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CBD drug interaction · Medicine group

CBD and opioid pain relievers: methadone and others

Prepared by: cbd.school editorial teamLast reviewed: 2 medicines, 1 warning13 sources

Opioids are medicines used for severe pain and to treat opioid use disorder; methadone, morphine, oxycodone, fentanyl, tramadol and buprenorphine are some of them. On this page you will find how CBD may interact with these medicines, what research has found, and what is monitored if they are used together.

What's on this page?7 sections

Medicines and the importance of their interactions

From peer-reviewed publications and drug labels: the warnings, most important first. The same warnings also appear in the interaction checker. A medicine that is not listed can still interact with CBD.

Opioid pain relievers: CBD interaction warnings
MedicineImportanceWarningSource
Methadone, Other opioids (morphine, oxycodone, fentanyl, tramadol, etc.)CautionMethadone and other opioids: In a child, a high methadone level was found and drowsiness developed while CBD was being used; two weeks after CBD was stopped, the level fell to less than half and the symptoms resolved. In small controlled studies with morphine and buprenorphine, no clear change in drug levels was seen; with a single intravenous dose of fentanyl, there was no respiratory depression. Drowsiness may increase together with opioids. Tell the doctor who manages your pain or addiction treatment.PMID 32444381, PMID 41622700, PMID 41467610, PMID 25748562, FDA Epidiolex label §7.4 (05/2026)

How does the interaction happen?

Methadone is broken down in the liver by many enzymes (CYP3A4, CYP2B6, CYP2C19, CYP2C9 and CYP2D6). The prescribing information states that when a medicine that slows these enzymes is added, the methadone level can rise and this can lead to dangerous respiratory depression, and that when such a medicine is stopped, the level can fall. CBD moderately slows CYP2C19. Its effect on CYP2B6 goes both ways: the US prescribing information for approved CBD says that in the lab CBD can both slow and speed up this enzyme. According to the same prescribing information, approved CBD at 7.5 mg/kg twice a day did not lower the levels of drugs broken down by CYP2B6 to a clinically significant degree; the effect at higher doses is unknown. The authors who reported the case pointed to CBD's effect on CYP3A4 and CYP2C19 as a possible cause; in a drug-level study with approved CBD, however, CYP3A4 was not affected. (Methadone prescribing information §5.7, FDA Epidiolex label §7.2 and §12.3 (05/2026), PMID 32444381, PMID 42162267)

Morphine, on the other hand, is cleared by a different route, mostly by being attached to another molecule by an enzyme called UGT2B7. In the lab, CBD slowed this enzyme; but in healthy volunteers, 9 days of CBD (2.5 mg/kg twice a day) did not change the blood levels of morphine and its breakdown products to a clinically significant degree. This shows that a lab finding does not always carry over to people. (PMID 41622700)

The second possible interaction does not depend on drug levels. CBD can cause drowsiness and sedation; the prescribing information says other substances that depress the central nervous system, such as alcohol, can increase this effect. Opioids are in this group too: the prescribing information for methadone warns that using it together with other opioids and with medicines that cause sleepiness increases the risk of excessive drowsiness and respiratory depression. (FDA Epidiolex label §5.2 and §7.4 (05/2026), EMA Epidyolex prescribing information 4.4, Methadone prescribing information §5.2)

There is a lot we don't know. No human studies were found that looked at CBD together with other opioids such as oxycodone, tramadol and codeine. The existing studies are small; most used a single dose or lasted a few weeks, and in some, opioid levels were not measured at all. (PMID 42162267, PMID 25748562, PMID 41467610, PMID 41622700)

What do studies and official drug information say?

Each finding shows the type of evidence it rests on. A case report describes a single patient; it does not prove cause and effect.

  1. Case report

    Methadone: level rose, drowsiness developed (2020)

    A 13-year-old girl with metastatic cancer and chronic pain, who had been taking 7.5 mg of methadone twice a day for 4 months, was started on CBD without her doctors' knowledge, and the amount of CBD was increased. She came in with increasing drowsiness and fatigue; her methadone level was measured at 271 ng/mL. 14 days after CBD was stopped, the level fell to 125 ng/mL, and the drowsiness and fatigue resolved.

    Source: PMID 32444381

  2. Drug-level study

    Morphine: no clear change in healthy volunteers (2026)

    In a study by US Food and Drug Administration (FDA) researchers with 20 healthy volunteers, 9 days of CBD (2.5 mg/kg twice a day), at a dose close to the amounts used in over-the-counter products, increased the total amount in the blood of a single 15 mg dose of morphine by about 12%. According to the publication's detailed results table and the study's ClinicalTrials.gov entry, in the same measurement the total amount in the blood of morphine-6-glucuronide, one of morphine's breakdown products, was also 26% higher. The authors saw no clinically significant change in morphine or its breakdown products; there were no serious side effects. In the same study, CBD increased the level of citalopram by 43%.

    Source: PMID 41622700, ClinicalTrials.gov NCT06192589

  3. Controlled study

    Buprenorphine: no drug-level interaction over 28 days (2025)

    In 30 people receiving inpatient buprenorphine treatment for opioid use disorder, 600 mg of CBD a day or a placebo was given for 28 days. CBD was well tolerated, there were no serious side effects, and no significant drug-level interaction was seen between CBD and buprenorphine.

    Source: PMID 41467610

  4. Controlled study

    A single dose of CBD in people on methadone treatment (2026)

    In 23 people receiving methadone treatment who had chronic pain, single doses of 400, 800 and 1200 mg of CBD were compared with placebo. CBD's safety profile was favorable, side effects were mild, and performance on mental (cognitive) tests did not worsen. However, after methadone was taken, 1200 mg of CBD increased pain sensitivity to heat. Methadone levels were not measured, and CBD was not given continuously for several days.

    Source: PMID 42162267

  5. Controlled study

    Fentanyl: no respiratory depression with a single dose (2015)

    In 17 healthy volunteers, 400 or 800 mg of CBD was compared with placebo, each given together with a low dose of fentanyl into a vein. None of the participants had respiratory depression or heart and blood vessel problems; CBD did not increase fentanyl's side effects. People with opioid dependence were not included, and the CBD and fentanyl doses were low or moderate.

    Source: PMID 25748562

  6. Controlled study

    Cancer patients: no increase in side effects among opioid users (2026)

    In a secondary analysis of a study comparing CBD oil with placebo in patients with advanced cancer, the amount of CBD patients chose for themselves was not related to opioid use, and CBD did not increase the chance of side effects with medicines taken at the same time. The analysis relies on indirect measures (the chosen amount of CBD and side effects); drug levels were not measured.

    Source: PMID 39539239

  7. Official drug information

    Prescribing information for approved CBD: added drowsiness

    The prescribing information for approved CBD says CBD can cause drowsiness and sedation, and that this risk can increase when it is used with substances that depress the central nervous system, such as alcohol. In epilepsy studies, drowsiness was more common in people taking CBD (32% according to the US prescribing information; 11% with placebo). The European product information advises not driving or operating machinery until you see how CBD affects you.

    Source: FDA Epidiolex label §5.2 and §7.4 (05/2026), EMA Epidyolex prescribing information 4.4 and 4.7

  8. Drug-level study

    Cannabis with THC: morphine and oxycodone levels did not clearly change (2011)

    In this study, 21 patients taking long-acting morphine or oxycodone for chronic pain stayed in the hospital for 5 days and inhaled vaporized cannabis (3.96% THC according to the study registration) three times a day. The total amount of morphine and oxycodone in the blood did not change significantly; morphine's peak level fell by about 10%. Patients' pain fell by 27% on average, but because the study had no comparison group and no blinding, it is not known how much of this drop came from the cannabis. This finding concerns cannabis containing THC, not CBD.

    Source: PMID 22048225, ClinicalTrials.gov NCT00308555

What is monitored?

What to tell your doctor

  • That you use CBD or are thinking of starting it; tell both the doctor who manages your pain or addiction treatment and your pharmacist. In the methadone case, CBD had been started without the doctors' knowledge. (PMID 32444381, NIH NCCIH)
  • The type of product (oil, capsule, spray, cream), whether it contains THC, how much and how often you use it, and when you started. (NIH NCCIH)
  • Whether you use other medicines that cause sleepiness (benzodiazepines, sleeping pills, gabapentin, pregabalin) or alcohol. The prescribing information for methadone states that using it together with these medicines increases the risk. (Methadone prescribing information §5.2, FDA Epidiolex label §7.4 (05/2026))

If you are not sure whom to ask: Thinking about CBD? Which specialist should you see?

Frequently asked questions

Can I use CBD while taking an opioid pain reliever?

Make this decision together with the doctor who manages your pain treatment. Small studies with morphine and buprenorphine found no clear drug-level interaction; with methadone, however, a case was reported in which the level rose. Because CBD can also cause drowsiness, drowsiness and changes in breathing are watched for when they are used together.

I'm on methadone treatment; will CBD change my methadone level?

It may. In a child who was started on CBD, the methadone level rose and then fell when CBD was stopped. In a single-dose study in people on methadone treatment, CBD was well tolerated, but methadone levels were not measured. Do not start CBD without talking to the team that manages your treatment.

I take tramadol, oxycodone or codeine; is there any data on these?

No human studies were found that looked at CBD together with these medicines. There is a small, uncontrolled study in which only cannabis containing THC was tried with oxycodone; the oxycodone level did not clearly change. A lack of data does not mean it is safe. Tell your doctor about CBD and watch for drowsiness and sedation, especially in the first few days.

Will CBD change the pain-relieving effect of my opioid medicine?

This is not known. In a study in people on methadone treatment, a high dose (1200 mg) of CBD given after methadone increased pain sensitivity to heat. Whether this affects day-to-day pain control was not studied.

Can I drive while using CBD together with an opioid?

Do not drive or operate machinery until you see how CBD affects you. The prescribing information for approved CBD gives this warning even for CBD alone; drowsiness can increase when it is used with an opioid.

Does cannabis containing THC change the level of my opioid medicine?

Not in one small study: in 21 chronic pain patients taking long-acting morphine or oxycodone, 5 days of vaporized cannabis with THC did not significantly change the total amount of these medicines in the blood. The study had no comparison group, and other opioids were not studied. If you use a product containing THC, tell the doctor managing your pain treatment about that too.

References

Show 13 references
  1. Madden K, Tanco K, Bruera E. Clinically Significant Drug-Drug Interaction Between Methadone and Cannabidiol. Pediatrics. 2020;145(6):e20193256. PMID 32444381
  2. Salcedo P et al. Clinical Study to Evaluate Drug Interactions of Cannabidiol with Citalopram and Morphine in Healthy Adults. Clin Pharmacol Ther. 2026;119(4):1095–1104. PMID 41622700
  3. ClinicalTrials.gov: NCT06192589, Clinical Study to Evaluate Cannabidiol Liver Enzyme Elevations and Drug Interactions. NCT06192589
  4. London ED et al. Adjunctive Cannabidiol in Inpatient Buprenorphine Treatment for Opioid Use Disorder: A Pilot Randomized Trial. J Addict Med. 2025 (online ahead of print). PMID 41467610
  5. Costa GPA et al. An opioid-withholding human laboratory paradigm during opioid agonist treatment for opioid use disorder and chronic pain: Phase- and dose-dependent effects of cannabidiol. Neuropsychopharmacology. 2026;51(11):2280–2289. PMID 42162267
  6. Manini AF et al. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. J Addict Med. 2015;9(3):204–210. PMID 25748562
  7. Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther. 2011;90(6):844–851. PMID 22048225
  8. ClinicalTrials.gov: NCT00308555, Opioid and Cannabinoid Pharmacokinetic Interactions: A Pilot Study. NCT00308555
  9. Downs G et al. Drug Interactions in People on Cannabidiol: Is There Cause for Concern? Cannabis Cannabinoid Res. 2026;11(2):138–146. PMID 39539239
  10. FDA: Epidiolex (cannabidiol) prescribing information, section 5.2, 7.2, 7.4 and 12.3 (05/2026), DailyMed. dailymed.nlm.nih.gov
  11. EMA: Epidyolex prescribing information, section 4.4 and 4.7. www.ema.europa.eu
  12. Methadone hydrochloride prescribing information, section 5.1, 5.2 and 5.7 (02/2026), DailyMed. dailymed.nlm.nih.gov
  13. NIH NCCIH: Cannabis (Marijuana) and Cannabinoids: What You Need To Know. www.nccih.nih.gov

Last reviewed: . On this date, each source was opened and checked against the related sentence.