What cannot be taken with tramadol? A guide to critical drug and substance interactions

October 5, 2025 •

4 min read

With millions of prescriptions written annually in the U.S., tramadol is a widely used painkiller. However, understanding what cannot be taken with tramadol is crucial, as mixing it with certain substances can lead to severe side effects, including life-threatening complications like serotonin syndrome and respiratory depression. This guide provides a comprehensive overview of the most critical drug and substance interactions to help ensure safe use of this medication.

Quick Summary

Combining tramadol with alcohol, benzodiazepines, other opioids, certain antidepressants, or MAOIs can cause severe respiratory depression, seizures, and serotonin syndrome. Other serious interactions involve blood thinners, grapefruit, and drugs that affect tramadol's metabolism or the central nervous system.

Key Points

Avoid CNS Depressants: Never combine tramadol with alcohol, benzodiazepines (e.g., Xanax), or other opioids due to the high risk of life-threatening respiratory depression.
Prevent Serotonin Syndrome: Mixing tramadol with antidepressants like SSRIs (e.g., Prozac), SNRIs, or MAOIs can cause a dangerous buildup of serotonin.
Never Take with MAOIs: A strict 14-day washout period is required between stopping an MAOI and starting tramadol to prevent severe serotonin syndrome.
Watch for Seizure Risk: Tramadol can lower the seizure threshold; this risk increases when taken with other drugs that have the same effect, such as Bupropion.
Be Cautious with Herbal Supplements: Certain supplements, like St. John's Wort and Valerian, can interact with tramadol, increasing the risk of serotonin syndrome or sedation.
Avoid Grapefruit: Grapefruit and its juice can interfere with tramadol's metabolism, increasing drug levels and the risk of adverse effects.
Monitor Blood Thinners and Heart Meds: Combining tramadol with anticoagulants like warfarin or heart medications like digoxin requires careful monitoring due to altered drug levels and bleeding risk.

Averting Serious Complications

Tramadol is a synthetic opioid analgesic that functions by binding to opioid receptors and inhibiting the reuptake of serotonin and norepinephrine. This dual mechanism of action makes it an effective pain reliever but also increases its potential for dangerous interactions with other medications and substances. The most severe risks include extreme sedation, life-threatening respiratory depression, and serotonin syndrome. Always consult a healthcare provider or pharmacist before combining any medications or substances with tramadol.

Central Nervous System (CNS) Depressants

Mixing tramadol with other CNS depressants is extremely dangerous and can lead to overdose and death. These substances amplify the sedative effects, causing severe drowsiness, impaired coordination, and a significant slowing of breathing.

Alcohol

Risk: Additive CNS depression, leading to extreme sedation, respiratory depression, coma, and death.
Action: It is best to avoid alcohol entirely while taking tramadol.

Benzodiazepines

Examples: Alprazolam (Xanax), lorazepam (Ativan), diazepam (Valium).
Risk: Profound sedation, respiratory depression, coma, and death. The FDA has issued strong warnings about this combination.

Other Opioids

Examples: Oxycodone, hydrocodone, morphine, codeine.
Risk: Compounding opioid effects can lead to severe breathing problems and overdose. Avoid taking tramadol with other opioids unless specifically directed by a doctor.

Muscle Relaxants and Sleep Medications

Examples: Cyclobenzaprine (Flexeril), tizanidine, zolpidem (Ambien).
Risk: Increased drowsiness, dizziness, and impaired motor skills, as both affect the central nervous system.

Antihistamines

Examples: Diphenhydramine (Benadryl).
Risk: Many antihistamines, especially those that cause drowsiness, can increase the sedating effects of tramadol.

Serotonergic Agents and Serotonin Syndrome

Tramadol's effect on serotonin levels means that combining it with other serotonergic drugs can lead to a potentially life-threatening condition called serotonin syndrome. This syndrome is caused by excessive serotonin accumulation and can manifest with mental status changes, autonomic hyperactivity, and neuromuscular abnormalities.

Symptoms to watch for:

Agitation or restlessness
Confusion or hallucinations
Rapid heart rate and high blood pressure
Sweating and flushing
Muscle stiffness or tremors

Antidepressants

SSRIs: Escitalopram (Lexapro), fluoxetine (Prozac), sertraline (Zoloft).
SNRIs: Duloxetine (Cymbalta), venlafaxine (Effexor).
TCAs: Amitriptyline.

Monoamine Oxidase Inhibitors (MAOIs)

Risk: This combination is considered contraindicated and presents the highest risk for serotonin syndrome.
Action: Tramadol should not be used within 14 days of taking an MAOI (e.g., phenelzine, selegiline).

Migraine Medications (Triptans)

Examples: Sumatriptan (Imitrex).
Risk: Can contribute to serotonin syndrome, especially at high doses.

Herbal Supplements

Examples: St. John's Wort.
Risk: Can increase serotonin levels and the risk of serotonin syndrome.

Drugs Affecting Tramadol's Metabolism

The liver's cytochrome P450 enzymes (specifically CYP2D6 and CYP3A4) break down tramadol. Interactions with inhibitors or inducers of these enzymes can dangerously alter tramadol levels.

CYP2D6 and CYP3A4 Inhibitors

Examples: Bupropion (Wellbutrin), fluoxetine, ketoconazole, erythromycin.
Risk: Increase tramadol levels in the body, which can raise the risk of seizures and serotonin syndrome.

CYP2D6 and CYP3A4 Inducers

Examples: Carbamazepine, phenytoin, rifampin, St. John's Wort.
Risk: Decrease tramadol levels, potentially reducing its effectiveness.

Comparison of Major Tramadol Interactions


Interaction Type	Common Examples	Primary Risks	Severity	Action
CNS Depressants	Alcohol, Benzodiazepines (Xanax), Other Opioids, Muscle Relaxants	Respiratory depression, sedation, coma	Severe/Life-Threatening	Avoid combination entirely.
Serotonergic Drugs	SSRIs (Zoloft), MAOIs, Triptans, St. John's Wort	Serotonin syndrome, seizures	Severe/Life-Threatening	Avoid or use with extreme caution; never mix with MAOIs.
Metabolism Inhibitors	Bupropion, Fluoxetine, Ketoconazole	Increased tramadol levels, seizures, serotonin syndrome	High	Dose adjustment and close monitoring necessary.
Metabolism Inducers	Carbamazepine, Rifampin, St. John's Wort	Reduced tramadol effectiveness	Moderate/High	Dose adjustment and monitoring for pain relief.
Blood Thinners	Warfarin	Increased risk of bleeding	Moderate/High	Close monitoring of blood clotting required.

Other Important Interactions

Medications that Lower the Seizure Threshold

Tramadol itself can lower the seizure threshold, and this effect is compounded when taken with other drugs that do the same.

Examples: Bupropion, antipsychotics, cyclobenzaprine.
Risk: Increased likelihood of having a seizure.

Blood Thinners (Anticoagulants)

Examples: Warfarin.
Risk: Tramadol can increase the levels of warfarin in the body, raising the risk of bruising and bleeding.

Heart Medications

Examples: Digoxin.
Risk: Tramadol can increase digoxin levels, potentially causing digoxin toxicity.

Grapefruit and Grapefruit Juice

Risk: Grapefruit can inhibit the CYP3A4 enzyme, leading to higher-than-normal levels of tramadol in the body and an increased risk of serious side effects.
Action: Avoid consuming grapefruit and grapefruit juice while on tramadol.

Conclusion

Understanding what cannot be taken with tramadol is essential for patient safety. The risks of combining tramadol with CNS depressants, serotonergic agents, and other metabolism-affecting drugs are serious and potentially fatal. Never mix tramadol with alcohol or MAOIs, and always inform your healthcare provider of all medications, over-the-counter products, and supplements you are taking. Safe tramadol use requires a comprehensive approach to medication management and strict adherence to medical advice. If you suspect an adverse reaction, seek immediate medical help. For more information on the complexities of tramadol metabolism and interactions, refer to the FDA prescribing information.

Frequently Asked Questions

No, you should not drink alcohol while taking tramadol. The combination significantly increases the risk of extreme sedation, slowed breathing, and potentially fatal overdose.

Mixing tramadol with an antidepressant like an SSRI (e.g., Prozac, Zoloft) can lead to serotonin syndrome. This is a potentially life-threatening condition caused by an excess of serotonin in the brain. Symptoms include agitation, rapid heart rate, and muscle stiffness.

Combining tramadol with MAOIs (a class of antidepressants) is extremely dangerous and can cause severe serotonin syndrome and seizures. It's crucial to wait at least 14 days after stopping an MAOI before starting tramadol.

Yes. Avoid over-the-counter antihistamines like Benadryl (diphenhydramine) and cough suppressants containing dextromethorphan. Both can increase the risk of CNS depression and serotonin syndrome.

You should avoid St. John's Wort, as it can increase serotonin levels and raise the risk of serotonin syndrome when combined with tramadol. Always inform your doctor of any herbal supplements you are taking.

It is generally safe to take tramadol with non-opioid painkillers like acetaminophen or ibuprofen under a doctor's guidance. However, mixing it with other opioids, such as codeine, is dangerous and should be avoided.

Yes, grapefruit juice can interact with tramadol by affecting how it is metabolized in the liver. This can increase the amount of tramadol in your body and heighten the risk of side effects. Avoid grapefruit products while taking this medication.