Trazodone interactions to avoid

Trazodone is a prescription antidepressant medication approved by the U.S. Food and Drug Administration (FDA) to treat major depressive disorder, or depression, a common mental health condition. The way trazodone works is by increasing serotonin levels in the brain. It is also sometimes prescribed off-label (for non-FDA-approved use) for conditions such as insomnia, anxiety, or fibromyalgia. Trazodone is a generic medication. It’s often referred to by the brand names Desyrel or Oleptro, but the brand name formulations are no longer available in the United States. 

Data as of 2020 shows that trazodone is the 21st most popularly prescribed medication in the U.S., with over five million patients filling more than 26 million prescriptions. When taking this medication, it is important to be aware of drug interactions that can affect how effective the medication is or cause a worsening of adverse effects. Continue reading to learn more about trazodone interactions.

Key takeaways:

• Trazodone interacts with various drugs, including other drugs that affect serotonin levels, blood thinners, drugs that cause central nervous system (CNS) depression, and others.
• Depending on the specific interaction, various effects could occur, such as serotonin syndrome or increased side effects of trazodone. 
• Always consult a healthcare provider regarding possible trazodone interactions to ensure this medication is taken as safely as possible.

Trazodone drug interactions

Trazodone interacts with various medications, and the mechanism by which they interact varies based on each category. Some of these medications are in two categories, as they can interact with trazodone in multiple ways.

Drugs that increase the risk of serotonin syndrome

Serotonin syndrome is a condition caused by the buildup of excess serotonin levels. Serotonin syndrome may occur if one takes more than one medicine that affects serotonin levels, if too much medication that increases serotonin levels is taken, or if starting or increasing the dose of a medication that increases serotonin levels. Symptoms of serotonin syndrome may include agitation, anxiety, restlessness, mood changes, confusion, incoordination, sweating, overheating, increased heart rate or blood pressure, nausea, vomiting, diarrhea, shaking, dilated pupils, and muscle stiffness. Serotonin syndrome is a medical emergency. It may start mild but can progress quickly to death if untreated. If symptoms of serotonin syndrome occur, get emergency medical help. 

Because trazodone increases serotonin levels, other drugs that affect serotonin levels can interact with trazodone. Monoamine oxidase inhibitors (MAO inhibitors or MAOIs), in particular, are contraindicated and should never be used in people who take trazodone. Some examples of MAOIs include Zyvox (linezolid), Marplan (isocarboxazid), Nardil (phenelzine), Eldepryl (selegiline), Parnate (tranylcypromine), and methylene blue. 

Other drugs can also increase serotonin levels. This does not always mean the combination needs to be avoided. However, the healthcare provider will determine if the combination with trazodone is safe. If one of these medications is taken with trazodone, the patient will be closely monitored for signs of serotonin syndrome. 

Examples of other medications that can increase serotonin levels include but are not limited to:

• Selective serotonin reuptake inhibitors (SSRIs) such as Lexapro (escitalopram), Prozac (fluoxetine), or Zoloft (sertraline)
• Serotonin and norepinephrine reuptake inhibitors (SNRIs) such as Cymbalta (duloxetine) or Effexor (venlafaxine)
• Tricyclic antidepressants such as Elavil (amitriptyline) or Pamelor (nortriptyline)
• Triptans for migraine, including Imitrex (sumatriptan)
• Mood stabilizers such as lithium
• Anxiolytics such as Buspar (buspirone Hcl)
• Opioid pain medications such as Ultram (tramadol), fentanyl and oxycodone
• Supplements such as L-Tryptophan and St. John’s wort

Drugs that increase bleeding risk

Taking a blood thinner with trazodone increases the risk of bleeding. Patients who take trazodone with a blood thinner will be carefully monitored. Examples of blood thinners include:

• Coumadin (warfarin)
• Eliquis (apixaban)
• Plavix (clopidogrel)
• Pradaxa (dabigatran)
• Xarelto (rivaroxaban)

Enzyme inhibitors

Many drugs, including trazodone, are processed in the body by an enzyme called cytochrome P450 3A4 (CYP3A4). Certain drugs inhibit this enzyme, slowing the processing of trazodone. The effect is a higher level of trazodone in the body, which could lead to increased side effects, including blurred vision, constipation, dry mouth, priapism (prolonged, painful erection), drowsiness, lightheadedness, and heart rhythm problems. The prescribing information recommends using a lower dose of trazodone if a strong CYP3A4 inhibitor must be taken. Examples of these drugs include:

• Biaxin (clarithromycin)
• Erythromycin
• Nizoral (ketoconazole)
• Sporanox (itraconazole)

Enzyme inducers

While enzyme inhibitors mentioned above slow down the processing of trazodone, enzyme inducers have the opposite effect. They speed up how fast trazodone is processed in the body. This means a higher dose of trazodone may be required. The patient will be monitored carefully if an enzyme inducer is combined with trazodone. Examples of these medications include:

• Dilantin (phenytoin)
• Rifampin
• St. John’s wort (dietary supplement)
• Tegretol (carbamazepine)

Drugs with a narrow therapeutic index

Some drugs have what is called a narrow therapeutic index. This means that a small change in dose or blood levels can lead to toxicity or other complications. Narrow therapeutic drugs that interact with trazodone include Lanoxin (digoxin) and Dilantin (phenytoin). The interactions involve trazodone acting on these narrow therapeutic drugs, increasing their blood levels, which may cause side effects or toxicity. Patients who take one of these medications with trazodone will be carefully and regularly monitored. A lower dose of digoxin or phenytoin may be required. 

Drugs and substances that cause central nervous system (CNS) depression

Trazodone (as well as many other medications) causes central nervous system (CNS) depression, slowing down nervous system activity. While this activity helps treat certain conditions, too much CNS depression can cause impairment, extreme sedation, slowed breathing, loss of consciousness, coma, or even death. Trazodone combined with another CNS depressant can have an additive effect. Ask a healthcare provider about this interaction if any other CNS depressants are being taken. It’s also a good idea to ask about safe alcohol consumption if consuming alcohol. Some cough and cold medications contain an antihistamine (or a small amount of alcohol), which can cause CNS depression, so check with the pharmacist or healthcare provider before taking any prescription or over-the-counter (OTC) cough and cold medications. Examples of drugs and substances that cause CNS depression include: 

• Alcohol
• Anxiety medications like Xanax (alprazolam) or Valium (diazepam)
• Barbiturates such as phenobarbital
• Certain antihistamines, like Benadryl (diphenhydramine)
• Muscle relaxants such as Flexeril (cyclobenzaprine)
• Opioid pain medications such as Percocet (oxycodone/acetaminophen)
• Sleep medications such as Ambien (zolpidem)

Drugs that can affect heart rhythm

Trazodone can affect the heart rhythm, causing QT prolongation, and if taken with another drug that affects heart rhythm, it could increase the risk of irregular heartbeat. Patients at high risk for heart rhythm conditions should not take trazodone. Trazodone should not be taken with drugs that affect the heart rhythm. Examples of medications that can affect heart rhythm when combined with trazodone include:

• Betapace (sotalol)
• Chlorpromazine
• Cordarone (amiodarone)
• Geodon (ziprasidone)
• Norpace (disopyramide)
• Procainamide
• Quinidine
• Thioridazine

Trazodone-food interactions

Trazodone and grapefruit 

Grapefruit and grapefruit juice products (including any type of juice that contains grapefruit) act as an enzyme inhibitor, which can increase trazodone levels in the body. Ask a healthcare provider how much, if any, grapefruit can be consumed while taking trazodone.

Trazodone and other interactions

Trazodone and alcohol 

As discussed above, trazodone and alcohol both cause CNS depression. Combining the two can increase the risk of serious side effects or complications, including impairment, extreme sedation, slowed breathing, loss of consciousness, coma, or even death. Consult a healthcare professional about alcohol consumption. 

Trazodone and caffeine 

Trazodone causes increased sedation, and caffeine causes decreased sedation. While the effect is unclear, check with a healthcare provider about caffeine consumption while taking trazodone.

Trazodone and dietary supplements

Combining trazodone with certain dietary supplements, such as St. John’s wort or tryptophan, can increase the risk of serotonin syndrome. Check with the pharmacist or healthcare provider before starting any dietary supplement.

Trazodone and marijuana

Marijuana may increase the trazodone levels and effects. Both cause sedation. Consult a healthcare provider if marijuana is also being used.

Trazodone and illicit drugs

Combining trazodone with an illicit drug such as LSD or cocaine could increase the risk of toxicity and serotonin syndrome. 

How to minimize trazodone interactions

Trazodone has many potential interactions but can still be taken safely with some precautions. 

Always talk to a healthcare provider before starting a new medication. Before taking trazodone, make sure the provider is aware of any medical conditions, including:

• Liver or kidney problems
• Heart problems (such as heart disease or a heart rhythm condition) or a recent heart attack
• A blood clotting disorder
• Seizures
• Glaucoma
• Suicidal thoughts
• Substance use disorder
• Bipolar disorder 

If pregnant or breastfeeding, always consult a healthcare provider. Inform the doctor of any medical history, history of any allergic reaction to medicine, and all medications being taken, including Rx and OTC drugs, vitamins, and supplements. 

A healthcare provider may need to change the medication or adjust a dosage in case of a possible interaction. Always take the medication as directed by a healthcare provider. 

While taking trazodone, be aware of potential warning signs of drug interactions, such as the serotonin syndrome symptoms described above or symptoms of CNS depression. Ask a healthcare provider if there are any questions about drug interactions. 

When to talk to a healthcare provider about trazodone interactions

This article lists various drug interactions but is not a complete list of all possible trazodone interactions. It is important to tell a healthcare provider about all medications being taken (including prescription drugs, OTC medicines, vitamins, and supplements) and medical conditions to ensure proper management and monitoring. While taking trazodone, do not start any new medications unless a healthcare provider approves.