Psilocybin, the active ingredient in “magic mushrooms,” has recently emerged as a promising treatment for depression, particularly in patients who have not responded well to traditional antidepressants. A systematic review and meta-analysis published in the BMJ compares the effects of high-dose psilocybin to the selective serotonin reuptake inhibitor (SSRI) escitalopram, a commonly prescribed antidepressant. The findings offer new insights into psilocybin’s potential as an antidepressant and how it stacks up against more conventional treatments like SSRIs.
Key findings: psilocybin and escitalopram show similar antidepressant effects
According to the study, high-dose psilocybin shows similar effects on depressive symptoms as escitalopram. In clinical trials, patients who were administered high-dose psilocybin experienced better responses than those given a placebo, with antidepressant effects that were on par with those seen in trials involving escitalopram. However, the researchers noted that the effect size for psilocybin was small, suggesting that while it can be effective, its antidepressant effects may not be significantly stronger than those of escitalopram 1.
The review also found that placebo responses in psilocybin trials were lower than in escitalopram trials, indicating that the nature of the psychedelic experience may reduce the likelihood of placebo effects. While psilocybin performed better than placebo in trials, only high doses showed antidepressant effects comparable to escitalopram in head-to-head trials, based on the Hamilton Depression Rating Scale (HAMD-17).
How psilocybin works in the brain
Psilocybin works primarily by affecting serotonin receptors in the brain, particularly the 5-HT2A receptor. This is the same neurotransmitter system targeted by SSRIs, but the mechanism of action differs significantly. SSRIs gradually increase the availability of serotonin in the brain, while psilocybin induces an immediate and profound alteration in consciousness.
One of the key aspects of psilocybin’s action is its ability to reduce activity in the brain’s default mode network (DMN), which is involved in self-referential thought and rumination—common in depression. By temporarily disrupting the DMN, psilocybin allows patients to experience a sense of “decentering,” where they can observe their thoughts and emotions from a different, often more objective perspective. This shift in consciousness can lead to deep emotional breakthroughs, giving patients the ability to process negative emotions and thought patterns that contribute to their depression.
Potential benefits and risks of psilocybin for depression
Psilocybin offers several potential advantages over traditional antidepressants. One of the most significant benefits is its rapid onset of effects. While SSRIs can take weeks or even months to show noticeable improvements, psilocybin can lead to significant reductions in depressive symptoms after just one or two sessions. In some studies, the antidepressant effects of psilocybin have been reported to last for months, reducing the need for continuous treatment.
Additionally, psilocybin therapy is typically conducted in a therapeutic setting with psychological support, which enhances its effectiveness. The therapeutic intention and decentering effect of psilocybin can facilitate introspection and emotional breakthroughs, providing patients with the tools to confront and resolve underlying psychological issues.
However, there are risks associated with psilocybin use. The psychedelic experience can be intense and unpredictable, leading to anxiety, paranoia, or what is often described as a “bad trip.” Although these experiences are usually short-lived, they can be distressing if not managed properly. Psilocybin is also not recommended for individuals with a history of psychosis or certain psychiatric conditions, as it may aggravate these issues.
Psilocybin vs. traditional SSRIs
When comparing psilocybin to SSRIs like escitalopram, both treatments show similar levels of effectiveness in alleviating depressive symptoms. However, their mechanisms of action and side-effect profiles differ significantly. SSRIs, which are typically taken daily, work gradually to balance serotonin levels in the brain. They can be effective for many patients, but they also come with side effects such as weight gain, sexual dysfunction, and emotional blunting, which can diminish the quality of life.
Psilocybin, on the other hand, is administered in one or a few therapeutic sessions and has a different side effect profile. It does not cause the same long-term side effects as SSRIs, but the immediate psychedelic experience can be intense and challenging for some patients. However, in controlled clinical settings, adverse events related to psilocybin are rare. Neither psilocybin nor escitalopram was associated with a higher rate of severe adverse events like hospitalization or suicide attempts, according to the review.
One notable advantage of psilocybin over SSRIs is its ability to induce a profound psychological shift, sometimes described as a “reset” for the brain. This reset effect, coupled with the decentering that occurs during the psychedelic experience, allows patients to break free from rigid thought patterns, which are often at the core of depression. While SSRIs offer symptom relief, they do not typically lead to the kind of deep emotional and cognitive shifts that psilocybin can produce.
The future of mental health treatment
The comparison between high-dose psilocybin and escitalopram in the treatment of depression reveals that both treatments offer similar levels of effectiveness, with neither showing a dramatically greater effect than the other. However, psilocybin’s unique ability to facilitate rapid improvements in mood and induce profound psychological shifts makes it an exciting alternative for patients who have not responded to traditional antidepressants. While psilocybin therapy is still in the experimental stages and carries certain risks that will need to be explored and addressed, particularly related to the intensity of the psychedelic experience, it represents a promising new frontier in the treatment of depression and could become a valuable tool in the mental health field.
References
- Hsu, Tien-Wei, et al. “Comparative Oral Monotherapy of Psilocybin, Lysergic Acid Diethylamide, 3,4-Methylenedioxymethamphetamine, Ayahuasca, and Escitalopram for Depressive Symptoms: Systematic Review and Bayesian Network Meta-Analysis.” BMJ, vol. 386, 21 Aug. 2024, https://doi.org/10.1136/bmj-2023-078607. ↩︎
