Excessive sleepiness (ES) is associated with several sleep disorders, including 
narcolepsy and obstructive sleep apnea (OSA). A role for monoaminergic systems 
in treating these conditions is highlighted by the clinical use of US Food and 
Drug Administration-approved drugs that act on these systems, such as 
dextroamphetamine, methylphenidate, modafinil, and armodafinil. Solriamfetol 
(JZP-110) is a wake-promoting agent that is currently being evaluated to treat 
ES in patients with narcolepsy or OSA. Clinical and preclinical data suggest 
that the wake-promoting effects of solriamfetol differ from medications such as 
modafinil and amphetamine. The goal of the current studies was to characterize 
the mechanism of action of solriamfetol at monoamine transporters using in vitro 
and in vivo assays. Results indicate that solriamfetol has dual reuptake 
inhibition activity at dopamine (DA; IC50 = 2.9 μM) and norepinephrine (NE; IC50 
= 4.4 μM) transporters, and this activity is associated in vivo with increased 
extracellular concentration of DA and NE as measured by microdialysis. 
Solriamfetol has negligible functional activity at the serotonin transporter 
(IC50 > 100 μM). Moreover, the wake-promoting effects of solriamfetol are 
probably owing to activity at DA and NE transporters rather than other 
neurotransmitter systems, such as histamine or orexin. The dual activity of 
solriamfetol at DA and NE transporters and the lack of significant 
monoamine-releasing properties of solriamfetol might explain the differences in 
the in vivo effects of solriamfetol compared with modafinil or amphetamine. 
Taken together, these data suggest that solriamfetol may offer an important 
advancement in the treatment of ES in patients with narcolepsy or OSA.