Drugs and Nutrients in Epilepsy: Vitamin B6 and the Ketogenic Diet

Abstract

Certain foods and specific drugs have been linked to epilepsy in the literature. Here, we query PubMed citations for the co-occurrence of epilepsy with foods and drugs, using a list of 217,776 molecules from the HMDB. Notably, the top associations with epilepsy include approved drugs and drug families, diagnostic markers, inducers, and vitamins. Drugs include fosphenytoin (40%), topiramate (37%), valproic acid (34%), hydantoin (20%), phenytoin (31%), carbamazepine (33%), carbamazepine-10,11-epoxide (40%), trimethadione (31%), gabapentin (14%), pregabalin (11%), flunarizine (7%), fenfluramine (4%), bumetanide (4%), KBr (18%), cannabidiol (14%), clonazepam (22%), nitrazepam (10%), diazepam (7%), lorazepam (6%), midazolam (3%), amobarbital (21%), phenobarbital (16%), flumazenil (7%) allopregnanolone (7%), pregnanolone (6%), epipregnanolone (6%), 3-hydroxypregnan-20-one (6%), and vitamin B6 (6%). Drug families and scaffolds include imidazolidine (18%), succinimide (10%), acetamide (7%), 2-pyrrolidinone (7%), pyrrolidine (6%), tetrahydropyridine (6%), and isoxazole (4%). Investigational compounds include cyano-7-nitroquinoxaline-2,3-dione (5%). Diagnostic markers include exametazime (10%) and quinolinic acid (3%). Inducers include flurothyl (37%), pentetrazol (32%), pilocarpine (25%), (+)-Bicuculline (8%), and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP, 6%). Our analysis highlights frequently cited associations between epilepsy and specific drugs and highlights the importance of supplementing nutrients with vitamin B6 and the ketogenic diet, which increases the gamma-aminobutyric acid (GABA)/glutamate ratio. As such, our study offers dietary approaches in the treatment of this neurodegenerative disease.

Keywords: epilepsy; ketogenic diet; nutrients; vitamin B6; vitamins.

Figure 1

Foods and drugs associated with epilepsy. Shown are the top normalized associations (percent value, red line) and co-citations (arbitrary units, pink bars) with epilepsy according to PubMed. Associations are not indicative of causation, and do not reflect whether correlation is positive or negative.

Figure 2

GABA shunt pathway. The gamma-aminobutyric acid (GABA) shunt pathway (right) connects to the citric acid cycle (left). Enzyme names are in red, substrate names are in black, and cofactor (i.e., vitamin B6) names are in green. Note that molecular intermediates that are dysregulated in epilepsy, namely glutamate, GABA, pyrrolidinone, and vitamin B6, are highlighted in yellow. In epilepsy, GABA, pyrrolidodinone, and vitamin B6 levels are low, while glutamate levels are high.