From PsychonautWiki
Jump to navigation Jump to search

Skull and crossbones darktextred2.png

Fatal overdose may occur when opiates are combined with other depressants such as benzodiazepines, barbiturates, gabapentinoids, thienodiazepines, alcohol or other GABAergic substances.[1]

It is strongly discouraged to combine these substances, particularly in common to heavy doses.

Summary sheet: Methadone
Chemical Nomenclature
Common names Methadone, Dolophine, Methadose
Systematic name (RS)-6-(dimethylamino)-4,4-diphenylheptan-3-one
Class Membership
Psychoactive class Opioid
Chemical class Diphenylpropylamine
Routes of Administration

WARNING: Always start with lower doses due to differences between individual body weight, tolerance, metabolism, and personal sensitivity. See responsible use section.

Bioavailability 40-99%
Threshold 1 mg
Light 3 - 5 mg
Common 5 - 15 mg
Strong 15 - 30 mg
Heavy 30 mg +
Total 10 - 19 hours
Onset 20 - 90 minutes
Come up 2 - 4 hours
Peak 4 - 6 hours
Offset 4 - 6 hours
After effects 1 - 24 hours

DISCLAIMER: PW's dosage information is gathered from users and resources for educational purposes only. It is not a recommendation and should be verified with other sources for accuracy.

Serotonin releasers

Methadone (sold under trade names such as Dolophine and Methadose) is a synthetic opioid analgesic used for the treatment of moderate to severe pain and for the treatment of opioid addiction. It is commonly used to treat and manage the symptoms of opioid addiction. The subjective effects are similar to those of other synthetic opioids such as fentanyl, however, most users note a significantly stronger euphoria. Like dextropropoxyphene, the use of methadone is associated with cardiac arrhythmia, however it is more common with dextropropoxyphene than it is with methadone.


Methadone is an opioid of the diphenylpropylamine class, featuring two phenyl rings attached to carbon R4 of the main 2-oxo-6-dimethylaminoheptane chain. It exists as a racemic mixture of both dextromethadone and levomethadone. It is also similar in structure to tapentadol and dextropropoxyphene.

Methadone and its major metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), are often measured in urine as part of a drug abuse testing program, in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims, or in whole blood to assist in a forensic investigation of a traffic or other criminal violation or a case of sudden death. Methadone usage history is considered in interpreting the results as a chronic user can develop tolerance to doses that would incapacitate an opioid-naive individual. Chronic users often have high methadone and EDDP baseline values.[2]

The protonated form of methadone takes on an extended conformation, while the free base is more compact. In particular, it was found that there is an interaction between the tertiary amine and the carbonyl carbon of the ketone function (R3N ••• >C=O) that limits the molecule's conformation freedom, though the distance (291 pm by X-ray) is far too long to represent a true chemical bond. However, it does represent the initial trajectory of attack of an amine on a carbonyl group and was an important piece of experimental evidence for the proposal of the Bürgi–Dunitz angle for carbonyl addition reactions.[3]


Opioids exert their effects by binding to and activating the μ-opioid receptor. This occurs because opioids structurally mimic endogenous endorphins which are naturally found within the body and also work upon the μ-opioid receptor set. The way in which opioids structurally mimic these natural endorphins results in their euphoria, pain relief and anxiolytic effects. This is because endorphins are responsible for reducing pain, causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or general excitement. The bioavailability of orally administered methadone can vary from 40% to around 99%. Methadone is metabolized by the cytochrome P450 system.

Unlike most opioids, methadone is a weak serotonin reuptake inhibitor as well as a weak NMDA antagonist. Similarly to dextropropoxyphene, methadone is a nicotinic acetylcholine receptor antagonist.[4]

The metabolic half life of methadone differs from its duration of action. The metabolic half life is 8 to 59 hours (approximately 24 hours for opioid-tolerant people, and 55 hours in opioid-naive people), as opposed to a half life of 1 to 5 hours for morphine. The length of the half life of methadone allows for exhibition of respiratory depressant effects for an extended duration of time in opioid-naive people.[5]

Levomethadone (the L enantiomer) is a μ-opioid receptor agonist with higher intrinsic activity than morphine, but lower affinity.[6] Dextromethadone (the S enantiomer) does not affect opioid receptors but binds to the glutamatergic NMDA (N-methyl-D-aspartate) receptor, and acts as an antagonist against glutamate. Methadone has been shown to reduce neuropathic pain, primarily through NMDA receptor antagonism. Glutamate is the primary excitatory neurotransmitter in the central nervous system. Acting as an NMDA antagonist may be one mechanism by which methadone decreases craving for opioids and tolerance, and has been proposed as a possible mechanism for its distinguished efficacy regarding the treatment of neuropathic pain.

Methadone also acted as a potent, noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines.[7]

Binding affinities (Ki)[8]


  • Mu opioid agonist - 24.8 nM
  • Kappa opioid agonist - 543 nM
  • Delta opioid agonist - 1674 nM

According to a study published in the Journal of Pharmacology and Experimental Therapeutics, the dissociation constants (Kd) of Levomethadone at the different opioid receptors are as follows:

  • Mu opioid agonist - 2.5 nM
  • Kappa opioid agonist - 54 nM
  • Delta opioid agonist - 97nM

Subjective effects

Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), an open research literature based on anecdotal user reports and the personal analyses of PsychonautWiki contributors. As a result, they should be viewed with a healthy degree of skepticism.

It is also worth noting that these effects will not necessarily occur in a predictable or reliable manner, although higher doses are more liable to induce the full spectrum of effects. Likewise, adverse effects become increasingly likely with higher doses and may include addiction, severe injury, or death ☠.

Physical effects

Cognitive effects

Visual effects

Experience reports

There are currently no anecdotal reports which describe the effects of this compound within our experience index. Additional experience reports can be found here:

Toxicity and harm potential

Table from the 2010 ISCD study ranking various drugs (legal and illegal) based on statements by drug-harm experts. Methadone was found to be the 12th overall most dangerous drug.[10]

Methadone has a moderate toxicity relative to dose. As with all opioids, long-term effects can vary but can include diminished libido, apathy and memory loss. It is also potentially lethal when mixed with depressants like alcohol or benzodiazepines and generally has a wider range of substances which it is dangerous to combine with in comparison to other opioids. Methadone is known to lower the seizure threshold. It should not be taken during benzodiazepine withdrawals as this can potentially cause seizures.

It is strongly recommended that one use harm reduction practices when using this drug.

Tolerance and addiction potential

As with other opioids, the chronic use of methadone can be considered extremely addictive with a high potential for abuse and is capable of causing psychological dependence among certain users. When addiction has developed, cravings and withdrawal symptoms may occur if a person suddenly stops their usage.

Tolerance to many of the effects of methadone develops with prolonged and repeated use. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the absence of further consumption). Methadone presents cross-tolerance with all other opioids, meaning that after the consumption of methadone all opioids will have a reduced effect.

The risk of fatal opioid overdoses rise sharply after a period of cessation and relapse, largely because of reduced tolerance.[11] To account for this lack of tolerance, it is safer to only dose a fraction of one's usual dosage if relapsing. It has also been found that the environment one is in can play a role in opioid tolerance. In one scientific study, rats with the same history of heroin administration were significantly more likely to die after receiving their dose in an environment not associated with the drug in contrast to a familiar environment.[12]

Dangerous interactions

Warning: Many psychoactive substances that are reasonably safe to use on their own can suddenly become dangerous and even life-threatening when combined with certain other substances. The following list provides some known dangerous interactions (although it is not guaranteed to include all of them).

Always conduct independent research (e.g. Google, DuckDuckGo, PubMed) to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions have been sourced from TripSit.

  • Alcohol - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. Place affected patients in the recovery position to prevent vomit aspiration from excess. Memory blackouts are likely
  • Stimulants - Stimulants increase respiration rate which allows for a higher dose of opiates than would otherwise be used. If the stimulant wears off first then the opiate may overcome the user and cause respiratory arrest.
  • Benzodiazepines - Central nervous system and/or respiratory-depressant effects may be additively or synergistically present. The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position blackouts/memory loss likely.
  • DXM - Generally considered to be toxic. CNS depression, difficulty breathing, heart issues, and liver toxicity have been observed. Additionally if one takes DXM, their tolerance of opiates goes down slightly, thus causing additional synergistic effects.
  • GHB/GBL - The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position
  • Ketamine - Both substances bring a risk of vomiting and unconsciousness. If the user falls unconscious while under the influence there is a severe risk of vomit aspiration if they are not placed in the recovery position.
  • MAOIs - Coadministration of monoamine oxidase inhibitors (MAOIs) with certain opioids has been associated with rare reports of severe adverse reactions. There appear to be two types of interaction, an excitatory and a depressive one. Symptoms of the excitatory reaction may include agitation, headache, diaphoresis, hyperpyrexia, flushing, shivering, myoclonus, rigidity, tremor, diarrhea, hypertension, tachycardia, seizures, and coma. Death has occurred in some cases.
  • MXE - MXE can potentiate the effects of opioids but also increases the risk of respiratory depression and organ toxicity.
  • Nitrous - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Memory blackouts are common.
  • PCP - PCP may reduce opioid tolerance, increasing the risk of overdose.
  • Tramadol - Increased risk of seizures. Tramadol itself is known to induce seizures and it may have additive effects on seizure threshold with other opioids. Central nervous system- and/or respiratory-depressant effects may be additively or synergistically present.
  • Grapefruit - While grapefruit is not psychoactive, it may affect the metabolism of certain opioids. Tramadol, oxycodone, and fentanyl are all primarily metabolized by the enzyme CYP3A4, which is potently inhibited by grapefruit juice[13]. This may cause the drug to take longer to clear from the body. it may increase toxicity with repeated doses. Methadone may also be affected[13]. Codeine and hydrocodone are metabolized by CYP2D6. People who are on medicines that inhibit CYP2D6, or that lack the enzyme due to a genetic mutation will not respond to codeine as it can not be metabolized into its active product: morphine.
  • Psychedelics - Methadone is known to lower the seizure threshold[citation needed] and psychedelics may act as triggers for seizures in those who are susceptible to them.

Serotonin syndrome risk

While methadone has been reported to occasionally cause serotonin syndrome when combined with certain substances (such as those listed below), anecdotal reports suggests that it does so at a much lower rate than tramadol. Combinations with the following substances can cause dangerously high serotonin levels. Serotonin syndrome requires immediate medical attention and can be fatal if left untreated.

Legal status


This legality section is a stub.

As such, it may contain incomplete or wrong information. You can help by expanding it.

  • Canada: Methadone is a Schedule I Controlled Substance.[15]
  • Germany: Methadone is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form.[16]
  • Russia: Methadone is a Schedule I controlled substance.[17]
  • Switzerland: Methadone is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted.[18]
  • United Kingdom: Methadone is a Class A, Schedule 2 drug in the United Kingdom.[19]
  • United States: Methadone is a Schedule II Controlled Substance.[20]

See also

External links


  1. Risks of Combining Depressants - TripSit 
  2. Barkin, R. L. (March 2009). "Disposition of Toxic Drugs and Chemicals in Man, 8th ed". American Journal of Therapeutics. 16 (2): 199. doi:10.1097/MJT.0b013e31818de2e2. ISSN 1075-2765. 
  3. Bürgi, H. B., Dunitz, J. D., Shefter, E. (August 1973). "Pharmacological Implications of the Conformation of the Methadone Base". Nature New Biology. 244 (136): 186–188. doi:10.1038/newbio244186b0. ISSN 0090-0028. 
  4. Xiao, Y., Smith, R. D., Caruso, F. S., Kellar, K. J. (1 October 2001). "Blockade of Rat α3β4 Nicotinic Receptor Function by Methadone, Its Metabolites, and Structural Analogs". Journal of Pharmacology and Experimental Therapeutics. 299 (1): 366–371. ISSN 0022-3565. 
  5. Grissinger, M. (August 2011). "Keeping patients safe from methadone overdoses". P & T: A Peer-Reviewed Journal for Formulary Management. 36 (8): 462–466. ISSN 1052-1372. 
  6. Davis, M. P., ed. (2009). Opioids in cancer pain (2nd ed ed.). Oxford University Press. ISBN 9780199236640. 
  7. Xiao, Y., Smith, R. D., Caruso, F. S., Kellar, K. J. (October 2001). "Blockade of rat alpha3beta4 nicotinic receptor function by methadone, its metabolites, and structural analogs". The Journal of Pharmacology and Experimental Therapeutics. 299 (1): 366–371. ISSN 0022-3565. 
  8. Schmidt, H., Vormfelde, S. V., Klinder, K., Gundert-Remy, U., Gleiter, C. H., Skopp, G., Aderjan, R., Fuhr, U. (August 2002). "Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors: DIHYDROCODEINE BINDING TO OPIOID RECEPTORS". Pharmacology & Toxicology. 91 (2): 57–63. doi:10.1034/j.1600-0773.2002.910203.x. ISSN 0901-9928. 
  9. John, J., Amley, X., Bombino, G., Gitelis, C., Topi, B., Hollander, G., Ghosh, J. (30 December 2010). "Torsade de Pointes due to Methadone Use in a Patient with HIV and Hepatitis C Coinfection". Cardiology Research and Practice. 2010: 524764. doi:10.4061/2010/524764. ISSN 2090-8016. 
  10. Nutt DJ, King LA, Phillips LD (November 2010). "Drug harms in the UK: a multicriteria decision analysis". Lancet. 376 (9752): 1558–1565. CiteSeerX accessible. doi:10.1016/S0140-6736(10)61462-6. PMID 21036393.  Unknown parameter |s2cid= ignored (help)
  11. Why Heroin Relapse Often Ends In Death - Lauren F Friedman (Business Insider) |
  12. Siegel, S., Hinson, R. E., Krank, M. D., McCully, J. (23 April 1982). "Heroin "Overdose" Death: Contribution of Drug-Associated Environmental Cues". Science. 216 (4544): 436–437. doi:10.1126/science.7200260. ISSN 0036-8075. 
  13. 13.0 13.1 Ershad, M., Cruz, M. D., Mostafa, A., Mckeever, R., Vearrier, D., Greenberg, M. I. (March 2020). "Opioid Toxidrome Following Grapefruit Juice Consumption in the Setting of Methadone Maintenance". Journal of Addiction Medicine. 14 (2): 172–174. doi:10.1097/ADM.0000000000000535. ISSN 1932-0620. 
  14. Gillman, P. K. (2005). "Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity". British Journal of Anaesthesia. 95 (4): 434–441. doi:10.1093/bja/aei210Freely accessible. eISSN 1471-6771. ISSN 0007-0912. OCLC 01537271. PMID 16051647. 
  15. Branch, L. S. (2022), Consolidated federal laws of Canada, Controlled Drugs and Substances Act 
  16. Anlage III BtMG - Einzelnorm 
  17. Постановление Правительства РФ от 01.10.2012 N 1002 (ред. от 09.08.2019) 
  18. "Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien" (in German). Bundeskanzlei [Federal Chancellery of Switzerland]. Retrieved January 1, 2020. 
  19. List of most commonly encountered drugs currently controlled under the misuse of drugs legislation 
  20. DEA Controlled Substances |