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Death may result 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
Systematic name (RS)-6-(dimethylamino)-4,4-diphenylheptan-3-one
Class Membership
Psychoactive class Opioid
Chemical class Diphenyl
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 - 3 mg
Light 3 - 5 mg
Common 5 - 15 mg
Strong 15 - 30 mg
Heavy 30 mg +
Onset 20 - 90 minutes
Peak 6 - 8 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
Selective serotonin re-uptake inhibitors
Serotonin-norepinephrine reuptake inhibitors

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 diphenyl 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.


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.[2]

Binding affinities (Ki)[3]

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

Subjective effects

The effects listed below are based upon the subjective effects index and personal experiences of PsychonautWiki contributors. These effects should be taken with a grain of salt and will rarely (if ever) occur all at once, but heavier doses will increase the chances of inducing a full range of effects. Likewise, adverse effects become much more likely on higher doses and may include serious injury or death.

Physical effects

Cognitive 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

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.[4] 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.[5]

Dangerous interactions

Although many psychoactive substances are reasonably safe to use on their own, they can quickly become dangerous or even life-threatening when taken with other substances. The following lists some known dangerous combinations, but cannot be guaranteed to include all of them. Independent research should always be conducted to ensure that a combination of two or more substances is safe to consume. Some interactions listed have been sourced from TripSit.

  • Stimulants - It can be dangerous to combine depressants with stimulants due to the risk of accidental excessive intoxication. Stimulants mask the sedative effect of depressants, which is the main factor most people use to gauge their level of intoxication. Once the stimulant effects wear off, the effects of the depressant will significantly increase, leading to intensified disinhibition, motor control loss, and dangerous black-out states. This combination can also potentially result in severe dehydration if one's fluid intake is not closely monitored. If choosing to combine these substances, one should strictly limit themselves to a pre-set schedule of dosing only a certain amount per hour until a maximum threshold has been reached.

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 issues


This legality section is a stub.

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

  • United States: Methadone is a Schedule II Controlled Substance.[7]
  • United Kingdom: Methadone is a Class A, Schedule 2 drug in the United Kingdom.[8]
  • Germany: Methadone is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form.[9]
  • Canada: Methadone is a Schedule I Controlled Substance.[10]

See also

External links


  1. Risks of Combining Depressants (Tripsit) |
  2. Blockade of Rat α3β4 Nicotinic Receptor Function by Methadone, Its Metabolites, and Structural Analogs |
  3. Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors - Helmut Schmidt et al. (August 2002) |
  4. Why Heroin Relapse Often Ends In Death - Lauren F Friedman (Business Insider) |
  5. Siegel, S., Hinson, R., Krank, M., & McCully, J. (1982). Heroin “overdose” death: contribution of drug-associated environmental cues. Science, 216(4544), 436–437.
  6. Gillman, P. K. (2005). Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. British Journal of Anaesthesia, 95(4), 434-441.
  7. DEA Controlled Substances |
  8. UK Controlled Drugs |
  9. Germany Controlled Substances |
  10. Canada Controlled Drugs and Substances |