How Psilocybin Can Rewire Our Brain, Its Therapeutic Benefits & Its Risks

Psilocybin is essentially serotonin in that its main effect is to mimic serotonin, but it does so in a very specific way by activating a subset of serotonin receptors in a very strong fashion, specifically the serotonin 2A receptor, leading to neuroplasticity at the level of neural circuits that serve memory and perception.

“psilocybin basically is serotonin...psilocybin main effect is to mimic serotonin. But it does it in a very specific way because it activates a subset of serotonin receptors in a very strong fashion leading to neuroplasticity at the level of the neural circuits”

The concentration of psilocybin in different strains of magic mushrooms varies tremendously, ranging anywhere from 0.5% to 2% of dry weight, meaning that someone taking the same gram amount of mushrooms from different batches could be ingesting anywhere from 5mg to 20mg of psilocybin depending on strain and batch variability.

“the concentration of psilocybin in different strains of mushrooms and in different batches, and depending on the age of those mushrooms, and how they've been stored, et cetera, can vary tremendously from batch to batch...The range is pretty broad. It's anywhere from 1/2% all the way up to 2%”

Trained guides can use real-time breathing techniques, specifically the physiological sigh, to help people under the influence of psilocybin reduce anxiety during the peak phase, preventing potential bad trips while allowing continued therapeutic benefit, with Dr. Matthew Johnson's laboratory incorporating this technique into psychedelic protocols.

“Dr. Matthew Johnson's laboratory has started to incorporate physiological size within these psychedelic sessions as a tool that the guides can refer people to before the session begins, teaching it to them. So they realize they can calm themselves down if necessary in real-time...when people are inside of the psychedelic session, if they feel their anxiety levels are going too high...By using the physiological sigh inside of the psychedelic session, Dr. Johnson's laboratory...are starting to use breathing techniques such as the physiological sigh as a way for these people who are under the influence of psilocybin to self-direct their own calm”

A reduction in dendritic spines in frontal cortex neurons occurs in depressed patients as shown in postmortem tissue, and treatments that relieve depression, both drug and behavioral treatments, correlate with increases in dendritic spine growth, suggesting that psilocybin's therapeutic effects for depression may operate through restoration of spine density.

“a reduction in the number of dendritic spines, these little mushroom shaped protrusions in the frontal cortex neurons of humans occurs in depressed patients. We know that from postmortem tissue. And that drugs that relieve depression or that treatments including behavioral treatments, that provide some relief from depression do seem to be correlated with increases in spine growth in frontal cortex neurons as well. So this raises a very interesting idea, which is perhaps it's the growth of new connections, these new dendritic spines in particular neurons. That's created by administration of psilocybin. That explains the relief from depression that people experience”

Having eyes closed for the majority of a psilocybin session is critical for therapeutic benefit because it limits focus on external visual hallucinations and allows the person to go inward to combine internal mind's eye visuals with thoughts, memories, and emotional changes, making the inward focus rather than external perception the key to effective therapeutic outcomes.

“if people are to take psilocybin and have their eyes open, much of their cognition, much of their thinking, much of the time spent in that psilocybin journey is focused on the altered perceptions of things in the outside environment...if one's goal is to derive long-lasting benefit from the psilocybin experience, it's very clear that having an eye mask or some other eye covering or something that ensures that one's eyes are closed for the majority, if not, the entire psilocybin session is going to be very useful”

After instances in the late 1960s and early 1970s when people took LSD without proper set and setting, such as staring at the sun until going blind or harming others, these incidents became bases for invoking the Controlled Substances Act to criminalize psychedelics, and the lesson is that proper set and setting is not optional but critical for legitimacy and future legalization.

“in the late 1960s and early 1970s when the Controlled Substances Act was invoked to make psychedelics like psilocybin illegal, one of the bases for that was not just the geopolitical unrest at the time...but also some highlighted instances in which people did not take set and setting into consideration, took things like LSD, stared at the sun, went blind. Or took psilocybin, went out, and harmed somebody else...the exact instances that lead to criminalization...it's such a critical time in the history and the use of psychedelics for therapeutic and other reasons...Getting setting correct, meaning making it absolutely as safe as possible for the person taking the psychedelic is absolutely key”

Approximately 90% of the serotonin in the brain and body is manufactured in the gut, but the serotonin in the brain is manufactured separately from gut serotonin by specific neurons in the brain, contradicting the popular belief that brain serotonin comes from gut serotonin.

“yes, it's true that about 90% of the serotonin in your brain and body is manufactured in your gut. However, contrary to popular belief, the serotonin in your brain is not manufactured from the serotonin in your gut. You have separate independent sources of serotonin. That is you have particular neurons that make serotonin in your brain. You also have serotonin in your gut and those work more or less in parallel separately.”

Neurogenesis (the addition of new neurons) is not the dominant mechanism of brain change in the adult human brain during learning, memory formation, or in response to psilocybin, despite being a popular concept, and probably accounts for only 1-2% of rewiring events important to us, with dendritic growth and spine formation being far more important.

“while neurogenesis is a really sticky idea and it makes great headlines, the addition of new neurons is not really the way that the brain changes under psilocybin, other psychedelics, or just generally. It's perhaps responsible for maybe 1% to 2%, and I'm being generous there, of the rewiring events that are going to be most important for all of us...Until further evidence comes out to the contrary, that's certainly where I and here I feel comfortable speaking for the majority of neuroscientists out there, professional neuroscientists. That is the paper showing adult neurogenesis are interesting, but they don't really explain most of the plasticity that occurs in the adult human brain”

Oceanic boundlessness—a sense of experiencing something mystical beyond ordinary experience, feeling connected to one's environment, guides, oneself, past, present, and perhaps the entire universe—is one of the key features of a positive psychedelic experience and is positively correlated with therapeutic outcomes from psilocybin for depression.

“one of the key features, if not, the key feature of a positive quote-unquote psychedelic experience is this sense of oceanic boundlessness occurring at some point during the psychedelic journey...The intensity of that experience of oceanic boundlessness, the mystical experience seems to be positively correlated with positive therapeutic outcomes. That is relief from major depression”

During psilocybin journeys, perceptual blending or synesthesia occurs where different sensory modalities merge, such as music changing the intensity of internal visual hallucinations, breathing becoming linked to auditory perception, or hand movements on a surface creating perceived changes in music frequency, representing a reduction in sensory modularity and integration of perception.

“if they take their fingertips and rub them across the couch or the chair that they happen to be lying down or sitting on, that they will experience a change in the music. Maybe even if they move their hand up, they hear an increase in frequency of sound. They move their hand down, they hear a decrease in frequency of sound. And all of this is linked to their emotional state at the same time and vice versa”

The typical duration of a psilocybin journey is 4 to 6 hours, with effects beginning 30 to 45 minutes after ingestion, a peak component with maximum emotional intensity and anxiety around 2 hours in, followed by gradual tapering described as 'parachuting back in' toward the 6-hour mark.

“the typical duration of the psilocybin journey is anywhere from 4 to 6 hours...people start experiencing about 30 to 45 minutes after ingesting psilocybin...There's a peak component in which there's a maximal intensity of emotion and often that's also associated with anxiety...tapers off slowly toward the 6-hour mark”

A 2022 New England Journal of Medicine study (No Surprise: Single Dose Psilocybin for Treatment-Resistant Major Depression) found that a single 25-milligram dose of synthetic psilocybin provided significantly greater relief from treatment-resistant depression at week 3 compared to 10-milligram or 1-milligram placebo doses, with relief remaining stable through week 12.

“the change in baseline levels of depression that is at week three following the psilocybin session was significantly better. That is people experienced more relief or more people experienced more relief from the 25 milligram dose than from the 1 milligram dose. And this is important. There was no significant difference between the 10 milligram dose and the 1 milligram dose...They still saw a significant degree of depression relief 12 weeks after the single 25-milligram psilocybin dose session”

People should not eat for at least four hours prior to a psilocybin journey because food in the gut impacts gut acidity, which affects the conversion of psilocybin to psilocin and thus the consistency and timing of drug effects.

“it was advised that people not have any food in their gut at the time in which they ingest or are injected with the psilocybin...psilocybin mushrooms...psilocybin that's converted to psilocin in the gut by the acidity of the gut. And the acidity of the gut is going to be impacted by the various foods that people eat. And so that's one of the major reasons why people are advised to not eat for at least four hours prior to the psilocybin journey”

People age 25 years and younger should not use psilocybin because their brains are still in a period of rampant developmental neuroplasticity, and the studies to date focus only on adults 25 years and older.

“everything I'm talking about today unless I say otherwise is really focused on adults, meaning people who are 25 years old or older. That is their basic wiring and rewiring of the brain that we call developmental neuroplasticity is completed...Most of the studies today that I'll talk about involve subjects ranging from 25 years of age out to about 70 years of age, but no one younger”

Adverse events were observed in essentially every dose group in the single-dose psilocybin trial, with higher incidence and severity in the 25-milligram group, ranging from mild transient side effects like headaches and anxiety to severe effects including suicidal ideation, illustrating the dose-response curve for both benefits and risks.

“there were adverse events in essentially every group. The number of adverse events was highest in the 25-milligram dose group...With higher dosages, there tends to be greater relief from depressive symptoms, but also a greater chance for adverse events. Some of those adverse events can be quite severe. So feelings of suicidal ideation, et cetera. Some of them one could consider a little less severe, mild headache, or severe headache that was transient, or anxiety that was transient”

Setting for a psilocybin journey must ensure physical safety with no windows to jump from, no streets with cars, no bodies of water, and requires presence of one or more sober individuals not also taking psychedelics to monitor the person and prevent self-harm or harm to others.

“The setting for a psychedelic journey needs to be one in which the person under the influence of the psilocybin or other psychedelic is safe. That means no windows they can jump out of, that means no streets of moving cars, they can run out into. That means no opportunity for getting lost. That means no opportunity for getting into bodies of water. In other words, it requires that there be at least one, and perhaps even two or more other individuals who are not also taking psychedelics who are not also taking psychedelics present in that setting to ensure that the person taking the psilocybin is not going to harm themselves or others”

Psilocybin should be contraindicated in people who have existing predisposition to psychotic episodes or bipolar episodes, people with first-degree relatives who have psychosis, schizophrenia, schizotypal issues, borderline personality disorder, or related psychiatric conditions, as psilocybin can trigger psychotic episodes both during and potentially in a long-standing way.

“people who have existing or have a predisposition to psychotic episodes or bipolar episodes, even having a first relative who has bipolar, or schizophrenic, or schizotypal issues can be a rule out condition, that is can get someone eliminated from a clinical study on psilocybin for fear of triggering psychotic episodes, not just during the psilocybin journey, but potentially in a long standing way”

Clinical trial participants with depression are typically required to stop taking antidepressant medications before psilocybin treatment, but all subjects are encouraged not to avoid restarting medications if their clinician determines it is necessary for survival, and the point is not to recommend that people on SSRIs should stop their medications but to note that trial protocols required this for study design reasons.

“it's a general feature of these trials that people are asked to stop taking their antidepressants prior to participating in the trial...all subjects were encouraged not to avoid taking those antidepressant medications if, in fact, their clinician felt that it was important for their immediate and long-term survival...no one should be reckless in thinking about what to add or delete from their drug protocol when dealing with depression”

Studies using mouse models to investigate psilocybin-induced structural plasticity typically used doses around 1 milligram per kilogram of body weight, which translates to approximately double the human therapeutic dose, so effects observed in rodent studies may require higher relative doses than what's used clinically.

“most of the studies looking at changes in plasticity in the mouse brain in response to psilocybin use the equivalent of 1 milligrams per kilogram of body weight...it's about double, the sorts of dosages that are typically used in humans. Maybe even triple in some cases”

Depression can be understood as people living out habitual negative contingencies (if A happens, then B will happen, leading to C) where attempts to improve situations repeatedly fail, and psilocybin can invoke new patterns of learning and consideration of different possibilities, ejecting people from these habitual thought patterns.

“when we look at depression, we often think diminished mood, people don't have an appetite, they're not interested in social relationships, or romantic relationships. They're really struggling. And all of that, of course, is true. But another lens to look at depression through is that a lot of that thinking and a lot of those emotional states that are negative are somewhat habitual. They relate to implicit understanding and living out of the idea that A leads to B leads to C. You seek out a relationship, it doesn't work out. Try a new job, you don't get the job. You get the job, it's no good. All these negative outcomes of if A, then B, then C. And it does seem that psilocybin can have this effect of invoking new patterns of learning. New considerations about what might be possible.”

Serotonin is involved in dozens, if not hundreds, and maybe even thousands of different functions throughout the body and brain—satiety, mood, pleasure, motivation, sleep, appetite, libido—which is why SSRIs that increase general serotonin transmission tend to have many side effects related to all these systems.

“Serotonin and all these different receptors that it binds to has dozens, if not hundreds, and maybe even thousands of different functions...serotonin is involved in so many different things because there are a lot of different so-called serotonin receptors...serotonin is involved in so many different things...And that is one reason why certain antidepressant medications which alter either increase or decrease the amount of serotonin transmission in the brain will often have a lot of side effects”