Pharmacogenetic Treatments for Drug Addiction: Cocaine, Amphetamine and Methamphetamine

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.