generation run 2026-04-27
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24 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | Web | methadone history discovery synthesis 1939 Germany Bockmühl Ehrhart IG Farbenindustrie | 10 | 2 | Historical sources confirm core facts about methadone discovery |
| 2 | Web | methadone Schedule II controlled substance DEA US legal status UK Class A Canada Australia | 10 | 3 | Legal status confirmed across major jurisdictions |
| 3 | PubMed | methadone QT interval prolongation torsades de pointes arrhythmia | 10 | 6 | Comprehensive coverage of methadone cardiac toxicity via hERG channel block |
| 4 | Web | — | 1 | 1 | Primary historical reference |
| 5 | Web | — | 1 | 1 | Corroborates synthesis history and US introduction |
| 6 | PubMed | Dole Nyswander heroin addiction methadone treatment 1965 JAMA | 1 | 1 | Foundational clinical paper for methadone maintenance |
| 7 | PubMed | methadone pharmacokinetics bioavailability half-life CYP3A4 metabolism human | 4 | 2 | Eap 2002 is the landmark PK review; Benmebarek 2004 on grapefruit juice (CYP3A4 inhibition) is relevant drug interaction data |
| 8 | PubMed | methadone pharmacology receptor binding opioid NMDA | 8 | 6 | All relevant to pharmacological mechanism of methadone at opioid and NMDA receptors |
| 9 | PubChem | methadone | 1 | 1 | Single verified compound entry for methadone |
| 10 | ClinicalTrials.gov | methadone chronic pain cancer pain management | 8 | 2 | Pain indication clinical trial evidence |
| 11 | PubMed | — | 1 | 1 | Primary regulatory history reference |
| 12 | PubMed | methadone serotonin norepinephrine reuptake inhibition monoamine transporter | 2 | 1 | Primary source for SNRI activity of methadone |
| 13 | OpenAlex | methadone maintenance treatment opioid dependence | 8 | 3 | Highest-citation evidence base for methadone treatment efficacy and mortality reduction |
| 14 | OpenAlex | methadone opioid receptor pharmacology | 10 | 3 | Selected Cochrane review and CDC guidelines for treatment context; broad addiction reviews not specifically about methadone pharmacology |
| 15 | PubMed | methadone drug interaction benzodiazepine alcohol CNS depressant respiratory depression fatal | 3 | 3 | Key interaction and mechanism data for safety section |
| 16 | ClinicalTrials.gov | methadone opioid use disorder treatment | 10 | 2 | Active and completed trials specifically involving methadone |
| 17 | PubMed | tramadol serotonin syndrome opioid interaction methadone serotonergic | 3 | 3 | Interaction mechanism for tramadol and serotonergic drug interactions |
| 18 | Web | methadone CAS 76-99-3 SMILES canonical InChIKey melting point solubility | 10 | 1 | Chemical property verification |
| 19 | PubMed | methadone blood concentration therapeutic toxic fatal forensic postmortem | 5 | 3 | Forensic toxicology data for toxicity section |
| 20 | PubMed/NCBI | — | 1 | 1 | WHO essential medicine status confirmed |
| 21 | PubMed | methadone CYP2B6 genetic polymorphism metabolism dose individualization | 6 | 4 | CYP2B6 pharmacogenomics data for metabolism and safety sections |
| 22 | PubMed | methadone EDDP metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine CYP metabolism | 5 | 3 | Critical metabolic enzyme data correcting earlier overemphasis on CYP3A4 |
| 23 | PubMed | methadone equianalgesic morphine conversion ratio opioid rotation dosing | 5 | 2 | Evidence for variable equianalgesic ratios relevant to dosing section |
| 24 | PubMed | methadone QT prolongation HERG methadone hERG IC50 mechanism | 3 | 2 | Confirms hERG block mechanism and IC50 for methadone cardiac toxicity |
115 claims by section — every cited sentence, checked against its source
safety46 · 42 ok
A systematic review and meta-analysis quantified the incidence during methadone maintenance treatment.supported
Systematic review and meta-analysis quantifying incidence of QTc prolongation and TdP in methadone maintenance treatment. md.0000000000045304
Additive respiratory depression is confirmed experimentally for the diazepam/methadone combinationsupported
Diazepam/methadone combination produces additive respiratory depression in rats. j.drugalcdep.2012.12.020
The mechanism is direct hERG (IKr) potassium channel blockade (IC₅₀ = 4.8 μM), confirmed in iPSC-derived cardiomyocytes where methadone also inhibits L-type calcium current (ICaL) and late sodium current (INaL)partially supported
Methadone IC50 for hERG inhibition = 4.8 microM. s12012-010-9074-y
The mechanism is direct hERG (IKr) potassium channel blockade (IC₅₀ = 4.8 μM), confirmed in iPSC-derived cardiomyocytes where methadone also inhibits L-type calcium current (ICaL) and late sodium current (INaL)supported
Methadone inhibited hERG (IhERG), ICaL, and INaL at clinically relevant concentrations; caused delayed repolarization in iPSC-CMs. journal.pone.0241362
The American Heart Association's scientific statement on drug-induced arrhythmias specifically names methadone among drugs capable of QTc prolongation and TdPsupported
AHA scientific statement on drug-induced arrhythmias. Methadone specifically mentioned as capable of prolonging QT interval and provoking torsades de pointes. cir.0000000000000905
Claim in safety — inconclusiveinconclusiveworking →
Risk factors include: doses exceeding 100 mg/day, co-administration of other QT-prolonging drugs, hypokalemia and hypomagnesemia, pre-existing cardiac disease, female sex, and CYP inhibition raising S-methadone levelssupported
AHA scientific statement on drug-induced arrhythmias. Methadone specifically mentioned as capable of prolonging QT interval and provoking torsades de pointes. cir.0000000000000905
Risk factors include: doses exceeding 100 mg/day, co-administration of other QT-prolonging drugs, hypokalemia and hypomagnesemia, pre-existing cardiac disease, female sex, and CYP inhibition raising S-methadone levelssupported
CYP2B6 poor metabolizers at elevated fatality risk. SNP rs3211371 associated with higher blood methadone concentrations. bkw135
Claim in safety — inconclusiveinconclusiveworking →
Respiratory depression is the primary mechanism of fatal methadone overdosesupported
Co-ingested CNS depressants more critical than tolerance reduction. j.forsciint.2015.01.004
The induction phase — the first weeks of treatment — carries the highest mortality risk.supported
Largest proportion of deaths during induction phase. pmid:21158011
The induction phase — the first weeks of treatment — carries the highest mortality risk.supported
Mortality drops sharply in first 4 weeks of treatment. bmj.j1550
Forensic data: a systematic review of methadone-related deaths found median postmortem blood concentration of 503 ng/mL (IQR 300–933 ng/mL) in adultssupported
Median blood methadone concentration in adults at death: 503 ng/mL (IQR 300-933). s00414-025-03620-0
In 176 Kentucky methadone fatalities, mean blood concentration was 0.535 mg/L (range 0.02–4.0 mg/L), and only 6.25% had methadone as the sole detected drugsupported
176 Kentucky methadone fatalities 2000-2004. Mean blood concentration 0.535 mg/L (range 0.02-4.0). Only 6.25% had methadone as sole detected drug. pmid:18093068
Co-detected substances included antidepressants (39.8%), benzodiazepines (32.4%), other opioids (27.8%), cannabinoids (28.4%), and cocaine (21.9%)partially supported
Antidepressants (39.8%), benzodiazepines (32.4%), other opioids (27.8%) co-detected. pmid:18093068
Polydrug combinations — especially with benzodiazepines — constitute the overwhelming context for methadone fatalities.supported
Extensive benzodiazepine co-use in all subgroups. Co-ingested CNS depressants more critical than tolerance reduction. j.forsciint.2015.01.004
The CYP2B6 poor metabolizer phenotype (especially the CYP2B6*6 allele) significantly elevates blood methadone concentrations and is independently associated with fatal outcomessupported
CYP2B6*6 allele associated with high methadone concentrations in fatalities. pmid:21158011
The CYP2B6 poor metabolizer phenotype (especially the CYP2B6*6 allele) significantly elevates blood methadone concentrations and is independently associated with fatal outcomessupported
CYP2B6 poor metabolizers at elevated fatality risk. SNP rs3211371 associated with higher blood methadone concentrations. bkw135
OPRM1 variants also influence methadone treatment outcomes and may modify dose requirements.supported
Study of OPRM1 and CYP2B6 genetic variants and methadone treatment outcomes in 1,172 patients. journal.pone.0261201
The overlap between therapeutic and fatal blood concentrations implies a narrow therapeutic index, particularly in opioid-naive individuals and CYP2B6 poor metabolizerssupported
Median blood methadone concentration in adults at death: 503 ng/mL (IQR 300-933), overlapping with therapeutic concentrations. s00414-025-03620-0
Dependence and compulsive use: Methadone is classified as having high abuse potential (DEA Schedule II). Psychological dependence develops alongside physical dependence.supported
Reviews neurobiology of addiction including opioid use disorder. nejmra1511480
Opioid tolerance develops through mu-opioid receptor desensitization, phosphorylation, uncoupling, and internalization — a cascade involving β-arrestin recruitment that reduces receptor density and signaling efficiencysupported
Review of opioid receptor desensitization mechanisms including phosphorylation, receptor uncoupling, internalization, and post-endocytic fate. Links receptor desensitization to clinical tolerance development. fphar.2014.00280
Methadone's β-arrestin-biased agonism may alter the kinetics of this desensitization relative to G-protein-biased agonists like morphine, though clinical confirmation is incomplete.supported
Characterization of methadone as a β-arrestin-biased μ-opioid receptor agonist. 1744806916654146
In vivo evidence for this is limited — spinal electrophysiology shows the NMDA component is modest and partially naloxone-reversible.supported
d-Methadone inhibitory effects on dorsal horn neurons are naloxone-reversible, suggesting predominantly opioid mechanism in vivo despite NMDA antagonist activity in vitro. pmid:10833552
Claim in safety — not_supportednot supportedworking →
Methadone maintenance treatment deliberately harnesses physical dependence therapeutically: the Cochrane meta-analysis confirms MMT retains patients and suppresses heroin use more effectively than non-opioid treatmentssupported
Methadone maintenance was first widely used ORT for heroin dependence. Retains patients better and decreases heroin use better than non-opioid treatments. 14651858.cd002209.pub2
The mortality benefit is substantial — all-cause mortality of 11.3 per 1,000 person-years during treatment versus 36.1 out of treatment.supported
All-cause mortality 11.3 vs 36.1 per 1000 person-years in vs out of methadone treatment. bmj.j1550
benzodiazepines and alcohol facilitate GABA-A-mediated inhibition, synergizing with methadone's mu-opioid respiratory depression through convergent but pharmacologically distinct pathwayssupported
Benzodiazepines and alcohol facilitate GABA inhibition; alcohol also decreases glutamate excitation at NMDA receptors. pmid:10707430
Benzodiazepines are the most prevalent co-detected substance in methadone fatalities.supported
Extensive benzodiazepine co-use in all subgroups. j.forsciint.2015.01.004
Methadone's SERT and NET inhibition creates clinically significant serotonin syndrome risk in combination with MAOIs (high risk, potentially lethal), SSRIs, SNRIs, and TCAs (moderate risk). tramadol poses dual risk: it inhibits SERT/NET and is a weak mu-opioid agonist, producing both serotonin syndrome and enhanced respiratory depression simultaneously.supported
Methadone inhibits SERT in HEK293 cells transfected with human SERT. Supports pharmacological class as SNRI-type activity. s00204-018-2244-6
Methadone's SERT and NET inhibition creates clinically significant serotonin syndrome risk in combination with MAOIs (high risk, potentially lethal), SSRIs, SNRIs, and TCAs (moderate risk). tramadol poses dual risk: it inhibits SERT/NET and is a weak mu-opioid agonist, producing both serotonin syndrome and enhanced respiratory depression simultaneously.supported
Methadone confirmed as SERT and NET inhibitor. Link to clinical reports of serotonin syndrome. bph.14105
Methadone's SERT and NET inhibition creates clinically significant serotonin syndrome risk in combination with MAOIs (high risk, potentially lethal), SSRIs, SNRIs, and TCAs (moderate risk). tramadol poses dual risk: it inhibits SERT/NET and is a weak mu-opioid agonist, producing both serotonin syndrome and enhanced respiratory depression simultaneously.supported
Methadone inhibits SERT in HEK293 cells transfected with human SERT. Also shows 5-HT2A receptor interaction. s00204-018-2244-6
Methadone's SERT and NET inhibition creates clinically significant serotonin syndrome risk in combination with MAOIs (high risk, potentially lethal), SSRIs, SNRIs, and TCAs (moderate risk). tramadol poses dual risk: it inhibits SERT/NET and is a weak mu-opioid agonist, producing both serotonin syndrome and enhanced respiratory depression simultaneously.supported
High-risk combinations (e.g., MAOIs with tramadol/methadone) must be avoided. s00482-015-1512-0
Methadone's SERT and NET inhibition creates clinically significant serotonin syndrome risk in combination with MAOIs (high risk, potentially lethal), SSRIs, SNRIs, and TCAs (moderate risk). tramadol poses dual risk: it inhibits SERT/NET and is a weak mu-opioid agonist, producing both serotonin syndrome and enhanced respiratory depression simultaneously.supported
Methadone inhibits SERT in HEK293 cells transfected with human SERT. Also shows 5-HT2A receptor interaction. s00204-018-2244-6
Methadone's SERT and NET inhibition creates clinically significant serotonin syndrome risk in combination with MAOIs (high risk, potentially lethal), SSRIs, SNRIs, and TCAs (moderate risk). tramadol poses dual risk: it inhibits SERT/NET and is a weak mu-opioid agonist, producing both serotonin syndrome and enhanced respiratory depression simultaneously.supported
Combined with serotonergic drugs, can provoke serotonin syndrome. High-risk combinations (e.g., MAOIs with tramadol/methadone) must be avoided. s00482-015-1512-0
CYP inhibitors (fluconazole, paroxetine, grapefruit juice) elevate methadone levels, increasing both opioid and cardiac risksupported
Grapefruit juice (intestinal CYP3A inhibitor) investigated for effect on steady-state methadone PK. pmid:15229464
Claim in safety — inconclusiveinconclusiveworking →
The stereoselective metabolism means some interactions preferentially alter S- or R-methadone levels, with different clinical consequences.supported
CYP2B6 preferentially metabolizes S-methadone; CYP2C19 preferentially metabolizes R-methadone; CYP3A4 no stereoselectivity. pmid:14628297
Methadone functions as an independent risk factor for life-threatening arrhythmias.supported
Methadone specifically mentioned as capable of prolonging QT interval and provoking torsades de pointes. cir.0000000000000905
Concurrent MAOI use: High risk of lethal serotonin syndrome via methadone's SERT inhibition.supported
Methadone inhibits SERT in HEK293 cells transfected with human SERT. s00204-018-2244-6
Concurrent MAOI use: High risk of lethal serotonin syndrome via methadone's SERT inhibition.supported
High-risk combinations (e.g., MAOIs with tramadol/methadone) must be avoided. s00482-015-1512-0
QT-prolonging conditions or medications: Significant TdP risk; ECG monitoring required at initiation and dose changes.supported
Systematic review and meta-analysis quantifying incidence of QTc prolongation and TdP in methadone maintenance treatment. md.0000000000045304
QT-prolonging conditions or medications: Significant TdP risk; ECG monitoring required at initiation and dose changes.supported
Methadone specifically mentioned as capable of prolonging QT interval and provoking torsades de pointes. cir.0000000000000905
CYP2B6 poor metabolizer phenotype (especially *6/*6 genotype): Elevated blood levels; dose reduction and enhanced monitoring required.supported
CYP2B6 poor metabolizers at elevated fatality risk. SNP rs3211371 associated with higher blood methadone concentrations. bkw135
CYP2B6 poor metabolizer phenotype (especially *6/*6 genotype): Elevated blood levels; dose reduction and enhanced monitoring required.supported
CYP2B6*6 allele associated with high methadone concentrations in fatalities. pmid:21158011
Concurrent benzodiazepine use: Additive respiratory depression; if unavoidable, dose reduction and respiratory monitoring are essential.supported
Extensive benzodiazepine co-use in all subgroups. Co-ingested CNS depressants more critical than tolerance reduction. j.forsciint.2015.01.004
pharmacology16 · 15 ok
Claim in pharmacology — inconclusiveinconclusiveworking →
Methadone has been characterized as a β-arrestin-biased μ-opioid receptor agonist, pharmacodynamically distinct from morphine and fentanyl in discriminative stimulus assays and in vitro measures of MOR internalization and β-arrestin recruitmentsupported
Investigates pharmacological profile of methadone vs fentanyl and morphine. Measures discriminative stimulus, NMDA receptor binding, mu-opioid receptor internalization, and beta-arrestin recruitment. 1744806916654146
Both enantiomers bind to the non-competitive (MK-801) site of the NMDA receptor in rat forebrain and spinal cord, with affinity in the low micromolar range comparable to dextromethorphan, while lacking affinity at the competitive (CGS-19755) sitesupported
dl-Methadone and d- and l-isomers exhibited low micromolar affinities for [3H]MK-801-labeled non-competitive NMDA site in rat forebrain and spinal cord. Ki values similar to dextromethorphan. No affinity at competitive site. pmid:9058409
Racemic methadone binds the MK-801-labeled site with Ki = 0.85 μMsupported
Methadone Ki for [3H]MK-801 binding = 0.85 microM. pmid:7624018
Functional inhibition of all rat NMDA receptor subtypes occurs at low micromolar IC₅₀ values that overlap with clinically achievable plasma concentrations, with NR1/2A and NR1/2B subtypes more sensitive than NR1/2C and NR1/2D; R(−)-methadone shows preferential selectivity for NR1/2Asupported
Racemic methadone inhibited all subtypes of rat NMDA receptors with IC50 in low micromolar range; concentrations overlap with clinically achievable levels. NR1/2A and NR1/2B more sensitive than NR1/2C and NR1/2D. Noncompetitive mechanism. R(-) methadone highly selective for NR1/2A. pmid:14980914
The mechanism is non-competitive channel block, reducing maximum NMDA-stimulated currents without shifting EC₅₀.supported
Noncompetitive mechanism. pmid:14980914
Methadone has been characterized alongside ketobemidone as a weak non-competitive NMDA antagonist with potential utility in neuropathic pain via combined opioid and NMDA mechanismssupported
Methadone, ketobemidone, and dextropropoxyphene demonstrated to be weak noncompetitive NMDA receptor antagonists in addition to being opioid agonists. Discusses structure-activity relationships and clinical relevance for neuropathic pain. pmid:9783723
Despite these in vitro findings, in vivo spinal cord electrophysiology in rats demonstrated that methadone's antinociceptive effects are predominantly opioid-receptor mediated and naloxone-reversible, with the NMDA antagonist component playing a lesser role than in vitro data might suggestsupported
d-Methadone inhibitory effects on dorsal horn neurons are naloxone-reversible, suggesting predominantly opioid mechanism in vivo despite NMDA antagonist activity in vitro. pmid:10833552
Methadone inhibits the human serotonin transporter (SERT) in HEK293 cells and shows interaction with 5-HT₂A receptorssupported
Methadone inhibits SERT in HEK293 cells transfected with human SERT. Also shows 5-HT2A receptor interaction. s00204-018-2244-6
Norepinephrine transporter (NET) inhibition has also been quantified, confirming SERT and NET inhibitory activity at therapeutic concentrationssupported
Systematic in vitro study of opioid effects on SERT and NET. Methadone confirmed as SERT and NET inhibitor. bph.14105
Methadone directly blocks the cardiac hERG (IKr) potassium channel with an IC₅₀ of 4.8 μM — approximately 100-fold more potent than heroin at this targetsupported
Methadone IC50 for hERG inhibition = 4.8 microM; heroin IC50 = 427 microM. Methadone ~100-fold more potent than heroin at blocking hERG currents. s12012-010-9074-y
In iPSC-derived cardiomyocytes, methadone also inhibits L-type calcium current (ICaL) and late sodium current (INaL) at clinically relevant concentrations, causing delayed repolarizationsupported
Methadone inhibited hERG (IhERG), ICaL, and INaL at clinically relevant concentrations; caused delayed repolarization in iPSC-CMs. journal.pone.0241362
Methadone's pharmacokinetics are defined by high oral bioavailability (~75%, range 36–100%), slow absorption (Tmax 2.5–4 hours), extensive tissue distribution (Vd ~4 L/kg), and a long, highly variable elimination half-life (mean ~22 hours, range 5–130 hours)supported
Methadone bioavailability mean ~75% (range 36-100%). Peak plasma at 2.5-4 hours. Mean half-life ~22 hours (range 5-130h). Volume of distribution ~4 L/kg. pmid:12405865
Interindividual variability in blood concentration can reach 17-fold for a given dose, driven primarily by CYP enzyme polymorphismssupported
17-fold interindividual variation in blood concentration. CYP3A4 and CYP2D6 metabolism. pmid:12405865
Metabolism proceeds via N-demethylation to the inactive metabolite EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine), with CYP2B6 as the primary enzyme, CYP2C19 as secondary, and CYP3A4 as tertiarysupported
CYP2B6 has highest Vmax/Km for EDDP formation from methadone. Hierarchy: CYP2B6 > CYP2C19 >= CYP3A4. pmid:14628297
Metabolism proceeds via N-demethylation to the inactive metabolite EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine), with CYP2B6 as the primary enzyme, CYP2C19 as secondary, and CYP3A4 as tertiarysupported
CYP2B6 identified as principal methadone metabolizing enzyme (more recent data). journal.pone.0231467
neuroscience12 · 11 ok
Sustained MOR occupancy during maintenance treatment reduces the neurobiological drive for exogenous opioid seeking, though it simultaneously suppresses endogenous peptide tone — contributing to the dependence and withdrawal syndrome observed upon discontinuation.supported
Reviews neurobiology of addiction including opioid use disorder. Discusses how brain disease model has led to effective treatments including methadone maintenance. nejmra1511480
Methadone maintenance stabilizes the allostatic set point by providing consistent MOR agonism, reducing the between-dose withdrawal cycles that drive further allostatic shift.supported
Reviews neurobiology of addiction including opioid use disorder. Discusses how brain disease model has led to effective treatments including methadone maintenance. nejmra1511480
Does β-arrestin-biased agonism at MOR meaningfully alter clinical tolerance and respiratory depression? Methadone's β-arrestin bias predicts distinct downstream signaling, but whether this translates to clinically relevant differences in tolerance kinetics or overdose risk versus G-protein-biased agonists remains unresolved.supported
Characterization of methadone as a β-arrestin-biased μ-opioid receptor agonist. 1744806916654146
Can pharmacogenomic-guided dosing reduce methadone-related mortality? CYP2B6 and OPRM1 variants predict treatment outcomes and fatality risk, but prospective implementation studies of genotype-guided methadone dosing are lacking.supported
Study of OPRM1 and CYP2B6 genetic variants and methadone treatment outcomes in 1,172 patients. journal.pone.0261201
Can pharmacogenomic-guided dosing reduce methadone-related mortality? CYP2B6 and OPRM1 variants predict treatment outcomes and fatality risk, but prospective implementation studies of genotype-guided methadone dosing are lacking.supported
CYP2B6*6 allele associated with high methadone concentrations in fatalities. OPRM1 A118G allele correlated with benzodiazepine co-detection. pmid:21158011
Can pharmacogenomic-guided dosing reduce methadone-related mortality? CYP2B6 and OPRM1 variants predict treatment outcomes and fatality risk, but prospective implementation studies of genotype-guided methadone dosing are lacking.supported
CYP2B6 SNPs rs3745274 and rs8192719 enhanced in fatality group. CYP2B6 poor metabolizers at elevated fatality risk. bkw135
This circuit mediates the reinforcing and euphoric effects of all mu-opioid agonistssupported
Reviews neurobiology of addiction including opioid use disorder. nejmra1511480
The additional NMDA receptor antagonism at spinal and supraspinal sites may provide supplementary antinociceptive activity, though in vivo evidence assigns a dominant role to opioid receptors.supported
d-Methadone inhibitory effects on dorsal horn neurons are naloxone-reversible, suggesting predominantly opioid mechanism in vivo despite NMDA antagonist activity in vitro. pmid:10833552
Methadone's non-competitive NMDA antagonism (Ki = 0.85 μM at the MK-801 site) may counteract central sensitization and wind-up, providing a mechanistic basis for its reported utility in neuropathic pain and opioid rotation settings where tolerance to other opioids has developed.partially supported
Methadone, ketobemidone, and dextropropoxyphene demonstrated to be weak noncompetitive NMDA receptor antagonists. Discusses clinical relevance for neuropathic pain. pmid:9783723
Claim in neuroscience — inconclusiveinconclusiveworking →
What is the quantitative contribution of NMDA antagonism to methadone's clinical analgesia? In vitro data show functionally relevant NMDA blockade at therapeutic concentrations, but in vivo evidence assigns a dominant role to opioid receptors. The NMDA contribution may be most significant in neuropathic pain states and tolerance attenuation — conditions difficult to isolate in clinical trials.supported
d-Methadone inhibitory effects on dorsal horn neurons are naloxone-reversible, suggesting predominantly opioid mechanism in vivo despite NMDA antagonist activity in vitro. pmid:10833552
Does SERT/NET inhibition contribute meaningfully to methadone's clinical effects? In vitro SERT and NET activity is documented, but no clinical study has isolated the monoaminergic contribution to methadone's analgesic or mood effects independent of MOR agonism.supported
Methadone inhibits SERT in HEK293 cells transfected with human SERT. Also shows 5-HT2A receptor interaction. s00204-018-2244-6
summary12 · 11 ok
Methadone (6-(dimethylamino)-4,4-diphenylheptan-3-one) is a synthetic full mu-opioid receptor agonist of the diphenylheptanone class, distinguished from other clinical opioids by its exceptionally long and variable elimination half-life (mean ~22 hours, range 5–130 hours) and oral duration of 10–19 hourssupported
Mean half-life ~22 hours (range 5-130h). pmid:12405865
Claim in summary — inconclusiveinconclusiveworking →
Methadone was added to the WHO Model List of Essential Medicines in 2005 and remains the most extensively studied pharmacotherapy for opioid use disorder.partially supported
In March 2005, methadone and buprenorphine added as 'complementary' medicines to the 14th WHO Model List of Essential Medicines. pmid:16544403
The R(−)-enantiomer drives mu-opioid receptor agonism — characterized as β-arrestin-biased — while both enantiomers block NMDA receptors at the MK-801 site (Ki = 0.85 μM)supported
Investigates pharmacological profile of methadone vs fentanyl and morphine. Measures discriminative stimulus, NMDA receptor binding, mu-opioid receptor internalization, and beta-arrestin recruitment. 1744806916654146
The R(−)-enantiomer drives mu-opioid receptor agonism — characterized as β-arrestin-biased — while both enantiomers block NMDA receptors at the MK-801 site (Ki = 0.85 μM)supported
Methadone Ki for [3H]MK-801 binding = 0.85 microM. pmid:7624018
Additional activity includes serotonin and norepinephrine transporter inhibition and hERG potassium channel blockade (IC₅₀ = 4.8 μM).supported
Methadone inhibits SERT in HEK293 cells transfected with human SERT. Also shows 5-HT2A receptor interaction. s00204-018-2244-6
Additional activity includes serotonin and norepinephrine transporter inhibition and hERG potassium channel blockade (IC₅₀ = 4.8 μM).supported
Methadone confirmed as SERT and NET inhibitor. bph.14105
Additional activity includes serotonin and norepinephrine transporter inhibition and hERG potassium channel blockade (IC₅₀ = 4.8 μM).supported
Methadone IC50 for hERG inhibition = 4.8 microM. s12012-010-9074-y
Methadone carries a narrow therapeutic index: postmortem blood concentrations in fatalities (median 503 ng/mL) overlap substantially with therapeutic levels in tolerant patientssupported
Median blood methadone concentration in adults at death: 503 ng/mL (IQR 300-933), overlapping with therapeutic concentrations. s00414-025-03620-0
QTc prolongation via hERG blockade constitutes an independent cardiac risk rare among opioidssupported
Systematic review and meta-analysis quantifying incidence of QTc prolongation and TdP in methadone maintenance treatment. md.0000000000045304
Physical dependence develops rapidly; tolerance proceeds through mu-opioid receptor desensitization, though NMDA antagonism may attenuate this process relative to pure mu agonistssupported
Review of opioid receptor desensitization mechanisms including phosphorylation, receptor uncoupling, internalization, and post-endocytic fate. Links receptor desensitization to clinical tolerance development. fphar.2014.00280
Interindividual pharmacokinetic variability is extreme — up to 17-fold differences in blood concentration for a given dose — driven primarily by CYP2B6 polymorphismspartially supported
17-fold interindividual variation in blood concentration. CYP3A4 and CYP2D6 metabolism. pmid:12405865
clinical-evidence10 · 7 ok
Overdose mortality: 2.6 versus 12.7 per 1,000 person-years in and out of treatment, respectivelysupported
Overdose mortality 2.6 vs 12.7 per 1000 person-years. bmj.j1550
A Cochrane review comparing methadone and buprenorphine maintenance found comparable efficacy overall, with methadone showing superior treatment retention at adequate doses and buprenorphine demonstrating a more favorable safety profile (lower overdose risk)partially supported
Methadone superior to buprenorphine in retaining people in treatment. 14651858.cd002207.pub4
Methadone remains the standard comparator in trials of diamorphine (pharmaceutical heroin) prescribing for treatment-refractory heroin dependence.supported
Supervised injectable heroin treatment as intensive alternative to standard oral methadone maintenance treatment for entrenched heroin users. bjp.bp.114.149195
A Cochrane systematic review confirmed that MMT retains patients in treatment and reduces heroin use significantly more than non-opioid treatments or placebosupported
Retains patients better and decreases heroin use better than non-opioid treatments. 14651858.cd002209.pub2
The induction phase carries the highest mortality risk; mortality rates are elevated in the first four weeks after treatment entry and in the period immediately following treatment cessation.supported
Largest proportion of deaths during induction phase. pmid:21158011
Claim in clinical-evidence — inconclusiveinconclusiveworking →
The CDC's 2022 clinical practice guideline notes methadone's unique risks (QT prolongation, variable pharmacokinetics) and recommends it be prescribed only by clinicians familiar with its specific properties.supported
Updated CDC clinical practice guideline for prescribing opioids for pain. Includes guidance on opioid selection and dosages. mmwr.rr7103a1
A systematic review documented wide variation in published conversion ratios, with the methadone:morphine ratio increasing at higher morphine-equivalent doses (a phenomenon unique to methadone among opioids).supported
Systematic review of methadone conversion methods and dosing ratios for pain treatment. Wide variability in published conversion ratios. j.1526-4637.2008.00461.x
Claim in clinical-evidence — not_supportednot supportedworking →
Claim in clinical-evidence — not_supportednot supportedworking →
pharmacokinetic-detail7 · 7 ok
All values from the definitive pharmacokinetic review.supported
Methadone bioavailability mean ~75% (range 36-100%). Peak plasma at 2.5-4 hours. Mean half-life ~22 hours (range 5-130h). R-enantiomer mean ~40h. CYP3A4 and CYP2D6 metabolism. 17-fold interindividual variation in blood concentration. pmid:12405865
Up to 17-fold variation in blood concentration for a given oral dose has been documented, primarily attributable to CYP enzyme polymorphismssupported
17-fold interindividual variation in blood concentration. CYP3A4 and CYP2D6 metabolism. pmid:12405865
The stereoselective CYP enzyme hierarchy, confirmed by subsequent population pharmacokinetic modeling:supported
CYP2B6 phenotype determinant of clearance of both R- and S-methadone enantiomers. psp4.12687
The stereoselective CYP enzyme hierarchy, confirmed by subsequent population pharmacokinetic modeling:supported
Comprehensive population PK model for R- and S-methadone and EDDP. Weight and CYP2B6 genotype but not CYP2C19, sex or race as key covariates. Enantiomeric differences in CYP2B6-catalyzed metabolism. cpt.70147
This hierarchy was revised and corroborated by subsequent work, firmly establishing CYP2B6 as the principal enzymesupported
CYP2B6 has highest Vmax/Km for EDDP formation from methadone. Hierarchy: CYP2B6 > CYP2C19 >= CYP3A4. pmid:14628297
This hierarchy was revised and corroborated by subsequent work, firmly establishing CYP2B6 as the principal enzymesupported
CYP2B6 identified as principal methadone metabolizing enzyme (more recent data). journal.pone.0231467
Grapefruit juice: Intestinal CYP3A4 inhibitorsupported
Grapefruit juice (intestinal CYP3A inhibitor) investigated for effect on steady-state methadone PK. pmid:15229464
comparative-pharmacology5 · 5 ok
A Cochrane comparison found methadone superior for treatment retention at adequate doses, while buprenorphine's safety profile (lower overdose risk, reduced QT liability) and office-based prescribing model expand its accessibility.partially supported
Methadone superior to buprenorphine in retaining people in treatment. 14651858.cd002207.pub4
The β-arrestin bias profile of methadone diverges from fentanyl's MOR signaling pattern, though the clinical implications of this difference for overdose risk remain under investigation.supported
Investigates pharmacological profile of methadone vs fentanyl and morphine. Measures discriminative stimulus, NMDA receptor binding, mu-opioid receptor internalization, and beta-arrestin recruitment. 1744806916654146
Methadone's β-arrestin-biased agonism at MOR contrasts with morphine's relatively G-protein-biased profile — a distinction with potential implications for tolerance kinetics and respiratory depression liability, though clinical confirmation is incomplete.supported
Investigates pharmacological profile of methadone vs fentanyl and morphine. Measures mu-opioid receptor internalization and beta-arrestin recruitment. 1744806916654146
Pharmacokinetically, methadone's oral bioavailability (~75%) far exceeds morphine's (~25–30%), and its elimination half-life (mean ~22 hours versus morphine's 2–3 hours) permits once-daily dosingsupported
Methadone bioavailability mean ~75% (range 36-100%). Mean half-life ~22 hours (range 5-130h). pmid:12405865
Equianalgesic conversion is not fixed: the methadone:morphine ratio shifts with increasing morphine-equivalent dose, reflecting methadone's incomplete cross-tolerance and possible NMDA-mediated anti-tolerance effects.supported
Systematic review of methadone conversion methods and dosing ratios for pain treatment. Wide variability in published conversion ratios. j.1526-4637.2008.00461.x
receptor-pharmacology4 · 3 ok
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Functional inhibition across NMDA receptor subtypes, measured in Xenopus oocytes expressing recombinant rat receptors, revealed a selectivity gradient: NR1/2A and NR1/2B subtypes are significantly more sensitive to methadone than NR1/2C and NR1/2Dsupported
Racemic methadone inhibited all subtypes of rat NMDA receptors with IC50 in low micromolar range. NR1/2A and NR1/2B more sensitive than NR1/2C and NR1/2D. pmid:14980914
R(−)-methadone: Higher mu-opioid receptor affinity; accounts for virtually all analgesic activity; longer elimination half-life (~40 hours); preferential selectivity for NR1/2A NMDA subtype.partially supported
R-enantiomer mean ~40h. pmid:12405865
S(+)-methadone: Weaker mu agonist; preferentially metabolized by CYP2B6; accumulates in CYP2B6 poor metabolizers; disproportionately responsible for QT prolongation.partially supported
CYP2B6 poor metabolizers at elevated fatality risk. SNP rs3211371 associated with higher blood methadone concentrations. bkw135
chemistry2 · 1 ok
Claim in chemistry — inconclusiveinconclusiveworking →
S(+)-methadone: a weaker mu-opioid agonist, preferentially metabolized by CYP2B6. Elevated S-methadone plasma concentrations are associated with QT prolongation and cardiotoxicity.partially supported
CYP2B6 poor metabolizers at elevated fatality risk. SNP rs3211371 associated with higher blood methadone concentrations. bkw135
history1 · 0 ok
Claim in history — inconclusiveinconclusiveworking →