Amitriptyline interactions to avoid

Drug interactions | Food interactions | Other interactions | Avoiding interactions | When to see a doctor

Amitriptyline (Envil) is a tricyclic antidepressant approved by the U.S. Food and Drug Administration (FDA) to treat depression. Amitriptyline interacts with grapefruit, some supplements, drugs that increase serotonin levels, drugs that cause central nervous system (CNS) depression, medicines that decrease the seizure threshold, and other medications. These interactions can cause or worsen side effects, such as dizziness, sedation, and orthostatic hypotension. Awareness of these interactions is important, as they can also affect amitriptyline’s effectiveness.

Amitriptyline drug interactions

Amitriptyline interacts with various medications. The mechanism by which they interact varies based on each category. You will even see some of these medicines in two categories, meaning they can interact with amitriptyline in multiple ways.

Drugs that increase the risk of serotonin syndrome

Serotonin syndrome is a condition caused by serotonin levels that are too high. While an appropriate amount of serotonin is associated with calmness and happiness, too much serotonin can be dangerous. Some instances where serotonin syndrome may occur include:

• If you take more than one medication that affects serotonin levels
• If you take too much of a medicine that increases serotonin levels (either on purpose or by accident)
• If you start taking—or increase the dose of—a drug that increases serotonin levels 

Serotonin syndrome is a medical emergency. Symptoms may start mild but can progress quickly to death if left untreated. If you have any symptoms of serotonin syndrome, get emergency medical help right away. Serotonin syndrome symptoms may include anxiety, agitation, restlessness, mood changes, confusion, incoordination, sweating or overheating, fast heart rate, high blood pressure, shaking, dilated pupils, stiff muscles, or stomach problems like nausea, vomiting, and diarrhea. 

Because amitriptyline increases serotonin levels, other medicines that affect serotonin have the potential to interact with amitriptyline. Monoamine oxidase inhibitors (MAO inhibitors, or MAOIs), in particular, are contraindicated (should never be used) in people who take amitriptyline. At least 14 days must pass between using an MAOI and using amitriptyline. Examples of MAOIs include: 

• Zyvox (linezolid)
• Marplan (isocarboxazid)
• Nardil (phenelzine)
• Eldepryl (selegiline)
• Parnate (tranylcypromine),
• Methylene blue. 

Many other medications also increase serotonin levels. This does not always mean the combination needs to be avoided. The healthcare provider will determine if the combination with amitriptyline is safe. If one of these medications is taken with amitriptyline, the patient will be closely monitored for serotonin syndrome symptoms. 

Some examples of medications that affect serotonin levels include but are not limited to:

• Selective serotonin reuptake inhibitors (SSRIs) such as Lexapro (escitalopram), Prozac (fluoxetine), Celexa (citalopram), or Zoloft (sertraline)
• Serotonin and norepinephrine reuptake inhibitors (SNRIs) such as Cymbalta (duloxetine) or Effexor (venlafaxine)
• Other tricyclic antidepressants such as Pamelor (nortriptyline) or Tofranil (imipramine)
• Triptans for migraine such as Imitrex (sumatriptan) or Maxalt (rizatriptan)
• Lithium
• Opioid pain medicines like Ultram (tramadol), fentanyl, or OxyContin (oxycodone)
• BuSpar (buspirone)
• The dietary supplements tryptophan and St. John’s wort
• The cough suppressant dextromethorphan 

Drugs that cause CNS depression

Central nervous system (CNS) depression is a slowing down of brain activity. Certain drugs, such as medications that help you sleep, anxiety medications, and pain medications, cause CNS depression. While doing so may be useful to how they work (for example, insomnia medications slow down the nervous system, which causes relaxation and helps you sleep), too much CNS depression can cause complications. These can range from extreme sedation and motor impairment to slowed breathing, loss of consciousness, coma, and death in severe cases. Combining two medications that cause CNS depression can be dangerous. Because alcohol can also cause CNS depression, you should ask your healthcare professional about safe alcohol consumption if you drink alcohol. Certain cough, cold, and flu medications contain an antihistamine—and a small amount of alcohol—which can also cause CNS depression. Consult a pharmacist or healthcare provider before taking any OTC or prescription cough, cold, or flu medications while taking amitriptyline. 

Some examples of drugs and substances that cause CNS depression include but are not limited to: 

• Alcohol
• Anti-anxiety medications like Xanax (alprazolam) or Valium (diazepam)
• Barbiturates such as phenobarbital
• First-generation antihistamines, like Benadryl (diphenhydramine)
• Muscle relaxants such as Flexeril (cyclobenzaprine) or Skelaxin (metaxalone)
• Opioid pain medications such as Percocet (oxycodone/acetaminophen) or Ultram (tramadol)
• Insomnia medications such as Ambien (zolpidem) or Sonata (zaleplon)

Drugs that increase the QT interval

Amitriptyline can affect heart rate and rhythm and cause QT prolongation. QT prolongation is a heart rhythm condition that can cause fast and chaotic heartbeats. Because amitriptyline can cause QT prolongation, it will generally not be prescribed with other drugs that can cause QT prolongation. Examples of these drugs include:

• Norpace (disopyramide)
• Ibutilide
• Indapamide
• Pentamidine
• Pimozide
• Procainamide
• Quinidine
• Sotalol

Drugs that increase amitriptyline levels

Cytochrome P450 2D6 is an enzyme that processes amitriptyline in the body. Some individuals are known as “poor metabolizers,” which means that this enzyme does not work as well in processing certain medications like amitriptyline. So, even with a normal dose, someone who is a poor metabolizer may have high levels of amitriptyline in the body, which could lead to worsened side effects or toxicity. In addition to people who are poor metabolizers, certain drugs affect the 2D6 enzyme, which can lead to worsened side effects or toxicity. Some examples of these medications include:

• Phenothiazine drugs such as Compazine (prochlorperazine)
• Quinidine
• SSRI antidepressants such as Paxil (paroxetine), Prozac (fluoxetine), and Zoloft (sertraline)
• Tagamet (cimetidine)
• Type 1C antiarrhythmics (drugs used for arrhythmias, or irregular heartbeat) such as propafenone and flecainide
• Topamax (topiramate) can also cause an increase in amitriptyline levels. 

If one of these medications must be combined with amitriptyline, the healthcare provider will generally prescribe a lower amitriptyline dose and monitor lab work closely. 

Anticholinergic drugs 

Anticholinergic drugs work by blocking a neurotransmitter (chemical messenger) called acetylcholine. Amitriptyline is known for its anticholinergic side effects, which include:

• Fast heart rate
• Problems urinating
• Constipation
• Dry mouth
• Blurred vision
• Worsening of glaucoma
• Difficulty thinking
• Confusion
• Sedation and drowsiness
• Delirium

These effects are worse in older adults and can contribute to falls. Older adults who take amitriptyline will be started at a low dose. 

If amitriptyline is combined with another drug that has similar anticholinergic effects, there is an increased risk for adverse reactions (including paralytic ileus, which is a paralysis of muscles in the intestines) and toxicity. Close monitoring and careful dosing are required. 

If you take an anticholinergic drug, be sure to consult your healthcare provider for medical advice before taking amitriptyline. Some examples of other anticholinergic drugs include:

• Benadryl (diphenhydramine) and other first-generation antihistamines
• Bentyl (dicyclomine)
• Cogentin (benztropine)
• Detrol (tolterodine)
• Ditropan (oxybutynin)
• Enablex (darifenacin)
• Glycopyrrolate
• Transderm-Scop (scopolamine)
• Vesicare (solifenacin)

Drugs that decrease the seizure threshold

Amitriptyline can decrease the seizure threshold, meaning that it can increase the risk of having a seizure. The risk increases with higher amitriptyline doses. The prescribing information notes that amitriptyline should be used with caution in individuals with a history of seizures. People who take other medications that lower the seizure threshold should consult their healthcare provider before using amitriptyline. Some examples of drugs that lower the seizure threshold include

• Other tricyclic antidepressants (TCAs)
• Ultram (tramadol)
• Wellbutrin (bupropion), and other medications that contain bupropion, such as Contrave and Auvelity

Amitriptyline food interactions

In addition to drug-drug interactions, we will review other interactions, starting with foods.

Amitriptyline and grapefruit 

Combining amitriptyline with grapefruit juice can increase amitriptyline levels in the body, which can lead to serious side effects and toxicity. This includes grapefruit, grapefruit juice, and any other juices that contain grapefruit as an ingredient. If you regularly consume grapefruit, consult your healthcare provider for advice.

Other amitriptyline interactions

In addition to drug-drug interactions, there are also some other interactions to consider.

Amitriptyline and alcohol 

When taking amitriptyline, you should avoid alcohol. As mentioned above, alcohol is a CNS depressant and can increase sedation caused by amitriptyline. In severe cases, it can cause breathing problems, coma, or death. Additionally, the prescribing information notes that amitriptyline may enhance the response to alcohol, and for those who consume excess alcohol, this means that taking amitriptyline can make the effects of alcohol stronger. And, if a person overdoses on the medication or tries to harm themselves, the risk of serious harm or death may be higher.

Amitriptyline and caffeine

Amitriptyline and caffeine may work against each other. Amitriptyline increases sedation, while caffeine has the opposite effect. This interaction’s effect is unclear, so consult your healthcare provider about caffeine consumption if you take amitriptyline.

Amitriptyline and older adults

The American Geriatrics Society (AGS) Beers Criteria® is a set of guidelines utilized to pinpoint medications that might not be suitable for older adults due to potential side effects or other complications. These criteria help identify potentially inappropriate medications (PIM) for use in older individuals. Tricyclic antidepressants such as amitriptyline appear several times in these guidelines for the following risks:

• Sedation
• Orthostatic hypotension
• Incoordination
• Impaired function
• Fainting
• Falls/fractures

Although amitriptyline is on the list, healthcare providers sometimes prescribe this medication to older adults when the benefits outweigh the risks. Lower doses and close monitoring will be necessary.

Amitriptyline and marijuana 

People who use marijuana should consult their healthcare provider before using amitriptyline, as both can cause sedation. When used together, the sedating effects may be enhanced.

Amitriptyline and dietary supplements

Amitriptyline is known to interact with certain dietary supplements, such as:

• DHEA
• SAMe
• St. John’s wort
• Tryptophan
• Yohimbe 

If you use any dietary supplements, check with your healthcare provider before taking amitriptyline.

How to minimize amitriptyline interactions

Although amitriptyline has many potential interactions, it can still be taken safely with some precautions in many cases. 

Always consult your healthcare provider before beginning a new medicine. Before you start taking amitriptyline, make sure your provider is aware of all of your medical conditions, especially if you have a history of: 

• Substance use disorder
• Asthma
• Mental health conditions, including schizophrenia or bipolar disorder
• Urinary retention
• Prostate conditions
• Glaucoma
• Heart disease
• Previous heart attack
• Liver problems
• Thyroid conditions
• Seizure history
• Suicidal thoughts or plans, a previous suicide attempt, or family history 
• An allergic reaction to amitriptyline or any tricyclic antidepressant

Consult your healthcare provider if you are pregnant, planning to become pregnant, or breastfeeding. Also, tell your doctor about all your medications, including prescription drugs, OTC medicines, vitamins, and dietary supplements. While taking amitriptyline, do not start any new medicines unless approved by your healthcare provider.

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

While taking amitriptyline, be aware of potential warning signs of drug interactions, such as the symptoms of serotonin syndrome or CNS depression described above. If you have any questions or concerns about drug interactions, ask your healthcare provider for medical advice. 

When to talk to a healthcare provider about amitriptyline interactions

This article reviews various amitriptyline interactions but is not a complete list of all possible interactions. Be sure to tell your healthcare providers about all your medicines, including prescription and over-the-counter drugs, vitamins, dietary supplements, and any medical conditions. This will help ensure proper management and monitoring while taking amitriptyline.