal = Depress Anxiety | volume = 7 | issue = 2 | pages = 92–95 | date = 1998 | pmid = 9614600 | doi = 10.1002/(SICI)1520-6394(1998)7:2<92::AID-DA9>3.0.CO;2-7| url = }}</ref><ref name="GoksanMercanKaramustafalioglu2005">{{cite journal | vauthors = Goksan B, Mercan S, Karamustafalioglu O | title = Bupropion is effective in depression in narcolepsy | journal = Int J Psychiatry Clin Pract | volume = 9 | issue = 4 | pages = 289–291 | date = 2005 | pmid = 24930928 | doi = 10.1080/13651500500241454 | url = }}</ref>

Bupropion has been used to treat [[disorders of diminished motivation]], like [[apathy]], [[abulia]], and [[akinetic mutism]].<ref name="Hailwood2018" /><ref name="MarinWilkosz2005">{{cite journal | vauthors = Marin RS, Wilkosz PA | title = Disorders of diminished motivation | journal = J Head Trauma Rehabil | volume = 20 | issue = 4 | pages = 377–88 | date = 2005 | pmid = 16030444 | doi = 10.1097/00001199-200507000-00009 | url = }}</ref> Accordingly, the drug has been found to increase [[effortfulness|effort expenditure]] and improve [[amotivational syndrome|motivational deficits]] in [[animal model]]s.<ref name="Hailwood2018">{{cite thesis | vauthors = Hailwood JM | title=Novel approaches towards pharmacological enhancement of motivation | publisher = University of Cambridge | date=27 September 2018 | doi=10.17863/CAM.40216 | pages=13–14 | url = https://api.repository.cam.ac.uk/server/api/core/bitstreams/bfa48cf2-6047-4400-b0c0-8801328d2776/content | quote = Bupropion also acts as a dopamine reuptake inhibitor (Dwoskin et al. 2006), and has been used as a treatment for depression as well as a smoking cessation aid (Stahl et al. 2004). Bupropion has been shown to produce a dose-dependent increase in PR breakpoints (Bruijnzeel & Markou 2003). Furthermore, systemic administration of bupropion increases selection of the higheffort, high reward option in a PR-choice task in rats (Randall, Lee, Podurgiel, et al. 2014). Bupropion is also effective at rescuing motivational impairments in rodents. Administration of bupropion can rescue deficits in effort-related decision-making induced by pre-treatment with tetrabenazine (Randall, Lee, Nunes, et al. 2014; Nunes, Randall, Hart, et al. 2013) and the proinflammatory cytokine interleukin-6 (Yohn, Arif, et al. 2016). Bupropion has been reported to improve symptoms of apathy in cases of acquired brain injury, major depression (Corcoran et al. 2004) and frontotemporal dementia (Lin et al. 2016). However, several larger placebo-controlled studies suggest only limited effects of bupropion. In a study of 40 patients with schizophrenia, bupropion was found to have no significant effect on apathy or negative symptoms as a whole (Yassini et al. 2014). Furthermore, in a recent RCT of bupropion in HD, apathy was not significantly affected by the drug (Gelderblom et al. 2017). It is not clear whether bupropion lacks clinical efficacy, or whether bupropion as a whole is not affective at treating motivational impairments, or simply not effective in the clinical populations tested.}}</ref> However, only limited benefits of bupropion in the treatment of apathy have been observed in [[clinical trial]]s in various conditions.<ref name="Hailwood2018" />

Bupropion has been used in the treatment of [[postural orthostatic tachycardia syndrome]] (POTS).<ref name="LyongaNgongeNyangeGhali2024">{{cite journal | vauthors = Lyonga Ngonge A, Nyange C, Ghali JK | title = Novel pharmacotherapeutic options for the treatment of postural orthostatic tachycardia syndrome | journal = Expert Opin Pharmacother | volume = 25 | issue = 2 | pages = 181–188 | date = February 2024 | pmid = 38465412 | doi = 10.1080/14656566.2024.2319224 | url = }}</ref><ref name="VyasNesheiwatRuzieh2020">{{cite journal | vauthors = Vyas R, Nesheiwat Z, Ruzieh M, Ammari Z, Al-Sarie M, Grubb B | title = Bupropion in the treatment of postural orthostatic tachycardia syndrome (POTS): a single-center experience | journal = J Investig Med | volume = 68 | issue = 6 | pages = 1156–1158 | date = August 2020 | pmid = 32606041 | doi = 10.1136/jim-2020-001272 | url = }}</ref>

=== Available forms ===

{{See also|Naltrexone/bupropion|Dextromethorphan/bupropion}}

Bupropion is available as an [[oral administration|oral]] [[tablet (pharmacy)|tablet]] in a number of different formulations.<ref name="Wellbutrin SR FDA label" /><ref name="Wellbutrin XL FDA label" /> It is mainly formulated as the [[hydrochloride]] [[salt (chemistry)|salt]]<ref name="Wellbutrin SR FDA label" /><ref name="Wellbutrin XL FDA label" /> but also as the [[hydrobromide]] salt.<ref name="Aplenzin FDA label" /> In addition to single-drug formulations, bupropion is formulated in [[combination drug|combinations]] including [[naltrexone/bupropion]] (Contrave) for obesity and [[dextromethorphan/bupropion]] (Auvelity) for depression.<ref>{{cite web | title=Auvelity- dextromethorphan hydrobromide, bupropion hydrochloride tablet, multilayer, extended release | website=DailyMed | date=18 September 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=dcefda7c-9a68-278e-e053-2995a90aec79 | access-date=17 October 2024}}</ref><ref name="pmid33682569">{{cite journal | vauthors = Majeed A, Xiong J, Teopiz KM, Ng J, Ho R, Rosenblat JD, Phan L, Cao B, McIntyre RS | title = Efficacy of dextromethorphan for the treatment of depression: a systematic review of preclinical and clinical trials | journal = Expert Opinion on Emerging Drugs | volume = 26 | issue = 1 | pages = 63–74 | date = March 2021 | pmid = 33682569 | doi = 10.1080/14728214.2021.1898588 | s2cid = 232141396 }}</ref>

== Contraindications ==

The US [[Food and Drug Administration]] (FDA) prescription label advises that bupropion should not be prescribed to individuals with [[epilepsy]] or other conditions that lower the [[seizure threshold]], such as [[anorexia nervosa]], [[bulimia nervosa]], or [[Benzodiazepine withdrawal syndrome|benzodiazepine]] or [[alcohol withdrawal]]. It should be avoided in individuals who are taking [[monoamine oxidase inhibitor]]s (MAOIs). The label recommends that caution should be exercised when treating people with liver damage, severe [[nephropathy|kidney disease]], and severe [[hypertension]], and in children, adolescents and young adults due to the increased risk of [[suicidal ideation]].<ref name="Wellbutrin SR FDA label">{{cite web | title=Wellbutrin SR – bupropion hydrochloride tablet, film coated | website=DailyMed | date=5 November 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cbc8c074-f080-4489-a5ae-207b5fadeba3 | access-date=6 May 2020 | archive-date=4 June 2020 | archive-url=https://web.archive.org/web/20200604173013/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cbc8c074-f080-4489-a5ae-207b5fadeba3 | url-status=live }}</ref>

== Side effects ==

The common adverse effects of bupropion with the greatest difference from placebo are dry mouth, nausea, constipation, insomnia, anxiety, tremor, and excessive sweating.<ref name="Wellbutrin SR FDA label" /><ref name="Wellbutrin XL FDA label" /> Bupropion has the highest incidence of insomnia of all second-generation antidepressants, apart from [[desvenlafaxine]].<ref name="pmid25874915">{{cite journal | vauthors = Alberti S, Chiesa A, Andrisano C, Serretti A | title = Insomnia and somnolence associated with second-generation antidepressants during the treatment of major depression: a meta-analysis | journal = Journal of Clinical Psychopharmacology | volume = 35 | issue = 3 | pages = 296–303 | date = June 2015 | pmid = 25874915 | doi = 10.1097/JCP.0000000000000329 | s2cid = 33102792 | url = http://journals.lww.com/psychopharmacology | access-date = 13 November 2022 | archive-date = 8 March 2023 | archive-url = https://web.archive.org/web/20230308050905/https://journals.lww.com/psychopharmacology/pages/default.aspx | url-status = live }}</ref> It is also associated with about 20% increased risk of headache.<ref name="pmid29715610">{{cite journal | vauthors = Telang S, Walton C, Olten B, Bloch MH | title = Meta-analysis: Second generation antidepressants and headache | journal = Journal of Affective Disorders | volume = 236 | issue = | pages = 60–68 | date = August 2018 | pmid = 29715610 | doi = 10.1016/j.jad.2018.04.047 | s2cid = 19196303 }}</ref>

Bupropion raises blood pressure in some people. One study showed an average rise of 6&nbsp;mm&nbsp;Hg in systolic blood pressure in 10% of patients.<ref name="pmid15705013">{{cite journal | vauthors = Wilens TE, Hammerness PG, Biederman J, Kwon A, Spencer TJ, Clark S, Scott M, Podolski A, Ditterline JW, Morris MC, Moore H | title = Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder | journal = The Journal of Clinical Psychiatry | volume = 66 | issue = 2 | pages = 253–259 | date = February 2005 | pmid = 15705013 | doi = 10.4088/jcp.v66n0215 }}</ref> The prescribing information notes that [[hypertension]], sometimes severe, is observed in some people taking bupropion, both with and without pre-existing hypertension.<ref name="Wellbutrin SR FDA label" /><ref name="Wellbutrin XL FDA label" /> Safety of bupropion in people with cardiovascular conditions and its general cardiovascular safety profile remain unclear due to the lack of data.<ref name="pmid28605035">{{cite journal | vauthors = Kittle J, Lopes RD, Huang M, Marquess ML, Wilson MD, Ascher J, Krishen A, Hasselblad V, Kolls BJ, Roe MT, McGuire DK, Russell SD, Mahaffey KW | title = Cardiovascular adverse events in the drug-development program of bupropion for smoking cessation: A systematic retrospective adjudication effort | journal = Clinical Cardiology | volume = 40 | issue = 10 | pages = 899–906 | date = October 2017 | pmid = 28605035 | pmc = 6490529 | doi = 10.1002/clc.22744 }}</ref><ref name="pmid24267809">{{cite journal | vauthors = Grandi SM, Shimony A, Eisenberg MJ | title = Bupropion for smoking cessation in patients hospitalized with cardiovascular disease: a systematic review and meta-analysis of randomized controlled trials | journal = The Canadian Journal of Cardiology | volume = 29 | issue = 12 | pages = 1704–1711 | date = December 2013 | pmid = 24267809 | doi = 10.1016/j.cjca.2013.09.014 }}</ref>

[[Seizure]] is a rare but serious adverse effect of bupropion. It is strongly dose-dependent: for the immediate release preparation, the seizure incidence is 0.4% at the dose 300–450&nbsp;mg per day; the incidence climbs almost ten-fold for the higher than recommended dose of 600&nbsp;mg.<ref name="Wellbutrin SR FDA label" /><ref name="Wellbutrin XL FDA label" /> For comparison, the incidence of unprovoked seizure in the general population is 0.07–0.09%, and the risk of seizure for a variety of other antidepressants is generally 0–0.5% at the recommended doses.<ref name="pmid11888352">{{cite journal | vauthors = Pisani F, Oteri G, Costa C, Di Raimondo G, Di Perri R | title = Effects of psychotropic drugs on seizure threshold | journal = Drug Safety | volume = 25 | issue = 2 | pages = 91–110 | year = 2002 | pmid = 11888352 | doi = 10.2165/00002018-200225020-00004 | s2cid = 25290793 }}</ref>

Cases of [[Hepatotoxicity|liver toxicity]] leading to death or [[liver transplantation]] have been reported for bupropion. It is considered to be one of several antidepressants with greater risk of hepatotoxicity.<ref name="pmid24362450">{{cite journal | vauthors = Voican CS, Corruble E, Naveau S, Perlemuter G | title = Antidepressant-induced liver injury: a review for clinicians | journal = The American Journal of Psychiatry | volume = 171 | issue = 4 | pages = 404–415 | date = April 2014 | pmid = 24362450 | doi = 10.1176/appi.ajp.2013.13050709 }}</ref>

The prescribing information warns about bupropion triggering an angle-closure [[glaucoma]] attack.<ref name="Wellbutrin SR FDA label" /> On the other hand, bupropion may decrease the risk of development of [[open angle glaucoma]].<ref name="pmid31595027">{{cite journal | vauthors = Wu A, Khawaja AP, Pasquale LR, Stein JD | title = A review of systemic medications that may modulate the risk of glaucoma | journal = Eye | volume = 34 | issue = 1 | pages = 12–28 | date = January 2020 | pmid = 31595027 | pmc = 7002596 | doi = 10.1038/s41433-019-0603-z }}</ref>

Bupropion use by mothers in the first trimester of pregnancy is associated with 23% increase of the odds in [[congenital heart defect]]s in their children.<ref name="pmid33354752">{{cite journal | vauthors = De Vries C, Gadzhanova S, Sykes MJ, Ward M, Roughead E | title = A Systematic Review and Meta-Analysis Considering the Risk for Congenital Heart Defects of Antidepressant Classes and Individual Antidepressants | journal = Drug Safety | volume = 44 | issue = 3 | pages = 291–312 | date = March 2021 | pmid = 33354752 | doi = 10.1007/s40264-020-01027-x | s2cid = 229357583 | url = https://unisa.alma.exlibrisgroup.com/view/delivery/61USOUTHAUS_INST/12212569530001831 | access-date = 17 May 2022 | archive-date = 7 March 2023 | archive-url = https://web.archive.org/web/20230307221618/https://unisa.alma.exlibrisgroup.com/view/delivery/61USOUTHAUS_INST/12212569530001831 | url-status = live }}</ref>

Bupropion has rarely been associated with instances of [[Stevens–Johnson syndrome]].<ref name="pmid26594724">{{cite journal | vauthors = | title = Naltrexone + bupropion (Mysimba). Too risky for only modest weight loss | journal = Prescrire International | volume = 24 | issue = 164 | pages = 229–233 | date = October 2015 | pmid = 26594724 | doi = }}</ref><ref name="pmid25097474">{{cite journal | vauthors = Herstowska M, Komorowska O, Cubała WJ, Jakuszkowiak-Wojten K, Gałuszko-Węgielnik M, Landowski J | title = Severe skin complications in patients treated with antidepressants: a literature review | journal = Postepy Dermatologii I Alergologii | volume = 31 | issue = 2 | pages = 92–97 | date = May 2014 | pmid = 25097474 | pmc = 4112250 | doi = 10.5114/pdia.2014.40930 }}</ref>

Bupropion has not been associated with [[QT prolongation]] at therapeutic doses, but has been associated with QT prolongation in [[overdose]].<ref name="GoodnickJerryParra2002">{{cite journal | vauthors = Goodnick PJ, Jerry J, Parra F | title = Psychotropic drugs and the ECG: focus on the QTc interval | journal = Expert Opin Pharmacother | volume = 3 | issue = 5 | pages = 479–498 | date = May 2002 | pmid = 11996627 | doi = 10.1517/14656566.3.5.479 | url = }}</ref><ref name="JasiakBostwick2014">{{cite journal | vauthors = Jasiak NM, Bostwick JR | title = Risk of QT/QTc prolongation among newer non-SSRI antidepressants | journal = Ann Pharmacother | volume = 48 | issue = 12 | pages = 1620–1628 | date = December 2014 | pmid = 25204465 | doi = 10.1177/1060028014550645 | url = }}</ref><ref name="CaillierPiloteCastonguay2012">{{cite journal | vauthors = Caillier B, Pilote S, Castonguay A, Patoine D, Ménard-Desrosiers V, Vigneault P, Hreiche R, Turgeon J, Daleau P, De Koninck Y, Simard C, Drolet B | title = QRS widening and QT prolongation under bupropion: a unique cardiac electrophysiological profile | journal = Fundam Clin Pharmacol | volume = 26 | issue = 5 | pages = 599–608 | date = October 2012 | pmid = 21623902 | doi = 10.1111/j.1472-8206.2011.00953.x | url = }}</ref>

=== Psychiatric ===

The US [[Food and Drug Administration]] (FDA) requires all antidepressants, including bupropion, to carry a [[boxed warning]] stating that antidepressants may increase the risk of suicide in people younger than 25. This warning is based on a statistical analysis conducted by the FDA which found a 2-fold increase in [[suicidal ideation|suicidal thought]] and behavior in children and adolescents, and 1.5-fold increase in the 18–24 age group.<ref name=FDA>{{cite web | vauthors = Levenson M, Holland C | title = Antidepressants and suicidality in adults: statistical evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006) | access-date = 13 May 2007 | url = https://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4272s1-04-FDA.ppt | publisher = U.S. [[Food and Drug Administration]] (FDA) | archive-url = https://web.archive.org/web/20070927214932/https://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4272s1-04-FDA.ppt | archive-date = 27 September 2007 | url-status = dead }}</ref> For this analysis the FDA combined the results of 295 trials of 11 antidepressants in order to obtain statistically significant results. Considered in isolation, bupropion was not statistically different from placebo.<ref name="FDA" />

Bupropion prescribed for smoking cessation results in 25% increase of the risk of psychiatric side effects, in particular, [[anxiety]] (about 40% increase) and [[insomnia]] (about 80% increase). The evidence is insufficient to determine whether bupropion is associated with suicides or suicidal behavior.<ref name="Hajizadeh_2023" />

In rare cases, bupropion-induced [[psychosis]] may develop. It is associated with higher doses of bupropion; many cases described are at higher than recommended doses. Concurrent antipsychotic medication appears to be protective.<ref name="Buproprion-induced psychosis">{{cite journal | vauthors = Kumar S, Kodela S, Detweiler JG, Kim KY, Detweiler MB | title = Bupropion-induced psychosis: folklore or a fact? A systematic review of the literature | journal = General Hospital Psychiatry | volume = 33 | issue = 6 | pages = 612–617 | date = November–December 2011 | pmid = 21872337 | doi = 10.1016/j.genhosppsych.2011.07.001 }}</ref> In most cases the psychotic symptoms are eliminated by reducing the dose, ceasing treatment or adding antipsychotic medication.<ref name="Wellbutrin SR FDA label" /><ref name="Buproprion-induced psychosis" />

Although studies are lacking, a handful of case reports suggest that abrupt discontinuation of bupropion may cause [[antidepressant discontinuation syndrome]].<ref name="pmid31288917">{{cite journal | vauthors = Henssler J, Heinz A, Brandt L, Bschor T | title = Antidepressant Withdrawal and Rebound Phenomena | journal = Deutsches Ärzteblatt International | volume = 116 | issue = 20 | pages = 355–361 | date = May 2019 | pmid = 31288917 | pmc = 6637660 | doi = 10.3238/arztebl.2019.0355 }}</ref>

== Overdose ==

Bupropion is considered moderately dangerous in overdose.<ref name="Maudsley">{{cite book | vauthors = Taylor D, Carol P, Shitij K |title=The Maudsley prescribing guidelines in psychiatry|year=2012|publisher=Wiley-Blackwell|location=West Sussex|isbn=978-0-470-97969-3}}</ref><ref>{{cite journal | vauthors = White N, Litovitz T, Clancy C | title = Suicidal antidepressant overdoses: a comparative analysis by antidepressant type | journal = Journal of Medical Toxicology | volume = 4 | issue = 4 | pages = 238–250 | date = December 2008 | pmid = 19031375 | pmc = 3550116 | doi = 10.1007/BF03161207 }}</ref> According to an analysis of [[American Association of Poison Control Centers#National Poison Data System (NPDS)|US National Poison Data System]], adjusted for the number of prescriptions, bupropion and [[venlafaxine]] are the two new generation antidepressants (that is excluding [[tricyclic antidepressants]]) that result in the highest [[mortality rate|mortality]] and [[morbidity]].<ref name="pmid28135844">{{cite journal | vauthors = Nelson JC, Spyker DA | title = Morbidity and Mortality Associated With Medications Used in the Treatment of Depression: An Analysis of Cases Reported to U.S. Poison Control Centers, 2000–2014 | journal = The American Journal of Psychiatry | volume = 174 | issue = 5 | pages = 438–450 | date = May 2017 | pmid = 28135844 | doi = 10.1176/appi.ajp.2016.16050523 | doi-access = free }}</ref> For significant overdoses, seizures have been reported in about a third of all cases; other serious effects include hallucinations, loss of consciousness, and [[Heart arrhythmia|abnormal heart rhythms]]. When bupropion was one of several kinds of pills taken in an overdose, fever, muscle rigidity, muscle damage, hypertension or hypotension, stupor, coma, and respiratory failure have been reported. While most people recover, some people have died, having had multiple uncontrolled seizures and myocardial infarction.<ref name="Wellbutrin SR FDA label" />

== Interactions ==

Since bupropion is metabolized to [[hydroxybupropion]] by the enzyme [[CYP2B6]], drug interactions with CYP2B6 inhibitors are possible: this includes such medications as [[paroxetine]], [[sertraline]], [[norfluoxetine]] (active metabolite of [[fluoxetine]]), [[diazepam]], [[clopidogrel]], and [[orphenadrine]]. The expected result is the increase of bupropion and decrease of hydroxybupropion blood concentration. The reverse effect (decrease of bupropion and increase of hydroxybupropion) can be expected with CYP2B6 [[enzyme induction and inhibition|inducers]] such as [[carbamazepine]], [[clotrimazole]], [[rifampicin]], [[ritonavir]], [[Hypericum perforatum|St John's wort]], and [[phenobarbital]].<ref name="pmid16368442">{{cite journal | vauthors = Jefferson JW, Pradko JF, Muir KT | title = Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations | journal = Clinical Therapeutics | volume = 27 | issue = 11 | pages = 1685–1695 | date = November 2005 | pmid = 16368442 | doi = 10.1016/j.clinthera.2005.11.011 }}</ref> Indeed, carbamazepine decreases exposure to bupropion by 90% and increases exposure to hydroxybupropion by 94%.<ref name="pmid8830063">{{cite journal | vauthors = Ketter TA, Jenkins JB, Schroeder DH, Pazzaglia PJ, Marangell LB, George MS, Callahan AM, Hinton ML, Chao J, Post RM | title = Carbamazepine but not valproate induces bupropion metabolism | journal = Journal of Clinical Psychopharmacology | volume = 15 | issue = 5 | pages = 327–333 | date = October 1995 | pmid = 8830063 | doi = 10.1097/00004714-199510000-00004 }}</ref> Ritonavir, [[lopinavir/ritonavir]], and [[efavirenz]] have been shown to decrease levels of bupropion and/or its metabolites.<ref name="ContraveLabel" /> [[Ticlopidine]] and clopidogrel, both potent CYP2B6 inhibitors, have been found to considerably increase bupropion levels as well as decrease levels of its metabolite hydroxybupropion.<ref name="ContraveLabel">{{cite web | title = Highlight os Prescribing Information: CONTRAVE (naltrexone hydrochloride and bupropion hydrochloride) extended-release tablets, for oral use | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/200063s015lbl.pdf | date = August 2020 | work = Currax Pharmaceuticals LLC | publisher = U.S. Food and Drug Administration | access-date = 1 December 2020 | archive-date = 19 October 2020 | archive-url = https://web.archive.org/web/20201019152920/https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/200063s015lbl.pdf | url-status = live }}</ref>

Bupropion and its metabolites are inhibitors of [[CYP2D6]], with hydroxybupropion responsible for most of the inhibition. Additionally, bupropion and its metabolites may decrease expression of CYP2D6 in the liver. The end effect is a significant slowing of the clearance of other drugs metabolized by this enzyme.<ref name="pmid31124380">{{cite journal | vauthors = Costa R, Oliveira NG, Dinis-Oliveira RJ | title = Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects | journal = Drug Metabolism Reviews | volume = 51 | issue = 3 | pages = 293–313 | date = August 2019 | pmid = 31124380 | doi = 10.1080/03602532.2019.1620763 | s2cid = 163167323 }}</ref> For instance, bupropion has been found to increase [[area-under-the-curve (pharmacokinetics)|area-under-the-curve]] of [[desipramine]], a CYP2D6 substrate, by 5-fold.<ref name="ContraveLabel" /> Bupropion has also been found to increase levels of [[atomoxetine]] by 5.1-fold, while decreasing the exposure to its main metabolite by 1.5-fold.<ref>{{cite journal | vauthors = Todor I, Popa A, Neag M, Muntean D, Bocsan C, Buzoianu A, Vlase L, Gheldiu AM, Briciu C | title = Evaluation of a Potential Metabolism-Mediated Drug-Drug Interaction Between Atomoxetine and Bupropion in Healthy Volunteers | journal = Journal of Pharmacy & Pharmaceutical Sciences | volume = 19 | issue = 2 | pages = 198–207 | date = 2016 | pmid = 27518170 | doi = 10.18433/J3H03R | doi-access = free }}</ref> As another example, the ratio of [[dextromethorphan]] (a drug that is mainly metabolized by CYP2D6) to its major [[metabolite]] [[dextrorphan]] increased approximately 35-fold when it was administered to people being treated with 300&nbsp;mg/day bupropion.<ref name="pmid16368442" /> When people on bupropion are given [[MDMA]], about 30% increase of exposure to both drugs is observed, with enhanced mood but decreased [[heart rate]] effects of MDMA.<ref name="pmid25655950">{{cite journal | vauthors = Schmid Y, Rickli A, Schaffner A, Duthaler U, Grouzmann E, Hysek CM, Liechti ME | title = Interactions between bupropion and 3,4-methylenedioxymethamphetamine in healthy subjects | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 353 | issue = 1 | pages = 102–111 | date = April 2015 | pmid = 25655950 | doi = 10.1124/jpet.114.222356 | s2cid = 14761997 | doi-access = free }}</ref><ref name="pmid32285503" /> Interactions with other CYP2D6 substrates, such as [[metoprolol]], [[imipramine]], [[nortriptyline]],<ref name="pmid32285503">{{cite journal | vauthors = Protti M, Mandrioli R, Marasca C, Cavalli A, Serretti A, Mercolini L | title = New-generation, non-SSRI antidepressants: Drug-drug interactions and therapeutic drug monitoring. Part 2: NaSSAs, NRIs, SNDRIs, MASSAs, NDRIs, and others | journal = Medicinal Research Reviews | volume = 40 | issue = 5 | pages = 1794–1832 | date = September 2020 | pmid = 32285503 | doi = 10.1002/med.21671 | s2cid = 215758102 | hdl = 11585/762375 | hdl-access = free }}</ref> [[venlafaxine]],<ref name="pmid16368442" /> and [[nebivolol]]<ref name="pmid31124380" /> have also been reported. However, in a notable exception, bupropion does not seem to affect the concentrations of CYP2D6 substrates fluoxetine and paroxetine.<ref name="pmid16368442" /><ref name="pmid18691982">{{cite journal | vauthors = Spina E, Santoro V, D'Arrigo C | title = Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update | journal = Clinical Therapeutics | volume = 30 | issue = 7 | pages = 1206–1227 | date = July 2008 | pmid = 18691982 | doi = 10.1016/s0149-2918(08)80047-1 }}</ref>

Bupropion lowers the [[seizure]] threshold, and therefore can potentially interact with other medications that also lower it, such as [[antipsychotic]]s, [[tricyclic antidepressant]]s, [[theophylline]], and systemic [[corticosteroid]]s.<ref name="Wellbutrin SR FDA label" /> The prescribing information recommends minimizing the use of [[alcohol (drug)|alcohol]], since in rare cases bupropion reduces alcohol tolerance.<ref name="Wellbutrin SR FDA label" />

Caution should be observed when combining bupropion with a [[monoamine oxidase inhibitor]] (MAOI), as it may result in [[hypertensive crisis]].<ref name="pmid15554766">{{cite journal | vauthors = Feinberg SS | title = Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication | journal = The Journal of Clinical Psychiatry | volume = 65 | issue = 11 | pages = 1520–1524 | date = November 2004 | pmid = 15554766 | doi = 10.4088/jcp.v65n1113 }}</ref>

== Pharmacology ==

{| class="wikitable plainrowheaders" style="float:right; clear:right; margin:1em auto 1em 1em;"

|+Pharmacology of bupropion and its metabolites

!scope="col"|&nbsp;

!scope="col"| Bupropion

!scope="col"| [[(2R,3R)-Hydroxybupropion|''R,R''-<br />Hydroxy<br />bupropion]]

!scope="col"| [[Radafaxine|''S,S''-<br />Hydroxy<br />bupropion]]

!scope="col"| [[Threohydrobupropion|''Threo''-<br />hydro<br />bupropion]]

!scope="col"| [[Erythrohydrobupropion|''Erythro''-<br />hydro<br />bupropion]]

!scope="row" colspan="6" | Exposure and half-life

!scope="row"| [[Area under the curve (pharmacokinetics)|AUC]] relative<br />to bupropion<ref name="pmid30460996">{{cite journal | vauthors = Kharasch ED, Neiner A, Kraus K, Blood J, Stevens A, Schweiger J, Miller JP, Lenze EJ | title = Bioequivalence and Therapeutic Equivalence of Generic and Brand Bupropion in Adults With Major Depression: A Randomized Clinical Trial | journal = Clinical Pharmacology and Therapeutics | volume = 105 | issue = 5 | pages = 1164–1174 | date = May 2019 | pmid = 30460996 | pmc = 6465131 | doi = 10.1002/cpt.1309 }}</ref><ref name="pmid32386065">{{cite journal | vauthors = Kharasch ED, Neiner A, Kraus K, Blood J, Stevens A, Miller JP, Lenze EJ | title = Stereoselective Steady-State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults | journal = Clinical Pharmacology and Therapeutics | volume = 108 | issue = 5 | pages = 1036–1048 | date = November 2020 | pmid = 32386065 | doi = 10.1002/cpt.1888 | s2cid = 218563059 }}</ref>

| 1

| 23.8

| 0.6

| 11.2

| 2.5

!scope="row"| Half-life<ref name="pmid27255113">{{cite journal | vauthors = Masters AR, Gufford BT, Lu JB, Metzger IF, Jones DR, Desta Z | title = Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 358 | issue = 2 | pages = 230–238 | date = August 2016 | pmid = 27255113 | pmc = 4959100 | doi = 10.1124/jpet.116.232876 }}</ref>

| 11&nbsp;h

| 19&nbsp;h

| 15&nbsp;h

| 31&nbsp;h

| 22&nbsp;h

!scope="row" colspan="6" | Inhibition [[IC50|IC₅₀]] (μM) in human cells, unless noted otherwise (Lesser values indicate greater potency.)

!scope="row"| [[Dopamine transporter|DAT]], uptake<ref name="pmid20509659">{{cite journal | vauthors = Lukas RJ, Muresan AZ, Damaj MI, Blough BE, Huang X, Navarro HA, Mascarella SW, Eaton JB, Marxer-Miller SK, Carroll FI | title = Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 12 | pages = 4731–4748 | date = June 2010 | pmid = 20509659 | pmc = 2895766 | doi = 10.1021/jm1003232 }}</ref>

| 0.66

| inactive

| 0.63

| 47 (rat)<ref name="pmid10379421">{{cite journal | vauthors = Sánchez C, Hyttel J | title = Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding | journal = Cellular and Molecular Neurobiology | volume = 19 | issue = 4 | pages = 467–489 | date = August 1999 | pmid = 10379421 | doi = 10.1023/a:1006986824213 | s2cid = 19490821 }}</ref>

| no data

!scope="row"| [[Norepinephrine transporter|NET]], uptake<ref name="pmid20509659" />

| 1.85

| 9.9

| 0.24

| 16 (rat)<ref name="pmid10379421" />

| no data

!scope="row"| [[Serotonin transporter|SERT]], uptake<ref name="pmid20509659" />

| inactive

| inactive

| inactive

| 67 (rat)<ref name="pmid10379421" />

| no data

!scope="row"| [[alpha-3 beta-4 nicotinic receptor|α{{sub|3}}β{{sub|4}}]] nicotinic<ref name="pmid20509659" />

| 1.8

| 6.5

| 11

| 14 (rat)<ref name="pmid12909199">{{cite journal | vauthors = Bondarev ML, Bondareva TS, Young R, Glennon RA | title = Behavioral and biochemical investigations of bupropion metabolites | journal = European Journal of Pharmacology | volume = 474 | issue = 1 | pages = 85–93 | date = August 2003 | pmid = 12909199 | doi = 10.1016/S0014-2999(03)02010-7 }}</ref>

| no data

!scope="row"| [[Alpha-4 beta-2 nicotinic receptor|α{{sub|4}}β{{sub|2}}]] nicotinic<ref name="pmid15322260">{{cite journal | vauthors = Damaj MI, Carroll FI, Eaton JB, Navarro HA, Blough BE, Mirza S, Lukas RJ, Martin BR | title = Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors | journal = Molecular Pharmacology | volume = 66 | issue = 3 | pages = 675–682 | date = September 2004 | pmid = 15322260 | doi = 10.1124/mol.104.001313 | s2cid = 1577336 }}</ref>

| 12

| 31

| 3.3

| no data

| no data

!scope="row"| [[CHRNA1|α{{sub|1}}β{{sub|1}}γδ]] nicotinic<ref name="pmid15322260" />

| 7.9

| 7.6

| 28

| no data

| no data

!scope="row"| [[5-HT3 receptor|5-HT{{sub|3A}}]]<ref>{{cite journal | vauthors = Stuebler AG, Jansen M | title = Bupropion Inhibits Serotonin Type 3AB Heteromeric Channels at Clinically Relevant Concentrations | journal = Molecular Pharmacology | volume = 97 | issue = 3 | pages = 171–179 | date = March 2020 | pmid = 31871303 | pmc = 6978693 | doi = 10.1124/mol.119.118349 }}</ref><ref>{{cite journal | vauthors = Pandhare A, Pappu AS, Wilms H, Blanton MP, Jansen M | title = The antidepressant bupropion is a negative allosteric modulator of serotonin type 3A receptors | journal = Neuropharmacology | volume = 113 | issue = Pt A | pages = 89–99 | date = February 2017 | pmid = 27671323 | pmc = 5148637 | doi = 10.1016/j.neuropharm.2016.09.021 }}</ref>

| 87 (mouse)

| 113

| no data

| no data

| no data

=== Pharmacodynamics ===

{| class="wikitable floatright" style="font-size:small;"

|+ Bupropion binding and activity<ref name="PDSP-Database">{{cite web | title = Bupropion – PDSP K_i Database | work = Psychoactive Drug Screening Program (PDSP)|author1-link=Bryan Roth | vauthors = Roth BL, Driscol J | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 19 August 2024 | url = https://pdsp.unc.edu/databases/pdsp.php?recDDRadio=recDDRadio&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testDDRadio=testDDRadio&testLigandDD=991&testLigand=&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}</ref><ref name="BindingDB">{{cite web | vauthors = Liu T | title=BindingDB BDBM50048392 2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one::BUPROPION::BUPROPION HYDROCHLORIDE::CHEMBL894::US9944618, Compound ID No. 176 | website=BindingDB | url=https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50048392 | access-date=19 August 2024}}</ref><ref name="PubChem-BioAssay">{{cite web | title=Bupropion – Biological Test Results | work = PubChem | publisher = U.S. National Library of Medicine | url=https://pubchem.ncbi.nlm.nih.gov/compound/444#section=BioAssay-Results | access-date=19 August 2024}}</ref>

|-

! Site !! Value (nM) !! Type !! Species

|-

| {{Abbrlink|DAT|Dopamine transporter}} || 173–1,800<br />372–2,780<br />330–2,900<br />550–2,170 || K_i<br />K_i<br />IC₅₀<br />IC₅₀ || Human<br />Rat<br />Human<br />Rat

|-

| {{Abbrlink|NET|Norepinephrine transporter}} || 3,640–52,000<br />940–1,900<br />443–3,240<br />1,400–1,900 || K_i<br />K_i<br />IC₅₀<br />IC₅₀ || Human<br />Rat<br />Human<br />Rat

|-

| {{Abbrlink|SERT|Serotonin transporter}} || 9,100–>100,000<br />1,000–>10,000<br />47,000–>100,000<br />15,600 || K_i<br />K_i<br />IC₅₀<br />IC₅₀ || Human<br />Rat<br />Human<br />Rat

|-

| [[alpha-1 adrenergic receptor|α_1/1A-{{Abbr|AdR|Adrenergic receptor}}]] || 4,200–16,000 || K_i || Human

|-

| [[alpha-2 adrenergic receptor|α_2/2A-{{Abbr|AdR|Adrenergic receptor}}]] || >10,000–81,000 || K_i || Human

|-

| [[H1 receptor|H₁]] || 6,600–>10,000 || K_i || Human

|-

| [[Sigma-1 receptor|σ₁]] || 580–2,100 || IC₅₀ || Rodent<!--Ref: <ref name="FerrisRussellTang1991" />-->

|-

| [[Nicotinic acetylcholine receptor|α₁-{{Abbr|nACh|Nicotinic acetylcholine receptor}}]] || 7,600–28,000 || IC₅₀ || Human

|-

| [[Nicotinic acetylcholine receptor|α₃β₂-{{Abbr|nACh|Nicotinic acetylcholine receptor}}]] || 1,000 || IC₅₀ || Human

|-

| [[Nicotinic acetylcholine receptor|α₃β₄-{{Abbr|nACh|Nicotinic acetylcholine receptor}}]] || 1,800 || IC₅₀ || Human

|-

| [[Nicotinic acetylcholine receptor|α₄β₂-{{Abbr|nACh|Nicotinic acetylcholine receptor}}]] || 12,000 || IC₅₀ || Human

|-

| [[Nicotinic acetylcholine receptor|α₄β₄-{{Abbr|nACh|Nicotinic acetylcholine receptor}}]] || 12,000–14,000 || IC₅₀ || Human

|-

| [[Nicotinic acetylcholine receptor|α₇-{{Abbr|nACh|Nicotinic acetylcholine receptor}}]] || 7,900–50,000 || IC₅₀ || Human

|-

| [[Nicotinic acetylcholine receptor|α/β/δ/γ-{{Abbr|nACh|Nicotinic acetylcholine receptor}}]] || 7,900 || IC₅₀ || Human

|-

| {{Abbrlink|hERG|human Ether-à-go-go-Related Gene}} || 34,000–69,000 || IC₅₀ || Human<!-- Additional ref: <ref name="CaillierPiloteCastonguay2012">{{cite journal | vauthors = Caillier B, Pilote S, Castonguay A, Patoine D, Ménard-Desrosiers V, Vigneault P, Hreiche R, Turgeon J, Daleau P, De Koninck Y, Simard C, Drolet B | title = QRS widening and QT prolongation under bupropion: a unique cardiac electrophysiological profile | journal = Fundam Clin Pharmacol | volume = 26 | issue = 5 | pages = 599–608 | date = October 2012 | pmid = 21623902 | doi = 10.1111/j.1472-8206.2011.00953.x | url = }}</ref>-->

|- class="sortbottom"

| colspan="5" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' (1) Values are in nanomolar (nM) units. The smaller the value, the more avidly the drug binds to or affects the site. (2) Affinities (K_i) were >10,000{{nbsp}}nM at a variety of other sites (5-HT₁, 5-HT₂, β-adrenergic, D₁, D₂, {{Abbr|mACh|muscarinic acetylcholine}}, {{Abbr|nACh|nicotinic acetylcholine}}, GABA_A). '''More:''' <ref name="RichelsonNelson1984">{{cite journal | vauthors = Richelson E, Nelson A | title = Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro | journal = J Pharmacol Exp Ther | volume = 230 | issue = 1 | pages = 94–102 | date = July 1984 | pmid = 6086881 | doi = | url = }}</ref><ref name="WanderNelsonOkazaki1986">{{cite journal | vauthors = Wander TJ, Nelson A, Okazaki H, Richelson E | title = Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro | journal = Eur J Pharmacol | volume = 132 | issue = 2–3 | pages = 115–121 | date = December 1986 | pmid = 3816971 | doi = 10.1016/0014-2999(86)90596-0 | url = }}</ref><ref name="CusackNelsonRichelson1994">{{cite journal | vauthors = Cusack B, Nelson A, Richelson E | title = Binding of antidepressants to human brain receptors: focus on newer generation compounds | journal = Psychopharmacology (Berl) | volume = 114 | issue = 4 | pages = 559–565 | date = May 1994 | pmid = 7855217 | doi = 10.1007/BF02244985 | url = }}</ref><ref name="TatsumiGroshanBlakely1997">{{cite journal | vauthors = Tatsumi M, Groshan K, Blakely RD, Richelson E | title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters | journal = Eur J Pharmacol | volume = 340 | issue = 2–3 | pages = 249–258 | date = December 1997 | pmid = 9537821 | doi = 10.1016/s0014-2999(97)01393-9 | url = }}</ref><ref name="SánchezHyttel1999">{{cite journal | vauthors = Sánchez C, Hyttel J | title = Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding | journal = Cell Mol Neurobiol | volume = 19 | issue = 4 | pages = 467–489 | date = August 1999 | pmid = 10379421 | doi = 10.1023/a:1006986824213 | url = }}</ref><ref name="DamajCarrollEaton2004">{{cite journal | vauthors = Damaj MI, Carroll FI, Eaton JB, Navarro HA, Blough BE, Mirza S, Lukas RJ, Martin BR | title = Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors | journal = Mol Pharmacol | volume = 66 | issue = 3 | pages = 675–682 | date = September 2004 | pmid = 15322260 | doi = 10.1124/mol.104.001313 | url = }}</ref>

|}

The [[mechanism of action]] of bupropion in the treatment of depression and for other indications is unclear.<ref name="pmid31124380" /> However, it is thought to be related to the fact that bupropion is a [[norepinephrine–dopamine reuptake inhibitor]] (NDRI) and [[negative allosteric modulator]] of several [[nicotinic acetylcholine receptor]]s.<ref name="pmid31124380" /> Bupropion does not act as a [[norepinephrine–dopamine releasing agent]].<ref name="pmid28220701">{{cite journal | vauthors = Shalabi AR, Walther D, Baumann MH, Glennon RA | title = Deconstructed Analogues of Bupropion Reveal Structural Requirements for Transporter Inhibition versus Substrate-Induced Neurotransmitter Release | journal = ACS Chemical Neuroscience | volume = 8 | issue = 6 | pages = 1397–1403 | date = June 2017 | pmid = 28220701 | pmc = 7261150 | doi = 10.1021/acschemneuro.7b00055 }}</ref> Pharmacological actions of bupropion, to a substantial degree, are due to its active metabolites [[hydroxybupropion]], [[threohydrobupropion|''threo''-hydrobupropion]], and [[erythrohydrobupropion|''erythro''-hydrobupropion]] that are present in the blood plasma at comparable or much higher levels.<ref name="pmid31124380" /> In fact, bupropion could accurately be conceptualized as a [[prodrug]] of these metabolites.<ref name="pmid31124380" /> Overall action of these metabolites, and particularly one enantiomer [[radafaxine|''S,S''-hydroxybupropion]], is also characterized by inhibition of norepinephrine and dopamine reuptake and nicotinic inhibition (see the chart on the right).<ref name="pmid31124380" /> Bupropion has no meaningful direct activity at a variety of [[receptor (biochemistry)|receptors]], including [[alpha-adrenergic receptor|α-]] and [[beta-adrenergic receptor|β-adrenergic]], [[dopamine receptor|dopamine]], [[serotonin receptor|serotonin]], [[histamine receptor|histamine]], and [[muscarinic acetylcholine receptor]]s.<ref name="Dhillon" />

The occupancy of [[dopamine transporter]] (DAT) by bupropion (300{{nbsp}}mg/day) and its metabolites in the human brain as measured by several [[positron emission tomography]] (PET) studies is approximately 20%, with a mean occupancy range of about 14 to 26%.<ref name="HartSpangemacherDefert2024">{{cite journal | vauthors = Hart XM, Spangemacher M, Defert J, Uchida H, Gründer G | title = Update Lessons from PET Imaging Part II: A Systematic Critical Review on Therapeutic Plasma Concentrations of Antidepressants | journal = Ther Drug Monit | volume = 46 | issue = 2 | pages = 155–169 | date = April 2024 | pmid = 38287888 | doi = 10.1097/FTD.0000000000001142 | url = }}</ref><ref name="pmid33977870">{{cite journal | vauthors = Eap CB, Gründer G, Baumann P, Ansermot N, Conca A, Corruble E, Crettol S, Dahl ML, de Leon J, Greiner C, Howes O, Kim E, Lanzenberger R, Meyer JH, Moessner R, Mulder H, Müller DJ, Reis M, Riederer P, Ruhe HG, Spigset O, Spina E, Stegman B, Steimer W, Stingl J, Suzen S, Uchida H, Unterecker S, Vandenberghe F, Hiemke C | title = Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants | journal = The World Journal of Biological Psychiatry | volume = 22 | issue = 8 | pages = 561–628 | date = October 2021 | pmid = 33977870 | doi = 10.1080/15622975.2021.1878427 | s2cid = 234472488 | url = https://serval.unil.ch/resource/serval:BIB_6FD14CC75A02.P001/REF.pdf | access-date = 10 April 2022 | archive-date = 5 May 2022 | archive-url = https://web.archive.org/web/20220505232003/https://serval.unil.ch/resource/serval:BIB_6FD14CC75A02.P001/REF.pdf | url-status = live }}</ref><ref name="pmid24484978">{{cite book | vauthors = Carroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI | title = Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse | chapter = Bupropion and bupropion analogs as treatments for CNS disorders | series = Advances in Pharmacology | volume = 69 | pages = 177–216 | date = 2014 | publisher = Academic Press | pmid = 24484978 | doi = 10.1016/B978-0-12-420118-7.00005-6 | isbn = 978-0-12-420118-7 }}</ref><ref name="pmid28965364" /> For comparison, the NDRI [[methylphenidate]] at therapeutic doses is thought to occupy greater than 50% of DAT sites.<ref name="pmid28965364" /> In accordance with its low DAT occupancy, no measurable dopamine release in the human brain was detected with bupropion (one 150{{nbsp}}mg dose) in a PET study.<ref name="HartSpangemacherDefert2024" /><ref name="pmid33977870" /><ref name="pmid24484978" /><ref name="pmid19969097">{{cite journal | vauthors = Egerton A, Shotbolt JP, Stokes PR, Hirani E, Ahmad R, Lappin JM, Reeves SJ, Mehta MA, Howes OD, Grasby PM | title = Acute effect of the anti-addiction drug bupropion on extracellular dopamine concentrations in the human striatum: an [11C]raclopride PET study | journal = NeuroImage | volume = 50 | issue = 1 | pages = 260–266 | date = March 2010 | pmid = 19969097 | doi = 10.1016/j.neuroimage.2009.11.077 | pmc = 4135078 }}</ref> Bupropion has also been shown to increase striatal [[Vesicular monoamine transporter 2|VMAT2]], though it is unknown if this effect is more pronounced than other DRIs.<ref>{{cite journal | vauthors = Rau KS, Birdsall E, Hanson JE, Johnson-Davis KL, Carroll FI, Wilkins DG, Gibb JW, Hanson GR, Fleckenstein AE | title = Bupropion increases striatal vesicular monoamine transport | journal = Neuropharmacology | volume = 49 | issue = 6 | pages = 820–830 | date = November 2005 | pmid = 16005476 | doi = 10.1016/j.neuropharm.2005.05.004 | series = New Perspectives in Neurotransmitter Transporter Biology | s2cid = 26035635 }}</ref> These findings raise questions about the role of [[dopamine reuptake inhibition]] in the pharmacology of bupropion, and suggest that other actions may be responsible for its therapeutic effects.<ref name="HartSpangemacherDefert2024" /><ref name="pmid33977870" /><ref name="pmid28965364" /><ref name="pmid24484978" /> No data are available on occupancy of the [[norepinephrine transporter]] (NET) by bupropion and its metabolites.<ref name="HartSpangemacherDefert2024" /><ref name="pmid33977870" /> However, due to the increased exposure of hydroxybupropion over bupropion itself, which has higher [[affinity (pharmacology)|affinity]] for the NET than the DAT,<ref name="pmid20509659" /> bupropion's overall pharmacological profile in humans may end up making it effectively more of a [[norepinephrine reuptake inhibitor]] than a dopamine reuptake inhibitor.<ref name="DeBattista2022">{{cite book | vauthors = DeBattista C | chapter = Other Antidepressants: Bupropion, Mirtazapine, and Trazodone | veditors = Nemeroff CB, Schatzberg AF, Rasgon N, Strakowski SM | date = 16 June 2022 | title = The American Psychiatric Association Publishing Textbook of Mood Disorders, Second Edition | publisher = American Psychiatric Pub | pages = 365–374 | isbn = 978-1-61537-331-4 | oclc = 1249799493 | chapter-url = https://books.google.com/books?id=VAJ8EAAAQBAJ&pg=PA365 | access-date = 27 August 2022 | archive-date = 8 March 2023 | archive-url = https://web.archive.org/web/20230308050858/https://books.google.com/books?id=VAJ8EAAAQBAJ&pg=PA365 | url-status = live }}</ref><ref name="pmid35068363">{{cite journal | vauthors = Gautam M, Patel S, Zarkowski P | title = Practice patterns of bupropion co-prescription with antipsychotic medications | journal = J Addict Dis | volume = 40| issue = 4| pages = 481–488 | date = January 2022 | pmid = 35068363 | doi = 10.1080/10550887.2022.2028531 | s2cid = 246238087 | url = }}</ref> Accordingly, the clinical effects of bupropion are more consistent with noradrenergic activity than with dopaminergic actions.<ref name="DeBattista2022" /><ref name="pmid35068363" />

Bupropion has been claimed to be a [[sigma receptor|sigma]] [[sigma-1 receptor|σ₁ receptor]] [[agonist]].<ref name="SałaciakPytka2022">{{cite journal | vauthors = Sałaciak K, Pytka K | title = Revisiting the sigma-1 receptor as a biological target to treat affective and cognitive disorders | journal = Neurosci Biobehav Rev | volume = 132 | issue = | pages = 1114–1136 | date = January 2022 | pmid = 34736882 | pmc = 8559442 | doi = 10.1016/j.neubiorev.2021.10.037 | url = }}</ref><ref name="DhirKulkarni2008">{{cite journal | vauthors = Dhir A, Kulkarni SK | title = Possible involvement of sigma-1 receptors in the anti-immobility action of bupropion, a dopamine reuptake inhibitor | journal = Fundam Clin Pharmacol | volume = 22 | issue = 4 | pages = 387–394 | date = August 2008 | pmid = 18705749 | doi = 10.1111/j.1472-8206.2008.00605.x | url = }}</ref> Its antidepressant-like effects in rodents depend on σ₁ receptor activation.<ref name="SałaciakPytka2022" /><ref name="DhirKulkarni2008" /><ref name="BrimsonBrimsonChomchoei2020">{{cite journal | vauthors = Brimson JM, Brimson S, Chomchoei C, Tencomnao T | title = Using sigma-ligands as part of a multi-receptor approach to target diseases of the brain | journal = Expert Opin Ther Targets | volume = 24 | issue = 10 | pages = 1009–1028 | date = October 2020 | pmid = 32746649 | doi = 10.1080/14728222.2020.1805435 | url = | quote = AXS-05 is a combination of dextromethorphan and bupropion and has been shown to have a rapid (within one week) positive effect in patients with depression. Dextromethorphan, as described above as part of Nuedexta, is a σ-1R agonist, an NMDA antagonist, and has affinity for the serotonin reuptake transporter. Whereas, bupropion is a moderately effective antidepressant when taken alone, thought to act by preventing dopamine and noradrenaline reuptake [230]. Studies in mice have shown that the antidepressant-like effects of bupropion are potentiated by σ-1R agonists, and inhibited by σ-1R antagonists [231]. These findings suggest that the combination of a σ-1R agonist and the dopamine/ noradrenaline reuptake inhibitor will be more effective than either treatment alone.}}</ref> They are enhanced and inhibited by σ₁ receptor agonists and antagonists, respectively.<ref name="SałaciakPytka2022" /><ref name="DhirKulkarni2008" /><ref name="BrimsonBrimsonChomchoei2020" /> However, no data on the binding or functional effects of bupropion at the human sigma receptors seem to be available.<ref name="PDSP-Database" /><ref name="BindingDB" /><ref name="PubChem-BioAssay" /> In any case, bupropion has been reported to bind to rodent σ₁ receptors with {{Abbrlink|IC₅₀|half-maximal inhibitory concentration}} values of 580 to 2,100{{nbsp}}nM.<ref name="FerrisRussellTang1991">{{cite journal | vauthors = Ferris RM, Russell A, Tang FL, Topham PA | title=Labeling in vivo of sigma receptors in mouse brain with [ 3 H]-(+)-SKF 10,047: Effects of phencyclidine, (+)- and (−)-N-allylnormetazocine, and other drugs | journal=Drug Development Research | volume=24 | issue=1 | date=1991 | issn=0272-4391 | doi=10.1002/ddr.430240107 | pages=81–92}}</ref> In contrast to many other [[substituted phenethylamine|phenethylamines]] and [[substituted amphetamine|amphetamines]],<ref name="pmid27092049">{{cite journal | vauthors = Pei Y, Asif-Malik A, Canales JJ | title = Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications | journal = Front Neurosci | volume = 10 | issue = | pages = 148 | date = 2016 | pmid = 27092049 | pmc = 4820462 | doi = 10.3389/fnins.2016.00148 | doi-access = free | url = }}</ref> bupropion is not an [[agonist]] of the [[trace amine-associated receptor 1]] (TAAR1).<ref name="SimmlerBuchyChaboz2016">{{cite journal | vauthors = Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME | title = In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1 | journal = J Pharmacol Exp Ther | volume = 357 | issue = 1 | pages = 134–144 | date = April 2016 | pmid = 26791601 | doi = 10.1124/jpet.115.229765 | url = }}</ref><ref name="GursahaniJolasMartin2023">{{cite journal | vauthors = Gursahani H, Jolas T, Martin M, Cotier S, Hughes S, Macfadden W, Parks G, Chepke C | title=Preclinical Pharmacology of Solriamfetol: Potential Mechanisms for Wake Promotion | journal=CNS Spectrums | volume=28 | issue=2 | date=2023 | issn=1092-8529 | doi=10.1017/S1092852923001396 | page=222 | quote = In vitro functional studies showed agonist activity of solriamfetol at human, mouse, and rat TAAR1 receptors. hTAAR1 EC50 values (10–16 μM) were within the clinically observed therapeutic solriamfetol plasma concentration range and overlapped with the observed DAT/NET inhibitory potencies of solriamfetol in vitro. TAAR1 agonist activity was unique to solriamfetol; neither the WPA modafinil nor the DAT/NET inhibitor bupropion had TAAR1 agonist activity.}}</ref>

Bupropion has been found to have a mixture of [[anti-inflammatory]] and [[pro-inflammatory]] activity through [[immunomodulation|modulation of the immune system]].<ref name="StrawbridgeIzurieta2023">{{cite journal | vauthors = Strawbridge R, Izurieta E, Day E, Tee H, Young K, Tong CC, Young AH, Cleare AJ | title=Peripheral inflammatory effects of different interventions for treatment-resistant depression: A systematic review | journal=Neuroscience Applied | publisher=Elsevier BV | volume=2 | year=2023 | issn=2772-4085 | doi=10.1016/j.nsa.2022.101014 | page=101014| s2cid=253283525 | doi-access=free }}</ref><ref name="pmid25657796">{{cite journal | vauthors = Hajhashemi V, Khanjani P | title = Analgesic and anti-inflammatory activities of bupropion in animal models | journal = Res Pharm Sci | volume = 9 | issue = 4 | pages = 251–7 | date = 2014 | pmid = 25657796 | pmc = 4314873 | doi = | url = }}</ref><ref name="pmid34218389">{{cite journal | vauthors = Karimollah A, Hemmatpur A, Vahid T | title = Revisiting bupropion anti-inflammatory action: involvement of the TLR2/TLR4 and JAK2/STAT3 | journal = Inflammopharmacology | volume = 29 | issue = 4 | pages = 1101–1109 | date = August 2021 | pmid = 34218389 | doi = 10.1007/s10787-021-00829-4 | s2cid = 234883621 | url = }}</ref><ref name="pmid36928557">{{cite journal | vauthors = Yetkin D, Yılmaz İA, Ayaz F | title = Anti-inflammatory activity of bupropion through immunomodulation of the macrophages | journal = Naunyn-Schmiedeberg's Arch Pharmacol | volume = 396 | issue = 9 | pages = 2087–2093 | date = September 2023 | pmid = 36928557 | doi = 10.1007/s00210-023-02462-0 | s2cid = 257583439 | url = }}</ref><ref name="pmid25670957">{{cite journal | vauthors = Chen WC, Lai HC, Su WP, Palani M, Su KP | title = Bupropion for interferon-alpha-induced depression in patients with hepatitis C viral infection: an open-label study | journal = Psychiatry Investig | volume = 12 | issue = 1 | pages = 142–5 | date = January 2015 | pmid = 25670957 | pmc = 4310912 | doi = 10.4306/pi.2015.12.1.142 | url = }}</ref><ref name="pmid23953570">{{cite journal | vauthors = Cámara-Lemarroy CR, Guzmán-de la Garza FJ, Cordero-Pérez P, Alarcón-Galván G, Ibarra-Hernández JM, Muñoz-Espinosa LE, Fernández-Garza NE | title = Bupropion reduces the inflammatory response and intestinal injury due to ischemia-reperfusion | journal = Transplant Proc | volume = 45 | issue = 6 | pages = 2502–5 | date = 2013 | pmid = 23953570 | doi = 10.1016/j.transproceed.2013.04.010 | url = }}</ref><ref name="pmid33186562">{{cite journal | vauthors = Tafseer S, Gupta R, Ahmad R, Jain S, Bhatia MS, Gupta LK | title = Bupropion monotherapy alters neurotrophic and inflammatory markers in patients of major depressive disorder | journal = Pharmacol Biochem Behav | volume = 200 | issue = | pages = 173073 | date = January 2021 | pmid = 33186562 | doi = 10.1016/j.pbb.2020.173073 | s2cid = 226292409 | url = }}</ref> One such mechanism underlying these effects may be reduced levels of the pro-inflammatory [[cytokine]] [[tumor necrosis factor alpha]] (TNFα).<ref name="StrawbridgeIzurieta2023" /><ref name="pmid33186562" /><ref name="pmid16644475" /> The catecholaminergic actions of bupropion may be involved in its immunomodulatory effects.<ref name="pmid16644475">{{cite journal | vauthors = Brustolim D, Ribeiro-dos-Santos R, Kast RE, Altschuler EL, Soares MB | title = A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice | journal = Int Immunopharmacol | volume = 6 | issue = 6 | pages = 903–7 | date = June 2006 | pmid = 16644475 | doi = 10.1016/j.intimp.2005.12.007 | url = https://www.arca.fiocruz.br/handle/icict/2741 | access-date = 25 October 2023 | archive-date = 16 October 2023 | archive-url = https://web.archive.org/web/20231016200627/https://www.arca.fiocruz.br/handle/icict/2741 | url-status = live }}</ref>

=== Pharmacokinetics ===

[[File:Metabolism of bupropion.png|thumb|250px|upright=1.7|Principal pathways of bupropion metabolism]]

After oral administration, bupropion is rapidly and completely absorbed reaching the peak blood plasma concentration after 1.5 hours ([[Cmax (pharmacology)|t_max]]). Sustained release (SR) and extended release (XL) formulations have been designed to slow down absorption resulting in t_max of 3 hours and 5 hours, respectively.<ref name="pmid16368442" /> Absolute [[bioavailability]] of bupropion is unknown but is presumed to be low, at 5–20%, due to the [[First pass effect|first-pass metabolism]]. As for the relative bioavailability of the formulations, XL formulation has lower bioavailability (68%) compared to SR formulation and immediate release bupropion.<ref name="pmid31124380" />

Bupropion is metabolized in the body by a variety of pathways. The [[oxidation|oxidative]] pathways are by [[cytochrome P450]] isoenzymes [[CYP2B6]] leading to [[(2R,3R)-Hydroxybupropion|''R,R'']]- and [[radafaxine|''S,S''-hydroxybupropion]] and, to a lesser degree, [[CYP2C19]] leading to 4'-hydroxybupropion. The [[reduction (chemistry)|reductive]] pathways are by [[11β-hydroxysteroid dehydrogenase type 1]] in the liver and [[AKR7A2]]/[[AKR7A3]] in the intestine leading to [[threohydrobupropion|''threo''-hydrobupropion]] and by yet unknown enzyme leading to [[erythrohydrobupropion|''erythro''-hydrobupropion]].<ref name="pmid31124380" />

The metabolism of bupropion is highly variable: the effective doses of bupropion received by persons who ingest the same amount of the drug may differ by as much as 5.5&nbsp;times (with a [[Biological half-life|half-life]] of 12–30&nbsp;hours), while the effective doses of [[hydroxybupropion]] may differ by as much as 7.5&nbsp;times (with a half-life of 15–25&nbsp;hours).<ref name="Wellbutrin SR FDA label" /><ref name="Bupropion half-life">{{cite book | isbn = 978-0-07-162442-8 | title = Goodman and Gilman's The Pharmacological Basis of Therapeutics | edition = 12th | vauthors = Brunton L, Chabner B, Knollman B | year = 2010 | publisher = McGraw-Hill Professional | location = New York | title-link = Goodman and Gilman's The Pharmacological Basis of Therapeutics }}{{page needed|date=December 2015}}</ref><ref name="pmid15083067">{{cite journal | vauthors = Hesse LM, He P, Krishnaswamy S, Hao Q, Hogan K, von Moltke LL, Greenblatt DJ, Court MH | title = Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes | journal = Pharmacogenetics | volume = 14 | issue = 4 | pages = 225–238 | date = April 2004 | pmid = 15083067 | doi = 10.1097/00008571-200404000-00002 }}</ref> Based on this, some researchers have advocated monitoring of the blood level of bupropion and hydroxybupropion.<ref name="pmid1813908">{{cite journal | vauthors = Preskorn SH | title = Should bupropion dosage be adjusted based upon therapeutic drug monitoring? | journal = Psychopharmacology Bulletin | volume = 27 | issue = 4 | pages = 637–643 | year = 1991 | pmid = 1813908 }}</ref>

The metabolism of bupropion also seems to follow biphasic pharmacokinetics: the redistribution alpha phase with half-life of about 1 hour<ref name="pmid6140095">{{cite journal | vauthors = Bryant SG, Guernsey BG, Ingrim NB | title = Review of bupropion | journal = Clinical Pharmacy | volume = 2 | issue = 6 | pages = 525–37 | date = 1983 | pmid = 6140095 | doi = | url = }}</ref> precedes the metabolism beta phase of about 12-30 hours. This might explain why abuse is unfeasible due to a short "high", as well as support the use of extended-release formulas to maintain a consistent concentration of bupropion.

The metabolism of bupropion is highly species-dependent.<ref name="CarrollBloughMascarella2014">{{cite book | vauthors = Carroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI | title = Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse | chapter = Bupropion and bupropion analogs as treatments for CNS disorders | series = Adv Pharmacol | volume = 69 | pages = 177–216 | date = 2014 | pmid = 24484978 | doi = 10.1016/B978-0-12-420118-7.00005-6 | isbn = 978-0-12-420118-7 | chapter-url = }}</ref><ref name="CostaOliveiraDinis-Oliveira2019">{{cite journal | vauthors = Costa R, Oliveira NG, Dinis-Oliveira RJ | title = Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects | journal = Drug Metab Rev | volume = 51 | issue = 3 | pages = 293–313 | date = August 2019 | pmid = 31124380 | doi = 10.1080/03602532.2019.1620763 | url = }}</ref><ref name="WelchLaiSchroeder1987">{{cite journal | vauthors = Welch RM, Lai AA, Schroeder DH | title = Pharmacological significance of the species differences in bupropion metabolism | journal = Xenobiotica | volume = 17 | issue = 3 | pages = 287–298 | date = March 1987 | pmid = 3107223 | doi = 10.3109/00498258709043939 | url = }}</ref> As an example, oral bupropion results in hydroxybupropion levels that are 16-fold higher than those of bupropion itself in humans, whereas in rats, oral bupropion results in levels of bupropion that are 3.4-fold higher than those of hydroxybupropion.<ref name="CarrollBloughMascarella2014" /> The species-dependent metabolism of bupropion is thought to be involved in species differences in its pharmacodynamic effects.<ref name="CarrollBloughMascarella2014" /><ref name="CostaOliveiraDinis-Oliveira2019" /><ref name="WelchLaiSchroeder1987" /> For example, bupropion produces [[psychostimulant]]-like and [[positive reinforcement|reinforcing]] effects in rodents, whereas oral bupropion at therapeutic doses seems to have much less or no potential for such effects in humans.<ref name="NaglichBrownAdinoff2019">{{cite journal | vauthors = Naglich AC, Brown ES, Adinoff B | title = Systematic review of preclinical, clinical, and post-marketing evidence of bupropion misuse potential | journal = Am J Drug Alcohol Abuse | volume = 45 | issue = 4 | pages = 341–354 | date = 2019 | pmid = 30601027 | doi = 10.1080/00952990.2018.1545023 | url = }}</ref>

== Chemistry ==

Bupropion is an [[aminoketone]] that belongs to the [[chemical classification|class]] of [[substituted cathinone]]s and the more general class of [[substituted phenethylamine]]s.<ref name=PubChem2018 /><ref name="Dye2017" /> It is also known structurally as 3-chloro-''N''-''tert''-butyl-β-keto-α-methylphenethylamine, 3-chloro-''N''-''tert''-butyl-β-ketoamphetamine, or 3-chloro-''N''-''tert''-butylcathinone. The clinically used bupropion is [[racemic]], that is a mixture of two [[enantiomer]]s: ''S''-bupropion and ''R''-bupropion. Although the [[optical isomer]]s on bupropion can be separated, they rapidly [[racemization|racemize]] under physiological conditions.<ref name="pmid31124380" /><ref name="doi">{{cite journal | vauthors = Musso DL, Mehta NB, Soroko FE, Ferris RM, Hollingsworth EB, Kenney BT | title = Synthesis and evaluation of the antidepressant activity of the enantiomers of bupropion | journal = Chirality | volume = 5 | issue = 7 | pages = 495–500 | year = 1993 | pmid = 8240925 | doi = 10.1002/chir.530050704 }}</ref>

Bupropion is a [[small molecule|small-molecule]] [[chemical compound|compound]] with the [[molecular formula]] C₁₃H₁₈ClNO and a [[molecular weight]] of 239.74{{nbsp}}g/mol.<ref name="PubChem">{{cite web | title=Bupropion | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/444 | access-date=4 August 2024}}</ref><ref name="DrugBank">{{cite web | title=Bupropion: Uses, Interactions, Mechanism of Action | website=DrugBank Online | date=30 March 2009 | url=https://go.drugbank.com/drugs/DB01156 | access-date=4 August 2024}}</ref> It is a highly [[lipophilic]] compound,<ref name="pmid31124380" /> with an experimental [[partition coefficient|log P]] of 3.6.<ref name="PubChem" /><ref name="DrugBank" /> Pharmaceutically, bupropion is used mainly as the [[hydrochloride]] [[salt (chemistry)|salt]] but also to a lesser extent as the [[hydrobromide]] salt.<ref name="Wellbutrin SR FDA label" /><ref name="Wellbutrin XL FDA label" /><ref name="IndexNominum2004">{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum: International Drug Directory | publisher=Medpharm Scientific Publishers | year=2004 | isbn=978-3-88763-101-7 | url=https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA173 | access-date=4 August 2024 | page=173}}</ref>

A number of [[structural analog|analogues]] of bupropion exist, such as [[hydroxybupropion]], [[radafaxine]], and [[manifaxine]], among others.<ref name="CarrollBloughMascarella2014">{{cite book | vauthors = Carroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI | title = Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse | chapter = Bupropion and bupropion analogs as treatments for CNS disorders | series = Adv Pharmacol | volume = 69 | pages = 177–216 | date = 2014 | pmid = 24484978 | doi = 10.1016/B978-0-12-420118-7.00005-6 | isbn = 978-0-12-420118-7 | chapter-url = }}</ref>

There have been reported cases of false-positive urine amphetamine tests in persons taking bupropion.<ref name="pmid10999247">{{cite journal | vauthors = Weintraub D, Linder MW | title = Amphetamine positive toxicology screen secondary to bupropion | journal = Depression and Anxiety | volume = 12 | issue = 1 | pages = 53–54 | year = 2000 | pmid = 10999247 | doi = 10.1002/1520-6394(2000)12:1<53::AID-DA8>3.0.CO;2-4 | s2cid = 43480769 | doi-access = free }}</ref><ref name="pmid7768026">{{cite journal | vauthors = Nixon AL, Long WH, Puopolo PR, Flood JG | title = Bupropion metabolites produce false-positive urine amphetamine results | journal = Clinical Chemistry | volume = 41 | issue = 6 Pt 1 | pages = 955–956 | date = June 1995 | pmid = 7768026 | doi = 10.1093/clinchem/41.6.955 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Casey ER, Scott MG, Tang S, Mullins ME | title = Frequency of false positive amphetamine screens due to bupropion using the Syva EMIT II immunoassay | journal = Journal of Medical Toxicology | volume = 7 | issue = 2 | pages = 105–108 | date = June 2011 | pmid = 21191682 | pmc = 3724447 | doi = 10.1007/s13181-010-0131-5 }}</ref>

=== Synthesis ===

It is synthesized in two chemical steps starting from 3'-chloro-[[propiophenone]]. The alpha position adjacent to the ketone is first [[ketone halogenation|brominated]] followed by [[nucleophilic displacement]] of the resulting alpha-bromoketone with [[Tert-Butylamine|''t''-butylamine]] and treated with [[hydrochloric acid]] to give bupropion as the hydrochloride salt in 75–85% overall yield.<ref name="USPatent" /><ref>{{cite journal |vauthors=Perrine DM, Ross JT, Nervi SJ, Zimmerman RH | title = A Short, One-Pot Synthesis of Bupropion (Zyban, Wellbutrin) | journal = Journal of Chemical Education | volume = 77 | issue = 11 | page = 1479 | year = 2000 | doi = 10.1021/ed077p1479 | bibcode = 2000JChEd..77.1479P }}</ref><br />{{Annotated image 4

| image = Synthesis of bupropion.svg

| height = 120

{{Annotation|10|90|3'-chloro-propiophenone}}

{{Annotation|200|90|3'-chloro-2-bromopropiophenone}}<!--AKA 2-bromo-1-(3-chlorophenyl)propan-1-one -->

{{Annotation|505|90|bupropion hydrochloride}}

== History ==

[[File:Comparison of bupropion levels with bupropion IR, bupropion SR, and bupropion XL.png|thumb|250px|Comparison of [[steady state (pharmacokinetics)|steady-state]] plasma bupropion levels with bupropion IR 100 mg t.i.d. (3x/day), bupropion SR 150 mg b.i.d. (2x/day), and bupropion XL 300 mg q.d. (1x/day)<ref name="pmid16027765">{{cite journal | vauthors = Fava M, Rush AJ, Thase ME, Clayton A, Stahl SM, Pradko JF, Johnston JA | title = 15 years of clinical experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL | journal = Primary Care Companion to the Journal of Clinical Psychiatry | volume = 7 | issue = 3 | pages = 106–113 | date = 2005 | pmid = 16027765 | pmc = 1163271 | doi = 10.4088/pcc.v07n0305 }}</ref><ref name="pmid16368442" />]]

Bupropion was invented by [[Nariman Mehta]] of Burroughs Wellcome (now [[GlaxoSmithKline]]) in 1969, and the US patent for it was granted in 1974.<ref name="USPatent" /> It was approved by the US [[Food and Drug Administration]] (FDA) as an antidepressant on 30 December 1985, and marketed under the name Wellbutrin.<ref name=approvals>{{cite web | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/018644Orig1s000rev.pdf | title=Wellbutrin approval package | website=U.S. [[Food and Drug Administration]] (FDA) | date=30 December 1985 | access-date=5 May 2020 | archive-date=27 November 2020 | archive-url=https://web.archive.org/web/20201127060724/https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/018644Orig1s000rev.pdf | url-status=live }}</ref><ref>{{cite web |title=Wellbutrin entry in the Orange Book |publisher=U.S. Food and Drug Administration Center for Drug Evaluation and Research |access-date=18 August 2007 |url=http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=018644&TABLE1=OB_Rx | archive-url=https://web.archive.org/web/20110225123027/http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=018644&TABLE1=OB_Rx | archive-date=25 February 2011 | url-status=dead }}</ref> However, a significant incidence of [[seizure]]s at the originally recommended dosage (400–600&nbsp;mg/day) caused the withdrawal of the drug in 1986. Subsequently, the risk of seizures was found to be highly dose-dependent, and bupropion was re-introduced to the market in 1989 with a lower maximum recommended daily dose of 450&nbsp;mg/day.<ref>{{cite web|url=http://www.emedexpert.com/facts/bupropion-facts.shtml|title=Bupropion (Wellbutrin)|publisher=eMedExpert.com|date=31 March 2008|access-date=20 August 2013|archive-date=6 August 2013|archive-url=https://web.archive.org/web/20130806062237/http://www.emedexpert.com/facts/bupropion-facts.shtml|url-status=live}}</ref>

In 1996, the US [[Food and Drug Administration]] (FDA) approved a [[time release technology|sustained-release]] formulation of alcohol-resistant bupropion called Wellbutrin SR, intended to be taken twice a day (as compared with three times a day for immediate-release Wellbutrin).<ref name="NIDA_notes">{{cite journal|url=http://drugabuse.gov/NIDA_notes/NNvol20N5/Bupropion.html |title=Bupropion helps people with schizophrenia quit smoking | vauthors = Whitten L |journal=National Institute on Drug Abuse Research Findings |volume=20 |issue=5 |date=April 2006 |access-date=27 May 2013 |url-status=dead |archive-url=https://web.archive.org/web/20070805053452/http://drugabuse.gov/NIDA_notes/NNvol20N5/Bupropion.html |archive-date=5 August 2007 }}</ref> In 2003, the FDA approved another sustained-release formulation called Wellbutrin XL, intended for once-daily dosing.<ref name="Wellbutrin XL FDA approval package">{{cite web | title=Drug Approval Package: Wellbutrin XL (Bupropion HCI) NDA #021515 | website=U.S. [[Food and Drug Administration]] (FDA) | date=22 April 2005 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/021515_Wellbutrin.cfm | archive-url=https://web.archive.org/web/20191205063010/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/021515_Wellbutrin.cfm | archive-date=5 December 2019 | url-status=live | access-date=4 December 2019}}</ref> Wellbutrin SR and XL are available in [[generic drug|generic]] form in the United States and Canada. In 1997, bupropion was approved by the FDA for use as a smoking cessation aid under the name Zyban.<ref name="Zyban FDA approval package">{{cite web | title=Drug Approval Package: Zyban NDA# 020711 | website=U.S. [[Food and Drug Administration]] (FDA) | date=8 August 2003 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020711_zyban_toc.cfm | archive-url=https://web.archive.org/web/20191205063510/https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020711_zyban_toc.cfm | archive-date=5 December 2019 | url-status=live | access-date=4 December 2019}}</ref><ref name="NIDA_notes" /> In 2006, Wellbutrin XL was similarly approved as a treatment for seasonal affective disorder.<ref>{{cite web | url=https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/021515s010,021515s018LTR.pdf | title=FDA approval letter | website=U.S. [[Food and Drug Administration]] (FDA) | date=6 December 2006 | access-date=21 October 2020 | archive-date=1 November 2020 | archive-url=https://web.archive.org/web/20201101185857/https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/021515s010,021515s018LTR.pdf | url-status=live }}</ref><ref name="wellbutrin_seasonal">{{cite news|url=http://www.cnn.com/HEALTH/library/DI/00069.html |title=Seasonal affective disorder drug Wellbutrin XL wins approval |publisher=CNN |date=14 June 2006 |access-date=19 August 2007 |url-status=dead |archive-url=https://web.archive.org/web/20070630052951/http://www3.cnn.com/HEALTH/library/DI/00069.html |archive-date=30 June 2007 }}</ref>

In October 2007, two providers of consumer information on nutritional products and supplements, ConsumerLab.com and The People's Pharmacy, released the results of comparative tests of different brands of bupropion.<ref name=peoples>{{cite web |url=http://www.peoplespharmacy.com/archives/generic_drug_problems/generic_drug_equality_questioned.php |title=Generic drug equality questioned |access-date=13 October 2007 |date=12 October 2007 |archive-date=20 October 2012 |archive-url=https://web.archive.org/web/20121020041011/http://www.peoplespharmacy.com/2007/10/12/generic-drug-eq/ |url-status=dead }}</ref> The People's Pharmacy received multiple reports of increased side effects and decreased efficacy of generic bupropion, which prompted it to ask ConsumerLab.com to test the products in question. The tests showed that "one of a few generic versions of Wellbutrin XL 300&nbsp;mg, sold as Budeprion XL 300&nbsp;mg, didn't perform the same as the brand-name pill in the lab."<ref name=msnbc>{{cite web |url=http://www.nbcnews.com/id/21142869 |title=Report questions generic antidepressant |access-date=13 October 2007 |vauthors=Stenson J |date=12 October 2007 |work=[[NBC News]] |archive-date=11 October 2013 |archive-url=https://web.archive.org/web/20131011111651/http://www.nbcnews.com/id/21142869/ |url-status=dead }}</ref> The FDA investigated these complaints and concluded that Budeprion XL is equivalent to Wellbutrin XL in regard to bioavailability of bupropion and its main active metabolite hydroxybupropion. The FDA also said that coincidental natural mood variation is the most likely explanation for the apparent worsening of depression after the switch from Wellbutrin XL to Budeprion XL.<ref name="urlReview of Therapeutic Equivalence: Generic Bupropion XL 300&nbsp;mg and Wellbutrin XL 300&nbsp;mg">{{cite web |url=https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm153270.htm|archive-url=https://web.archive.org/web/20110606092603/https://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm153270.htm |archive-date=6 June 2011|title=Review of therapeutic equivalence: generic bupropion XL 300&nbsp;mg and Wellbutrin XL 300&nbsp;mg |website=[[Food and Drug Administration]] |access-date=19 April 2008 }}</ref> On 3 October 2012, however, the FDA reversed this opinion, announcing that "Budeprion XL 300&nbsp;mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300&nbsp;mg."<ref name=PR_FDA20121023>{{cite web |title=Budeprion XL 300&nbsp;mg not therapeutically equivalent to Wellbutrin XL 300&nbsp;mg |publisher=U.S. [[Food and Drug Administration]] (FDA) |date=3 October 2012 |url=https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/update-bupropion-hydrochloride-extended-release-300-mg-bioequivalence-studies |access-date=23 March 2013 |archive-date=13 December 2019 |archive-url=https://web.archive.org/web/20191213201311/https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/update-bupropion-hydrochloride-extended-release-300-mg-bioequivalence-studies |url-status=live }} {{PD-notice}}</ref> The FDA did not test the bioequivalence of any of the other generic versions of Wellbutrin XL 300&nbsp;mg, but requested that the four manufacturers submit data on this question to the FDA by March 2013.<ref name="PR_FDA20121023" /> {{as of|2013|October|}} the FDA has made determinations on the formulations from some manufacturers not being bioequivalent.<ref name="PR_FDA20121023" />

In April 2008, the FDA approved a formulation of bupropion as a hydrobromide salt instead of a hydrochloride salt, to be sold under the name Aplenzin by [[Sanofi|Sanofi-Aventis]].<ref name="Aplenzin FDA label">{{cite web | title=Aplenzin – bupropion hydrobromide tablet, extended release | website=DailyMed | date=2 June 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6494d2d9-0ce4-4126-b1c7-49684395942b | access-date=21 October 2020 | archive-date=26 October 2020 | archive-url=https://web.archive.org/web/20201026101907/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6494d2d9-0ce4-4126-b1c7-49684395942b | url-status=live }}</ref><ref>{{cite web |url=http://www.medscape.com/viewarticle/574187 |title=FDA Approvals: Advair, Relistor, Aplenzin |access-date=9 May 2008 |vauthors=Waknine Y |date=8 May 2008 |publisher=[[Medscape]] |archive-date=6 July 2022 |archive-url=https://web.archive.org/web/20220706100503/https://login.medscape.com/login/sso/getlogin?urlCache=aHR0cDovL3d3dy5tZWRzY2FwZS5jb20vdmlld2FydGljbGUvNTc0MTg3 |url-status=live }}</ref><ref name="Aplenzin FDA approval package">{{cite web | title=Drug Approval Package: Aplenzin (Bupropion Hydrobromide) NDA 22108 | website=U.S. [[Food and Drug Administration]] (FDA) | date=24 December 1999 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022108s000TOC.cfm | access-date=5 May 2020 | archive-date=15 August 2020 | archive-url=https://web.archive.org/web/20200815141633/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022108s000TOC.cfm | url-status=live }}</ref>

In 2009, the FDA issued a health advisory warning that the prescription of bupropion for smoking cessation has been associated with reports about unusual behavior changes, agitation and hostility. Some people, according to the advisory, have become depressed or have had their depression worsen, have had thoughts about suicide or dying, or have attempted suicide.<ref name=warning>{{cite web|title=Public Health Advisory: FDA requires new boxed warnings for the smoking cessation drugs Chantix and Zyban |date=1 July 2009 |access-date=3 July 2009 |url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm169988.htm |publisher=U.S. [[Food and Drug Administration]] (FDA) |url-status=dead |archive-url=https://web.archive.org/web/20101019032042/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm169988.htm |archive-date=19 October 2010 }}</ref> This advisory was based on a review of anti-smoking products that identified 75 reports of "suicidal adverse events" for bupropion over ten years.<ref>{{cite journal |title=The smoking cessation aids varenicline (marketed as Chantix) and bupropion (marketed as Zyban and generics) suicidal ideation and behavior |journal=Drug Safety Newsletter |volume=2 |issue=1 |pages=1–4 |year=2009 |url=https://www.fda.gov/downloads/Drugs/DrugSafety/DrugSafetyNewsletter/UCM107318.pdf |access-date=16 December 2019 |archive-url=https://web.archive.org/web/20170211101131/http://www.fda.gov/downloads/Drugs/DrugSafety/DrugSafetyNewsletter/UCM107318.pdf |archive-date=11 February 2017 |url-status=dead }}</ref> Based on the results of follow-up trials this warning was removed in 2016.<ref>{{cite web |title=Safety Alerts for Human Medical Products – Chantix (varenicline) and Zyban (bupropion) | work = Drug Safety Communication – Mental Health Side Effects Revised | date = 16 December 2016 |url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm533517.htm| publisher = U.S. [[Food and Drug Administration]] (FDA)|access-date=20 December 2016|archive-url=https://web.archive.org/web/20161220045956/http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm533517.htm|archive-date=20 December 2016|url-status=dead}}</ref>

In 2012, the US Justice Department announced that GlaxoSmithKline had agreed to plead guilty and pay a $3 billion fine, in part for promoting the unapproved use of Wellbutrin for weight loss and sexual dysfunction.<ref>{{cite news |title=Glaxo agrees to pay $3 billion in fraud settlement |newspaper=The New York Times |date=2 July 2012 |url=https://www.nytimes.com/2012/07/03/business/glaxosmithkline-agrees-to-pay-3-billion-in-fraud-settlement.html |vauthors=Thomas K, Schmidt MS |access-date=26 February 2017 |archive-date=2 March 2017 |archive-url=https://web.archive.org/web/20170302145001/http://www.nytimes.com/2012/07/03/business/glaxosmithkline-agrees-to-pay-3-billion-in-fraud-settlement.html |url-status=live }}</ref>

In 2017, the [[European Medicines Agency]] (EMA) recommended suspending a number of nationally approved medicines due to misrepresentation of bioequivalence study data by Micro Therapeutic Research Labs in India.<ref>{{cite web |url=https://www.ema.europa.eu/en/news/ema-recommends-suspension-medicines-due-unreliable-studies-micro-therapeutic-research-labs |author=Committee for Medicinal Products for Human Use (CHMP) |title=EMA recommends suspension of medicines due to unreliable studies from Micro Therapeutic Research Labs |date=24 March 2017 |work=European Medicines Agency |access-date=26 November 2020 |archive-date=26 October 2020 |archive-url=https://web.archive.org/web/20201026020349/https://www.ema.europa.eu/en/news/ema-recommends-suspension-medicines-due-unreliable-studies-micro-therapeutic-research-labs |url-status=live }}</ref> The products recommended for suspension included several 300&nbsp;mg modified-release bupropion tablets.<ref>{{cite web | url = https://www.ema.europa.eu/en/documents/referral/micro-therapeutic-research-article-31-referral-products-which-marketing-authorisations-are_en.pdf | title = Products for which the marketing authorisations are recommended for suspension and marketing authorisation applications which do not satisfy the criteria for authorisation as adopted by the CHMP | date = 23 March 2017 | author = Committee for Medicinal Products for Human Use (CHMP) | work = European Medicines Agency | access-date = 26 November 2020 | archive-date = 19 January 2021 | archive-url = https://web.archive.org/web/20210119024519/https://www.ema.europa.eu/en/documents/referral/micro-therapeutic-research-article-31-referral-products-which-marketing-authorisations-are_en.pdf | url-status = live }}</ref>

Following EMA's call for an industry-wide review of medicines for the possible presence of nitrosamines,<ref>{{cite web |date=26 September 2019 |title=EMA advises companies on steps to take avoid nitrosamines in human medicines |url=https://www.ema.europa.eu/en/news/ema-advises-companies-steps-take-avoid-nitrosamines-human-medicines |access-date=24 October 2023 | work = European Medicines Agency (EMA) |language=en |archive-date=11 November 2023 |archive-url=https://web.archive.org/web/20231111123045/https://www.ema.europa.eu/en/news/ema-advises-companies-steps-take-avoid-nitrosamines-human-medicines |url-status=live }}</ref> GlaxoSmithKline paused batch release and distribution of bupropion 150&nbsp;mg tablets in November 2022. In July 2023, EMA raised the acceptable daily intake of nitrosamines impurities, leading GlaxoSmithKline to announce that distribution of bupropion 150&nbsp;mg tablets would resume "across the EU and Europe" by the end of 2023.<ref>{{cite web | vauthors = Lipanovic D |date=6 September 2023 |title=Bupropion to be made available in the UK again from December 2023, says manufacturer |url=https://pharmaceutical-journal.com/article/news/bupropion-to-be-made-available-in-the-uk-again-from-december-2023-says-manufacturer |access-date=24 October 2023 |website=The Pharmaceutical Journal |language=en-US |archive-date=11 October 2023 |archive-url=https://web.archive.org/web/20231011112505/https://pharmaceutical-journal.com/article/news/bupropion-to-be-made-available-in-the-uk-again-from-december-2023-says-manufacturer |url-status=live }}</ref>

== Society and culture ==

=== Recreational use ===

While bupropion demonstrates some potential for misuse, this potential is less than of other commonly used stimulants, being limited by features of its pharmacology.<ref name="pmid30601027">{{cite journal | vauthors = Naglich AC, Brown ES, Adinoff B | title = Systematic review of preclinical, clinical, and post-marketing evidence of bupropion misuse potential | journal = The American Journal of Drug and Alcohol Abuse | volume = 45 | issue = 4 | pages = 341–354 | date = 2019 | pmid = 30601027 | doi = 10.1080/00952990.2018.1545023 | s2cid = 58587857 }}</ref> Case reports describe misuse of bupropion as producing a "high" similar to cocaine or amphetamine usage but with less intensity. Bupropion misuse is uncommon.<ref name="pmid30601027" /> There have been a number of anecdotal and case-study reports of bupropion abuse, but the bulk of evidence indicates that the subjective effects of bupropion when taken orally are markedly different from those of addictive stimulants such as cocaine or amphetamine.<ref name="LileNader2003">{{cite journal |title=The abuse liability and therapeutic potential of drugs evaluated for cocaine addiction as predicted by animal models |journal=Current Neuropharmacology |volume=1 |year=2003 |pages=21–46|vauthors=Lile JA, Nader MA |doi=10.2174/1570159033360566 |citeseerx=10.1.1.325.9635 }}</ref> However, bupropion, by non-conventional routes of administration like injection or insufflation, has been reported to be misused in the United States and Canada, notably in prisons.<ref>[http://globalnews.ca/news/846576/antidepressant-wellbutrin-becomes-poor-mans-cocaine-on-toronto-streets/ Antidepressant Wellbutrin becomes 'poor man's cocaine' on Toronto streets] {{Webarchive|url=https://web.archive.org/web/20201026081846/https://globalnews.ca/news/846576/antidepressant-wellbutrin-becomes-poor-mans-cocaine-on-toronto-streets/ |date=26 October 2020 }} Global News 18 September 2013.</ref><ref>{{cite journal | vauthors = Phillips D | title = Wellbutrin®: misuse and abuse by incarcerated individuals | journal = Journal of Addictions Nursing | volume = 23 | issue = 1 | pages = 65–69 | date = February 2012 | pmid = 22468662 | doi = 10.3109/10884602.2011.647838 | s2cid = 1310940 }}</ref><ref>{{cite journal | vauthors = Baribeau D, Araki KF | title = Intravenous bupropion: a previously undocumented method of abuse of a commonly prescribed antidepressant agent | journal = Journal of Addiction Medicine | volume = 7 | issue = 3 | pages = 216–217 | date = May–June 2013 | pmid = 23519045 | doi = 10.1097/ADM.0b013e3182824863 }}</ref><ref name="pmid27504927">{{cite journal | vauthors = Stassinos GL, Klein-Schwartz W | title = Bupropion "Abuse" Reported to US Poison Centers | journal = Journal of Addiction Medicine | volume = 10 | issue = 5 | pages = 357–362 | date = 2016 | pmid = 27504927 | doi = 10.1097/ADM.0000000000000249 | s2cid = 24870292 }}</ref>

=== Legal status ===

In Russia bupropion is banned as a [[narcotic drug]], due to it being a derivative of [[methcathinone]].<ref name="Order681">{{cite web|url=http://base.garant.ru/12112176/|title=Постановление Правительства РФ от 30 июня 1998 г. N 681 "Об утверждении перечня наркотических средств, психотропных веществ и их прекурсоров, подлежащих контролю в Российской Федерации" (с изменениями и дополнениями)|quote=Эфедрон (меткатинон) и его производные, за исключением производных, включенных в качестве самостоятельных позиций в перечень|publisher=[[Гарант (справочно-правовая система)|Гарант]]|access-date=28 April 2019|language=ru|archive-date=20 April 2013|archive-url=https://web.archive.org/web/20130420064645/http://base.garant.ru/12112176/|url-status=live}}</ref>

In Australia, France, and the UK, smoking cessation is the only licensed use of bupropion, and no generics are marketed.<ref name="AMH">{{cite book | title = Australian Medicines Handbook | year = 2013 | publisher = The Australian Medicines Handbook Unit Trust | isbn = 978-0-9805790-9-3 | edition = 2013 | place = Adelaide | veditors = Rossi S }}</ref><ref>{{cite web |title=Autorisation – ZYBAN L.P. 150 mg, comprimé à libération prolongée |url=http://agence-prd.ansm.sante.fr/php/ecodex/extrait.php?specid=64556383 |access-date=9 April 2023 |website=agence-prd.ansm.sante.fr |archive-date=9 April 2023 |archive-url=https://web.archive.org/web/20230409132210/http://agence-prd.ansm.sante.fr/php/ecodex/extrait.php?specid=64556383 |url-status=live }}</ref><ref name="BNF">{{cite book | author = Joint Formulary Committee | title = British National Formulary (BNF) | year = 2015| isbn = 978-0-85711-156-2 | edition = 69 | location = London, UK | publisher = Pharmaceutical Press }}</ref>

=== Brand names ===

Brand names include Wellbutrin,<ref name="Wellbutrin SR FDA label" /><ref name="Wellbutrin XL FDA label" /> Aplenzin,<ref name="Aplenzin FDA label" /> Budeprion, Buproban, buprapan, Forfivo, Voxra, Zyban,<ref name="Zyban CA PI" /> Bupron, Bupisure, Bupep, Smoquite, Elontril, and Buxon.{{cn|date=September 2024}}

== Research ==

Bupropion has been studied limitedly in the treatment of [[social anxiety disorder]].<ref name="Schneier2011">{{cite journal | vauthors = Schneier FR | title = Pharmacotherapy of social anxiety disorder | journal = Expert Opin Pharmacother | volume = 12 | issue = 4 | pages = 615–625 | date = March 2011 | pmid = 21241211 | doi = 10.1517/14656566.2011.534983 | url = }}</ref><ref name="EmmanuelLydiardBallenger1991">{{cite journal | vauthors = Emmanuel NP, Lydiard RB, Ballenger JC | title = Treatment of social phobia with bupropion | journal = J Clin Psychopharmacol | volume = 11 | issue = 4 | pages = 276–277 | date = August 1991 | pmid = 1918431 | doi = 10.1097/00004714-199108000-00023 | url = }}</ref><ref name="EmmanuelBrawman-MintzerMorton2000">{{cite journal | vauthors = Emmanuel NP, Brawman-Mintzer O, Morton WA, Book SW, Johnson MR, Lorberbaum JP, Ballenger JC, Lydiard RB | title = Bupropion-SR in treatment of social phobia | journal = Depress Anxiety | volume = 12 | issue = 2 | pages = 111–113 | date = 2000 | pmid = 11091936 | doi = 10.1002/1520-6394(2000)12:2<111::AID-DA9>3.0.CO;2-3 | url = | doi-access = free }}</ref>

== See also ==

* [[List of antidepressants]]

== References ==

{{Reflist}}

{{Dependence treatment}}

{{Sigma receptor modulators}}

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