Ketamine is a dissociative anesthetic that has myriad mechanisms of actions and binds to multiple receptors in the brain. Consequently, it is difficult to pin down the precise mode of action, and it appears that there are multiple mechanisms through which ketamine exerts its action on the brain.
Regarding depression, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and chronic anxiety, these mental health disorders are all thought to be due to the destructive effect of continual stress on the brain, leading to neuronal damage and creation of maladaptive neural activity and abnormal thought patterns indicative of these disorders.
Research suggests that one of ketamine’s major actions is as an N-methyl-D-aspartate (NMDA) receptor antagonist, that is it blocks activation of the NMDA receptor. This action leads to increased release of glutamate which is known to be involved in neuronal plasticity and synaptic growth and repair. Through complex pathways, these effects lead to the release of Brain-derived neurotrophic factor (BDNF), a substance responsible for the maintenance of healthy neurons and their connections, known as synapses.
Increased BDNF has been shown to bring about repair and regrowth of damaged synapses and their neuronal connections caused by chronic stress in animal models. Likewise, in humans, ketamine is thought to lead to the creation of new neuronal circuits and/or repair of the healthy neuronal connections that existed in the brain before the patient suffered with depression, PTSD, OCD, and/or chronic anxiety.
Increased glutamate release is associated with activation of spinal inhibitory interneurons which are thought to be responsible for its efficacy in treating chronic pain, by blocking activation of the neural pathways that are thought to play a role in chronic pain through central sensitization, a theory that suggests the neurons that mediate the perception of pain become continuously active, even when no painful stimuli are present.
By causing the inhibition of the neural pathways responsible for pain perception, ketamine is thought to allow these pathways in the brain to “reset” so they are not firing with the rate and/or frequency that they did before treatment. Less activation of these neural pathways translates into decreased perception of pain.