Sulforaphane treatment of autism spectrum disorder (ASD)

Contributed by Paul Talalay, September 4, 2014 (sent for review August 12, 2014; reviewed by Bryan H. King, Robert K. Naviaux, and Cecilia Giulivi)
October 13, 2014
111 (43) 15550-15555
Letter
Uncommon use of common measures in sulforaphane trial
Lawrence Scahill
Letter
Reply to Scahill: Behavioral outcome measures in autism
Paul Talalay, Andrew W. Zimmerman

Significance

Autism spectrum disorder (ASD), encompassing impaired communication and social interaction, and repetitive stereotypic behavior and language, affects 1–2% of predominantly male individuals and is an enormous medical and economic problem for which there is no documented, mechanism-based treatment. In a placebo-controlled, randomized, double-blind clinical trial, daily oral administration for 18 wk of the phytochemical sulforaphane (derived from broccoli sprouts) to 29 young men with ASD substantially (and reversibly) improved behavior compared with 15 placebo recipients. Behavior was quantified by both parents/caregivers and physicians by three widely accepted measures. Sulforaphane, which showed negligible toxicity, was selected because it upregulates genes that protect aerobic cells against oxidative stress, inflammation, and DNA-damage, all of which are prominent and possibly mechanistic characteristics of ASD.

Abstract

Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medico-economic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled, double-blind, randomized trial, young men (aged 13–27) with moderate to severe ASD received the phytochemical sulforaphane (n = 29)—derived from broccoli sprout extracts—or indistinguishable placebo (n = 15). The effects on behavior of daily oral doses of sulforaphane (50–150 µmol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication (P = 0.015–0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation.

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Acknowledgments

We thank the participants and their families who were consistently interested and gave generously of their time; Scott Zeger for discussions on biostatistics; Jessica Helt and Karmen Koesterer for patient testing and Luisa Masclans for data collection; Ann Neumeyer, who chaired the Data Safety Monitoring Board and was consulted regarding safety and side effects; Jennifer Mullett for assisting with study procedures; and Christine Ferrone and Lisa Nowinski for advising us on regulatory matters and outcome measures. The quality of data collection, retrieval, and analysis were certified by Quality Associates Incorporated. The study was supported by gifts from the Nancy Lurie Marks Family Foundation, the Hussman Foundation, the Lewis B. and Dorothy Cullman Foundation, the Agnes Gund Foundation, the N of One Foundation, and the Brassica Foundation for Chemoprotection Research.

Supporting Information

Supporting Information (PDF)
Supporting Information
pnas.1416940111.sd01.xlsx

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 111 | No. 43
October 28, 2014
PubMed: 25313065

Classifications

Submission history

Published online: October 13, 2014
Published in issue: October 28, 2014

Acknowledgments

We thank the participants and their families who were consistently interested and gave generously of their time; Scott Zeger for discussions on biostatistics; Jessica Helt and Karmen Koesterer for patient testing and Luisa Masclans for data collection; Ann Neumeyer, who chaired the Data Safety Monitoring Board and was consulted regarding safety and side effects; Jennifer Mullett for assisting with study procedures; and Christine Ferrone and Lisa Nowinski for advising us on regulatory matters and outcome measures. The quality of data collection, retrieval, and analysis were certified by Quality Associates Incorporated. The study was supported by gifts from the Nancy Lurie Marks Family Foundation, the Hussman Foundation, the Lewis B. and Dorothy Cullman Foundation, the Agnes Gund Foundation, the N of One Foundation, and the Brassica Foundation for Chemoprotection Research.

Authors

Affiliations

Kanwaljit Singh
Lurie Center for Autism, Department of Pediatrics, Massachusetts General Hospital for Children, Harvard Medical School, Lexington, MA 02421;
Department of Pediatrics (Neurology), University of Massachusetts Medical School, Worcester, MA 01655;
Susan L. Connors
Lurie Center for Autism, Department of Pediatrics, Massachusetts General Hospital for Children, Harvard Medical School, Lexington, MA 02421;
Eric A. Macklin
Department of Medicine, Massachusetts General Hospital Biostatistics Center and Harvard Medical School, Boston, MA 02114; and
Kirby D. Smith
McKusick–Nathans Institute for Genetic Medicine and
Jed W. Fahey
Department of Pharmacology and Molecular Sciences, Lewis B. and Dorothy Cullman Chemoprotection Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
Paul Talalay1 [email protected]
Department of Pharmacology and Molecular Sciences, Lewis B. and Dorothy Cullman Chemoprotection Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
Andrew W. Zimmerman1 [email protected]
Lurie Center for Autism, Department of Pediatrics, Massachusetts General Hospital for Children, Harvard Medical School, Lexington, MA 02421;
Department of Pediatrics (Neurology), University of Massachusetts Medical School, Worcester, MA 01655;

Notes

1
To whom correspondence may be addressed. Email: [email protected] or [email protected].
Author contributions: K.D.S., P.T., and A.W.Z. designed research; K.S., S.L.C., and A.W.Z. performed research; J.W.F. and P.T. contributed new reagents/analytic tools; K.S., E.A.M., J.W.F., P.T., and A.W.Z. analyzed data; K.S., K.D.S., J.W.F., P.T., and A.W.Z. wrote the paper; and J.W.F. and P.T. supplied sulforaphane-rich broccoli sprout extract.
Reviewers: B.H.K., Seattle Children's Autism Center; R.K.N., University of California, San Diego; and C.G., University of Southern California.

Competing Interests

Conflict of interest statement: U.S. patent applications have been filed by The Johns Hopkins University (inventors K.D.S., P.T., and A.W.Z.). P.T. and A.W.Z. have divested themselves from all potential financial benefits. The sulforaphane-rich broccoli sprout extract is not a commercial product. Broccoli sprouts and seeds rich in glucosinolates have been licensed by Johns Hopkins to Brassica Protection Products LLC (A. Talalay, son of P.T., is chief executive officer).

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    Sulforaphane treatment of autism spectrum disorder (ASD)
    Proceedings of the National Academy of Sciences
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