Markedly decreased levels of energy-rich phosphates were seen in cerebral cortex after severe hypoglycemia, followed by their partial restitution during the recovery period. During hypoglycemia the nonglucose endogenous substrates were provided by glycolytic intermediates, by Krebs cycle intermediates, and by related amino acids. Other potential substrates for brain oxidation were provided by the breakdown of phospholipids and fatty acids. After a 20-min period of posthypoglycemic recovery, partial restoration of carbohydrates and amino acids occurred, although the amino acid pool size was still reduced. The alterations in phospholipids and fatty acids persisted, while there was a tendency toward normalization of the free fatty acid content. During the posthypoglycemic recovery, treatment with some specific metabolic modulators (6-aminonicotinamide, hopantenate, uridine, L-acetylcarnitine) suggested the possibility of an alternative cerebral substrate utilization owing to modulation of the cerebral biochemical machinery. Thus, increased carbohydrate utilization by hopantenate was consistent with decreased lipid breakdown, while increased carbohydrate utilization by uridine was concomitant with decreased amino acid degradation. In this way, decreased cerebral carbohydrate utilization by 6-amino-nicotinamide was associated with increased lipid and amino acid breakdown. Furthermore, the increased loss of cerebral phospholipids and phospholipid-bound fatty acids by L-acetylcarnitine occurred in the presence of a large glucose availability and was associated with an extensive reduction of cerebral glycolytic flux.