What Drugs Interact With Methadone? | Negative Drug Interactions

Medically Reviewed by Johnelle Smith, M.D. on December 29, 2021

Methadone can interact with a variety of drugs. Effects of drug interactions can range from serious effects on breathing, to increased overdose risk or reduced effectiveness.

Negative Drug Interactions With Methadone

Methadone is an opioid medication that is used during opioid detox to prevent withdrawal, treat pain, and is used as a maintenance treatment for opioid use disorder.

Before taking methadone, tell your doctor if you are taking any other medications, vitamins, or supplements. Some drugs can interact with methadone and disrupt methadone treatment.

Read more about taking methadone for opioid withdrawal

Types Of Drugs That Can Interact With Methadone

A variety of prescription and over-the-counter substances can negatively interact with methadone. The effects of this can be mild to severe in nature.

Potential effects of drug interactions can include:

  • reduced effectiveness of methadone
  • disruption to methadone metabolism
  • increased risk for overdose
  • respiratory depression
  • heart problems

The potential effects of mixing methadone with certain drugs can vary based on the type of drug taken with methadone, co-occurring health conditions, and other personal factors.

Types of drugs that can interact with methadone include:

Central Nervous System Depressants

Methadone is a central nervous system (CNS) depressant, meaning it slows activity in the nervous system. This can affect breathing, heart rate, cognition, and blood pressure.

Mixing methadone with other CNS depressants can cause a synergistic effect, which can have serious and potentially life-threatening effects on breathing and the heart.

Common CNS depressants include:

  • alcohol
  • benzodiazepines: alprazolam (Xanax), diazepam (Valium), lorazepam (Ativan), chlordiazepoxide (Librium), clonazepam (Klonopin), temazepam (Restoril)
  • barbiturates: phenobarbital (Luminal), secobarbital (Seconal), pentobarbital
  • opioids: buprenorphine (Subutex, Suboxone), oxycodone (OxyContin), morphine, codeine, hydrocodone (Vicodin), meperidine, fentanyl, heroin
  • other sedative-hypnotics: zolpidem (Ambien), zaleplon (Sonata), eszopiclone (Lunesta), suvorexant (Belsomra)
  • other cough and pain medicine: dextromethorphan (Robitussin)

If you’re taking a CNS depressant, talk to your doctor about the potential risks of continuing to use this drug while taking methadone. Alternative treatments may be recommended.


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Opioid Antagonists

Opioid antagonists are drugs that can block the effects of opioids (including methadone) in the brain and nervous system.

Opioid antagonists that can interact with methadone include:

  • naloxone
  • naltrexone (Vivitrol)
  • Suboxone (a mixed agonist-antagonist)
  • nalmefene

Taking an opioid antagonist while receiving methadone maintenance therapy can cause the methadone to be ineffective, or may potentially trigger acute withdrawal symptoms.

Anticonvulsant Medications

Some drugs used to control seizures or convulsions as a result of a medical condition can interact with methadone.

Anticonvulsants that can interact with methadone include:

  • carbamazepine (Tegretol)
  • phenytoin
  • pregabalin (Lyrica)
  • gabapentin (Horizant, Neurontin)
  • primidone

Antibiotics And Antiretroviral Agents

Some antibiotics and antiretroviral agents (e.g. HIV/AIDs medications) can interact with methadone.

Mixing the two may reduce the effectiveness of methadone, which can result in opioid withdrawal and other effects.

Antibiotics and HIV drugs that can interact with methadone include:

  • rifampicin
  • ciprofloxacin
  • troleandomycin
  • ritonavir
  • abacavir
  • darunavir
  • indinavir
  • amprenavir
  • nelfinavir
  • AZT

This is not a complete list. If you’re taking medication for HIV or another viral infection, tell your doctor before you begin taking methadone.


Antifungals are medications that may be used to treat conditions such as athlete’s foot, ringworm, and other infections that affect the skin, hair, and nails.

Antifungals that can interact with methadone include:

  • fluconazole (Diflucan)
  • ketoconazole
  • itraconazole (Onmel, Sporanox)
  • voriconazole (Vfend)

These drugs can inhibit the metabolism of methadone, resulting in higher concentrations of the drug in a person’s system, which can lead to toxicity.

Antidepressant Medications

Some drugs used for the treatment of depression can inhibit the metabolism of methadone, causing higher levels of the drug in a person’s system.

Antidepressants that can interact with methadone:

  • monoamine oxidase inhibitors: e.g. Marplan, Nardil, Parnate
  • SSRIs: fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa)
  • SNRIs: trazodone, duloxetine (Cymbalta), venlafaxine (Effexor)
  • tricyclic antidepressants: amitriptyline (Elavil), desipramine (Norpramin), doxepin (Silenor), amoxapine, nortriptyline (Pamelor)

This is an incomplete list of antidepressants that can interact with methadone. If you are taking medication for depression, talk to your doctor before starting methadone for OUD.

Read more about the negative interactions of methadone and antidepressants

Arrhythmogenic Agents

Arrhythmogenic agents are drugs that can affect the heart or cause electrolyte imbalances. Combined with methadone, this has the potential to cause heart problems.

Arrhthymogenic agents might include:

  • antipsychotics/neuroleptics: haloperidol (Haldol), quetiapine (Seroquel), risperidone (Risperdal), olanzapine (Zyprexa), aripiprazole (Abilify), clozapine
  • heart medications: moricizine, quinidine, dofetilide, amiodarone (Nexterone), disopyramide (Norpace), flecainide
  • diuretics: caffeine, torsemide (Demadex), blood pressure medications
  • laxatives: Miralax, Dulcolax, senna, Colace

Antihistamines/Allergy Medications

Antihistamines are drugs that are commonly marketed for allergy relief, insomnia, and may be prescribed for anxiety. These can interact with methadone.

Antihistamines that can interact with methadone include:

  • diphenhydramine (Benadryl, over-the-counter sleep aids)
  • hydroxyzine
  • cetirizine (Zyrtec)
  • fexofenadine (Allegra)
  • loratadine (Claritin)
  • clemastine (Tavist)
  • cyclizine
  • promethazine

Antihistamines can be bought over-the-counter (e.g. Allegra) or be prescribed for a specific medical condition, such as chronic allergies.

Migraine Medications

Some prescription and over-the-counter medications used to treat migraine headaches can interact with methadone.

Migraine headache medications that can interact with methadone include:

  • almotriptan (Axert)
  • naratriptan (Amerge)
  • sumatriptan (Alsuma)
  • frovatriptan (Frova)
  • eletriptan (Relpax)
  • rizatriptan (Maxalt)
  • zolmitriptan (Zomig)


Anticholinergics are drugs that can be used to treat a variety of conditions, including overactive bladder, COPD, gastrointestinal disorders, and symptoms of Parkinson’s disease.

Anticholinergics that can interact with methadone include:

  • atropine (Atropen)
  • Enablex (darifenacin)
  • Ditropan (oxybutynin)
  • aclidinium
  • benztropine mesylate
  • trihexyphenidyl
  • antihistamines
  • tricyclic antidepressants
  • antipsychotic medications

These drugs can interact with methadone. Taking anticholinergics while taking methadone may cause severe constipation and difficulty urinating (severe urinary retention).

Illicit Drugs

Taking illicit drugs while using methadone can have harmful and potentially life-threatening effects on breathing, heart function, and liver and kidney function.

Illicit drugs that can interact with methadone include:

  • cocaine
  • heroin
  • illicitly-manufactured fentanyl

Mixing any illicit drugs with methadone could potentially lead to reduced effectiveness of methadone treatment. Avoiding the use of illicit drugs while taking methadone is recommended.

What To Do Before Taking Methadone If You Take Other Medications

Before starting methadone, tell your doctor about any supplements, prescription medications, or other substances you are taking. This includes the use of alcohol and over-the-counter drugs.

Learn More About Methadone Treatment Options Today

If you’re concerned about other drugs interacting with methadone, an addiction treatment professional can help you develop a treatment plan that is suited to meet your needs.

Some medications that interact with methadone can still be taken with precautionary measures in place to prevent harmful health outcomes.

For more information about methadone treatment options, call our helpline to speak to one of our trained staff members today.

This page does not provide medical advice. See more

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Medically Reviewed by
Johnelle Smith, M.D. on December 29, 2021


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