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Niacinamide
Introduction
Niacinamide, also known
as nicotinamide, is a
water-soluble amide of
nicotinic acid.
Niacinamide is one of
two principal forms of
the B-complex vitamin,
B3. Niacin was first
isolated from rice bran
in 1911. Niacinamide,
the amide of niacin, was
later isolated in 1934
by Warburg and Christian
when coenzyme II, NADP,
was extracted from horse
erythrocytes.1 While
niacinamide and niacin
have identical vitamin
activities (i.e., they
both prevent development
of the vitamin
B3-deficiency condition,
pellagra), they have
very different
pharmacological
activities.
Biochemistry
The structure of
niacinamide consists of
a pyridine ring with an
amide group in position
three. Niacinamide is a
component of
nicotinamide adenine
dinucleotide (NAD), also
known as coenzyme I, and
nicotinamide adenine
dinucleotide phosphate (NADP),
also known as coenzyme
II. These coenzymes are
involved in many
intracellular
oxidation-reduction
reactions. They
participate in hydrogen
transfer reactions,
functioning as hydride
ion carriers of
biological systems.
Pharmacokinetics
The pharmacokinetics of
niacinamide depend on
dose, species, gender,
and route of
administration. 2
Niacinamide is readily
absorbed from all parts
of the gastrointestinal
tract.3 A negligible
portion of niacinamide
is metabolized to
niacin, mostly due to
bacterial activity.4
Peak serum
concentrations are
reached in humans within
one hour of oral
ingestion of standard
preparations.5
Niacinamide is rapidly
cleared from the
circulation and
distributed in all
tissues. It has a high
hepatic excretion ratio
and plasma clearance can
be reduced in patients
with hepatic
insufficiency.6
Mechanisms of Action
Niacinamide acts as an
antioxidant by
preventing NAD depletion
during DNA repair by
inhibiting poly
(ADP-ribose) polymerase
(PARP), which also
modulates major
histocompatibility
complex (MHC) class II
expression. Niacinamide
inhibits free radical
formation and
facilitates beta-cell
regeneration in vivo and
in vitro.7,8 Additional
protection from
macrophage toxins may be
involved in prevention
of type 1 diabetes.9
Specifically,
niacinamide has been
shown, via PARP
inhibition, to protect
pancreatic islet-cell
lysis after exposure to
oxygen free radicals10
and nitric oxide.11,12
Niacinamide has also
been found to stimulate
GABA receptors, without
binding to the receptor
sites, thus creating a
benzodiazepine-like
effect.13
Anti-inflammatory action
affecting neutrophil
chemotaxis has been
reported for
niacinamide.14
Additionally, due to its
inhibition of ADP-ribosylation,
niacinamide has been
shown to suppress
cytokinemediated
induction of nitric
oxide synthase in a
number of cells, thus
effecting
interleukin-1-exposed
chondrocytes, resulting
in decreased
inflammation.15
Deficiency States
Pellagra, a disease
consisting of
bilaterally symmetrical
lesions on both sides of
the body and hands,
occurs as a result of a
niacin deficiency. The
disease is characterized
by hyperpigmentation and
thickening of the skin,
inflammation of the
tongue and mouth, and
digestive disturbances
including indigestion,
anorexia, and diarrhea.
In late stages of the
disease, irritability,
amnesia, and delirium
occur.
Clinical Indications
Diabetes
The time of diagnosis of
type 1 diabetes is
crucial for the
potential success of any
intervention. Early
diagnosis is associated
with higher residual
C-peptide secretion and
a better chance of
clinical remission.16
Treatment with high-dose
niacinamide has been
shown to exert
protective effects on
beta-cell function in
humans. In a recent
meta-analysis, 10
randomized, controlled
trials were analyzed. A
combined analysis of 158
niacinamide-treated and
129 control patients
with recent-onset type 1
diabetes revealed
significantly
better preservation of
basal C-peptide
secretion in the
niacinamide-receiving
cohort after one year.
Sub-analysis of the five
placebo-controlled
trials yielded the same
result.17
There are studies that
show no beneficial
effect of niacinamide in
terms of clinical
remission of type 1
diabetes. The patients
enrolled in negative
studies were diagnosed
with diabetes between
the ages of 10 and 15,
suggesting increased
insulin resistance,
occurring during and
around the time of
puberty, may be the
reason for a lack of
positive outcome using
niacinamide in this
population.18-20
Niacinamide has been
used successfully to
prevent or delay the
onset of type 1 diabetes
among high-risk
individuals, defined by
high islet-cell
antibodies and family
history of type
1diabetes. In a New
Zealand study of 80,000
children, 5-7 years old,
20,000 were screened for
islet-cell antibodies.21
The 150 children with
positive islet-cell
antibodies received
niacinamide therapy. The
incidence of type 1
diabetes in the treated
group was eight per
100,000/year, well below
the rate of 15-20 per
100,000/year observed
among the 60,000
children who were not
screened or subsequently
treated. Currently, the
European Nicotinamide
Diabetes Intervention
Trial (ENDIT), begun in
1993, is investigating
40,000 first-degree
relatives of type 1
diabetic patients, age
4-40 years. All
individuals will be
followed to endpoints of
type 1 diabetes or for
five years free of frank
disease with a
prediction of 50 percent
efficacy. The study will
be completed in 2003.22
The Deutsche
Nicotinamide
Intervention Study
(DENIS) also evaluated
the clinical efficacy of
high-dose niacinamide in
children at high risk
for type 1 diabetes.
Individuals at risk for
developing ype 1
diabetes within three
years were identified by
screening of siblings
(age 3-12 years) of
patients with type 1
diabetes. They were
assessed for the
presence of a high
islet-cell antibody
titer and further
randomized into placebo
and niacinamide (slow
release, 1.2 g) groups.
Rates of diabetes onset
were similar in both
groups throughout the
observation period – a
maximum of 3.8 years and
a median of 2.1 years.23
Treatment with
niacinamide appears to
delay rather than
completely reverse
disease development in
those with pre-existing
type 1 diabetes.
However, treatment of
“at risk” groups, in the
majority of studies,
shows promise in disease
prevention.
Schizophrenia
Niacinamide and niacin
have been used since
1940 or earlier to treat
a number of psychiatric
conditions. Hoffer is a
strong advocate of the
use of niacinamide in
the management of
schizophrenia and has
collected data on more
than 1,000 patients
given either niacinamide
or niacin (1.5-6 g/day)
for three months to five
years duration.24
Hoffer concluded in
further studies that
this treatment is most
effective for early and
acute schizophrenics,
while it appears to be
ineffective, especially
when given alone, for
chronic sufferers. 25 A
study by Mohler found
niacinamide to produce
an anti-anxiety effect
equivalent to a highly
potent benzodiazepine.
Like benzodiazepines,
niacinamide appears to
stimulate GABA receptors
without binding to
receptor sites.13
It has also been
presumed that patients
with sub-clinical
pellagra, who have
developed perceptual
changes and
neurasthenia, could be
labeled as schizophrenic
and would benefit from
treatment with
niacinamide.26 Treatment
remains controversial as
both positive27 and
negative28 double-blind
studies appear in the
literature.
Arthritis
For the past five
decades Kaufman has
written extensively
about clinical
experience treating
joint dysfunction with
megadoses of niacinamide,
found to be particularly
effective for
degenerative arthritis
of the knee. Kaufman’s
work in this regard had
its roots in the chance
observation that joint
dysfunction improved in
arthritic patients using
frequent high doses of
niacinamide. Using an
index of joint range of
motion, the outcome of
455 patients receiving
1,500-4,000 mg (divided
doses) of niacinamide
daily was measured and
compared with results of
untreated age-matched
control patients.29,30
While niacinamide did
not appear to have an
analgesic effect, pain
decreased in the
niacinamide-treated
group as a result of
increased joint
mobility. The joint
range index usually
increased after 1-2
months of treatment. A
double-blind study has
substantiated Kaufman’s
findings. Three months
following administration
of 3,000 mg/day
niacinamide for 12
weeks, compared to
patients who received
placebo, treated
patients had significant
improvement in joint
mobility and overall
severity of arthritis.
The treated group showed
a decrease in
erythrocyte
sedimentation rate and
was able to reduce
anti-inflammatory
medication by 13
percent.31
Dermatological
Conditions
Niacinamide has been
used to treat several
types of dermatological
pathologies.32,33 In a
review of treatments for
bullous pemphigoid,
treatment with a
niacinamide/tetracycline
combination showed
promising results
compared to other
treatment effectiveness
and side effects.34 In
addition, niacinamide
has been used
successfully in the
treatment of other
blistering skin diseases
when used in conjunction
with tetracycline.35
Niacinamide has also
been shown to be
effective in the
treatment of cutaneous
hyperpigmentation, which
occurs in multiple
conditions. In clinical
trials, a five-percent
niacinamide moisturizer
provided 35-68 percent
inhibition of melanosome
transfer from
melanocytes to
keratinocytes, proving
to be an effective
skin-lightening agent.36
Further studies to
investigate the use of
niacinamide in
regulating
melanocytekeratinocyte
interactions are
underway.37
Radiation Sensitivity
Animal studies found
simultaneous
supplementation of
niacinamide with
radioactive iodine
treatment of
hyperthyroid goiter
increased effectiveness
of radiation at lower
doses due to
niacinamide’s
radiosensitization.38 A
review of clinical
research on radiation in
cancer therapy has
confirmed niacinamide’s
ability to increase
tissue sensitivity to
radiation.39
Drug-Nutrient
Interactions
Concomitant use of
niacinamide and
antiepileptic drugs,
specifically
carbamazepine, diazepam,
and sodium valproate,
apparently potentiates
the anticonvulsant
action of these drugs.40
In addition, niacinamide
may decrease clearance
of carbamazepine when
used simultaneously.41
Side Effects and
Toxicity
Because the literature
on niacinamide spans
more than 50 years,
evaluation of toxicity
is conflicting. Data on
the side effects of
niacinamide and niacin
are often confused as
earlier studies used
mixtures of the two in
preparations.
Furthermore, the purity
of niacinamide
preparations varies
considerably as some
preparations include
trace amounts of
niacin.6 Older
clinical studies report
relatively frequent
liver enzyme
abnormalities;42
however, recent studies
using purified
niacinamide have not
detected such
abnormalities.17,23
Nausea is usually the
first side effect noted
with niacinamide. Other
side effects associated
with high-dose
niacinamide include
heartburn, vomiting,
flatulence, and
diarrhea. Mild headaches
and dizziness have been
reported after giving
niacinamide
parenterally.43
Dosage
The recommended daily
intake (RDA) is 20 mg
per day for an adult.
The dose used in
diabetic and prediabetic
individuals ranges from
1.75- 3.5 grams per day.
In diabetic children, a
daily dose of 150-300
mg/year of age, up to 3
grams is often used.44
Self medication of
high-dose niacinamide
should be discouraged.
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