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Drugs targeting the sphingosine\u20101\u2010phosphate receptor show potential anti\u2010convulsant effects in animal models and decrease cortical excitability in patients with multiple sclerosis, but available compounds alter lymphocyte trafficking and cause immunosuppression, limiting their clinical anti\u2010epileptic potential. TRV045 is a selective sphingosine\u20101\u2010phosphate subtype 1 receptor agonist without effects on lymphocyte trafficking, demonstrating efficacy in animal models of epilepsy, with the potential to target abnormal cortical excitability. This randomized, double\u2010blind, placebo\u2010controlled, two\u2010way cross\u2010over, multiple\u2010dose study evaluated the effects of TRV045 on cortical excitability in healthy male adults, measured by pharmaco\u2010electroencephalography and transcranial magnetic stimulation (TMS). Subjects received TRV045 250\u2009mg or placebo, once daily for 4\u2009days, in randomized order. Endpoints were analyzed with a mixed effects model analysis of covariance. Twenty\u2010five of the 27 subjects completed the study. There was a significant increase in alpha power with eyes open after treatment with TRV045 on Day 1, increasing after 4\u2009days of dosing. Less pronounced significant effects in beta, gamma, and delta power were observed after 4\u2009days. For TMS\u2010Electromyography there was a non\u2010significant decreased post\u2010dose single\u2010pulse peak\u2010to\u2010peak amplitude on Day 1 only, and there were no effects on paired\u2010pulse parameters. Several significant TMS\u2010Electroencephalography clusters were seen after 4\u2009days of dosing. These findings show that TRV045 has central nervous system activity with evolving effects following repeated dosing. These data support further studies to elucidate the mechanism of action of TRV045 and its potential anti\u2010epileptic effects.<\/jats:p>","DOI":"10.1002\/cpt.3521","type":"journal-article","created":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T12:24:28Z","timestamp":1733487868000},"page":"787-797","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp>TMS<\/scp> and <scp>EEG<\/scp> Pharmacodynamic Effects of a Selective Sphingosine\u20101\u2010Phosphate Subtype 1 Receptor Agonist on Cortical Excitability in Healthy Subjects"],"prefix":"10.1002","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2998-708X","authenticated-orcid":false,"given":"Catherine M. K. 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