Clinicians have long desired the ability to introduce either exogenous or endogenous neuropeptides directly into the brain in order to alter brain chemistry, but have been thwarted by the blood–brain barrier (BBB). The BBB blocks the introduction of most peptides and proteins into the brain. Glycosylation can be employed as an effective and practical strategy that allows the sys-temic use of neuropeptides in vivo. A series of glycopeptides based on the Leu-enkephalin analogue YtGFS*-CONH 2 led to greatly enhanced stability in vivo and effective penetration of the BBB. Transport through the BBB hinges on the biousian nature of the glycopeptides. That is, the amphipathic glycopeptides possess two conflicting solubility states; one state that is completely water soluble, and another at water-membrane phase boundaries. Multiple lines of evidence suggest that the BBB transport is absorptive endocytosis. Several Leu-enkephalin analogues studied showed antinociceptive potencies greater than morphine. Moreover, these d-selective glycopeptides lacked many of the l-opioid side effects generally associated with classical opiate analgesics. The biousian design was extended to much larger glycopeptides (16–17 residues) related to b-endorphin, which also penetrated the BBB and pro-duced antinociception in mice. Plasmon-waveguide resonance (PWR) studies showed that the amphipathic helices bound to mem-brane bilayers with micromolar to low nanomolar K D Õs. The presence of diverse endogenous neuropeptide transmitters and neuromodulators in the human brain is potentially applicable to the treatment of a wide range of behavioral disorders.