Psilocybin might not be the most psychoactive ingredient in magic mushrooms, new research suggests

A new study published in Scientific Reports suggests that the therapeutic effects of psychedelic mushrooms likely rely on a complex interplay of multiple chemical compounds rather than just a single active ingredient. Scientists found evidence that several minor compounds in these mushrooms work together to interact with brain receptors, potentially explaining why natural extracts often produce different effects than synthetic versions.

Psychedelic mushrooms, often called magic mushrooms, belong to a group of fungi that naturally produce mind-altering chemicals. These fungi have been used in spiritual ceremonies for centuries and are currently gaining mainstream medical attention. Clinical trials frequently use these substances as tools alongside psychotherapy to treat severe depression and anxiety.

Most modern clinical studies use a synthetic, lab-made version of psilocybin, the primary psychoactive compound in the mushrooms. When a person consumes psilocybin, their body converts it into psilocin, which interacts with the brain to alter perception and emotion. However, people who use whole mushroom extracts often report different or enhanced experiences compared to those taking synthetic psilocybin.

“Mental illness is increasing globally, creating significant health and economic burdens, particularly in countries like South Africa, where access to healthcare remains unequal. At the same time, psychedelics such as psilocybin are gaining attention as potential treatments for disorders like depression and anxiety,” said study author Abdul Rashid Issahaku, a researcher at the University of the Free State.

“However, the biological mechanisms underlying their effects (particularly those of naturally occurring psilocybin-producing mushrooms) remain poorly understood. This study was motivated by the need to address this knowledge gap by investigating the molecular mechanisms and potential ‘entourage effects’ of these mushrooms on the brain.”

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The entourage effect describes a scenario where multiple natural compounds interact synergistically, meaning their combined effect is greater or different than the sum of their individual parts. Understanding the biological mechanisms of these natural compounds could help refine future psychiatric therapies.

To investigate this entourage effect, the scientists used a detailed computational framework. Instead of testing the compounds in human or animal subjects, they utilized advanced computer modeling to simulate how these chemicals behave in the body. They began by identifying fifteen different biologically active compounds known to exist in psilocybin-producing mushrooms based on existing scientific literature.

The researchers first evaluated these fifteen chemicals to see if they could survive the human digestive system and reach the brain. They specifically looked for compounds capable of crossing the blood-brain barrier, which is a highly selective protective shield that prevents most substances in the bloodstream from entering brain tissue. The computer models predicted that eight of the fifteen compounds could successfully absorb into the gut and cross this barrier.

These eight compounds included psilocin, along with lesser-known chemicals such as harmane, harmol, and specific variants of tryptamine. Next, the scientists used structural similarity databases to predict which proteins in the human brain these eight chemicals would target. The software identified forty-four specific brain proteins that these compounds would likely bind to and interact with.

The researchers then mapped out how these forty-four protein targets connect with one another in the brain. They found that the targets are heavily involved in the brain’s serotonin and dopamine systems. Serotonin and dopamine are chemical messengers that regulate mood, reward, and cognitive processes.

To see exactly how well the mushroom compounds would attach to these brain targets, the scientists performed molecular docking. This is a computer simulation that tests the physical fit between a chemical molecule and a protein receptor, much like testing different keys in a lock. The simulations showed that all eight compounds fit strongly into key neurological receptors.

The researchers observed that the compounds formed strong electrical connections, known as salt bridges, with a specific part of the primary serotonin receptor. This mimics the exact way natural serotonin binds to the brain, offering further evidence of their biological activity. One specific finding suggests that psilocybin might not even be the most active ingredient in the mushrooms.

The computational models provided evidence that a compound called 4-hydroxy-N,N,N-trimethyltryptamine might bind to serotonin receptors even more strongly than psilocin does. This specific chemical is a broken-down form of aeruginascin, another natural compound found in the fungi.

“One surprising finding was that psilocybin itself may not be the most biologically active compound in these mushrooms,” Issahaku told PsyPost. “Our computational modelling suggested that another indole alkaloid, 4 hydroxy-N,N,N-trimethyltryptamine (a dephosphorylated form of aeruginascin), may bind even more strongly to serotonin receptors.”

The scientists also ran molecular dynamics simulations for a duration of two hundred nanoseconds to test how stable these chemical connections were over time. They focused their stability tests on the main serotonin receptor associated with hallucinations and an enzyme called monoamine oxidase A (MOA). This enzyme is normally responsible for clearing away excess serotonin and dopamine in the brain. The simulations revealed that certain mushroom compounds, specifically a group known as beta-carbolines, bind exceptionally well to this cleanup enzyme.

By binding to the enzyme, these beta-carbolines block it from breaking down serotonin. This chemical blockade would theoretically leave more serotonin and psilocin active in the brain for a longer period. This interaction provides a clear mechanical explanation for the entourage effect. By blocking the cleanup enzymes while simultaneously stimulating serotonin receptors, the minor chemical compounds in the mushroom tend to amplify the effects of the primary psychedelic compound. ”

“We were also surprised by the presence of beta-carbolines, such as harmane, harmol, and harmaline, which can inhibit monoamine oxidase, the enzyme responsible for breaking down serotonin and related compounds,” Issahaku said. “This suggests that natural psilocybin-producing mushrooms may have the potential to produce stronger or longer-lasting effects than synthetic psilocin alone, possibly through an ‘entourage effect’ involving multiple bioactive compounds.”

While these findings offer a detailed look into the chemistry of psychedelics, the researchers note limitations to their approach. Because the study relied entirely on computer simulations and existing databases, the results only represent theoretical predictions.

“Because the data were derived from previously published databases and computational modelling, the results suggest potential mechanisms rather than definitive biological effects,” Issahaku said. “The concentration of these compounds can vary significantly depending on the mushroom strain, developmental stage, and environmental conditions that influence growth.”

“In addition, other psilocybin-producing genera, such as Panaeolus or Gymnopilus, may contain different bioactive compounds. Therefore, while the findings highlight possible “entourage effects,” further experimental studies are needed to determine their practical biological significance.”

The researchers also caution against interpreting the findings to suggest that whole mushrooms are inherently safer or more effective than synthetic psilocybin based on these results. Some of the targeted brain receptors are also involved in regulating blood pressure and cardiovascular function. The scientists point out that using whole mushroom extracts could carry distinct physical risks that require formal medical evaluation.

Future research will focus on testing these computer predictions in actual biological environments. The scientists plan to use cerebral organoids, which are miniature models of human brain tissue grown in a lab, to compare how synthetic psilocin and whole mushroom extracts alter genetic expression.

“Apart from assessing the mechanisms of action of psychedelics, research also needs to focus on the individual undergoing the therapy,” Issahaku said. “Different genetic profiles may be correlated with the efficacy and/or risk of psychedelic treatments. Generalizations across populations should therefore be avoided, as population-specific variation may significantly contribute to therapeutic outcomes.”

The study, “Network pharmacology and molecular simulation reveal the entourage effect mechanisms of psilocybin-producing mushrooms on the brain,” was authored by Zurika Murray, Angélique Lewies, Johannes Frederik Wentzel, Marietjie Schutte-Smith, Elizabeth Erasmus, Anwar Noreljaleel, Hendrik Visser, Anke Wilhelm, and Abdul Rashid Issahaku.