Trazodone
Trazodone is an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) class, chemically classified as a triazolopyridine derivative.12 First approved by the FDA in 1981, it is primarily indicated for the treatment of major depressive disorder.1 Trazodone is notable for its pronounced sedative and anxiolytic properties, which have led to widespread off-label use for insomnia and anxiety disorders.23 Its antidepressant efficacy is considered comparable to that of TCAs, SSRIs, and SNRIs.23
Contents
Dosage & Duration
Dosage
Duration
Subjective Effects
The trazodone experience is dominated by heavy sedation and anxiolysis rather than any recreational or psychedelic character. As a serotonin antagonist and reuptake inhibitor prescribed for depression and insomnia, its acute effects center on a strong pull toward sleep, a calmed emotional state, and a general dulling of mental sharpness. There is little to no euphoria or sensory alteration at typical doses.
Physical
The body feel is heavy and deeply sedated, often accompanied by dizziness or lightheadedness on standing, and grogginess that can persist into the following morning. Rarely, trazodone can cause priapism, a persistent and painful erection that constitutes a medical emergency if untreated.
Sedation
Cognitive
The headspace is foggy and slowed, with reduced alertness and a noticeable blunting of anxiety. Memory and general cognition can be measurably impaired while the drug is active, an effect that is more pronounced in elderly users.
Suppressions
Cognitive effects are almost entirely suppressive, consistent with the drug's central nervous system depressant profile.
Reagent Testing
Loading reagent data
Pharmacology
Pharmacodynamics
Trazodone functions primarily as a serotonin receptor antagonist and reuptake inhibitor (SARI). Its most prominent action is potent antagonism of the 5-HT2A receptor, with roughly half of brain 5-HT2A receptors occupied at doses as low as 1 mg and near-complete saturation at 10 mg.4 It also antagonizes 5-HT2B receptors and acts as a partial agonist at the 5-HT1A receptor, while binding to the 5-HT2C receptor with lower affinity. Trazodone inhibits the serotonin transporter, with SERT occupancy estimated at approximately 86% at 100 mg/day.4 It additionally blocks α1- and α2-adrenergic receptors and weakly antagonizes histamine H1 receptors, while lacking affinity for muscarinic acetylcholine receptors.5
Pharmacokinetics
Trazodone is well-absorbed after oral administration, with a bioavailability of approximately 65 to 80%.5 Absorption is somewhat delayed and enhanced by food, though food may sometimes decrease peak blood levels.5 The drug is 89 to 95% protein-bound with a volume of distribution of 0.8 to 1.5 L/kg.5 It undergoes extensive hepatic metabolism through hydroxylation, N-oxidation, and N-dealkylation. CYP3A4 mediates N-dealkylation to produce the active metabolite m-chlorophenylpiperazine (mCPP),6 while CYP2D6 contributes to hydroxylation of the meta-chlorophenyl ring.7 Elimination is biphasic, with an initial distribution phase half-life of 3 to 6 hours and a terminal elimination half-life of approximately 5 to 9 hours.2 Roughly 70 to 75% of trazodone is excreted renally, about 21% via feces, and less than 1% as unchanged drug in urine.85
Caution
Use cautionThese combinations are not usually physically harmful, but may produce undesirable effects, such as physical discomfort or overstimulation. Extreme use may cause physical health issues. Synergistic effects may be unpredictable. Care should be taken when choosing to use this combination.
Tolerance
Harm Potential
Addiction & Dependence
Psychological
Extremely LowTrazodone is not associated with abuse potential or recreational use.9 No reports of compulsive use patterns or psychological dependence have been documented.
Physical
LowTrazodone shares properties with SSRIs including the possibility of discontinuation syndrome if stopped too quickly.9 Gradual tapering is recommended when discontinuing treatment.9
Toxicity
QT prolongation and cardiac arrhythmias have been reported with trazodone therapy, including in patients without pre-existing cardiac disease; identified arrhythmias include isolated PVCs, ventricular couplets, and short episodes of ventricular tachycardia.9
Rare cases of liver toxicity have been observed, possibly due to the formation of reactive metabolites.11
Priapism is a relatively rare but serious side effect that can cause permanent neurological damage if left untreated; the risk appears greatest during the first month of treatment at low dosages.12
Memory, alertness, and cognition may be decreased, especially in elderly patients due to CNS depressant effects; sedation commonly occurs and may impair ability to operate machinery or drive.9
Trazodone is associated with an increased risk of falls and hip fractures in older adults, likely related to sedation and orthostatic hypotension.13
Elevated prolactin concentrations have been observed in people taking trazodone, appearing to increase by approximately 1.5- to 2-fold.14
Psychosis Risk
The unmasking of bipolar disorder and mania may occur with trazodone and other antidepressants.9 No specific psychotic symptoms documented beyond manic episodes.
Seizure Risk
Trazodone is classified as an agent that reduces seizure threshold. Patients with seizure disorders or risk factors should be monitored.
History & Culture
Development and Approval
Trazodone was developed in Italy during the 1960s by Angelini Research Laboratories as a second-generation antidepressant.15 Its development was guided by the mental pain hypothesis, a theory derived from clinical observations proposing that major depression is…
Legality
International
1961 Single Convention: trazodone is not scheduled.
1971 Convention on Psychotropic Substances: trazodone is not scheduled.
1988 Convention: trazodone is not listed in precursor Tables I or II.
By Country
References
Source Pages
Citations
- (n.d.). Trazodone Hydrochloride Tablets — Prescribing Information (DailyMed, setid f56633a5). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f56633a5-f58e-a3d9-e053-2995a90a10a312
- (n.d.). Trazodone — StatPearls (NBK470560). https://www.ncbi.nlm.nih.gov/books/NBK470560/1234
- (n.d.). Rediscovering trazodone for the treatment of major depressive disorder (Fagiolini et al., 2012) — PMC3693429. https://pmc.ncbi.nlm.nih.gov/articles/PMC369342912
- (January 2018). Evaluating the dose-dependent mechanism of action of trazodone by estimation of occupancies for different brain neurotransmitter targets. J Psychopharmacol, 32(1), 96–104. https://doi.org/10.1177/026988111774210112
- (n.d.). Trazodone Hydrochloride Tablets Prescribing Information. DailyMed / FDA. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68bcae4b-f4c3-4d28-af76-d182b707fc7312345
- (June 1998). Trazodone is metabolized to m-chlorophenylpiperazine by CYP3A4 from human sources. Drug Metabolism and Disposition, 26(6), 572–75. https://pubmed.ncbi.nlm.nih.gov/9616194/1
- (2025). CYP2D6 Phenotype as a Predictor of Adverse Drug Reactions in Patients Treated With Trazodone: An Explorative Pharmacogenetic Study. Frontiers in Pharmacology. https://pmc.ncbi.nlm.nih.gov/articles/PMC12931868/1
- (n.d.). The elimination half-life of mCPP is 2.6 to 16.0 hours and is longer than that of trazodone. <ref name="pmid22115401" /. https://pubmed.ncbi.nlm.nih.gov/1037253/1
- (n.d.). Trazodone Hydrochloride Tablets - Prescribing Information. DailyMed / National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9b022ae9-dd52-43ae-804b-ddf8e7cfd5301234567
- (n.d.). Fatal overdose with trazodone: case report and literature review. https://pubmed.ncbi.nlm.nih.gov/11603256/1
- (n.d.). Trazodone - LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.ncbi.nlm.nih.gov/books/NBK548557/1
- (n.d.). Pretreatment screening and counseling on prolonged erections for patients prescribed trazodone. https://icurology.org/DOIx.php?id=10.4111%2Ficu.202001951
- (n.d.). Risk of Fall-Related Injuries Associated with Antidepressant Use in Elderly Patients: A Nationwide Matched Cohort Study. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8872471/1
- (n.d.). Trazodone treatment increases plasma prolactin concentrations in depressed patients. https://pubmed.ncbi.nlm.nih.gov/7673654/1
- Fagiolini A, & et al.. (2023). Treating depression in clinical practice: new insights on the multidisciplinary use of trazodone. Frontiers in Psychiatry. https://doi.org/10.3389/fpsyt.2023.1207621123
- (n.d.). Trazodone Hydrochloride Tablets — DailyMed (setid ed3039d8). U.S. National Library of Medicine / FDA. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ed3039d8-3d27-4b71-a4b0-812943c9457f&type=display1
- (n.d.). Trazodone Drug Usage Statistics, United States, 2014 - 2023. ClinCalc. https://clincalc.com/DrugStats/Drugs/Trazodone1
- Yates G, & Melon E. (2024). Trip-killers: a concerning practice associated with psychedelic drug use. Emergency Medical Journal. https://pubmed.ncbi.nlm.nih.gov/38123961/12
- (n.d.). Poisons Standard; TGA scheduling framework. legislation.gov.au. https://www.legislation.gov.au/F2026L00060/asmade/2026-01-30/text/original/pdf1
- (n.d.). Health Canada Drug Product Database. health-products.canada.ca. https://health-products.canada.ca/dpd-bdpp/info?code=102668&lang=eng1
- (n.d.). Trazodone Hydrochloride Tablets — DailyMed Label (setid 8eb85c26-a6cb-4a10-a990-ccc0b20aff08). U.S. National Library of Medicine / FDA. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8eb85c26-a6cb-4a10-a990-ccc0b20aff081
Further Reading
Automated synthesisInformation aggregated and synthesized using an autonomous workflow built by Josie Kins.
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