View source for Trazodone

{{Short description|Antidepressant medication}}
{{Use dmy dates|date=January 2024}}
{{Cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| Watchedfields = verified
| verifiedrevid = 457287206
| image = Trazodone.svg
| image_class = skin-invert-image
| width = 250
| image2 = Trazodone-from-HCl-xtal-Mercury-3D-balls.png
| image_class2 = bg-transparent
| width2 = 250

<!--Clinical data-->| tradename = Desyrel, Trittico, others<ref name=genericnames>{{cite web |title=Trazodone |url=https://www.drugs.com/international/trazodone.html |website=Drugs.com |access-date=9 February 2019 }}</ref>
| Drugs.com = {{drugs.com|monograph|trazodone-hydrochloride}}
| MedlinePlus = a681038
| DailyMedID = Trazodone
| dependency_liability = Low<ref name=Hub2001>{{cite book | vauthors = Hubbard JR, Martin PR |title=Substance Abuse in the Mentally and Physically Disabled |date=2001 |publisher=CRC Press |isbn=978-0-8247-4497-7 |page=26 |url=https://books.google.com/books?id=MY1kFYk98mQC&pg=PA26 }}</ref>
| addiction_liability = Low–moderate<ref name=Hub2001/>
| routes_of_administration = [[Oral administration|By mouth]]
| ATC_prefix = N06
| ATC_suffix = AX05

<!-- Legal status -->| legal_AU = S4
| legal_AU_comment = 
| legal_BR = C1
| legal_BR_comment = <ref>{{Cite web |author=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=16 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>
| legal_CA = Rx-only
| legal_CA_comment = 
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = POM
| legal_UK_comment = 
| legal_US = Rx-only
| legal_US_comment = <ref name="Desyrel FDA label" /><ref name="Trazodone FDA label" />
| legal_EU = 
| legal_EU_comment = 
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment = 
| legal_status = Rx-only

<!--Pharmacokinetic data-->| bioavailability = [[Oral administration|By mouth]]: 65%<ref name="DrugPoint">Truven Health Analytics, Inc. DrugPoint System (Internet) [cited 2013 Oct 1]. Greenwood Village, CO: Thomsen Healthcare; 2013.</ref>{{Failed verification|date=April 2017|reason=search for "Trazodone" fails on Truven Web site}}
| protein_bound = 89–95%<ref>{{cite web|url=http://www.drugbank.ca/drugs/DB00656| title=Trazodone|website=DrugBank|access-date=7 June 2015}}</ref>
| metabolism = [[Liver]] ([[CYP3A4]], [[CYP2D6]], [[CYP1A2]]?)<ref name="pmid10379419" /><ref name="pmid31379379" /><ref name="pmid22115401" /><ref name="pmid9836023" /><ref>{{cite book | vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry |date=2012 |publisher=Lippincott Williams & Wilkins |isbn=978-1-60913-345-0 |page=615 |url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA615 }}</ref>
| metabolites = {{abbrlink|mCPP|meta-Chlorophenylpiperazine}}<ref name="PreskornStanga2012">{{cite book| vauthors = Preskorn SH, Stanga CY, Feighner JP, Ross J |title=Antidepressants: Past, Present and Future|url=https://books.google.com/books?id=Ue3uCAAAQBAJ&pg=PA68|year=2012|publisher=Springer Science & Business Media|isbn=978-3-642-18500-7|pages=68–}}</ref>
| onset = [[Oral administration|By mouth]]: 1 hour ([[Tmax (pharmacology)|{{abbr|T<sub>max</sub>|Time to peak concentrations}}]])<ref>{{cite web |url=http://www.pharmacychoice.com/mdx/drugpoint.cfm?docID=622860&letter=T&type=Generic%20Name |title=MicroMedex DrugPoints – Trazodone|website=Pharmacy Choice|access-date= 20 April 2017}}</ref>
| elimination_half-life = • Trazodone ({{abbr|IR|immediate-release}}): 4–15 hours<ref name="pmid10379419" /><ref name="pmid22115401" /><ref name="pmid23192413" /><ref name="pmid20173086" /><br />• Trazodone ({{abbr|ER|extended-release}}): 9–13 hours<ref name="pmid26678742" /><ref name="pmid22115401" /><ref name="pmid23192413" /><br />• {{abbrlink|mCPP|meta-Chlorophenylpiperazine}}: 3–16 hours<ref name="pmid10379419" /><ref name="pmid22115401" /><ref name="pmid20173086" /><ref name="SchatzbergNemeroff2017">{{cite book|vauthors = Schatzberg AF, Nemeroff CB|title=The American Psychiatric Association Publishing Textbook of Psychopharmacology|edition=5th|url=https://books.google.com/books?id=KfHEDgAAQBAJ&pg=PA460|year=2017|publisher=American Psychiatric Pub|isbn=978-1-58562-523-9|pages=460–}}</ref>
| excretion = [[Urine]]: 70–75%<ref name="DrugPoint" /><br />[[Feces]]: 21%<ref name="DrugPoint" />

<!--Identifiers-->| index2_label = as HCl
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 19794-93-5
| PubChem = 5533
| IUPHAR_ligand = 213
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00656
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5332
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = YBK48BXK30
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08626
| KEGG2_Ref = {{keggcite|correct|kegg}}
| KEGG2 = D00820
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 9654
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 621
| synonyms = AF-1161

<!--Chemical data-->| IUPAC_name = 2-<nowiki/>{3-[4-(3-Chlorophenyl)piperazin-1-yl]propyl}[1,2,4]triazolo[4,3-''a'']pyridin-3(2''H'')-one
| C = 19
| H = 22
| Cl = 1
| N = 5
| O = 1
| SMILES = Clc4cccc(N3CCN(CCCN1/N=C2/C=C\C=C/N2C1=O)CC3)c4
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C19H22ClN5O/c20-16-5-3-6-17(15-16)23-13-11-22(12-14-23)8-4-10-25-19(26)24-9-2-1-7-18(24)21-25/h1-3,5-7,9,15H,4,8,10-14H2
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = PHLBKPHSAVXXEF-UHFFFAOYSA-N

<!--Physical data-->| melting_point = 87
}}
<!-- Definition and symptoms -->
'''Trazodone''' is an [[antidepressant]] medication<ref name=AHFS2021/> used to treat [[major depressive disorder]], [[anxiety disorder]]s, and [[insomnia]].<ref name=AHFS2021/> It is a [[phenylpiperazine]] compound of the [[serotonin antagonist and reuptake inhibitor]] (SARI) class.<ref>{{cite book| vauthors = Stahl SM |title=Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications|date=2008|publisher=Cambridge University Press|isbn=978-0-521-85702-4|page=567|url=https://books.google.com/books?id=cWbYxSfKN3cC&pg=PA567}}</ref><ref>{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|date=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6879-5|page=586|url=https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA586}}</ref> The medication is taken [[oral administration|orally]].<ref name=AHFS2021>{{cite web|title=Trazodone |url=https://www.drugs.com/monograph/trazodone.html|publisher=The American Society of Health-System Pharmacists|date=17 March 2021|access-date=24 December 2021}}</ref>

<!-- Side effects and mechanism -->
Common side effects include [[dry mouth]], feeling faint, vomiting, and headache.<ref name=AHFS2021/> More serious side effects may include [[suicide]], [[mania]], [[irregular heart rate]], and [[priapism|pathologically prolonged erections]].<ref name=AHFS2021/> It is unclear if use during [[pregnancy]] or [[breastfeeding]] is safe.<ref>{{cite web|title=Trazodone Use During Pregnancy|url=https://www.drugs.com/pregnancy/trazodone.html|website=Drugs.com|access-date=7 January 2018}}</ref>  Trazodone also has sedating effects.<ref name=BNF69>{{cite book|title=British national formulary: BNF 69 |date=2015|publisher=British Medical Association |isbn=978-0-85711-156-2|pages=257–58 |edition=69th}}</ref>

<!-- Society and culture -->
Trazodone was approved for medical use in the United States in 1981.<ref name=AHFS2021/> It is available as a [[generic medication]].<ref name=AHFS2021/> In 2022, it was the eighteenth most commonly prescribed medication in the United States, with more than 27{{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 = Trazodone Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Trazodone | access-date = 30 August 2024 }}</ref>
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==Medical uses==

===Depression===
The primary use of trazodone is the treatment of unipolar major depression with or without [[anxiety]].<ref name="Desyrel FDA label">{{cite web | title=Desyrel (trazodone HCl) | website=DailyMed | date=19 March 2013 | url=https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=103088 | access-date=4 April 2022}}</ref> Data from open and [[double-blind trial]]s suggest that the antidepressant [[efficacy]] of trazodone is comparable to that of [[amitriptyline]], [[doxepin]], and [[mianserin]]. Furthermore, trazodone has shown [[anxiolytic]] properties, low [[cardiotoxicity]], and relatively mild side effects.<ref name="Textbook of Psychopharmacology">{{cite book | veditors = Schatzberg AF, Nemeroff CB |title=Textbook of Psychopharmacology |edition=4th |year=2009 |publisher= American Psychiatric Publishing |location=Washington, D.C. |isbn=978-1-58562-309-9}}</ref>

Because trazodone has minimal [[anticholinergic]] activity, it was especially welcomed as a treatment for [[Geriatrics|geriatric]] patients with depression when it first became available. Three double-blind studies reported trazodone had antidepressant efficacy similar to that of other antidepressants in geriatric patients. Unfortunately, a side effect of trazodone, [[orthostatic hypotension]], which may cause dizziness and increase the risk of falling, can have devastating consequences for elderly patients.<ref name="pmid25735839">{{cite journal | vauthors = Ruxton K, Woodman RJ, Mangoni AA | title = Drugs with anticholinergic effects and cognitive impairment, falls and all-cause mortality in older adults: A systematic review and meta-analysis | journal = Br J Clin Pharmacol | volume = 80 | issue = 2 | pages = 209–20 | date = August 2015 | pmid = 25735839 | pmc = 4541969 | doi = 10.1111/bcp.12617 | url = }}</ref> Therefore, this side effect, along with sedation, often makes trazodone less acceptable for this population compared to newer compounds that share its lack of anticholinergic activity (but not the rest of its side effect profile). Still, trazodone is often helpful for geriatric patients with depression who have severe [[Agitation (dementia)|agitation]] and insomnia.<ref name="Textbook of Psychopharmacology" />

Trazodone is usually used at a dosage of 150 to 300{{nbsp}}mg/day for the treatment of depression.<ref name="pmid31379379">{{cite journal | vauthors = Cuomo A, Ballerini A, Bruni AC, Decina P, Di Sciascio G, Fiorentini A, Scaglione F, Vampini C, Fagiolini A | title = Clinical guidance for the use of trazodone in major depressive disorder and concomitant conditions: pharmacology and clinical practice | journal = Riv Psichiatr | volume = 54 | issue = 4 | pages = 137–49 | date = 2019 | pmid = 31379379 | doi = 10.1708/3202.31796 }}</ref><ref name="pmid23192413" /> Lower doses have also been used to augment other antidepressants or when initiating therapy.<ref name="pmid31379379" /><ref name="pmid23192413" /> Higher doses, up to 600{{nbsp}}mg/day, have been used in more severe cases of depression (in hospitalized patients, for example).<ref name="pmid8019056">{{cite journal | vauthors = Haria M, Fitton A, McTavish D | title = Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders | journal = Drugs Aging | volume = 4 | issue = 4 | pages = 331–55 | date = April 1994 | pmid = 8019056 | doi = 10.2165/00002512-199404040-00006 | s2cid = 265772823 | url = }}</ref> Trazodone is usually administered multiple times per day, but once-daily administration may be similarly effective.<ref name="pmid2211561">{{cite journal | vauthors = Fabre LF | title = Trazodone dosing regimen: experience with single daily administration | journal = J Clin Psychiatry | volume = 51 | issue = Suppl | pages = 23–26 | date = September 1990 | pmid = 2211561 }}</ref>

===Insomnia===
Low-dose trazodone is used [[off-label use|off-label]] in the treatment of [[insomnia]] and is considered to be effective and safe for this indication.<ref name="pmid29552421" /><ref name="pmid23192413" /><ref name="pmid26088119">{{cite journal | vauthors = Bossini L, Coluccia A, Casolaro I, Benbow J, Amodeo G, De Giorgi R, Fagiolini A | title = Off-Label Trazodone Prescription: Evidence, Benefits and Risks | journal = Curr Pharm Des | volume = 21 | issue = 23 | pages = 3343–51 | date = 2015 | pmid = 26088119 | doi = 10.2174/1381612821666150619092236 }}</ref> It may also be used to treat [[antidepressant]]-related insomnia.<ref name="pmid8010365">{{cite journal |vauthors=Nierenberg AA, Adler LA, Peselow E, Zornberg G, Rosenthal M |title=Trazodone for antidepressant-associated insomnia |journal=Am J Psychiatry |volume=151 |issue=7 |pages=1069–72 |date=July 1994|pmid=8010365 |doi=10.1176/ajp.151.7.1069}}</ref> Trazodone was the second-most prescribed agent for insomnia in the early 2000s even though most studies of trazodone for the treatment of sleep disturbances have been in depressed individuals.<ref name="pmid23192413" /><ref name="pmid15816789">{{cite journal | vauthors = Mendelson WB | title = A review of the evidence for the efficacy and safety of trazodone in insomnia | journal = J Clin Psychiatry | volume = 66 | issue = 4 | pages = 469–76 | date = April 2005 | pmid = 15816789 | doi = 10.4088/jcp.v66n0409 | url = }}</ref><ref name="pmid16517453">{{cite journal | vauthors = Rosenberg RP | title = Sleep maintenance insomnia: strengths and weaknesses of current pharmacologic therapies | journal = Ann Clin Psychiatry | volume = 18 | issue = 1 | pages = 49–56 | date = 2006 | pmid = 16517453 | doi = 10.1080/10401230500464711 | url = }}</ref>

[[Systematic review]]s and [[meta-analysis|meta-analyses]] published in the late 2010s, including a [[Cochrane review]], found low-dose trazodone to be an effective medication for short-term treatment of insomnia in both depressed and [[Euthymia (medicine)|euthymic]] people.<ref name="pmid29552421" /><ref name="pmid29680424">{{cite journal | vauthors = Yi XY, Ni SF, Ghadami MR, Meng HQ, Chen MY, Kuang L, Zhang YQ, Zhang L, Zhou XY | title = Trazodone for the treatment of insomnia: a meta-analysis of randomized placebo-controlled trials | journal = Sleep Med | volume = 45 | pages = 25–32 | date = May 2018 | pmid = 29680424 | doi = 10.1016/j.sleep.2018.01.010 }}</ref><ref>{{cite journal | vauthors = Wang J, Liu S, Zhao C, Han H, Chen X, Tao J, Lu Z | title = Effects of Trazodone on Sleep Quality and Cognitive Function in Arteriosclerotic Cerebral Small Vessel Disease Comorbid With Chronic Insomnia | journal = Frontiers in Psychiatry | volume = 11 | page= 620 | date = 2020 | pmid = 32714220 | doi = 10.3389/fpsyt.2020.00620 | pmc = 7344257 | doi-access = free }}</ref><ref name="pmid29761479">{{cite journal | vauthors = Everitt H, Baldwin DS, Stuart B, Lipinska G, Mayers A, Malizia AL, Manson CC, Wilson S | title = Antidepressants for insomnia in adults | journal = Cochrane Database Syst Rev | volume = 2018 | issue = 5| pages = CD010753 | date = May 2018 | pmid = 29761479 | pmc = 6494576 | doi = 10.1002/14651858.CD010753.pub2 | url = }}</ref> Trazodone slightly improves subjective [[sleep quality]] ({{Abbrlink|SMD|standardized mean difference}} = –0.34 to –0.41) and reduces the number of [[nocturnal awakening|nighttime awakening]]s ({{Abbr|MD|Mean difference}} = –0.31, {{Abbr|SMD|standardized mean difference}} = –0.51), on average.<ref name="pmid29680424" /><ref name="pmid29761479" /> Conversely, it does not appear to affect [[sleep onset]], [[total sleep time]], [[wake after sleep onset|time awake after sleep onset]], or [[sleep efficiency]].<ref name="pmid29680424" /><ref name="pmid29761479" /><ref name="pmid34994734">{{cite journal | vauthors = Wichniak A, Wierzbicka AE, Jarema M | title = Treatment of insomnia - effect of trazodone and hypnotics on sleep | journal = Psychiatr Pol | volume = 55 | issue = 4 | pages = 743–55 | date = August 2021 | pmid = 34994734 | doi = 10.12740/PP/125650 | s2cid = 243329243 | url = | doi-access = free }}</ref> It appears to increase [[deep sleep]]—in contrast to certain other [[hypnotic]]s.<ref name="pmid34994734" /> The [[quality of evidence]] of trazodone for short-term treatment of insomnia was rated as low to moderate.<ref name="pmid29680424" /><ref name="pmid29761479" /> There is no evidence available at present to inform the long-term use of trazodone in the treatment of insomnia.<ref name="pmid29761479" /><ref>De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, et al. Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis. The Lancet. 2022 Jul;400(10347):170-84.</ref>

The benefits of trazodone for insomnia must be weighed against potential [[adverse effect]]s, such as [[morning grogginess]], [[daytime sleepiness]], [[cognitive impairment|cognitive]] and [[motor impairment]], and [[postural hypotension]], among others.<ref name="pmid29552421" /><ref name="pmid29761479" /> Quality safety data on the use of trazodone as a sleep aid are currently lacking.<ref name="pmid29680424" /><ref name="pmid29761479" />

Trazodone is used at low doses in the range of 50 to 150{{nbsp}}mg/day for insomnia.<ref name="pmid29552421" /><ref name="pmid20095366" /><ref name="pmid29680424" /><ref name="pmid29761479" /> Higher doses of 200 to 600{{nbsp}}mg/day have also been studied.<ref name="pmid29552421" /><ref name="pmid16517453" />

The [[American Academy of Sleep Medicine]]'s 2017 [[clinical practice guideline]]s recommended against the use of trazodone in the treatment of insomnia due to inadequate evidence and due to harms potentially outweighing benefits.<ref name="pmid27998379">{{cite journal | vauthors = Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL | title = Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline | journal = J Clin Sleep Med | volume = 13 | issue = 2 | pages = 307–49 | date = February 2017 | pmid = 27998379 | pmc = 5263087 | doi = 10.5664/jcsm.6470 | url = }}</ref>

===Other disorders===
Trazodone is often used in the treatment of [[anxiety disorder]]s {{emdash}} such as [[generalized anxiety disorder]] and [[panic disorder]] {{emdash}} as well as in [[post-traumatic stress disorder]] (PTSD) and [[obsessive–compulsive disorder]] (OCD).<ref name="pmid27744763" /><ref name="pmid22712761" /><ref name="pmid26088119" /><ref name="pmid7018873">{{cite journal |vauthors=Brogden RN, Heel RC, Speight TM, Avery GS |date=June 1981 |title=Trazodone: a review of its pharmacological properties and therapeutic use in depression and anxiety |url= |journal=Drugs |volume=21 |issue=6 |pages=401–29 |doi=10.2165/00003495-198121060-00001 |pmid=7018873 |s2cid=30562398}}</ref><ref name="BNF 65">{{cite book |url=https://archive.org/details/bnf65britishnati0000unse/page/247 |title=British National Formulary (BNF) 65 |publisher=Pharmaceutical Press |year=2013 |isbn=978-0-85711-084-8 |location=London |page=[https://archive.org/details/bnf65britishnati0000unse/page/247 247]}}</ref> Trazodone is often used as an alternative to [[benzodiazepine]]s in the treatment of anxiety disorders.<ref name="pmid22712761" /><ref name="pmid26088119" /> However, use of trazodone in anxiety disorders is [[off-label use|off-label]] and evidence of its effectiveness for these indications is variable and limited.<ref name="pmid26088119" /><ref name="pmid22712761" /><ref name="pmid27744763" /><ref name="pmid12804478">{{cite journal |vauthors=[[Flávio Kapczinski|Kapczinski F]], Lima MS, Souza JS, Schmitt R |date=2003 |title=Antidepressants for generalized anxiety disorder |url= |journal=Cochrane Database Syst Rev |volume= |issue=2 |pages=CD003592 |doi=10.1002/14651858.CD003592 |pmid=12804478}}</ref><ref name="pmid14969574">{{cite journal |vauthors=Asnis GM, Kohn SR, Henderson M, Brown NL |date=2004 |title=SSRIs versus non-SSRIs in post-traumatic stress disorder: an update with recommendations |url= |journal=Drugs |volume=64 |issue=4 |pages=383–404 |doi=10.2165/00003495-200464040-00004 |pmid=14969574 |s2cid=38329753}}</ref> Benefits for OCD appear to be mild.<ref name="pmid22712761" /><ref name="pmid26088119" /> Trazodone has been used to treat [[sleep disturbance]]s and [[nightmare]]s in PTSD.<ref name="pmid25894359">{{cite journal |vauthors=Brownlow JA, Harb GC, Ross RJ |date=June 2015 |title=Treatment of Sleep Disturbances in Post-Traumatic Stress Disorder: A Review of the Literature |url= |journal=Curr Psychiatry Rep |volume=17 |issue=6 |pages=41 |doi=10.1007/s11920-015-0587-8 |pmid=25894359 |s2cid=45471039}}</ref><ref name="pmid26088119" /><ref name="pmid22712761" />

===Combination with other antidepressants===
Trazodone is often used in combination with other antidepressants such as [[selective serotonin reuptake inhibitor]]s in order to augment their antidepressant and anxiolytic effects and to reduce [[side effect]]s such as [[sexual dysfunction]], anxiety, and insomnia.<ref name="pmid22712761">{{cite journal | vauthors = Bossini L, Casolaro I, Koukouna D, Cecchini F, Fagiolini A | title = Off-label uses of trazodone: a review | journal = Expert Opin Pharmacother | volume = 13 | issue = 12 | pages = 1707–17 | date = August 2012 | pmid = 22712761 | doi = 10.1517/14656566.2012.699523 | s2cid = 10638259 | url = }}</ref><ref name="pmid23192413" /><ref name="pmid27744763" /><ref name="pmid30342856" />

===Available forms===
Trazodone is provided as the [[hydrochloride]] [[salt (chemistry)|salt]] and is available in the form of 50{{nbsp}}mg, 100{{nbsp}}mg, 150{{nbsp}}mg, and 300{{nbsp}}mg [[oral administration|oral]] [[tablet (pharmacy)|tablet]]s.<ref name="Trazodone FDA label">{{cite web | title=Trazodone hydrochloride tablet | website=DailyMed | date=29 June 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=71961ab1-951d-1493-f76c-2ff25cca2a85 | access-date=3 April 2022}}</ref> In Italy, it is also available as an oral solution (Trittico 60&nbsp;mg/mL) with a dosing pipette marked at 25&nbsp;mg and 50&nbsp;mg.<ref>{{Cite web | url=https://farmaci.agenziafarmaco.gov.it/aifa/servlet/PdfDownloadServlet?pdfFileName=footer_000219_022323_RCP.pdf&sys=m0b1l3 | title=Riassunto delle caratteristiche del prodotto | language=it | trans-title=Summary of Product Characteristics | archive-url=https://web.archive.org/web/20231125144756/https://farmaci.agenziafarmaco.gov.it/aifa/servlet/PdfDownloadServlet?pdfFileName=footer_000219_022323_RCP.pdf&sys=m0b1l3 | archive-date=2023-11-25}}</ref>

An [[modified-release dosage|extended-release]] oral tablet formulation at doses of 150{{nbsp}}mg and 300{{nbsp}}mg is also available.<ref>{{Cite journal|date=2011|title=Oleptro (trazodone hydrochloride) extended-release tablets|journal=Pharmacy and Therapeutics|volume=36|issue=2|pages=2–18|issn=1052-1372|pmc=3059557|pmid=21431085}}</ref><ref>{{Cite web|url=https://www.mayoclinic.org/drugs-supplements/trazodone-oral-route/proper-use/drg-20061280|title=Trazodone (Oral Route) Proper Use Clinic|website=www.mayoclinic.org – Mayo Clinic|access-date=11 February 2020}}</ref>

==Side effects==
{{See also|List of adverse effects of trazodone}}

Because of its lack of [[anticholinergic]] side effects, trazodone is especially useful in situations in which [[antimuscarinic]] effects are particularly problematic (e.g., in patients with [[benign prostatic hyperplasia]], closed-angle glaucoma, or severe constipation). Trazodone's propensity to cause sedation is a dual-edged sword. For many patients, the relief from agitation, anxiety, and insomnia can be rapid; for other patients, including those individuals with considerable [[psychomotor retardation]] and feelings of low energy, therapeutic doses of trazodone may not be tolerable because of sedation. Trazodone elicits [[orthostatic hypotension]] in some people, probably as a consequence of α<sub>1</sub>-adrenergic receptor blockade. The unmasking of [[bipolar disorder]] may occur with trazodone<ref name=AHFS2021/> and other antidepressants.<ref name="pmid26459471">{{cite journal | vauthors = Malhi GS | title = Antidepressants in bipolar depression: yes, no, maybe? | journal = Evid Based Ment Health | volume = 18 | issue = 4 | pages = 100–02 | date = November 2015 | pmid = 26459471 | doi = 10.1136/eb-2015-102229 | doi-access = free | pmc = 11234584 }}</ref>

Precautions for trazodone include known [[hypersensitivity]] to trazodone and under 18 years and combined with other antidepressant medications, it may increase the possibility of suicidal thoughts or actions.<ref>{{cite web|url=http://www.webmd.com/drugs/drug-11188-Trazodone+Oral.aspx?drugid=11188&drugname=Trazodone+Oral |title=Webmd.com |publisher=Webmd.com |access-date=14 March 2014}}</ref>

While trazodone is not a true member of the [[SSRI]] class of antidepressants, it does still share many properties of SSRIs, especially the possibility of [[SSRI discontinuation syndrome|discontinuation syndrome]] if the medication is stopped too quickly.<ref name="pmid16913164">{{cite journal | vauthors = Warner CH, Bobo W, Warner C, Reid S, Rachal J | title = Antidepressant discontinuation syndrome | journal = Am Fam Physician | volume = 74 | issue = 3 | pages = 449–56 | date = August 2006 | pmid = 16913164 }}</ref> Thus, care must be taken when coming off the medication, usually by a gradual process of tapering down the dose over time.

===Suicide===
Antidepressants may increase the risk of suicidal thoughts and behaviors in children and young adults. Close monitoring for the emergence of suicidal thoughts and behaviors is thus recommended.<ref>{{Cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018207s032lbl.pdf|archive-url=https://web.archive.org/web/20200710110753/https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018207s032lbl.pdf|url-status=dead|archive-date=10 July 2020|title=FDA – Trazodone Prescribing Information}}</ref>

===Sedation===
Since trazodone may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned not to engage in such activities while impaired. Compared to the reversible MAOI antidepressant drug [[moclobemide]], more impairment of vigilance occurs with trazodone.<ref name="pmid2677245">{{cite journal | vauthors = Wesnes KA, Simpson PM, Christmas L, Anand R, McClelland GR | title = The effects of moclobemide on cognition | journal = J. Neural Transm. Suppl. | volume = 28 | pages = 91–102 | date = 1989 | pmid = 2677245 }}</ref> Trazodone has been found to impair [[driving]] ability.<ref name="pmid28718182">{{cite journal | vauthors = Brunnauer A, Laux G | title = Driving Under the Influence of Antidepressants: A Systematic Review and Update of the Evidence of Experimental and Controlled Clinical Studies | journal = Pharmacopsychiatry | volume = 50 | issue = 5 | pages = 173–81 | date = September 2017 | pmid = 28718182 | doi = 10.1055/s-0043-113572 | s2cid = 3425898 | url = }}</ref>

===Cardiac===
Case reports have noted cardiac arrhythmias emerging in relation to trazodone treatment, both in patients with pre-existing [[mitral valve prolapse]] and in patients with negative personal and family histories of cardiac disease.<ref name="ReferenceA">{{cite book | veditors = Schatzberg AF, Nemeroff CB |title=Textbook of Psychopharmacology |edition=4th |year=2009 |publisher= American Psychiatric Publishing|location=Washington, D.C. |isbn=978-1-58562-309-9}}</ref>

[[Long QT syndrome|QT prolongation]] has been reported with trazodone therapy. [[Heart arrhythmia|Arrhythmia]] identified include isolated [[premature ventricular contraction|PVC]]s, ventricular couplets, and in two patients short episodes (three to four beats) of [[ventricular tachycardia]]. Several post-marketing reports have been made of arrhythmia in trazodone-treated patients who have pre-existing cardiac disease and in some patients who did not have pre-existing cardiac disease. Until the results of prospective studies are available, patients with pre-existing cardiac disease should be closely monitored, particularly for cardiac arrhythmias. Trazodone is not recommended for use during the initial recovery phase of myocardial infarction. Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia.<ref>{{Cite web|url=https://pdf.hres.ca/dpd_pm/00030282.PDF|title=Trazodone Product Monograph |date=2015}}</ref><ref>{{Cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018207s032lbl.pdf|archive-url=https://web.archive.org/web/20200710110753/https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018207s032lbl.pdf|url-status=dead|archive-date=10 July 2020|title=Highlights of Prescribing Information |date=2017|publisher=U.S. Food and Drug Administration}}</ref>

===Priapism===
A relatively rare side effect associated with trazodone is [[priapism]], likely due to its antagonism at α-adrenergic receptors.<ref name="pmid3573170">{{cite journal | vauthors = Abber JC, Lue TF, Luo JA, Juenemann KP, Tanagho EA | title = Priapism induced by chlorpromazine and trazodone: mechanism of action | journal = J. Urol. | volume = 137 | issue = 5 | pages = 1039–42 | date = May 1987 | pmid = 3573170 | doi = 10.1016/s0022-5347(17)44355-2 }}</ref> More than 200 cases have been reported, and the manufacturer estimated that the incidence of any abnormal erectile function is about one in 6,000 male patients treated with trazodone. The risk for this side effect appears to be greatest during the first month of treatment at low dosages (i.e. &lt;150{{nbsp}}mg/day). Early recognition of any abnormal erectile function is important, including prolonged or inappropriate erections, and should prompt discontinuation of trazodone treatment. [[Spontaneous orgasm]]s have also been reported with trazodone in men.<ref name="pmid29194112">{{cite journal | vauthors = Chen WH, Chu YH, Chen KY | title = Drug-Associated Spontaneous Orgasm: A Case Report and Systematic Review of Literature | journal = Clin Neuropharmacol | volume = 41 | issue = 1 | pages = 31–37 | date = 2018 | pmid = 29194112 | doi = 10.1097/WNF.0000000000000259 | s2cid = 39522632 | url = }}</ref>

Clinical reports have described trazodone-associated psychosexual side effects in women as well, including increased [[libido]], priapism of the clitoris, and [[spontaneous orgasm]]s.<ref name="ReferenceA" /><ref name="pmid19674253">{{cite journal | vauthors = Battaglia C, Venturoli S | title = Persistent genital arousal disorder and trazodone. Morphometric and vascular modifications of the clitoris. A case report | journal = J Sex Med | volume = 6 | issue = 10 | pages = 2896–900 | date = October 2009 | pmid = 19674253 | doi = 10.1111/j.1743-6109.2009.01418.x }}</ref>

===Others===
Rare cases of [[hepatotoxicity|liver toxicity]] have been observed, possibly due to the formation of reactive metabolites.<ref name="pmid15978881">{{cite journal | vauthors = Kalgutkar AS, Henne KR, Lame ME, Vaz AD, Collin C, Soglia JR, Zhao SX, Hop CE | title = Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4 | journal = Chem. Biol. Interact. | volume = 155 | issue = 1–2 | pages = 10–20 | date = June 2005 | pmid = 15978881 | doi = 10.1016/j.cbi.2005.03.036 | bibcode = 2005CBI...155...10K }}</ref>

Elevated [[prolactin]] concentrations have been observed in people taking trazodone.<ref name="pmid8019056" /><ref name="pmid7673654">{{cite journal | vauthors = Otani K, Yasui N, Kaneko S, Ishida M, Ohkubo T, Osanai T, Sugawara K, Fukushima Y | title = Trazodone treatment increases plasma prolactin concentrations in depressed patients | journal = Int Clin Psychopharmacol | volume = 10 | issue = 2 | pages = 115–17 | date = June 1995 | pmid = 7673654 | doi = 10.1097/00004850-199506000-00009| s2cid = 41490922 }}</ref> They appear to be increased by around 1.5- to 2-fold.<ref name="pmid8019056" /><ref name="pmid7673654" />

Studies on trazodone and [[cognitive function]] are mixed, with some finding improvement, others finding no change and some finding impairment.<ref name="pmid34097124">{{cite journal | vauthors = Gonçalo AM, Vieira-Coelho MA | title = The effects of trazodone on human cognition: a systematic review | journal = Eur J Clin Pharmacol | volume = 77 | issue = 11 | pages = 1623–37 | date = November 2021 | pmid = 34097124 | pmc = 8182348 | doi = 10.1007/s00228-021-03161-6 | url = }}</ref>

Trazodone does not seem to worsen periodic limb movements during sleep.<ref name="pmid28822709">{{cite journal | vauthors = Kolla BP, Mansukhani MP, Bostwick JM | title = The influence of antidepressants on restless legs syndrome and periodic limb movements: A systematic review | journal = Sleep Med Rev | volume = 38 | issue = | pages = 131–40 | date = April 2018 | pmid = 28822709 | doi = 10.1016/j.smrv.2017.06.002 | url = }}</ref>

Trazodone is associated with an increased risk of [[falling (accident)|falls]] in older adults.<ref name="pmid25735839" /> It has also been associated with increased risk of [[hip fracture]]s in older adults.<ref name="pmid22811347">{{cite journal | vauthors = Oderda LH, Young JR, Asche CV, Pepper GA | title = Psychotropic-related hip fractures: meta-analysis of first-generation and second-generation antidepressant and antipsychotic drugs | journal = Ann Pharmacother | volume = 46 | issue = 7–8 | pages = 917–28 | date = 2012 | pmid = 22811347 | doi = 10.1345/aph.1Q589 | s2cid = 22681213 | url = }}</ref>

===Pregnancy and lactation===
Sufficient data in humans are lacking. Use should be justified by the severity of the condition to be treated.<ref name="pmid12655908">{{cite journal | vauthors = Einarson A, Bonari L, Voyer-Lavigne S, Addis A, Matsui D, Johnson Y, Koren G | title = A multicentre prospective controlled study to determine the safety of trazodone and nefazodone use during pregnancy | journal = Can J Psychiatry | volume = 48 | issue = 2 | pages = 106–10 | date = March 2003 | pmid = 12655908 | doi = 10.1177/070674370304800207 | doi-access = free }}</ref><ref name="pmid3768252">{{cite journal | vauthors = Verbeeck RK, Ross SG, McKenna EA | title = Excretion of trazodone in breast milk | journal = Br J Clin Pharmacol | volume = 22 | issue = 3 | pages = 367–70 | date = September 1986 | pmid = 3768252 | pmc = 1401139 | doi = 10.1111/j.1365-2125.1986.tb02903.x }}</ref>

==Overdose==
There are reported cases of high doses of trazodone precipitating [[serotonin syndrome]].<ref name="Medscape2014"/> There are also reports of patients taking multiple SSRIs with trazodone and precipitating serotonin syndrome.<ref name="Medscape2014">{{cite web|vauthors = Cushing TA |url=https://emedicine.medscape.com/article/821737-overview |title= Selective Serotonin Reuptake Inhibitor Toxicity |date=24 April 2018 |website=Medscape |publisher=WebMD LLC |access-date=22 December 2018}}</ref>

Trazodone appears to be relatively safer than [[Tricyclic antidepressant|TCAs]], [[MAOI]]s, and a few of the other [[second-generation antidepressant]]s in overdose situations, especially when it is the only agent taken. The typical dose is around 150 mg, though some individuals may require higher amounts. However, taking more than 600 mg within 24 hours substantially increases the risk of overdose.<ref>{{Cite web | vauthors = Tangradi M |date=2025-02-25 |title=Can You Overdose on Trazodone? |url=https://achievewellnessnj.com/can-you-overdose-on-trazodone/ |access-date=2025-06-15 |website=Achieve Wellness & Recovery |language=en-US}}</ref>

Fatalities are rare, and uneventful recoveries have been reported after ingestion of doses as high as 6,000–9,200{{nbsp}}mg. In one report, 9 of 294 cases of overdose were fatal, and all nine patients had also taken other central nervous system (CNS) depressants. When trazodone overdoses occur, clinicians should carefully monitor for [[hypotension|low blood pressure]], a potentially serious toxic effect. In a report of a fatal trazodone overdose, [[torsades de pointes]] and complete [[atrioventricular block]] developed, along with subsequent multiple organ failure, with a trazodone plasma concentration of 25.4{{nbsp}}mg/L on admission.<ref name="Textbook of Psychopharmacology" /><ref name="pmid15975258">{{cite journal | vauthors = Martínez MA, Ballesteros S, Sánchez de la Torre C, Almarza E | title = Investigation of a fatality due to trazodone poisoning: case report and literature review | journal = J Anal Toxicol | volume = 29 | issue = 4 | pages = 262–28 | date = 2005 | pmid = 15975258 |doi=10.1093/jat/29.4.262 | doi-access = free }}</ref><ref name="pmid11603256">{{cite journal | vauthors = de Meester A, Carbutti G, Gabriel L, Jacques JM | title = Fatal overdose with trazodone: case report and literature review | journal = Acta Clin Belg | volume = 56 | issue = 4 | pages = 258–61 | date = 2001 | pmid = 11603256 | doi = 10.1179/acb.2001.038 | s2cid = 21487479 }}</ref><ref>{{cite journal| vauthors = Rakel RE |title=The greater safety of trazodone over tricyclic antidepressant agents: 5-year experience in the United States |journal=Psychopathology |volume=20 |issue=Suppl 1|pages=57–63 |year=1987 |pmid=3321131 |doi=10.1159/000284524 }}</ref>

==Interactions==
===Cytochrome P450 inhibitors and inducers===
Trazodone is [[drug metabolism|metabolized]] by several [[liver]] [[enzyme]]s, including [[CYP3A4]], [[CYP2D6]], and [[CYP1A2]].<ref name="pmid10379419" /><ref name=Rotzinger/> Its [[active metabolite]] [[meta-chlorophenylpiperazine|''meta''-chlorophenylpiperazine (mCPP)]] is known to be formed by CYP3A4 and metabolized by CYP2D6.<ref name="pmid10379419" /> Inhibition or induction of the aforementioned enzymes by various other substances may alter the metabolism of trazodone and/or mCPP, leading to increased and/or decreased blood concentrations.<ref name="pmid31379379" /><ref name="pmid23192413" /> The enzymes in question are known to be inhibited and induced by many medications, herbs, and foods, and as such, trazodone may [[drug interaction|interact]] with these substances. [[Potency (pharmacology)|Potent]] CYP3A4 inhibitors such as [[clarithromycin]], [[erythromycin]], [[fluvoxamine]], [[grapefruit juice]], [[ketoconazole]], and [[ritonavir]] may lead to increased concentrations of trazodone and decreased concentrations of mCPP, while CYP3A4 inducers like [[carbamazepine]], [[enzalutamide]], [[phenytoin]], [[phenobarbital]], and [[St. John's wort]] may result in decreased trazodone concentrations and increased mCPP concentrations.<ref name="pmid31379379" /><ref name="pmid23192413" /><ref name="pmid22115401">{{cite journal | vauthors = Mittur A | title = Trazodone: properties and utility in multiple disorders | journal = Expert Rev Clin Pharmacol | volume = 4 | issue = 2 | pages = 181–96 | date = March 2011 | pmid = 22115401 | doi = 10.1586/ecp.10.138 | s2cid = 6068710 }}</ref><ref name="FDA2023">{{cite web | title=Table of Substrates, Inhibitors and Inducers | website=U.S. Food and Drug Administration | date=5 June 2023 | url=https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers | archive-url=https://web.archive.org/web/20190503132546/https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers | url-status=dead | archive-date=3 May 2019 | access-date=5 July 2024}}</ref> CYP2D6 inhibitors may result in increased concentrations of both trazodone and mCPP, while CYP2D6 inducers may decrease their concentrations.<ref name="pmid10379419" /><ref name="pmid31379379" /><ref name="pmid9836023">{{cite journal |vauthors=Rotzinger S, Fang J, Coutts RT, Baker GB | title = Human CYP2D6 and metabolism of m-chlorophenylpiperazine | journal = Biological Psychiatry | volume = 44 | issue = 11 | pages = 1185–91 |date=December 1998 | pmid = 9836023 | doi = 10.1016/S0006-3223(97)00483-6| s2cid = 45097940 }}</ref> Examples of potent CYP2D6 inhibitors include [[bupropion]], [[cannabidiol]], [[duloxetine]], [[fluoxetine]], [[paroxetine]], [[quinidine]], and ritonavir, while CYP2D6 inducers include [[dexamethasone]], [[glutethimide]], and [[haloperidol]].<ref name="FDA2023" /> CYP1A2 inhibitors may increase trazodone concentrations, while CYP1A2 inducers may decrease trazodone concentrations. Examples of potent CYP1A2 inhibitors include [[ethinylestradiol]] (found in [[hormonal birth control]]), [[fluoroquinolone]]s (e.g., [[ciprofloxacin]]), fluvoxamine, and [[Hypericum perforatum|St. John's wort]], while potent CYP1A2 inducers include phenytoin, [[rifampin]], ritonavir, and [[tobacco]].<ref name="FDA2023" />

A study found that ritonavir, a strong CYP3A4 and CYP2D6 inhibitor and moderate CYP1A2 inducer, increased trazodone peak levels by 1.4-fold, trazodone [[area-under-curve (pharmacokinetics)|area-under-the-curve]] levels by 2.4-fold, and decreased trazodone [[clearance (pharmacology)|clearance]] by 50%.<ref name="pmid31379379" /><ref name="pmid22115401" /> This was associated with [[adverse effect]]s such as [[nausea]], [[hypotension]], and [[syncope (medicine)|syncope]].<ref name="pmid31379379" /> Another study found that the strong CYP3A4 inducer [[carbamazepine]] reduced concentrations of trazodone by 60 to 74%.<ref name="pmid31379379" /> The strong CYP2D6 inhibitor [[thioridazine]] has been reported to increase trazodone levels by 1.4-fold and concentrations of mCPP by 1.5-fold.<ref name="pmid10379419" /><ref name="pmid7482685">{{cite journal | vauthors = Yasui N, Otani K, Kaneko S, Ohkubo T, Osanai T, Ishida M, Mihara K, Kondo T, Sugawara K, Fukushima Y | title = Inhibition of trazodone metabolism by thioridazine in humans | journal = Ther Drug Monit | volume = 17 | issue = 4 | pages = 333–35 | date = August 1995 | pmid = 7482685 | doi = 10.1097/00007691-199508000-00003 | s2cid = 1979283 }}</ref> Fluoxetine, a strong inhibitor of CYP2D6 and a weak or moderate inhibitor of CYP3A4,<ref name="pmid10379419" /><ref name="pmid24569517">{{cite journal | vauthors = Sager JE, Lutz JD, Foti RS, Davis C, Kunze KL, Isoherranen N | title = Fluoxetine- and norfluoxetine-mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4 | journal = Clin Pharmacol Ther | volume = 95 | issue = 6 | pages = 653–62 | date = June 2014 | pmid = 24569517 | pmc = 4029899 | doi = 10.1038/clpt.2014.50 }}</ref> has been reported to increase levels of trazodone by 1.3- to 1.7-fold and of mCPP by 3.0- to 3.4-fold.<ref name="pmid10379419" /><ref name="pmid9315986">{{cite journal | vauthors = Maes M, Westenberg H, Vandoolaeghe E, Demedts P, Wauters A, Neels H, Meltzer HY | title = Effects of trazodone and fluoxetine in the treatment of major depression: therapeutic pharmacokinetic and pharmacodynamic interactions through formation of meta-chlorophenylpiperazine | journal = Journal of Clinical Psychopharmacology | volume = 17 | issue = 5 | pages = 358–64 | date = October 1997 | pmid = 9315986 | doi = 10.1097/00004714-199710000-00004 }}</ref> Conversely, CYP2D6 [[genotype]] has not been found to predict trazodone or mCPP concentrations with trazodone therapy, although CYP2D6 genotype did correlate with side effects like [[dizziness]] and [[QT interval|prolonged corrected QT interval]].<ref name="pmid27744763" /><ref name="pmid9335086">{{cite journal | vauthors = Mihara K, Otani K, Suzuki A, Yasui N, Nakano H, Meng X, Ohkubo T, Nagasaki T, Kaneko S, Tsuchida S, Sugawara K, Gonzalez FJ | title = Relationship between the CYP2D6 genotype and the steady-state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine | journal = Psychopharmacology (Berl) | volume = 133 | issue = 1 | pages = 95–98 | date = September 1997 | pmid = 9335086 | doi = 10.1007/s002130050376 | s2cid = 11521715 }}</ref><ref name="pmid29061081">{{cite journal | vauthors = Saiz-Rodríguez M, Belmonte C, Derqui-Fernández N, Cabaleiro T, Román M, Ochoa D, Talegón M, Ovejero-Benito MC, Abad-Santos F | title = Pharmacogenetics of trazodone in healthy volunteers: association with pharmacokinetics, pharmacodynamics and safety | journal = Pharmacogenomics | volume = 18 | issue = 16 | pages = 1491–502 | date = November 2017 | pmid = 29061081 | doi = 10.2217/pgs-2017-0116 }}</ref> [[Smoking|Smoker]]s have lower levels of trazodone and higher ratios of mCPP to trazodone.<ref name="pmid10379419" /><ref name="pmid8675966">{{cite journal | vauthors = Ishida M, Otani K, Kaneko S, Ohkubo T, Osanai T, Yasui N, Mihara K, Higuchi H, Sugawara K | title = Effects of various factors on steady state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine | journal = Int Clin Psychopharmacol | volume = 10 | issue = 3 | pages = 143–46 | date = September 1995 | pmid = 8675966 | doi = 10.1097/00004850-199510030-00002 }}</ref> Trazodone levels were 30% lower in smokers and mCPP to trazodone ratio was 1.3-fold higher in smokers, whereas mCPP concentrations were not different between smokers and non-smokers.<ref name="pmid8675966" /> Smoking is known to induce CYP1A2, and this may be involved in these findings.<ref name="pmid10379419" />

===Serotonergic agents and serotonin syndrome===
Combination of trazodone with [[selective serotonin reuptake inhibitor]]s (SSRIs), [[tricyclic antidepressant]]s (TCAs), or [[monoamine oxidase inhibitor]]s (MAOIs) has a theoretical risk of [[serotonin syndrome]].<ref name="pmid31379379" /><ref name="pmid23192413" /> However, trazodone has been studied in combination with SSRIs and seemed to be safe in this context.<ref name="pmid31379379" /><ref name="pmid23192413" /> On the other hand, cases of excessive [[sedation]] and serotonin syndrome have been reported with a combination of trazodone and fluoxetine or paroxetine.<ref name="pmid10379419" /> This may be due to the combined potentiation of the serotonin system.<ref name="pmid10379419" /> On the other hand, it may be related to the inhibition of cytochrome P450 enzymes by fluoxetine and paroxetine and consequently increased trazodone and mCPP levels.<ref name="pmid10379419" /><ref name="pmid9315986" />

===Antagonism of serotonergic psychedelics===
[[Serotonergic psychedelic]]s like [[lysergic acid diethylamide]] (LSD) and [[psilocybin]] are thought to mediate their [[halucinogen]]ic effects by activating [[serotonin]] [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]]s.<ref name="HalmanKongSarris2024">{{cite journal | vauthors = Halman A, Kong G, Sarris J, Perkins D | title = Drug-drug interactions involving classic psychedelics: A systematic review | journal = J Psychopharmacol | volume = 38 | issue = 1 | pages = 3–18 | date = January 2024 | pmid = 37982394 | pmc = 10851641 | doi = 10.1177/02698811231211219 | url = }}</ref> By displacing them from the 5-HT<sub>2A</sub> receptor, serotonin 5-HT<sub>2A</sub> receptor [[receptor antagonist|antagonist]]s can block the hallucinogenic effects of serotonergic psychedelics.<ref name="HalmanKongSarris2024" /> Serotonin 5-HT<sub>2A</sub> receptor antagonists like [[ketanserin]] and [[risperidone]] have been found to fully block or [[dose dependence|dose-dependently]] reduce the subjective effects of LSD and psilocybin in [[clinical study|clinical studies]].<ref name="HalmanKongSarris2024" />

Trazodone is a [[potency (pharmacology)|potent]] serotonin 5-HT<sub>2A</sub> receptor antagonist and may have similar effects.<ref name="HalmanKongSarris2024" /> Studies have estimated that trazodone occupies 90 to 97% of 5-HT<sub>2A</sub> receptors at doses of 50 to 200{{nbsp}}mg/day.<ref name="pmid29332554" /><ref name="pmid20095366" /><ref name="pmid22115401" /><ref name="pmid30342856" /> Trazodone is less-studied in blocking the effects of serotonergic psychedelics than other serotonin 5-HT<sub>2A</sub> receptor antagonists like ketanserin and risperidone, but has been reported to reduce the effects of psychedelics in published [[case report]]s.<ref name="HalmanKongSarris2024" /><ref name="BonsonBuckholtzMurphy1996">{{cite journal | vauthors = Bonson KR, Buckholtz JW, Murphy DL | title = Chronic administration of serotonergic antidepressants attenuates the subjective effects of LSD in humans | journal = Neuropsychopharmacology | volume = 14 | issue = 6 | pages = 425–436 | date = June 1996 | pmid = 8726753 | doi = 10.1016/0893-133X(95)00145-4 | url = }}</ref><ref name="RosenblatLeon-CarlyleAli2023" /> Specifically, a woman on trazodone 200{{nbsp}}mg/day who received a "moderate" dose of LSD was reported to have had reduced LSD-related hallucinogenic and physiological effects.<ref name="HalmanKongSarris2024" /><ref name="BonsonBuckholtzMurphy1996" /> In addition, in another instance, a man on trazodone 200{{nbsp}}mg/day who received 25{{nbsp}}mg psilocybin (a moderate dose) experienced no psychedelic effects at all.<ref name="ChenChen-LiChisamore2025">{{cite journal | vauthors = Chen MJ, Chen-Li D, Chisamore N, Husain MI, Di Vincenzo JD, Mansur R, Phan L, Johnson D, McIntyre RS, Rosenblat JD | title=Non-hallucinogenic psychedelics for mood and anxiety disorders: A systematic review | journal=Psychiatry Research | volume=349 | date=2025 | doi=10.1016/j.psychres.2025.116532 | doi-access=free | page=116532| pmid=40354769 }}</ref><ref name="RosenblatLeon-CarlyleAli2023">{{cite journal | vauthors = Rosenblat JD, Leon-Carlyle M, Ali S, Husain MI, McIntyre RS | title = Antidepressant Effects of Psilocybin in the Absence of Psychedelic Effects | journal = Am J Psychiatry | volume = 180 | issue = 5 | pages = 395–396 | date = May 2023 | pmid = 36945824 | doi = 10.1176/appi.ajp.20220835 | url = }}</ref>

Trazodone has been used and discussed extensively online as a so-called "[[trip killer]]" by [[recreational drug use|recreational]] psychedelic users.<ref name="YatesMelon2024">{{cite journal | vauthors = Yates G, Melon E | title = Trip-killers: a concerning practice associated with psychedelic drug use | journal = Emerg Med J | volume = 41 | issue = 2 | pages = 112–113 | date = January 2024 | pmid = 38123961 | doi = 10.1136/emermed-2023-213377 | url = https://s3.amazonaws.com/crawl.prod.proquest.com/fpcache/71f445805bfb61341cbc438c8ae23bd3.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEBMaCXVzLWVhc3QtMSJIMEYCIQDETX7YpaG5THA%2FNbKR0d92wr6h%2Bgg9preNcKjAsEqo%2BQIhAIlPGGWOeUc23LqhBzRYbxvSXB9aqSe2vVonl4nacAhhKp0CCLz%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEQABoMNTE4MzQ2ODQ4MzQxIgy9ji58Qtbi%2BavuKeYq8QEDL1U5KZDQ0bXFyVapeqJgE%2FX6x8DcJfFU8DAXYZPSQEwrIdfPbZWcYsH340deru%2FUHnNaGGpuHFoVzui%2FMbqBz7MANcowj%2FL1%2BQZzQ5hXh5KM3BW8E6NRzrQyuPRmBy7kQUkx8%2BjTN%2BXSMgF%2FCAs6Dn9fScgBGz3ddkwRZXDkjasqMP65RCPKhagK68cyMbf3oX%2BKS8a4Kltc2rk3CnWEhOKrZU4mIxq07DikLAXQbl8YRZJIkeOhN5TgBaLWJqyn1td2VWCMymAaFsqtPWHwXnEfsolRlfDooe6QXfE2YwX5PxBVJU7GPXRgrAqPjwtJMOCHgsEGOpwBYif%2BaDMBdz3IEghuvCvorAS0mkHzdcOz%2Fi7AzuN9nch%2FIm8llhMsN41aAWHuSG25pnhhftauFsg7rbGsrW2nl2kq2upi9zP7y%2Fnqk93jcP0kr0jM8zU12bYoSTsToQJsshH4N%2BTQUMwlzRQfeVv8MXdq%2BgSTTzJrWNwT1yNzye3rSHjvOumbNl6sgBISw7QqRzhB6hZTuf8AcI%2B7&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20250511T111826Z&X-Amz-SignedHeaders=host&X-Amz-Credential=ASIAXRL7BHBKRAKCQVVB%2F20250511%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Expires=3600&X-Amz-Signature=20bb1b90e4c8dbaa4115c954387617ebe2f55269bdd517692f1380193ed3f769 | archive-url = https://web.archive.org/web/20250511111827/https://s3.amazonaws.com/crawl.prod.proquest.com/fpcache/71f445805bfb61341cbc438c8ae23bd3.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEBMaCXVzLWVhc3QtMSJIMEYCIQDETX7YpaG5THA%2FNbKR0d92wr6h%2Bgg9preNcKjAsEqo%2BQIhAIlPGGWOeUc23LqhBzRYbxvSXB9aqSe2vVonl4nacAhhKp0CCLz%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEQABoMNTE4MzQ2ODQ4MzQxIgy9ji58Qtbi%2BavuKeYq8QEDL1U5KZDQ0bXFyVapeqJgE%2FX6x8DcJfFU8DAXYZPSQEwrIdfPbZWcYsH340deru%2FUHnNaGGpuHFoVzui%2FMbqBz7MANcowj%2FL1%2BQZzQ5hXh5KM3BW8E6NRzrQyuPRmBy7kQUkx8%2BjTN%2BXSMgF%2FCAs6Dn9fScgBGz3ddkwRZXDkjasqMP65RCPKhagK68cyMbf3oX%2BKS8a4Kltc2rk3CnWEhOKrZU4mIxq07DikLAXQbl8YRZJIkeOhN5TgBaLWJqyn1td2VWCMymAaFsqtPWHwXnEfsolRlfDooe6QXfE2YwX5PxBVJU7GPXRgrAqPjwtJMOCHgsEGOpwBYif%2BaDMBdz3IEghuvCvorAS0mkHzdcOz%2Fi7AzuN9nch%2FIm8llhMsN41aAWHuSG25pnhhftauFsg7rbGsrW2nl2kq2upi9zP7y%2Fnqk93jcP0kr0jM8zU12bYoSTsToQJsshH4N%2BTQUMwlzRQfeVv8MXdq%2BgSTTzJrWNwT1yNzye3rSHjvOumbNl6sgBISw7QqRzhB6hZTuf8AcI%2B7&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20250511T111826Z&X-Amz-SignedHeaders=host&X-Amz-Credential=ASIAXRL7BHBKRAKCQVVB%2F20250511%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Expires=3600&X-Amz-Signature=20bb1b90e4c8dbaa4115c954387617ebe2f55269bdd517692f1380193ed3f769 | url-status = dead | archive-date = 2025-05-11 | quote = Table 1 Trip-killers recommended by Reddit users [...] Antidepressants, n=100 [...] Drug Name: Trazodone; N: 77. [...] Table 2 Trip-killer doses recommended by Reddit users: Drug name: Trazodone. Dose range: 50–150 mg.}}</ref><ref name="Suran2024">{{cite journal | vauthors = Suran M | title = Study Finds Hundreds of Reddit Posts on "Trip-Killers" for Psychedelic Drugs | journal = JAMA | volume = 331 | issue = 8 | pages = 632–634 | date = February 2024 | pmid = 38294772 | doi = 10.1001/jama.2023.28257 | url = }}</ref> It was recommended on the [[social media]] website [[Reddit]] for such purposes 77{{nbsp}}times by 2024 with a suggested dose range of 50 to 150{{nbsp}}mg.<ref name="YatesMelon2024" /><ref name="Suran2024" /> Trazodone was one of the most commonly recommended drugs for such purposes, exceeded only by [[alprazolam]], [[benzodiazepine]]s generally, and [[quetiapine]].<ref name="YatesMelon2024" /><ref name="Suran2024" />

==Pharmacology==

===Pharmacodynamics===
{| class="wikitable floatright" style="font-size:small;"
|+ Trazodone (and metabolite)<ref name="PDSP">{{cite web | title = PDSP K<sub>i</sub> Database | work = Psychoactive Drug Screening Program (PDSP) | vauthors = Roth BL, Driscol J|author1-link=Bryan Roth | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 14 August 2017 | url = https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=trazodone&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}</ref>
|-
! Site !! Trazodone !! {{abbrlink|mCPP|meta-Chlorophenylpiperazine}} !! Species !! Ref
|-
|{{abbrlink|SERT|Serotonin transporter}}|| 160–>10,000<ref>Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 25 May 2018.</ref>|| 202–432 || Human ||<ref name="PDSP" /><ref name="pmid9400006">{{cite journal | vauthors = Owens MJ, Morgan WN, Plott SJ, Nemeroff CB | title = Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites | journal = J. Pharmacol. Exp. Ther. | volume = 283 | issue = 3 | pages = 1305–22 | year = 1997 | doi = 10.1016/S0022-3565(24)37161-7 | pmid = 9400006 }}</ref><ref name="pmid9537821">{{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 = 249–58 | year = 1997 | pmid = 9537821 | doi = 10.1016/s0014-2999(97)01393-9}}</ref>
|-
| {{abbrlink|NET|Norepinephrine transporter}} || ≥8,500 || ≥1,940 || Human || <ref name="pmid9537821" /><ref name="pmid9400006" />
|-
| {{abbrlink|DAT|Dopamine transporter}} || ≥7,400 || {{abbr|ND|No data}} || Human || <ref name="pmid9537821" /><ref name="PDSP" />
|-
|[[5-HT1A receptor|5-HT<sub>1A</sub>]]|| 96–118 || 44–400 || Human ||<ref name="PDSP" /><ref name="pmid7855217">{{cite journal | vauthors = Cusack B, Nelson A, Richelson E | title = Binding of antidepressants to human brain receptors: focus on newer generation compounds | journal = Psychopharmacology | volume = 114 | issue = 4 | pages = 559–65 | year = 1994 | pmid = 7855217 | doi = 10.1007/bf02244985| s2cid = 21236268 }}</ref><ref name="pmid2537663">{{cite journal | vauthors = Hamik A, Peroutka SJ | title = 1-(m-chlorophenyl)piperazine (mCPP) interactions with neurotransmitter receptors in the human brain | journal = Biol. Psychiatry | volume = 25 | issue = 5 | pages = 569–75 | year = 1989 | pmid = 2537663 | doi = 10.1016/0006-3223(89)90217-5| s2cid = 46730665 | doi-access = free }}</ref>
|-
|[[5-HT1B receptor|5-HT<sub>1B</sub>]]|| >10,000 || 89–501 || Human ||<ref name="PDSP" /><ref name="pmid7984267">{{cite journal | vauthors = Boess FG, Martin IL | title = Molecular biology of 5-HT receptors | journal = Neuropharmacology | volume = 33 | issue = 3–4 | pages = 275–317 | year = 1994 | pmid = 7984267 | doi = 10.1016/0028-3908(94)90059-0| s2cid = 35553281 }}</ref>
|-
|[[5-HT1D receptor|5-HT<sub>1D</sub>]]|| 106 || 210–1,300 || Human ||<ref name="PDSP" /><ref name="pmid2537663" /><ref name="pmid1652050">{{cite journal | vauthors = Hamblin MW, Metcalf MA | title = Primary structure and functional characterization of a human 5-HT1D-type serotonin receptor | journal = Mol. Pharmacol. | volume = 40 | issue = 2 | pages = 143–48 | year = 1991 | doi = 10.1016/S0026-895X(25)12918-0 | pmid = 1652050 }}</ref>
|-
| [[5-HT1E receptor|5-HT<sub>1E</sub>]] || >10,000 || {{abbr|ND|No data}} || Human || <ref name="PDSP" />
|-
| [[5-HT1F receptor|5-HT<sub>1F</sub>]] || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
|[[5-HT2A receptor|5-HT<sub>2A</sub>]]|| 20–45 || 32–398 || Human ||<ref name="PDSP" /><ref name="pmid15322733">{{cite journal | vauthors = Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, Bickerdike M | title = Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors | journal = Naunyn-Schmiedeberg's Arch. Pharmacol. | volume = 370 | issue = 2 | pages = 114–23 | year = 2004 | pmid = 15322733 | doi = 10.1007/s00210-004-0951-4 | s2cid = 8938111 }}</ref><ref name="pmid7582481">{{cite journal | vauthors = Bonhaus DW, Bach C, DeSouza A, Salazar FH, Matsuoka BD, Zuppan P, Chan HW, Eglen RM | title = The pharmacology and distribution of human 5-hydroxytryptamine2B (5-HT2B) receptor gene products: comparison with 5-HT2A and 5-HT2C receptors | journal = Br. J. Pharmacol. | volume = 115 | issue = 4 | pages = 622–28 | year = 1995 | pmid = 7582481 | pmc = 1908489 | doi = 10.1111/j.1476-5381.1995.tb14977.x}}</ref><ref name="pmid19505264">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Serotonergic drugs and valvular heart disease | journal = Expert Opin Drug Saf | volume = 8 | issue = 3 | pages = 317–29 | year = 2009 | pmid = 19505264 | pmc = 2695569 | doi = 10.1517/14740330902931524 }}</ref>
|-
|[[5-HT2B receptor|5-HT<sub>2B</sub>]]|| 74–189 || 3.2–63 || Human ||<ref name="PDSP" /><ref name="pmid15322733" /><ref name="pmid11104741">{{cite journal | vauthors = Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL | title = Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications | journal = Circulation | volume = 102 | issue = 23 | pages = 2836–41 | year = 2000 | pmid = 11104741 | doi = 10.1161/01.cir.102.23.2836| doi-access = free }}</ref><ref name="pmid10498829">{{cite journal | vauthors = Porter RH, Benwell KR, Lamb H, Malcolm CS, Allen NH, Revell DF, Adams DR, Sheardown MJ | title = Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells | journal = Br. J. Pharmacol. | volume = 128 | issue = 1 | pages = 13–20 | year = 1999 | pmid = 10498829 | pmc = 1571597 | doi = 10.1038/sj.bjp.0702751 }}</ref>
|-
|[[5-HT2C receptor|5-HT<sub>2C</sub>]]|| 224–402 || 3.4–251 || Human ||<ref name="pmid15322733" /><ref name="pmid15081042">{{cite journal | vauthors = Bentley JM, Adams DR, Bebbington D, Benwell KR, Bickerdike MJ, Davidson JE, Dawson CE, Dourish CT, Duncton MA, Gaur S, George AR, Giles PR, Hamlyn RJ, Kennett GA, Knight AR, Malcolm CS, Mansell HL, Misra A, Monck NJ, Pratt RM, Quirk K, Roffey JR, Vickers SP, Cliffe IA | title = Indoline derivatives as 5-HT(2C) receptor agonists | journal = Bioorg. Med. Chem. Lett. | volume = 14 | issue = 9 | pages = 2367–70 | year = 2004 | pmid = 15081042 | doi = 10.1016/j.bmcl.2003.05.001 }}</ref><ref name="pmid9225287">{{cite journal | vauthors = Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, McNeeley PM, Szczepanski K, Fontana DJ, Trinh J, Rocha CL, Dawson MW, Flippin LA, Eglen RM | title = RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist | journal = Neuropharmacology | volume = 36 | issue = 4–5 | pages = 621–29 | year = 1997 | pmid = 9225287 | doi = 10.1016/s0028-3908(97)00049-x| s2cid = 24930608 }}</ref><ref name="pmid19505264" />
|-
| [[5-HT3 receptor|5-HT<sub>3</sub>]] || >10,000 || 427 || Human || <ref name="PDSP" />
|-
| [[5-HT4 receptor|5-HT<sub>4</sub>]] || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[5-HT5A receptor|5-HT<sub>5A</sub>]] || >10,000 || 1,354 || Human || <ref name="PDSP" />
|-
| [[5-HT6 receptor|5-HT<sub>6</sub>]] || >10,000 || 1,748 || Human || <ref name="PDSP" />
|-
|[[5-HT7 receptor|5-HT<sub>7</sub>]]|| 1,782 || 163 || Human ||<ref name="PDSP" />
|-
|[[Alpha-1 adrenergic receptor|α<sub>1</sub>]]|| 12–42 || 97–2,900 || Human ||<ref name="pmid9400006" /><ref name="pmid7855217" /><ref name="pmid2537663" /><ref name="pmid6086881">{{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 | year = 1984 | doi = 10.1016/S0022-3565(25)21446-X | pmid = 6086881 }}</ref>
|-
| &nbsp;&nbsp;[[Alpha-1A adrenergic receptor|α<sub>1A</sub>]]|| 153 || 1,386 || Human ||<ref name="PDSP" />
|-
| &nbsp;&nbsp;[[Alpha-1B adrenergic receptor|α<sub>1B</sub>]] || {{abbr|ND|No data}} || 915 || Human || <ref name="PDSP" />
|-
| &nbsp;&nbsp;[[Alpha-1D adrenergic receptor|α<sub>1D</sub>]] || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
|[[Alpha-2 adrenergic receptor|α<sub>2</sub>]]|| 106–490 || 112–570 || Human ||<ref name="pmid7855217" /><ref name="pmid9400006" /><ref name="pmid2537663" /><ref name="pmid6086881" />
|-
| &nbsp;&nbsp;[[Alpha-2A adrenergic receptor|α<sub>2A</sub>]]|| 728 || 145 || Human ||<ref name="PDSP" />
|-
| &nbsp;&nbsp;[[Alpha-2B adrenergic receptor|α<sub>2B</sub>]]||{{abbr|ND|No data}} || 106 || Human ||<ref name="PDSP" />
|-
| &nbsp;&nbsp;[[Alpha-2C adrenergic receptor|α<sub>2C</sub>]]|| 155 || 124 || Human ||<ref name="PDSP" />
|-
| [[Beta adrenergic receptor|β]] || >10,000 || 2,500 || Human || <ref name="PDSP" /><ref name="pmid2537663"/>
|-
| &nbsp;&nbsp;[[Beta-1 adrenergic receptor|β<sub>1</sub>]] || >10,000 || 2,359 || Human || <ref name="PDSP" />
|-
| &nbsp;&nbsp;[[Beta-2 adrenergic receptor|β<sub>2</sub>]] || >10,000 || 3,474 || Human || <ref name="PDSP" />
|-
| [[Dopamine D1 receptor|D<sub>1</sub>]] || 3,730 || 7,000 || Human || <ref name="PDSP" /><ref name="pmid2537663" />
|-
| [[Dopamine D2 receptor|D<sub>2</sub>]] || ≥3,500 || >10,000 || Human || <ref name="PDSP" /><ref name="pmid7855217" /><ref name="pmid8100134" /><ref name="pmid2537663" />
|-
| [[Dopamine D3 receptor|D<sub>3</sub>]] || 353 || >10,000 || Rat || <ref name="PDSP" /><ref name="pmid2537663" />
|-
| [[Dopamine D4 receptor|D<sub>4</sub>]] || 703 || {{abbr|ND|No data}} || Human || <ref name="PDSP" />
|-
| [[Dopamine D5 receptor|D<sub>5</sub>]] || >10,000 || >10,000 || Human || <ref name="PDSP" /><ref name="pmid2537663" />
|-
|[[Histamine H1 receptor|H<sub>1</sub>]]|| 220–1,100 || 326 || Human ||<ref name="PDSP" /><ref name="pmid6086881" /><ref name="pmid7855217" />
|-
| [[Histamine H2 receptor|H<sub>2</sub>]] || 3,290 || {{abbr|ND|No data}} || Human || <ref name="PDSP" />
|-
| [[Histamine H3 receptor|H<sub>3</sub>]] || >10,000 || {{abbr|ND|No data}} || Guinea pig || <ref name="PDSP" />
|-
| [[Histamine H4 receptor|H<sub>4</sub>]] || >10,000 || {{abbr|ND|No data}} || Human || <ref name="PDSP" />
|-
| {{abbrlink|mAChRs|Muscarinic acetylcholine receptors}} || >10,000 || >10,000 || Human || <ref name="PDSP" /><ref name="pmid8100134">{{cite journal | vauthors = Stanton T, Bolden-Watson C, Cusack B, Richelson E | title = Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics | journal = Biochem. Pharmacol. | volume = 45 | issue = 11 | pages = 2352–54 | year = 1993 | pmid = 8100134 | doi = 10.1016/0006-2952(93)90211-e}}</ref><ref name="pmid7855217" /><ref name="pmid2537663" />
|-
| {{abbrlink|nAChRs|Nicotinic acetylcholine receptors}} || >10,000 || >10,000 || Human || <ref name="PDSP" />
|-
| [[Sigma-1 receptor|σ<sub>1</sub>]] || >10,000 || {{abbr|ND|No data}} || Rat || <ref name="PDSP" />
|-
| [[Sigma-2 receptor|σ<sub>2</sub>]] || 536 || 8,350 || Rat || <ref name="PDSP" />
|-
| [[Imidazoline receptor|I<sub>1</sub>]] || {{abbr|ND|No data}} || 759 || Rat || <ref name="PDSP" />
|-
| [[NMDA receptor|{{abbr|NMDAR|N-Methyl-D-aspartate receptor}}<br />(MK-801)]] || >10,000 || {{abbr|ND|No data}} || Rat || <ref name="PDSP" />
|-
| {{abbrlink|VDCCs|Voltage-dependent calcium channels}} || >10,000 || 6,043 || Rat || <ref name="PDSP" />
|- class="sortbottom"
| colspan="5" style="width: 1px;" | Values are [[Binding affinity|K<sub>i</sub> (nM)]]. The smaller the value, the more strongly the drug binds to the site.
|}

Trazodone is a mixed [[agonist]] and [[receptor antagonist|antagonist]] of various [[serotonin receptor]]s, antagonist of [[adrenergic receptor]]s, weak [[histamine]] [[H1 receptor|H<sub>1</sub> receptor]] antagonist, and weak [[serotonin reuptake inhibitor]].<ref name="pmid22115401" /><ref name="pmid23192413">{{cite journal | vauthors = Fagiolini A, Comandini A, Catena Dell'Osso M, Kasper S | title = Rediscovering trazodone for the treatment of major depressive disorder | journal = CNS Drugs | volume = 26 | issue = 12 | pages = 1033–49 | year = 2012 | pmid = 23192413 | pmc = 3693429 | doi = 10.1007/s40263-012-0010-5 }}</ref> More specifically, it is an antagonist of [[5-HT2A receptor|5-HT<sub>2A</sub>]] and [[5-HT2B receptor|5-HT<sub>2B</sub> receptor]]s, a [[partial agonist]] of the [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]], and an antagonist of the [[alpha-1 adrenergic receptor|α<sub>1</sub>-]] and [[alpha-2 adrenergic receptor|α<sub>2</sub>-adrenergic receptor]]s.<ref name="pmid23192413" /><ref name="pmid22115401" /> It is also a [[ligand (biochemistry)|ligand]] of the [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]] with lower [[affinity (pharmacology)|affinity]] than for the 5-HT<sub>2A</sub> receptor.<ref name="pmid22115401" /><ref name="pmid23192413" /> However, it is unknown whether trazodone acts as a [[full agonist]], partial agonist, or antagonist of the 5-HT<sub>2C</sub> receptor.<ref name="pmid22115401" /> Trazodone is a 5-HT<sub>1A</sub> receptor partial agonist similarly to [[buspirone]] and [[tandospirone]] but with comparatively greater [[intrinsic activity]].<ref name="PDSP" /><ref name="pmid1387963">{{cite journal | vauthors = Raffa RB, Shank RP, Vaught JL | title = Etoperidone, trazodone and MCPP: in vitro and in vivo identification of serotonin 5-HT1A (antagonistic) activity | journal = Psychopharmacology | volume = 108 | issue = 3 | pages = 320–26 | date = 1992 | pmid = 1387963 | doi = 10.1007/BF02245118 | s2cid = 24965789 }}</ref><ref name="pmid15888508">{{cite journal | vauthors = Odagaki Y, Toyoshima R, Yamauchi T | title = Trazodone and its active metabolite m-chlorophenylpiperazine as partial agonists at 5-HT1A receptors assessed by [35S]GTPgammaS binding | journal = J. Psychopharmacol. (Oxford) | volume = 19 | issue = 3 | pages = 235–41 | date = May 2005 | pmid = 15888508 | doi = 10.1177/0269881105051526 | s2cid = 27389008 }}</ref> A range of weak [[Binding affinity|affinities (K<sub>i</sub>)]] have been reported for trazodone at the human [[histamine]] [[H1 receptor|H<sub>1</sub> receptor]], including 220{{nbsp}}nM,<ref name="PDSP" /> 350{{nbsp}}nM,<ref name="pmid6086881" /> 500{{nbsp}}nM,<ref name="pmid23357028">{{cite journal | vauthors = Krystal AD, Richelson E, Roth T | title = Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications | journal = Sleep Med Rev | volume = 17 | issue = 4 | pages = 263–72 | year = 2013 | pmid = 23357028 | doi = 10.1016/j.smrv.2012.08.001 }}</ref> and 1,100{{nbsp}}nM.<ref name="pmid7855217" />

Trazodone has a minor [[active metabolite]] known as [[meta-chlorophenylpiperazine|''meta''-chlorophenylpiperazine]] (mCPP), and this metabolite may contribute to some degree to the pharmacological properties of trazodone.<ref name="pmid10379419" /><ref name="LemkeWilliams2008">{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA586|year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6879-5|pages=586–}}</ref> In contrast to trazodone, mCPP is an agonist of various serotonin receptors.<ref name="pmid1663792">{{cite journal | vauthors = Kahn RS, Wetzler S | title = m-Chlorophenylpiperazine as a probe of serotonin function | journal = Biol. Psychiatry | volume = 30 | issue = 11 | pages = 1139–66 | year = 1991 | pmid = 1663792 | doi = 10.1016/0006-3223(91)90184-n| s2cid = 13007057 }}</ref> It has relatively low affinity for α<sub>1</sub>-adrenergic receptors unlike trazodone, but does have high affinity for α<sub>2</sub>-adrenergic receptors and weak affinity for the H<sub>1</sub> receptor.<ref name="pmid22115401" /> In addition to direct interactions with serotonin receptors, mCPP is a [[serotonin releasing agent]] similarly to agents like [[fenfluramine]] and [[MDMA]].<ref name="pmid22115401" /><ref name="pmid7255270" /><ref name="pmid6128394" /><ref name="pmid9315986" /> In contrast to these serotonin releasing agents however, mCPP does not appear to cause long-term serotonin depletion (a property thought to be related to serotonergic [[neurotoxicity]]).<ref name="pmid22115401" />

Trazodone's 5-HT<sub>2A</sub> receptor antagonism and weak serotonin reuptake inhibition form the basis of its common label as an antidepressant of the [[serotonin antagonist and reuptake inhibitor]] (SARI) type.<ref name="pmid27744763">{{cite journal | vauthors = Khouzam HR | title = A review of trazodone use in psychiatric and medical conditions | journal = Postgrad Med | volume = 129 | issue = 1 | pages = 140–48 | year = 2017 | pmid = 27744763 | doi = 10.1080/00325481.2017.1249265 | s2cid = 205452630 }}</ref>

====Target occupancy studies====
Studies have estimated occupancy of target sites by trazodone based on trazodone concentrations in blood and brain and on the affinities of trazodone for the human targets in question.<ref name="pmid29332554" /><ref name="pmid30342856" /><ref name="pmid22115401" /> Roughly half of brain [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]]s are blocked by 1{{nbsp}}mg of trazodone and essentially all 5-HT<sub>2A</sub> receptors are saturated at 10{{nbsp}}mg of trazodone, but the clinically effective hypnotic doses of trazodone are in the 25–100{{nbsp}}mg range.<ref name="pmid29552421">{{cite journal | vauthors = Jaffer KY, Chang T, Vanle B, Dang J, Steiner AJ, Loera N, Abdelmesseh M, Danovitch I, Ishak WW | title = Trazodone for Insomnia: A Systematic Review | journal = Innovations in Clinical Neuroscience | volume = 14 | issue = 7–8 | pages = 24–34 | date = 1 August 2017 | pmid = 29552421 | pmc = 5842888 }}</ref><ref name="pmid20095366">{{cite journal | vauthors = Stahl SM | title = Mechanism of action of trazodone: a multifunctional drug | journal = CNS Spectrums | volume = 14 | issue = 10 | pages = 536–46 | date = October 2009 | pmid = 20095366 | doi = 10.1017/s1092852900024020 | s2cid = 2977125 }}</ref> The occupancy of the [[serotonin transporter]] (SERT) by trazodone is estimated to be 86% at 100{{nbsp}}mg/day and 90% at 150{{nbsp}}mg/day.<ref name="pmid31379379" /><ref name="pmid29332554">{{cite journal | vauthors = Settimo L, Taylor D | title = Evaluating the dose-dependent mechanism of action of trazodone by estimation of occupancies for different brain neurotransmitter targets | journal = J Psychopharmacol | volume = 32 | issue = 1 | pages = 96–104 | date = January 2018 | pmid = 29332554 | doi = 10.1177/0269881117742101 | s2cid = 28804036 | url = https://kclpure.kcl.ac.uk/portal/en/publications/evaluating-the-dosedependent-mechanism-of-action-of-trazodone-by-estimation-of-occupancies-for-different-brain-neurotransmitter-targets(595a2884-d192-432a-a025-1101a0377b1b).html | doi-access = free }}</ref> Trazodone may almost completely occupy the 5-HT<sub>2A</sub> and [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]]s at doses of 100 to 150{{nbsp}}mg/day.<ref name="pmid31379379" /><ref name="pmid29332554" /> Significant occupancy of a number of other sites may also occur.<ref name="pmid31379379" /><ref name="pmid29332554" /> However, another study estimated much lower occupancy of the SERT and 5-HT<sub>2A</sub> receptors by trazodone.<ref name="pmid22115401" />

{| class="wikitable"
|+ Estimated occupancy of biological targets by trazodone at different doses<ref name="pmid29332554" /><ref name="pmid30342856">{{cite journal | vauthors = Pyke RE | title = Trazodone in Sexual Medicine: Underused and Overdosed? | journal = Sex Med Rev | volume = 8 | issue = 2 | pages = 206–16 | date = April 2020 | pmid = 30342856 | doi = 10.1016/j.sxmr.2018.08.003 | s2cid = 53042045 }}</ref>
! rowspan="2" | Target
! colspan="3" | Estimated target occupancy
|-
! 50{{nbsp}}mg/day
! 100{{nbsp}}mg/day
! 150{{nbsp}}mg/day
|-
| SERT
| 75%
| 86%
| 90%
|-
| 5-HT<sub>1A</sub>
| 91%
| 95%
| 97%
|-
| 5-HT<sub>1D</sub>
| 91%
| 95%
| 97%
|-
| 5-HT<sub>2A</sub>
| 97%
| 98%
| 99%
|-
| 5-HT<sub>2B</sub>
| 94%
| 97%
| 98%
|-
| 5-HT<sub>2C</sub>
| 83%
| 91%
| 94%
|-
| 5-HT<sub>7</sub>
| 39%
| 56%
| 66%
|-
| α<sub>1A</sub>
| 88%
| 94%
| 96%
|-
| α<sub>2A</sub>
| 61%
| 75%
| 82%
|-
| α<sub>2C</sub>
| 88%
| 94%
| 96%
|-
| D<sub>4</sub>
| 62%
| 76%
| 83%
|-
| H<sub>1</sub>
| 84%
| 91%
| 94%
|-
| colspan="4" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Very low''' (<25–33%): NET, DAT, 5-HT<sub>1B</sub>, 5-HT<sub>1E</sub>, 5-HT<sub>3</sub>, 5-HT<sub>5A</sub>, 5-HT<sub>6</sub>, β<sub>1</sub>, β<sub>2</sub>, D<sub>5</sub>, H<sub>4</sub>, mAChRs, nAChRs. '''Low''' (<50%): D<sub>1</sub>, D<sub>2</sub>. '''Not determined''': α<sub>1B</sub>, α<sub>2B</sub>, D<sub>3</sub>. '''Note:''' Another study estimated much lower occupancies.<ref name="pmid22115401" />
|}

====Effects in preclinical studies====
Trazodone shows [[antidepressant]]- and [[anxiolytic]]-like effects in animals.<ref name="Al-YassiriAnkierBridges1981" /><ref name="AydSettle1982">{{cite journal | vauthors = Ayd FJ, Settle EC | title = Trazodone: a novel, broad-spectrum antidepressant | journal = Mod Probl Pharmacopsychiatry | series = Modern Trends in Pharmacopsychiatry | volume = 18 | issue = | pages = 49–69 | date = 1982 | pmid = 6124884 | doi = 10.1159/000406236 | isbn = 978-3-8055-3428-4 | url = }}</ref><ref name="Rawls1982">{{cite journal | vauthors = Rawls WN | title = Trazodone (Desyrel, Mead-Johnson Pharmaceutical Division) | journal = Drug Intell Clin Pharm | volume = 16 | issue = 1 | pages = 7–13 | date = January 1982 | pmid = 7032872 | doi = 10.1177/106002808201600102 | url = }}</ref> However, it shows differences from certain other antidepressants, like the [[tricyclic antidepressant]]s, in animals.<ref name="Al-YassiriAnkierBridges1981">{{cite journal | vauthors = Al-Yassiri MM, Ankier SI, Bridges PK | title = Trazodone--a new antidepressant | journal = Life Sci | volume = 28 | issue = 22 | pages = 2449–2458 | date = June 1981 | pmid = 7019617| doi = 10.1016/0024-3205(81)90586-5 | url = }}</ref><ref name="Rawls1982" /> For example, it does not reverse the behavioral effects of the [[monoamine depleting agent]] [[reserpine]] and does not potentiate the effects of [[amphetamine-type stimulant|amphetamine]] or [[levodopa]].<ref name="Al-YassiriAnkierBridges1981" /><ref name="AydSettle1982" /><ref name="Rawls1982" /> Similarly to [[antipsychotic]]s, trazodone reduces [[locomotor activity|spontaneous motor activity]], spontaneous and elicited [[aggression|aggressive behavior]], and [[exploration|exploratory behavior]], among other effects.<ref name="Al-YassiriAnkierBridges1981" /><ref name="AydSettle1982" /><ref name="TuckerFile1986">{{cite journal | vauthors = Tucker JC, File SE | title = The effects of tricyclic and 'atypical' antidepressants on spontaneous locomotor activity in rodents | journal = Neurosci Biobehav Rev | volume = 10 | issue = 2 | pages = 115–121 | date = 1986 | pmid = 3737024 | doi = 10.1016/0149-7634(86)90022-9 | url = }}</ref> In addition, trazodone diminishes [[amphetamine]]-induced [[hyperlocomotion|locomotor hyperactivity]], although it does not inhibit [[apomorphine]]- or [[amphetamine]]-induced [[stereotypy]].<ref name="Al-YassiriAnkierBridges1981" /><ref name="AydSettle1982" /><ref name="BaranMajRogóz1979">{{cite journal | vauthors = Baran L, Maj J, Rogóz Z, Skuza G | title = On the central antiserotonin action of trazodone | journal = Pol J Pharmacol Pharm | volume = 31 | issue = 1 | pages = 25–33 | date = 1979 | pmid = 482164 | doi = | url = }}</ref> On the other hand, unlike antipsychotics, trazodone does not produce [[catalepsy]], although it can do so at sufficiently high doses.<ref name="Al-YassiriAnkierBridges1981" /><ref name="AydSettle1982" /><ref name="BalsaraJadhavGaonkar2005" />

Activation of the serotonin 5-HT<sub>2A</sub> receptor enhances striatal dopaminergic neurotransmission, while stimulation of the serotonin 5-HT<sub>2C</sub> receptor inhibits striatal dopaminergic neurotransmission.<ref name="Sarwar2018">{{cite journal | vauthors = Sarwar AI | title = Trazodone and Parkinsonism: The Link Strengthens | journal = Clin Neuropharmacol | volume = 41 | issue = 3 | pages = 106–108 | date = 2018 | pmid = 29634584 | doi = 10.1097/WNF.0000000000000278 | url = | quote = Although the exact underlying mechanism causing parkinsonism after the exposure of trazodone in this or any of the previously described cases remains elusive, it likely involves trazodone's inhibitory effect, either directly or via the serotonergic system on striatal dopaminergic neurotransmission.7,8,12–16 It is known that serotonin (5-hydroxytryptamine [5-HT]), via stimulation of 5-HT2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT2A receptors enhances dopaminergic neurotransmission. The antidepressant trazodone is a 5-HT2A and 5-HT2C receptor antagonist.7,16 However, its antagonism at 5-HT2A receptors is more robust than that at 5-HT2C receptors (15-fold difference).7,8 Hence, the differential antagonist effect of trazodone on 5-HT2A versus 5-HT2C receptors "at a certain dose point" could potentially result in the inhibition of dopaminergic neurotransmission in the striatonigral region. In addition, a direct dose-dependent blocking effect of trazodone on postsynaptic striatal D2 dopamine receptors has been demonstrated in the rat model.8}}</ref> Trazodone is both a serotonin 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> receptor antagonist, but has about 15-fold greater [[potency (pharmacology)|potency]] as an antagonist of the 5-HT<sub>2A</sub> receptor relative to the 5-HT<sub>2C</sub> receptor.<ref name="Sarwar2018" /> In addition, at higher doses, trazodone acts as a dopamine D<sub>2</sub> receptor antagonist in animals.<ref name="Sarwar2018" /><ref name="BalsaraJadhavGaonkar2005">{{cite journal | vauthors = Balsara JJ, Jadhav SA, Gaonkar RK, Gaikwad RV, Jadhav JH | title = Effects of the antidepressant trazodone, a 5-HT 2A/2C receptor antagonist, on dopamine-dependent behaviors in rats | journal = Psychopharmacology (Berl) | volume = 179 | issue = 3 | pages = 597–605 | date = May 2005 | pmid = 15614572 | doi = 10.1007/s00213-004-2095-0 | url = }}</ref> As a result of the preceding actions, trazodone may inhibit striatal dopaminergic neurotransmission.<ref name="Sarwar2018" /> This may underlie exacerbation of [[parkinsonism]] seen in [[marmoset]]s and in human [[case report]]s.<ref name="Sarwar2018" /><ref name="Höllerhage2019">{{cite journal | vauthors = Höllerhage M | title = Secondary parkinsonism due to drugs, vascular lesions, tumors, trauma, and other insults | journal = Int Rev Neurobiol | series = International Review of Neurobiology | volume = 149 | issue = | pages = 377–418 | date = 2019 | pmid = 31779822 | doi = 10.1016/bs.irn.2019.10.010 | isbn = 978-0-12-817730-3 | url = }}</ref>

====Correspondence to clinical effects====
{{Update section|reason=Needs to be updated in light of new occupancy studies.|date=October 2020}}

Trazodone may act predominantly as a 5-HT<sub>2A</sub> receptor antagonist to mediate its therapeutic benefits against [[anxiety]] and [[major depression|depression]].<ref name="pmid1365657">{{cite journal | vauthors = Marek GJ, McDougle CJ, Price LH, Seiden LS | title = A comparison of trazodone and fluoxetine: implications for a serotonergic mechanism of antidepressant action | journal = Psychopharmacology | volume = 109 | issue = 1–2 | pages = 2–11 | date = 1992 | pmid = 1365657 | doi = 10.1007/BF02245475 | s2cid = 25140746 }}</ref> Its inhibitory effects on serotonin reuptake and 5-HT<sub>2C</sub> receptors are comparatively weak.<ref name="pmid1365657"/> In relation to these properties, trazodone does not have similar properties to [[selective serotonin reuptake inhibitor]]s (SSRIs)<ref name="pmid1365657"/> and is not particularly associated with increased [[appetite]] and [[weight gain]] – unlike other 5-HT<sub>2C</sub> antagonists like [[mirtazapine]].<ref name="pmid12096167">{{cite journal | vauthors = Vanina Y, Podolskaya A, Sedky K, Shahab H, Siddiqui A, Munshi F, Lippmann S | title = Body weight changes associated with psychopharmacology | journal = Psychiatr Serv | volume = 53 | issue = 7 | pages = 842–47 | date = July 2002 | pmid = 12096167 | doi = 10.1176/appi.ps.53.7.842 }}</ref><ref name="pmid20030418">{{cite journal | vauthors = Watanabe N, Omori IM, Nakagawa A, Cipriani A, Barbui C, McGuire H, Churchill R, Furukawa TA | title = Safety reporting and adverse-event profile of mirtazapine described in randomized controlled trials in comparison with other classes of antidepressants in the acute-phase treatment of adults with depression: systematic review and meta-analysis | journal = CNS Drugs | volume = 24 | issue = 1 | pages = 35–53 | date = January 2010 | pmid = 20030418 | doi = 10.2165/11319480-000000000-00000 |s2cid = 7459081 }}</ref> Moderate 5-HT<sub>1A</sub> partial agonism may contribute to trazodone's antidepressant and anxiolytic actions to some extent as well.<ref name="pmid1387963"/><ref name="pmid15888508"/><ref name="pmid10065919">{{cite journal | vauthors = Kinney GG, Griffith JC, Hudzik TJ | title = Antidepressant-like effects of 5-hydroxytryptamine1A receptor agonists on operant responding under a response duration differentiation schedule | journal = Behav Pharmacol | volume = 9 | issue = 4 | pages = 309–18 | date = July 1998 | pmid = 10065919 | doi = 10.1097/00008877-199807000-00002 }}</ref>

The combined actions of 5-HT<sub>2A</sub> and 5HT<sub>2C</sub> receptor antagonism with serotonin reuptake inhibition only occur at moderate to high doses of trazodone.<ref name="Stahl2013">{{cite book | vauthors = Stahl SM |title=Stahl's Essential Psychopharmacology|edition=4th |year=2013 |publisher=Cambridge University Press |isbn=978-1-107-68646-5 }}</ref> Doses of trazodone lower than those effective for antidepressant action are frequently used for the effective treatment of insomnia.<ref name="Stahl2013" /> Low doses exploit trazodone's potent actions as a 5-HT<sub>2A</sub> receptor antagonist, and its properties as an antagonist of H<sub>1</sub> and α<sub>1</sub>-adrenergic receptors, but do not adequately exploit its SERT or 5-HT<sub>2C</sub> inhibition properties, which are weaker.<ref name="Stahl2013" /> Since insomnia is one of the most frequent residual symptoms of depression after treatment with an SSRI, a hypnotic is often necessary for patients with a major depressive episode.<ref name="Stahl2013" /> Not only can a hypnotic potentially relieve the insomnia itself, but treating insomnia in patients with major depression may also increase remission rates due to the improvement of other symptoms such as loss of energy and depressed mood.<ref name="Stahl2013" /> Thus, the ability of low doses of trazodone to improve sleep in depressed patients may be an important mechanism whereby trazodone can augment the efficacy of other antidepressants.<ref name="Stahl2013" />

Trazodone's potent α<sub>1</sub>-adrenergic blockade may cause some [[side effect]]s like [[orthostatic hypotension]] and [[sedation]].<ref name="pmid3802006">{{cite journal | vauthors = Asayesh K | title = Combination of trazodone and phenothiazines: a possible additive hypotensive effect | journal = Canadian Journal of Psychiatry | volume = 31 | issue = 9 | pages = 857–58 |date=December 1986 | pmid = 3802006 | doi = 10.1177/070674378603100913| s2cid = 43202340 }}</ref> Conversely, along with 5-HT<sub>2A</sub> and H<sub>1</sub> receptor antagonism, it may contribute to its efficacy as a [[hypnotic]]. Trazodone lacks any affinity for the [[muscarinic acetylcholine receptor]]s, so does not produce [[anticholinergic]] side effects.<ref>{{Cite web | vauthors = Brunton LL, Knollmann BC |title=Goodman & Gilman's: The Pharmacological Basis of Therapeutics |url=https://accessmedicine.mhmedical.com/content.aspx?bookid=3191&sectionid=267774973 |access-date=2025-06-15 |website=accessmedicine.mhmedical.com |publisher=McGraw Hill Medical |pages=Chapter 21 |edition=14th}}</ref>

mCPP, a non-selective [[serotonin receptor]] [[receptor modulator|modulator]] and [[serotonin releasing agent]], is an active metabolite of trazodone and has been suggested to possibly play a role in its therapeutic benefits.<ref name="pmid22115401" /><ref name="pmid7255270">{{cite journal | vauthors = Melzacka M, Rurak A, Vetulani J | title = Preliminary study of the biotransformation of two new drugs, trazodone and etoperidone | journal = Polish Journal of Pharmacology and Pharmacy | volume = 32 | issue = 4 | pages = 551–56 | year = 1980 | pmid = 7255270 }}</ref><ref name="pmid6128394">{{cite journal | vauthors = Fong MH, Garattini S, Caccia S | title = 1-m-Chlorophenylpiperazine is an active metabolite common to the psychotropic drugs trazodone, etoperidone and mepiprazole | journal = The Journal of Pharmacy and Pharmacology | volume = 34 | issue = 10 | pages = 674–75 | date = October 1982 | pmid = 6128394 | doi = 10.1111/j.2042-7158.1982.tb04701.x | s2cid = 44968564 }}</ref><ref name="pmid9315986" /> However, research has not supported this hypothesis and mCPP might actually antagonize the efficacy of trazodone as well as produce additional side effects.<ref name="pmid12142643">{{cite journal | vauthors = Mihara K, Yasui-Furukori N, Kondo T, Ishida M, Ono S, Ohkubo T, Osanai T, Sugawara K, Otani K, Kaneko S | title = Relationship between plasma concentrations of trazodone and its active metabolite, m-chlorophenylpiperazine, and its clinical effect in depressed patients | journal = Therapeutic Drug Monitoring | volume = 24 | issue = 4 | pages = 563–66 | date = August 2002 | pmid = 12142643 | doi = 10.1097/00007691-200208000-00016 | s2cid = 25709000 }}</ref><ref name="pmid2311675">{{cite journal | vauthors = Li AA, Marek GJ, Hand TH, Seiden LS | title = Antidepressant-like effects of trazodone on a behavioral screen are mediated by trazodone, not the metabolite m-chlorophenylpiperazine | journal = European Journal of Pharmacology | volume = 177 | issue = 3 | pages = 137–44 | date = February 1990 | pmid = 2311675 | doi = 10.1016/0014-2999(90)90263-6 }}</ref><ref name="pmid6431467">{{cite journal | vauthors = Vetulani J, Sansone M, Baran L, Hano J | title = Opposite action of m-chlorophenylpiperazine on avoidance depression induced by trazodone and pimozide in CD-1 mice | journal = Psychopharmacology | volume = 83 | issue = 2 | pages = 166–68 | date = 1984 | pmid = 6431467 | doi = 10.1007/BF00429728 | s2cid = 38913696 }}</ref>

===Pharmacokinetics===

====Absorption====
Trazodone is well-[[absorption (pharmacokinetics)|absorbed]] after [[oral administration]].<ref name="pmid22115401" /> Its [[bioavailability]] is 65 to 80%.<ref name="pmid22115401" /> [[Cmax (pharmacology)|Peak blood levels]] of trazodone occur 1 to 2{{nbsp}}hours after ingestion and peak levels of the [[metabolite]] mCPP occur after 2 to 4{{nbsp}}hours.<ref name="pmid22115401" /><ref name="pmid10379419">{{cite journal | vauthors = Rotzinger S, Bourin M, Akimoto Y, Coutts RT, Baker GB | title = Metabolism of some "second"- and "fourth"-generation antidepressants: iprindole, viloxazine, bupropion, mianserin, maprotiline, trazodone, nefazodone, and venlafaxine | journal = Cell Mol Neurobiol | volume = 19 | issue = 4 | pages = 427–42 | date = August 1999 | pmid = 10379419 | doi = 10.1023/a:1006953923305 | s2cid = 19585113 | pmc = 11545446 }}</ref> Absorption is somewhat delayed and enhanced by food.{{Citation needed|date=October 2020}}

====Distribution====
Trazodone is not sequestered into any [[tissue (biology)|tissue]].<ref name="pmid22115401" /> The medication is 89 to 95% [[plasma protein binding|protein-bound]].<ref name="pmid10379419" /><ref name=drugbank>{{cite web |title=Trazodone |url=https://www.drugbank.ca/drugs/DB00656 |website=www.drugbank.ca |access-date=31 January 2019}}</ref> The [[volume of distribution]] of trazodone is 0.8 to 1.5{{nbsp}}L/kg.<ref name="pmid22115401" /> Trazodone is highly [[lipophilic]].<ref name="pmid10379419" />

====Metabolism====
The [[metabolic pathway]]s involved in the metabolism are not well-characterized.<ref name="pmid31379379" /><ref name="pmid27744763" /> In any case, the [[cytochrome P450]] [[enzyme]]s [[CYP3A4]], [[CYP2D6]], and [[CYP1A2]] may all be involved to varying extents.<ref name="pmid10379419" /><ref name="pmid31379379" /><ref name="pmid22115401" /><ref name="pmid9836023" /> Trazodone is known to be extensively [[metabolism|metabolized]] by the liver via [[hydroxylation]], [[oxidation|''N''-oxidation]], and [[dealkylation|''N''-dealkylation]].<ref name="pmid10379419" /> Several [[metabolite]]s of trazodone have been identified, including a [[:wikt:dihydrodiol|dihydrodiol]] metabolite (via hydroxylation), a metabolite hydroxylated at the ''para'' position of the ''meta''-chlorophenyl ring (via CYP2D6), oxotriazolepyridinepropionic acid (TPA) and mCPP (both via ''N''-dealkylation of the piperazinyl nitrogen mediated by CYP3A4), and a metabolite formed by N-oxidation of the piperazinyl nitrogen.<ref name="pmid10379419" /><ref name=Rotzinger>{{cite journal | vauthors = Rotzinger S, Fang J, Baker GB | title = Trazodone is metabolized to m-chlorophenylpiperazine by CYP3A4 from human sources | journal = Drug Metabolism and Disposition | volume = 26 | issue = 6 | pages = 572–75 | date = June 1998 | pmid = 9616194 }}</ref> CYP1A2, CYP2D6, and CYP3A4 [[genotype]]s all do not seem to predict concentrations of trazodone or mCPP.<ref name="pmid27744763" /><ref name="pmid9335086" /><ref name="pmid29061081" /><ref name="pmid11393588">{{cite journal | vauthors = Mihara K, Kondo T, Suzuki A, Yasui-Furukori N, Ono S, Otani K, Kaneko S | title = Effects of genetic polymorphism of CYP1A2 inducibility on the steady-state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine in depressed Japanese patients | journal = Pharmacol Toxicol | volume = 88 | issue = 5 | pages = 267–70 | date = May 2001 | pmid = 11393588 | doi = 10.1034/j.1600-0773.2001.d01-115.x | doi-broken-date = 17 March 2025 }}</ref> In any case, there are large [[interindividual variability|interindividual variations]] in the metabolism of trazodone.<ref name="pmid10379419" /> In addition, poor metabolizers of [[dextromethorphan]], a CYP2D6 substrate, eliminate mCPP more slowly and have higher concentrations of mCPP than extensive metabolizers.<ref name="pmid10379419" />

mCPP is formed from trazodone by CYP3A4 and is metabolized via hydroxylation by CYP2D6 (to a ''para''-hydroxylated metabolite).<ref name="pmid31379379" /><ref name="pmid22115401" /><ref name="pmid9836023" /><ref name="pmid10379419" /> It may contribute to the pharmacological actions of trazodone.<ref name="pmid22115401" /><ref name="pmid31379379" /><ref name=Garattini>{{cite journal | vauthors = Garattini S | title = Active drug metabolites. An overview of their relevance in clinical pharmacokinetics | journal = Clinical Pharmacokinetics | volume = 10 | issue = 3 | pages = 216–27 | date = 1985 | pmid = 2861928 | doi = 10.2165/00003088-198510030-00002 | s2cid = 21305772 }}</ref> mCPP levels are only 10% of those of trazodone during therapy with trazodone, but is nonetheless present at concentrations known to produce psychic and physical effects in humans when mCPP has been administered alone.<ref name="pmid10379419" /><ref name="VazKlabunde2008">{{cite book| vauthors = Vaz RJ, Klabunde T |title=Antitargets: Prediction and Prevention of Drug Side Effects|url=https://books.google.com/books?id=oSnSk1kv0dAC&pg=PA149|year=2008|publisher=John Wiley & Sons|isbn=978-3-527-62147-7|pages=149–}}</ref> In any case, the actions of trazodone, such as its serotonin antagonism, might partially overwhelm those of mCPP.<ref name="pmid31379379" /> As a consequence of the production of mCPP as a metabolite, patients administered trazodone may test positive on [[EMIT]] II urine tests for the presence of [[MDMA]] ("ecstasy").<ref name="pmid21073812">{{cite journal | vauthors = Logan BK, Costantino AG, Rieders EF, Sanders D | title = Trazodone, meta-chlorophenylpiperazine (a hallucinogenic drug and trazodone metabolite), and the hallucinogen trifluoromethylphenylpiperazine cross-react with the EMIT®II ecstasy immunoassay in urine | journal = J Anal Toxicol | volume = 34 | issue = 9 | pages = 587–89 | date = November 2010 | pmid = 21073812 | doi = 10.1093/jat/34.9.587 | doi-access = free }}</ref>

====Elimination====
The [[elimination (pharmacology)|elimination]] of trazodone is biphasic: the first phase's half-life (distribution) is 3 to 6{{nbsp}}hours, and the following phase's half-life (elimination) is 4.1 to 14.6{{nbsp}}hours.<ref name="pmid10379419" /><ref name="pmid22115401" /><ref name="pmid23192413" /><ref name="pmid20173086">{{cite journal | vauthors = Karhu D, Groenewoud G, Potgieter MA, Mould DR | title = Dose proportionality of once-daily trazodone extended-release caplets under fasting conditions | journal = J Clin Pharmacol | volume = 50 | issue = 12 | pages = 1438–49 | date = December 2010 | pmid = 20173086 | doi = 10.1177/0091270009360979 | s2cid = 36104356 | url = }}</ref> The elimination half-life of extended-release trazodone is 9.1 to 13.2{{nbsp}}hours.<ref name="pmid26678742">{{cite journal | vauthors = Goracci A, Forgione RN, De Giorgi R, Coluccia A, Cuomo A, Fagiolini A | title = Practical guidance for prescribing trazodone extended-release in major depression | journal = Expert Opin Pharmacother | volume = 17 | issue = 3 | pages = 433–41 | date = 2016 | pmid = 26678742 | doi = 10.1517/14656566.2016.1133587 | s2cid = 26833385 | url = }}</ref><ref name="pmid22115401" /><ref name="pmid23192413" /> The elimination half-life of mCPP is 2.6 to 16.0{{nbsp}}hours and is longer than that of trazodone.<ref name="pmid10379419" /><ref name="pmid22115401" /><ref name="pmid20173086" /> Metabolites are conjugated to gluconic acid or glutathione and around 70 to 75% of <sup>14</sup>C-labelled trazodone was found to be excreted in the urine within 72{{nbsp}}hours.<ref name="pmid1037253">{{cite journal | vauthors = Jauch R, Kopitar Z, Prox A, Zimmer A | title = [Pharmacokinetics and metabolism of trazodone in man (author's transl)] | language = de | journal = Arzneimittel-Forschung | volume = 26 | issue = 11 | pages = 2084–89 | date = 1976 | pmid = 1037253 }}</ref> The remaining drug and its metabolites are excreted in the faeces via biliary elimination. Less than 1% of the drug is excreted in its unchanged form.<ref name=drugbank /> After an oral dose of trazodone, it was found to be excreted 20% in the urine as TPA and conjugates, 9% as the dihydrodiol metabolite, and less than 1% as unconjugated mCPP.<ref name="pmid10379419" /> mCPP is glucuronidated and sulfated similarly to other trazodone metabolites.<ref name="pmid10379419" />

==Chemistry==
Trazodone is a [[triazolopyridine]] [[chemical derivative|derivative]] and a [[phenylpiperazine]] that is [[chemical structure|structurally related]] to [[nefazodone]] and [[etoperidone]], each of which is a derivative of it.<ref>{{cite book| vauthors = Akritopoulou-Zanze I | veditors = Dinges J, Lamberth C |title=Bioactive heterocyclic compound classes pharmaceuticals|date=2012|publisher=Wiley-VCH|location=Weinheim|isbn=978-3-527-66445-0|chapter=6. Arylpiperazine-Based 5-HT1A Receptor Partial Agonists and 5-HT2A Antagonists for the Treatment of Autism, Depression, Anxiety, Psychosis, and Schizophrenia}}</ref><ref>{{cite book| veditors = Dörwald FZ |title=Lead optimization for medicinal chemists: pharmacokinetic properties of functional groups and organic compounds|date=2012|publisher=Wiley-VCH|location=Weinheim|isbn=978-3-527-64564-0|chapter=46. Arylalkylamines}}</ref><ref name="pmid8019056" />

==History==
Trazodone was developed in [[Italy]], in the 1960s, by [[Angelini]] Research Laboratories as a second-generation [[antidepressant]].<ref>{{cite book| vauthors = Gorecki DK, Verbeeck RK | veditors = Forey K |title=Profiles of Drug Substances, Excipients and Related Methodology Vol. 16|date=1987|publisher=Academic Press|isbn=978-0-08-086111-1|page=695|chapter-url=https://books.google.com/books?id=tQiZCwMb2jAC&pg=PA695|chapter=Trazondone Hydrochloride}}</ref><ref>{{cite web|vauthors=Wegener G|title=Ban & Silvestrini's Trazodone|url=https://inhn.org/inhn-projects/books/books/ban-silvestrinis-trazodone|website=International Network for the History of Neuropsychopharmacology|access-date=4 June 2017|date=30 March 2016|archive-date=20 March 2017|archive-url=https://web.archive.org/web/20170320210754/http://inhn.org/books/books/ban-silvestrinis-trazodone.html|url-status=live}}</ref> It was developed according to the [[Psychological pain|mental pain]] hypothesis, which was postulated from studying patients and which proposes that [[Major depressive disorder|major depression]] is associated with a decreased pain threshold.<ref>{{cite journal | vauthors = Silvestrini B | title = Trazodone: from the mental pain to the "dys-stress" hypothesis of depression | journal = Clinical Neuropharmacology | volume = 12 | issue = Suppl 1 | pages = S4–10 | year = 1989 | pmid = 2568177 | doi = 10.1097/00002826-198901001-00002 | s2cid = 34798378 }}</ref> In sharp contrast to most other antidepressants available at the time of its development, trazodone showed minimal effects on muscarinic cholinergic receptors. Trazodone was patented and marketed in many countries all over the world. It was approved by the [[Food and Drug Administration]] (FDA) in 1981<ref>{{cite news|title=Trazodone: Common sleep drug is little-known antidepressant |url=http://www.consumerreports.org/cro/2012/04/trazodone-common-sleep-drug-is-little-known-antidepressant/index.htm|work=Consumer Reports|date=August 2015}}</ref> and was the first non-[[tricyclic]] or [[MAOI]] antidepressant approved in the US.<ref>{{cite book| vauthors = Eisen MS, Taylor DB, Riblet LA | veditors = Williams M, Malick JB |title=Drug Discovery and Development|date=2012|publisher=Springer Science & Business Media|isbn=978-1-4612-4828-6|page=388|chapter-url=https://books.google.com/books?id=O0LuBwAAQBAJ&pg=PA388|chapter=Atypical Psychotropic Agents}}</ref>

==Society and culture==

===Generic names===
''Trazodone'' is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|BAN|British Approved Name}}, and {{abbrlink|DCF|Dénomination Commune Française}}, while ''trazodone hydrochloride'' is its {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|USP|United States Pharmacopeia}}, {{abbrlink|BANM|British Approved Name}}, and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ|year=2014|publisher=Springer|isbn=978-1-4757-2085-3}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA1051|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=1050–52}}</ref><ref name="MortonHall2012">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA279|year=2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=279–}}</ref><ref name="Drugs.com">{{cite web | url=https://www.drugs.com/international/trazodone.html|website=Drugs.com |title=Trazodone}}</ref>

===Brand names===
Trazodone has been marketed under a large number of brand names throughout the world.<ref name="IndexNominum2000" /><ref name="Drugs.com" /> Major brand names include Desyrel (worldwide), Donaren (Brazil), Molipaxin (Ireland, United Kingdom), Oleptro (United States), Trazorel (Canada), and Trittico (worldwide).<ref name="IndexNominum2000" /><ref name="Drugs.com" />

==Research==
Trazodone may be effective in the treatment of [[sexual dysfunction]], for instance [[female sexual dysfunction]] and [[erectile dysfunction]].<ref name="pmid30342856" /><ref name="pmid33967614">{{cite journal | vauthors = Ramli FF, Azizi MH, Syed Hashim SA | title = Treatments of Sexual Dysfunction in Opioid Substitution Therapy Patients: A Systematic Review and Meta-Analysis | journal = Int J Med Sci | volume = 18 | issue = 11 | pages = 2372–80 | date = 2021 | pmid = 33967614 | pmc = 8100642 | doi = 10.7150/ijms.57641 | url = }}</ref> A 2003 [[systematic review]] and [[meta-analysis]] found some indication that trazodone may be useful in the treatment of erectile dysfunction.<ref name="pmid12930437">{{cite journal | vauthors = Fink HA, MacDonald R, Rutks IR, Wilt TJ | title = Trazodone for erectile dysfunction: a systematic review and meta-analysis | journal = BJU Int. | volume = 92 | issue = 4 | pages = 441–46 | date = September 2003 | pmid = 12930437 | doi = 10.1046/j.1464-410X.2003.04358.x | s2cid = 7499389 | doi-access = free }}</ref> Besides trazodone alone, a [[combination drug|combination]] of trazodone and [[bupropion]] (developmental code names and tentative brand names S1P-104, S1P-205, Lorexys, and Orexa) is under development for the treatment of [[erectile dysfunction]] and [[female sexual dysfunction]].<ref name="AdisInsight-Bupropion/Trazodone">{{Cite web|url=https://adisinsight.springer.com/drugs/800035655|title=Bupropion/trazodone - AdisInsight|website=adisinsight.springer.com}}</ref><ref name="pmid30251897">{{cite journal | vauthors = Miller MK, Smith JR, Norman JJ, Clayton AH | title = Expert opinion on existing and developing drugs to treat female sexual dysfunction | journal = Expert Opin Emerg Drugs | volume = 23 | issue = 3 | pages = 223–30 | date = September 2018 | pmid = 30251897 | doi = 10.1080/14728214.2018.1527901 | s2cid = 52813769 | url = }}</ref><ref name="pmid25376023">{{cite journal | vauthors = Belkin ZR, Krapf JM, Goldstein AT | title = Drugs in early clinical development for the treatment of female sexual dysfunction | journal = Expert Opin Investig Drugs | volume = 24 | issue = 2 | pages = 159–67 | date = February 2015 | pmid = 25376023 | doi = 10.1517/13543784.2015.978283 | s2cid = 207477620 | url = }}</ref> As of September 2021, it is in [[Phases of clinical research#Phase II|phase 2]] [[clinical trial]]s for these indications.<ref name="AdisInsight-Bupropion/Trazodone" /> It has been in this stage of clinical development since at least February 2015.<ref name="pmid25376023" />

Trazodone may be useful in the treatment of certain symptoms like [[sleep disturbance]]s in [[alcohol withdrawal]] and recovery.<ref name="pmid22712761" /><ref name="pmid26088119" /><ref name="pmid21715413">{{cite journal | vauthors = Kolla BP, Mansukhani MP, Schneekloth T | title = Pharmacological treatment of insomnia in alcohol recovery: a systematic review | journal = Alcohol Alcohol | volume = 46 | issue = 5 | pages = 578–85 | date = 2011 | pmid = 21715413 | doi = 10.1093/alcalc/agr073 | url = | doi-access = free }}</ref><ref name="pmid27744763" /> However, reviews have recommended against use of trazodone for alcohol withdrawal due to inadequate evidence.<ref name="pmid22712761" /><ref name="pmid26088119" /><ref name="pmid27744763" /> Very limited evidence suggests that trazodone might be useful in the treatment of certain symptoms in [[cocaine use disorder]].<ref name="pmid27744763" /> Trazodone has been reported to be effective in the treatment of [[sleep apnea]].<ref name="pmid31720982">{{cite journal | vauthors = AbdelFattah MR, Jung SW, Greenspan MA, Padilla M, Enciso R | title = Efficacy of Antidepressants in the Treatment of Obstructive Sleep Apnea Compared to Placebo. A Systematic Review with Meta-Analyses | journal = Sleep Breath | volume = 24 | issue = 2 | pages = 443–53 | date = June 2020 | pmid = 31720982 | doi = 10.1007/s11325-019-01954-9 | s2cid = 207939482 | url = }}</ref><ref name="pmid25719754">{{cite journal | vauthors = Smales ET, Edwards BA, Deyoung PN, McSharry DG, Wellman A, Velasquez A, Owens R, Orr JE, Malhotra A | title = Trazodone Effects on Obstructive Sleep Apnea and Non-REM Arousal Threshold | journal = Ann Am Thorac Soc | volume = 12 | issue = 5 | pages = 758–64 | date = May 2015 | pmid = 25719754 | pmc = 4418332 | doi = 10.1513/AnnalsATS.201408-399OC | url = }}</ref><ref name="pmid24899767">{{cite journal | vauthors = Eckert DJ, Malhotra A, Wellman A, White DP | title = Trazodone increases the respiratory arousal threshold in patients with obstructive sleep apnea and a low arousal threshold | journal = Sleep | volume = 37 | issue = 4 | pages = 811–19 | date = April 2014 | pmid = 24899767 | pmc = 4044741 | doi = 10.5665/sleep.3596 | url = }}</ref> [[Cochrane review]]s found that trazodone was not effective in the treatment of [[psychomotor agitation|agitation]] in [[dementia]].<ref name="pmid15495135">{{cite journal | vauthors = Martinon-Torres G, Fioravanti M, Grimley EJ | title = Trazodone for agitation in dementia | journal = Cochrane Database Syst Rev | volume = | issue = 4 | page= CD004990 | date = October 2004 | pmid = 15495135 | doi = 10.1002/14651858.CD004990 | url = }}</ref><ref name="pmid21328305">{{cite journal | vauthors = Seitz DP, Adunuri N, Gill SS, Gruneir A, Herrmann N, Rochon P | title = Antidepressants for agitation and psychosis in dementia | journal = Cochrane Database Syst Rev | volume = | issue = 2 | page= CD008191 | date = February 2011 | pmid = 21328305 | doi = 10.1002/14651858.CD008191.pub2 | url = }}</ref> Another Cochrane review found that trazodone might be useful in the treatment of sleep disturbances in dementia.<ref name="pmid33189083">{{cite journal | vauthors = McCleery J, Sharpley AL | title = Pharmacotherapies for sleep disturbances in dementia | journal = Cochrane Database Syst Rev | volume = 2020 | issue = 11| page= CD009178 | date = November 2020 | pmid = 33189083 | pmc = 8094738 | doi = 10.1002/14651858.CD009178.pub4 | url = }}</ref> Further systematic reviews have found that trazodone may be effective for behavioral and psychological symptoms in dementias such as [[frontotemporal dementia]] and [[Alzheimer's disease]].<ref name="pmid24164931">{{cite journal | vauthors = Nardell M, Tampi RR | title = Pharmacological treatments for frontotemporal dementias: a systematic review of randomized controlled trials | journal = Am J Alzheimers Dis Other Demen | volume = 29 | issue = 2 | pages = 123–32 | date = March 2014 | pmid = 24164931 | doi = 10.1177/1533317513507375 | s2cid = 13491951 | url = | pmc = 10852735 }}</ref><ref name="pmid33340800">{{cite journal | vauthors = Chen A, Copeli F, Metzger E, Cloutier A, Osser DN | title = The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An update on management of behavioral and psychological symptoms in dementia | journal = Psychiatry Res | volume = 295 | issue = | page = 113641 | date = January 2021 | pmid = 33340800 | doi = 10.1016/j.psychres.2020.113641 | s2cid = 228158773 | url = }}</ref><ref name="pmid32132398">{{cite journal | vauthors = Trieu C, Gossink F, Stek ML, Scheltens P, Pijnenburg YA, Dols A | title = Effectiveness of Pharmacological Interventions for Symptoms of Behavioral Variant Frontotemporal Dementia: A Systematic Review | journal = Cogn Behav Neurol | volume = 33 | issue = 1 | pages = 1–15 | date = March 2020 | pmid = 32132398 | doi = 10.1097/WNN.0000000000000217 | s2cid = 212417082 | url = }}</ref><ref name="pmid16216158">{{cite journal | vauthors = Chow TW | title = Treatment approaches to symptoms associated with frontotemporal degeneration | journal = Curr Psychiatry Rep | volume = 7 | issue = 5 | pages = 376–80 | date = October 2005 | pmid = 16216158 | doi = 10.1007/s11920-005-0040-5 | s2cid = 8766330 | url = }}</ref><ref name="pmid27744763" />

Trazodone has been studied as an [[adjunctive therapy]] in the treatment of [[schizophrenia]].<ref name="pmid22712761" /><ref name="pmid26088119" /><ref name="pmid20807960">{{cite journal | vauthors = Singh SP, Singh V, Kar N, Chan K | title = Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis | journal = Br J Psychiatry | volume = 197 | issue = 3 | pages = 174–79 | date = September 2010 | pmid = 20807960 | doi = 10.1192/bjp.bp.109.067710 | doi-access = free }}</ref> It has been reported to decrease [[negative symptoms]] without worsening [[positive symptoms]] although improvement in negative symptoms was modest.<ref name="pmid22712761" /><ref name="pmid26088119" /><ref name="pmid20807960" /> Trazodone has also been reported to be effective in treating [[antipsychotic]]-related [[extrapyramidal symptoms]] such as [[akathisia]].<ref name="pmid22712761" /><ref name="pmid26088119" /><ref name="pmid20807960" /><ref name="pmid25991654">{{cite journal | vauthors = Terevnikov V, Joffe G, Stenberg JH | title = Randomized Controlled Trials of Add-On Antidepressants in Schizophrenia | journal = Int J Neuropsychopharmacol | volume = 18 | issue = 9 | page= pyv049| date = May 2015 | pmid = 25991654 | pmc = 4576515 | doi = 10.1093/ijnp/pyv049 | url = }}</ref> Trazodone has been studied and reported to be effective in the treatment of [[bulimia]],<ref name="pmid22712761" /><ref name="pmid26088119" /><ref name="pmid27744763" /> but there is limited evidence to support this use.<ref name="pmid14583971">{{cite journal | vauthors = Bacaltchuk J, Hay P | title = Antidepressants versus placebo for people with bulimia nervosa | journal = Cochrane Database Syst Rev | volume = | issue = 4 | page = CD003391 | date = 2003 | pmid = 14583971 | doi = 10.1002/14651858.CD003391 | url = | pmc = 6991155 }}</ref> It might be useful in the treatment of [[night eating disorder]] as well.<ref name="pmid27744763" /> Trazodone might be effective in the treatment of [[adjustment disorder]].<ref name="pmid32520732">{{cite journal | vauthors = Constantin D, Dinu EA, Rogozea L, Burtea V, Leasu FG | title = Therapeutic Interventions for Adjustment Disorder: A Systematic Review | journal = Am J Ther | volume = 27 | issue = 4 | pages = e375–86 | date = 2020 | pmid = 32520732 | doi = 10.1097/MJT.0000000000001170 | s2cid = 219586994 | url = }}</ref> It may also be effective in the treatment of [[bruxism]] in children and adolescents.<ref name="pmid31858254">{{cite journal | vauthors = Chisini LA, San Martin AS, Cademartori MG, Boscato N, Correa MB, Goettems ML | title = Interventions to reduce bruxism in children and adolescents: a systematic scoping review and critical reflection | journal = Eur J Pediatr | volume = 179 | issue = 2 | pages = 177–89 | date = February 2020 | pmid = 31858254 | doi = 10.1007/s00431-019-03549-8 | s2cid = 209411316 | url = }}</ref>

Trazodone may be useful in the treatment of certain [[chronic pain disorder]]s.<ref name="pmid22712761" /><ref name="pmid26088119" /> There is limited but conflicting evidence to support the use of trazodone in the treatment of [[headache]]s and [[migraine]]s in children.<ref name="pmid14583952">{{cite journal | vauthors = Victor S, Ryan SW | veditors = Hobson A | title = Drugs for preventing migraine headaches in children | journal = Cochrane Database Syst Rev | volume = | issue = 4 | pages = CD002761 | date = 2003 | pmid = 14583952 | doi = 10.1002/14651858.CD002761 | url = }}</ref><ref name="pmid16674757">{{cite journal | vauthors = Damen L, Bruijn J, Verhagen AP, Berger MY, Passchier J, Koes BW | title = Prophylactic treatment of migraine in children. Part 2. A systematic review of pharmacological trials | journal = Cephalalgia | volume = 26 | issue = 5 | pages = 497–505 | date = May 2006 | pmid = 16674757 | doi = 10.1111/j.1468-2982.2005.01047.x | s2cid = 37252070 | url = }}</ref><ref name="pmid23358935">{{cite journal | vauthors = El-Chammas K, Keyes J, Thompson N, Vijayakumar J, Becher D, Jackson JL | title = Pharmacologic treatment of pediatric headaches: a meta-analysis | journal = JAMA Pediatr | volume = 167 | issue = 3 | pages = 250–28 | date = March 2013 | pmid = 23358935 | pmc = 4692044 | doi = 10.1001/jamapediatrics.2013.508 | url = }}</ref><ref name="pmid23752070">{{cite journal | vauthors = Shamliyan TA, Kane RL, Ramakrishnan R, Taylor FR | title = Episodic migraines in children: limited evidence on preventive pharmacological treatments | journal = J Child Neurol | volume = 28 | issue = 10 | pages = 1320–41 | date = October 2013 | pmid = 23752070 | doi = 10.1177/0883073813488659 | s2cid = 9178257 | url = }}</ref> Trazodone may be useful in the treatment of [[fibromyalgia]]<ref name="pmid22712761" /><ref name="pmid26088119" /><ref name="pmid35184627">{{cite journal | vauthors = Migliorini F, Maffulli N, Eschweiler J, Knobe M, Tingart M, Colarossi G | title = Pharmacological management of fibromyalgia: a Bayesian network meta-analysis | journal = Expert Rev Clin Pharmacol | volume = 15 | issue = 2 | pages = 205–14 | date = February 2022 | pmid = 35184627 | doi = 10.1080/17512433.2022.2044792 | s2cid = 247006915 | url = }}</ref> as well as [[diabetic neuropathy]].<ref name="pmid22712761" /><ref name="pmid26088119" /> It may also be useful in the treatment of [[burning mouth syndrome]].<ref name="pmid33713052">{{cite journal | vauthors = Farag AM, Kuten-Shorrer M, Natto Z, Ariyawardana A, Mejia LM, Albuquerque R, Carey B, Chmieliauskaite M, Miller CS, Ingram M, Nasri-Heir C, Sardella A, Carlson CR, Klasser GD | title = WWOM VII: Effectiveness of systemic pharmacotherapeutic interventions in the management of BMS: A systematic review and meta-analysis | journal = Oral Dis | volume = 29| issue = 2| pages = 343–368| date = March 2021 | pmid = 33713052 | doi = 10.1111/odi.13817 | hdl = 10072/425825 | s2cid = 232217908 | url = }}</ref><ref name="pmid28247977">{{cite journal | vauthors = Liu YF, Kim Y, Yoo T, Han P, Inman JC | title = Burning mouth syndrome: a systematic review of treatments | journal = Oral Dis | volume = 24 | issue = 3 | pages = 325–34 | date = April 2018 | pmid = 28247977 | doi = 10.1111/odi.12660 | url = }}</ref> A 2004 [[narrative review]] claimed that trazodone could be used in the treatment of [[complex regional pain syndrome]].<ref name="pmid15948431">{{cite journal | vauthors = Koman LA, Smith BP, Ekman EF, Smith TL | title = Complex regional pain syndrome | journal = Instr Course Lect | volume = 54 | issue = | pages = 11–20 | date = 2005 | pmid = 15948431 | doi = | url = https://www.researchgate.net/publication/304253373}}</ref> Trazodone may also be effective in the treatment of [[functional gastrointestinal disorder]]s.<ref name="pmid30564156">{{cite journal | vauthors = Xiong N, Duan Y, Wei J, Mewes R, Leonhart R | title = Antidepressants vs. Placebo for the Treatment of Functional Gastrointestinal Disorders in Adults: A Systematic Review and Meta-Analysis | journal = Front Psychiatry | volume = 9 | issue = | pages = 659 | date = 2018 | pmid = 30564156 | pmc = 6288425 | doi = 10.3389/fpsyt.2018.00659 | url = | doi-access = free }}</ref> It may be effective in the treatment of non-cardiac [[chest pain]] as well.<ref name="pmid22239853">{{cite journal | vauthors = Nguyen TM, Eslick GD | title = Systematic review: the treatment of noncardiac chest pain with antidepressants | journal = Aliment Pharmacol Ther | volume = 35 | issue = 5 | pages = 493–500 | date = March 2012 | pmid = 22239853 | doi = 10.1111/j.1365-2036.2011.04978.x | s2cid = 21793648 | url = | doi-access = free }}</ref><ref name="pmid22077344">{{cite journal | vauthors = Hershcovici T, Achem SR, Jha LK, Fass R | title = Systematic review: the treatment of noncardiac chest pain | journal = Aliment Pharmacol Ther | volume = 35 | issue = 1 | pages = 5–14 | date = January 2012 | pmid = 22077344 | doi = 10.1111/j.1365-2036.2011.04904.x | s2cid = 293910 | url = | doi-access = free }}</ref>

Trazodone may be useful in promoting motor recovery after [[stroke]].<ref name="pmid27744763" /><ref name="pmid20032921">{{cite journal | vauthors = Berends HI, Nijlant JM, Movig KL, Van Putten MJ, Jannink MJ, Ijzerman MJ | title = The clinical use of drugs influencing neurotransmitters in the brain to promote motor recovery after stroke; a Cochrane systematic review | journal = Eur J Phys Rehabil Med | volume = 45 | issue = 4 | pages = 621–30 | date = December 2009 | pmid = 20032921 | doi = | url = }}</ref>

Trazodone is sometimes prescribed to treat premature ejaculation<ref>{{Cite web |title=Trazodone for Premature Ejaculation: Is It the Answer? |url=https://the.coach/blog/insights/trazodone-for-premature-ejaculation-is-it-the-answer |access-date=2025-06-15 |website=The Coach |language=en-US}}</ref> but [[clomipramine]] and [[paroxetine]]<ref>{{cite journal | vauthors = Zhang D, Cheng Y, Wu K, Ma Q, Jiang J, Yan Z | title = Paroxetine in the treatment of premature ejaculation: a systematic review and meta-analysis | journal = BMC Urology | volume = 19 | issue = 1 | pages = 2 | date = January 2019 | pmid = 30606186 | pmc = 6318994 | doi = 10.1186/s12894-018-0431-7 | doi-access = free }}</ref> may be more effective.

==Veterinary use==
Trazodone has been used to reduce [[anxiety]] and [[psychological stress|stress]], to improve [[sleep]], and to produce [[sedation]] in dogs and cats in [[veterinary medicine]].<ref name="pmid34475580">{{cite journal | vauthors = Erickson A, Harbin K, MacPherson J, Rundle K, Overall KL | title = A review of pre-appointment medications to reduce fear and anxiety in dogs and cats at veterinary visits | journal = Can Vet J | volume = 62 | issue = 9 | pages = 952–60 | date = September 2021 | pmid = 34475580 | pmc = 8360309 | doi = | url = }}</ref><ref name="pmid30861632">{{cite journal | vauthors = Lefman SH, Prittie JE | title = Psychogenic stress in hospitalized veterinary patients: Causation, implications, and therapies | journal = J Vet Emerg Crit Care (San Antonio) | volume = 29 | issue = 2 | pages = 107–20 | date = March 2019 | pmid = 30861632 | doi = 10.1111/vec.12821 | s2cid = 76667125 | url = }}</ref><ref name="pmid29415813">{{cite journal | vauthors = Sinn L | title = Advances in Behavioral Psychopharmacology | journal = Vet Clin North Am Small Anim Pract | volume = 48 | issue = 3 | pages = 457–71 | date = May 2018 | pmid = 29415813 | doi = 10.1016/j.cvsm.2017.12.011 | url = }}</ref>

== See also ==
{{Portal|Medicine}}
* [[List of antidepressants]]

==References==
{{Reflist}}

==External links==
* {{Commons category-inline}}

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