Trazodone Interactions with Other Drugs

Legacy Healing Center Blog

Trazodone is a medication commonly prescribed for depression as well as insomnia. Taking trazodone with other drugs or substances, however, can lead to serious side effects. As one of the leading rehab providers in the country, Legacy Healing Center discusses what you should know about mixing trazodone with different drugs.

Common Trazodone Interactions with Medications

Trazodone can interact with several types of medications and substances, which may increase the risk of serious side effects.

Central Nervous System Depressants

Benzodiazepines (e.g., diazepam, lorazepam)
Opioids (e.g., morphine, oxycodone)
Barbiturates (e.g., phenobarbital)
Alcohol

Combining trazodone with other CNS depressants can enhance its sedative effects, causing increased sedation, drowsiness, respiratory depression, and risk of overdose.

Other Antidepressants

SSRIs (e.g., fluoxetine, sertraline)
SNRIs (e.g., venlafaxine, duloxetine)
MAOIs (e.g., phenelzine, tranylcypromine)
Tricyclic antidepressants (e.g., amitriptyline)

Combining trazodone with other serotonergic drugs (especially MAOIs) increases the risk of serotonin syndrome—a potentially life-threatening condition. A study published in Frontiers in Pharmacology highlighted that combining trazodone with SSRIs may lead to serotonin syndrome, emphasizing the need for careful monitoring when these medications are co-prescribed.¹ Symptoms can include confusion, agitation, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, or seizures.

Antifungal Medications

Ketoconazole
Itraconazole

These drugs can inhibit the metabolism of trazodone, leading to higher blood levels of trazodone. This increases the risk of side effects like sedation, hypotension, or arrhythmias.

Anticonvulsants

Carbamazepine
Phenytoin

These drugs can decrease the effectiveness of trazodone by increasing its metabolism in the liver. A study in Frontiers in Psychiatry found that trazodone did not significantly impair cognitive function in healthy adults, suggesting its relative safety in this regard. 2>This means there are fewer antidepressant or sedative effects, defeating the purpose of taking this medication in the first place.

Anticoagulants

Warfarin

Trazodone may enhance the anticoagulant effect of warfarin, increasing the risk of bleeding. Regular monitoring of blood clotting parameters, such as INR, is recommended.

Blood Pressure Medications

Alpha blockers (e.g., doxazosin)
Beta-blockers (e.g., propranolol)
Calcium channel blockers (e.g., amlodipine)

Trazodone may add to the blood pressure-lowering effects of these medications, leading to hypotension (low blood pressure), dizziness, or fainting, especially when standing up quickly.

Other Drugs Affecting the Liver

CYP3A4 Inhibitors (e.g., grapefruit juice, certain HIV medications, some antibiotics like erythromycin)

Inhibition of the enzyme CYP3A4 can increase trazodone levels in the body, leading to an increased risk of side effects like drowsiness, hypotension, and arrhythmias.

Drugs That Affect Heart Rhythm

Antiarrhythmic drugs (e.g., amiodarone, quinidine)
Certain antipsychotics (e.g., haloperidol)

Trazodone can prolong the QT interval (a heart rhythm measure). Combining it with other drugs that have this effect increases the risk of serious arrhythmias.

St. John’s Wort

An herbal supplement often used for depression

It can increase the metabolism of trazodone, reducing its effectiveness. There is also a potential risk of serotonin syndrome if both are used together.

Other Drugs That Can Lower Seizure Threshold

Antipsychotics (e.g., haloperidol)
Tricyclic antidepressants (e.g., amitriptyline)

Trazodone can lower the seizure threshold; combining it with other drugs that do the same increases the risk of seizures.

Monitoring Trazodone Interactions with Other Drugs

Consult your doctor before starting or stopping any medications, especially if you are taking other CNS depressants, serotonergic drugs, or heart rhythm-altering medications. Dose adjustments may be needed if trazodone is combined with certain drugs to avoid excessive sedation, serotonin syndrome, or cardiovascular complications.

How to Discontinue Use of Multiple Medications

The discontinuation process could be more complex for those taking trazodone with other drugs. Stopping multiple medications at once could lead to heightened withdrawal symptoms, serotonin syndrome, or other complications, particularly if there are withdrawal effects from the other drugs involved.

While medical detox specifically refers to managing withdrawal from substances like alcohol, opioids, or benzodiazepines, those who are discontinuing trazodone in combination with other medications should still be monitored for adverse reactions or withdrawal symptoms.

For individuals who have been using multiple drugs that may have overlapping effects on the brain or nervous system, medical professionals may recommend supervised withdrawal or short-term inpatient care to ensure safe discontinuation, particularly in cases of multiple medications or co-occurring medical conditions.

Support at Legacy Healing Center

If you or a loved one is working to manage trazodone use or any other medications, Legacy Healing Center can help. We offer drug and alcohol treatment and addiction therapy programs that are designed to support recovery in a safe, understanding environment. Our team can guide you in exploring safer medication options and provide the support you need on your journey. Reach out to Legacy Healing Center to find out more about how we can help with medication safety and lasting recovery. Our addiction treatment blog offers more insights into recovery options and living a fulfilling sober life.

Sources

Dudek D, Chrobak AA, Krupa AJ, et al. Ted-Trazodone Effectiveness in depression: A naturalistic study of the effeciveness of Trazodone in extended release formulation compared to ssris in patients with a major depressive disorder. Frontiers. October 13, 2023. Accessed January 3, 2025. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1296639/full.
Wang J, Liu S, Zhao C, et al. Effects of trazodone on sleep quality and cognitive function in arteriosclerotic cerebral small vessel disease comorbid with chronic insomnia. Frontiers. June 15, 2020. Accessed January 3, 2025. https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2020.00620/full.