Efficacy of methylcobalamin and folinic acid treatment on glutathione
redox status in children with autism1–3
S Jill James, Stepan Melnyk, George Fuchs, Tyra Reid, Stefanie Jernigan, Oleksandra Pavliv, Amanda Hubanks, and
David W Gaylor
Background: Metabolic abnormalities and targeted treatment trials
have been reported for several neurobehavioral disorders but are
relatively understudied in autism.
Objective: The objective of this study was to determine whether or
not treatment with the metabolic precursors, methylcobalamin and
folinic acid, would improve plasma concentrations of transmethyl-
ation/transsulfuration metabolites and glutathione redox status in
Design: In an open-label trial, 40 autistic children were treated with
75 lg/kg methylcobalamin (2 times/wk) and 400 lg folinic acid (2
times/d) for 3 mo. Metabolites in the transmethylation/transsulfura-
tion pathway were measured before and after treatment and compared
with values measured in age-matched control children.
Results: The results indicated that pretreatment metabolite concen-
trations in autistic children were significantly different from values
in the control children. The 3-mo intervention resulted in significant
increases in cysteine, cysteinylglycine, and glutathione concentra-
tions (P , 0.001). The oxidized disulfide form of glutathione was
decreased and the glutathione redox ratio increased after treatment
(P , 0.008). Although mean metabolite concentrations were im-
proved significantly after intervention, they remained below those in
unaffected control children.
Conclusion: The significant improvements observed in trans-
methylation metabolites and glutathione redox status after treatment
suggest that targeted nutritional intervention with methylcobalamin
and folinic acid may be of clinical benefit in some children who
have autism. This trial was registered at clinicaltrials.gov as
NCT00692315.Am J Clin Nutr 2009;89:425–30.
Autism is a behaviorally defined neurodevelopmental disorder
characterized by significant impairment in reciprocal social in-
teraction and communication as well as restricted interests and
repetitive behaviors. The metabolic pathology of autism has been
less explored than broad-scale genomic approaches despite
metabolic abnormalities implicated in the pathogenesis of many
other neurologic disorders (1–5). We have used a targeted ap-
proach to autism metabolomics by focusing on the dynamics of
an integrated metabolic pathway that is important for the regu-
lation of normal redox homeostasis and cellular methylation
potential. In a recent case-control study, we reported that the
metabolic profile of children diagnosed with autism was ab-
normal compared with that of unaffected control children (6, 7).
Briefly, the mean ratio of plasma S-adenosylmethionine (SAM)
to S-adenosylhomocysteine (SAH) was reduced significantly,
and the mean concentration of reduced glutathione (GSH), the
major intracellular antioxidant and mechanism for detoxi-
fication, also was decreased significantly. The oxidized disulfide
form of GSH (GSSG) was increased significantly, which re-
sulted in a 2-fold reduction in the mean GSH:GSSG redox ratio.
Several metabolic precursors for GSH synthesisalsowerelower in
the autistic children, suggesting that GSH synthesis may be in-
and antioxidant/detoxification capacity (YGSH:GSSG) and an
increase in oxidative stress ([GSSG) in autistic children.
A diagram of the 3 interconnected pathways of folate, me-
thionine, and GSHmetabolism thatare abnormal in many autistic
children is shown in Figure 1. The metabolic interdependency
between these pathways translates into broader impact on 1)
DNA synthesis or repair and proliferation, 2) cellular methyla-
tion, and 3) GSH redox homeostasis, as indicated in Figure 1.
GSH is a tripeptide of cysteine, glycine, and glutamate that is
synthesized de novo in all cells and serves as the major in-
tracellular antioxidant and redox buffer. The intracellular GSH-
GSSG redox status provides the essential intracellular reducing
environment required for normal immune function, detoxification
capacity, redox-sensitive enzyme activity, and membrane redox
signaling (8–12). Oxidative stress occurs when antioxidant de-
fense mechanisms fail to counterbalance and control reactive
oxygen species generated from endogenous oxidative metabolism
or from pro-oxidant environmental exposures. Several recent re-
views and research studies lend support to the hypothesis that
1From the Departments of Pediatrics (SJJ, SM, GF, TR, SJ, OP, and AH)
and Biostatistics (DWG), University of Arkansas for Medical Sciences, Ar-
kansas Children’s Hospital Research Institute, Little Rock, AR.
2Supported in part by funding from the National Institute of Child Health
and Development (RO1 HD051873; to SJJ) and grants from the University of
Arkansas for Medical Sciences Children’s University Medical Group and the
Arkansas Biosciences Institute (SJJ). Methylcobalamin was donated by
Hopewell Compounding Pharmacy (Hopewell, NJ).
3Reprints not available. Address correspondence to SJ James, Arkansas
Children’s Hospital Research Institute, 1120 Marshall Street, Slot 512-41B,
Little Rock, AR 72202. E-mail: email@example.com.
Received June 29, 2008. Accepted for publication September 23, 2008.
First published online December 3, 2008; doi: 10.3945/ajcn.2008.26615.
Am J Clin Nutr 2009;89:425–30. Printed in USA. ? 2009 American Society for Nutrition
redox imbalance and oxidative stress may be a contributing factor
to autism pathology (6, 7, 13–19).
The investigation was prompted by the observed decrease in
GSH redox status and methylation capacity in many autistic
children and by the plausible potential for micronutrient defi-
ciencies in these children that result from inadequate dietary
intake or gastrointestinal pathology (20–22). The primary goal of
this study was to show whether or not targeted nutritional in-
tervention designed to provide cofactors for methionine re-
methylation and GSH synthesis would be effective in improving
methylation capacity and redox status in a cohort of autistic
SUBJECTS AND METHODS
label trial to test whether or not supplementation with the met-
abolic cofactors, methylcobalamin and folinic acid, for 3 mo
would improve plasma concentrations of transmethylation
metabolites or the synthesis of GSH. Inclusion criteria included
a diagnosis of autistic disorder defined by the Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition, criteria
(299.0) and a Childhood Autism Rating Scale score .30. Ex-
clusion criteria included Asperger’s disorder; pervasive de-
velopmental disorder, not otherwise specified; genetic disorders
with comorbid autism; chronic seizures; severe gastrointestinal
symptoms; recent infection; and use of high-dose vitamin or
A flow diagram of the intervention study design is presented in
Figure 2. Sixty-five autistic children met the inclusion criteria
and were initially screened for metabolic evidence of reduced
methylation capacity (SAM:SAH) or reduced GSH redox ratio
(GSH:GSSG). Of these, 48 (75%) children met these metabolic
qualifications and 17 (25%) were excluded because their base-
line metabolic profile was within normal range. Four children
dropped out during the study and another 4 children were lost to
follow up. Of the 40 remaining children who completed the
study, 87% were white, 8% were African American, and 5%
were Asian. There were 33 boys (82%) and 7 girls (18%) rang-
ing in age from 2 to 7 y (mean age: 4.8 6 0.8 y). The control
group for the baseline metabolite concentrations consisted of 42
apparently healthy age-matched children who had no previous
history of developmental delay or neurologic symptoms (mean
age: 4.5 6 0.9 y). All parents signed informed consent approved
by the institutional review board at the University of Arkansas
for Medical Sciences and were instructed not to introduce any
new interventions during the treatment period.
Methylcobalamin was obtained as a sterile injectable liquid
from Hopewell Pharmacy and Compounding Center (Hopewell,
NJ). The subcutaneous injectable route of administration was
selected on the basis of empiric observations of clinical im-
provement in speech and cognition in a recent pilot study (6) and
the possibility that it might enhance methionine synthase ac-
tivity under conditions of oxidative stress by substituting for
oxidized inactive coenzyme B12. Tuberculin syringes fitted with
a 0.25-inch 31-gauge needle were prefilled with 75 lg/kg meth-
weight in kilograms. Parents were given a demonstration and in-
structions for the sterile subcutaneous injection of methyl-
cobalamin in the fatty tissue of the buttocks, which was given
every third day for 3 mo. Folinic acid (400 lg) obtained from
Custom Compounding Pharmacy (Little Rock, AR) was admin-
food. Folinic acid (5-formyl tetrahydrofolate) is absorbed as the
available for folate-dependent reactions than folic acid.
Sample treatment and HPLC method for
Fasting blood samples were collected into EDTA-evacuated
for 10 min at 4?C. To prevent metabolite interconversion, the ice-
and the plasma stored at 280?C until HPLC quantification ?2
wk after receipt. Details of the method for HPLC with elec-
trochemical detection and metabolite quantitation are described
elsewhere (23, 24).
FIGURE 2. Study design and patient follow-up.
FIGURE 1. Diagram of tetrahydrofolate (THF)-dependent pathway of
methionine transmethylation to homocysteine and the transsulfuration pathway
from homocysteine to GSH synthesis. MS, methionine synthase; SAH,
S-adenosylhomocysteine; SAHH, SAH hydrolase; GSSG, oxidized glutathione
disulfide; SAM, S-adenyosylmethionine; MTase, methyltransferase.
JAMES ET AL
Metabolic data are presented as the means 6 SD. The data
were prospectively collected and analyzed using SigmaStat
(version 2.0) and Excel software (Microsoft Office 2003;
Microsoft Corp, Redmond, WA). Statistical differences between
plasma metabolites before and after intervention were de-
termined using the paired Student’s t test with significance set at
0.05. Comparisons between case and control children were done
using the Student’s t test.
children completed the 3-mo intervention trial with methyl-
because the parents were uncomfortable giving the methyl-
cobalamin injections and 2 children dropped out because of
hyperactivity and reduced sleep. Four families moved during the
study or were lost to follow-up after the baseline visit. Most
parents (80%) reported no increase in hyperactivity, although
10% (4 children) reported moderate hyperactivity that was re-
duced when the dose of folinic acid was decreased to 400 lg/d.
Other potential adverse effects (one child each) included sleep
disruption, difficulty getting to sleep, increased impulsiveness,
and irritability. On completion of the study, 78% of the parents
expressed the desire to continue independently with the sup-
plements, one parent chose not to continue, and 8 parents did not
provide this information.
The primary outcome measure for this open-label trial was
impact of the intervention on the pretreatment baseline metabolic
profile. Methionine transmethylation metabolites all were sig-
nificantly different from those in the control children (P , 0.005)
at baseline with the exceptions of homocysteine and SAH
(Table 1). The 3-mo intervention did not alter methionine, SAM,
and SAH concentrations significantly even though methyl-
cobalamin and folinic acid provide methyl groups for the
methionine cycle. In contrast, mean concentrations of cysteine
and cysteinylglycine were increased significantly after the in-
tervention and no longer were statistically different compared
with those in the healthy control children. Although total and
free GSH concentrations and the GSH:GSSG redox ratios
were increased significantly by the intervention, they remained
below those in control subjects (P , 0.01). The mean con-
centration of oxidized GSSG was decreased significantly after
intervention (P , 0.001) but remained above the mean con-
centration in the control children (P , 0.01). In Figure 3,
scatterplots showing the distribution of the individual data
points before and after intervention are presented for cysteine,
GSSG, and GSH:GSSG ratio (Figure 3A).
This intervention trial was undertaken to determinewhether or
not treatment with metabolic precursors for methionine and GSH
synthesis would improve plasma biomarkers of impaired meth-
ylation capacity (SAM:SAH) and GSH-dependent antioxidant-
detoxification status (GSH:GSSG) in children who have autistic
disorder. Children meeting the entrance criteria were initially
screenedfor metabolic evidence ofreduced SAM:SAHorreduced
intervention. Measures of autistic behavior were assessed by
a trained study nurse before and after treatment using the Vineland
Adaptive Behavior Scales. Although significant improvement
was observed after treatment, the scores remained significantly
below standard normal scores. Because parent report in an
open-label trial is subject to expectation bias, these results are
not conclusive and therefore not presented. Nonetheless, the
Mean plasma metabolite concentrations (6SD) in age-matched control children, children who had autism at baseline before
intervention, and children with autism after 3-mo intervention with methylcobalamin and folinic acid1
Children with autism
Plasma metabolite concentration Control children (n ¼ 42)
24 6 3
78 6 22
14.3 6 4.3
5.6 6 2.0
5.0 6 1.2
210 6 18
45 6 6
7.5 6 1.8
2.8 6 0.8
0.18 6 0.07
47 6 18
17 6 6.8
Pretreatment (n ¼ 40)
21 6 43
66 6 133
15.2 6 5
4.7 6 1.53
4.8 6 1.8
191 6 243
40 6 93
5.4 6 1.33
1.5 6 0.43
0.28 6 0.083
21 6 63
6 6 23
Posttreatment (n ¼ 40)
22 6 34
69 6 124
14.8 6 4
5.0 6 2.0
5.3 6 1.1
215 6 19
46 6 9
6.2 6 1.24
1.8 6 0.44
0.22 6 0.064
30 6 94
9 6 34
1fGSH, free glutathione; SAH, S-adenosylhomocsyteine; SAM, S-adenosylmethionine; tGSH, total glutathione;
GSSG, oxidized glutathione disulfide. NS, P . 0.05.
2Pre- and posttreatment comparison.
3Significantly different from control children, P , 0.005.
4Significantly different from control children, P , 0.01.
NUTRITIONAL INTERVENTION IN AUTISTIC CHILDREN
improvement in Vineland Adaptive Behavior Scale scores pro-
crossover study that currently is underway.
The 3-mo treatment was successful in increasing mean con-
centrations of the transsulfuration metabolites, cysteine, cys-
teinylglycine, and GSH, while reducing the concentration of the
oxidized disulfide GSSG. However, plasma concentrations of
methionine and SAM were unaffected and remained significantly
below those in the control subjects (P , 0.005). This was an
unexpected finding because methylcobalamin and folinic acid
directly and indirectly provide methyl groups for synthesis of
methionine and SAM and secondarily provide metabolic pre-
cursors for more distant transsulfuration reactions (Figure 1).
Because supplements improved but did not normalize methio-
adaptation to incompletely resolved oxidative stress. Within the
methionine cycle, methionine synthase, betaine-homocysteine
methyltransferase, and methionine adenosyltransferase are redox-
sensitive enzymes that tend to be down-regulated with oxidative
stress (25–28). The reciprocal regulation of transmethylation and
transsulfuration under pro-oxidant conditions serves to promote
GSH synthesis as the metabolic priority at the expense of methi-
onine transmethylation. Adaptive up-regulation of cystathionine
by irreversibly diverting homocysteine away from methionine
remethylation and down the transsulfuration pathway (29). The
increases enzyme activity with oxidation to the ferric state and
truncation of the enzyme protein (30). Acutely, this metabolic
adaptation provides a mechanism to restore GSH concentrations
and to maintain intracellular redox status during oxidative stress.
With chronic oxidative stress, however, the synthesis of methio-
nine and its product, SAM, can progressively decline as a result of
oxidative inactivation of the cobalamin cofactor of methionine
precursor depletion and a progressive decrease in cysteine and
GSH synthesis. Treatment with methylcobalamin and folinic acid
seems to have rescued GSH synthesis in this cohort of children at
the expense of transmethylation metabolites.
Plasma metabolite concentrations provide only a static cross-
sectional view of a highly dynamic homeostatic process that is
constantly responding to the changing functional needs and
metabolic priorities of the body (32). Thus, to obtain accurate,
reproducible, and comparative results, it is imperative that sam-
pling be done in the fasting state at the same time of day and that
potential confounding factors, such as acute infection and seiz-
ures, are excluded (33). Because the complete transsulfuration
of methionine to GSH occurs primarily in the liver, plasma
concentrations of cysteine and GSH generally reflect hepatic
synthesis and export (9, 34). Approximately 80% of GSH syn-
thesized in the liver is exported to the plasma where it is hy-
drolyzed to cysteinylglycine and cysteine for uptake by tissues,
such as the brain, that lack or weakly express the complete
transsulfuration pathway (35). Thus, viral infection, nutritional
deficiencies, impaired detoxification, and other factors that
negatively affect GSH synthesis in the liver can indirectly affect
peripheral redox status in brain and immune cells that require
cyst(e)ine import from the liver to complete transsulfuration and
GSH synthesis. Cysteine generally is considered a semiessential
amino acid because it can be synthesized from methionine via
the transsulfuration pathway. The consistent decrease in plasma
methionine and cysteine concentrations observed in autistic
children suggests that cysteine may be an essential amino acid
for these children.
If increased vulnerability to pro-oxidant exposures and de-
creased GSH-dependent antioxidant capacity is a constitutive
feature of autism, then autistic children should exhibit systemic
evidence of oxidative stress. In addition to evidence of oxidative
FIGURE 3. Scatterplots of individual data for plasma cysteine (A), GSH:GSSG ratios (B), and GSSG concentrations (C) from 40 autistic children before
and after 3-mo treatment with methylcobalamin and folinic acid. GSH, glutathione; GSSG, oxidized disulfide form of glutathione.
JAMES ET AL
stress in immune cells (36), several clinical studies documented
an increased prevalence of gastrointestinal inflammation and
increased mucosal permeability in the upper and lower intestines
in autistic children (21, 22, 37). A recent report documented the
presence of chronic inflammation in the autistic brain that seems
mediated by innate microglial activation and proinflammatory
cytokines (18, 38). The inflammatory response is augmented
when GSH concentrations are low, and chronic inflammation
depletes GSH further and promotes a self-perpetuating cycle that
could exacerbate gastrointestinal and central nervous system in-
flammation associated with autism. These reports and the results
reported herein support the hypothesis that unresolved oxidative
stress may contribute to the clinical pathology of autism.
The prevalence of nutritional intervention and complementary
and alternative medicine (CAM) in children diagnosed with an
autism spectrum disorder is estimated at ’74% (39). Parents
report that most nutritional and CAM-associated treatments are
helpful or without effect but not harmful. The main reasons
parents cite for choosing to use alternative therapies are con-
cerns about the safety and side effects of available medications
for autism and a need to be involved in decisions involving care
of their child (40). Because the majority of CAM use is based on
anecdotal evidence, there is a need for clinical trials to evaluate
the efficacy of these treatments. The broad heterogeneity of
clinical and behavioral symptoms in autistic children predicts
that no single treatment will benefit every autistic child. Thus,
definition and characterization of subgroups of children who
respond positively or negatively to intervention are necessary to
identify more clearly those children most likely to benefit from
a given treatment or medication. In summary, the significant
improvement in GSH-mediated redox status in some children
who have autism provides evidence consistent with a moderate
beneficial effect after 3-mo treatment with methylcobalamin and
We thank the Arkansas families affected by autism whose participation
made this study possible. We also thank the pediatricians and nurses at the
University of Arkansas for Medical Sciences Dennis Developmental Center
for patient referrals and Hopewell Pharmacy and Compounding Center
(Hopewell, NJ) for their generous donation of methylcobalamin for the study.
The authors’ responsibilities were as follows—SJJ (principal investiga-
tor): conducted the study, interpreted the data, and wrote the manuscript; SM
(laboratory director): provided HPLC expertise for metabolite analysis; GF
and TR: provided clinical advice, assisted with the interpretation of data, and
provided critical review of the manuscript; SJ: provided technical assistance
and served as study coordinator; OP: provided technical assistance for the
HPLC analysis; AH (study nurse): recruited patients and administered the
Vineland behavior testing; and DWG: provided statistical support for data
analysis. None of the authors had a conflict of interest to report.
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