Methadone
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Methadone is a synthetic opioid of the diphenylheptanone class. Structurally unrelated to morphine, it was designed as an open-chain alternative to traditional opioid scaffolds. Methadone is a β-arrestin-biased full agonist at µ-opioid receptors[1] with additional NMDA antagonism[2] and monoamine reuptake inhibitor,[3][4] producing its effects through multiple converging mechanisms.
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Synthesized in 1937–1938 by Max Bockmühl and Gustav Ehrhart at IG Farbenindustrie in Germany, methadone entered clinical use in the United States in 1947.[5] In 1965, Dole and Nyswander established methadone maintenance treatment for heroin dependence,[6] transforming it from analgesic to cornerstone of addiction medicine. It remains the most extensively studied pharmacotherapy for opioid use disorder, added to the WHO Model List of Essential Medicines in 2005.[7]
Subjective effects include analgesia, sedation, anxiolysis, and mild euphoria. The experience builds gradually over hours rather than arriving as a rush — a slow, sustained warmth and emotional quieting that resembles equilibrium more than acute intoxication. Nausea, constipation, cognitive slowing, and excessive sedation are characteristic unsought effects.
Methadone produces rapid physical dependence, and its therapeutic index is narrow — fatal blood concentrations overlap with therapeutic levels in tolerant patients.[8] Its long, variable half-life creates an accumulation hazard where analgesic effects fade before respiratory depression resolves, compounded by direct cardiac ion channel blockade[9] that prolongs the QT interval[10] — a risk rare among opioids. Seven decades of clinical data and extensive forensic study make methadone one of the best-characterized opioids, though extreme between-individual pharmacokinetic variability remains incompletely predictable.[11]
History[edit]
Discovery
Methadone was synthesized between 1937 and 1938 by Max Bockmühl and Gustav Ehrhart at Farbwerke Hoechst, a subsidiary of I.G. Farbenindustrie in Germany.[12][13] The program sought analgesics structurally dissimilar to morphine — motivated by Germany's desire to reduce dependence on imported opium, not by any directive from Hitler (a persistent myth unsupported by evidence).[12] Designated Hoechst 10820, the compound saw limited wartime use; following Allied seizure of German pharmaceutical patents, it was approved in the United States in 1947 as an analgesic and antitussive under the trade name Dolophine.[5]
Clinical significance
The compound's trajectory transformed in 1964–1965 when Vincent Dole and Marie Nyswander at Rockefeller University demonstrated that daily oral methadone could suppress heroin craving and block its reinforcement — establishing methadone maintenance treatment.[6] By 1995, approximately 115,000 individuals in the United States received methadone for opioid addiction.[5] In 2005, methadone and buprenorphine were added to the WHO Model List of Essential Medicines, driven partly by evidence that opioid agonist therapy reduces HIV transmission among people who inject drugs.[7]
Regulation
Methadone occupies a uniquely restrictive regulatory position in the United States: a three-tier federal framework — FDA manufacturing standards, DEA Schedule II controls, and SAMHSA certification of treatment programs — governs its use in addiction treatment, a structure applied to no other medication.[5] When prescribed for pain, standard Schedule II rules apply without the treatment program requirement. This bifurcated structure has been criticized for limiting access to addiction treatment.
The name Dolophine derives from the Latin dolor (pain) and French fin (end), not from "Adolf" — a folk etymology that persists without historical support.[12] The earlier German designation Polamidon survives as the trade name for levomethadone (the pure R-enantiomer) in several European markets.
Chemistry[edit]
Structural class
Methadone belongs to the diphenylheptanone class of synthetic opioids — an open-chain architecture deliberately designed to circumvent morphine's polycyclic framework while retaining analgesic activity.[12] The parent structure features two phenyl rings attached to a central carbon bearing a ketone group and a dimethylaminomethyl side chain.
This scaffold is structurally unrelated to the morphinan, benzomorphan, or phenylpiperidine frameworks that define most other clinical opioids. Structural relatives include levacetylmethadol (LAAM) and propoxyphene, both diphenylheptane derivatives with divergent clinical histories.
Molecular properties
| Molecular formula | C₂₁H₂₇NO |
| Molecular weight | 309.4 g/mol |
Stereochemistry
Methadone has a single chirality center at C-6, producing two enantiomers. R(−)-methadone (levomethadone) accounts for virtually all µ-opioid receptor activity and analgesic efficacy.[11] S(+)-methadone is a weaker opioid agonist; elevated plasma concentrations of this enantiomer are associated with QT prolongation and cardiac toxicity.[14]
Both enantiomers show comparable affinity at the NMDA.[15] Clinically, methadone is administered as the racemic mixture. In some European markets, the pure R-enantiomer is available as levomethadone (Polamidon), allowing half the racemic dose.
Physical properties
The hydrochloride salt (methadone HCl) is the standard pharmaceutical form.[16] It appears as a white crystalline powder, freely soluble in water, with a melting point of approximately 235°C. The free base melts at 76–77°C and is sparingly soluble in water.
Pharmacology[edit]
Mechanism of action
Methadone is a full agonist at µ-opioid receptors — the primary target responsible for its analgesic, sedating, and respiratory depressant effects. The R(−)-enantiomer drives nearly all opioid activity.[11] Unlike most clinical opioids, methadone also blocks NMDA receptors at clinically relevant concentrations,[2][15] a property thought to contribute to its effectiveness in neuropathic pain and potentially slow the development of opioid tolerance.[17]
Additional activity includes inhibition of serotonin and norepinephrine transporters,[3][4] which accounts for the risk of serotonin syndrome when combined with other serotonergic drugs. Methadone also blocks cardiac hERG potassium channels,[9] directly causing QT interval prolongation — a toxicity rare among opioids.
Despite the multi-target profile, in vivo evidence indicates that methadone's pain-relieving effects are predominantly opioid-receptor mediated and reversible with naloxone.[18] The NMDA and monoamine components are considered secondary contributors to the overall clinical profile.
Pharmacokinetics
Methadone is well absorbed orally, with bioavailability averaging around 75% (range 36–100%).[11] Peak blood levels are reached slowly — typically 2.5 to 4 hours after an oral dose — contributing to the gradual onset that distinguishes it from short-acting opioids.
The defining pharmacokinetic feature is a long, highly variable half-life: mean approximately 22 hours, but ranging from 5 to 130 hours across individuals.[11] The R(−)-enantiomer is eliminated more slowly (half-life ~40 hours) than the S(+)-enantiomer. This variability can produce up to 17-fold differences in blood concentration for a given dose.[11]
Methadone is metabolized primarily by the liver enzyme CYP2B6, with CYP2C19 and CYP3A4 playing secondary roles.[19][20] The principal metabolite, EDDP, is inactive. Because CYP2B6 preferentially clears the S(+)-enantiomer, genetic variation in this enzyme alters the balance between enantiomers — with clinical consequences for both opioid and cardiac risk.[14]
Neuroscience[edit]
Where it acts
Methadone activates the mesolimbic dopamine system through µ-opioid receptors in the ventral tegmental area, disinhibiting dopamine neurons projecting to the nucleus accumbens — the circuit underlying opioid reinforcement and euphoria.[21] In maintenance treatment, steady-state plasma levels produce tonic rather than phasic dopamine signaling, smoothing out the surge-and-crash pattern that characterizes short-acting opioids like heroin.
Pain relief operates through a separate descending pathway: µ-opioid receptors in the periaqueductal gray and spinal cord inhibit ascending pain signals,[18] with NMDA antagonism at spinal sites potentially countering the amplification of chronic pain.[2][17]
Why it matters
The neurobiological rationale for methadone maintenance rests on normalizing two disrupted systems. The incentive salience model distinguishes "wanting" (dopamine-driven motivation) from "liking" (opioid-mediated pleasure) — methadone's tonic receptor occupancy reduces the "wanting" triggered by drug cues while flattening the "liking" peaks that reinforce heroin use.[21]
Repeated opioid exposure also shifts the brain's baseline hedonic state downward through recruitment of stress systems — a process termed allostatic load. Methadone maintenance stabilizes this shifted set point by providing consistent opioid receptor activation, interrupting the between-dose withdrawal cycles that drive further deterioration.[21]
Whether methadone's characterization as a β-arrestin-biased agonist[1] translates to clinically meaningful differences in tolerance or overdose risk compared to other opioids is unknown. The quantitative contribution of NMDA antagonism to analgesia in humans — potentially most significant in neuropathic pain and tolerance attenuation — has not been isolated from the dominant opioid component.[22][18]
Subjective Effects[edit]
Methadone's subjective character is defined by gradualism. Effects build over hours rather than arriving in a rush, producing a sustained warmth, emotional quieting, and bodily heaviness that feel more like stabilization than intoxication. At lower therapeutic doses — particularly in maintenance patients — the experience is often described as normalized function rather than overt psychoactivity; at higher doses or in opioid-naive individuals, sedation and euphoria become pronounced. Set and setting strongly modulate the anxiolytic dimension: the same dose that produces comfortable equilibrium in a stable treatment context may feel oppressively sedating in an unfamiliar environment.
Compared to heroin or oxycodone, methadone delivers less acute euphoric intensity but far greater duration — a pharmacokinetic trade-off that defines both its therapeutic value and its accumulation risk. Relative to buprenorphine, methadone provides fuller µ-opioid activation without a ceiling effect, yielding deeper analgesia and sedation at high doses but also greater respiratory depression liability.
Effect Grid
At common doses, the full opioid effect profile manifests: pronounced analgesia, significant sedation, and cognitive euphoria — a warm, contented mental state with reduced emotional reactivity. Anxiety suppression is strong. Pain awareness diminishes substantially. The experience lacks the intense rush of IV heroin but produces sustained well-being over many hours.
Physically, pupil constriction is marked. Nausea occurs frequently in those without tolerance. Constipation is reliable. Respiratory rate decreases measurably. Itching and sweating are common. Urinary retention may occur.
The extended duration (10–19 hours of total effects) and long half-life mean residual sedation persists well beyond the peak. Sleep is easily induced. Cognitive and psychomotor impairment is significant.
Modeled from the effect's dose-dependence curve — not per-substance measurements.
Internal hallucinations
Sedation · Nausea · Bodily heaviness · Body high · Breathing alteration · Excessive sweating · Muscle relaxation · Tactile euphoria · Spontaneous body sensations · Sexual arousal suppression · Appetite suppression · Dizziness · Physical fatigue · Dry mouth · Temperature dysregulation · Vomiting · Abnormal heartbeat · Headache · Tingling / electric sensations · Heart rate perception changes · Nystagmus (eye wobbles) · Pain enhancement · Bodily dissociation
Body high · Breathing alteration · Excessive sweating · Muscle relaxation · Tactile euphoria · Spontaneous body sensations · Sexual arousal suppression · Appetite suppression · Dizziness · Physical fatigue · Dry mouth · Vomiting · Abnormal heartbeat · Headache · Tingling / electric sensations · Heart rate perception changes · Nystagmus (eye wobbles) · Pain enhancement · Bodily dissociation
Focus suppression · Information processing suppression · Thought deceleration · Cognitive euphoria · Motivation suppression · Confusion · Language suppression · Memory suppression · Cognitive dysphoria · Memory fragmentation · Thought disorganization · Amnesia · Delirium
Cognitive euphoria · Motivation suppression · Confusion · Language suppression · Memory suppression · Cognitive dysphoria · Memory fragmentation · Thought disorganization · Delirium
Irritability · Dysphoria
Sociability suppression · Social disconnection · Depersonalization · Derealization · Cognitive disconnection
Cognitive disconnection
Timeline
First subtle awareness emerges 20–90 minutes after ingestion: faint warmth, slight mood shift, initial hint of pain relief. Effects are easily overlooked at lower doses.
Gradual intensification over 1. 5–4 hours as plasma levels approach Tmax. Sedation, analgesia, and anxiolysis build steadily.
Maximum subjective intensity at 4–6 hours: full analgesia, deepest sedation, strongest euphoria and anxiolysis. Respiratory depression is at its greatest. Pupil constriction is maximal.
Sustained but gradually diminishing opioid effects over 3–5 hours. Sedation and analgesia remain significant. The long half-life maintains plasma levels well above the minimum effective concentration.
Slow decline over 4–6 hours. Residual sedation and mild analgesia persist. Mood returns toward baseline.
Residual effects lasting 1–24 hours after primary effects resolve: mild drowsiness, constipation, subtle mood effects. Psychomotor impairment and cognitive slowing may persist beyond subjective awareness.
⚠ Do not drive or operate heavy machinery for at least 24 hours after ingestion, as residual sedation and slowed reaction time persist well beyond the perceived end of effects.
Safety[edit]
- Acute toxicity
- Critical
- Chronic toxicity
- High
- Withdrawal
- Severe
- Tolerance buildup
- moderate
- Tolerance reset
- 10 days
- Physical
- High
- Psychological
- High
- Compulsive redosing
- Moderate
- Dose escalation
- High
- Cross-tol.
- morphine · heroin · oxycodone
Toxicity
QT prolongation and cardiac risk
Methadone's most distinctive toxicity is QT interval prolongation — a disruption of the heart's electrical rhythm that can trigger torsades de pointes, a potentially fatal irregular heartbeat. This results from direct blockade of cardiac ion channels,[9][25] and the American Heart Association specifically names methadone among drugs capable of this effect.[26]
Risk factors include doses exceeding 100 mg/day, co-administration of other QT-prolonging drugs, low potassium or magnesium levels, pre-existing heart conditions, female sex, and genetic variations that elevate S-methadone levels.[10][26][14]
Respiratory depression and overdose
Respiratory depression is the primary mechanism of fatal methadone overdose.[27] The long, variable half-life creates an accumulation hazard: pain suppression may fade before respiratory depression fully resolves, tempting redosing into dangerous territory. The first weeks of treatment carry the highest mortality risk.[24][28]
Fatal blood concentrations (median 503 ng/mL) overlap substantially with therapeutic levels in tolerant patients,[8] meaning concentration alone cannot determine cause of death. In a study of 176 Kentucky methadone fatalities, only 6.25% had methadone as the sole detected substance — the vast majority involved combinations with other drugs, especially benzodiazepines (32.4%), antidepressants (39.8%), and other opioids (27.8%).[29]
Genetic risk factors
The CYP2B6 poor metabolizer phenotype (especially the CYP2B6*6 variant) significantly elevates methadone blood levels and is independently associated with fatal outcomes.[24][14] Because this enzyme preferentially clears S(+)-methadone — the more cardiotoxic enantiomer — reduced function compounds both respiratory and cardiac risk. Variants in the OPRM1 gene also influence treatment response and dose requirements.[23]
Therapeutic index
No formal therapeutic index has been published. The overlap between therapeutic and fatal blood concentrations[8] indicates a narrow therapeutic index, particularly in opioid-naive individuals and those with CYP2B6 poor metabolizer status. The margin narrows further with concurrent depressant use.
Psychological risks
Methadone does not produce perceptual disturbances, psychosis, or hallucinations. The principal psychological risks are:
- Dependence and compulsive use: Psychological dependence develops alongside physical dependence.[21]
- Cognitive impairment: sedation and reduced mental processing speed, particularly during early treatment and dose increases.
- Withdrawal mood disturbance: dysphoria, anxiety, irritability, and insomnia during dose reduction or discontinuation.
- Psychosocial burden: Stigma, perceived loss of autonomy, and ambivalence about indefinite treatment are commonly reported by maintenance patients.
Tolerance & dependence
Tolerance develops through desensitization and downregulation of µ-opioid receptors.[30] Tolerance to sedation and euphoria develops faster than tolerance to analgesia, which can drive dose escalation. Cross-tolerance occurs with all µ-opioid agonists; prior opioid use significantly affects initial dose requirements.
Physical dependence is high. Withdrawal onset is delayed (36–72 hours after the last dose) compared to short-acting opioids, reflecting the long half-life, but symptoms can persist for weeks. Withdrawal features include yawning, watery eyes, runny nose, goosebumps, muscle aches, diarrhea, insomnia, anxiety, and low mood.[31]
Methadone maintenance treatment deliberately uses this dependence therapeutically: the Cochrane meta-analysis confirms that MMT retains patients and suppresses heroin use more effectively than non-opioid treatments.[32] The mortality benefit is substantial — all-cause mortality of 11.3 per 1,000 person-years during treatment versus 36.1 out of treatment.[28]
Drug interactions
Respiratory depression synergy
benzodiazepines and alcohol act through different mechanisms but synergize with methadone's respiratory depression.[33][34] Benzodiazepines are the most commonly co-detected substance in methadone fatalities.[27] The combination with GHB or Alcohol carries lethal risk through additive depression of breathing and consciousness. Combined use with ketamine poses theoretical risk through overlapping sedation.safety citation needed
Serotonin syndrome
Methadone's serotonin and norepinephrine reuptake inhibitor[3][4] creates serious serotonin syndrome risk with MAOIs (high risk, potentially lethal), SSRIs, SNRIs, and tricyclic antidepressants.[3][35] Tramadol poses dual risk: it both inhibits serotonin reuptake and activates µ-opioid receptors, producing serotonin syndrome and enhanced respiratory depression simultaneously.[3][35]
Drugs that alter methadone levels
Drugs that speed up liver metabolism (rifampicin, phenytoin, carbamazepine, efavirenz, nevirapine) can drop methadone levels sharply, potentially triggering withdrawal in maintained patients. Drugs that slow metabolism (fluconazole, paroxetine, grapefruit juice[36]) raise methadone levels, increasing both opioid and cardiac risk. Some interactions selectively alter one enantiomer, producing different patterns of toxicity.[11][19]
QT-prolonging drug combinations
Co-administration with other QT-prolonging medications (antipsychotics, azithromycin, antiarrhythmics) synergistically increases the risk of torsades de pointes.[26]
Contraindications
Absolute contraindications
- Concurrent MAOI use: High risk of lethal serotonin syndrome.[3][35]
- Severe respiratory insufficiency: Methadone's respiratory depressant effects may be fatal in those with pre-existing breathing compromise.
Relative contraindications
- QT-prolonging conditions or medications: Significant cardiac risk; ECG monitoring required at initiation and dose changes.[10][26]
- CYP2B6 poor metabolizer phenotype (especially *6/*6 genotype): Elevated blood levels; dose reduction and enhanced monitoring required.[14][24]
- Liver impairment: Impaired methadone metabolism increases accumulation risk.
- Concurrent benzodiazepine use: Additive respiratory depression; if unavoidable, dose reduction and respiratory monitoring are essential.[27]
- Pregnancy: Methadone maintenance is the standard of care for pregnant women with opioid use disorder, but it crosses the placenta and causes neonatal withdrawal syndrome. Monitoring to day of life 5 is recommended.citation needed
Harm Reduction[edit]
Forms & Identification
Methadone in clinical settings comes in tightly controlled pharmaceutical forms — tablets, liquid concentrate, and dispersible wafers — with consistent dosing. Outside clinical dispensing, the primary challenge is confirming identity and dose strength when tablets are diverted without labeling. Reagent testing has limited utility for confirming methadone specifically; fentanyl test strips should be used on any opioid obtained from unregulated sources, as fentanyl contamination is the leading cause of unexpected opioid overdose.
Guidelines
- Test before use. If obtaining methadone outside a clinical program, confirm identity and dose. Use fentanyl test strips on any opioid from unregulated sources.
- Start low, wait long. Methadone's peak effect takes hours, not minutes. Never redose within 4 hours of an oral dose — accumulation kills more people than initial overdose.
- Keep naloxone accessible. Anyone using methadone — prescribed or not — should have naloxone (Narcan) within reach. Multiple doses may be needed given methadone's long duration.
- Avoid mixing with depressants. Alcohol and benzodiazepines are the most common co-factors in methadone deaths. Even prescribed benzodiazepines increase risk substantially.
- Have a sitter during induction. The first days of methadone use carry the highest mortality risk. Another person present who knows the signs of overdose can save a life.
- Stay hydrated and nourished. Methadone causes constipation and can suppress appetite. Maintain fluid and fiber intake proactively.
Set & Setting
Methadone's slow onset and long duration reward patience and punish impulsivity. The 2.5–4 hour time to peak effect means that redosing before the full effect is felt is one of the most dangerous patterns associated with this substance. A calm, familiar environment reduces the sedation-amplifying effects of anxiety and disorientation, particularly during the first days of use or dose adjustment.
Aftercare & integration. For people using methadone in maintenance treatment, aftercare is an ongoing process rather than a post-experience recovery. Regular medical monitoring — including periodic ECG assessment for QT prolongation — is standard. Managing side effects such as constipation, sweating, and reduced sex drive improves quality of life and treatment retention.
For people considering tapering or discontinuation, the process is slow by necessity: methadone withdrawal is protracted, and gradual dose reduction over months minimizes discomfort and relapse risk. Professional guidance during tapering is strongly recommended. Post-discontinuation, sleep disruption and low mood may persist for weeks to months.
Recovery & Support
Methadone maintenance itself is a recovery intervention — the Cochrane meta-analysis confirms it retains patients and suppresses heroin use more effectively than non-opioid treatments,[32] and all-cause mortality is threefold lower during treatment than out of treatment.[28] Ambivalence about ongoing treatment is common and does not indicate failure.
For those seeking to end methadone use, medically supervised tapering combined with psychosocial support offers the best outcomes. Mutual aid groups (NA, SMART Recovery) and peer support services can supplement clinical care. The transition from methadone to abstinence or buprenorphine should be medically guided — abrupt discontinuation carries high relapse risk and significant physical distress.
Recovery resources, crisis lines, and support pathways → View all
Emergency Response
Recognizing an emergency: Slow, shallow, or stopped breathing; blue or gray lips and fingertips; snoring or gurgling sounds in an unresponsive person; pinpoint pupils with loss of consciousness. Methadone overdose can develop gradually — a person who seems "just sleepy" may deteriorate over hours due to accumulation.
Immediate steps:
- Call emergency services immediately.
- Administer naloxone (intranasal or intramuscular) if available. Methadone's long duration means naloxone may wear off before the methadone does — be prepared to give additional doses and monitor continuously.
- Place the person in the recovery position (on their side) if breathing but unresponsive.
- Stay with the person until help arrives.
- Do NOT induce vomiting. Do NOT leave the person alone.
What to tell the dispatcher: Name the substance (methadone), estimated amount and time taken, symptoms observed, and whether naloxone has been given. Good Samaritan laws in many jurisdictions protect people who call for help during an overdose.
Reversal agent: Naloxone reverses opioid respiratory depression. Because methadone outlasts naloxone, repeated doses or continuous monitoring after administration are essential — relapse into respiratory depression is expected.
Legal Status[edit]
International framework
Methadone is controlled internationally under the UN Single Convention on Narcotic Drugs (1961) as a Schedule I substance. Despite this classification, the WHO simultaneously recognizes it as an essential medicine — added to the Model List of Essential Medicines in 2005 alongside buprenorphine.[7] This dual status reflects the compound's acknowledged medical utility alongside its high abuse liability. National scheduling universally classifies methadone as a controlled substance requiring prescription, with most jurisdictions imposing additional restrictions on its use in addiction treatment.
| Jurisdiction | Classification | Key provisions |
|---|---|---|
| United States | Schedule II (Controlled Substances Act) | DEA Schedule II; for addiction treatment, dispensing restricted to licensed Opioid Treatment Programs (OTPs); three-tier regulation: FDA + DEA + SAMHSA[5] |
| United Kingdom | Class A, Schedule 2 (Misuse of Drugs Act 1971) | Illegal without prescription; maximum penalties for unauthorized possession and supply |
| Canada | Schedule I (Controlled Drugs and Substances Act) | As of 2018, no Health Canada exemption required to prescribe; accessible through standard prescribing authority |
| Germany | Anlage III (Betäubungsmittelgesetz) | Prescribable on special narcotic prescription form; levomethadone (Polamidon) available as pure R-enantiomer |
| Australia | Schedule 8 (Controlled Drug) | Drug of dependence under state/territory controlled substances regulationscitation needed |
| International | Schedule I (UN Single Convention on Narcotic Drugs, 1961) | WHO Essential Medicine (14th Model List, 2005)[7] |
Regulatory distinctiveness
Methadone is the only medication in the United States subject to a three-tier federal regulatory framework (FDA + DEA + SAMHSA) when used for addiction treatment.[5] When prescribed for pain, standard Schedule II prescribing rules apply without the treatment program requirement. This bifurcated structure — more restrictive for addiction treatment than for pain management — has been criticized for limiting treatment access.
references
- [1] ^abDoi S, Mori T, Uzawa N, et al. (2016) Characterization of methadone as a β-arrestin-biased μ-opioid receptor agonist. — Molecular Pain doi:10.1177/1744806916654146
- [2] ^abcEbert B, Andersen S, Krogsgaard-Larsen P (1995) Ketobemidone, methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord. — Neuroscience Letters PMID:7624018
- [3]
- [4] ^abcRickli A, Liakoni E, Hoener MC, Liechti ME (2018) Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome — British Journal of Pharmacology doi:10.1111/bph.14105
- [5]
- [6] ^abDole VP, Nyswander M (1965) A MEDICAL TREATMENT FOR DIACETYLMORPHINE (HEROIN) ADDICTION. A CLINICAL TRIAL WITH METHADONE HYDROCHLORIDE. — JAMA PMID:14321530