The cytochrome P450-dependent “first-pass” biotransformation provides higher systemic exposure to 2,6-hydroxynorketamines after oral administration of ketamine compared to intravenous (IV) infusion, which shows promising analgesic activity and antidepressant effects. Hypothesizing to increase the active 2,6-hydroxynorketamines by administering a prolonged-release ketamine dosage form, Hasan et al. initiated a non-confirmative pharmacokinetic exploratory study with a newly developed prolonged-release ketamine multi-unit tablet formulation in healthy subjects. The research group demonstrated that the plasma exposure to 2,6-hydroxynorketamines was up to 30–40 times greater (with greater values for the R− than the S+ stereoisomer) than to parent racemic ketamine after oral administration of a prolonged-release formulation. No serious adverse events or suspected unexpected serious adverse drug reactions were reported. Overall, Hasan et al. suggested that the risk of undesirable psychoactive effects with prolonged-release ketamine tablets is much lower compared to IV infusion of similar doses commonly used for neuropathic pain and treatment-resistant depression therapy. Despite these initial promising results for routine clinical use treating pain and/or depression, much more data are necessary regarding the mechanisms of action of the ketamine metabolites. Evidence for possible clinical indications for slow-release ketamine preparations is needed.