Synthetic vs. Natural Psilocybin: What’s the Real Difference?

Psychedelic Science 2025 Dispatch #9: Exploring How Different Forms of Psilocybin Shape the Journey—And If Patients Notice the Difference

Last month, North Spore was on the ground in Denver, Colorado at Psychedelic Science 2025—the world’s largest gathering dedicated to psychedelic research, therapy, and culture, hosted by MAPS- the Multidisciplinary Association for Psychedelic Studies. We’ve been spending the last few weeks sharing dispatches from our notes and time at the conference, and starting today we’ll be sharing articles from another North Spore voice, Avi Fox. Avi’s focus is on psilocybin as a healing tool beyond just psychotherapy. Later this summer, we’ll be releasing a slate of video content on YouTube, diving deeper into the conversations and discoveries that took place there. Stay tuned. - Matt

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After more than a decade on my own winding path with healing and wellness, mushrooms have come across my journey as partners in my healing more than once. This spring, at Psychedelic Science 2025 in Denver, I stepped into a space where the conversation around mushrooms reached beyond familiar territory, past culinary mainstays like chaga and lion’s mane, into the unsettled terrain of psilocybin’s medicinal promise. Ever since reading Michael Pollan’s How to Change Your Mind, I’ve watched the psilocybin conversation with growing curiosity. At the conference, that quiet curiosity felt mirrored on a larger scale: researchers presented new clinical data, advocates debated policy, and the question hovered everywhere—how, and if, these medicines might soon become accessible, legal tools for public health.

One talk in particular caught my attention because it touched on something I’ve long wondered about: our human tendency to recreate in the lab what already exists in nature. Sometimes these synthetic ventures yield breakthroughs, but just as often, something essential seems to slip away in translation. In conversation with speakers and scientists, I learned that legal barriers in the U.S. push most clinical research toward synthetic psilocybin—cheaper, easier to standardize, and less complicated by regulation than the mushroom itself. This pattern is hardly unique to psychedelics; again and again, our systems privilege the synthetic over the natural, the standardized over the complex. My instinct, shaped by experience, is that something vital can be lost in the trade.

That tension was the focus of the Roots to Thrive Psilocybin-Assisted Therapy program for end-of-life distress, where Dr. Pamela Kryskow and Dr. Joseph La Torre explored the differences in therapeutic outcomes between synthetic psilocybin and whole psilocybe mushrooms. Their research took on a rare and direct question: does the form—synthetic, extract, or whole mushroom—make a difference in the experience of healing?

Context: Bringing Legal Psilocybin Therapy into the Real World

The Roots to Thrive Psilocybin-Assisted Therapy program is one of the rare, fully legal settings in North America where people with end-of-life distress can receive psilocybin as part of group-supported therapy. Participants, screened and referred by their palliative care physicians, move through eight weeks of preparation, ceremony, and integration, supported by a multidisciplinary team including doctors, therapists, Indigenous Elders, and somatic practitioners.

The study, presented by Dr. Kryskow and Dr. La Torre, arose from a unique opportunity: within their program, several patients had the rare experience of receiving all three forms of psilocybin—synthetic, mycological extract, and whole Psilocybe cubensis mushrooms—each in a ceremonial, therapeutic context. Their voices, captured in post-treatment interviews, offer a window into how different forms of psilocybin are experienced in the places where it matters most: at the edge of life, in the company of others.

Core Insights: A Study of Lived Difference

Three Forms, Three Journeys

The study design was as pragmatic as it was profound. As Dr. Kryskow put it, “Most of the clinical trials are studying synthetic psilocybin, but I would make a safe guess that everyone in this room who’s ever had a psilocybin journey in the real world used whole mushrooms.” The team recognized a gap between the clinical research—reductionist by necessity, focused on single molecules—and the organic, messy, complex reality of how people actually use these medicines.

Participants received three forms:

• Synthetic psilocybin (25mg, PsyGen)

• Whole mushrooms (5g, Psilocybe cubensis)=

• Mycological extract (25mg, ethanol extraction of Psilocybe cubensis)

Each form was delivered with ceremony: “Even the synthetic was added to juice and presented in beautiful goblets… we like to really be ceremonial and intentional with the medicines we’re working with.”

Phenomenology and Subjective Effects

The most striking findings were not about efficacy, all three forms were described as therapeutic, but about the felt sense, the texture, and the meaning of the experience.

Whole mushroom: “Things were brighter, green was greener, red was redder, sort of thing. It was a brightness, a clarity, a cleanness.”

Synthetic: “It felt more medicine-y and less spiritual.”

Synthetic: “It was like I was looking through a window, looking at it. I wasn’t in it.”

Across interviews, natural forms were described as “clear, vibrant, and alive.” There was a persistent sense that mushrooms were sentient, while synthetics felt more “mechanical” and “controlling.” One participant summed up the difference: with the mushrooms, it felt like going on the journey together, but with the synthetic, it was like the substance was taking you for a ride.

The distinction, subtle but consistent, was as much about relationship as about chemistry: “The mushroom and the mycological extract felt like they were more sentient, like they were meeting them as their human self-being, co-going on this journey together… whereas the synthetic was more like being taken.”

“Nature is complex. Nature has put together plants and animals over millennia for good reasons, much of which we don’t yet understand.”

Spiritual and Mystical Experiences

All forms induced spiritual or mystical experiences, but there was an intangible difference in depth and resonance. Capsule forms, both synthetic and extract, were perceived as “less spiritual.” The whole mushroom, by contrast, was felt as “sacred and alive,” evoking the sense of participating in a ceremony, not just ingesting a substance.

“The (mycological extract) was alive as well, but I think there’s something still sort of sacred and alive with taking it as the mushroom itself.”

The shape of the journey also differed. Whole mushrooms and mycological extracts had a “bell curve” onset, gradual, gentle, with a long, daydreamy tail for reflection. Synthetic psilocybin was described as “box-like”: a sharper, more abrupt onset and offset, “like an elevator ride up.” Participants valued the extended tail of the mushroom experience, which allowed for more contemplation and emotional processing.

Preference and Emotional Resonance

When asked directly, participants were clear:

“I would (if given the choice) probably want the real mushroom, the whole mushroom.”

“If all you have is synthetic, it’ll get the job done, but not a first choice.”

The consensus: all forms can be therapeutic, but whole mushrooms are preferred, not only for their efficacy, but for their felt relationship, the quality of empathy, connection, and meaning they engender.

One participant reflected, “The synthetic… it didn’t bring the whole emotion that the whole mushroom did. The whole mushroom was more empathetic. I felt like I was in relationship with it.”

A Call for Complexity in Research

The implications of these findings are as much philosophical as scientific. Dr. Kryskow challenged the field: “We’re way too reductionist. We need to be more complex, and it’s time for complexity to step forward in research.” The urge to isolate, standardize, and replicate is understandable, but it risks flattening the very qualities—mystery, sentience, relationality—that make these medicines transformative.

“We really should be using more whole mushrooms, whole plants in these studies… not just limit it to these monomolecular approaches.”

This is not an argument against synthetic psilocybin; participants agreed it is effective, and for many, it may be the only accessible option. But something is lost when we separate the molecule from its natural context. The study’s authors argue persuasively for head-to-head research comparing whole mushrooms to synthetics, and for regulatory pathways (like a Botanical Drug Act) that can accommodate the complexity of living medicines.

Resonance and Reflection

It is hard to escape the feeling that what we are glimpsing here is something that cannot be fully measured, only lived. The difference between synthetic and whole mushrooms may never be captured by clinical scales or chemical assays. It is, in the words of one participant, “the feeling of being in ceremony”, of being accompanied, of stepping into a relationship with something alive and mysterious.

There is power in that relationship. As Dr. La Torre reflected, “Nature is complex. Plants and fungi have co-evolved with us for reasons we’re only beginning to understand.” The question is not just what works, but what heals most deeply, what restores meaning at the threshold of life and death.

Looking Forward

What’s clear from this study is that the story of psilocybin therapy is still being written. The call for more research is not just a formality, it’s a recognition that we’re only beginning to understand the full complexity and potential of these medicines. Head-to-head studies with standardized dosing, investigations into the subtle effects of mushroom alkaloids, and new projects with other species like Amanita are all on the horizon.

But more than anything, there’s a sense of being present at the very edge of something transformative. It is a privilege, and a responsibility, to bear witness as the field grapples with questions that reach beyond molecules and mechanisms, into the very heart of what it means to heal.

As this research continues to unfold, I’ll remain deeply curious: How might the unique intelligence of whole mushrooms continue to shape the future of care, ceremony, and community? What new insights will emerge as researchers and clinicians learn, adapt, and share their findings?

At North Spore, we’re committed to following these developments with care and clarity, bringing you stories from the frontlines as this work evolves. We invite you to stay with us, to ask questions, and to reflect as we trace the living edge of psychedelic medicine’s potential to serve humanity in meaningful ways.