Ketamine in Diabetes Care: Metabolic Insights and Clinical Applications.

Depression and diabetic neuropathy often co-occur with diabetes, worsening blood sugar control and quality of life. Ketamine and its S-enantiomer, esketamine, offer rapid antidepressant and pain-relieving effects, but diabetes-related changes and other medications may alter their effectiveness and safety. A scoping review of 11 studies (including human case reports, one randomized trial, narrative reviews, and rodent studies) found short-term improvements in treatment-resistant depression and neuropathic pain, including opioid-sparing postoperative pain relief in gestational diabetes. Blood sugar effects varied, with both high and low blood sugar reported. Interactions with common diabetes drugs and liver enzymes (CYP3A4, CYP2B6) remain poorly studied. The authors call for dedicated pharmacokinetic and pharmacodynamic studies to guide individualized dosing in diabetes.

Study at a glance

Abstract

Background: Depression and diabetic neuropathy (DN) commonly complicate diabetes and impair glycemic control and quality of life. Ketamine and its S-enantiomer, esketamine, provide rapid antidepressant and analgesic effects, yet diabetes-related pathophysiology and co-therapies may modify exposure, response, and safety. Methods: We conducted a scoping review following PRISMA-ScR. MEDLINE/PubMed, CINAHL, and APA PsycInfo were searched (January 2020-31 May 2025). Eligible human and animal studies evaluated ketamine, esketamine, or norketamine in the context of diabetes (type 1 [T1DM], type 2 [T2DM], gestational [GDM]), or DN, and reported psychiatric, analgesic, metabolic, or mechanistic outcomes. Two reviewers independently screened and charted data; no formal risk-of-bias assessment was performed. Results: Eleven studies met inclusion criteria: four human case reports/series (three T1DM, one T2DM), one randomized trial in GDM, two narrative reviews of topical ketamine for DN, and four preclinical rodent studies using streptozotocin- or diet-induced diabetes models. Short-term improvements were reported for treatment-resistant depression and neuropathic pain, including opioid-sparing postoperative analgesia in GDM. Glycemic effects varied across settings, with both hyperglycemia and hypoglycemia reported. Mechanistic and clinical drug-drug and drug-disease interactions (particularly involving metformin, GLP-1 receptor agonists, SGLT2 inhibitors, and CYP3A4/CYP2B6 modulators) remain insufficiently studied. We outline a forward-looking population pharmacokinetic (popPK) and pharmacokinetic-pharmacodynamic (PK-PD) research agenda, including priority covariates (eGFR, hepatic function, inflammatory status, HbA1c, genotype, co-medications) and sparse-sampling windows for future model-informed precision dosing. Conclusions: Current evidence supports cautious, selective use of ketamine for refractory depression and DN within multidisciplinary diabetes care. Purpose-built popPK/PK-PD studies in both human and preclinical diabetic models cohorts are needed to quantify variability, define drug-disease-drug interactions and glycemic risk, and inform individualized dosing strategies.