Naltrexone for Individuals of East Asian Descent

Recent pharmacogenetic studies have advanced the gene coding for µ-opioid receptors (OPRM1)
gene as a potential moderator of responses to naltrexone. The most widely studied
polymorphism of the OPRM1 gene is the Asn40Asp single nucleotide polymorphism (SNP), a
functional mutation thought to affect receptor activity such that the Asp40 variant binds
β-endorphin three times stronger than the Asn40 allele. Recent studies have found that Asp40
carriers have a stronger striatal dopamine response to intravenous alcohol administration
and report stronger feelings of alcohol reward. Findings from the COMBINE Study demonstrated
that if treated with Medication Management alone and naltrexone, 87.1% of Asp40 carriers had
a good clinical outcome, compared with only 54.8% of Asn40 homozygotes. While these findings
are promising, studies have also highlighted allele frequency imbalance as a function of
ethnicity such that the Asp40 allele frequency is approximately 20% in Caucasians, 5% in
individuals of African Ancestry, and as high as 50% among individuals of East Asian descent.
Therefore, to the extent to which this SNP moderates behavioral and clinical responses to
NTX, ethnicity must be carefully considered in order to extend the findings from primarily
Caucasian samples to ethnic minorities, such as Asian Americans. Preliminary work by our
team has found that among individuals of East Asian descent, Asp40 carriers show greater
NTX-induced blunting of alcohol craving as well as potentiation of the aversive effects of
alcohol. This pilot study also found support for a gene dose-response, such that Asp40Asp
individuals showed greater NTX responsivity than those with the Asn40Asp genotype. This
study seeks to build upon these preliminary findings by testing heavy drinkers of East Asian
descent across three OPRM1 genotypes (Asn40Asn, n = 30; Asn40Asp, n = 30, and Asp40Asp, n =
30). Participants will complete two double-blinded, counterbalanced alcohol infusion and
self-administration sessions, one after taking NTX (50 mg/day) and one after taking matched
placebo for five days. In each medication condition, participants will complete a functional
neuroimaging task examining cue-induced craving for alcohol. This study will elucidate the
pharmacogenetic effects of the Asn40Asp SNP of the OPRM1 gene on biobehavioral and neural
markers of response to naltrexone in individuals of Asian descent, an ethnic group most
likely to express the positive predictive allele (Asp40). The long-term objective of this
research is to optimize alcoholism pharmacotherapy and to address health disparities by
advancing pharmacogenetic studies in ethnic minority groups.

Inclusion Criteria:

- current (i.e., past month) alcohol dependence

- East Asian ethnicity (i.e., Chinese, Korean, or Japanese)

- Prospective genotyping for the A118G SNP of the mu opioid receptor (OPRM1) gene to
allow for balanced groups on all three genotypes (AA, AG, GG)

Exclusion Criteria:

- lifetime DSM-IV of drug dependence (other than alcohol or nicotine)

- current use of psychoactive drugs as determined by self-reports and verified using
toxicology testing

- lifetime diagnosis of bipolar disorder or any psychotic disorder

- contraindications to an MRI scan (including left handedness)