D-Serine: A Cross Species Review of Safety

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 (DAAO) 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 dAAO 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 <2,000 nmol/mL. For comparison, the Cmax of D-serine 120 mg/kg, the highest dose tested in humans, is similar to 500 nmol/mL in acute dosing. Across all published human studies, only one subject has been reported to have abnormal renal values related to D-serine treatment. This abnormality did not clearly map on to the acute tubular necrosis syndrome seen in rats, and fully resolved within a few days of stopping treatment. DAAO inhibitors may be nephroprotective. D-Serine may have a physiologic role in metabolic, extra-pyramidal, cardiac and other systems, but no other clinically significant safety concerns are revealed in the literature. Conclusions: Even before considering human to rat differences in renal physiology, using current FDA guided monitoring paradigms, D-serine appears safe at currently studied maximal doses, with potential safety in combination with DAAO inhibitors.

Automated summary

D-Serine, a potential treatment for psychiatric and neurological conditions, has been limited in human studies due to concerns of nephrotoxicity observed in rats. However, D-serine induced nephrotoxicity has not been reported in other species and only one subject in human studies showed abnormal renal values, which resolved after stopping treatment. DAAO inhibitors may have nephroprotective effects.