ARRA IMPACT REPORT:
Advancing Treatment for Alcohol-Related Problems
Public Health Burden
Alcohol use disorders cost U.S. society an estimated $235 billion annually through injury, death, lost wages, property damage, and other consequences. In any given year, approximately 18 million Americans age 18 or older suffer from alcohol use disorders, including dependence, which put them at increased risk for alcohol-related injuries and organ pathologies. Most people who suffer from alcohol dependence do not receive formal treatment.
Pharmacotherapy for Alcohol Dependence
In the U.S. only three medications (acamprosate, disulfiram and naltrexone ) have been approved for the treatment of alcohol dependence. Because alcohol dependence is a complex disease with genetic and environmental risk factors that vary among subpopulations of drinkers, no single alcohol medication has been effective for all patients. Understanding the factors that influence treatment response to these and other medications can help identify individuals who are most likely to respond and make screening and clinical testing of experimental drugs more efficient. ARRA-supported research has made advances towards an improved understanding of these factors.
Genetic Profile May Help Predict Response to Alcohol Medications: An ARRA-funded project at the University of Virginia contributed to a clinical trial that used a pharmacogenetic approach to predict treatment success for alcohol dependence. This trial extended previous findings that variants in the gene encoding the serotonin transporter protein 5-HTT influence drinking severity. Serotonin is one of several neurotransmitters in the brain that regulate alcohol dependence. In the current study, two 5-HTT genetic variants (LL and TT) were used to predict treatment response to odansetron, an FDA-approved anti-nausea medication that blocks the action of serotonin. Subjects with the LL variant who received odansetron drank fewer drinks per drinking day and maintained abstinence longer than those who received the placebo. Those with both the LL and TT variants had an even more pronounced treatment response to odansetron compared to LL subjects and control groups. These results suggest that a patient’s genetic profile can be used to predict response to alcohol medications, such as odansetron, and can inform health care providers’ decisions in prescribing alcohol medications to their patients.1
Reducing Glutamate Levels may lead to Reduced Alcohol Consumption: The alcohol medication acamprosate interacts with the neurotransmitters glutamate and gamma-aminobutyric acid (GABA), both of which play important roles in alcohol dependence. However, acamprosate’s exact mechanism of action in unknown. Studies that provide additional insight into its mechanism of action may reveal new molecular targets for treatment as well as help identify populations who are more likely to respond to treatment with the drug. In a study investigating the pharmacological effects of acamprosate, ARRA-supported researchers at the Mayo Clinic College of Medicine utilized a mouse lacking the gene ENTI (“ENTI null mice”) to model drinking behavior during chronic alcohol exposure. Reduced ENT1 expression in mice produces alcohol dependence-related effects, i.e. increased drinking. The researchers found that acamprosate significantly reduced ethanol consumption in ENT1 null mice and restored glutamate to near normal levels in a specific brain region involved in alcohol dependence, compared to mice with a normal ENT1 gene. The results confirm that acamprosate regulates glutamate levels in the brain and show that reducing glutamate levels may lead to reduced alcohol consumption.2
Effects of Acamprosate Treatment on Alcohol Withdrawal: The same team of ARRA-supported researchers used the ENT1 null model system to examine the effects of acamprosate on withdrawal (withdrawal symptoms often lead to relapse in alcohol dependent individuals). Withdrawal is also associated with changes in various neurotransmitters, including glutamate and GABA. The investigators found that withdrawal from chronic alcohol exposure resulted in decreased GABA levels in both normal and ENT1 null mice, and acamprosate restored GABA levels in ENT1 null mice only. Withdrawal also produced elevated glutamate levels and, interestingly, acamprosate restored glutamate levels in both normal and ENT null mice. Taken together with the study described above, these findings provide insight into the pharmacological effects of acamprosate and pave the way for future research on genetic variants of ENT1 that may be useful in predicting treatment success with acamprosate and similar drugs.3
Contributing NIH Institutes & Centers
- National Institute on Alcohol Abuse and Alcoholism (NIAAA)