Cyanide (CN) intoxication inhibits cellular oxidative metabolism and may result in brain damage. Hydroxycobalamin (OHCob) is one among other antidotes that may be used following intoxication with CN. Hyperbaric oxygen (HBO2) is recommended when supportive measures or antidotes fail. However, the effect of hydroxycobalamin or HBO2 on brain lactate and glucose concentrations during CN intoxication is unknown. We used intracerebral microdialysis to study the in vivo effect of hydroxycobalamin or HBO2 treatment on acute CN-induced deterioration in brain metabolism. Anesthetized rats were allocated to four groups receiving potassium CN (KCN) 5.4 mg/kg or vehicle intra-arterially: 1) vehicle-treated control rats; 2) KCN-poisoned rats; 3) KCN-poisoned rats receiving hydroxycobalamin (25mg); and 4) KCN-poisoned rats treated with HBO2 (284 kPa for 90 minutes). KCN alone caused a prompt increase in interstitial brain lactate and glucose concentrations peaking at 60 minutes. Both hydroxycobalamin and HBO2 abolished KCN-induced increases in brain lactate and glucose concentration. However, whereas HBO2 treatment increased cerebral PtO2 and reduced respiratory distress and cyanosis, OHCob did not have this beneficial effect. In conclusion, CN intoxication in anesthetized rats produces specific uncoupling of cerebral oxidative metabolism resulting in interstitial lactate and glucose surges that may be ameliorated by treatment with either hydroxycobalamin or HBO2.