5 Amitriptyline Interactions to Watch Out for

Amitriptyline is an antidepressant medication. It’s in a group of medications called tricyclic antidepressants (TCAs). It’s FDA approved to treat depression, but it’s not used as often as other antidepressants. It’s more likely to cause side effects than other antidepressants, like selective serotonin reuptake inhibitors (SSRIs). But it's sometimes used off-label for other medical conditions. This includes anxiety, insomnia, and nerve pain (neuropathy).

If you've been prescribed amitriptyline, you should be aware of possible drug interactions. We’ll talk about some of these interactions below, but it’s not a complete list. Talk with your healthcare provider and pharmacist before taking amitriptyline. They can check for possible amitriptyline interactions and make sure it’s safe for you to take.

1. Medications that raise serotonin levels

Serotonin affects many body functions, including sleep, mood, and bowel movements. TCAs like amitriptyline raise serotonin levels. But too much serotonin can be dangerous and lead to serotonin syndrome. Luckily, this condition is very rare. It’s most likely to happen if you take multiple medications that raise serotonin levels (at high doses).

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Often, symptoms of serotonin syndrome are mild. They include sweating and tremor. But symptoms can also be serious. If you experience extremely high blood pressure, agitation, or a high fever, seek immediate medical care.

Besides amitriptyline, examples of medications and supplements that raise serotonin levels include:

• SSRIs like escitalopram (Lexapro)

• Serotonin and norepinephrine reuptake inhibitors (SNRIs) like duloxetine (Cymbalta)

• Monoamine oxidase inhibitors (MAOIs) like selegiline (Zelapar, Emsam)

• Linezolid (Zyvox)

• Tramadol (Ultram, ConZip)

• St. John’s wort 

Talk to your healthcare provider before taking amitriptyline with any of these medications. They may recommend monitoring for signs of serotonin syndrome. Or they may recommend avoiding amitriptyline or the interacting medication. 

This is especially true if you’re taking an MAOI. Amitriptyline and MAOIs shouldn’t be used together. In fact, if you're prescribed amitriptyline, talk to your provider about how to stop your MAOI. You shouldn’t start amitriptyline within 2 weeks of taking an MAOI.

2. Medications and substances that cause sedation

Many medications, including amitriptyline, have sedative effects. This means that they slow down brain activity and cause drowsiness. Sometimes this is helpful. For example, some people with depression may have trouble sleeping. Since amitriptyline causes sedation, it can help with this symptom of depression. 

Combining multiple medications that cause sedation can have dangerous effects. This includes confusion, slowed breathing, and even death. Medications that have sedative effects include:

• Opioids like hydrocodone/acetaminophen

• Benzodiazepines like alprazolam (Xanax)

• Sleep medications like zolpidem (Ambien, Edluar, ZolpiMist)

• Barbiturates like phenobarbital

• Muscle relaxants like baclofen

• Diphenhydramine (Benadryl)

• Alcohol

Tell your healthcare provider if you’re taking medications that have sedative effects. And make sure to let them know if you drink alcohol, especially in large quantities. They may avoid prescribing amitriptyline or suggest a lower dose. 

Pay special attention to how you feel after starting amitriptyline. It’s best to avoid activities that require alertness until you see how it affects you. This includes things like driving or operating heavy machinery. Let your healthcare provider know if you feel especially tired or dizzy. If you’re having trouble breathing or feeling confused, seek emergency medical care.

3. Medications that affect amitriptyline metabolism

Amitriptyline is metabolized (broken down) by proteins (enzymes) in the liver. Certain medications and substances can block these proteins. This prevents amitriptyline from being metabolized as it normally would. This can cause higher levels of amitriptyline in the body and more side effects. These side effects might include drowsiness, dizziness, or nausea. More serious side effects could include falls and heart problems.

Medications that can block amitriptyline metabolism include other antidepressants like paroxetine (Paxil) and fluoxetine (Prozac). Cimetidine (Tagamet HB) and quinidine can also increase amitriptyline levels. It’s also possible that topiramate (Topamax) and disulfiram can raise levels of amitriptyline. 

It can be hard to know which medications affect amitriptyline metabolism. Give your provider and pharmacist a list of your medications before starting amitriptyline. They can help you check for potential interactions.

If you take a medication that increases amitriptyline levels, you may need a lower dose of amitriptyline. Or you may need a lower dose of the interacting medication. But don’t make any changes to your medications without talking to your provider first.

4. Anticholinergic medications

Anticholinergic medications block a chemical called acetylcholine in the body. Acetylcholine helps your muscles and brain work effectively. Anticholinergic examples include oxybutynin (Ditropan XL), scopolamine (Transderm Scop), and dicyclomine.

Many other medications have anticholinergic properties. This means they also act on acetylcholine, but it’s usually not why they’re used. Examples include some TCAs (like amitriptyline) and antipsychotics. Antipsychotics can have anticholinergic side effects. Anticholinergic side effects include constipation, dry mouth, and trouble urinating. It can also cause you to sweat less, making it easier to overheat. 

Taking more than one medication with anticholinergic properties can worsen the side effects mentioned above. For example, severe constipation can lead to bowel obstruction (a blockage in the intestine). And anticholinergic toxicity can also occur. A few classic symptoms include skin flushing, fever, and dilated pupils. This can be life-threatening, especially if your fever gets extremely high.

If you take any anticholinergic medications, your healthcare provider may suggest avoiding amitriptyline. Or they may suggest starting at a lower dose. If amitriptyline is necessary for you, you should watch closely for anticholinergic side effects.

5. Medications that lower the seizure threshold

Some medications, like amitriptyline, can make it more likely to have a seizure. This effect is not common at usual doses of amitriptyline. But at much higher doses, the risk of seizure increases. The risk is also greater if you have had seizures in the past.

Combining amitriptyline with other medications that raise the seizure risk can be dangerous. Examples of medications that raise the risk of seizures include:

• Other tricyclic antidepressants like imipramine (Tofranil)

• Antipsychotics like clozapine (Clozaril)

• Diphenhydramine

• Bupropion (Wellbutrin SR, Wellbutrin XL)

• Tramadol

Before taking amitriptyline, tell your healthcare provider if you’ve had seizures before. And let them know all the other medications you take, including over-the-counter products and supplements. They may recommend an alternative to amitriptyline if your risk of seizures is high. Or they may recommend close monitoring for seizures. Symptoms to watch for include trouble speaking or breathing, jerky movements, and tingling sensations.

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Written by:

Austin Ulrich, PharmD, BCACP

Austin Ulrich, PharmD, BCACP, is a board-certified ambulatory care clinical pharmacist. In his early career, he provided direct patient care in a variety of settings, including hospital and community pharmacies, and in a primary care clinic as a clinical pharmacist.

Edited by:

Amy B. Gragnolati, PharmD, BCPS

Amy Gragnolati, PharmD, BCPS, is a pharmacy editor for GoodRx. Amy currently holds her pharmacist license in Georgia and California.

Reviewed by:

Joshua Murdock, PharmD, BCBBS

Joshua Murdock, PharmD, BCBBS, is a licensed pharmacist in Arizona, Colorado, and Rhode Island. He has worked in the pharmacy industry for more than 10 years and currently serves as a pharmacy editor for GoodRx.

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