Psychoactive medication is frequently used in methadone maintenance treatment programs (MMP) to treat comorbid mental disorders (depression, anxiety, schizophrenia) in opiate-addicts. Thus, several pharmacological interactions are possible. This problem becomes more relevant with the introduction of new CNS-drugs like SSRI, atypical antipsychotics or new anticonvulsants. The most common interactions seen in practice are pharmacodynamic in nature, most often due to the cumulative effects of different drugs on the central nervous system (e.g. neuroleptics or benzodiazepine interactions). However important pharmacokinetic interactions may occur particularly between methadone and antidepressant drugs: Desipramine plasma levels are increased by methadone; further fluvoxamine (and fluoxetine to a less extent) may cause an important increase in serum methadone concentrations. The inhibition of different clusters of the cytochrome P450 system are involved in these interactions. Several lines of evidence suggest that benzodiazepines and methadone may have synergistic interactions and that opiate sedation or respiratory depression could be increased. This is a serious problem, given the widespread use of benzodiazepines among MMPpatients. Experimental but not clinical data support methadone and lithium interactions. Finally, classic anticonvulsant drugs, such asphenytoin, carbamazepine and phenobarbital, produce dramatic decreases in methadone levels, which may precipitate a withdrawal syndrome; valproic acid and the new anticonvulsant drugs do not have these effects. Accordingly, caution is advised in the clinical use of methadone when other CNS-drugs are administered.