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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” (or at least a less rigid experience of negativity) 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, like ketamine, 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 clarity and mental flexibility that allows people to jump outside their patterns.”

What Happens During a Psilocybin Therapy 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. (Note: While psilocybin may be legal in Oregon, it remains illegal on a federal level.) 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.” (For more information on the role of music in psychedelic  psychotherapy, see the work of Mendel Kaelen, PhD.)

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 role of the trained therapist is to maintain safety,  reassure the participant when anxiety arises, and witness the process.  Participants are encouraged to direct their attention inward and focus on changing unhealthy behaviors or healing painful emotions. This part—what Johnson calls “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.”

Psilocybin Risks: Important Things to Know

Psilocybin Risks: Important Things to Know

How to Join a Psychedelic Clinical Trial

If you’re interested in becoming a psychedelic lab rat, there are a number of research trials in various phases recruiting both healthy volunteers and those with specific mental health conditions. Here’s a list of research institutes with ongoing or future trials you can explore for possible participation.

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Why People Take Hallucinogens

Hallucinogens are a type of substance that causes hallucinations, or sensations and pictures that appear real but are not. Hallucinogens (also known as psychedelics) have been used for millennia by people from many cultures for religious ceremonies, by artists to spur creativity, and for enjoyment. People experiment with hallucinogens for a variety of reasons, but for the most part, they change perception, ideas, and feelings. Although most are not addictive, some may be, and there may be some hazards and advantages to using hallucinogens.

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How Are Psychedelic Drugs Used?

Psychedelics are frequently smoked (and inhaled), consumed, or made into tea. Many societies have utilized hallucinogens for ages, and some are still employed in religious rites to experience spiritual or heightened states of consciousness.
In the 1960s, hallucinogens were utilized in psychotherapy, although this was discontinued for primarily political reasons until recently.
2 Psychedelics have now been reintroduced into experimental psychological treatment as a result of recent psychological research.

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Effects of LSD Use

LSD is a mind-altering substance. It is assumed that LSD produces its typical hallucinogenic effects by interacting with serotonin receptors in the brain. Serotonin is a neurotransmitter that regulates your mood and behavior, as well as your senses and thoughts.
The physical effects of LSD vary from individual to person. When taken by mouth, the first effects of the medicine are usually noticed 30 to 45 minutes after taking it, peak around 2 to 4 hours, and may continue 12 hours or longer. The intravenous (IV) method has substantially faster results, generally within 10 minutes. Among the consequences are:

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