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1984; Loots et al., 1982; Olney et al., 1981; Spector, 1972; Weller et al., 1994) suggests that folate in the form of folic acid is neurotoxic and epileptogenic in animals; however, there is no clear evidence of folate-induced neurotoxicity in humans. Concerns have been raised about the possibility of decreased effectiveness of treatment if individuals treated with anticonvulsant drugs take high doses of folate. However, the UL does not apply to drug-drug interactions or to high doses taken under medical supervision (see “Anticonvulsants” and “Methotrexate”).

General Toxicity. In one nonblinded uncontrolled trial, oral doses of 15 mg/day of folate for 1 month were associated with mental changes, sleep disturbances, and gastrointestinal effects (Hunter et al., 1970). However, studies using comparable or higher doses, longer durations, or both failed to confirm these findings (Gibberd et al., 1970; Hellstrom, 1971; Richens, 1971; Sheehy, 1973; Suarez et al., 1947).

Reproductive and Developmental Effects. Many studies have evaluated the periconceptional use of supplemental folate (in doses of approximately 0.4 to 5.0 mg) to prevent neural tube defects (Table 8-13). No adverse effects have been demonstrated, but the studies were not specifically designed to assess adverse effects. No reports were found of adverse effects attributable to folate in long-term folate supplement users or in infants born each year to mothers who take supplements, but this has not been investigated systematically. Because it is possible that subtle effects might have been missed, investigations designed to detect adverse effects are needed.

Carcinogenicity. In a large epidemiological study, positive associations were found between supplemental folate intake and the incidence of cancer of the oropharynx and hypopharynx and of total cancer (Selby et al., 1989). However, the authors of this study suggest that these associations might have been related to unmeasured confounding variables such as alcohol and smoking. Additionally, other studies suggest that folate might be anticarcinogenic (see “Cancer”) (Campbell, 1996).

Hypersensitivity. Individual cases of hypersensitivity reactions to oral and parenteral folate administration were reported (Gotz and Lauper, 1980; Mathur, 1966; Mitchell et al., 1949; Sesin and Kirschenbaum, 1979; Sparling and Abela, 1985). Such hypersensitivity is rare, but



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