Can you take amitriptyline with wellbutrin? Understanding the Major Drug Interaction

October 10, 2025 •

3 min read

According to reputable sources like Drugs.com, combining amitriptyline and Wellbutrin (bupropion) is a major, highly clinically significant drug interaction that typically requires avoidance. Therefore, the critical question, "Can you take amitriptyline with wellbutrin?", must be addressed with extreme caution and professional medical guidance due to the potential for severe health complications.

Quick Summary

Taking amitriptyline and Wellbutrin together is generally discouraged because of a significant drug interaction that can elevate seizure risk and increase side effects. This is primarily due to Wellbutrin's effect on the metabolic enzyme CYP2D6, which affects how the body processes amitriptyline. Patients should never combine these medications without strict medical supervision.

Key Points

Major Interaction: Combining amitriptyline and Wellbutrin (bupropion) is a major, highly significant drug interaction that is generally advised against due to safety concerns.
Increased Seizure Risk: Both medications independently lower the seizure threshold, and taking them together creates an additive risk, significantly increasing the potential for seizures.
CYP2D6 Inhibition: Wellbutrin inhibits the CYP2D6 enzyme, which is responsible for metabolizing amitriptyline. This leads to increased levels of amitriptyline in the body, intensifying its effects and side effects.
Enhanced Side Effects: The combination can cause or worsen neuropsychiatric and cardiovascular side effects, such as increased anxiety, agitation, uneven heartbeats, and elevated blood pressure.
Required Medical Supervision: This combination should never be used without strict medical supervision, and is contraindicated in patients with a history of seizures, uncontrolled hypertension, or glaucoma.
Consult Your Doctor: Always discuss all medications, including supplements and herbs, with your doctor to ensure a safe treatment plan and avoid dangerous drug interactions.

Combining certain medications can have dangerous consequences, and the interaction between the tricyclic antidepressant (TCA) amitriptyline and the norepinephrine-dopamine reuptake inhibitor (NDRI) bupropion (sold under the brand name Wellbutrin) is one of significant concern. Both medications are used to treat depression and other conditions, but their distinct pharmacological profiles create a hazardous combination. The risks are so pronounced that medical professionals typically advise against this combination, and when it is considered necessary, it is only under special circumstances with stringent medical oversight.

The Significant Risks of Combining Amitriptyline and Wellbutrin

One of the most critical dangers of taking amitriptyline and Wellbutrin concurrently is the increased risk of seizures. Both medications independently lower the seizure threshold, and when taken together, this effect is cumulative, significantly increasing the likelihood of a seizure.

Beyond the seizure risk, the combination can lead to a host of other serious adverse effects, including increased neuropsychiatric effects like heightened anxiety, agitation, confusion, or insomnia, and cardiovascular complications such as uneven heartbeats or uncontrolled hypertension. The combination can also amplify the typical side effects associated with each drug, such as extreme drowsiness, blurred vision, dry mouth, or vomiting.

The Pharmacological Interaction: Why It Happens

Bupropion is a potent inhibitor of the cytochrome P450 2D6 (CYP2D6) enzyme. This enzyme metabolizes many other drugs, including amitriptyline. When Wellbutrin inhibits CYP2D6, the body cannot metabolize amitriptyline as quickly, causing its concentration in the bloodstream to build up to potentially toxic levels and intensifying its adverse effects.

Signs and Symptoms of a Dangerous Interaction

Patients taking or considering this combination must be aware of warning signs requiring immediate medical attention. These include:

Seizures
Extreme drowsiness or confusion
Agitation or restlessness
Vomiting
Blurred vision
Sweating
Muscle stiffness
Feeling light-headed or dizzy
Uneven or rapid heartbeats

Comparison of Amitriptyline and Wellbutrin (Bupropion)


Feature	Amitriptyline (TCA)	Wellbutrin (Bupropion)	Combined Interaction Profile
Mechanism	Inhibits reuptake of norepinephrine and serotonin. Also has strong anticholinergic effects.	Inhibits reuptake of norepinephrine and dopamine, with stimulant properties.	Heightened risk due to different mechanisms and overlapping side effects.
Primary Uses	Depression, nerve pain, migraines.	Major Depressive Disorder (MDD), Seasonal Affective Disorder (SAD), Smoking cessation.	Risk of unpredictable effects due to complex interaction.
Key Risks	Sedation, anticholinergic effects (dry mouth, blurred vision), heart problems.	Seizure risk, anxiety, agitation, insomnia, hypertension.	Additive seizure risk, increased cardiovascular and neuropsychiatric side effects, and potential toxicity.
Metabolism	Metabolized significantly by the CYP2D6 enzyme.	Strong inhibitor of the CYP2D6 enzyme.	Wellbutrin inhibits the metabolism of amitriptyline, causing dangerously high levels of amitriptyline in the body.

What to Do If You Are on Both Medications

If you are taking both medications, do not stop abruptly. If a specialist has prescribed this combination cautiously, strict monitoring is essential, potentially involving lower doses, regular blood pressure and heart rate checks, and vigilance for any signs of increased anxiety, agitation, insomnia, or seizure activity. For most individuals, safer alternatives are recommended.

Conclusion: Prioritizing Your Safety

Combining amitriptyline and Wellbutrin is a high-risk interaction that should be avoided by most patients. The potential for seizures, cardiovascular problems, and intensified side effects is significant. While rare clinical scenarios might warrant specialized oversight, the danger of coadministration is widely recognized. Always have an open conversation with your healthcare provider about all medications you are taking. Patient safety is paramount, and a knowledgeable physician is crucial for navigating drug interactions. For more information, consult a pharmacist or reputable online resources like Drugs.com.

Frequently Asked Questions

The primary danger is a significantly increased risk of seizures, as both medications lower the seizure threshold in the brain. This is compounded by Wellbutrin's inhibition of the CYP2D6 enzyme, which can lead to dangerously high levels of amitriptyline.

Wellbutrin (bupropion) is a strong inhibitor of the enzyme CYP2D6. This enzyme is crucial for the metabolism of amitriptyline. By inhibiting CYP2D6, Wellbutrin prevents the body from clearing amitriptyline effectively, causing its levels to rise and increasing its effects and potential toxicity.

When combined, side effects like anxiety, agitation, insomnia, increased blood pressure, and uneven heartbeats can be amplified. You may also experience extreme drowsiness, confusion, vomiting, or blurred vision.

While a specialist might consider the combination in very specific, rare circumstances, it is not a standard practice. It would require starting with very low doses and involve extremely close monitoring of the patient's blood pressure, heart rate, and overall mental state.

Yes, the combination should be absolutely avoided in patients with a history of seizures or seizure disorders, uncontrolled high blood pressure, and closed-angle glaucoma.

Do not stop taking either medication suddenly. Contact your prescribing healthcare provider immediately to discuss your medication regimen. They can assess your individual risk and determine a safer course of action, which may involve switching to an alternative medication.

Transitioning between these medications must be done under strict medical supervision. Due to the potential for significant drug interactions, a healthcare provider will carefully manage the transition to minimize risks and ensure proper clearance of the first medication before starting the second.