We propose to continue our studies of the Chinese herb, kudzu (Puerariae lobata), as a potential treatment for alcohol abuse/dependence. We are extremely encouraged by the results obtained during the first 2.75 years of this project as we have demonstrated that a two-day treatment regimen with raw kudzu root attenuates ethanol-induced subjective reports of intoxication in light, but not heavy drinkers. Our safety data indicate that the isoflavones are devoid of any physiologic, behavioral or medical side effects, and subjects cannot detect the active preparation from the placebo. A Supplement to this grant was awarded to develop an isoflavone extract and a matched placebo under GMP. They are both ready for testing and we now propose to explore the consumption-related and sex-related differences in alcohol effects using this isoflavone extract. Using a multidisciplinary battery of subjective, physiologic and behavioral measures as well as plasma ethanol levels, we propose new studies to systematically evaluate the efficacy of this extract in treating alcohol-related problems. We will first determine the dose that is effective in reducing the subjective and physiologic effects of acute ethanol challenges in male and female non-dependent heavy drinkers. The second experiment will determine if the isoflavone extract attenuates alcohol-related cue-induced craving. Third, the effects of isoflavone extract on ethanol self-administration will be measured in a natural environment to simulate realistic drinking conditions. Fourth, the extract's amethystic properties will be assessed in acutely intoxicated subjects under controlled laboratory conditions. Finally, using brain imaging techniques, we will explore the possible mechanism of action of this isoflavone preparation using proton magnetic resonance spectroscopy (MRS) to determine whether isoflavone pretreatment alters the amount of ethanol that actually enters the brain. We plan to continue and expand this experiment and, in addition, will measure changes in cerebral blood flow and cerebral vasculature using functional MR imaging (fMRI). The results of these studies will help define the role that isoflavones may have in treating alcohol-related problems. Because of its complete lack of toxicity this isoflavone preparation may be a useful addition to treating alcohol-related problems in special populations such as adolescents and pregnant women. Further, its anti-inebriating effects may make it useful in keeping """"""""slips"""""""" from becoming full relapses.
