S‐adenosylmethionine (SAM) is an over‐the‐counter supplement marketed at improving mood and overall mental health. Although well known for decades to be an antidepressant, very little data exists with respect to the impact of oral SAM administration on whole brain concentrations of specific neurotransmitters. Male Sprague‐Dawley rats were fed a AIN93 diet and provided a daily oral supplement of SAM (10 mg/ kg bwt), a level that is comparable to the recommended dosage for humans. After 20 d of treatment, rats were killed and whole brain samples were analyzed for the concentration of dopamine, norepinephrine, and serotonin, as well as their respective transporters. Oral SAM supplementation increased the intracellular concentration of SAM in the liver and brain approximately 2‐ and 4‐fold respectively. S‐adenosylhomocysteine (SAH) concentrations were significantly elevated by oral SAM treatment in the brain, but were not affected in liver tissue. For whole brain tissue, SAM also markedly increased the concentration of dopamine and norepinephrine 15‐fold and 50%, respectively, whereas it did not have a statistically significant impact on serotonin concentrations. Moreover, SAM administration was without effect on the concentrations of the transporters for dopamine, norepinephrine, or serotonin. Therefore, oral daily provision of SAM to rats at a dosage recommended for humans dramatically increased the intracellular concentrations of specific neurotransmitters, dopamine in particular. The significant increase in brain SAH concentrations may result in the allosteric inhibition of a number of SAM‐dependent methyltransferases that function to metabolize dopamine and norepinephrine, thereby elevating their tissue concentrations.