Psilocybin

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Unknown Speaker 0:00
This is a Kun V studios original program.

Speaker 1 0:03
The content of this program does not reflect the views or opinions of 91.5 jazz and more the University of Nevada, Las Vegas, or the Board of Regents of the Nevada System of Higher Education.

Speaker 2 0:20
Box Welcome

Speaker 3 0:26
to another episode of the chemical collective. Today.

Speaker 4 0:30
We're talking about psilocybin, which we seem to have mentioned in almost every episode. So I'm really excited to do a deeper dive into the topic. Today.

Unknown Speaker 0:37
I'm April Contreras,

Unknown Speaker 0:38
I'm Missy Buffalo,

Speaker 5 0:39
and I'm Dr Dustin Hines. So as stated, today, we're going to talk about psilocybin, which is a naturally occurring compound found in shrooms, magic mushrooms, all kinds of different names. And what this compound does, or these plant materials, do, is they alter perception. It's not actually the magic mushroom that does all the work. It's a alkaloid found deep inside the mushroom called silosin. It's a prodrug, which means when you ingest it, it changes into that silos and it interacts with serotonergic receptors. It has been used for cultures for centuries. We now know in our lab and other labs it has a vast therapeutic potential. So that's a brief introduction into it. We're going to dive more into these topics as we go in. Again, it's really known that these compounds found in Magic Mushrooms profoundly alter perception, mood, consciousness. Typically, they're ingested into the body, they become active in that silos. And we can have all kinds of hallucinations. We don't really understand the nature of hallucinations right now, and what I mean by that is, there's auditory hallucinations, there's visual hallucinations. Some people have reported synesthetic hallucinations, but historically, magic mushrooms have been used ritualistically and have this huge potential that we're talking about. So to get it started off, missy, can you describe or discuss the drug class of psilocybin and tell us a little more about its chemical structure? Yeah,

Speaker 4 1:59
so psilocybin belongs to the drug class term psychedelics, which is a term derived from the Greek word psyche, which means mind or soul in Delos, which means to make visible or manifest. And this term was coined in 1956 by the British psychiatrist Humphrey Osmond, who was looking for a name for substances that expand or reveal the mind. So he famously wrote to the writer Aldous Huxley. And Aldous Huxley wrote famously to fathom hell or sore angelic just take a pinch of psychedelics. That's a famous quote. Osman favored the term psychedelic over other terms like psycho mimetic, which means to mimic psychosis, and the term hallucinogen, he liked psychedelic because he thought it was clear and uncontaminated by other associations. So unlike psycho mimetic, which suggests a link to mental illness, psychedelic better captures the substances ability to reveal later aspects of the mind and consciousness. And this term psychedelic became widely used during the 1960s counterculture movement to describe substances like LSD, psilocybin, mescaline and DMT, which were celebrated for their capacity to induce profound changes in perception, emotion and thought, providing a powerful tool for probing the human mind.

Speaker 5 3:18
So Missy, you mentioned Aldous Huxley. Do you know any of his famous works, or what he did, or famous books?

Unknown Speaker 3:24
No, I'm not familiar. April.

Speaker 5 3:25
Do you know any the doors of perception? Yeah, huge book. So he was one of the first people to really talk about this idea that you can alter perception. I would say, not a must read, but kind of a very interesting read on this idea that there's a different realm you can go to and he really got into this idea of hallucinations, or hypnagogic dreams, or dreams. Do you know anything about that? April, about the nature of hallucinations? Yeah.

Speaker 3 3:50
And I think when I started kind of, you know, researching psychedelics, I remember kind of thinking a lot of the words that we use to kind of talk about these compounds. So psychedelics are also referred to, sometimes as hallucinogens, depending on maybe the time that you're looking like based on the time period you might see psychedelics be called one thing versus the other, and they're called hallucinogens because they generate these really distinct perceptual distortions and psychological experiences. They can change your mood, and these changes are often accompanied by imaginary percepts that are a lot like hallucination. So that's kind of why you might see them called this too. So

Speaker 5 4:33
really, in the circles I roll, and we really don't call them hallucinogens as much anymore. There's many different words. Can you dive into that a little bit? Missy,

Speaker 4 4:43
yeah, in our lab, we often refer to psilocybin as a psycho plastic in which really emphasizes the compound's ability to promote neuroplasticity, so promoting the growth and reorganization of neural circuits in the brain. And I like the use of the root plastic. Stove in there, which really reminds me of like molding or forming. So it emphasizes the compound's ability to induce adaptability and capacity for change in the brain, which is particularly relevant for therapeutic purposes, as we're going to talk about. And I

Speaker 5 5:14
think words come and go. So like I said, the word hallucinogen and even psychedelic kind of all falling out of favor a little bit already, psycho blasts falling into favor. Have you? Have you guys been aware of this? Why it is falling into favor?

Speaker 3 5:28
No, but I've noticed that I don't see it in as many papers, only from a certain like research labs. So

Speaker 5 5:34
a couple, a couple reasons are and something again, that our lab really put out there is that you have the burden of proof to show that you're actually creating neuroplasticity. So it's easier just to call it something else and not do that. But a bigger reason is drugs like ketamine have a profound effect on the number of spines, yet, really they're non dissociative. They're a very different subclass of drugs. So I'm having a feeling that we're still talking about psychoblast ins, at the scientific level, but I think that's gonna go away. And what I see happening is the kind of plant people are taking over now, and we're really seeing the word entheogen a lot, so something that brings you closer to yourself, but stay tuned. And then in that context, we would call ketamine a intactogen, intactogen, yeah,

Speaker 3 6:27
well, to build off of that, you know, cycle, the plastic changes that we're seeing in different papers and that you might be reading about are really related to, you know how psilocybin actually binds to different receptors and cells in the brain. So psilocybin that actual like, if you were to look up the molecule, it looks a lot like the serotonin molecule that we have in our brain. And serotonin is a neurotransmitter that regulates mood, perception and cognition. And so because psilocybin looks so much like serotonin, it can bind really well to serotonin receptors, particularly the five ht, to a receptor, which is been associated with altering states of consciousness and perception. And some additional, you know things to think about when you're thinking about how psilocybin acts on the brain is that we mentioned it earlier. But once psilocybin is ingested, it turns into psilocin, and that involves a couple of changes to the molecular structure that will promote its stability as it's being converted in the body. So again, psilocybin structure is essential because it acts as a pro drug. And a hallmark of psychedelics is their high their ability to, you know, get into the brain and pass the blood brain barrier, which is, you know, really important for making sure that your brain stays safe and all the nutrients and things are supposed to get in there. The way

Speaker 5 7:59
that penetrance is a critical beneficial effect, particularly of that drug. In fact, it's, you know, how most mushrooms are toxin that we're kind of adapting to, that it is a toxin at some level. So really, before, when we get more into psilocybin, how it exerts its effects on the brain the body, let's talk about what those effects are. The effects of psilocybin in humans vary significantly from one person to another, also from one dose to another, ranging from mild perceptual changes at low doses to, you know, on a heroic trip, some emotional processing, and, you know, even out of worldliness. So Missy, would you like to touch a bit on the effects of how psilocybin works at different doses and potentially different people? Yeah, so

Speaker 4 8:41
a low dose, which we're defining here, around like point two, five to half a gram of dried mushrooms, what you might hear being called micro dosing. The effects are usually subtle, and they're often compared to a mild stimulant or a mild mood enhancer. Users may experience enhanced focus, enhanced creativity and a general sense of well being, but there's not a lot of research for the effects of micro dosing, so kind of up in the air might depend on the individual and definitely on the dose that you're taking, but we do hear that perception might feel slightly sharpened, colors might appear brighter and sound more distinct, but at this dose, there's typically no significant visual distortions or hallucinations. At a moderate dose, which is about two to three and a half grams, the effects become more pronounced, and users often report altered perception, such as seeing patterns or movement in static objects and experience synesthesia, which sounds really interesting to me. I've never experienced what it would be like to hear a color or see a sound. Also, at this dose, emotional responses are intensified, ranging from euphoria and awe to introspection and catharsis. This dose is also associated with what's called ego dissolution, where the sense of. Self becomes less distinct, leading to feelings of interconnectedness with others or the universe. And there's also cognitive changes, such as altered time perception and deep introspection. And mystical or spiritual experiences are often reported at this moderate dose as well, and then at high doses, which would be five grams of dried mushrooms and up, the effects are profound, and can include ego death, where the boundaries of the self completely dissolve, and then visual and auditory hallucinations become a lot more intense, often involving complex geometric patterns, vivid imagery and even encounters with perceived entities. At this level, the experience can be very overwhelming. It's often described as transcendental, deeply meaningful, or life altering. And emotional experiences can range from intense joy and clarity to intense fear and confusion, depending on the user's mindset and environment, which is known as set and setting, which we're going to get more into.

Speaker 5 10:58
Now you said something interesting. You said you've never experienced synesthesia, but I have it a lot. I think it's because I'm left handed and many other reasons. Doesn't number two feel different than the number three too.

Speaker 4 11:14
Yeah, I I see where you're going with that. I definitely have different associations with different numbers. Like number 12 is my favorite number. I just like it. I can't tell you why, but it's nice to me. So

Speaker 5 11:25
if you're a 12 person, I bet you 13 is not a good number two at all. I agree, right? And so those feelings, that's like a rudimentary level of synesthesia, and you probably like linear things like two plus two plus two plus two. Enough of those, you get 12. The work on micro dosing really is coming out a lot right now. So there's a lot of bodies of research looking at micro dosing. And probably the big issue is, how do you go about doing that research? So if I give you a massive dose and tell you you could be in the control group or in the treatment group, you know, right? If you're, you know, on a different planet with llamas yelling at you, you know, you caught the psychedelics. If you are sub threshold, you don't know. And then that creates all kinds of biases. So there's a citizen report by Carhartt Harris and David Nutt, that I think does a pretty good job. It's had a lot of criticism about the statistics and the way that went about it, but the take home from that is that it's really hard to get a micro dose because of these individual differences and how you're treated. And then on top of that, the placebo effect is an effect, and it's always contained within that. Yeah,

Speaker 3 12:43
and I noticed too, it seems like a lot of different psychedelic research institutes have, like, an area on their website where, yes, they're running clinical trials, but they actually ask for a lot of the public to self report experiences at varying doses. And a lot of that has to do with, you know, a lot of those reports include how long these effects are lasting for people, depending on their dose. So psilocybin doses, the experience can last anywhere from four to six, maybe even eight hours. But the psychological impact can be very long lasting, with users reporting enduring changes in prospective mood and well being. But it's really important to note that these trips can be very intense and more often than not, overwhelming, because you're going to be experiencing vivid emotions, severe sensory distortions, and, you know, a feeling of kind of losing control. And again, that's why the idea of set and setting is really important here, which was a concept coined by Timothy Leary, a psychologist and prominent figure in the study of psychedelics during the 60s, which emphasizes that the set so the person's mindset, expectations, their emotional state, and setting the physical and social environment play a crucial role in shaping the quality and outcome of a psychedelic experience. And there's even tons of papers that are just talking about this like aspect alone. So there's a lot to unpack there still, especially as you know, we're starting to consider how psychedelics can be mental health therapies, you know, in the country, so

Speaker 5 14:13
for sure. So one of the things I get a lot a topic that I want to dive into is, and let me just ask the question, can you overdose on psilocybin? Right? I think this is a really big question. I would say no or no. I would say you have to define what an overdose

Speaker 3 14:31
is, yeah. And I think when people hear the word overdose, they think of like overdose death,

Speaker 5 14:37
Pulp Fiction. Somebody's on heroin, they're there, yeah, yeah. But

Speaker 3 14:41
psilocybin itself has, like a very low risk of that. There are not really any lethal overdoses. I can't think of any in any scientific studies that have been reported. The

Speaker 5 14:56
way I hear people talk about it is you would have to eat enough. I. A nauseous tastes really bad. Plant material, like pounds, right? That it would be really hard. It'd be like eating your pillow. You would have to eat your whole pillow to get there. But it can be toxic. It's super, super high doses. But, you know, never would you get there. But we hear all of these. They overdosed on psilocybin. I hear that weekly. What is meant by that April? Well,

Speaker 3 15:26
what's meant is that there's, like, a combination of factors. So there is something called a therapeutic index. So the ratio of a toxic dose to an effective dose, which is extremely high, indicating that it's, you know, physical. It's pretty safe. But I guess I don't know how to unpack that. Yeah, I

Speaker 5 15:48
think the big way is that if you were to, you know, take an amount of a drug that, you know, worked, say, on inflammation, and you took too much, and it shut your liver off. We would call that an overdose. But here we're working on a drug that deals with your mind, whatever that is. And so as soon as somebody gets into a distressed state in their mind where it shuts their mind off, they start hallucinating. We have a prevalence to call that an overdose. They're not the same. One is toxic, right? And so I think paired with that is that typically, when you have these higher doses, you can get confusion, right? And you can get some form of psychological stress. This is the bad trip, exactly, and people will call that overdose, and it kind of goes back to your set and setting, and somebody is having a lot of trauma, and they go in and they get the high dose where they can deal with their trauma. Now you have somebody on the strip right, and somebody illegally hands them a whole bunch of mushrooms, and they take and they're walking around the strip, and they have that exact same experience. We would call that an overdose, right? That makes so it's tricky from from a toxicity point, it's very hard to get a toxic dose from a psychologically distressing dose. It's not as hard as you would think, right? And I think that's what people call it. So I always think similarly with you know, THC, it's kind of hard to get a really, really toxic dose of that. Again, I think they gave a 70 kilogram pig in the 80s, something like 12 kilograms, right, of of cannabis. Deed, ate at all, right, and then slept and did all these other things. But again, in Las Vegas, we have a whole bunch of people to come to town. Weeds, not legal, where they're from. They try a little bit of an edible, and they end up in the, you know, er saying that they can't breathe. And they're, they're saying that I can't breathe. I'm not able to take a breath. I'm not breathing, clearly, breathing, right? So they would report that as an overdose too. So it's, it's really our relationship with drugs, our relationship with their psyche, but physiologically, it's probably not toxic, okay?

Speaker 3 18:00
And so, well, with your example of, you know, doing drugs on the strip, I'm sure there's poly drug use involved. Like, do they tease apart? No, any of that? No, it's

Speaker 5 18:10
a huge issue, right? Yeah. And we get a lot of this also from festivals where people come in. And now stats are being saying, well, there were seven people in the tent saying that they were on mushrooms and they were having problems, and then we'll just take that whole report and say there was seven overdoses, lump it all together. So yeah, the devil's in the details.

Unknown Speaker 18:30
Yeah, that makes a lot of sense.

Speaker 5 18:35
So on that note, April, do you want to touch on how it's typically prepared and consumed. And again, this isn't something we're promoting. You shouldn't do. This is mostly from indigenous cultures and other things, and then also in clinic. Yeah,

Speaker 3 18:49
there's a really rich history of, you know, using psilocybin mushrooms in a variety of cultures, kind of around the world, and typically psilocybin containing mushrooms that were consumed fresh or dry during ceremonial practices, depending on which group was using them. And Mesoamerican groups like the Mazatec would traditionally grind the mushrooms into a paste, brew them into a tea, or even eat them raw. And in the context of modern Western society, psilocybin is consumed in a variety of ways, still depending on the context, and probably the person how they heard about it. Recreational users tend to eat dried mushrooms directly, brew them in a tea, also to mask the flavor because it's kind of stringent, or incorporate them into foods like chocolates. So many people describe the taste as kind of earthy, bitter and unpleasant, kind of compared to eating dirt, and so to avoid the flavor, people kind of grind the mushrooms into powder and kind of find different forms to consume it. And

Speaker 5 19:48
I always like when I get educated. I got educated by a couple people this week, shamans. And one of them told me that a very modern way to prepare mushrooms that I don't know. Or standard all. But actually I'm curious to understand the mechanism is called lemon tecking, and so you use citric acid, or typically lemon peels and other things, which pull out the alkaloids, allowing for, typically, a better trip, no science on this whatsoever, and a faster trip. So even this is evolving, I think now is we have a lot more people using it.

Speaker 4 20:23
And then I've also heard about in the Netherlands, where psilocybin containing mushrooms are illegal, they will typically consume what are called psilocybin truffles. And the truffles are the sclerotia, which is the underground part of the mushroom, and they also contain psilocybin. So the truffles are typically consumed raw or dried, and they're available in specialized shops. It's often marketed as a way to explore consciousness in a controlled and safe manner, because they're sold in pre packaged, vacuum sealed doses. So it's easy to know how much you're taking. And you also find truffles infused into chocolates or candies or even steeped into teas with honeys or herbs to make them more palatable.

Speaker 5 21:04
It's fascinating to see all the ways that are coming about. And I know anecdotally, the other Dr Hines was at a conference on drug use and misuse, and there was a booth at the back in Nevada where people had chocolate with mushrooms in it, right? So legal or not, it's starting to become all around us, and it's in all kinds of interesting ways to be prepared. So briefly, we discussed the chemical structure of psilocybin earlier and how it's similar to serotonin. April brought that up, and how it acts on that specific receptor, the 5h two a receptor. Let's talk more about the mechanism action and how psilocybin exerts those effects. I think there's lots of evidence. I think when I started in this field, you know about 2012 2011 the crystal structure of the two a receptor wasn't out there, and people were arguing to a, 1b, 2c, but then a couple papers out of Brian Ross lab really have nailed down that not all the effects, but a lot of the effects are from the two way could you talk more about this research? Missy and how we really came to that? Maybe ideas about Ken? Sarah, yeah.

Speaker 4 22:16
So Ken Sarin is a five HT two, a receptor receptor antagonist. So it actually will block the action of the five HT to a receptor it'll block binding there. And in humans, if you give them this ket and sarin, that five HT to a receptor antagonist before they take psilocybin, it will dose dependently block the ability of psychedelics like psilocybin and LSD to alter subjective experience, so it'll dose dependently block the trip. So that's pretty good evidence to me. And further, the occupancy of five HT to a receptors in the brain also relates closely to the intensity of the psychedelic effect. And these human data are also corroborated by studies using animal models. And I want to take a moment here to talk about how the psychedelic experience can be measured in research studies, because I found these assays really interesting. So with subjective experience in humans, it's assessed through self reports and questionnaires, right? You can ask them how they're feeling, and they can tell you my perception is altered compared to my everyday and but obviously we can't just ask animals how they're feeling. So in studies, usually utilizing animal mom models for preclinical research, the main methods for evaluating the psychedelic trip involves drug discrimination assays and analysis of the head Twitch response. So in a drug discrimination assay, I thought this was really cool. They'll train an animal to associate the effects of a psychedelic with a specific action, such as pressing a particular level lever. Now that the animal has associated the effects of this drug, give the animal a different drug and see if they hit the lever so if they recognize it as being similar or not. And research using these assays show that human hallucinogenic potencies and potencies in these drug discrimination assays scale with five HT to a binding affinity. So this is also really good support that the hallucinogenic effects in humans are closely tied to their ability to bind to five HT to a receptors. And even

Speaker 5 24:16
cooler than that, there's somebody in this room that's come up with a new way to figure out dose and drugs,

Speaker 3 24:22
yeah. So we, you know, need to look beyond just like looking at one measure, one behavior. That's April, by the way, yeah, kind of utilize different types of methods to kind of understand so we in the lab have paired EEG to identify hallmarks or signatures of different dose and different psychedelic compounds with actual spine changes, so those psychoplastic changes, so we're looking at behavior, EEG, signature and morphological changes to kind of paint a picture and give an idea of how to screen for these different types of super important,

Speaker 5 24:55
because we know there's highly specific five HG drugs don't screen. Able to dose even animal discrimination models. So what is the current climate April like? Where are we at with our how people feel about psychedelics, and where are we going?

Speaker 3 25:10
Yeah, in these last two minutes, I kind of really want to talk about the current climate of psychedelics and how we need to consider thoughtful regulation and ethical practices. And that's really going to be related to science, and having looking to science to inform this information. So as of right now, psilocybin is still schedule one in the US, which means it doesn't it's not considered to have any therapeutic potential. And so can we talk a little bit, maybe about just some quick treatments, I mean psychiatric conditions that psychedelic could be used clinically. Yeah,

Speaker 5 25:44
so I think we're on time, so I can go over some just briefly, and there's lots. And I'm always worried when we have a drug that has, you know, this is going to cure everything. But there are some clear winners here clinically for psilocybin. One of them is PTSD. I think another one's going to be and this is more than my opinion, but I'll say it as my opinion is going to be depression, major depressive disorder. The problem with major depressive disorder is how to run an effective trial, and really, the FDA has struggled with that for a while. We also know for forms of addiction, it's going to be super useful anxiety, and then there's a lot on pain and eating disorders now, so there's probably a couple more out there. I'm probably not being all inclusive, but those are the ones that I would, you know, bet on we see trials and we actually see people getting help in the next while.

Speaker 3 26:33
Yeah, and have you seen that documentary? Something that really struck me was what documentary? There was a documentary a few years ago, car her, Harris and Dave and Nutt from UC London, magic mushrooms or Yeah, I know the magic medicine, yeah, yeah. That really strikes home how useful it can be for depression, yeah,

Unknown Speaker 26:53
treatment resistance depression, yeah.

Speaker 3 26:54
Would have never had a like. You can't argue, when you see those testimonies from those people, how effective this could possibly be in treating female resistant depression. Well.

Speaker 4 27:02
In conclusion, psilocybin represents a promising avenue in modern medicine with the potential to revolutionize treatments for mental health conditions, addiction and beyond. And by continuing rigorous research and respecting and learning from its cultural origins, psilocybin can offer transformative solutions while deepening our understanding of the human brain and behavior. Okay, thank

Speaker 5 27:22
you both for your discussion. I really enjoyed this back and forth. Thanks for listening to the chemical collective. I hope you came here to get your weekly dose of Drug Facts, and I hope that we dispelled some of your fictions. You

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