Summary
Methadone is extensively metabolized by cytochrome P450 enzymes (primarily CYP3A4, CYP2B6, CYP2D6), leading to significant interindividual variability in effects and high risk of drug interactions. It can prolong the QT interval, increasing the risk of torsades de pointes and sudden cardiac death, especially at higher doses or with interacting medications. The half-life varies widely (8-59 hours) and is much longer than the duration of analgesic effects, leading to accumulation with repeated dosing. Overdose risk is extremely high in opioid-naïve individuals or when combined with other depressants. Methadone is a cornerstone of opioid substitution therapy and medication-assisted treatment (MAT) programs.
Dose Information
| ROA | Light | Common | Strong | Heavy |
|---|---|---|---|---|
| Oral | 3-5mg | 5-15mg | 15-30mg | 30mg+ |
Light
Common
Strong
Heavy
Onset, Duration & After-effects
| ROA | Onset | Comeup | Peak | Offset | After Effects |
|---|---|---|---|---|---|
| Oral | 20-90 min | 2-4 hrs | 4-6 hrs | 4-6 hrs | 1-24 hrs |
| Intravenous | 1-5 min | 5-15 min | 2-4 hrs | 12-36 hrs | 48 hrs |
Tolerance
Build-up
develops within days of regular use; analgesic tolerance faster than respiratory depression tolerance
Reset
7–14 days for partial reset; full reset may take weeks — tolerance loss greatly increases overdose risk
Cross-tolerance
Effects
Positive
- Physical Euphoria
- Pain Relief
- Cough Suppression
- Reduced Opioid Cravings
- Analgesia
Negative
- Respiratory Depression
- Nausea
- Dry Mouth
- Sedation
- Pupil Constriction
- Itchiness
- Difficulty Urinating
- Relaxant
Positive
- Anxiety Suppression
- Euphoria
- Mood lift
- Reduced anxiety
- Relaxation
- Motivation Enhancement
Negative
- Constipation
- Dream Suppression
- Anxiety
- Time distortion
Positive
- Increased music appreciation
- Color enhancement
- Tactile enhancement
- Increased libido
Negative
- Appetite Suppression
- Light sensitivity
- Dehydration
- Appetite suppression
- Disinhibition
- Dulled perception