Psilocybin use has risen sharply in US states that have moved to decriminalise the substance. Scientists are now uncovering why whole mushrooms may affect the brain very differently from purified compounds alone.

A study published in JAMA drew on survey data from nearly half a million people, collected between 2018 and 2025. It found that Oregon saw a 2.1 percentage point increase in past-year psilocybin use following its 2020 decriminalisation policy. That translates to roughly 90,000 additional users every year. Colorado, which decriminalised in 2022, recorded a 1.8 percentage point rise. Researchers cautioned the follow-up period was too short to draw firm conclusions.

What is particularly striking is that the surge in psilocybin use far outpaces clinic access. The number of people using the substance through licensed, supervised settings is a fraction of the overall increase. That gap points strongly to a rise in unregulated, private consumption. Researchers say this warrants careful thought when weighing the risks and benefits of loosening drug policy.

Why Psilocybin Use Looks Different in the Whole Mushroom

At the same time, a separate study published in Scientific Reports is shedding new light on what happens in the brain during magic mushroom consumption. Researchers from the University of the Free State in South Africa used computational pharmacology methods to map how the many compounds in Psilocybe species interact with brain proteins. Their toolkit included molecular docking and molecular dynamics simulations.

Their findings point towards what scientists call the “entourage effect.” This is the idea that the full cocktail of bioactive compounds in a mushroom may work together to produce effects that isolated psilocybin simply cannot replicate alone.

Of fifteen compounds identified in Psilocybe mushrooms, eight were found to cross the blood-brain barrier. They also showed high gastrointestinal absorption. These include not just psilocin, the active metabolite of psilocybin, but also norpsilocin, harmaline, harmane, harmol, phenylethylamine, 4-hydroxytryptamine and 4-hydroxy-N,N,N-trimethyltryptamine.

A Web of Brain Targets Linked to Magic Mushroom Consumption

Network analysis identified 44 brain-localised protein targets for these compounds. They showed strong connections to both the serotonin and dopamine systems. The primary receptor implicated in the psychedelic experience is HTR2A. All eight compounds formed stable interactions with a key binding site residue known as Asp155. This is the same site that serotonin itself uses.

This matters because several mushroom compounds, not just psilocin, are capable of engaging the brain’s primary psychedelic receptor. Magic mushroom consumption is therefore a pharmacologically far broader event than simply taking a dose of purified psilocybin.

The study also found that beta-carboline compounds in the mushrooms, specifically harmane, harmol and harmaline, bind tightly to monoamine oxidase A (MAOA). MAOA is the enzyme that normally breaks down serotonin, dopamine and norepinephrine. By potentially inhibiting this enzyme, these beta-carbolines could extend and amplify the effects of psilocin. The result is an increase in both the duration and intensity of the neurological impact.

Molecular dynamics simulations run over 200 nanoseconds confirmed the stability of these compound-protein interactions. Harmaline showed an exceptionally stable binding to MAOA with an RMSD of just 0.09 Å. That figure suggests a persistent and clinically meaningful interaction.

What Rising Psilocybin Use Means in the Real World

These findings carry significant weight. The JAMA research confirms that decriminalisation policies are changing behaviour at scale. Psilocybin use is climbing well beyond regulated settings. Meanwhile, the Scientific Reports study makes clear that people taking magic mushrooms are not consuming a single, predictable substance. They are taking a complex mixture capable of acting on multiple brain systems at once.

The beta-carbolines identified in the South African study share structural similarities with harmine, a compound already known to inhibit MAOA. Co-administration of MAOA inhibitors with serotonergic substances carries the risk of serotonin syndrome. This is a potentially dangerous accumulation of serotonin in the body. Anyone taking antidepressants such as SSRIs, tricyclic antidepressants or monoamine oxidase inhibitors should be aware that magic mushroom consumption could interact seriously with their medication.

The Scientific Reports team also flagged cardiovascular concerns. Several of these compounds interact with HTR2A receptors in peripheral tissues. They may influence blood pressure, platelet aggregation and pro-inflammatory pathways.

An Incomplete Picture

Both research teams are candid about the limits of their work. The JAMA study notes that Colorado’s data covers only a short window. A longer follow-up will be needed before the full impact of the policy can be assessed. The South African computational study is based entirely on in silico modelling. Its results are predictions that still require validation through laboratory and clinical research.

What is clear is that the science of psilocybin use is moving quickly. The policy landscape is moving with it. Oregon and Colorado are not alone in reassessing their approach to psychedelic substances. As public interest grows, so too does unregulated access.

Understanding what happens in the brain during magic mushroom consumption, and what risks that entails for different individuals, has never been more pressing.

Reference: JAMA (2026), DOI: 10.1001/jama.2026.1952 | Scientific Reports (2026), DOI: 10.1038/s41598-026-39483-7

Source: dbrecoveryresources