Methadone is not an inhibitor or an inducer of CYP3A4 in vivo. Risk for gastrointestinal adverse events in the form of vomiting, nausea, constipation and fatigue motivates vigilance against insufficient intake of food, especially of carbohydrate.

Methadone is indicated for the treatment of dependence on opioid drugs. Very common and common side effects that can be potentially porphyrinogenic through reduction in carbohydrate intake and that also can be confused with an acute porphyria attack are vomiting, nausea, constipation and fatigue. Other common side effects are euphoria, hallucination, drowsiness and fatigue.

Methadone is metabolised mainly by CYP3A4 with minor contribution by CYP2D6 and CYP2B6 (SPC). It is metabolised primarily via N-demethylation and the two most important metabolites are 2-ethyl-1,5-dimethyl-2,2-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenyl-1-pyrrolidinee (EMDP). Both are inactive (SPC and Tolson 2009). In vitro it has been shown to be extensively metabolised by CYP3A4 and to a lesser extent by 1A2, 2D6, 2D8, 2C9/2C8, 2C19 and 2B6 (Kapur 2011). In vitro data also indicates that methadone can induce CYP3A4 (Tolson 2009), but in vivo data shows the opposite. Methadone did not change the AUC or Cmax of rilpivirine (CYP3A4 substrate) when co-administrated, which indicates that it is not an inhibitor or an inducer of CYP3A4 (Crauwels 2013 and SPC). No drug interaction with methadone as a perpetrator has been shown, but the pharmacokinetics of methadone is affected by several drugs (Ferrari 2004). Gruber (2010) states that methadone is not a major inducer or inhibitor of CYP450 enzymes.

Methadone is listed as safe for use in acute porphyria and has not been associated with human porphyric attacks (Moore 1997). Methadone is reported to be safely used in porphyria, or not produce experimental porphyria (Rifkind 1976) Methadone is listed as safe (Disler 1982, Kalman 1998).