title: Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: a transnational study.
abstract: OBJECTIVE
  To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics.
  
  
  METHODS
  Trough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose.
  
  
  RESULTS
  Cannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14-16% and 17-25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4.
  
  
  CONCLUSIONS
  Cannabis use and higher methadone doses in MMT could in part be a response to-or a cause of-more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT.
authors.affiliation: The Byrne Surgery, Redfern, NSW, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Hallinan
authors.forename: Séverine
authors.initials: S
authors.lastname: Crettol
authors.forename: Kingsley
authors.initials: K
authors.lastname: Agho
authors.forename: John
authors.initials: J
authors.lastname: Attia
authors.forename: Jacques
authors.initials: J
authors.lastname: Besson
authors.forename: Marina
authors.initials: M
authors.lastname: Croquette-Krokar
authors.forename: Robert
authors.initials: R
authors.lastname: Hämmig
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Déglon
authors.forename: Andrew
authors.initials: A
authors.lastname: Byrne
authors.forename: John
authors.initials: J
authors.lastname: Ray
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Somogyi
authors.forename: Chin B
authors.initials: CB
authors.lastname: Eap
mesh_terms: D000328:Adult; D000428:Alcohol Drinking; D001315:Australia; D001569:Benzodiazepines / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology*; D002188:Cannabis; D005260:Female; D006801:Humans; D008297:Male; D008691:Methadone / Q000097:blood* / Q000493:pharmacokinetics; D012907:Smoking; D013557:Switzerland
chemical_list: D002186:Cannabinoids; D001569:Benzodiazepines; D008691:Methadone