Psilocybin – What if the Trip Isn’t the Point?

If you ask someone what psilocybin does, they’ll likely describe hallucinations as the main event. However, scientists are discovering that the most important effects of “magic mushrooms” might be changes to neuronal connections. This raises an interesting question: could we keep these changes and lose the trip?

Psilocybin is converted into the active metabolite psilocin once ingested, activating serotonin 5-HT2A receptors (Thomann et al. 2024). Apart from altering perception, psilocybin and other psychedelics may promote neuroplasticity, the brain’s ability to reorganize its connections (Siegel et al. 2026). In mice, Jiang et al. (2026) found that psilocybin selectively strengthened and weakened some neural pathways. What is even more interesting is that the rewiring depended on which neurons were active during drug exposure, so perhaps the state you are in when using psilocybin is more important than previously imagined.

Now, what if someone seeks these effects of psilocybin without, or with a more tolerable psychedelic experience? Floris et al. (2026) paired psilocybin with a PDE9 inhibitor, preventing the breakdown of cGMP, a cellular signalling molecule. They proposed that increased cGMP might reduce neural hyperexcitability, improving tolerability of psilocybin. In mice, this combination reduced head-twitching and preserved antidepressant responses. This being said, head-twitching is an indirect measure of psychedelic-related activity, not hallucinations, and the chronic-stress experiments included only male mice. Whether this approach improves tolerability in humans remains unknown.

While Floris et al. approached this question by modifying psilocybin’s effects with another drug, Baker et al. (2026) investigated whether neuroplastic and psychedelic-related effects relied on the same neuronal mechanisms. Using genetically modified mice and repeated brain imaging, they manipulated 5-HT2A receptors in pyramidal neurons, located deep in the cerebral cortex. When 5-HT2A receptors were restored only in those neurons, psilocybin promoted the formation of new synaptic connections, but did not produce the head-twitch response. Removing these receptors from the same neurons produced the opposite result: head-twitching continued, but synaptic remodeling did not. This suggests that the neural mechanisms responsible for these two effects may be distinct.

But what does this mean for humans? In a small study, Johansen et al. (2026) found no significant overall increase in a marker of synaptic density after psilocybin administration. However, participants treated in a therapeutic-like environment reported more intense psychedelic experiences and greater positive psychological effects three months later. Similarly, Stoliker et al. (2026) found that psilocybin-induced brain activity varied with the surrounding environment and was associated with subjective experiences and next-day changes in mindset. Although neither study proves that the experience causes lasting therapeutic benefits, both suggest it may play a meaningful role in psychological change.

This creates an interesting dilemma for psychedelic medicine. Removing psychedelic perceptual changes could reduce the need for lengthy supervised sessions, making treatment more accessible and affordable. However, Heller and Hendlin (2026) argue that the subjective experience and social environment may be essential to its benefits, rather than simply unwanted side effects. 

If we remove the trip, are we improving psychedelic medicine, or removing part of what makes it effective?

References

Baker, Jacob J., et al. 2026. “5-HT2A Receptors in Layer 5 Pyramidal Neurons Mediate the Neuroplastic but Not the Hallucinogenic Effects of Psilocybin.” Nature Neuroscience. https://doi.org/10.1038/s41593-026-02490-y 

Floris, Gabriele, et al. 2026. “Enhancing cGMP Signaling with Psilocybin Reduces Head Twitch and Restructures the Synaptic Proteome While Maintaining Antidepressant Response.” Neuropsychopharmacology. https://doi.org/10.1038/s41386-026-02569-x 

Heller, Julian, and Yogi Hale Hendlin. 2026. “Why Taking the Trip out of Psychedelic Medicine Is a Mistake.” International Journal of Drug Policy 157: 105487. https://doi.org/10.1016/j.drugpo.2026.105487 

Jiang, Quan, et al. 2026. “Psilocybin Triggers an Activity-Dependent Rewiring of Large-Scale Cortical Networks.” Cell 189: 659–675. https://doi.org/10.1016/j.cell.2025.11.009

Johansen, Annette, et al. 2026. “Psilocybin’s Effect on Human Brain Synaptic Plasticity.” Translational Psychiatry 16: 544. https://doi.org/10.1038/s41398-026-04285-y

Siegel, Joshua S., et al. 2026. “The Science of Psychedelic Medicine.” Nature Medicine 32: 449–462. https://doi.org/10.1038/s41591-025-04194-5 

Stoliker, Devon, et al. 2026. “Psychedelics Align Brain Activity with Context.” Nature 656. https://doi.org/10.1038/s41586-026-10910-z

Thomann, J., et al. 2024. “In vitro and in vivo metabolism of psilocybin’s active metabolite psilocin.” Frontiers in Pharmacology 15. https://doi.org/10.3389/fphar.2024.1391689