In 1952, one of the authors, Dr. Abram Hoffer, was the Director of Psychiatric Research
for the Canadian Province of Saskatchewan. The Department of Public Health, in which he
operated maintained two large mental hospitals, which together housed 5,000 patients, half of
whom were schizophrenics. Since there was no viable treatment for this illness, such
schizophrenic patients could be expected to remain hospitalized for life. The situation was
similar elsewhere in North America.
Hoffer's interest in treating schizophrenic patients with high dose niacin began in 1951
when Dr. Humphrey Osmond became medical director of one of Saskatchewan's mental
hospitals, in Weyburn. Earlier, Osmond and Smythies [8] had compared the experiences
caused to taking mescaline, an hallucinogen derived from biological sources, such as the
Mexican cactus peyote (Lophophra spp.) with schizophrenic symptoms. Although not
identical, numerous similarities could be identified. As a result, Osmond and Smythies
hypothesized that schizophrenia might be the result of a similar hallucinogen. Mescalin
The Causes and Consequences of Vitamin B-3 Deficiency… 25
resembles adrenaline in chemical structure. It was suggested, therefore, that since
schizophrenia was often associated with stress, the hallucinogen causing it might be linked,
At a meeting of the Saskatchewan Committee on Schizophrenia Research, Professor
Vernon Woodford proposed that since adrenochrome, an oxidation product of adrenaline,
was a recognized mitotic poison, it might be the hallucinogen involved in schizophrenia. If
this suggestion was correct, then this mental illness might be effectively treated by safe,
inexpensive methods of blocking adrenochrome's negative impact. Hoffer, who in addition to
being an MD also had a doctoral degree in biochemistry, had studied vitamin B-2 for his
thesis. He was, therefore, familiar with the then current literature on vitamins. The ability of
niacin and niacinamide to prevent another major mental illness, pellagra also was quickly
recognized as significant, with potential in the treatment of schizophrenia.
The questions naturally arose over the possible toxicity of vitamin B-3. This fortunately
is not an issue. It has been shown that the LD50 in test animals is approximately four grams
per kilogram. This means that, if humans reacted in a similar manner, it would take roughly a
200 gram dose to kill a 50 kilogram woman or 320 grams to cause death in a 80 kilogram
male. Even these assumptions were apparently overcautious since it has been found that it is
almost impossible to take a fatal overdose of vitamin B-3 [9]. It was decided, therefore, that
the assumption would be made that adrenochrome played some sort of causal role in
schizophrenia. Given the value of vitamin B-3, seen in the successful treatment of pellagra,
and this nutrient's very low toxicity, the decision was taken to use it to treat schizophrenics in
mental hospitals in Saskatchewan. Since the formation of adrenochrome from adrenaline
involved oxidation, Hoffer and Osmond also decided that high doses of the only anti-oxidant
identified at that time, vitamin C, should also be utilized.
The first patient tested in this manner was a dying schizophrenic in a catatonic coma,
who was hospitalised at Weyburn Hospital. The patient was on his back, breathing
stertorously, unable to respond. He could not drink. As a result, he was given five grams of
niacin and five grams of ascorbic acid, dissolved in water, by stomach tube. The next day he
sat up unaided and drank the dissolved vitamin mixture. Two weeks later he appeared
normal, returning home one month after his high dose vitamin treatment had begun. About
thirteen years later, Hoffer traced this patient and found him in good health, a contractor who
had relatively recently been the Chair of the Board of Trade in the town in which he lived.
This appears to be the first instance, demonstrating the potential health benefits, in this case
the reversal of the symptoms of schizophrenia, that may be achieved by the acceptance of the
validity of the vitamins-as-drugs paradigm for vitamin B-3.
There can be little doubt that schizophrenics have an abnormal need for niacin. They also
display an abnormal reaction when given high doses of this vitamin. While normal controls
typically flush pronouncedly when given 500 mg or more of niacin, this response is often
absent in schizophrenics, even when doses are several times higher than this [10]. The recent
discovery of two niacin-responsive receptors, HM74A and HM74B [11] has led to a greater
understanding of why schizophrenics do not flush and why this lack of reaction to high doses
of niacin may be a very useful diagnostic test for this illness. HM74B appears to have a low
affinity for niacin, while HM74A is a high affinity receptor that mediates the stimulation of
the synthesis of prostaglandin by niacin. The binding of niacin, therefore, activates the
26 Harold D. Foster and Abram Hoffer
synthesis of prostaglandins E2 and D2 by cyclooxygenase. These prostaglandins appear to be
the inflammatory agents that are responsible for the skin flush that accompanies high niacin
dosages in normal controls [12].
In a very interesting recent paper, Miller and Dulay [13] have described using real-time
PCR and Western blots to quantify the expansion of HM74A and HM74B in postmortem
anterior cingulate brain tissue that had been taken from twelve schizophrenics and fourteen
bipolar disorder and fourteen controls. In schizophrenics, the protein for HM74A was found
to be significantly decreased relative to both total protein and HM74B protein levels seen in
controls. This study, therefore, confirmed a niacin-related abnormality in schizophrenics. The
protein for the high affinity niacin receptor, but not the low affinity receptor, was found to be
significantly down-regulated in the anterior cingulate cortex of schizophrenics. This seems
bound to alter the need for, and the reaction to, niacin in individuals suffering from this
illness. That is effective treatment for schizophrenia must logically involve high dose niacin
and the acceptance of the vitamins-as-drugs paradigm.
Pellagra is a disease caused by niacin deficiency. It is characterized by what are known
as the four D's: diarrhea, dermatitis, dementia and eventually death. Other symptoms of
pellagra include depression, ulcerations within the mouth, nausea, vomiting, seizures and
balance disorder. This illness is now rare in the Developed World, especially where foods are
fortified with nicotinamide, but less than a century ago pellagra used to be a major health
problem in the United States [14]. It is estimated that between 1906 and 1940, three million
Americans developed pellagra and 100,000 of these died from it. Pellagra was particularly
common amongst the Southern poor, who ate niacin-deficient meals that were typically
dominated by meat (pork fatback), molasses and cornmeal. Pellagra is still a significant
problem in those areas of the Developing World where niacin-deficient white rice, or maize,
In 1914, Dr. Joseph Goldberg was assigned by the United States Public Health Service to
identify the cause of the pellagra epidemic in the southern states. He soon discovered that the
well-fed staff of both mental hospitals and prisons did not develop pellagra while
malnourished patients and inmates often did. He concluded that pellagra must be a nutritional
illness, not one caused by germs as was generally believed. To prove the validity of his
hypothesis, Goldberg and his assistants and even his wife held "filth parties", at which they
injected themselves with the blood of pellagra patients. Goldberg and supporters also
ingested patients scabs, feces and body fluids but did not develop pellagra as a consequence.
In addition, in exchange for full pardons, a group of Mississippi prison inmates volunteered
to eat very poor quality diets. Within a few months, many developed pellagra. When fresh
vegetables, milk and meat were added to such inmates' diets, all symptoms of pellagra
quickly reversed. Although Goldberg had clearly shown that pellagra was a nutritional
deficiency disease, that could be prevented and cured by changes in diet, it was not until 1937
that researchers at the University of Wisconsin discovered the key vitamin involved to be
niacin. Interestingly, early pellagrologists found that long-term classical pellagra had to be
The Causes and Consequences of Vitamin B-3 Deficiency… 27
treated with up to 600 milligrams of vitamin B-3 daily. In contrast only 10 milligrams of
but were totally inadequate to cure the illness in long-term patients, who needed the high
vitamins-as-drugs paradigm dosages.
During the Second World War, Canadian troops were sent to help defend Hong Kong
against the invading Japanese. The city, however, was quickly overrun and these soldiers
captured. They were kept in infamous prisoner-of-war camps such as Changi, for about 44
months. Here prisoners were fed less than 1000 calories daily and suffered from diarrhea and
numerous other deficiency diseases. About one-third of captured Canadian soldiers died in
these camps. The remaining two-thirds lost roughly 30 percent of their body weight. Once
freed, at the end of the War in the Pacific, these Canadians were repatriated and fed well,
being given rice bran extracts which, at that time, were the only known source of B vitamins.
At first they appeared to regain their health, but in reality, malnutrition had caused long-term
problems. Such former prisoner-of-war camp inmates suffered from very high rates of
depression, other mental disorders, cardiovascular disease, blindness and early death. Their
permanent disabilities were recognized by the Canadian federal government. All such
soldiers were awarded a special disability Hong Kong pension. It appeared that each year,
spent in a Japanese prisoner-of-war camp, had reduced inmates' life expectancies by about
four years. Interestingly, the only Canadian soldiers, captured at the fall of Hong Kong, who
completely recovered, were those eventually given several grams a day of niacin. As with
long-term classical pellagra, it would seem that the effects of the extreme niacin deficiencies,
suffered in prisoner-of-war camps for several years, could only be rectified by high dosages
associated with the vitamins-as-drugs paradigm [15].
Typically, alcoholics are very niacin deficient. This is because vitamin B-3 plays an
essential role in the metabolism of alcohol and is depleted by it, a process that takes place in a
series of steps, the first of which is the oxidation of ethanol into acetaldehyde. This occurs in
the liver, where the enzyme alcohol dehydrogenase removes the hydrogens. In a second step,
acetaldehyde is converted to acetate by the enzyme aldehyde dehydrogenase. Acetate then in
a third step, becomes changed into acetyl Co-A, which subsequently enters the Tricarboxylic
Acid Cycle and eventually becomes a source for energy [16].
This multiple step alcohol breakdown process is niacin-dependent because vitamin B-3 is
required as cofactor for aldehyde dehydrogenase. However, since many alcoholics eat poor
diets, lacking adequate niacin, they may not have enough vitamin B-3 to adequately break
down the high levels of ethanol they are consuming. As a result, some of them develop a
niacin dependency, similar to that seen in prisoners-of-war who have been malnourished for
Dr. Russell Smith [17] was a pioneer in the treatment of alcoholics with high dose niacin.
He conducted a five year longitudinal study which began with 500 such patients using
28 Harold D. Foster and Abram Hoffer
nicotinic acid. After four years, benefits had become so obvious that roughly 5,000 more
adult alcoholics and several hundred adolescents with drinking problems had also been added
to the trial. Eventually, the study included alcoholics at all stages of their illness and
adolescents with alcohol-related acute toxic and chronic organic brain syndromes.
The 4,500,000 patient days of clinical experience that Smith accumulated allowed him to
generalize that, in alcoholics, benefits derived from niacin may occur within weeks or
perhaps take several years to appear. When vitamin B-3 is interrupted, the resultant
subjective changes invariably prompted restarting the medication. Interestingly, about 75% of
patients derived benefits from vitamin B-3 and demonstrated dramatic changes in their
abilities to abstain from alcohol. The benefits accompanying high dose niacin treatment
included an improved sleep pattern, mood stabilization and reduced anxiety levels, an
increased ability to problem solve, absence of "dry drunks", reduced tolerance of alcohol and
mitigation of withdrawal symptoms. Other benefits of the use of vitamin B-3 in the treatment
of alcoholism included occasional dramatic improvements in judgement and memory,
protection against cardiac and cerebral vascular accidents, sustained job performance,
improved family life and greater participation in the activities of Alcoholics Anonymous.
Interestingly, 25% of alcoholic patients showed no such improvements. Similarly,
nicotinamide demonstrated no beneficial effects in alcoholics, who had no other mental
In an overview of his works, Smith wrote:
I am convinced that nicotinic acid provides the opportunity of striking at the heart of
the physiologic mechanisms underlying alcohol tolerance, withdrawal, and perhaps even
the alcoholic disease process. Its apparent mode of action does not really fit the
traditional concepts of a vitamin but rather that of a hormone. In any event, it seems to
make a significant difference in the ability to obtain and maintain alcohol abstinence.
This assistance has been denied a large segment of the alcohol population. Considerable
experience has been amassed with nicotinic acid, including its effective-ness and a
knowledge of its adverse reactions. With this information at hand it should be possible to
Interestingly, Larsen [18] who operated the Health Recovery Center and outpatient clinic
also appeared to achieve a 75% abstinence rate in alcoholics after nutritional treatment.
However, beyond niacin supplementation, the elimination of sugar and refined foods and
supplementation with other vitamins, minerals and amino acids were used.
Bill W was the first person to attempt to evaluate niacin as a treatment for members of
Alcoholics Anonymous [19]. These individuals were no longer drinking alcohol, but
generally still suffered from a variety of mood disorders, including depression, fatigue and
anxiety. He discovered that out of a group of thirty members of AA, 10 improved
significantly by the end of one months treatment with high dose niacin, another 10 showed
benefits by the end of the second month, while the remaining 10 were not helped by the
vitamin. Bill W was so impressed by these results that he strongly advocated the widespread
adoption of vitamin B-3 as a treatment for alcoholics within AA. In this he failed because AA
rejected his recommendations, probably leading to enormous, unnecessary individual and
The Causes and Consequences of Vitamin B-3 Deficiency… 29
It is interesting to note that alcoholic pellagra is a well-known illness that like classical
Some alcoholics, however, suffer from more than a simple dietary deficiency of niacin,
created by an overconsumption of alcohol. According to Ames and his colleagues [7] there is
a clear, genetically-created need for high dose niacin in individuals who carry a naturally
occurring variant of ALDH2 (aldehyde dehyrogenase) which contains a Glu487→Lys
substitution. This Lys487 allele of aldehyde dehydrogenase is very common in Asiatics. As
will be recalled, aldehyde dehydrogenase is an enzyme required to convert acetaldehyde to
acetate, an essential step in the breakdown of alcohol. The obvious treatment for some
alcoholics, individuals who are genetically inclined towards this addiction, therefore, is very
high dose niacin. This vitamin is required to improve the reaction rate of aldehyde
dehydrogenase and so prevent the build-up of levels of acetaldehyde in the blood.
Fetal alcohol syndrome is a major problem in the children of female alcoholics. Ieraci
and Herrera [21], however, have shown that nicotinamide protects against ethanol-induced
apoptotic neurodegeneration in the developing mouse brain. These results suggest that
nicotinamide might be able to prevent some of the alcohol damage seen in fetal alcohol
syndrome, especially if pregnant women took it soon after drinking. While helping such
females stop alcohol consumption must be the key goal, if this is impossible, nicotinamide
may help protect against ethanol induced apoptotic cell death and unwanted associated adult
Hoffer has treated two cases of fetal alcohol syndrome, using high dose nutrients,
including vitamin B-3. An elder sister had been diagnosed with fetal alcohol syndrome and
her younger sibling was at risk from the same problem. Both showed significant
improvement after ten months on the programme. Obviously, much larger clinical trials are
required to further assess the value of nicotinamide and niacin in the treatment of fetal
alcohol syndrome. However, since this disorder is one of the most common causes of mental
illness in the Developed World, such trials are clearly warranted.
In 1980, Clarkes [22] pointed out that niacin is chemically similar to nicotine, and that
the latter may occupy niacin receptor sites in the central nervous system. Beyond this, he
suggested that the calming effects of cigarette smoking may actually be the result of this
occupation of niacin receptor sites by nicotine and, if so, tobacco addiction might be treated
by the prescription of high dose niacin. Prousky [23] reported the use of daily doses of niacin
or niacinamide, in the 1.5-3 gram range, to treat tobacco addiction. Some patients were
weaned off cigarettes easily, within a two to 3 week period, others reported a decline in
cravings for tobacco and roughly halved their cigarette use.
Prousky points out that, if Clarkes' hypotheses are correct the:
Addiction to and cravings for nicotine might exacerbate or promote a vitamin B3
deficiency and stimulate a biological need to have niacin receptor sites occupied.
Nicotine addiction and other conditions such as alcoholism, diabetes, early porphyrias,
30 Harold D. Foster and Abram Hoffer
eating disorders, heart failure, hypertension and pellagra, appear to be among a category
of diseases known as the NAD Deficiency Diseases (NAD-DD). NAD-DD result from
long-term, sub-optimal intake of vitamin B3, which leads to a deficiency of NAD, and
results in `diseases or unwanted behaviours and addictions geared towards the filling of
unoccupied NAD receptor sites. The principle treatment for the NAD-DD is the
administration of optimal amounts of vitamin B3 in order to cover the NAD receptor sites
and shut-off the vicious addiction-withdrawal cycle.
Interestingly, niacin has been used to successfully treat addictions ranging from alcohol
and tobacco to cocaine and heroin. One of this chapter's authors, Dr. Hoffer has had extensive
experience with the use of high dose niacin in the treatment of the LSD reaction. The LSD
molecule per se does not cause the usual LSD psychedelic or hallucinogenic reactions. Many
subjects do not respond even when given 200 micrograms of LSD. When they react, they do
not do so immediately, as would be the case with other hallucinogens. The LSD appears to
induce a series of reactions in the body. Dr. Hoffer has found that a few alcoholics, given
psychedelic therapy, did not have the usual reactions until they were given an injection of
adrenochrome. They would then respond in about ten minutes. It appears that LSD induces
oxidative stress which increases the oxidation of catechol amines to their oxidized chrome
derivatives, such as adrenochrome or dopachrome. It was also found that niacin was a good
antagonist to LSD when given before or during the reaction. In addition, it was discovered
that one hundred milligrams of niacin, given intravenously, would bring subjects back to
It appears that dopamine deficiency probably plays an important role, not just in
Parkinson's disease, but also in Encephalitis lethargica, multiple sclerosis and amyotrophic
lateral sclerosis [24]. However, attempts to correct such inadequacies with L-DOPA,
especially at high dosages, while initially beneficial because they relieved the deficiency,
quickly produced a wide range of negative side effects. According to Foster and Hoffer:
The most logical interpretation of the L-DOPA experience is that patients with
untreated Parkinson's disease, Encephalitis lethargica, multiple sclerosis and amyotrophic
lateral sclerosis all display two distinct types of symptoms. Some of these are due
directly to a deficiency of dopamine and are quickly improved by L-DOPA. A second set
of symptoms, however, are the result of neurological damage caused by the metabolites
of dopamine. The use of L-DOPA, therefore, increases the severity of these symptoms
over time until they outweigh any improvement observed from the correction of
dopamine deficiency. It is suggested that the damaging side-effects of L-DOPA's use
stem not directly from the drug but from its oxidation products which include
dopachrome and other chrome indoles which are hallucinogenic, toxic to neurons and
have been seen to hasten death in Parkinsonism patients.
If this hypothesis is correct, four corollaries must follow. Firstly, patients suffering from
any of the four neurological disorders just described should display evidence of excessive
The Causes and Consequences of Vitamin B-3 Deficiency… 31
oxidative stress. There is a significant literature to support this reality [25-26]. Secondly, high
doses of natural methyl acceptors should slow the development of these neurological
disorders. Thirdly, in untreated patients, one might expect serious deficiencies of natural
methyl acceptors, such as thiamine (vitamin B-1), riboflavin (vitamin B-2), niacin (vitamin
B-3) and ubiquinone (coenzyme Q10). Fourthly, elevated antioxidant supplementation, given
with L-DOPA, ought to prolong the period in which this drugs benefits outweigh side-effects.
Of particular concern here is the role of the natural methyl acceptor niacin. Shults and
coworkers [27] have shown that in animals given Parkinsonism by the administration of
MPTP, coenzyme Q10 and vitamin B-3 provide protection against dopamine depletion. As a
result, they appear to help prevent the cellular damage of dopamine's oxidative biproducts,
such as dopachrome. This may help to explain Hoffer's success in adding high doses of
coenzyme Q10 and vitamin B-3 to the normal treatment for Parkinsonism [5]. Hoffer and
Walker [28] also have documented the long-term survival, 22 years and increasing, of an
amyotrophic lateral sclerosis patient taking high doses of coenzyme Q10, selenium, zinc,
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