Medical Hypotheses, 18:61-77, 1985.
(C) Robert F. Cathcart, III Allergy, Environmental, and Orthomolecular Medicine 127 Second Street, Los Altos, California 94022, USA Telephone 650-949-2822
The amount of oral ascorbic acid that a patient can tolerate without diarrhea, increases somewhat proportionately to the "toxicity" of his disease. Clinically, in a disease ameliorated by ascorbate, there is a suppression of symptoms only with very high doses and approximately to that extent which a nonrate-limited,_antioxidant_free_radical_scavenger, might be expected to affect that disease process if all harmful free radicals and highly reactive oxidizing substances were quenched. In most pathologic processes, the rate at which free radicals and highly reactive oxidants are produced, exceeds the rate at which the ordinary rate-limited antioxidant free radical scavenging mechanisms can quench those free radicals and oxidants. When ascorbate acts as a scavenger, dehydroascorbate is formed; but if the ascorbate/dehydroascorbate (AA/DHA) ratio is kept high (the redox potential kept reducing) until the unstable dehydro- ascorbate undergoes hydrolysis or can be reduced back to ascorbate, the dehydroascorbate will do no harm. Since even at very high doses, ascorbate is virtually nontoxic, it may be given in the enormous doses necessary to quench almost all unwanted free radicals and oxidants. The wide spectrum of infectious diseases ameliorated by massive doses of ascorbate indicates some common pathologic processes in these diseases.
Based on my experience with over 11,000 patients during the past 14 years, it has been my consistent observation that the amount of ascorbic acid dissolved in water which a patient, tolerant to ascorbic acid, can ingest orally without producing diarrhea, increases considerably somewhat proportionately with the "toxicity" of his illness. A person who can tolerate orally 10 to 15 grams of ascorbic acid per 24 hours when well, might be able to tolerate 30 to 60 grams per 24 hours if he has a mild cold, 100 grams with a severe cold, 150 grams with influenza, and 200 grams per 24 hours with mononucleosis or viral pneumonia. The clinical symptoms of these diseases and other conditions previously described, are markedly ameliorated only as bowel_tolerance dose levels (the amount that almost, but not quite, causes diarrhea) are approached (1-6).
GRAMS PER NUMBER OF DOSES CONDITION 24 HOURS PER 24 HOURS normal 4 - 15 4 - 6 mild cold 30 - 60 6 - 10 severe cold 60 - 100+ 8 - 15 influenza 100 - 150 8 - 20 ECHO, coxsackievirus 100 - 150 8 - 20 mononucleosis 150 - 200+ 12 - 25 viral pneumonia 100 - 200+ 12 - 25 hay fever, asthma 15 - 50 4 - 8 environmental and food allergy 0.5 - 50 4 - 8 burn, injury, surgery 25 - 150+ 6 - 20 anxiety, exercise and other mild stresses 15 - 25 4 - 6 cancer 15 - 100 4 - 15 ankylosing spondylitis 15 - 100 4 - 15 Reiter's syndrome 15 - 60 4 - 10 acute anterior uveitis 30 - 100 4 - 15 rheumatoid arthritis 15 - 100 4 - 15 bacterial infections 30 - 200+ 10 - 25 infectious hepatitis 30 - 100 6 - 15 candidiasis 15 - 200+ 6 - 25
There was a remarkable lack of systemic difficulties in these patients that could be directly related to the massive doses of ascorbate. The majority of these patients, ill with some acute or chronic disease, were able to take massive doses of ascorbic acid orally without difficulties. Minor complaints about ascorbic acid such as it causing gas, diarrhea, or acid stomach, while common in well persons even at low doses, were rare in very sick patients. Low or moderate doses (doses substantially below bowel tolerance) usually had no noticeable immediate beneficial effects, but high doses (doses just below the amount that would produce diarrhea in a patient tolerant to ascorbate) would have the effect of markedly suppressing symptoms as the high dose levels were reached. This sudden effect is often quite dramatic clinically and is not usually obtained even partially at lower doses. It is as if a threshold were reached at which point the ascorbate becomes very effective.
Mixtures of mineral ascorbates (calcium, magnesium, potassium, zinc, and sometimes sodium) are used in certain circumstances to increase bowel tolerance for even more clinical effectiveness but do not clearly demonstrate the increasing bowel tolerance phenomenon being discussed here.
Knowledge of the known vitamin functions of ascorbate would not have allowed one to predict these beneficial results. The lack of serious difficulties with these massive doses is surprising.
Part of the unexpected benefit at the high dose levels is frequently a feeling of well-being. This feeling of well-being, especially with the more toxic conditions, is despite the gas and diarrhea sometimes produced. If the malaise from the basic disease is great (e.g. mononucleosis, acute hepatitis, viral pneumonia, etc.), the obvious benefit from ascorbic acid is usually so great that the patient usually cares little about the minor gastrointestinal disturbances. Lowering dose levels too soon before bowel tolerance decreases, results in the return of the malaise and other acute symptoms of the disease. The_clinical_sensation_experienced_with_the_massive doses_of_ascorbate_is_one_of_"detox- ification"_as_a_threshold_is_reached. By raising and lowering the doses, the symptoms of "toxicity" can be readily turned off and on rapidly by some skilled patients.
I cannot emphasize enough that in "selected" patients (selected only by excellent tolerance to ascorbic acid, good understanding of the principles of determining the flexible bowel tolerance doses, and the willingness to follow directions in fine detail), this effect is invariable, dramatic, and unmistakable. The patient most likely to experience this effect is the psychologically stable, not suggestible, practical, not liking to be sick patient, with a "cast iron stomach." Children and teenagers, much as they may hate the taste of ascorbic acid in water, make particularly good patients once they experience the ameliorating effects of these massive doses. Infants, upon receiving very large intramuscular or intravenous injections, frequently "detoxify" in minutes to the astonishment and marked relief of their parents.
These feelings of well-being experienced by tolerant patients from the ingestion of massive doses of ascorbic acid are definite clinical indications that no acidosis or other acute toxic metabolic effect is resulting. Massive intravenous doses of sodium ascorbate are even more impressive than oral ascorbic acid, because the beneficial effects are even more dramatic and gastrointestinal gas and diarrhea are not produced. Patients who ordinarily would be relatively incapacitated, can usually remain functional and sometimes even participate in athletics if frequent and massive ascorbate doses are maintained.
Patients must be encouraged to take these massive doses. Patients taking vitamin C on their own, seldom take doses high enough to discover this effect. I do not want to give the impression that this method is easy to use; the mechanics of taking these doses can be very difficult for many patients. Nevertheless, when properly instructed, the majority of patients are able to achieve these effects. If a patient is relatively intolerant to oral ascorbate only because of gastrointestinal complaints, and if his disease is one that usually responds to oral ascorbate in tolerant patients, and if the severity of the condition warrants the inconvenience and expense, then intravenous ascorbate is indicated.
Such effects of these large doses of ascorbate cannot be readily explained from its known vitamin functions. The spectrum of diseases affected by massive doses of ascorbate is a wonder in itself, but also gives some hint at the probable mechanisms involved. The sudden detoxifying effect experienced clinically only at the very high threshold doses, suggests that ascorbate is participating in chemical reactions where a critical concentration of ascorbate is necessary, or where a certain ratio between ascorbate and certain other reactants must be achieved. The concept that free radicals and other highly reactive oxidants are a frequent factor in pathologic processes (7,8) and that ascorbate is an antioxidant free radical scavenger, could explain much of this.
Chemical reactions involving free radicals and highly reactive oxidants are necessary in the normal metabolism of cells. Metabolic processes utilizing oxygen (aerobic metabolism) which release energy are important examples. Ordinarily, these reactions occur in conjunction with appropriate enzymes or in the proper places within the cells. While it has been documented that potentially harmful reactants leak from their normal cellular confines and are potentially toxic (9), these rates of leakage are usually low enough for the natural antioxidant, free radical scavenging mechanisms to handle. One of the causes of natural aging may be that some (albeit small) portion of stray free radicals inevitably escape quenching (10). While the human body does contain many free radical scavenging mechanisms for the purpose of mopping up free radicals, I hypothesize that in_pathologic processes_these_rate-limited,_mechanisms_are_acutely_inadequate_t o_neutralize the_volume_of_free_radicals_produced. A threshold is reached where these additional free radicals produced, initiate an inflammatory cascade, can cause immune suppression, and can result in degenerative diseases.
In general free radical scavenging occurs through complex metabolic pathways involving many steps which are rate-limited. Deficiencies of nutrients, vitamins and minerals, which make up the enzymes and coenzymes of these systems can slow down or halt certain pathways.
It is apposite to describe one of these rate-limited, free radical scavenging mechanisms, to give the impression of its complexity and why it is rate-limited. The example chosen involves the glutathione pathway which is possibly one of the most important pathways.
When, for example, a superoxide radical must be destroyed, superoxide dismutase can catalyze its conversion to O2 and H2O2 (11). Ascorbate, nonenzamatically, also converts superoxide to H202 but is oxidized in the process to the ascorbate free radical and dehydroascorbate. The ascorbate free radical and the dehydroascorbate are reduced back to ascorbate either by NADH (catalyzed by semidehydroascorbate reductase and forming NAD) or reduced glutathione (GSH) (catalyzed by dehydroascorbate reductase and forming oxidized glutathione (GSSG)) (12). Some of the peroxide can be converted to oxygen and water by catalase but most will be destroyed by a glutathione-requiring enzyme system. GSH (catalyzed by glutathione peroxidase) reduces the peroxide to water but in the process is oxidized to GSSG. The resulting GSSG is reduced by NAD(P)H (catalyzed by glutathione reductase). The resulting NAD is reduced back to NADH by way of the Krebs cycle or resulting NADP is reduced back to NADPH by the hexose monophosphate (HMP) pathway. It is thought that commonly the rate-limiting step in the last series of reactions is that catalyzed by glutathione peroxidase and its cofactor selenium, but other substances which could limit all this are the vitamin E, vitamin C, vitamin B2, vitamin B3, cysteine, etc. Note: the ascorbate used in this example is as in the vitamin C sense; the small amount available is oxidized to dehydroascorbate and then must be reduced back to ascorbate by the pathway described, to be reused as ascorbate. One can easily see how this mechanism and similar mechanisms could be overwhelmed by a toxic pathogen liberating free radicals or by an inflammatory cascade regardless of its cause.
More recently, I have found ascorbate useful in the management of the acquired immune deficiency syndrome (AIDS). The AIDS patient who has already suffered a marked suppression of helper T-cells, presents a clinical problem of management similar to a bubble baby. If, in addition to the other measures described in my previous reports (24,25), the patient takes bowel tolerance doses of ascorbic acid orally almost every hour (intra- venously in emergencies), he may remain clinically well despite the continuing severe suppression of the helper T-cells. All this must be started before multiple infections riddle the patient's body with excessive sources of free radicals. There have been suggestive anecdotal cases which indicate that in the prodromal period, before the destruction of the helper T-cells, there might be avoidance of the development of the AID syndrome by this program. Confirmation of this possibility awaits long- term laboratory follow-up. There is evidence that a retroviral infection in cats, the feline leukemia virus, can be cured in the prodromal stage with large oral doses of ascorbate used in combination with other nutrients (26).
It is my hypothesis that what makes ascorbate truly unique is that very large amounts can act as a nonrate-limited antioxidant free radical scavenger.
Clinically, ascorbate is virtually nontoxic (27,28,4). But as ascorbate acts as an antioxidant free radical scavenger in the body, it is oxidized to dehydroascorbate. There are animal experiments that indicate that dehydroascorbate is toxic (29-31). However, dehydroascorbate is not administered directly to humans as it was in the animal experiments. Whatever dehydro- ascorbate comes to exist in the human body, comes by way of the oxidation of ascorbate, as the ascorbate is utilized to reduce free radicals or other reactive oxidizing substances. The potential of the dehydroascorbate to do damage should be less than the harmful potential of the substances it reduces to become dehydroascorbate (the oxidizing redox potential has been diminished). Therefore a patient should not be expected to be more toxic from the dehydroascorbate formed than he was from the original disease unless there is some peculiar specific sensitiv- ity to dehydroascorbate (see discussion of G-6-PD deficiencies below).
Used in the doses I suggest, there is an even more important mechanism which prevents toxicity from dehydroascor- bate. I take advantage of a combination of the facts that even in enormous doses, ascorbate is not clinically toxic, and that dehydroascorbate is only toxic when there is a low AA/DHA ratio.
Several (32-36) have hypothesized and reviewed many of the biochemical advantages of large doses of ascorbate. Of particular interest are Lewin's calculations and hypotheses (34) that high tissue concentrations of ascorbate to dehydroascorbate can directly reduce various substances (e.g. the disulfides). I doubt that tissue levels of ascorbate achieved with doses much below bowel tolerance are sufficient to significantly accomplish these reductions under pathological circumstances. Clinically however, something very dramatic happens as bowel tolerance is approached. I hypothesize that as a certain threshold ratio of ascorbate to dehydroascorbate is reached, certain direct reductions of substances such as oxidized glutathione and adreno- chrome by ascorbate begin. When a patient is sick or experiencing much stress, the amounts of these substances which can potentially and beneficially be reduced, increases greatly. If ascorbate is not available to reduce these substances, those that escape reduction to nontoxic derivatives by the rate-limited, antioxidant free radical scavenging mechanisms, damage the patient and cause symptoms. Under these circumstances, when made available, large amounts of ascorbate are utilized for these direct reducing purposes. These ascorbate reductions are not rate-limited, and therefore quench the harmful oxidants and free radicals almost instantly.
When the potential need for ascorbate for these purposes is satisfied, the blood level of ascorbate rises and retards the absorption of ascorbate from the gut. Soon, sufficient amounts of ascorbate reach the rectum to produce diarrhea.
Based on clinical evidence, I hypothesize that ascorbate can maintain this reducing redox potential under very adverse circumstances, but that the doses necessary to do this are enormous by any other standards. This antioxidant free radical scavenging effect of enormous doses of ascorbate seems not particularly contingent upon other nutrients. However, vitamin functions of lower doses of vitamin C are frequently potentiated by and work in conjunction with vitamin A, zinc, selenium, bioflavonoids, and other nutrients which play roles in various defense mechanisms.
Chayen has discussed the significance of redox couples and has emphasized that whether a reaction will proceed left to right, or in reverse, depends upon the ratio of the oxidized to the reduced members of a redox couple. He suggests designing "redox drugs" as a possible way of treating imbalances of oxidation-reduction potentials of critical intracellular systems (37).
I would anticipate that if it were possible to eliminate the vast majority of stray free radicals and highly reactant oxidative substances, the usual inflammatory cascade would not occur following injury or surgery. Pain, complications, and recovery times would be reduced. In conditions resulting from combinations of mechanical derangements, nutritional deficien- cies, immune dysregulations, hemorrhage with release of free radical generating iron and copper atoms, and then secondary inflammatory cascades (e.g. degenerative disc disease, degenera- tive arthritis, rheumatoid arthritis, ankylosing spondylitis, blunt trauma of the spine, etc.), therapeutic effects could be expected proportional to what might result from blocking of the free radicals and the inflammatory cascade. Reversal of the mechanical and nonfree radical injury could not be expected, although certain healing mechanisms might be enhanced.
Toxic substances, whose mechanisms of action involve free radical generation, e.g. toxic poisons such as snake bites and spider bites, certain drugs, such as barbiturates, chemotherapeutic agents, narcotics, and powerful oxidizing pollutant chemicals, might be neutralized. Conditions triggered by allergic reactions and perpetuated by the inflammatory cascade might be expected to be partially alleviated. Psychological symptoms resulting from oxidative products such as adrenochrome and noradrenochrome (38), would be expected to be ameliorated to a degree.
Tumors invading the body or holding off the immune system by way of free radical toxicity might be expected to respond to varying degrees. As an increasing number of human cancers are recognized as probably being caused and possibly maintained by infectious organisms (e.g. Kaposi's lesions by the CMV (39), some adult T-cell lymphomas by the HTLV (40), certain cervical and vaginal cancers by the papilloma virus (41,42)), it should not be surprising if such tumors would respond in various degrees to ascorbate. Since any treatment of cancers by a physician with nutritional substances is incredibly a felony in California in 1984, it may be practical to recognize early that a tumor caused by a virus should no longer be considered a cancer (e.g. Kaposi's lesions).
If, to these diseases, we add conditions benefitted which could be caused or aggravated by actual dietary deficiency of vitamin C, or from an acute induced deficiency of vitamin C, there is a very close approximation to the clinical spectrum of disease conditions which in the experience of those actually using such doses (4,26-28,32,33,43,44), appear to be beneficially affected. In a rough way, these conditions are ameliorated to the degree that one might anticipate if this ideal mechanism of being able to quench all stray free radicals and highly reactant oxidative substances, were actually accomplished.
One might remain unnecessarily cautious in the use of ascorbate because of my qualification about "tolerant" patients. Any real problems have been rare. I cannot recall any patient who has been damaged by large doses of ascorbate (other than the topical effect of the acid on tooth enamel). Some preexisting gastrointestinal tract difficulties, such as peptic ulcer or colitis, may have been aggravated by topical effects, but advice on these is difficult to give because more frequently the same conditions may be benefitted. All these topical difficulties are circumvented by using intravenous ascorbate.
A high percentage of persons with food and/or chemical sensitivities may have nuisance difficulties with vitamin C. However, attempts to have these sensitive patients take ascorbate should be made because great benefits can often be obtained, particularly from calcium, magnesium, and potassium ascorbate, in many of these patients. Frequently, after the administration of selenium, ascorbate is better tolerated by chemically allergic patients. Levine has suggested that chemically allergic patients frequently benefit from selenium because selenium augments the glutathione peroxidase activity (8). I have had some clinical evidence that certain chemically allergic patients who force through nuisance problems of low doses of ascorbate, can derive benefits from consistently taken large doses. It may be that chemically allergic persons accumulate dehydroascorbate more readily than others because of a deficiency of glutathione per- oxidase. I had one chemically allergic patient who responded well to intravenous ascorbate until an hour after it was discon- tinued. She then developed a severe headache that lasted several hours. In retrospect, it seems possible that the intravenous ascorbate was able to maintain a reducing redox potential, which then returned to the oxidizing side after the intravenous ascorbate was discontinued.
True allergic reactions seem always traceable to substances from which the ascorbate is made, or chemicals used in its manufacture, and not to the ascorbate itself.
Oxalate kidney stones have been suggested as a theoretical problem, in that oxalate is one of the breakdown products of ascorbate (50). In my experience clinically, ascorbate in these doses not only does not cause kidney stones but seems to prevent stones in patients who have had them previously. The slight increase in the acidity of the urine from ascorbate (51,52), and the slight diuresis (53) solubilizes calcium salts. I think that high concentrations of ascorbate, by being bacteriostatic in the urine, should prevent many of the niduses of infection around which oxalate stones frequently form. The increased ascorbate concentration complexes Ca++ and thereby decreases the amount of Ca++ available to complex with oxalate (34). Here again is the paradoxical situation where with small doses of vitamin C, it is possible that where most of the nutrient is oxidized to dehydro- ascorbate and then some to oxalic acid, it is theoretically possible that there could be a slight increase in tendency to form stones. However, I find it difficult to believe that if this were the case, that this tendency would not have been noticed with the millions taking small doses of vitamin C. I hypothesize that by using the bowel tolerance method of determining the dosages of ascorbate to be taken, that no matter how much dehydroascorbate is formed and hence oxalic acid, the spill of ascorbate in the urine will be kept very high and should prevent oxalate stones.
I suggest that the enormous draw on ascorbate for free radical scavenging purposes, can exhaust the vitamin C available for known housekeeping functions of the vitamin. I term this condition acute_induced_scurvy. This deficiency starts in the tissues directly involved in the disease; then blood levels of vitamin C drop (anascorbemia); and then tissues distant from the primary focus of the disease become involved. Secondary complications occur which can be averted by fully satisfying the increased need for ascorbate (4).
A very important part of these very large doses of ascorbate being able to assist the immune system against pathogens is likely that serum levels and leukocyte levels of ascorbate are raised enough to drive ascorbate into the depths of infected tissues. The amount of ascorbate needed to satisfy the enormous potential utilization of ascorbate as an antioxidant free radical scavenger in the depths of the diseased tissues is provided. The shut down of vitamin C dependent housekeeping functions of affected cells and the shut down of vitamin C dependent immune system functions are prevented.
I think that many crib deaths are caused by this acute induced scurvy even before it is evident that the infant is sick with some infectious disease. Kalokerinos (28) has demonstrated the value of vitamin C in preventing crib deaths. I have seen enormous increases in bowel tolerance to ascorbate in adults several hours before there was any outward sign of their getting sick. It is easy to imagine certain vital centers in an infant failing when suddenly deprived of vitamin C by the ascorbate being used up for acute free radical scavenging purposes. For_many_reasons, it is unfortunate that the free radical scavenger ascorbate is the same substance as vitamin C.Infants tolerate ascorbate well. In addition to substantial maintenance doses of vitamin C, even infants should be given large doses of ascorbate when ill. Amounts should be given sufficient to relieve fever, irritability, and other outward signs of toxicity (4).
While it is not denied that there could be very rare serious complications associated with the use of massive doses of ascorbate, fear of this possibility should not retard use of the substance in patients with normal metabolism. In my experience, the margin of safety (therapeutic index or selectivity) for massive doses of ascorbate as related to significant complica- tions is greater than aspirin, antihistamines, antibiotics, all pain medications, muscle relaxants, tranquilizers, sedatives, diuretics, etc. Not only is the margin of safety of ascorbate extremely favorable but when used with most of these drugs, the combination frequently acts synergistically and has a margin of safety greater than with the drug alone. While ascorbate may block the effects of some sedatives and narcotics, massive doses of ascorbate frequently alleviate the need for those substances.
Clinically, ascorbate in the very large doses described is very effective and safe as part of the treatment of a wide variety of conditions, especially infectious diseases. It is my hypothesis that this clinical effectiveness when a critical threshold is reached, as indicated by bowel intolerance to ascorbic acid in the form of diarrhea, occurs both because massive doses of ascorbate can act as a nonrate-limited, antioxidant free radical scavenger and because acute induced scurvy is avoided. When high enough tissue levels are reached in tissues directly affected by the disease processes, the redox potential of the AA/DHA system in those tissues is kept reducing; substances such as oxidized glutathione are directly reduced; and stray free radicals are rapidly quenched.
This effect of ascorbate is rate-limited only by the lack of courage of those administering ascorbate or the tolerance of the patient taking it. I hope to increase that courage by pointing out the observed lack of toxicity clinically and the theoretical reasons for that lack of toxicity.
This effect, when understood, opens up a wide range of opportunities to understand certain pathological processes. It is especially important in the case of infectious diseases because of the probable common mechanism of free radical toxicity that many pathogens have of suppressing the immune system. The increasing bowel tolerance to ascorbic acid can be used as a fairly accurate measure of the "toxicity" and activity of certain disease processes.
In toxic conditions, the use of ascorbate by the body for these scavenging purposes, results in such a localized and systemic deficiency of vitamin C that there is not enough of the nutrient remaining for vitamin C dependent housekeeping functions. I call this condition acute_induced scurvy. This condition can be induced by any stress and is responsible for a high percentage of the secondary complications of many diseases. The magnitude of this scavenging drain on ascorbate is enormous as revealed by the increasing bowel tolerance to ascorbic acid somewhat proportional to the toxicity of the disease process. Only the doses discussed can fully satisfy this need.
I think that most crib deaths are due to acute induced scurvy.
I have hypothesized here that massive doses of ascorbate may paradoxically be of benefit in G-6-PD deficiency, but have urged caution until more data is obtained. Ascorbate, when used with care, can be of great benefit in chemically allergic patients.
Rinse ascorbic acid and carbonated ascorbates off the teeth as prolonged exposure may cause damage to the enamel.
Partly supported by the Burton Goldberg Foundation. The author appreciates the comments of Stephen A. Levine and Parris M. Kidd.
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