Key points

• Evidence for psilocybin’s antidepressant potential is maturing quickly with industry trials and FDA interest.
• 5-HT1B work from Dartmouth College raises hope therapeutic effects can be separated from hallucinations.
• A new human neuroimaging model may become a brain testing/screening mechanism for pharmacological treatments.

Sadly, many depressed people have “treatment-resistant depression." About 15% of people with depression report no benefit, and 30-40% are partial antidepressant responders. They may suffer severely. Yet multiple phase 2 and emerging phase 3 clinical trials have found that 1-2 doses of psilocybin, administered in a medically-supervised setting with psychological support, led to a clinically significant sustained reduction in depressive symptoms. Recent research has shown that some hallucinogenic drugs reduce depressive symptoms when antidepressants fail. Research has also been progressing on psilocybin as a treatment for posttraumatic stress disorder (PTSD).

Today, the key scientific and regulatory question is shifting away from if psilocybin could produce major durable improvements in depression and anxiety—because we’ve already come close to establishing, yes, it can—to whether benefits can be delivered affordably and safely.

What about hallucinations? Getting rid of depression is great, but the person taking hallucinogens must spend hours with in-person professional guides, safe facilities, and long-term monitoring.

Psilocybin

Psilocybin is therapeutically promising. Recent mechanistic and clinical milestones—such as Fleury and Nautiyal’s January 2026 report in Molecular Psychiatry on a potential “non-hallucinogenic receptor target” for psilocybin-like medicines, along with Joshua Siegel’s systems-neuroscience work in Nature, and Compass Pathways’ late-stage clinical and FDA interactions—together outline a credible pathway toward psilocybin’s approval and next-generation, potentially non-hallucinogenic ‘psilocybin-like’ therapeutics.

For the past decade, most discussions of how psilocybin works have centered on serotonin 2A (5-HT2A) receptor activation; however, that’s also the principal driver of hallucinogen effects. If all hallucinations come from 5-HT2A, we might be able to reduce or remove 5-HT2A, but then we might also remove or diminish the therapeutic benefit. New research seeks to identify molecular and circuit targets in the brain that contribute to mood benefits, yet are independent of hallucinogenic signaling. And after that identification, the goal is to create drug candidates meeting those targets.

Dartmouth researchers showed that psilocybin’s receptor-binding profile is broad, spanning multiple serotonin receptor families. It also questions the previous focus on 5-HT2A as too narrow, raising the possibility that therapeutic effects are partly “routed” through *other *receptors. They reported that serotonin 1B (5-HT1B) signaling contributes meaningfully to behavioral and neural effects on psilocybin in mice. The framing is consequential: 5-HT1B is not the “hallucination receptor," but the 5-HT1B receptor governs adaptive changes underlying therapeutic involvement (measured by antidepressant-like effects and learning benefits). Deleting this receptor erased the antidepressant benefits in mice, while head-twitching (hallucinogenic symptom) persisted.

If 5-HT1B (or related downstream circuitry) is a meaningful contributor to antidepressant benefits, then new medicines might be invented, like psilocybin analogs, partial agonists, or others with psilocybin’s therapeutic value but no or reduced hallucinations. A feasible strategy is to attempt to positively engage non-hallucinogenic serotonergic pathways and test for antidepressant- and anxiolytic-like outcomes.

Josh Siegel’s Imaging

Joshua Siegel’s 2024 Nature human study provides a complementary systems-level map showing how psilocybin reorganizes the human brain during the acute drug state and which changes persist beyond it. Specifically, Siegel and colleagues reported that psilocybin “desynchronizes” functional connectivity across large-scale brain networks, notably the default mode network (DMN) and related systems. Most importantly, psilocybin results in a persistent decrease in functional connectivity between the anterior hippocampus and the DMN lasting weeks. Separating acute short-term psilocybin effects from persistent effects offers hope that antidepressant or anti-PTSD effects may not require maintaining a full hallucinogenic state and longer-lasting network recalibration may be a related, but distinct process. Siegel interpreted persistent hippocampal-DMN change as a potential human brain marker for therapeutic effects of psilocybin and other psychedelics.

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Siegel’s work identifies a measurable, human, network-level phenotype of psilocybin action—acute network desynchronization with individual-specific features—providing a human bioassay for evaluating next-generation compounds. Siegel told me, “There are other fascinating questions that keep coming up. Acute vs. persistent brain changes might be the common underlying mechanism shared by psychedelics and non-hallucinogenic analogues.” If 5-HT1B (or related pathways) could be engaged in humans to produce persistent network changes (e.g., hippocampal–DMN shifts) *without an acute hallucinogenic experience, *the field would have a plausible mechanistic pathway toward psilocybin treatment without hallucinations.

The hypothesis is now strong enough to justify medicinal chemistry programs, receptor-bias optimization, and human biomarker studies designed to separate hallucinations from mood and network endpoints. The next step is to see if we can separate hallucinations out. We think we can, but we won’t know until we try.

SSRIs Essential Reads

As a result, regulatory and clinical momentum is building for psilocybin. As it moves through FDA pathways, I expect to see testing of safe and effective next-generation compounds. Ultimately, it is clinical efficacy and regulatory feasibility—not mere plausibility—that will shape the future of patient care.

FDA Progress in Psilocybin as a Medicine

On the drug-development side, Compass Pathways has become the most visible “classic psychedelic” sponsor pursuing a pharmaceutical psilocybin product at a late stage. In June 2025, Compass announced that its first Phase 3 trial (COMP005) of COMP360 psilocybin for treatment-resistant depression had achieved its primary endpoint, reporting statistically significant improvement versus placebo at six weeks following a single 25 mg administration. In January 2026, Compass reported that the FDA had accepted its IND application to develop COMP360 for PTSD, enabling the initiation of a Phase 2b/3 program (COMP202).

If COMP360 (or another psilocybin-assisted therapy model) achieves approval, it will likely do so with a REMS-structured clinical delivery framework, including screening, monitoring, prolonged observation, and psychotherapy support. Approval would validate psilocybin’s therapeutic class but also highlight its cost and implementation. Those limits underlie the commercial incentive for next-generation agents that could be delivered with fewer intensive support requirements and a wider patient population, including those at high risk for adverse psychotic reactions. The most realistic near-term narrative is not that non-hallucinogenic psilocybin replacements will supplant psychedelic-assisted therapy, but a “two-track” future with supervised psilocybin therapy and scalable psilocybin-like, non-hallucinogenic medications.

The two tracks inform each other scientifically. Siegel’s network phenotypes can serve as translational biomarkers to compare classic psilocybin against candidate non-hallucinogenic agents. For example, do they produce similar persistent hippocampal DMN shifts? Do they produce a smaller acute desynchronization signature while still producing durable network recalibration? Meanwhile, receptor-level work from the Dartmouth group suggests which molecular levers might be pulled without necessarily producing full psychedelic phenomenology.

Summary

The paradigm-shifting potential of psychedelic compounds, which promotes rapid neural rewiring, offers hope for addictions and psychiatric illnesses.

The evidence base for psilocybin’s antidepressant and PTSD potential is maturing quickly, including late-stage industry trials, NIMH support and increasing FDA engagement. The field may eventually offer clinicians a supervised psychedelic-assisted modality for selected patients and a more commercially-friendly, scalable non-hallucinogenic medication inspired by the same neurobiology.

What remains to be demonstrated is whether “psilocybin without the hallucinations” is a testable development program, anchored by the receptor discovery (with 5-HT1B as a candidate mediator) and human imaging biomarkers (persistent hippocampal–DMN connectivity changes).

References

Fleury S, Nautiyal KM. The serotonin 1B receptor is required for some of the behavioral effects of psilocybin in mice. Mol Psychiatry. 2025 Dec 20. doi: 10.1038/s41380-025-03387-1. Epub ahead of print. PMID: 41422160.

Heal DJ, Smith SL, Henningfield JE. Psychedelic research - Going global. J Psychopharmacol. 2025 Dec 1:2698811251399575. doi: 10.1177/02698811251399575. Epub ahead of print. PMID: 41324318.

Siegel JS, Subramanian S, Perry D, Kay BP, Gordon EM, Laumann TO, Reneau TR, Metcalf NV, Chacko RV, Gratton C, Horan C, Krimmel SR, Shimony JS, Schweiger JA, Wong DF, Bender DA, Scheidter KM, Whiting FI, Padawer-Curry JA, Shinohara RT, Chen Y, Moser J, Yacoub E, Nelson SM, Vizioli L, Fair DA, Lenze EJ, Carhart-Harris R, Raison CL, Raichle ME, Snyder AZ, Nicol GE, Dosenbach NUF. Psilocybin desynchronizes the human brain. Nature. 2024 Aug;632(8023):131-138. doi: 10.1038/s41586-024-07624-5. Epub 2024 Jul 17. PMID: 39020167; PMCID: PMC11291293.

Subramanian S, Reneau TR, Perry D, Chacko R, Laumann TO, Flavin K, Horan C, Schweiger J, Metcalf N, Lenze EJ, Snyder AZ, Dosenbach NUF, Nicol G, Siegel JS. Psilocybin’s acute and persistent brain effects: a precision imaging drug trial. Sci Data. 2025 Jun 5;12(1):941. doi: 10.1038/s41597-025-05189-0. Erratum in: Sci Data. 2025 Jun 18;12(1):1029. doi: 10.1038/s41597-025-05397-8. PMID: 40473634; PMCID: PMC12141498.

Henningfield JE, Comer SD, Banks ML, Coe MA, Collins GT, Cooper ZD, Fantegrossi WE, Durgin CJ, Heal DJ, Huskinson SL, Lanier RK, Lynch WJ, Meisch RA, Rowlett JK, Strickland JC, Gannon BM. Abuse potential assessment of novel central nervous system active and psychedelic substances for controlled substances act scheduling recommendations. J Psychopharmacol. 2025 Nov 3:2698811251378511. doi: 10.1177/02698811251378511. Epub ahead of print. PMID: 41185108.

McGowan NM, Rucker JJ, Yehuda R, Agrawal M, Modlin NL, Simmons H, Tofil-Kaluza A, Das S, Goodwin GM. Investigating the safety and tolerability of single-dose psilocybin for post-traumatic stress disorder: A nonrandomized open-label clinical trial. J Psychopharmacol. 2025 Aug 29:2698811251362390. doi: 10.1177/02698811251362390. Epub ahead of print. PMID: 40883964.