• njikomes

Sam Banister: Psychedelic Startups, Biotech, Drug Discovery, Psilocybin, DMT, Psychedelics & Society

Full episode transcript below. Beware of typos!

Nick Jikomes

Dr. Sam Banister, thank you for joining me.

Sam Banister 4:18

Yeah, great. Great to be here, Nick. Thanks for having me

Nick Jikomes 4:21

on. Can you describe for everyone a little bit about who you are and what your scientific background is just to provide context?

Sam Banister 4:29

Yeah, sure. So as you can probably tell from my accent, I'm from Australia. I do my training here in synthetic and medicinal chemistry. So I got my PhD here a number of years ago, and then sort of moved into radio pharmaceutical development at Stanford looking at Pet tracers and things, did a little bit of chemistry supporting structural biology work there with Brian Kobilka, and a number of other people and finally moved into a bit of drug dev for ALS Engelmann slab and Mike Smith at CAMH at Stanford. He was eventually sort of recruited back to his Australia to help run a philanthropic cannabinoid drug discovery effort here, called the lemon initiative. And then most recently, I have just started my own company with my co founder, Josh isn't in the field of psychedelic medicine. So we're looking at sort of taking inspiration from natural psychedelics in the design of next generation medicines.

Nick Jikomes 5:18

Yeah, and that's something I definitely want to talk about. So, you know, one of the questions that a lot of people have is, when they sort of look at the emerging psychedelic biotech industry, there is a lot of focus on developing new forms of existing drugs. There's also a lot of emphasis on developing novel drugs. But when you think about, for example, something like psilocybin, the, the compound for magic mushrooms that many people will have heard of, you know, there's psilocybin, literally the thing that you can get from mushrooms and doing extractions and things. But there's a lot of companies now working on creating new forms of psilocybin, which are different in some way, and presumably have some some kind of benefit with respect to bioavailability, or the route of administration or things like this. Can you talk a little bit about that? Like, why? Why do we need to create new forms of psilocybin? And how does that even work?

Sam Banister 6:10

Yeah, that there's a number of different considerations here, I think, Nick, so one, one is around creating sort of commercializable products, so very hard to do with with natural products, as you'd be well aware from the cannabis space. So a lot of companies have started looking at sort of what I've termed low hanging fruit approaches to creating protectable IP in this area. So I guess, one, and you have sort of isoforms, as you know, various salt forms of psilocybin, which, which is quite straightforward, in terms of generating those and defining them. And then you've got people making very minor modifications in terms of sort of generating psilocybin itself, which might change the metabolism and gives you a sort of technical, novel chemical. And then you've got groups like mindset making sort of even more, larger changes in that. So changing the sort of very structure of the drug itself in in sort of pretty minor ways, in an attempt to improve its profile. So you have this whole kind of spectrum of activity, a lot of formulations, a lot of pro drug work. But I sort of view a lot of that as it really does seem to be geared towards creating protective IP rather than developing better drugs. I mean, there's a lot of preclinical evidence showing that some of these formulations and things, you know, confer slight benefits in terms of bioavailability, or, you know, the sort of exposure curve. But, yeah, a lot of it does seem to be geared around generating IP.

Nick Jikomes 7:31

I see. So the primary motivation here is to create something that's patentable and commercializable, rather than something that's necessarily going to be, you know, a step change in terms of how effective it is as a medication. Yeah, that's,

Sam Banister 7:43

that's out of commercial necessity. And the reason I think that's that's probably the case is that psilocybin is already a pretty good drug, right? It doesn't have any sort of major drawbacks. Apart from a few notable ones, most of it seems to be around commercialization.

Nick Jikomes 7:55

I see. And so what, what, are you guys doing it silo? Are you doing psilocybin stuff? Or what's your primary aim?

Sam Banister 8:01

No, we're not doing psilocybin or any natural psychedelics. As such, we're truly focused on next generation compounds. So we're looking at using a number of innovative medicinal chemistry approaches to actually modifying first generation psychedelics in a more dramatic way. And our hypothesis here is that we will get different target receptor engagements, which we've already demonstrated for a number of these compounds, and that that will lead to different benefits in the clinic.

Nick Jikomes 8:26

I see. So the idea is you take existing psychedelics that have some known beneficial qualities, medicinally readily relevant qualities? Do you modify them or use them for inspiration to create novel drugs that probably have some of their benefits, but maybe get rid of some of the drawbacks? Is that the idea?

Sam Banister 8:43

Yeah, yeah, that's it. So one, one specific example is thinking about, or maybe I could just say we're designing sort of three product classes here. So one of these is a shorter acting, psychedelic for use in psychedelic assisted psychotherapy. And that's really, from a commercial standpoint, you make that treatment more widely accessible by patients. If you have these shorter treatment sessions, instead of these full day to therapist treatment sessions. We're also looking at sub psychedelic drugs. So there's some some really interesting work going on here. In Australia, actually, Vince Polito at Macquarie University, he's doing one of the largest studies of what you know what people might term sort of micro dosing, but certainly not a fully psychedelic dose of psilocybin, so about five milligrams, and looking at the effects of that in terms of repeat dosing in moderate depression. And then we're also looking just compounds that can induce neuroplasticity in a beneficial way. So very much like the sort of sacrifices in class that that Dave Olson and Alex are looking at. And thinking about that, that second product class, one of the reasons psilocybin won't be, won't be perfect for that sort of use this sort of repeated dosing use, is that activates the five HTTP receptor. So this is, you know, an unknown liability in terms of five HTTP agonists for cardiac valve philosophy, which is a pretty serious pretty serious artifact of five HTTP agonism.

Nick Jikomes 10:02

Can you Can you unpack that a little bit for people? So, so, you know, I don't think we need to go into 5g to a stuff. I've had a lot of episodes where we talked about that that's the psychedelic receptor that's basically needed for most of the classic psychedelic effects of things like psilocybin or LSD and so forth. But you're saying there's this other receptor serotonin to B. And so what do we know about that? And what exactly is going on there?

Sam Banister 10:25

Yeah, five HT to be expressed in a number of places, including in the hot psilocybin, and a number of in vitro assays or Cillessen. To be more technically correct, actually has greater potency it to be that it doesn't to AOTC depending on what essay you're using. So it's a definite target a physiologically relevant target of Cillessen in the body. But it's associated with this sort of hardening of the valves of the heart. This cardiac availability. And the reason we know this is an issue is because of the drug Fanfan, which was ultimately pulled from the market a number of years ago. So this was a combination of phentermine and fenfluramine. It was sold as sort of an anorectic, sort of diet agent to reduce obesity. So you had a stimulant type drug. And then fenfluramine was a, you know, to see and to be agonist, but it was withdrawn from the market precisely because people are taking this pill every day, we're getting velocity as a result. So a real world sort of face for post marketing surveillance, look at that, the effects of that sort of agent. And now as a result, five HTP is largely a sort of development liability and anti target.

Nick Jikomes 11:29

I see I see. So 5g to be is expressed in the heart and a number of other places. There have been drugs in the past that have been used that have been pulled from the market, because people were using them on a daily basis, and it was causing heart issues. Can you go into a little bit more detail on what those heart issues were? And how common was that was it? You know, was it common enough, but still relatively rare that they pulled it? Or was it was it actually quite common?

Sam Banister 11:51

That's that's a really good question. I don't know if I have satisfying answers for that. It's obviously not such a major issue. I mean, they are repurposing fenfluramine, now in Dravet syndrome at a different a different dose. But the I don't know if I have a good answer on exactly how common it was just that it's sort of known risk for compounds that are five HTTP agonists.

Nick Jikomes 12:12

Yeah. But at the very least, it was common enough that they actually pulled out Yeah, in the market. Yeah, it

Sam Banister 12:16

could be picked up in post marketing surveillance, and it was substantial enough that the FDA decided to pull it. So yeah. So

Nick Jikomes 12:23

you know what, that's sort of interesting from the perspective of one of the one of the big trends that you're seeing with respect to psilocybin and other psychedelics, which is micro dosing, as you mentioned, so is the concern there that if you're taking even a micro dose of something like psilocybin on a regular basis, whether it's every day or multiple times per week, that there could be the similar the similar kind of risk for heart? Heart issues?

Sam Banister 12:49

Yeah, yeah. valvular disease as a result of TB agonism is is definitely one of the possibilities for psilocybin use at the doses that people are using it. So no one's no one's actually done a really rigorous study to show sort of whether it is likely to be physiologically relevant. And micro dosing, you know, as many people have probably already discussed, it's a pretty vague term anyway, it's not really precisely defined. So the doses that people are using is not really super well known. But Brian Ross had had an interesting tweet on this recently, that half recently, there was a sort of back of the envelope calculation of whether this is or is not likely to be relevant for a number of different psychedelics at the doses they're taken. And the sort of consensus from that tweet was that it's a possibility, and it's something that people will should definitely be looking out for.

Nick Jikomes 13:33

I see. Yeah. So it's, it's definitely something that we should think about, do we know, I mean, beyond the anecdotal reports around the potential benefits of micro dosing, you know, people are reporting that it boosts mood and enhances creativity and so forth. Has anything actually been demonstrated there for any of the classic psychedelics? Yeah,

Sam Banister 13:53

it's one of the studies like the one Vince is doing is so interesting, because a lot of it, obviously, it's people have been doing these studies of sort of increased rigor and attempt to get as close to, you know, the placebo controlled trial, that blinded trial that we consider the gold standard for clinical trials at this point. And this is involved some previous studies that people have looked at self blinding, you know, setting participants who obtained their own illicit drugs, capsules that are coded in various ways, so they can self blind and microdose and try to do it that way. But that doesn't really get around the issue that, you know, you're still typically if people are bringing their own substances, these trials, you're talking about, you know, drugs of unknown provenance, and so you don't actually know what the dose of psilocybin mushrooms is you don't actually know how much LSD is on a piece of blood or that you're cutting off and putting into this, this capsule. So no matter how well you do those studies, unless you're using sort of pharmaceutical grade material in a in a sensible way. It's very hard to know what the effects are. But certainly there's there's a huge amount of community support and anecdotal support for micro dosing, having positive benefits on mood creativity, all of these things. Yeah, but I think without without doing The proper blinded studies, it's very hard to know how much of that is placebo and how much of that is drug effects. So Vincent studies a super good one for that reason, because they are using GMP psilocybin, five milligrams per dose, I think they're dosing three times a week. So, you know, it's a reasonably large study of willpower studies to be able to see if there are sort of real effects there on depression. I see.

Nick Jikomes 15:19

So they're calling five milligrams of microdose. How does that compare to like what they use, and some of the big studies at Hopkins and others have done with the full dose of psilocybin?

Sam Banister 15:27

Right? Yeah, so the the standard dose for psychedelic assisted psychotherapy is usually 25 milligrams, which I believe is sort of equivalent to you know, what, what you might term a row what Sam Harris would term a heroic dose of, of psilocybin cubensis, containing a psilocybin cubensis. So around five grams or so that I think, which is, you know, pretty, pretty hefty, I'm led to believe that's a full blown mystical experience, possibly with quite a bit of ego disillusion.

Nick Jikomes 15:56

Interesting. Yeah, it'll be interesting to see the results of that. So the other thing that you mentioned, was developing psychedelic inspired drugs or derivatives that are still psychedelic, but they have a shorter duration of action. And one of the obvious reasons for doing something like that, that you mentioned, is is the commercial side, you know, these sessions, when you when you take these these heroic doses of psilocybin, you know, it requires monitoring for several hours, because the experience is going to last that long. You know, you usually have a couple of professionals on in the room with the person and just it's very time consuming and laborious, especially when you think about scaling that up to potentially millions of people. So a shorter duration of action makes sense there. And it starts to get into questions of the experience itself, and the duration and the intensity of the experience and whether or not those those subjective experiences are actually part of the therapeutic efficacy that's been seen so far. So how do you start to think about that?

Sam Banister 16:53

Yeah, that's a super interesting question. I mean, one of the coolest things about this space right now is that there are so many of these unanswered questions. There's truly just like an endless list of really interesting topics to explore. So there's, there's no consensus right now, around whether the full psychedelic experience is necessary for therapeutic effects in at least some of the conditions that have been explored. It seems like having, you know, what's termed a sort of, quote, unquote, mystical type experience does correlate with therapeutic benefit in a number of different indications, especially sort of end of life anxiety and depression. But but no one's done the other control study that would be needed there, right, which is lower doses of psychedelics dosed in various ways. So that's sort of the work that's, that's happening right now.

Nick Jikomes 17:35

I see interesting. And, you know, give us a sense for how you know, so depression is one of the things where psychedelics have been most studied so far. And there's clearly a very big need for new treatment protocols and new drugs in the realm of depression. For a number of reasons, can you start to give people just a general sense for how big and how burdensome the problem of depression is?

Sam Banister 18:00

Oh, yeah. I mean, it's one of the largest, one of the largest sort of disease burdens in the world right now. And we know this is, we know, this has only increased since COVID, for sure, that sort of massive compounding effect on this issue. So I think the stat we talk about is that you know, about one in eight Australians are on antidepressants. And, yeah, I think, you know, the, sorry, let me step back. So the steps that the stats of the people typically talk about, are, you know, on the orders of hundreds of millions of people suffering depression globally. And and you see this both in sort of diagnoses and other statistics, but also in the rates of prescriptions of antidepressants. So by some measures, prescriptions across large parts of the world have increased sort of two or 300%, since the beginning of COVID-19. And, yeah, it's pretty crazy. Depending on what stats you look at, obviously, we don't have perfect reporting. And any prisons are not really that effective compared to placebo, when you look at the clinical trials that have been done. So this is clearly an area that's, you know, ripe for, for some huge innovation. I think that's why people are so excited about the promise of psychedelics here.

Nick Jikomes 19:08

Can you can you want to step back to something you just said, you mentioned that at least some antidepressants don't seem to do better than placebo? When you look at some recent clinical trials, Can you unpack that for us? Because I know that there's a lot of sort of debate and confusion out there about how good like SSRIs actually are.

Sam Banister 19:25

Yeah, super interesting class of drugs. I mean, you know, they were developed brought to market in the 90s. We haven't really had any innovation in in neuro psychiatry around affective disorder since then. But the main classes of antidepressants that are used as sort of your historical tri cyclic antidepressants is a pretty, pretty dirty drugs that had a lot of different targets and a lot of different things and they're widely used in neuro psychiatry for a number of indications including depression SSRIs were thought to be you know, these are things that inhibit the reuptake of serotonin so the idea that the hypothesis there was that increase serotonin you know, the synaptic junction would be positive and produce mood enhancing effects. But that mechanisms not entirely correct, because you should see those sorts of effects quite rapidly after taking antidepressants, SSRIs. And we know that there's actually a latency in terms of onset of benefit, therapeutic benefit. So yeah, there's an unusual class of drugs, we still don't understand the mechanism of action entirely. They definitely don't work for everyone. And the benefits in some studies are only about 20% Better than placebo. And for that 20% benefit in some patients, you obviously have a huge number of side effects. So the ones that come up are sort of, it's sort of described by some patients as like, just a normalizing of state. So you know, sort of lower lows, but also lower highs, higher lows, but but also lower highs. So people describe frequently loss of libido, loss of enjoyment of food, and other things. And some of those effects, effects campuses. So that loss of the beta, for example, which is a pretty big one, for a number of people, that they can persist even after you stop taking the drug, which is quite problematic. You've got weight gain and other things as well. So it's definitely not, they're not a risk free class for drug for sure.

Nick Jikomes 21:09

Yeah. And you know, you hear that a lot when you talk to people. And it's also been documented in the literature that, you know, to put it informally you when people take SSRIs, they typically describe some kind of like, emotional flattening, so yeah, that's it. Yeah, they're not maybe yeah, maybe they do feel better as an as they're not as depressed anymore. We're not as prone to feeling as sad when sad things happen. But that's also true on the other end of the valence spectrum, that that the things that we enjoy most in life also also get reduced in their magnitude. Yeah, yeah, that's exactly right. And you know, one of the things that super interesting that I think you just hinted at is the question of the chronic use of SSRIs. Because not only are many, many millions of people on SSRIs, many of them have been on them for years, or even decades at a time. And that's pretty much commonplace at this point in many different countries. Use you mentioned the sexual dysfunction thing. So that's an acute effect, people have often lower libido on SSRIs. But you mentioned that can actually persist even after they stop taking the drug. Can you unpack that for us and maybe talk about anything else that you know, because I know very little about this in terms of what the potential chronic negative effects could be?

Sam Banister 22:20

Yeah, I haven't looked at the statistics on loss of libido and sexual dysfunction. But it's yeah, it's reported, definitely, there's literature out there, around this sort of almost permanent anecdotal support to the sort of almost permanent modification of sexual drive, which, which is problematic for a drug that you stopped taking, you know, if you're still having those kinds of effects. The other one that I wasn't so aware of that I learned about speaking to a friend recently, is a for some classes of SSRIs, that there can be pretty serious withdrawal effects as well, which is not something we really think about, typically, I would say, for this class of drugs. And so this person was actually trying to reduce her dose slowly of an SSRI in order to change medicines, and was getting sort of, you know, electric electric zaps, as she described it electric zaps in the brain, which is, and I looked it up, and it's, it's a known side effect for some classes of SSRIs is this, this feeling of like, very unusual, like electric zaps is the only way people seem to really describe it. But this sort of zapping effect in your brain is what it feels like, which sounds quite unpleasant.

Nick Jikomes 23:15

Interesting. Interesting. Yeah. And my understanding is, we know that there are some of these chronic effects. But there hasn't been a lot of study of this, in part, because it's difficult because you got to follow people for so long to track it. And because there's a natural, there's naturally not a strong incentive for the developers to go and look for that.

Sam Banister 23:34

Yeah. Yeah, that's right. I think unless you're seeing something like, you know, like, valvuloplasty, with with Fanfan, unless you're seeing something that's really, you know, physiologically, sort of identifiable, and, and happening at a decent rate. It's, it's very hard to reveal some of these effects. But I mean, SSRIs, are, you know, surely one of the most overly prescribed classes of drugs that we're sort of using widely these days. So I think we'll see increasing amounts of data around some of the sort of long term negative impacts of that class.

Nick Jikomes 24:02

And, you know, as you said, those were, those were basically the the current, the latest generation of widely used antidepressants. They sort of came on the scene in the 90s, I think, in the early 90s, maybe starting in the late 80s, or something, and there hasn't been a lot of development since then, until, you know, unless you count the current sort of psychedelic Renaissance that's going on. Why do you think that is? Why do you think the there was kind of that stagnation and drug development with respect to depression and related psychiatric conditions?

Sam Banister 24:29

Yeah, just because it's, it's just so hard. It's a super challenging area of drug development. So if you look at neuro Psychiatry and Neurology, generally, all of the drugs that we use widely were sort of discovered in phenotypic screens back in the days. So looking at effects in mice is sort of a one of the first sort of gating decision points that you might use in in progressing a drug. And yet, it's an area of medicine that's not really a metaphor to the sort of more modern target based approaches. So following the the genomic revolution, people have moved to very much target based drug testing. Every high throughput screens identify a new hit, you know, select a lead, optimize it, and hope that that engagement of this single target has an effect as a disease modifying effect. That works super well, for some areas of disease, it's, you know, it's been very successful in some types of cancer, for example, where you target particular enzymes or proteins. It doesn't work so well for Neuro psychiatry, just because the brain is so complex. And we know that there's a, you know, a whole bunch of activity going on in a very complex way at a sort of systems level, that, you know, engaging any single target there typically doesn't produce, you know, a desirable sort of therapeutic outcome. So it's just a super challenging area of drug Dev. A lot of money has been spent on various hypotheses in Alzheimer's disease, and that hasn't really borne fruit. A huge amount of money has been been expended there. And as a result, I think the larger pharma companies have sort of pulled back on their their central nervous system programs. They've sort of divested themselves of doing this, this really challenging drug dev in house.

Nick Jikomes 25:56

Interesting. And I mean, so since since you've got the scientific background, but you're also in the in the biotech in the business space for psychedelic medicine. What do you think, in some ways, this almost seemed to come out of nowhere? I mean, I know that you know, Roland Griffiths and the Hopkins studies that you know, that was going on, I don't know, 2010 11 ish, maybe. And there was some some buildup of excitement there. But it was sort of contained and it still didn't really come to the fore for a while. Then all of a sudden, just in the past few years, you've had this explosion. Is there anything that you can identify as a kind of catalyst for that?

Sam Banister 26:33

Yeah, there's, there's a few there's a lot of thought. It's it. You're right. It's super interesting like this. I remember I applied after my PhD, I applied for a Fulbright Fulbright scholarship to go work with Richard Glennon, who was doing some sort of stimulant and psychedelics chemistry. I think at that time, he was one of maybe three people in the world, I could identify who was doing psychedelics, chemistry, he was at the end of his career. So you had him David Nicholls, maybe a couple of other people. And there wasn't much happening. And I've met some people in sort of shoguns network, Paul Daley, and others who are now associated with ESRI. And you know, there were these small numbers of groups doing interesting things. And then I think it's probably around the time, I think there's a few different sort of effects in popular consciousness. And that's probably Michael Pollan. You know, people refer to the polling effect when when how to change your mind was published, making them more, making this whole sort of area more mainstream bit of the Joe Rogan effect because his podcast also featured psychedelics pretty prominently, it has a pretty large number of listeners. So I think it was just sort of yeah, this this interesting, you know, confluence of people talking about it, people were sort of loud voices online talking about it, all at the same time. And as a result, you know, other people have become interested, if you speak to sort of investors and people in, in drug debt working in this space, almost everyone has been touched sort of directly or indirectly by depression or suicide. And so there's a lot of sort of personal driver, I think people, you know, to sort of gain momentum. And it's reached this sort of snowball level where now there's just too much money flowing into the space, because so many people are interested in the promise of this area. Yeah,

Nick Jikomes 28:01

yeah. No, I think you're making interesting points. So, you know, you had sort of a psychedelic dark ages for literally decades, you know, back to the 60s, up until, you know, maybe the mid 2010s, or something, you had a few people doing research on psychedelics, you had sort of Roland Griffith Griffiths group at Hopkins did some of the initial really exciting human clinical stuff for psilocybin, you sort of had, you know, a slow drip of these things coming out at the time. And then you had, as you mentioned, these cultural factors, you had the Michael Pollan effect, you had Joe Rogan becoming super popular and talking about DMT and mushrooms on his podcast. And then, you know, the other piece there that you mentioned, is just how prevalent depression and things like this are. And so the cultural amplification through through those channels, together with how many people are touched by these things directly, or indirectly, seem to somehow, you know, shine a light on some of that emerging research that was being done at Hopkins and elsewhere now, and now we're, now we almost have the opposite problem where there's this explosive sort of explosive influx of funding, and presumably, a lot of it won't go anywhere. But it's, it's better that we have it than we don't.

Sam Banister 29:09

Yeah, I agree. I think there's so much interesting work to be done with psychedelics, I think there's still a lot we don't know, one of the sort of unintended benefits of having this this sort of psychedelic Dark Ages, that that you'd be well aware of Nick with your background is that we get to put all of the cool tools from neuroscience to work in these areas. So you've got like sort of Robin Carhartt Harris doing all this interesting work with psilocybin and brain imaging. We're using some very modern sort of molecular biology tools in neuroscience now to study exactly how you know ketamine is having the effects that it's having. It's a rapid and antidepressant. So, yeah, I didn't have the benefit of the dark ages for sure. Yeah, absolutely.

Nick Jikomes 29:45

I mean, I've had a few guests on who are neuroscientists at different levels of resolution, you know, human brain imaging, all the way down to cellular, new neurophysiology and you know, molecular, molecular and crystal structure stuff, Brian, Brian Roth, for example. And so you You really have all of the the horsepower of modern neuro technology as it's used in, in labs all over the world, really coming to this in full force. Right now there's people really dissecting some of these things at every level of analysis, it seems.

Sam Banister 30:14

Yeah, it's super exciting. I think. I can't believe how much is going on, you know, there's probably been some counts, like more than 100 companies working on preclinical and clinical development in this space, you've now got, you've got whole centers, you know, Tim Ferriss funding, a media center for psychedelics, you've just got like, a huge amount of really exciting stuff happening in the private world and academic institutions as well. You know, well, world leading institutions. So yeah, super exciting time for psychedelic science.

Nick Jikomes 30:39

Yeah, one of the one of the one subclass of psychedelics that I think is super interesting, because it speaks to some of the commercial and clinical needs are DMT and DMT. Analog. So we've already talked about, you know, the interest in having versions of psilocybin or other drugs that don't act for six hours or 10 hours, that extra shorter duration of time. But it's also interesting that we have existing psychedelics that only lasts for a few minutes, but give you a full blown psychedelic experience, and have at least some hints that they might have some therapeutic benefit for things like depression as well. So have you thought much about DMT and DMT? analogues? And can you tell people what's maybe going on there?

Sam Banister 31:18

Yeah, yeah, so the thing to appreciate about all of these psychedelics is they're all quite different, you know, that they, they have similarities, but they also have very important differences. Psilocybin clearly has clinically demonstrable effects in depression, that's been shown, details of the mechanism. And the sort of nature of the subjective effects that are required for that is not entirely clear cut with DMT. That's sort of a new area of study. But I believe there are groups looking at a DMT and five, methoxy, DMT, both, both of which are typically vaporized for inhalation, they have a very rapid onset of effect, very short duration of action, very, very intense experiences. And there's sort of some debate in the community about whether that sort of rate of onset and the intensity of those experiences will actually be clinically useful, you've got sort of camps of people who suggest that this sort of slow onset of action peaking to, you know, really intense experience, and then sort of fading away is necessary for people to sort of consolidate their their experience and use it in an integrated way. But obviously, that's not really possible with DMT and five, methoxy DMT. It's sort of like a, you know, a rocket to another dimension. So you don't really get that time to process what's going on. But but people are suddenly looking at it. So we'll have data from those trials as well.

Nick Jikomes 32:28

So how did you actually, can you tell talk a little bit more about the story for how from for how you went from your academic life as a postdoc into a startup founder, because that's not so common. It's certainly not unheard of, but it's certainly not the main track people go down. And I know that there's a lot of probably PhD students and postdocs out there that would be interested in hearing how that happened.

Sam Banister 32:54

Yeah, yeah, I was, as I've been in most parts of my career, I was just really fortunate to meet my co founder, Josh herzman. So the short answer is I'd moved back to Australia in 2018. For this recruitment for this philanthropic cannabinoid drug discovery effort. We've done a lot of really good work there trying to develop new treatments for epilepsy. A lot of my work has focused on neuro Psychiatry and Neurology, so diseases of the brain generally, I've done quite a bit of natural product optimization, you know, looking for new treatments and improve on what nature has provided. But after working for this, for the Lambert initiative for a number of years is.

Nick Jikomes 33:32

Hold on to me, I lost you.

Sam Banister 33:41

Sorry, I think we just dropped out there for a second.

Nick Jikomes 33:43

Yeah. So you were at Lambert for a number of years. And then and then we dropped up.

Sam Banister 33:47

Yes. Sorry about that. I'm just gonna make sure I haven't got anything running here. I think I do. Yeah, so So I was at the Lambert initiative for, for a number of years, had done a lot of good work there. I think a lot of the kind of really interesting work in the cannabis space has sort of already been completed. Obviously, that's sort of a developed field of medicine now for a number of patients around the world. And then sort of right as I was thinking about what to do next, I was looking at a number of options. Overseas back in the beaks. I loved living there. And working there. So many, just so many exciting scientists doing such cool stuff. And then I lost a friend to suicide at the start of last year. So yeah, it was pretty, pretty shocking. It's the fourth friend that I've lost to suicide since I was 15 years old. I'd been following the clinical trials in psychedelics I've always been interested in this area. Right around the time that had happened. I met Josh, he's a you know, this amazing sort of repeat founder with a tech background. He's a big, you know, big into Effective Altruism. He's a angel investor in a number of biotech companies himself, that are focused on sort of human benefit. And yeah, he's a New Yorker, although he's been living here for a number of years and I you know, we just kind of hit it off like I really love To sort of drive and hustle. And you know, he's he's just a super honest, straight shooter. So we we got talking about what we could do in this space for depression, what what sort of a biotech company in Australia might focus on in terms of bringing these these new treatments to market, you know, especially to patients who are not going to have access to potentially the very costly psilocybin clinics that we rolled out.

Nick Jikomes 35:22

So you're the CEO of silo? Correct?

Sam Banister 35:26

I'm, we're co founders, and I'm CSR was my formal title base. Yeah, yeah. Josh is the CEO.

Nick Jikomes 35:31

Okay, and what I mean, what does that been like, so far being, you know, being an executive at a biotech company? And how do you feel like you were, you know, even though when you go to graduate school, and you do your posts, like you're not being explicitly trained for that purpose? Do you feel like there was something in your training that set you up to do something like this? Well,

Sam Banister 35:52

yeah, I think living in the Bay and being, you know, living in Palo Alto, going to Stanford, like, it definitely sort of changes your perspective on things. And the funniest thing about all of this is when I went to Stanford, I just want to do a postdoc, find an academic position somewhere and just be a professor and study really interesting science for the rest of my life. And then in the bay, you just meet so many people who are doing such cool stuff outside the academic sphere, this you know, everyone's a founder, you sit down at a bar in Palo Alto and get talking to a guy who's, you know, designing rockets to mine that rare minerals from asteroids and things, you know, everyone's just doing the craziest stuff. So by the time I was wrapping up at Stanford, I was pretty set on like getting involved in a startup somehow, like doing something a little bit more entrepreneurial than I moved back to Australia, there's there's not as much going on here. It's a smaller community, for sure. But yeah, in my mind, I took this academic position at a philanthropic initiative. And you know, the whole time I was really just thinking about how I really would just want to start something else in biotech, move back to the bay or start something in Australia. So I think that that experience at Stanford, those years, it sort of really, really changed my mind on what my career might look like.

Nick Jikomes 36:55

Yeah, I think one of the things, one of the things that translated very well, for me, when I went from academia to the world of startups, is just the ability to tell a story. So you know, a spin, essentially, everything you're doing when you're doing academic sciences, you're just constantly preparing a story to tell people and you practice a lot, telling that story verbally and visually and with numbers and without numbers. And so it just sort of strengthens that muscle and you and you go through the gauntlet of academia did did that you feel like that helped you when it came time to do things like raising money for a startup?

Sam Banister 37:32

Oh, yeah, I think one of these things, it's kind of really disheartening to see is, you know, you work with all these incredible postdocs who feel quite trapped by the academic job market. And they really think they have this niche, specialized set of skills. And when you get out into the wider world start interviewing for jobs, outside academia, you realize, actually, you've developed all of these skills that are super useful that most people do not have. And you just think of them as sort of common because they're so deeply ingrained, but storytelling is for sure one of them I'd say, Oh, good, or good academic scientists are good storytellers. Because you're constantly constantly pitching a narrative around a scientific discovery that you've made, or in a grant, you know, science that you want to do and why it's so important, like, so much of academic science is actually really good storytelling. So I'd say yeah, you know, academic scientists and and postdocs are very good at this stuff.

Nick Jikomes 38:19

And so how did you tell us a little bit about how you crafted a story for how, you know yet another psychedelics, startup was going to work and differentiate itself from the other ones? How did you? How did you figure that out for yourself? And then how did you communicate that to investors and to other people,

Sam Banister 38:37

we had quite a few discussions, it was a pretty evolving concept as an early company. And we were really just thinking about what we might do in this space where the greatest need is and what we might do. And early on, we were talking about using synthetic biology for psychedelics manufacture. But manufacture is kind of a solved problem from a synthetic chemistry standpoint, at least for the common psychedelics. And then we were thinking about drug Dev, and we've done a lot of diligence around what others were doing. And I'm not a huge fan of this sort of more commercial play of just making a pro drug or a formulation just because you can't I don't think that adds much, much benefit usually. So we decided that we're actually gonna have to do some, some novel drug development and really sort of continue a lot of the early psychedelic chemistry that that had been done by Shogun and others. So yeah, the reason we settled on that is that we identified a number of immediate needs, you know, shorter acting psychedelics are one, obviously, they're not going to be suitable that that whole psychedelic assisted psychotherapy model will not be suitable for absolutely every person at the trials even now, they have a number of exclusions, they obviously focusing on particular patient groups, but huge numbers of people will be explicitly excluded from that treatment for various reasons. So then we got thinking about what you might do with sub psychedelic drugs with this expand access for people who can't have a full psychedelic experience. And then further down the line that sort of neuroplasticity promoting compounds you know, for for people who aren't interested in any sort of psychoactive effect, but really would love a new You really innovative antidepressant treatment that's completely different from SSRIs. So that's sort of what we settled on quite early on. It was always very, very patient centered. And thinking about both the sort of sliding scale of clinical validity from that first class of products all the way through to the sort of psycho question class.

Nick Jikomes 40:19

And so given where you guys are at now, what kind of employees do you have at silo? Where did you find them? And then what did they actually do?

Sam Banister 40:27

Um, yeah, it's a great question. So early on, for the longest time, it was just Josh and I, we were kind of doing everything together. You know, we were sort of both co CEOs and CSOs has been doing just every part of the business. We were doing a lot of the work in a decentralized way remotely with with partner CROs in the US and China and elsewhere. And that's, that's a model that I'm pretty familiar with. It's pretty common for small biotechs just to outsource components of the work. So doing a lot of the admin and intellectual work in Australia and then outsourcing other parts. It's very recently, we switched to a colocation at UNSW in January, so it's a university here in Sydney. They've been phenomenal to work with. So we essentially sublet space from them, they have no stake in our IP. We sublet space for them, but we get to interact with the academic community and they get to, you know, send interns and things our way people that want to have exposure to sort of more sort of commercial work or startup culture. So yeah, it's been super good so far. We have now about nine employees. Some of these are fractional, some of them are remote, but the core team is based at UNSW. It's myself and Josh, we've recruited a really phenomenal medicinal chemist will Jorgensen so he's a chemist who did a lot of the foundational chemistry for a company here called Connexus therapeutics. So they're looking at sort of oxytocin, oxytocin modifying drugs, as well as drugs for opioid use disorder. So they're actually taking one of the assets, okay, next 100 into the clinic at the moment in a big NIDA funded study, which is super cool. So he's He's a phenomenal chemist who brings a huge amount of knowledge about the sort of bench to bedside translational aspects. We've also recruited Dr. Jin tan, so he's a computational chemist from the University of Sydney, who's basically wrote the the training manual for Mosaic, which is one of the bits of molecular modeling software that we're using. And then on our pharmacology team, we've got Laura Jacobson and Danny Hoyer. So they're both academics in Melbourne. They've also spent a lot of time in Nevada, so they really get drugged of Laura's heading off sort of behavioral pharmacology and Danny's heading up molecular pharmacology. Danny, you'll see Danny's name and a lot of the old papers around psychedelic activity and serotonin signaling is a real OG in this field. And he's pointed out to us when we were first sort of recruiting him that his grandfather actually worked at Sandoz with Albert Hoffman, when LSD was discovered. So he's definitely been in this field for a long time. We've got Dr. DE Lara potentially doing a lot of our media and comms and she's really phenomenal at that all the psychedelic science outreach. And that's, that's kind of most of the team right there.

Nick Jikomes 42:53

I see. So at the core of it, you've got, you've got synthetic chemists, you've got on the science side, at least you've got synthetic chemists, you've got Computational chemists and you've got pharmacologist, so you're making drugs, you're modeling their potential effects, probably to streamline and think about what you might want to go into the wet lab and do and then you've got the pharmacology folks probably actually testing what these drugs are doing at various receptors and seeing whether or not they're stimulating five HT to B or to a or

Sam Banister 43:19

whatever. Yeah, that's exactly it. So that the pharmacology team, the reason they're, they're sort of remotely located is because they're guiding a lot of our compound selection and optimization decisions. So we're still doing we're largely a chemistry company. So there's this huge amount of benefit in getting your hands dirty with chemistry and learning sort of the details of these molecules, you know, how they actually sort of function. So we're doing a lot of that in house in terms of, you know, quality control around manufacturing and thinking about designing these things. But we're doing all the pharmacology with various partners, just because it makes it makes the most sense from a commercial perspective. So in order to set up our own in house screening for our whole pipeline, it wouldn't be very cost effective. Certainly not this year, and probably not to we we sort of doubled in size.

Nick Jikomes 44:03

I see and then do you I mean, are you aiming to get to the point where you guys yourselves will be doing clinical work?

Sam Banister 44:11

Yeah, yeah, that's the plan. So we're fundraising at the moment. And the plan for that raise is to develop at least one of these assets through ind enabling studies and get it ready for for phase one in the clinic. So the sort of view we take of it is that you know, the most direct path to market is for shorter acting psychedelics will be rolled out through clinic networks. I think clinical evidence will emerge one way or the other for sub psychedelic drugs have sort of product family too, that I mentioned. And for psycho, passagens it's sort of only that these effects have only been demonstrated to the animal level. So some clinical work still needs to be done there. But our view is we'll have a number of really optimized candidates that are ready to be deployed in sort of any political indication across these sort of three classes. But our plan is to take one of those probably from product family, one to the clinic ourselves.

Nick Jikomes 44:57

And our you got you guys measure it all. that silo. Any plasticity inducing effects that might happen downstream of, you know receptor activation? Are you guys looking for that type of thing? Yeah, yeah, we

Sam Banister 45:09

are. So one of the best things about doing sites in Australia is we have one of the world's most generous r&d tax credits, which a lot of people are not aware of. So about 43% 43, and a half percent of every dollar you spend on r&d Here is rebated at the end of the tax year, which is June for us here media. And we're doing some work with the Commonwealth Scientific and Industrial Research. Org CSIRO, so they're a big government science organization here probably the largest they partner with a lot of different commercial partners, you know, biotech startups and things. And we got we were involved applicants for the something called the Kickstart program, which is a pretty amazing program rolled out by CSIRO, where they'll provide matched funding. So there's a voucher system for match funding, we contribute the other part of that funding, and we get half of our contribution back as an r&d tax credit. So effectively, we're getting, you know, four times as much research done for every dollar spent that we would probably anywhere else. So with with syro, we're looking at neuroplasticity, so they're setting up a bespoke assay for us using cortical neurons. And we're going to screen our entire library to see their effects on what are typically thought of as sort of positive changes in in neuron morphology and connectivity.

Nick Jikomes 46:17

Yeah, can you can you unpack that a little bit for people? I mean, I think a lot of my listeners will be aware, but what are some of the, what are some of the more general statements we can make about what's been observed so far in the literature about the kinds of effects on neuroplasticity that tryptamines and other classic psychedelics tend to have?

Sam Banister 46:34

Yeah, so a lot of this work has been done, certainly in in vitro cell cultures, some of it to the the animal level with microscopy. But the general idea here is that, you know, the brain is a very complex system of, you know, trillions of neuronal connections, things are constantly being pruned and reconnected. And this is how we, you know, do everything from sort of store memories to, you know, develop disease or, or treat disease. So, the idea with, with neuroplasticity inducing effects of psychedelics, and this is common to some sort of Ibogaine analogs, ketamine and classical psychedelics like psilocybin, but the idea is that these drugs, even when, you know, falling sort of acute exposure, lead to sort of increased neuronal branching, increased connectivity between neurons, things like neurite, outgrowth, and sort of axonal budding. So the idea here is that when these drugs are administered, we can show that these sorts of effects occur in neuronal cultures, and that those effects typically correlate with sort of improved profiles in animals in terms of a depressive type phenotype and, and recovery from that. So yeah, no one's demonstrated these, these will be useful in the clinic, I guess, with the exception of ketamine where, you know, people are or spravato, for example, has been approved as a rapid acting antidepressant. Although the mechanisms not entirely clear, neuroplasticity probably plays a role.

Nick Jikomes 47:51

Yeah, and it's important to I think it connects to the idea that, you know, you can, you can give some of these drugs, and some of the trials that have been psilocybin, you know, part of part of what makes the result so exciting is, you only give the drug once or twice, or maybe three times, you have the acute effects, the psychedelic experience, but then there's presumably inside the brains of a living person, this sort of window in which neuroplasticity has been changed in some way. And so now you've got this therapeutic window of opportunity, in which something like psychotherapy can be extra efficacious, even though you're not chronically taking the drug.

Sam Banister 48:25

Yeah, yeah, for sure. So, yeah, this is this is the whole sort of sub psychedelic dosing idea, it's that, you know, you get these positive changes that lasts for some period after that acute treatment. I mean, obviously, with the psychedelic assisted psychotherapy, it's actually like a really terrible model for pharma in some ways, because this is the opposite of an SSRI that you take every day. If you look at the data from groups like compass pathways, in their large sort of phase two studies with psilocybin, people are getting sort of immediate effects the following day, in terms of depression scores. And what's really interesting, if you're watching this space, is that a lot of those effects is sustained, like three months out, a number of people in those studies are still having very positive effects in terms of reduced depression score, you know, months and months after they've had this, this sort of catalytic experience. So it's a super interesting model, because, you know, that suggests that for different, presumably different patients will respond differently. But you might be able to go to a, you know, psilocybin clinic and have a session sort of one to four times a year, even with very serious conditions like major depressive disorder or treatment resistant depression, so Yeah, certainly a super interesting super interesting model for for pharmaceutical, you know, for a drug.

Nick Jikomes 49:35

Yeah, one one person that you mentioned a couple times as we've been speaking, was Shogun Did did you ever get a chance to meet him?

Sam Banister 49:43

It's a very sad story. It was my my life dream to meet Shogun at one point I moved to the Bay in 2014. He actually died not long after that. So I I ended up going to his week, which was amazing. Met a bunch of the maps people there and yeah, it was just just in Berkeley at a huge To the kind of the who's who of the psychedelic community in the bay and beyond, was there. Super interesting, and then didn't really think much more about it afterwards. I was doing work with a guy named bridge arena at UCSF. And he told me, he was looking for deuterated tryptamine analogs for analytical tox work. And he asked if I knew anyone in the Bay Area and you know, if it was possible for me maybe to synthesize some of these, and I explained it probably wasn't. And he said, oh, you should reach out to Paul Daley. Paul has, I think he's got this archive of generated tryptamines. He used to work with Nick Cozzi and others and I was like, Okay, I'll give him a call. He invited me out to lunch at the farm, as he called it, and I didn't really put the pieces together until I got there and saw, you know, one, one Shogun road on the side. But essentially, Paul runs the Alexander Shula Research Institute does a lot of archival, so I got to go out and have lunch with him and and Shogun and Antonio Manning, which was super cool. Definitely one of the sort of life highlights for me hanging out with and got a little cheeky photo taken at the end, because I just couldn't resist and instead of sort of saying cheese, where you usually would at a photo op, she said to CB

Nick Jikomes 51:06

to CB, TC is interesting. I believe that was, you know, like one of his favorites, one of Alexander Shelton's favorites. For those that don't know, can you just give a little brief synopsis over of who he was and what he did?

Sam Banister 51:18

Yeah, sure. Yeah. Alexandre Shogun is a chemist who worked at Dow for a number of years, he developed a really, really commercially successful pesticide film called Zack Tran. As a result, you know, they gave him a pretty long leash, given that he was working at a big chemical company. And what he did with that leash was start to systematically look at structure activity, relationships around initially, mescaline, and then other trip domains and things. And at some point, he was publishing a lot of these studies in really, you know, reputable journals, a lot of these things, which is pretty wild to think about to scientists these days. But even in the 70s, there's stuff being published in J med cam. So generally, medicinal chemistry, which is a very reputable, you know, usually pretty dry academic journal. But a number of reports with like, self experimentation with these various new psychedelic molecules that Shogun and others were designing. So eventually, Tao asked him not to publish with their affiliation on these papers. And he decided then to set up a lab at his own home and continue this work. So he designed hundreds of different systematic modifications of phenethylamines, which are the class of mescaline and Tusi belongs to in terms of psychedelics, and then herbal lands and tryptamine. So herbal, Enza are things like LSD and tryptamines are things like like DMT or psilocybin. So yeah, he made hundreds of these molecules, he tested them on himself initially for for signs of toxicity, you know, sort of sensible, escalating dose matter. And then if they were promising in terms of sort of therapeutic tools, he he'd actually share them with psychiatrists and psychologists and musician, friends and things in the base, or the sort of intellectual intellectual circles in the bay, who who might have interest in using these things. And that was all going super well. For him. He was an expert witness to the DEA, he was one of the leading experts on these sorts of classes of drugs, until he decided to publish his biography as both an autobiography, but also recipes for manufacture and description of effects of these substances. So he published these two volumes, pick out and tick l phenethylamines. I have known and loved and tryptamines, I've known and loved. And probably a lot of people advised him not to do that. But he was a bit of a sort of bit of a libertarian in that sense. And he believed that knowledge should be free. And as a result, the DA took away his his license to work with Szechuan substances, they raided his lab. He was never convicted of any crime, I don't think but they shut the lab down over some small amount of mercury and in the soil somewhere because it hadn't been properly disposed of. I think that was all that happens.

Nick Jikomes 53:41

Yeah, no, he's definitely an interesting character. For those who don't know who he is just read his Wikipedia page. Or check out those books, which, you know, everyone that I know, who has read them always cites them as some of the most interesting and influential books they've ever read. Do you remember when you first got a hold of those and read those? Yeah, yeah, I

Sam Banister 53:58

read them as a, I think it was in my late teens or early 20s. So I'd realized I taught myself a lot of chemistry because that's organic chemistry, especially because it's the language of pharmacology, which is what I was really interested in. I remember getting a copy at a at a local bookstore here and then finding out that we have some of the strictest censorship laws in the world, apparently, and actually, it's it's illegal to instruct on the manufacture of an illicit drug. And these books were probably technically illegal and people have had them confiscated at the border level, but I managed to pick them up at a local bookstores. Luckily, there's not a lot that's enforced all the time.

Nick Jikomes 54:32

And what they have a very unique structure. Can you talk about that a little bit more? That the structure of the books Yes, yes. Yeah. So

Sam Banister 54:40

the first half of each book pick L is sort of autobiography of an and Sasha and then their lives, and the first half of Tikal is sort of just just really interesting notes on different things that have happened to Shogun that relate to his career or to drugs or other things. And then the second half of each book is is really this sort of almost like a scientific manuscript. So it has the sort of chemical code and structural name for each chemical, a little picture of it. It has the sort of dose and duration method for the synthesis, and then a number like an extended discussion on various aspects of the drugs. So yes, for what sort of would be considered an academic textbook in some senses. It's a super interesting, Rachel is a great writer. He's very, he's a really passionate communicator. And super interesting to read for sure.

Nick Jikomes 55:25

So what do you think, you know? How should we think about the time horizon for the clinical development of some of these novel psychedelic and psychedelic derived medicines? Are we going to start seeing these things actually hit the clinic in two or three years? Or is it gonna be five or 10 years? Like, how should people think about how long this type of stuff takes to do?

Sam Banister 55:46

Yeah, it's not a traditional, psychedelic, but empty MDMA for PTSD. The trials that maps is running is looking like it might have an approval timeline that's sort of into next year, which is pretty interesting. The FDA is already granted breakthrough therapy designation, meaning that this treatment shows enormous promise over existing treatments for PTSD. The trials data is quite good so far. So assuming there are no other issues, it's very likely maps believes that the FDA will approve that as a treatment by next year, I think psilocybin will probably follow maybe the year after once, compasses wrapped up their phase three clinical trials, which they're they're setting up now. And I think they'll probably be first to market with psilocybin assisted psychotherapy. And I think that's probably likely to happen in 2024. And that's just on the approved FDA approved medicines, you know, formal clinical setup, end of things. You also have, like huge number of sort of states and local municipalities, enacting various, you know, considering various ballots or enacting various laws that decriminalize natural psychedelics at least. So quite a bit going on in Oregon, for example, where they're talking about rolling out mushroom clinics of various kinds under this sort of decriminalization model. Yeah, how

Nick Jikomes 56:58

do you how do you actually feel about that? Just not not just as like a scientist, but as a person? The question of legalization versus decriminalization of these things?

Sam Banister 57:08

Yeah, I think we've learned a lot from decriminalization in other parts of the world, you know, every country is different. In the US, I would say every state is different, like having having lived and traveled there quite widely. It's, I think of a really a sort of 50 different nations that have sort of all been pushed together. Because it's, you know, it's a very diverse place. I think full legalization should be done sort of cautiously for a number of things. And we've certainly learned a lot from cannabis even in the US about where that doesn't does not work. So I think decriminalization is absolutely sensible. I think most drug issues are really the problems that arise with drug use of any kind of really health issues, not criminal issues, I think decrypt makes a lot of sense. And I think ultimately, the legalization under the right sort of regulatory framework also makes a lot of sense for these things. And I have a pretty, pretty staunch believer in, in drug legalization only because it is an inherently risky activity that we can absolutely regulate, you know, we do we have a lot of other risky activities that people partake in, either medically or recreationally you know, I'm a recreational skydiver, you can get a license to jump out of a plane, it's not a big deal. Like you, you absorb some of the risk there and you consider it and there's training programs in place, and people will teach you how to do it as safely as possible. And I think this sort of idea of, you know, potentially like a drug license is one way to get around a lot of the problems with with prohibition as it stands.

Nick Jikomes 58:28

That's interesting. I've never actually thought about that. So instead of thinking of legalization as just being just meaning, you walk into the store, and you can buy X, Y or Z, you would actually obtain a license, which would, you know, potentially require you to take certain courses or be certified in some way.

Sam Banister 58:43

Yeah, I mean, we do this for other medicines already. Right? You get the you get your little leaflet that tells you about the risks and benefits of the drug, you have a conversation with a doctor, there's no reason you couldn't apply that model. We already do a medically there's no reason you couldn't apply that to recreational drug use as well. So you want to use ketamine? Have you used it before? How often are you using it, you go have a chat with a doctor about at times and your personal situation, you prescribe some small amount of ketamine for your own use. And if you mess up, you know, if you end up accidentally overdosing or doing doing something really silly, you know, maybe get some demerit points, and you're not allowed to use that substance, again, for a little while, or without additional training. It's, it's, you know, it's a pretty straightforward model that we already employed a number of different places, and I think could absolutely be sort of, you know, enacted in a practical way.

Nick Jikomes 59:25

And, you know, as, as a startup founder, and as a scientist, and it's just just a citizen. You know, when you look back at the history of these things, and you go back to the 50s 60s 70s, and what happened from then till today, do you think there's any risk that, you know, depending on what happens and how people start using these things, as they become decriminalized or legalized? And things like that, that, you know, despite all of the development we're seeing on the science side of the medicine side, that there could be some kind of backlash and we could go into retrograde. Do you ever worry about that or think about the risk of that? Yeah,

Sam Banister 59:59

I definitely do it. Even on the medical front row for these for trials that are conducted in ways that are sort of less than ethical or less than rigorous, that that's always a real risk. I think, you know, we've seen, we've seen bits of it in the cannabis space, you know, there are still people who are staunch prohibitionist for cannabis, which is a relatively innocuous substance. Yeah, it doesn't have you earth shattering effects in terms of, you know, increasing road fatalities or causing domestic violence or anything else? Certainly not. Certainly less than alcohol, for example, which is completely legal. So, yeah, I think there's always a risk because all drug drug use carries some risk. I think, yeah, there's absolutely the possibility that, you know, regulators or, you know, legislators take a sort of dim view of the space, if you get too many people doing the wrong thing. I also think it's, it's pretty unlikely, I don't foresee that happening, most likely, because there are, there's a huge minority of people who are already using psychedelics in an illegal way. Without much, you know, without much harm. If you look at, you know, David nuts study of drug harms, considered across a number of factors harm to self harm to society, harm to others, you know, psilocybin, for example, rates, you know, way down at the lowest end of harms on that scale and that study, so I think it's pretty unlikely.

Nick Jikomes 1:01:14

So one of the things that I often hear about is that, so when you, when you look at the clinical trials with psilocybin, for example, one of the things that they screen people out for is a history of mental illness in particular, things like schizophrenia or other forms of psychosis. And the fear there is that something like a high dose, full blown psychedelic experience, could at least in certain individuals who are predisposed to things like schizophrenia or other forms of mental illness, it could actually precipitate those those forms of psychosis coming online. And, you know, occasionally I'll hear an anecdotal report of someone who knows someone who, you know, took too much acid, and went crazy in whatever way. But I've actually because I've been asked this so much, then because, you know, it seems plausible, right? Given if you've ever had a psychedelic experience, or even heard someone talk about it certainly seems plausible if this type of experience could precipitate some kind of psychotic break. But I've actually had trouble myself finding clear cut documentation of that in the literature. So what do you need to know about what's actually been documented there and actually demonstrated,

Sam Banister 1:02:22

a lot of these risks have been massively overblown for various, very obvious, you know, propaganda war reasons. So I have a good friend from my teen years who actually developed psychosis as a result of cannabis use. And it's likely that he was genetically predisposed to this. And I've known people who've admitted to me that they've used cannabis, psychedelics, all sorts of things. He is the only person I know who's ever had a sort of profound psychotic reaction to a psychoactive substance. So the stories I've heard the ones that go around, you know, you hear of a a psych nurse who knew someone in the 60s who tried to appeal himself because he thought he was an orange after taking LSD or, you know, this can almost never be verified. There's no evidence that these things have actually happened. The other 41 that used to get thrown around a lot with PCP, and with LSD and other things, was, you know, someone thought they could fly and try to jump off the top floor of a building. Also, probably not verified, probably someone who already has some other serious mental illness. But I think it was Bill Hicks, who said, you know, the comedian who said, you know, if you think you can fly, maybe take off from the ground floor first, it's like, you know, these aren't very compelling stories. And when you dig into them, there's not really much evidence for them at all, and certainly no sort of clinical confirmation that these were the result of a drug induced experience.

Nick Jikomes 1:03:36

I see what, you know, from a scientist perspective, and from a drug development perspective, what do you think are some of the bigger unanswered questions right now, in psychedelic science, broadly speaking, that we will likely learn the answers to in say, the next two or three years?

Sam Banister 1:03:53

Oh, that's such a good question. One of the things that I'm very personally fascinated by is this idea of sort of the precise molecular pharmacology of agents that are psychedelic first, not psychedelics. So you can get things that interact with the to a receptor, that gives you an agonist profile so that so they activate it, they give you a head Twitch response in my suggesting the psychedelic in humans, and then you dosimeter person or they're absolutely psychedelic, you can get things that are very closely related to things like six fluid, dt, dipole tryptamine, which can sort of activate the to a receptor, or at least interact with it, they can bind to it, they can activate it along some signaling lines, but don't really give you a head Twitch response and not psychedelic in humans. So this is one of these questions that I'm super interested in is what is the precise molecular pharmacology of a psychedelic first non psychedelic agent? And I think with all the work that's been thrown into this area by sort of Brian Roth Alex client, a number of other people, Dave Olson, even I think we're going to have answers to that in the next two or three years and that's going to you know, rapidly expedite A lot of the drugs that we do in this area in terms of both psychedelics and psycho passagens.

Nick Jikomes 1:05:04

So for for some of the the major results that are out there with respect to psilocybin in particular. And going back to that question of like, how much of the effect is actually requiring that subjective experience that comes with taking a classical psychedelic? What's what's at least your gut there? For what you think the answer is going to be? Do you think there's going to be at least some therapeutic effects that do require that? Or do you think that we'll likely start developing drugs that completely that allow us to get all the same therapeutic outcomes we've seen so far, but without any psychedelic effect?

Sam Banister 1:05:40

I hope it's the latter only because the market for those types of drugs and the need for those types of drugs from people that suffer from depression, and who may not be able to take psychedelics is absolutely enormous. And I think, you know, neuro psychiatry is absolutely ready for a new, fundamentally new mechanism of action in depression treatment. So I really hope it's the latter. But part of me thinks based on on the clinical data and and speaking to people who participate in some of these trials, that there is something about that profoundly intense psychedelic experience and the sort of it acting as a sort of catalyst for psychotherapy integration. So you hear people talk about this quite a lot in some of the old trials that were done. With smoking cessation, for example. People have a psilocybin experience with therapy. And they don't describe it's not, it's not like a slow learning. It's like this flash of insight that's consolidated in the therapy afterwards, they just give up smoking, they're like, I just took a completely different view of myself as a smoker, you know, it, I could see it for what it was, and I just instantly gave it up overnight. And there's quite a few of those sorts of stories is really profound insights, this sort of objective view of oneself that then lead to, you know, really dramatic changes in behavior. So I think the chance that you get those sorts of outcomes from a drug that's not psychedelic, that that's just inducing neuroplasticity, doing other things, I think that's less likely. So my my sort of gut instinct at this point is that the sort of sub psychedelic or non psychedelic psycho passagens will be effective in some conditions. But for these really serious affective disorders, maybe that full blown sort of psychedelic experience with therapies is what's needed.

Nick Jikomes 1:07:09

Interesting. Have You Ever Have you ever tried a psychedelic yourself?

Sam Banister 1:07:15

I have never admitted publicly to trying a psychedelic, but I can tell you without disclosing which one because there are presumably are some legal ones historically that I absolutely have tried psychedelics? Yes.

Nick Jikomes 1:07:26

Yeah. And so how did that impact you in terms of going in this direction, or, or just in your life in general?

Sam Banister 1:07:34

I would say. So I've tried psilocybin, in the form of mushrooms in a, in a jurisdiction where it was legal. And it had a pretty, pretty profound impact on my view of the world, my view of myself the sort of interconnectedness of things. And I would say, it's really, you hear this a lot when you ask people about their psychedelic experiences, listening to a recent Sam Harris podcast that the paradox of psychedelics no one, no one says that boring, you might have a really, you might have a really great time, you might have a really bad time, but absolutely no one is bored by a psychedelic experience. And when you talk to people about this, a lot of people describe it as one of the more profound experiences of their lives. And that was certainly my experience, enough that I redirected my career from one area of science into chemistry out of a, you know, serious fascination with with the pharmacology of psychedelics. And that's a super common story. If you look at the the self reporting and a number of these trials for people who've never tried psychedelics before, and do so in a clinical context. They say it's like one of the most impactful experiences of their lives right up there with the death of a parent or the birth of their first child, you know, which is pretty remarkable for an alkaloid that is found in some fungi that produce it for reasons we don't understand. It's a pretty wild, pretty wild David sort of consider that a drug effect. It's sort of diminishes it almost it's it's so much more profound than that. So I yeah, I think most really do psychedelics are profoundly moved by them.

Nick Jikomes 1:08:57

Yeah. And I think this speaks to something that I think is really interesting, which is, you know, if you look across human cultures today, and human cultures, historically, a very large percentage of human cultures have had some kind of rite of passage, sometimes just once per lifetime, sometimes, you know, certain times of year that involve the ingestion of something psychoactive, very often times something psychedelic. And this was not done just to cure someone who had some significant illness, it was seen as part of the normal development of one's life was part of the normal trajectory of what it was to be in that culture and to become, you know, become the person you were supposed to become. Do you think there's any place for psychedelics to in the Western world, come back into that, that kind of cultural niche and be something that's not just used as medicine to cure someone who has a problem, but that's used that maybe certain certain phases of development or certain times of life, even in perfectly healthy individuals, I

Sam Banister 1:09:59

think That's probably where we'll get to with decriminalization and legalization. And there's certainly plenty of people historically who thought that was a valid use of the substances I heard. I think it might have been Hamilton Morris talking about William Leonard Picard, the prominent LSD chemist from a number of years ago, produce more LSD probably than anyone on the planet. He didn't think this was for medical purposes at all. He believes these were this is a substance that should only be given to people who are already very healthy to sort of improve wellness and, you know, their understanding of the world and their place in it. So certainly a lot of different views on this topic. I think. I don't think these are things that that are that should be fully medicalized only I don't think that's the right way to think about them. And we certainly don't for like for cannabis, for example, right? There's, there's very few classes of drugs that are psychoactive that we think of as having, you know, sort of only one intended use, medical or otherwise. So, yeah, cannabis is another good example. Certainly useful medically for a number of people with various pain conditions. Also great for enhancing music, you know, the taste of food. And I think these are all valid uses of these substances,

Nick Jikomes 1:10:58

or Sam banister, we've covered a lot, is there anything else that you want to talk about or leave people with or perhaps reiterate, from what we've talked about so far?

Sam Banister 1:11:08

Nothing comes to mind just that, you know, having having spoken to a lot of people in the space who have lost friends, as a result of depression. I hope that we can have a big impact in this area soon. So silo and others working in this space, hopefully, there are new treatment options available as soon as 2024. The last

Nick Jikomes 1:11:27

thing I'll ask you is just, this is a very exciting and very interesting and very complex area, just the area of psychedelic science in general. There's a lot of great research out there, there's, you know, as with any field, a lot of not so great research out there. There's a lot of good reporting out there in the popular press, and there's a lot of bad reporting. What are some of the places you would point people to whether they're scientists or non scientists, if they want to stay up to speed on the general area? And what's coming out?

Sam Banister 1:11:54

Oh, yeah, there's a lot of really good resources online. Obviously, psychedelic alpha is a really great site. I subscribe to a number of sub stacks that are really good or other newsletters. Zak Hades one's quite interesting on the in the US focus on the sort of clinical space, and then legal space. But yeah, just just I'd say there's there's no shortage of resources for, for podcasts, for news in the area from cycling alpha and other other places, and for the clinical trials that are going on. So yeah, just subscribe to these newsletters. Subscribe to siloes newsletter, we have Dilbert Tschechien rolling out an incredible newsletter for us. So you can subscribe to that and our website Sylar dot bio, but Yeah, certainly no shortage of good information out

Nick Jikomes 1:12:37

there. All right, well, Sam Bannister, thank you for your time. Yeah, thanks

Sam Banister 1:12:42

so much. Nick was great speaking with

Unknown Speaker 1:12:43


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