Results of DMSA Treatment Study
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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
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Current studyGoal: 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 enrolled65 completed phase 141 completed phase 2
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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
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Toxic Metal Excretion after DMSA – 1st & 9th dose% changes in median values (N=63)
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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
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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 RDAVanadium – 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.
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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
Change in Glutathione
-750
-500
-250
0
250
500
0 300 600 900
Initial Glutathione
Ch
an
ge
in
Glu
tath
ion
e
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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.
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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.
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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 functionWhite 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
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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
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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
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Long-term Effect of DMSA on Urinary Excretion of Toxic Metals – Changes in Median Values
Treatment Group Only (n=26)
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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.
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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 okAST (liver enzyme) -6% - all normalBUN/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 highBasophils +50%, n.s. - all normalAlkaline Phosphatase + 12%, n.s. all normal, then 5 high (growth spurt?)
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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)
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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)
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Evaluations of Autism Symptoms
Parents
• Severity of Autism Scale
• ATEC – parents
• PDD-BI
• Global Impressions
Research-certified professionals did ADOS
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Severity of Autism Scale
0-10 point scale
• 7 round group: -18% (improvement)
• 1-round group: -18% (improvement)
Significant improvement in both groups.
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ATEC Results
Scale 7 rounds 1 round
I. Speech/Language Comprehension
-21% -13%
II.Sociability -27% -25%
III. Sensory/ Cognitive Awareness
-27% -26%
IV. Health/ Physical/ Behavior
-28% -15%
ATEC Total -26% -19%
Both groups significantly improved
7 round group improved more in Language, Physical Health, and
Total ATEC, but not statistically significant
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Pervasive Developmental Disorders Behavior Inventory (PDD-BI)
Significant improvement in both groups
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Overall Impressions - ResultsBased 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
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Parent Global Impressions
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Parent Impressions- Overall
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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
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ADOS results7 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;
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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?
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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.
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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. + Social)
68% 15% 17%
PDD-BI (modified Autism Composite)
75% 2% 22%
Parent Global Impression
86% 8% 6%
Average of all 5 assessments
77% 12% 11%
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Regression Analysis – Severity of Autism
Compare severity of autism with glutathione and metal testsadjusted 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.
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Regression Analysis – ImprovementCompare improvements in severity of autism with glutathione and
metal testsadjusted 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
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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 ageATEC -.20SAS -.19PDD-BI -.12ADOS -.06
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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
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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.
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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)
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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 neededOther chelators may be needed for mercury and other metals
(arsenic, antimony).More research should be done!
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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
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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