Methylcobalamin and Diabetic Neuropathy

Clinical usefulness of intrathecal injection of Methylcobalamin in patients with diabetic

neuropathy
Ide H Fujiya S Asanuma Y Tsuji M Sakai H Aishi Y! Clin Ther "#$%&'
$"(')#%*+$(

Se,en men and four women with symptomatic diabetic neuropathy were treated with
Methylcobalamin "(!-.. microrams in #. ml of saline' injected intrathecally/ Treatment
was beun when patients had ood metabolic control! as determined by measurements of
plasma lucose and hemolobin! and was repeated se,eral times with a one+month
inter,al between injections/ Three patients were re+treated one year after the last
intrathecal injection/ Symptoms in the les! such as paresthesia! burnin pains! and
hea,iness! dramatically impro,ed/ The effect appeared within a few hours to one week
and lasted from se,eral months to four years/ The mean peroneal motor+ner,e conduction
,elocity did not chane sinificantly/ The mean "01+ S2' concentration of
Methylcobalamin in spinal fluid was ##3 01+ *( p1ml before intrathecal injection "n 4 -'
and 3!&-( 01+ (!-.3 p1ml one month after intrathecal Methylcobalamin treatment "n 4
##'/ Methylcobalamin caused no side effects with respect to subjecti,e symptoms or
characteristics of spinal fluid/ These findins suest that a hih concentration of
Methylcobalamin in spinal fluid is hihly effecti,e and safe for treatin the symptoms of
diabetic neuropathy/

METHYLCOBALAMIN

Methylcobalamin is the neuroloically acti,e form of ,itamin 5#(/ The li,er does not
con,ert cyanocobalamin! the commonly a,ailable form of ,itamin 5#(! into ade6uate
amounts of methylcobalamin! which the body uses to treat or correct neuroloical
defects/ Animal studies ha,e shown that hih doses of methylcobalamin are effecti,e in
neuron reeneration and that there is no known to7icity at these doses/
Those who ha,e low le,els of ,itamin 5#( in the blood ha,e lon resorted to injections
of this essential 5 ,itamin! an uncomfortable deli,ery method at best/ 8ew e,idence
suests that oral 5#( works as well as injections! accordin to a study published in the
journal 5lood +but hih doses must be taken/ This ,erifies reports from Sweden datin
from the #$&.s that pernicious anemia! a disease of 5#( deficiency! can be controlled
with oral 5#(/ 9esol,in the debate o,er oral+,ersus+injections is ,ery timely! i,en that
,itamin 5#( is a homocysteine+lowerin factor/ Homocysteine has emered as a stron
and independent risk factor for heart disease and stroke! and is also connected to chronic
diseases such as arthritis! Al:heimer;s and diabetes/

Accordin to the recent data! (!... microrams1day of oral 5#( cures the symptoms of
5#( deficiency! includin ele,ated homocysteine! neuroloical problems! and ele,ated
methylmalonic acid "a marker of 5#( deficiency'/ The oral ,ersion works as well as
injections! with the added feature of maintainin hih le,els in the blood o,er time/ The
study showed that after a month! the blood le,els of the ,itamin in people recei,in
injections dropped and stayed at a plateau! whereas blood le,els of those recei,in oral
5#( continued to rise/

5#( lowers homocysteine Althouh oral 5#( did not reduce homocysteine in e,ery
case! when it did! the results were dramatic/ Some of the people in the study had
homocysteine le,els as hih as #&- micromoles per liter "the optimal safe rane for
homocysteine is under <'/ In the case of one patient! (!... microrams of oral 5#( for
four months reduced their homocysteine from ##*/3 micromoles per liter to %/(/ Injected
5#( also sinificantly reduced homocysteine + the main difference bein that the injected
,ersion worked faster/ Interestinly! some of the patients did not respond to
supplemental ,itamin 5#(/ It was disco,ered that they were also deficient in folate! and
until folate was replaced! their homocysteine remained ele,ated/ =itamin 5#( and folate
work syneristically in the chemical reactions that recycle homocysteine back to
methionine in the methylation cycle/ It is also interestin to note that participants in the
study with both 5#( and folate deficiencies were depressed! had anore7ia! and addiction
to alcohol/ It is well+established that folate or 5#( deficiency causes psychiatric problems
ranin from loss of memory to insanity/ This is probably due to the ,itamin;s role in
methylation + a biochemical process crucial for the maintenance of brain chemistry and
ner,es/ 5#( plays a role in the synthesis of serotonin! dopamine and norepinephrine/

Intrinsic factor is secreted by the stomach to help the body absorb 5#(/ >lder people
produce less intrinsic factor! and are thus more ,ulnerable to 5#( deficiency/ In the study
mentioned at the beinnin of this article! hih+dose oral 5#( was absorbed as well as
injectable/ 8o supplemental intrinsic factor was i,en/ Intrinsic factor is usually
associated with a chronic 5#( deficiency known as pernicious anemia/ ?atients with
pernicious anemia lack intrinsic factor usually because of insufficient stomach acid/
>thers may ha,e antibodies to the factor + an inappropriate autoimmune response to one;s
own proteins/ Injected 5#( has traditionally been used for pernicious anemia because it
bypasses the absorption problem/ Howe,er! doctors are beinnin to reali:e that
pernicious anemia patients are not the only patients they see with 5#( deficiencies/
Anyone with ele,ated homocysteine! psychiatric disorders! eatin disorders! sleep
disorders! or who is elderly is potentially 5#(+deficient/ These conditions are more likely
caused by diet+induced 5#(+deficiency than a lack of intrinsic factor/ All should respond
to oral 5#(/

Different orm! Of "itamin B#$

Cyanocobalamin is the usual form of 5#( sold in this country/ Hydro7ocobalamin and
adenosylcobalamin are two other forms/ For the past (. years @nlish doctor Anthony A/
Freeman has been attemptin to et the cyano form of 5#( remo,ed from the market and
replaced with the hydro7ocobalamin/ He points out that the cyano form is not effecti,e
for certain eye deenerations caused by smokin and alcohol/

5ut another form! methylcobalamin! may be the best of all/ 9esearch shows that this
acti,e form of 5#( has the uni6ue ability to pro,oke the reeneration of ner,es without
ad,erse side effects/ This is because 5#( facilitates methylation! the process that creates
and maintains ner,es and brain chemicals/ 9esearch shows that a lack of
methylcobalamin causes deeneration of the brain and spinal cord + a condition known as
subacute combined deeneration/ In this disease! ner,es lose their insulation and bein to
deteriorate/ This process! known as demyelination! occurs in other neuroloical diseases
such as multiple sclerosis and chronic inflammatory demyelinatin polyneuropathy/

Hih doses of methylcobalamin ha,e been used to treat deenerati,e neuroloical
diseases in rodents and humans/ ?eople with amyotrophic lateral sclerosis "Bou Aehri;s
disease' took (- m a day of methylcobalamin for a month/ In this disease! the neurons
that control muscle mo,ements deteriorate/ The double+blind! controlled study showed
that methylcobalamin impro,ed muscle response after a month of treatment/
Methylcobalamin has been i,en to mice with the mouse ,ersion of muscular dystrophy/
A remarkable re,ersal of deeneratin ner,es occurred/ Methylcobalamin did not stop the
disease! but it slowed it down/

It has been documented that the le,el of 5#( decreases e,ery year with ae/ Ae+related
deficiency is associated with hearin loss! memory impairment and psychiatric disorders!
alon with heart disease and stroke/ Al:heimer;s disease "A2' patients ha,e less 5#( in
their spinal fluid than people without the disease/ They also ha,e less SAMe + the
substance re6uired to methylate cobalamin "5#(' to methylcobalamin! the acti,e form/
The failure of 5#( supplementation to impro,e A2 patients in some studies may be due
to their inability to acti,ate 5#( in the brain/ Methylcobalamin is already methylated) it
doesn;t re6uire SAMe/

Another feature of ain is the increase of free radicals/ Free radicals are ele,ated in
?arkinson;s disease "?2' and A2/ In ?2! a substance known as MA>+5 is also ele,ated/
MA>+5 creates free radicals! and the MA>+5 inhibitor! seleiline! is often i,en to ?2
patients/ MA>+5 is linked to memory impairment/ In #$$( Italian researchers reported
that ele,ated MA>+5! dementia and 5#( deficiency all o toether/

B#$ Deficiency Di!ea!e!

2iet! ae and drus are the prime culprits behind 5#( deficiency/ Meat is the primary
source of ,itamin 5#(/ Strict ,eetarians + people who eat no animal products whatsoe,er
are at risk for 5#( deficiency/ "=eetarians who eat es and fish will et 5#( in their
diet/ In addition! some seaweeds contain the ,itamin! and the ut may manufacture a
certain amount/' Howe,er! a meat diet doesn;t uarantee that a person won;t be 5#(
deficient/ Some elderly people! for e7ample! can eat hih 6uantities of meat but still be
5#( deficient because they don;t ha,e enouh hydrochloric acid in their stomach to
maintain intrinsic factor/ Meat+eaters takin certain drus are also at risk for 5#(
deficiency/ Cimetidine "Taamet'! omepra:ole "?rilosec'! and other drus that inhibit
astric secretion can cause 5#( deficiency/ Anyone who chronically takes drus for
stomach ulcers! CheartburnC or astroesophaeal reflu7 may be creatin 5#( deficiency in
themsel,es/

There appears to be somethin else causin 5#( deficiency in older people that
researchers don;t yet understand/ In a 2utch study! researchers found that about (-D of
the participants had low 5#(/ 5ut ut problems only accounted for (%D of those cases/
The cause in the remainin &(D is a mystery/ 9esearchers do know that more people may
be deficient than currently appreciated/ Ehen researchers at the =eterans Administration
Hospital in >klahoma used modified criteria for 5#( deficiency "ele,ations in
homocysteine and methylmalonic acid! plus serum 5#( up to *.. p1mB+the norm is
usually (..'! they unco,ered twice as many people with 5#( deficiency than would ha,e
been detected by serum ,alues alone/

@le,ated homocysteine is found in many chronic diseases includin arthritis and
diabetes/ 9esearchers in Fapan ha,e disco,ered that noninsulin+dependent diabetes
patients with blood ,essel problems ha,e ele,ated homocysteine/ Ehen treated with #...
microrams of ,itamin 5#( "methylcobalamin' daily for three weeks! homocysteine
le,els dropped sinificantly/ Althouh the study didn;t follow the patients lon enouh to
see the effects of lon+term treatment! the condition of the patients; blood ,essels will
likely impro,e as the le,els of homocysteine are reduced! as homocysteine is e7tremely
to7ic to blood ,essels/

B#$ and %leep

Those who can;t et to sleep at niht may need ,itamin 5#(/ Studies show that 5#(
causes an earlier release of melatonin at niht which resets the sleep+wake cycle/
"Melatonin has been called Cthe sleep hormoneC because of its effects on sleep'/ 5#( acts
directly on the pineal land to pro,oke a faster release of melatonin/ At the tail end! 5#(
causes melatonin to drop off faster/ 5#( helps you et to sleep earlier! and may help you
wake up earlier if you lea,e a curtain open to the mornin sun/ 5#( sensiti:es you to
mornin liht! which helps you wake up/ =ery serious sleep+wake disorders ha,e been
successfully treated with ,itamin 5#( in the methylcobalamin form! althouh it may not
work for e,eryone/ Gnfortunately! the ,itamin doesn;t help people who want to cut down
on their sleep time altoether/

2urin the #$-.s! 5#( was fre6uently i,en to heart patients/ The ,itamin fell out of
,oue as drus took o,er the therapeutic picture/ 8ew findins on the connection
between homocysteine and ,ascular disease! plus the failure of drus to ha,e an impact
on the number of heart attacks and strokes! ha,e shifted the focus back to 5#( and other
homocysteine+lowerin ,itamins/ The notion that 5#( must be injected to be effecti,e
has been dispro,en in recent studies/ Swedish e7perience shows that oral 5#( is effecti,e
for the treatment of pernicious anemia/

5#( has many benefits! includin the reduction of homocysteine! restoration of normal
sleep patterns! and mood effects/ 5#( deficiency is a fairly common deficiency in elderly
people who fre6uently ha,e disrupted diestion/ It can cause symptoms that look e7actly
like Al:heimer;s disease! and it;s crucial for the retention of folate in cells/

Te!tin& or B#$ Deficiency

There are se,eral tests eared towards dianosin 5#( deficiency/ Homocysteine is an
indirect test/ A more direct method is to measure methylmalonic acid which becomes
ele,ated in 5#( deficiency/ There are other tests which measure ut secretions or
antibodies to ut secretions/ The Schillin test can help ferret out what is causin the
deficiency! and a simple blood test can show blood le,els/

Do!a&e

The dose of oral 5#( supplements for sleep disorders is *... mc a day! while (...
mc a day has pro,en useful in lowerin homocysteine and correctin 5#( deficiency/ In
published studies! it took four weeks for the sleep effect! and four months for the
homocysteine+lowerin effect+so be patient/ ?eople with deenerati,e diseases! includin
Al:heimer;s! should take ,ery hih doses in the rane of *+3... m! supplemented with
SAMe/

There is also the option of takin methylcobalamin! which is the neuroloically acti,e
form of 5#(/ The potential ae+re,ersin benefits are well+worth the modest price/
Methylcobalamin is a form of 5#( that is sold as a dru in Fapan/ It is the
methylcobalamin form of 5#( that has been used in most @uropean and Fapanese studies
showin efficacy aainst neuroloical disease/ The li,er con,erts about #D of inested
cyanocobalamin into methylcobalamin! but it is far more efficient to dissol,e a ood
tastin methylcobalamin lo:ene in the mouth for immediately assimilation into the
brain/
Methylcobalamin: A Potential
Breakthrough in Neurological Disease
Japanese scientists have identified a form of vitamin B12 that protects against
neurological disease and aging by a unique mechanism that differs from current
therapies. Some of the disorders that may be preventable or treatable with this
natural vitamin therapy, called methylcobalamin, include chronic fatigue syndrome,
Parinson!s disease, peripheral neuropathies, "l#heimer!s disease, muscular
dystrophy and neurological aging. "mericans have immediate access to this unique
and new form of vitamin B12, and, unlie prescription drugs, it costs very little and is
free of side effects.
vitamin B12 is a general label for a group of essential biological compounds nows as
cobalamins. $he cobalamins are structurally related to hemoglobin in the blood, and
a deficiency of vitamin B12 can cause anemia. $he primary concern of conventional
doctors is to maintain adequate cobalamin status to protect against anemia.
$he most common form of vitamin B12 is called cyanocobalamin. %owever, over the
last ten years, a number of central and peripheral neurological diseases have been
lined to a deficiency of a very specific cobalamin, the methylcobalamin form, that is
required to protect against neurological diseases and aging. $he liver converts a
small amount of cyanocobalamin into methylcobalamin within the body, but larger
amounts of methylcobalamin are necessary to correct neurological defects and
protect against aging.
Published studies show that high doses of methylcobalamin are needed to regenerate
neurons as well as the myelin sheath that protects nerve a&ons and peripheral
nerves.
CFIDS and B-!
'n the Summer 1(() issue of Healthwatch, an important research article reported a
fascinating new finding. *ver +,- of ./'0S and /1 patients cerebral spinal fluids
contained subnormal levels of vitamin B12. *n the other hand, vitamin B12 levels in
the blood did not significantly deviate from normal ranges.
"ccording to 0r. Paul .heney!s treatment pyramid for ./'0S, vitamin B12 in its non2
cyanocobalamin form 3the type commercially available4 is a potent deto&ifier of the
brain. 5ecent studies in 6urope suggest that it needs to be given in large doses in
the range of 1, 2 2, mg per day, or even more. $his supplementation of
methylcobalamin might protect the cognitive function of patients with ./'0S by
preventing the death of brain cells.
*ne cause of brain cell death is glutamate to&icity. Brain cells use glutamate as a
neurotransmitter, but unfortunately glutamate is a double2edged sword in that it can
also ill brain cells. $he release of glutamate from the synapses is a usual means by
which neurons communicate with each other.
6ffective communication means controlled release of glutamate at the right time to
the right cells, but when glutamate is released in e&cessive amounts, intercellular
communication ceases. $he flood of glutamate into the receiving neurons drives
them into hyperactivity, and the e&cessive activity leads to cellular degradation.
$he good news is that it may now be possible to protect brain cells against glutamate
to&icity by taing methylcobalamin supplementation. 'n a study in the European
Journal of Pharmacology, it was shown that methylcobalamin protected against
glutamate2, aspartate2 and nitroprusside2 induced neuroto&icity in rat cortical
neurons.
5esearchers concluded that methylcobalamin protects against neuroto&icity by
enhancing brain cell methylation. $he ./'0S 7 /ibromyalgia %ealth 5esource
recommends methylation2enhancing therapies such as vitamin B+, vitamin B12, folic
acid and trimethylglycine 3$184, taen together, to protect against heart disease,
stroe and other aging2related diseases.
$he scientists who conducted the methylcobalamin studies emphasi#e that ongoing
intae of methylcobalamin is necessary to protect against neuroto&icity. $hus for
methylcobalamin to be effective in protecting against neurological disease, daily
supplementation may be required.
"n appropriate dose to protect against neurological aging might be 1 to 9 mg a day
taen under the tongue in lo#enge form.
Slee"
" recent 8erman study appearing in Neuropharmacology showed methylcobalamin
reduced the amount of time sub:ects slept; sleep quality was better and sub:ects
awoe feeling refreshed, with better alertness and concentration. Part of this effect
was apparently due to melatonin suppression during the daytime because morning
methylcobalamin supplementation reduces drowsiness by decreasing daytime
melatonin levels.
Multi"le Sclerosis
"ccording to a recent study at <anderbilt =niversity, chlamydia pneumoniae might
lin multiple sclerosis 31S4 to ./'0S. $his maes the published effect of
methylcobalamin treatment on 1S of great importance to those who suffer from
./'0S.
" study in the Journal of Internal Medicine investigated the daily administration of +,
mg of methylcobalamin to patients with chronic progressive multiple sclerosis 31S4,
a disease that has a poor prognosis and feature side spread demyelination in the
central nervous system.
"lthough motor disability did not improve, there were clinical improvements in visual
and auditory 1S related disabilities. $he scientist stated that methylcobalamin might
be an effective ad:unct to immunosuppressive treatment for chronic, progressive 1S.
$hose with less serious forms of 1S may consider adding methylcobalamin to their
daily treatment regimen.
$he effects of methylcobalamin were studied on an animal model of muscular
dystrophy. $his study, published in Neuroscience Letter looed at degeneration of
a&on motor terminals. 'n mice receiving methylcobalamin, nerve sprouts were more
frequently observed and regeneration of motor nerve terminals occurred in sites that
had been previously degenerating.
#egenerating Ner$es
/ew substances have been shown to regenerate nerves in humans with peripheral
neuropathies. %owever, a study in the Journal of Neurological Science postulated
that methylcobalamin could increase protein synthesis and help regenerate nerves.
$he scientists showed that very high doses of methylcobalamin produce nerve
regeneration in laboratory rats.
$he scientists stated that ultra2high doses of methylcobalamin might be of clinical
use for patients with peripheral neuropathies. $he human equivalent dose the
scientists used is about >, mg of sublingually administered methylcobalamin on a
daily basis.
$hose suffering from peripheral neuropathies often tae alpha lipoic acid. Based on
our new understanding of peripheral neuropathy, it may be prudent that anyone
using alpha lipoic acid also tae at least 9 mg a day of sublingually administered
methylcobalamin to ensure that alpha lipoic acid will be bioavailable to the peripheral
nerves.
Cancer%Immune Function
" study in the :ournal Oncology e&amined the effects of methylcobalamin on several
different inds of tumors in mice. $he administration of methylcobalamin for seven
days suppressed liver, lung and ascites tumor growth. 1ice receiving
methylcobalamin survived longer than control mice did. 'n mice irradiated before
tumor cell inoculation, methylcobalamin did not improve survival.
$he effects of methylcobalamin on human immune function was investigated in the
Journal of Clinical Immunology. $he study showed that methylcobalamin
demonstrated remarable $ cell2enhancing effects when the $ cells were e&posed to
certain antigens.
$he scientists also showed that methylcobalamin improved the activity of $ helper
cells. $he scientists concluded that methylcobalamin could modulate lymphocyte
function by augmenting regulatory $ cell activities.
"mericans need to now about this important natural therapy that could e&tend the
healthy human life span. " search of the scientific literature reveals ??> published
studies on methylcobalamin. %owever, it would not be an e&aggeration to say that
virtually no doctors now of it or are recommending it.
1ethylcobalamin should be considered for the treatment of any neurological disease.
/or e&ample, based on its unique mechanisms of action, methylcobalamin could be
effective in slowing the progression of @untreatable@ diseases such as "AS 3Aou
8erhig!s disease4.
Since methylcobalamin is not a drug, there is little economic incentive to conduct
e&pensive clinical studies on it, so it may be a long time before we now :ust how
effective this unique form of vitamin B12 is in slowing the progression of common
diseases lie Parinson!s disease.
$he sublingual intae of methylcobalamin is an affordable and effective natural
therapy, and has proven even safe when given in large doses.
B-! Methylcobalamin - &horne Article -
Marilyn Bachmann - March !'( !''
1onograph 1ethylcobalamin
22222222222222222222222222222222222222222222222222222222222222222222222222222222
Introduction
1ethylcobalamin is one of the two coen#yme forms of vitamin B12 3the other being
adenosylcobalamin4. 't is a cofactor in the en#yme methionine synthase which
functions to transfer methyl groups for the regeneration of methio2nine from
homocysteine.
22222222222222222222222222222222222222222222222222222222222222222222222222222222
Pharmacokinetics
6vidence indicates methylco2balamin is utili#ed more efficiently than cyanocobalamin
to increase levels of one of the coen#yme forms of vitamin B12. 6&periments have
demonstrated similar absorption of methylcobalamin following oral administration.
$he quantity of cobalamin detected following a small oral dose of methylcobalamin is
similar to the amount following administration of cyanocobalamin; but significantly
more cobalamin accumulates in liver tissue following administration of
methylcobalamin. %uman urinary e&cretion of methylcobalamin is about one2third
that of a similar dose of cyanocobalamin, indicating substantially greater tissue
retention.1
22222222222222222222222222222222222222222222222222222222222222222222222222222222
Clinical A""lications
Bell!s PalsyB 6vidence suggests methylcobalamin dramatically increased the recovery
time for facial nerve function in Bell!s palsy.2
.ancerB .ell culture and in vivo e&perimental results indicated methylcobalamin
inhibited the proliferation of malignant cells.? 5esearch indicated that
methylcobalamin enhanced survival time and reduced tumor growth following
inoculation of mice with 6hrlich ascites tumor cells.> 1ethylcobalamin has been
shown to increase survival time of leuemic mice. =nder the same e&perimental
conditions, cyanocobalamin was inactive.9 "lthough more research is required to
verify findings, e&perimental evidence suggested methylcobalamin might enhance
the efficacy of methotre&ate.+
0iabetic CeuropathyB *ral administration of methylcobalamin 39,, mcg three times
daily for four months4 resulted in sub:ective improvement in burning sensations,
numbness, loss of sensation, and muscle cramps. "n improvement in refle&es,
vibration sense, lower motor neuron weaness, and sensitivity to pain was also
observed.D
6ye /unctionB 6&periments indicated chronic administration of methylcobalamin
protected cultured retinal neurons against C2methyl202aspartate2receptor2mediated
glutamate neuroto&icity.) 0eterioration of accommodation following visual wor has
also been shown to improve in individuals receiving methylcobalamin.(
%eart 5ate <ariabilityB %eart rate variability is a means of detecting the relative
activity and balance of the sympatheticEparasympathetic nervous systems.
1ethylcobalamin produces improvements in several components of heart rate
variability, suggesting a balancing effect on the nervous system.1,
%'<B =nder e&perimental conditions, methylcobalamin inhibited %'<21 infection of
normal human blood monocytes and lymphocytes.11
%omocysteinemiaB 6levated levels of homocysteine can be a metabolic indication of
decreased levels of the methylcobalamin form of vitamin B12. $herefore, it is not
surprising that elevated homo2cysteine levels were reduced from a mean value of
1>.D to 1,.2 nmolEml following parenteral treatment with methylcobalamin.12
1ale 'mpotenceB 'n one study, methylcobalamin, at a dose of + mgEday for 1+
wees, improved sperm count by ?D.9 percent.1? 'n a separate investigation,
methylcobalamin, given at a dose of 1,9,, micrograms per day for >22> wees,
resulted in sperm concentration increases in ?) percent of cases, total sperm count
increases in 9> percent of cases, and sperm motility increases in 9, percent of
cases.1>
Sleep 0isturbancesB $he use of methylcobalamin in the treatment of a variety of
sleep2wae disorders is very promising. "lthough the e&act mechanism of action is
not yet elucidated, it is possible that methylcobalamin is needed for the synthesis of
melatonin, since the biosynthetic formation of melatonin requires the donation of a
methyl group. Supplementation appears to have a great deal of ability to modulate
melatonin secretion, enhance light2sensitivity, normali#e circadian rhythms, and
normali#e sleep2wae rhythm.1922,
22222222222222222222222222222222222222222222222222222222222222222222222222222222
Dosage
$he dosage for clinical effect is 19,,2+,,, mcg per day. Co significant therapeutic
advantage appears to occur from dosages e&ceeding this ma&imum dose.
1ethylcobalamin has been administered orally, intramuscularly, and intravenously;
however, positive clinical results have been reported irrespective of the method of
administration. 't is not clear whether any therapeutic advantage is gained from the
non2oral methods of administration.
22222222222222222222222222222222222222222222222222222222222222222222222222222222
Sa)ety( &o*icity( and Side +))ects
1ethylcobalamin has e&cellent tolerability and no nown to&icity.
What is it?
Vitamin B12 or cobalamin is an essential nutrient found in meat products. Vitamin
B12 is absorbed in the small intestine and is necessary for proper nerve function
and converting food into energy. Deficiencies of vitamin B12 cause anemia and
neurological impairments including memory loss and disorientation.
What do people with HIV use this supplement for?
To avoid deficiency
Depending on the way vitamin B12 levels are measured, studies suggest that
between ten and 50 per cent of people living with !V"#!D$ %&#s' are deficient
in this nutrient. (his deficiency is most li)ely due to !V*related damage to the
small intestine that prevents the body from absorbing ade+uate amounts of B12.
,ertain drugs, such as #-( and the antibiotics used to treat tuberculosis, can
decrease levels of vitamin B12. $everal studies suggest that deficiency in this
vitamin increases the rate at which a person becomes ill %disease progression'.
!n a study conducted by Dr. #lice (ang and colleagues, serum levels of vitamin
B12 were measured in !V*positive people without symptoms of disease. .ven
when factors such as ,D/0 counts were considered, the team found that serum
vitamin B12 levels could be used to predict which sub1ects would become ill most
+uic)ly.
B12 deficiency seems to be lin)ed to poor absorption2 most nutritionists suggest
therefore that supplements of B12 be in1ected or ta)en sublingually %dissolved
under the tongue'. #lthough these methods have been shown to increase serum
levels of B12 in !V*positive people, no trials have been done to assess the
impact of B12 supplements on disease progression.
To prevent and treat dementia
3iven that B12 deficiencies are associated with confusion and memory, many
physicians and researchers have speculated that vitamin B12 might play a role in
dementia and other !V*related cognitive disorders. 4ne case report described
the dramatic recovery of a !V*positive man suffering from dementia who was
treated with B12. ,linical trials have produced less impressive results and it is now
generally accepted that B12 may be a factor in some but not all cases of !V*
related dementia. B12 supplements have also been useful in treating elderly
people with B12 deficiencies who showed signs of memory loss and senility.
To treat peripheral neuropathy
&eripheral neuropathy is a tingling or burning in the hands and feet. !t is often
associated with anti*!V drugs, particularly dd,, dd! and d/(. 4ne early study of
&#s suggested that people with low B12 levels were more li)ely to e5perience
neuropathy, but subse+uent studies have not confirmed this connection. B12 has,
however, been used successfully to treat diabetic neuropathy, a fact that argues
its case for the management of nerve damage in &#s.
Available forms and usage
!n ,anada, B12 is ta)en orally or by intramuscular or intravenous in1ections.
#lthough other forms of B12 have been developed, such as nasal sprays, gels
and sublingual tablets, not all of these formulations are widely available in
,anada. 3iven that vitamin B12 may be poorly absorbed in !V*positive people,
most nutritionists and physicians recommend B12 shots. (hese shots can be
ta)en at a doctor6s office or an !V clinic and, in most cases, they are covered by
provincial and private insurance plans. # monthly in1ection can be used to boost
a daily oral dose of B12. !f obvious signs of B12 deficiency are present, more
fre+uent in1ections are possible %up to several times a wee)'. 4ral doses of 25 or
50 mg of B12 are found in B25 or B50 vitamin tablets respectively. (hese B*
comple5 combination vitamins are described further in ,#(!.6s supplement sheet
on vitamin B*comple5.
Cautions and Concerns
Vitamin B12 supplements are safe to use. .5cess amounts of the vitamin are
eliminated in the urine. #t high doses, however, B12 may cause an5iety in some
people and mild diarrhea in others. $ome people are sensitive to B12 and may
develop a s)in rash while ta)ing this supplement. $ince B*vitamins tend to wor)
best together, it6s important to maintain the balance of Vitamin B12 and another B*
vitamin called folate %folic acid' in the body. (a)ing large doses of one B*vitamin
alone is not a good idea so if you are ta)ing e5tra B12, you might want to ta)e a
B*comple5 pill as well.
Peripheral Neuropathy(polyneuropathy)
A common !ide'effect of chemotherapy''i!
there any !olution(
%)MMA*Y
?eripheral neuropathy "or! polyneuropathy' is normally attributed to diabetes!
thyroid problems! alcohol abuse! and consistent e7posure to chemotherapy
treatments/ 5ut it can likewise be attributed to the use of drus other than
chemotherapy aents/ 8otwithstandin multiple statements and ad,ertisements
proclaimin that statins are safe and ,ital to lowerin cholesterol and
pre,entin coronary e,ents! contrary e,idence e7ists that lon+term e7posure to
statins may substantially increase the risk of1induce and e7acerbate peripheral
neuropathy by #-D in the first year and (<D for two or more years (1, 2, 3)/
Moreo,er! statins can contribute to suppression of our immune system and
acti,ation of helper T+cells "lymphocyctes produced in the thymus land' (4)H
likewise statins ha,e been attributed to li,er and kidney injury (5)! as well as
reduction in bone mineral density and resultin osteoporosis (6)/ Contrary to
some studies that report statins as reducin the risks of ad,anced prostate
cancer (7)! other peer+re,iewed studies 6uestion whether lon+term use of
statins actually cause cancer (8) and report findins that statins do not pro,ide a
protection aainst breast or prostate cancer/ (9)
Also! while antianioenic "retard blood ,essel rowth' drus are in ,oue this
year "Celebre71=io77! thalidomide' and low+dose fre6uent chemotherapy is
reconi:ed as bein both cytoto7ic and antianioenic! how does the reduced
blood ,essel formation from the accumulation of these ,arious antianioenic
aents affect continued health of our ner,esI I suest that lon+term use of
antianioenic aents certainly deny blood supplies to ner,es "as well as cancer
and healthy tissue' and either alone or combined! certainly induce peripheral
neuropathy/
Therefore! while statins are most effecti,e in pre,entin coronary e,ents! C>J+
( inhibitors are essential for pain and antianioenesis! and thalidomide miht
e,entually pro,e to be an effecti,e antianioenic aent+++I suest that it is
incumbent on us to analy:e our own chemical1dru cocktails and combinations
in order to optimi:e the cumulati,e and combined effects on our 6uality and
lenth of life+++I likewise suest that in our monthly #- minute sessions with
our doctors! they are not doin so on our behalf/
Many cancer patients are also takin a myriad of other drus! and most of us
take some statin and antianioenic aents/ Are we thus assurin that we will
suffer treatment+limitin and debilitatin "and possibly permanent' peripheral
neuropathy by takin Bipitor for its cholesterol+lowerin effects! Celebre7 for
pain and antianioenesis! blood pressure medicines! and thalidomide for
antianioenesis "thalidomide is well+known for causin peripheral
neuropathy'I Ehen we de,elop peripheral neuropathy! do our doctors analy:e
our medication list to assess the indi,idual and cumulati,e effects of all of our
medicationsI "My 6uestion is ob,iously cynical and rhetorical/'
Many cancer patients who undero se,eral months of chemotherapy will
de,elop peripheral neuropathy to some e7tent/ The ner,e damain effects of
chemotherapy are cumulati,e and as the chemotherapy treatments are
continued! the condition often becomes treatment+limitin and physically
debilitatin/ Medical science does not know of any aent to relie,e or delay the
onset of peripheral neuropathy and we are often told that C///it is just our old
friend Ta7otere///C! without any analysis of the cumulati,e antianioenic
effects of our other drus as possibly contributin in a major way to our
peripheral neuropathy/
The probable side+effect of peripheral neuropathy resultin from lon+term
chemotherapy is well+known by our oncoloists! yet they ha,e no suestions
about how to alle,iate it e7cept to reduce the dose of the chemotherapy aent or
suspend treatment/ In my opinion! our doctors are not comfortable with any
aent we can buy in a dru or health food store and often just shru their
shoulders and tell us to try it if we want/ 8or do I belie,e that our doctors are
aware of the many side effects "and accumulation thereof' of the many drus
we take to support and aument our cancer treatments or alle,iate side+effects
there from/
After #& weekly Ta7otere treatments and while I was still respondin "I was
also takin 3.. m of Celebre71day 0 daily 8or,asc and Accupril for blood
pressure control'! I was forced to stop treatment due to e7treme peripheral
neuropathy and resultin onychosis (10)/ I wrote about this in Chemotherapy +
?art (/ In that paper I suested Alutamine as a possible aent to relie,e or
delay peripheral neuropathy/ In subse6uent chemo treatments I continue with
daily Alutamine and belie,e that it offers some reliefH but after (0 years of
chemotherapy! I still suffer considerable peripheral neuropathy/ Howe,er!
below I suest other possibilities that miht partially relie,e and1or delay this
treatment+limitin side+effect of chemotherapy/
In addition to a mandatory re,iew of e,ery complementary dru we are takin
that miht ha,e any characteristics of inducin peripheral neuropathy! and
optimi:in their utili:ation in ,iew of our own concept of 6uality16uantity of
life++++ in %)MMA*Y! I suest se,eral possible solutions to alle,iate1delay
peripheral neuropathy while enaed in our saa of prostate cancer and the
treatments therefor+++with the e7ception of shakuyaku+kan:o+to! all of these
items are a,ailable in a dru1health food store)
#' Alutamine at #. m J 31day as delineated in my abo,e paper/
(' Shakuyaku+kan:o+to "not a,ailable in a dru1health food store'+++an ancient
Chinese1Fapanese herbal concoction for muscle spasms and tinlin in the
hands and feet/
*' Aamma+linolenic acid "ABA'! fish oil concentrate! and ascorbyl palmitate
++corrects fatty acid imbalance/
3' =itamin 5#( in the form of methylcobalmin "methl 5#(' 0 folic acid/
-' Alpha+lipoic acid 0 acety+B+carnitine 0 8+acetylcysteine 0 ,itamin C/
"8>T@) we must be coni:ant of the fact that the studies1reports of aents
effecti,e aainst peripheral neuropathy state that such aent"s' only delay or
partially mitigate peripheral neuropathy+++none proclaim to prevent it+++so!
with our cancer and lon+term use of statins! antianioenic aents! and
chemotherapy! we must accept the fact that we will all suffer peripheral
neuropathy to some e7tent/'
2@FI8ITI>8S
...Neuropathy is the wastin and inflammation of ner,e tissues! often manifest
in peripheral e7tremities "hands1feet'/ Symptoms are burnin! shootin pain
possibly concurrent with a cold sensation! transient numbness! and weakness of
the e7tremities/ The sensation"s' can be transient! mo,in from finer to
finer1toe to toe! and radiatin up the arm or le/ Symptoms usually impro,e
upon stoppin the dru! althouh impro,ement can take <+% weeks and pain
can worsen before it impro,es/ 8europathy is commonly caused by diabetes!
fatty acid imbalance! restriction of blood supply to ner,es "could C>J+(
inhibitors add to the conditionI'! nutritional deficiencies! and chemotherapy
aents/ (11) If peripheral neuropathy is bilateral! dru induction is usually
attributed thereto++++but if it is unilateral! there are possibly other non+dru
related problems/
+++gamma-linolenic acid (GLA)++known as Cthe ood omea+<C fatH reulates
metabolic processes down to the cellular le,el+++amon se,eral e7pected effects
of ABA) a cytoto7ic aent for cancer and an arthritis relie,er/ (12).
...ascorbyl palmitate++fat+soluble form of ascorbic acid ",itamin C'H unlike
ascorbic acid! which is water soluble! ascorbyl palmitate is stored in cell
membranes until needed by the bodyH free+radical antio7idant/ (13)
...folic acid1folate ",itamin 5$'+++water+soluble and important in red blood cell
formation! protein metabolism! rowth and cell di,ision/ (14)
...alpha-lipoic acid (ALC)+++ser,es as a coen:yme in the Krebs cycle and in the
production of cellular enery+++possibly the Cperfect and idealC antio7idant+++in
Aermany it is an appro,ed treatment for peripheral neuropathyH in the GS it is
sold as a dietary supplement! usually in -. m tablets/ (15)
...N-acetylcysteine (NAC)+++promotes deto7ification and acts directly as a free
radical sca,ener+++protects normal cells! but not malinant cells! from the
to7ic effects of chemotherapeutic aents and radiation+++can reduce tumor
formation and pre,ent metastases! but does not interfere with cytoto7icity of
chemo aents/ (16)
...acetyl-L-carnitine (ALC) ++modulates cellular functions! includin the
transfer of fatty acids for enery production+++restores ner,e rowth factor
function+++neuropathies respond to ABC (17)+++daily administration of ABC
durin Ta7ol treatment completely pre,ents occurrence of neuropathy and
myelosuppression (18)+++it is associated with increased ner,e conduction
,elocityH in a trial it pre,ented &*D of ner,e conduction defects and
promoted1accelerated ner,e+fiber reeneration/ (11, pp. 476)
...vitamin !"+++the common form of ,itamin 5#( found in the drustore is
cyanocobalamin "cyano 5#('! but this form of 5#( is inferior to
methylcobalamin "methyl 5#(' as an antio7idant+++look on your 5#( bottle to
see which form of the ,itamin you ha,eH and assure that you are takin the
methyl form+++studies ha,e shown that methl 5#( pro,ides protection from
neuroto7icity and is neurotrophic "promotes rowth of ner,e cells'! which may
help reenerate peripheral ner,e damae (19)+++methl 5#( should be taken
sublinual "under the tonue'/
...sha#uya#u-#an$o-to "TF+<%' is an ancient oriental herbal concoction used for
many ailments! includin acute muscle spasms! tinlin hands1feet! and
peripheral neuropathy+++it is a blend of two crude drus) shakuyaku "peony
root' and kan:o "lycyrrhi:a root' (20)+++"note) these were amon the
inredients of ?C S?@S'+++the herb is manufactured as prescription only in
Fapan by TsumuraH their contact in the GS is $3$+%**+&%%(+++likewise! some
men ha,e found the herbal mi7 at the Academy of >riental Medicine "-#(+*(*+
<&(.' and 8ew 5ree:e "Ken Morehead++$#$+*%3+#3*&! or kfmk@aol.com'/
Shakutaku+Kan:o+to has been reported as effecti,ely reducin the se,erity of
peripheral neuropathy! arthralia "joint pain'! and myalia "muscular pain' in
Ta7ol1Carboplatin protocols/ (21)
...statins 4 aents capable of acceleratin the rate of secretion of a i,en
hormone by the anterior pituitary land+++ cholesterol+lowerin medications
known as reductase inhibitors "inhibitors of en:ymes' offerin up to *&D
reduction in the risk of coronary e,ents (22, 23)+++estimates are that half of the
GS population will shortly be takin a statin dru (24)++common statins are
Bipitor! Locar! ?ra,achol! Bescol! and Me,acor (25)/
%P&C'('C )*%'NG AN) P+*,*C*L %-GG&%,'*N% (*+
C.&/*,.&+AP0 AN) *,.&+ )+-G(%)-'N)-C&) P&+'P.&+AL
N&-+*PA,.0
#' Alutamine M #. m "about one heapin teaspoon' J 31day++++see
Chemotherapy + ?art ( for loic and references/
(' Shakuyaku+kan:o+to M (/- m J *1day/
*' Aamma+linolenic acid "ABA' 0 fish oil concentrate 0 ascorbyl palmitateNN/
3' =itamin 5#( "methylcobalamin' M -+3. m1day sublinual "under the
tonue' 0 (...+-... mc folic acidNN/
-' Alpha+lipoic acid M (-. m J (1day 0 acetyl+B+carnitine M #... m J
(1day 0 8+acetylcysteine M <.. m J (1day 0 *... m ,itamin C J (1dayNN/
**(2, @ pp. 479)
Bill Ai!hman September (..(
O Copyrihted by 5ill Aishman + all rihts reser,ed + (..(
N*,&) I am not a doctor and can not i,e medical ad,ice/ I am not a medical
researcher/ I am an unemployed prostate cancer patient in my si7th year of this
saa and I performed this laymanPs analysis for my own edification and
decision+makin purposes/ In conjunction with a competent medical team!
e,ery cancer patient must make their own decisions reardin treatment
options/ I make no claim that this analysis is definiti,e or complete and I in,ite
any and all competent suestions1corrections that will pro,ide salient
information to prostate cancer patients in our search for methods to e7tend
6uality and 6uantity of life while battlin a terminal disease/
methylcobalamin , Neuropathy
This articl s!"mitt# "$ %#li& o& 8'12'99.
(mail )##rss*
Intern Med #$$$ FunH*%"<')3&(+-
Intra,enous methylcobalamin treatment for uremic and diabetic neuropathy in
chronic hemodialysis patients/
Kuwabara S! 8aka:awa 9! A:uma 8! Su:uki M! Miyajima K! Fukutake T! Hattori T
2epartment of 8euroloy! Chiba Gni,ersity School of Medicine/
QMedline record in processR
>5F@CT) To study the effects of the intra,enous administration of methylcobalamin! an
analoue of ,itamin 5#(! for uremic or
uremic+diabetic polyneuropathy in patients who are recei,in maintenance hemodialysis/
An ultra+hih dose of ,itamin 5#( has been
reported to promote peripheral ner,e reeneration in e7perimental neuropathy/
M@TH>2S) 8ine patients recei,ed a -.. micro
methylcobalamin injection * times a week for < months/ The effects were e,aluated usin
neuropathic pain radin and a ner,e
conduction study/ 9@SGBTS) Serum concentrations of ,itamin 5#( were ultra+hih
durin treatment due to the lack of urinary e7cretion/
After < months of treatment! the patients; pain or paresthesia had lessened! and the ulnar
motor and median sensory ner,e conduction
,elocities showed sinificant impro,ement/ There were no side effects/ C>8CBGSI>8)
Intra,enous methycobalamin treatment is a safe
and potentially beneficial therapy for neuropathy in chronic hemodialysis patients/
Autism 2!
Understand, Act and Heal
Dr. 7eubrander is board*certified in .nvironmental 8edicine with special
interests in heavy metals and B12 biochemistry. e practices in .dison, 79
where he dedicates :0; of his time to patients see)ing the D#7< approach
to autism.
"iochemical Conte#t And Clinical $se %f
&ethylcobalamin
=or years ! have prescribed vitamin B12, administered orally, sublingually, or by in1ection. ! have
used it for a number of disorders, none of which were autism until 1:::. !n the past ! referred to
>B12> in a generic sense, assuming that there was no difference clinically between using any of
its three easily available forms? cyanocobalamin, hydro5ycobalamin, and methylcobalamin. 7ow,
four years after beginning to treat autism with >B12> ! hold a very different view, that view being
the methylcobalamin form of B12 holds the greatest promise for treating children on the autistic
spectrum.
(hough methylcobalamin has never been studied for its effects on autism, this presentation will
demonstrate that the literature cites many studies performed on humans, animals, or in laboratory
settings that indicate positive results from several disorders that share similar symptoms or
pathophysiology. (he results of my study using in1ectable methylcobalamin for @5 children who
carry the diagnosis of #utism, &DD, or #spergerAs syndrome will be presented. # literature review
will discuss the profound effects methylcobalamin has on the central and peripheral nervous
systems, the cellular and humoral immune systems, on sleep*wa)e cycles, and on deto5ification
biochemistry. 8ethylcobalaminAs biochemistry and its )ey role in methylation will be discussed as
it applies to the formation of purines, pyrimidines, and nucleic acids. #n attempt will be made to
present a plausible hypothesis why >methylcobalamin loading> spares tetrahydrofolate and methyl
reserves, thereby resulting in increased D7# and purine synthesis and their secondary
biochemical reactions, total body transmethylation reactions, and deto5ification biochemistry.

The DAN movement continues to gain momentum among the scientific and lay communities
validating that autism does have a strong biological component that can be manipulated for the
benefit of those afflicted. (he D#7 8anual is replete with references documenting reasons why
D#7 &ractitioners who treat children from this biological"biochemical paradigm often obtain
results. Bnfortunately the results reveal varying degrees of mi5ed successes and failures. !t is
possible that our failures and"or limited degrees of success are at least partially due from the fact
that we are 1ust now beginning to understand some of the )ey biochemical pathways involved in
our childrenAs bodies. $o much more research needs to be done to predict which children may
respond to which therapies. Bnfortunately none of the childrenAs bodies have read the literature or
the biochemical te5tboo)s<
8ethylcobalamin therapy is one such avenue that needs to be e5plored. (he biochemistry of B12
%also )nown as >cobalamin>' with its scientific conclusions shares a consensus opinion among
scientists as to its mechanism of action. B12"cobalamin has a comple5 ring structure with an ion
of cobalt found at its core. !t can only be synthesiCed by microorganisms and would pose a
problem for vegans to avoid a deficiency condition e5cept for food contamination that is
ubi+uitous and cannot be avoided. Dietary sources are richest in liver and yeast. # substance
)nown as intrinsic factor, derived from the parietal cells in a healthy stomach, are re+uired for
absorption to ta)e place in the distal portion of the small intestine, the terminal ileum. 4nce
absorbed, (ranscobalamin !! carries cobalamin to the liver and tissues. !n the liver, cobalamin is
stored by attaching to (ranscobalamin !. ,obalamin is uni+ue in its ability as a water*soluble
vitamin to be stored in the liver rather than being +uic)ly lost from the body.
(hree forms of cobalamin e5ist? cyanocobalamin, hydro5ycobalamin, and methylcobalamin. (he
cyano form is the most common form, the least e5pensive commercially available form, but it is
not natural to the body. ydro5cobalamin is primarily found in the cytoplasm where it is converted
into its active coenCyme forms? adenosylcobalamin coenCyme %deso5yadenosylcobalamin
coenCyme' and methylcobalamin coenCyme. #denosylcobalamin coenCyme moves into the
mitochondria and remains fairly stationary in that location while methylcobalamin coenCyme is the
cobalamin coenCyme form that either remains in the cytosol or is returned to the plasma for
transport to other tissues.
!n the mitochondria, adenosylcobalamin coenCyme acts in concert with the enCyme
methylmalonyl*,o# mutase on the substrate methylmalonic acid to form succinic acid. $uccinic
acid is an important component of the Drebs cycle and gluconeogenesis. !t is plausible, though
not proven, that the fre+uent reports of >increased energy> clinicians hear from patients receiving
B12 in1ections may partially be the result of this biochemical pathway. #nother possible reason
could be the role of adenosylcobalamin coenCyme in the mitochondria and the mitochondriaAs
primary role in energy metabolism that begins with glucose and ends in the formation of #(&.
=rom my study, it is possible that this glucose*inducing function supplying increased fuel to the
brain was one of the reasons parents fre+uently reported higher cognitive abilities in their
children.
(he hydro5ycobalamin"methylcobalamin coenCyme reactions are more complicated. =irst, in the
presence of ade+uate hydro5ycobalamin and the enCyme methyl*tetrahydrofolate reductase, the
methyl group from methyl*tetrahydrofolate is transferred to hydro5ycobalamin to become
methylcobalamin coenCyme. 7otice that two things are happening at once. =irst,
methylcobalamin coenCyme, in the presence of the enCyme methionine mutase, immediately
passes its newly ac+uired one*carbon methyl group to homocysteine to regenerate the essential
amino acid methionine. 8ethionine is then +uic)ly converted to $*adenosylmethione %$#8', a
)ey player in the bodyAs overall methylation biochemistry. $econd, methyl*tetrahydrofolate, by
losing its one carbon methyl group to methylcobalamin, now becomes tetrahydrofolate. !t is this
end product, tetrahydrofolate that is vital to the formation of purines, pyrimidines, and nucleic
acids.
,obalamin">B12> deficiency leads to three problems. =irst, when adenosylcobalamin coenCyme is
deficient, the substrate methylmalonic acid cannot be converted into succinic acid. (herefore
levels of methylmalonic acid with continue to increase and spill over into the urine, a phenomenon
)nown as methylmalonic aciduria. $econd, when the methylcobalamin coenCyme is deficient, the
substrate homocysteine cannot be converted to methionine. (herefore levels of homocysteine will
continue to increase and may be seen in the blood or urine resulting in homocystinemia and
homocystinuria respectively. (hird, a phenomenon )nown as >folate trapping> occurs when
hydro5ycobalamin is deficient in the presence of ade+uate methyl*tetrahydrofolate. Ehen this
situation occurs, the methyl group on methyl*tetrahydrofolate is trapped because >it wants to
leave %to become tetrahydrofolate' but canAt get away>.
Between 8ay 2002 and 8arch 200F ! obtained data on @5 children with the diagnosis of #utism,
&DD, or #spergerAs syndrome. (he study was an open trial using in1ectable methylcobalamin.
,hildren ranged in age from 2 to 1: with the ma1ority between ages F and G. (he in1ections were
started when the children were stable and not ma)ing other significant changes to their therapies,
either biological or non*biological. =ollow*up was done every G wee)s with me, either in person or
by telephone. &arents were instructed to write a letter describing what they saw happening with
their children. (hese letters from parents were to be spontaneous and written >in their own
words>. (herefore the parentAs responses were not "directed" by a uestionnaire. (he parents
were instructed that conclusions or summary statements were all right to give but only if they
gave as many specific e5amples as possible describing why they arrived at the conclusions that
they did.
4f the @5 children included in the study, H1 were males and 1/ were females. =ifty*one males
%H2;' and 12 %@G;' females responded. %(he number of females was probably too small for the
percentage of responders to be meaningful.' #ppro5imately 50; of the parents reported 15 or
more symptoms improved. $i5ty*seven urinary 88#As were performed of which @1; were
negative in the total group of GH and @0; were negative in the responders group. =orty*nine
homocysteine levels were performed of which :0; were negative in the total group of /: and
:2; were negative in the group of responders. (herefore, it was my conclusion that the current
>gold standard> lab tests documenting B12 deficiency as we presently define it has no predictive
value as to which children may or may not respond to methylcobalamin therapy.

The "Top Ten" symptoms parents reported had improved are as follow: a) Language and
Communication !"# $) Awareness %&"# c) Cognition and Higher Levels of Cognition and
'easoning &("# d) )ngagement *+"# e) )ye Contact +"# f) ,etter ,ehavior +&"# g) -ore
.ocused +&"# h) /reater Understanding +&"# i) 0ocali1ation +&"# 2) Trying 3ew Things
++"4 4ther significant and surprising symptom improvements included many parents stating that
their child? >Eas much happier, much more affectionate %even if her or she already was
affectionate', much more interactive, calmer, more resilient to changes in routines2 had more
spontaneous speech, began to use pretend play or fantasy, was able to finally sit at the table with
the family and"or sit and attend to a tas)>, etc. (here were over 100 different symptom
improvements parents reported %for a complete list, see the slide presentation in this syllabus'.
$ide effects were few2 the primary one of hyperactivity was reported in 10;. (he second most
common problem was sleep disturbance, this being reported in G; of the children. 4ften giving
the in1ections in the morning instead of at bedtime alleviated this problem. Eith only one
e5ception, parents stated that the positives so far outweighed the negatives that they would deal
with the negatives, e.g. hyperactivity. (he one e5ception was a child who responded positively to
over 20 symptoms but developed a severe sleep problem over a period of G wee)s.
Ehen first deciding to do the study, the route of administration was discussed with many
colleagues. 8y final decision, for several reasons, was to perform the original study using an
in1ectable form. (he literature admits that the absorption of B12 is a "comple! process" involving
numerous physiological and biochemical steps. (hese steps include binding to saliva, formation
of intrinsic factor from healthy gastric parietal cells, proper stomach acid release, proper
pancreatic protease release, a healthy terminal ileum, the appropriate mi5 of intestinal
microorganisms, enterocytes properly functioning, etc. #s ! contemplated our children, it was my
conclusion that most of them chew poorly and therefore would have minimal salivary binding of
cobalamin. undreds of nutritional analyses gathered from this population have repeatedly
demonstrated poor nutritional status with inade+uate amounts of protein, carbohydrate, and
essential fatty acids, the re+uired precursor building bloc)s of healthy cells. (herefore there was
no guarantee that the children would be able to meet the re+uirements necessary for >functional
release> of gastric acid or intrinsic factor. #lso, due to the belief shared by D#7 practitioners that
inappropriate functional release of pancreatic enCymes often e5ists %consider the Iepligen study
and the positive benefit of secretin in some children', there was no way to insure ade+uate
digestive enCyme function. #s previously demonstrated and"or continues to be documented by
the wor) of Ea)efield, Drigsman, and Buie, the terminal ileum is fre+uently inflamed and
demonstrates varying degrees of ileitis. (his finding alone was enough to e5clude the oral route
of administration as a valid >initial step> in determining the potential effectiveness of
methylcobalamin therapy for my study. 4ther factors ! had to consider included dysbiosis and the
mi5 of microorganisms in the terminal ileum that may interfere with my ability to )now the >dose
absorbed> by the child relative to the >dose produced> by microorganisms and"or the >dose
administered> by me. (herefore, it was my strong opinion then %and even stronger now' that until !
answered the first +uestion definitively Jemdash2 does methylcobalamin play a vital role in the
autistic populationK Jemdash2 that these multiple variables inherent to the gastrointestinal tract,
variables that were impossible to predict who suffered from them and variables that were
impossible to consistently control due to many factors, must be bypassed by in1ections. !t was
also my strong conviction that unless the dose and route of administration were fairly free of
variables, there would be no way to interpret the data to predict optimum dosing or to evaluate a
childAs response, either positive or negative.
4nce ! decided to use in1ectable methylcobalamin, the ne5t dilemma that needed to be addressed
was whether to use the intramuscular" intravenous" or subcutaneous route of administration.
!nitially ! used both the intramuscular and"or subcutaneous routes. owever, within G to @ wee)s it
was my >impression> that ! was getting a higher response rate in the group of children that were
using the subcutaneous route of administration. ypothetically" subcutaneous in#ections may
produce a "slow time$release" process" allowing a "leaching effect" of the methylcobalamin. (his
theoretically could allow a >relatively higher dose> of the substance to remain in the body for
longer periods of time if this was compared to the in intramuscular or intravenous routes of
administration. 4ne reason for this is that the )idneys are )nown to +uic)ly clear any e5cess
cobalamin. Because cobalamin is a red substance, ! have occasionally been called by panic)ing
parents reporting >red urine> in their childAs urine who were worried the child was bleeding. ! have
never seen red urine with the subcutaneous route of administration but ! have seen it infre+uently
with intravenous and intramuscular administration. =ormal research will need to be conducted to
determine whether or not my theory is valid.
8y protocol as of early 7ovember 2002 and the techni+ues ! had the parents use can be seen in
detail on the slides that follow. !t should be noted that this protocol is in a dynamic state of
change as ! continue to search for >the optimum dose and the ideal fre+uency of in1ections>.
Ehen ! advised parents to give doses lower than H5 mcg per )ilogram, there was a lower
percentage of responders and there was a different >mi5> of symptoms improved. &arents no
longer seemed to report improvements from the >top 10> symptom response list that
accompanies my higher dose protocol. !nstead, there were only minor symptom improvements,
e.g. >he seems to have more energy>. 8ost parents that stopped the in1ections because they did
not see what they believed to be significant degrees of improvement usually were on the phone
within 2*/ wee)s begging to restart the in1ections because their children regressed. (he most
common >regressions> reported were language, awareness, and cognition Jemdash2 these were
also my >Big (hree> ** the symptoms most commonly reported to improve<

The 5uestion arises: "6s there any research to support any of my findings or hypotheses7"
.ortunately the answer is a resounding "yes" as shown from the references cited4 !t should
be noted that hundreds more references are available but only those necessary to complete this
presentation are listed. # few pertinent articles with )ey points are important to draw your
attention to and discuss. !)eda
10
demonstrated that communication' cognition and intellectual
functions' and emotion in #lCheimer patients were improved in the group that achieved the
highest levels of methylcobalamin and that maintained these high levels for the longest period of
time. all
@
discussed methylcobalamin deficiency found in early infancy shows
developmental delay' hypotonia' lethargy' poor responsiveness' and fre(uent sei)ures.
(wo types of treatment responses were noted? a' the first type showed slow steady psychomotor
improvement over a long period of time suggesting improvement in myelination2 b' the second
type showed rapid improvement within 2/*/@ hours of hypotonia, responsiveness, and lethargy.
Lamamoto
/1
suggests that transmethylation by methylcobalamin may induce functional recovery
from ischemia. !t should be noted that much con1ecture has occurred regarding flow*function
discrepancies in the brains of autistic children. =our articles
1/, 21, 22, FH
were chosen to illustrate the
possible role methylcobalamin plays in protection from to#ic agents, e.g. from heavy metals,
chemicals, and biological agents, possibly as they wor) through deto5ification pathways involving
glutathione and sulfation. !)euchi
11
concluded that methyl groups, induced only by the
methylcobalamin form of B12, are re(uired for *long+lasting* postsynaptic field potential
amplification. =our references
1G, 21, F@, /2
are presented to illustrate that ultra+high doses of
methylcobalamin' either oral or in,ectable' may result in nerve regeneration- #)ai)e
1

describes chronic use of methylcobalaminAs role in the protection of cortical neurons from
cytoto5icity. (hree references
@, 1G, FG
are cited to present the possibility of methylcobalaminAs direct
and"or indirect role in protection from demyelination and.or its potential role in
remyelination. 3otoAs study
H
is reviewed indicating methylcobalaminAs role in the prevention of
encephalopathy. =our references
5, F0 F/, F5
are cited that definitively show methylcobalaminAs role
in immune enhancement. (hese studies document that both the cellular and the humoral arms
of the immune system are positively affected- =unadaAs study
G
is reviewed indicating
methylcolbalamin may downregulate allergic responses. $andberg
F1
discusses that
methylcobalamin is the ma,or form of "/2 present in breast mil0. MindenbaumAs study
1@

discusses the vital role of methylcobalamin in rapidly dividing tissues of the body'
specifically the brain. (he reference also addresses inherited errors of cobalamin metabolism
and their management. Dira
1G
and 4hta
2H
report that patients who respond to therapy may
have been shown to have normal lab values prior to treatment. (hree references
11, 20, 2
have
been selected to show that the methyl form of "/2 is the form most li0ely to result in
positive responses- (wo references
@, 2H
show that the response to methylcobalamin therapy
may be immediate- =ive references
10, 1G, 21, 2H, F@
are cited indicating that high to ultra+high doses
of methylcobalamin may be re(uired and"or needed to produce positive results. (hree
references are cited
1, 10, 1G
to illustrate that long+term chronic use may be necessary to achieve
or maintain positive clinical results. (wo references
F, 10
were cited showing there were no
to#ic effects or side effects' even with high dose long+term use-

%n conclusion" methylcobalamin appears to play a vital role in autistic biochemistry. % hypothesi&e
that loading with high dose methylcobalamin spares the body's need to convert hydro!cobalamin
into methylcobalamin by using methyl$tetrahydrofolate to regenerate tetrahydrofolate. Therefore
the "additional" tetrahydrofolate is now available to be shunted to methiene$tetrahydrofolate to
produce DNA( and directly or indirectly through methenyl$tetrahydrofolate to form purines. These
"additional" purines are now available to participate in DNA formation" )$regulatory protein
reactions" protein *inase reactions" and to enter into deto!ification pathways. % further
hypothesi&e that loading with high dose methylcobalamin spares the body's limited methyl
reserves that are necessary to convert homocysteine into +A, and necessary to participate in
general body transmethylation reactions. -oading doses also result in more regeneration of
homocysteine" a prereuisite for cysteine and deto!ification reactions.
&1TH23C%"A3A&I4
methylcobalamin research methylcobalamin for brain methylcobalamin B12
&ethylcobalamin is one of the two coen)yme forms of vitamin "/2
5cyanocobalamin6- Vitamin "/2 plays an important role in red blood cells'
methylation reactions' and immune system regulation- 1vidence indicates
methylcobalamin has some metabolic and therapeutic applications not
shared by the other forms of vitamin "/2-
7imple &ethylcobalamin biochemistry
&ethylcobalamin is the active form of vitamin "/2 that acts as a cofactor
for methionine synthase in the conversion of homocysteine to methionine'
thus lowering blood levels of homocysteine- &ethylcobalamin acts as a
methyl donor and participates in the synthesis of 7A&+e 57+
adenosylmethionine6' a nutrient that has powerful mood elevating
properties-
Clinical $ses of &ethylcobalamin
&ethylcobalamin supplements increase alertness and body temperature-
&ethylcobalamin may slightly help those with diabetic neuropathy- A better
nutrient for this condition is 3ipoic Acid-
&ethylcobalamin has been found to be helpful in "ell8s palsy-
&ethylcobalamin ta0en orally is effective in the treatment of pernicious
anemia' says a 9apanese study-
&ethylcobalamin may inhibit the ototo#ic 5hearing damage6 side effects of
the antibiotic gentamicin-
1mail if you would li0e to receive our 7upplement :esearch $pdate
newsletter emailed for free the first wee0 of each month- We email a brief
abstract of ; to < studies on supplements and natural medicine topics' and
their practical interpretation by =r- 7ahelian-
Inde# of 7upplements and Herbs
%ver ! listings ++ by :ay 7ahelian' &-=-

&ethylcobalamin :esearch $pdate
&others with low levels of vitamin "/2 in their blood are at increased ris0
of having an infant with spina bifida ++ a birth defect in which the spinal
cord fails to form properly- "ased on previous research' pregnancy
guidelines recommend that women consume enough folic acid to reduce
the ris0 of spina bifida and related problems- The new findings suggest that
these guidelines should also include recommendations about vitamin "/2-
The many faces of vitamin "/2> catalysis by cobalamin+dependent
en)ymes-
#nnu Iev Biochem. 200F2H2?20:*/H.
Vitamin "/2 is a comple# organometallic cofactor associated with three
subfamilies of en)ymes> the adenosylcobalamin+dependent isomerases'
the methylcobalamin+dependent methyltransferases' and the
dehalogenases- =ifferent chemical aspects of the cofactor are e#ploited
during catalysis by the isomerases and the methyltransferases- Thus' the
cobalt+carbon bond ruptures homolytically in the isomerases' whereas it is
cleaved heterolytically in the methyltransferases- The reaction mechanism
of the dehalogenases' the most recently discovered class of "/2 en)ymes'
is poorly understood- %ver the past decade our understanding of the
reaction mechanisms of "/2 en)ymes has been greatly enhanced by the
availability of large amounts of en)yme that have afforded detailed
structure+function studies' and these recent advances are the sub,ect of
this review-
Cobalamin+dependent methyltransferases-
#cc ,hem Ies. 2001 #ug2F/%@'?G@1*:.
Cobalamin cofactors play critical roles in radical+cataly)ed rearrangements
and in methyl transfers- This Account focuses on the role of
methylcobalamin and its structural homologues' the methylcorrinoids' as
intermediaries in methyl transfer reactions' and particularly on the reaction
cataly)ed by cobalamin+dependent methionine synthase- In these methyl
transfer reactions' the cobalt5I6 form of the cofactor serves as the methyl
acceptor- "iological methyl donors to cobalamin include 4?+
methyltetrahydrofolate' other methylamines' methanol' aromatic methyl
ethers' acetate' and dimethyl sulfide- The challenge for chemists is to
determine the en)ymatic mechanisms for activation of these unreactive
methyl donors and to mimic these ama)ing biological reactions-
1ffects of vitamin "/2 on performance and circadian rhythm in normal
sub,ects-
7europsychopharmacology. 1::G 7ov215%5'?/5G*G/.
This preliminary study investigates effects of methyl+ and cyanocobalamin
on circadian rhythms' well+being' alertness' and concentration in healthy
sub,ects- 7i# women 5mean age !? years6 and /; men 5mean age !@ years6
were randomly assigned to treatment for /; days with ! mg cyano+5C"/26
or methylcobalamin 5&"/26 after A days of pre+treatment observation-
3evels in the C"/2 group increased rapidly in the first' then slowly in the
second treatment wee0' whereas increase in the &"/2 group was linear-
$rinary a&T<s e#cretion was reduced by both forms of vitamin "/2 over 2;
hours with a significant decrease between @+// hours' whereas
urinary e#cretion of potassium was significantly increased between @+
// hours- Activity from 2!+@ hours increased significantly under
both forms of vitamin "/2- 7leep time was significantly reduced under
&"/2 inta0e- In this group the change in the visual analogue scales items
*sleep (uality'* *concentration'* and *feeling refreshed* between
pretreatment and the first wee0 of treatment showed significant
correlations with vitamin "/2 plasma levels- Cortisol e#cretion and
temperature were not affected by either medication- We conclude that
vitamin "/2 e#erts a direct influence on melatonin- %nly &"/2 has a
positive psychotropic alerting effect with a distribution of the sleep+wa0e
cycle toward sleep reduction-
Coen)yme "/2 5cobalamin6+dependent en)ymes-
.ssays Biochem. 1:::2F/?1F:*5/.
The "/2 or cobalamin coen)ymes are comple# macrocycles whose
reactivity is associated with a uni(ue cobalt+carbon bond- The two
biologically active forms are methylcobalamin and AdoCbl and their closely
related cobamide forms- &ethylcobalamin participates as the intermediate
carrier of activated methyl groups- =uring the catalytic cycle the coen)yme
shuttles between methylcobalamin and the highly nucleophilic cob5I6alamin
form- 1#amples of methylcobalamin +dependent en)ymes include
methionine synthase and &e+H;+&BT> coen)yme & methyl transferase-
AdoCbl functions as a source of carbon+based free radicals that are
unmas0ed by homolysis of the coen)yme8s cobalt+carbon bond- The free
radicals are subse(uently used to remove non+acid hydrogen atoms from
substrates to facilitate a variety of reactions involving cleavage of carbon+
carbon' carbon+o#ygen and carbon+nitrogen bonds- &ost reactions involve
/'2 migrations of hydro#y+' amino+ and carbon+containing groups' but there
is also one class of ribonucleotide reductases that uses AdoCbl- The
structures of two cobalamin+dependent en)ymes' methionine synthase and
methylmalonyl+CoA mutase' have been solved- In both cases the cobalt is
co+ordinated by a histidine ligand from the protein- The significance of this
binding motif is presently unclear since in other cobalamin+dependent
en)ymes spectroscopic evidence suggests that the coen)yme8s nucleotide
8tail8 remains co+ordinated to cobalt when bound to the protein-
8ost #mericans can6t do it
because they aren6t getting any
8.(LM,4B#M#8!7
$tress, obesity, infections, hormones, or alcohol
,an !7,I.#$. your ris) of
1. ,ancer
2. Dementia
F. Depression
/. eart disease
Vitamin B*12 0 =olate
,an D.,I.#$. your ris) of
1. ,ancer
2. Dementia
F. Depression
/. eart disease
2ou may want to get all the Vitamin "+/2 and folate you need from what you8re eating or by
ta0ing your multivitamin- "ut' you8re really 4%T getting what you need-
If you want to combat the ris0s of stress' obesity' infections' hormones' or alcohol' you need
to learn about medical brea0throughs that ta0es you beyond homocysteine and cholesterol-
They empowers you in your efforts to stay healthy- They help you ma0e the most of your Cod+
given abilities' ma#imi)ing your performance-
8ethylcobalamin is the most potent form of Vitamin B12
found in nature. Ee need methylcobalamin for the
healthy development and sustenance of our circulatory,
immune and nervous systems.
.ggs, dairy products, fish and meat, especially organ
meat li)e liver, are good sources of Vitamin B*12. !n
fact, meals incorporating large amounts of liver
represented the main treatment for Vitamin B*12
deficiency in the past.
8ethylcobalamin is the only active form of Vitamin B*12
in the brain outside the mitochondrion. (he liver must
convert cyanocobalamin to methylcobalamin in order for
Vitamin B*12 to do its biochemical wor) in the brain.
Ehen the comple5 conversion of cyanocobalamin is not
completed, the brain is robbed of the benefits of
methylcobalamin. ,yanocobalamin is a by*product of
Vitamin B*12 charcoal e5traction. $cientific methods led
people to believe that cyanocobalamin, not
methylcobalamin was the naturally occurring form of
Vitamin B*12. ,yanide in the charcoal replaces the
methyl group in much the same way as it does in the
body of a cigarette smo)er. Vitamin B*12 re+uires the
assistance of !ntrinsic =actor to enter the body from the
small intestine. Eithout !ntrinsic =actor, dietary Vitamin
B*12 or B*12*containing supplements go unabsorbed.
#utoimmune reactions and diseases sometimes destroy
the stomach6s parietal cells that produce !ntrinsic =actor.
&ernicious anemia results from this destructive process.
8ore rarely, pernicious anemia develops when the body
ma)es antibodies against the binding site of !ntrinsic
=actor. (he antibodies rob Vitamin B*12 of the binding
spot on !ntrinsic =actor as it tries to ma)e its way into
the small intestine. 8onthly in1ections of Vitamin B*12
can correct the anemia, immune and neurological
problems that snea) up on people with pernicious
anemia.
$urveys of depressed patients indicate nearly one*third
of them do not receive enough folic acid or Vitamin B*
12. !t is e5tremely important to ta)e Vitamin B*12 when
ta)ing folic acid supplements. Eithout Vitamin B*12
supplementation, worse physical problems might
develop during folic acid supplementation.
$mall amounts of Vitamin B*12 are absorbed directly
through the mucosal tissue of the mouth. (his discovery
led to the development of Vitamin B12 loCenges and
sprays. Ehen Vitamin B*12 is absorbed in the mouth, it
goes into the blood and then to the enCymes that
re+uire Vitamin B*12 as a coenCyme. Eith other forms
of Vitamin B*12, the liver must use its enCyme systems
to produce methylcobalamin.
Eith increased availability of methylcobalamin, medical
research has shown that methylcobalamin has
important benefits not seen with cyanocobalamin. !t acts
to reverse nerve damage and promote nerve cell
regeneration.
8ethylcobalamin plays a )ey role in sleep. !t helps the
brain fill up its neurotransmitter >gas tan)> when
neurotransmitters are produced from amino acids.
$imilarly, depression also improves more +uic)ly and
completely when patients ta)e methylcobalamin.
Depression also can worsen even while using
antidepressants if a restrictive diet is started to lose
weight. # diet can run the neurotransmitter >gas tan)>
dry.
omocysteine has emerged on center*stage as a
biochemical culprit associated with vascular and brain
disease. Vitamin B*12 and folic acid are crucial to the
elimination of homocysteine. Vitamin supplementation
reduces the chances of building up levels of
homocysteine associated with stress.
,linical e5perience and scientific research have clearly
established the importance of Vitamin B*12. (he
discovery of Vitamin B*12 was considered so
monumental that the responsible researchers were
honored with the 7obel &riCe. Iecent discoveries have
demonstrated the value of using methylcobalamin for
improvement in the cardiovascular, immune and
nervous systems.N
Efficacy of methylcobalamin on lo-erin& total homocy!teine pla!ma concentration! in
haemodialy!i!
patient! recei.in& hi&h'do!e folic acid !upplementation+
8ephrol 2ial Transplant/ (..( MayH #&"-') $#<+((/
5ACKA9>G82) Hyperhomocysteinaemia! which is considered to be induced by impairment of
the
remethylation pathway in patients with chronic renal failure "C9F'! cannot be cured solely by
folic acid therapy/
In the present study! we in,estiated the additional benefit of administration of methylcobalamin!
which is a coen:yme
in the remethylation pathway! on lowerin total homocysteine "tHcy' plasma concentrations in
haemodialysis "H2' patients recei,in hih+dose folic acid supplementation/ M@TH>2S) In
order to assess the
efficacy on lowerin plasma tHcy le,els "fastin concentration'! (# H2 patients! were randomly
assined and
pro,ided folic acid supplementation) #- m1day orally "roup I! n 4 &'H methylcobalamin -.. m
intra,enously
after each H2! in addition to folic acid "roup II! n 4 &'H or ,itamin 5"<' "5"<''! <. m1day orally!
in addition to
folic acid and methylcobalamin "roup III! n 4 &'/ All patients were treated for *
weeks/Amethionine+loadin test
was conducted before and after supplementation/ The followin measurements were also made
before and after
supplementation for each roup) serum folic acid! 5"<'! and ,itamin 5"#(' "5"#('' concentrations
"includin
measurement of proportion of methylcobalamin fraction'/ Twel,e H2 patients recei,in
methylcobalamin alone
ser,ed as the H2 control roup and se,en healthy ,olunteers ser,ed as the normal control roup
for this study/
9@SGBTS) In our randomi:ed H2 patients the proportions of methylcobalamin fraction "3%/*01+
&/-D' and
plasma ,itamin 5"<' concentration "(/$01+#/# n1ml' were sinificantly lower than in the normal
controls
"methylcobalamin -%/&01+(/(D! ?S./.#H 5"<' (./#01+#./% n1ml! ?S./.#'! while folic acid and
,itamin 5"#('
were not sinificantly different from the normal controls/ Mean percentae reduction in fastin
tHcy was #&/*01+
%/3D in roup I! -&/301+#*/*D in roup II! -$/$01+-/<D in roup III! and #%/&01+&/-D in H2
controls/ The power
of the test to detect a reduction of tHcy le,el was $$/<D in roup II and $$/$D in roup III when
type I error le,el
was set at ./.-/ Aroups II and III had normal results for the methionine+loadin test after
treatment/ Treatment
resulted in normali:ation of fastin tHcy le,els "S#( n1ml' in all #3 patients treated by the
combined
administration of methylcobalamin and supplementation of folic acid reardless of whether there
was
supplementation of ,itamin 5"<'/
The benefit of methylcobalamin administration on lowerin plasma tHcy le,els inH2patients
was remarkable/ >ur study suested that both supplementations of hih+dose folic acid and
methylcobalamin are
re6uired for the remethylation pathway to reain its normal acti,ity/ This method could be a
therapeutic stratey to
combat the risk associated with atherosclerosis and cardio,ascular disease in patients with
chronic renal failure/
CONCL)%ION/
The Coen:yme Forms of =itamin 5#()
Toward an Gnderstandin of their
Therapeutic ?otential
0re&ory 1elly2 N+D+
Ab!tract
Althouh cyanocobalamin and hydro7ycobalamin are the most commonly
encountered supplemental forms of ,itamin 5#(! adenosyl+ and
methylcobalamin are the primary forms of ,itamin 5#( in the human body! and
are the metabolically acti,e forms re6uired for 5#(+dependent en:yme
function/ @,idence indicates these coen:yme forms of ,itamin 5#(! in addition
to ha,in a theoretical ad,antae o,er other forms of 5#(! actually do ha,e
metabolic and therapeutic applications not shared by the other forms of ,itamin
5#(/ This article will pro,ide an o,er,iew of the metabolism and function of
adenosyl+ and methylcobalamin! and will discuss the potential therapeutic
rele,ance of the coen:yme forms of ,itamin 5#( in a ,ariety of clinical
conditions! includin anemia! anore7ia! cancer! HI=! and li,er and sleep
disorders/ "Alt Med 9e, #$$&H("-')3-$+3&#'
Introduction
Cyanocobalamin "C8+Cbl' is the most commonly supplemented form of
,itamin 5#(! but it is present in the body in trace amounts and its biochemical
sinificance remains uncertain/ Althouh the amount of cyanide is considered
to7icoloically insinificant! humans must remo,e and deto7ify the cyanide
molecule! reduce the cobalamin to its usable 0# o7idation state! and then
en:ymatically con,ert the cobalamin into one of two metabolically acti,e
coen:yme forms/ 8utritional inade6uacies! en:yme defects! and patholoical
chanes to tissues can all contribute to a reduced ability of the body to
accomplish the synthesis of the acti,e forms of ,itamin 5#( from C8+Cbl/
The two forms of ,itamin 5#( ha,in acti,ity in 5#(+dependent en:ymes
within the human body are adenosylcobalamin "AdeCbl' and methylcobalamin
"MetCbl'/ AdeCbl is occasionally referred to as coen:yme 5#(! cobamamide!
cobinamide! or dibenco:ide/ In some biochemical or therapeutic situations! the
clinical utili:ation of either AdeCbl or MetCbl "alone or in combination' can
produce results not found with the supplementation of either C8+Cbl or
hydro7ycobalamin ">H+Cbl'/
Biochemi!try2 Metaboli!m2 and En3yme unction!
Cobalamin is a ,ery comple7 molecule! containin cobalt surrounded by fi,e
nitroen atoms/ Surroundin this central cobalt is a corrin rin! which
structurally resembles the porphyrin rin found in hemolobin! the
cytochromes! and chlorophyll/ The use of cobalt in the coen:yme forms of
cobalamin is the only known function of this metal in bioloical systems/
In humans! the cobalt in the coen:yme forms of ,itamin 5#( e7ists in a
uni,alent "0#' o7idati,e state! desinated as cob"I'alamin/ Cobalamin
molecules can also contain cobalt in a 0* "cob"III'alamin' or 0(
"cob"II'alamin' o7idati,e stateH howe,er! in these forms the cobalt must be
reduced prior to ha,in en:yme acti,ity/
The compound most commonly referred to as ,itamin 5#( is C8+CblH
howe,er! this molecule does not occur naturally in plants! micro+oranisms! or
animal tissues/
#
C8+Cbl has a cyanide molecule at the metal+carbon position
and its cobalt atom e7ists at an o7idati,e state of 0*! not the bioloically acti,e
0# state/ In order to be utili:ed in the body! the cyanide molecule must be
remo,ed and eliminated throuh phase II deto7ification/ It is thouht that
lutathione "ASH' miht be the compound performin the function of
decyanation in ,i,o! since lutathionylcobal+amin "AS+Cbl' has been isolated
from mammalian tissue/
(
If! in fact! ASH is needed as a cofactor to acti,ate
C8+Cbl to the coen:yme forms of ,itamin 5#(! clinical situations characteri:ed
by decreased tissue le,els of ASH miht be e7pected to result in a functional
deficiency of ,itamin 5#(! e,en in the presence of ade6uate plasma or tissue
le,els of the cobalamin moiety "typically labs are lookin only for a cobalamin
moiety and do not differentiate between C8+Cbl and the acti,e forms of
,itamin 5#('/
Humans are incapable of synthesi:in the corrin rin structure! and so are
completely dependent upon dietary sources of ,itamin 5#(/ The ultimate
source of all ,itamin 5#( occurrin in the diet is bacteria! with animal products
pro,idin the majority of the dietary intake/ It had been proposed that humans
could absorb ,itamin 5#( formed by colonic floraH howe,er! this appears to be
untrue since no sinificant amount of cobalamin can be absorbed in the colon/#
The optimal absorption of dietary ,ita+min 5#( re6uires the formation of a
comple7 between dietary cobalamins and 9+proteins! and the secretion! by the
stomach parietal cells! of intrinsic factor/ The cobalamin+9+protein comple7 is
diested by pancreatic en:ymes in the small intestine! and the released
cobalamin molecule binds with intrinsic factor and is absorbed in the distal
ileum/ Cobalamin is then detached from intrinsic factor in the enterocyte cells
of the small intestine! and is bound to transcobalamin II for transport into
tissues/
Althouh the basic cobalamin molecule is only synthesi:ed by micro+
oranisms! all mammalian cells can con,ert it into the coen:ymes AdeCbl and
MetCbl/ >H+Cbl! MetCbl! and AdeCbl are the three forms of cobalamin most
fre6uently isolated from mammalian tissue/ Howe,er! only MetCbl and AdeCbl
actually function as cofactors in human en:ymes/ AdeCbl is the major form in
cellular tissues! where it is retained in the mitochondria/ MetCbl predominates
in blood plasma and certain other body fluids! such as cerebral spinal fluid! and!
in cells is found in the cytosol/
*
AdeCbl functions in reactions in which hydroen roups and oranic roups
e7chane places/ In humans! AdeCbl is re6uired for the en:yme
methylmalonyl+CoA mutase which is used in the catabolic isomeri:ation of
methylmalonyl+CoA to succinyl+CoA "used in the synthesis of porphyrin' and
as an intermediate in the deradati,e pathway for ,aline! isoleucine! threonine!
methionine! thymine! odd+chain fatty acids and cholesterol/
#
2eficiencies in this
coen:yme form of ,itamin 5#( result in increased amounts of methylmalonyl+
CoA and enerally in an increase in lycine/
MetCbl;s only known bioloical function in humans is as a cofactor in the
en:yme methionine synthase/ The methionine synthase en:yme is located in the
cytosol of cells and participates in the transfer of methyl roups from -+
methyltetrahydrofolate to homocysteine! resultin in the subse6uent
reeneration1remethylation of methionine/
?e:acka et al ha,e proposed that at least four steps are re6uired to con,ert
supplementary C8+Cbl to the coen:yme forms of ,itamin 5#(/ These are) "i'
decyanationH "ii' reduction of the 0* and 0( formsH "iii' synthesis of MetCbl in
the cytosolH and "i,' synthesis of AdeCbl in the mitochondria/ The initial step
of decyanation is probably dependent on ASH! possibly in combination with
8A2?H and FA2/( This results in the formation of cob"III'alamin/ >H+Cbl is
also a cob"III' form but has an ad,antae o,er C8+Cbl since it bypasses the
need for decyanation/ The ne7t step re6uired is the reduction of cob"III'alamin
to cob"II'alamin/ This reduction is probably dependent upon 8A2H and
possibly either FA2 or FM8/
(
>nce cob"II'alamin is formed! a similar
reduction can shunt it into the formation of cob"I'alamin and subse6uently!
with AT?! AdeCbl/ An alternate pathway can! with the donation of a methyl
roup from S+adenosylmethionine "SAM'! result in the formation of MetCbl
from cob"II'alamin/ MetCbl becomes cob"I'alamin after donatin its methyl
roupH howe,er! MetCbl can be reenerated! by acceptin a methyl roup from
-+methyltetrahydrofolate! for reuse in methionine synthase "see fiure #/'/
@,idence indicates alpha+tocopherol protects aainst a reduction in AdeCbl in
o7idati,ely stressed cells/
3
@7perimental e,idence suests alpha+tocopherol
miht be needed for formation of AdeCblH howe,er! further studies are re6uired
to clarify this relationship/ If alpha+tocopherol is used in the reducin steps! a
deficiency would be e7pected to decrease the formation of both AdeCbl and
MetCbl/
-

It is important to be aware that nitrous o7ide inacti,ates the coen:yme forms of
,itamin 5#( by o7idi:in cob"I'alamin to either cob"II'alamin or
cob"III'alamin/ 8itrous o7ide also interferes with the acti,ity of methio+nine
synthase/
<

Ab!orption
@,idence indicates cobalamin from MetCbl is utili:ed more efficiently than
C8+Cbl to increase the le,els of coen:yme forms of ,itamin 5#(/ Althouh
free MetCbl is not ,ery stable in the astrointestinal tract! and considerable loss
of the methyl roup can take place under e7perimental conditions! in
physioloical situations intrinsic factor probably partially protects MetCbl from
deradation/ ?aper chromatoraphy of diested ileal mucosa has demonstrated
unchaned absorption of MetCbl followin oral administration/ The 6uantity of
cobalamin detected followin a small oral dose of MetCbl is similar to the
amount followin administration of C8+CblH but! sinificantly more cobalamin
accumulates in li,er tissue followin administration of MetCbl/ Human urinary
e7cretion of MetCbl is about one+third that of a similar dose of C8+Cbl!
indicatin substantially reater tissue retention/
&

In humans! about *- percent of AdeCbl appears to be absorbed intact followin
oral administration! and about && percent of the absorbed oral dose is retained
in body tissues/ Althouh a hiher percentae of C8+Cbl appears to be
absorbed! only -. percent is retained in tissues! and assumin an ade6uate
supply of necessary cofactors is a,ailable! probably is con,erted to the
coen:yme forms of ,itamin 5#( o,er a period of #+( months/
%

Althouh indi,iduals with pernicious anemia do not produce the intrinsic factor
needed for ,itamin 5#( absorption! hih doses of oral ,itamin 5#( "abo,e
#... mc' ha,e been shown to be an ade6uate treatment of 5#( deficiency and
pernicious anemia! indicatin there is some mechanism of absorption
independent of intrinsic factor/
$!#.
It is likely that with supra+physioloical doses
of the coen:yme forms of ,itamin 5#(! some of the absorption is also
independent of intrinsic factor/
Clinical Implication!
Anemia/ The use of the coen:yme forms of ,itamin 5#( will be useful in some
types of anemia and miht offer an ad,antae o,er supplementation of the non+
bioloically acti,e forms of ,itamin 5#(/ Gnder e7perimental conditions!
poisonin of rabbits with phenylhydra:ine results in the de,elopment of
hemolytic hyperchromic anemia and impairment of hematopoiesis in the bone
marrow/ A decrease in the MetCbl content of the blood serum is obser,ed
durin spontaneous reco,ery from this e7perimentally induced anemia/
Administration of MetCbl results in a complete normali:ation of some blood
and hematopoiesis patterns! as well as a restoration of total cobalamin content!
and an impro,ed ratio of the spectrum of cobalamin forms/ AdeCbl! althouh
somewhat effecti,e! e7hibited a distinctly lower effect on the patterns studied/
##
A -.+day treatment with a ferritin preparation combined with folinic acid and
AdeCbl was well tolerated and demonstrated efficacy in normali:in ,arious
hematoloical parameters "hemolobin! hematocrit! red cell count! mean
corpuscular ,olume! iron! and transferrin iron bindin capacity' in prenant
women/
#(
Aranese et al similarly report a positi,e result from the
supplementation of a ferritin+AdeCbl+folinic acid preparation to 3. women
durin prenancy/ A proressi,e increase in hematoloical parameters was
demonstrated and a complete normali:ation of red cell morpholoy was
obser,ed/
#*

Anore4ia/ Carnitine and AdeCbl were shown to promote cerebral mass
rowth! increase neocortical layer thickness and pyramidal neuron ,olume! and
fully restore normal structure of the neocorte7 in an e7perimental model of
anore7ia ner,osa/ In patients with anore7ia ner,osa! carnitine and AdeCbl
accelerate body weiht ain and normali:ation of astrointestinal function/
Batent fatiue was reported to disappear and mental performance increase
under this treatment reimen/
#3
Korkina et al report the combined use of
carnitine and AdeCbl eliminate fluctuations in the work rate and impro,e the
scope and producti,ity of intellectual work in patients with anore7ia ner,osa in
the stae of cache7ia/ Batent fatiue in the population studied was not fully
remo,ed/
#-

Children with infantile anore7ia were di,ided into two roups/ >ne roup of
children was i,en (... mc of AdeCbl and #... m of carnitine! while the
other roup was i,en cyproheptadine! an anti+histamine used to stimulate
appetite/ The results of usin the AdeCbl and carnitine mi7ture were juded
ood by the authors! were comparable to the effects of the pharmaceutical
aent! and were produced with no side+effects/
#<

Cancer/ Ehile information is ,ery limited! both AdeCbl and MetCbl miht
e,entually be shown to ha,e a supporti,e role in the pre,ention or treatment of
cancer/ A sinificant body of e7perimental e,idence suests a deficiency of
,itamin 5#( can enhance the acti,ity of ,arious carcinoens/
#&
@7perimental
results also indicate a link between alterations in the intracellular metabolism of
cobalamin and the increased rowth of human melanoma cells/
#%

A methyl roup+deficient diet "MA22' has been shown to result in
hypomethylation of 28A and t98A! and to promote cancer in the li,er of rats
in as short a period of time as one week/ 9esults of e7periments conducted by
Eainfan and ?oirier support the hypothesis that intake of a MA22! by causin
depletion of SAM pools! results in 28A hypomethylation! and subse6uently
leads to chanes in ene e7pression/
#$
Althouh many of the MA22+induced
alterations in methylation and ene e7pression occur rapidly! Christman et al
ha,e demonstrated they are essentially re,ersible/
(.

It is not surprisin that MetCbl! because of its ability to donate a methyl roup
and because of its role in the reeneration of SAM! the body;s uni,ersal methyl
donor! miht be protecti,e aainst cancer/ Cell culture and in ,i,o e7perimental
results indicate MetCbl can inhibit the proliferation of malinant cells/
(#

@7perimental results also indicate MetCbl can enhance sur,i,al time and
reduce tumor rowth followin inoculation of mice with @hrlich ascites tumor
cells/
((
5oth of the coen:yme forms of ,itamin 5#( ha,e been shown to
increase sur,i,al time of leukemic mice/ Gnder the same e7perimental
conditions! C8+Cbl was inacti,e/
(*
Althouh more research is re6uired to ,erify findins! MetCbl miht also
enhance the efficacy of methotre7ate/ MetCbl appears to stimulate the rate of
*H+methotre7ate influ7 into tumors in e7perimental animals/ Miasishche,a et
al ha,e suested! based on kinetic analysis! a dose of ./.# m1k of MetCbl
miht be an optimal dose for impro,in the antitumor dru action of
methotre7ate/
(3
Heimburer et al ha,e reported that in a preliminary study! four months;
treatment with #. m of folate plus -.. mc of >H+Cbl resulted in a reduction
of atypia in male smokers with bronchial s6uamous metaplasia/
(-
Since folate
and cobalamin interact in re+methylation! it is possible MetCbl would ha,e
worked as well or better than the >H+Cbl/
Diabetic Neuropathy/ Ya6ub et al conducted a double+blind study on the
clinical and neurophysioloical effects of MetCbl administration in -. patients
with diabetic neuropathy/ @ach patient in the acti,e roup was i,en -.. mc
of MetCbl orally three times per day for four months/ Indi,iduals recei,in
MetCbl reported subjecti,e impro,ement in somatic and autonomic symptoms
"parasthesias! burnin sensations! numbness! loss of sensation! and muscle
cramps'! and reression of sins of diabetic neuropathy "refle7es! ,ibration
sense! lower motor neuron weakness! and sensiti,ity to pain'/ Howe,er! motor
and sensory ner,e conduction studies showed no statistical impro,ement after
four months/ MetCbl was well tolerated by the patients and no side+effects
were encountered/
(<

?ower spectral analysis of heart rate ,ariability is a means of detectin the
relati,e acti,ity and balance of the sympathetic1parasympathetic ner,ous
systems! and has been suested to be a ood 6ualitati,e method of e,aluatin
sub+clinical diabetic autonomic neuropathy/ Yoshioka et al ha,e shown for
indi,iduals with 8I22M! oral administration of #-.. mc1day of MetCbl
produces impro,ements in se,eral components of heart rate ,ariability/
(&

Eye function/ @7periments indicate chronic administration of MetCbl protects
cultured retinal neurons aainst 8+methyl+2+aspartate+receptor+mediated
lutamate neuroto7icity/ Kikuchi et al suest the action is probably due to
alteration in the membrane properties mediated throuh methylation by SAM/
In their e7periments! an acute e7posure to MetCbl was not effecti,e in
protectin retinal neurons/
(%
9esults also indicate MetCbl enhances the ability
to e,oke a field potential in rat suprachiasmatic nucleus slices/ C8+Cbl had no
acti,ity in this e7perimental model/
($

Iwasaki et al studied the effect of MetCbl on subjects with e7perimentally
induced deterioration of ,isual accommodation/ The authors report the
deterioration of accommodation followin ,isual work was sinificantly
impro,ed in indi,iduals recei,in MetCbl/
*.

0enital')rinary/ Administration of (1k of di"(+ethylhe7yl'+phthalate
"2@H?' induces se,ere testicular atrophy! reduction of testicular specific
lactate dehydroenase acti,ity! and decreased :inc! manesium and potassium
concentrations in rats/ Co+administration of AdeCbl with 2@H? is reported to
pre,ent these chanes/ MetCbl! when co+administered with 2@H?! was unable
to pre,ent the testicular atrophy induced by 2@H? under similar e7perimental
conditions/
*#

Thirty+nine patients with dianosed olio:oospermia were di,ided into two
roups and administered MetCbl at a dose of either < m or #( m per day for
#< weeks/ MetCbl appeared to be transported to seminal fluid ,ery efficiently!
and no dose+dependent difference between ,itamin 5#( concentrations in the
serum or seminal fluid was obser,ed between roups/ The efficacy rate for the
roup recei,in < m per day was *&/- percent and for the roup recei,in #(
m per day was *$/# percent/
*(

MetCbl was administered daily "#!-.. microrams1day! for 3+(3 weeks' to (<
infertile male patients/ ?atients with a:oospermia were e7cluded from the trial/
Sperm concentration increased in #. cases "*%/3D'! total sperm count increased
in #3 cases "-*/%D'! sperm motility increased in #* cases "-./.D'! and total
motile sperm count increased in #* cases "-./.D'/ Serum luteini:in hormone!
follicle stimulatin hormone! and testosterone were unchaned/
**

HI"/ It has been obser,ed that human immunodeficiency ,irus "HI='
seropositi,e indi,iduals ha,e decreased le,els of metabolites in,ol,ed in
methylation! and that low serum ,itamin 5#( le,els are associated with an
increased risk of proression to AI2SH howe,er! the effect of supplementation
of coen:yme forms of ,itamin 5#( on disease proression is unknown/
May has proposed that the replication of HI= miht be! in part! modulated by
28A methylation! and has suested hypermethylation of the HI= pro,irus
miht suppress ,iral replication and play a role in the establishment of latency/
5ecause of its central role in methylation! MetCbl! as well as SAM and
methyltetrahydrofolate! miht ha,e potential as therapeutic aents in HI=+
infected indi,iduals/
*3

@,idence is beinnin to suest low serum ,itamin 5#( concentrations miht
precede disease proression in indi,iduals positi,e for HI=/ Tan et al ha,e
reported the risk of proression to AI2S is increased in indi,iduals with low
serum ,itamin 5+#( concentrations "9H 4 (/(#! $-D CI 4 #/#*+3/*3'/
*-

Eeinber et al in,estiated cobalamins to determine their ability to modify
HI=+# infection of hematopoietic cells in ,itro/ Their results indicate! under
e7perimental conditions! >H+Cbl! MetCbl! and AdeCbl inhibit HI=+# infection
of normal human blood monocytes and lymphocytes/ They suest that
because of the relati,e ease with which hih blood and tissue le,els of
cobalamins can be achie,ed in ,i,o! these aents Cshould be considered as
potentially useful aents for the treatment of HI=+# infection/C
*<

Homocy!teinemia and Methyl'malonic Acidemia/ @le,ated le,els of
homocysteine and methylmalonic acid can be metabolic indications of
decreased le,els of the coen:yme forms of ,itamin 5#(! or the presence of a
enetic en:yme defect/
?ropelled by e,idence that ele,ated concentrations are associated with an
increased risk for a ,ariety of chronic clinical conditions! homocysteine has
recei,ed a tremendous amount of emphasis in the scientific literature/ 5ecause
MetCbl is a potential donor of the methyl roup re6uired to reenerate methio+
nine from homocysteine! a theoretical arument can be used to justify this
coen:yme form of ,itamin 5#( as a part of the nutritional protocol for lowerin
homocysteine/ Araki et al ha,e demonstrated that ele,ated homocysteine le,els
are reduced followin parenteral treatment with MetCbl/ In their trial! ten
diabetic patients with ele,ated plasma le,els of homocysteine were
administered #... mc of MetCbl i/m/ daily for three weeks/ Followin
treatment! the plasma le,els of homocysteine decreased from a mean ,alue of
#3/& to #./( nmol1ml "? S ./.#'/
*&
Methylmalonic acidemia is enerally the result of an inherited metabolic
defect! althouh it is possible to ha,e ele,ated le,els of this metabolite due to a
functional deficiency of AdeCbl in the absence of an inherited defect/ 5hatt et
al ha,e suested a transient response to >H+Cbl miht be misleadin and
miht subse6uently impair the therapeutic response to AdeCbl/ They further
suest AdeCbl be the cobalamin therapy of choice for indi,iduals with
biochemically uncharacteri:ed methylmalonic acidemia/
*%

Li.er Di!ea!e/ AdeCbl and MetCbl appear to offer a theoretical ad,antae
o,er either C8+Cbl or >H+Cbl in the treatment of li,er disorders/ Althouh
hih blood le,els of ,itamin 5#( ha,e been reported in patients with hepatitis!
cirrhosis! and other li,er disease! it is not unusual to actually ha,e a
correspondinly low li,er tissue concentration of ,itamin 5#( and its
coen:ymes/ Alass et al proposed this obser,ation miht be due to an impaired
ability of the li,er to absorb ,itamin 5#( from the portal circulation/
*$

5ecause a ,itamin deficiency can persist durin li,er disease despite oral
,itamin supplementation! Bee,y et al ha,e suested the li,er;s ability to
con,ert ,itamins into metabolically acti,e forms miht be compromised/
3.
It is
possible! durin these patholoical conditions! the li,er will not contain
ade6uate supplies of the needed cofactors to optimally form coen:yme
analoues of ,itamin 5#(/ 5ecause of these factors! Iwarson et al suested
that ,itamins used in the treatment of li,er disorders should be i,en in their
metabolically acti,e form! thereby eliminatin the need for con,ersion to occur
in damaed li,er cells/
3#
In e7perimentally induced lipid pero7idation of li,er microsomes resultin
from poisonin of rabbits with phenylhydra:ine! MetCbl and AdeCbl were
shown to modulate the acti,ity of the monoo7yenase system/ MetCbl
appeared to induce the system! and AdeCbl seemed to repress the system/
Administration of MetCbl into poisoned rabbits stimulated the acti,ities of
dimethyl aniline 8+demethylase! aniline p+hydro7ylase! 8A2?H+cytochrome
?+3-.! and 8>2H+cytochrome b- reductases as compared with normal state!
while AdeCbl inhibited the reduction of all the monoo7yenase system patterns
studied/ Althouh the therapeutic rele,ance of these actions of the coen:yme
forms of ,itamin 5#( on the monoo7yenase system is open to debate! the
authors obser,ed that both of these coen:ymes contributed to normali:ation of
lipid pero7idation in li,er microsomes of poisoned rabbits/
3(
AdeCbl also e7erts
hepato+protecti,e acti,ity after carbon tetrachloride+induced hepatitis in rabbits/
The normali:ation of results from the sulfobromophthalein test and the
normali:ation of acti,ity of sorbitol dehydroenase and alanine
aminotransferase indicate AdeCbl enhanced the reco,ery process/
3*

In an e7perimental model! a low protein choline+deficient diet! althouh it did
not chane total cobalamin content in the li,er of rats! sinificantly decreased
total and non+protein sulfhydryl "SH'+roup le,els as well as ASH transferase
acti,ity in the li,er/ MetCbl "but not AdeCbl' administration restored non+
protein SH+roup le,els and ASH transferase acti,ity! and administration of
both MetCbl and AdeCbl normali:ed total SH+roup content/
33

AdeCbl appears to be a useful supplement for support of patients with hepatitis
A/ Two roups of patients from the same hepatitis A epidemic recei,ed either
AdeCbl or >H+Cbl/ ?atients were i,en # m per day i/m/ for the first #( days
and then recei,ed # m orally for the ne7t (* days/ The roup treated with
AdeCbl had a 6uicker return to normal of serum aminotransferase le,els/3#
Fossati reported impro,ements in body weiht and appetite in adults with li,er
disease and chronic pulmonary tuberculosis followin supplementation with <
m1day of AdeCbl for three months/
3-

Medina et al treated *& people sufferin from ,iral hepatitis with either AdeCbl
or C8+Cbl/ Their obser,ations indicate the AdeCbl was sinificantly more
efficacious than C8+Cbl in normali:in total bilirubin! serum lutamic
o7aloacetic transaminase "SA>T'! serum lutamic pyru,ic transaminase
"SA?T'! and alkaline phosphatase ,alues/ The AdeCbl was administered i/m/ at
a dose of # m per day for the first #( days and then orally for the ne7t #( days/
After (3 days total bilirubin was normal in #*1#%! SA>T in #-1#%! SA?T in
#.1#%! and alkaline phosphatase in #%1#% subjects recei,in AdeCbl/
3<

9esta et al ha,e reported a combination of AdeCbl! alon with li,er e7tract!
adrenal corte7 e7tract! and nucleosides! is effecti,e in normali:in SA>T!
SA?T! and total bilirubin ,alues in patients with a ,ariety of acute li,er
diseases/ In their study! one roup of patients recei,ed the e7tracts "@' and
another roup of patients recei,ed the e7tracts plus AdeCbl "@ 0 C'/ After (#
days of supplementation! total bilirubin! SA>T and SA?T were normali:ed in
#% of (. patients in the @ 0 C roup/ Correspondin ,alues in the roup
recei,in @ alone were #-1(.! #*1(.! and #(1(./
3&
Teti et al ha,e similarly
reported impro,ements in parameters of li,er function followin administration
of a comple7 containin * m of AdeCbl/
3%

%leep Di!turbance!/ The use of MetCbl in the treatment of a ,ariety of sleep+
wake disorders is ,ery promisin/ Althouh the e7act mechanism of action is
not yet elucidated! it is possible MetCbl is needed for the synthesis of
melatonin! since the biosynthetic formation of melatonin re6uires the donation
of a methyl roup/ 5ased on a,ailable information! MetCbl appears to be
capable of modulatin melatonin secretion! enhancin liht+sensiti,ity! and
normali:in circadian rhythm/
Gchiyama et al ha,e reported that intra,enous injections of MetCbl increased
rectal temperature in the later hours of the daytime and correspondinly
impro,ed alertness! as assessed with a ,isual analo scale! durin the same time
inter,al/ They suest these obser,ations were mediated by an effect of MetCbl
on the circadian clock/
3$

Tomoda et al report a case of a #*+year+old male with adrenoleukodystrophy
who had de,eloped a sleep+wake disorder subse6uent to his complete loss of
,ision/ His sleep+wake cycle had been (- hoursH howe,er! followin
administration of MetCbl! his sleep+wake rhythm was normali:ed/ After
MetCbl therapy! circadian rhythms in his plasma melatonin and beta+endorphin
le,els appro7imated those of healthy ,olunteers! and his peak cortisol time
shifted backward/
-.
Yamada et al ha,e reported the successful treatment of a *(+year+old male
patient! who had suffered from recurrent hypersomnia for #( years! with
administration of MetCbl/ 2urin this period of time! the indi,idual had
e7perienced se,eral episodes of hypersomnia! lastin a few days at a time!
reoccurrin each year/ The indi,idual had also reported the fre6uency of these
episodes had increased durin the past two years/ MetCbl was administered for
si7 months! durin which time no episodes of hypersomnia were e7perienced/
After cessation of treatment! o,er a follow+up obser,ation period of #& months!
no episodes of hypersomnia were noted/
-#

>hta et al report that two adolescent patients sufferin from persistent sleep+
wake schedule disorders appear to ha,e responded to treatment with MetCbl/ In
this report! a #-+year+old irl dianosed with delayed sleep phase syndrome
"2S?S' and a #&+year+old boy with free+runnin sleep+wake rhythm
"hypernychthemeral syndrome'! had consistently complained of not bein able
to attend school despite trials of se,eral different medications/ Immediately
followin administration of * m1day of MetCbl! an impro,ement of both
sleep+wake rhythm disorders was obser,ed/ Serum concentrations of ,itamin
5#( durin treatment were in the hih rane of normal or abo,e normal/ The
duration of the sleep period of the 2S?S patient decreased radually from #.
hours to & hours! and the time of sleep onset ad,anced from ( a/m/ to midniht/
The period of the sleep+wake cycle of the hypernychthemeral patient was (3/<
hours before treatment and (3/. hours after treatment/ 8either of these patients
had shown any laboratory or clinical e,idence suesti,e of ,itamin 5#(
deficiency prior to the therapy/
-(

Mayer et al in,estiated the effects of MetCbl and C8+Cbl on circadian
rhythms! well+bein! alertness! and concentration in healthy subjects/ Si7
women and #3 men were randomly assined to recei,e either * m of MetCbl
or * m of C8+Cbl for #3 days/ All indi,iduals were initially obser,ed for nine
days prior to beinnin either supplementation reime/ Acti,ity from (*..+
.&.. hours increased sinificantly with supplementation of both forms of
,itamin 5#(/ Howe,er! sleep time was only sinificantly reduced in the roup
recei,in MetCbl/ In this roup! impro,ements in subjecti,e parameters of
Csleep 6uality!C Cconcentration!C and Cfeelin refreshed!C as determined by a
,isual analo scale! were correlated with ,itamin 5#( plasma le,els durin the
first week of MetCbl supplementation/ 8o obser,ed chanes in either cortisol
e7cretion or temperature were noted in indi,iduals recei,in either form of
,itamin 5#(/ The authors concluded that! C///only methylcobalamin has a
positi,e psychotropic alertin effect with a distribution of the sleep+wake cycle
toward sleep reduction/C
-*

@iht youn males were subjected to a sinle+blind cross+o,er test to determine
the effects of MetCbl on the phase+response of the circadian melatonin rhythm
to a sinle briht liht e7posure/ MetCbl "./- m1day' was injected
intra,enously at #(*. hours for ## days/ Startin on day #(! this reimen was
superseded by oral administration of MetCbl "( m tid' for se,en days/ The
melatonin rhythm before the liht e7posure showed a smaller amplitude in the
indi,iduals treated with MetCbl than in those recei,in the placebo/ The liht
e7posure phase+ad,anced the melatonin rhythm sinificantly in the MetCbl
roup! but not in the placebo roup! indicatin MetCbl enhanced the liht+
induced phase+shift in the human circadian rhythm/
-3

Mi!cellaneou!/ A combination of a coen:yme comple7 combinin AdeCbl!
pyrido7al phosphate! and phosphaden appears to be efficacious in the treatment
of patients with infectious alleric myocarditis/ Ma:urets et al report a
correcti,e action of this metabolic therapy on myocardial en:ymatic status/
Antiarrhythmic and cardiotonic actions of the coen:yme comple7 were also
noted/
--

Faludin et al included si7ty patients with 5ell;s palsy in an open randomi:ed
trial/ ?atients were assined to one of three treatment roups) steroid! MetCbl!
or MetCbl 0 steroid/ The 6uickest time re6uired for complete reco,ery of facial
ner,e function occurred in the roup recei,in MetCbl alone "mean of #/$- 01+
./-# weeks'H howe,er! the mean reco,ery time of the roup recei,in MetCbl
and steroid treatment was similar "(/.- 01+ #/(* weeks'/ Indi,iduals recei,in
only steroid treatment had a mean reco,ery time of $/<. 01+ &/&$ weeks'/ The
authors also noted the facial ner,e score after #+* weeks of treatment was
sinificantly better in indi,iduals recei,in MetCbl than in those only recei,in
steroid therapy/ The impro,ement of concomitant symptoms was also better in
the roups treated with MetCbl/
-<

Katsuoka et al reported a case of a 3%+year+old woman with a positi,e response
to MetCbl/ Her initial complaint was ait disturbanceH howe,er! by the time she
was e,aluated! her symptoms had proressed to motor weakness! sensory
disturbances in her limbs! and dementia/ She also had widespread coarse hair/
In response to injections of -.. mc of MetCbl e,ery other day! the patient;s
paresthesia resol,ed! hand rip strenth impro,ed! and her dementia was
e,aluated as reduced/ Her ait also impro,ed! until she was able to walk on
tiptoe! and her hair te7ture returned to normal/
-&
Do!a&e and To4icity
A therapeutic dose for conditions re6uirin MetCbl would be a minimum of
#-.. mc and a ma7imum of <... mc per day/ 8o sinificant therapeutic
ad,antae appears to occur from dosaes e7ceedin this ma7imum doseH
howe,er! it is likely that beneficial physioloical effects occur at dosaes as
low as #.. mc per day! especially if this dose is i,en repetiti,ely o,er time/
A therapeutic dose for AdeCbl is #...+<... mc per day/ Similarly! some
physioloical benefits are likely to occur at repetiti,e doses far below this
therapeutic rane/
5oth MetCbl and AdeCbl ha,e been administered orally! intramuscularly! and
intra,enouslyH howe,er! positi,e clinical results ha,e been reported irrespecti,e
of the method of administration/ It is not clear whether any therapeutic
ad,antae is ained from non+oral methods of administration/
MetCbl and AdeCbl ha,e usually been administered in di,ided doses three
times daily/ These supplements ha,e e7cellent tolerability and no known
to7icity/ AdeCbl has been administered safely durin prenancy/ 8o rationale
e7ists to suspect MetCbl would not also be safe durin prenancy/
Conclu!ion
AdeCbl and MetCbl are the coen:yme forms of ,itamin 5#( utili:ed in the
,itamin 5#(+dependent en:ymes in humans/ 5ecause the coen:yme forms
bypass se,eral of the en:ymatic reactions re6uired for the formation of the
functional forms of ,itamin 5#(! they offer a theoretical ad,antae in
cobalamin supplementation/ 5oth AdeCbl and MetCbl are retained in the body
better and increase tissue concentrations of cobalamin better than C8+Cbl/
Additionally! the coen:yme forms of ,itamin 5#( demonstrate a rane of
acti,ity and clinical results not shown by the other supplemental forms of
,itamin 5#(/
It is important to remember that circulatin le,els of ,itamin 5#( are not
always a reflection of tissue le,els! and that e,en if an ade6uate supply of
cobalamin appears in the circulation! a functional deficiency of the coen:yme
forms miht coe7ist in tissues and other body fluids/ Althouh C8+Cbl will
usually increase circulatin le,els of cobalamin! its ability to increase tissue
le,els of the acti,e forms of ,itamin 5#( can be limited in a rane of sub+
clinical and clinical conditions/ @,en in a best case scenario! the acti,ation of
C8+Cbl to either AdeCbl or MetCbl does not occur instantly! possibly
occurrin o,er #+( months! and re6uires the interaction of ASH! reducin
aents! possibly alpha+tocopherol! and in the case of MetCbl! SAM and the
acti,e form of folic acid/
The use of either AdeCbl and1or MetCbl offers a sinificant biochemical and
therapeutic ad,antae o,er other e7istin forms of ,itamin 5#(! and should be
considered as a first+line choice for correctin ,itamin 5#( deficiency and
treatin conditions shown to benefit from cobalamin administration/
*eference!
#/ Tureshi AA! 9osenblatt 2S! Cooper 5A/ Inherited disorders of cobalamin
metabolism/ Crit 9e, >ncol Hematol #$$3H#&)#**+#-#/
(/ ?e:acka @! Areen 9! Facobsen 2E/ Alutathionylcobalamin as an
intermediate in the formation of cobalamin coen:ymes/ 5iochem 5iophys 9es
Comm #$$.H()33*+3-./
*/ Cooper 5A! 9osenblatt 2S/ Inherited defects of ,itamin 5#( metabolism/
Ann 9e, 8utr #$%&H&)($#+*(./
3/ Turley C?! 5rewster MA/ Alpha+tocopherol protects aainst a reduction in
adenosylcobalamin in o7idati,ely stressed human cells/ F 8utr #$$*H#(*)#*.-+
#*#(/
-/ ?appu AS! Fatterpaker ?! Sreni,asan A/ ?ossible interrelationship between
,itamins @ and 5#( in the disturbance in methylmalonate metabolism in
,itamin @ deficiency/ 5iochem F #$&%H#&()##-+#(#/
</ Alusker F?/ =itamin 5#( and the 5#( coen:ymes/ =itam Horm #$$-H-.)#+
&</
&/ >kuda K! Yashima K! Kita:aki T! Takara I/ Intestinal absorption and
concurrent chemical chanes of methylcobalamin/ F Bab Clin Med
#$&*H%#)--&+-<&/
%/ Heinrich HC! Aabbe @@/ Metabolism of the ,itamin 5#(+coen:yme in rats
and man/ Ann 8Y Acad Sci #$<3H##()%&#+$.*/
$/ Bederle FA/ >ral cobalamin for pernicious anemia/ Medicines best kept
secretI FAMA #$$#H(<-)$3+$-/
#./ 5erlin H! 5rante A! ?ibrant A/ =itamin 5#( body stores durin oral and
parenteral treatment of pernicious anemia/ Acta Med Scand #$&%H(.3)%#+%3/
##/ Tsukerman @S! ?omerantse,a TIa! ?o:nanskaia AA! et al/ @ffect of methyl+
cobalamin and adenosylcobalamin on the process of hematopoiesis and ,itamin
5#( e7chane in e7perimental phenylhydra:ine+induced anemia in rabbits/
=opr Med Khim #$%$H*-)#.<+###/ QArticle in 9ussianR
#(/ Fochi F! Ciampini M! Ceccarelli A/ @fficacy of iron therapy) a comparati,e
e,aluation of four iron preparations administered to anaemic prenant women/
F Int Med 9es #$%-H#*)#+##/
#*/ Aranese 2! 9etto A! Scurria B! 5orese 9/ Associa:ione ferritina! coen:ima
adenosilcobalaminico! coen:ima folico) impieo in ra,idan:a/ Min Ainecol
#$%<H*%)$*+#../ QArticle in ItalianR
#3/ Korkina M=! Korchak AM! Med,ede, 2I/ Clinico+e7perimental
substantiation of the use of carnitine and cobalamin in the treatment of anore7ia
ner,osa/ Lh 8e,ropatol ?sikhiatr #$%$H%$)%(+%&/ QArticle in 9ussianR
#-/ Korkina M=! Korchak AM! Kare,a MA/ @ffects of carnitine and
cobamamide on the dynamics of mental work capacity in patients with anore7ia
ner,osa/ Lh 8e,ropatol ?sikhiatr Im S S Korsako,a #$$(H$()$$+#.(/ QArticle
in 9ussianR
#</ Aiordano C! ?errotti A/ Clinical studies of the effects of treatment with a
combination of carnitine and cobamamide in infantile anore7ia/ Clin Ter
#$&$H%%)-#+<./ QArticle in ItalianR
#&/ @to I! Krumdieck CB/ 9ole of ,itamin 5#( and folate deficiencies in
carcinoenesis/ Ad, @7p Med 5iol #$%<H(.<)*#*+**./
#%/ Biteplo 9A! Hipwell S@! 9osenblatt 2S! et al/ Chanes in cobalamin
metabolism are associated with the altered methionine au7otrophy of hihly
rowth autonomous human melanoma cells/ F Cell ?hysiol #$$#H#3$)**(+**%/
#$/ Eainfan @! ?oirier BA/ Methyl roups in carcinoenesis) effects on 28A
methylation and ene e7pression/ Cancer 9es #$$(H-()(.&#S+(.&&S/
(./ Christman FK! Sheikhnejad A! 2i:ik M! et al/ 9e,ersibility of chanes in
nucleic acid methylation and ene e7pression induced in rat li,er by se,ere
dietary methyl deficiency/ Carcinoenesis #$$*H#3)--#+--&/
(#/ 8ishi:awa Y! Yamamoto T! Terada 8! et al/ @ffects of methylcobalamin on
the proliferation of androen+sensiti,e or estroen+sensiti,e malinant cells in
culture and in ,i,o/ Int F =itam 8utr 9es #$$&H<&)#<3+#&./
((/ Shimi:u 8! Hama:oe 9! Kanayama H! et al/ @7perimental study of
antitumor effect of methyl+5#(/ >ncoloy #$%&H33)#<$+#&*/
(*/ Tsao CS! Myashita K/ Influence of cobalamin on the sur,i,al of mice
bearin ascites tumor/ ?athobioloy #$$*H<#)#.3+#.%/
(3/ Miasishche,a 8=! Aerasimo,a AK! Il;ina 8S! Sof;ina L?/ @ffect of
methylcobalamin on methotre7ate transport in normal and tumorous tissues/
5iull @ksp 5iol Med #$%-H$$)&*<+&*%/ QArticle in 9ussianR
(-/ Heimburer 2C! Ale7ander C5! 5irch 9! et al/ Impro,ement in bronchial
s6uamous metaplasia in smokers treated with folate and ,itamin 5#(/ 9eport of
a preliminary randomi:ed! double+blind inter,ention trial/ FAMA
#$%%H(-$)#-(-+#-*./
(</ Ya6ub 5A! Siddi6ue A! Sulimani 9/ @ffects of methylcobalamin on
diabetic neuropathy/ Clin 8eurol 8eurosur #$$(H$3)#.-+###/
(&/ Yoshioka K! Tanaka K/ @ffect of methylcobalamin on diabetic autonomic
neuropathy as assessed by power spectral analysis of heart rate ,ariations/
Horm Metab 9es #$$-H(&)3*+33/
(%/ Kikuchi M! Kashii S! Honda Y! et al/ ?rotecti,e effects of
methylcobalamin! a ,itamin 5#( analo! aainst lutamate+induced
neuroto7icity in retinal cell culture/ In,est >phthalmol =is Sci #$$&H*%)%3%+
%-3/
($/ 8ishikawa Y! Shibata S! Shima:oe T! Eatanabe S/ Methylcobalamin
induces a lon+lastin enhancement of the field potential in rat suprachiasmatic
nucleus slices/ 8eurosci Bett #$$<H((.)#$$+(.(/
*./ Iwasaki T! Kurimoto S/ @ffect of methylcobalamin in accommodati,e
dysfunction of eye by ,isual load/ Sanyo Ika 2aiaku Lasshi #$%&H$)#(&+#*(/
QAbstractR
*#/ >ishi S/ ?re,ention of di"(+ethylhe7yl' phthalate+induced testicular atrophy
in rats by co+administration of the ,itamin 5#( deri,ati,e adenosylcobalamin/
Arch @n,iron Contam To7icol #$$3H(<)3$&+-.*/
*(/ Moriyama H! 8akamura K! Sanda 8! et al/ Studies on the usefulness of a
lon+term! hih+dose treatment of methylcobalamin in patients with
olio:oospermia/ Hinyokika Kiyo #$%&H**)#-#+#-</ QAbstractR
**/ Isoyama 9! Kawai S! Shimi:u Y! et al/ Clinical e7perience with
methylcobalamin "CH*+5#(' for male infertility/ Hinyokika Kiyo #$%3H*.)-%#+
-%</ QAbstractR
*3/ May 5A/ A no,el anti,iral stratey for HI= infection/ Med Hypotheses
#$$*H3.)$*+$3/
*-/ Tan AM! Araham 8M! Chandra 9K! Saah AF/ Bow serum ,itamin 5+#(
concentrations are associated with faster human immunodeficiency ,irus type #
"HI=+#' disease proression/ F 8utr #$$&H#(&)*3-+*-#/
*</ Eeinber F5! Sauls 2B! Misukonis MA! Shuars 2C/ Inhibition of
producti,e human immunodeficiency ,irus+# infection by cobalamins/ 5lood
#$$-H%<)#(%#+#(%&/
*&/ Araki A! Sako Y! Ito H/ ?lasma homocysteine concentrations in Fapanese
patients with non+insulin+dependent diabetes mellitus) effect of parenteral
methylcobalamin treatment/ Atherosclerosis #$$*H#.*)#3$+#-&/
*%/ 5hatt 9H! Binnell FC! 5arltrop 2/ Treatment of hydro7ycobalamin+resistant
methylmalonic acidemia with adenosylcobalamin/ Bancet #$%<H()3<-/ QBetterR
*$/ Alass A5F! 5oyd BF! @bin B/ 9adioacti,e ,itamin 5#( in the li,er/ F Bab
Clin Med #$-%H-()%3$+%-$/
3./ Bee,y CM! Thompson A! 5aker H/ =itamins and li,er injury/ Am F Clin
8utr #$&.H(*)3$*+3$$/
3#/ Iwarson S! Bindber F/ Coen:yme 5+#( therapy in acute ,iral hepatitis/
Scand F Infect 2is #$&&H$)#-&+#-%/
3(/ Korso,a TB! Moro:o,a 8A! ?o:nanskaia AA! Kurano, 5I/ Comparati,e
study of the effect of ,itamin 5#( coen:ymes on monoo7yenase system and
lipid pero7idation in the li,er of rabbits poisoned with phenylhydra:ine/ =opr
Med Khim #$%$H*-)$&+#.(/ QArticle in 9ussianR
3*/ Tebenchuk AM! Bukashuk =2! Bipkan A8! Stepanenko ==/ Antito7ic
action of cobamamide in e7perimental hepatitis/ Farmakol Toksikol
#$%3H3&)%&+$./ QArticle in 9ussianR
33/ Tsukerman @S! Korso,a TB! ?o:nanskaia AA/ =itamin 5#( metabolism
and the status of sulfhydryl roups in protein+choline deficiency in rats/ @ffects
of methyl+ and adenosyl+cobalamins/ =opr ?itan #$$(H#)3.+33/ QArticle in
9ussianR
3-/ Fossati C/ >n use of cobamamide in a roup of hospitali:ed patients with
pulmonary tuberculosis/ Miner,a Med #$&#H<()3<*%+3<3</ QArticle in ItalianR
3</ Medina F! =itali 2/ Controlled clinical research with cobamamide in the
treatment of ,iral hepatitis/ Clin Ter #$<%H3<)#*$+#33/ QArticle in ItalianR
3&/ 9esta M! =itali 2! Medina F/ Controlled clinical trial of a li,er e7tract
combined with hih doses of nucleosides! cobamamide and adrenal corte7
e7tract in the treatment of acute li,er diseases/ Clin Ter #$&(H<()(#*+((*/
QArticle in ItalianR
3%/ Teti =! Acerbi F! 8itti A/ ?rotection of li,er by a cortico+,itamin+li,er
e7tract combination and cobamamide/ Clin Ter #$&3H<%)<&+&*/ QArticle in
ItalianR
3$/ Gchiyama M! Mayer A! >kawa M! Meier+@wert K/ @ffects of ,itamin 5#(
on human circadian body temperature rhythm/ 8eurosci Bett #$$-H#$()#+3/
-./ Tomoda A! Miike T! Matsukura M/ Circadian rhythm abnormalities in
adrenoleukodystrophy and methyl 5#( treatment/ 5rain 2e, #$$-H#&)3(%+3*#/
-#/ Yamada 8/ Treatment of recurrent hypersomnia with methylcobalamin
",itamin 5#(') a case report/ ?sychiatry Clin 8eurosci #$$-H3$)*.-+*.&/
-(/ >hta T! Ando K! Iwata T! et al/ Treatment of persistent sleep+wake
schedule disorders in adolescents with methylcobalamin ",itamin 5#('/ Sleep
#$$#H#3)3#3+3#%/
-*/ Mayer A! Kroer M! Meier+@wert K/ @ffects of ,itamin 5#( on
performance and circadian rhythm in normal subjects/ 8europsycho+
pharmacoloy #$$<H#-)3-<+3<3/
-3/ Hashimoto S! Kohsaka M! Morita 8! et al/ =itamin 5#( enhances the
phase+response of circadian melatonin rhythm to a sinle briht liht e7posure
in humans/ 8eurosci Bett #$$<H((.)#($+#*(/
--/ Ma:urets AF! Aure,ich MA! Kubyshkin =F! et al/ Coen:yme metabolic
therapy in infectious alleric myocarditis/ Klin Med "Mosk' #$$-H&*)3#+3*/
QArticle in 9ussianR
-</ Falaludin MA/ Methylcobalamin treatment of 5ell;s palsy/ Methods Find
@7p Clin ?harmacol #$$-H#&)-*$+-33/ QAbstractR
-&/ Katsuoka H! Eatanabe C! Mimori Y! 8akamura S/ A case of ,itamin 5#(
deficiency with broad neuroloic disorders and canities/ 8o To Shinkei
#$$&H3$)(%*+(%</ QAbstractR