Four deaths related to the drug 4-methylmethcathinone (mephedrone) are reported. Qualitative and quantitative analysis of mephedrone was performed by high-performance liquid chromatography-diode-array detection. Of the four deaths, one was attributed to the adverse effects of mephedrone, with cardiac fibrosis and atherosclerotic coronary artery disease as a contributing factor. A 49-year-old female insufflated mephedrone; analysis disclosed mephedrone in femoral venous blood (0.98 mg/L). The second death was attributed solely to mephedrone. A 19-year-old male took mephedrone as well as alcohol and "ecstasy"; analysis disclosed mephedrone (2.24 mg/L femoral venous blood) and 3-trifluoromethylphenylpiperazine (3-TFMPP). In the third fatality, a 55-year-old female was found dead in bed; the death was attributed to the combined effects of mephedrone and methadone. Analysis of femoral venous blood revealed the prescribed drugs diazepam, nordiazepam, olazepine, and chlorpromazine metabolites together with methadone (0.3 mg/L) and mephedrone (0.13 mg/L). In the fourth case, a 17-year-old male car driver was involved in a vehicular collision and died of multiple blunt force injuries. Analysis revealed mephedrone in femoral venous blood (0.24 mg/L).

Methadone is a medication valued for its effectiveness in the treatment of heroin addiction; however, many fatal poisonings associated with its use have been reported over the years. We have examined the association between CYP2B6 and micro-opioid receptor (OPRM1) gene variations and apparent susceptibility to methadone poisoning. Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning. The presence of CYP2B6*4,*9, and *6 alleles and the OPRM1 A118G variant was determined by SNP genotyping. CYP2B6 *4, *9, and *6 alleles were found to be associated with higher postmortem methadone concentrations in blood (P < or = 0.05). OPRM1 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance (P = 0.39). In these methadone-related deaths, OPRM1 118GA was associated with higher postmortem benzodiazepine concentrations (P = 0.04), a finding not associated with morphine-related deaths. The risk of a methadone-related fatality during treatment may be evaluated in part by screening for CYP2B6*6 and A118G.

The largest proportion of methadone-associated deaths occurs during the drug induction phase. We analysed methadone-related fatalities for gene variations linked with methadone action. A significant association between high methadone concentrations and the CYP2B6*6 allele characteristic of the slow metabolizer phenotype was identified. We suggest that the risk of methadone fatality may be predetermined in part by the CYP2B6*6 allele. A significant correlation was also observed between post-mortem benzodiazepine concentrations and the OPRM1 A118G allele GA in methadone-related fatalities. Screening for these susceptibility variations prior to methadone prescription could assist in reducing the potential for serious adverse effects.

Methadone is used worldwide for the treatment of heroin addiction; however, fatal poisonings are increasingly reported. The prevalence of CYP2B6 and μ-opioid receptor (OPRM1) gene variations were examined between a postmortem population where the deaths were associated with methadone and a live nondrug-using control population using Taqman™ SNP Genotyping assays. The CYP2B6*6 allele was higher in the postmortem population, but the difference was not significant (P = 0.92). The CYP2B6 T750C promoter variation was similar in frequency for both populations. Linkage between T750C and CYP2B6*6 was identified for both populations (P < 0.01). The prevalence of the OPRM1 A118G variation was significantly higher in the control population (P = 0.0046), which might indicate a protective mechanism against opioid toxicity. Individual susceptibility to methadone may be determined by screening for CYP2B6*6.