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Kudzu and its extracts and flowers have been used in traditional Chinese folk medicine to treat alcoholism for about 1,000 years. Kudzu contains daidzin, an antidrinking substance. Daidzin inhibits human aldehyde dehydrogenase 2 (ALDH2), which metabolizes alcohol into acetaldehyde. Inhibiting ALDH2 promotes the accumulation of acetaldehyde, which has aversive effects. A recent test of a synthetic ALDH2 inhibitor (CVT10216) on rodents shows that it reduces drinking and prevents relapse by increasing acetaldehyde while drinking and later decreasing dopamine in the brain region that controls relapse during abstinence.

Results will be published in the November issue of Alcoholism Clinical & Experimental Research and are currently available at Early View.

“I think the overarching issue here is medical treatment,” said Ivan Diamond, vice president of neuroscience at Gilead Science, Professor Emeritus of neurology, cellular and molecular pharmacology and neuroscience at the University of California, San Francisco, and corresponding author for the study.

“Alcoholism is a medical disorder, not just a problem of will power,” he said. “Physicians treat medical disorders in order to prevent harm, while not necessarily curing the disease being treated for example, drug treatment of hypertension, statins for high cholesterol, insulin for diabetes and the same will become true for treating alcoholism. Heavy drinking causes harm. We need to prevent heavy drinking in order to prevent harm.”

Diamond added that relapse may be the biggest problem facing physicians today. “We are talking about a patient who has the motivation to undergo a very unpleasant detoxification to try to stop drinking, and then gets into trouble afterward,” he said. “Nearly 80 percent of abstinent alcoholics or addicts relapse within a year. Current therapies for alcoholism help, but we can do much better.”

“Extracts of various parts of the kudzu vine have been used in many Chinese herbal medicine formulas and are said to be helpful in treating a variety of maladies, including alcoholism and intoxication,” said TingKai Li, a professor in the department of psychiatry at Duke University Medical Center, and former director of the National Institute on Alcohol Abuse and Alcoholism. “Recent research has found that several compounds of the isoflavone family puerarin, daidzin, daidzein in the kudzu extract decrease alcohol intake in experimental animals.”

“Drs. Wing Ming Keung and Bert Vallee at Harvard were the first to confirm kudzus effects and isolate daidzin as the most potent of the isoflavones in kudzu,” added Diamond. “They went further by searching for the basis of daidzins antidrinking properties, discovering that daidzin was a selective inhibitor of ALDH2. Based on xray crystallographic studies of daidzin binding to ALDH2, our team set out to design a compound that would interact more efficiently with ALDH2, finally choosing CVT10216 as our best candidate to date.”

Diamond and his colleagues administered CVT10216 to groups of rats bred for moderate and high levels of drinking, after having exposed them to various scenarios of alcohol administration twobottle choice, deprivationinduced drinking, operant selfadministration, and cueinduced reinstatement. The researchers then tested for blood acetaldehyde levels, alcoholinduced dopamine release in the nucleus accumbens, and effects of the inhibitor on drinking behavior and relapse.

“We had several key findings,” said Diamond. “We found that, one, CVT10216 is a highly selective reversible inhibitor of ALDH2 without apparent toxicity. This means that it does not cause serious damage to other proteins and functions. Two, treatment with our ALDH2 inhibitor increases acetaldehyde in the test tube and in living animals.” Acetaldehydes aversive effects can include a flushing reaction and feeling ill, which tend to reduce drinking. “And three, we found that our ALDH2 inhibitor suppresses drinking in a variety of rodent drinking models.”

But thats not the whole story, Diamond added. “Most importantly, we also found that CVT10216 prevents the usual increase in drinking (binge drinking) that occurs after five days of abstinence, and also prevents relapse to drink, even when alcohol is not present. This means that something else besides acetaldehyde helps to suppress craving for, and prevent relapse to, drinking alcohol. We believe that something else is dopamine.” He said that current concepts suggest that increased dopamine in the nucleus accumbens drives craving and relapse into drinking.

“Alcoholinduced increases in dopamine in the nucleus accumbens are prevented by CVT10216 in a dosedependent manner,” said Diamond. “This means the drug has a therapeutic effect in the brain, probably on the desire to drink. Importantly, CVT10216 does not reduce basal dopamine levels when there is no stimulation to increase dopamine levels. This is consistent with our findings that CVT10216 does not appear to affect moderate drinking, and does not have adverse side effects at the therapeutic doses used.”

“The findings show promise that CVT10216 might be better tolerated than Antabuse™,” said Li. “How this happens is yet unknown, but suggests that the compound may be useful in treating alcohol relapse and perhaps for other psychoactive, potentially addictive compounds.”

Diamond agreed “Disulfiram or Antabuse™ has been around for 50 years,” he explained. “It is called an ALDH2 inhibitor, but it actually inhibits far more than that. Most believe that disulfiram would not be approved today as a new drug for alcoholism because of its many toxicities. Instead, we have developed CVT10216, a reversible inhibitor with a very favorable profile, so far.” Diamond hopes this novel compound will become an effective therapeutic agent for alcoholism.

“The goal of medicine is harm reduction,” emphasized Diamond. “Excessive drinking causes harm while moderate drinking appears to be safe. Increasing numbers of doctors believe abstinence is an unrealistic goal. It sounds like heresy, but it isnt. Therefore, an ideal drug might be able to prevent uncontrolled relapse, convert heavy drinkers into moderate drinkers, and avoid the harmful consequences of excessive alcohol intake. If our compound works and is safe to use, then I think most physicians would not hesitate to prescribe a new drug to prevent relapse and reduce heavy drinking. My goal is to make this happen.”

Source
Ivan Diamond, M.D., Ph.D.
University of California, San Francisco
TingKai Li, M.D.
Duke University Medical Center