How Does Ketamine Work?

Ketamine, an FDA approved anesthetic agent, is being used off-label to treat a variety of mental health issues. While there is the most research for treatment refractory depression (including bipolar depression), suicidal ideation, PTSD, and addiction, there is also research suggesting beneficial effects for OCD, anxiety, eating disorders, and end-of-life care.

A Unique Mechanism of Action

Compared to other antidepressants, ketamine has a unique mechanism of action. Whereas most antidepressants affect levels of serotonin, ketamine works on a different receptor, called the NMDA receptor. The NMDA receptor plays a role in how glutamate transmits messages between brain cells. Ketamine also has smaller effects on other receptor subtypes, such as the dopaminergic and opioid receptors. In addition, ketamine has some anti-inflammatory properties. Although scientists don’t know exactly how ketamine leads to an antidepressant response, there is a hypothesis that some of these molecular effects result in brain neuroplasticity, which may be correlated with new ways of approaching the world and oneself and ultimately lead to increased wellness.

If a patient hasn’t responded to traditional antidepressants, this doesn’t mean they won’t respond to ketamine. In fact, research has shown that 70% of patients who have not responded to previous trials of antidepressants will respond to ketamine.

Neuroplasticity

Ketamine treatments result in neurogenesis and neuroplasticity in our brains for about 72 hours. Neurogenesis refers to laying down new neurons. We know that in rodent studies, ketamine can cause the brain to grow new nerve cells and can make existing nerve cells sprout new connections between each other. It is thought that the creation of new cells and strengthening of nerve pathways may be correlated with new learning. This is one reason professionals are interested in adding talk therapy or new learning to the ketamine treatment process, as the ability to think in new ways and engage in new behaviors may be amplified during and after ketamine treatment.

We still don’t understand the best way to take advantage of this 72-hour neuroplastic window. Some advocate for more talk therapy, and many believe that increasing wellness interventions like practicing gratitude and meditation, engaging in lifestyle changes, increasing relaxation and self-care, and spending time in nature may also be helpful. Perhaps tapping into positive memories could also lead to increasing pathways of joy. I believe there will be much research in the future as to how patients may leverage this neuroplastic window. It is likely that there are different answers to this question based on each individual’s neurobiology, preferences, and particular suffering they are looking to overcome.

Ketamine Decreases Rumination

Ketamine also works by turning down ruminations. We have a circuit in our brain, called the default mode network, whose activity is linked to the endless ruminating chatter in our mind about the past and the future. During ketamine treatments, the default mode network is turned down, so that our usual ways of thinking are suspended, and we are able to be more present, and perhaps access more compassion for ourselves and others. Depressive thinking often manifests in a lot of negative and critical thinking, which is correlated with an increase in activity in the default mode network. It can feel like a miracle when this negative thinking, which may feel like it’s going in torturous loops, is decreased. Ketamine can also work to turn down the obsessive, ruminative thinking that occurs in OCD.

It is important to note, that for many, once the ketamine treatment is over, ruminative thoughts may slowly seep back. Therefore, in the case of OCD, being able to engage in therapy, such as exposure response prevention, may help enhance the effects of ketamine. Also, just having a break from negative thinking can help one to have a reset, and give one hope of a different way of thinking and being. It should be noted that mindfulness and meditation may also help with decreasing ruminations, and there may be potential in engaging in mindfulness and meditation in the days following one’s ketamine treatments.

Spiritual and Mystical Experiences

We’ve covered the major neurobiological aspects of how ketamine works, so we can now introduce some hypothetical psychological ways ketamine may also help with suffering. At certain doses, ketamine can result in a mystical or spiritual experience. One may experience oneness with the universe, or feel they are a part of something greater. Others may experience increased feelings of love and compassion towards oneself and others. Some patients report feelings of well-being and coming to terms with existential anxiety. There is some debate whether this kind of experience may augment or be correlated to an antidepressant response. As a physician, I am able to witness firsthand the healing power of these types of experiences that may occur. It should be noted that these experiences do not occur for every patient, and it is unclear to me why some patients seem to consistently have this type of experience while others do not.

With the potential for an experience of transcendence, I believe ketamine may be well-suited for patients who are experiencing end-of-life depression and anxiety. Not only could ketamine help with the neurobiology of depression and anxiety, but ketamine could also help one to achieve a sense of inner peace. In addition, ketamine can be helpful for pain, which many people experience during the late stages of terminal illness.