JOM Volume 26, Number 4, 2011 Review Article 163

Treating Dementia with B3 and NADH

Jonathan E. Prousky, ND, MSc1,2

1 Chief Naturopathic Medical O!cer, Professor, Canadian College of Naturopathic Medicine, 1255 Sheppard Avenue East, Toronto, Ontario, M2K 1E2, Tel: 416-498-1255 ext. 235, email: [email protected] 2 Editor, Journal of , email: [email protected]

Abstract Dementia a!ects approximately 5 million people in the United States, and about 475,000 elderly Canadians. Dementia is a debilitating and often progressive illness. "e most common type of dementia is Alzheimer’s disease, followed by vascular types. "ere is a need to investigate novel treatments because the current crop of medications have limited value. might be a worthwhile treatment to consider. Research has shown that the risks of incident AD increase when patients have insu#cient intakes of niacin from diet or medical conditions that precipitate niacin de$ciency. Clini- cal reports have documented therapeutic bene$ts when patients receive optimum daily doses of niacin. Preliminary trials evaluating the reduced form of nicotinamide adenine dinucleotide (NADH) found it a safe and e!ective treatment for AD. At present, research evaluating the therapeutic applications of niacin and/or NADH for dementia is at a standstill. However, niacinamide is being evaluated in a clinical trial to determine if it is safe and bene$cial for patients with AD. Hopefully, the forthcoming results will encourage researchers and clinicians to study niacinamide further, and revisit the therapeu- tic potential of vitamin B3 as a safe and an e!ective treatment for dementia.

Introduction functions, including language, motor skills, Among elderly patients, Alzheimer’s judgment, orientation ability, and, most disease (AD) is the most common type of notably, memory. Patients eventually lose dementia, followed by vascular types. World- themselves in the disease, unable to remem- wide, more than 30 million people su!er ber even vestiges of the lives they once lived. from AD. In the United States, AD a!ects #e cognitive declines of AD are asso- approximately 5 million people.1 About ciated with problems in the cerebral cortex 475,000 elderly Canadians have dementia, including the formation of senile plaques, with the majority of cases being attributed to neuro$brillary tangles, and granulovascular AD.2 Experts predict that the number of pa- degeneration of neurons.3 Various risk fac- tients a"icted with dementia in Canada will tors have been implicated in the suscepti- increase to 778,000 by the year 2031.2 #e bility to AD. #ese include advancing age, burden that this disease will place on health family history, apolipoprotein E epsilon 4 care systems is staggering when you consider genotype, obesity, insulin resistance, vascular that the elderly constitute the fastest growing factors, dyslipidemia, hypertension, in%am- population in all industrialized countries.1 matory markers and Down syndrome.1 Dementia is a debilitating and often #e medical treatment of AD uses ace- progressive illness characterized by intellec- tylcholinesterase inhibitors or n-methyl-d- tual decline and the loss of higher cognitive aspartic acid glutamate receptor antagonists,

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with the former treatment having only weak participants were reported to have pellagra evidence of bene$t on cognitive function.4 (i.e., diarrhoea, dermatitis, dementia, and Clearly there is a need to investigate other shortly thereafter, death), some participants treatments because the current crop of med- who demonstrated mental and cognitive de- ications have limited value in mitigating the clines may not have met the recommended progression and symptoms of dementia, most dietary allowance for niacin (14 mg for adult notably, AD. In this article, I will summarize females and 16 mg for adult males6). Some and comment on: (1) research linking a re- of the study participants may have had sub- duction in the incidence of AD with high clinical pellagra. dietary intakes of vitamin B3; (2) the merits #e mental signs of mild niacin de$cien- of using niacin or the reduced form of nico- cy (a.k.a., pellagra sine pellagra) often occur tinamide adenine dinucleotide (NADH) as in the absence of any dermatologic, mucous treatments for dementia; and (3) current re- membrane, or gastrointestinal symptoms.7,8 search investigating the safety and e&cacy of #e researchers did not acknowledge that niacinamide as a treatment for AD. niacin de$ciency can lead to symptoms of AD, and thereby play a role in the patho- Preventing AD with Vitamin B3 genesis of AD. Decades ago Aring and Spies Research has shown a relationship be- reported that neurasthenic symptoms in 225 tween dietary niacin and the development of mild pellagrins were ameliorated by taking AD.5 A total of 3,718 participants aged 65 300 to 600 mg of niacin every day for 1-12 years and older underwent at least two clini- days (3-6 pills, with each pill providing 100 cal assessments and provided dietary data for mg of niacin).8 #e neurasthenic symptoms analyses over a median of 5.5 years. In this reversed by niacin appeared long before any large, prospective study, dietary niacin de$- other manifestations of the disease. #ese ciencies were associated with incident AD included fatigue, insomnia, anorexia, vertigo, and cognitive decline. Niacin intake from burning sensations in various parts of the foods was inversely associated with AD body, numbness, palpitation, nervousness, a (p for trend = 0.002). A higher food intake feeling of unrest and anxiety, headache, for- of niacin was associated with a slower annual getfulness, apprehension, and distractibil- rate of cognitive decline. Speci$cally, an in- ity. #ese niacin-de$ciency manifestations creased food intake of niacin slowed the an- could easily be confused with prodromal nual cognitive decline by 0.019 standardized symptoms of AD, and, if left untreated, they units per natural log increase in intake (mg), could become severe enough for a diagnosis which was statistically signi$cant (p=0.05). of AD. #e dementia of pellagra looks much #e participants in intake quintiles 2-4 had a like AD since its clinical presentation, while statistically signi$cant 70% reduction in risk varied, includes aggression, apathy, confu- compared to participants in the lowest quin- sion, depression, disorientation, hallucina- tile (median niacin intake 12.6 mg/day). #e tions, insomnia, psychosis, and seizures.9 participants in the highest quintile (median Low dietary intakes of niacin would not niacin intake 22.4 mg/day) had an 80% sta- entirely account for the increased incidence tistically signi$cant reduction in risk. of AD among the study participants. Many #ese researchers did not provide any participants had varying intakes of alcohol robust explanations as to why diagnoses of and cigarette consumption, as well as the AD increased among participants with low presence of diabetes and/or cardiovascu- dietary intakes of niacin but they did note lar disease. #ese and other possible factors that the level of dietary niacin associated could have increased the participants’ vulner- with pellagra (8.8 mg of niacin equivalents ability to niacin de$ciency during the study per 2000 kilocalories) was lower than the period (Table 1, opposite).7 range of intake for the lowest quintile (13.2- Above all, this study demonstrates that 27 mg per day). While none of the study insu&cient intake of niacin from diet or

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Table 1. Possible causes of niacin deficiency

Precipitating Factors Explanations Inadequate amount of niacin in diet Inability to procure an adequate diet (e.g., socioeco- nomic reasons), or choosing a nutritionally unbal- anced diet (e.g., due to ignorance, individual prefer- ence, or lack of advice about nutrition)

Interference with ingestion Functional and organic conditions leading to an- orexia or vomiting, gastrointestinal disease, psychi- atric disorders (e.g., psychoneuroses, both organic and functional psychoses, and addiction to alcohol or other ), neurological and traumatic disorders that interfere with self-feeding, and oral diseases (e.g., sore mouth, or loss of teeth)

Interference with bio-synthesis Inadequate intake of tryptophan, ingestion of structurally similar compounds that would inhibit the formation of niacin by substrate competition (e.g., maize), and destruction of intestinal bacteria (e.g., bowel “sterilizing” antibiotics)

Interference with absorption Absence of normal digestive secretions (e.g., achlo- rhydria and obstructive jaundice), intestinal hypermotility (e.g., various types of diarrhoea), reduction in absorptive surface (e.g., disease or surgical removal of the gastrointes- tinal tract), and medications (e.g., mineral oil)

Interference with utilization Problems with cellular metabolism (e.g., alcohol, general anaesthesia, and metabolic disorders such as hypothyroidism or diabetes), specific inactivation (e.g., sulphonamides exert an anti-vitamin effect by substrate competition with para-aminobenzioc acid, corn, and isoniazid)

Interference with storage Any condition causing impairment of liver function would interfere with the amount of niacin retained in the body

Increased excretion or loss Elevated metabolic rate (e.g., hyperthyroidism), periods of rapid growth, pregnancy and lactation, pyrexia from any cause, any condition requiring increased muscular activity, and specific treatments (e.g., high carbohy- drate diets, insulin, thyroid medication, and overuse of stimulants (such as caffeine or amphetamines)

Increased nutritive requirements Urinary loss (e.g., renal disease, and diabetes), or other routes (e.g., lactation, serous exudates due to burns, and severe blood loss)

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conditions that can precipitate vitamin de$- if a patient’s psychiatric condition was due to ciency can increase the risks of incident AD. a de$ciency of niacin (i.e., an “avitaminosis”) As more data emerges linking niacin insuf- even though the aetiology was uncertain. In a $ciency to AD, it might be prudent to create discussion following their paper, other clini- public health programmes to promote niacin cians remarked that the therapeutic value of consumption from foods or increase niacin niacin could not necessarily be attributed to forti$cation. Such measures could protect the correction of a vitamin de$ciency. #ey more of the population from mental and reported that niacin might have helped some cognitive decline, and reduce the incidence patients as a result of its physiological e!ects of dementia. upon cerebral circulation, and/or as a result of its ability to facilitate carbohydrate metabo- Treating Dementia with Niacin lism within the brain. Subsets of patients with early or even In 1952, Gregory administered large established dementia appear to require large doses of niacin orally (300 mg three times daily doses of niacin to reverse and/or slow daily) and intravenously (100 mg/day) to 54 the progress of their disease. In 1941, Syden- patients having organic psychoses of senil- stricker and Cleckley were two of the $rst ity immediately following their admission clinicians to report impressive bene$ts from to a private mental hospital.11 During their oral and intravenous niacin administration in hospital stays, patients were also given a nu- 29 patients with stuporous or active psycho- tritious diet and liberal amounts of other ses of unknown origin.10 Two-thirds of their . All patients were evaluated before patients were in the presenile or senile age treatment and immediately following any range with severe psychiatric symptoms of degree of improvement. #e evaluations in- a confusional nature, but none had physical cluded thorough psychiatric examinations signs of malnutrition or pellagra. Twenty- (with particular reference to orientation, eight patients recovered after niacin treat- memory, and secondary symptoms), as well ment. Eight patients received oral niacin as intelligence tests. #e duration of niacin treatment, while the remaining 21 patients treatment was approximately 3-12 weeks. received intravenous niacin or a combination Once patients became maximally improved, of oral and intravenous niacin. #e oral niacin they were placed on a maintenance dose of prescribed to patients ranged from 75-4500 niacin (100 mg orally/day). In the group mg daily until discharge. #e intravenous of 14 patients 65 years of age and under, 8 doses of niacin ranged from 100-900 mg. patients improved dramatically following For most patients, the intravenous admin- niacin treatment. #ey were able to leave the istration continued until discharge, but for hospital, whereas the remaining 6 patients some patients, intravenous treatments were improved symptomatically or not at all. In stopped and replaced by oral niacin until dis- the group of 40 patients over the age of 65, charge. Within 4 days of niacin treatment, 31 completed the course of niacin treatment. the majority of these patients experienced Only 4 patients from the over-65 group rapid and usually impressive improvements. improved enough to re-socialize. #e au- While the duration of niacin treatment was thor concluded that “nicotinic acid is most unclear, estimates from the cited case reports e!ective in those psychoses of senility that suggest 7-30 days or longer since some pa- are of recent, and fairly rapid, onset,” which tients continued with the niacin treatment was reported to be of a duration less than 6 following their hospital stay. #e authors months. #e $ndings showed that the earlier concluded that the majority of patients with niacin treatment was started, the better the toxic psychosis or exhaustion delirium, as well prognosis, especially among patients 65 years as those with unexplained clouding of con- of age and under. With respect to mecha- sciousness, should be given a therapeutic trial nism of action, the author discussed several of niacin. #is was the only way to determine possibilities including: (1) the correction of

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a niacin de$ciency; (2) a “saturation” e!ect leagues discovered that 3,000 mg/day of in the absence of any de$ciency; and/or (3) niacin improved and sometimes reversed cerebral vasodilatation. #e author also sug- dementia.12 Ho!er’s patients required large gested that lesser amounts of niacin might daily doses of niacin to remain well (Table delay or prevent the psychoses of senility if 2, below). given to individuals in the presenile and se- In total, 12 of 15 elderly patients re- nile age groups. sponded favourably to large doses of niacin. In 1962, Dr. Abram Ho!er and his col- Table 3 (p. 168) describes the type of clinical Table 2. Treatment response from large (3000 mg/day) doses of niacin in 15 elderly patients fast becoming senile or with clear evidence of senile mental changes Patient Age Diagnosis Clinical response Duration Initials (years)

OR 62 Psychosis Recovered 4 with arteriosclerosis

JC 80 Presenile psychosis Recovered 1

HC 67 Presenile changes Recovered 6

FM 72 Normal Remains well 6

MT(f) 58 Normal Remains well 3

MT(m) 63 Normal Remains well 2

AC 79 Senile depression Recovered 1.5

LW 74 Senile psychosis Recovered 0.25

MC 70 Normal Remains normal 0.75

BB 68 Senile depression No response 0.25

GC 75 Psychosis with Marked 0.5 arteriosclerosis improvement

RR 67 Psychosis with Marked 1 month arteriosclerosis improvement

DG 68 Psychosis with No change Not provided arteriosclerosis

NR 77 Psychosis with No change Not provided arteriosclerosis

HV 70 Depression Remains well 1

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Table 3. Brief clinical descriptions of the therapeutic effects of niacin in elderly patients

Case JC (Age 80): In February, 1959, this woman had a mild coronary occlusion. She developed generalized weakness, weakness grasping with one hand, anorexia, and ataxia. She was also nervous and had feelings of confusion and hopelessness. During April, 1959, she began to take three grams of nicotinic acid daily. Within a few weeks, her appetite improved and she felt stronger. By June, she was able to walk slowly but well. Mentally, she was much improved. She still had a few episodes of nervousness preceding social events. There was no more confusion and her memory was good. For the next year, she continued to improve and in April, 1960, she was quite well. In May, 1960, she had influenza and later that month she died from a coronary occlusion and secondary metastasis of a bowel carci- noma. She had been mentally alert up to three days before dying, when she sank quietly into her fatal coma.

Case GC (Age 75): For several months Mr. G.C. complained of violent dizzy spells, with headaches, vomiting and general deterioration. Physically he was normal. In November, 1959, he was given nicotinic acid, three grams daily. Two months later he was much im- proved. He had no more dizzy spells and regained his normal vigour. April 13, 1960, he ran out of tablets. There was a rapid relapse and again he complained of headaches and dizzy spells. Nicotinic acid tablets were sent to him and again he improved.

responses that were observed by Ho!er and cursor), other amino acids and thiamine, and 16 his colleagues.12 In many of these cases, pa- found them reduced in patients with AD. tients who responded to niacin remained im- In these three studies, dietary intakes did not proved as long as they did not stop the vita- satisfactorily explain the $ndings. min. Once they discontinued it, they relapsed Niacin might also aid dementia as a fairly quickly, but they improved again when result of its well-established cholesterol- they resumed the vitamin. Ho!er reasoned modifying properties (i.e., lowers low den- that these patients had metabolic conditions; sity lipoprotein-cholesterol, increases high- vitamin dependencies which required more density lipoprotein-cholesterol, and lowers 17 niacin than they obtained from their diets. triglycerides). Research has shown choles- Another case reported by Ho!er in 1974 terol reduction to possibly aid in the treat- 18,19 (and mentioned in his book, Smart Nutrients) ment of dementia. While data regarding involved his mother who was 86 years old at this relationship is emerging, some published the time of publication (Table 4, opposite).13 reviews have shown contradictory results From the cited clinical reports, it is ap- and even negative outcomes from cholester- 20,21 parent that niacin administration o!ers clin- ol-modifying medication. More studies ical bene$ts irrespective of dietary intakes. are needed to determine whether cholesterol #ere is likely some metabolic need for ad- modi$cation is a reasonable and e!ective in- ditional amounts of niacin among a subset of tervention for dementia. patients who show early signs of dementia Another possibility for niacin’s e!ective- or have established dementia. Two case-con- ness might involve its ability to increase cere- trolled studies reported lower blood levels of bral blood %ow due to its presumed ability to a nicotinic acid metabolite among patients increase cerebral vasodilatation. When niacin with dementia compared to similarly aged is administered orally in amounts of 500 mg -1 controls.14,15 Another study assessed plasma or topically via a 6-inch patch of 10 M aque- concentrations of tryptophan (a niacin pre- ous methylnicotinate on the forearm, prosta-

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Table 4. Hoffer’s clinical description of his mother’s response to a daily dose of 3000 mg of niacin

Case CH (Age 86): In 1954…my mother, then 67 years old, was very nervous and de- pressed and complained of severe pain in her joints, failing vision in one eye, generalized weakness and fatigue, and severe arthritis of her hands…Her memory was beginning to fail. It was clear that she was aging very quickly. I knew no treatment was effective but I was by then familiar with nicotinic acid used in megadoses. I decided to start her on 3 grams per day, more or less as a placebo…To my amazement, mother was nearly well six weeks later. Her arthritis had cleared, her fingers were straight, and Heberden’s nodes be- gan to soften and regress. Her vision in both eyes was normal, and her tension, anxiety, and depression were gone…Today (1974) at 86 she is physically weaker, does not hear as well, but is mentally well…She has been taking 3 grams each day of nicotinic acid for 18 years. I have not seen any evidence of toxicity, and there has been no progression of mental senil- ity which was so apparent 18 years ago.

glandin D2 (PGD2) is markedly released in rebral blood %ow and in arterial blood pres- the skin and high amounts of its metabolite sure in venous vessels of the head, but this appear in the plasma.22,23 It is not known if was followed by a lowering of these parame- PGD2 causes vasodilatation of the intracra- ters.27 In a study assessing cerebral blood %ow nial blood vessels, but niacin’s ability to abort in baboons under anaesthesia using single acute migraine headaches suggests that this photon emission computed tomography of might be occurring.24 the brain, a combination of niacin and pen- Old reports cited by Bicknell and tifylline increased cerebral blood %ow com- Prescott,25 indicated that niacin causes vaso- pared to the control baseline (p<0.01).28 In dilatation of the cerebral and spinal vessels. another study of similar design, the cerebral #ey also noted that intravenous niacin ad- blood %ow was increased above that of the ministration increases the rate of intracranial control when a combination of pentyifylline blood %ow in human beings for 20-60 min- and niacin were administered to baboons.29 utes without any signi$cant change in blood #e increase in cerebral perfusion (denoted pressure. Other published data pertaining to as an increase in R-value) was +29 % from niacin’s e!ects on cerebral vasodilatation has the pentyifylline-niacin combination (2.31 ± been equivocal. In one study, subjects hav- 0.19) compared to the control (1.79 ± 0.13). ing various diseases (e.g., pernicious anemia, Based on these reports, it appears that congestive heart failure, hysteria, diabetes, intravenously-administered niacin might and hypertensive vascular disease) were giv- increase cerebral blood %ow. More intra- en intravenous niacin (300-800 mg in 200- venous niacin studies are warranted. Al- 300 mL of saline over 20-25 minutes). Nu- though no reports examine the e!ects of merous measurements were obtained, such orally-administered niacin upon cerebral as arterial pressures, blood oxygen contents, blood %ow in human or animal subjects, nia- glucose, cerebral oxygen utilization, cerebral cin could be increasing cerebral blood %ow glucose utilization, and cerebrovascular re- since it has been shown to abort acute mi- sistance.26 #e results of this study failed to graine headaches presumably by vasodilata- $nd any e!ect upon cerebral vasodilatation tion of the intracranial blood vessels.24 #is by the intravenous administration of niacin. potential mechanism of action is important. In an animal study using anesthetized Data demonstrate that as dementias of the cats, intravenous injection of niacin (0.5 mL/ Alzheimer and vascular types progress, ce- kg) caused a short-term increase in both ce- rebral blood %ow and metabolism become

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functionally low.30 #e severity of demen- in%ammatory cytokine known as S100.35 tia symptoms have been correlated to de- IL-1 promotes the synthesis of beta-amy- viations in cerebral blood %ow and metabo- loid precursor protein (β-APP) in neurons, lism.30 A more recent study found marked and promotes β-APP outside the cell where cerebral blood %ow reductions in the frontal it forms plaques.35 A preliminary study us- (p=0.001) and parietal (p=0.001) cortices in ing rats found that slow-release niacin, or a both vascular dementia and AD, when com- combination of slow-release niacin and sim- pared to aged-matched cognitively normal vastatin, were able to reduce axonal damage controls.31 Since orally-administered niacin and increase axonal density by decreasing the bene$ts some patients, its therapeutic prop- expression of amyloid precursor protein.36 erties might facilitate cerebral vasodilatation While this study is very preliminary, these re- and increase cerebral blood %ow. sults suggest that supplemental niacin might Niacin might also bene$t patients with o!set the production of amyloid plaques, dementia as a result of its ability to stimulate which are perhaps the most important histo- cellular metabolism. #e brain is almost en- pathological markers in AD. Amyloid plaques tirely dependent on the metabolism of glu- also occur within the brain when ischemia is cose by oxidative processes. In a decades-old present,36 which suggests that supplemental study, patients with organic brain syndromes niacin might lessen axonal damage associ- (mean age: 68 years) had their cerebral blood ated with vascular types of dementia as well. %ows evaluated.32 Clinical deterioration and Table 5, (opposite) summarizes niacin’s pur- functional decompensation was associated ported mechanisms of action in the treat- with a worsening in cerebral and oxidative ment of AD and vascular types of dementia. metabolism, and a resultant shift to anaero- bic glycolysis. Signi$cantly heightened ce- Treating Dementia with NADH rebral metabolic rates of lactate were con- NADH is a coenzyme in all living cells, sidered a causal quantitative factor in the including the brain. As a component of the pathogenesis, manifestation, and severity of electron transport chain, it plays a central role organic brain syndromes. in intracellular energy production. NADH An insu&cient supply of nicotinamide is also believed to increase the synthesis of adenine dinucleotide (NAD) is known to the dopamine and norepi- inhibit the conversion of lactate to pyruvate, nephrine in the brain. and contribute to a high lactate-to-pyruvate In an open-label pilot trial involving 17 ratio.33 #erapeutic doses of niacin might di- AD patients taking 10 mg of NADH 30- minish the shift in anaerobic glycolysis (and minutes before their $rst meal for 8 to 12 lower lactate levels) as a result of niacin’s abil- weeks, all patients had demonstrable cogni- ity to increase the synthesis of NAD.34 #e tive improvements (as per favorable changes increased synthesis of NAD might drive the in their mini-mental state exams and global conversion of lactate to pyruvate, enhance ox- deterioration scales).37 No side e!ects were idative processes within the brain, and miti- associated with the NADH treatment. Some gate cerebral metabolic disturbances associ- patients took NADH for more than one year. ated with increased cerebral lactate levels. #ey also reported no side e!ects. Yet another potential mechanism might Following the pilot trial, 25 patients with explain how niacin bene$ts some patients mild to moderate dementia of the Alzheimer, with dementia. Niacin might reduce axonal vascular, and fronto-temporal types received damage and increase axonal density. Re- 10 mg of NADH daily in addition to their search has shown that neuronal damage in cholinomimetic medication.38 Nineteen of the brains of patients with AD leads to acti- the 25 patients completed this 3-month vation of brain immune cells – microglia and open-label trial. #e results showed no evi- astrocytes – and stimulates them to produce dence of bene$t (as per established psycho- interleukin-1 (IL-1) and a soluble astrocyte metric tests), so the authors concluded that

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NADH is unlikely to enhance cognitive and visual-construction ability (p=0.038), ability and could not treat dementia. with a trend toward improved abstract ver- #e most recent trial, published in 2004, bal reasoning (p=0.08). No di!erences were was favorable.39 In this randomized, place- found between the AD patients and placebo bo-controlled, matched-pairs, double-blind, group in measures of attention, memory, or 6-month clinical study, patients with prob- clinician ratings of dementia severity. able AD (n = 26) were randomized to re- #e rationale for using NADH as a ceive either NADH (10 mg/day) or placebo. treatment for dementia comes from several At the conclusion of the trial, AD patients sources of evidence which suggest that this who received the NADH treatment had no treatment can reverse some of the defects as- 40 evidence of further cognitive deterioration. sociated with AD (Table 6, below). Clearly #eir dementia rating scales showed im- more studies are needed. #e initial dosage proved scores compared to the AD patients of NADH should be 10 mg/day about 30- in the placebo group (p<0.05). Speci$cally, minutes prior to a meal. #e label or package the NADH treatment was associated with insert must state that the particular NADH signi$cantly better verbal %uency (p=0.019) product is stabilized; otherwise, it will be de-

Table 5. Niacin’s purported mechanisms of action in the treatment of AD and vascular types of dementia t3FTPMWFTNFUBCPMJDEFQFOEFODZCZSFQMFUJOHFO[ZNFDPGBDUPST

t.PEJmFTMJQJEMFWFMT JF UIFDIPMFTUFSPMQSPmMF

t*ODSFBTFTDFSFCSBMCMPPEnPXWJBWBTPEJMBUBUJPO

t4UJNVMBUFTDFMMVMBSNFUBCPMJTNCZJODSFBTJOHUIFQSPEVDUJPOPGOJDPUJOBNJEFBEFOJOF dinucleotide

t3FEVDFTBYPOBMEBNBHFBOEJODSFBTFTBYPOBMEFOTJUZCZEFDSFBTJOHUIFFYQSFTTJPOPG amyloid precursor protein

Table 6. NADH’s purported mechanisms of action in the treatment of AD

AD Defects reported in the scientific literature NADH’s biochemical effect

Dopaminergic Increases dopamine production by system dysfunction regenerating tetrahydrobiopterin, an essential cofactor in tyrosine hydroxylase

Increased oxidative stress Repletes antioxidant level

Reduced activity of enzymes (i.e., NADH Reverses oxidative phosphorylation ubiquinone oxidoreductase and NADH diaphorase) defects important for energy metabolism in the brain

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Conclusion graded by the hydrochloric acid in the stom- ach and rendered ine!ective. Numerous clinical reports have shown that patients with dementia can bene$t from Current Research niacin supplementation. Niacin can also help At present, research evaluating the ther- to prevent the incidence of AD. #is makes apeutic applications of niacin and/or NADH niacin therapy a clinically-plausible inter- for dementia is at a standstill. However, nia- vention which merits further study. One cinamide is being evaluated in a clinical trial open-label and one small randomized con- to determine if it is safe and bene$cial for trolled trial have shown NADH to bene$t patients with AD.41 Patients will be random- patients with AD, but no substantive clini- ized to treatment or placebo groups. #ose cal trials have been done to con$rm these given niacinamide will take 1,500 mg twice preliminary $ndings. Only niacinamide daily for 24 weeks. #e results of this study is currently being investigated as a treat- should be available within the next year. #e ment for AD. Hopefully, the forthcoming rationale for using niacinamide is that it can results will be positive and encourage re- prevent nerve cell degeneration in animal searchers and clinicians to review the lit- models of various neurodegenerative diseases erature and perform additional research to (e.g., amyotrophic lateral sclerosis, Hunting- verify the bene$ts of vitamin B3 therapy for ton’s disease, and Parkinson’s disease).42-44 In treating dementia, develop dosage recom- addition, niacinamide was shown to markedly mendations and revise clinical guidelines. improve learning and memory in transgenic Acknowledgements mice that develop AD. Treatment with the vitamin also resulted in decreased accumula- I thank Mr. Bob Sealey for his helpful tion and increased stabilization of tau, a pro- editing suggestions and input on the con- tein that accumulates excessively in AD.45 tents of this paper. #e earliest report showing that niacin- Competing Interests amide can assist in dementia was written by Foster, in 1949, after he gave niacinamide to #e author is a consultant for Veeva Inc., 40 patients with toxic psychosis (considered a company that develops and sells natural an organic reaction accompanied by mem- health products with a strong focus on stress, ory defect, disorientation, and other mental anxiety, sleep and overall mental health well- de$cits).46 Twenty-three of the 40 patients ness. Veeva Inc. has not seen this manuscript were over the age of 60. Foster concluded nor do they have any knowledge of it. that niacinamide therapy should be com- References menced at the onset of psychosis. He noted that the response is usually rapid and dra- 1. Kuljis RO: Alzheimer’s disease. EMedicine. Re- trieved from [www.emedicine.com/neuro/topic13. matic even when the toxic psychosis presents htm]. without signs of vitamin de$ciency. 2. Canadian Study of Health and Aging Working Current research demonstrates that nia- Group: Canadian study of health and aging: study cinamide is likely to bene$t patients with methods and prevalence of dementia. CMAJ, AD and vascular types of dementia because 1994; 150: 899-913. 3. Reisberg B: Alzheimer`s disease: the standard ref- it provides global protection against neu- 47 erence. New York, NY. #e Free Press. 1983. ronal and vascular injury. Although the 4. Mancuso C, Siciliano R, Barone E, et al: Pharma- mechanisms that account for the vitamin’s cologists and Alzheimer disease therapy: to boldly unique therapeutic properties are complex go where no scientist has gone before. Expert Opin and require further delineation, niacinamide Investig Drugs, 2011; 20: 1243-1261. 5. Morris MC, Evans DA, Bienias JL, et al: Dietary therapy may bene$t patients by reducing niacin and the risk of incident Alzheimer’s disease neuronal damage associated with anoxia and and of cognitive decline J Neurol Neurosurg Psy- 47 nitric oxide cytodegeneration. chiatry, 2004; 75: 1093-1099.

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