The COVID-19 pandemic has resulted in a surge in depression cases, a pervasive and debilitating mental illness1. This trend is evident in the increased prescriptions for antidepressants. Depression is a chronic condition that affects a significant proportion of the global population, with ~280 million people, or about 3.8%, suffering from it. As a result, it is a significant mental health concern worldwide2. The National Institute for Health and Care Excellence in the United Kingdom recommends medication as the primary treatment for individuals with moderate to severe depression. However, it has limitations and may yield unsatisfactory outcomes. Conversely, research suggests that psychological interventions, social support, and exercise are significant factors in addressing depression3. Treatment-resistant depression (TRD), which refers to the failure to achieve remission after multiple attempts of first-line antidepressants, is a significant limitation of pharmacotherapy. The Sequenced Therapy Alternatives to Relieve Depression experiment has demonstrated the challenge of treating TRD4. Approximately 30% of individuals receiving treatment for a severe episode of depression experience TRD, which is associated with more severe illness, increased risk of recurrence, prolonged functional impairments, medical comorbidities, and higher rates of suicidal ideation and nonsuicidal deaths5. Depression is one of the primary causes of suicide, with over 700,000 reported deaths from suicide annually. Reports from clinical experience and data from placebo-controlled trials indicate that suicidal thoughts and behaviors may increase during the initial weeks of antidepressant treatment in young adults and adolescents2. Moreover, conventional antidepressants pose challenges such as a delayed onset of action that can take up to 4 weeks or more to manifest, as well as common side effects including sexual dysfunction, loss of libido, headaches, gastrointestinal problems, anxiety, and agitation. Discontinuation of these medications and high rates of relapse are also concerns6. Hence, there is a need to review current treatment approaches and incorporate novel, fast-acting therapies that result in sustained remission. Neuroimaging research has revealed that depression is characterized by abnormal brain functioning, particularly in the default mode network, which is associated with self-awareness and tends to be overactive in depression. Other higher-order brain networks, such as the executive network and salience network, have also been linked to depression. Interestingly, the serotonin 2A (5-HT2A) receptor subtype, which is the primary binding site for traditional serotonergic psychedelic drugs like psilocybin, is highly expressed in a cortical region that closely resembles a conjunction map of the default mode network, executive network, and salience network1. Psilocybin is a naturally occurring indoleamine found in mushrooms, which rapidly breaks down in living tissue to form psilocin, the hallucinogenic component that produces psychedelic effects similar to serotonin7. In 1957, Wasson first proposed that serotonergic hallucinogens could be used to treat depression, but research on their therapeutic potential was suspended due to societal and political issues. However, in recent years, with multiple successful studies and advances in neurobiology, research on the potential therapeutic benefits of psilocybin for depression has been revived8. Over the past 15 years, at least 6 clinical trials have documented significant reductions in depression symptoms with psilocybin therapy9. One of these trials was an open-label study in TRD with pretreatment and post-treatment functional magnetic resonance imaging, which showed a reduction in brain modularity linked to improvements in depressed symptomatology10. Notably, escitalopram, a common SSRI antidepressant, did not cause any changes in modularity, suggesting that this antidepressant activity may be unique to psilocybin therapy11. Psilocybin also induces an altered consciousness or hallucinogenic experience, which is thought to play a crucial role in its therapeutic effects for depression. The psychedelic experience is believed to promote introspection, emotional processing, and insights into one’s thoughts, feelings, and behaviors, leading to increased self-awareness, changes in perception, and shifts in perspective that can result in meaningful and long-lasting changes in mood and behavior12. Psilocybin therapy for depression typically involves a structured and supervised approach, with a trained therapist providing support and guidance throughout the experience. The therapy session may also include preparatory and integrative elements to optimize the therapeutic outcome. Recent clinical trials have shown promising results, with rapid reductions in depressive symptoms observed after just 1 or 2 sessions of psilocybin-assisted therapy and sustained treatment response rates that persist for several weeks or even months after treatment13. One of the unique aspects of psilocybin therapy is its potential for a rapid onset of action, with many patients reporting improvements in mood and well-being within hours or days after a single session. This is in stark contrast to traditional antidepressant medications, which typically take weeks or even months to show significant effects. The rapid and sustained antidepressant effects of psilocybin therapy may be particularly beneficial for individuals with severe depression or TRD, who may not respond adequately to conventional treatments14. Furthermore, psilocybin therapy has been reported to be well-tolerated, with a low risk of addiction and minimal withdrawal symptoms. Unlike some traditional antidepressants, which can cause side effects such as sexual dysfunction, gastrointestinal issues, and anxiety, psilocybin therapy is generally considered to be safe and well-tolerated when administered in controlled settings by trained professionals15. Despite the promising results, it is important to note that psilocybin therapy is not without risks. The psychedelic experience induced by psilocybin can be intense and overwhelming and may not be suitable for everyone. It may also cause transient psychological distress, such as anxiety, fear, or confusion during the session. Therefore, it requires careful screening, preparation, and integration to ensure safe and optimal outcomes. In addition, the long-term effects of repeated psilocybin therapy are still unknown, and further research is needed to fully understand its safety and potential risks16. In conclusion, psilocybin therapy has shown promising results as a novel and potentially effective treatment for depression, particularly for individuals with TRD or those who do not respond adequately to traditional antidepressant medications. The rapid onset of action, sustained treatment response rates, and unique psychological effects of psilocybin therapy make it a compelling option for further research and exploration in the field of mental health. However, it is important to approach psilocybin therapy with caution, ensuring proper screening, preparation, and integration, and further research is needed to fully understand its safety, optimal dosages, and long-term effects. Psilocybin therapy may represent a paradigm shift in the treatment of depression, but it should only be administered in controlled settings by trained professionals as part of an integrated treatment approach. Ethical approval Not applicable. Sources of funding None. Author contribution The conceptualization was done by TN and BSR. The literature and drafting of the manuscript were conducted by TN, AS, AWK, SMFZ and HSR. The editing and supervision were performed by BSR. All authors have read and agreed to the final version of the manuscript. Conflict of interest disclosures The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number (UIN) Not applicable. Guarantor All authors take responsibility for the work, access to data and decision to publish.