Hostname: page-component-78c5997874-ndw9j Total loading time: 0 Render date: 2024-11-10T08:01:43.976Z Has data issue: false hasContentIssue false
  • English
  • Français

Cytochrome P450-2D6 extensive metabolizers are more vulnerable to methamphetamine-associated neurocognitive impairment: Preliminary findings

Published online by Cambridge University Press:  23 August 2010

MARIANA CHERNER ,
CHAD BOUSMAN ,
IAN EVERALL ,
DANIEL BARRON ,
SCOTT LETENDRE ,
FLORIN VAIDA ,
J. HAMPTON ATKINSON ,
ROBERT HEATON  and
IGOR GRANT
MARIANA CHERNER*
Affiliation:
Department of Psychiatry, University of California San Diego, La Jolla, California
CHAD BOUSMAN
Affiliation:
Department of Psychiatry, University of California San Diego, La Jolla, California
IAN EVERALL
Affiliation:
Department of Psychiatry, University of California San Diego, La Jolla, California
DANIEL BARRON
Affiliation:
University of California San Diego, La Jolla, California
SCOTT LETENDRE
Affiliation:
Department of Medicine, University of California San Diego, La Jolla, California
FLORIN VAIDA
Affiliation:
Department of Family and Preventive Medicine, Division of Biostatistics, University of California San Diego, La Jolla, California
J. HAMPTON ATKINSON
Affiliation:
Department of Psychiatry, University of California San Diego, La Jolla, California VA San Diego Healthcare System, La Jolla, California
ROBERT HEATON
Affiliation:
Department of Psychiatry, University of California San Diego, La Jolla, California
IGOR GRANT
Affiliation:
Department of Psychiatry, University of California San Diego, La Jolla, California VA San Diego Healthcare System, La Jolla, California
*
†Correspondence and reprint requests to: Mariana Cherner, Department of Psychiatry, University of California, 9500 Gilman Drive, La Jolla, CA 92093-0847. E-mail: mcherner@ucsd.edu
Get access Rights & Permissions [Opens in a new window]

Abstract

While neuropsychological deficits are evident among methamphetamine (meth) addicts, they are often unrelated to meth exposure parameters such as lifetime consumption and length of abstinence. The notion that some meth users develop neuropsychological impairments while others with similar drug exposure do not, suggests that there may be individual differences in vulnerability to the neurotoxic effects of meth. One source of differential vulnerability could come from genotypic variability in metabolic clearance of meth, dependent on the activity of cytochrome P450-2D6 (CYP2D6). We compared neuropsychological performance in 52 individuals with a history of meth dependence according with their CYP2D6 phenotype. All were free of HIV or hepatitis C infection and did not meet dependence criteria for other substances. Extensive metabolizers showed worse overall neuropsychological performance and were three times as likely to be cognitively impaired as intermediate/poor metabolizers. Groups did not differ in their demographic or meth use characteristics, nor did they evidence differences in mood disorder or other substance use. This preliminary study is the first to suggest that efficient meth metabolism is associated with worse neurocognitive outcomes in humans, and implicates the products of oxidative metabolism of meth as a possible source of brain injury. (JINS, 2010, 16, 890–901.)

Keywords

Substance abuseCYP2D6PolymorphismsNeurotoxicityMetabolismCognition
Type
Research Articles
Information
Journal of the International Neuropsychological Society , Volume 16 , Issue 5 , September 2010 , pp. 890 - 901
Copyright
Copyright © The International Neuropsychological Society 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Aklillu, E., Herrlin, K., Gustafsson, L.L., Bertilsson, L., & Ingelman-Sundberg, M. (2002). Evidence for environmental influence on CYP2D6-catalysed debrisoquine hydroxylation as demonstrated by phenotyping and genotyping of Ethiopians living in Ethiopia or in Sweden. Pharmacogenetics, 12, 375–383.Google Scholar
Aklillu, E., Persson, I., Bertilsson, L., Johansson, I., Rodrigues, F., & Ingelman-Sundberg, M. (1996). Frequent distribution of ultrarapid metabolizers of debrisoquine in an ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. The Journal of Pharmacology and Experimental Therapeutics, 278, 441–446.Google Scholar
Batki, S.L., Moon, J., Bradley, M., Hersh, D., Smolar, S., & Mengis, M. (1999). Fluoxetine in methamphetamine dependence-a controlled trial: Preliminary analysis. Paper presented at the 61st Annual Scientific Meeting of the College on Problems of Drug Dependence, Acapulco, Mexico.Google Scholar
Bernal, M.L., Sinues, B., Johansson, I., McLellan, R.A., Wennerholm, A., & Dahl, M.L. (1999). Ten percent of North Spanish individuals carry duplicated or triplicated CYP2D6 genes associated with ultrarapid metabolism of debrisoquine. Pharmacogenetics, 9, 657–660.CrossRefGoogle ScholarPubMed
Bradford, L.D. (2002). CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics, 3, 229–243.Google Scholar
Cadet, J.L., Jayanthi, S., & Deng, X. (2003). Speed kills: Cellular and molecular bases of methamphetamine-induced nerve terminal degeneration and neuronal apoptosis. The FASEB Journal, 17, 1775.CrossRefGoogle ScholarPubMed
Caldwell, J., Dring, L.G., Franklin, R.B., Koster, U., Smith, R.L., & Williams, R.T. (1977). Comparative metabolism of the amphetamine drugs of dependence in man and monkeys. Journal of Medical Primatology, 6, 367–375.CrossRefGoogle ScholarPubMed
Caldwell, J., Dring, L.G., & Williams, R.T. (1972). Comparative metabolism of [C14]methamphetamine in man, the guinea pig, and the rat. The Biochemical Journal, 129, 11–22.Google Scholar
Carey, C.L., Woods, S.P., Gonzalez, R., Conover, E., Marcotte, T.D., & Grant, I. (2004). Predictive validity of global deficit scores in detecting neuropsychological impairment in HIV infection. Journal of Clinical and Experimental Neuropsychology, 26, 307–319.CrossRefGoogle ScholarPubMed
Carmo, H., Brulport, M., Hermes, M., Oesch, F., de Boer, D., & Remiao, F. (2007). CYP2D6 increases toxicity of the designer drug 4-methylthioamphetamine (4-MTA). Toxicology, 229, 236–244.Google Scholar
Carmo, H., Brulport, M., Hermes, M., Oesch, F., Silva, R., & Ferreira, L.M. (2006). Influence of CYP2D6 polymorphism on 3,4-methylenedioxymethamphetamine (’Ecstasy’) cytotoxicity. Pharmacogenetics and Genomics, 16, 789–799.Google Scholar
Cascorbi, I. (2003). Pharmacogenetics of cytochrome p4502D6: Genetic background and clinical implication. European Journal of Clinical Investigation, 33(Suppl. 2), 17–22.Google Scholar
Cherner, M., Heaton, R.K., Gonzalez, R.G., Rippeth, J., Carey, C., & Grant, I. (2002). Exposure to methamphetamine and neuropsychological functioning. Journal of the International Neuropsychological Society, 8, 250.Google Scholar
Cherner, M., Suarez, P., Casey, C.Y., Deiss, R., Letendre, S., & Marcotte, T. (2010). Methamphetamine use parameters do not predict neuropsychological impairment in currently abstinent dependent adults. Drug and Alcohol Dependence, 106, 154–163.CrossRefGoogle Scholar
Cherner, M., Suarez, P., Lazzaretto, D., Fortuny, L.A., Mindt, M.R., & Dawes, S. (2007). Demographically corrected norms for the Brief Visuospatial Memory Test-revised and Hopkins Verbal Learning Test-revised in monolingual Spanish speakers from the U.S.-Mexico border region. Archives of Clinical Neuropsychology, 22, 343–353.CrossRefGoogle ScholarPubMed
Citron, B.P., Halpern, M., McCarron, M., Lundberg, G.D., McCormick, R., & Pincus, I.J. (1970). Necrotizing angiitis associated with drug abuse. New England Journal of Medicine, 283, 1003–1011.Google Scholar
Clement, B., Behrens, D., Moller, W., & Cashman, J.R. (2000). Reduction of amphetamine hydroxylamine and other aliphatic hydroxylamines by benzamidoxime reductase and human liver microsomes. Chemical Research in Toxicology, 13, 1037–1045.Google Scholar
Colado, M.I., Williams, J.L., & Green, A.R. (1995). The hyperthermic and neurotoxic effects of ’Ecstasy’ (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype. British Journal of Pharmacology, 115, 1281.Google Scholar
Dahl, M.L., Johansson, I., Bertilsson, L., Ingelman-Sundberg, M., & Sjoqvist, F. (1995). Ultrarapid hydroxylation of debrisoquine in a Swedish population. Analysis of the molecular genetic basis. The Journal of Pharmacology and Expimental Therapeutics, 274, 516–520.Google Scholar
Dahl, M.L., Yue, Q.Y., Roh, H.K., Johansson, I., Sawe, J., & Sjoqvist, F. (1995). Genetic analysis of the CYP2D locus in relation to debrisoquine hydroxylation capacity in Korean, Japanese and Chinese subjects. Pharmacogenetics, 5, 159–164.Google Scholar
de la Torre, R., & Farre, M. (2004). Neurotoxicity of MDMA (ecstasy): The limitations of scaling from animals to humans. Trends in Pharmacological Sciences, 25, 505.Google Scholar
de Leon, J., Susce, M.T., Pan, R.M., Koch, W.H., & Wedlund, P.J. (2005). Polymorphic variations in GSTM1, GSTT1, PgP, CYP2D6, CYP3A5, and dopamine D2 and D3 receptors and their association with tardive dyskinesia in severe mental illness. Journal of Clinical Psychopharmacology, 25, 448–456.CrossRefGoogle ScholarPubMed
Dorado, P., Berecz, R., Caceres, M.C., Gonzalez, I., Cobaleda, J., & Llerena, A. (2005). Determination of debrisoquine and 4-hydroxydebrisoquine by high-performance liquid chromatography: Application to the evaluation of CYP2D6 genotype and debrisoquine metabolic ratio relationship. Clinical Chemistry and Laboratory Medicine, 43, 275–279.Google Scholar
Dring, L.G., Smith, R.L., & Williams, R.T. (1970). The metabolic fate of amphetamine in man and other species. The Biochemical Journal, 116, 425–435.CrossRefGoogle ScholarPubMed
First, M.B., Spitzer, R.L., Gibbon, M., & Williams, J.B.W. (1994). Structured clinical interview for Axis I DSM-IV disorders (SCID). Washington, DC: Psychiatric Press.Google Scholar
Gaedigk, A., Bhathena, A., Ndjountche, L., Pearce, R.E., Abdel-Rahman, S.M., & Alander, S.W. (2005). Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans. The Pharmacogenomics Journal, 5, 173–182.CrossRefGoogle ScholarPubMed
Gaedigk, A., Bradford, L.D., Marcucci, K.A., & Leeder, J.S. (2002). Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans. Clinical Pharmacology and Therapeutics, 72, 76–89.Google Scholar
Gonzalez, F.J., Vilbois, F., Hardwick, J.P., McBride, O.W., Nebert, D.W., & Gelboin, H.V. (1988). Human debrisoquine 4-hydroxylase (P450IID1): cDNA and deduced amino acid sequence and assignment of the CYP2D locus to chromosome 22. Genomics, 2, 174–179.Google Scholar
Gonzalez, R., Rippeth, J.D., Carey, C.L., Heaton, R.K., Moore, D.J., & Schweinsburg, B.C. (2004). Neurocognitive performance of methamphetamine users discordant for history of marijuana exposure. Drug and Alcohol Dependence, 76, 181–190.CrossRefGoogle ScholarPubMed
Gough, A.C., Miles, J.S., Spurr, N.K., Moss, J.E., Gaedigk, A., & Eichelbaum, M. (1990). Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature, 347, 773–776.CrossRefGoogle ScholarPubMed
Grant, I., Gonzalez, R., Carey, C.L., Natarajan, L., & Wolfson, T. (2003). Non-acute (residual) neurocognitive effects of cannabis use: A meta-analytic study. Journal of the International Neuropsychological Society, 9, 679–689.CrossRefGoogle ScholarPubMed
Heaton, R.K., Grant, I., Butters, N., White, D.A., Kirson, D., & Atkinson, J.H. (1995). The HNRC 500–neuropsychology of HIV infection at different disease stages. Journal of the International Neuropsychological Society, 1, 231–251.Google Scholar
Heaton, R., Miller, S., Taylor, M., & Grant, I. (2004). Revised comprehensive norms for an expanded Halstead-Reitan Battery: Demographically adjusted neuropsychological norms for African American and caucasian adults. Lutz, FL: Psychological Assessment Resources.Google Scholar
Heaton, R., Taylor, M., & Manly, J. (2003). Demographic effects and use of demographically corrected norms with the WAIS III and the WMS-III. In Tulsky, D., Saklofske, D., Heaton, R.K., Cheline, G., Ivnik, R., Bornstein, R.A., Prifitera, A., & Ledbetter, M.F. (Eds.), Clinical interpretation of the WAIS-III and WMS-III (pp. 183–210). San Diego: Academic Press.Google Scholar
Hemeryck, A., & Belpaire, F.M. (2002). Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: An update. Current Drug Metabolism, 3, 13.CrossRefGoogle ScholarPubMed
Hendrickson, H.P., Hardwick, W.C., McMillan, D.E., Owens, S.M. (2008). Bioavailability of (+)-methamphetamine in the pigeon following an intramuscular dose. Pharmacology Biochemistry and Behavior, 90, 382–386.CrossRefGoogle ScholarPubMed
Inada, T., Senoo, H., Iijima, Y., Yamauchi, T., & Yagi, G. (2003). Cytochrome P450 II D6 gene polymorphisms and the neuroleptic-induced extrapyramidal symptoms in Japanese schizophrenic patients. Psychiatric Genetics, 13, 163–168.Google Scholar
Iyo, M., Namba, H., Yanagisawa, M., Hirai, S., Yui, N., & Fukui, S. (1997). Abnormal cerebral perfusion in chronic methamphetamine abusers: A study using 99MTc-HMPAO and SPECT. Progress in Neuro-psychopharmacology & Biological Psychiatry, 21, 789–796.Google Scholar
Johansson, I., Lundqvist, E., Bertilsson, L., Dahl, M.L., Sjoqvist, F., & Ingelman-Sundberg, M. (1993). Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proceedings of the National Academy of Sciences of the United States of America, 90, 11825–11829.Google Scholar
Kalechstein, A.D., Newton, T.F., & Green, M. (2003). Methamphetamine dependence is associated with neurocognitive impairment in the initial phases of abstinence. The Journal of Neuropsychiatry and Clinical Neurosciences, 15, 215–220.Google Scholar
Kimura, S., Umeno, M., Skoda, R.C., Meyer, U.A., & Gonzalez, F.J. (1989). The human debrisoquine 4-hydroxylase (CYP2D) locus: Sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. American Journal of Human Genetics, 45, 889–904.Google Scholar
Kobayashi, S., Murray, S., Watson, D., Sesardic, D., Davies, D.S., & Boobis, A.R. (1989). The specificity of inhibition of debrisoquine 4-hydroxylase activity by quinidine and quinine in the rat is the inverse of that in man. Biochemical Pharmacology, 38, 2795.Google Scholar
Lin, L.Y., Di Stefano, E.W., Schmitz, D.A., Hsu, L., Ellis, S.W., & Lennard, M.S. (1997). Oxidation of methamphetamine and methylenedioxymethamphetamine by CYP2D6. Drug Metabolism and Disposition, 25, 1059–1064.Google Scholar
Marez, D., Legrand, M., Sabbagh, N., Guidice, J.M., Spire, C., & Lafitte, J.J. (1997). Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: Characterization of 48 mutations and 53 alleles, their frequencies and evolution. Pharmacogenetics, 7, 193–202.Google Scholar
McCann, U.D., Wong, D.F., Yokoi, F., Villemagne, V., Dannals, R.F., & Ricaurte, G.A. (1998). Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: Evidence from positron emission tomography studies with [11C]WIN-35,428. The Journal of Neuroscience, 18, 8417–8422.Google Scholar
McKetin, R., & Mattick, R.P. (1997). Attention and memory in illicit amphetamine users. Drug and Alcohol Dependence, 48, 235–242.Google Scholar
McKetin, R., & Mattick, R.P. (1998). Attention and memory in illicit amphetamine users: Comparison with non-drug-using controls. Drug and Alcohol Dependence, 50, 181–184.Google Scholar
Miranda, G.E., Sordo, M., Salazar, A.M., Contreras, C., Bautista, L., & Rojas Garcia, A.E. (2007). Determination of amphetamine, methamphetamine, and hydroxyamphetamine derivatives in urine by gas chromatography-mass spectrometry and its relation to CYP2D6 phenotype of drug users. Journal of Analytical Toxicology, 31, 31–36.Google Scholar
Monks, T.J., Jones, D.C., Bai, F., & Lau, S.S. (2004). The role of metabolism in 3,4-(+)-methylenedioxyamphetamine and 3,4-(+)-methylenedioxymethamphetamine (ecstasy) toxicity. Therapeutic Drug Monitoring, 26, 132.Google Scholar
Moore, D.J., Masliah, E., Rippeth, J.D., Gonzalez, R., Carey, C.L., & Cherner, M. (2006). Cortical and subcortical neurodegeneration is associated with HIV neurocognitive impairment. Aids, 20, 879–887.Google Scholar
Piasecki, M.P., Steinagel, G.M., Thienhaus, O.J., & Kohlenberg, B.S. (2002). An exploratory study: The use of paroxetine for methamphetamine craving. Journal of Psychoactive Drugs, 34, 301.Google Scholar
Quinton, M.S., & Yamamoto, B.K. (2006). Causes and consequences of methamphetamine and MDMA toxicity. The AAPS Journal, 8, E337.Google Scholar
Raimundo, S., Fischer, J., Eichelbaum, M., Griese, E.U., Schwab, M., & Zanger, U.M. (2000). Elucidation of the genetic basis of the common ’intermediate metabolizer’ phenotype for drug oxidation by CYP2D6. Pharmacogenetics, 10, 577–581.Google Scholar
Rippeth, J.D., Heaton, R.K., Carey, C.L., Marcotte, T.D., Moore, D.J., & Gonzalez, R. (2004). Methamphetamine dependence increases risk of neuropsychological impairment in HIV infected persons. Journal of the International Neuropsychological Society, 10, 1–14.Google Scholar
Robins, L.N., Wing, J., Wittchen, H.U., Helzer, J.E., Babor, T.F., & Burke, J. (1988). The Composite international diagnostic interview. An epidemiologic Instrument suitable for use in conjunction with different diagnostic systems and in different cultures. Archives of General Psychiatry, 45, 1069–1077.Google Scholar
Rumbaugh, C.L., Bergeron, R.T., Scanlan, R.L., Teal, J.S., Segall, H.D., & Fang, H.C. (1971). Cerebral vascular changes secondary to amphetamine abuse in the experimental animal. Radiology, 101, 345–351.Google Scholar
Sachse, C., Brockmoller, J., Bauer, S., & Roots, I. (1997). Cytochrome P450 2D6 variants in a Caucasian population: Allele frequencies and phenotypic consequences. American Journal of Human Genetics, 60, 284–295.Google Scholar
Scott, J.C., Woods, S.P., Matt, G.E., Meyer, R.A., Heaton, R.K., & Atkinson, J.H. (2007). Neurocognitive effects of methamphetamine: A critical review and meta-analysis. Neuropsychology Revies, 17, 275–297.CrossRefGoogle ScholarPubMed
Sekine, Y., Iyo, M., Ouchi, Y., Matsunaga, T., Tsukada, H., & Okada, H. (2001). Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET. American Journal of Psychiatry, 158, 1206–1214.CrossRefGoogle ScholarPubMed
Shima, N., Kamata, H.T., Katagi, M., & Tsuchihashi, H. (2006). Urinary excretion of the main metabolites of methamphetamine, including p-hydroxymethamphetamine-sulfate and p-hydroxymethamphetamine-glucuronide, in humans and rats. Xenobiotica, 36, 259–267.Google Scholar
Shoptaw, S., Huber, A., Peck, J., Yang, X., Liu, J., & Jeff, D. (2006). Randomized, placebo-controlled trial of sertraline and contingency management for the treatment of methamphetamine dependence. Drug and Alcohol Dependence, 85, 12.Google Scholar
Sim, T., Simon, S.L., Domier, C.P., Richardson, K., Rawson, R.A., & Ling, W. (2002). Cognitive deficits among methamphetamine users with attention deficit hyperactivity disorder symptomatology. Journal of Addictive Diseases, 21, 75–89.CrossRefGoogle ScholarPubMed
Singh, M., Khan, A., Shah, P., Shukla, R., Khanna, V., & Parmar, D. (2008). Polymorphism in environment responsive genes and association with Parkinson disease. Molecular and Cellular Biochemistry, 312, 131–138.Google Scholar
Skvortsova, V.I., Slominskii, P.A., Shadrina, M.I., Levitskii, G.N., Levitskaia, N.I., & Alekhin, A.V. (2006). [Detoxication gene polymorphism and susceptibility to sporadic motor neuron disease in Russian population]. Zhurnal nevropatologii i psikhiatrii imeni S.S. Korsakova (Moscow, Russia: 1952), 106, 4–13.Google Scholar
Tiwari, A.K., Deshpande, S.N., Rao, A.R., Bhatia, T., Lerer, B., & Nimgaonkar, V.L. (2005). Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: III. Lack of association of CYP3A4 and CYP2D6 gene polymorphisms. Schizophrenia Research, 75, 21–26.Google Scholar
Volkow, N.D., Chang, L., Wang, G.J., Fowler, J.S., Ding, Y.S., & Sedler, M. (2001). Low level of brain dopamine D2 receptors in methamphetamine abusers: Association with metabolism in the orbitofrontal cortex. American Journal of Psychiatry, 158, 2015–2021.Google Scholar
Volkow, N.D., Chang, L., Wang, G.J., Fowler, J.S., Leonido-Yee, M., & Franceschi, D. (2001). Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. American Journal of Psychiatry, 158, 377–382.CrossRefGoogle ScholarPubMed
Vorhees, C.V., Morford, L.L., Inman, S.L., Reed, T.M., Schilling, M.A., & Cappon, G.D. (1999). Genetic differences in spatial learning between Dark Agouti and Sprague-Dawley strains: Possible correlation with the CYP2D2 polymorphism in rats treated neonatally with methamphetamine. Pharmacogenetics, 9, 171–181.Google Scholar
Wijnen, P.A., Op den Buijsch, R.A., Drent, M., Kuipers, P.M., Neef, C., & Bast, A. (2007). Review article: The prevalence and clinical relevance of cytochrome P450 polymorphisms. Alimentary Pharmacology & Therapeutics, 26(Suppl. 2), 211.CrossRefGoogle ScholarPubMed
Wu, D., Otton, S.V., Inaba, T., Kalow, W., & Sellers, E.M. (1997). Interactions of amphetamine analogs with human liver CYP2D6. Biochemical Pharmacology, 53, 1605–1612.Google Scholar
Zanger, U.M., Raimundo, S., & Eichelbaum, M. (2004). Cytochrome P450 2D6: Overview and update on pharmacology, genetics, biochemistry. Naunyn-Schmiedeberg’s Archives of Pharmacology, 369, 23.CrossRefGoogle ScholarPubMed