Reply to Hashimoto: Ketamine is not an opioid but requires opioid system for antidepressant actions.

We agree with Hashimoto (1) that the molecular mechanisms underlying the psychiatric properties of ( R , S )-ketamine remain active areas of investigation. Racemic ketamine as well as esketamine [( S )-ketamine] are potent N -methyl-d-aspartate receptor (NMDAR) antagonists and have displayed acute antidepressant and antisuicidal effects in multiple clinical studies (2, 3). However, these compounds display activity, albeit with lower affinity, on a number of receptors, including μ-opioid receptors (MORs), complicating the issue of mechanism of action. Clinical studies arguing for (4) and against (5) a role for MORs … [↵][1]1To whom correspondence may be addressed. Email: meklein{at}ucsd.edu. [1]: #xref-corresp-1-1