lowest dose of the patch method of delivery, 6 mg/24 hours, does not require any dietary restrictions. Higher doses of the patch and oral formulations, whether in combination with the older non-selective MAOIs or in combination with the reversible MAO-A inhibitor moclobemide, require a low-tyramine diet. Pharmacology Pharmacodynamics Selegiline is a selective inhibitor of MAO-B, irreversibly inhibiting it by binding to it covalently. It is generally believed to exert its effects by blocking the breakdown of dopamine, thus increasing its activity; however, recent evidence suggests that MAO-A is solely or almost entirely responsible for the metabolism of dopamine. Its possible neuroprotective properties may be due to protecting nearby neurons from the free oxygen radicals that are released by MAO-B activity. At higher doses, selegiline loses its selectivity for MAO-B and inhibits MAO-A as well. Selegiline potentiates the release of catecholamines independent of its MAO-B inhibiting action. As such, it has been called the "first synthetic catecholaminergic activity enhancer substance". Selegiline also inhibits CYP2A6 and can increase the effects of nicotine as a result. Selegiline also appears to activate σ1 receptors, having a relatively high affinity for these receptors of approximately 400 nM. Pharmacokinetics Selegiline has an oral bioavailability of about 10%, which increases when ingested together with a fatty meal, as the molecule is fat soluble. Selegiline and its metabolites bind extensively to plasma proteins (at a rate of 94%). They cross the blood–brain barrier and enter the brain, where they most concentrated at the thalamus, basal ganglia, midbrain, and cingulate gyrus. Selegiline is mostly metabolized in the intestines and liver; it and its metabolites are excreted in the urine. Buccal administration of selegiline results in 5-fold higher bioavailability, more reproducible blood concentration, and produces fewer amphetamine metabolites than the oral tablet form. Metabolism Selegiline is metabolized by cytochrome P450 to L-desmethylselegiline and levomethamphetamine. Desmethylselegiline has some activity against MAO-B, but much less than that of selegiline. It is thought to be further metabolized by CYP2C19. Levomethamphetamine (the less potent of the two enantiomers of methamphetamine) is converted to levoamphetamine (the less potent of the two enantiomers of amphetamine, with regards to psychological effects). Due to the presence of these metabolites, people taking selegiline may test positive for "amphetamine" or "methamphetamine" on drug screening tests. While the amphetamine metabolites may contribute to selegiline's ability to inhibit reuptake of the neurotransmitters dopamine and norepinephrine, they have also been associated with orthostatic