Poetry in motionBackground:
This study investigated the effects of oral dimercapto succinic acid (DMSA) therapy on the behavioral symptoms of children with autism spectrum disorders (ASD) ages 3-8 years.
Methods: Phase 1 involved 65 children with ASD who received one round of DMSA (3 days). Participants who had high urinary excretion of toxic metals were selected to continue on to phase
2. In phase 2, 49 participants were randomly  assigned in a double-blind design to receive an additional 6 rounds of either DMSA or placebo.

Results:

The groups receiving one round and seven rounds of DMSA had significant improvements on all the assessment measures. For the seven round group, the degree of improvement on the
assessment measures could be partially explained by a regression  analysis  based  on  excretion  of toxic metals and changes in glutathione (adjusted R2 of 0.28-0.75, p < 0.02 in all cases). One round
of DMSA had nearly the same benefit as seven rounds. The assessment  measures  correlated reasonably with one another at the beginning of the study (r = 0.60-0.87) and even better at the
end of the study (r = 0.63-0.94).

Conclusion:

Overall, both one and seven rounds of DMSA therapy seems to be reasonably safe in children with ASD who have high urinary excretion of toxic metals,  and possibly helpful in
reducing some of the symptoms of autism in those children.

Read the full report here. Chelation for Autism, Behavioral Results.

BioMed Central
Page 1 of 9
(page number not for citation purposes)
BMC Clinical Pharmacology
Research article Open Access
Safety and efficacy of oral DMSA therapy for children with autism
spectrum disorders: Part B – Behavioral results
James B Adams*1
, Matthew Baral2
, Elizabeth Geis3
, Jessica Mitchell2
,
Julie Ingram3
, Andrea Hensley3
, Irene Zappia3
, Sanford Newmark4
,
Eva Gehn3
, Robert A Rubin5
, Ken Mitchell3
, Jeff Bradstreet2,6
and Jane ElDahr7
Address: 1Division of Basic Medical Sciences, Southwest College of Naturopathic Medicine, Tempe, AZ, USA, 2Department of Pediatric Medicine,
Southwest College of Naturopathic Medicine, Tempe, AZ, USA, 3
Autism Research Institute, San Diego, CA, USA, 4
Center for Integrative Pediatric
Medicine, Tucson, AZ, USA, 5Department of Mathematics, Whittier College, Whittier, CA, USA, 6
International Child Development Resource
Center, Phoenix, AZ, USA and 7Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, USA
Email: James B Adams* – jim.adams@asu.edu; Matthew Baral – m.baral@scnm.edu; Elizabeth Geis – autismstudynurseasu@gmail.com;
Jessica Mitchell – j.mitchell@scnm.edu; Julie Ingram – julieaingram@yahoo.com; Andrea Hensley – ahensley11@cox.net;
Irene Zappia – izappia@aol.com; Sanford Newmark – snewmark@email.arizona.edu; Eva Gehn – egehn@asu.edu;
Robert A Rubin – brubin698@earthlink.net; Ken Mitchell – kbmpd@yahoo.com; Jeff Bradstreet – drbradstreet@aol.com; Jane ElDahr – jeldahr@tulane.edu
* Corresponding author
Abstract
Background: This study investigated the effects of oral dimercapto succinic acid (DMSA) therapy
on the behavioural symptoms of children with autism spectrum disorders (ASD) ages 3-8 years.
Methods: Phase 1 involved 65 children with ASD who received one round of DMSA (3 days).
Participants who had high urinary excretion of toxic metals were selected to continue on to phase
2. In phase 2, 49 participants were randomly  assigned in a double-blind design to receive an
additional 6 rounds of either DMSA or placebo.
Results: The groups receiving one round and seven rounds of DMSA had significant improvements
on all the assessment measures. For the seven round group, the degree of improvement on the
assessment measures could be partially explained by a regression  analysis  based  on  excretion  of
toxic metals and changes in glutathione (adjusted R2
of 0.28-0.75, p < 0.02 in all cases). One round
of DMSA had nearly the same benefit as seven rounds. The assessment  measures  correlated
reasonably with one another at the beginning of the study (r = 0.60-0.87) and even better at the
end of the study (r = 0.63-0.94).
Conclusion: Overall, both one and seven rounds of DMSA therapy seems to be reasonably safe
in children with ASD who have high urinary excretion of toxic metals,  and possibly helpful in
reducing some of the symptoms of autism in those children.
Published: 23 October 2009
BMC Clinical Pharmacology 2009, 9:17 doi:10.1186/1472-6904-9-17
Received: 10 April 2009
Accepted: 23 October 2009
This article is available from: http://www.biomedcentral.com/1472-6904/9/17
© 2009 Adams et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.BMC Clinical Pharmacology 2009, 9:17 http://www.biomedcentral.com/1472-6904/9/17
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Background
Autism is a severe developmental disorder which involves
social withdrawal, communication deficits, and stereotypic/repetitive behaviors. The cause(s) of autism are
unknown, but both genetic and environmental factors
have been implicated. One environmental factor that has
received significant attention is the body burden of mercury, lead and other toxic metals [1-5].
The purpose of this paper is to evaluate the safety and efficacy of DMSA therapy on children with autism spectrum
disorders (ASD), focusing on behavioral effects. The
effects of DMSA on medical issues (urinary excretion of
toxic metals, glutathione, blood count, blood chemistry)
are discussed in the accompanying paper [6]. DMSA is
FDA-approved for the treatment of lead poisoning in children as young as 2 years, and this study investigated its use
for an off-label application, namely treating children with
ASD who have evidence of significant heavy metal exposure (based on urinary excretion after DMSA challenge).
DMSA preferentially binds to lead, but can also increase
the excretion of several other toxic metals (including tin,
bismuth, thallium, mercury, antimony, and tungsten) to
a lesser extent. Another paper resulting from this study
discusses the strong correlation of the initial severity of
autism with the body burden of toxic metals [7].
Methods
The methodology is primarily discussed in the accompanying paper [6]. This study was conducted with the
approval of the Human Subjects Institutional Review
Board of Southwest College of Naturopathic Medicine. All
parents and (where possible) children signed informed
consent/assent forms.
The study was designed with a screening round (nine
doses over three days) of DMSA in Phase 1, followed by a
randomized, double-blind, placebo-controlled study of
six additional rounds (see Figure 1). The purpose of the
screening round was to only allow participants with high
excretion of toxic metals into phase 2. However, as discussed in the accompanying paper [6], the single screening round of DMSA had an unexpectedly dramatic effect
on improving abnormal glutathione and platelet levels,
and that effect lasted through the end of phase 2, so that
phase 2 turned out in practice not to be a placebo-controlled investigation. Instead, it appears best to interpret this
study as a comparison of the effect of one round of DMSA
(and six rounds of placebo) versus seven rounds of DMSA.
In discussing these two groups below, we will refer to
them at the “1-round” group and the “7-round” group.
Four tools were used to assess the severity of autism,
namely the Pervasive Developmental Disorder Behavior
Inventory (PDD-BI) [8] Autism Treatment Evaluation
Checklist (ATEC) [9], Severity of Autism Scale (SAS) [7],
and the Autism Diagnostic Observation Schedule (ADOS)
[10]. Different methods were used because they each
assess somewhat different aspects of autism. The ATEC
was evaluated at the beginning of Phase 1 and the end of
phase 2, and the other three instruments were evaluated at
the beginning of Phase 2 and the end of Phase 2. Also, a
new instrument, the Parent Global Impressions (PGI) was
used at the end of the study to evaluate changes in symptoms; it complements the other scales because is only
evaluates changes in symptoms, rather than absolute levels of severity. The ATEC, SAS, PDD-BI, and PGI were
assessed by the participants’ parents, and the ADOS was
evaluated by a certified ADOS evaluator. It should be
noted that the ADOS was developed primarily for diagnosing autism, and it is unclear if it sensitive enough for
treatment studies, whereas the other instruments were
designed to assess severity of symptoms, not to diagnose.
Statistical Analysis
Several types of statistical analyses were used, depending
on the research question being addressed. In comparing
pre/post levels within a treatment group (such as changes
in a participant’s autism severity), 2-sided paired t-tests
were used, and for each individual hypothesis a p value of
0.05 or lower was assumed significant. Pearson correlation coefficients were obtained to determine the strengths
of linear relationships among the variables involved in
the analyses.
Regression analysis was employed to examine the relationship between the change in the severity of autism
(assessed by the ATEC, PDD-BI, SAS, and ADOS) and the
Figure 1 Study design
Study design. Both groups of participants received a single
challenge round of oral DMSA; those excreting significant
heavy metals continued on to Phase 2, and received additional 6 additional rounds of DMSA or placebo.
Children with ASD
Randomized in double-blind manner
Topic al
Glutathione
Placebo
cream
One round
of oral DMSA
(9 doses)
(n=33 completed)
One round
of oral DMSA
(9 doses)
(n=31 completed)
low-excretors
of metals
low-excretors
Metal of metals
excretors
Metal
excretors
Subsequent
Rounds of
DMSA
(n=26 completed)
Subsequent
Rounds of
Placebo
(n=15 completed)
Phase
One
Phase
TwoBMC Clinical Pharmacology 2009, 9:17 http://www.biomedcentral.com/1472-6904/9/17
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urinary excretion of toxic metals, (after the 9th
dose of
DMSA in phase 1), and the change in glutathione (in the
red blood cells). To reduce the number of variables, for
the behavioral assessments we focus primarily on the
summary measures (e.g, we analyzed ATEC and ADOS
total scores, rather than dealing with the individual subscores comprising the total). For the selected dependent
and independent variables, step-wise linear regression
analyses were conducted: initially all independent variables were included in the regression; then at each step, the
variable with the highest p-value was eliminated, and this
process was continued until the adjusted R2
value began
declining. Thus, the goal was to determine the best fit to
the sample data for the selected model, taking into
account the correlation among the independent variables.
Since the data had several missing values (due to missing
lab or behavioral data), the regression analyses were conducted in two slightly different ways which generally
yielded very similar results: 1) eliminate all participants
with missing data for any of the variables in the model at
the beginning of the analysis, and 2) eliminate participants on an as-needed basis (i.e., only where there is missing data for any variable in the current step in the
analysis). Since these two methods yielded very similar
results, for brevity we only report the results for method 1.
Results
ATEC
Table 1 summarizes the ATEC results for the participants
who finished Phase 2. Note that some parents did not
complete Section IV of Health/Physical Behavior due to a
clerical error. For the total ATEC score, each group had a
statistically significant improvement, with the 7-round
group improving more (-26%) than the 1-round group (-
19%), but the difference in improvement between groups
was not statistically significant. The 7-round group
improved more than the 1-round group on the Speech
subscale and the Health/Physical Behavior subscales, but
the differences were not statistically significant. Both
groups improved similar amounts on the Sociability and
Sensory/Cognitive Awareness subscales.
Because of concerns about the possible side-effects of
DMSA on gut function, two of the questions on the ATEC
which relate to gut function were analyzed. Those questions (on constipation and diarrhea) have a severity scale
of 0 = none, 1 = mild, 2 = moderate, 3 = severe. For the
participants who finished phase 2, there was little change
in severity of diarrhea (0.52 +/-0.79 at beginning, 0.57 +/
– 0.79 at end) and a small increase in severity of constipation (0.61 +/- 0.89 to 0.87 +/- 1.1, not significant).
PDD-BI
Table 2 lists the results for the PDD-BI. The PDD-BI is split
into 2 sections, one for Maladaptive Behaviors (7 subscales) and one for Adaptive Behaviors (3 subscales). One
of the Maladaptive subscales, the Semantic/Pragmatic
Problems (SPP), was difficult to interpret, since some children initially had no spoken language, and then began
speaking with simple words or phrases during the study;
this results in a worsening of their SPP score when their
language is actually beginning. Therefore, we chose not to
report the results of this subscale, and not to include it in
the composite scores. This modified Autism Composite
score was discussed with I. Cohen, the developer of the
PDD-BI.
For the modified composite score for the Maladaptive section (Sensory/Perceptual Approach, Ritualisms/Resistance to Change, Social Pragmatic Problems, Arousal
Regulation, Specific Fears, and Aggressiveness), there was
a similar improvement in both the 7-round and 1-round
groups of 24%. For the composite score for the Adaptive
Behaviors (Social Approach Behaviors, Phonological and
Table 1: ATEC scores at beginning at beginning of phase 1 and end of phase 2, for those who completed phase 2.
Initial St dev Final St dev % change
I. SPLC 7 rounds 13.4 7.7 10.6 7.0 -21%***
1 round 12.0 8.4 10.5 8.9 -13%
II. Sociability 7 rounds 16.6 8.5 12.1 6.5 -27%***
1 round 14.9 6.8 11.2 6.5 -25%*
III. Sensory/Cognitive Awareness 7 rounds 16.0 7.4 11.7 7.9 -27%***
1 round 13.0 6.8 9.6 5.9 -26%*
IV. Health/Physical/Behavior 7 rounds 29.9 14.4 21.6 10.1 -28%**
1 round 21.5 9.4 18.3 9.2 -15%
ATEC Total 7 rounds 80.8 24.0 60.14 27.9 -26%***
1 round 66.2 20.7 53.4 23.5 -19%**
* P < 0.05
**P < 0.01
*** P < 0.001
For the 7-round group n = 25 (n = 14 for Section IV & Total), and for the 1-round group n = 15 (n = 10 for Section IV & Total). The statistical
significance of the change is indicated, based on a paired t-test.BMC Clinical Pharmacology 2009, 9:17 http://www.biomedcentral.com/1472-6904/9/17
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Semantic Pragmatic, Learning, Memory, and Receptive
Language) there were similar improvements in the 7-
round and 1-round groups (9% and 11%, respectively).
For the modified Autism composite of Maladaptive and
Adaptive behaviors (Sensory/Perceptual Approach, Ritualisms/Resistance to Change, Social Pragmatic Problems,
Social Approach Behaviors, Phonological and Semantic
Pragmatic), there were large and similar improvements in
both the 7-round and 1-round groups (38% and 40%,
respectively). Overall, there were very similar improvements for the 7-round and 1-round groups, and the
improvements on the Autism composite score was highly
statistically significant.
Severity of Autism Scale (SAS)
Table 3 summarizes the results for the SAS. Both the 7-
round and 1-round groups improved similar amounts
(18-19% reduction of their SAS scores), and the improvements were statistically significant.
Table 2: Results of PDD-BI evaluations by Parents N = 25 for the 7-round group, and N = 15 for the 1-round group.
Initial St. Dev Final St. Dev % Change
Maladaptive Behaviors
Sensory/Perceptual Approach Behaviors 7 Rounds 22.8 14.7 17.8 13.9 -22%*
1 Round 20.0 13.6 13.7 13.4 -31%**
Ritualisms/Resistance to Change 7 Rounds 13.9 10.5 10.0 7.8 -28%**
1 Round 15.0 8.5 11.5 8.2 -23%**
Arousal Regulation Problems
7 Rounds 17.9 9.0 13.9 8.5 -22%**
1 Round 14.9 6.6 12.1 8.8 -19%
Specific Fears
7 Rounds 21.7 16.0 14.6 12.1 -33%**
1 Round 18.7 10.3 15.9 11.1 -15%
Aggressiveness
7 Rounds 13.4 9.8 9.8 6.7 -27%*
1 Round 11.4 8.1 8.4 7.2 -26%*
Social Pragmatic Problems
7 Rounds 16.9 9.2 14.5 9.2 -14%
1 Round 13.9 7.5 9.9 7.5 -29%**
Semantic/Pragmatic Problems
7 Rounds 15.2 7.6 12.5 7.3 -18%
1 Round 11.1 5.6 9.6 4.5 -13%
AWP/C Composite Sensory+Ritual+SocPrag+Semantic+
Arousal+Fears+Agg
7 Rounds 105. 58.6 79.5 49.9 -24%***
1 Round 93.8 29.5 71.6 38.8 -24%***
Adaptive Behaviors:
Social Approach Behaviors
7 Rounds 63.8 20.6 70.8 23.6 11%**
1 Round 68.2 25.4 72.6 20.2 6%
Express (Phonological & Semantic Pragmatic)
7 Rounds 41.4 28.2 43.6 27.1 +5%
1 Round 44.0 34.9 51.3 31.5 +17%*
Learning, Memory, and Receptive Language
7 Rounds 22.7 8.1 25.4 8.7 12%*
1 Round 23.2 10.1 26.5 8.9 14%**
REXSCA/C Composite SocialApp+Express+LMRL
7 Rounds 127 52.7 139 54.5 9%**
1 Round 135 65.5 150 53.6 11%*
Autism Composite
(Sensory, Ritual & Social Problems – Social Approach Behaviors – Expressive
Language)
7 Rounds -53.1 66.4 -73.3 67.9 38%**
1 Round -63.5 65.1 -88.8 58.3 40%**
* P < 0.05
** P < 0.01
*** P < 0.001
The statistical significance of the change is indicated, based on a paired ttest.BMC Clinical Pharmacology 2009, 9:17 http://www.biomedcentral.com/1472-6904/9/17
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ADOS
Table 4 summarizes the results for the ADOS. At the
beginning of the study, based on the combined score of
the Communication + Sociability scores, 81% of the participants met the criteria for autism, 12% met the criteria
for ASD, and 7% were below the criteria for ASD. Overall,
changes in ADOS scores were less than for the other scales.
The 7-round group had slightly better improvements in
sociability, play, and stereotypical behavior/repetitive
interests, but the differences were not statistically significant. The two groups had similar changes in their communication and communication + sociability score. The 7-
round group had statistically significant improvements in
their Sociability and Communication + Sociability scores,
but the 1-round group did not have any statistically significant improvements.
Parental Global Impressions (PGI)
At the end of phase 2, parents filled out a PGI questionnaire, with a scale ranging from much worse (-3) to same
(zero) to much better (+3) for 10 different areas, and an
Overall score. Tables 5 lists the results. In general, there
was no significant difference between the 7-round group
and the 1-round group. Both groups reported similar
improvements in the Overall score, and in the areas of
expressive language, receptive language, cognition/thinking, play skills, and eye contact. The 1-round group
reported slightly more improvement in sociability, but the
difference was not statistically significant. There was little
change in tantrums, stools/gastrointestinal issue or sleep
problems in either group. There was a slight worsening of
hyperactivity in the 7-round group. It is interesting that
the average scores of the two groups were very similar in
each category, with a 95% correlation between them.
Table 6 shows a detailed breakdown of the Overall category, for each group and for their combination.
Summary of autism severity scales
Since the improvement in scores for the 7-round and 1-
round groups were similar for all the metrics, it is useful
to group both groups together and analyze the average
effect of treatment for the two groups. As summarized in
Table 7, if we average over the 5 assessment tools, about
77% of the participants had improved autism severity
scores, about 12% had no change, and about 11% had a
worsening of their scores. So, although the DMSA treatment appeared to be beneficial in most cases, there was a
small subset whose symptoms appeared to worsen
slightly. The most common adverse effect seemed to be
hyperactivity, according to the PGI, and this effect was
usually temporary.
Table 3: Scores of Autism Severity Scale by parents at the
beginning of Phase 2 and the end of Phase 2.
Initial St dev Final St dev % change
7 Rounds 5.2 2.2 4.2 2.0 -19%***
1 Round 5.5 2.7 4.5 2.6 -18%**
* P < 0.05
** P < 0.01
*** P < 0.001
N = 22 for the 7-round treatment group and N = 14 for the 1-round
group. The statistical significance of the change is indicated, based on
a paired ttest.
Table 4: ADOS Scores at beginning and end of Phase 1 for 7-
round group (n = 26) and 1-round group (n = 15).
Initial Final % change
Communication
7 Rounds 7.8 7.1 -9%
1 Round 6.7 5.9 -11%
Sociability
7 Rounds 9.3 8.3 -10%**
1 Round 8.1 7.9 -2%
Communication + Sociability
7 Rounds 17.0 15.4 -9%***
1 Round 14.7 13.7 -7%
Play
7 Rounds 3.2 3.0 -5%
1 Round 2.8 2.8 0%
SBRI
7 Rounds 3.9 3.5 -9%
1 Round 3.5 3.5 -2%
* P < 0.05
** P < 0.01
*** P < 0.001
The statistical significance of the change is indicated, based on a paired
ttest.
Table 5: Results of “Parent Global Impression” questionnaire,
administered at end of Phase 2.
7 rounds (n = 24) 1 round (n = 12)
Overall 1.7 1.6
Expressive Language 2.0 1.6
Receptive Language 1.8 1.9
Cognition/Thinking 1.8 1.8
Play Skills 1.5 1.6
Sociability 1.3 1.8
Eye Contact 1.1 0.8
Tantruming 0.5 0.3
Stools/Gastrointestinal
Isssues 0.0 -0.2
Sleep -0.3 -0.1
Hyperactivity -0.5 -0.1
Scale ranges from no change (0), slightly better/worse (+1, -1), better/
worse (+2, -2), much better/worse (+3, -3). There were no
statistically significant differences between the two groups. Arranged
in order of degree of improvement for 7 rounds group.BMC Clinical Pharmacology 2009, 9:17 http://www.biomedcentral.com/1472-6904/9/17
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Correlations of Severity Scales
Table 8 shows the correlations among the initial scores,
and Table 9 shows the correlations among the final scores.
Initially, there is a high correlation between the ATEC and
the PDD-BI (r = 0.87), and a good correlation of the SAS
with the ATEC (r = 0.70) and the PDD-BI (r = 0.72). The
correlation of the ADOS with the other scales is lower (r =
0.57-0.58). At the end of the study, the correlations
among the final scores are slightly higher, especially for
the correlations of the ADOS with the other scales (r =
0.63-0.73). It should be noted that the ADOS evaluation
was done by a professional evaluator, whereas the other
assessments were done by the same parent.
Correlation of Improvement in Severity Scales with Age
A correlation analysis of age with changes in the severity
scales revealed a slight positive correlation for two autism
severity scales (ATEC (r = 0.24), SAS (r = 0.17), neither significant) and little correlation for the other two scales.
(PDD-BI (r = 0.09), ADOS (r = -0.05). This means that the
older children had almost the same degree of improvement as the younger children.
Regression Analyses of Changes in the Severity of Autism
Table 10 shows the results of stepwise linear regression
analyses for changes in the various autism severity scales
as a function of urinary excretion of toxic metals (after the
9th dose of DMSA in phase 1) and the change in glutathione. The 1-round and 7-round groups were combined for
this analysis, with separate coefficients for each group.
The prediction of PDD-BI and ATEC yielded significant
results, but only the terms related to the 7-round groups
were significant. For the ADOS and SAS there were no significant results. Table 10 displays the results.
Since only the 7-round group had significant coefficients,
all the regression analyses were redone for the 7-round
group only. The results are listed in Table 11. This re-analysis yielded much better predictions (adjusted R2
from
0.28 to 0.75), and all of the results were significant (p-values from 0.02 to 0.0006). This demonstrates that the
behavioral changes observed in the 7-round group could
be significantly described by urinary excretion of toxic
metals and change in glutathione. For the PDD-BI (which
had the highest adjusted R2
and the most significant pvalue), the major factors were excretion of thalium (Tl)
and arsenic (As) and changes in RBC glutathione, followed by excretion of lead (Pb) and antimony (Sb). Overall, the most consistent significant factors between the
different scales were excretion of As (ATEC, ADOS, PDDBI), excretion of Tl (SAS, PDD-BI), excretion of Pb (SAS,
PDD-BI), and change in RBC gluathione (SAS, PDD-BI).
Other significant contributors were mercury (Hg) (ATEC),
aluminum (Al) (ADOS), and Sb (PDD-BI). Since the toxic
metal excretions exhibit considerable correlation amongst
themselves [6], one should refrain from reading too much
into the relationships between specific metals and severity
of autism. Instead, one should interpret the results as indicating a general relationship between changes in autism
severity and urinary excretion of toxic metals and change
in glutathione for the 7-round group, but much less significance when combined with the 1-round group.
Table 6: Results of “Parent Global Impressions” questionnaire, for the “Overall” category
Rating 7-round group 1 round Both groups combined
Much Better 29% 27% 28%
Better 33% 27% 31%
Slightly Better 25% 27% 28%
No Change 4% 18% 8%
Slightly Worse 4% 0% 3%
Worse 4% 0% 3%
Table 7: Summary of changes in autism severity scores, combining both 1-round and 7-round groups
% Improved % No Change % Worsened
ATEC 96% 2% 2%
SAS 61% 33% 6%
ADOS (Comm. + Social) 68% 15% 17%
PDD-BI (modified 75% 2% 22%
Autism Composite)
Parent Global Impression 86% 8% 6%
Average of all 5 assessments 77% 12% 11%BMC Clinical Pharmacology 2009, 9:17 http://www.biomedcentral.com/1472-6904/9/17
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Discussion
Discussion – Effect of DMSA on Symptoms of Autism
Five different tools (ATEC, SAS, PDD-BI, ADOS, PGI)
were used to assess changes in the severity of autism during the course of the study. Four of the scales (ATEC, SAS,
PDD-BI, and ADOS) could be analyzed for correlations,
and reasonable correlations were found between them at
the beginning (pre vs pre) and end of the study (post vs
post), which supports the validity of each of them. The
correlations were highest among the ATEC, SAS, and
PDD-BI, which is expected since the same parent conducted those, whereas the ADOS was evaluated by a certified professional.
Three of the assessments (PDD-BI, SAS, and PGI) found
significant but similar improvements in both the 1-round
and 7-round groups. Two of the assessment tools (ATEC
and ADOS) found somewhat more improvement in the 7-
round group, but the difference was not statistically significant. Overall, one round of DMSA seemed to provide
almost as much benefit as seven rounds of DMSA.
If phase 2 were a true placebo-controlled study, then this
result would mean that the DMSA had little or no effect
on behavior. However, it is important to remember two
major points:
1) As discussed in the accompanying paper (Adams et al
2009), the single round of DMSA in Phase One had a dramatic effect on normalizing glutathione and improving
platelet levels, and additional doses did not further
improve platelet levels, and probably did not significantly
affect glutathione since it was already normal or near-normal after the first round. 2) The degree of improvement
correlated with excretion of toxic metals and changes in
glutathione, especially for the PDD-BI, with an extremely
high adjusted R2
of 0.75, and a highly significant p-value
of 0.0006. If the reported improvements were purely a
random placebo-effect, adjusted R2
values would be near
zero and not significant. Thus, most of these improvements appear to be real and directly related to excretion of
toxic metals and changes in glutathione.
Thus, this data suggests that the DMSA may have had a
beneficial effect on the symptoms of autism. A future randomized, double-blind, placebo-controlled study without
an initial screening round of DMSA would help confirm
this.
The findings of this paper are consistent with our findings
that the initial severity of autism significantly correlated
with the body burden of toxic metals, assessed pre and
post DMSA challenge [7]. It was surprising that just one
round of DMSA had significant behavioral effects, but this
is consistent with the finding that just one round of DMSA
was sufficient to normalize glutathione and improve
platelet levels (a marker of inflammation). It seems likely
that a longer treatment study may yield even more beneficial results, since 80% of the children were still excreting
high levels of lead and other toxic metals at the end of 7
rounds of DMSA therapy. It appears that monitoring urinary excretion of toxic metals may be a useful guide as to
how long to continue therapy, especially if ongoing exposure to toxic metals is minimized.
Overall, the results of this study and others suggest that
toxic metals contribute to the severity of autism, and may
be a factor in causing autism in some cases. This is consistent with the general role of toxic metals as neurodevelopmental toxins. If this is the case, a reduction in exposure
to toxic metals might be helpful in partially reducing the
incidence of autism. More research is needed to investigate this possibility.
Table 8: Correlation of Initial Severity Scores (pre vs. pre)
ATEC SAS ADOS (Social + Communication) PDD-BI (modified autism)
ATEC 1
SAS 0.70 1
ADOS 0.60 0.60 1
PDD-BI 0.87 0.72 0.67 1
Table 9: Correlation of Final Severity Scores (post vs. post)
ATEC SAS ADOS (Social + Communication) PDD-BI (modified autism)
ATEC 1
SAS 0.74 1
ADOS 0.66 0.73 1
PDD-BI 0.94 0.73 0.63 1BMC Clinical Pharmacology 2009, 9:17 http://www.biomedcentral.com/1472-6904/9/17
Page 8 of 9
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Age Effects
Improvements in the various autism severity scores had a
slight positive correlation with age for the ATEC and SAS,
(not statistically significant, but essentially no correlation
for the PDD-BI or ADOS. This suggests that age had little
effect on degree of improvements, with the older children
improving as much or almost as much as the younger children.
Gut symptoms
There has been some concern that DMSA therapy may
result in gut problems, possibly related to the overgrowth
of yeast. However, following the protocol of this study, we
did not observe any evidence of significant change in gut
problems. Based on the PGI, there was no change in gut
problems on average, and based on the individual questions on the ATEC, there was, on average, no change in
diarrhea and only a slight worsening of constipation (not
significant). Thus, it appears that oral DMSA, by itself,
does not cause or significantly exacerbate gut problems in
most cases. A limitation of this study is that we did not
perform extensive evaluations of gut flora or gut function.
Comparison with other treatments
It is interesting to compare the efficacy of DMSA therapy
with other therapies. This is difficult because different
scales are used in different treatment studies (which is part
of the reason why we included several scales in this study).
The PGI assessment used in this study is very similar to an
earlier version of the PGI used in a 3-month double-blind,
placebo-controlled vitamin/mineral treatment study [11].
DMSA therapy appeared to provide similar improvements
to vitamin/mineral therapy in the areas of Expressive Language, Receptive Language, Sociability, and Overall. However, the vitamin/mineral therapy yielded better
improvements in sleep and gastrointestinal problems,
and possibly slightly better eye contact.
Table 10: Regression Analyses of Changes in Autism Severity vs. Urinary Metal Excretion (after 9th
dose of DMSA in Phase 1) and
Changes in Glutathione (Dglut).
Adjusted R2
P-value Equation Most significant variables
Change in PDD-BI (n = 32) 0.59 0.002 7-rnd group
(17.9 -2.62 Pb9 +0.230 Sn9 +102Tl9 -135Sb9 –
1.01 As9 -0.0695 Dglut)
1-rnd group
(-32.7 -0.564 Pb9 +0.0755Sn9 +17.4 Tl9 +13.8
Sb9 -0.476 As9 +0.045 Dglut)
7-rnd group: Dglut***, As9**,
Sb9**, Tl9**, Pb9*
1-round group: No significant
terms
Change in ATEC (n = 32) 0.25 0.02 7-rnd group (1.93 -7.82 Hg9 -0.352 As9)
1-rnd group (-4.91 -0.672 Hg9 -0.260 As9)
7-rnd group: Hg9**, As9*
1-rnd group: No significant
terms
Change in SAS (n = 29) 0.22 n.s. (not listed since not significant)
Change in ADOS (comm.. +
social) (n = 32)
0.18 n.s. (not listed since not significant)
Both treatment groups analyzed together, with individual coefficients for each group. Only the PDD-BI and ATEC yielded significant results, and
only the 7-round group variables had significant coefficients. In the regression equation, the suffixes for the metals refer to the value at Baseline (B)
and after the 9
th
dose of DMSA (9). Note that initial glutathione did not contribute to any of the final equations.
Table 11: Regression Analyses of Changes in Autism Severity vs. Urinary Metal Excretion (after 9th
dose of DMSA in Phase 1) and
Changes in Glutathione (Dglut).
Adjusted R2
P-value Equation Most significant variables
Change in PDD-BI (n = 20) 0.75 0.0006 10.25 -2.48Pb9 +0.169Sn9 +113.5Tl9 –
119.1Sb9 – 1.199As9 +0.726Al9 –
0.0608DGlut
Tl9**, As9**, DGlut**, Pb9*, Sb9*
Change in ATEC (n = 20) 0.44 0.006 9.41 -0.663Pb9 -8.80Hg9- 0.352As9 Hg9**, As9*
Change in SAS (n = 18) 0.57 0.002 -1.01 +0.0985Pb9- -0.00169DGlut Tl9**, Pb9*, DGlut*
Change in ADOS (comm.. +
social) (n = 20)
0.28 0.02 -1.91+00.0472As9 – 0.0877Al9 As9*, Al9*
This is the same analysis as Table 10, except it is for the 7-round group only, resulting in much better regression fit and much greater significance in
all cases. This demonstrates that the changes in the 7-round group are much better predicted by their excretion of heavy metals and change in
glutathione.BMC Clinical Pharmacology 2009, 9:17 http://www.biomedcentral.com/1472-6904/9/17
Page 9 of 9
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Conclusion
1) The severity of autism, as assessed by five different
assessment tools, significantly decreased during the
study for both the group receiving 1 round of DSMA
(and 6 rounds placebo) and 7 rounds of DMSA.
2) Regression analysis of improvement in autistic
symptoms with glutathione and metal excretion
(especially thallium, arsenic, mercury, and lead) suggests most of the improvement was real (not due to a
placebo effect), and thus suggests DMSA may have
resulted in reduction of some symptoms of autism.
3) Age had little effect on the degree of improvement;
older children improved as much or almost as much
as the younger children on the various scales.
4) Overall, DMSA therapy appears to be generally safe,
and possibly effective in reducing the symptoms of
autism in some children.
Future studies should consider a double-blind, placebocontrolled design (no screening round) to definitively
determine the effect of a single round of DMSA on behavior. Also, a longer term treatment study (longer than 7
rounds) should be considered to determine if longer treatment results in greater benefits.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
JBA was the primary organizer of the study, did the initial
data analysis, and was the primary author. He was the official co-principal investigator for the study. MB was the primary physician for the greater Phoenix area. He was the
official principal investigator, and worked with JBA on
study design and study approval. EG was the study coordinator and lead study nurse. JM was a secondary physician who assisted MB. JI was the ADOS evaluator for the
greater Phoenix area. AH was a study nurse. IZ was the
ADOS evaluator for the greater Tucson area. SN was the
physician for the greater Tucson area. EG handled data
entry and helped with data analysis. RAR was the primary
statistician for the study, and did the regression analysis.
KM was the pharmacist who assisted with compounding
the DMSA. JB was a physician who served as consultant
for the study. JME was a physician who served as a consultant for the study. All authors read and approved of the
final manuscript.
Acknowledgements
First and foremost, we thank the many autism families who volunteered as
participants in this research study. We thank the Wallace Foundation and
the Autism Research Institute for financial support of this study. We thank
Nellie Foster of SCNM for help with blood draws. We thank David Burk
for assistance with analyzing the CBC and ChemPanel data. We thank
Women’s International Pharmacy for assistance with compounding the
DMSA individually for each child. We thank Spectrum Chemicals for providing the DMSA. We thank Doctor’s Data and Immunosciences for providing testing at reduced cost. We thank the Autism Society of America –
Greater Phoenix Chapter and the Arizona Division of Developmental Disabilities for their help in advertising the study.
References
1. Bernard S, Enayati A, Roger H, Binstock T: Autism: a novel form
of mercury poisoning.  Med Hypotheses 2001, 56(4):462-471.
2. Bradstreet J, Geier DA, Kartzinel JJ, Adams JB, Geier MR: A CaseControl Study of Mercury Burden in Children with Autistic
Spectrum Disorders.  J Am Phys Surg 2003, 8(3):76-79.
3. Windham GC, Zhang L, Gunier  R,  Croen  LA,  Grether  JK: Autism
spectrum disorders in relation to distribution of hazardous
air pollutants in the San Francisco bay area.  Environ Health Perspect 2006, 114(9):1438-44.
4. DeSoto MC, Hitlan RT: Blood Levels of Mercury are Related to
Diagnosis of Autism: A Reanalysis of an Important Data Set.
J Child Neurology 2007, 22:1308-11.
5. Adams JB, Romdalvik J, Levine KE, Hu L-W: Mercury in First-Cut
Baby Hair of Children with Autism vs. Typically-Developing
Children.    Toxicological and Environmental Chemistry  2008,
90(4):739-753.
6. Adams JB, Baral M, Geis E, Mitchell J, Ingram J, Hensley A, Zappia I,
Newmark S, Gehn E, Rubin RA, Mitchell K, Bradstreet J, El-Dahr JM:
Safety and Efficacy of Oral DMSA Therapy for Children with
Autism Spectrum Disorders: Part A – Medical Results.  BMC
Clinical Pharmacology 2009, 9:16.
7. Adams JB, Baral M, Geis E, Mitchell J, Ingram J, Hensley A, Zappia I,
Newmark S, Gehn E, Rubin RA, Mitchell K, Bradstreet J, El-Dahr JM:
The Severity of Autism Is Partially Explained by Toxic Metal
Body Burden and Red Blood Cell Glutathione Levels.  Journal
of Toxicology 2009, 2009:.
8. Cohen IL, Schmidt-Lackner S, Romanczyk R, Sudhalter V: The PDD
Behavior Inventory: a rating scale for assessing response to
intervention in children with pervasive developmental disorder.  J Autism Dev Disord 2003, 33(1):31-45.
9. Rimland B, Edelson S: Autism Treatment Evaluation Checklist:
Statistical Analyses.  Autism Research Institute, San Diego; 2000.
10. Lord C, Rutter M, Goode S, Heemsbergen J, Jordan H, Mawhood L,
Schopler E: Autism diagnostic observation schedule: a standardized observation of communicative and social behavior.  J
Autism Dev Disord 1989, 19(2):185-212.
11. Adams JB, Holloway C: Pilot study of a moderate dose multivitamin/mineral supplement for children with autistic spectrum disorder.    J Altern Complement Med  2004,  10(6):1033-9.
Erratum in: J Altern Complement Med. 2005 Aug;11(4):749
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