trazodone

The primary use of trazodone is the treatment of unipolar major depression with or without anxiety.{{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}} Data from open and double-blind trials 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.{{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}}

Because trazodone has minimal anticholinergic activity, it was especially welcomed as a treatment for 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.{{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 = }} 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 and insomnia.

Trazodone is usually used at a dosage of 150 to 300{{nbsp}}mg/day for the treatment of depression.{{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 }} Lower doses have also been used to augment other antidepressants or when initiating therapy. Higher doses, up to 600{{nbsp}}mg/day, have been used in more severe cases of depression (in hospitalized patients, for example).{{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 = }} Trazodone is usually administered multiple times per day, but once-daily administration may be similarly effective.{{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 }}

Low-dose trazodone is used off-label in the treatment of insomnia and is considered to be effective and safe for this indication.{{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 }} It may also be used to treat antidepressant-related insomnia.{{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}} 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.{{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 = }}{{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 = }}

Systematic reviews and 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 euthymic people.{{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 }}{{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 }}{{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 = }} Trazodone slightly improves subjective sleep quality ({{Abbrlink|SMD|standardized mean difference}} = –0.34 to –0.41) and reduces the number of nighttime awakenings ({{Abbr|MD|Mean difference}} = –0.31, {{Abbr|SMD|standardized mean difference}} = –0.51), on average. Conversely, it does not appear to affect sleep onset, total sleep time, time awake after sleep onset, or sleep efficiency.{{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 }} It appears to increase deep sleep—in contrast to certain other hypnotics. The quality of evidence of trazodone for short-term treatment of insomnia was rated as low to moderate. There is no evidence available at present to inform the long-term use of trazodone in the treatment of insomnia.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.

The benefits of trazodone for insomnia must be weighed against potential adverse effects, such as morning grogginess, daytime sleepiness, cognitive and motor impairment, and postural hypotension, among others. Quality safety data on the use of trazodone as a sleep aid are currently lacking.

Trazodone is used at low doses in the range of 50 to 150{{nbsp}}mg/day for insomnia. Higher doses of 200 to 600{{nbsp}}mg/day have also been studied.

The American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended against the use of trazodone in the treatment of insomnia due to inadequate evidence and due to harms potentially outweighing benefits.{{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 = }}

Trazodone is often used in the treatment of anxiety disorders {{emdash}} such as generalized anxiety disorder and panic disorder {{emdash}} as well as in post-traumatic stress disorder (PTSD) and obsessive–compulsive disorder (OCD).{{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}}{{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]}} Trazodone is often used as an alternative to benzodiazepines in the treatment of anxiety disorders. However, use of trazodone in anxiety disorders is off-label and evidence of its effectiveness for these indications is variable and limited.{{cite journal |vauthors=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}}{{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}} Benefits for OCD appear to be mild. Trazodone has been used to treat sleep disturbances and nightmares in PTSD.{{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}}

Trazodone is often used in combination with other antidepressants such as selective serotonin reuptake inhibitors in order to augment their antidepressant and anxiolytic effects and to reduce side effects such as sexual dysfunction, anxiety, and insomnia.{{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 = }}

Trazodone is provided as the hydrochloride salt and is available in the form of 50{{nbsp}}mg, 100{{nbsp}}mg, 150{{nbsp}}mg, and 300{{nbsp}}mg oral tablets.{{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}} In Italy, it is also available as an oral solution (Trittico 60 mg/mL) with a dosing pipette marked at 25 mg and 50 mg.{{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}}

An extended-release oral tablet formulation at doses of 150{{nbsp}}mg and 300{{nbsp}}mg is also available.{{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}}{{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}}

{{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 α₁-adrenergic receptor blockade. The unmasking of bipolar disorder may occur with trazodone and other antidepressants.{{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 }}

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.{{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}}

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 discontinuation syndrome if the medication is stopped too quickly.{{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 }} Thus, care must be taken when coming off the medication, usually by a gradual process of tapering down the dose over time.

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.{{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}}

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.{{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 }} Trazodone has been found to impair driving ability.{{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 = }}

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.{{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}}

QT prolongation has been reported with trazodone therapy. Arrhythmia identified include isolated PVCs, 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.{{Cite web|url=https://pdf.hres.ca/dpd_pm/00030282.PDF|title=Trazodone Product Monograph |date=2015}}{{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}}

A relatively rare side effect associated with trazodone is priapism, likely due to its antagonism at α-adrenergic receptors.{{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 }} 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. <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 orgasms have also been reported with trazodone in men.{{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 = }}

Clinical reports have described trazodone-associated psychosexual side effects in women as well, including increased libido, priapism of the clitoris, and spontaneous orgasms.{{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 }}

Rare cases of liver toxicity have been observed, possibly due to the formation of reactive metabolites.{{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 }}

Elevated prolactin concentrations have been observed in people taking trazodone.{{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 }} They appear to be increased by around 1.5- to 2-fold.

Studies on trazodone and cognitive function are mixed, with some finding improvement, others finding no change and some finding impairment.{{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 = }}

Trazodone does not seem to worsen periodic limb movements during sleep.{{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 = }}

Trazodone is associated with an increased risk of falls in older adults. It has also been associated with increased risk of hip fractures in older adults.{{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 = }}

Sufficient data in humans are lacking. Use should be justified by the severity of the condition to be treated.{{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 }}{{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 }}

There are reported cases of high doses of trazodone precipitating serotonin syndrome. There are also reports of patients taking multiple SSRIs with trazodone and precipitating serotonin syndrome.{{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}}

Trazodone appears to be relatively safer than TCAs, MAOIs, and a few of the other second-generation antidepressants in overdose situations, especially when it is the only agent taken. 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 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.{{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 }}{{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 }}{{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 }}

Trazodone is metabolized by several liver enzymes, including CYP3A4, CYP2D6, and CYP1A2. Its active metabolite meta-chlorophenylpiperazine (mCPP) is known to be formed by CYP3A4 and metabolized by CYP2D6. 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. The enzymes in question are known to be inhibited and induced by many medications, herbs, and foods, and as such, trazodone may interact with these substances. 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.{{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 }}{{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}} CYP2D6 inhibitors may result in increased concentrations of both trazodone and mCPP, while CYP2D6 inducers may decrease their concentrations.{{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 }} Examples of potent CYP2D6 inhibitors include bupropion, cannabidiol, duloxetine, fluoxetine, paroxetine, quinidine, and ritonavir, while CYP2D6 inducers include dexamethasone, glutethimide, and haloperidol. 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), fluoroquinolones (e.g., ciprofloxacin), fluvoxamine, and St. John's wort, while potent CYP1A2 inducers include phenytoin, rifampin, ritonavir, and tobacco.

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-the-curve levels by 2.4-fold, and decreased trazodone clearance by 50%. This was associated with adverse effects such as nausea, hypotension, and syncope. Another study found that the strong CYP3A4 inducer carbamazepine reduced concentrations of trazodone by 60 to 74%. The strong CYP2D6 inhibitor thioridazine has been reported to increase trazodone levels by 1.4-fold and concentrations of mCPP by 1.5-fold.{{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 }} Fluoxetine, a strong inhibitor of CYP2D6 and a weak or moderate inhibitor of CYP3A4,{{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 }} 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.{{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 }} 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 prolonged corrected QT interval.{{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 }}{{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 }} Smokers have lower levels of trazodone and higher ratios of mCPP to trazodone.{{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 }} 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. Smoking is known to induce CYP1A2, and this may be involved in these findings.

Combination of trazodone with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), or monoamine oxidase inhibitors (MAOIs) has a theoretical risk of serotonin syndrome. However, trazodone has been studied in combination with SSRIs and seemed to be safe in this context. On the other hand, cases of excessive sedation and serotonin syndrome have been reported with a combination of trazodone and fluoxetine or paroxetine. This may be due to the combined potentiation of the serotonin system. 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.

Serotonergic psychedelics like lysergic acid diethylamide (LSD) and psilocybin are thought to mediate their halucinogenic effects by activating serotonin 5-HT_2A receptors.{{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 = }} By displacing them from the 5-HT_2A receptor, serotonin 5-HT_2A receptor antagonists can block the hallucinogenic effects of serotonergic psychedelics. Serotonin 5-HT_2A receptor antagonists like ketanserin and risperidone have been found to fully block or dose-dependently reduce the subjective effects of LSD and psilocybin in clinical studies.

Trazodone is a potent serotonin 5-HT_2A receptor antagonist and may have similar effects. Studies have estimated that trazodone occupies 90 to 97% of 5-HT_2A receptors at doses of 50 to 200{{nbsp}}mg/day. Trazodone is less-studied in blocking the effects of serotonergic psychedelics than other serotonin 5-HT_2A receptor antagonists like ketanserin and risperidone, but has been reported to reduce the effects of psychedelics in published case reports.{{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 = }} 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. 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.{{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}}{{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 = }}

Trazodone has been used and discussed extensively online as a so-called "trip killer" by recreational psychedelic users.{{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.}}{{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 = }} 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. Trazodone was one of the most commonly recommended drugs for such purposes, exceeded only by alprazolam, benzodiazepines generally, and quetiapine.

Trazodone is a mixed agonist and antagonist of various serotonin receptors, antagonist of adrenergic receptors, weak histamine H₁ receptor antagonist, and weak serotonin reuptake inhibitor.{{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 }} More specifically, it is an antagonist of 5-HT_2A and 5-HT_2B receptors, a partial agonist of the 5-HT_1A receptor, and an antagonist of the α₁- and α₂-adrenergic receptors. It is also a ligand of the 5-HT_2C receptor with lower affinity than for the 5-HT_2A receptor. However, it is unknown whether trazodone acts as a full agonist, partial agonist, or antagonist of the 5-HT_2C receptor. Trazodone is a 5-HT_1A receptor partial agonist similarly to buspirone and tandospirone but with comparatively greater intrinsic activity.{{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 }}{{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 }} A range of weak affinities (K_i) have been reported for trazodone at the human histamine H₁ receptor, including 220{{nbsp}}nM, 350{{nbsp}}nM, 500{{nbsp}}nM,{{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 }} and 1,100{{nbsp}}nM.

Trazodone has a minor active metabolite known as meta-chlorophenylpiperazine (mCPP), and this metabolite may contribute to some degree to the pharmacological properties of trazodone.{{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–}} In contrast to trazodone, mCPP is an agonist of various serotonin receptors.{{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 }} It has relatively low affinity for α₁-adrenergic receptors unlike trazodone, but does have high affinity for α₂-adrenergic receptors and weak affinity for the H₁ receptor. In addition to direct interactions with serotonin receptors, mCPP is a serotonin releasing agent similarly to agents like fenfluramine and MDMA. 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).

Trazodone's 5-HT_2A 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.{{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 }}

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. Roughly half of brain 5-HT_2A receptors are blocked by 1{{nbsp}}mg of trazodone and essentially all 5-HT_2A 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.{{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 }}{{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 }} 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.{{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 }} Trazodone may almost completely occupy the 5-HT_2A and 5-HT_2C receptors at doses of 100 to 150{{nbsp}}mg/day. Significant occupancy of a number of other sites may also occur. However, another study estimated much lower occupancy of the SERT and 5-HT_2A receptors by trazodone.

Trazodone shows antidepressant- and anxiolytic-like effects in animals.{{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 = }}{{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 = }} However, it shows differences from certain other antidepressants, like the tricyclic antidepressants, in animals.{{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 = }} For example, it does not reverse the behavioral effects of the monoamine depleting agent reserpine and does not potentiate the effects of amphetamine or levodopa. Similarly to antipsychotics, trazodone reduces spontaneous motor activity, spontaneous and elicited aggressive behavior, and exploratory behavior, among other effects.{{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 = }} In addition, trazodone diminishes amphetamine-induced locomotor hyperactivity, although it does not inhibit apomorphine- or amphetamine-induced stereotypy.{{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 = }} On the other hand, unlike antipsychotics, trazodone does not produce catalepsy, although it can do so at sufficiently high doses.

Activation of the serotonin 5-HT_2A receptor enhances striatal dopaminergic neurotransmission, while stimulation of the serotonin 5-HT_2C receptor inhibits striatal dopaminergic neurotransmission.{{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}} Trazodone is both a serotonin 5-HT_2A and 5-HT_2C receptor antagonist, but has about 15-fold greater potency as an antagonist of the 5-HT_2A receptor relative to the 5-HT_2C receptor. In addition, at higher doses, trazodone acts as a dopamine D₂ receptor antagonist in animals.{{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 = }} As a result of the preceding actions, trazodone may inhibit striatal dopaminergic neurotransmission. This may underlie exacerbation of parkinsonism seen in marmosets and in human case reports.{{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 = }}

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

Trazodone may act predominantly as a 5-HT_2A receptor antagonist to mediate its therapeutic benefits against anxiety and depression.{{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 }} Its inhibitory effects on serotonin reuptake and 5-HT_2C receptors are comparatively weak. In relation to these properties, trazodone does not have similar properties to selective serotonin reuptake inhibitors (SSRIs) and is not particularly associated with increased appetite and weight gain – unlike other 5-HT_2C antagonists like mirtazapine.{{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 }}{{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 }} Moderate 5-HT_1A partial agonism may contribute to trazodone's antidepressant and anxiolytic actions to some extent as well.{{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 }}

The combined actions of 5-HT_2A and 5HT_2C receptor antagonism with serotonin reuptake inhibition only occur at moderate to high doses of trazodone.{{cite book | vauthors = Stahl SM |title=Stahl's Essential Psychopharmacology|edition=4th |year=2013 |publisher=Cambridge University Press |isbn=978-1-107-68646-5 }} Doses of trazodone lower than those effective for antidepressant action are frequently used for the effective treatment of insomnia. Low doses exploit trazodone's potent actions as a 5-HT_2A receptor antagonist, and its properties as an antagonist of H₁ and α₁-adrenergic receptors, but do not adequately exploit its SERT or 5-HT_2C inhibition properties, which are weaker. 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. 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. 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.

Trazodone's potent α₁-adrenergic blockade may cause some side effects like orthostatic hypotension and sedation.{{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 }} Conversely, along with 5-HT_2A and H₁ receptor antagonism, it may contribute to its efficacy as a hypnotic. Trazodone lacks any affinity for the muscarinic acetylcholine receptors, so does not produce anticholinergic side effects.

mCPP, a non-selective serotonin receptor modulator and serotonin releasing agent, is an active metabolite of trazodone and has been suggested to possibly play a role in its therapeutic benefits.{{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 }}{{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 }} However, research has not supported this hypothesis and mCPP might actually antagonize the efficacy of trazodone as well as produce additional side effects.{{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 }}{{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 }}{{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 }}{{cite journal | vauthors = Kast RE | title = Trazodone generates m-CPP: in 2008 risks from m-CPP might outweigh benefits of trazodone | journal = The World Journal of Biological Psychiatry | volume = 10 | issue = 4 Pt 2 | pages = 682–85 | year = 2009 | pmid = 19384678 | doi = 10.1080/15622970902836022 | s2cid = 901077 }}{{cite journal | vauthors = Workman EA, Tellian F, Short D | title = Trazodone induction of migraine headache through mCPP | journal = The American Journal of Psychiatry | volume = 149 | issue = 5 | pages = 712b–712 | date = May 1992 | pmid = 1575270 | doi = 10.1176/ajp.149.5.712b }}

Trazodone is well-absorbed after oral administration. Its bioavailability is 65 to 80%. 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.{{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 }} Absorption is somewhat delayed and enhanced by food.{{Citation needed|date=October 2020}}

Trazodone is not sequestered into any tissue. The medication is 89 to 95% protein-bound.{{cite web |title=Trazodone |url=https://www.drugbank.ca/drugs/DB00656 |website=www.drugbank.ca |access-date=31 January 2019}} The volume of distribution of trazodone is 0.8 to 1.5{{nbsp}}L/kg. Trazodone is highly lipophilic.

The metabolic pathways involved in the metabolism are not well-characterized. In any case, the cytochrome P450 enzymes CYP3A4, CYP2D6, and CYP1A2 may all be involved to varying extents. Trazodone is known to be extensively metabolized by the liver via hydroxylation, N-oxidation, and N-dealkylation. Several metabolites of trazodone have been identified, including a 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.{{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 }} CYP1A2, CYP2D6, and CYP3A4 genotypes all do not seem to predict concentrations of trazodone or mCPP.{{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 }} In any case, there are large interindividual variations in the metabolism of trazodone. In addition, poor metabolizers of dextromethorphan, a CYP2D6 substrate, eliminate mCPP more slowly and have higher concentrations of mCPP than extensive metabolizers.

mCPP is formed from trazodone by CYP3A4 and is metabolized via hydroxylation by CYP2D6 (to a para-hydroxylated metabolite). It may contribute to the pharmacological actions of trazodone.{{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 }} 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.{{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–}} In any case, the actions of trazodone, such as its serotonin antagonism, might partially overwhelm those of mCPP. 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").{{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 }}

The 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.{{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 = }} The elimination half-life of extended-release trazodone is 9.1 to 13.2{{nbsp}}hours.{{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 = }} The elimination half-life of mCPP is 2.6 to 16.0{{nbsp}}hours and is longer than that of trazodone. Metabolites are conjugated to gluconic acid or glutathione and around 70 to 75% of ¹⁴C-labelled trazodone was found to be excreted in the urine within 72{{nbsp}}hours.{{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 }} 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. 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. mCPP is glucuronidated and sulfated similarly to other trazodone metabolites.

Trazodone is a triazolopyridine derivative and a phenylpiperazine that is structurally related to nefazodone and etoperidone, each of which is a derivative of it.{{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}}{{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}}

Trazodone was developed in Italy, in the 1960s, by Angelini Research Laboratories as a second-generation antidepressant.{{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}}{{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}} It was developed according to the mental pain hypothesis, which was postulated from studying patients and which proposes that major depression is associated with a decreased pain threshold.{{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 }} 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{{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}} and was the first non-tricyclic or MAOI antidepressant approved in the US.{{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}}

Trazodone is the 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}}.{{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}}{{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}}{{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–}}{{cite web | url=https://www.drugs.com/international/trazodone.html|website=Drugs.com |title=Trazodone}}

Trazodone has been marketed under a large number of brand names throughout the world. Major brand names include Desyrel (worldwide), Donaren (Brazil), Molipaxin (Ireland, United Kingdom), Oleptro (United States), Trazorel (Canada), and Trittico (worldwide).

Trazodone may be effective in the treatment of sexual dysfunction, for instance female sexual dysfunction and erectile dysfunction.{{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 = }} A 2003 systematic review and meta-analysis found some indication that trazodone may be useful in the treatment of erectile dysfunction.{{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 }} Besides trazodone alone, a 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.{{Cite web|url=https://adisinsight.springer.com/drugs/800035655|title=Bupropion/trazodone - AdisInsight|website=adisinsight.springer.com}}{{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 = }}{{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 = }} As of September 2021, it is in phase 2 clinical trials for these indications. It has been in this stage of clinical development since at least February 2015.

Trazodone may be useful in the treatment of certain symptoms like sleep disturbances in alcohol withdrawal and recovery.{{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 }} However, reviews have recommended against use of trazodone for alcohol withdrawal due to inadequate evidence. Very limited evidence suggests that trazodone might be useful in the treatment of certain symptoms in cocaine use disorder. Trazodone has been reported to be effective in the treatment of sleep apnea.{{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 = }}{{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 = }}{{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 = }} Cochrane reviews found that trazodone was not effective in the treatment of agitation in dementia.{{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 = }}{{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 = }} Another Cochrane review found that trazodone might be useful in the treatment of sleep disturbances in dementia.{{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 = }} 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.{{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 }}{{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 = }}{{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 = }}{{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 = }}

Trazodone has been studied as an adjunctive therapy in the treatment of schizophrenia.{{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 }} It has been reported to decrease negative symptoms without worsening positive symptoms although improvement in negative symptoms was modest. Trazodone has also been reported to be effective in treating antipsychotic-related extrapyramidal symptoms such as akathisia.{{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 = }} Trazodone has been studied and reported to be effective in the treatment of bulimia, but there is limited evidence to support this use.{{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 }} It might be useful in the treatment of night eating disorder as well. Trazodone might be effective in the treatment of adjustment disorder.{{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 = }} It may also be effective in the treatment of bruxism in children and adolescents.{{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 = }}

Trazodone may be useful in the treatment of certain chronic pain disorders. There is limited but conflicting evidence to support the use of trazodone in the treatment of headaches and migraines in children.{{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 = }}{{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 = }}{{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 = }}{{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 = }} Trazodone may be useful in the treatment of fibromyalgia{{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 = }} as well as diabetic neuropathy. It may also be useful in the treatment of burning mouth syndrome.{{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 | s2cid = 232217908 | url = }}{{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 = }} A 2004 narrative review claimed that trazodone could be used in the treatment of complex regional pain syndrome.{{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}} Trazodone may also be effective in the treatment of functional gastrointestinal disorders.{{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 }} It may be effective in the treatment of non-cardiac chest pain as well.{{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 }}{{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 }}

Trazodone may be useful in promoting motor recovery after stroke.{{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 = }}

Trazodone is sometimes prescribed to treat premature ejaculation but clomipramine and paroxetine may be more effective.

Trazodone has been used to reduce anxiety and stress, to improve sleep, and to produce sedation in dogs and cats in veterinary medicine.{{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 = }}{{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 = }}{{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 = }}

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