Psilocybin and Mental Health: The Magic of Mushrooms​

Humans have traditionally used fungi’s metabolic products for medicinal purposes (e.g., penicillin). Psilocybin is a fungus metabolite that has gained popularity among media outlets, physicians, and academics in recent years. The chemical, which is naturally found in a variety of mushroom species (often referred to as “magic mushrooms”), interacts with serotonin receptors in the brain to produce a variety of psychedelic effects.

A increasing body of studies suggests that the chemical, when delivered under controlled conditions and accompanied by supportive therapy, may be useful for treating a variety of psychiatric diseases, including depression. However, uncertainties about psilocybin’s mechanism of action, as well as stigma, finance, and regulatory barriers, must be resolved before it may be used for regular therapeutic purposes.

What is psilocybin, and how does it work?

Psilocybin is naturally generated by over 200 species of basidiomycetes fungi, sometimes known as psilocybin mushrooms. These mushrooms come in a variety of shapes and sizes and are found all over the world. Psilocybin may be synthesized and supplied in standardized doses, making it commonly employed in clinical settings.

Psilocybin is a serotonergic psychedelic, like LSD and mescaline. Depending on the individual and dosage, psilocybin can produce euphoria, alterations in perception, perceived spiritual experiences, and feelings of detachment, among other effects.

These effects are not caused by psilocybin itself; rather, it is processed after ingestion to produce psilocin, the compound’s active form. Psilocin stimulates the serotonin 5-HT2a receptors on cortical pyramidal cells in the brain. These cells are the brain’s key computational units, where everything comes together. According to David Nichols, Ph.D., a professor emeritus at Purdue University School of Pharmacy who has been researching psychedelics since the late 1960s, they aid in forming our perception of reality. By activating these receptors, psilocin affects brain metabolic activity and neural connections, influencing cognitive function and perception.

History of Psilocybin Research: A Winding Road

Despite decades of use in Central America (and presumably other places), psychedelic mushrooms remained virtually unknown in Western countries until the 1950s, when an American mycologist, R. Gordon Wasson, visited Huautla de Jiménez in Oaxaca, Mexico. In 1957, Life magazine published an article titled “Seeking the Magic Mushroom,” which introduced psychedelic mushrooms to a wider audience.

Albert Hofmann, a chemist at Sandoz Pharmaceuticals, extracted psilocybin from dried Psilocybe mexicana mushrooms and recognized it as the psychedelic “magic” in the mushrooms. Sandoz manufactured and distributed Indocybin®, a tablet containing psilocybin, for use in psychiatric research investigations.

The clinical potential of psilocybin

Throughout the 1960s, trials were done to determine the efficacy of psilocybin. However, research on psilocybin, along with other psychedelics like LSD and mescaline, bottomed out after the substance was categorized as a Schedule 1 narcotic by the United States narcotic Enforcement Agency (DEA) in 1970 as part of “the war on drugs.” It is possible to study Schedule 1 substances, but it requires costly and time-consuming institutional and government permits. The stigmatization and legal hurdles surrounding psilocybin hindered research into its therapeutic potential.

However, the gears have gently begun to move again.In the mid-2000s, seminal clinical research cleared the path for subsequent attempts supported by benefactors and private groups, such as the Heffter Research Institute, formed by Nichols to help design and fund psilocybin investigations.

Scientists around the U.S. are researching psilocybin’s potential medical applications, using modern best practices for psychedelic research. Make no mistake: psilocybin is a Schedule I substance, and it is still associated with stigma. However, the more scientists investigate it, the more interested they are in continuing to do so.According to Sandeep Nayak, M.D., an assistant professor at the John Hopkins University Center for Psychedelic and Consciousness Research, “in the short [span] of a couple of months, we’re getting lots of studies out.”

Nichols acknowledged that there is a great deal of interest in psilocybin. On, there are approximately 130 ongoing or upcoming experiments employing psilocybin. “Five years ago, you wouldn’t have found any,” Nichols added.

Recent study suggests that psilocybin can effectively treat psychiatric problems such as obsessive-compulsive disorder, alcohol use disorder, and substance use disorders when administered under medical supervision in controlled settings. It is being studied for several conditions, including smoking cessation, Alzheimer’s illness, and eating problems.

While the number of illnesses is expanding, many studies have focused on psilocybin’s ability to alleviate depression. Psilocybin has been shown in multiple clinical trials to improve depression symptoms, even in those with treatment-resistant depression (those who have not responded to at least two courses of standard antidepressants, such as SSRIs).In the largest phase 2 double blind experiment to date, a single 25 mg dose of synthetic psilocybin combined with psychotherapy significantly reduced depressed symptoms after 3 weeks compared to the control dose (1 mg). How? Researchers don’t yet know.

Psilocybin is provided clinically in a controlled setting with supportive care.

Source: Thomas Angus, Imperial College London/Wikimedia Commons.

“The only thing we know for sure is that [psychedelics, like psilocybin] activate serotonin receptors, but we really don’t know their mechanism for producing an antidepressant—and not just antidepressant, but an antianxiety, antiaddictive—effect,” he said. It is possible that psilocybin changes neural connections in brain regions associated with rumination, receptivity, and emotions. COMPASS Pathways, the business that conducted the trial, is starting a phase 3 trial this year with the objective of obtaining FDA approval by the end of 2025.

Benefits of Psilocybin Treatment

When it comes to treating depression, Nichols identified psilocybin’s quickness and efficacy as two of its most appealing characteristics. Psilocybin’s effects are seen shortly after administration (days), as opposed to traditional antidepressants, which, when effective, can take weeks to completely manifest. Antidepressant effects can endure for a long time, ranging from 4 weeks to 6-12 months, depending on the study. While someone may have to take a normal SSRI on a regular basis for months or years, they may only receive one dose of psilocybin every few months, if not once a year. For Nayak, the “transdiagnostic” aspect of psilocybin (i.e., its capacity to be used for different reasons) is an added benefit.

The risks of psilocybin treatment

Still, Nayak stressed that psilocybin does not work for everyone, and the effectiveness varies from person to person. Furthermore, in some situations, psilocybin can be dangerous. “People who take [psychedelics] who should not take them can have panic attacks and confusion, and it may precipitate psychosis in people who are predisposed to psychosis,” such as those with schizophrenia or bipolar illness, Nichols noted. Clinical trial recruitment is dependent on meticulous screening to establish whether a participant’s personal and familial medical history predisposes them to unfavorable reactions.

Nonetheless, even after meticulous screening, psilocybin is not ideal. In the COMPASS Pathways trial, regardless of psilocybin dosage, 77% of individuals experienced headache, nausea, exhaustion, and dizziness. Some individuals reported suicide ideation and self-injurious conduct, which is “common in treatment-resistant depression studies,” according to the business. This should be considered as research advances.

While many of the above effects are not unique to psilocybin in comparison to standard antidepressants, the stigma associated with its recreational use casts it in a more negative light from a regulatory standpoint—according to Nayak, these types of outcomes could be a hurdle to FDA clearance. “I don’t think it’s [ever] going to be a situation where your doctor writes you a prescription for psilocybin,” said Nichols. “I think it’s always going to have a level of control for safety.”

Psilocybin’s Path Forward

Several states, including Colorado and Oregon, have allowed therapeutic psilocybin use. However, there are certain basic questions about psilocybin that do not have reliable answers. Clinicians are still studying how psilocybin works, who it benefits, and when and how often it should be administered. To answer these questions, more clinical trials with a larger sample size will be required.

Obtaining funding for such studies is difficult; the stigmatization of psilocybin has caused government funding bodies to avoid work containing the substance. However, Nichols believes that when more studies confirming the potential advantages of psilocybin emerge, there will be a stronger push and motivation for funding. He and Nayak believe this will be dependent, in part, on a “reeducation process” to help people decouple historical connotations about psilocybin from growing scientific facts, which suggest that psilocybin-assisted therapy can be useful in some circumstances.

Should psilocybin-assisted therapy be approved by the FDA, both researchers emphasized the significance of determining the medication’s scalability and cost. In experimental studies, psilocybin-assisted therapy can cost tens of thousands of dollars per patient. It will be critical to get to the stage where it is broadly available (for example, covered by insurance companies).

All of this takes time, but things are progressing. “It’s kind of like a snowball rolling downhill very, very slowly,” said Nichols. “It’s a work in progress.”