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In many experimental animal models, MTX has been found to increase serum urea and creatinine levels (Reference Moodi, Hosseini and Abedini16,Reference Tousson, Zaki and Abu-Shaeir50,Reference Jafaripour, Naserzadeh and Alizamani51) , but there are also studies showing that MTX reduces serum urea concentration (Reference Budancamanak, Kanter and Demirel52Reference Severin, Campagno and Brandoni54)

The most commonly reported side effects are vivid dreams, mild insomnia, or light nausea, but they are usually transient and dose-dependent

The presence of the bloodbrain barrier (BBB) is one of the major obstacles and strictly inhibits the delivery of therapeutic drugs into the brain

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Blinding was assessed by asking participants which order of placebo and naltrexone pretreatments they believed they received after the final dosing session at the day 1 follow-up, with Dont know a valid option