Methadone Interactions: What You Can and Cannot Take with Methadone

Methadone has been used for the treatment of opioid use disorder since 1947.1 It is generally safe and effective when taken as prescribed. However, methadone does interact with many substances, which can cause adverse effects. Some methadone interactions are life-threatening, and those drugs should be avoided entirely while taking methadone.2 As a patient taking methadone, it’s important to always listen to your doctor and to follow their prescribing instructions closely.

In this article:

What Is Methadone?

Methadone is a synthetic, full agonist opioid medication that is commonly prescribed for the treatment of opioid use disorder or chronic pain.2 Methadone helps reduce opioid cravings and withdrawal and serves to blunt, dampen, or block the effects of other opioids completely.3

When methadone is used to treat opioid addiction, your doctor will prescribe you a higher daily dose to prevent opioid withdrawal symptoms and cravings and block the euphoria or “high” that occurs with short-acting opioids. Because methadone has a long half-life, withdrawal symptoms will be less severe.2

Methadone maintenance or methadone treatment helps people to recover from opioid addiction and reclaim their lives. According to research, people who participate in methadone maintenance treatment are 4.44 times more likely to stay in treatment and have 33% fewer opioid-positive drug screens.1

Why Does Methadone Interact With Other Substances?

Methadone interactions occur due to a change in metabolism, absorption, or elimination of the drug. Some substances may have additive effects, meaning they act in a similar way as methadone and amplify its effects. Other substances may have a canceling effect, acting in an opposite way as methadone and end up dampening or canceling methadone’s effects completely.2

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Which Drugs Disqualify You From Methadone Treatment?

Methadone can cause central nervous system (CNS) depression. It should not be used in conjunction with other central nervous system depressants as the sedating effects of both are amplified, increasing the risk of methadone interactions, overdose, and death.2

Central Nervous System Depressants

Central nervous system depressants to be avoided include:4

  • Other opioids
  • Alcohol
  • Barbiturates
  • Benzodiazepines
  • Cough medicines
  • Pain medications
  • Muscle relaxants
  • Sedatives
  • Sleeping pills
  • Tranquilizers

Methadone alcohol interactions can cause significant intoxication and increase the risk of overdose. Alcohol should be avoided completely while taking methadone.4

Other Drugs

You should talk to your doctor if you are taking nausea medications or any of the following substances, which can increase the risk of serious side effects:4

Antipsychotics such as:

  • Aripiprazole (Abilify)
  • Haloperidol (Haldol)
  • Lurasidone (Latuda)
  • Asenapine (Saphis)
  • Quetiapine (Seroquel)
  • Ziprasidone (Geodon)
  • Clozapine (Versacloz)
  • Olanzapine (Zyprexa)
  • Cariprazine (Vraylar)
  • Paliperidone (Invega)
  • Pimavanserin (Nuplazid)
  • Chlorpromazine
  • Fluphenazine
  • Loxapine
  • Molindone
  • Thioxetine
  • Perphenazine
  • Iloperidone (Fanapt)
  • Risperidone (Risperdal)
  • Thioridazine
  • Trifluoperazine

Benzodiazepines such as:4

  • Alprazolam (Xanax)
  • Clonazepam (Klonopin)
  • Diazepam (Valium, Diastat)
  • Lorazepam (Ativan)
  • Triazolam (Halcion)
  • Chlordiazepoxide (Librium)
  • Clorazepate (Tranxene, Gen-Xene)
  • Temazepam (Restoril)
  • Oxazepam
  • Estazolam
  • Flurazepam

If you take any of these medications with methadone and experience any of the following symptoms, contact your doctor or seek emergency care immediately:4

  • Lightheadedness
  • Unusual dizziness
  • Extreme sleepiness
  • Slowed breathing
  • Difficulty breathing
  • Unresponsiveness

Methadone Drug Interactions That Increase Methadone’s Effects

The following substances may increase methadone’s effects and increase the risk of overdose:2,5

  • Grapefruit juice
  • Fluoxetine
  • Fluconazole
  • Benzodiazepines
  • Alcohol
  • Cimetidine
  • Quinidine
  • Verapamil
  • Azole antifungals
  • Macrolides
  • Urine alkalinizing agents
  • Ciprofloxacin

These substances may cause additive effects when combined with methadone:5

  • Benzodiazepines
  • Ethanol
  • Muscle relaxants
  • Anticholinergic drugs

Methadone Interactions That Decrease Methadone’s Effects

The following drugs may decrease methadone’s effect and increase the risk of withdrawal symptoms:2,5

  • Phenobarbital and other barbiturates
  • Risperidone
  • Rifampin
  • Ritonavir
  • Rifampin
  • Protease inhibitors
  • Phenytoin
  • Efavirenz
  • Carbamazepine
  • Urine acidifying agents

The following drugs may block methadone’s effects and make it ineffective:5

  • Buprenorphine
  • Naltrexone
  • Naloxone
  • Nalbuphine
  • Pentazocine
  • Butorphanol

If you have certain health conditions such as heart problems or are on medications that would interact adversely with methadone and you cannot safely come off these substances, your doctor may recommend an alternative course of treatment instead of methadone.2

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Which Substances Should You Avoid While on Methadone?

Methadone should not be used with other CNS depressants including benzodiazepines, antipsychotics, other opioids, or alcohol, unless absolutely necessary.2 Do not drink alcohol, take any medications that contain alcohol, or use street drugs while on methadone.4

Most antidepressants should be avoided while taking methadone. If necessary, mirtazapine and venlafaxine cause the lowest potential for interaction. Gabapentin can be used as an anticonvulsant.5

You should also avoid certain herbal supplements while taking methadone such as St. John’s Wort and tryptophan as they can cause interactions as well.4

Are There Dangerous Methadone Interactions?

Some medications can interact with methadone and cause heart conditions.3 Others can have serious, life-threatening effects such as breathing problems, sedation, or coma.4

Any substances that would potentiate the respiratory depression caused by opiates would be dangerous. Both alcohol and benzodiazepines increase the risk of death from overdose.5

Talk to your doctor if you are taking any of the following medications:4

Antidepressants such as:

  • Amoxapine
  • Trimipramine (Surmontil)
  • Doxepin (Silenor)
  • Imipramine (Tofranil)
  • Amitriptyline
  • Clomipramine (Anafranil)
  • Protriptyline (Vivactil)
  • Nortriptyline (Pamelor)
  • Desipramine (Norpramin)

Antifungals such as:

  • Voriconazole (Vfend)
  • Fluconazole (Diflucan)
  • Ketoconazole
  • Itraconazole (Onmel or Sporanox)

Medications for irregular heartbeat, such as:4

  • Disopyramide (Norpace)
  • Ibutilide (Corvert)
  • Dofetilide (Tikosyn)
  • Amiodarone (Nexterone, Pacerone)
  • Quinidine (in Nuedexta)
  • Flecainide
  • Procainamide

Other prescription medications that may cause serious methadone interactions include:4

  • Certain laxatives
  • Diuretics (water pills)
  • Erythromycin (Eryc, Eryothicin, etc.)
  • Nicardipine (Cardene)
  • Risperidone (Risperdal)
  • Sertraline (Zoloft)

Side Effects of Methadone Interactions

If you experience any of the following symptoms contact your doctor immediately:4

  • Pounding heartbeat
  • Lightheadedness
  • Dizziness
  • Fainting

Signs of Methadone Overdose

It’s important to be aware of the signs of a methadone overdose so you can seek help if you accidentally overdose, either due to taking too much or taking a medication that interacts with methadone. Methadone overdose signs include:2

  • Slow or stopped breathing
  • Slow or stopped heartbeat
  • Stupor
  • Extreme lethargy
  • Extreme sleepiness
  • Pinpoint pupils

If you suspect a methadone overdose, call 911 immediately. Administer naloxone (Narcan) if any is available.

How Can You Avoid Methadone Drug Interactions?

While methadone drug interactions can be dangerous, they can be avoided. Below are some tips to help you avoid methadone interactions:3

  • Take your methadone exactly as prescribed. Do not take higher doses or take the drug more often than prescribed.
  • Talk to your doctor about any prescription medications or over-the-counter drugs or herbal supplements you currently take and discuss any new medications or supplements with your methadone doctor before taking them.
  • Tell your doctor about any side effects you experience.
  • Speak with your doctor about any co-occurring medical conditions you may have.
  • Avoid using alcohol or street drugs while taking methadone.
  • Call 911 if you suspect or have symptoms of overdose.

When in doubt, ask your doctor before beginning to take any other medications, even over-the-counter (OTC) medications.


  1. National Institute on Drug Abuse. (2021). Medications to Treat Opioid Use Disorder Research Report.
  2. Durrani, M. & Bansal, K. (2022, February 12). Methadone. StatPearls.
  3. Substance Abuse and Mental Health Services Administration. (2022, March 4). Methadone.
  4. S. National Library of Medicine. (2021, February 15). Methadone.
  5. Terpening, C. & Johnson, W.M. (February 2007). Methadone as an Analgesic: A Review of the Risks and Benefits. West Virginia Medical Journal, Vol 103.
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