Unintended consequences of inhibiting dihydrofolate reductase through folic acid supplementation: inattentive-type attention deficit hyperactivity disorder and ASD connections

Sir, In ‘‘Voluntary fortification of breakfast cereals with folic acid: contribution to dietary intake in Australia,’’ (Japar et al. 2016) the authors call for exploration of the potential detrimental effects of voluntary folic acid fortification of food in light of the large doses young children (ages 2–3) are receiving in breakfast cereal. This is a timely call, for recent research gives reason to suspect connections between folic acid – a substance that hardly existed in human bodies or diets before the mid-twentieth century – and increased prevalence of inattentive-type attention deficit hyperactivity disorder (ADHD-I) and autism spectrum disorders (ASD). These possible links stem from folic acid’s inhibition of the enzyme dihydrofolate reductase (DHFR), a chemotherapy target which is essential to folate-mediated one-carbon metabolism in that it catalyzes the conversion of dihydrofolate (DHF) to tetrahydrofolate (THF). Why do sufferers of post-chemotherapy cognitive impairment often have the same symptoms as those with ADHD-I? A clue comes from the discovery that DHFR, which is required to reduce folic acid to usable folate, has a crucial, non-folate-related role in converting 7,8-dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4) (Crabtree et al. 2009). The inhibition of DHFR causes both (1) a decrease in BH4, which is an essential element of the biosynthesis of dopamine and other important neurotransmitters, and (2) a decrease in the BH4:BH2 ratio, which increases endothelial nitric oxide synthase (eNOS) uncoupling and reduces the production of nitric oxide (NO). These latter effects are even greater when levels of BH4 are initially low (Crabtree et al. 2011). Dopamine and NO play critical roles in learning and executive functions that are impaired in individuals with ADHD-I and are being examined as possible contributors in its pathogenesis (Volkow et al. 2011; Gao & Heldt 2015). The common chemotherapy drug methotrexate inhibits DHFR almost completely; folic acid also inhibits DHFR to a lesser but significant degree. DHFR activity is already very low and variable in humans and should not be casually inhibited (Bailey & Ayling 2009). Yet residents of the United States, where there is both mandatory and much voluntary fortification of food with folic acid, exhibit a high level of folic acid saturation with studies finding unmetabolized folic acid in up to 95% of study participants (Pfeiffer et al. 2015). This unmetabolized folic acid easily moves through the choroid plexus into the brain via folate receptor alpha, which has a higher affinity for folic acid than for reduced folate (Kelemen 2006). The United States has coincidentally experienced dramatic increases in its ADHD burden (Visser et al. 2014) during the past 18 years since it mandated folic acid fortification of enriched grain products. Research should be undertaken to examine whether folic acid negatively impacts NO and attention-related neurotransmitters in the brain in such a way as to induce ADHD-I symptoms. In the meantime, it seems prudent to consider the use of levomefolic acid or folinic acid – forms of folate that do not inhibit DHFR activity – in place of folic acid. Moreover, ASD prevalence has also risen roughly in step with folic acid fortification and supplementation initiatives (Rogers 2008). Due to folic acid’s known ability to inhibit DHFR’s recycling of DHF to THF, more DHF remains available to bind to the enzyme methylenetetrahydrofolate reductase (MTHFR) and so inhibits MTHFR in turn (Matthews & Daubner 1982). Folic acid appears to have the recently-uncovered effect of inducing pseudoMTHFR deficiencies when given in high doses to mice (Christensen et al. 2015). ASD has repeatedly been found connected to folate in ways that are as of yet unclear (DeVilbiss et al. 2015), and MTHFR gene polymorphisms are associated with increased ASD risk (Pu et al. 2013). There is a promising field for more research investigating whether excessive folic acid supplementation and food fortification have inadvertently contributed to a rise in ASD. This is not as controversial a hypothesis as it might sound, for some recent studies support it (Barua et al. 2015; Barua et al. 2016; Bloomberg School of Public Health 2016).