Are “mystical experiences” essential for antidepressant actions of ketamine and the classic psychedelics?

The growing interest in the rapid and sustained antidepressant effects of the dissociative anesthetic ketamine and classic psychedelics, such as psilocybin, is remarkable. However, both ketamine and psychedelics are known to induce acute mystical experiences; ketamine can cause dissociative symptoms such as out-of-body experience, while psychedelics typically bring about hallucinogenic experiences, like a profound sense of unity with the universe or nature. The role of these mystical experiences in enhancing the antidepressant outcomes for patients with depression is currently an area of ongoing investigation and debate. Clinical studies have shown that the dissociative symptoms following the administration of ketamine or (S)-ketamine (esketamine) are not directly linked to their antidepressant properties. In contrast, the antidepressant potential of (R)-ketamine (arketamine), thought to lack dissociative side effects, has yet to be conclusively proven in large-scale clinical trials. Moreover, although the activation of the serotonin 5-HT_2A receptor is crucial for the hallucinogenic effects of psychedelics in humans, its precise role in their antidepressant action is still under discussion. This article explores the importance of mystical experiences in enhancing the antidepressant efficacy of both ketamine and classic psychedelics.