Provided herein are ketamine gel formulations, transdermal delivery devices comprising ketamine, methods of preparation and methods of using thereof. The transdermal delivery device can be a drug-in-reservoir (DIR) patch comprising ketamine, which typically includes a backing layer, a reservoir layer comprising a ketamine gel formulation, a rate-controlling membrane, an adhesive layer, and a release liner. The ketamine gel formulation generally includes one or more skin permeation enhancers. The transdermal delivery devices can be configured, for example, by adjusting the ketamine gel formulation and other release control mechanisms, to provide certain skin flux characteristics, and can be used for treating a variety of indications such as depression and/or pain.
