The present invention relates to a method for decreasing the abuse liability and psychotomimetic side effects and enhancing the antidepressant-like effects of ketamine by the combination of ketamine with a methyl glycine derivative. The combination can be applied in the treatment of treatment-resistant depression/bipolar disorders, anxiety disorders and pain.

As NMDA receptor partial agonists, TMG/DMG exhibited antidepressant property and enhance ketamine’s antidepressant effect. However, TMG/DMG decreased the psychotomimetic effect and abuse liability of ketamine. Repeated treatment TMG/DMG with ketamine abolished the persistent psychotypical behavior and memory deficits. A better safety profile of ketamine in combination with TMG/DMG was revealed.

Combination use of methylglycine derivatives and ketamine can potentially develop formulas to resolve the safety concern of ketamine use in psychiatric disorders. The combination use can reduce the costs and limitation compared to Spravato. It can be applied in the treatment of suicidal ideation, treatment-resistant depression/bipolar disorders, anxiety disorders and pain.