Journal
AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE
Volume 35, Issue 3, Pages 161-177Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/00952990902825447
Keywords
Gene variants; pharmacotherapies; drug therapy; stimulants; individualized therapy; gene-based therapeutics; polymorphisms; genetic variation; subjective effects; drug dependence; addiction psychiatry
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Funding
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [U01AA013476] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R21DA020117] Funding Source: NIH RePORTER
- NIAAA NIH HHS [U01 AA013476, U01 AA013476-08, U01-AA013476] Funding Source: Medline
- NIDA NIH HHS [DA020117, R21 DA020117] Funding Source: Medline
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Background: Pharmacogenetics uses genetic variation to predict individual differences in response to medications and holds much promise to improve treatment of addictive disorders. Objectives: To review how genetic variation affects responses to cocaine, amphetamine, and methamphetamine and how this information may guide pharmacotherapy. Methods: We performed a cross-referenced literature search on pharmacogenetics, cocaine, amphetamine, and methamphetamine. Results: We describe functional genetic variants for enzymes dopamine-beta-hydroxylase (DH), catechol-O-methyltransferase (COMT), and dopamine transporter (DAT1), dopamine D4 receptor, and brain-derived neurotrophic factor (BDNF). A single nucleotide polymorphism (SNP; C-1021T) in the DH gene is relevant to paranoia associated with disulfiram pharmacotherapy for cocaine addiction. Individuals with variable number tandem repeats (VNTR) of the SLC6A3 gene 3'-untranslated region polymorphism of DAT1 have altered responses to drugs. The 10/10 repeat respond poorly to methylphenidate pharmacotherapy and the 9/9 DAT1 variant show blunted euphoria and physiological response to amphetamine. COMT, D4 receptor, and BDNF polymorphisms are linked to methamphetamine abuse and psychosis. Conclusions: Disulfiram and methylphenidate pharmacotherapies for cocaine addiction are optimized by considering polymorphisms affecting DH and DAT1 respectively. Altered subjective effects for amphetamine in DAT1 VNTR variants suggest a 'protected' phenotype. Scientific Significance: Pharmacogenetic-based treatments for psychostimulant addiction are critical for successful treatment.
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