Mechanism of Antidipsotropic (Anti-Alcohol Abuse) Action
Mechanism of Antidipsotropic (Anti-Alcohol Abuse) Action
August 2000; Volume 3; 95
Kudzu is hypothesized to work in one of two ways. First, kudzu suppresses the appetite for ethanol, and second, it improves the function of ethanol-affected vital organs without toxic side effects.7
The most important pathway of ethanol metabolism in humans occurs in the liver via cytosolic alcohol dehydrogenase. This reaction results in the production of acetaldehyde, which is destroyed by aldehyde dehydrogenase (ALDH), which is present as different isoenzyme forms in the cytosol and the mitochondria. Of these two types of isoenzymes, the affinity of acetaldehyde for mitochondrial ALDH is greater than for cytosolic ALDH. Thus, the mitochondrial ALDH is felt to be the isoenzyme primarily involved in aldehyde detoxification.8
Approximately 50% of Asians have a genetic variant of the mitochondrial ALDH isoenzyme that is catalytically inactive, resulting in a significantly impaired ability to metabolize acetaldehyde. Alcohol abuse is extremely rare in these individuals because of the toxic side effects of acetaldehyde accumulation upon ethanol ingestion.9
Utilizing this knowledge, Keung and Vallee fractionated the RP root extract chromatographically. This analysis revealed that each gram of the root extract contained seven isoflavones. (See Table 2 for proportionate composition of each.) Depending on the growing season, conditions, and geographic location, this total isoflavone content can vary from 1.77-12.0%.10
| Table 2-Composition of RP isoflavones | |||||
| RP Isoflavone | R1 | R2 | R3 | R4 | Amount present in mg/g of RP extract |
| Daidzein* | H | H | H | H | 2.6 |
| Daidzin* | Glc | H | H | H | 22.0 |
| Puerarin§ | H | H | H | C-Glc | 160.0 |
| Genistein | H | H | OH | H | 0.2 |
| Genistin | Glc | H | OH | H | 3.7 |
| Formononetin | H | Me | H | H | 0.16 |
| Daidzein-4, 7-diglucoside | Glc | Glc | H | H | 1.2 |
| *Antidipsotropic effect demonstrated in Syrian golden hamsters, rats | |||||
| §Antidipsotropic effect demonstrated in rats, not Syrian golden hamsters | |||||
| Adapted from: Keung WM, Vallee BL. Daidzin and daidzein suppress free choice ethanol intake by Syrian golden hamsters. Proc Nat Acad Sci USA 1993;90:10008-10012. | |||||
The two antidipsotropic isoflavones, daidzin and daidzein, are the primary biologically active ingredients of the RP extract. They are theorized to suppress ethanol ingestion by modulation of central reward pathways since mitochondrial ALDH also plays a role in the catabolism of monoamine neurotransmitters such as serotonin and dopamine.5
Animal Studies
The Syrian golden hamster (Mesocricetus aruatus) was the first animal model used to test the antidipsotropic effect of RP. This species is an outbred strain of laboratory rodent unique for its spontaneous exhibition of a marked preference for and consumption of large amounts of ethanol under a two-bottle, free-choice regimen.
With an ALDH enzyme activity assay, Keung and Vallee also found the component isoflavones had variable abilities to inhibit human mitochondrial ALDH selectively. This ability was correlated with each isoflavone’s capacity to suppress ethanol intake in hamster studies.
Acetaldehyde clearance studies performed by Keung and Vallee elucidated the fact that daidzin did not act by a chemical sensitizing mechanism as does disulfiram. They found that the daidzin treatment, which suppressed the hamsters’ alcohol intake by 50%, had no effect on ethanol or acetaldehyde metabolism when these hamsters received an ethanol challenge. In contrast, however, disulfiram-treated hamsters receiving the same ethanol challenge showed a significant accumulation of plasma acetaldehyde levels since disulfiram is a potent, nonselective ALDH inhibitor.5,11
Human Studies
Shebek and Rindone performed a small prospective, randomized, double-blind pilot study in a group of veterans in a substance abuse program.12 All had a diagnosis of chronic alcoholism, based upon DSM-IV criteria. Of the 38 patients who began the study, only 38% from the initial kudzu-treated group and 41% of the control group completed the full four months of follow-up questionnaires and regimen of study drugs. Side effects including headache, dry mouth, and anxiety were noted in three treatment group patients, but did not result in withdrawal from the study.
Although the study showed no statistical differences between kudzu and placebo patients for sobriety and craving of ethanol, problems with the study included small sample size and self-reporting on the questionnaires. According to a conversation with J. Rindone, PharmD (June 2000), a low dose of kudzu root extract was used.
Keung compiled approximately 300 clinical case reports from Chinese practitioners. According to reports of patients with chronic alcoholism treated with kudzu tea or kudzu-based medications, approximately 80% reported no longer craving ethanol after two to four weeks of therapy.7 Improvement in impaired organ functions is thought to take at least 4-6 months of treatment.7
Ongoing Trials
The National Institute on Alcohol Abuse and Alcoholism has funded studies of Scott Lukas, PhD since 1995. In a conversation with S. Lukas (June 2000), Lukas reported treating approximately 70 patients with problem ethanol drinking and found kudzu root doses ranging from 9-27 g/d in divided doses two to three times daily to be an effective adjunct in reducing cravings. Lukas also reports that his patients noted a decrease in ethanol cravings within one to two weeks of therapy initiation and reported no adverse side effects. His research will attempt to identify the population(s) of problem drinkers for whom kudzu may be most useful.13
Dosage and Formulation
In China, where crude root and extract are used to treat patients, the general dosage regime is a standardized tablet containing 5 g crude root taken two to three times per day.4 The 1985 Chinese Pharmacopoeia suggests a daily dosage range of 9-15 g of crude root to suppress alcohol cravings.10
There is great variability of the kudzu extract content in kudzu medications, both within the same manufacturer and certainly among different manufacturers. Many kudzu products are not standardized for root extract content; several products are standardized to daidzin or isoflavone content.
Most U.S. vitamin manufacturers recommend starting with a dosage of 300-600 mg crude root two to three times daily as a means to decrease the craving in individuals who have alcohol dependency. Optimal doses for the suppression of ethanol cravings in alcoholics have not been established in human clinical trials.
Toxicity
The toxicity of kudzu is very low. An oral daily dosage of 50-100 g produced no adverse effects in humans.4 The kudzu root, the primary portion of the plant that has been studied for medicinal use, is used as a food source in southern China. As observed in Table 2, the isoflavones contained in the root extract, especially daidzein and genistein, are also contained in soybeans and have important beneficial antioxidant effects.14
Adverse Drug Effects
Since kudzu inhibits platelet-activating factor, it could potentiate the effects of aspirin and other platelet-inhibiting medications as well as warfarin anticoagulants. Therefore, it should be used cautiously in patients on these medications with frequent monitoring of international normalized ratios and blood and platelet counts as indicated. Animal studies have shown kudzu to have hypoglycemic effects; it may potentiate the effects of diabetes medications including insulin and other oral hypoglycemics.
There are insufficient data to justify use during pregnancy and lactation.
Kudzu root extract has been shown to cause increases in coronary and cerebral blood flow, and to have smooth muscle relaxant effects, blood pressure lowering effects, and antiarrhythmic effects including lowering heart rate.15
Conclusion
Kudzu’s ubiquity, low cost and side effect profile, coupled with the suggestive animal data and the historical data compiled by Chinese practitioners over 2,000 years, make it an interesting subject for future human clinical studies of alcoholism treatment. Very little published clinical data, however, support its current use.
Recommendation
At the present time, given the dearth of prospective, double-blind, randomized clinical trials that show efficacy in the treatment of alcoholism in humans, kudzu cannot be recommended as an adjunctive therapy for patient use.
Kudzu may be included in a comprehensive treatment plan for the alcoholic within a research protocol. It should be studied in conjunction with effective therapy to treat withdrawal syndrome and to correct nutritional, vitamin, and mineral deficiencies and metabolic derangements that accompany chronic ethanol ingestion.
Individuals electing to take kudzu outside of a research protocol should be carefully monitored, and should ingest a low dose initially.
Current trials in progress may provide clinicians with information about the dosage range and efficacy of kudzu that would merit its consideration for use in the therapeutic armamentarium for alcoholism.
Dr. Marcolina is a board-certified internist and geriatrician in Issaquah, WA.
References
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8. Schuckit MA. Alcohol and Alcoholism. In: Fauci A, et al, eds. Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill Companies, Inc.; 1998:2503-2507.
9. Keung WM, Vallee BL. Daidzin: A potent, selective inhibitor of human mitochondrial aldehyde dehydrogenase. Proc Natl Acad Sci USA 1993;90:1247-1251.
10. Lininger SW, et al. Kudzu. In: The Natural Pharmacy. 2nd ed. Rocklin, CA: Prima Health, Inc.; 1999:438-439,492.
11. Banys P. The clinical use of disulfiram (Antabuse®). A review. J Psychoactive Drugs 1988;20:243-261.
12. Shebek J, Rindone JP. A pilot study exploring the effect of kudzu root on the drinking habits of patients with chronic alcoholism. J Altern Complement Med 2000;6:45-48.
13. Computer Retrieval of Information on Scientific Projects database. Available at: http://www-commons.cit.nih.gov/crisp/. Accessed June 21, 2000.
14. Reinli K, Block G. Phytoestrogen content of foods—A compendium of literature values. Nutr Cancer 1996;26:123-148.
15. Natural Medicines Comprehensive Database. Therapeutic Research Faculty. Available at: http://www.naturaldatabase.com. Accessed June 14, 2000.
August 2000; Volume 3; 95
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