Raldesy Drug Interactions: What to Avoid and What to Tell Your Doctor

Raldesy (trazodone hydrochloride oral solution) can interact with a range of other medications, supplements, and substances. Some interactions are dangerous and require you to avoid certain combinations entirely. Others require monitoring or dose adjustments. Here's what you need to know — and what to share with your doctor and pharmacist before starting Raldesy.

Contraindicated: MAOIs (Do Not Take Together)

The most serious drug interaction with Raldesy involves monoamine oxidase inhibitors (MAOIs). Combining Raldesy with an MAOI can cause serotonin syndrome — a potentially life-threatening condition characterized by dangerously high serotonin levels.

Classic MAOIs: Phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan), selegiline (Emsam)

Atypical MAOIs: Linezolid (Zyvox) — an antibiotic with MAOI activity; intravenous methylene blue (used in some surgeries)

Raldesy is contraindicated within 14 days of stopping an MAOI. Similarly, allow at least 14 days after stopping Raldesy before starting an MAOI. If you're prescribed linezolid or methylene blue IV for any reason while on Raldesy, contact your prescriber immediately.

CYP3A4 Inhibitors: May Increase Raldesy Levels

Raldesy is metabolized primarily by the CYP3A4 liver enzyme. Medications that inhibit (slow down) CYP3A4 can cause trazodone levels in the blood to rise, increasing the risk of side effects including cardiac arrhythmias. When adding a potent CYP3A4 inhibitor, your doctor may need to reduce your Raldesy dose.

Common CYP3A4 inhibitors to discuss with your doctor:

Azole antifungals: ketoconazole, itraconazole, fluconazole

HIV protease inhibitors: ritonavir, atazanavir, lopinavir

Certain macrolide antibiotics: clarithromycin, erythromycin

Grapefruit juice: A natural CYP3A4 inhibitor — avoid large amounts while on Raldesy

CYP3A4 Inducers: May Reduce Raldesy Effectiveness

Medications that induce (speed up) CYP3A4 can lower trazodone blood levels, potentially reducing the effectiveness of Raldesy. Your doctor may need to increase your Raldesy dose if you're also taking:

Rifampin (a tuberculosis antibiotic)

Carbamazepine (Tegretol) — a seizure and mood medication

Phenytoin (Dilantin) — a seizure medication

St. John's Wort (an herbal supplement) — a CYP3A4 inducer and serotonergic agent; double risk: reduces Raldesy levels AND may increase serotonin syndrome risk

CNS Depressants: Enhanced Sedation

Raldesy can enhance the sedative effects of other central nervous system (CNS) depressants. Using Raldesy with these medications or substances increases the risk of excessive sedation, respiratory depression, and impaired coordination:

Alcohol — avoid entirely while on Raldesy

Benzodiazepines (e.g., alprazolam/Xanax, diazepam/Valium, lorazepam/Ativan)

Barbiturates (e.g., phenobarbital)

Sleep medications (e.g., zolpidem/Ambien, eszopiclone/Lunesta)

Opioids — combined sedation and respiratory depression risk

Antihistamines (e.g., diphenhydramine/Benadryl) — additive sedation

Blood Thinners and Antiplatelet Agents: Increased Bleeding Risk

Raldesy can increase the risk of bleeding when combined with drugs that affect platelet function or clotting. This is because serotonin plays a role in platelet aggregation:

Warfarin (Coumadin): Raldesy may increase or decrease prothrombin time (INR). Monitor INR carefully when starting, adjusting dose, or stopping Raldesy.

NSAIDs (e.g., ibuprofen/Advil, naproxen/Aleve, aspirin) — increased GI bleeding risk

Other anticoagulants (e.g., heparin, apixaban/Eliquis, rivaroxaban/Xarelto) — tell your doctor

Digoxin and Phenytoin: Elevated Blood Levels

Raldesy may increase blood levels of digoxin (a heart medication) and phenytoin (an anticonvulsant). If you take either of these, your doctor should monitor your levels more closely when starting or stopping Raldesy.

Serotonergic Medications: Serotonin Syndrome Risk

While Raldesy itself has a lower risk of causing serotonin syndrome compared to SSRIs (because its 5-HT2 receptor blocking activity acts as a counterweight), combining it with highly serotonergic medications at high doses requires monitoring:

Other SSRIs or SNRIs — discuss with your doctor; combining trazodone with an SSRI for sleep augmentation is common in clinical practice, but requires prescriber oversight

Tramadol — opioid with serotonergic activity; use with caution

Triptans (e.g., sumatriptan) — monitor for serotonin syndrome symptoms

What to Tell Your Doctor and Pharmacist

Before starting Raldesy, give your doctor and pharmacist a complete list of all medications you take, including:

All prescription medications (including any recently stopped)

Over-the-counter medications (NSAIDs, antihistamines, sleep aids)

Herbal supplements (especially St. John's Wort)

Alcohol and recreational substances

Any heart conditions, kidney disease, liver disease, or seizure history

For a complete overview of Raldesy's side effects, read our guide on Raldesy side effects: what to expect and when to call your doctor.