Singh K, Connors SL, Macklin EA, et al. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci U S A. 2014;111(43):15550-15555.
Placebo-controlled, double-blind, randomized trial. Participants were given 50-150 μmol of sulforaphane derived from broccoli sprouts per day by mouth. Dosage of sulforaphane was dependent on body weight: 50 μmol (1 capsule) for participants 100 lb and less; 100 μmol (2 capsules) for participants between 101 lb and 199 lb; and 150 μmol (3 capsules) for participants over 200 lb. The placebo group received capsules without any medication for the same dosing regimen and duration. The duration of treatment was 18 weeks followed by 4 weeks without treatment.
Forty-three males aged 13 to 27 years with moderate to severe autism began the trial. By the end of the trial, the treatment group had 26 participants and the placebo group 14.
Follow-up evaluations included the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). The results were compared to baseline assessments gathered before treatment.
Participants receiving sulforaphane showed significant improvement upon evaluation with ABC, SRS, and CGI-I assessments vs baseline. Significantly greater improvement was shown among participants in the treatment group at 4, 10, and 18 weeks for irritability, lethargy, stereotypy, and hyperactivity subscales of the ABC and in awareness, communication, motivation, and mannerism subscales of the SRS. Of those in the treatment group, 35% showed these improvements on the SRS vs 0% in the placebo group, and 60% of the treatment group showed improvements on the ABC vs 20% in the placebo group. CGI-I analysis of scores at 18 weeks in the treatment group were much or very much improved in 46% (12 of 26), 54% (14 of 26), and 42% (11 of 26) of the participants on social interaction, aberrant behavior, and verbal communication, respectively, compared to 0% (0 of 11; P=.007), 9% (1 of 11; P=.014), and 0% (0 of 11; P=.015) for those in the placebo group. After discontinuation of sulforaphane treatment, all scales reverted back to baseline levels.
The treatment of autistic children can often be a challenging experience for both the parents and the practitioner. With the prevalence of autism in the United States reaching 1 in 68 children—a 30% increase from 2 years ago1 and up 78% in the last decade2—the demand for effective therapies is at an all-time high. Currently the only US Food and Drug Administration–approved treatments for the symptoms of autism are risperidone and aripiprazole,3 which both have several adverse effects including but not limited to weight gain, aggressive behavior, insomnia, seizures, suicidal ideation, tardive dyskinesia, and anxiety.4,5 Ironically, these are symptoms that can appear in children with autism, so taking these medications may significantly magnify symptoms that already exist in autistic children.
Sulforaphane serves several functions that address significant biochemical aberrations routinely found in the autistic population, mostly by upregulating genes that protect the body from oxidative stress and those that control inflammation. Due to its global effects as an antioxidative and antiinflammatory compound, it has been studied for years as an adjunctive treatment for inflammatory conditions including cancerous processes. The same properties that have been well defined in cancer research also make it an attractive consideration for children on the autistic spectrum. Similar cellular aberrations such as mitochondrial dysfunction,6,7 neurological inflammation,8,9 oxidative stress,10 low levels of reduced glutathione,11 and increased lipid peroxidation12 occur at higher rates in autistics compared to controls, and sulforaphane is emerging as a treatment to address those problems.
Another theory as to why sulforaphane may be benefitting these children is activation of the heat shock response.13 This includes upregulation of heat shock proteins in the brain, which are thought to improve communication between synapses during a fever.14 This is intriguing, since autistics have shown behavioral improvement during fever.15,16 This means that, at least theoretically, suppressing fever in children with autism may not be in their long-term best interest. It is also important to note there is ample evidence that suppressing fever increases morbidity and mortality.17 In regard to the current study under review, the majority (80%) of the participants had a history of positive response to fever. This is higher than the observed rate of “fever responders” in the autistic population of 35%.18 If heat shock is indeed the mechanism of sulforaphane’s effect, this study has a skewed cohort with overrepresentation of those deriving benefit from its use. Future autism research that compares results of sulforaphane administration in fever responders to fever nonresponders may reveal a reliable predictor of success with this treatment.
Sulforaphane serves several functions that address significant biochemical aberrations routinely found in the autistic population, mostly by upregulating genes that protect the body from oxidative stress and those that control inflammation.
Adverse effects observed in the treatment group included weight gain and seizures. Some autistic children may have increased intestinal permeability,19 possibly as a result of gastrointestinal (GI) inflammation. Considering that sulforaphane could have an antiinflammatory effect, weight gain may be a result of improved nutrient absorption from the GI tract and/or improving appetite by decreasing abdominal discomfort. Two participants experienced seizures during the study period. One seizure occurred during the treatment period, and the other occurred several weeks after discontinuing treatment. Both participants had a history of seizures. This may not be a significant concern, since patients with autism are at an already 3-fold to 22-fold increased risk of seizure,20 so the seizures seen in this trial were likely not caused by sulforaphane.
Clearly, more research in the autistic population is needed for sulforaphane, specifically utilizing reliable biomarkers for inflammation and oxidation that have been established in past research.21 This study only addressed autism symptoms, and while it still provides insight on the potential of sulforaphane, having biomarker data to explain its effectiveness can only add to the body of knowledge that exists on natural and alternative therapies for autism.
Editor’s note: The product used in this study is not currently sold. The researchers used a broccoli sprout extract that underwent further treatment with myrosinase enzymes obtained from daikon radish. It contained more sulforaphane than the sulforaphane glucosinolate (SGS) products currently on the market.
- Autism and Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators.Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years—Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2010. MMWR Morb Mortal Wkly Rep. 2014;63(2):1-24.
- Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators. Prevalence of Autism Spectrum Disorders—Autism and Developmental Disabilities Monitoring Network, 14 Sites, United States, 2008. MMWR Morb Mortal Wkly Rep. 2012;61(3):1-24.
- US Food and Drug Administration. Beware of False or Misleading Claims for Treating Autism. Available at: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm394757.htm. Accessed November 21, 2014.
- WebMD. Ablify: side effects. Available at: http://www.webmd.com/drugs/2/drug-64439/abilify-oral/details/list-sideeffects. Accessed November 21, 2014.
- WebMD. Drugs and medications: risperidone. Available at: http://www.webmd.com/drugs/2/drug-6283-2034/risperidone-oral/risperidone-oral/details#side-effects. Accessed November 21, 2014.
- Oliveira G, Ataíde A, Marques C, et al. Epidemiology of autism spectrum disorder in Portugal: prevalence, clinical characterization, and medical conditions. Dev Med Child Neurol. 2007;49(10):726-733.
- Cassells C. Mitochondrial dysfunction may play a role in autism spectrum disorders etiology. Medscape Medical News. April 15, 2008. Available at: http://www.medscape.com/viewarticle/573004. Accessed December 1, 2014.
- Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):67-81.
- Connolly AM, Chez MG, Pestronk A, Arnold ST, Mehta S, Deuel RK. Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J Pediatr. 1999;134(5):607-613.
- Rose S, Frye RE, Slattery J, et al. Oxidative stress induces mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines in a well-matched case control cohort. PLoS One. 2014;9(1):e85436.
- James SJ, Melnyk S, Jernigan S, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet. 2006;141B(8):947-956.
- Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC. Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids. 2005;73(5):379-384.
- Gan N, Wu YC, Brunet M, et al. Sulforaphane activates heat shock response and enhances proteasome activity through up-regulation of Hsp27. J Biol Chem. 2010;285(46):35528-35536.
- Stetler RA, Gan Y, Zhang W, et al. Heat shock proteins: cellular and molecular mechanisms in the central nervous system. Prog Neurobiol. 2010;92(2):184-211.
- Mehler MF, Purpura DP. Autism, fever, epigenetics and the locus coeruleus. Brain Res Rev. 2009;59(2):388-392.
- Curran LK, Newschaffer CJ, Lee LC, et al. Behaviors associated with fever in children with autism spectrum disorders. Pediatrics. 2007;120(6):e1386-e1392.
- Bryant RE, Hood AF, Hood, CE, Koenig MG. Factors affecting mortality of gram-negative rod bacteremia. Arch Intern Med. 1971;127(1):120-1281.
- Moorman D. Workshop report: fever and autism. Available at: http://sfari.org/news-and-opinion/workshop-reports/2010/workshop-report-fever-and-autism. Accessed November 21, 2014.
- D’Eufemia P, Celli M, Finocchiaro R, et al. Abnormal intestinal permeability in children with autism. Acta Paediatr. 1996;85(9):1076-1079.
- Volkmar FR, Nelson DS. Seizure disorders in autism. J Am Acad Child Adolesc Psychiatry. 1990;29(1):127-129.
- Bradstreet JJ, Smith S, Baral M, Rossignol DA. Biomarker-guided interventions of clinically relevant conditions associated with autism spectrum disorders and attention deficit hyperactivity disorder. Altern Med Rev. 2010;15(1):15-32.