The Difference Between Pure Psilocybin and Full Spectrum Mushrooms with Lerer Bernard and Orr Shahar
Alisa Nappa
Today we sit down with two researchers who just published the paper: "Effect of chemically synthesized psilocybin and psychedelic mushroom extract on molecular and metabolic profiles in mouse brain" to discuss the clinical difference between pure chemically synthesized psilocybin versus full spectrum mushrooms with the entourage effect of different compounds. This has always been a debate in the psychedelic community and we're pleased to uncover the truth on todays episode.
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TRANSCRIPT
Unknown Speaker 0:11
Welcome, welcome. You are listening to the mushroom revival podcast. This is your host Alex dore, and we are absolutely obsessed with the wonderful, wacky, mysterious world of mushrooms and fungi. We bring on guests and experts from all around the globe to geek out with us and go down this mysterious rabbit hole and try to figure out what the heck is going on with these fungal and mushroom beings. So today, we have some folks talking about
Unknown Speaker 0:40
the differences between a full spectrum
Unknown Speaker 0:44
real mushroom psilocybin containing mushrooms versus the isolated compound psilocybin and the effects on mice. So how're you guys doing?
Unknown Speaker 0:58
Right, right. Thank you for having us.
Unknown Speaker 1:02
Yeah, why don't why don't you start in tell everyone who you are and what you're up to?
Unknown Speaker 1:09
Well, I'm Bernard Lera. I'm a professor of psychiatry and head of the Center for psychedelic research at Hadassah brain labs in Jerusalem. I'm a psychopharmacologist of many years vintage as my gray will tell you. And I'm very interested in the past few years in the potential of psychedelics including psychedelic mushrooms as treatments for major psychiatric, neuro psychiatric and other disorders.
Unknown Speaker 1:42
So my name is Otto Shahar. I was born in Israel, I moved back and forth over the years, but I lived in Canada during my formative years.
Unknown Speaker 1:52
Until I graduated from high school, I moved back to Israel to serve in protecting the army. And following that I traveled around the world until I felt my natural time has come to start getting into the scientific research and help better humanity did my bachelor's in animal sciences continued to Master's degree in biotechnology. And now I'm doing my PhD in medical neuroscience under the guidance of professor lair. And I'm also blessed in having an amazing supporting wife and three small amazing kids.
Unknown Speaker 2:25
So how did you both get into mushrooms and and psilocybin containing mushrooms.
Unknown Speaker 2:33
I've spent all of my career looking for more effective treatments for psychiatric disorders. This has been my obsession for more than 50 years, or 40 years, 50 years. It's a bit long but and in the last few years, I suddenly realized that the potential for discovering novel treatments that are based on psychedelic compounds, is very great. So I decided to remove to move the focus of my entire research group to this area. And that's how I got involved in psychedelic mushrooms and psychedelics in general.
Unknown Speaker 3:14
So I grew up in a culinary household, I was exposed to mushrooms as a very, very highly sought after food,
Unknown Speaker 3:23
different species of mushrooms, and really ignited my passion for mushrooms in general in mycology. Growing up in Canada and my formative years, I was exposed culturally, the way it is in Canada,
Unknown Speaker 3:40
to mind altering substances conscious, conscious enhancing substances when I was 16. I had my first psilocybin trip really changed my perspective on reality and life and nature, how we are as humans and the connectedness that we all have together, we're basically one big organism. And I kind of saw the potential in this knowledge and in the healing potential of mushrooms in general, after researching into it for the betterment of all humanity, especially in our modern times.
Unknown Speaker 4:16
And
Unknown Speaker 4:18
I did my bachelor's degree in, in animal sciences, but at the end, they went into mushroom cultivation in the lab that research mushroom cultivation not only for cultivating mushrooms, different substrates for higher yields, but also to increase active bioactive compounds in the mushrooms like alpha and beta glucans, for example, with different growing parameters.
Unknown Speaker 4:42
We explored anti cancer properties of extracts and my master's degree. After my master's degree, I kind of like putting my foot down. I said, that's it now, I'm in a position I can start going into psychedelic research psychedelic mushroom research. And I looked everywhere for a lab that will be interested in incorporating so let's
Unknown Speaker 5:00
typing in their research. And I got to Professor layer, there is lab, kind of the stars aligned, he needed a PhD student to start the psychedelic research
Unknown Speaker 5:11
that he was starting, I needed a supervisor in an amazing lab. And that's how we came to be.
Unknown Speaker 5:20
And so you you recently just published a really interesting paper on comparing the effects of full full spectrum. psilocybin containing mushrooms versus the isolated compound psilocybin and the effects on on mice. What was the inspiration behind this paper?
Unknown Speaker 5:41
Well,
Unknown Speaker 5:43
we're very interested in how psychedelic compounds can be used to treat psychiatric disorders. And I have been fascinated by the fact that psychedelic mushrooms, containing psilocybin have many other components. This is not just a chemical, a single chemical, but it's an interest of entire, an entire universe of chemicals that make up these mushrooms. And I became convinced very early on that
Unknown Speaker 6:12
there must be something in the entourage that makes a difference. So together with Oren with other members of my group we designed to study and the purpose of the study was to determine whether there was a difference in the effects of
Unknown Speaker 6:29
chemically pure psilocybin versus the effect of psychedelic mushrooms, and whether we could see differences in several important parameters in the action of these two preparations. And that is the core of our paper, it came from the belief that we need to discover if there is something in the interest in the additional molecules that make up the psychedelic mushroom extract that influence how the extract works.
Unknown Speaker 7:01
And can you talk about what exactly the entourage effect is, I think that term was popularized in the cannabis industry.
Unknown Speaker 7:12
But I'm just curious, what what knowledge do we have about the entourage effect with Salafi mushrooms?
Unknown Speaker 7:20
So great, Dion.
Unknown Speaker 7:23
Go ahead, please. Okay, well, first of all, I wanted to
Unknown Speaker 7:29
understand what is the entourage effect, right and the entourage effect, the term usually used to describe the synergistic effect that additional compounds that are found in the natural source will have with the main active compounds in a therapeutic outcome. Okay, so it's not looking at isolated, pure compounds. And like you said, we don't like it our field to use to bring up cannabis too often, right? But it's, it can be a very good example in understanding right so like you said, there's additional compounds in cannabis, not only the THC and CBD that everyone knows,
Unknown Speaker 8:05
that also have bioactive effects. And with psilocybin mushrooms, the story becomes very interesting because we can look at it from a few levels. In a broader sense. We get the benefit of the vessel here being a mushroom, and being a mushroom has a lot of bioactive compounds, like complex complex carbohydrates, like the alpha and beta glucans, like I brought up before,
Unknown Speaker 8:32
that have anti inflammatory and positive effects on the immune system. We also have proteins and terpenoids that are also being researched as well for anti inflammation and anti cancer effects.
Unknown Speaker 8:46
And when we delve deeper into psilocybin mushrooms in specific we have a menu of alkaloids. alkaloid compounds are believed to be created in the organism in the form of protection. Many of the therapeutic compounds we have isolated in western medicine come from alkaloids from nature, like caffeine, you know, for example, or is caffeine to psilocybin has a wide range of active alkaloids, but basically the fun compounds. So in these mushrooms, we find compounds that are more structurally related to psilocybin, the active form of psilocybin, such as biosystem, nor biosystem, nor Cillessen. And very important, beta beta carbon liens and beta carbon liens are inhibitors of natural enzymes that we have in our bodies that normally break down and metabolize neurotransmitters. So in our case, it actually inhibits the metabolism bacillus Cillessen.
Unknown Speaker 9:45
And all these compounds have synergistic effects. Even though some, some of them are not psychoactive. Some of them do have some subjective effects to them, but most of them are not psychoactive parts of the psilocybin.
Unknown Speaker 10:00
So if we combine these compounds, the special compounds that come from Simon mushroom and the compounds that come from the mushroom itself being a mushroom, we get a heck of a medicine here in our hands. And this is one aspect that I haven't seen much people bring up in the field yet, is the fact that
Unknown Speaker 10:19
almost all psychiatric diseases are involved with an increase of brain inflammation. And this being a mushroom has a lot of anti inflammation compounds in it already being a mushroom, and that can help alleviate the mental health conditions that we see. So we treat it kind of like in a few, we attack it from a few aspects.
Unknown Speaker 10:42
See you you had a an excerpt in your latest paper talking about Glatfelter it's all his work, and recently showing that only, quote unquote only the tertiary A means psilocybin Tilson and Seaton, I think is how you pronounce it, induced head Twitch response in mice, and then the secondary, a means bassist in Norse Olson.
Unknown Speaker 11:12
And compounds like rumination had little to no effect. I'm just curious
Unknown Speaker 11:20
what we know about these compounds? And
Unknown Speaker 11:26
what exactly are the secondary A means doing? Like biosystem nor Solisten, originais, scenic is etc.
Unknown Speaker 11:36
Well, you know, we're very familiar with Glatfelter. His work and we have great admiration, I think Glatfelter is a great researcher and he does amazing stuff.
Unknown Speaker 11:46
You know, I think that
Unknown Speaker 11:48
it's clear that the secondary amines do not directly in themselves, adduce, hit twitch. But
Unknown Speaker 11:55
we have to not forget that we're talking about synergistic effects and synergistic effects are not additive effects. In other words, if you have synergism, it does not mean that the second compound does the same as the first one, one plus one equals two, it means that you can have a compound that by various mechanisms enhances the effect of the first compound, but it does not do so by one plus one mechanism. So that is our view. We haven't finished yet, you know, there's a world of research to do on what it is within the psychedelic mushroom, beyond psilocybin, and citizen, which is this metabolite that induces the effects. But in the bottom line, it doesn't necessarily have to be an additive effect could be a synergistic effect.
Unknown Speaker 12:47
We're going to talk about it a lot during this episode, and you talked a lot about it in in your latest paper, which is the head Twitch response. What exactly is that?
Unknown Speaker 12:59
So the head Twitch response is the current best tool that is used, utilized in the field of psychedelic research to measure the trip in rodents. So when you give a psychedelic to a mouse, you can't really ask him how hard he's tripping, right? How, what is what he's feeling. So this first head which was kind of like established in the 50s, or 60s, I believe, with five HTP. So given a high amount of five HTP, which is the precursor to serotonin, induced this twitching of the head in mice, it was later understood that strong five HT to a agonist which psychedelics are, induces this Twitch response, because when you give a psychedelic and a five HD to a antagonist, you actually reduce the HDR in the mice. And then it was understood that well wait, you can give this five HD to a antagonist in humans, it reduces trip as well. So you get here a very good proxy to the trip in humans also.
Unknown Speaker 14:00
The more you give the psychedelic drug to the mouse, the more he's going to shake his head, the stronger it's going to be in the human kind of like one plus one and this is the current best tool, translational tool to understanding
Unknown Speaker 14:14
the strength of a psychedelic and also the pharmacology of the psychedelic we can now give different receptor modulators so agonist and antagonist and see how it affects the head twitch and the mice does it increase does it reduce? And it can be a very powerful tool later on.
Unknown Speaker 14:34
Have you heard of a concept called would lover's paralysis hypothesize to be caused by a rock in a scene?
Unknown Speaker 14:47
No, I've heard of the concept. Yeah.
Unknown Speaker 14:51
Yeah, it's really interesting phenomena were certain species of wood loving
Unknown Speaker 14:59
philosophy.
Unknown Speaker 15:00
eat mushrooms like as their essence and sign essence.
Unknown Speaker 15:04
They Some people report an experience called wood lovers paralysis where they
Unknown Speaker 15:13
they're almost like paralyzed for a certain amount of time and they can't move their body.
Unknown Speaker 15:20
And it researchers hypothesize that it could be from the compound root in a scene. And I'm just curious if that had had an effect on on head Twitch response, if it kind of subdues the movements of the body, would that have an effect on on?
Unknown Speaker 15:38
Head Twitch response? I'm not sure. Well, in the citta Intertape, we showed that there was there was no difference between the extract we gave and the synthetic psilocybin with regards to the head twitch.
Unknown Speaker 15:51
And we gave the same dose of psilocybin in the extract. So the extract had 1.3 or 1.5%, psilocybin in it, and we corrected the dosage accordingly. So the mice receive the same doses of psilocybin in both treatments. And we didn't see a difference. It was very interesting.
Unknown Speaker 16:12
And I noticed that you were looking at other things, which I want to get into a little bit later. But you started the paper talking about, you know, current research in the field. And I thought a couple of the papers that you brought up were really interesting. One was about marble burying habits in mice. And the other was about serotonin five HT to a receptor behavioral assays in in mice, can you talk about these two papers and just kind of where, where you're starting from? What What was the current understanding of this research before he started this paper?
Unknown Speaker 16:51
And you have to understand where we coming from. I'm a psychiatrist and a neurobiologist, and a psychopharmacologist. And my life has been devoted to looking for novel treatments for psychiatric disorders. And that's why I'm so excited about psychedelic compounds and both chemical and naturally occurring.
Unknown Speaker 17:14
And one of the disorders that is really in need of novel and effective treatments in psychiatry is obsessive compulsive disorder. And so there have been reports, clinical as well, and a lot of anecdotal reports about P from people that took psychedelic mushrooms to help their OCD, and said that it helped a great deal. So we were very interested in how could psilocybin help OCD and more important by what mechanism. And so we set up a very comprehensive research project, in which Dr. Singh, a postdoc from India was very, very pivotal. And we decided to look into the whole issue. And we found, as did other researchers before us that psilocybin inhibits Marvel berry marble bearing is a very interesting natural behavior of certain species of mice, that really gets gets on their nerves that marbles are lying around, they can and almost obsessively, they kind of bury them, they dig and they bury them. And the drugs that are effective in treating OCD like SSRIs and psilocybin, they block the small theory. So we've used this as a platform to understand not only the phenomenon, but which receptors are involved with a five HT to a fabisch T one a five is to see, we're trying to deselect the receptor mechanisms try and get to a more a better understanding of how psychedelics help this disorder, which by the way has been shown in a human study as well. It's quite an old study published several years ago in the American Journal of Psychiatry, which showed that psychedelics particularly in this case, psilocybin, are effective in treating patients with OCD was an open study. It wasn't a randomized control trial, but it was very, very suggestive nevertheless.
Unknown Speaker 19:19
And in this paper, I know that you were focusing on Synaptic neuroplasticity and,
Unknown Speaker 19:28
or plasticity and you're focusing on this synaptic proteins gap for three PSD 95 synaptic phi zine and SV to a
Unknown Speaker 19:41
for someone who is not familiar in this field at all. What exactly are these synaptic proteins doing? What are they? Why did you target them? And yet what what effect do these psychedelics have on them?
Unknown Speaker 19:58
So these for protein
Unknown Speaker 20:00
Beans are very important markers for neuroplasticity gap 43 It's actually growth associated protein everywhere that axonal growth or
Unknown Speaker 20:13
neuronal growth across a course. Also in the development stages, you see an increase of this protein. So it's, it's a key aspect of neuroplasticity, the function of it is not necessarily known fully. But everywhere that you see an increase in synaptic plasticity, you see an increase of this protein. That's why I got the name growth associated protein.
Unknown Speaker 20:35
The next protein we we checked for was PSD 95.
Unknown Speaker 20:40
So neurons communicate with synapses, and synapses, you have two, two aspects, you have the presynaptic neuron and the postsynaptic neuron.
Unknown Speaker 20:52
PSD 95, plays a significant role in forming
Unknown Speaker 20:57
in functioning synapses in the post,
Unknown Speaker 21:01
post neuron. And
Unknown Speaker 21:05
it's a very strong marker for function of synapses. And that's why we use it for increase in synaptic plasticity, it's something that's very well known and used. Synaptic phising is a member is a membrane protein,
Unknown Speaker 21:21
present in the presynaptic vesicles. So vesicles that hold neurotransmitters,
Unknown Speaker 21:28
it, it's involved in the neurotransmitter release. So the more you see synaptic phising, the more you know, this area of the brain is active. And the same thing for SV two, a sv tways, also implicated in the regulation of these vesicles and other processes that are essential for the neuronal communication. So where you see an increase of this protein, it's an increase of synaptic plasticity.
Unknown Speaker 21:56
You know, in gold rushes in various parts of the world, there used to be a saying that if you want to get rich invested the gold lions, if you want to get really rich, invest in the companies that make the shovels, and the synaptic protein or the shovels. In other words, if you want to see synaptic plasticity, if you want to see growth of new neurons, you can look at it and we're doing that. But if you want to get a good marker of how many neurons are growing, look at these proteins, because every one of them is involved in one way or another in the process of generating new synapses. And we believe, and many have shown before us that psychedelics stimulate the growth of new synapses. So if new synapses are going to grow, you're going to need the shovels, you're going to need the synaptic proteins that make those synapses. And so that's why we measure them. And that's why we believe they're a very,
Unknown Speaker 22:54
very good indicator of synaptic plasticity.
Unknown Speaker 23:00
And
Unknown Speaker 23:02
neurons are all are are all over the central nervous system. Is that correct?
Unknown Speaker 23:09
So the brain and the spine central nervous? Yeah, yeah, they are the core of the central nervous. Yeah, I'm, I just had a thought, you know, whenever I heard the term, you know, neural plasticity, I was just focused on the brain.
Unknown Speaker 23:25
And, you know, this is not my field of study. So I'm just throwing an idea out there. But what would you hypothesize, hypothesize? Or Is anyone doing research on the effects of
Unknown Speaker 23:38
neuroplasticity in the spine and say, someone had, you know, some nerve damage in their spine? Do you think that maybe this could have a positive effect on on that?
Unknown Speaker 23:51
I think you have to differentiate between
Unknown Speaker 23:54
them between loss of neurons and loss of plasticity and loss of synaptic connection, and, and physical damage transaction, which is, of course, the core issue. And I believe that, in the long run, psychedelics could have a role in synaptic plasticity in the spine and in other areas of the body, or, as mentioned, inflammation, the role of psychedelics in inflammation in the brain and in other areas of the body as well. So I think that, you know, yes, this is a totally unexplored area, we're just beginning to see these papers coming out. People talking about psychedelic effects on synaptic plasticity in different syndromes in a brain. For example, to give just one example, but
Unknown Speaker 24:46
we have to also differentiate between neuro plan neuro plan
Unknown Speaker 24:54
Sorry, I lost my thought.
Unknown Speaker 24:57
Neuro plans neuro no in new
Unknown Speaker 25:00
Roger sorry, yeah, in neurogenesis and synaptogenesis. Okay, so when we talk about neuroplasticity, we're not necessarily talking about increase in neurons, we're talking about the increase in connections, this is a natural phenomenon of the brain, right? The increase in decrease in, in synapses. So any any memory that you don't need your brain frees up frees up the hard drive right to make room for new
Unknown Speaker 25:29
memories or new experiences that shape us. For example, in, in PTSD, there's an increase in synaptic plasticity, right. And that's what really formulates the the memory of the trauma.
Unknown Speaker 25:44
But in psychiatric diseases abroad, you see in the long run a decrease in synaptic plasticity, across the main brain areas. And here we have a tool that increases synaptic plasticity, this is really the kind of like the Hallmark and the core of utilizing these compounds as a medicinal tool for these mental health conditions.
Unknown Speaker 26:10
And it's kind of a
Unknown Speaker 26:13
at, I want to say, blanket cure, but you know, the more synaptic connections,
Unknown Speaker 26:20
the more able
Unknown Speaker 26:23
someone is, is more able to kind of rewrite old narratives, right? So going back to those, those mice who had just had a drive to bury the marbles,
Unknown Speaker 26:37
to put this kind of simply is they're rewriting that neural pathway inside their brain saying that they have to do that and they're making new connections of other ways to live is that kind of the
Unknown Speaker 26:51
more rudimentary way to describe it.
Unknown Speaker 26:55
That could be where we are, we have to be really careful in neuroscience not to over hypothesize, we have to focus on limited hypotheses and, and test them incrementally. I think that, you know, the temptation is always there to over hypothesize and to extend to to fall. But then if you're wrong, then the fall is even greater if you just make a simple, small, incremental suggestion and you're wrong, or then you go back and rewrite it. But if you hypothesize the whole world and it doesn't work, then the whole world falls down. So that is a really basic approach in my in my research philosophy, and when I try and teach my students, everything is reductionistic. In the end of the day, if you say that a drag is going to be effective in OCD first show that it does a b and c or d and meist. If you do show that then work out how it does it. And after that you can get closer to to making more extensive hypotheses.
Unknown Speaker 28:04
Well, I'm glad you're the one doing the research. That's not me.
Unknown Speaker 28:09
So I'm more is more PhD and students and fellows.
Unknown Speaker 28:15
Well, I'm I'm always curious, you know, people working with psychedelics, there's so much red tape, and I'm always curious about the process of going around that red tape with all the rules and regulations. I'm not too familiar with the laws in Israel. And I'm guessing it must have been quite a feat to ship
Unknown Speaker 28:41
mushrooms and also pure psilocybin internationally. It said in the paper, you got the pure psilocybin from Madison, Wisconsin in the US. And then the full spectrum fruits from Chicago. In the US what what was that whole process like to get permits and shipping and XYZ?
Unknown Speaker 29:03
Well, it's quite something for me to be in the position of defending bureaucrats because I spend my time criticizing them. But in actual fact, it was not all that bad at all. There is a process that you have to go through there is a importation series of importation requirements, you have to get license you have to store these compounds in a way that the authorities approve of in a safe with limited access, but it's doable we had we didn't have a real problem importing psilocybin from you Sona and I must express my gratitude to them. They gave us a significant quantity without payment, and nor importing the psilocybin extract nor importing five Meo DMT and DMT from companies in Canada that supplied us with them. So yeah, it works. It works if the if you follow the regulations and you submit your application
Unknown Speaker 30:00
Since according to you can get the compounds in not too long a period of time, and we're planning our clinical studies with psilocybin, and we're doing the same process. And it's not a significant barrier.
Unknown Speaker 30:17
I was talking to someone years ago who was shipping psilocybin. And I think they said they just use FedEx like, did you just use a regular shipping carrier? To ship?
Unknown Speaker 30:33
Well, do you use FedEx or DHL or UPS, but you have to have the necessary arrangements in place where the customs authorities, when a shipment of something that is not permitted to be used on a regular basis in the country arrives, you have to have the necessary
Unknown Speaker 30:54
permits to important and the necessary permits to hold it. But it's not an issue. It's something that you just have to do. It's a bureaucracy, that if you follow the rules, you can get it done. It's not been a problem for us, sometimes a hassle. Sometimes we fumigating and get furious at how long it takes them. But it's not all that long. I've heard from people in the USA that it takes much longer to import stuff.
Unknown Speaker 31:23
Well, yeah, that's a good attitude to have. And I'm glad that it wasn't an issue for you that that seems to be quite a hassle for some people. So
Unknown Speaker 31:33
I'm glad you have the right mindset about it to go through those bureaucratic loopholes. I'm also curious about determining dosage with the rats and how you came up with the adequate dosage. And what that would be equivalent to, if you were to compare it to an adult human.
Unknown Speaker 32:00
So it's very interesting actually how we got to it.
Unknown Speaker 32:03
First of all, we use a calculation method. For translational dose calculations between species, it's known as the km factor. And the km factor, it accounts for differences in body surface area and metabolic rates of different species.
Unknown Speaker 32:21
So for example, a mouse mouse metabolism is much faster than an elephant, right, and the way it works is actually counterintuitive. For the larger animal, you need less of the drug per weight than you need for a smaller animal. For app for us, we actually previously done a dose response with psilocybin. psilocybin induction of HDR of the head Twitch response, we published very interesting results there regarding how the profile of the HDR changes with the dose. So for lower doses of psilocybin, we kind of saw a gradual increase of HDR and a gradual decrease. And after a certain dose, the more we increased, we saw a very sharp increase of the HTR and a very sharp decrease that decreased even lower than those lower doses.
Unknown Speaker 33:13
And for us, when we try to look at what dose is going to be the dose for us to represent an acute dose for all of our studies in the lab, we looked at the clinical trials, and in human clinical trials, they give 25 milligrams of psilocybin per 70 kilograms of body weight. We translated it with this KM factor with a very nice virtual calculator. Everyone can go in and, and translate doses between species dose cow calculator on Google the first one, it's an amazing tool. And we saw that 25 milligrams in humans is actually 4.4 milligrams per kilograms in mice.
Unknown Speaker 33:55
And we looked at for performing milligrams or kilograms in our dose response that we did. And it kind of fell in the middle of the high response that I talked about. So for us, it was very, like we had a few points here that this is a very good dose to to choose, it was also the high dose that we saw with HDR, and it's also translational to humans. It's what's given in human clinical trials. If you look at other groups in the world, that are researching psychedelics in mice, 4.4 milligrams per kilograms is is much higher than what people use.
Unknown Speaker 34:32
People experiment with one milligram per kilogram, two milligram per kilogram, but I haven't really seen convincing evidence why especially when we show that it's 4.4 is a very translational relevant dose.
Unknown Speaker 34:48
So that's what we saw. That's what we used also in the synthetic and also in the extract we use 4.4 milligrams per kilogram.
Unknown Speaker 34:58
That's brilliant. That
Unknown Speaker 35:00
To calculate the digestion rate, and I'd love how the, there's a calculator as well that you can use. That's awesome. Whoever made that. That's, that's really cool. That's the first time I've ever heard someone calculating it that way. And I think that that
Unknown Speaker 35:17
is really smart. I think that's the way to do it.
Unknown Speaker 35:20
You ran a bunch of tests that I'm not too familiar with. So I'm hoping that you could
Unknown Speaker 35:28
kind of talk a little bit about them. You ran tests, including the western blot, plasma screening, meta, meta block, metal bowl, llama belong at the top of llamas save
Unknown Speaker 35:43
up a lux? Yeah, can you talk about all the different tests that you that you ran by you why you ran them and just kind of
Unknown Speaker 35:52
a more dumbed down version of what exactly these tests are. For people who aren't familiar, including myself, give a general overview and, or could perhaps go deep dive into what those that you're interested in.
Unknown Speaker 36:06
Essentially, our paper we focused on three
Unknown Speaker 36:11
broad test category. The first is the head Twitch response, which we talked about, and that is measured. In a system we set up in our lab, it's automated, it's quick, and very reliable. The second area, which we measured were the synaptic proteins. And we talked about these earlier, these are the measures that we use in order to get an idea of the proteins involved in synaptic plasticity and the extent to which these proteins are differentially affected by the treatments that we give specifically, in this case, the psilocybin and the psilocybin containing mushroom extract. metabolomics is a multi omics
Unknown Speaker 36:57
system in which essentially, one is measuring all or most or at least a lot of the metabolites that are generated when Ron administers a compound, anything you do in the body, you have a metabolic response. And the mechanisms now exist to because of advances in in scientific approaches and research and technology, I can actually measure a vast number of metabolites at once. So what we do is, and what we did in the paper is we looked at the profile of metabolites that are released in the brain, when one gives psychedelic mushroom extract to the mouse or when gives
Unknown Speaker 37:42
psilocybin chemical psilocybin. And what is important here is we didn't look immediate, we look 12 days later, at the same time, as we measured the synaptic proteins. And we saw a very interesting differential, we saw that the mice given psilocybin and the mice given the mushroom extract had different metabolic profiles, in terms of their effects on the release of metabolites. And this is very, very significant, very, very important. That means that the whole effect of these is different. So the sideburn does one set of stuff. And so the Seibon, plus the interest molecules, and everything else that is in the mushroom extract as a different set of stuff in the body. And this is the advantage of these omics procedures, that you get a general panoramic picture, you then need to dive in and work out what exactly is different. But at first, you have this panoramic snapshot of what's happening to the metabolism of the body 12 days after the mice got the drugs. And at the same time as the differences in synaptic proteins that we reported, were measured.
Unknown Speaker 39:01
What I what I also loved about
Unknown Speaker 39:06
it, I loved how in the beginning when you're talking about
Unknown Speaker 39:10
the, the psilocybin mushroom extract the full spectrum fruit extract, was you broke down the different tryptamines in different compounds present and that percentages, which I haven't really seen that much in a lot of papers.
Unknown Speaker 39:31
You know, a lot of times researchers will just say, Oh, we use two grams of this and that's it. And it's, you know, I don't think grams is a really good measurement and even in, you know, in the US we're having a lot of,
Unknown Speaker 39:47
you know, legalization or medicalization of of psilocybin and like an Oregon they're just saying, Oh, two grams of fruits and it's like two grand
Unknown Speaker 40:00
Have one mushroom could be radically different from two grams of another. And, you know, in the beginning, you're talking about alpha beta glucans. You know,
Unknown Speaker 40:09
my field is functional mushrooms now, and it's it's frustrating reading papers and just saying, Oh, two grams of Lion's Mane, and it's like, well,
Unknown Speaker 40:18
you know, when lion's mane is way different than another Lion's Mane, and to replicate the paper, it's like you can't, you know, automatically you can't, because you didn't list the the compounds that I really liked. How you did list the percentage of, you know, psilocybin, psilocybin, nor base is all the different compounds. So this could be replicated in the future, or at least gives more information to be transparent for for future research. So I just wanted to give like a kudos to you for doing that.
Unknown Speaker 40:52
Because I think that's really important in the field moving forward to just be transparent of what exactly are you using in this study, right.
Unknown Speaker 41:02
And I really liked that you brought that up, because
Unknown Speaker 41:06
we can look at it from also again, using cannabis that cannabis in the 60s was much weaker than now, right? People started indoor cultivation, bumping up the THC to like 3034. It's like, why, why do it so strong? It there's a trade off on the other entourage molecules when you're doing that. And we also see the same thing happening with psilocybin mushrooms in different dispensaries or different cultivators around the world, cultivating indoors species, doing hybrids, doing mutations, all these ape and all these, you know, species that are very high in psilocybin, but then it comes on part of the of the other entourage molecules, and we really need to go back to the source kind of like explore the traditional the wild type, philosophy cubensis, and with the balance of the entourage molecules in order to replicate it, and that's very much true, we don't need to, we might be doing a disservice. I mean, zeroing in on psilocybin,
Unknown Speaker 42:10
when we know there's effects of the entourage molecules, also people that participated in the psilocybin clinical trials report that the synthetic psilocybin they received is a different trip than the natural mushroom that they take the natural trip is more relaxing and feels better on the body than the synthetic ones. So I mean, this can work in a pivotal role right now in the research and we can, we need to shift maybe the understanding that we need to kind of explore these substances, all the psychedelics that we can, in their natural form, also five Meo DMT, DMT and ayahuasca, I mean, you have compounds like MDMA and LSD that are of course, synthetically synthesized, so you can't do anything about those. But the rest of them, you know, first, we need to explore them in their natural settings with a natural entourage molecules, because that's how humanity dealt with it for 1000s of years, and use it as medicines, all these medicinal
Unknown Speaker 43:12
effects that are attributed to these mushrooms, for example, we need to explore it in the original preparation, and that it came with.
Unknown Speaker 43:25
And so I'm curious, without over hypothesizing, Bernard,
Unknown Speaker 43:31
what, what are, what were your results of the paper? And what does this show you or inspire you to do in the future with these results?
Unknown Speaker 43:44
Well, you know, the results, I think were fascinating. First of all, we did not find a difference in the head Twitch response, which meant that the psychedelic mushroom extract answer a chemical psilocybin at the same psilocybin dose, someone can't. Over belabor that. We're not talking about a difference in how much psilocybin the mice are getting. They're all getting the same amount of psilocybin. We're talking about psilocybin alone, or Salam psilocybin plus whatever else makes up the extra, there was no difference in his Twitch response in that we differ from one other paper by a researcher called Zook to did show some differences, we did not find that.
Unknown Speaker 44:28
The second area was the area of synaptic proteins in here we did find that overall, the extract effect on Synaptic protein levels reflecting in our estimation, degrees of synaptic plasticity, the effect was greater for the psilocybin in the context of the mushroom extract than the effect of the psilocybin alone. And for us, that is a very, very signal
Unknown Speaker 45:00
We contain important finding. And the third key finding of the research. And again, I'm simplifying but just summarizing is that in the area of metabolomics. And we saw that the psilocybin mushroom extract,
Unknown Speaker 45:16
and the chemical psilocybin had different patterns of effect on metabolites.
Unknown Speaker 45:24
We go into in the paper, we go into what were the specific metabolites involved. But overall, the key finding is that the overall metabolomic, metabolite metabolic effect is different. It's not the same thing. Taking psilocybin and taking psilocybin in the context of mushroom extract is not the same thing. It's the way in which it affects the brain metabolism. And these are all key findings, which sets us up to go and delve further into the question of what is behind all this? What is responsible?
Unknown Speaker 46:04
And there was one more result a kind of like a small result that we had there inside the plasma screening. Right, so we did a plasma screening, because the question arose,
Unknown Speaker 46:16
that maybe the effects we're seeing is due to psilocybin being in the extract, the extract also has psilocybin also Cillessen a bit. So we did this plasma screening, it's basically we sampled blood from mice that we administered the psilocybin or extract at different time points, we tested the amount of
Unknown Speaker 46:35
psilocybin in the blood, so we tested 15 minutes, 30 minutes and 60 minutes, we saw that the amount of psilocybin increases 30 minutes stays somewhat stable 60 minutes, and there was no difference between the extract and the psilocybin. So again, the effects we saw in the increase of proteins must be from the entourage molecules and not from the little bit extra Cillessen. That is inside the extract. Also, this result was very interesting, because when we look at HTR, in the head Twitch response, it kind of like, subsides and
Unknown Speaker 47:10
goes down to baseline levels at 10 minutes. Okay, but here, we saw an increase of systemic blood Cillessen levels going up 15 and 30 minutes and staying stable until 60 minutes. So again, it brings up the question if the HDR is, is a good tool is a good translational proxy for the trip. And it's a big question in the whole field. Is the HDR, a good tool? And is the answer is just it's the best we have, we know it has some problems. Okay, here, for example, we see this. But it's still it's a very strong tool to see pharmacologically how the substances work, we can play with different receptor modulators, we see the effect in HDR. So it does have some short term acute effects that we do see with HDR, but it's not one to one psychedelic trip and human.
Unknown Speaker 48:01
But I have to say, though, that that HDR is an outstanding measure.
Unknown Speaker 48:06
It really is outstanding in the context of what it does, but always correct. And this is something that he observed together with other people in the lab, that the doesn't end there. When you give a mouse
Unknown Speaker 48:21
a dose of psychedelic orange, his colleagues pointed out very clearly, and I agreed with him that it doesn't end there. The HDR stops, but the mouse doesn't go back to being a normal mouse. The mouse is still trippy for quite a while after that. And there's something else going on. And we don't know how to measure that. We don't know how to quantify that. And we don't know what the implications are. But it's something that interests us a great deal.
Unknown Speaker 48:49
You know, I just read an article recently, about some researchers and I don't know all the details, but they were using an AI
Unknown Speaker 49:00
computing program to hook up people's brainwaves or something like that, to basically
Unknown Speaker 49:08
visualize people's dreams, and, and using AI to actually visualize them. And I think it'd be cool maybe in the future if we, if we can kind of see what if if the mice are are quote unquote, hallucinating if we can actually, you know, put that up on a projector and actually see what what they're seeing in their brain
Unknown Speaker 49:32
including other things that you know, you're you're saying like the full spectrum, they felt more relaxed. So measuring kind of,
Unknown Speaker 49:40
you know, nervous system response of like relaxation, cortisol or, or certain things like that. I mean, there's a million million tests that one could do. I just thought that was that was really interesting. And I also wanted to
Unknown Speaker 49:55
I wanted to ask because I thought this is really interesting. You used a
Unknown Speaker 50:00
extracts and the company grew out the the actual mushrooms, the fruiting bodies of these philosophie mushroom, extracted it with with various solvents, and then spray dried that those liquid extracts into a powder.
Unknown Speaker 50:18
And then you injected, you basically
Unknown Speaker 50:24
made it liquid soluble and then injected both that pure psilocybin and then also that extract into the bloodstream of the mice, it seems a lot like a lot of steps. And, you know, I, that's what we do for mushroom revival minus the injection is extracted with solvents, and then do a spray drying technique to make a powder.
Unknown Speaker 50:49
But you can't really chew on a reishi. But you can chew on a couple of grams of philosophy of mushroom. So I'm just curious, like, why, why you choose why you chose to do that that complex extraction is spray drying and then
Unknown Speaker 51:06
do an injection afterwards?
Unknown Speaker 51:11
Well, I think go order some very interesting theories about that we talked about a lot in the lab, I just want to say that, you know, we're psychopharmacologists, and I'm used to getting a powder and putting it in water and injecting it into my soil in human experiments, giving it to people.
Unknown Speaker 51:30
But you know, that's what I do for a living. But clearly here, there are different ways of approaching it, or do you want to relate to that? I think it's an important point.
Unknown Speaker 51:42
Yeah, first of all, I want to say that you can't chew on a reishi it's just gonna take you a lot of time to get through it you a few days, but yeah,
Unknown Speaker 51:53
well, they did a methanol extract in the company, they gave us the extract, which tried to kind of incorporate the alkaloids kind of take the whole umbrella of the alkaloids inside. But it doesn't take in their complex sugars and complex polysaccharides. Right, like the glue cans are not in this extract, which is also very interesting to, to research, just like what I talked about before, going back to the source, right. And it has its reasons why we're using a
Unknown Speaker 52:26
kind of narrow extract has to do with Western medicine and how the whole field deals with
Unknown Speaker 52:32
how the pharmaceutical field deals with medicines and compounds, a lot of it has to do with knowing the exact dosage that you're giving
Unknown Speaker 52:44
to the patient getting a replicated effect of the treatment.
Unknown Speaker 52:50
I think that with mushrooms, there's a big misunderstanding. And this is something I saw in my in the previous lab was in that when you cultivate mushrooms,
Unknown Speaker 52:59
they're very sensitive to their growing parameters, right? Not only the substrate, but also their temperature, humidity, co2 levels, all that.
Unknown Speaker 53:08
But because they're so sensitive, you can actually cultivate them to have a very specific profile into fruiting bodies as well, we saw in my previous lab with alpha and beta glucans, that we produce the exact same extract, but with a very precise and controlled protocol of cultivation protocol. So I mean, this big misunderstanding with mushrooms and comparing it to plants, we're kind of pushing this is kind of like a change of mind with what we published here, that we can use mushrooms and maybe go back to extracts in two whole extracts, right, combining water soluble and organic extract together and getting a consistent extract that we can later on use and understand the profile of this extract with controlled cultivation. So something that we can achieve with mushroom.
Unknown Speaker 54:05
And what was your other question? Sorry.
Unknown Speaker 54:09
There was another way to speak to why you chose to inject it.
Unknown Speaker 54:14
Yeah, so injecting first of all, we don't inject to the bloodstream, we inject IP intraperitoneal alien to the, to the stomach area, right? And it gets absorbed into the bloodstream like that. And
Unknown Speaker 54:31
it's just gives us a very precise and fast onset of effects, as opposed to pare OS, what it's called. So Grivas you give the mouse also you need to know that the mouse is getting the dose you want, right? You can't just give it to them in the food and expect them to eat it. So you have to devise it with a needle into their,
Unknown Speaker 54:53
into their stomach and this whole process is very stressful for the mouse. And we're trying to reduce the stresses
Unknown Speaker 55:00
much as we can for the mice, and restraining them in the hand and injecting them into the stomach area into the abdominal area is very fast, very painless, the mice barely feel it.
Unknown Speaker 55:13
And as a little side note, we actually did compare the HTR of Grivas. psilocybin as opposed to the IP. And we saw very interestingly, the same profile. Now this is mice not human, right, the HDR got to a peak of four minutes and reduced by 10 minutes, the exact we put it one to one on the IP and pear OS that we gave, it was the same profile of HDR, which was very interesting.
Unknown Speaker 55:42
Well, I mean,
Unknown Speaker 55:44
there's a big thing happening in California right now in and around LA, where people are going to these IV clinics in the morning, like after a night of drinking, and they get electrolytes and all these different things in an IV, and they just sit in the chair. So, you know, maybe, maybe there's something to that, and we might see some, some psilocybin IV clinics popping up and maybe some reishi in IV clinics coming up here soon. So it's interesting,
Unknown Speaker 56:15
actually,
Unknown Speaker 56:18
for psilocybin, people tried to give IV psilocybin in a few clinical trials, and they saw that the effects come up and drop off, like 20 minutes effect. So the effect is saving is much shorter than taking it through the stomach and slowly absorbing into the body, which is seven to 10 hours, right? So I mean, maybe what you're saying can be something a quick burst of positive neurobiological effects, IV psilocybin and 20 minutes are out of there.
Unknown Speaker 56:50
Do you know if the effects were it's 20 minutes, but 20 minutes of very high intensity or
Unknown Speaker 56:59
not? We've Yeah, they report
Unknown Speaker 57:01
in
Unknown Speaker 57:03
the the HDR goes up quite rapidly, and then declines. And the dose
Unknown Speaker 57:11
is an issue here that the HDR with a higher dose goes up much quickly, but an equal but declines to more quickly. I think these things are very well with that. But I think that, you know, the issue here is really not so much how does one give it to the mouse.
Unknown Speaker 57:29
Because at the end of the day, it's just a pharmacokinetic issue. If you if the mouse swallowed that, then it goes via the stomach, and the liver, and a lot of it gets metabolized before it gets to the brain. These are technical questions. For my from my perspective, the key and really fascinating question here is what are the additional components of the extract doing what is then we have other research which are not going to go into tonight, but we have other research using other animal models, which is totally fascinating and supports the the approach that there is something in the mushrooms beyond the psilocybin, which is what the entire industry is concentrating on today, the chemical psilocybin, the pure psilocybin, there's a lot more there, which is doing a great deal. And there could be huge benefit in understanding that, you know, there was a German researcher called the OChem guards, who published papers in which he described the effects of different mushrooms, and very, very elegantly, he describes totally different effects for mushrooms that contain high and low levels of psilocybin that contains more of certain tryptamines and more of other tryptamines. And you know, this is fascinating stuff. And I think that we can learn a lot not only about how to treat psychiatric disorders but how the psyche works from from studying this and that is why this area is so fascinating to me I came to this I'm not a mushroom person for knows at least 100 times more about mushrooms than I do. But I came to this because I was totally fascinated with how we can understand how the mind works and which chemical effects are affecting the way in which the mind works and the way in which feelings are felt and thoughts are thought
Unknown Speaker 59:36
well maybe you just answered this but I'm curious if you if you both had unlimited time, Money Team equipment, all the
Unknown Speaker 59:47
bureaucracy red tape was lifted and you know you had access to everything you ever wanted to needed. What would you do and why?
Unknown Speaker 59:57
I mean off till I finished my extended vacation on the
Unknown Speaker 1:00:00
To
Unknown Speaker 1:00:03
the, I would certainly implement a research program directed at dissecting out what it is within psychedelic mushrooms that makes the difference. And I would extend this research to other
Unknown Speaker 1:00:21
to other psychedelic compounds. For example, a company we work with in the USA, has produced
Unknown Speaker 1:00:29
five Meo DMT, by growing paratyphoid cells and extracting it from paratyphoid cells without damaging or inflicting harm on the toad, and just from the cell culture, and there's a whole lot of stuff.
Unknown Speaker 1:00:45
Besides the fact that five Meo DMT and I think there's a whole world of Psychopharmacology, there's a whole world of potential treatments for severe psychiatric neuro cycle, neuro psychiatric, inflammatory and other disorders there. So if I had a great deal of money, I'd hire about 100, PhD, and postdocs, like Oren we'd get to work
Unknown Speaker 1:01:11
when you are?
Unknown Speaker 1:01:14
Well,
Unknown Speaker 1:01:16
I would love to understand the mechanisms that psilocybin acts upon psilocybin, if you actually look at it structurally, chemically, it's four Oh, H DMT. And when you look at it from that perspective, it's very interesting to understand if the brain system that is activated by psilocybin
Unknown Speaker 1:01:35
actually belongs to the inherently enigmatic DMT based system that's in the brain, and it's poorly understood, the MT has already been shown to be an endogenous neuromodulator.
Unknown Speaker 1:01:47
Its production is increased by six fold during death. And it's gonna be very interesting to uncover the role of endogenous DMT. And its meaning in our lives. DMT has been shown to increase synaptic plasticity greatly.
Unknown Speaker 1:02:01
It's interesting to postulate a fin. When in life, the brain produces large amount of DMT it's actually rewarded by an increase in synaptic plasticity, kind of like a self improving mechanism that's facilitated by DMT. And of course, once we understand it, we can start better utilize it for healing and self improvement, personal self improvement,
Unknown Speaker 1:02:21
and then understand how molecules like psilocybin are five Meo DMT that are very similar to DMT act upon in the brain and produce different effects as well. Right, the all these compounds DMT doesn't affect you, cognitively, you know who you are, where you are with DMT when you take it exogenously, but with five Meo DMT and psilocybin, you kind of like your cognition changes, you know, you start losing sense of time, who you are, the more you take this something that's not apparent with DMT it's very interesting to see how these molecules play on the piano, that is the mind.
Unknown Speaker 1:03:02
I would say the opposite. I definitely lose track of who I am in time and everything on on pure DMT for sure. Yeah, but you know, who you know who you are and what you did, right? Like it's not?
Unknown Speaker 1:03:15
Yeah, yeah, I think dosage, you know, yeah, I guess no sewage, but I will say it's very interesting. I've never taken pure psilocybin or psilocybin. But I've taken, you know, vaporize pure DMT and ayahuasca and I will say, way different experiences, and I will say that Ayahuasca is way more similar to, like, the pure fruits of philosophy, mushrooms, like, the space that I go into the feelings, everything reminds me of the same space that I feel after drinking Ayahuasca but pure vaporize. DMT is just totally different.
Unknown Speaker 1:04:00
And I'm curious if I were to take pure psilocybin or psilocybin, if it would be more closely related to, you know, pure vaporize, DMT if that would be a similar kind of space that I would enter. You asked me about where you can follow us, we've got an active website of our center, and we post all the news items, papers, interviews, podcasts, everything that reflects the activities of the center gets posted the politics left brain labs center for psychedelic research do you put into Google come up as a brain lab center decreases and that is our center and
Unknown Speaker 1:04:43
you know, it explains what we do, why we do it. And also we have an active section where we post all our papers and post the news items. The news item section has been totally monopolized by all the
Unknown Speaker 1:04:58
citations under
Unknown Speaker 1:05:00
From websites above our recent paper, but there's more on the way. Yeah, I think I think we'll just wrap up. You know, it's it's been a pleasure having you both on and talking about your research. I'm just curious where people can can follow your work. If they want to keep updated on future papers and projects coming out of your lab. Where Where can they do that?
Unknown Speaker 1:05:27
Well, you can,
Unknown Speaker 1:05:29
we have a website, I'll send to it's called the sub brain labs center for psychedelic research. And we have a very active website, which you can identify or get to through Google. And we post all our research papers on the website, and also all news items related to our activities, and also all podcasts, which we hope this will be the next one to be featured. And so anybody who wants to visit us there is very welcome. And you can also contact us via the website, if you're interested in talking. And we also have a very strong presence on LinkedIn. And I post all our papers, the comment on other papers and so on.
Unknown Speaker 1:06:18
Well, thank you again, I think this research is incredibly important. Obviously, we are just just beginning to understand, you know, the beneficial attributes of philosophy, mushrooms, and to really understand all the different compounds inside of them and how they're acting on different parts of the body.
Unknown Speaker 1:06:40
And what exactly they're doing, I think is incredibly important. So thank you for doing this work. I'm looking forward to continue to follow to see what other work you're continuing to do and
Unknown Speaker 1:06:55
and also thank you for everyone tuning in and tuning in for another episode of the mushroom revival podcast.
Unknown Speaker 1:07:03
We couldn't do it without you listening wherever you're listening in the world. And if you want to support we don't have a patreon for you to financially donate directly. But we do have a kind of mother brand called mushroom revival where he sell functional mushroom products from gummies capsules, tinctures powders, and if you want any for you, your friends family, you can use the coupon code just for listeners called pod treat. And if you don't want to spend any money, that's totally cool. We have a giveaway going on where you can win some free stuff every month. We also have a whole line of free ebooks on our site that you can download all about cooking, and one about psilocybin and others unfunctional mushrooms, things like that. And we have a whole line of blog posts, right, but it doesn't blogs a month. And all of our podcasts are on there as well with all the show notes and transcripts and things like that if you want to dive a little bit deeper, and leaving a review goes a really long way and also if you learn something cool in this episode or another episode, tell your friends and family you know keep keep the conversations about psychedelics and psilocybin mushrooms and and just just mushrooms in general alive and get more people invested in these conversations and excited about these conversations.
Unknown Speaker 1:08:34
Because mushrooms are the future and they're also in the now so thank you everyone, as always much love and made the spores be with you.
Unknown Speaker 1:08:44
Thank you
Transcribed by https://otter.ai
