D-Serine: A Cross Species Review of Safety

• Published in: Frontiers in psychiatry 2021-08, Vol.12
• Main Authors: Meftah, Amir, Hasegawa, Hiroshi, Kantrowitz, Joshua T.
• Format: Article
• Language: English
• Subjects: D-serine; kidney; NMDA–N-methyl-D-aspartate; Psychiatry; safety; schizophrenia
• ISSN: 1664-0640; 1664-0640
• DOI: 10.3389/fpsyt.2021.726365

Background: D- Serine, a direct, full agonist at the D- serine/glycine modulatory site of the N-methyl-D-aspartate-type glutamate receptors (NMDAR), has been assessed as a treatment for multiple psychiatric and neurological conditions. Based on studies in rats, concerns of nephrotoxicity have limited D- serine research in humans, particularly using high doses. A review of D- serine's safety is timely and pertinent, as D- serine remains under active study for schizophrenia, both directly (R61 MH116093) and indirectly through D- amino acid oxidase ( D AAO) inhibitors. The principal focus is on nephrotoxicity, but safety in other physiologic and pathophysiologic systems are also reviewed. Methods: Using the search terms “ D- serine,” “ D- serine and schizophrenia,” “ D- serine and safety,” “ D- serine and nephrotoxicity” in PubMed, we conducted a systematic review on D- serine safety. D- serine physiology, dose-response and efficacy in clinical studies and d AAO inhibitor safety is also discussed. Results: When D- serine doses >500 mg/kg are used in rats, nephrotoxicity, manifesting as an acute tubular necrosis syndrome, seen within hours of administration is highly common, if not universal. In other species, however, D -serine induced nephrotoxicity has not been reported, even in other rodent species such as mice and rabbits. Even in rats, D- -serine related toxicity is dose dependent and reversible; and does not appear to be present in rats at doses producing an acute Cmax of