Oral controlled-release ketamine tablets improve safety and tolerability compared with injected ketamine by reducing peak drug exposures. In a randomized, placebo-controlled ascending-dose study of 24 healthy volunteers, doses of 60, 120, or 240 mg or placebo were given. Drug release occurred over about 10 hours, with most drug present as norketamine (approximately 90%). Elimination half-life was prolonged (7–9 hours) versus published data from immediate-release oral forms. No changes in blood pressure or heart rate occurred after any dose. Mild dissociation was reported only after 240 mg, with mean ratings of 1–2 out of 76. No clinically significant ECG or lab changes were observed. Reducing and delaying peak ketamine concentration improves tolerability for patients with depression or anxiety.
An extended-release oral ketamine tablet was tested in seven patients with treatment-resistant depression and anxiety who had previously responded to subcutaneous ketamine. Over 96 hours, all patients showed more than 50% improvement in mood ratings, with gradual reductions in anxiety and depression. The tablet was safe and well tolerated, with no changes in vital signs and only one brief report of dissociation. The ratio of norketamine to ketamine increased over time, suggesting ketamine may induce its own metabolism. Serum BDNF concentrations did not change. The findings suggest extended-release oral ketamine may improve safety and tolerability while offering a slightly delayed onset of mood improvement compared to injected forms.