Trazodone Stats & Data
Clc1cccc(c1)N1CCN(CCCn2nc3ccccn3c2=O)CC1PHLBKPHSAVXXEF-UHFFFAOYSA-NPharmacology
DrugBankDescription
Trazodone is triazolopyridine derivative from the serotonin receptor antagonists and reuptake inhibitors (SARIs) class of antidepressants. It is used in adults and has been shown to be comparable in efficacy to other drugs such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine receptor inhibitor (SNRIs) in the treatment of depression. A unique feature of this drug is that it does not promote the anxiety symptoms, sexual symptoms, or insomnia, which are commonly associated with SSRI and SNRI therapy. Trazodone acts on various receptors, including certain histamine, serotonin, and adrenergic receptors, distinguishing it from other antidepressants that cover a narrow range of neurotransmitters. It was initially granted FDA approval in 1981.
Mechanism of Action
The mechanism of action of trazodone is not fully understood, however, it is known to inhibit the reuptake of serotonin and block both histamine and alpha-1-adrenergic receptors. Despite the fact that trazodone is frequently considered a selective serotonin reuptake inhibitor, several reports have shown that other mechanisms including antagonism at serotonin 5-HT1a, 5-HT1c, and 5-HT2 receptor subtypes may occur. The strongest antagonism of trazodone is reported to occur at the serotonin 5-HT21c receptors, preventing serotonin uptake. In addition to acting on serotonin receptors, trazodone has been shown to inhibit serotonin transporters. The antidepressant effects of trazodone result from the inhibition of receptor uptake, which normally decreases circulating neurotransmitters, contributing to depressive symptoms.
Pharmacodynamics
Trazodone treats depressed mood and other depression-related symptoms and shows benefit in the treatment of insomnia due to its sedating effects. It is known to prolong the cardiac QT-interval. Memory, alertness, and cognition may be decreased by trazodone, especially in elderly patients due to its central nervous system depressant effects. A note on priapism Trazodone has been associated with the occurrence of priapism, a painful and persistent incidence of penile tissue erection that is unrelievable and can cause permanent neurological damage if left untreated. Patients must be advised to seek immediate medical attention if priapism is suspected.
Metabolism
Trazodone is heavily metabolized and activated in the liver by CYP3A4 enzyme to the active metabolite, m-chlorophenylpiperazine (mCPP). The full metabolism of trazodone has not been well characterized. Some other metabolites that have been identified are a dihydrodiol metabolite and carboxylic acid.
Absorption
Trazodone is rapidly absorbed in the gastrointestinal tract after oral administration, with a bioavailability ranging from 63-91% and an AUC0−t of 18193.0 ng·h/mL. Food may impact absorption in a variable fashion, and may sometimes lead to decreases in the Cmax of trazodone. In the fed state in 8 healthy volunteers, the Cmax was measured to be 1.47 +/- 0.16 micrograms/mL, and in the fasted state, was measured at 1.88 +/- 0.42 micrograms/mL. The average Tmax after a single dose of 300 mg was 8 hours. Food may increase absorption by up to 20%.
Toxicity
The oral LD50 of trazodone is 690 mg/kg in rats. An overdose of trazodone may result in central nervous system, cardiac, respiratory effects. Signs and symptoms may include dyspnea, bradycardia, hypotension, mental status changes, lack of coordination, and coma, among others. In addition, an overdose may result in priapism, a persistent unrelievable penile tissue erection that may cause permanent damage if not treated promptly. No specific antidote exists for a trazodone overdose. If an overdose occurs, consider the possibility that trazodone may have been combined with other drugs. Contact a poison control center in case of overdose for the most current management guidelines. Dialysis does not accelerate trazodone clearance.
Indication
Trazodone is indicated for the treatment of major depressive disorder (MDD). It has been used off-label for adjunct therapy in alcohol dependence, and off-label to treat anxiety and insomnia. It may also be used off-label to treat symptoms of dementia, Alzheimer’s disease, schizophrenia, eating disorders, and fibromyalgia due to its effects on various neurotransmitter receptors.
Half-life
The plasma elimination half-life was markedly prolonged (13.6 versus 6 hours) elderly volunteers in the fasted state when compared with younger volunteers. Another study of 8 healthy individuals taking a single dose of trazodone indicated a terminal elimination half-life of 7.3 +/- 0.8 hr. A two-phase pattern of trazodone elimination has been reported. Initially, the half-life is reported to range from 3 to 6 hours and the second phase of elimination to range from 5 to 9 hours.
Protein Binding
The plasma protein binding of trazodone is 89-95% according to in vitro studies.
Elimination
Less than 1% of an oral dose is excreted unchanged in the urine. In a pharmacokinetic study, about 60-70% of radiolabeled was excreted urine within 48 hours. Approximately 9-29% was found to be excreted in feces over a range of 60 to 100 hours. According to the FDA medical review, the kidneys are responsible for 70 to 75% of trazodone excretion. About 21% of trazodone is reported to be excreted by the fecal route and 0.13% of the parent drug is eliminated in the urine as unchanged drug.
Volume of Distribution
A single-dose pharmacokinetic study of 8 volunteers taking trazodone determined a volume of distribution of 0.84 +/- 0.16 L/kg. The FDA medical review of trazodone reports a volume of distribution of 0.47 to 0.84 L/kg.
Clearance
A decrease in total apparent clearance (5.1 versus 10.8 L/h) was seen elderly volunteers in the fasted state when compared with younger volunteers. Another pharmacokinetic study determined the total body clearance of trazodone to be 5.3 +/- 0.9 L/hr in 8 healthy patients taking a single dose of trazodone.
Receptor Profile
Receptor Actions
Receptor Binding
History & Culture
1960s–1981
Trazodone was developed in Italy during the 1960s by Angelini Research Laboratories as a second-generation antidepressant. Its development was guided by the mental pain hypothesis, a theory derived from clinical observations proposing that major depression is associated with a decreased pain threshold. In contrast to most antidepressants available at the time, trazodone demonstrated minimal effects on muscarinic cholinergic receptors, distinguishing it pharmacologically from its predecessors. The drug was patented and marketed internationally, beginning with Italy in 1972 and West Germany in 1977. In 1981, trazodone received approval from the United States Food and Drug Administration, becoming the first antidepressant approved in the country that was neither a tricyclic nor a monoamine oxidase inhibitor. The medication has since become widely prescribed, ranking as the 21st most commonly prescribed medication in the United States by 2023 and the fifth most common antidepressant, with over 24 million prescriptions annually.
Within recreational psychedelic communities, trazodone has gained recognition as a "trip killer"—a medication employed to attenuate or terminate unwanted psychedelic experiences. By 2024, it had been recommended for this purpose 77 times on the social media platform Reddit, with suggested doses ranging from 50 to 150 mg. Among substances discussed for trip termination, trazodone ranked among the most frequently recommended, exceeded only by alprazolam, benzodiazepines as a class, and quetiapine.
Tolerance & Pharmacokinetics
drugs.wikiExperience Report Analysis
ErowidDemographics
Gender Distribution
Age Distribution
Reports Over Time
Effect Analysis
ErowidEffects aggregated from 60 experience reports (60 Erowid)
Effect Sentiment Distribution
Confidence Distribution
Positive Effects 9
Adverse Effects 7
Dose-Response Correlation
How effect frequency changes across dose levels
View data table
| Effect | Common (n=13) | Heavy (n=16) |
|---|---|---|
| Stimulation | 61.5% | 56.2% |
| Sedation | 38.5% | 56.2% |
| Focus Enhancement | 0% | 37.5% |
| Anxiety Suppression | 30.8% | 31.2% |
| Confusion | 23.1% | 25.0% |
| Headache | 15.4% | 25.0% |
| Color Enhancement | 0% | 25.0% |
| Euphoria | 0% | 25.0% |
| Nausea | 0% | 25.0% |
| Visual Distortions | 15.4% | 18.8% |
| Memory Suppression | 15.4% | 0% |
| Empathy | 15.4% | 12.5% |
| Closed-Eye Visuals | 0% | 12.5% |
| Hospital | 0% | 12.5% |
| Music Enhancement | 0% | 12.5% |
Dose–Effect Mapping
Experience ReportsHow reported effects shift across dose tiers, based on 60 experience reports.
Limited tier coverage — most reports fall within the Common / Heavy range. Effects at other dose levels may not be represented.
| Effect | Common (n=13) | Heavy (n=16) | |
|---|---|---|---|
| stimulation | → | ||
| sedation | ↑ | ||
| focus enhancement | — | → | |
| anxiety suppression | → | ||
| confusion | → | ||
| headache | ↑ | ||
| color enhancement | — | → | |
| euphoria | — | → | |
| nausea | — | → | |
| visual distortions | ↑ | ||
| memory suppression | — | → | |
| empathy | ↓ | ||
| closed-eye visuals | — | → | |
| hospital | — | → | |
| music enhancement | — | → |
Risk Escalation
Sentiment AnalysisAverage frequency of positive vs adverse effects across dose tiers
View effect breakdown
Adverse Effects
| Effect | Common (n=13) | Heavy (n=16) | Change |
|---|---|---|---|
| Anxiety Suppression | 1% | ||
| Confusion | 8% | ||
| Headache | +62% | ||
| Nausea | — | 0% | |
| Memory Suppression | — | 0% |
Positive Effects
| Effect | Common (n=13) | Heavy (n=16) | Change |
|---|---|---|---|
| Stimulation | -8% | ||
| Focus Enhancement | — | 0% | |
| Color Enhancement | — | 0% | |
| Euphoria | — | 0% | |
| Empathy | -18% | ||
| Music Enhancement | — | 0% |
Dosage Distribution
Dose distribution from experience reports
Real-World Dose Distribution
62K DosesFrom 101 individual dose entries
Oral (n=87)
Insufflated (n=6)
Form / Preparation
Most common forms and preparations reported
Body-Weight Dosing
Dose relative to body weight from reports with weight data
Redose Patterns
Redosing behavior across 51 reports
Legal Status
| Country | Status | Notes |
|---|---|---|
| Canada | Prescription only | Available as both brand name and generic prescription products. Regulated as a prescription medication under federal pharmaceutical law. Not classified as a controlled substance. |
| United States | Prescription only (FDA approved) | Granted FDA approval in 1981 for the treatment of major depressive disorder. Trazodone is not a scheduled controlled substance under the Controlled Substances Act; it is regulated as a prescription-only medication requiring a valid prescription from a licensed healthcare provider. |
Harm Reduction
drugs.wikiTrazodone is a SARI that at low doses primarily blocks 5‑HT2A/H1/alpha‑1 receptors and is sedating, while at higher antidepressant doses it also meaningfully inhibits the serotonin transporter; this dose‑dependent pharmacology explains why 25–100 mg often helps sleep but does not treat depression without daytime dosing. It should be taken after food when possible to lessen lightheadedness and orthostatic hypotension, a common early adverse effect due to alpha‑1 blockade. Clinically important risks include QT prolongation and rare torsades de pointes; combinations with other QT‑prolonging agents or in patients with cardiac disease/electrolyte derangements warrant extra caution and consideration of ECG monitoring. Priapism is a rare but serious emergency; an erection lasting more than 4 hours or painful erections require immediate ER evaluation; risk may be higher early in treatment and in those with hematologic diseases (e.g., sickle cell) or penile anatomic variants. CNS depression is additive with alcohol, benzodiazepines, Z‑drugs, opioids, and gabapentinoids; combining increases risk of respiratory depression, impaired driving, and falls—avoid or minimize and use the lowest effective doses with planned timing. Serotonin syndrome can occur when combined with MAOIs, linezolid, IV methylene blue, or other serotonergic agents (e.g., SSRIs/SNRIs/TCAs, tramadol, triptans, dextromethorphan, fentanyl, St John’s Wort); observe a 14‑day washout from MAOIs and monitor for agitation, tremor/clonus, hyperthermia, and autonomic instability. Potent CYP3A4 inhibitors (clarithromycin, azole antifungals, ritonavir) and grapefruit juice can raise trazodone exposure—leading to more sedation, hypotension, and arrhythmia risk—while CYP3A4 inducers (carbamazepine, phenytoin, rifampin, St John’s Wort) can reduce efficacy. Older adults are more susceptible to hyponatremia/SIADH and orthostatic hypotension; check sodium if confusion, headache, seizures, or falls occur, and consider dose reductions. Hepatic metabolism is primary and rare idiosyncratic liver injury has been reported; obtain baseline LFTs and recheck if clinically indicated or if symptoms (e.g., jaundice, dark urine, pruritus) develop. There are reports of increased INR with warfarin and increased digoxin levels; monitor especially after initiation or dose changes. Screen for bipolar spectrum illness before starting because antidepressant‑induced switching or mania has been reported; discontinue if mania emerges. Avoid driving, cycling, operating machinery, or engaging in safety‑critical tasks until you know your next‑day alertness; next‑morning impairment is more likely with higher doses, interactions, sleep deprivation, or when combined with other depressants. Discontinuation should be gradual to reduce rebound insomnia and withdrawal‑like symptoms (nausea, dysphoria, agitation, paresthesias).
References
Cited References
- NCBI StatPearls: Trazodone
- PLoS ONE: Dual inhibitory action of trazodone
- PsychonautWiki: Antidepressants
- PsychonautWiki: Ketamine (Trazodone interaction)
- Stahl 2009: Mechanism of Action of Trazodone
- DrugBank: Trazodone Biointeractions
- DrugBank: Trazodone Article A985
- DrugBank: Trazodone Article A181177
- DrugBank: Trazodone Salt Information