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Interpretation of toxicological findings can be challenging if no further information about the case history is available. The aims of this study were (1) to determine whether brain\/blood ratios can assist in the interpretation of methadone findings in fatalities; (2) to examine whether polymorphisms in the gene encoding the P-glycoprotein (also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1)), which functions as a multispecific efflux pump in the blood\u2013brain barrier, affect brain\/blood ratios of methadone. Femoral venous blood and brain tissue (medulla oblongata and cerebellum) from 107 methadone-related deaths were analysed for methadone by gas chromatography-mass spectrometry. In addition, all the samples were genotyped for three common <jats:italic>ABCB1<\/jats:italic> single nucleotide polymorphisms (SNPs rs1045642, rs1128503, and rs2032582) using ion-pair reversed-phase high-performance liquid chromatography-electrospray ionization mass spectrometry (ICEMS). In nearly all cases, methadone concentrations were higher in the brain than in the blood. Inter-individual brain\/blood ratios varied (0.6\u201311.6); the mean ratio was 2.85 (standard deviation 1.83, median 2.35). Moreover, significant differences in mean brain\/blood ratios were detected among the synonymous genotypes of rs1045642 in <jats:italic>ABCB1<\/jats:italic> (<jats:italic>p<\/jats:italic> = 0.001). Cases with the T\/T genotype had significantly higher brain\/blood ratios than cases with the other genotypes (T\/T vs. T\/C difference (<jats:italic>d<\/jats:italic>) = 1.54, 95% CI [1.14, 2.05], <jats:italic>p<\/jats:italic> = 0.002; T\/T vs. C\/C <jats:italic>d<\/jats:italic> = 1.60, 95% CI [1.13, 2.29], <jats:italic>p<\/jats:italic> = 0.004). Our results suggest that the rs1045642 polymorphisms in <jats:italic>ABCB1<\/jats:italic> may affect methadone concentrations in the brain and its site of action and may be an additional factor influencing methadone toxicity.<\/jats:p>","DOI":"10.1007\/s00414-021-02502-5","type":"journal-article","created":{"date-parts":[[2021,1,17]],"date-time":"2021-01-17T05:02:15Z","timestamp":1610859735000},"page":"473-482","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Brain\/blood ratios of methadone and ABCB1 polymorphisms in methadone-related deaths"],"prefix":"10.1007","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7687-1388","authenticated-orcid":false,"given":"S.","family":"Iwersen-Bergmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Plattner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Hischke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Andresen-Streichert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Jungen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Erb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Beer-Sandner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,17]]},"reference":[{"issue":"1","key":"2502_CR1","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1186\/s13054-020-02915-5","volume":"24","author":"M Schulz","year":"2020","unstructured":"Schulz M, Schmoldt A, Andresen-Streichert H, Iwersen-Bergmann S (2020) Revisited: Therapeutic and toxic blood concentrations of more than 1100 drugs and other xenobiotics. 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