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Methadone
Methadone
Dolophine, Methadose, Physeptone, Amidone, Polamidon
Methadone is a synthetic opioid analgesic of the diphenylheptane class.1 First developed in Germany in 1937 by Gustav Ehrhart and Max Bockmühl, it is primarily used for the management of severe pain and as a maintenance therapy for opioid dependence.citation needed It is distinguished from other opioids by its comparatively long duration of action, good oral bioavailability, and additional activity as an NMDA receptor antagonist.2 It shares the typical risks associated with other opioids such as morphine and fentanyl.1
Dosage & Duration
Dosage
Doses are population estimates that vary widely between individuals.
Threshold~2 mg
Light2-5 mg
Moderate5-15 mg
Strong15-30 mg
Heavy30+ mg
Bioavailability
36-100%
Methadone is characterized by an extended and highly variable half-life. Peak effects and complete absorption may be significantly delayed, so additional doses should not be taken within several hours of the initial dose. In clinical opioid agonist therapy settings, typical maintenance doses range from 40 to 100 mg per day.
Duration
Onset20-90 minutes
Come Up2-4 hours
Peak4-6 hours
Offset4-6 hours
After Effects1-24 hours
Total10-19 hours
Half-life
15-60 hours
Subjective Effects
Legacy content. A statistically backed ontology from Mindstate Design Labs is coming soon.
Methadone produces a classic opioid experience centered on heavy sedation, pain relief, and a calm, contented mood, though its euphoria is generally considered muted and slower in onset compared to shorter-acting opioids such as heroin or oxycodone. First-hand accounts describe a mild, heady inebriation that retains far more mental clarity than alcohol, sometimes characterized as a lucid or sober intoxication in which the user remains largely in control of themselves. A pronounced anxiolytic undercurrent runs throughout the experience, with anxiety extinguished early and a stable, tranquil state persisting for many hours in keeping with the drug's exceptionally long duration. The experience typically resolves into tiredness and an earlier-than-usual readiness for sleep.
Physical
The body load is dominated by relaxation, sedation, and analgesia, accompanied by a gentle body warmth. Typical opioid side effects are prominent, including itching, constipation, pupil constriction, dry mouth, sweating, nausea, and at higher doses dangerous respiratory depression.
Autonomic
Cardiovascular
Perception
Sedation
Sedation is a core feature, presenting as a heady, mellow inebriation that transitions into drowsiness and fatigue over the long duration.
Cognitive
The headspace is tranquil, contented, and notably anxiolytic, with a mellow inebriation that preserves clarity at common doses and shifts toward a more zoned-out, less clear state as effects deepen. Mood is reliably lifted, though full-blown euphoria is not guaranteed, and memory impairment and disorientation can occur.
Emotional
The emotional tone is warm, calm, and contented rather than intensely euphoric.
Suppressions
Visual
Visual effects are limited to suppressions, primarily blurred vision.
Pharmacology
Pharmacodynamics
Methadone acts primarily as a full agonist at the μ-opioid receptor, mimicking the activity of endogenous endorphins.citation needed In the racemic mixture, the (R)-enantiomer carries the bulk of opioid activity, with roughly 10-fold higher μ-opioid affinity than the (S)-enantiomer.2 Methadone also activates κ-opioid, δ-opioid, and σ receptors.citation needed Beyond opioid targets, it antagonizes the NMDA glutamate receptor, dampening a major excitatory pathway in the central nervous system. It further acts as a weak serotonin and norepinephrine reuptake inhibitor, antagonizes 5-HT3A receptors and several nicotinic acetylcholine receptor subtypes (notably α3β4 and α4β2), and functions as an agonist at the α7 nicotinic acetylcholine receptor.
Pharmacokinetics
Methadone undergoes extensive first-pass metabolism in the liver, with oral bioavailability ranging widely from 36% to 100% due to marked interindividual variation.citation needed The primary metabolic pathway involves sequential N-demethylation, catalyzed mainly by CYP3A4 and CYP2B6, with additional contributions from CYP2C19, CYP2C9, CYP2C8, and CYP2D6. Methadone is also a substrate of P-glycoprotein, an efflux transporter expressed in the intestines and brain. Its high lipid solubility contributes to a prolonged and highly variable elimination half-life, typically 15 to 60 hours (mean approximately 22 hours), though individual values can span from as few as 4 hours to as many as 190 hours due to genetic variability in cytochrome P450 enzyme activity.
Dangerous
Highest riskThese combinations are considered extremely harmful and should always be avoided. Reactions to these drugs taken in combination are highly unpredictable and have a potential to cause death.
Unsafe
AvoidThere is considerable risk of physical harm when taking these combinations, they should be avoided where possible.
Caution
Use cautionThese combinations are not usually physically harmful, but may produce undesirable effects, such as physical discomfort or overstimulation. Extreme use may cause physical health issues. Synergistic effects may be unpredictable. Care should be taken when choosing to use this combination.
Tolerance
Tolerance timelines are rules of thumb, not exact schedules, and vary widely between individuals and use patterns.
Full Tolerance
With sustained repeated methadone use, tolerance may develop to many effects. The timeline depends on the effect, and constipation-related tolerance tends to build especially slowly compared with other opioid effects. Methadone's NMDA receptor antagonist activity may also help limit tolerance development relative to other opioids.
Baseline Reset
1-2 weeks
Half Tolerance
3-7 days
Cross Tolerance
Opioids (incomplete cross-tolerance; patients tolerant to other μ-opioid agonists may be incompletely tolerant to methadone, complicating dose conversion and creating overdose risk)
Harm Potential
Addiction & Dependence
Psychological
Extremely HighChronic use of methadone is considered extremely addictive with a high potential for abuse, comparable to morphine.citation needed It is capable of causing psychological dependence, with cravings developing when regular use is established.
Physical
HighPhysical dependence develops with repeated administration through neuroadaptation of opioid receptors.citation needed Withdrawal symptoms are reported as significantly more protracted than other opioids due to methadone's long half-life, and include body aches, diarrhea, nausea, anxiety, tremors, tachycardia, sweating, insomnia, fever, and elevated pain sensitivity.
Toxicity
Cardiovascular
QT interval prolongation can occur even at therapeutic doses, with risk of potentially fatal torsades de pointes arrhythmia; higher doses (>200 mg/day) and pre-existing cardiac conditions increase this risk significantly.citation needed
Respiratory
Serious, life-threatening, or fatal respiratory depression may occur, particularly during dose initiation or titration; the respiratory depressant effects peak later and persist longer than analgesic effects, contributing to iatrogenic overdose risk.citation needed
Male Reproductive
Long-term use is associated with impaired male reproductive function, including decreased testosterone levels, reduced sperm motility and morphology, reduced ejaculate volume, and decreased libido.citation needed
Dental
Chronic use is associated with significant tooth decay due to dry mouth (xerostomia), which reduces saliva's protective role against decay; behavioral factors such as opioid-related carbohydrate cravings and reduced dental hygiene may contribute.citation needed
Pulmonary
Injection of oral methadone tablets containing talc filler can cause progressive, irreversible pulmonary hypertension due to particle accumulation in lung vasculature; this risk is specific to intravenous misuse of oral formulations.citation needed
Psychosis Risk
Compared to other opioids, methadone has fewer active metabolites and therefore a lower risk of neuropsychiatric toxicity such as delirium at higher doses.citation needed However, withdrawal from methadone can cause cognitive symptoms including delirium, auditory and visual hallucinations, paranoia, and delusions.
Seizure Risk
Methadone is known to lower the seizure threshold.citation needed However, due to fewer active metabolites, higher doses are less likely to result in seizures compared to other opioids. Particular caution is warranted during benzodiazepine withdrawal as the combination may potentiate seizure risk.
History & Culture
Discovery and Development
Methadone was developed in 1937 in Germany by chemists Gustav Ehrhart and Max Bockmühl, working for I.G. Farbenindustrie AG at the Farbwerke Hoechst facility.citation needed The research was motivated by Germany's shortage of opium and morphine, creating demand for a synthetic opioid that could…
Legality
International
1961 Single Convention on Narcotic Drugs: Schedule I
1971 Convention on Psychotropic Substances: not listed
1988 Convention against Illicit Traffic: not listed
By Country
Illegal1
Prescription15
United StatesPrescription onlyControlled Substances Act, 21 U.S.C. § 812; 21 CFR § 1308.1238
Controlled under the Controlled Substances Act as a Schedule II substance.39 Illegal to sell without DEA licensure and illegal to possess without a valid prescription. May be prescribed for severe pain management. When used for opioid addiction treatment, methadone can only be dispensed through licensed clinics where patients typically receive liquid formulations under direct observation.40
By state
Most states, the District of Columbia, and the permanent territories schedule methadone consistently with federal Schedule II treatment; South Carolina imposes additional methadone-specific limits.
South CarolinaRestrictedS.C. Code Ann. §§ 44-53-210(c)(11), 44-53-710 to -73041
Methadone is a Schedule II controlled substance in South Carolina. State law gives the Department exclusive control over methadone and restricts methadone and its salts to approved treatment, maintenance, or detoxification programs, hospital dispensing for specified purposes, and retail-pharmacy dispensing for analgesia. These methadone-specific limits are more restrictive than the general prescription-only treatment.
CanadaPrescription onlyControlled Drugs and Substances Act, Schedule I8
Controlled as a Schedule I substance under the Controlled Drugs and Substances Act.9 Illegal to sell without authorization and illegal to possess without a valid prescription. Prescriptions can only be obtained from specially licensed physicians, and dispensing is restricted to authorized pharmacies where consumption is typically supervised.
ChilePrescription onlyDecreto Supremo N.º 404 de 1983, Reglamento de Estupefacientes (Lista I; as amended, including the official Decreto N.º 8/2020 amendment to D.S. 404)10111213
Methadone is listed in Lista I under D.S. 404 and is subject to controlled-prescription rules and prescription-only treatment. The official MINSAL norms index, modified 15 July 2026, lists D.S. 404/1983. D.S. 404 was amended on 19 November 2020. The official MINSAL text of D.S. 404 incorporates modifications through 2011.
DenmarkPrescription onlyDanish Regulation on Euphoriant Substances, List B14
Methadone is for controlled medical use, not unrestricted possession or over-the-counter access.
FrancePrescription onlyArrêté du 22 février 1990 fixant la liste des substances classées comme stupéfiants15
Classified as an Annexe I medication under French pharmaceutical regulations.15 Illegal to sell without appropriate licensure and illegal to possess without a valid prescription. Prescription methadone is subject to strict controls.
GermanyPrescription only
ItalyPrescription onlyDecreto del Presidente della Repubblica 9 ottobre 1990, n. 309, Tabelle delle sostanze stupefacenti e psicotrope19
Listed in Tabella I of the official tables of narcotic and psychotropic substances (Tabelle delle sostanze stupefacenti e psicotrope). Unauthorized possession, purchase, or sale is prohibited under national drug legislation.
MexicoPrescription onlyMexico Ley General de Salud Article 23420
Article 234 lists methadone as a narcotic but does not specify all prescription or dispensing requirements.
PolandPrescription onlyObwieszczenie Ministra Zdrowia z dnia 17 czerwca 2024 r. w sprawie ogłoszenia jednolitego tekstu rozporządzenia Ministra Zdrowia w sprawie wykazu substancji psychotropowych, środków odurzających oraz nowych substancji psychoaktywnych2122232425
Methadone is listed in Group I-N. The schedule does not state dispensing conditions for every methadone preparation.
PortugalPrescription onlyDecreto-Lei n.º 15/93, de 22 de janeiro, Tabela I-A26
Personal use was decriminalized under Law 30/2000, effective July 2001.27 Possession of less than one gram is not treated as a criminal offense, though the substance may be seized and the individual referred to a dissuasion commission for potential treatment. Sale and possession of quantities exceeding personal use limits remain criminal offenses subject to imprisonment.
United KingdomPrescription onlyMisuse of Drugs Act 1971 and Misuse of Drugs Regulations 200135
References
Source Pages
Citations
- Amber N. Edinoff, Leah A. Kaplan, Sami Khan, Murray Petersen, Emily Sauce, Christopher D. Causey, Elyse M. Cornett, Farnad Imani, Omid Moradi Moghadam, & Adam M. Kaye. (2021). Full Opioid Agonists and Tramadol: Pharmacological and Clinical Considerations. Anesthesiology and Pain Medicine. https://pmc.ncbi.nlm.nih.gov/articles/PMC8520671/12
- Sunilkumar M. M., & Kiran Lockman. (2018). Practical Pharmacology of Methadone: A Long-acting Opioid. Indian Journal of Palliative Care, 24(Suppl 1), S10–S14. https://doi.org/10.4103/ijpc.ijpc_180_17123
- Bengt Danielsson, Julius Collin, Anastasia Nyman, Annica Bergendal, Natalia Borg, Maria State, Lennart Bergfeldt, & Johan Fastbom. (2020-03-12). Drug use and torsades de pointes cardiac arrhythmias in Sweden: a nationwide register-based cohort study. BMJ Open, 10(3). https://doi.org/10.1136/bmjopen-2019-0345601
- Function of the male sex organs in heroin and methadone users. Clinical Pharmacology & Therapeutics (1974). https://pubmed.ncbi.nlm.nih.gov/1117911/1
- The History of Methadone. INDRO e.V. (n.d.). https://indro-online.de/en/the-history-of-methadone/123
- Lista de substâncias sujeitas a controle especial no Brasil. gov.br (n.d.). https://www.gov.br/anvisa/pt-br/assuntos/medicamentos/controlados/lista-substancias1
- Portaria SVS/MS nº 344, de 12 de maio de 1998 (consolidated text). anvisalegis.datalegis.net (n.d.). https://anvisalegis.datalegis.net/action/ActionDatalegis.php?acao=abrirTextoAto&cod_menu=1696&cod_modulo=134&numeroAto=00000344&orgao=SVS%2FMS&pesquisa=true&seqAto=000&tipo=POR&valorAno=19981
- Controlled Drugs and Substances Act — Schedule I. laws-lois.justice.gc.ca (n.d.). https://laws-lois.justice.gc.ca/eng/acts/C-38.8/section-sched95314.html1
- Controlled Drugs and Substances Act, Schedule I, Section 5 (Amidones). Justice Laws Website (1996). https://laws-lois.justice.gc.ca/eng/acts/c-38.8/page-9.html1
- Reglamento de Estupefacientes, D.S. N.º 404 de 1983 — Ministerio de Salud de Chile. juridico1.minsal.cl (n.d.). https://juridico1.minsal.cl/DTO_404_83.doc1
Further Reading
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Recent changes8 human edits · latest
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15 August 2026
Lyrea · Updated the article
24 January 2026
Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
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