A new method was developed to measure cerebrovascular permeability to poorly permeable as well as rapidly permeable substances. Pharmacokinetic principles for the central nervous system were established that demonstrate in rats that cerebrovascular permeability of nonelectrolytes and organic electrolytes is related linearly to the octanol/water partition coefficient. Synthetic opioid peptides are significantly permeable at the blood-brain barrier. Entry of blood-proteins into spinal fluid is governed by pores and vesicles at the choroid plexus. Barrier permeability can be increased by 10 to 20 fold, by infusing a hypertonic solution of arabinose or mannitol into the carotid artery of animals or man, and has been used to increase brain uptake of methotrexate (an anti-tumor agent) in humans with brain tumors, and of exogenous enzymes (for use in enzyme replacement therapy). Barrier opening is accompanied by a transient elevation of brain metabolism and uncoupling of flow from metabolism. Hypertension increases the permeability of cerebral but not retinal blood vessels, whereas hypercapnia increases permeability of retinal pigmented epithelium to fluorescein.