Tim Mcmillan
January 13, 2025
Recent research has uncovered that the profound sense of awe experienced during ketamine treatment could be the key to its rapid antidepressant effects.
This revelation not only sheds light on the psychological mechanisms behind ketamine’s efficacy but also supports previous research suggesting that the mystical experience brought on by altered states of consciousness is vital to the medicinal potential of psychedelic therapies.
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“Our findings are consistent with a growing literature documenting the therapeutic and/or quality-of-life benefits of awe experiences, which can be invoked through a wide range of stimuli, including contact with nature, art, moral courage illustrated by others, and even everyday surroundings,” researchers wrote. “Pioneers in this field have argued that awe is a fundamental human emotion, and its expression plays a critical role in our social behavior and sense of self.”
Ketamine is a dissociative anesthetic initially developed for medical use to induce and maintain anesthesia during surgeries due to its ability to sedate patients while preserving protective airway reflexes.
Over the years, it has gained recognition as a groundbreaking treatment for depression, particularly for individuals with treatment-resistant depression who have not responded to traditional therapies.
When administered in controlled doses, ketamine offers rapid relief from depressive symptoms, often within hours, making it a valuable tool for addressing severe mood disorders.
Ketamine’s hallucinogenic and dissociative effects have also led to its use as a recreational drug, commonly known among users as “Special K.” In the United States, ketamine is classified as a Schedule III controlled substance, rendering its recreational use illegal.
Past research into the clinical use of ketamine has primarily been limited to its neurochemical and neuroplastic effects. However, a recent randomized controlled trial published in Biological Psychiatry: Global Open Science explored an intriguing psychological dimension: the feelings of awe, typically associated with substances that induced altered states of consciousness.
“Given the potential benefits of ketamine, it is critical to consider mechanisms by which its effects can be prolonged and/or heightened,” researchers wrote. “One such mechanism may relate to ketamine’s psychological properties, including possible psychedelic or mystical elements.”
The study, conducted with 116 participants, compared the effects of ketamine to a saline placebo. Participants who received ketamine reported significantly higher scores on the Awe Experience Scale (AWE-S) shortly after infusion.
Moreover, the study revealed that the degree of awe experienced directly correlated with improvements in depression symptoms, as measured by the Montgomery–Åsberg Depression Rating Scale (MADRS), at five distinct time points over 30 days.
Unlike general dissociative effects, as measured by the Clinician-Administered Dissociative States Scale (CADSS), the experience of awe uniquely predicted longer-lasting antidepressant benefits.
“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, which suggests that individuals who do not report experiencing strong awe-like experiences during the infusion are more likely to experience a rapid return of depression,” researchers wrote. “By contrast, individuals who reported very strong experiences of awe during the infusion were relatively buffered against depression’s return for at least 1 month after a single infusion.”
Defined as a complex emotion elicited by encounters with vastness or novelty that challenge existing mental frameworks, awe has been shown to reduce self-focused attention and increase feelings of connectedness. These effects are particularly relevant for individuals with depression, where self-focused rumination is a core symptom.
The current study utilized the AWE-S to measure six subdomains of awe, including connectedness, accommodation (restructuring mental schemas), and self-diminishment.
Participants in the ketamine group reported marked increases across all subdomains compared to the placebo group. The accommodation and self-diminishment subdomains were particularly pronounced, aligning with ketamine’s known capacity to disrupt entrenched thought patterns.
This isn’t the first time feelings of awe or mystical experiences have been linked to the therapeutic effects of psychoactive substances. Previous research into psychedelics like psilocybin and MDMA has emphasized the critical role of “mystical-type experiences” in fostering psychological breakthroughs and emotional healing.
In a 2021 study published in the Journal of Psychopharmacology, researchers raised doubts about the effectiveness of psychedelic therapy using controlled microdosing, as it did not enable users to achieve altered states of consciousness.
“The consensus [is] you need the subjective effects, or the altered states of consciousness, to get the full and enduring benefits from these drugs,” study co-author and current Ph.D. candidate at the University of Konstanz, George Fejer, previously told The Debrief. “These effects are quite dose-specific, and I think that it is a disadvantage of microdosing that it does not aim to facilitate explicit changes in subjective experience.
In line with Fejer’s comments, a 2023 large-scale study by Ohio State University researchers, which surveyed over 1,000 participants, found that the lasting mental health benefits of psychedelic therapy were directly tied to experiencing mystical or insightful states of consciousness.
Ketamine is categorized as a dissociative anesthetic rather than a traditional psychedelic. However, it has drawn comparisons to psychedelics due to its capacity to induce dream-like dissociative states and hallucinations, making it a subject of similar research and exploration.
Past studies have suggested its effects on consciousness might facilitate a form of psychological insight akin to that elicited by psychedelics. This new research bolsters the notion that ketamine’s psychological effects are as crucial as its neurochemical mechanisms.
The study’s findings suggest that fostering awe during ketamine treatments could enhance and prolong its antidepressant effects. Integrating techniques such as guided mindfulness during ketamine therapy can amplify the awe experience. This aligns with practices in psychedelic therapy, where “set and setting” play a critical role in shaping outcomes.
Adjunctive therapies, such as cognitive-behavioral therapy or mindfulness training, might also help patients integrate their awe experiences into everyday life, ensuring the psychological benefits persist long after the ketamine’s pharmacological effects wane.
One of the study’s most striking findings was the contrast between awe and dissociation. While dissociation—a hallmark of ketamine’s psychoactive effects—was observed in participants, it failed to predict or mediate depression outcomes.
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In fact, CADSS scores bore little relationship to improvements in MADRS ratings, challenging previous assumptions that dissociation is integral to ketamine’s therapeutic effects.
This distinction underscores the need for more nuanced research tools to capture the multifaceted psychological effects of ketamine. As a specific and measurable construct, awe offers a promising avenue for further exploration.
The implications of these findings extend beyond ketamine. Awe is increasingly recognized as a transformative emotion with far-reaching psychological benefits.
Researchers noted past studies have shown that awe-inducing activities, such as “awe walks” in nature, can improve mood, foster prosocial behavior, and reduce stress. Leveraging awe in therapeutic settings could provide a novel, non-invasive approach to mental health care.
“Given that negative emotions are often found in a self-focused state, awe-inducing events may be an effective and rapid tool to aid individuals in connecting to something greater than themselves, with potential transformative impacts on life outlook, mental state, and social relationships,” researchers wrote.
While the study provides compelling evidence, it is not without limitations. The sample size was relatively small, though the largest to date for such research.
Additionally, the study population lacked diversity, limiting the generalizability of the findings. Researchers noted that future studies should explore whether awe-induced benefits are consistent across different demographics and cultural contexts.
Moreover, the study relied on self-reported measures of awe and depression, which may be influenced by placebo effects or individual expectations. Incorporating objective biomarkers and longitudinal designs could strengthen the robustness of future research.
Nevertheless, as depression rates continue to climb worldwide, the need for innovative and effective treatments is more urgent than ever. This recent study adds a critical layer of understanding to ketamine’s antidepressant mechanisms, positioning awe as a potential game-changer in mental health care.
By integrating awe-inducing practices into treatment protocols, clinicians may unlock new levels of therapeutic potential, offering hope to those battling the debilitating effects of depression.
“Humans have a natural tendency toward a narrow focus on both the self and cause-effect relationships, which may be further exacerbated in the context of depression,” researchers wrote. “The experience of awe challenges this by bringing forth a systems view of life, which can have important implications for survival and provide a potential path to improved mental and physical health.”
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