There is increasing evidence supporting dietary and alternative therapies for epilepsy, including the ketogenic diet, modified Atkins diet, and omega-3 fatty acids. Vitamin D is actively under investigation as a potential intervention for epilepsy. Vitamin D is fat soluble steroid which shows promise in animal models of epilepsy. Basic research has shed light on the possible mechanisms by which Vitamin D may reduce seizures, and animal data support the efficacy of Vitamin D in rat and mouse models of epilepsy. Very little clinical data exists to support the treatment of human epilepsy with Vitamin D, but positive findings from preliminary clinical trials warrant larger Phase I and II clinical trials in order to more rigorously determine the potential therapeutic value of Vitamin D as a treatment for human epilepsy.
Epilepsy affects approximately two million Americans and 65 million people worldwide (1). Among those with epilepsy, 22–30% have drug-resistant epilepsy (DRE) (1, 2). DRE causes cognitive and mood impairment, injuries, and increased risk of death including sudden death in epilepsy (SUDEP) (1–3). Antiepileptic drugs (AEDs) are the primary medical treatment for epilepsy. However, even for those whose seizures are well controlled by AEDs, allergies, neurological and systemic toxicity, depression, memory loss, and osteoporosis are common problems (4, 5). Because of the limitations and potential toxicity of existing AEDs, there is significant clinical interest in finding alternative therapies for epilepsy.
In the search for alternative epilepsy treatments, Vitamin D3 is an intriguing candidate (6). As early as 1974, Christiansen postulated that supplementation of Vitamin D might improve calcium and magnesium levels and may decrease hyperexcitability in patients with epilepsy. In the four decades since, progress has been made in understanding the biochemical and cellular mechanisms of Vitamin D3’s anticonvulsant properties. Animal data have supported the anticonvulsant effects of Vitamin D3 in mice and rats (7–11). Existing evidence for the use of Vitamin D3 in treating human epilepsy is very limited (6, 12). There is a critical need for larger clinical trials to establish the safety and efficacy of vitamin D3 in epilepsy. In this review, we will critically analyze the animal and human evidence to date supporting the use of Vitamin D3 as a treatment for epilepsy.
Vitamin D3 Overview: Biochemistry and Role in Human Health
The most biologically active form of Vitamin D in humans is Vitamin D3 (cholecalciferol), which is a fat-soluble steroid hormone (13). Dietary sources of Vitamin D3 include dairy, meat, fish, and mushrooms (14). The primary source of Vitamin D3 is exposure of the skin to ultraviolet sunlight (14). The metabolic pathway of Vitamin D3 is summarized in Figure 1. 7-dehydrocholesterol is converted to Vitamin D3 in the skin after exposure to sunlight. Vitamin D3 is converted to 25-hydroxy-cholecalciferol (25-OH Vitamin D3) in the liver. 25-OH Vitamin D3 is the major circulating form of Vitamin D, but it itself is biologically inactive and must be converted to the active form 1,25-dihydroxy-Vitamin D3 (1,25 Vitamin D3) in the kidneys (13–15). Vitamin D3 is important for calcium metabolism, bone health, cardiac function, and blood pressure maintenance, among other health benefits (14, 16, 17). Vitamin D3 deficiency is a marker of poor health and overall mortality (16). However, 40–50% of Americans have insufficient Vitamin D3 levels, and insufficiency is even more prevalent in underserved populations, including Hispanics (69%) and African Americans (82%) (18).