Recent research conducted by teams from the Center for Psychedelic and Consciousness Research at Johns Hopkins School of Medicine and the Centre for Psychedelic Research at Imperial College London has taken a significant step forward in understanding the therapeutic mechanisms behind psilocybin therapy for treating major depressive disorder (MDD).
Their study, published in the International Journal of Mental Health and Addiction, reveals that specific psychological experiences during psilocybin therapy, particularly mystical experiences and ego dissolution, play a critical role in the therapy’s efficacy compared to traditional treatment.
Psilocybin, a naturally occurring psychedelic substance found in certain species of mushrooms, has been the focus of renewed research interest due to its potential therapeutic benefits. When ingested, psilocybin is converted into psilocin, which influences serotonin receptors in the brain, leading to profound alterations in perception, emotion, and cognition. These effects have been hypothesized to contribute to psilocybin’s therapeutic potential.
Previous research has highlighted the importance of the acute psychological experiences induced by psychedelics, such as mystical experiences and emotional breakthroughs, in facilitating positive mental health outcomes. However, the specific role these experiences play in the context of psilocybin therapy, and how they compare to conventional treatments like antidepressants, remained unclear.
The researchers conducted a randomized, double-blind controlled trial to verify whether the unique psychological experiences induced by psilocybin contribute to its therapeutic efficacy in treating depression. A total of 59 participants diagnosed with MDD were enrolled in the study and randomly assigned to one of two treatment arms: psilocybin therapy or escitalopram treatment, a common selective serotonin reuptake inhibitor (SSRI).
The psilocybin therapy group underwent two sessions where they received 25 mg of psilocybin, while the escitalopram group received a placebo-like low dose of 1 mg of psilocybin, coupled with daily escitalopram. Both groups were provided with psychological support and exposed to a preset music playlist during the psilocybin dosing sessions to enhance the therapeutic setting. The study’s design allowed for a direct comparison between the effects of a significant psychedelic experience and those of a standard antidepressant treatment, with both groups receiving an equivalent level of psychological support.
The researchers found that participants in the psilocybin group experienced significantly greater improvements in depressive symptoms compared to those in the escitalopram group. This difference was strongly associated with the quality of acute psychological experiences during the therapy sessions.
The magnitude of mystical experiences and ego dissolution during psilocybin therapy sessions was significantly related to the reduction in depressive symptoms. Mystical experiences were characterized by a profound sense of unity, transcendence of time and space, deeply felt positive mood, and ineffability. Ego dissolution is characterized by a blurring or complete loss of the boundaries between the self and the external world.
Importantly, these key experiences retained their significance as mediators of therapeutic effectiveness even when controlling for other factors, such as the general intensity of the drug experience. This indicates that the benefits of psilocybin extend beyond the generic effects of experiencing altered states of consciousness and are specifically related to the qualities of the experiences themselves.
The researchers also identified several moderators — variables that influence the strength or direction of the therapeutic effect of psilocybin therapy on depressive symptoms. One of the most powerful moderators identified was the emotional breakthrough experience. This refers to moments during the therapy sessions where patients were able to confront and work through deep-seated emotional issues, leading to significant insights or resolutions.
Interestingly, the emotional response to music was another moderator of depressive symptom change. Music is an integral component of psilocybin therapy sessions, aimed at supporting the therapeutic process by eliciting emotional responses and facilitating introspection. Participants who experienced a stronger emotional impact from the music played during their psilocybin sessions showed greater improvements in depression levels.
Another significant finding was the role of individual differences in shaping participants’ responses to psilocybin therapy. Traits such as absorption and suggestibility, which reflect a person’s openness to immersive experiences and responsiveness to external suggestions, respectively, were found to amplify the therapeutic effects of mystical experiences and emotional breakthroughs. This suggests that individual psychological characteristics can influence the degree to which patients benefit from the unique experiences facilitated by psilocybin therapy.
But the study, like all research, includes some limitations to consider.
While the study provides valuable insights by comparing psilocybin with escitalopram treatment, this comparison itself introduces limitations. The mechanisms underlying psilocybin therapy and escitalopram treatment are likely different, and the study’s findings on the specific psychological experiences associated with psilocybin may not directly translate to a critique of the effectiveness of traditional antidepressants.
Another limitation is the issue of unblinding. In psychedelic research, the intense and distinctive effects of substances like psilocybin make it challenging to maintain effective blinding for participants and researchers. Participants may easily discern whether they have received psilocybin or a placebo, which could influence their expectations and self-reported outcomes. However, preliminary research has provided evidence that the therapeutic benefits of psilocybin therapy are unrelated to expectancy effects.
“In sum, these findings advance our understanding of how psychedelic therapies may differ from conventional SSRI pharmacotherapy at the mechanistic level,” the researchers concluded.
“These results also illustrate the value of psychological mechanisms in psychedelic therapy. Despite recent propositions about the potential sufficiency of physiological mechanisms, we remind the reader that the face valid model for psychedelic therapy involves a standard package of psychological preparation, dosing supervision with music listening and psychological integration.
“This is the model that has yielded the promising results that are now attracting major public and private interest in psychedelic medicine. The idea of giving a psychedelic but stripping away its psychedelic subjective effects (and perhaps stripping away psychological support also) while hoping to preserve the therapeutic response is an entirely untested model in humans.”
The study, “Unique Psychological Mechanisms Underlying Psilocybin Therapy Versus Escitalopram Treatment in the Treatment of Major Depressive Disorder,” was authored by Brandon Weiss, Leor Roseman, Bruna Giribaldi, David J. Nutt, Robin L. Carhart-Harris, and David Erritzoe.
