by James O’Hanlon, Ph.D., Psychopharmacologist
Those who follow research on autism spectrum disorder (ASD) were astonished by a recent article describing the beneficial effects of sulforaphane (SFN), a broccoli extract, on the behavior of young men with ASD participating in a clinical trial. Most of us became aware of the article from sensational and misleading media reports. I greeted the news with skepticism. However after reading the article and noting the qualifications of its authors, skepticism was replaced by wonder. Could this be a breakthrough? For me at least, it was time to learn about SFN.
SFN exists in all cruciferous vegetables with highest concentrations found in broccoli sprouts and seeds. SFN is not normally free in plants. Rather it is bound to glucose in an inert compound called glucoraphanin. Rupture of plant cells by insect predators or infection releases an enzyme, myrosinase, which breaks the bond between SFN and glucose. In plants, SFN acts as an insect repellent, a selective antibiotic and antifungal agent. SFN was first isolated in 1992 by a team of pharmacologists led Paul Talalay at Johns Hopkins University. They shortly recognized that its biological activity was not limited to the plants that produce it. Their initial studies, followed by an explosion of worldwide research, revealed that SFN is capable of inducing the genomic expression of protective proteins to withstand a variety of stressors. Although the effects of SFN are mediated through several metabolic pathways, each achieving a different result, that for coping with oxidative stress is best understood. Oxidative stress occurs when the concentration of certain anions (“free radicals”) exceeds the natural antioxidant system’s capacity to neutralize them. Free radicals are generated in several metabolic processes, most notably the one occurring in intracellular mitochondria that transfers the energy from nutrients to a molecule providing energy for virtually every metabolic reaction. Free radicals are highly reactive. If unchecked they oxidize cellular components causing loss of vital functions, cell degeneration and eventually cell destruction. Cell injury triggers an innate immune reaction releasing even more free radicals and promoting local inflammation. So what began as an intracellular event can expand to affect functions of an entire organ. The brain is the most vulnerable organ to oxidative stress owing to its high metabolic rate and relatively low antioxidant capacity. Yet a mechanism exists for increasing that capacity. The key element is a protein, Nrf2, which has been called the “Master Regulator of Cell Defense.” Under normal conditions Nrf2 is inert and bound to other proteins but when oxidative stress exceeds a threshold, Nrf2 is released to travel to the genome where it acts as a “transcription factor” to activate numerous genes that produce antioxidants and enzymes for neutralizing free radicals. This mechanism does not normally operate at maximal capacity and certain nutraceuticals and their synthetic analogs are known to boost its activity. Of this number none is as potent and as capable of penetrating the brain as SFN.
Unequivocal signs of oxidative stress and neuroinflammation were discovered in the majority of individuals with ASD more than 10 years ago. The discovery was made in part by neurologists working at the same university where pharmacologists were busily seeking medical indications for SFN. Leaders of these groups, Andrew Zimmerman and Paul Talalay, recognized their complimentary interests. In 2011 they joined forces for designing a placebo-controlled, double-blind, clinical trial for assessing the effects of SFN on symptoms of ASD.1 Zimmerman, who had moved to the University of Massachusetts, was responsible for conducting the trial and Talalay for providing pharmaceutical-grade SNF. Participants were young men, aged 13-27y, with moderate-severe ASD. Twenty-nine received SFN and 15 received placebo for 18 weeks. Their behavior was systematically rated by parents/caregivers using two scales. One, the Aberrant Behavior Checklist (ABC), has become the standard instrument for measuring untoward behavioral symptoms of ASD. The other, Social Responsiveness Scale (SRS) is less widely used but uniquely sensitive to one of the core symptoms of ASD; i.e., deficient social/emotional reciprocity. Additionally, clinicians rated the changes in many of the same symptoms from the beginning to the end of the trial. The results were dramatic. The SFN group’s average improvement on the ABC was 10 times larger than that shown by the placebo group (confirmed by clinicians’ ratings). The SFN group’s average improvement on the SRS was likewise 10 times that of the placebo group’s (also confirmed by clinicians’ ratings). This is not to say that everyone’s responded to SFN in the same manner. Most members of the SFN group did improve but the behavior of a substantial minority either did not change or actually worsened. Still, the demonstration that SFN can globally improve the symptoms of a subset of individuals with ASD was unprecedented.
Developments that followed publication of this study were also unprecedented. Within a month, two major clinical trials with SFN involving individuals with ASD were commissioned by Governmental agencies. The first will be conducted at Rutgers University to completely replicate the original suforaphane trial with a new group of participants. The second allows continuation of Zimmerman and Talalay’s research. Similar methods will be used at the University of Massachusetts for measuring the effects of SFN in children with ASD, aged 3-12y. Additionally, tests will be applied for defining the biological basis for any improvement in the children’s behavior and mental functions. The former is scheduled for completion in 2022 and the latter in 2019. The results of these studies and others undertaken in the interim may show SFN to be the first effective treatment for core symptoms of ASD. They may also show that this hope was unjustified.
SFN used in research is not commercially available. Consuming commercial broccoli extracts or the plant as sold in markets would not be expected to achieve any beneficial effects.
1 Singh K, Conners SL, Macklin EA, et al. Sulforaphane Treatment of Autism Spectrum Disorder (ASD). Proceedings of the National Academy of Science USA 2014; 111: 15550-5