The relationship between oxidative stress and the catecholamines, seen, for example, in

Parkinson's disease and multiple sclerosis, is now apparent. This is largely because of the

research conducted in Winnipeg by Behonick and colleagues [29] who first developed a

method for measuring adrenolutin in blood. This is very significant because adrenochrome

rapidly is converted to adrenolutin in the body. Beyond this, Rouleau and colleagues [30]

have demonstrated that high levels of adrenolutin in patients with severe heart failure is

associated with a poor prognosis. Macarthur and colleagues [31] also have shown that, in

septic shock, excess oxidation occurs and adrenalin is very rapidly oxidized to adrenochrome

and noradrenalin to noradrenochrome. This process results in septic shock, in which blood

pressure no longer responds to injections of catecholamines. Inhibiting the oxidation helps to

restore the vasopressor properties of these catecholamines. Interestingly, vitamin B-12, in

large doses, seems very effective in the treatment of septic shock or in preventing the organ

failure seen too often during or after surgery.

In 1960, the hallucinogenic drug LSD was being used to treat alcoholics [5]. Hoffer

realized that this protocol was causing alcoholics to hallucinate in a manner similar to many

schizophrenics. This coincidence led him to believe that LSD use might be triggering

biochemical imbalances in alcoholics similar to those seen in schizophrenia. To test this

hypothesis, urine samples were collected from alcoholic patients before and after receiving

therapeutic doses of LSD. Urine from the first of these patients showed a mauve staining spot

on the paper chromatogram after development with Ehrlich's regeant. Such a mauve spot did

not appear in tests of the urine from alcoholics before they were given LSD, but it appeared

in tests of the urine of many, but not all of them, after taking this drug. Schizophrenic

patients' urine was then tested in the same way. The characteristic mauve stain also appeared

on the chromatogram paper for many, but again not all, of the samples from these patients.

The mauve factor was structurally identified in 1969 by Irvine, [32] and is now thought to be

2-hydroxy-hemopyrrolene-5-one [33]. As it circulates in the body it "forms a stable Schiff's

base with pyridoxal (the aldehyde form of pyridoxine or vitamin B-6) and subsequently

complexes with zinc, stripping the body of these two essential substances as it is excreted."

32 Harold D. Foster and Abram Hoffer

As a result of these reactions, schizophrenics producing large quantities of it are

simultaneously also very zinc and vitamin B-6 deficient.

Just how common is elevated "kryptopyrrole" in disorders involving excess oxidative

stress? In 1965, O'Reilly and Hughes [34] claimed that it was present in 11 percent of healthy

controls, 24 percent of disturbed children, 42 percent of psychiatric patients, and 52 percent

of schizophrenics. Hoffer's experience after testing a much larger sample consisting of

thousands of patients at our four research centers was somewhat different. Elevated

"kryptopyrrole" was found in the urine of 75 percent of acute schizophrenics, 25 percent of

all non-psychotic patients, and 5 percent of physically ill patients. It was absent from the

urine of normal subjects and most interestingly was never found in the urine of recovered

schizophrenics. The evidence suggests that although urinary "kryptopyrrole" (probably 2-

hydroxy-hemopyrrolene-5-one) is not an absolute sign of schizophrenia, it occurs with much

greater regularity in schizophrenics than in anyone else.

It does, however, seem to be a good indicator of excessive oxidative stress. It is found in

all classes of patients exposed to this problem, such as those suffering from schizophrenia

and autism. As previously discovered, the use of high dose vitamin B-3 as a methyl acceptor

can help prevent the cellular damage associated with derivatives of dopamine and

adrenochrome. As a result, niacin can play a key role in reducing the adverse effects of

oxidative stress identified by elevated urine "kryptopyrrole".

Malabsorption in the Elderly

The ability to absorb nutrients typically declines with age. As a result, vitamin

deficiencies are commonly seen in the elderly [35]. These are associated with a wide variety

of disorders. To illustrate the elevated blood levels seen in many patients are linked to an

inadequacy of niacins and related illnesses.

(1) Cholesterol Excess and Imbalance

The discovery that niacin lowered cholesterol levels arose from research conducted by

Professor Rudl Altschul, Chair, Department of Anatomy, University of Saskatchewan and

one of this chapter's authors, Dr. Abram Hoffer, then Director of Psychiatric Research in the

Department of Health. Professor Altschul had found that rabbits developed

hypercholesterolemia very rapidly, if they were fed cooked egg yolk in a specially baked

cake. Raw egg yolk did not have the same effect. He had also discovered that exposing

rabbits to ultraviolet light decreased their cholesterol levels. He wanted to try ultraviolet light

on people, but could not find any doctor in Saskatoon willing to work with him. Hoffer

agreed to provide subjects in one of the provincial mental hospitals. Since the treatment was

safe and patients could not be harmed by it, he considered that it would be good for them to

mix with healthy young people who would be conducting the research. At that time, Hoffer

had been suffering from bleeding gums, but found that large doses of vitamin C did not help.

After taking niacin for two weeks for other reasons, his gums were healed. From this Dr.

Hoffer concluded that the niacin had increased the rate of repair of gum tissues, which had

been under a lot of physical stress from maloccluded teeth.

The Causes and Consequences of Vitamin B-3 Deficiency… 33

Professor Altschul thought that the most important single pathological factor in coronary

disease was the inability of the intima (the inner wall of the blood vessel) to repair itself,

especially where the blood stream changed direction, causing the greatest stress to the

arteries. As Professor Altschul explained this hypothesis to Hoffer, the latter suddenly

recalled his bleeding gums and suggested that niacin might be able to heal the arterial wall's

intima. Hoffer then gave the professor one pound of crystalline niacin to test the effects on

experimental rabbits. A few months later, Altschul reported back that the niacin had lowered

rabbit cholesterol levels. On receiving this news, Hoffer organized a similar study using

humans [9]. The results were published in 1995 and were soon corroborated as a result of the

interest and enthusiasm of Dr. William Parsons Jr., than at the Mayo Clinic in Rochester,

Minnesota.

In 1986, a study by Canner and colleagues [36] showed that men who experience a

coronary and who were then given niacin died less frequently than normal and lived longer.

Specifically, there was a ten percent decrease in death rate and a two-year increase in

longevity. Since that time niacin has become the gold standard for normalizing lipid levels,

even though this fact is rarely taught in medical school. Niacin also lowers triglycerides and

lipoprotein(a) and elevated HDL (the good cholesterol fraction) which is its most important

function.

(2) Cardiovascular System

Niacin has been shown to be valuable in the treatment of disorders of the cardiovascular

system. This is not news. Condorelli [37] began to study the therapeutic applications of

niacin in 1938, very soon after it was identified as the anti-pellagra factor and its vasodilator

properties were observed. He reported the following properties of niacin, given by

intravenous injection or by mouth (1) increase in the velocity of the circulation (2) increase in

cardiac output (3) increase in systolic stroke volume (4) decrease in total pulmonary pressure

(5) increase in peripheral circulation in the viscera, brain and muscles (6) increased

oxygenation (7) increase in pulmonary oxygen diffusion (8) decrease in EEG abnormalities

caused by hypoxia of the myocardium. In short, niacin improves the body's blood flow,

improves circulation of oxygen and restores organ function. It does not increase blood

pressure.

Condorelli also described niacin's therapeutic effect on the following conditions (1)

Angiospasms, includes headaches and other regional spasms as in the retina which may occur

with hypertensive spells, are relieved by niacin but it must be given intravenously. Spasm in

the limbs also responded to niacin but it did not benefit Raynaud's disease (2) Niacin also

helped in embolism by relaxing the spastic vessels around and in the embolus (3) Thrombotic

arteriopathies such as intermittent claudication (4) Angina (5) Coronary insufficiency (6)

Eclampsia and (7) Nephritis. Condorelli reported "The experience of twenty years has always

confirmed the efficacy of nicotinic acid in acute diffuse glomerulonephritis, and we also

established that in sub-acute or chronic forms and in other nephritis disorders this treatment

may be in some way beneficial".

34 Harold D. Foster and Abram Hoffer

(3) Stroke

Evidence is accumulating that niacin helps recovery of the damaged brain. Yang and

coworkers [38] for example, found that nicotinamide could rescue viable but injured nerve

cells, within the ischemic area, after experimental strokes in animals. Early injection of

nicotinamide reduced the number of necrotic and apoptotic neurons. Later injections were not

as effective. Yang and Adams [39] concluded "Early administration of nicotinamide may be

of therapeutic interest in preventing the development of stroke, by rescuing the still viable but

injured and partially preventing infarction". They also found that this vitamin decreased the

progression of neurodegenerative disease. It prevented learning and memory impairment

caused by cerebral oxidative stress. According to these studies nicotinamide works more

quickly than niacin but both are interconvertable and in our opinion niacin will have an

advantage because it dilates the capillaries.

(4) Arthritis

Kaufman [40-41] was the first to report that niacinamide in large doses, starting from 250

milligrams taken four times daily, was useful in reversing the changes normally associated

with old age. His primary interest was in reversing arthritic symptoms, but he observed

significant associated improvement in other functions. A few months after the first report by

Hoffer and colleagues was published on the therapeutic effect of vitamin B-3 on

schizophrenic patients, Dr. Kaufman wrote that they were wrong in claiming that they had

used larger doses of this vitamin than anyone else had, Kaufman pointed out that he had, in

fact, been using these doses since the early 1940's. Dr. Hoffer asked him for copies of his

books and promptly received two which he still cherishes. Dr. Kaufman wrote "Ever since

1943 I have tried to call my work on niacinamide to the attention of leading hematologists,

nutritionists and gerontologists through conversation with them, by sending them copies of

my monograph and paper on this subject and by two talks given on the usefulness of

niacinamide and other vitamins which I gave at International Gerontological Congresses in

1951 and 1954, I think two factors have made it difficult for doctors to accept the concept

that continuous therapy with large doses of niacinamide could cause improvement to joint

dysfunction and give other benefits; (a) the advent of cortisone and (b) the fact that my use of

the vitamins was such a departure from the recommended daily allowance for vitamins by the

National Research Council". Dr. Hoffer then prepared a brief report of his work supported by

the results of six cases [42]. One patient with osteoarthritis became normal, another with

rheumatoid arthritis became much better, two arthritis cases became normal, one patient with

both schizophrenia and arthritis became completely well, while the last, who suffered from

vascular nodulitis, was much improved. Since this time, Dr. Hoffer has beneficially treated

many more arthritis patients with niacin. Large numbers have significantly improved.

In November 1999, Nutrition Science by Dan Lukaczer, reported "A few years ago,

Wayne Jonas [43] from the NIH Office of Alternative Medicine in Bethesda, Md., conducted

a 12-week, double-blind, placebo-controlled study of 72 patients to assess the validity of

Kaufman's earlier observations that niacin was of great benefit to the elderly, reducing

arthritis. Jonas reported that niacinamide at 3 g/day reduced overall disease severity by 29

percent, inflammation by 22 percent and use of anti-inflammatory medication by 13 percent."

Patients in the placebo group either had no improvement or worsened. Although these may be

The Causes and Consequences of Vitamin B-3 Deficiency… 35