What is Psilocybin?
Ask people who’ve tried so-called “magic mushrooms” what the experience was like, and many will tell you it’s life-changing.
Turns out, those aren’t just the ravings of a hallucinogenic mind. In fact, a growing group of researchers is excited about the potential benefits of psilocybin, the primary hallucinogenic compound in ’shrooms, which is showing a lot of promise for helping people overcome hard-to-treat (or treatment-resistant) and life-disrupting conditions like addiction and major depression.
Yet since 1970, psilocybin has been classified as a Schedule 1 illicit drug, which is defined as having no currently accepted medical use in the US, as well as a high potential for abuse. So, why the recent resurgence in psilocybin interest, and what is the research showing in terms of benefits, mechanism of action, and even safety? Here’s the lowdown, but first, a history lesson:
’Shrooms: A Long Strange Trip Through Time
Magic mushrooms have been used for more than 10,000 years in various spiritual and medical rituals for their ability to alter consciousness and trigger mystical experiences.
As the story goes, R. Gordon Wasson, an American banker, and mushroom enthusiast was vacationing with his wife in Mexico in 1955 when they became the first outsiders to participate in the Mazatec Indians’ sacred mushroom rituals. He brought some of the mushrooms back to his home in New York City, and later shared his experience in Mexico in a Life magazine article published in 1957, when LSD—a chemically-similar psychedelic but about 100 times more potent—was already being studied for its ability to treat alcoholism and other psychiatric illnesses.
Three years later, two Harvard psychologists—Timothy Leary and Richard Alpert—began to explore how cognition, perception, and emotion are impacted by psychedelic drugs. They started the notorious Harvard Psilocybin Project, which involved administering psilocybin to student volunteers to document its effects. Bear in mind, psilocybin and LSD were legal then, but both Leary and Alpert were also tripping during their experiments, which ultimately got them fired in 1963.
By now, psychedelics were gaining a reputation in mainstream culture as being dangerous. Numerous states began banning their use, and in 1970, Congress passed the Controlled Substances Act and classified both psilocybin and LSD as Schedule 1 drugs. With both now illegal, funds for research on psychedelics disappeared and research slowed to a drip.
But it didn’t stop altogether, and decades of findings slowly accumulated, showing the benefits of psilocybin. In 2018, the FDA took note of studies looking at its ability to ease treatment-resistant depression, and designated it as a Breakthrough Therapy, a classification that indicates significant therapeutic potential, and fast-tracked the development and review process.
Another sign of its potential as a clinical treatment: Johns Hopkins University launched the Center for Psychedelic & Consciousness Research in September 2019, where research continues to reveal psilocybin’s therapeutic effects. A small handful of other, reputable centers for psychedelic research have also cropped up including the Center for Neuroscience of Psychedelics at Massachusetts General Hospital and the Imperial Psychedelic Research Programme at Imperial College London.
What the Research on Psilocybin Shows
What’s most interesting about psilocybin is its ability to address a few different types of conditions. “The most promising potential is for addiction—smoking, alcoholism, cocaine,” says Matthew W. Johnson, PhD, a professor of psychiatry at Johns Hopkins University and associate director of the Center for Psychedelic & Consciousness Research. His ongoing pilot study on nicotine addiction has found that 80% of participants who underwent psilocybin therapy quit smoking, and 60% of them were still abstinent 16 months later—impressive compared to the 35% success rate of varenicline, the most effective of other smoking cessation therapies. “The idea that something could be efficacious for multiple substances is, itself, very atypical and exciting,” says Johnson. “There’s a very good case that psilocybin can treat the psychology of addiction, not just alleviate the withdrawal symptoms and reduce cravings.”
In addition to treating addiction, psilocybin has also shown impressive results in treating depression and death anxiety. For instance, one small recent study published in JAMA Psychiatry found that patients with major depressive disorder experienced significant improvement after being treated with psilocybin in combination with psychotherapy, and more than half were in remission four weeks afterward. “The most advanced work is with patients with life-threatening cancer, where we saw dramatic reductions in depression and anxiety that showed persistent benefits six months later, which is extremely atypical,” says Dr. Johnson.
Beyond those applications, researchers are also looking at psilocybin for anorexia, Alzheimer’s (related to both depression and cognitive decline), post-traumatic stress disorder, and obsessive-compulsive disorder. “We don’t have the answers yet, but I would say they’re good bets,” says Johnson.
How Psilocybin Works Its “Magic” in the Brain
Exactly what psilocybin does to the brain to trigger changes in mood and behavior is still a big mystery, but we know that, acutely, when someone’s on a psychedelic drug, the brain communicates in a much different way than it was “programmed” to, says Michael McGee, MD, staff psychiatrist at Atascadero State Hospital in California and author of The Joy of Recovery. He explains that the programming begins in mid to late childhood to handle the roughly 90 to 100 billion neurons in the cerebral cortex, the outermost layer of the brain that plays a key role in higher-order functions such as perception, thought, memory, and judgment. “If all of those neurons could communicate with each other, the number of potential connections is probably higher than the number of atoms in the universe,” says Dr. McGee.
But the brain can’t function like that—it has to be efficient for its survival. “So there’s a pruning process, where perceptions of the way we understand ourselves in the world are narrowed, and the ego-consciousness develops,” explains Dr. McGee. “And what happens to all of those neural connections is that some get prioritized and are very efficient, like highways with a lot of neural traffic going through, and the others are paired down and rarely used, like dirt roads.” That’s where psilocybin can come into play—it can basically open up those dirt roads again and send a lot more traffic down them.
“Psilocybin and other psychedelics that are serotonin HT2A receptor agonists or stimulators massively increase brain entropy, so you have all of the neurons talking to each other in a very open, non-focused, and less organized way,” Dr. McGee says. At the same time, he says, there’s a reduction of activity in the Default Mode Network (DMN), a network of interacting brain regions that’s active when you’re not focused on the outside world. In other words, an inhibited DMN means there’s less of that stream of self-reflective thought going on that we associate with our independent thinking self.
“When that goes away, and it’s combined with all of these novel neural connections, the brain is capable of making radically different associations and developing new understandings of reality,” says Dr. McGee. For instance, if the operating paradigm of the brain is trauma-based and defines others and the world as “bad” and “unsafe,” it could be replaced with a larger paradigm of “goodness” that sees the essence of the universe as love, and thus produces more feelings of love and compassion.
Animal studies also suggest that psychedelic drugs can prompt the growth of new neurons and branch between dendrites, the parts of brain cells that reach out and communicate with other brain cells, Johnson says “It could be that these types of changes are unfolding in the days and weeks following a psilocybin session, and they represent a kind of fluidity and plasticity in the system,” he explains. “It’s like a plastic that’s been heated and becomes malleable enough to reshape. Eventually, it’s going to cool down, but you’ve established a new normal during this time.”
Big picture, Johnson suspects that the drug is augmenting the process of how people change their behavior by increasing their sense of openness, which could lead to a future world with less depression, anxiety, and addiction. “In all of the disorders we’re studying, you’re essentially talking about people who are stuck in a very narrow mental and behavioral repertoire, and it’s very hard to get out once you’re there,” says Johnson. “There are so many self-reinforcing properties—more negative thinking leads to less social interaction and then more focus on the addictive substance—and it’s that ‘stuckness’ that really seems to be affected by psychedelic experiences. They seem to supply a clarity and mental flexibility that allows people to jump outside their patterns.”
What Happens During a Psilocybin Session?
Let’s start with the fact that psilocybin is still illegal in all states except Oregon, which in November 2020 became the first state to permit regulated use in a therapeutic setting only—it doesn’t have the same legal status as cannabis. If you don’t live in Oregon or have access to a licensed facilitator and you’re interested in trying psilocybin, there are a number of research trials in various phases that are recruiting both healthy participants and those with specific mental health conditions. (To learn more, check out “How to Join a Psychedelic Clinical Trial,” below.)
As with all clinical trials, not everyone is qualified to participate. Volunteers are first carefully screened to ensure they’re not at risk of an adverse reaction because psilocybin can exacerbate or trigger the onset of underlying psychotic conditions. This means people with a personal or family history of conditions like schizophrenia are at high risk of long-lasting harm and should steer clear of psilocybin.
If selected, a participant is set up in a controlled environment with a comfortable place to lie down with an eye mask and some well-chosen music. “Soothing music has been part of the psilocybin research protocols for decades,” says Dr. McGee. “I’m not sure of any evidence that it’s necessary for change, but intuitively it seems that it would help facilitate the experience.” Then they’re given a controlled dose of synthetic psilocybin; Johnson says 20 mg to 30 mg, adjusted to body weight, is used to bring on the mystical experience.
Throughout the 6- to 8-hour session, at least one trained therapist with a master’s degree (or higher) in clinical research stays with the participant at all times. The trained therapist guides the experience and later encourages the participant to share their thoughts and insights, with a focus on changing unhealthy behaviors or healing painful emotions. This part—what Johnson calls “the integration”—is critical.
“You need to talk with the patient about what the experience means for their life. And if they’re prompted to make changes, discuss how they’re going to establish those changes in their life,” he says. “The brain is in a changeable state, and what you do during that time of malleability, and in the several follow-up sessions (it can take one to three sessions, or more, to make a difference), is what determines the real-world outcome.”
Dr. McGee likens the integration process to burning gasoline in a car. “If you channel it through an engine, a gallon of gasoline could take you 30 miles. But if you just burn that gallon of gas in a pail, you won’t get anything out of it. These psychedelic experiences are kind of like that: They need to be channeled through an integrative process where a new narrative and a new repertoire of life skills is created and revised, just as happens in any kind of good therapy.”
Psilocybin Risks: Important Things to Know
Despite its Schedule 1 status, psilocybin appears to have only mild addiction potential. “It doesn’t act in the same way on the reward center of the brain or trigger compulsive use the way addictive substances do,” says Johnson. His research, published in Neuropharmacology, suggested that it be scheduled as a Schedule 4 substance, which is comparable in the addictive potential to benzodiazepines. But, he stresses, psilocybin can absolutely be abused. “There are cases of teenagers driving on it, or people falling from heights or stepping into traffic. It’s a powerful tool that, if used in a dangerous way, could harm the person or the people around them.”
What’s more, anyone can have a negative, emotionally painful, or frightening experience while on psilocybin, which again stresses the importance of a therapist and the integrative process. “Pain is not negative—you can have an extraordinarily painful experience that turns out to be the most positive experience of your life,” says Dr. McGee. “That’s why you need to be prepared beforehand, and coached to lean into the experience and accept it, not resist it. You’ve got to feel it to heal it.”
Dr. McGee also notes that most people who use psilocybin repeatedly experience tachyphylaxis, a rapidly diminishing response to successive doses of a drug, which renders it less effective. “The effect is common with repeat use of drugs that act on the nervous system,” he explains.
Finally, chronic use of psilocybin does come with cardiovascular risks. “It binds to HT2B receptors, which can cause dangerous changes in the structure and shape of heart valves,” Johnson says. Fen-phen—another drug that binds to HT2B receptors—was pulled from the market due to the risk of valvular heart disease, one cause of heart failure. “This likely isn’t an issue at all when you’re taking the drug once or a few times for therapeutic effect,” says Johnson. “But when you start talking about taking it once every three or four days for years on end, that’s a major issue that people aren’t talking about enough.”
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