[ Home ] [ Up ] [ Asthma & B Vitamins ] [ Body Types ] [ B Vitamins ] [ Chronic Fatigue Syndrome ] [ Ciguatera ] [ Dietary Supplements ] [ Thyroid ]

Vitamin B Deficiency: Megavitamin Therapy, Side Effects and Allergic Reactions

B Vitamins - an introduction

When I initially started using supplements of B vitamins I found that they could cause dramatic side effects, side effects which were little understood. Although it was suggested by a practitioner that I was allergic to B vitamins the evidence did not seem to support such a conclusion. Since it was clearly impossible to suffer from an allergy to the B vitamins themselves since they are essential for life and are present in many foods, perhaps I was reacting to the filler or base used to manufacture the tablets. However, every brand and formulation of B complex vitamins I tried, even low allergy or totally synthetic formulations, caused similar side effects or adverse reactions. I began to notice however, that I could avoid these side effects by taking the B vitamins individually instead of as a balanced B complex formulation.

Since at that time I was quite ill, and as a result of my requests, my doctor started me on a course of B complex vitamin injections. The effect was amazing and dramatic. The effect of the injections, in spite of the various potentially allergenic chemicals they contained, was totally different to the effect of oral B vitamins. Unfortunately however, although I maintained this positive response for a considerable period of time, eventually, when I commenced a new packet of the vitamin injections, I experienced dramatic ill effects. Subsequent analysis proved that this new packet was faulty, and it is for this reason that I cannot recommend injectable vitamins.

Although it took me a considerable period of time to recover from the faulty vitamins, my experience with the injectable vitamins had motivated me to persist with oral B vitamins until I had eliminated all the side effects. I eventually achieved this goal by individualising the dose of each separate B vitamin. I noticed, with several B vitamins, particularly vitamins B5 ( pantothenate ) and B6, the minimum dose I required for a positive effect was much higher than was needed when these vitamins were injected. In fact, in the case of B5, the minimum effective oral dose was more than 100 times greater than the effective injected dose. This type of dependence on higher than normal doses of vitamins and an inability to sustain health using normal doses, is often described as a "vitamin dependency" and is due to genetic changes in vitamin utilisation ( see Genetic Nutrition, Nutrition Breakthroughs ).

Throughout the modern community it seems, anecdotal reports of the advantages of B vitamin therapy abound. Supplementary B vitamins have gained a widespread reputation for their ability to counteract stress and depression and promote vitality and well being. As a result of these benefits B vitamins are widely prescribed by alternative practitioners, and yet, in spite of these facts, the reasons why so many people seem to benefit from extra B vitamins remains uncertain. Why, particularly in this age of alleged nutritional abundance, and nutritional fortification of foods, do so many people seem to respond to supplementary B vitamins? Is it possible that people vary in their ability to efficiently extract these vitamins from their diet? Since it is generally accepted that the use of B vitamin supplements will not have any benefits unless there is a deficiency of these vitamins, the nutritional implications of these observations are rather disturbing

While we owe our awareness of the extent of this nutritional problem to anecdotal reports and the use of B supplements by alternative practitioners, the scientific community generally refuses to accept this evidence. In fact, the dismissal of anecdotal evidence by the scientific community creates a situation in which no nutritional problem is believed to exist. However, to blatantly dismiss widespread anecdotal reports is to reject real life human experiences as being irrelevant, something which we do at our own peril.

The purpose of this article is twofold. Firstly, by reviewing the relevant scientific literature I will examine the possibility that various persons in the community may suffer from a deficiency of specific B vitamins, not because of inadequate dietary intake, but rather because their metabolism creates an excessive need for these nutrients. According to Rivlin ( 1a ), vitamin deficiencies may be caused either by an inability to convert the vitamins to their physiologically active forms or, on the other hand, by "abnormalities of intestinal absorption, plasma transport, tissue storage, binding to proteins, or excretion" ( 1a ). It is these instances of inefficient utilisation of B vitamins, particularly malabsorption, with which this article is primarily concerned.

Often, the correction of these types of vitamin deficiencies can only be achieved by the use of megavitamin therapy, otherwise known as orthomolecular nutrition. It is the aim of megavitamin therapy to compensate for these inefficiencies in vitamin metabolism and ensure that the correct or optimum, but not excessive, quantity of all nutrients are delivered to every cell in the body where they are required. Megadoses of vitamins therefore, are only promoted in order to attain this condition of optimum cellular nutrition. Used correctly, there is no question of side effects from toxic doses

The second purpose of this article is to explore any evidence which might contribute to an understanding of the reasons for the side effects and difficulties of oral B vitamin treatment which I experienced and hopefully contribute to an understanding of the possible mechanisms involved so that others may be able to avoid these side effects. Since in my case the ill effects of B vitamins were related to the relative dosage or balance of the separate B vitamins, it is this aspect which I will consider first.

B Vitamins - balance or imbalance?

It is commonly accepted that the B complex vitamins with which this article is concerned, that is, vitamins B1 ( thiamine), B2 ( riboflavin ), B3 (niacinamide ), B5 pantothenic acid ), and B6 ( pyridoxine ), are synergistic and therefore must be taken together in a balanced form ( 1, 2, 3 ). There is it seems, a very good reason for this since the ingestion of large doses of single B vitamins has been reported by various workers to cause an imbalance which results in the excretion of other B vitamins from the body ( 2 - 9, 111, 112 ). If ill effects are experienced as a result of this type of imbalance reaction then clearly the resulting symptoms should be those which would normally result from a deficiency of the lesser vitamin.

There have been various reports in the literature of adverse reactions to single B vitamins which cannot be explained by allergic or toxic reactions. Symptoms of such reactions may be similar to symptoms which result from deficiencies of other B vitamins. Niacinamide for instance, which was found to be so effective in calming the behaviour of difficult children, actually made some children worse ( 11a,11b ). Similarly, although pantothenic acid supplements also made some children much calmer and more amenable, in others the effect was quite the opposite ( 11a, 11b ). Vitamin B6 supplements have also been reported to cause "gritty eyes, sore tongue, and angular stomatitis", all of which could be reversed by taking riboflavin ( 112 ). Since these sort of effects cannot be explained by normal mechanisms of vitamin toxicity, they tend to be dismissed and forgotten.

Similar observations have also been made by Brenner ( 98 ) during his detailed study of 100 behaviourally disturbed children. Brenner noted that the condition of 9 out of 16 children who responded positively to thiamine supplements was considerably aggravated when they were given vitamin B6. Conversely, 6 out of 10 children who responded positively to vitamin B6 were made significantly worse when they were given thiamine. Pantothenic acid, riboflavin, and niacin were also observed by Brenner to considerably aggravate the condition of some of the children although in other children, both pantothenic acid and niacin had very positive effects.

One interesting patient reported by Brenner ( 98 ) responded to 218mg of pantothenic acid daily with "disappearance of crying episodes, mood swings, and inability to relate to others." However, this child responded to thiamine supplements with increased hyperactivity while supplements of either B3 or B6 caused depression. Perhaps the most interesting aspect of this case is the fact that when this child was treated with a balanced combination of 50mg of all the B vitamins his condition was aggravated with increasing hyperactivity. How is it possible for a patient to have such a positive response to 218mg of vitamin B5 and yet experience such a negative response to a balanced 50mg combination of all the B vitamins? Brenner ( 98 ) also cites various other studies which illustrate this interaction between the various vitamins.

Interestingly, according to Melton ( 37a ), although 16 out of 19 asthmatic patients treated with 50 - 100mg injections of vitamin B3 experienced a significant improvement in their asthmatic symptoms, two experienced a marked deterioration. Once again, aggravation of asthma would not normally be considered a typical sign of vitamin toxicity. On the other hand however, given the well known relationship of vitamin B6 deficiency to asthma ( 37 ), such an effect is not too surprising. It should be noted that of the asthmatic patients described by Melton ( 37a ), and also the children described by Rimland ( 11a, 11b ), only a minority were adversely affected by supplements of single B vitamins. This would suggest perhaps, that not everyone is equally susceptible to these effects, a fact which could make the researching of this phenomena rather difficult.

Other workers have also drawn attention to the complex interaction between B vitamins which may result in significant ill effects when taking single B vitamins. Lonsdale for instance ( 95 ) reported the case of a child with Leigh's disease whose condition was greatly exacerbated by treatment with vitamin B6 without thiamine. Other reports cited by Lonsdale also draw attention to the close interrelationship between B vitamins although the mechanism of this interaction is not always clear.

Since imbalance reactions, should they occur, could only occur within the body, that is, after the vitamins are absorbed, it must be realised that it is the absorbed dose of these vitamins which must be balanced and not the oral dose, a point which seems to be frequently overlooked. This is an extremely important point since it would seem that even balanced B complex tablets, if all the separate constituent B vitamins are not absorbed with equal efficiency, may arrive in the blood in a very imbalanced form. We can see a possible example of this with the abovementioned child described by Brenner ( 95 ) whose condition was improved by taking 218mg of vitamin B5 daily, and yet his condition was greatly exacerbated by taking a balanced combination of 50mg of all the B vitamins.

Unlike reductionist medicine, which teaches that the absorption and metabolism of vitamins is exactly the same in all normal persons, according to the principles of biochemical individuality pioneered by Roger Williams ( 10, 11 ), the efficiency of absorption and metabolism of nutrients varies widely, even in people who are medically normal ( see Nutrition Breakthroughs, Is Illness Holistic?  ). In the words of Williams in this regard ( 10 ): "digestion, absorption and transportation are not automatic processes that always take place with perfection." Williams further notes that ( 55 ) "faultless optimal nutrition at the cellular level is not something that can be taken for granted; whether or not it prevails is a big question, not only for every cell in our bodies, but also for every cell and tissue existing on earth." According to Burton ( 21 ), the person who has a perfect digestive system and exactly average requirements for all nutrients is likely to be so rare that they merit little consideration.

Given the possibility that some B vitamins may not be absorbed efficiently in certain persons, it is clear that such people could suffer from nutritional deficiencies which are impossible to correct by dietary means. Since such cases would involve a defect in vitamin metabolism, there is also the possibility here of a genetic influence. Furthermore, if we accept that it is the absorbed dose of B vitamins that must be balanced, there is also a possibility that such people may not respond favourably to balanced B complex tablets.

Malabsorption of B Vitamins and B Vitamin Dependency

Traditionally, malabsorption of single B vitamins (excluding B12 ) has generally been regarded as virtually impossible in the absence of gastrointestinal disease, alcoholism, or surgery. Various studies however, have revealed the presence of B vitamin deficiencies in people whose dietary intake was adequate and also in others who had been taking oral B vitamins ( 12, 13, 14, 15, 16, 17, 18, 19, 20, 96 ). Often in such cases, people who did not respond to low dosages of oral B vitamins were found to respond when high potency supplements or injectable vitamins were used ( 11, 12, 14, 15,16, 19 ). In theory at least, if only 5% of a particular vitamin is absorbed, then oral doses of 20 times the normal dose may ensure a sufficient dose reaches the blood.

Evidence of rnalabsorption of single B vitamins, including deficiencies of vitamins B1 ( 12, 13, 18 ), B2 ( 17 ), B3 ( 12, 20 ), and B6 ( 12, 19 ), are commonly considered to be most prevalent in the elderly ( 12, 17, 18, 19, 20 ), perhaps because of ageing, or perhaps because the nutritional status of this age group has generally been studied in more detail than have other age groups. These deficiencies may occur regardless of dietary intake and often respond better to injected vitamins as compared to oral supplements ( 12, 17,19, 20 ). For the purposes of this discussion, the important point is that such studies have either found no definite reason for this malabsorption or they have assumed that it has been caused by ageing ( 12, 17 ). As we will see however, similar nutritional problems also occur throughout the wider community, regardless of age or diet.

Nutritional deficiencies which cannot be corrected by consumption of a normal balanced diet are, as I have previously mentioned, usually described as vitamin dependencies. Although vitamin dependencies, as is the case with many other disorders, cover a complete spectrum of severity ranging from mild subclinical disorders through to severe possibly life threatening disorders, orthodox medicine is traditionally only interested in the more severe end of this spectrum. As has been pointed out by Roger Williams more than thirty years ago ( 55 ) "according to the principle of genetic gradients, if some infants require eight times the amount ( of vitamins ), it is to be expected that there will be others that require two, four or six times the average." While I will briefly mention below some severe dependency conditions, it is the more common and more neglected subclinical end of the spectrum with which this discussion is primarily concerned.

Of the various medically recognised vitamin dependency conditions which afflict younger sections of the community, it is probably the convulsive or anemic disorders caused by vitamin B6 dependency which are best known ( 44, 45, 46, 47, 48, 49 ). Less well known perhaps, are reports of vitamin dependency conditions in asthma ( 14, 15 ) and mental disorders ( 11 ), both of which I will consider later, and sickle cell anemia ( 50 ). Interestingly, sickle cell disease may also be characterised by riboflavin deficiency, possibly caused by malabsorption ( 52 ).

There have also been isolated reports of thiamine dependency in the medical literature ( 16, 53, 95 ). This variable syndrome, which may be caused by malabsorption or a blockage of the metabolism of thiamine ( 16, 53 ), may occur in families ( 16, 53 ). Thiamine dependency may cause disease of the central nervous system (16) or mitochondrial muscular disease ( 53 ).

While these severe thiamine and pyridoxine dependency conditions are considered extremely rare, there are numerous reports in the medical literature of various subclinical vitamin B deficiency syndromes which could not be corrected by diet. Non dietary related thiamine deficiency for instance, has been associated with glaucoma (13 ). In an interesting study of Californian glaucoma patients ranging in age from 29 to 85 years, Asregadoo (13 ) found that the mean thiamine level in the glaucoma group was significantly lower than in the control group. Furthermore, the mean dietary thiamine intake during the course of the study was actually higher in the glaucoma group. Asregadoo concluded that the glaucoma patients suffered from thiamine malabsorption. Since the glaucoma patients in this study consumed, on average, more dietary thiamine than controls and yet had lower blood levels of this vitamin, there are clear preliminary indications here of a thiamine dependency condition. Interestingly, according to Woon and colleagues ( 13a ), dramatic visual improvements have occurred in patients with optic nerve disease who were treated with various B vitamins even though no nutritional deficiencies could be demonstrated.

Recently, in an interesting study of Chronic Fatigue Syndrome patients by Heap and colleagues ( 51 ), it was found that there was biochemical evidence of deficiencies of vitamins B1, B2, and B6, although the latter deficiency was found to be the most significant. Heap et al noted that the deficiency of vitamin B6 was without any obvious explanation since the dietary intake of B6 in these CFS sufferers was believed to be adequate. Here once again we have clear evidence of vitamin B deficiencies occurring in spite of normal dietary intake.

The prevalence of unrecognised vitamin B6 deficiency in the general community is such a problem that even "control" subjects used for research studies have been found to be deficient in this vitamin ( 100 ). Although it is normally assumed that "healthy" controls are free of vitamin deficiencies, the study of Azuma and co-workers ( 100 ) has disproved this assumption. Azuma et al, in a study of 21 healthy controls, found that all had biochemical evidence of B6 deficiency. This is in spite of the fact that all these control subjects were free of disease and "had some knowledge of balanced nutrition." Azuma et al conclude ( 100 ): "contrary to the understanding that the diet provides an adequate intake of vitamin B6, the dietary intake of vitamin B6 of these controls was inadequate."

The study of Azuma et al has been confirmed by more recent studies which reveal that vitamin B deficiencies are widely prevalent in the community even when dietary intake is claimed to be "adequate". Bender ( 96 ) has noted that biochemical tests for the presence of vitamin deficiencies reveals that "a significant proportion of the population shows evidence of inadequate status, despite apparently adequate levels of intake" ( 96 ). According to reports cited by Bender, up to 68% of pregnant women, and up to 25% of hospital patients or adult men, have been shown to be deficient in B6. Bender emphasises the fact that deficiencies of vitamin B6 occur in Britain in spite of the fact that "average intakes of vitamin B6 in Britain are significantly above the RDI" ( 96 ). 

While some may doubt the clinical or symptomatic significance of these widespread non-diet related B vitamin deficiencies ( 96, 99 ), there is a remarkable consistency here with the prevalence of positive anecdotal reports of the use of B vitamin supplements throughout the community. Furthermore, in a quantum leap forward for mainstream medicine it has recently been acknowledged that subclinical or "suboptimal" vitamin status, which incidentally cannot be corrected by dietary intake of vitamins, may be associated with chronic diseases such as cancer and heart disease ( 104, 105, 106, 107, 109, 110 ). Elevated homocysteine levels ( see Health Trends ), which may cause heart disease, are lower in persons who take vitamin supplements ( 108 ) but these levels cannot be adequately reduced by diet alone ( 106, 107 ). 

The accuracy of the brilliant research conducted by Roger Williams, Linus Pauling, and others, is perhaps at last being acknowledged by modern medicine as they realise that many people may be suffering from serious chronic diseases due to their inability to obtain optimal amounts of nutrients from their diet (see Nutrition Breakthroughs). In further confirmation of the observation by Bender ( 99 ) that many people seem to be suffering from non diet related subclinical B vitamin deficiencies, Fletcher and Fairfield ( 105 ) claim that "most people do not consume an optimal amount of all vitamins by diet alone"......and "we recommend that all adults take one multivitamin tablet daily." Additionally, according to Hathcock ( 109 ), "Substantial evidence indicates that intakes greater than the recommended dietary allowances (RDAs) of certain vitamins and minerals such as calcium, folic acid, vitamin E, selenium, and chromium reduce the risk of certain diseases for some people."

Perhaps the most important aspect of the above studies is the recognition that subclinical vitamin deficiency conditions may cause serious chronic diseases such as cancer and heart disease. Previously it has been widely assumed by modern medicine that suboptimal levels of vitamin intake, that is, levels which are not sufficiently low to cause the classical vitamin deficiency symptoms or diseases, were of little or no consequence to public health. Now we have the emergence of a completely new concept in mainstream medicine and nutrition - "mild" chronic nutritional deficiencies which are not reliably detectable by medical tests, may be extremely common and may cause serious chronic diseases. For the best part of the past century doctors have assumed that the absence of ( all ) the signs and symptoms of a classical nutritional deficiency disease, especially when combined with the consumption of a "balanced" diet, is absolute proof that a patient has perfect nutrition. This belief has now been scientifically exposed ( for further comments about this topic refer to Nutrition is for the Birds ).

The common belief that the consumption of a normal balanced diet will guarantee freedom from nutritional deficiencies is clearly unsupportable by modern science. This belief is now proven to be unscientific and outdated. Scientific evidence indicates that those who rely upon diet alone for their vitamin intake may even be risking the onset of serious chronic diseases, a view which is being further supported by genetic nutrition or "nutrigenomics" (see Nutrition Breakthroughs).

What is especially interesting about all these observations is the implications from the point of view of biochemical individuality. While the suggestion that everyone should take vitamin supplements represents a huge step in the right direction we must look deeper and understand why this has become necessary. We must always strive to understand the cause. Why is it that some people who consume a normal diet can maintain nutritional normality while many others on the same diet develop vitamin deficiencies? How can we state with any certainty that the simple ingestion of a multivitamin will correct the problem when the nature and extent of the nutritional problem remains unclarified? While endorsement of the use of multivitamins is a step forward, it remains an imprecise, unscientific and non-holistic approach. 

This matter is of vital importance. For many years studies from around the world have shown that there is a marked variation in the efficiency with which people utilise nutrients and yet, in spite of all this, there is amazingly little interest in the reasons for this variation. How can we ever hope to understand illness if we cannot understand fundamental nutritional variability? While the multivitamin approach may help many, those with more severe metabolic nutritional derangements could not be expected to derive maximum benefits from such a non-individualised approach. Individualised nutrition, as pioneered by Roger Williams and colleagues, is the way of the future (Nutrition Breakthroughs).

Apart from B vitamin deficiency conditions resulting from metabolic problems such as malabsorption, it is also possible to cause a deficiency by ingesting various chemicals or drugs which destroy, or interfere with the action of, certain vitamins in the body. These substances are called vitamin antagonists ( 80, 85 ). Vitamin B6 in particular, may be adversely affected by B6 antagonists which include food additives, oral contraceptives, alcohol ( 80 ), and various prescription drugs as listed below.

It is clear from the evidence cited above that the medical literature contains various reports of vitamin B deficiency conditions which affect the general community but which often remain unrecognised. Furthermore, increasing amounts of scientific evidence reveal that these B vitamin deficiencies occur regardless of dietary intake. Although these vitamin deficiencies may frequently be regarded as being subclinical, the inability of adequate dietary intake to correct these deficiencies means that they represent, by definition, vitamin dependency conditions. Scientific evidence is increasingly substantiating the need for the use of vitamin B supplements by the general community.

In the following sections I will examine in more detail three groups of vitamin B dependency patients, namely, asthmatics and victims of heart disease or mental disorders.

The whole history of the relationship between asthma and vitamin B6 is beginning to resemble the discovery and treatment of other nutritional diseases. Although, according to Hoffer ( 22 ), most medical treatments are not generally accepted until around 40 years after their initial discovery or introduction, history shows quite clearly that when it comes to nutritional treatments such as vitamin B6 therapy for asthma or thiamine treatment for beri beri, the figure of 40 years may be extremely conservative. To learn more of my personal experiences with B vitamins and asthma, click here.

Deficiency of vitamin B6, which causes altered metabolism of tryptophan and serotonin and subsequent excretion of substances such as xanthurenic acid and kynurenic acid in the urine, has long been suspected in asthmatic patients because of the prevalence of these urinary changes in earlier studies of asthmatic patients ( 23, 26, 29 ). These studies were confirmed by later studies showing further evidence of vitamin B6 deficiency in asthmatics ( 14, 15 ). Additionally, and more significantly, large doses of vitamin B6 have been shown to be remarkably effective in reducing symptoms of asthma in various patients ( 14, 15, 27 ), although Kaslow ( 40 ) claims that this vitamin is only effective in children. Although Hall et al ( 30 ) could not confirm the presence of vitamin B6 deficiency as a result of their study of asthmatic patients, in a subsequent reanalysis of their data, Reynolds and Natta (14 ) claimed that the B6 treatment used by Hall and co-workers caused a "possible improvement in the B6 status of the children" ( 14 ).

The report by Hall et al ( 30 ) is notable in several important respects. Firstly, it is a study of B6 status only, not an assessment of the effectiveness of B6 supplements as a treatment for asthma. Secondly, unlike most studies, the control subjects selected for this study were all suffering from various illnesses. These sick children formed the yardstick by which the B6 status of the asthmatic children was assessed. In view of the fact that it had previously been demonstrated by Azuma et al ( 100 ) that even 'healthy" controls are likely to be deficient in B6, the deliberate choice of sick children effectively invalidates the reliability of this study. In view of the results of the earlier study of Azuma et al ( 100 ), the question must be asked as to precisely why Hall et al ( 30 ) chose to use sick children for their controls.

From a practical point of view the most important aspect of all these studies is the demonstrated effectiveness of vitamin B6 supplements as a treatment for asthma 14, 15, 27 ). According to Reynolds and Natta in this regard ( 14 ), "all subjects reported a dramatic decrease in frequency and severity of wheezing or asthmatic attacks" while taking the vitamin B6 supplements. For the purposes of this study it must be emphasised that the dose of B6 which was necessary to bring about this response was around 100mg or more daily ( 14, 15 ). In fact, the symptomatic and biochemical response to 50mg daily ( 15 ), or 50mg twice daily ( 14 ), was inferior to the response to 100mg daily ( 14, 15 ). Only by using the larger dose could the vitamin B6 status of these patients be corrected. Interestingly, according to Simon and Reynolds ( 54 ), even after daily supplements of 100mg of pyridoxine, plasma pyridoxal phosphate ( the active form of B6 ) levels were still 30% lower in asthmatics than in controls.

These studies confirm that these asthmatics suffered from a vitamin B6 dependency condition, that is they were unable to efficiently utilise this vitamin and were therefore dependent upon higher than normal doses. It should be emphasised that these large doses of vitamin B6 were necessary in order to restore body stores of this vitamin to a normal level.

In a later study by Sur and co-workers ( 31 ), 31 asthmatic patients failed to respond to B6 therapy. However, the point must be made that these workers were deliberately selective in choosing participants for the trial since they only chose patients who were dependent upon steroids for control of their asthma. In defence of this decision Sur et al claim that pyridoxine is an "over the counter drug with the potential for abuse" and "in order to justify the usage of a drug that has a potential for significant toxicity, this trial was restricted to steroid requiring asthmatic patients who are more likely to be closely followed by physicians." If these concerns are scientifically valid ( bearing in mind that Sur et al chose to use a dose of 300mg of pyridoxine, or three times the effective dose used by other workers ), then trials of prescription anti-asthma drugs, in accord with their infinitely greater toxicity, could never be justified. Perhaps this matter has been most appropriately summarised by Hoffer ( 22 ): "vitamins which are safe even in large doses have not been acceptable to the profession, and their negative side effects have been consistently exaggerated and over emphasised, to the point that many of these so called toxicities have been invented, without there being any scientific evidence that these side effects are real."

Recently, research into the connection between vitamin B6 status and asthma has taken a different direction. It is now well known that the anti-asthma drug theophylline is a vitamin B6 antagonist and actually causes a B6 deficiency ( 31, 32, 33, 34 ). According to this line of thought the vitamin B6 deficiency which occurs in asthmatic patients is actually caused by the prescription drug treatment they receive, that is, theophylline ( 31, 32, 33, 34 ). In other words, it is an iatrogenic deficiency. In spite of the fact that Sur et al ( 31 ) reported significantly lower B6 levels in theophylline taking asthmatics, they subsequently concluded that there is "no justification for megavitamin B6 therapy for the treatment of asthma in such patients", a conclusion which must surely be rejected. In fact, their report further justifies the use of B6 supplements, especially in theophylline taking asthmatics.

Although there is no reason to doubt the considerable volume of evidence that theophylline may cause B6 deficiency, this does not explain the dramatic effectiveness of vitamin B6 as an anti-asthma treatment. This is of fundamental importance. Neither does it explain why children who were kept off all asthma medications for two weeks before testing still had "urinary tryptophan metabolites 5 to 30 times that of normal controls" ( 27, 31 ). While it has been shown that theophylline is capable of causing B6 deficiency, there is no evidence to suggest that this drug is the sole cause of B6 deficiency in all asthmatic patients. Since theophylline is a dangerous drug ( 35 ) which may, in addition to its other adverse effects, cause a deficiency of vitamin B6, its use hardly seems warranted when alternatives are available ( 36 ). Given the abovementioned scientific evidence that B6 deficiency may cause or aggravate asthmatic symptoms, the use of theophylline seems especially inappropriate.

Consideration of the nutritional treatment of asthma also involves the use of other nutrients such as vitamin C, vitamin B12, essential fatty acids, and magnesium, all of which have been shown to benefit wheezing or asthma ( 37 ). Vitamin A is also essential for the mucous membranes ( 2 ) and may assist where there is more bronchitic inflammation. However, since this discussion involves the B complex vitamins which must be balanced, I will briefly consider the importance of two other B complex vitamins which may be useful in the treatment of asthma, namely, vitamin B3 ( niacin or niacinamide), and vitamin B5 ( pantothenic acid ).

In addition to vitamin B6, vitamin B3 has also been shown to be an effective treatment in some cases of asthma ( 37 ). This vitamin, which has been reported to have an antihistamine effect ( 37 ), has been shown in one study to be deficient in 83% of asthmatics ( 37 ). Out of 19 patients who were given B3 treatment, 16 showed a definite reduction in attacks of asthma while two cases deteriorated ( 37a ), a fact which, as I have previously mentioned, may be related to the possibility of a simultaneous pyridoxine deficiency in these two patients.

Perhaps the most underrated of all the B complex vitamins is pantothenic acid. Although a deficiency of this vitamin is commonly considered impossible because of its widespread availability in foods ( 38 ), this of course does not rule out the possibility of deficiencies arising from malabsorption or vitamin dependency or genetic deviations in vitamin utilisation such as occurs with the other B vitamins (see Nutrition Breakthroughs). There is also a difficulty in accurately diagnosing a pantothenic acid deficiency since reliable tests have yet to be developed ( 39 ). Additionally, the precise dietary requirement also remains unknown (39 ). Given these facts and the important metabolic role which pantothenic acid plays in the production of cortisone and coenzyme A, and its role therefore in stress resistance and normalisation of blood sugar levels, it seems both foolish and premature to glibly dismiss the possibility of pantothenic acid deficiency occurring in humans.

In view of the general feeling that a deficiency of pantothenic acid is impossible, it is hardly surprising that there is a shortage of clinical research regarding this vitamin as compared to the other B vitamins. However, in light of the well known importance of pantothenic acid for steroid production and adrenal function ( 1,1a, 2, 3 ), and the ability of pantothenic acid supplements to increase resistance to stress ( 11, 55 ), combined with the fact that several researchers have reported asthmatics to have reduced adrenal function ( 41, 42, 43 ), the use of single B vitamins in steroid dependent asthma is an oversight which warrants urgent attention. If there is an excessive need for one B vitamin in asthmatics, is there any evidence to prove that other vitamins are not involved also?

Researchers exploring the therapeutic use of B vitamins from a reductionist perspective usually seem to dismiss the combined use of vitamins for the treatment of disease, perhaps preferring to use vitamins as drugs ( 31, 95 ), even though experts suggest that B vitamins especially, must be taken together in a balanced form. Unlike prescription drugs, which play no role in rebuilding the body and therefore may be used singly, the very essence of nutritional therapy is its ability to restore and repair the body, a fact which underlines the interdependence and teamwork nature of nutritional therapy. In the words of Roger Williams ( 55 ): "nutrients are effective because they are constructive; they enter into the makeup of enzyme systems and can function in this constructive way only when all the other building blocks are available. If only one link is conspicuously missing, then supplying this one link by itself will be effective. This is exceptional however............... "

Scientific evidence shows quite clearly that some asthmatics suffer from vitamin dependency conditions, especially B6 dependency, and may therefore respond dramatically to megadoses of the particular vitamin/s they need. Scientific evidence also shows that doctors commonly treat asthmatics with a drug which causes a deficiency of vitamin B6. In spite of these facts doctors rarely seem to advise their patients to try a course of vitamin B6 supplements and also commonly prefer to avoid testing their asthmatic patients to determine their vitamin B6 status. With the exception of some holistic practitioners, preference always seems to be given to the use of toxic symptom suppressing drug industry promoted drugs, while the possibility of any B6 deficiency, iatrogenic or otherwise, seems to be ignored. 

Given these facts it is hardly surprising that all levels of medicine, from research through to publication and clinical practice, are characterised by a considerable degree of anti-nutrition bias ( 103; Medical Bias, Nutrition Breakthroughs,  Doctors Discover Malnutrition in Elderly, Pan Crisis, Medical Rationing, How Did the Flawed Medical Paradigm Become Dominant?). The review by Merrill and Henderson entitled "Diseases Associated with Defects in Vitamin B6 Metabolism or Utilisation" ( 44 ) makes no reference to the well documented connection between asthma and B6. Similarly, the review by Bender ( 96 ), the aim of which was "to examine the evidence for the efficacy of vitamin B6 supplements in treating a variety of conditions", is notable for the fact that Bender chose to cite the negative report by Sur et al ( 31 ) and totally ignore the remaining scientific literature concerning asthma and B6. Similarly, a recent review by Steurer-Stey and colleagues (182) entitled "Complementary and alternative medicine in asthma – do they work?", failed to make any mention whatsoever of the scientific literature concerning asthma and vitamin B6.

Unfortunately, the poor quality of medical research ( 101 ), including the "sloppy" ( 102 ) or selective use of medical literature, is all too well known ( 101, 102, 103 ). Reviewers, have a responsibility to ensure that their reviews impartially reflect the available scientific evidence. Since so called evidence based medicine is claimed to be based upon the content of such reviews, any bias in these reviews effectively removes any justification for the claim that medicine is evidence based.

Megavitamin therapy of mental illness is based upon the fact that deficiencies of B vitamins are known to be capable of causing a diverse range of mental symptoms. The mental symptoms of the various B vitamin deficiencies are listed below.

 

	Mental Effects of B Vitamin Deficiencies
B1 - Thiamine ( 2, 11, 16, 56, 57 )	Anorexia, confusion, poor memory, sensitivity to noise, irritability, aggressive behaviour, auditory hallucinations including the hearing of voices or noises, nightmares or night terrors, psychosis, depression, apathy, anxiety, emotional lability, and a feeling of impending doom.
B2 - Riboflavin  ( 2, 37, 68, 180 )	Depression, hypothyroidism
B3 - Niacin ( 2, 11, 38, 55 - 58)	Irritability, depression, hyperactivity, headache, dementia, apathy, anxiety, mania, emotional lability, delirium, poor memory, schizophrenia, insomnia, delusions of persecution, hallucinations, and paranoia.
B6 - Pyridoxine ( 2, 37, 56, 80, 177, 178, 179 )	Nervousness, irritability, depression, inability to concentrate, learning problems, convulsions, stress, "electric shock" phenomena, and counteracts excess cortisol..
B5 - Pantothenate ( 2, 3, 55, 56 )	Insomnia, fatigue, depression, emotional lability, restlessness, adrenal hypofunction, sensitivity to stress, and insulin sensitivity.

B vitamins can clearly have profound effects upon brain function, a fact which further underlines the importance of nutrition at the cellular level. According to the theory underpinning the practice of orthomolecular psychiatry, mental disease is caused by a less than optimum cellular environment, especially nutritional environment, of brain cells ( 11, 55, 57 ). In view of the fact that psychiatric patients are frequently deficient in B vitamins ( 55, 63, 64, 65, 66, 67, 80 ), megavitamin therapy is used to ensure that brain cells maintain an optimum nutritional environment (11, 55, 57 ).

Given these facts it is hardly surprising that megavitamin treatment of mental disorders has produced some startling results ( 2, 3, 11, 55, 57, 59, 61, 62, 68, 113, 113a ) results which are made even more startling by the failure of orthodox drug orientated psychiatric treatment. The following case history is typical ( 57 ).

In an interesting study of 30 psychiatric patients by Watson and Currier ( 60 ), 80% improved significantly following combined treatment with high doses (less than 1000mg ) of the B complex vitamins. The degree of improvement was confirmed by use of the Minnesota Multiphasic Personality Inventory test. Similar clinical trials have confirmed the beneficial effects of vitamin B supplements in schizophrenia ( 11, 55, 57, 60, 68, 69, 113, 113a ), depression ( 11, 55, 57, 68, 71, 72, 80, 177, 178, 179 ), agoraphobia and anxiety ( 59, 68, 70 ), and autism or hyperactivity ( 11, 61, 62, 68, 73, 80, 98 ). According to Hoffer ( 113 ), the use of niacin to treat schizophrenia is so effective that "the American Psychiatric Association bears major responsibility for preventing the introduction of a treatment which would have saved millions of patients from the ravages of chronic schizophrenia."

When it comes to vitamin B treatment of mental disease the overwhelming impression gleaned from these studies is that the dosage and combination of B vitamins are of paramount importance, a fact which is typically illustrated by the detailed study of Brenner ( 98 ). While many patients seem unable to respond adequately to low doses of B vitamins, extremely high dosages, such as more than 1000mg daily of B3, could only be justified in exceptional circumstances. There is no doubt however, that some mental patients, like asthmatics and others with vitamin dependency conditions, require extraordinarily large doses of certain B vitamins in order to maintain health, one sample of 800 psychiatric patients for instance, requiring from 5 - 400mg of vitamin B6 daily ( 74 ).

It must be emphasised that the factors which determine the required vitamin dose in a given individual are the clinical response, maintenance of optimum health and normalisation of biochemical indicators of vitamin deficiency. The actual vitamin dose, being merely a means to these ends, is only of secondary importance. The person with a genetically increased need for certain vitamins therefore (Nutrition Breakthroughs), should not be forced to endure malnutrition simply because some authorities prefer to see everyone taking the same dose of vitamins.

The reasons for this metabolic inefficiency or increased need for certain B vitamins seems in many cases to be unknown, although malabsorption or genetic deviations in vitamin metabolism (see Nutrition Breakthroughs) may often provide the answer. Hoffer ( 11) has noted that some schizophrenic patients have responded much better to small injected doses of B3 than they did to large oral doses, leading Hoffer to conclude that vitamin dependent patients "may have difficulty absorbing vitamins" ( 11 ). This has been confirmed by Hall ( 11 ) and also by Cott ( 69, 94 ).

It is indeed interesting to note that a deficiency of vitamin B3, such as occurs in pellagra, can eventually result in an increased need for this vitamin or a permanent vitamin dependency condition( 113 ). As a result of this phenomena, experimental pellagra produced in human volunteers by Goldberger was not always reversible when B3 was added back to the diet ( 38 ). It was subsequently discovered that some victims of pellagra who developed this dependency condition required 600mg of B3 daily in order to avoid this disease ( 11 ), a dose which was considered by nutritionists to be 60 times higher than normal ( 11 ). Further evidence of this B3 dependency condition came from prisoners of war who developed permanent mental and physical disability as a result of starvation diets ( 75 ). Apparently the only exceptions to this chronic ill health were a group of 12 veterans who, although initially just as sick as the others, were able to maintain good health by using supplements of 3000mg of B3 daily ( 11 ).

This same phenomena also occurs with thiamine deficiency. Severe longstanding thiamine deficiency results in impaired metabolism of this nutrient and creates a deficiency condition which can only be reversed slowly by the use of very high doses of thiamine ( 95 ). According to Lonsdale in this regard ( 95 ): "it has long been known that absorption and activation of dietary thiamine are impaired when the intracellular deficiency is severe. Treatment must be continued for a long time with very large doses......."

Since the person with a B vitamin dependency requires large doses of one or more vitamins simply to maintain normal nutrition and avoid cellular malnutrition, it is extremely disturbing to witness the energy and persistence with which some medical practitioners have sought to discredit or prevent this form of therapy ( 113, 113a ). This campaign of discrimination is based upon medical negativity, an obsession with disproving or discrediting a belief or practice rather than contributing positively to determining the cause and cure of disease. In the absence of universal scientific perfection, it is possible to criticise virtually any scientific study, a fact which underlies the established unscientific nature of orthodox medicine ( see Medical Evidence or Medical Ignorance? ). However, most people do not make a career out of negativity.

It is also tragic that those who know least about nutrition frequently display a preoccupation with any dangers, no matter how slight, of nutritional supplementation, while simultaneously expressing little or no interest in the potential benefits of nutrition (Nutrition Breakthroughs, Dietary Supplements, Pan Crisis). These concerns were expressed by Professor Mayer three decades ago (76 ): "studies at Harvard among resident physicians suggest that the average physician knows little more about nutrition than the average secretary, unless the secretary has a weight problem and then she probably knows more than the average physician." Mayer continues: "all in all , it seems that most physicians tend to be happy about this state of affairs." But according to Professor Bolin, it seems nothing has changed in 2007 (181): "Unfortunately, nutrition and malnutrition are not priorities for physicians and surgeons and only come to notice when a patient's recovery is not progressing. Often this is too late." 

Vitamin B6 and Cardiovascular Disease

Evidence of the importance of vitamin B6 for treating or preventing CVD has been accumulating for more than 50 years. According to this evidence vitamin B6 has various positive effects upon the heart and circulatory system, the most important of which are listed below.

• Vitamin B6 lowers cholesterol levels while B6 deficiency is associated with elevated cholesterol levels in the blood and tissues.
• Vitamin B6 is necessary for production of lecithin, a deficiency of which may cause elevated cholesterol levels.
• Vitamin B6 has an anti-platelet anti-clotting effect.
• Vitamin B6 deficiency causes increased levels of homocysteine.
• Vitamin B6 deficiency causes damage to the arterial wall.
• Vitamin B6 is intricately linked to the metabolism of fatty acids.
• Vitamin B6 deficiency is associated with deep vein thrombosis.

Early studies into the effects of vitamin B6 on cholesterol and heart disease were reviewed by Williams ( 55 ). Numerous animal studies during the 1950's and 1960's indicated that vitamin B6 deficiency increased cholesterol levels while supplements of B6 had the reverse effect ( 114 ). According to Mueller ( 115 ): "the major evidence seems to support the proposition that pyridoxine deficiency in animals is more often than not associated with hypercholesterolemia and cholesterolosis of the tissues." In fact, B6 deficiency in animals causes atherosclerosis and cholesterol accumulation in the blood and tissues with such consistency that Williams comments ( 55 ): "it is most interesting that vitamin B6 performs the same functions throughout the whole biological kingdom."

Early human studies revealed that CVD patients displayed evidence of vitamin B6 deficiency ( 116 ) which, because increased fat consumption was shown to cause a B6 deficiency, was worse in those who consumed more fat (117 ). Human studies, like animal studies, revealed that people who were deficient in B6 had increased cholesterol levels ( 118 ). In fact, according to Mueller ( 119 ), the effects of B6 deficiency in humans are "consistent with those found by the majority of investigators in animals." 

The ability of vitamin B6 to lower cholesterol levels ( 55, 118, 139 ) may be due to various mechanisms, such as its ability to act as a transporter of cholesterol ( 115 ). Vitamin B6 is also necessary for the production of lecithin ( 120 ). Lecithin, being an emulsifier, reduces the size of the fat particles in the blood, prevents fats from accumulating and lowers cholesterol levels ( 121, 122, 123 ). Not surprisingly, lecithin may also prevent or reverse atherosclerosis ( 126 ). Furthermore, excess cholesterol and triglycerides have been attributed to a defect in phospholipid metabolism ( 55, 124 ), possibly because of a deficiency of vitamin B6 ( 55 ). In fact it has been claimed that "all atherosclerosis is characterised by an increase of the blood cholesterol and a decrease in lecithin" ( 125 ). According to Williams ( 55 ), it is not the level of cholesterol per se but rather the ratio of phospholipids such as lecithin to cholesterol which is more important in the pathogenesis of atherosclerosis. Vitamin B6 is necessary for the fat metabolising actions of choline ( 173 ) and is also intricately linked to the metabolism of essential fatty acids ( 55, 127, 128, 129, 130, 131 ) which are known to play a vital part in fat metabolism and atherosclerosis ( 55, 132, 133, 134, 135, 136, 137, 138 ). Interestingly, the effectiveness of cholesterol lowering statin drugs may be mediated by their effects upon the metabolism of essential fatty acids ( 146 ). 

More recently the ability of B6 deficiency to effect cardiovascular health has been attributed to its effects upon platelets and blood clotting ( 139, 140, 141, 164, 165 ), its ability to cause deep vein thrombosis ( 142 ), its effect upon the integrity of the arterial wall ( 143, 144, 145, 163  ), and its effect on homocysteine levels ( 147, 148, 150, 151, 152, 153, 154, 155 ). Extensive evidence has accumulated linking elevated homocysteine levels, which may result from vitamin deficiencies, with atherosclerosis and heart disease ( 147, 156, 157, 158, 159, 166, 167; See also Heart Disease as an Indicator of Health Trends ). According to Fanapour and colleagues ( 148 ), excess homocysteine "increases the risk of myocardial infarction, cardiovascular related morbidity and mortality, peripheral vascular disease, atherosclerosis, coronary heart disease, and cerebrovascular disease." Homocysteine is believed to cause arterial disease by oxidising cholesterol deposits or by directly damaging the arterial wall ( 147, 148, 149 ). Elevated homocysteine levels have also been associated with dementia, Alzheimer's disease and mental deterioration in the elderly ( 160, 161, 176 ).  The relationship between cardiovascular disease and depression has also raised the possibility that both are the result of a single cause ( 162 ) such as elevated homocysteine levels or a deficiency of vitamin B6. This is a particularly interesting observation since doctors tend to treat all the separate symptoms of nutritional diseases as separate disorders.

In spite of the extensive evidence regarding B6 and homocysteine recent evidence has indicated that the ability of B6 to prevent or reverse heart disease is independent of its effects upon homocysteine ( 143, 168, 169 ), the suggestion being made recently that elevated homocysteine levels may be a consequence of CVD rather than the cause of it ( 169, 170 ). Various studies have demonstrated an inverse relationship between vitamin B6 status and the incidence of heart disease ( 143, 168, 169 ). While B6 deficiency is known to be common in modern society ( 105, 143, 147, 154, 176 ), it is even more common amongst victims of heart disease ( 143, 169 ). The reduced B6 levels of heart disease patients has also been attributed to elevation of the levels of C-reactive protein which is a marker of inflammatory diseases ( 171 ). Additionally, vitamin B6 has been claimed to prevent heart disease by reducing blood pressure and counteracting the ill effects of cortisol ( 172, 179 ). 

Whatever the mechanism/s underlying the effectiveness of vitamin B6 as a treatment or preventative for CVD it is clear that the evidence of its effectiveness is absolutely overwhelming. Even 30 years ago the evidence was such that Williams made the following summary ( 55 ):

When it comes to evidence regarding the dose of vitamin B6 which is necessary to prevent or reverse heart disease and atherosclerosis the astute reader will have noticed the amazing similarity with the literature pertaining to other disorders such as asthma and mental disease. Like these diseases, doses well in excess of the RDA's are necessary to successfully treat or prevent CVD ( 105, 147, 152, 169 ). Although Rimm and coworkers ( 152 ) demonstrated a relationship between dietary intake of vitamin B6 and the incidence of heart disease, other workers have used B6 supplements containing 50mg ( 174 ) to 250mg ( 150 ) to effectively reduce the risk of heart disease. According to Folsom and colleagues ( 169 ) on the other hand, the incidence of heart disease is not related to dietary B6 content and can only be reduced by supplements of this vitamin. What makes all this even more disturbing is the common occurrence of B6 deficiency throughout modern society ( 105, 143, 147, 154, 176 )  and the fact that these deficiencies are not detectable by normal laboratory tests which may reveal normal levels of this vitamin even when a deficiency is present ( 105, 143, 154 ). I should emphasise here that when it comes to the required dose of a vitamin, a vitamin deficiency is most accurately defined as an insufficient intake to maintain optimum health. I totally reject the suggestion that some "deficiencies", such as "subclinical deficiencies", are not "true deficiencies". This raises the ridiculous question; at what point does a deficiency become a true deficiency?

While researchers continue to argue about the underlying reasons for the effectiveness of vitamin B6 and the precise dose which is necessary ( sounds like pellagra, beri beri, folic acid, etc. ), a fundamental lesson in common sense has yet to be learned, namely - optimum nutrition is necessary for optimum health. How much longer will health authorities continue to reject this message in favour of their drug oriented approach to health care? 

In summary, as has been noted by Hathcock ( 175 ), people who only consume the RDA's of certain nutrients are increasing their risk of suffering from serious diseases. But weren't these warnings issued by Williams, Pauling, Hoffer, and others 30-40 years ago?

Avoiding Side Effects of B Vitamin Therapy

Particularly when compared to prescription drugs, B vitamins, even in megadoses, are extremely safe. However, nothing is completely devoid of the potential for ill effects if taken in sufficient doses. Any adverse reactions to B vitamins which do occur may be due to toxic or allergic reactions, or, more commonly perhaps, may be due to more obscure mechanisms. These latter types of reactions, which tend to be less severe and more vague or non-specific than either toxic or allergic reactions, may be caused by imbalance effects or deficiencies of associated nutrients. I will consider these different types of reactions below, followed by some suggestions for avoiding them.

a) Toxic or Allergic Reactions

Genuine toxic or allergic reactions to B vitamins are rare and are generally confined to vitamins B3 and B6, although very rarely, injections of thiamine, but not oral supplements, have resulted in severe allergic reactions ( 77, 78, 79 ). In order to avoid toxic reactions to B vitamins serious consideration must be given to generally accepted safe upper intake levels when taking vitamins B3 and B6 in particular. However, it must be realised that the safety and effectiveness of both these vitamins is determined by the absorbed dose and not the oral dose.

It is well known that vitamin B3, in the form of niacin, may dilate blood vessels and cause an unpleasant flushing of the skin with itching, tingling and throbbing in the head ( 2, 37, 68, 80 ), even with doses as low as 50mg ( 80 ). This effect may be avoided by taking vitamin B3 in the form of niacinamide ( 2, 80 ). Although this flushing may also be avoided by using "slow release" or "timed release" forms of niacin, these products have been shown to be toxic to the liver, especially when taken in doses exceeding 2g daily ( 2, 37, 68, 80, 81, 82, 83, 84 ). High doses of niacin may also adversely effect glucose tolerance, gout, and peptic ulcers ( 2, 37, 80, 84 ). As a result of these effects high doses of this vitamin should be used with caution in those suffering from liver disease, diabetes, gout, or peptic ulcers ( 2, 80 ).

The available evidence suggests that vitamin B3 is safe and free of toxic effects if taken in the form of niacinamide at doses of up to 1000mg daily ( 97 ). If using pure niacin, the flushing effect may perhaps be minimised by starting with small doses and gradually increasing the dose ( 80 ). Recently a new form of vitamin B3, inositol hexaniacinate, has become available and it has been suggested that this is the safest form of niacin ( 80, 97 ).

An awareness of the possible ill effects of niacin has largely come about as a result of the increasing use of huge doses of this vitamin as an anti-lipidemic or anti-diabetic agent. As is also the case with vitamin D, when drug oriented orthodox medicine adopts the therapeutic use of nutrients, they are frequently used as drugs in massive doses. In my view, it is difficult to justify such large doses of niacin or niacinamide from a nutritional point of view.

The other B vitamin which may cause allergic ( 90, 91 ) or toxic effects is vitamin B6. High doses of B6, that is, doses in excess of 200mg daily, may cause nerve toxicity with symptoms of numbness and tingling in the fingers and toes and a loss of muscular coordination which may cause difficulty in walking ( 2, 37, 80, 86, 87, 88, 89 ). These effects generally result from the chronic ingestion of large doses of this vitamin for months or years although doses in excess of 2g daily may produce toxic effects more quickly ( 86 ). One of the interesting features of B6 "toxicity" is that these toxic symptoms may actually be caused by a deficiency of vitamin B6 ( 80, 86, 87 ), however I will consider this matter in more detail below.

Since vitamin B6 is believed to be safe, even long term, when taken in doses of 100mg daily ( 92, 93 ), from the point of view of toxicity, this dose should not pose a problem. Since long term administration of vitamin B6 at doses in excess of 150mg daily may pose a risk of toxicity, such doses should not be taken long term unless under the guidance of a practitioner.

b) Other Reactions

Strange as it may seem, it appears that the more common types of adverse reaction to B vitamins, which may cause fatigue, depression, headache, seborrhea, sore mouth, sore eyes, etc., are actually caused by associated B vitamin deficiencies. Such reactions may occur at doses considerably below toxic dose levels and may also involve B vitamins which are not known to be toxic. Evidence suggests there are three common mechanisms by which these types of reactions may occur.

Firstly, as I have discussed previously, taking high doses of single B vitamins, or, on the other hand, taking high potency balanced B complex tablets which are inefficiently absorbed, may cause an imbalance of the vitamin of lesser concentration and an aggravation of B vitamin deficiency symptoms ( 2 - 9, 111, 112 ). If this type of reaction occurs, then it is not a sign of vitamin toxicity but rather incorrect dosage, or, in the case of balanced B complex tablets, inefficient absorption. In order to avoid these types of reactions it may be necessary to individualise the dose of each B vitamin.

The second means by which the taking of nutritional supplements may cause additional nutrient deficiencies is based upon the close interrelationship of nutrients within the body and the ability of one nutrient to increase the need for other nutrients by uncovering other related nutritional deficiencies ( 16, 58, 95, 98 ). Nutritional supplementation with a single nutrient may, by strengthening the weakest nutritional link in the chain, greatly exacerbate any other associated nutritional deficiencies ( 16, 58, 95 ). In other words, increasing the intake of one nutrient may necessitate that the intake of other nutrients are increased also until body stores of all nutrients have been normalised ( 16, 58 ). This is particularly true when a serious longstanding nutritional deficiency is being addressed. As in the first case, adverse effects which occur in this way are not toxicity reactions but rather deficiencies of other nutrients and therefore may be rectified by supplementing the intake of all associated nutrients until body stores have been replenished. 

Perhaps the best known example of one nutrient increasing the need for other nutrients is the reaction which may occur during treatment of severe longstanding anaemia. Typically, after 3-7 days of supplements to treat anaemia there will be a sudden exacerbation of symptoms caused by a sudden explosion in the number of new red blood cells as the body attempts to restore normality. The sudden production of so many new red cells causes an increased need for all nutrients which are necessary for the formation of these cells. Treatment of pernicious anaemia in particular, may cause fatal hypokalemia ( potassium deficiency ) and an increased need for other blood forming nutrients such as iron and folate ( 1a, 1b ).

Also of concern are deficiencies of nutrients which effect glands or hormone levels. To suddenly supply a deficient nutrient which effects hormone levels may cause very disturbing symptoms. If for instance there is a degree of hypothyroidism due to nutritional deficiencies, then suddenly supplying these nutrients may cause rather dramatic symptoms until the body adjusts to normal levels of thyroid hormone. The same is true for nutrients which effect adrenal function. Additionally, a sudden increase in thyroid hormone may "stress" the adrenal gland and temporarily cause adrenal failure.

The third way in which B vitamin supplements may cause ill effects is related to the fact that B vitamins are commonly ingested in an inactive form which must be converted by the body into the physiologically active form. Any breakdown in this conversion process may result in adverse effects when inactive vitamins are ingested. It has been suggested that it is this mechanism which may be responsible for the "toxic" effects of large doses of vitamin B6 ( 80, 86, 87 ). Vitamin B6 supplements normally contain pyridoxine hydrochloride, an inactive form of this vitamin which must be converted in the body to pyridoxal-5-phosphate before it becomes active. It seems that the phoshorylating enzyme which adds the phosphate group during the conversion process may be overwhelmed by excessive levels of pyridoxine thereby permitting a build up of inactive forms of B6 to displace the active form from receptors and create a relative deficiency of vitamin B6 ( 80, 86, 87 ). 

Adverse reactions caused by inability to convert the B vitamins to their active forms may be addressed by supplements of other nutrients, particularly magnesium, zinc, and riboflavin, which may assist in stimulating the conversion process ( 98 ).

Conclusion

From the evidence cited above, a number of important facts emerge. Firstly, it is possible for certain people to malabsorb single B vitamins even in the absence of any explanation for this malabsorption. Secondly, even with perfect absorption it is possible to have various blockages in the utilisation or metabolism of vitamins which may increase the need for such vitamins. Thirdly, nutritional deficiencies caused by these mechanisms may be associated with diseases such as asthma or heart disease, which are not commonly considered to be caused by vitamin deficiencies. Additionally, because the widespread prevalence of vitamin B deficiencies throughout affluent Western societies has been repeatedly confirmed by scientific studies, diet can no longer be exclusively relied upon to supply adequate amounts of B vitamins for many people. Finally, since the absorbed dose of B vitamins must be balanced, the available evidence suggests that the use of potent B complex tablets by people who malabsorb one or more of these vitamins, may produce serious ill effects by aggravating an already existing deficiency.

While the existence of vitamin dependency disorders is well known, it is their incidence which is not so clear. Certainly the established vitamin dependency conditions are considered quite rare, although from the evidence I have cited, such conditions merely represent the extreme end of the spectrum. Numerous reports in the medical literature confirm the widespread occurrence of vitamin dependency conditions due to malabsorption or other metabolic problems. However, unlike the severe established dependency conditions, many of these conditions are probably regarded as being subclinical and are therefore beyond the scope of orthodox medicine. As far as orthodox medicine is concerned, such conditions are unexplained and are therefore dismissed. If there is the remotest possibility that a common disease like asthma, which modern medicine has no answer for, is related in any way to a vitamin dependency condition, then surely no research effort should be spared in an attempt to restore health to people who suffer from this disorder. The importance of clinical effectiveness and safety should surely override any deficiency in scientific justification or knowledge.

In view of the fact that individuality in nutritional needs has long been known thanks to the work of brilliant scientists such as Williams, Hoffer, and Pauling (10, 11 ), it is a tragedy that the medical community at large has chosen to ignore this evidence in favour of the more lucrative drug oriented reductionist paradigm of modern medical science. Modern medicine it seems, accepts genetic variation in almost every respect other than variability in metabolism of nutrients. It appears that this attitude has become predominant in spite of the available evidence, not because of it.

The commonly accepted medical viewpoint that everyone has perfect absorption and metabolism of nutrients is scientifically unsustainable. It is based upon an assumption, and remarkably, it is an assumption which has been central to the attitude of the medical profession to nutrition for decades. Considering the complexity of the body, the presumptuous expectation that every nutrient, once ingested, will be automatically delivered to every cell in the body in optimum amounts, is most appropriately described as quackery, certainly not science. Since vitamin deficiencies have been repeatedly shown to occur in otherwise normal people who ingest allegedly adequate amounts of these nutrients, either from the diet or from supplements, then the general assumption that adequacy of dietary intake guarantees optimum cellular nutrition must be rejected as a fallacious generalisation which is without scientific basis. When it comes to health and nutrition, we must surely err on the side of safety.

The widespread use of vitamin B supplements in the general community can only be regarded as a sensible response to increasing scientific evidence that for many people, diet alone does not ensure freedom from vitamin deficiencies. Widespread anecdotal reports of the effectiveness of B vitamin supplements are also consistent with this scientific evidence.

Unfortunately however, there continues to be an enormous amount of unscientific resistance or bias towards nutritional therapy ( see Medical Bias, Nutrition Breakthroughs, Dietary Supplements ). Patients who attempt to improve their cellular nutrition by utilising higher than normal doses of vitamins are often derided by the medical establishment, the suggestion being made that all they are doing is creating "expensive urine" (Pan Crisis). Sadly, such statements reflect a total disinterest in the scientific facts of cellular nutrition and a complete lack of awareness of the complexities of nutrient absorption and utilisation.

How many asthmatics are there out there who are suffering from inefficient absorption or metabolism of vitamin B6 but yet have been told increased doses of vitamins are dangerous ( there's that assumption of perfect utilisation again ) and they should always opt for drug treatment? How many victims of heart disease are there who are actually suffering from vitamin deficiencies? How many victims of mental disease, whose symptoms are being suppressed by the use of potent psychiatric drugs, are actually suffering from undiagnosed malnutrition? Due to the regrettable drug oriented focus of orthodox medicine it is exceedingly unlikely that such patients will receive appropriate nutritional treatment from conventional medical practitioners.

Recognition that an increasing number of "diseases", including asthma, heart disease, and mental disease, may be caused by nutritional deficiencies necessitates that any possibility of such deficiencies must be positively eliminated BEFORE resorting to the use of symptom concealing drugs.

Given the facts of biochemical individuality and nutrigenomics and the importance of optimum nutrition of all the cells in the body, the responsibility of the nutritional therapist goes far beyond simple dietary changes or the ingestion of a vitamin or mineral tablet. Therapeutic nutrition should not be based upon an assumption of perfect absorption and metabolism of each and every nutrient, but rather should positively eliminate any possibility of inefficiency in nutrient utilisation and ensure optimum nutrition at the cellular level. Not to do so is an abandonment of science, reason, and common sense.

Although, according to Kalita ( 11 ), "the greatest enemy of any science is a closed mind", let us hope that this is not an impediment to future progress in megavitamin therapy.

Links and References

1. Balch, J.F., Balch, P.A., Prescription for Nutritional Healing, Avery Publishing Group Inc., New York, USA, 1990. 
1a.Wyngaarden, J.B., Smith, L.H., Cecil Textbook of Medicine, 17th edn., W. B. Saunders Company, Philadelphia, USA, 1985. 
1b.MIMS Annual, 1998, MIMS Australia. http://www.mims.com.au/products.htm
2. Kirschmann, G.J., Kirschmann, J.D., Nutrition Almanac, 4th edn, McGraw Hill, New York, USA, 1996. 
3. Davis, A., Let's Get Well, George Allen and Unwin Ltd., London, 1978. 
4. Shinagawa, T., et al, J. Vitaminology, 3, 135, 1957, cited by Davis ( 3 ). 
5. Alexander, B., et al, J. Clin. Invest., 25, 294,1946, cited by Davis ( 3 ). 
6. Yamada, K., et al, J. Vitaminology, 5, 188, 1959, cited by Davis ( 3 ). 
7. Tanaka, T., Nu tr. Abstr. Rev., 30, 860, 1960, cited by Davis ( 3 ). 
8. Tower, D.B., Am. J. Clin. Nutrit., 4, 329, 1956, cited by Davis ( 3 ). 
9. Ralli, E.P., et al, Vitamins and Hormones, Academic Press, New York, 1953, cited by Davis ( 3 ). 
10. Williams, R.J., Biochemical Individuality, University of Texas Press, Austin, Texas, USA, 1979.
11. Williams, R.J., Kalita, D.K., A Physician's Handbook on Orthomolecular Medicine, Keats Publishing Inc., New Canaan, Connecticut, USA, 1977. 
11a.Rimland, B., High Dosage Levels of Certain Vitamins in the Treatment of Children with Severe Mental Disorders, Institute for Child Behaviour Research, San Diego, USA, 1968. Cited by Hall ( 11 ).
11b.Hawkins, D., Pauling, L., Eds., Orthomolecular Psychiatry, Treatment of Schizophrenia, W.H. Freeman and Co., 1973. Cited by Hall ( 11 ).
12.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=P See: Baker, H., et al, J. Amer. Geriatric Soc., 28, 42,1980.
13.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&d  See: Asregadoo, E.R., Ann. Opthalmol., 11, 1095, 1979.
13a.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed  See: Woon C, Tang RA, Pardo G, Semin Ophthalmol 1995 Sep;10(3):195-202.
14.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&d  See: Reynolds, R.D., Natta, C.L., Am. J. Clin. Nutrit., 41, 684,1985.
15.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db  See: Collipp, P.J., et al, Ann. Allergy, 35, 93,1975.
16.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&d See: Lonsdale, D., J. Amer. Coll. Nutrit., 9, 13,1990.
17.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retri See: Gonzalez-Gross, M., et al, In t. J. Vitamin Res ., 61,120, 1991.
18. Bowman, B.B., Rosenberg, I.H., Amer. J. Clin. Nutrit., 35, 1142,1982.
19. Frank, O., et al, Amer. J. Clin. Nutrit., 30, 630, 1977.
20. Baker, H., et al, J. Amer. Geriatric Soc., 27, 44, 1979.
21. Burton, B.T., Executive Editor, The Heinz Handbook of Nutrition, McGraw Hill, New York, USA, 1959, cited by Williams ( 11 ).
22. http://www.healthy.net/library/journals/ortho/issue7.1/Jom-ed2.htm   See: Hoffer, A, J. Orthomolec. Med., Vol 7, No. 1, 1995.
23. Warraki, S. E., et al, Chest, 57, 148, 1970.
24. Levy, L.H., et al, Acta Allerg., 16, 121, 1961.
25. Knapp, A., Clin. Chim. Acta., 5, 6, 1960.
26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubM
See: Collipp, P.J., et al, Ann. Allergy, 35, 153,1975.
27. Sur, A.M., Anekar, U.J., Ann. Paed. Japonic., 28, 96, 1982.
28. Machaffie, R.A., et al, J. Allergy, 31, 106, 1960.
29. Hanna, H., Jap. J. Allergy, 10, 504, 1961.
30. Hall, M.A., et al, Ann. Allergy, 47, 464, 1981.
31.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&d See: Sur, S., et al, Ann. Allergy, 70, 147, 1993.
32.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Delport, R., et al, Int. J. Vit. Nutr. Res., 58, 67, 1988.
33.Ubbink, J.B., et al, Ann. NY Acad. Sci., 585, 285, 1990.
34.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Shimizu, T., et al, Pharmacology, 49, 392, 1994.
35.http://www.mercola.com/1999/may/23/theophylline_asthma_therapy_ See: Arch. Int. Med., 159, 989, 1999.
36.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&d See: Jacobson, G.A., J. Clin. Pharm. Ther., 21, 317, 1996.
37.Werbach, M.R., Nutritional Influences on Illness: A Sourcebook of Clinical Research, 2nd ed, Third Line Press, Tarzana, California, USA, 1993.
37a.Melton, G., Brit. Med. J., 15th May, 1943, p600. Cited by Werbach ( 37 ).
38. Wardlaw, G.M., Insel, P.M., Perspectives in Nutrition, CV Mosby Company, St Louis, MO, USA, 1990,
39.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Bender, D.A., Proc. Nutr. Soc., 58, 427, 1999.
40. Kaslow, J. E., Ann. Allergy, 71, 492, 1993.
41. Robson, A.O., Kilborn, J.R., Thorax, 20, 93, 1965.
42. Heim, C., et al, Psychoneuroendocrinology, Jan., 2000.
43.http://members.aol.com/jefferiesw/articles/1994.html
44.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Merrill, A.H. Jr., Henderson, J.M., Ann. Rev. Nutr., 7, 137, 1987.
45. Hunt, A.D. Jnr., et al, Pediatrics, 13, 140, 1954
46. Harris, J.W., Harrigan, D.D., Vitamins and Hormones, 22, 721, 1964.
47.http://adc.bmjjournals.com/cgi/content/full/archdischild%3b81/5/431 See: Baxter, P., Arch. Dis. Child., 81, 431, 1999.
48.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve See: Burd, L., et al, J. Child Neurol., 15, 763, 2000.
49.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=Pu See: Shih, J.J., Neurology, 47, 824, 1996.
50.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retri See: Natta, C.L., Reynolds, R.D., Am. J. Clin. Nutr., 40, 253, 1984.
51.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=P See: Heap, L.C., et al, J. Roy. Soc, Med., 92, 183, 1999.
52.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Varma, R.N., et al, Am. J. Clin. Nutr., 38, 884,1983.
53.http://www3.interscience.wiley.com/cgi-bin/abstract/72509620/START See: Sato, Y., et al, Muscle Nerve, 23, 1069, 2000.
54. Simon, R.A., Reynolds, R.D., Current Topics in Nutrition and Disease, 19, 307, 1988. Cited by Ubbink ( 33 ).
55. Williams, R.J., Nutrition Against Disease, Pitman Publishing Corp., New York. USA, 1971.
56.Murray, M., Pizzorno, J., Encyclopaedia of Natural Medicine, Macdonald and Co., Ltd., London, 1990. 
57.Gerras, C., Hanna, J.E., Feltman, J. (eds), The Encyclopaedia of Common Diseases, Rodale Press, 1976. 
58.Robinson, C.H., Normal and Therapeutic Nutrition, 14th edn., Macmillan Publishing Co., New York, 1972. 
59.Abbey, L.C., J. Orthomolec. Psychiat.,11, 243,1982. 
60.Watson, G., Currier, W.D., J. Psychol., 49, 1960. Cited by Rodale (57 ). 61.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve& See: Rimland, B., et al, Am. J. Psychiat., 135, 472, 1978. 
62.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db See: Kleijnen, J., Knipschild, P., Biol. Psychiat., 29, 931,1991. 
63.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Carney, M.W., et al, Brit. J. Psychiat., 141, 271, 1982. 
64.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Carney, M.W., et al, Brit. J. Psychiat., 135, 249, 1979. 
65.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Bell, I.R., et al, J. Am. Geriat. Soc., 39, 252, 1991. 
66.Stewart, JW., et al, Biol. Psychiat., 19, 613, 1984. 
67.Russ, C.S., et al, Nutr. Rep. Int., 27, 867, 1983. 
68.Werbach, M.R., Nutritional Influences on Mental Illness: A Sourcebook of Clinical Research, Third Line Press Inc., Tarzana, California, USA, 1991.
69.Cott, A., Schizophrenia, 3, 2, 1971. 
70.Hoes, M.J., et al, J. Orthomolec. Psychiat., 10, 7, 1981. 
71.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Benton, D., Donohoe, R.T., Public Health Nutr., 2, 403, 1999. 
72.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Smidt, L.J., et al, J. Gerontol., 46, M16, 1991. 
73.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Rimland, B., J. Child Neurol., 3, Suppl. S68, 1988. 
74.Stein, S.I., Ann. N.Y. Acad. Sci., 166, 210, 1969. Cited by Williams (55 ). 
75.Richardson, H.J., A Study and Survey of the Disabilities and Problems of Hong Kong Veterans, Dept. of Health and Welfare, Ottawa, Canada, 1964. Cited by Hoffer ( 11 ). 
76.Mayer. J., Medical Tribune World Wide Report, 19th Jan., 1970. Cited by Cott (11 ).
77.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Wrenn, K.D., et al, Ann. Emerg. Med.,18, 867, 1989. 
78.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Stephen, J.M., et al, Am. J. Emerg. Med., 10, 61 1992. 
79.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Morinville, V., et al, Schweiz. Med. Wochenschr., 128, 1743,1998.
80.Murray, M.T., Encyclopedia of Nutritional Supplements, Prima Publishing, 1996. 
81.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Coppola, A., et al, South. Med. J., 87, 30, 1994. 
82.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Lawrence, S.P., J. Clin. Gastroenterol., 16, 234, 1993. 
83.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: McCarty, M.F., Med. Hypotheses, 55, 189, 2000. 
84.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Knip, M., et al, Diabetologia, 43, 1337, 2000. 
85.Osiecki, H., The Physician's Handbook of Clinical Nutrition, 5th edn., Bioconcepts Publishing, Kelvin Grove, Queensland, Australia, 1998. 
86.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Parry, G.J., Neurology, 35, 1466, 1985. 
87.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Waterston, J.A., Gilligan, B.S., Med. J. Aust., 146, 640, 1987. 
88.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Bassler, K.H., Int. J. Vitamin Nutr. Res. Suppl., 30, 120, 1989. 
89.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Santoro, L., et al, Acta Neurol., 13, 13, 1991. 
90.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Murata, Y., et al, J. Am. Acad. Dermatol., 39, 314, 1998. 
91.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Tanaka, M., et al, J. Dermatol., 23, 708, 1996.
92.http://www.iahf.com/upper_limits.html
93.http://books.nap.edu/html/dri_thiamin/index.html
94.Cott, A., Schizophrenia, 1, 3, 1967. Cited by Hall ( 11 ).
95.Lonsdale, D., CRC Critical Rev. Clin. Lab. Sci., 5, 289, 1975.
96.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Bender, D.A., Brit. J. Nutr., 81, 7, 1999.
97.Lininger, S.(ed), The Natural Pharmacy, Prima Publishing Company, USA, 1998.
98.Brenner, A., J. Learning Disabilities, 15, 258, 1982
99.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Bender, D.A., Eur. J. Clin. Nutr., 43, 289, 1989.
100.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= See: Azuma, J., et al, Res. Commun. Chem. Pathol. Pharmacol., 14, 343, 1976.
101.http://www.bmj.com/cgi/content/full/308/6924/283?maxtoshow=&HITS= See: Altman, D.G., BMJ, 308, 283, 1994.
102.http://www.bmj.com/cgi/content/full/308/6928/591?maxtoshow=&HITS= See: Jones, R., et al, BMJ, 308, 591, 1994.
103.http://archinte.ama-assn.org/issues/v158n20/rfull/icm80223.html   See: Goodwin, J.G., Tangum, M.R., Arch. Int. Med., 158, 2187, 1998.
104.http://jama.ama-assn.org/issues/v287n23/abs/jsr20000.html See: Fairfield, K.M., Fletcher, R.H., JAMA, 287, 3116, 2002
105.http://jama.ama-assn.org/issues/v287n23/abs/jsr20001.html See: Fletcher, R.H., Fairfield, K.M., JAMA, 287, 3127, 2002
106.http://circ.ahajournals.org/cgi/content/full/99/1/178?maxtoshow=&HITS= See: Malinow, M.R., et al, Circulation, 99, 178, 1999.
107.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubme See: Ubbink, J.B., et al, Clin. Invest., 71, 993, 1993.
108.http://atvb.ahajournals.org/cgi/content/full/17/6/1157?ijkey=Y8l84bj95hky See: Malinow, M.R., et al, Arteriosclerosis, Thrombosis, and Vascular Biology, 1997;17:1157-1162.
109.http://www.ajcn.org/cgi/content/abstract/66/2/427 See: Hathcock, J.N., Amer. J. Clin. Nutr., 66, 427, 1997.
110.http://www.jacn.org/cgi/content/full/19/5/613 See: McKay, D.L., et al, Journal of the American College of Nutrition, Vol. 19, No. 5, 613-621 (2000).
111.http://www.acnem.org/journal/14-1_july_1995/pyridoxine-vitamin_b6.htm See: Holman, P., Journal of the Australasian College of Nutritional & Environmental Medicine, Vol. 14, No. 1, July 1995, pages 5-16.
112.Buist, Int. Clin. Nut. Rev. 4(4): 163-178, 1984. Cited by Holman ( 111 ).
113.http://www.internetwks.com/pauling/hoffer.html See: Hoffer, A., The Vitamin Paradigm Wars, Townsend Letter for Doctors and Patients, June, 1996.
113a.http://www.islandnet.com/~hoffer/
114. Rinehart, JF, Greenberg, LD, Proc. Soc. Exp. Biol. Med., 76, 580, 1951; Am. J. Clin. Nutr., 4, 320, 1956; Arch. Pathol., 51, 12, 1951; Am. J. Pathol., 25, 481, 1949; Greenberg, LD, et al, Arch. Biochem., 21, 237, 1949; Mushett, Emerson, Fed. Proc., 15, 526, 1956; Cambridge, CD, Brit. J. Nutr., 10, 347, 1956; Dam, H., et al, Acta Physiol. Scand., 44, 67, 1958; Shah, S., et al, J. Nutr., 72, 81, 1960; Swell, L., et al, J. Nutr., 75, 181, 1961; Maggi, V., et al, Nutr. Rev., 24, 274, 1966;
115.Mueller, J.F., Vitamins and Hormones, 22, 787, 1964. Cited by Williams ( 55 ).
116. Kheim, Kirk, Am. J. Clin. Nutr., 4, 325, 1956; Mueller, J.F., Iancono, J.M., Am. J. Clin. Nutr., 12, 358, 1963; Gvozda, L.G., et al, Viprosy Pitanyia, 25, 40, 1966; Nutr. Rev., 25, 116, 1967.
117.Kotake, J. Vitaminology, 1, 73, 1955. Cited by Williams ( 55 ).
118.Gvozda, L.G., et al, Viprosy Pitanyia, 25, 40, 1966; Nutr. Rev., 25, 116, 1967; Mueller, J.F., Iancono, J.M., Am. J. Clin. Nutr., 12, 358, 1963.
119.Mueller, J.F., Iancono, J.M., Am. J. Clin. Nutr., 12, 358, 1963. Cited by Williams ( 55 ).
120.Engel, R.W., J. Nutr., 24, 175, 1942; Whittier, P.W., et al, Arch. Biochem., 41, 266, 1952; Pilgeram, L.O., Fed. Proc., 14, 728, 1955.
121.Wagner, A.L., et al, J. Lab. Clin. Med., 40, 324, 1952; Gross, K.L., et al, NY State J. Med., 30, 2683, 1950; Sinclair, H.M., Lancet, 2, 271, 381, 1956; Havel, R.J., J. Clin. Invest., 36, 848, 1957; Vroulis, G., et al, Am. J. Psychiat., 139, 1633, 1982;
122.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubM See: Brook, J.G., et al, Biochem. Med. Metab. Biol., 35, 31, 1986.
123.http://members.aol.com/althealth/lecithin.html
124.Kuo, P.T., et al, Am. J. Clin. Nutr., 20, 116, 1967; Morrison, L.M., Gonzales, W.F., Proc. Soc. Exp. Biol. Med., 73, 37, 1950.
125.Hirsch, E.F., et al, Physiol. Rev., 23, 185, 1943. Cited by: Davis, A., Let's Get Well, George Allen and Unwin Ltd., London, 1976.
126.Downs, W.G., Amer. Med., 41, 460, 1935; Kesten, H.G., et al, Proc. Soc. Exp. Biol. Med., 49, 71, 1942; Ladd, A.T., et al, Fed. Proc., 8, 360, 1949; Horlick, L., Circulation, 10, 30, 1956.
127.Tower, D.B., Am. J. Clin. Nutr., 4, 329, 1956; Witten, Holman, Arch. Biochem., 41, 266, 1952.
128.http://www.nutrition.org/cgi/content/full/130/2/333S See: H. Tsuge, et al, Journal of Nutrition. 2000;130:333S-334S.
129.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMe See: Bordoni A, et al, Prostaglandins Leukot Essent Fatty Acids 1998 Jun;58(6):417-20.
130.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Maranesi M, et al, Prostaglandins Leukot Essent Fatty Acids 1993 Jul;49(1):531-6
131.http://www.lef.org/newsarchive/vitamins/2001/10/10/eng-essentialfats/eng- See: E. Siguel, Life Extension Magazine, October 10, 2001.
132.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Djousse L, et al, Am J Clin Nutr 2001 Nov;74(5):612-9.
133.http://www.efasense.com/efa_research_heart.html
134.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Das UN, Nutrition 2001 Apr;17(4):337-46.
135.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: von Schacky C, Am J Clin Nutr 2000 Jan;71(1 Suppl):224S-7S.
136.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMe See: Ballantyne CM, Curr Atheroscler Rep 1999 Jul;1(1):6-8.
137.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Angerer P, von Schacky C., Curr Opin Clin Nutr Metab Care 2000 Nov;3(6):439-45.
138.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Connor WE, Connor SL, Adv Intern Med 1990;35:139-71.
139.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Brattstrom L, et al, Scand J Clin Lab Invest 1990 Dec;50(8):873-7.
140.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: van Wyk V, Luus HG, Heyns AD, Thromb Res 1992 Jun 15;66(6):657-68.
141.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Sermet A, et al, Arzneimittelforschung 1995 Jan;45(1):19-21.
142.http://circ.ahajournals.org/cgi/content/abstract/104/20/2442 See: M. Cattaneo, et al, Circulation. 2001;104:2442.
143.http://circ.ahajournals.org/cgi/content/full/97/5/437 See: Killian Robinson, et al, Circulation,1998;97:437-443.
144.Rinehart JF, Greenberg LD,  Am J Pathol. 1949;25:481–491
145.Smolin LA, et al, J Nutr. 1983;113:2122–2133
146.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Das UN, Prostaglandins Leukot Essent Fatty Acids 2001 Jul;65(1):37-40.
147.http://jama.ama-assn.org/issues/v279n5/ffull/jed71076.html See: Kilmer S. McCully, JAMA, Vol. 279 No. 5, February 4, 1998.
148.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMe See: Fanapour PC, Yug B, Kochar MS, WMJ 1999 Dec;98(8):51-4.
149.http://www.quackwatch.org/03HealthPromotion/homocysteine.html
150.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Vermeulen EG, et al, Lancet 2000 Feb 12;355(9203):517-22.
151.http://www.ajcn.org/cgi/content/abstract/57/1/47?ijkey=K.GMJ2MTB7l6. See: JB Ubbink, WJ Vermaak, A van der Merwe and PJ Becker, American Journal of Clinical Nutrition, Vol 57, 47-53.
152.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Rimm EB, et al, JAMA 1998 Feb 4;279(5):359-64.
153.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Selhub J, et al, JAMA 1993 Dec 8;270(22):2693-8.
154.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Naurath HJ, et al, Lancet 1995 Jul 8;346(8967):85-9.
155.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: van Guldener C, Stehouwer CD, Expert Opin Pharmacother 2001 Sep;2(9):1449-60.
156.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Gupta A, et al, Transplantation 1998 Feb 27;65(4):544-50.
157.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Gensini GF, Comeglio M, Colella A, Eur Heart J 1998 Feb;19 Suppl A:A53-61.
158.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Djuric D, Wisotzki R, Mitrovic V, Am J Ther 2000 Nov;7(6):381-7.
159.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Schnyder G, et al, N Engl J Med 2001 Nov 29;345(22):1593-600.
160.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Miller JW, et al, Neurology 2002 May 28;58(10):1471-5.
161.http://www.ajcn.org/cgi/content/abstract/71/2/614s See: Jacob Selhub, et al, American Journal of Clinical Nutrition, Vol. 71, No. 2, 614S-620s.
162.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Severus WE, Littman AB, Stoll AL, Harv Rev Psychiatry 2001 Nov-Dec;9(6):280-93.
163. Levine, C.I., Murray, J.C., Lancet, 1, 628, 1977.
164. Lam, S.C.T., et al, Thrombosis Res., 20, 633, 1980.
165. Subbarao, K., et al, Biochem. Pharmacol., 28, 531, 1979.
166.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed See: Clarke R, et al, N Engl J Med 1991 Apr 25;324(17):1149-55.
167.http://www.lef.org/magazine/mag97/july97_cover.html See: Paul Frankel, Terri Mitchell, Life Extension Magazine, July 1997.
168.http://circ.ahajournals.org/cgi/content/full/92/10/2825?ijkey=SwXUwFnar7 See: Killian Robinson, et al, Circulation. 1995;92:2825-2830.
169.http://circ.ahajournals.org/cgi/content/full/98/3/204 See: Aaron R. Folsom, et al, Circulation. 1998;98:204-210.
170.http://atvb.ahajournals.org/cgi/content/full/17/10/1947?ijkey=HQcNex6 See: Rhobert W. Evans, et al, Arteriosclerosis, Thrombosis, and Vascular Biology, 1997;17:1947-1953.
171.http://circ.ahajournals.org/cgi/content/full/103/23/2788 See: Simonetta Friso, et al, Circulation. 2001;103:2788.
172.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubM See: McCarty MF, Med Hypotheses 2000 May;54(5):808-13.
173.Engel, R.W., J.Nutr., 24, 175, 1942.
174.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubM See: van Guldener C, Stehouwer CD, Expert Opin Pharmacother 2001 Sep;2(9):1449-60.
175.http://www.ajcn.org/cgi/content/abstract/66/2/427 See: JN Hathcock, American Journal of Clinical Nutrition, Vol 66, 427-437.
176.http://psychsoc.gerontologyjournals.org/cgi/content/abstract/56/6/P327 See: Eva Calvaresi, Janet Bryan, The Journals of Gerontology Series B: 
Psychological Sciences and Social Sciences 56:P327-P339 (2001)
177.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubM See: Shiloh R, et al, Harefuah 2001 May;140(5):369-73, 456.
178.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubM See: Baldewicz T, et al, Psychosom Med 1998 May-Jun;60(3):297-308. See: McCarty MF, Med Hypotheses 2000 May;54(5):803-7.
179.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubM  See: McCarty MF, Med Hypotheses 2000 May;54(5):803-7.
180.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubM  See: Bell IR, et al, Acta Psychiatr Scand 1992 May;85(5):360-3.
181.http://www.theaustralian.news.com.au/story/0,20867,21695484-23289,00.html Clara Pirani,  Malnutrition widespread in elderly patients, The Australian, 9th May 2007; see also, Doctors Discover Malnutrition in Elderly.
182.http://www.smw.ch/docs/pdf200x/2002/25/smw-09972.pdf Claudia Steurer-Steya, Erich W. Russib, Johann Steurerc, Complementary and alternative medicine in asthma – do they work? :A summary and appraisal of published evidence, SWISS MED WKLY 2002;132:338–344.

The author of this web site expressly disclaims all liability to any person arising directly or indirectly from the use of, or for any errors or omissions in, the information in this web site. The adoption and application of the information in this site is at the reader's discretion and is his or her sole responsibility.

This page was last updated on 18/05/09
Copyright © 2000 Graham Williamson
webmaster@holistichealthtopics.com