Original Article

Effectiveness of N,N-Dimethylglycine in Autism

and Pervasive Developmental Disorder
Janet K. Kern, PhD, RN; Van S. Miller, MD, PhD; Lawrence Cauller, PhD; Roger Kendall, PhD;
Jyutika Mehta, DHMS, MS; Mary Dodd, MA

ABSTRACT

N,N-dimethylglycine, a dietary supplement, has been reported to be beneficial in children with autism and pervasive devel-
opmental disorder. We examined the effectiveness of dimethylglycine in children with autism and pervasive developmental
disorder in a double-blind, placebo-controlled study. Thirty-seven children between 3 and 11 years of age with a diagno-
sis of autism and/or pervasive developmental disorder were gender and age matched and randomly assigned to receive
either placebo or dimethylglycine for 4 weeks. All children were assessed before and after treatment on two behavioral
measures, the Vineland Maladaptive Behavior Domain and the Aberrant Behavior Checklist. Standardized neurologic exam-
inations before and after treatment on 33 children showed no change. An overall improvement on all behavioral measures
was observed for both the placebo and the dimethylglycine groups. However, the improvement among the children who

received dimethylglycine was not statistically different from the improvement observed among the children who received
the placebo. The children who participated in this study were a heterogeneous group, and their apparent responses to the
dimethylglycine varied. Some children appeared to respond positively to the dimethylglycine, and there was a smaller pro-
portion of negative changes in the dimethylglycine group, but the quantitative changes in the dimethylglycine behavioral
assessments were not significantly different from what was observed among children who received placebo. ( J Child
Neurol 2001;16:169-173).

Autism and pervasive developmental disorder of childhood
are common neurodevelopmental disorders estimated to
occur in more than 1 of every 1000 children.1,2 Diagnostic
criteria for these disorders include impairment in social
interaction and communication and restricted, repetitive, and
stereotyped patterns of behavior and activities.3,4
Medical treatments in autism/pervasive developmental
disorder have been disappointing. Anecdotal reports and an
unpublished study completed at the Center for Child Prob-
Received Dec 9, 1999. Accepted for publication June 15, 2000.
From the Department of Human Development (Drs Kern, Cauller, and Mehta
and Ms Dodd), University of Texas at Dallas, Dallas, Department of Pediatric
Neurology (Dr Miller), University of Texas Southwestern Medical Center,
Dallas, TX, and the Department of Biochemistry (Dr Kendall), University
of Bridgeport, Bridgeport, CT.
The study was completed at the University of Texas at Dallas and was sup-
ported by FoodScience Corporation, Essex Junction, VT.
Address correspondence to Dr Janet K. Kern, University of Texas
Southwestern Medical Center, St. Paul Professional Building I, 5959 Harry
Hines Blvd., Suite 520, Dallas, TX 75235-9101. Tel: 214-648-1751; fax: 214-
648-4278 ; e-mail: jkern1@mednet.swmed.edu.
lems in Korea~ suggest that dimethylglycine, a dietary sup-
plement, may be useful in children with autism/pervasive
developmental disorder. In the Korean study on 39 chil-
dren with autism, dimethylglycine was helpful in 80%, with
most notable improvements in the ability to talk, improved
eating, toilet training, and &dquo;willingness.&dquo; Dimethylglycine, the
N,N-dimethylated derivative of the amino acid glycine, is
found naturally in low levels in certain foods such as beans,
cereal grains, and liver.6 Dimethylglycine is a normal con-
stituent of the cell and is produced from choline via betaine
by loss of a methyl group. Dimethylglycine is metabolized
in the liver into sarcosine (monomethylglycine) via an oxida-
tive demethylation. By this pathway, dimethylglycine can act
as an indirect methyl donor and provide both methyl groups
via transfer to folate for synthesis of methionine from homo-
cysteine. Certain studies with dimethylglycine indicate that
the nutrient can reduce lactic acid build-up in the blood dur-
ing times of stress,8,9 enhance oxygen use during times of
hypoxia,8 and reduce seizure activity. 10-14 Extensive studies
with dimethylglycine have shown no significant adverse
effects in humans or animals. 5,8-23 _

169
170
We evaluated the effectiveness of dimethylglycine in a
double-blind, placebo-controlled study of a heterogeneous
population of children with diagnoses of autism and/or per-
vasive developmental disorder. Standardized quantitative
behavioral and neurologic assessments were completed
before treatment and 4 weeks after the treatment began to
measure the effects of dimethylglycine.
METHODS
... ’&dquo;
Subject Selection and Participation
Patients were recruited from local autism societies, schools, doc-
tors, and the Internet (by posting on an autism site). Thirty-nine
children, 3 to 11 years of age, with a diagnosis of autism/pervasive
developmental disorder were enrolled in the study. The study was
approved by the institutional review boards of the University of
Texas at Dallas and the University of Texas Southwestern Medical
School. Informed consent was obtained from the parents. Each child
met the diagnostic criteria for autism or pervasive developmental
disorder, according to the Diagnostic and Statistical Manual of
Mental Disorders-IV (DSM-IV) criteria,&dquo;3 confirmed independently
by the authors. The children who participated in this study were
heterogeneous, although all had either autism or pervasive devel-
opmental disorder. Because dimethylglycine may be beneficial
only in certain subtypes of autism we did not attempt to limit par-
ticipation to strictly defined subtypes of patients. The children
were randomly assigned to receive either dimethylglycine or
placebo by the research pharmacists at the Children’s Medical
Center of Dallas. The groups were matched for gender and age.
Group assignments were made by the pharmacist, who assisted with
the study without knowledge of the diagnostic status, severity, or
behavioral characteristics of the patients.
Thirty-nine children began the study, and 37 children completed
the study (19 in the placebo group and 18 in the treatment group).
One child discontinued the study due to negative behavioral effects
of the dimethylglycine (hyperactivity and increased agitation),
and another child discontinued due to damage to the foil wrappers
around the tablets. Four of the children were not examined by the
neurologist at the post-test because of scheduling conflicts.
Children in this study displayed a wide range and variety of
autistic features and soft neurologic findings common in such
children. For example, delays in gross and/or fine motor skills
were noted in 26 of the children. Problems with smooth ocular pur-
suit were noted in 4 of the children, and 4 children had obvious bal-
ance problems. Poor muscle tone was noted in 5 of the children.
Ten children were completely nonverbal, 12 were echolalic, and 4
had only slightly limited verbal skills. The children ranged in social
skills from friendly to completely asocial (even with family mem-
bers). Whereas some were quiet and/or passive, others were vio-
lent and/or aggressive. Sixteen children had difficulty sleeping,
which ranged from waking up several times per night to having to
be medicated to sleep. Eating disorders were described by the par-
ents in 16 of the children, ranging from eating an extremely
restricted choice of foods to having to be fed with a syringe because
of sensory issues (two children). Motor activity levels ranged from
almost immobile to constantly running around the room. Four
children were hyperlexic, teaching themselves to read before 4 years
of age. Sensory defensiveness was reported to be a problem in 13
of the children. Thirty-one of the children were normal in appear-
ance, whereas 8 had craniofacial and/or other physical anomalies.
Seven children were on psychoactive medications (clonidine, thio-
ridazine, paroxetine, imipramine, methylphenidate, and fluoxe-
tine) at the beginning of the study, but regimens were held constant
for the duration of the study.
Setting
Neurologic and behavioral assessments were completed at the
University of Texas at Dallas in the childcare room, a large, child-
friendly room with toys and activity centers. A variety of items were
available to use during the behavioral observations, such as wooden
blocks, crayons, pencils, paper, and balls. Patients were accom-
panied by their parents/guardians, who remained present during
the assessments.
Behavioral Assessments
Behavioral assessments were completed using two assessment
tools, the Vineland Maladaptive Behavior Domain, a section of
the Vineland Adaptive Behavior Scales Survey Form,24 and the
Aberrant Behavior Checklist, Subscales I to V. 25 These measures
were obtained immediately before treatment (week 0) and 4 weeks
after the treatment began (week 4). The assessment tools were com-
pleted by the examiner (J.K.K.). The Maladaptive Behavior Domain
was completed by interviewing the parent/guardian. The Aberrant
Behavior Checklist was completed by both observing the child and
obtaining input from the parent/guardian. Both the examiner and
the parent/guardian were blinded as to the child’s group assignment.
All assessments were videotaped and were later reviewed to ensure
the accuracy of the changes noted during the assessments.
The Maladaptive Behavior Domain was chosen because it
assesses several features relevant to autism (eg, eye contact, prob-
lems with eating or sleeping, attention, concentration, aggres-
siveness, peculiar occupations, peculiar mannerisms or habits,
self-injurious behavior, awareness of environment, bizarre speech,
rocking). The Vineland Adaptive Behavior Scales have been used
in other recent biomedical treatment studies for children with
autism.26 The Maladaptive Behavior Domain is a parent interview
format containing 36 items, of which 16 are specifically relevant
to autism/pervasive developmental disorder. Such items include &dquo;has
excessive or peculiar preoccupations with objects or activities,&dquo;
&dquo;is unaware of what is happening in immediate surroundings,&dquo;
&dquo;
and &dquo;rocks back and forth when sitting or standing.&dquo;
The Aberrant Behavior Checklist was chosen because it is a
scale for rating inappropriate and maladaptive behavior. The Aber-
rant Behavior Checklist was designed to monitor the behavioral
effects of psychotropic drugs. This same Aberrant Behavior Check-
list assessment was used in a recent Taiwanese study on the effec-
tiveness of dimethylglycine in children with autism/pervasive
developmental disorder (Bernard Rimland, PhD, personal com-
munication, January 1998). The Aberrant Behavior Checklist con-
sists of 58 items, many of which are pertinent to autism/pervasive
developmental disorder. Such items include &dquo;injures self on pur-
pose&dquo; ; &dquo;seeks isolation from others&dquo;; &dquo;fixed facial expression, lacks
emotional responsiveness&dquo;; &dquo;repetitive speech&dquo;; &dquo;repetitive hand,
&dquo;
body, or head movements&dquo;; &dquo;is difficult to reach, get through to.&dquo;

These 58 items on the Aberrant Behavior Checklist are grouped into
five categorical subscales as follows: Subscale I,Irritability and Self-
Abusive Behavior (15 items); Subscale II, Lethargy, Social With-
drawal, and Withdrawal (16 items); Subscale III, Stereotypic
Behavior (7 items); Subscale IV, Hyperactivity (16 items); and Sub-
scale V, Inappropriate Speech (4 items). These question items rate
the severity of the behavioral problem across three levels such that
a score of 0 indicates no problem and 3 indicates very severe.
Each subscale is scored as the sum of all items (eg, the maximum
possible Aberrant Behavior Checklist Subscale II score equals 48,
ie, three times 16 questions), such that improvements are indicated
by a reduction in the subscale score. All statistics were performed
on these sum scores for each subscale.
Data from the behavioral assessments were analyzed with Sta-
tistical Analysis Software.
Neurologic Assessments
A standardized general and neurologic examination was performed
on 33 of the children (16 placebo and 17 dimethylglycine) by a
pedi-
atricneurologist (V S.M.) at each visit. This examination included
assessment of alertness, duration of eye contact, ability to follow
verbal and nonverbal commands, gait, strength, muscle tone, and
deep tendon reflexes. Fine motor skills were assessed by asking
each child to stack building blocks and to draw simple geometric
figures such as a straight line, circle, and square. Running and
walking gaits were assessed. The examinations were performed in
as consistent a manner as possible across visits.
Dimethylglycine and Dosage
Foil-wrapped dimethylglycine and placebo (mannitol) tablets,
identical in appearance, were supplied by FoodScience Laborato-
ries. The pharmacists at Children’s Medical Center of Dallas pack-
aged and labeled the tablets and were responsible for randomized
group assignments (dimethylglycine or placebo). The dosage used
in thestudy was recommended by the Autism Research Institute.55
Both placebo and dimethylglycine tablets were 125 mg each and
were taken by mouth once every morning for 4 weeks. The dosage
was as follows: one tablet for children weighing less than 40 lbs,
two tablets for 41 to 70 lbs, three tablets for 71 to 100 lbs, four tablets
for 101 to 130 lbs, and five tablets for > 131 lbs.
RESULTS
Behavioral Assessments
All five measures of the Aberrant Behavior Checklist were
analyzed together as a three-factor analysis of variance: (1)
post-treatment versus pretreatment assessment scores, (2)
behavioral assessment measure (ie, Vineland Maladaptive
Behavior Domain and Aberrant Behavior Checklist Sub-
scales I-V), and (3) dimethylglycine group versus placebo
group. Two of these factors were treated as repeated mea-
sures : (1) post- versus preassessments and (2) behavioral
measures. We found a main effect for post- versus pre-
assessment scores (F(4,32) 15.00, P < .0005). This indicates
=
that across all subjects (ie, placebo and treatment groups)
and all behavioral measures, there was a significant improve-
ment over the duration of the experiment. Although this
171
effect was evident across all six behavioral measures, it
was modest in amplitude: (1) for the placebo group, the aver-
age improvement was just 0.87 points, with a range from 0.32
for Aberrant Behavior Checklist Subscale V to 1.68 for the
36 questions of the Vineland; (2) for the dimethylglycine
group, the average improvement was 0.71, with a range
from 0.06 for the Aberrant Behavior Checklist Subscale V
to 1.94 for the 16 questions of the Aberrant Behavior Check-
list Subscale II. However, there was no group by time inter-
action (F(4,32) =
0.067, P < .7967), such that the overall
improvement across all behavioral measures for the
dimethylglycine group was not different from the improve-
ment for the placebo group.
To evaluate each of the behavioral measures, we per-
formed one-tailed t-tests on the Vineland Maladaptive Behav-
ior Domain and each of the Aberrant Behavior Checklist
Subscales I to V, based on the differences of the post- ver-
sus pretreatment assessment scores. Statistical analysis
showed no effects of dimethylglycine treatment on any of
the behavioral measures. Although some of the children
appeared to improve over the 4 weeks of the study, the
improvements seen in the dimethylglycine group (58%)
were not statistically significantly different from the placebo
group (53%). Although one child was withdrawn for possi-
ble adverse behavioral changes, no negative behavioral
effects of dimethylglycine were noted by the examiner dur-
ing the assessments. In fact, more children in the placebo
group (32%) were reported to have negative effects than in
the treatment group (16%). These negative effects will be dis-
cussed in the section on parental reports.
Neurologic Assessments
The influence of dimethylglycine on neurologic status in chil-
dren with autism/pervasive developmental disorder was
evaluated by comparing the pre- and post-treatment neu-
rologic assessments. A chi-square statistic was computed
on the proportion of children in each group who improved.
We found that dimethylglycine treatment did not affect the
neurologic status of these children (XI [1, N 33] 0.31,
= =
P < .57). However, three children in the dimethylglycine
group did show improvement in gross motor function, one
with improved muscle tone, one with improved coordination,
and one with less posturing and toe walking. This improve-
ment was not noted in any of the children in the placebo group.
None of the children showed any adverse neurologic effects
due to either the placebo or the dimethylglycine treatment.
Parental Reports
Of the 19 children who participated in the dimethylglycine
group, parents reported that 11 children (58%) responded
positively to dimethylglycine, 3 children (16%) responded
negatively (including the 1 child who discontinued due to
negative behavioral effects), and 5 children (26%) showed
no response. Of the 19 children in the placebo group, par-
ents reported that 10 children (53%) responded positively,
6 children (32%) responded negatively, and 3 children (16%)
showed no response.
172
Positive effects reported in the placebo and dimethyl-
glycine groups were similar, such as (1) talking more; (2)
more interested in others; (3) improved bowel and bladder
control; (4) more &dquo;cuddly&dquo;; (5) less sensory defensiveness;
(6) less resistant to change; (7) improved sleeping; (8)
increase in vocabulary, use of sentences, and use of personal
pronouns; (9) more interest in their immediate surroundings;
(10) more responsive to their name; (11) more interactive;
(12) increased ability to tolerate therapy; (13) decrease in
frequency or complete cessation in self-injury; and (14)
improved eating. Of these responses, an increased interest
in others was the most predominant in the treatment group.
Negative effects were reported by some parents of chil-
dren in the study and were similar in both the placebo and
treatment groups. These parental reports of negative effects
included (1) increased activity (hyperactivity); (2) difficulty
sleeping; and/or (3) increased aggressiveness. In the dimethyl-
glycine group, parents reported difficulty sleeping in one
child, increased aggressiveness in one child, and increased
activity (hyperactivity) in two children. In the placebo group,
parents reported increased aggressiveness in two children
and increased activity (hyperactivity) in four children, two
of whom also experienced sleeping problems.
Group Differences
Although the children who participated in this study were
a heterogeneous group, the dimethylglycine and placebo
groups were not statistically significantly different on any
of the pretreatment behavioral measures except for Subscale
II of the Aberrant Behavior Checklist (Table 1). On this
measure of lethargy, the children who were randomly
assigned to the dimethylglycine group were more severely
affected than the children in the placebo group. Although
there was an a priori difference by chance between the two
groups on this one of the six behavioral measures, there was
room for improvement among the children in the placebo
group (the mean Aberrant Behavior Checklist Subscale II
pretreatment score was 6.2 in the placebo group and 14.8
in the dimethylglycine group). The difference in the amount
of improvement in this Aberrant Behavior Checklist Subscale
II between the dimethylglycine and placebo groups was
not statistically significant (see Table 1; 0.95 points = 13.6%
improvement in the placebo group compared to 1.94 points
= 15.3% improvement in the dimethylglycine group; t = 1.21,
[df 35] P < .12). In addition, the dimethylglycine versus
=
placebo difference decreased as the dimethylglycine subjects
with the highest Aberrant Behavior Checklist Subscale II pre-
treatment scores were eliminated from this t-test analysis
to equalize the pretreatment group means.
DISCUSSION
Autism/pervasive developmental disorder is a neurologic
disorder of unknown etiology. Whether the neurologic sys-
tem is the system of origin or whether the neurologic prob-
lems are a result of a malfunction in another system is
unclear. Biologic research in autism/pervasive develop-
Table 1. Comparison of Dimethylglycine versus Placebo
Pretreatment Scores on Each of the Behavioral Measures
Positive ivalues indicate dimethylglycine score exceeded placebo.
MBD Maladaptive Behavior Domain, ABC Aberrant Behavior Checklist.
= =
**Statistically significant.
mental disorder reveals abnormalities beyond the neuro-
logic system. Nonspecific and variable abnormalities have
been found in the immunologic system, digestive system, and
certain metabolic pathways. The variety and extent of abnor-
mal biologic findings in autism/pervasive developmental
disorder combined with the variability of features and symp-
tomatology support the hypothesis that autism/pervasive
developmental disorder is not a single disorder, and descrip-
tive studies indicate that there are subtypes in autism that
differ according to etiology. Heterogeneity regarding pathol-
ogy makes finding effective treatments more difficult.
Researchers have used various methods to subtype autism
and the broader pervasive developmental disorder class of
conditions,4 but, at present, no clear delineation has been
established, behavioral or biomedical. The varied apparent
response seen in this study may have been due to the het-
erogeneity of the group in regard to pathology. In this case,
the results of the study may corroborate the hypothesis that
autism is not a single disorder in regard to pathology.
A number of studies in autism indicate abnormal
immune function.27&dquo;1 Dimethylglycine has demonstrated
significant immunologic effects in cell cultures, animals, and
humans. For example, Reap and Lawsonzl found that
dimethylglycine may have significant benefits to individu-
als with impaired immune systems. Further studies would
be needed to determine if dimethylglycine has any effect on
modulating immune parameters in persons with autism
with abnormal immune function.
CONCLUSION
Dimethylglycine is promoted in health food stores as a
dietary supplement for athletes and persons with autism/per-
vasive developmental disorder. Anecdotal reports indicate
that many parents of children with autism supplement their
child’s diet with dimethylglycine in the hope of improving
the child’s condition. The children in this study were a het-
erogeneous group, and their apparent responses to the
dimethylglycine varied. Some of the children were reported
by their parents to respond positively to dimethylglycine; oth-
ers were reported to show no response or were reported to
respond negatively. As mentioned earlier, more children
were reported to have negative side effects from the placebo
than the dimethylglycine. Neither examiner noted any neg-
ative effects from the dimethylglycine or the placebo.

We conclude that in a heterogeneous group of children
with a diagnosis of autism/pervasive developmental disor-
the effect of dimethylglycine was not statistically sig-
der,
nificantly different from the placebo. It is unclear the extent
to which the heterogeneity of the children lessened the
power in statistical analyses.
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