Trazodone Drug-Drug Interactions: A Complete Clinical Profile

Which trazodone interactions does the label flag?

The current trazodone label sorts clinically important interactions into eight groups: MAOIs, other serotonergic drugs, antiplatelet agents and anticoagulants, strong CYP3A4 inhibitors, strong CYP3A4 inducers, digoxin and phenytoin, CNS depressants, and drugs that prolong the QT interval [1]. The instructions differ by group — one combination is contraindicated, several call for a dose change, some for level or INR monitoring, and the QT combinations for avoidance [1].

Strong CYP3A4 inhibitors: what happens to trazodone levels

CYP3A4 is the primary enzyme involved in trazodone metabolism, and it also produces the active metabolite mCPP [2][4]. In human liver microsomes and expressed enzymes, only CYP3A4 formed mCPP, and ketoconazole inhibited that step [2]. A second in vitro study reached the same conclusion, with ketoconazole and ritonavir both potent inhibitors of the reaction and indinavir a strong inhibitor as well [5]. A 2025 in vitro study found that CYP2D6, CYP2C19 and flavin monooxygenases contribute to other, inactive metabolites, with CYP3A4 still the primary enzyme [4].

For strong inhibitors — the label names itraconazole, ketoconazole, clarithromycin and indinavir — the instruction is to consider a lower trazodone dose based on tolerability. Exposure rises, and the label says the risk of adverse reactions, including cardiac arrhythmias, may increase [1].

The clearest human numbers come from a single-dose, blinded, four-way crossover study in 10 healthy volunteers. Trazodone 50 mg taken with low-dose ritonavir (four doses of 200 mg each) had its apparent oral clearance cut from 155 to 75 mL/min, its elimination half-life lengthened from 6.7 to 14.9 hours, and its peak plasma concentration raised from 842 to 1,125 ng/mL, compared with trazodone plus placebo. Sedation and fatigue increased, three volunteers had nausea, dizziness or hypotension, and one fainted [3].

Strong CYP3A4 inducers: the mirror image

The label gives the opposite instruction for strong inducers: exposure falls, so the dose may need to be increased based on therapeutic response, with close monitoring [1]. The named examples are rifampin, carbamazepine, phenytoin and St. John's wort [1]. St. John's wort appears twice in the label — as a CYP3A4 inducer that lowers trazodone levels, and as a serotonergic drug that adds to serotonin syndrome risk [1].

Does trazodone raise other drugs' levels?

The label describes trazodone only as a CYP3A4 substrate, meaning a drug whose own levels other drugs change. It does not list trazodone as a CYP inhibitor or inducer, and trazodone does not appear in the FDA's tables of CYP substrates, inhibitors and inducers [1][6]. So the CYP3A4 relationship points one way: inhibitors raise trazodone, inducers lower it. Trazodone is not the drug doing the inhibiting.

The exception in the label is digoxin and phenytoin. Both have a narrow therapeutic index, and the label says trazodone can increase their concentrations. It advises measuring serum digoxin or phenytoin levels before starting the combination, continuing to monitor, and reducing the digoxin or phenytoin dose as needed. The label states no mechanism for this effect [1].

Serotonin syndrome and MAOIs

Serotonin syndrome can occur with trazodone alone, and the label says the risk climbs with other serotonergic drugs: triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's wort, SSRIs, SNRIs and MAOIs [1]. The label lists the signs as mental status changes such as agitation, hallucinations, delirium and coma; autonomic instability such as tachycardia, labile blood pressure, sweating and fever; neuromuscular findings such as tremor, rigidity, myoclonus and hyperreflexia; seizures; and gastrointestinal symptoms such as nausea, vomiting and diarrhea [1].

MAOIs are the only contraindication in the label. The label contraindicates trazodone in patients taking an MAOI, or within 14 days of stopping one, including linezolid and intravenous methylene blue [1]. The label specifies a 14-day interval between stopping trazodone and starting an MAOI antidepressant [1]. The label notes that no reports involved methylene blue given by other routes, such as oral tablets or local tissue injection [1].

QT prolongation: combinations the label says to avoid

Trazodone prolongs the QT/QTc interval, and postmarketing reports include torsades de pointes and ventricular tachycardia at doses of 100 mg/day or less with the immediate-release tablets [1]. The label says to avoid combining trazodone with other drugs known to prolong QTc and gives examples: the Class 1A antiarrhythmics quinidine, procainamide and disopyramide; the Class 3 antiarrhythmics amiodarone and sotalol; the antipsychotics ziprasidone, chlorpromazine and thioridazine; and the antibiotic gatifloxacin [1]. It also says to avoid trazodone in people with known QT prolongation, a history of cardiac arrhythmia, low potassium or magnesium, congenital long QT, and during the initial recovery phase after a heart attack [1]. The same warning also names the CYP3A4 inhibitors itraconazole, clarithromycin and voriconazole as combinations to avoid [1].

Bleeding risk: warfarin, aspirin, NSAIDs and antiplatelets

The label warns that combining trazodone with aspirin, NSAIDs, other antiplatelet drugs, warfarin or other anticoagulants may increase bleeding risk, and it lists warfarin, rivaroxaban, dabigatran and clopidogrel as examples [1]. For warfarin specifically, the label says to monitor INR carefully when trazodone is started or discontinued and notes that prothrombin time may rise or fall [1]. A published case series of three patients found INR changes of 1.0 or more after trazodone was started or stopped — INR fell when trazodone was started and rose when it was stopped — with no adverse effects from the changes, although warfarin doses had to be adjusted. The mechanism is unknown [7].

Alcohol and other CNS depressants

The label says trazodone may enhance the response to alcohol, barbiturates and other CNS depressants, and it directs that patients be told this [1]. It also records overdose deaths when trazodone was taken with alcohol, chloral hydrate or diazepam, amobarbital, chlordiazepoxide or meprobamate [1]. The sedation is measurable: in the outpatient depression trials, drowsiness occurred in 41% of patients on trazodone versus 20% on placebo [1]. The label also warns that trazodone can impair judgment, thinking and motor skills [1].

Blood pressure drugs and orthostatic hypotension

The label links trazodone's alpha-1 adrenergic blockade to postural hypotension, and orthostatic hypotension and syncope have been reported [1]. In the outpatient depression trials, hypotension occurred in 4% of patients on trazodone versus 0% on placebo, and syncope in 5% versus 1% [1]. The label states that when trazodone is taken with blood pressure medicines, lowering the blood pressure drug dose may be required [1].