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Trazodone

Trazodone molecule structureTrazodone molecule structure
Desyrel, Oleptro, Molipaxin, Trazorel, Trittico
Psychoactive Class
AntidepressantSedative

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.citation needed Its antidepressant efficacy is considered comparable to that of TCAs, SSRIs, and SNRIs.23

Dosage & Duration

Dosage

Doses are population estimates that vary widely between individuals.

Threshold~25 mg
Light25-50 mg
Moderate50-100 mg
Strong100-150 mg
Heavy150+ mg
Bioavailability
63-91%

Duration

Onset20-40 minutes
Total6-10 hours
Half-life
5-9 hours

Subjective Effects

Legacy content. A statistically backed ontology from Mindstate Design Labs is coming soon.

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

Uncomfortable

NauseaDry mouth

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

Expected colorimetric results for common reagent tests. Colors show reaction change over 1–2 minutes.

Marquis(MQ)
No reaction
No reaction
Mecke(ME)
No reaction
No reaction
Mandelin(MD)
No reaction
No reaction
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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.citation needed 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.citation needed

Pharmacokinetics

Trazodone is well-absorbed after oral administration, with a bioavailability of approximately 65 to 80%.citation needed 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.citation needed It undergoes extensive hepatic metabolism through hydroxylation, N-oxidation, and N-dealkylation. CYP3A4 mediates N-dealkylation to produce the active metabolite m-chlorophenylpiperazine (mCPP), while CYP2D6 contributes to hydroxylation of the meta-chlorophenyl ring. 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. Roughly 70 to 75% of trazodone is excreted renally, about 21% via feces, and less than 1% as unchanged drug in urine.

Interactions

Caution

Use caution

These 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.

1,2-BenzodiazepineAbametapirAbataceptAbciximabAbemaciclib
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Tolerance

Tolerance timelines are rules of thumb, not exact schedules, and vary widely between individuals and use patterns.

Full Tolerance
Evidence on tolerance to trazodone's hypnotic effects is limited and inconsistent. A critical review of trazodone as a hypnotic found no available data establishing tolerance to its possible hypnotic effects. A later systematic review of trazodone for insomnia stated that low-dose trazodone may avoid tolerance, but the reviewed studies were heterogeneous and generally too short to establish numerical tolerance or recovery timelines. No baseline-tolerance, half-tolerance, full-tolerance, or cross-tolerance values can be supported from this evidence.

Harm Potential

Addiction & Dependence

Psychological

Extremely Low

Trazodone is not associated with abuse potential or recreational use.citation needed No reports of compulsive use patterns or psychological dependence have been documented.

Physical

Low

Trazodone shares properties with SSRIs including the possibility of discontinuation syndrome if stopped too quickly.6 Gradual tapering is recommended when discontinuing treatment.6

Toxicity

Cardiovascular

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.citation needed

Hepatic

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

Genitourinary

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.citation needed

Central Nervous System

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.citation needed

Musculoskeletal

Trazodone is associated with an increased risk of falls and hip fractures in older adults, likely related to sedation and orthostatic hypotension.citation needed

Endocrine

Elevated prolactin concentrations have been observed in people taking trazodone, appearing to increase by approximately 1.5- to 2-fold.citation needed

Psychosis Risk

The unmasking of bipolar disorder and mania may occur with trazodone and other antidepressants.citation needed 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.8 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

Prescription7
United States flagUnited StatesPrescription only
Australia flagAustraliaPrescription only
Canada flagCanadaPrescription only
Ireland flagIrelandPrescription only
Japan flagJapanPrescription only
New Zealand flagNew ZealandPrescription only
Singapore flagSingaporePrescription only

References

Source Pages

  1. DrugBank
  2. DrugBank: Trazodone Article A181177
  3. DrugBank: Trazodone Article A985
  4. DrugBank: Trazodone Biointeractions
  5. DrugBank: Trazodone Salt Information
  6. PsychonautWiki: Antidepressants
  7. PsychonautWiki: Ketamine (Trazodone interaction)
  8. Wikipedia

Citations

  1. Trazodone Hydrochloride Tablets — Prescribing Information (DailyMed, setid f56633a5). (n.d.). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f56633a5-f58e-a3d9-e053-2995a90a10a312
  2. Trazodone — StatPearls (NBK470560). (n.d.). https://www.ncbi.nlm.nih.gov/books/NBK470560/12
  3. Rediscovering trazodone for the treatment of major depressive disorder (Fagiolini et al., 2012) — PMC3693429. (n.d.). https://pmc.ncbi.nlm.nih.gov/articles/PMC36934291
  4. Luca Settimo, & David Taylor. (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/10.1177/02698811177421011
  5. Trazodone Hydrochloride Tablets Prescribing Information. DailyMed / FDA (n.d.). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68bcae4b-f4c3-4d28-af76-d182b707fc731
  6. Trazodone Hydrochloride Tablets - Prescribing Information. DailyMed / National Library of Medicine (n.d.). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9b022ae9-dd52-43ae-804b-ddf8e7cfd530123
  7. Fatal overdose with trazodone: case report and literature review. (n.d.). https://pubmed.ncbi.nlm.nih.gov/11603256/1
  8. 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.2023.12076211
  9. Trazodone Hydrochloride Tablets — DailyMed (setid ed3039d8). U.S. National Library of Medicine / FDA (n.d.). https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ed3039d8-3d27-4b71-a4b0-812943c9457f&type=display1
  10. 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

Further Reading

  1. PLoS ONE: Dual inhibitory action of trazodone
  2. Stahl 2009: Mechanism of Action of Trazodone

Article Status

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