Methadone

6-(dimethylamino)-4,4-diphenylheptan-3-one

Overview

Methadone belongs to Opioids.

Key safety note: Methadone is one of the most dangerous opioids to dose, because of its pharmacokinetics, not its potency.^[6]^[7]

Effects

Subjective effects vary. What a substance feels like depends on dose, individual physiology, mindset, and setting. The points below describe commonly reported effects, not guaranteed, uniform, or desirable outcomes.

Opioid effects: analgesia, warmth, contentment and mild euphoria, relaxation and sedation, with less of the intense 'rush' of shorter-acting opioids because of its slow onset and long action.
Physical signs: pinpoint pupils (miosis), respiratory depression, constipation, itching, sweating, nausea, dry mouth and reduced libido.
With chronic use: tolerance, physical dependence and a protracted withdrawal syndrome. QT prolongation and, in overdose, deepening sedation and life-threatening respiratory depression.

Dosing & duration

Harm-reduction note: These are commonly cited reference ranges, not a recommendation or a “safe” dose. Potency, purity, body chemistry, tolerance, and drug combinations vary widely. Start low, go slow, wait for full effects before redosing, and never assume an unknown product matches these figures. Missing data is not evidence of safety.

Oral (liquid/solution in treatment, also tablets). The tiers below are approximate ORAL recreational figures for people with SOME opioid tolerance. They are NOT maintenance doses and are dangerous for anyone without tolerance.. Methadone is uniquely dangerous to dose. Its long, variable half-life makes it accumulate over the first days, so overdose is often delayed and cumulative, never redose on a short-acting-opioid timeline. Doses far below a maintenance dose can be fatal to opioid-naive people, and the great majority of deaths involve combination with benzodiazepines, alcohol, gabapentinoids or other opioids. Maintenance doses used in treatment (often 60–120 mg/day) are only safe when reached by slow, supervised titration in tolerant patients. Higher doses prolong the QT interval, and naloxone wears off long before methadone does.

Dose ranges

Threshold

1 mg

Light

3–5 mg

Common

5–15 mg

Strong

15–30 mg

Heavy

30 mg +

Duration

onset

20–90 min

total

10–19 h (subjective effects, shorter than the elimination half-life)

after effects

1–24 h

Chemical & Physical Properties

Formula	C21H27NO
Molar mass	309.45 g/mol
State	Solid (usually the hydrochloride salt, white crystalline powder, values below are for the hydrochloride unless noted)
Melting point	235 °C (hydrochloride salt)
Boiling point	Not reported
Density	Not reported
Vapor pressure	Not reported
pKa	9.2
LogP	3.93 (free base)
Solubility	Hydrochloride salt: ~1 g in 13 mL water, ~8 mL ethanol and ~3 mL chloroform. Practically insoluble in ether and glycerol
Refractive index	Not reported

Identifiers & Synonyms

CAS	76-99-3
CAS (enantiomer)
PubChem CID	4095
InChIKey	USSIQXCVUWKGNF-UHFFFAOYSA-N
InChI	InChI=1S/C21H27NO/c1-5-20(23)21(16-17(2)22(3)4,18-12-8-6-9-13-18)19-14-10-7-11-15-19/h6-15,17H,5,16H2,1-4H3
SMILES	CCC(=O)C(CC(C)N(C)C)(C1=CC=CC=C1)C2=CC=CC=C2

Synonyms

Dolophine
Methadone
Physeptone
Heptadon
Methadose

Pharmacodynamics & Biochemistry

Methadone is a synthetic, long-acting opioid analgesic (a diphenylheptanone, structurally unrelated to morphine) whose defining feature is that it is a racemate of two pharmacologically distinct enantiomers. Almost all of the opioid effect comes from R-(−)-methadone (levomethadone): it is a full µ-opioid receptor agonist, roughly ten-fold more potent at the µ receptor than S-(+)-methadone. Kristensen et al. (1995) measured a µ1-site IC50 of 3.0 nM for R-methadone versus 26.4 nM for S-methadone (µ2: 6.9 vs 88 nM), with only weak δ- and κ-receptor affinity for either isomer, so S-methadone contributes little to the opioid action. The two enantiomers are not redundant, however. S-(+)-methadone drives most of methadone's non-opioid pharmacology: both isomers are non-competitive NMDA-receptor antagonists (low-micromolar affinity, ~2.8–3.4 µM), which may contribute to efficacy in neuropathic pain and to slower tolerance development, and S-methadone is a potent blocker of the cardiac hERG (Kv11.1) potassium channel (IC50 ~10–12 µM): the basis of methadone's dose-dependent QT-interval prolongation and torsades-de-pointes risk. Methadone also weakly inhibits serotonin and noradrenaline reuptake. Clinically its most important property is pharmacokinetic: a long and highly variable elimination half-life (~15–60 h, longer in opioid-naive people) that makes the drug accumulate over the first days of dosing, producing a characteristic delayed, cumulative respiratory-depressant overdose risk during induction.

Biological targets

MOR
NMDA

Binding & functional measurements

Target	Measurement	Species
δ-opioid receptor	Ki 37 ± 2.3 nM	Guinea pig
δ-opioid receptor	Ki 132 ± 11 nM	Human
κ-opioid receptor	Ki 728 ± 120 nM	Guinea pig
κ-opioid receptor	Ki 324 ± 18 nM	Human
μ-opioid receptor	Ki 1.4 ± 0.05 nM	Guinea pig
μ-opioid receptor	Ki 3.4 nM	Human

Pharmacokinetics

Bioavailability	Oral ≈70–80%
T_max	≈2.5–4 h
Half-life	≈8–59 h (highly variable, accumulates)
V_d	Not reported
Protein binding	≈85–90%
Metabolism	Hepatic CYP3A4/CYP2B6/CYP2D6 to inactive EDDP
Excretion	Renal and faecal

Toxicology & Safety

Harm-reduction note: Toxicity and risk depend on dose, route, purity, combinations, setting, and individual health factors. Missing harms should never be interpreted as evidence of safety.

Not reported

Methadone is one of the most dangerous opioids to dose, because of its pharmacokinetics, not its potency. Its long, highly variable half-life (around a day in tolerant users but up to ~55 h in opioid-naive people) means it accumulates over the first 3–5 days of regular dosing, so a dose that feels tolerable on day one can cause fatal respiratory depression a few days later: the classic delayed, cumulative overdose of induction ('start low, go slow'). It is especially lethal to people without opioid tolerance: doses well below a maintenance dose can kill an opioid-naive adult, and most methadone deaths involve induction, diversion to non-tolerant users, or combination with other depressants (benzodiazepines, alcohol, gabapentinoids, other opioids): the single biggest cause of fatal overdose. Separately, methadone prolongs the cardiac QT interval and can trigger torsades de pointes, especially at higher doses, with other QT-prolonging drugs, or with low potassium/magnesium: an ECG is advised before and during higher-dose treatment. As with all opioids, tolerance to euphoria and analgesia outpaces tolerance to respiratory depression, and lost tolerance after any break (detox, prison, hospital) sharply raises overdose risk on resumption. Naloxone reverses an overdose but wears off long before methadone does, so repeated dosing and observation are needed.^[6]^[7]

Legal Status

Legal note: Legal status can change over time and may vary by country, region, formulation, analogue status, prescription context, and enforcement practice. Always confirm with current official sources before relying on this section.

US: Schedule II. UK: Class A. DE: BtMG Anlage III

Interactions & Contraindications

Drug interactions

Benzodiazepines, Alcohol, Gabapentinoids (gabapentin, pregabalin) Additive respiratory depression, the commonest cause of fatal methadone overdose.^[6]^[7]

QT-prolonging drugs (some antipsychotics, antibiotics, antiarrhythmics) QT prolongation with other QT-prolonging drugs, or with low potassium or magnesium, risking torsades.^[6]

CYP2B6 / CYP3A4 inhibitors or inducers Inducers (rifampicin, carbamazepine, efavirenz) lower methadone levels and can precipitate withdrawal, while inhibitors can raise levels.^[6]^[5]

MAOIs, Other serotonergic drugs Serotonin syndrome (methadone weakly inhibits serotonin reuptake).^[6]

Contraindications

Significant respiratory depression or acute severe asthma or acute severe asthma.^[6]

Concurrent MAOI, SSRI/SNRI or other serotonergic medication concurrent or recent (within 14 days) MAOI use.^[6]

Cardiovascular disease, hypertension or arrhythmia known long-QT syndrome or serious arrhythmia.^[6]

Paralytic ileus or gastrointestinal obstruction paralytic ileus.^[6]

Opioid-naive (no tolerance) caution or avoid in opioid-naive individuals.^[6]

Usage & Context

The mainstay of opioid-substitution (maintenance) treatment for opioid dependence: a single supervised daily oral dose suppresses withdrawal and craving and blunts the euphoria of other opioids, with maintenance doses (commonly ~60–120 mg/day) reached only by slow titration in already-tolerant patients.
A long-acting analgesic for moderate-to-severe and neuropathic or cancer pain, used in opioid rotation: valued for its NMDA antagonism and low cost but hard to dose because of its variable kinetics.
Also encountered through diversion and non-medical use, because it is cheap, long-acting and widely prescribed, diverted methadone, especially reaching opioid-naive people or combined with depressants, is a recurrent cause of fatal poisoning.

Sources & Evidence

Further Information

More in this subclass