Drug & supplement interaction

Kratom + Methadone

Methadone brand name: Dolophine.

Moderate Interaction
Medically reviewed by · Updated September 2026
The bottom line Moderate

Methadone falls into 4 drug categories that Kratom can interact with; the most serious is rated moderate. Theoretically, concomitant use might increase the risk for adverse CNS depressant effects.

Read the full interaction report
SeverityModerate
LikelihoodPossible
Interactions4
EvidenceD
What do Severity, Likelihood & Evidence mean?
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Interaction report

Kratom and Methadone

These two interact in 4 distinct ways. Each one is explained separately below.

Why Are There 4 Interactions?

Kratom interacts with whole categories of medication. Methadone falls into 4 of those categories, so it can interact with Kratom in 4 different ways. We’ve listed each one below — your overall risk is driven by the most serious of them (Moderate).

Moderate

CNS DEPRESSANTS

1 of 4

Why this applies to Methadone

Methadone falls under CNS DEPRESSANTS — the group Kratom interacts with.

Theoretically, concomitant use might increase the risk for adverse CNS depressant effects.
Kratom contains mitragynine, a mu-receptor agonist that may cause respiratory depression. Although results from animal research suggest that mitragynine causes less respiratory depression than the CNS depressant codeine, fatalities have been reported for patients who ingested a combination of kratom and O-desmethyltramadol, another mu-receptor agonist. Additionally, observational research suggests that adverse effects such as drowsiness and coma are more likely to occur in individuals taking kratom in combination with agents such as opioids and sedatives. Theoretically, ingesting kratom along with other CNS depressants can increase the risk of adverse effects, including drowsiness, coma, and/or severe or fatal respiratory depression.
Severity Moderate Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the thing with this combination: methadone is already a powerful opioid that slows your breathing and calms your whole nervous system. Kratom's main compound, mitragynine, acts on those same opioid receptors in the brain. So when you stack them together, you're essentially doubling down on the same kind of effect, and that can pile up faster than you'd expect.

What worries me most is breathing. Both can cause deep drowsiness, very slow or shallow breathing, and in serious cases, unresponsiveness or coma. This warning is mostly theoretical, based on how the two work and on some real-world reports, not large studies. But methadone is potent and stays in your body a long time, so I wouldn't gamble here. Please talk with your doctor or pharmacist before mixing them.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Backstrom BG, Classon G, Lowenhielm P, Thelander G. [Krypton--new, deadly Internet drug. Since October 2009 have nine young persons died in Sweden]. Lakartidningen 2010;107(50):3196-3197.
  2. Kronstrand R, Roman M, Thelander G, Eriksson A. Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton. J Anal Toxicol 2011;35(4):242-247. PubMed
  3. Jansen KL, Prast CJ. Ethnopharmacology of kratom and the Mitragyna alkaloids. J Ethnopharmacol 1988;23(1):115-119. PubMed
  4. Davidson C, Cao D, King T, et al. A comparative analysis of kratom exposure cases in Thailand and the United States from 2010-2017. Am J Drug Alcohol Abuse. 2020:1-10. PubMed
Moderate

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES

2 of 4

Methadone also falls under CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES.

Theoretically, kratom might increase the levels and clinical effects of drugs metabolized by CYP2D6.
In vitro research suggests that kratom extract inhibits CYP2D6 enzyme activity. However, human research shows that a single low dose of kratom tea 2 grams does not inhibit CYP2D6 activity. However, this kratom dose is lower than what is normally taken for psychoactive effects. In one case report, a 63-year-old male presented with possible serotonin syndrome after taking an unknown dose of kratom for up to 3 months along with serotonergic prescription medications bupropion, buspirone, desvenlafaxine, trazodone, and ziprasidone. It was hypothesized that kratom inhibited CYP2D6-mediated metabolism of buspirone and consequently increased systemic exposure to serotonin. In another case, a 37-year-old male stable for 15 years on amitriptyline presented with anticholinergic symptoms including xerostomia, dry eyes, and constipation, along with mildly elevated bilirubin and liver enzymes after taking progressively higher doses of up to 14 grams of kratom daily for 12 weeks. It was hypothesized that the adverse effects of amitriptyline were precipitated by CYP2D6 inhibition by kratom.
Severity Moderate Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the concern with combining kratom and methadone. Your body partly relies on an enzyme called CYP2D6 to break methadone down. Lab studies suggest kratom may slow that enzyme, which could let methadone build up higher than expected. Methadone is an active opioid (not a prodrug), so more of it in your system means stronger opioid effects: heavy drowsiness, slowed breathing, low blood pressure, and a dangerous heart rhythm change called QT prolongation.

On top of that, kratom itself acts on opioid receptors, so stacking the two can add up even without the enzyme issue. The CYP2D6 part is mostly theoretical right now, but methadone has a narrow safety margin, so I'd treat this seriously. Please talk with your doctor or pharmacist before mixing them.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Kong WM, Chik Z, Ramachandra M, et al. Evaluation of the effects of Mitragyna speciosa alkaloid extract on cytochrome P450 enzymes using a high throughput assay. Molecules. 2011;16(9):7344-7356. PubMed
  2. Eudaley ST, Brooks SP, Hamilton LA. Case Report: Possible Serotonin Syndrome in a Patient Taking Kratom and Multiple Serotonergic Agents. J Pharm Pract 2022. PubMed
  3. Tanna RS, Nguyen JT, Hadi DL, et al. Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom. Clin Pharmacol Ther 2023;113(6):1315-1325. PubMed
  4. Vanani NB, Stevanovic SG, Stevanovic N. Adverse Drug Interaction Between Kratom and Amitriptyline With Gastrointestinal and Mild Hepatic Effects. Cureus 2023;15(1):e33809. PubMed
Moderate

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

3 of 4

Methadone also falls under CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES.

Kratom might increase the levels and clinical effects of drugs metabolized by CYP3A4.
In vitro research shows that kratom extract inhibits CYP3A4 enzyme activity. A pharmacokinetic study in adults shows that taking kratom tea 2 grams modestly increases the plasma concentration time-curve (AUC) and maximum concentration (Cmax) of CYP3A4 probe midazolam by 40-50% and its CYP3A4-mediated metabolites 18-27%. However, a lack of change in the half-life of midazolam and a simulation of the kratom-midazolam interaction suggest that kratom inhibits CYP3A4 enzymes in the small intestine but not the liver. Additionally, there is one case report of a 27-year-old male who died from neuroleptic malignant-like symptoms after concomitant use of kratom and quetiapine, a CYP3A4 substrate. Although it did not appear that the patient had consumed large quantities of quetiapine, postmortem plasma levels were in the lethal range, indicating possible inhibition of CYP3A4 by kratom. In another case report, a 63-year-old male presented with possible serotonin syndrome after taking an unknown dose of kratom for up to 3 months along with serotonergic prescription medications bupropion, buspirone, desvenlafaxine, trazodone, and ziprasidone. It is hypothesized that CYP3A4 inhibition by kratom reduced metabolism of desvenlafaxine, trazodone, and ziprasidone and consequently increased systemic exposure to serotonin.
Severity Moderate Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the concern with combining kratom and methadone. Your body uses an enzyme called CYP3A4 to help break methadone down. Kratom appears to slow that enzyme, at least in the gut, so methadone may clear a little more slowly and build up in your system. On top of that, kratom itself acts on the same opioid receptors methadone does, so the two can pile their effects on each other.

That stacking is what worries me most. More methadone effect can mean heavier sedation, slowed or shallow breathing, and dangerous heart rhythm changes (methadone already affects the heart's QT interval). The lab and case-report evidence here is fairly weak, but methadone is unforgiving when things go wrong. Please talk with your doctor or pharmacist before mixing these.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Kong WM, Chik Z, Ramachandra M, et al. Evaluation of the effects of Mitragyna speciosa alkaloid extract on cytochrome P450 enzymes using a high throughput assay. Molecules. 2011;16(9):7344-7356. PubMed
  2. Hughes RL. Fatal combination of mitragynine and quetiapine - a case report with discussion of a potential herb-drug interaction. Forensic Sci Med Pathol. 2019 Mar;15(1):110-113. PubMed
  3. Eudaley ST, Brooks SP, Hamilton LA. Case Report: Possible Serotonin Syndrome in a Patient Taking Kratom and Multiple Serotonergic Agents. J Pharm Pract 2022. PubMed
  4. Tanna RS, Nguyen JT, Hadi DL, et al. Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom. Clin Pharmacol Ther 2023;113(6):1315-1325. PubMed
Moderate

SEROTONERGIC DRUGS

4 of 4

Methadone also falls under SEROTONERGIC DRUGS.

Theoretically, taking kratom in combination with serotonergic drugs may increase levels of serotonin, increasing the risk of serotonin syndrome.
A 63-year-old male presented with possible serotonin syndrome after taking an unknown dose of kratom for up to 3 months along with serotonergic prescription medications bupropion, buspirone, desvenlafaxine, trazodone, and ziprasidone. It was hypothesized that kratom inhibited the cytochrome P450 3A4-, 2C9-, 2D6-, and 1A2-mediated metabolism of several of these serotonergic medications, consequently increasing systemic exposure to serotonin.
Severity Moderate Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the thing to keep in mind if you take methadone and are curious about kratom. Methadone is more than just a pain reliever, it also has mild effects on serotonin, the brain chemical tied to mood. Kratom can nudge serotonin too. Combining the two could, in theory, push serotonin too high and trigger what we call serotonin syndrome: agitation, a racing heart, sweating, shivering, muscle twitching, or confusion.

On top of that, both methadone and kratom act on opioid receptors, so stacking them raises the real risk of heavy sedation and dangerously slowed breathing. The serotonin concern here is mostly theoretical and based on one case report, but methadone is a serious drug with a narrow safety margin. Please talk with your pharmacist or doctor before mixing anything with it.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Eudaley ST, Brooks SP, Hamilton LA. Case Report: Possible Serotonin Syndrome in a Patient Taking Kratom and Multiple Serotonergic Agents. J Pharm Pract 2022. PubMed

What These Ratings Mean

Every interaction above is graded three ways — here’s the key to each label.

Severity how clinically significant the interaction is
Major

Clinically significant. Avoid the combination, or use only under close professional supervision.

Moderate

Usually worth avoiding or managing — may need monitoring, a dose change, or timing apart.

Minor

Generally not serious. Be aware of it and mention it to your pharmacist.

Likelihood how strong the evidence is that the interaction actually happens in people
  • LikelyWell-controlled human studies have demonstrated the likely existence of this interaction.
  • ProbableInteraction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports.
  • PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.
  • UnlikelyInteraction has been demonstrated in animal or in lab research but has been shown not to occur in humans.
Evidence the quality of the studies behind the rating (graded A–D)
  • AHigh-quality meta-analysis (quantitative systematic review).
  • BCase-control study.
  • CConsensus.
  • DAnecdotal evidence.

These ratings are for information only. Never start, stop, or otherwise change your therapy before speaking with your provider.

Keep it in perspective

Kratom Also Interacts With Other Medications

Kratom has 982 moderate, 12 minor known drug interactions in our database — the Methadone one above is among them. If you take anything else, check it against the full list below.

Moderate 982 Minor 12 No known interaction 1,836 (incl. Methadone)
Taking anything else?

Check Another of Your Medications Against Kratom

Covers the 2,830 medications we’ve checked against Kratom. Pick one to open its full report.

From our Q&A

Questions About Kratom or Methadone

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers Kratom or Methadone, not necessarily both, but if one is close to what you were about to ask it will usually go further than a database entry can:

Not quite your question? Ask our pharmacists directly — it is free, there is no account required, and answers usually come back within 24 hours.

Everything else you take

See Every Supplement That Interacts With Methadone

This page covers Kratom only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Methadone page lists 223 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: 1,4-butanediol (major), Activated Charcoal (major), Beer (major), Gamma-hydroxybutyrate (ghb) (major) and Grapefruit (major).

By severity: 10 major · 174 moderate · 39 minor.

From our pharmacist’s overview on the Methadone page

“If you take methadone, choose your supplements with genuine care. Of the 223 ingredients on this page, most either add to methadone's sedating effect or change how fast your body clears it, which can push its blood level up or down.”

Reviewed by 2 · Jul 18, 2026

Open the Methadone interaction page

One more smart check

Taking Kratom as Part of a Dietary Supplement Product? Check It for Interactions

We hold 8 real supplement products containing Kratom, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Kratom. Your product may carry other ingredients that interact with Methadone too, on top of Kratom — and those would not show on this page. Find your product and we’ll check every ingredient on its label:

How much people look this up

Where Kratom and Methadone Sit Against Everything Else

Out of every supplement and medication people look up on HelloPharmacist, here is where these two land this week — and which way each has been moving.

Supplement Kratom
Top 25%

#304 of 1,452 supplements looked up here in the last 7 days

29 days ago today
Medication Methadone
Top half

#1,112 of 2,830 medications looked up here in the last 7 days

29 days ago today

Position among everything looked up on this site, not a measure of how commonly either one is used or how important it is. A supplement can climb this list because of a news story. It counts every request to the page, automated ones included, and nothing here identifies anyone.

Supplement

About Kratom

What is Kratom?

Kratom
  • Pain relief
  • Opioid withdrawal symptoms
  • Anxiety and stress
  • Low energy or fatigue
  • Mood enhancement

Kratom is a Southeast Asian plant whose leaves act on the brain's opioid receptors and can produce both stimulant-like and opioid-like effects. It is not approved or proven safe by health regulators, carries real risks of dependence and serious harm, and its legal status varies widely. Talk to a pharmacist or doctor before considering it.

Read the full Kratom monograph & all interactions
Medication

About Methadone

What Is Methadone Used For?

Brand name: Dolophine

Methadone treats severe and persistent pain that requires daily, around-the-clock, long-term opioid treatment and cannot be managed adequately with other options. It is available in several forms for this use, including oral solution, oral tablets, oral concentrate, and injectable forms (intravenous, intramuscular, and subcutaneous). Injectable methadone is not approved for outpatient pain treatment — it is reserved for hospitalized patients unable to take oral medication.

Methadone is also used for the detoxification and maintenance treatment of opioid addiction (dependence on heroin or other morphine-like drugs). Oral forms — including tablets, dispersible tablets (such as Methadose Dispersible and DISKETS), and oral concentrates (such as Methadone Hydrochloride Intensol™, Methadose, and others) — are approved for this use. By law, methadone for opioid addiction treatment must be dispensed only by certified opioid treatment programs. Injectable methadone is not approved for outpatient addiction treatment.

See full Methadone drug information
Keep checking

Other Drugs & Kratom

Browse every other medication we’ve checked against Kratom — both the ones with a known interaction and the ones without. Select any drug for the full detail.

0Major
982Moderate
12Minor
1,835No known interaction
982 Moderate 12 Minor 1,835 No interaction
Moderate

982 interactions

Showing 60 of 982 moderate interactions — see all 982 on the Kratom page.

Minor

12 interactions

No interaction 1,835 drugs checked — show the list

We also checked Kratom against these medications and found no known interaction in our sources. Open any page to confirm.

Showing the 60 most looked-up of 1,835 medications checked with no known interaction — see the full Kratom list.

See the full Kratom interactions page
See every supplement checked against Methadone, ranked by severity
Sources

Sources & How We Checked

Interaction details are evidence-graded and sourced from the Natural Medicines database. The medication overview comes from MedlinePlus.

Content is written and reviewed by licensed HelloPharmacist pharmacists. See our data sources and editorial standards for how this information is built and checked.

Parts of this content are provided by the Therapeutic Research Center, LLC.

DISCLAIMER: Currently this does not check for drug-drug interactions. This is not an all-inclusive comprehensive list of potential interactions and is for informational purposes only. Not all interactions are known or well-reported in the scientific literature, and new interactions are continually being reported. Input is needed from a qualified healthcare provider including a pharmacist before starting any therapy. Application of clinical judgment is necessary.

© 2021 Therapeutic Research Center, LLC

Keep exploring
Kratom monograph › Uses, safety, and every drug interaction in one place Methadone supplement interactions › Every supplement checked against Methadone, ranked by severity Methadone drug information › The full plain-English guide to this medication Supplement interaction checker › Check any supplement or product against your medications Browse medications A–Z › Every drug we've checked against herbs & supplements Ask a pharmacist › Free, personal answer from our licensed team
Pharmacist Counseling Corner

Taking Kratom and Methadone Together: Common Questions

Can you take Kratom with Methadone?
There is a moderate interaction, so it may be acceptable with monitoring or timing changes — but check with your pharmacist first. Read the full details on this page and confirm with your pharmacist before combining them.
Why are there 4 interactions listed for Kratom and Methadone?
Methadone belongs to more than one drug category, and Kratom interacts with each of those categories a little differently. We list every one so nothing is missed — your overall risk is driven by the most serious of them.
How serious is the Kratom and Methadone interaction?
We rate it Moderate. This combination may require monitoring, a dose adjustment, or separating the times you take each one. Consult your pharmacist before using them together.

Written and reviewed by the HelloPharmacist editorial staff. Our editorial policy

Still Have a Question About Methadone and Kratom?

Our pharmacists answer your medication & supplement questions — free.

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This information is for education only and is not a substitute for professional medical advice. Always check with your pharmacist or doctor before starting, stopping, or combining supplements and medications.