Public Health Service Assessment of EDTA Chelation Therapy for Atherosclerosis, 1981

September 25, 2006

Chelation is the formation of a bond between a metal ion and two or more polar groupings of a single molecule (Stedman’s Medical Dictionary, 1966). Chelation is a fundamental process used by living organisms for utilizing inorganic metals. For example, chlorophyll, hemoglobin, and many important enzymes are chelates. Chelation is also used widely in a variety of industrial applications (Halstead, 1979).

Chelation therapy is the application of chelation techniques for the therapeutic and/or preventive effects of removing unwanted metal ions from the body. Chelation is used to treat lead intoxication and iron overload and many drugs (for example, some antibiotics) are chelators. The application of chelation therapy under consideration in this assessment, is ethylenediamine-tetra-acetic acid (EDTA) chelation for the treatment and prevention of atherosclerosis.

Atherosclerosis is a chronic, progressive disease of the large and medium -sized muscular arteries (e.g., carotid, coronary, and arteries of the lower extremities) and the larger elastic arteries (e.g., aorta and iliac arteries). The basic lesion is the atheroma which consists of a raised focal plaque within the intima which has a liquid core (mostly cholesterol) and a covering fibrous cap. The plaques increase in number and size, encroach on the lumen of the artery, compromise arterial blood flow, and weaken the arterial wall (sometimes leading to aneurysm formation). The atheromas can undergo a variety of complications including internal hemorrhage, ulceration, thrombus formation, and embolization. These complications can lead 10 myocardial infarction, ischemic cardiomyopathy, cerebral infarction, ischemic encephalopathy, gangrene of the legs, and mesenteric infarction and ischemia. In 1968, cardiovascular disease (heart, brain, kidneys) accounted for approximately 54 percent of all deaths in the United States. Almost all of these cases were related to atherosclerosis. In the past decade, there has been some decrease in the death rate for this disease group; however, it overwhelmingly remains the number one killer of Americans (Robbins and Cotran, 1979).

EDTA was first synthesized in Germany during the 1930’s as a substitute for citric acid which was used for removing calcium from hard water. The EDTA molecule has six potential sites for binding a metal ion (or ligand). The in vitro avidity of EDTA for metal ions and the stability of the chelated complexes depends upon the metal and the pH of the solution. The following is a list of metals in order of decreasing EDTA avidity and stability for in vitro complexation:

Cu++ –

Metal ions that form more stable complexes with EDTA will compete with ions forming less stable complexes (Halstead, 1979). However, in vivo activity does not always perfectly reflect in vitro activity. For example, mercury readily displaces calcium from calcium disodium EDTA in vitro but does not in vivo (Levine, 1975).

Disodium EDTA can effectively chelate calcium ions and the calcium disodium EDTA product is excreted rapidly in the urine. Calcium disodium EDTA has a half-life in the circulation of 20 to 60 minutes, with approximately 95 percent being excreted in 24 hours (Levine, 1975).

The method of treatment being assessed is the intravenous infusion of disodium EDTA for atherosclerosis. A treatment consists of infusing 0.5 to 3.0 grams (50 milligrams/kilogram) EDTA in 500 to 1,000 milliliters of intravenous fluid (e.g., Ringer’s lactate or fructose 10 percent). Additional ingredients are added to the infusing solution for a variety of reasons and include heparin (1,000 to 5,000 units), vitamin C (4 to 20 grams), magnesium chloride (800 to 1,000 milligrams) or magnesium sulfate (I to 5 grams), lidocaine 2 percent (1 to 6 milliliters for relief of venous irritation caused by the EDTA), pyridoxamine (50 to 30 milligrams), B complex vitamins (in “fairly high doses”), vitamin B12 (1 milligram) and adrenal cortical extract (if available)(amount not specified). This solution is infused slowly over a period of 3 1/2 to 4 hours (not less than 3 hours) and the recommended frequency of treatments is 1 to 3 per week (preferably not on consecutive days). An initial treatment series consists of 20 to 40 such treatments, depending upon the severity of the disease. Follow-up treatments may be needed; as many as 100 or, more treatments over a period of 1 to 3 years have been advocated, when necessary. In addition, adjunctive and supportive treatments are considered essential to the efficacy and safety of chelation therapy. This includes oral vitamin C (1 to 2 grams per day), vitamin E (1OO to 200 international units per day), magnesium (300 to 600 milligrams per day), calcium (in a ratio of 2 to 1 to the amount of magnesium taken), potassium (amount not specified), .copper (1 to 2 milligrams, unless elevated), iron (if’ needed), zinc (20 to 75 milligrams per day), manganese (amount not specified), chromium in chelated form ODD to 200 micrograms per day), and all other vitamins except the B vitamins are supplemented in doses of at least 2 to 5 times the recommended daily allowances. Optional vitamins and supplements include folic acid 0 to 20 milligrams, once or twice a day), niacin (100 to 400 milligrams, once to four times a day), vitamin A (25,000 units per day and an additional 75,000 units per day for 1 to 4 weeks, if necessary), vitamin D3 instead of vitamin D2, whole pancreas enzyme supplements, thyroid (0.25 grains), estrogen (0.3 milligrams, once to three times a week), fiber supplementation, dimethylglycine (60 to 120 milligrams), and iodine. Lifestyle modification, with an aim toward reducing the risk of atherosclerosis, is also considered an essential part of the complete therapeutic program. This includes stress reduction, caffeine avoidance, alcohol limitation to two drinks per day, nicotine avoidance, aerobic exercise, and nutrition counseling (high fiber, low fat, low sugar, low phosphorous diet) (Protocol for E.D.T.A. Chelation Therapy, American Academy of Medical Preventics, 1981).


A variety of possible mechanisms of action of EDTA chelation for atherosclerosis have been proposed. Calcification of the atheromata is common in advanced atherosclerosis and removal of this calcium via chelation was an early rationale proposed for this therapy. This rationale is rather simplistic since. the calcium deposit is likely to constitute only a small portion of the bulk of the whole atheroma or plaque and its removal could only modestly reduce the ,amount of obstruction (Communication from the National Institutes of Health).

Other possible mechanisms of action for chelation therapy have been offered after it was pointed out that the removal of calcium from atheroma would not be an adequate mechanism to explain any benefit. These include an increase in collateral blood flow, decrease in blood viscosity, improvement in cell membrane functions, improvement in organelle function (e.g., oxidative phosphylation of the mitochondria), and decrease in vasospasm. Some underlying (and unknown) aberration of calcium metabolism, due to a variety of possible nutritional factors, . has been postulated as a cause of vasospasm. Such nutritional factors include calcium-phosphorous imbalance, excess vitamin D2, excess fat intake, excess refined carbohydratesJ chronic heavy metal and aluminum pollution, lack of exercise, lack of fiber, lack of magnesium, lack of selenium, and “multiple other factors.” Chelation therapy and its associated holistic health program attempts to address all these factors (Halstead, 1979; and Protocol for E.D.T.A. Chelation, American Academy of Medical Preventics, 1981). Additional mechanisms of action, along with modifications of those listed above have been proposed (Gordon and Vance, 1976).

Review of Available Information

The safety of EDTA chelation therapy has been questioned. Fatal and nonfatal renal toxicity in humans has been ‘associated with large doses (5 grams or more per day) of EDTA. The fatal cases have had autopsy findings of renal tubular epithelial degeneration (Dudley and Ritchie, 1955). The nonfatal, renal findings have included albuminuria, cylindruria, hematuria, and renal parenchymal cells in the urine associated with symptoms’ of nocturia, frequency, urgency, and dysuria (Foreman, et al., 1956). Additional toxic reactions which have been observed include thrombophlebitis proximal to the site of administration; hypocalcemia including tetany, convulsions, and numbness and tingling of the fingers and perioral areas; systemic reactions; histamine-like reactions; glycosuria; anemia; dermatitis; hypotension; nausea and vomiting; and abdominal cramps (Seven, 1960).

Fatal emboli were observed in a patient with calcific cardiac valves treated with EDTA and were attributed to too rapid dissolution of these calcium deposits (Clarke, et al., 1956). Insulin shock with hypoglycemia, trace mineral depletion, and congestive heart failure induced by the excess sodium load of disodium EDTA have been reported (Halstead, 1979).

Most of these complications are avoidable with ·proper attention to the rate and frequency of EDTA administration and appropriate vehicle solution and mineral replacement (Gordon and Vance, 1976). Meltzer, Kitchell, and Palmon found no serious side effects or toxicity in 81 patients who received a collective total of 2,000 chelation treatments over 2 years when the dose of EDTA was 3 grams, administered over 2 1/2 to 3 hours (Meltzer, et al., 1961). Halstead asserts that ” … after three decades of using EDTA (in the treatment of chronic degenerative disease (e.g., atherosclerosis», involving in excess of 100,000 patients, and more than two million treatments; the number of significant untoward reactions is probably less than any other major therapeutic modality.” (Halstead, 1979).

The clinical application of EDTA chelation therapy for atherosclerosis was first ‘reported by Clarke, Clarke, and Mosher in 1956. They presented case reports of 20 patients with angina pectoris that they had treated with five grams of disodium EDTA each day for five days, omitted the therapy for two days, and repeated this cycle for a total of 15 to 60 (average 35) infusions. One patient, who failed to respond, had a convulsion and. died within a few hours. The authors speculated that the death was due to a calcium embolus to the brain from a large arterial plaque. The remaining 19 survivors obtained “unusual symptomatic relief.”  Six patients with initially abnormal electrocardiograms reverted to normal patterns after the EDTA therapy (Clarke, et al., 1956). In an editorial, Clarke reported on additional experiences with chelation therapy and several hundred patients. He observed his best results with patients who had intermittent claudication (prior to frank gangrene) and all had gained a greater ability to walk without pain in the legs. He also found good response in’ patients with occlusive vascular disease and impressive symptomatic relief in 87 percent of patients with angina pectoris (Clarke, Sr., 1960).

Meltzer, Ural, and Kitchell administered an average of 3.5 grams of disodium EDTA two to four times a week to 10 white males with intractable anginal syndrome. Six of these had a history of myocardial infarction, three had claudication, nine had abnormal electrocardiograms, and three had radiologic evidence of cardiomegaly. After 20 infusions, there was a rest period of 10 days followed by additional infusions, for a total of 20 to 50 (average 32) infusions per patient. The therapy was discontinued. after three to four months because the patients were discouraged and none considered himself improved. There was no electrocardiographic or radiologic evidence of improvement at the time therapy was discontinued. However, two to three months after discontinuing treatment, nine of the patients noticed a reduction in the number and severity of angina episodes which was associated with decreased nitroglycerine usage, five of the nine abnormal electrocardiograms were considered improved, and the three patients with cardiomegaly had an apparent decrease in heart size on their chest films. The three patients with claudication had no relief. Some unexpected changes were also noticed including dramatic improvement in one patient’s keratotic skin lesions and a decrease in severity of arthritic symptoms in one patient with osteoarthritis and another with rheumatoid spondylitis. No significant undesirable side effects were noted (Meltzer, et al., 1960).

In 1963, Kitchell, et al., reappraised their earlier report on the treatment of coronary artery disease with disodium EDTA. They followed-up their original 10 patients and studied 28 additional patients. Nine were selected for a double blind, crossover study; however, this study was inconclusive because of the small numbers and an inability to switch three of the five placebo patients to EDTA therapy. Nearly four years after beginning chelation therapy, five of the original 10 patients had died of myocardial infarctions (13 to 16 months after starting chelation therapy). No evidence of calcium removal from the coronary arteries was found in the three patients who were autopsied. Only two of the five living patients were still considered subjectively improved. The other three had temporary improvement lasting 6, 12, and 16 months despite additional courses of therapy. None of the electrocardiographic improvement seen initially had persisted. In the second group, only 2 of 28 felt improved and had increased exercise tolerance immediately after completion of a course of treatment with 20 injections of EDTA. One of these and another patient, who was not subjectively improved, showed electrocardiographic improvement. Two other patients had deterioration of the electrocardiograms without, appreciable change in their condition. At 12 weeks, nine patients felt some improvement in their symptoms and had improved exercise tolerance; seven patients had improved electrocardiograms. The remaining patients were unchanged. At three months, 16 patients had subjective and exercise tolerance improvement and 10 patients had improvement on electrocardiogram. At the same time, two patients had worsening of symptoms, three had worsening of their electrocardiograms, and one had decreased exercise tolerance. After 18 months, seven (25 percent) of the patients had died. Six had myocardial infarctions and one died of congestive heart failure. Two others were worse, six showed no change, and 13 remained improved. The authors concluded that the improvement was not lasting, that chelation therapy was no more effective than other commonly used therapeutic methods and was not a useful clinical tool in the treatment of coronary artery disease at that time (Kitchell, et al., 1963).

Following this negative report, little additional information about chelation for atherosclerosis appeared in the western medical literature except for some case reports of its application in treating occlusive arteriosclerosis (Lamar, 1964 and 1966). Russian and Czechoslavakian reports of chelation therapy for atherosclerosis appeared in 1972. The Russian study included 25 patients with coronary artery disease, eight with cerebrovascular disease, and seven with peripheral vascular disease. Hypertension was also present in 12 of these patients. Treatment consisted of 10 to 25 infusions of five grams of disodium EDTA. Significant improvement was observed in all patients with complete relief of the pain syndrome (presumably angina pectoris, claudication, and/or headache) in 36 of 40 patients. No adverse reactions were noted (Nititina and Abramova, 1972). The Czechoslavakian study included 31 patients with occlusive atherosclerosis of the lower extremities who underwent a series of 35 chelation treatments with three grams of disodium EDTA. They found a statistically significant difference in outcome between patients with and without gangrene (those without had a more favorable outcome). They concluded that chelation was the treatment of choice for occlusive atherosclerosis and claudication without gangrene (Brucknerova and Tulacek, 1972).

More recently, Casdorph has reported on two studies of chelation therapy for arteriosclerotic heart disease and brain disorders. Using 18 patients with arteriosclerotic heart disease as their own controls, he utilized cardiac nuclear  scintigraphy (technetium 99m) to evaluate their left ventricular ejection fractions before and after 20 infusions of 3 grams of disodium EDTA. Oral vitamin and mineral supplementation was administered. All patients improved clinically and all but two had complete subsidence of angina. There was a statistically significant improvement in the mean ejection fraction after therapy. No serious side effects were observed (Casdorph, 1981).

The second study evaluated the effect of chelation therapy on cerebral blood flow in 15 patients with a variety of brain diseases. Radionuclide studies (technetium 99m) were done before and after 20 infusions of EDTA supplemented with oral vitamins and minerals. A significant improvement in cerebral blood flow was measured in 14 patients and all 15 showed clinical improvement. No serious side effects were observed (Casdorph, in press).

In response to the PHS Federal Register announcement of this assessment, several members of the American Academy of Medical Preventics and other societies submitted case reports of many additional patients who have been treated with EDTA chelation therapy for a variety of the manifestations of atherosclerosis. These appeared to show uniformly positive results.


EDTA chelation therapy for the treatment and prevention of atherosclerosis is controversial. The Food and Drug Administration (FDA) considers the promoting of the use of disodium EDTA for arteriosclerosis to constitute misbranding the drug because this is a condition not listed in the current labeling of the drug and there is inadequate evidence to demonstrate the safety and effectiveness of this application. In fact, the current labeling states that the drug “is not indicated for the treatment of generalized arteriosclerosis associated with advancing age.” The only approved uses for disodium EDTA injections are for emergency treatment of hypercalcemia and for control of ventricular arrhythmias and heart block associated with digitalis toxicity. Calcium disodium EDTA is approved for use as a chelator in lead poisoning.

As mentioned above, the safety of EDTA chelation therapy has been questioned. A major concern has been over its nephrotoxicity which can result in renal tubular necrosis and death from renal failure (Levine, 1975). Renal damage has been associated with prolonged administration of doses exceeding three grams of EDTA (AMA, 1980). Its use in patients with renal disease should be avoided (Medical Letter, 1981). Due to its potent calcium depleting effect, rapid infusion of disodium EDTA can cause hypocalcemic tetany (Craven and Morelli, 1975). EDTA can also cause many other untoward effects which were discussed above. The complications can be avoided by proper attention to dosage, the rate of administration, and the need for adequate replacement of trace minerals and other bodily constituents inadvertently removed by EDTA; however, the presence of these risks is cause for concern.

There is no evidence to support any of the numerous theoretical mechanisms of action proposed to explain the claimed effect of EDTA chelation therapy on a therosclerosis. The clinical effectiveness of EDTA chelation therapy for atherosclerosis has never been established. There are numerous case reports and testimonials which suggest a dramatic improvement following chelation therapy; however, these findings have never been validated by well designed, controlled clinical trials. Kitchell, et al., tried to mount a small double blind, crossover study, but had to abandon it when they were unable to effect an adequate crossover (Kitchell, et al., 1963). The two most recent reports of trials of EDTA chelation therapy for arteriosclerotic heart disease and brain disorders were uncontrolled trials (Casdorph, 1981, and in press).

The clinical effectiveness of EDTA chelation therapy for atherosclerosis has been questioned. Kitchell, et al., concluded after several years of using this therapy that it was not a useful clinical tool in the treatment of coronary artery disease (Kitchell, et al., 1963). Several reviews of this therapy have concluded that  EDTA chelation therapy should be regarded as experimental or investigational because of questions about its safety and lack of objective evidence of clinical effectiveness (Craven and Morrelli, 1975; Soffer, 1975; AMA, 1980; and Medical Letter, 1981). This opinion is shared by the American College of Physicians, the American Academy of Family Practice, the American Society for Clinical Pharmacology and Therapeutics, the American College of Cardiology, and the American Osteopathic Association. Proponents of this therapy who advocate its acceptance as safe and effective include the American Academy of Medical Preventics, the Orthomolecular Medical Society, the American Holistic Medical Association, the International Academy of Preventive Medicine, and the Northwest Academy’ of Preventive Medicine.

Before one could conclude that EDTA chelation therapy for atherosclerosis is effective, one would need confirmatory data from well designed, controlled clinical trials. It is especially important for the assessment of therapy for the treatment of symptoms of atherosclerosis that double blinded clinical trials against a placebo be conducted because of the fluctuating nature of the symptomatology. Proponents of this therapy argue .that such trials may be impossible because of the complexities introduced by the multifaceted approach to the treatment of atherosclerosis which is embodied in the term “chelation therapy.” In addition to the chelation treatments, there is vitamin and mineral supplementation, lifestyle modification and other components of a holistic approach to this disease group. They also point out that many of the alternative treatments for atherosclerosis have not been better validated. The cost of conducting such a validation is also a problem.

Research on experimental drug therapies has traditionally been funded by the drug manufacturers; however, in the case of EDTA, this is highly unlikely because the patent on EDTA has expired.


EDTA chelation therapy for the treatment and prevention of atherosclerosis is controversial. There is no widely accepted rationale to explain the beneficial effects attributed to this therapy. Its safety is questioned and its clinical effectiveness has never been established by well designed, controlled clinical trials. It is not widely accepted and practiced by American physicians. EDTA chelation therapy for atherosclerosis is considered experimental. Its safety and clinical effectiveness will need to be established by well designed, controlled clinical trials.


This assessment is based on a search of the medical literature with assistance from the Food and Drug Administration and the National Institutes of Health. The American College of Physicians, American Academy of Family Practice, American Society for Clinical Pharmacology and Therapeutics, American College of Cardiology, American Osteopathic Association, American Academy of Medical Preventics, Orthomolecular Medical Society, American Holistic Medical Association, the International Academy of Preventive Medicine, and Northwest Academy of Preventive Medicine provided assistance with this evaluation either directly or through their members.

This PHS assessment is based on information available at this time. It will be revised, as appropriate, when additional information warrants a revision.

Anyone wishing to submit or obtain additional information should contact:

National Center for Health Services Research
Office of Health Technology Assessment
Room 310 #2, Park Building
5600 Fishers Lane
Rockville, Maryland 20901
(301) 443-4990

This page was posted on September 25, 2006.