A Year of Insight: Understanding the Long-Term Effects of Psilocybin for Major Depression

Posted: July 2, 2025

The Long Road of Depression and the Search for Lasting Solutions

Major Depressive Disorder (MDD) can feel like a long, arduous journey with no clear end in sight. For many individuals, especially those with treatment-resistant depression (TRD)—where several standard treatments haven't brought relief—the search for effective and lasting solutions is a constant pursuit. In recent years, psychedelic-assisted therapy, particularly using psilocybin (the active compound in "magic mushrooms"), has emerged as a beacon of hope, showing rapid and significant antidepressant effects in initial studies. However, a crucial question for anyone considering such a novel therapy, especially if you're hesitant or uncertain, is: do these benefits last? What happens a year down the line? This article delves into this very question by exploring the 52-week (one-year) follow-up results from significant clinical trials, such as those conducted by Compass Pathways with their COMP360 psilocybin formulation (Goodwin et al., 2025; Compass Pathways Investor Relations, 2025). Understanding these longer-term outcomes is vital. It helps paint a more complete picture of psilocybin's potential role in managing depression, moving beyond the initial impressive results to see how individuals fare over an extended period. We'll break down what these findings mean in an accessible way, addressing the hopes and the realities for those looking for sustained relief from major depression.

The Promise of Psilocybin: Why the Initial Excitement?

Before we look at the long-term data, it’s worth briefly revisiting why psilocybin-assisted therapy has garnered so much attention for depression. Unlike traditional antidepressants, which can take weeks or months to work (if they work at all for some individuals) and often require daily dosing, psilocybin has shown the potential to produce rapid and profound antidepressant effects after just one or two administrations in a therapeutic setting (European Pharmaceutical Review, 2025).These effects are often accompanied by intense psychological experiences that can lead to shifts in perspective, emotional breakthroughs, and a greater sense of interconnectedness. The theory is that psilocybin, by promoting neuroplasticity (the brain's ability to form new connections), helps to disrupt rigid, negative thought patterns characteristic of depression, allowing for new, healthier ways of thinking and feeling to emerge. The initial studies have been promising enough to lead to larger, more rigorous clinical trials, including those exploring its use in treatment-resistant depression, a particularly challenging form of the illness.

Looking at the Long Haul: The COMPASS Pathways 52-Week Follow-Up

Compass Pathways, a company at the forefront of developing psilocybin therapy, conducted a significant Phase 2b trial (COMP 001) which was one of the largest randomized studies of psilocybin to date. This study compared the effects of a single administration of their COMP360 psilocybin at doses of 25mg, 10mg, and 1mg (a very low, often considered non-therapeutic dose) in participants with treatment-resistant depression. The initial results were promising, particularly for the 25mg dose (Goodwin et al., 2025).To understand the durability of these effects, Compass conducted an observational follow-up study called COMP 004. This study tracked participants from the original COMP 001 trial (and a smaller open-label study, COMP 003) for 52 weeks after they received the psilocybin. The primary goal was to see how long the antidepressant effects lasted and to monitor for any long-term adverse events (Goodwin et al., 2025; Compass Pathways Investor Relations, 2025).

Key Findings from the 52-Week Data:

Durability of Antidepressant Effect: The results published from the COMP 004 study indicated that a single 25mg dose of COMP360 psilocybin suggested a longer maintenance of antidepressant effect compared to both the 10mg and 1mg doses over the 52-week period (Goodwin et al., 2025; Blossom Analysis, 2025). Specifically, the median time before participants experienced a "depressive event" (a predefined measure of relapse or worsening of depression) was longer for the 25mg group. For all participants in the original COMP 001 trial, the median time to a depressive event was 92 days for the 25mg group, compared to 83 days for the 10mg group and 62 days for the 1mg group. While many participants across all groups did experience a depressive event by week 12, the trend favored the 25mg dose (Goodwin et al., 2025).
Response in Those Followed Longer: A post-hoc analysis (an analysis done after the study was completed, looking at specific subgroups) of those who enrolled in the COMP 004 follow-up study showed an even more striking difference, though the number of participants experiencing a depressive event after entering COMP 004 was smaller. For this subgroup, the median time to a depressive event was reported as 189 days for the 25mg group, 43 days for the 10mg group, and 21 days for the 1mg group (Goodwin et al., 2025). This suggests that for a portion of individuals receiving the 25mg dose, the benefits could extend for a considerable period, potentially many months.
Adverse Events: Importantly, the 52-week follow-up continued to monitor for safety. Few adverse events were reported after participants entered the COMP 004 follow-up phase. One instance of mild suicidal ideation in the 1mg group was deemed possibly related to the study drug, but overall, the long-term safety profile appeared consistent with earlier findings, suggesting no new safety concerns emerged over the year-long observation (Goodwin et al., 2025).
Use of Other Antidepressants: The study also noted that participants in the 1mg group (the lowest dose) tended to be on other antidepressant medications more frequently and started them earlier during the follow-up period compared to the 25mg group. This indirectly supports the idea that the 25mg psilocybin dose provided a more sustained standalone benefit for some (Goodwin et al., 2025).

What Do These Long-Term Results Mean?

For individuals struggling with treatment-resistant depression, these 52-week follow-up results offer several important takeaways:

Potential for Sustained Benefit: The data suggests that for some people, a single high dose of psilocybin (like 25mg), given in a therapeutic context, can lead to antidepressant effects that last for several months, and in some cases, perhaps even longer (GeneOnline, 2025). This is a significant departure from traditional antidepressants that require daily dosing to maintain their effect.
Not a Cure-All, But a Powerful Tool: It’s also clear that psilocybin is not a universal or permanent cure for depression. Many participants, even in the 25mg group, did experience a return of depressive symptoms within the year. This highlights that psilocybin therapy might be one powerful intervention that could be part of a longer-term mental health strategy, which might involve other therapies or potentially repeat psilocybin sessions in the future (though research on repeat dosing is still ongoing).
Dose Matters: The findings consistently point to the 25mg dose being more effective in the longer term than the 1mg or 10mg doses. This underscores the importance of appropriate dosing in achieving therapeutic benefits.
Safety Profile: The long-term follow-up data contributes to a growing body of evidence suggesting that when administered in a controlled medical setting, psilocybin has a manageable safety profile, with no major new safety issues emerging over a year (Goodwin et al., 2025).

Addressing Hesitancy: Hope Tempered with Realism

If you are hesitant about psychedelic therapy, these long-term findings might offer a mix of reassurance and realistic expectations. The Reassurance: The potential for months of relief from severe depression after a single administration is a compelling prospect, especially for those who have found little success with other treatments. The continued favorable safety profile over a year is also encouraging. The Realism: It’s important to understand that individual responses vary greatly. While some may experience long-lasting benefits, others may find the effects wane sooner. The research is still evolving, and scientists are working to understand who is most likely to benefit and for how long. The Compass Pathways trials are part of a larger, ongoing effort, with Phase 3 trials underway to gather more definitive evidence (Compass Pathways, 2025, Q1 Financial Results; Business Wire, 2025).These studies also highlight that psychedelic therapy is more than just taking a substance. It involves careful preparation, a supportive therapeutic environment during the psilocybin session, and crucial integration therapy afterward to help process the experience and translate insights into lasting change. The long-term benefits are likely tied to this entire therapeutic package.

The Path Forward: Larger Studies and Personalized Approaches

The authors of the 52-week follow-up study rightly conclude that larger, long-term studies are needed to confirm these findings and provide greater clarity on the longer-term effects of psilocybin (Goodwin et al., 2025). Future research will also likely focus on:

Predicting Response: Identifying factors that predict who will have a sustained response to psilocybin therapy.
Repeat Dosing: Investigating the safety and efficacy of repeat administrations of psilocybin for those whose symptoms return.
Combination with Other Therapies: Understanding how psilocybin therapy might be integrated with other forms of psychotherapy or lifestyle interventions to enhance and prolong its benefits.

Conclusion: A Glimpse into a More Enduring Remission?

The 52-week follow-up data from studies like Compass Pathways’ COMP 004 provides a crucial piece of the puzzle in understanding the potential of psilocybin for major depression. It suggests that the rapid and profound antidepressant effects observed in the short term can, for a meaningful number of individuals with treatment-resistant depression, extend into a more sustained period of relief, potentially lasting many months (Goodwin et al., 2025; European Pharmaceutical Review, 2025).For those who are uncertain or hesitant about psychedelic therapy, these findings offer a message of cautious optimism. They underscore that psilocybin is being rigorously studied not just for its immediate impact but for its potential to offer a more enduring change in the trajectory of severe depression. While not a panacea, and with individual results varying, the prospect of a therapy that can provide such lasting benefits from a limited number of administrations is a significant step forward. As research continues, the hope is that psilocybin therapy will become a well-understood and valuable option for those who have long struggled to find relief from the heavy burden of depression.

Disclaimer: Psychedelic Assisted Psychotherapy has not been approved by any regulatory agencies in the United States, and the safety and efficacy are still not formally established at the time of this writing.

References

Blossom Analysis. (2025). Results From a Long-Term Observational Follow-Up Study of a Single Dose of Psilocybin for a Treatment-Resistant Episode of Major Depressive Disorder. https://blossomanalysis.com/papers/results-from-a-long-term-observational-follow-up-study-of-a-single-dose-of-psilocybin-for-a-treatment-resistant-episode-of-major-depressive-disorder/

BusinessWire. (2025 ). Compass Pathways Announces Dosing Complete for All Participants in Part A of Phase 3 COMP005 Trial of COMP360 Psilocybin for Treatment-Resistant Depression. https://www.businesswire.com/news/home/20250422821349/en/Compass-Pathways-Announces-Dosing-Complete-for-All-Participants-in-Part-A-of-Phase-3-COMP005-Trial-of-COMP360-Psilocybin-for-Treatment-Resistant-Depression

Compass Pathways. (2025 ). First Quarter 2025 Financial Results and Business Highlights. https://ir.compasspathways.com/News--Events-/news/news-details/2025/Compass-Pathways-Announces-First-Quarter-2025-Financial-Results-and-Business-Highlights/default.aspx

Compass Pathways Investor Relations. (2025 ). Compass Pathways Announces Publication of Results from COMP004 Study on COMP360 Psilocybin for Treatment-Resistant Depression. https://ir.compasspathways.com/News--Events-/news/news-details/2025/Compass-Pathways-Announces-Publication-of-Results-from-COMP004-Study-on-COMP360-Psilocybin-for-Treatment-Resistant-Depression/default.aspx

European Pharmaceutical Review. (2025 ). Psilocybin demonstrates sustained benefit in TR-depression. https://www.europeanpharmaceuticalreview.com/news/250990/psilocybin-therapy-demonstrates-sustained-clinical-benefit-in-treatment-resistant-depression/

GeneOnline. (2025 ). Psilocybin Therapy Shows Sustained Benefits for Treatment-Resistant Depression. https://www.geneonline.com/psychedelics-inching-forward-psilocybin-therapy-shows-sustained-benefits-for-treatment-resistant-depression/

Goodwin, G. M., Nowakowska, A., Atli, M., Dunlop, B. W., Feifel, D., Hellerstein, D. J., Marwood, L., Shabir, Z., Mistry, S., Stansfield, S. C., Teoh, E., Tsai, J., Young, M. B., & Malievskaia, E. (2025 ). Results From a Long-Term Observational Follow-Up Study of a Single Dose of Psilocybin for a Treatment-Resistant Episode of Major Depressive Disorder. Journal of Clinical Psychiatry, 86(1), 24m15449. https://pubmed.ncbi.nlm.nih.gov/40047545/