Today's episode journeys into the neuroscience behind magic mushrooms! Psilocybin, the psychoactive ingredient, is known for making its users feel like their senses are mixing, their brains are dissociating, and the walls are melting? Does it all come down to cortical deactivation in the brain region responsible for encoding our sense of self? Come and listen to learn a little bit more about magic mushrooms effects, their huge potential as therapies for mental health disorders, and the potential consequences of their use.
If you have any comments, questions, concerns, queries, or complaints, please email me at NeuroscienceAmateurHour@gmail.com or DM me at @NeuroscienceAmateurHour on Instagram. Citations below:
Hartney E. What to Know About Magic Mushroom Use. Verywell Mind. Published February 26, 2012.
Psilocybin (Magic Mushrooms) Uses, Effects & Hazards. Drugs.com. https://www.drugs.com/illicit/psilocybin.html.
Lowe H, Toyang N, Steele B, et al. The Therapeutic Potential of Psilocybin. Molecules. 2021;26(10):2948. doi:10.3390/molecules26102948
Aronson JK, ed. Psilocybin. ScienceDirect. Published January 1, 2016. Accessed January 26, 2022. https://www.sciencedirect.com/science/article/pii/B978044453717100158X
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Carhart-Harris RL, Erritzoe D, Williams T, et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of the National Academy of Sciences. 2012;109(6):2138-2143. doi:10.1073/pnas.1119598109
Bhagwagar Z, Hinz R, Taylor M, Fancy S, Cowen P, Grasby P. Increased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [(11)C]MDL 100,907. The American Journal of Psychiatry. 2006;163(9):1580-1587. doi:10.1176/ajp.2006.163.9.1580
Psychedelic Treatment with Psilocybin Relieves Major Depression, Study Shows. Johns Hopkins Medicine Newsroom. Published November 4, 2020.
More promise for psilocybin in depression but safety remains a concern. Clinical Trials Arena. Published November 15, 2021.
Vollenweider FX, Vollenweider-Scherpenhuyzen MFI, Bäbler A, Vogel H, Hell D. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. NeuroReport. 1998;9(17):3897-3902.
Mozhdehipanah H, Gorji R. Subarachnoid Hemorrhage as a Manifestation of Magic Mushroom Abuse: A Case Report and Review Literature. Journal of Vessels and Circulation. 2020;1(3):40-42. doi:10.52547/jvesselcirc.1.3.40
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Hello! My name is Barbara and this is Neuroscience: Amateur Hour.
Welcome back, you wonderful wonderful people. Thank you so much for tuning back in! This is one of my favorite parts of the week - learning about some cool stuff and sharing it with you!
Today I want to talk about shrooms. Mushrooms. Magic mushrooms. Psilocybin. Lucy in the sky with diamonds. A little bit of alice, a little bit of boomers, buttons, mushies, pizza toppings.
Shrooms.
I was having a conversation with a couple of friends and I realized I have a lot of prejudices against certain drugs (thanks DARE, classical American upbringing, and some wack family history) but I don’t know a lot about their uses, potencies, side effects, or long term effects. My personal perception of mushrooms is negative but I hope to challenge myself to learn more, to understand their therapeutic uses and potential as treatments for mental health disorders, and then form a more educated opinion.
And I appreciate you guys for being along for the ride!
So what are magic mushrooms? They are recreational drugs, which can be eaten on their own, mixed with foods, pickled, brewed into a tea, mixed with cannabis or tobacco and smoked, or taken as a liquid with the psychoactive ingredient.
The psychoactive ingredient in question is psilocybin, which was isolated in 1958 by Dr. Albert Hofmann, who incidentally also discovered lysergic acid diethylamide, or as its more commonly known - LSD. The man really dedicated his life to hallucinogenic substances.
I’ll do another episode about LSD later on but I think it is hilarious to know that Hofmann ingested a small amount of LSD through his fingertips (wear gloves in the lab guys, that Bio101) and promptly got really high and was like “wow that’s weird”. Three days later, he ingested 250 micrograms of LSD and started feeling the effects from it on his bike ride home, leading LSD enthusiasts from then on to celebrate his first intentional trip as “Bicycle Day”.
Hofmann was a huge fan of hallucinogens and called them “medicine for the soul” which is the energy I will be bringing to the rest of this episode.
So let’s talk a little bit about what people feel on mushrooms. So as I said before, they are most often eaten and absorbed through the stomach lining. Most of the time, this is the slowest method of absorbing a substance. I mean think about injecting something or smoking or snorting - the route from there to the brain is much shorter than if you are eating something, waiting for it to be absorbed through the stomach lining or processed somewhere in the gastrointestinal tract and pumped through your blood until it reaches your brain.
Effects peak about 1-2 hours after consumption and last about six hours so if you are planning a trip - I would portion out about half a day, maybe more. Like all drugs, effects can be unpredictable and vary from person to person depending on your size, weight, tolerances, mental health history, star alignment etc.
So psilocybin has a variety of psychological effects constituting a “trip”. These include intensified feelings and sensory experiences. You might feel that the walls are melting or the plants are talking. You might feel like time is passing too slowly or too quickly. Your heart rate, blood pressure, and body temperature may increase while you lose your appetite and your mouth dries out.
Another cool side effect is the mixing of senses - synesthesia. You can see sounds or hear colors or smell names. Many people report having had a spiritual experience, a union with some sort of higher power. Fundamentally, a good trip is generally characterized by feelings of relaxation and detachment from the sense of self and the environment.
But fundamentally, what you feel under the effect of psilocybin is based on your mental state and surroundings. All too often, people report bad trips, sensations of excessive sweating, panic, paranoia, and even psychosis. I had to google the formal definition of psychosis and it simply means losing touch with reality, seeing, hearing, or believing things that aren’t *real*.
So let’s dive deeper. What’s the mechanism of action of psilocybin? So upon consumption, psilocybin is transported to the liver where a phosphate group is removed so it becomes the active metabolite psilocin. Importantly, psilocybin can cross the blood-brain barrier to get to the brain.
Psilocin is a tryptamine and acts on serotonergic receptors, specifically, it acts as an agonist (activator) of serotonin 5HT2A receptors, which are especially prominent in the prefrontal cortex, a brain region responsible for planning, personality development, attention, impulsive control, prospective memory and other aspects of cognitive control. We know this because in mice that have had the 5HT2A receptor knocked out - classical hallucinogens are devoid of effects.
For a long time, it was thought that by binding to these 5HT2A receptors, and others (5HT1A, HT1D, and HT2C -though these are thought to play lesser effects), magic mushrooms increase cortical activity.
However, given medical, legal, and societal concerns, we haven't had much research in this area since the 1960s. Psilocybin is a Schedule 1 substance under the Controlled Substances Act in the United States which means that the government has decided that mushrooms have no accepted medical use and a high potential for abuse. Other schedule 1 drugs include LSD, heroin, marijuana, ecstasy, and peyote to name some.
I have some questions about whether these classifications are accurate given that weed is literally used as a medication by some people and is legal in certain states and as I will get into later, psilocybin and LSD may also have some pretty substantive treatment uses. Sounds like we need to reschedule a lot of drugs.
But given their classification, obtaining magic mushrooms for research purposes is complex and there are so many loopholes to jump into. Everyone that works in the lab will probably need to get screened and you need additional safety measures for storage etc. Long story short - there isn’t a lot of research in this area.
But I was able to find a study by Carhart-Harris et al that had some pretty unexpected results. Researchers demonstrated that psilocybin significantly decreased, not increased, brain blood flow and venous oxygenation (markers of brain activity) in a manner that correlated with its subjective effects, or how strongly you feel the effects. In addition, taking psilocybin significantly decreased the functional connectivity between two brain regions - the medial prefrontal cortex and the posterior cingulate cortex - brain regions responsible for cognitive control.
Why is this? We thought this drug would increase cortical activity, not decrease? One idea is that stimulation of these 5HT2A serotonergic receptors increases cell inhibition which may explain some of the deactivation that's occurring here but there could also be another explanation - we simply don’t know yet.
It is noteworthy to mention that the regions which showed the most consistent deactivation after psilocybin use are also those that have disproportionately high activity under normal conditions. For example, metabolism in the posterior cingulate cortex is 20% higher than most other brain regions, yet psilocybin decreased its blood flow by up to 20% in some subjects.
These brain regions have also been postulated to be important in forming our understanding of consciousness and other high-level constructs like “self” or “ego” which explains why significant deactivation after drug use in these brain regions has such a profound effect on consciousness, our understanding of ourselves and our environments.
This is super cool. This finding is also consistent with Karl Friston’s - free energy principle - which proposes that the mind/brain works to constrain its experience of the world. Fundamentally the parts of our brain that regulate cognitive control limit the number of ways that we can experience something. Like if you see a water bottle on a table, you're gonna say alright - it's a water bottle, it's a blue color, it's standing still on the table. This theory states that we are limited in the number of states we can experience in order to maintain a steady-state and remain functional in our daily lives.
But if your brain self-restricts and you DEACTIVATE the brain regions actively doing that - you might experience things in new ways? You might no longer be confined to a certain number of states that you can experience, the water bottle might change colors or start melting or talking to you or something else! But if you think about it - it makes sense that our brains limit the number of states we can experience to maintain homeostasis because we aren’t particularly functional when we’re tripping balls. Like at all. Can’t work, can’t hunt, can’t take care of ourselves or others.
Isn’t that insane???? Like mushrooms may unlock new ways of experiencing the world around us. I’m fangirling because I think there’s a gap between our understanding of consciousness and the biology we can see in experiments and this is one of those theories and findings that seems to unify those two pretty disparate fields of study.
So moving forward - one of the fascinating things about mushrooms is that they have huge potential as a therapy for mental health and psychiatric disorders. One of those is depression.
Depression has been characterized as an “overstable” state, in which cognition is rigidly pessimistic. Trait pessimism has been linked to a deficiency of 5HT2A, that serotonergic receptor stimulation, particularly in - you guessed it - the medial prefrontal cortex.
Some recent studies have shown that psilocybin can increase the personal sense of well-being and openness and depression scores in terminally ill cancer patients significantly decreased after treatment.
Johns Hopkins conducted a study in 2020 in a small group of adults with major depression and reported that after two doses of the psilocybin and supportive psychotherapy, patients reported rapid and huge reductions in depressive symptoms. These results were four times larger than what has been seen in clinical trials with traditional antidepressants. Given that traditional antidepressants are often unreliable and may take weeks to take effect, psilocybin may be a really viable treatment option for patients with depression.
On November 8th of last year, a pharmaceutical company called Compass Pathways reported positive results from the largest clinical trial to date of psilocybin. The Phase 2b trials enrolled 233 patients and evaluated a single dose of psilocybin in conjunction with psychological support from specially trained therapists for treatment-resistant depression.
However, the results raised big concerns about safety. Three participants in the highest dose group displayed suicidal behavior and some others in the lower dose group also reported suicidal ideation. Given that suicide is the most serious consequence of depression, any treatment that could potentially make that symptom worse needs to be evaluated and studied with great care.
Beyond the potential benefits for mental health, many people report their mushroom-induced trips as positive experiences. They may have had a spiritual experience felt closer to friends or even learned more about themselves. Overall, trips do seem to be very very meaningful to the user.
But like anything mind-altering, there may be consequences as well.
The first thing to consider is that anyone can have a bad trip. I’ve read that most bad experiences have to do with expectations. If you go into the trip expecting bad things to happen or you have serious worries or anxieties, you’re more likely to experience panic or paranoia while under the influence.
Another major concern with many drugs is the possibility of addiction. We’ve all heard about people on opioid medications, cocaine, heroin, or other drugs whose addictions have taken everything that they love.
Psilocybin is not considered physically addictive and normally does not trigger compulsive use. In fact it has been proposed as a treatment for addiction! Mushrooms can be psychologically addictive though which is a bit more of a complex issue.
The difference between physical and psychological addiction is that during physical addiction, the body physically craves the substance, for example, if a user with active alcoholism gets the shakes after not drinking for a little while. Psychological addiction is more like having a conditioned response to taking a certain drug. Going back to the alcohol example - it's like NEEDING a glass of wine to feel relaxed after work or feeling cranky if you can’t take the drug you want to. Mushroom users can get addicted to the feeling of taking shrooms, the dissociation from self, or the high they get.
People who abuse other drugs may also abuse hallucinogens and there may be some sort of tolerance buildup. This is especially true if the drugs act on the same serotonergic receptors. Over time, people may need to take larger and larger doses to achieve the same result which can be dangerous because the drug is fairly unpredictable.
If you or anyone you know is struggling with addiction or substance abuse, please reach out to your healthcare provider or the substance abuse and mental health services administration free, confidential hotline. The number will be posted in the show notes.
A larger concern is that the use of hallucinogens such as magic mushrooms may aggravate or trigger certain mental health disorders. There have been some reports that if someone is at risk for schizophrenia, a condition defined by hallucinations, trouble thinking, trouble motivating oneself, and delusions, abusing psychedelic drugs may trigger the onset of the condition. The paper I found for this finding was from 1998 so there are more updated findings, I’m sure or at the very least the research is in progress.
There was also a case study published in 2020 about a 20-year-old man who arrived at the emergency room with a thunderclap headache after ingesting an unknown quantity of mushrooms four hours earlier.
He was found to have a subarachnoid hemorrhage, a brain bleed, the kind which is normally found in amphetamine abuse. It was the first instance of these subarachnoid hemorrhages ever being linked to psilocybin products and defined an interesting new side-effect and area of research for cases of mushroom abuse.
There have also been some studies on psilocybin-induced migraines but mushrooms have also been proposed as a treatment for cluster headaches so I think it comes down to the fact that we simply don’t know enough at the moment.
Finally, there is something to be said for the fact that people do harm to themselves and others during trips, especially bad ones. There have been some studies linking users taking high doses to medical emergencies and psychological distress. Some people may self-harm, hurt others, at times even take their own lives.
In summary, mushrooms are unpredictable and fascinating. I kinda skipped over their history and their uses in spiritual ceremonies, which can be traced as far back as 9000 BC with some experts claiming that cave drawings in North Africa may allude to magic mushroom use.
Like any mind-altering substance, there are some causes of concerns for individual safety, especially for people with pre-existing mental health conditions that could be aggravated by drug use but it would be incredibly remiss to ignore the profound potential therapeutic effects of psilocybin for everything from addiction to treatment-resistant depression to cluster headaches. I can only hope that perhaps reclassification and decriminalization may improve access to mushrooms for researchers so we finally figure out what the heck they’re doing in our brains.
That is a bite-sized overview of the neuroscience of magic mushrooms. I hope that you enjoyed the episode and you learned something new! I’ve cited all my relevant sources and papers in the show notes and you should keep an eye out on Instagram for some cool figures I think are pertinent.
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Happy researching! Hope to see you again soon!