Experiences of awe may drive ketamine’s antidepressant benefits

A recent study examining the effects of ketamine infusion on depression found that the infusion induces psychological experiences of awe. These experiences may mediate the effects of ketamine on the improvement of depression symptoms. The paper was published in Biological Psychiatry Global Open Science.

Ketamine is a medication primarily used as an anesthetic in both humans and animals. In this role, it is valued for its rapid onset and safety in maintaining cardiovascular function. It disrupts the activity of the neurotransmitter glutamate in the brain, which accounts for its unique anesthetic effects.

Beyond its use in anesthesia, ketamine has gained attention for its rapid-acting antidepressant effects, particularly in cases of treatment-resistant depression and in individuals contemplating suicide. For mental health applications, it is typically administered intravenously or as a nasal spray in controlled settings. However, ketamine is sometimes abused for its dissociative and hallucinogenic effects, raising concerns about misuse and addiction.

Study author Julia Aepfelbacher and her colleagues sought to explore the role of awe in the antidepressant effects of ketamine. Awe is defined as a constellation of reactions that occur when a person encounters a “vast mystery” or experiences a need for “accommodation” to reorganize their knowledge structures to make sense of what they have encountered. To investigate this, the researchers conducted a randomized controlled trial.

The study included 116 individuals with moderate to severe depression. Participants were randomly divided into two groups in a 2:1 ratio. One group consisted of 77 participants who received a single ketamine infusion (0.5 mg/kg over 40 minutes), while the remaining 39 participants received a saline solution (50 mL of 0.9% sodium chloride) as a placebo. Approximately 40 minutes after receiving their assigned infusion, participants completed assessments of awe (using the AWE scale) and dissociative symptoms (using the Clinician-Administered Dissociative States Scale). They also completed depression symptom assessments (using the Montgomery-Asberg Depression Rating Scale) at multiple points over the following 30 days.

The results showed that participants who received the ketamine infusion tended to score higher on the AWE scale, indicating stronger experiences of awe. These participants also reported more pronounced dissociative symptoms. Individuals who experienced stronger feelings of awe tended to show greater improvement in depression symptoms, particularly 12 days after the infusion. Interestingly, correlations between improvements in depression and the intensity of dissociative symptoms were negligible, suggesting that the experiences of awe might play a central role in ketamine’s antidepressant effects.

“Our study suggests that the experience of awe during ketamine infusion may play a mediating role in both rapid and more sustained antidepressant effects over the course of one month,” the study authors concluded. “These enduring statistical mediation effects were observed even beyond the period when a significant overall impact of ketamine was noted across all ketamine-treated individuals, suggesting that individuals who do not strongly endorse awe-like experiences during the infusion are more likely to experience the rapid return of depression. By contrast, those reporting very strong experiences of awe during the infusion were relatively buffered against depression’s return, for at least one month after a single infusion.

The study sheds light on the mechanisms underlying ketamine’s antidepressant effects. However, it is important to note that the associations between AWE scores and depression do not fully explain ketamine’s effects, indicating that additional factors may contribute to its antidepressant properties.

The paper, “Experiences of Awe Mediate Ketamine’s Antidepressant Effects: Findings from a Randomized Controlled Trial in Treatment-Resistant Depression,” was authored by Julia Aepfelbacher, Benjamin Panny, and Rebecca B. Price.