The Science

Official Journal of the International Society for Orthomolecular Medicine International Standard Serial Number 0317-0209

Volume 18 Third & Fourth Quarters, 2003 Numbers 3 & 4

 

Index

 

Editorial: "Toxic" Vitamins - A. Hoffer, M.D., Ph.D

"Safe Upper Levels" for Nutritional Supplements: One Giant Step Backward -A. R. Gaby, M.D.

Riboflavin Guidance Level

Vitamin B6 Safe Upper Level

Manganese Guidance Level

Niacin (nicotinic acid) Guidance Level

Conclusion

Side Effects of Over-the-Counter Drugs - A. Hoffer, M.D., Ph.D.

Comparing Side Effects of OTC Drugs and Vitamins

Acetylsalicylic Acid, also called Aspirin

Ranitidine, also called Zantac

Iboprofen, also called Motrin

Summary

 

"Toxic" Vitamins

The safety of vitamins has been clearly demonstrated by the toxicological literature and further by the experience of orthomolecular physicians over the past forty years. Why then, is the public subjected to periodic outbursts of information about how toxic vitamins are? We do not have similar outbursts against the use of drugs even though vitamins have a zero death rate while drugs in the United States alone kill 106,000 patients in hospitals annually.

The Food Standard Agency (FSA) in England released a press statement early in May, 2003, entitled "New FSA advice on safety of high doses of vitamins and minerals." Why they titled their statement "new" puzzles me since this is the sort of advice we have been getting from various government agencies for the past 50 years.

The toxicological facts about vitamins gathered over the past 60 years do not support their advice. It is advice which follows from the vitamins-as-prevention paradigm established over 100 years ago and rejects the extensive research over the past 50 years that established the vitamin-as-treatment paradigm. The press release was dutifully copied and reprinted in the mass media with very little, if any, critical examination of the claims made in the FSA statement. The headlines in the National Post, Canada, May 13, 2003, ran: "Searching for a Magic Bullet;" The Globe and Mail, Canada, May 31,2003, went under the heading "Too Much of a Good Thing?"; the BBC News, May 7,2003, harked a "Warning Over Vitamin Doses"; and The Times, England, May 8, 2003, warned "Vitamins Can Damage Your Health" and so on. An EMedicine report on "Vitamin Toxicity" by Mark Rosenbloom carries the same information.

The FSA recommends that while most vitamins are safe a few have to be taken with great caution. The FSA states it is an independent food safety watchdog but later on adds they are accountable to Parliament through Ministers of Health. A board that is appointed and is supposed to have a wide range of relevant skills and experience leads it. The readers of this issue will be able to deduce on their own what skills are represented on the board. In my opinion they did not include any relevant clinicians experienced in using vitamins as supplements. There are not enough clinicians so experienced in Great Britain to form such a board. Orthomolecular medicine in Great Britain has been thoroughly rejected for years.

A paradigm is a system of thought or ideas based on observations, hypotheses and theories. It is an attempt to coordinate the acceptable observations about a topic, which makes some sense to its practitioners. Paradigms are evanescent since newer observations will make older paradigms out of date and mostly wrong. But replacing one paradigm by a newer and better one does not happen smoothly. It occurs in quantum leaps. The old paradigm is taught and studied and defended vigorously by scientists in that area. It will be changed with great difficulty because it has a large body of adherents who will protect its main hypotheses to the end. When there is sufficient new information and enough adherents to the new information there may be a shift to the new paradigm, which in turn will be replaced. Paradigms are very useful and serve science well but as they become well established they prevent new information from being gathered and from being published in the literature, which is part of that paradigm.

In the field of vitamin use and theory the first paradigm is called the vitamin-asprevention (VAP) paradigm. It was introduced after many years against the opposition of the medical establishment. Here is an example. In 1916, the U.S.A. Department of Agriculture announced that Dr. J. Goldberger had discovered the cause of pellagra; it was caused by a diet deficient in something. Around the same time two U.S.A. physicians, from the establishment, announced that they had discovered the cause of pellagra; it was caused by the bite of the stable fly. As late as 1950 I read in a medical textbook that it is alleged that niacin cures pellagra.

The principles of VAP paradigm are (1) that vitamins are needed only in very small amounts, as declared by the recommended daily doses in common use; (2) that they are used only to prevent certain classical deficiency diseases. Thiamine prevents beri beri, vitamin C prevents scurvy, vitamin D prevents rickets, and vitamin B prevents pellagra. If these principles are gospel truth it follows (1) that large doses, above the recommended vitamin doses are not to be used, are contraindicated, may be dangerous even though the evidence for this is nonexistent, and indicates that the clinician is probably not fit to practice medicine. Several of my colleagues lost their licence because they used large doses of vitamin C; (2) that giving any vitamins to patients with diseases not known to be vitamin deficiency diseases is contraindicated. The VAP paradigm is accepted by almost every nutritionist, physician, government agency and food board such as FSA. The statement issued by the FSA is a typical statement from adherents to this paradigm.

The modern paradigm is the vitaminsas-treatment paradigm (VAT), which is defined by a different set of principles. These are: (1) that vitamins are therapeutic for a large number of conditions not considered to be vitamin deficiency diseases; (2) optimum doses are used which vary in quantity but are much larger than those recommended by the original paradigm and by the recommended daily requirements. The best example of the VAT paradigm in practice is the use of niacin, which is used in 3 to 9 grams dosages daily to lower total cholesterol, to elevate high-density lipoprotein cholesterol and to lower elevated triglycerides. This unexpected property of niacin was reported in 1955' and marks the beginning of the new VAT paradigm.

There were several pioneers ahead of us. The first pioneers were Drs. Evan Shute and Wilfrid Shute from Ontario who found that vitamin E was very useful in treating and preventing heart disease. Their work wa s vilified, ignored and suppressed. At about the same time Dr W Kaufman reported that niacinamide was very helpful for the arthritides and for many of the conditions associated with aging. His work was totally ignored. Then Dr. Fred Klenner, North Carolina, found that very large doses of vitamin C were very therapeutic for a large number of conditions including cancer, viral and bacterial infections, multiple sclerosis and more. His work was totally ignored by medicine but is enjoying a renaissance especially for his treatment program for multiple sclerosis and his use of large doses of vitamin C for cancer. Our niacin cholesterol work was not ignored due to a series of talks I gave the Mayo Research Foundation in 1955. During the last farewell dinner I told Dr. Howard Rome about our work. He passed it on to the Chief of Medicine. His senior resident, Dr. William Parsons became interested and as a result of this interest our work was quickly confirmed. Coming from the Mayo Clinic it carried much more weight and of course it was easy to confirm whether cholesterol was lowered or not. Other pioneers included Dr. Irwin Stone, Dr. Linus Pauling and recently Dr. Bruce Ames.

Information about drugs released to the public in the Compendium, in letters to doctors, in advertisements and in press releases is usually accurate. The PDA in the United States and the FDD in Canada vet efficacy information. Side effects and toxicity information is vetted by the manufacturers of the drugs, the companies that hold the patents. There is no doubt that the descriptions in the compendiums do not appear until their proprietors have rigorously examined them. Vitamins have no proprietors. They are not patentable. Efficacy claims are vetted by the same agencies as 124 Editorial those vetting drugs but descriptions of efficacy and toxicity are not. This is why descriptions in the Compendiums have to be read very carefully because they carry information which is wrong or out of date. We need someone or some agency to do for the nutrients what the drug companies do for their drugs. Unfortunately, university departments of nutrition, and the companies that sell the vitamins have not undertaken this role. This special issue of the Journal of Orthomolecular Medicine is a first attempt to correct the record. Clinicians and scientists who are familiar with vitamins, with the literature and with long experience in having used them in treatment, will discuss the vitamins that are commonly used in the VAT range.

At the beginning of this editorial I posed the question, "Why are we subjected to periodic outbursts of information as to how toxic vitamins are?" I think the reason is fairly obvious. The attack on the safety of vitamins is really an attack on the efficacy of these nutrients. If the critics really conceded that the vitamins have therapeutic properties they would not be attacking their efficacy. It is an indirect method of downgrading the value of orthomolecular medicine. That means that the protestations we all make about the uninformed criticisms of the critics will have little effect. We must emphasize the therapeutic value of vitamins when used properly. We must continue to study their therapeutic properties, and as the drug companies do with their drugs, repeat the message that they are valuable. We cannot advertise but we can publish. My complaint against my colleagues is that having published a paper once or twice reporting the advantages of vitamins they are content to sit back and do nothing more. This must stop.

I urge you all to do the following: (1) research and publish your studies in orthomolecular medicine and psychiatry; (2) continue to protest the false claims made by the opposition. Use all the media you have access to. The Journal of Orthomolecular Medicine will consider all manuscripts. The web site, International Bulletin Board for Orthomolecular Medicine (IBBOM), can become a very valuable worldwide medium. Please use it. http://www.orthoeurope.com/ IBBOM/index.php

Abram Hoffer, M.D., Ph.D., FRCP(C)

References

1. Altschul R, Hoffer A, Stephen JD: Influence of nicotinic acid on serum cholesterol in man. Arch Biochem Biophys, 1955; 54: 558-559.

2. Shute WE: Vitamin E. Keats Publishing, New Canaan, CT 1978.

3. Kaufman W: The Common Form of Niacinamide Deficiency Disease. Aniacinamidosis. Yale University Press. New Haven, CT. 1943

4. Klenner FR: Massive doses of vitamin C and the viral diseases. Southern Med Surg, 1951; 113: 101-107.

5. Parsons WB Jr: Cholesterol control without diet. TheNiacin Solution. Lilac Press, Scottsdale, AR. 1998, Revised 2003.

6. Stone I: The Healing Factor: Vitamin C Against Disease. Grosset and Dunlap, New York, 1967.

7. Pauling L: Orthomolecular Psychiatry. Science 1968; 160: 265-271.

8. Ames BN, Elson-Schwab I, Silver EA: High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased Km)): relevance to genetic disease and polmorphisms.AmJClinNutr, 2002; 75:616-658. 125

"Safe Upper Levels" for Nutritional Supplements: One Giant Step Backward

Alan R. Gaby, M.D.

Introduction In May, 2003, the Expert Group on Vitamins and Minerals (EVM), an advisory group originally commissioned in 1988 by the then Ministry of Agriculture Fisheries and Food, and subsequently reporting to the Food Standards Agency in England, published a report that set "Safe Upper Levels" (SULs) for the doses of most vitamin and mineral supplements. The establishment of SULs was based on a review of clinical and epidemiological evidence, as well as animal research and in vitro studies. For those nutrients for which the available evidence was judged insufficient to set an SUL, the EVM instead established "Guidance Levels", which were to be considered less reliable than SULs.

This writers analysis of the EVM report reveals that the dose limits were set inappropriately low for many vitamins and minerals, well below doses which have been used by the public for decades with apparent safety. While the release of this 360-page document would be of little import, were it to be used solely as a manifesto for the pathologically risk-averse, preliminary indications are that it could be used very actively to support the arguments of those who are seeking to ban the over-the-counter sale of many currently available nutritional supplements. If the report is used that way, then the public health could be jeopardized.

On May 30, 2002, the European Union adopted Directive 2002/46/EC, which established a framework for setting maximum limits for vitamins and minerals in food supplements. The EVM report is seen by the UK government as the basis for its negotiating position in the process of setting these pan-European limits.

The apparent anti-nutritional-supplement, anti-self-care bias that permeated the process of setting safety levels is evident both in the way in which the SUL was defined and in the fact that the benefits of nutritional supplements were purposely ignored. The SUL was defined as the maximum dose of a particular nutrient "that potentially susceptible individuals could take daily on a life-long basis, without medical supervision in reasonable safety." In other words, it is the highest dose that is unlikely to cause anyone any harm, ever, under any circumstance. Furthermore, the EVM was specifically instructed not to consider the benefits of any of the nutrients, and not to engage in risk/benefit analysis.

There is little or no precedent in free societies for restricting access to products or activities to levels that are completely riskfree. Aspirin causes intestinal bleeding, water makes people drown, driving a car causes accidents, and free speech may offend the exquisitely offendable. Politicians and bureaucrats do not seek to ban aspirin or water or driving or free speech, because their benefits outweigh their risks. For vitamins and minerals, however, some authorities seem to believe that unique safety criteria are needed.

Moreover, the government's instructions to disregard the many documented benefits of nutritional supplements introduced a serious bias into the evaluation process. As the EVM acknowledged, determining safety limits involves an enormous degree of uncertainty and a fairly wide range of possible outcomes. The committee might have established higher safety limits than it did, had it been told to weigh benefits against risks. The government's instructions appeared to be an implicit directive to err on the side of excluding doses that are being used to prevent or treat disease. And that is what the EVM did, often by making questionable interpretations of the data, and doing so in what appears to have been an arbitrary and inconsistent manner.

Riboflavin Guidance Level

A typical example of the EVM s dubious approach to establishing safety limits is its evaluation of riboflavin. The committee acknowledged that no toxic effects have been reported in animals given an acute oral dose of 10,000 mg/kg of body weight, or after longterm ingestion of 25 mg/kg/day (equivalent to 1,750 mg/day for a 70-kg human). Moreover, in a study of 28 patients taking riboflavin for migraine prophylaxis, a dose of 400 mg/day for 3 months did not cause any adverse effects. Despite a complete absence of side effects at any dose in either humans or animals, the EVM set the Guidance Level for riboflavin at 40 mg/day. That level was established by dividing the 400 mg/day used in the migraine study by an "uncertainty factor" of 10, to allow for variability in the susceptibility of human beings to adverse effects.

A more appropriate conclusion regarding riboflavin would have been that no adverse effects have been observed at any dose, and that there is no basis at this time for establishing an upper limit. If the EVMs recommendation is used to limit the potency of riboflavin tablets to 40 mg, then migraine sufferers will have to take 10 pills per day, in order to prevent migraine recurrences.

Vitamin B6 Safe Upper Level

Similar reasoning led to an SUL of 10 mg/ day for vitamin B6, even though this vitamin has been used with apparent safety, usually in doses of 50 to 200 mg/day, to treat carpal tunnel syndrome, premenstrual syndrome, asthma, and other common problems. The SUL for vitamin B6 was derived from an animal study, in which a dose of 50 mg/kg of body weight/day (equivalent to 3,000 mg/day for a 60-kg person) resulted in neurotoxicity. The EVM reduced that dose progressively by invoking three separate "uncertainty factors:" 1) by a factor of 3, to extrapolate from the lowestobserved-adverse-effect-level (LOAEL) to a noobserved-adverse-effect-level (NOAEL); 2) by an additional factor of 10, to account for presumed inter-species differences; and 3) by a further factor of 10 to account for inter-individual variation in humans. Thus, the neurotoxic dose in animals was reduced by a factor of 300, to a level that excludes the widely used 50and 100-mg tablets.

The decision to base the SUL for vitamin B6 on animal data (modified by a massive "uncertainty factor") was arbitrary, considering that toxicology data are available for humans.1 A sensory neuropathy has been reported in some individuals taking large doses of vitamin Be.45 Most people who suffered this adverse effect were taking 2,000 mg/day or more of pyridoxine, although some were taking only 500 mg/day. There is a single case report of a neuropathy occurring in a person taking 200 mg/day of pyridoxine, but the reliability of that case report is unclear. The individual in question was never examined, but was merely interviewed by telephone after responding to a local television report that publicized pyridoxine-induced neuropathy.

Because pyridoxine neurotoxicity has been known to the medical profession for 20 years, and because vitamin B6 is being taken by millions of people, it is reasonable to assume that neurotoxicity at doses below 200 mg/day would have been reported by now, if it does occur at those doses. The fact that no such reports have appeared strongly suggests that vitamin B, does not damage the nervous system when taken at doses below 200 mg/day. As the EVM did with other nutrients for which a LOAEL is known for humans, it could have divided the vitamin B6 LOAEL (200 mg/day) by 3 to obtain an SUL of 66.7 mg/day. Had the committee been allowed to evaluate both the benefits and risks of vitamin B6, it probably would have established the SUL at that level, rather than the 10 mg/day it arrived at through serial decimation of the animal data.

Manganese Guidance Level

Chronic inhalation of high concentrations of airborne manganese, as might be encountered in mines or steel mills, has been reported to cause a neuropsychiatric syndrome that resembles Parkinson's disease. In contrast, manganese is considered one of the least toxic trace minerals when ingested orally, and reports of human toxicity from oral ingestion are "essentially nonexistent."7 The neurotoxicity that occurs in miners and industrial workers may result from a combination of high concentrations of manganese in the air and, possibly, direct entry of nasally inhaled manganese into the brain (bypassing the blood-brain barrier).

In establishing a Guidance Level for manganese, the EVM cited a study by Kondakis et al., in which people exposed to high concentrations of manganese in their drinking water (1.8-2.3 mg/L) had more signs and symptoms of subtle neurological dysfunction than did a control group whose drinking water contained less manganese.8 The committee acknowledged that another epidemiological study by Vieregge et al. showed no adverse effects among individuals whose drinking water contained up to 2.1 mg/L of manganese.1' The EVM hypothesized that these studies may not really be contradictory, since the subjects in the Kondakis study were, on average, 10 years older than were those in the Vieregge study, and increasing age might theoretically render people more susceptible to manganese toxicity. Based on the results of these two studies, the EVM established a Guidance Level for supplemental manganese of 4 mg/day for the general population and 0.5 mg/day for elderly individuals.

There are serious problems with the EVM's analysis of the manganese research. First, the committee overlooked that fact that in the Kondakis study the people in the high-manganese group were older than were those in the control group (mean age, 67.6 vs. 65.6 years). Many of the neurological symptoms that were investigated in this study are nonspecific and presumably age related, including fatigue, muscle pain, irritability, insomnia, sleepiness, decreased libido, depression, slowness in rising from a chair, and memory disturbances. The fact that the older people had more symptoms than did the younger people is not surprising, and may have been totally unrelated to the manganese content of their drinking water.

Second, the EVM broke its own rules regarding the use of uncertainty factors, presumably to avoid being faced with an embarrassingly low Guidance Level for the general population. In setting the level at 4 mg/day, the committee stated: "No uncertainty factor is required as the NOAEL [obtained from the Vieregge study] is based on a large epidemiological study." As a point of information, the Nurses' Health Study was a large epidemiological study, enrolling more than 85,000 participants. The Beaver Dam Eye Study was a medium-sized epidemiological study, enrolling more than 3,000 participants. In contrast, in the Vieregge study, there were only 41 subjects in the high-manganese group, making it a very small epidemiological study. In its evaluation of the biotin, riboflavin, and pantothenic acid research, the EVM reduced the NOAEL by an uncertainty factor of 10, in part because only small numbers of subjects had been studied. Considering that more subjects were evaluated in the pantothenic acid research (n=94) than in the Vieregge study (n=41), it would seem appropriate also to use an uncertainty factor the for manganese data. Applying an uncertainty factor of 10 to the Vieregge study would have produced an absurdly low Guidance Level of 0.4 mg/day for supplemental manganese, which is well below the amount present in a typical diet (approximately 4 mg/day) and which can be obtained by drinking several sips of tea. Parenthetically, in a study of 47,351 male health professionals, drinking large amounts 128 "Safe Upper Levels" for Nutritional Supplements: One Giant Step Backward of tea (a major dietary source of manganese) was associated with a reduced risk of Parkinson's disease, not an increased risk." In changing its methodology to avoid reaching an indefensible conclusion, the EVM revealed the arbitrary and inconsistent nature of its evaluation process.

Niacin (nicotinic acid) Guidance Level

Large doses of niacin (such as 3,000 mg/day) can cause hepatotoxicity and other significant side effects. The EVM focused its evaluation, however, on the niacin-induced skin flush, which occurs at much lower doses. The niacin flush is a sensation of warmth on the skin, often associated with itching, burning, or irritation that occurs after the ingestion of niacin and disappears relatively quickly. It appears to be mediated in part by the release of prostaglandins. The niacin flush is not considered a toxic effect per se, and there is no evidence that it causes any harm. People who do not like the flush are free not to take niacin supplements or products that contain niacin. For those who are unaware that niacin causes a flush, an appropriate warning label on the bottle would provide adequate protection.

Granting, for the sake of argument, that the niacin flush is an adverse effect from which the public should be protected, the EVM's Guidance Level still is illogical. The committee noted that flushing is consistently observed at a dose 50 mg/day, which it established as the LOAEL. That dose was reduced by an uncertainty factor of 3, in order to extrapolate the LOAEL to a NOAEL. Thus, the Guidance Level was set at 17 mg/day, which approximates the RDA for the vitamin. The EVM also noted, however, that flushing has been reported at doses as low as 10 mg, so the true LOAEL is 10 mg/day. Applying the same uncertainty factor of 3 to the true LOAEL would have yielded a Guidance Level of a paltry 3.3 mg/day, which probably is not enough to prevent an anorexic person from developing pellagra. As with manganese, the EVM applied its methodology in an arbitrary and inconsistent manner, so as to avoid being faced with an embarrassing result. Vitamin C Guidance Level

The EVM concluded that vitamin C does not cause significant adverse effects, although gastrointestinal (GI) side effects may occur with high doses. The committee therefore set a Guidance Level based on a NOAEL for GI side effects. It is true that taking too much vitamin C, just like eating too many apples, may cause abdominal pain or diarrhea. The dose at which vitamin C causes GI side effects varies widely from person to person, but can easily be determined by each individual. Moreover, these side effects can be eliminated by reducing the dose. Most people who take vitamin C supplements know how much they can tolerate; for those who do not, a simple warning on bottles of vitamin C would appear to provide the public all the protection it needs. Considering the many health benefits of vitamin C, attempting to dumb down the dose to a level that will prevent the last stomachache in Europe is not a worthwhile goal. However, as mentioned previously, the EVM was instructed to ignore the benefits of vitamin C.

Granting, for the sake of argument, that there is value in setting a Guidance Level for GI side effects, the EVM did a rather poor job of setting that level. The committee established the LOAEL at 3,000 mg/day, based on a study of a small number of normal volunteers.12 An uncertainty factor of 3 was used to extrapolate from the LOAEL to a NOAEL, resulting in a Guidance Level of 1,000 mg/day. However, anyone practising nutritional medicine knows that some patients experience abdominal pain or diarrhea at vitamin C doses of 1,000 mg/day or less, and the EVM did acknowledge that GI side effects have been reported at doses of 1,000 mg.

It is disingenuous to set a NOAEL and then to concede that effects do occur at the no-effect level. To be consistent with the methodology it used for other nutrients, the committee should have set the LOAEL at 1,000 mg/day, and reduced it by a factor of 3 to arrive at a NOAEL of 333 mg/day. The EVM was no doubt aware of the credibility problems it would have faced, had it suggested that half the world is currently overdosing on vitamin C. To resolve its dilemma, the committee used a scientifically unjustifiable route to arrive at a seemingly politically expedient outcome.

Conclusion

These and other examples from the report demonstrate that the EVM applied its methodology in an arbitrary and inconsistent manner, in arriving at "safety" recommendations that are excessively and inappropriately restrictive. While the directive to evaluate only the risks, and to ignore the benefits, of nutritional supplements created a rigged game, the members of the EVM appeared to be willing participants in that game.

If the EVM report is used to relegate currently available nutritional supplements to prescription-only status, then millions of people would be harmed, and very few would benefit. It would be of little consolation that the higher doses of vitamins and minerals could still be obtained with a doctor's prescription, because most doctors know less about nutrition than do many of their patients. Moreover, the overburdened health-care system is in no position to take on the job of gatekeeper of the vitamin cabinet; nor is there any need for it to do so.

Ironically, as flawed as the EVM report is, its recommendations may ultimately prove to be "as good as it gets" in Europe. Other European countries are recommending that maximum permitted levels be directly linked to multiples of the RDA, which could result in limits for some nutrients being set substantially lower than those suggested in the EVM report.

While some nutritional supplements can cause adverse effects in certain clinical situations or at certain doses, appropriate warning labels on vitamin and mineral products would provide ample protection against most of those risks.

References

1. Expert Group on Vitamins and Minerals. Safe Upper Levels for vitamins and minerals, May 2003, p. 28. Available at http://www.food.gov.uk/multimedia/pdfs/vitmin2003.pdf

2. SchoenenJ,JacquyJ, Lenaerts M: Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology, 1998:50:466-470.

3. Gaby AR: The safe use of vitamin b6, Nutr Med, 1990; 1: 153-157.

4. Schaumburg H, Kaplan J, Windebank A, et al: Sensory neuropathy from pyridoxine abuse: a new megavitamin syndrome. N Engl J Med, 1983; 309: 445-448.

5. Parry GJ: Sensory neuropathy with low-dose pyridoxine. Neurology, 1985; 35: 1466-1468.

6. Parry GJ. Personal communication. July 14,1986.

7. Nielsen FH: Ultratrace minerals. In Shils ME, Olson JA, Shike M (eds.). Modern Nutrition in Health and Disease, Eighth Edition, Philadelphia, 1994, p. 276.

8. Kondakis XG, Makris N, Leotsinidis M, et al: Possible health effects of high manganese concentration in drinking water. Arch Environ Health, 1989; 44: 175-178.

9. Vieregge P, Heinzow B, Korf G, et al: Long term exposure to manganese in rural well water has no neurological effects. Can J Neurol Sci, 1995; 22: 286-289.

10. Calcium pantothenate in arthritic conditions. A report from the General Practitioner Research Group. Practitioner, 1980; 224: 208-211.

11. Ascherio A, Zhang SM, Hernan MA, et al: Prospective study of caffeine consumption and risk of Parkinson's disease in men and women. Ann Neurol, 2001; 50: 56-63.

12. Cameron E, Campbell A: The orthomolecular treatment of cancer. II. Clinical trial of highdose ascorbic acid supplements in advanced human cancer. Chem Biol Interact, 1974; 9:285315. 130

Side Effects of Over-the-Counter Drugs

Abram Hoffer, M.D., Ph.D.

Primum non nocere.

Every doctor has learned the Hippocratic Oath, the most well-known and most important ethical rule in medicine: "Above all, do no harm." This is the physicians first rule: a treatment prescribed to a patient must not harm the patient. It does not say harm should be relative, although that is how the rule is interpreted. It does make the point that the harm, ideally, should be as little as is humanly possible. Paracelsus wrote, Sola dosisfacit venenumtoo much of anything will hurt you. For centuries, this has precipitated the question, How much is too much?

Any discussion of side effects or of toxic reactions without specifying the doses is meaningless, for at zero levels nothing is toxic and at sufficiently high levels everything is toxic, including oxygen and water. Critics of optimum (often high) doses of vitamins generally talk about toxic reactions without any reference to the doses being used. They report that vitamins "may" be toxic. Note they do not write "are" harmful because the word "may" is a very useful term; it has little meaning but can be used to appear to be very scientific. How often have we seen screaming headlines "Vitamin C May be Harmful" or "May Cause Cancer?" One of the well entrenched fictions is that vitamin C "may" cause kidney stones. This is not based on fact. There are no reports in the literature which prove that this is true, yet there are many good studies that show that it is not true. Nevertheless, the statement has developed a life of its own which is not anchored by any observation of facts. Yes, it "may" cause kidney stones if the word "may" is allowable when the odds that this will happen are less than one million to one. Millions of people take vitamin C. So far not one finding has established that vitamin C causes kidney stones. So in discussing side effects and toxicity we must always use the simplest, most accurate language possible referring to the doses being discussed.

In this review, I will report the side effects of a few very common overthe-counter drugs. They are freely available in drug stores and some in department stores. These compounds are analgesics, antihistamines, and anti-inflammatory drugs. I will not discuss the efficacy of these compounds. I accept that they have value or they would not be in common use and I also use them occasionally. This discussion focuses on potential side effects and toxicity; it is not about efficacy. The information comes from the medical literature and from the drug companies.

Comparing Side Effects of OTC Drugs and Vitamins

A comparison of the side effects of vitamins to those of over-the-counter drugs will provide the reader with an estimate of the degree of safety associated with vitamins. Vitamins should not be compared against prescription drugs since all drugs have side effects and toxic effects, even within the recommended dose ranges. That is why they are controlled by prescription and drug stores. The Compendiums are huge, larger than telephone books, with hundreds of pages devoted to these reactions, to side effects, to toxic reactions, to contraindications. These long descriptions, usually in small print, scare most patients and many doctors as well. Some of the side effects seem exaggerated since it is seldom indicated how often they occur. On the other hand, the toxic reactions ascribed to placebo are exaggerated because they are listed but not defined. Thus nausea caused by a drug is usually much more severe than nausea caused by a placebo and the placebo reaction is usually short lived. If 10% of the placebo group and 12% of the drug group complain of nausea, it does not mean that the drug is not much worse than placebo. It may well be that the drug induced nausea is much more severe and debilitating. The intensity of all the side effects should be, but is not, recorded.

The best protection patients can have is to keep in close touch with the doctor who prescribed the medication. At the first indication of any adverse reaction they should contact their doctor. Xenobiotics (substances foreign to the body) interfere with reactions in the body and often suppress some reactions, but because they are foreign they must be converted to less toxic substances and then excreted. If excretion is too slow the drug and its metabolic products will build up in the body. This is the reason they cause toxic reactions and also why energy is used to eliminate them, energy that might be better used for the normal reactions in the body. Nutrients on the other hand do not interfere. Vitamins enhance reactions that are inhibited. Larger doses force reactions that have been retarded by other factors.

Over-the-counter drugs are considered much safer than prescription drugs. That is why they are more freely available. Some over-the-counter drugs were first issued as prescription items and later were allowed to be sold over-the-counter. Some products such as aspirin and niacin are both prescription and OTC. Folic acid which once was OTC in 25 mg tablets is now available by prescription in 5 mg tablets; the OTC tablets now contain 800 meg. I have selected five very popular OTC drugs and will discuss the side effects and toxicity patterns of these five, not because I disapprove of them but to illustrate what is considered acceptable for OTC drugs.

Acetylsalicylic Acid, also called Aspirin

Aspirin is the most popular OTC drug and most often recommended by doctors . It is also available on prescription, which is an advantage for patients who have drug plans. There is even an Aspirin Foundation, established in 1981, which extols the efficacy of this drug. It is effective in dealing with heart disease, for arthritis, perhaps inhibiting colon cancer, and for headaches. Here are some of the official warnings that are listed for aspirin.1

Fluid and electrolyte effects: Increased metabolic rate, pyrexia, tachypnea, and vomiting lead to fluid loss and dehydration. Compensation for respiratory alkalosis leads to increased renal excretion of bicarbonate and increased excretion of sodium and potassium. Because of significant water losses, hyponatremia might not be present; however, hypokalemia is prominent.

Central nervous system effects: Toxic effects in the CNS range from mild confusion to coma. The exact mechanism that produces CNS toxicity is not known, but the degree of CNS effects, as well as overall mortality, correlates with the concentration of salicylates in brain tissue. Acidemia increases the non-ionized form of salicylates, allowing for movement across the blood-brain barrier and, therefore, increasing CNS toxicity. Gastrointestinal effects: Salicylate ingestion can cause nausea, vomiting, and abdominal pain. Emesis is produced by salicylate stimulation of medullary chemoreceptors and by local irritation of the GI tract. Upper GI ulceration and bleeding can occur. Gastrointestinal effects are much more prominent in acute ingestion. Ototoxicity: Salicylate toxicity results in a reversible Ototoxicity characterized by tinnitus, deafness, and dizziness.

Pulmonary effects: Non-cardiogenic pulmonary edema is the most common cause of major morbidity and might be related to an increase in permeability of pulmonary vasculature caused by salicylates. Acute respiratory distress syndrome (ARDS) is more prominent in chronic ingestions than in acute ingestions.

Hematological effects: Salicylates inhibit vitamin K-dependent synthesis of factors II, VII, IX, and X, leading to a prolonged prothrombin time (PT). Salicylates prolong bleeding time by inhibiting a prostaglandin-initiated sequence required for platelet aggregation.

Hepatic effects: Dose-dependent hepatotoxicity can occur with salicylate poisoning. A small percentage of patients might develop hepatitis, but the majority will have asymptomatic elevation of transaminases.

Renal effects: Acute renal failure has been reported rarely.

Mortality/Morbidity: Mortality rates vary with chronicity of exposure. Chronic toxicity carries a higher morbidity and mortality rate than acute toxicity and is more difficult to treat.

Acute overdose: Mortality rate of less than 2%

Chronic overdose: Mortality rate as high as 25%

Azer et al.2 used more than 11 pages of printed material to describe the toxicity of aspirin including treatment information and medical care. The British Medical Journal,* promotes a new elixir of youth called polypill. One of the six ingredients is aspirin.

Ranitidine, also called Zantac

Its use is described as follows: "Zantac is prescribed for the short-term treatment (4 to 8 weeks) of active duodenal ulcer and active benign gastric ulcer, and as maintenance therapy for gastric or duodenal ulcer, at a reduced dosage, after the ulcer has healed. It is also used for the treatment of conditions in which the stomach produces too much acid, such as Zollinger-Ellison syndrome and systemic mastocytosis, for gastroesophageal reflux disease (backflow of acid stomach contents) and for healingand maintaining healing of-erosive esophagitis (severe inflammation of the esophagus)." As I have written earlier, close contact with one's doctor is the best safeguard. More common side effects include: headache, sometimes severe. Less common and rare side effects include: abdominal discomfort and pain, agitation, changes in blood count (anemia), changes in liver function, constipation, depression, diarrhea, difficulty sleeping, dizziness, hair loss, hallucinations, heart block, hepatitis, hypersensitivity reactions, inflamed blood vessels, inflammation of the pancreas, involuntary movements, irregular heartbeat, jaundice (yellowing of eyes and skin), joint pain, muscle pain, nausea and vomiting, rapid heartbeat, rash, reduced white blood cells, reversible mental confusion, severe allergic reactions, sleepiness, slow heartbeat, swollen face and throat, vague feeling of bodily discomfort, vertigo.

The following special warnings are listed: a stomach malignancy could be present, even if your symptoms have been relieved by Zantac. If you have kidney or liver disease, this drug should be used with caution. If you have phenylketonuria, you should be aware that the "Efferdose" tablets and granules contain phenylalanine.

Here are more possible food and drug interactions when taking this medication: If Zantac is taken with certain other drugs, the effects of either could be increased, decreased, or altered. It is especially important to check with your doctor before combining Zantac with the following: Alcohol, Blood-thinning drugs such as Coumadin, Diazepam (Valium), Diltiazem (Cardizem), Glyburide (DiaBeta, Micronase), Ketoconazole (Nizoral), Metformin (Glucophage), Nifedipine (Procardia), Phenytoin (Dilantin), Theophylline (Theo-Dur), Triazolam (Halcion) and several others I have omitted.

Iboprofen, also called Motrin

Iboprofen is another very poplar OTC drug. Here is how it is described: It is a nonsteroidal, anti-inflammatory drug available in both prescription and nonprescription forms. Prescription Motrin is used in adults for relief of the symptoms of rheumatoid arthritis and osteoarthritis, treatment of menstrual pain, and relief of mild to moderate pain. In children aged 6 months and older it can be given to reduce fever and relieve mild to moderate pain. It is also used to relieve the symptoms of juvenile arthritis.

Common side effects may include: Abdominal cramps or pain, abdominal discomfort, bloating and gas, constipation, diarrhea, dizziness, fluid retention and swelling, headache, heartburn, indigestion, itching, loss of appetite, nausea, nervousness, rash, ringing in ears, stomach pain, vomiting. Less common or rare side effects may include: Abdominal bleeding, anemia, black stool, blood in urine, blurred vision, changes in heart beat, chills, confusion, congestive heart failure, depression, dry eyes and mouth, emotional volatility, fever, hair loss, hearing loss, hepatitis, high or low blood pressure, hives, inability to sleep, inflammation of nose, inflammation of the pancreas or stomach, kidney or liver failure, severe allergic reactions, shortness of breath, skin eruptions or peeling, sleepiness, stomach or upper intestinal ulcer, ulcer of gums, vision loss, vomiting blood, wheezing, yellow eyes and skin.

Special warnings about this medication: Peptic ulcers and bleeding can occur without warning. Tell your doctor if you have bleeding or any other problems. This drug should be used with caution if you have kidney or liver disease, or are severely dehydrated; it can cause liver or kidney inflammation or other problems in some people. Do not take aspirin or any other antiinflammatory medications while taking Motrin unless your doctor tells you to do so. If you have a severe allergic reaction, seek medical help immediately. Motrin may cause vision problems. If you experience any changes in your vision, inform your doctor. Motrin may prolong bleeding time. If you are taking blood-thinning medication, this drug should be taken with caution. This drug can cause water retention. It should be used with caution if you have high blood pressure or poor heart function. Avoid the use of alcohol while taking this medication.

Motrin may mask the usual signs of infection or other diseases. Use with care in the presence of an existing infection.

Advice about taking it (and indeed any other OTC analgesic) should always be sought from a pharmacist. Individuals who should be especially cautious are:

• Pregnant women

• Nursing mothers

• The elderly

• Those suffering from asthma

• Individuals who have suffered from gastric ulcers or gastric bleeds in the past

• Those with bleeding disorders

• Those who suffer from allergies

• As with all painkillers, if symptoms persist for more than three days, you should consult your doctor.

• Acetaminophen, also called Tylenol

Acetaminophen is primarily metabolized by the liver. Too much acetaminophen can overwhelm the way the liver normally functions.4 If the liver is already damaged because of infection, alcohol abuse, or other illness, you may be more susceptible to damage from acetaminophen overdose. For this reason, people with liver illnesses or who chronically consume large amounts of alcohol should be particularly careful when taking acetaminophen and should consult their doctor prior to taking acetaminophen compounds.

Long-term use of acetaminophen in recommended doses has not been shown to be harmful to the liver, even when combined with moderate alcohol consumption.

There are no immediate symptoms from taking a toxic amount. You may remain symptom free for up to 24 hours after taking a toxic overdose of acetaminophen. After this initial period, the following symptoms are common: Nausea, vomiting, not feeling well, not able to eat or poor appetite, abdominal pain.

Tylenol can cause kidney damage, 171 Journal of Orthomolecular Medicine Vol. 18, Nos. 3 & 4, 2003 which can be lethal if there is underlying kidney damage. Dosages exceeding 10-15 g daily are toxic and 25 g can be immediately fatal. Symptoms include jaundice and pain in upper abdomen, hypoglycemia, encephalopathy, kidney failure and analgesic rebound.

Loratadine, also called Claritin

This popular anti-histamine is used to relieve hay fever and allergy symptoms such as sneezing, runny nose, red, itchy, tearing eyes. It causes less drowsiness than other anti-histamines. Generally anti-histamines are among the safest OTC compounds but even with this good safety record, some of the side effects and warnings include: headache, dry mouth, nose and throat, drowsiness, rapid heartbeat, difficulty urinating, vision problems, dizziness and muscle weakness. If these occur you are warned to call your doctor immediately.

Before you take it tell your doctor and pharmacist what else you are taking, if you have ever had kidney or liver disease, if you are pregnant or breast feeding, if you plan to have surgery, and avoid prolonged exposure to sunlight.

Summary

These are the side effects, toxic reactions, contraindications and warnings that have to be studied before taking any of these five very popular OTC drugs. None of the vitamins have side effects and toxic reactions remotely similar to this. It is clear that drugs allowed to be sold overthe-counter have to be used with caution because they are xenobiotic and within the recommended dose range can be, and often are, harmful. This cannot be said about the vitamins. Within the recommended doses vitamins are safe. The fat soluble vitamins can accumulate in the body but the effects are reversible.

A survey in the United States showed that in one year 106,000 patients died from the proper use of medication in hospital.

Over the past three decades there have been no deaths from the proper use of vitamins.

References

1. The Physician's Desk Reference. Medical Economics. 2002.

2. eMedicine.com March 1, 2002.

3. NJ Wald, Law MR: A strategy to reduce cardiovascular disease by more than 80%. Brit Med J, 2003; 326: 1419.

4. Ameres MJ: eMedicine.com March 23, 2003