Brain uptake of radiolabeled D and L-lactate, D-glucose and nicotine, as measured by the intra-carotid bolus method, was examined over a range of pH of the injected solution. The uptake of L-lactate was highest at pH 6.1, and lowered significantly at pH 7.2, 7.5 and 8.4. In contrast, the uptake of the D-enantiomer was not as dramatically affected. Glucose uptake was not affected by alterations in pH. Nicotine uptake decreased with pH reduction through a range of 8.3-4.2. These data suggest that it is the uncharged molecule which penetrates the blood-brain barrier by both carrier and lipid mediation. A mechanism relating to these observations is postulated and possible relevance to lactate washout from ischemic brain discussed.