Methadone

For an informed discussion with your doctor or pharmacist. This information collection is not a clinically validated interaction checker. Missing data do not establish safety. Do not change or stop prescribed medicines on the basis of this information. The findings apply to the specific conditions studied; laboratory and animal studies cannot be directly extrapolated to humans.

Active substance: Methadone

Examples of brand names: Methaddict [DE]

ATC code: N07BC02

Main use (for orientation): Opioid dependence

Documented research summary

EX03: paediatric CBD case report with fatigue and increased methadone concentration; decrease after CBD discontinuation, mechanism unproven. Observational findings with natural cannabis contradict a uniform direction: Hallinan 2009, n=151, lower dose-related R/S-methadone trough concentrations with use; Meini 2015, n=94, lower dose-adjusted l-methadone concentrations; Chalabianloo 2021, n=83, small positive association with methadone concentration (p=0.049). None proves a causal cannabis-induced clearance change. Costa 2026 controlled crossover, n=23 receiving methadone: CBD 400/800/1200 mg shows time-dependent pain modulation; 1200 mg after methadone reduced heat-pain threshold, no craving change, cognition preserved; no plasma pharmacokinetics reported. De Aquino 2023, n=25, dronabinol 10/20 mg: subjective but not experimental pain relief greater at 10 mg, inconsistent cognitive effects, no THC–methadone-dose interaction. Do not count secondary analyses as independent RCTs. Zaman 2024 cardiotoxicity case with systemic infection and cannabis use, and Messick 2026 respiratory-depression case with additional high-dose hydromorphone, are highly confounded. Keep animal data separate, including the null finding for mouse brain methadone concentrations after CBD.

Uncertainties and limitations

CBD case report, natural-cannabis cohorts and acutely controlled dronabinol/CBD are not interchangeable. No confirmed universal CYP3A4 explanation. Rare plant cannabinoids without a clinical pair study in this search; synthetic full receptor agonists separate. Small laboratory studies do not establish overall safety in routine clinical care.

Hine 1975 (PMID 1241452) investigates acute Δ9-THC before naloxone-precipitated withdrawal in methadone-dependent male rats. A reduced withdrawal signal in this model establishes neither a safe/effective combination in methadone maintenance nor altered human methadone concentrations. Original abstract assessed; group sizes, complete methods and statistics unresolved without verified full text.

Separately recorded findings

4 separately recorded findings. Each statement applies to its documented study context.

CBD – clinical signals

Finding ID: B0090

Type of result: Context-specific finding; read the limitations

Observation: Drowsiness/fatigue; methadone concentration initially 271 ng/ml, 125 ng/ml 14 days after CBD discontinuation; concurrent clinical improvement.

Mechanism: Enzyme mechanism in the CBD–methadone case unproven. An independent human pharmacokinetic study with ticlopidine supports a substantial CYP2B6 role in methadone clearance; it did not investigate a cannabinoid. Infer neither an exclusively CYP3A4 explanation nor proven CYP2B6 mediation of the CBD case.

Study type: Case report

Context studied: 13-year-old female patient with cancer and long-term medication; single case.

Clinical interpretation: Individual medical / pharmaceutical assessment; do not use as dosage instructions

Limitations and uncertainties: Single case without certain causality or frequency estimate. EX03 assessed only in the original abstract here; CBD product, precise CBD dose, sampling times relative to methadone administration and complete co-medication not full-text verified. CA_P_23361846 is a separate human ticlopidine–methadone study, not a CBD–methadone pair study.

Original sources for this finding: Clinically Significant Drug-Drug Interaction Between Methadone and Cannabidiol [EX03]; Role of cytochrome P4502B6 in methadone metabolism and clearance [CA_P_23361846]

CBD, oral – clinically investigated

Finding ID: B0131

Type of result: Mixed/context-dependent finding

Observation: Stronger conditioned pain modulation before opioid-agonist treatment (dose p=0.034); lower heat-pain threshold after treatment with 1200 mg (d′ −0.63, p=0.017). Not a simple general enhancement of analgesia.

Mechanism: Time- and dose-dependent pharmacodynamic pain modulation

Study type: Randomised crossover study

Context studied: n=23; mean methadone 85.7±29.7 mg/day; CBD 400/800/1200 mg, experimental pain tests before/after opioid-agonist treatment.

Clinical interpretation: Clinical significance limited; no methadone pharmacokinetic conclusion

Limitations and uncertainties: Acute administration, laboratory endpoints; craving not significant, cognition preserved. Study amounts are not dosage recommendations.

Original sources for this finding: An opioid-withholding human laboratory paradigm during opioid agonist treatment for opioid use disorder and chronic pain: Phase- and dose-dependent effects of cannabidiol. [CA_P_42162267]

Oral THC/dronabinol – clinically investigated

Finding ID: B0132

Type of result: Mixed/context-dependent finding

Observation: Subjective pain improvement, particularly 10 mg, but no improvement in experimental pain; no demonstrated interaction with methadone dose group.

Mechanism: Pharmacodynamic

Study type: Randomised placebo-controlled crossover study

Context studied: n=25 receiving methadone; dronabinol 10/20 mg. Methadone strata below/above 90 mg.

Clinical interpretation: Limited symptomatic finding

Limitations and uncertainties: No pharmacokinetics; cognition inconsistent. Do not count post-hoc publications as independent cohorts.

Original sources for this finding: Delta-9-tetrahydrocannabinol modulates pain sensitivity among persons receiving opioid agonist therapy for opioid use disorder: A within-subject, randomized, placebo-controlled laboratory study. [CA_P_37644897]

Cannabis, composition of use not standardised – clinical signals

Finding ID: B0133

Type of result: Contradictory findings

Observation: Hallinan 2009 and Meini 2015 reported lower dose-related methadone concentrations with cannabis use; Chalabianloo 2021 a slightly higher serum concentration (p=0.049). Direction inconsistent.

Mechanism: Observed concentration association; cause not established

Study type: Clinical observational studies

Context studied: Hallinan: 77 Australian/74 Swiss patients; Meini: 94; Chalabianloo: 83.

Clinical interpretation: No reliable quantitative prediction

Limitations and uncertainties: Use, adherence, dose/sampling time and other factors confound results; do not equate R/S-methadone with levomethadone.

Original sources for this finding: Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: a transnational study. [CA_P_19639308]; Relationship between plasma concentrations of the l-enantiomer of methadone and response to methadone maintenance treatment. [CA_P_25891369]; Subjective symptoms and serum methadone concentrations: what should guide dose adjustments in methadone maintenance treatment? A naturalistic cohort study from Norway. [CA_P_33941217]

References and access status

[CA_L_D0144] METHADOSE DISPERSIBLE (METHADONE HYDROCHLORIDE) TABLET METHADONE HYDROCHLORIDE TABLET [SPECGX LLC]

Original source / bibliographic reference

Authors: SpecGx LLC

Year: 2026

Source type: Current published human-use SPL / product information

Source access – 23 October 2026: Source destination was accessible when checked.

Bibliographic attribution or source identity cross-checked.

[EX03] Clinically Significant Drug-Drug Interaction Between Methadone and Cannabidiol

Original source / bibliographic reference

Authors: Madden K; Tanco K; Bruera E

Year: 2020

Source type: Case report

DOI: 10.1542/peds.2019-3256

PMID: 32444381

Source access – 23 October 2026: Direct retrieval could not be fully verified; availability remains unresolved.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

[CA_P_42162267] An opioid-withholding human laboratory paradigm during opioid agonist treatment for opioid use disorder and chronic pain: Phase- and dose-dependent effects of cannabidiol.

Original source / bibliographic reference

Authors: P A Costa G, Sofuoglu M, Compton P, Ranganathan M, Pittman B, De Aquino JP.

Year: 2026

Source type: research-article; Randomized Controlled Trial; Journal Article

DOI: 10.1038/s41386-026-02443-w

PMID: 42162267

Source access – 23 October 2026: Source destination was accessible when checked.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

[CA_P_41496743] Exploring the effects of cannabidiol on pain sensitivity using quantitative sensory testing among individuals receiving methadone or buprenorphine for opioid use disorder: an open-label, proof-of-concept study.

Original source / bibliographic reference

Authors: Costa GPA, Suh R, Sofuoglu M, De Aquino JP.

Year: 2026

Source type: brief-report; Journal Article

DOI: 10.1016/j.abrep.2025.100654

PMID: 41496743

Source access – 23 October 2026: Direct retrieval could not be fully verified; availability remains unresolved.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

PubMed Central – full-text access according to the literature database – Archive attribution confirmed by Europe PMC metadata. Direct retrieval was not fully verified here; access may require a browser check.

Europe PMC – full-text access according to the literature database – Listed as freely available HTML full text in the official Europe PMC metadata. Direct retrieval was not fully verified here.

[CA_P_37644897] Delta-9-tetrahydrocannabinol modulates pain sensitivity among persons receiving opioid agonist therapy for opioid use disorder: A within-subject, randomized, placebo-controlled laboratory study.

Original source / bibliographic reference

Authors: De Aquino JP, Meyerovich J, Xie CZ, Ranganathan M, Compton P, Pittman B, Rogan M, Sofuoglu M.

Year: 2023

Source type: Research Support, Non-U.S. Gov't; research-article; Randomized Controlled Trial; Research Support, U.S. Gov't, Non-P.H.S.; Journal Article; Research Support, N.I.H., Extramural

DOI: 10.1111/adb.13317

PMID: 37644897

Source access – 23 October 2026: Direct retrieval could not be fully verified; availability remains unresolved.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

PubMed Central – full-text access according to the literature database – Archive attribution confirmed by Europe PMC metadata. Direct retrieval was not fully verified here; access may require a browser check.

Europe PMC – full-text access according to the literature database – Listed as freely available HTML full text in the official Europe PMC metadata. Direct retrieval was not fully verified here.

[CA_P_38991269] A preliminary investigation of the acute effects of delta-9-tetrahydrocannabinol on pain and opioid attentional bias among persons with opioid use disorder.

Original source / bibliographic reference

Authors: Wolkowicz NR, Sofuoglu M, Pittman B, Meyerovich J, MacLean RR, De Aquino JP.

Year: 2024

Source type: Research Support, Non-U.S. Gov't; research-article; Randomized Controlled Trial; Journal Article

DOI: 10.1016/j.jpsychires.2024.06.047

PMID: 38991269

Source access – 23 October 2026: Direct retrieval could not be fully verified; availability remains unresolved.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

PubMed Central – full-text access according to the literature database – Archive attribution confirmed by Europe PMC metadata. Direct retrieval was not fully verified here; access may require a browser check.

Europe PMC – full-text access according to the literature database – Listed as freely available HTML full text in the official Europe PMC metadata. Direct retrieval was not fully verified here.

[CA_P_38059660] Brief report: The influence of childhood trauma on the effects of delta-9-tetrahydrocannabinol in persons with opioid use disorder.

Original source / bibliographic reference

Authors: Rogan M, Nunes JC, Xie CZ, Sofuoglu M, Pittman B, De Aquino JP.

Year: 2024

Source type: research-article; Randomized Controlled Trial; Journal Article; Research Support, N.I.H., Extramural

DOI: 10.1111/ajad.13504

PMID: 38059660

Source access – 23 October 2026: Direct retrieval could not be fully verified; availability remains unresolved.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

PubMed Central – full-text access according to the literature database – Archive attribution confirmed by Europe PMC metadata. Direct retrieval was not fully verified here; access may require a browser check.

Europe PMC – full-text access according to the literature database – Listed as freely available HTML full text in the official Europe PMC metadata. Direct retrieval was not fully verified here.

[CA_P_40488149] The Electrocardiographic Conundrum in a Patient on Methadone Maintenance Therapy and Cannabis Coingestion: A Case Report of a Heartbreaking Puzzle.

Original source / bibliographic reference

Authors: Zaman MA, Amir A, Mastrine L.

Year: 2024

Source type: Journal Article; Case Reports; case-report

DOI: 10.4103/heartviews.heartviews_124_24

PMID: 40488149

Source access – 23 October 2026: Source destination was accessible when checked.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

[CA_P_19639308] Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: a transnational study.

Original source / bibliographic reference

Authors: Hallinan R, Crettol S, Agho K, Attia J, Besson J, Croquette-Krokar M, Hämmig R, Déglon JJ, Byrne A, Ray J, Somogyi AA, Eap CB.

Year: 2009

Source type: Research Support, Non-U.S. Gov't; Journal Article

DOI: 10.1007/s00228-009-0706-8

PMID: 19639308

Source access – 23 October 2026: Source destination was accessible when checked.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

[CA_P_25891369] Relationship between plasma concentrations of the l-enantiomer of methadone and response to methadone maintenance treatment.

Original source / bibliographic reference

Authors: Meini M, Moncini M, Daini L, Giarratana T, Scaramelli D, Chericoni S, Stefanelli F, Rucci P.

Year: 2015

Source type: Research Support, Non-U.S. Gov't; Journal Article

DOI: 10.1016/j.ejphar.2015.03.081

PMID: 25891369

Source access – 23 October 2026: Automated direct retrieval was restricted; this does not establish that the link is broken.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

[CA_P_33941217] Subjective symptoms and serum methadone concentrations: what should guide dose adjustments in methadone maintenance treatment? A naturalistic cohort study from Norway.

Original source / bibliographic reference

Authors: Chalabianloo F, Fadnes LT, Høiseth G, Ohldieck C, Vold JH, Aas C, Løberg EM, Johansson KA, Bramness JG.

Year: 2021

Source type: Research Support, Non-U.S. Gov't; research-article; Journal Article

DOI: 10.1186/s13011-021-00367-w

PMID: 33941217

Source access – 23 October 2026: Source destination was accessible when checked.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

[CA_P_21716095] THC-methadone and THC-naltrexone interactions on discrimination, antinociception, and locomotion in rats.

Original source / bibliographic reference

Authors: Wakley AA, Craft RM.

Year: 2011

Source type: Journal Article

DOI: 10.1097/fbp.0b013e328348ed22

PMID: 21716095

Source access – 23 October 2026: Direct retrieval could not be fully verified; availability remains unresolved.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

[CA_P_11331071] Cannabinoid-induced alterations in brain disposition of drugs of abuse.

Original source / bibliographic reference

Authors: Reid MJ, Bornheim LM.

Year: 2001

Source type: Research Support, U.S. Gov't, P.H.S.; Journal Article

DOI: 10.1016/s0006-2952(01)00616-5

PMID: 11331071

Source access – 23 October 2026: Direct retrieval could not be fully verified; availability remains unresolved.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

[CA_P_17466429] Chronic cannabis use does not affect the normalization of hypothalamic-pituitary-adrenal (HPA) axis induced by methadone in heroin addicts.

Original source / bibliographic reference

Authors: Nava F, Manzato E, Lucchini A.

Year: 2007

Source type: Journal Article

DOI: 10.1016/j.pnpbp.2007.03.013

PMID: 17466429

Source access – 23 October 2026: Source destination was accessible when checked.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

[CA_P_42822008] Respiratory depression with concomitant use of opioids and cannabinoids: a case report.

Original source / bibliographic reference

Authors: Messick CL, Svendsen M, Codding J, Rejbi M.

Year: 2026

Source type: Journal Article

DOI: 10.1080/00325481.2026.2739680

PMID: 42822008

Source access – 23 October 2026: Source destination was accessible when checked.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

[CA_P_37065899] Impact of cannabidiol on reward- and stress-related neurocognitive processes among individuals with opioid use disorder: A pilot, double-blind, placebo-controlled, randomized cross-over trial.

Original source / bibliographic reference

Authors: Suzuki J, Prostko S, Szpak V, Chai PR, Spagnolo PA, Tenenbaum RE, Ahmed S, Weiss RD.

Year: 2023

Source type: brief-report; Journal Article

DOI: 10.3389/fpsyt.2023.1155984

PMID: 37065899

Source access – 23 October 2026: Direct retrieval could not be fully verified; availability remains unresolved.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

PubMed Central – full-text access according to the literature database – Archive attribution confirmed by Europe PMC metadata. Direct retrieval was not fully verified here; access may require a browser check.

Europe PMC – full-text access according to the literature database – Listed as freely available HTML full text in the official Europe PMC metadata. Direct retrieval was not fully verified here.

[CA_P_19887017] Interaction of drugs of abuse and maintenance treatments with human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2).

Original source / bibliographic reference

Authors: Tournier N, Chevillard L, Megarbane B, Pirnay S, Scherrmann JM, Declèves X.

Year: 2010

Source type: Journal Article

DOI: 10.1017/s1461145709990848

PMID: 19887017

Source access – 23 October 2026: Source destination was accessible when checked.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

[CA_P_1241452] Attenuation of precipitated abstinence in methadone-dependent rats by delta 9-THC.

Original source / bibliographic reference

Authors: Hine B, Torrelio M, Gershon S.

Year: 1975

Source type: Rat experiment with naloxone-precipitated withdrawal; original abstract assessed, original full text not verified

PMID: 1241452

Source access – 23 October 2026: Automated direct retrieval was restricted; this does not establish that the link is broken.

Bibliographic attribution or source identity cross-checked.

Unresolved access questions / further review: The official original abstract was scientifically reassessed on 23 October 2026. It concerns Δ9-THC before naloxone-precipitated withdrawal in methadone-dependent male rats, not clinical methadone maintenance treatment. Europe PMC provides bibliographic data and abstract, not full text. Group sizes, complete methods and statistics remain unassessed; no clinical pharmacokinetic/safety conclusion possible.

Europe PMC – bibliographic data and abstract (JSON; not full text) – Official bibliographic record successfully checked. The view is machine-readable and is not the original full text.

[CA_P_6245206] Methadone-induced attenuation of the effects of delta 9-tetrahydrocannabinol on temporal discrimination in pigeons.

Original source / bibliographic reference

Authors: Daniel SA, Thompson T.

Year: 1980

Source type: Research Support, U.S. Gov't, P.H.S.; Journal Article

DOI: 10.1016/s0022-3565(25)32052-5

PMID: 6245206

Source access – 23 October 2026: Automated direct retrieval was restricted; this does not establish that the link is broken.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

[CA_P_23361846] Role of cytochrome P4502B6 in methadone metabolism and clearance

Original source / bibliographic reference

Authors: Kharasch ED, Stubbert K.

Year: 2013

Source type: Controlled sequential human pharmacokinetic study with ticlopidine as a CYP2B6 inhibition probe; no cannabinoid administration.

DOI: 10.1002/jcph.1

PMID: 23361846

Source access – 23 October 2026: Direct retrieval could not be fully verified; availability remains unresolved.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

PubMed Central – full-text access according to the literature database – Archive attribution confirmed by Europe PMC metadata. Direct retrieval was not fully verified here; access may require a browser check.

Europe PMC – full-text access according to the literature database – Listed as freely available HTML full text in the official Europe PMC metadata. Direct retrieval was not fully verified here.

Research as of 23 October 2026. Not all original full texts could be reviewed in full. Source accessibility and the strength of scientific evidence must be assessed separately. An accessible link does not establish medical approval; a bibliographic record with an abstract does not replace the original full text.

Drug search and explanation of the evidence · Guide: cannabinoids and medicines · Author and responsibility