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168
Supplemental Niacinamide Mitigates Anxiety Symptoms: Three Case Reports
169
Journal of Orthomolecular Medicine Vol. 20, No. 3, 2005
On July 2, 2004, the patient emailed me was diagnosed with panic attacks, dyspep-
with an update. She discontinued all the pre- sia (possible irritable bowel syndrome), and
scribed treatments except for the niacina- mild obesity. She was advised to continue
mide. She found her anxiety and depression with her liquid multiple vitamin/mineral
to be much relieved due to being at home and preparation, take 500 mg of niacinamide three
not teaching during the summer months. times each day for two days, and was told to
When she felt anxiety she would take niaci- increase the dose to 1,000 mg twice daily. Two
namide and it would help. In her words, I capsules of lactobacillus acidophilus were
take the niacinamide and Im fine afterwards. prescribed every morning upon rising.
A follow-up visit occurred on May 26,
Case #3 2004. The patient felt a little better during
A 42-year-old female first presented to the first week on niacinamide. However, she
my private practice on May 16, 2004, for felt jittery and related this to her fathers
chief complaints of constipation and anxi- grim prognosis. Her sleep was unaffected,
ety. About three weeks ago her father had even though she did wake-up once each
been diagnosed with advanced carcinoma night to go to the bathroom. Overall, she
of the stomach. For three days following his felt much more under control. She was
diagnosis the patient experienced very soft advised to increase the niacinamide to
stools once or twice daily. For her entire life 1,000 mg three times each day.
she had been constipated, requiring regu- On July 12, 2004, she came in for an-
lar laxatives in order to have a daily bowel other visit. She cut back on the niacinamide
movement. The patient reported additional since she felt that it caused her to have feel-
gastrointestinal symptoms of bloating, gas, ings of not being present. Instead of 3,000
and right-sided abdominal pain. She had mg daily she lowered the dose to 2,000 mg
taken fiber therapy in the past but had per day. Her constipation was not a prob-
never stayed on it long enough to see the lem and she was having one bowel move-
benefits. She was not concerned about the ment daily. Her anxiety was much im-
constipation since she had been having at proved on this dose and the previous shaki-
least one-to-two soft stools per day. ness had completely resolved. In fact, she
Since her fathers diagnosis she had had not experienced any episodes of shaki-
been feeling very anxious with symptoms ness since the last visit. She was told to
of shakiness, light-headedness, numbness continue the prescribed treatments and to
of the extremities, and balance problems. take a B-complex vitamin preparation and
Her medical doctor had her do a twenty- 1 mg of folic acid each day.
four-hour holter monitor and the results
were normal. She was unable to correlate Subclinical Pellagra
her anxiety with feelings of hunger. In the These three case reports and an addi-
past, she would have the same kind of anxi- tional case report by this author,14 demon-
ety symptoms when stressful events oc- strate that niacinamide is capable of reduc-
curred. Her medical doctor felt that the ing symptoms of anxiety. All the patients
patients anxiety was related to hyperven- responded favourably to large pharmaco-
tilation. On physical examination, the pa- logical doses of niacinamide (2,000-2,500
tient was well nourished, slightly over- mg per day or as needed). These amounts
weight, with normal blood pressure and were much greater than the amounts of
normal heart sounds. All other systems vitamin B3 or protein (containing tryp-
were within normal limits. Even though her tophan) that would be necessary to prevent
mother currently has heart disease, the rest full-blown pellagra. The initial symptoms
of her family history was unremarkable. She of pellagra tend to involve the gastro-
170
Supplemental Niacinamide Mitigates Anxiety Symptoms: Three Case Reports
intestinal system, which are known to pre- note a deficiency state that could not be
cede the dermatological ones.15 In these ameliorated by dietary modifications, but
three patients, the gastrointestinal symp- required daily pharmacological doses (150-
toms formed part of their clinical presen- 350 mg) of niacinamide to reverse its clini-
tation. It was impossible to determine if cal manifestations. Table 1, (below) de-
these symptoms preceded their anxieties or scribes some of the psychological symp-
neuropsychiatric symptoms. In case #3, the toms associated with aniacinamidosis.
patient reported a long-standing history of Some of the symptoms listed in Table 1 are
constipation many years before the onset similar to the symptoms exhibited by the
of acute anxiety. In the other two cases, the patients in these case reports.
patients had anxiety symptoms with mild Green, in his paper on subclinical pel-
gastro-intestinal manifestations. The pa- lagra, noted that mental symptoms oc-
tient in case#1 had stomachaches when she curred in patients without frank deficiency
felt anxious, and in case #2 the patient of vitamin B3.17 Similarly, Hoffer reported
passed gas when she experienced anxiety. that the earliest symptoms of pellagra in
It appears that these patients did have its subclinical form manifest as modern
pellagra-like symptoms primarily involving mood disorders (e.g., anxiety, depression,
the neuropsychiatric system. One of the ear- fatigue, and vague somatic complaints)
liest reports describing the psychological followed by the development of other
patterning of central nervous system impair- symptoms.18 It is evident that subclinical
ments due to an inadequate supply of niaci- pellagra can present with symptoms prima-
namide came from the work of Kaufman.16 rily affecting the neuropsychiatric system,
He used the term aniacinamidosis, to de- yet the reasons for its genesis remain un-
171
Journal of Orthomolecular Medicine Vol. 20, No. 3, 2005
known. One possible explanation might for the vitamin. Its cause is unknown, but
involve a phenomenon known as a local- it has been purported to result from a com-
ized cerebral deficiency disease. Pauling bination of malnutrition and long-term en-
discussed the possibility of having grossly vironmental-genetic stresses that disrupts
diminished cerebrospinal fluid (CSF) con- the in vivo conversion of dietary tryptophan
centrations of a vital substance while its into a sufficient amount of vitamin B3.18
concentration in the blood and lymph re- Over time, this disruption would impair all
main essentially normal.19 This localized the biochemical processes dependent on a
cerebral deficiency, according to Pauling, constant supply of the nicotinamide
might occur from decreased rates of trans- coenzymes. In order to sustain adequate
fer (i.e., decreased permeability) of the vi- health, it would be necessary to obtain a
tal substance across the blood-brain bar- daily intake of vitamin B3 in amounts far
rier, an increased rate of destruction of the greater than what could be accomplished
vital substance within the CSF, or from from dietary sources alone.21 This is not so
some other unknown factor.19 If the serum unreasonable since many enzyme systems
and CSF were to be examined for micronu- within the body require large pharmacologi-
trient status, extreme perturbations be- cal doses of vitamins to remedy defects in
tween these compartments might demon- the synthesis of vital metabolic products to
strate the presence of a localized cerebral sustain adequate health. Pauling reported
deficiency. For example, in a study involv- that, mental disease is for the most part
ing 49 patients with organic mental disor- caused by abnormal reaction rates, as de-
ders, deficient CSF levels of vitamin B12 (<5 termined by genetic constitution and diet,
pg/mL) were found in 30 of the patients.20 and by abnormal molecular concentrations
When the serum levels of vitamin B12 were of essential substances.19 He described how
tested, normal values (200-800 pg/mL) megavitamin therapy would be necessary for
were found in 45 of them, indicating a the optimal treatment of mental disease
marked difference between both compart- since the saturating capacity would be much
ments. Given that serum levels of vitamin greater for defective enzymes that have di-
B12 can be normal yet deficient in the CSF, minished combining capacity for their re-
other micronutrients (such as vitamin B3) spective substrates. In other words, an en-
might follow a similar pattern of deficiency zyme-catalyzed reaction could be corrected
if the CSF and serum were to be respec- by pharmacologically increasing the concen-
tively analyzed. The correction of subclini- tration of its substrate when high doses of a
cal pellagra might be one of the reasons for particular micronutrient are provided.
niacinamides effectiveness. Conversely, we Paulings ideas were later confirmed by
need to understand the role of localized Abbey who found various B-vitamin de-
cerebral deficiency of niacinamide, includ- pendent enzymopathies in 12 patients with
ing niacinamides metabolism with the CSF, agoraphobia.22 All of Abbeys patients re-
before this diagnosis can be given the con- quired 200-500 mg of the various B-com-
firmation it requires. plex factors in order to resolve both the as-
sociated enzymatic defects and symptoms
Vitamin B3 Dependency as a Result of of their anxiety and panic. In a more recent
Enzymatic Defects report, the need for large pharmacological
The patients positive responses to ni- doses of micronutrients were deemed nec-
acinamide suggest that this vitamin might essary as a means to increase coenzyme
have corrected an underlying vitamin B3 concentrations and to correct defective
dependency disorder. A vitamin B3 depend- enzymatic activity in some 50 human ge-
ency denotes an increased metabolic need netic diseases.23 Certainly, there must be a
172
Supplemental Niacinamide Mitigates Anxiety Symptoms: Three Case Reports
certain percentage of patients that would those who received placebo. These results
be responsive to large pharmacological suggest that intravenous administration of
doses of vitamin B3 to correct both the dis- xantinol nicotinate can reduce withdrawal
ordered biochemistry and the resulting neu- symptoms in patients withdrawing from
ropsychiatric manifestations; presumably, flunitrazepam. Even though intravenous
the result of defective enzymatic activity. xantinol nicotinate would achieve higher
blood concentrations than oral niacinamide,
Benzodiazepine-like Properties both nutrients are forms of vitamin B3, and
Additional reasons for niacinamides ef- therefore, the parenteral and oral methods
fectiveness likely have to do with its might similarly help to withdraw patients
benzodiazepine-like effects. In a previous re- from their benzodiazepine medications.
view of the literature by Hoffer, both niacin
and niacinamide were shown to have some Serotonin Synthesis
sedative activity, and were able to potentiate Another biochemical reason for niaci-
the action of sedatives, anticonvulsant namides anxiolytic effects might have to do
medications and certain tranquilizers.24 In a with the vital role that it has upon the syn-
recent case report by this author, a review of thesis of serotonin. For example, in a patient
the literature was undertaken to determine with anorexia nervosa an insufficient sup-
the biological mechanism for niacinamides ply of vitamin B3 or protein resulted in re-
anxiolytic effects.14 Table 2 (p.174) summa- duced urinary levels of the serotonin break-
rizes this data.25-30 It appears that niacinamide down product, 5-hydroxy-indolacetic acid
has therapeutic effects comparable to the (5-HIAA).32 The authors of this report pos-
benzodiazepines. Its therapeutic effects are tulated that a deficiency of vitamin B3 re-
probably not related to it acting as a ligand duced the feedback inhibition upon the
for the benzodiazepine receptor, although it kynurenine pathway, resulting in more tryp-
acts centrally and might have a weak bind- tophan being diverted to the kynurenine
ing affinity for the benzodiazepine receptor. pathway, making less substrate available for
Both the benzodiazepines and niacinamide the synthesis of serotonin. By contrast, the
exert similar anxiolytic effects through the use of pharmacological doses of vitamin B3
modulation of neurotransmitters commonly can increase the production of serotonin.33
unbalanced in anxiety. In a rat study, the administration of 20 mg
Niacinamide might also be helpful when of niacin resulted in increased levels of 5-
weaning patients off their benzodiazepine HIAA and decreased levels of xanthurenic
medications. Benzodiazepine withdrawal acid via the kynurenine pathway.34 Taking
symptoms include tinnitus, involuntary pharmacological doses of niacinamide (or
movements, paresthesias, perceptual any other form of vitamin B3) would increase
changes and confusion. Twenty-eight pa- the production of serotonin, by diverting
tients who had been abusing flunitrazepam more tryptophan to become substrate for
for at least six months were abruptly taken serotonin synthesis. Niacinamides therapeu-
off the drug.31 The patients were randomly tic ability to increase serotonin production
assigned to receive intravenous nicotinic might explain why it was successful in re-
acid (xantinol nicotinate; 3 g in 1,500 mL of ducing the anxiety symptoms of the three
10% glucose per day over the first 48 hours, patients.
followed by 1.5 g over the following 48 hours)
or placebo (glucose solution alone). Al- Modulation of Blood Lactate (lactic acid)
though blinding was not specified, patients The final biochemical reason for niaci-
who received xantinol nicotinate had signifi- namides favourable effect might have to do
cantly fewer withdrawal symptoms than with its ability to modulate the metabolism
173
Journal of Orthomolecular Medicine Vol. 20, No. 3, 2005
Reference Results
of blood lactate (lactic acid). Before this tween lactic acid and anxiety. This re-
therapeutic mechanism is explained, it is search will demonstrate a consistent link
necessary to review some of the studies between PD and lactate provocation.
that have explored the relationship be- In a single-blind study using sodium
174
Supplemental Niacinamide Mitigates Anxiety Symptoms: Three Case Reports
lactate infusions, 11 out of 15 patients with the conversion of lactate back to pyruvate,
PD had panic attacks with the lactate.35 The which would contribute to a high lactate-
15 control subjects did not experience to-pyruvate ratio and therefore to anxiety.22
panic attacks during the infusions. Even In 3 out of 12 patients, Abbey found defi-
though no biochemical abnormalities were cient levels of urinary N1 methylnicotina-
seen between the groups, it was hypoth- mide (indicating deficient intake of niaci-
esized that the treatment group had an namide) normalized when large pharma-
increased baseline arousal level causing cological doses of B-complex vitamins
them to be more susceptible to panic at- were provided, to which she conjectured
tacks. In another study, 72% of the treat- that an excess of NAD was required to
ment group (n=43) developed panic attacks drive the conversion of lactate to pyruvate.
with intravenous sodium lactate infu- Buist also hypothesized that anxiety neu-
sions.36 The treatment group was com- rosis is associated with elevated blood lac-
prised of patients with either PD, or agora- tate and an increased lactate-to-pyruvate
phobia with panic attacks. In the control ratio to which effective treatment requires
group (n=20) none of the participants de- increasing niacin status (i.e., increasing
veloped panic attacks with the infusions. NAD levels) through supplementation.39
There was increased activity of the central The formation of lactate by the en-
noradrenergic system in most of the pa- zyme, lactate dehydrogenase, is the final
tients in the treatment group who experi- product of anaerobic glycolysis in
enced panic attacks. A similar study involv- eukaryotic cells. Niacinamide supple-
ing 43 subjects having PD or agoraphobia mentation might result in an increased
with panic attacks were administered in- conversion of lactate to pyruvate, thus re-
fusions of sodium lactate.37 Thirty-one of versing the equilibrium of the pyruvate
the subjects panicked in response to the to lactate reaction. For example, when a
infusions, whereas none of the 20 subjects patient with MELAS (mitochondrial en-
in the control group had any panic attacks. cephalopathy, myopathy, lactic acidosis,
It was concluded that the lactate-induced and stroke-like episodes) syndrome was
panic attacks were associated with height- treated with 1,000 mg of niacinamide
ened central noradrenergic activity and hy- four times daily, large reductions (50% or
perventilation. It now appears that the lac- more) in blood lactate and pyruvate con-
tate-induced panic response involves angi- centrations occurred by the third day of
otensin-II, which interfaces with the treatment.40 Large pharmacological doses
basolateral nucleus of the amygdala (BLA) of niacinamide appear to be capable of
and the autonomic nervous system in the reducing blood lactate and pyruvate con-
generation of anxiety disorders.38 centrations. Patients with panic attacks
All of the patients in the case reports likely have a greater demand placed upon
experienced frequent panic attacks in ad- anaerobic glycolysis due to the rapidity
dition to their other anxiety symptoms. or shallowness of breathing that so often
Lactate sensitivity or an increased respon- accompanies their anxiety attacks.
siveness to lactate might have caused some Therefore, a greater amount of NAD ob-
of their anxiety symptoms. Only one of the tained by means of niacinamide supple-
patients (case #3) appeared to have hyper- mentation might help the tissues of the
ventilation as part of her clinical presenta- body, including the central nervous sys-
tion. All of them had a therapeutic response tem, to readily oxidize lactate (obtained
to niacinamide demonstrating its ability to from the blood) to pyruvate, and conse-
reduce panic attacks. Abbey suggested that quently mitigate panic attacks, and hy-
an insufficient supply of NAD would inhibit perventilation (if present).
175
Journal of Orthomolecular Medicine Vol. 20, No. 3, 2005
176
Supplemental Niacinamide Mitigates Anxiety Symptoms: Three Case Reports
References 2004;43:1-5.
1. Ansseau M, Dierick M, Buntinkx F, et al: High 16. Kaufman W: The Common Form of Niacin
prevalence of mental disorders in primary care. Amide Deficiency Disease: Aniacinamidosis.
J Affect Disord, 2004;78:49-55. Bridgeport, CT: Yale University Press; 1943.
2. Sansone RA, Hendricks CM, Gaither GA, 17. Green RG: Subclinical pellagra among peniten-
Reddington A: Prevalence of anxiety symptoms tiary inmates. J Orthomol Psychiat, 1976; 5: 68-
among a sample of outpatients in an internal 83.
medicine clinic: a pilot study. Depress Anxiety, 18. Hoffer A: Vitamin B3 dependency: chronic pel-
2004; 19: 133-136. lagra. Townsend Lett Doctors Patients, 2000;
3. Diagnostic and Statistical Manual of Mental Disor- 207: 66-73.
ders. Fourth Edition, Text Revision. Washing- 19. Pauling L: Orthomolecular psychiatry. Varying
ton, DC: American Psychiatric Association; the concentrations of substances normally
2000. present in the human body may control men-
4. Colman SS, Brod M, Potter LP, Buesching DP, tal disease. Science, 1968;160:265-271.
Rowland CR: Cross-sectional 7-year follow-up 20. van Tiggelen CJM, Peperkamp JPC, Tertoolen
of anxiety in primary care patients. Depress JFW: Vitamin B12 levels of cerebrospinal fluid
Anxiety, 2004; 19: 105-111. in patients with organic mental disorders. J
5. Prousky JE: Pellagra may be a rare secondary Orthomol Psychiat, 1983;12:305-311.
complication of anorexia nervosa: a systematic 21. Hoffer A: Vitamin B3: niacin and its amide.
review of the literature. Altern Med Rev, 2003; Townsend Lett Doctors Patients, 1995; 147: 30-
8: 180-185. 39.
6. Hawn LJ, Guldan GJ, Chillag SC, Klein L: A case 22. Abbey LC: Agoraphobia. J Orthomol Psychiat,
of pellagra and a South Carolina history of the 1982; 11: 243-259.
disorder. J S C Med Assoc, 2003;99:220-223. 23. Ames BN, Elson-Schwab I, Silver EA: High-dose
7. Prasad PVS, Babu A, Paul EK, Balasubramaniyan vitamin therapy stimulates variant enzymes
S: Myxoedema pellagraa report of two cases. with decreased coenzyme binding (increased
J Assoc Physicians India, 2003;51:421-422. Km): relevance to genetic diseases and
8. Wallengren J, Thelin I: Pellagra-like skin lesions polymorphisms. Am J Clin Nutr, 2002; 75: 616-
associated with Wernickes encephalopathy in 658.
a heavy wine drinker. Acta Derm Venereol, 2002; 24. Hoffer A: Nicotinic acid and niacinamide as
82: 152-154. sedatives. Niacin Therapy In Psychiatry.
9. Pitsavas S, Andreou C, Bascialla F, Bozikas VP, Springfield: Charles C Thomas; 1962:24-31.
Karavatos A: Pellagra encephalopathy follow- 25. Mhler H, Polc C, Cumin R, Pieri L, Kettler R:
ing B-complex vitamin treatment without ni- Nicotinamide is a brain constituent with
acin. Int J Psychiatry Med, 2004; 34: 91-95. benzodiazepine-like actions. Nature, 1979; 278:
10. Kertesz SG: Pellagra in 2 homeless men. Mayo 563-565.
Clin Proc, 2001; 76: 315-318. 26. Slater P, Longman DA: Effects of diazepam and
11. Lyon VB, Fairley JA: Anticonvulsant-induced muscimol on GABA-mediated neurotrans-
pellagra. J Am Acad Dermatol, 2002;46:597-599. mission: interactions with inosine and nicoti-
12. Kaur S, Goraya JS, Thami GP, Kanwar AJ: Pella- namide. Life Sci, 1979; 25: 1963-1967.
grous dermatitis induced by phenytoin. Pediatr 27. Kennedy B, Leonard BE: Similarity between the
Dermatol, 2002;19:93. action of nicotinamide and diazepam on neu-
13. The case reports, the analysis pertaining to ni- rotransmitter metabolism in the rat. Biochem
acinamides benzodiazepine-like effects, some Soc Trans, 1980; 8: 59-60.
of the discussion, and the prescribing informa- 28. Lapin IP: Nicotinamide, inosine and hypoxan-
tion have been previously published in Prousky thine, putative endogenous ligands of the
JE: Orthomolecular treatment of anxiety dis- benzodiazepine receptor, opposite to diazepam
orders. Townsend Lett Doctors Patients, 2005 are much more effective against kynurenine-
[in press]. Written permission was obtained induced seizures than against pentylenetetra-
from the publisher for the reproduced mate- zol-induced seizures. Pharmacol Biochem
rial contained in this report. Behav, 1981; 14: 589-593.
14. Prousky JE: Niacinamides potent role in allevi- 29. Markin RS, Murray WJ: Searching for the en-
ating anxiety with its benzodiazepine-like dogenous benzodiazepine using the graph theo-
properties: a case report. J Orthomol Med, 2004; retical approach. Pharm Res, 1988;5:408-412.
19: 104-110. 30. Akhundov RA, Dzhafarova SA, Aliev AN: The
15. Hegyi J, Schwartz RA, Hegyi V: Pellagra: der- search for new anticonvulsant agents based on
matitis, dementia, and diarrhea. Int J Dermatol, nicotinamide. Eksp Klin Farmakol, 1992;55:27-29.
177
Journal of Orthomolecular Medicine Vol. 20, No. 3, 2005
31. Vescovi PP, Gerra G, Ippolito L, et al: Nicotinic cal and physiological findings. Arch Gen Psy-
acid effectiveness in the treatment of chiatry, 1985; 42: 709-719.
benzodiazepine withdrawal. Curr Ther Res, 38. Shekhar A, Sajdyk TJ, Gehlert DR, Rainnie DG:
1987; 41: 1017-1021. The amygdala, panic disorder, and cardiovascu-
32. Judd LE, Poskitt BL: Pellagra in a patient with an lar reponses. Ann N Y Acad Sci, 2003;985:308-325.
eating disorder. Br J Dermatol, 1991;125:71-72. 39. Buist RA: Anxiety neurosis: the lactate con-
33. Gedye A: Hypothesized treatment for migraine nection. Int Clin Nutr Rev, 1985;5:1-4.
using low doses of tryptophan, niacin, calcium, 40. Majamaa K, Rusanen H, Remes AM, Pyhtinen
caffeine, and acetylsalicylic acid. Med Hypoth- J, Hassinen IE: Increase of blood NAD+ and at-
eses, 2001;56:91-94. tenuation of lactacidemia during nicotinamide
34. Shibata Y, Nishimoto Y, Takeuchi F, Tatsuma Y: treatment of a patient with MELAS syndrome.
Tryptophan metabolism in various nutritive con- Life Sci, 1996;58:691-699.
ditions. Acta Vitamin Enzymol, 1973; 29: 190-193. 41. Hoffer A: Vitamin B3 dependent child. Schizo-
35. Den Boer JA, Westenberg HG, Klompmakers AA, phrenia, 1971;3:107-113.
van Lint LE: Behavioral biochemical and neu- 42. Hoffer A: Dr. Hoffers ABC of Natural Nutrition for
roendocrine concomitants of lactate-induced Children. Kingston, ON: Quarry Press Inc; 1999.
panic anxiety. Biol Psychiatry, 1989; 26: 612-622. 43. Werbach MR: Adverse effects of nutritional sup-
36. Leibowitz MR, Gorman JM, Fyer A, et al: Possi- plements. Foundations of Nutritional Medicine.
ble mechanisms for lactates induction of panic. Tarzanna: Third Line Press, Inc; 1997:133-160.
Am J Psychiatry, 1986;143:495-502. 44. Winter SL, Boyer JL: Hepatic toxicity from large
37. Leibowitz MR, Gorman JM, Fyer AJ, et al: Lac- doses of vitamin B3 (nicotinamide). N Engl J
tate provocation of panic attacks. II. Biochemi- Med, 1973;289:1180-1182.
178