Results of DMSA Treatment Study

James Adams, Liz Geis, Matthew Baral, Jessica

Mitchell, Julie Ingram, Andrea Hensley,
Sanford Newmark, Eva Gehn, Bob Rubin,
Warren Tripp, Ken Mitchell, Jeff Bradstreet,
Jane El-Dahr

Southwest College of Naturopathic Medicine

Funded by Wallace Foundation and

Autism Research Institute
 Current study
Goal: Determine if DMSA/glutathione therapy helps
children with autism.
Phase 1: 9 doses of DMSA over 3 days, 10 mg/kg-
dose; collect urine at baseline, after 1st dose, and
after 9th dose; daily doses of “glutathione”
- if high toxic metal excretion, continue to phase 2
Phase 2: 3 month, double-blind, 1 round-controlled
treatment study;
3 days on DMSA, 11 days off; repeat 6x
82 children enrolled
65 completed phase 1
41 completed phase 2
 Phase 1
• Started with 82 participants
• 1 did not qualify due to elevated liver enzymes
• 4 stopped after physical exam
• 11 stopped after initial blood draw (2 could not
collect baseline urine)
• 1 collected urine after DMSA but did not send to
lab (busy family)
• 65 collected urine after DMSA and sent to lab for
testing
Toxic Metal Excretion after DMSA – 1st & 9th dose
% changes in median values (N=63)
 Loss of essential minerals
Potassium:
1st dose – lost 27% of RDA;
9th dose: lost 12% of RDA;
So 1st day probably lost about 75% of RDA, 2nd day about 55% of
RDA, and 3rd day about 40% of RDA; p<.0000000001
Equivalent to loss of about 7 bananas worth of potassium over 3 days
However, blood levels normal when tested 3-4 weeks later, so no
long-term effect

Chromium: 1st dose – lose 45% of RDA; 9th dose – lose 15% of
RDA; p=0.0005; so, several days of DMSA results in several days
loss of chromium
 Loss of essential minerals (cont.)
Molybdenum – decreased excretion by 6% on 1st day, 30% on 9th dose.
Probably not a concern.
Sodium: 1st dose – increased excretion of 30%, normal by 9th dose; not a
concern
Copper and Zinc: Increased excretion, but less than 1% of RDA
Vanadium – small loss (about 1/3 of daily intake)
Little change: calcium, phosphorus, magnesium, sulfur, selenium

Conclusion: DMSA causes some loss of potassium and chromium, small

loss of vanadium; excretion of other minerals is unimportant
Recommendation: when using DMSA, eat extra fruits/vegetables for
potassium (cannot supplement it), and supplement chromium and
possibly vanadium.
 Change in Glutathione

500
250
Glutathione
Change in

0
-250 0 300 600 900
-500
-750
Initial Glutathione

Initial Glut: 31-1033 - many lower/higher than adult RR of 427-714

Final Glutathione: 355-695 - almost all within reference range
For low RBC glutathione, DMSA greatly increased values to normal
For high RBC glutathione, DMSA reduced values towards normal
 Why are some RBC Glutathione
unusually low and high?
Initial glutathione correlates with Pb-9 (.25), Sb-
b (0.26), Cd-9 (0.30), Al-9 (0.29), and
inversely correlates with Hg-9 (-.27).
Hypothesis: body responds to Pb, Sb, Cd, Al by
making more glutathione. But, mercury
blocks production of glutathione, and
decreases it.
 Why does 1 round of DMSA
normalize glutathione?
• Change in glutathione correlates with Hg-9
(0.31), and inversely correlates with W-9
(-0.45) and Cd-9 (-0.47).

• So, removing some mercury increases low

glutathione, and removing tungsten and
cadmium reduces high glutathione.
 Changes in Blood Chemistry after 1 round of DMSA
(measured 3-6 weeks later, n=41)
Major Tests – no major problems, possible improvement of kidney function
White Blood Cell -3%
Platelet Count -6%, p=0.02 (12/42 high, 1 low; then 6/42 high, 0 low)
Lymphocytes -4%
Potassium +1%
ALT (liver enzyme) +4%
AST (liver enzyme) 0%
BUN/creatinine -6%, n.s. (17/42 high, 0 low, then 14/42 high, 1/42 low)
Creatinine -2% (0 high, 8/42 low, then 0 high, 9/42 low)
Other changes (none were statistically significant)
Basophils +24%
Bilirubin -15%, n.s.

Suggests no major safety concerns for 1 round;

Platelet levels improve (less inflammation);
BUN/creatinine often high, since creatinine low, BUN high
 Transition to Phase 2
• 8 children not allowed to continue due to low excretion of
toxic metals
• 1 child not allowed to continue due to extremely high lead
• 1 family left on extended travel
• 1 family wanted to try other treatments
• 1 child discontinued due to extended use of antibiotics due
to urinary tract infections
• 1 family too busy/overwhelmed
• 1 child had extreme anxiety over blood draws
• 1 wanted to start private treatment (avoid risk of placebo)
• 1 had mild adverse reactions (lethargy, increased appetite)

49 continued to Phase 2
 Phase 2 : Randomized, double-blind,
placebo-controlled

• 2 dropped due to family reasons (parents busy, parent died)

• 2 dropped due to lack of improvement
• 4 dropped due to behavior problems
– Mild – slept very little, but not tired (on DMSA)
– Moderate – behavior worsened, more stimming – (on placebo)
– Moderate – behavior worsening, regressing – (on placebo)
– ???? – parents reported gain and lose skills, similar pattern for 2 years
prior to study, but ADOS scores improved (on DMSA)

• 41 finished full study, including 4 in treatment group who

finished early due to low excretion after 3rd round
Long-term Effect of DMSA on Urinary Excretion of
Toxic Metals – Changes in Median Values
Treatment Group Only (n=26)
 Summary of long-term metal excretion

• For 5 children, DMSA treatment resulted in

substantial decrease in excretion of lead, so they
were only treated for 3-4 rounds
• For most of the children receiving DMSA (19),
lead excretion continued at a high level.
• Moderate excretion of mercury, tin, thallium.
• Al excretion initially decreased, then increased.
Changes in Blood Chemistry after 7 rounds of DMSA n=21
No major problems; platelets improved; kidney function
remains abnormal
Platelets -18%, p=0.05
(initially 10 high, 1 low to 4 high, 0 low – improved!)

White Blood Cell -7% n.s. (initially 1 high, 0 low; then 1 high, 1
low)
Lymphocytes 0%
Potassium +0%
ALT (liver enzyme) +3% - initially 1 high, then all ok
AST (liver enzyme) -6% - all normal
BUN/creatinine (kidney) +8% - initially 10 high, then 9 high, 1 low
Statistically Significant changes:
Triglycerides: +47%, p=0.06 (trend) - initially zero high, then 2 high
Other changes (not significant):
Eosinophils: -19%, p=0.08 3 high, then 2 high
Basophils +50%, n.s. - all normal
 Changes in blood chemistry after 1
round DMSA, 7 rounds placebo
Platelets: -13%, p=0.01 initially 1 high, then all normal;
measured 3-4 months after treatment, so effects are long-
lasting

Similar to 7 dose case (-18%)

Nothing else significant (no long-term effects; safe)

 Regression analysis of Platelets
Change in platelet level could be partially
explained (adjusted R2=0.41, p=0.02) with
major factors being excretion of Thallium
(p=0.002), Arsenic (p=0.01), Cadmium
(p=0.03), and change in glutathione
(p=0.04)
Evaluations of Autism Symptoms
Parents
• Severity of Autism Scale
• ATEC – parents
• PDD-BI
• Global Impressions

Research-certified professionals did ADOS

 Severity of Autism Scale
0-10 point scale
• 7 round group: -18% (improvement)
• 1-round group: -18% (improvement)

Significant improvement in both groups.

 ATEC Results
Scale 7 rounds 1 round

I. Speech/Language -21% -13%

Comprehension
II.Sociability -27% -25%

III. Sensory/ Cognitive -27% -26%

Awareness
IV. Health/ Physical/ -28% -15%
Behavior
ATEC Total -26% -19%

Both groups significantly improved

7 round group improved more in Language, Physical Health, and
Total ATEC, but not statistically significant
Pervasive Developmental Disorders Behavior Inventory (PDD-BI)

Significant improvement in both groups

 Overall Impressions - Results
Based on parent evaluations on final day of study

7 point scale
3=much better
2=better
1=slightly better
0=same
-1=slightly worse
-2=worse
-3=much worse
Parent Global Impressions
Parent Impressions- Overall
 ADOS exam
• Autism Diagnostic Observation Schedule
• Based on 1-hour standardized interaction
with child by ADOS-certified professional
• One of the “gold standards” for evaluating
severity of autism
 ADOS results
7 rounds 1 round
Communication -9% -11%
Social Interaction -10% -2%
Play/Creativity -5% 0%
SBRI (stereotyped behavior and restricted
interests) -9% -2%

ADOS less sensitive than other instruments (developed

to diagnose autism, not monitor changes).
Overall, 7-round group improved slightly more, but not
significant difference;
Summary of Autism Evaluations
Significant improvements on all scales for both groups

7 dose group had slightly better improvements on ATEC and

ADOS, but not statistically significant
Similar improvements in PDD-BI, SAS, Global Impressions

Since most kids still excreting high amounts of lead after 7

rounds, suggests longer treatment needed to reduce lead
excretion.
Question: would longer treatments result in more behavioral
improvements?
 Why little difference between
7 rounds and 1 round?
Hypothesis 1: DMSA ineffective on autism symptoms
(placebo effect).

Hypothesis 2: 1st round of DMSA normalized

glutathione and improved platelet levels, so that
further treatment had little additional effect.

Correlations of behavioral improvement with

biochemical changes suggest hypothesis 2 is correct.
 Overall change in autism severity, including
both 7-round and 1-round groups

% Improved % No Change % Worsened

ATEC 96% 2% 2%
SAS 61% 33% 6%
ADOS (Comm. + 68% 15% 17%
Social)
PDD-BI 75% 2% 22%
(modified Autism
Composite)
Parent Global 86% 8% 6%
Impression
Average of all 5 77% 12% 11%
assessments
Regression Analysis – Severity of Autism
Compare severity of autism with glutathione and metal tests
adjusted R2 Most significant metals
• ATEC: 0.22 p=0.003 Pb-9, Sb-b
• SAS: 0.36 p=0.002 Pb-b
• PDD-BI: 0.25 p= 0.004 Sb-9, W-b, Sn-9
• ADOS: 0.49 p=0.0003 Hg-b, Al-b, Hg-9

All four scales of autism severity can be partially explained in

terms of heavy metal excretion, with a very high statistical
significance.

Suggests 22-49% of autism severity appears to be due to toxic

metals, especially lead, antimony, and mercury.
 Regression Analysis – Improvement
Compare improvements in severity of autism with glutathione and
metal tests
adjusted R2 Most significant metals
• ATEC: 0.44 p=0.006 Hg-9, As-9
• SAS: 0.57 p=0.002 Tl-9, Pb-9, glut change
• PDD-BI: 0.75 p=0.0006 Tl-9, As-9, glut change, Pb-9,
Sb-9
• ADOS: 0.28 p=0.02 As-9, Al-9

Changes in all four scales can be partially explained (28-75%) in

terms of urinary excretion of metals
Arsenic, thallium, lead, and change in glutathione are most important

When glutathione increases, symptoms generally decrease.

When metal excretion increases, symptoms generally decrease
 Effect of Age on Improvement
Slight negative correlation suggests that older
children possibly tended to improve slightly
more than younger children (not significant)

Test Correlation with age

ATEC -.20
SAS -.19
PDD-BI -.12
ADOS -.06
 Conclusions - benefits
• DMSA greatly increases excretion of lead, and
some increase in excretion of tin, mercury,
thallium.
• 1 round of DMSA dramatically normalized
glutathione levels for at least 1-2 months, and
helped normalize platelet levels (marker of
inflammation) for at least 4 months
 Conclusions - safety
• DMSA increases excretion of potassium and
chromium; suggests need for more vegetables/fruit
and modest chromium supplementation during
chelation
• DMSA had little effect on other essential minerals
• DMSA had no adverse effect on liver enzymes,
kidney function, or complete blood count (CBC)
• DMSA possibly raised triglycerides – concern to
watch for
• Check cysteine levels, since 90% of DMSA is
excreted bound to 1-2 cysteine.
 Conclusions – Effect on Symptoms
• Both groups had significant improvements on
autism scores
• 7-round group had slightly more improvements on
ATEC and ADOS, but not significant
• More improvement in those with low glutathione
and high initial metal excretion – strong
correlations and regression analysis strongly
suggest that improvement is real (not just placebo
effect)
 Bottom Line
Toxic metals (especially lead, antimony, and mercury)
account for 22-49% of autism severity.
DMSA is a safe way to remove toxic metals, normalize
glutathione, normalize platelets/inflammation
Correlation of improvement in autistic symptoms with
glutathione and metal excretion suggests DMSA did result
in reduction of some symptoms of autism.
Longer treatment needed by most children to decrease lead
levels – unknown if longer treatment might provide
additional behavior benefit.
Double-blind, placebo-controlled study of DMSA needed
Other chelators may be needed for mercury and other metals
(arsenic, antimony).
More research should be done!
 Questions
• Will longer treatment with DMSA result in more
benefit?
– Probably, but need to study

• How to test for and remove antimony?

– DMPS, somewhat Ca-EDTA

• How to test for and remove mercury?

– DMPS challenge, urinary porphyrins, other
 Acknowledgements
• Many children and parents who participated
in the study
• ARI and Wallace Foundation for funding
• Doctor’s Data for urine testing
• Immunosciences for RBC glutathione and
immune testing