• njikomes

David Olson: Psychedelics, Psychoplastogens, Brain Chemistry, Microdosing & Mental Health

Full episode transcript below. Beware of typos!

Nick Jikomes

David Olson, thank you for joining me.

He's happening, saddening. Can you start off by just telling everyone who you are and what your background is scientifically?

David Olson 4:20

Sure. So I'm an associate professor at the University of California Davis and the Department of Chemistry in the Department of Biochemistry and Molecular Medicine. And I'd say my my background scientific background is in chemical neuroscience, broadly speaking, my undergraduate degree was in chemistry and biology. I did my postdoctoral training at Stanford in chemistry, but I worked in a lab that was you know, very, you know, heavily involved in chemical neuroscience the development of new molecules for treating for treating neurological conditions, particularly in this case, you know, it's the lab that's very well known for taking traditional toxins. Like saxitoxin into Trota toxin, and modifying their chemical structures to turn them into medicines for neuropathic pain. And then I went on from from there to do my postdoctoral research in neuroscience in the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. And there, you know, I did everything from small molecule, CNS, medicinal chemistry, to Molecular Cellular neurobiology to behavioral neuropharmacology. And I started my independence career at UC Davis in 2015. And my academic lab

in there, you know, it spans the gamut, you know, soup to nuts, molecules to mice, we have a lot of chemists in the group, we also have a lot of Molecular Cellular neurobiologist. And we have a whole bunch of behavioral neuroscientists as well. And our primary focus is on the development of new drugs for treating brain disorders. Interesting. So you mentioned in some of your earlier training, you had done work where you were modifying existing drugs or toxins in order to basically try and create medicines. Can you talk a little bit about

Nick Jikomes 6:06

how that process works? So you mentioned something called to try Botox, and we can maybe take that as an example. What is something like that? Where is it found in nature? And what are you actually doing in the lab to tinker with it?

David Olson 6:17

Yeah, so to be clear, when I was in that lab, it's the Dubois Lab at Stanford. The lab was very interested in this. So I was very immersed in neuroscience. But what I specifically focused on there was the synthesis of nitrogen containing compounds. And so I develop new reactions and new methods, new strategies to producing these types of molecules. And the reason that's important is because in my mind as a CNS medicinal chemist is that pretty much all of the psychoactive drugs that we care about have nitrogens in them. And so, you know, just from a basic chemistry perspective, you know, I gained a lot of experience and how to construct these molecules. Now, the rest of the lab there was, you know, another section of the lab that were actually modifying toxins like saxitoxin, into Trota toxin. And you know, those molecules come from a couple of different places, but to try to toxin is probably best known for being the toxin found in the fugu fish, you know, puffer fish. And so puffer fish toxin, and every neuroscientist knows of tetreau desoxyn, because we use it in, you know, in our assays to block voltage gated sodium channels. And it turns out that these voltage gated sodium channels are also involved in chronic pain. And so by tweaking the structure of these molecules, you can, you know, change the pharmacokinetic properties of the molecule, you can change the pharmacodynamic properties, how it binds to the receptor, where it binds to the receptor, and then hopefully, you can produce therapies that can that can be used in the clinic without a whole bunch of adverse effects. And so that's actually the, the, the basis for a company that's my my good friend, John Mulcahy, and, and my former boss, just a new BA, they started a company called site one therapeutics and they're trying to use these toxins to treat to treat neuropathic pain.

Nick Jikomes 8:07

So what would for someone without a neuroscience background? How would you describe the the difference between a molecule that is a toxin something like to try to toxin that's very deadly, versus a molecule that's a psychoactive drug versus something that is more innocuous? What is the difference in terms of how those molecules are actually behaving inside the brain that explains that difference?

David Olson 8:30

Well, first, we need to separate this completely like to try to toxin saxitoxin, these are super water soluble compounds, they don't cross the blood brain barrier, these are not acting as central, essentially acting agents that are working in the periphery, you know, affecting, you know, neurons in the spinal cord and other parts of the body, but not necessarily in the brain. What I feel, now, my academic lab are molecules that work centrally, you know, they get into the brain to produce their effects. Now, in terms of how you modify a drug to make it safer, involves a lot of a lot of medicinal chemistry. And so the idea is, is pretty simple. Actually, if you think about a drug, and you know the structure of a drug, there are certain features of it that give rise to the beneficial properties that you're looking for. And there are other features of it that give rise to kind of the the more undesired properties. And so you basically have to look for a way to remove the the sections of the drug that give rise to the undesired properties but retain the parts of the drug that are necessary for its desired effects.

Nick Jikomes 9:38

I see and would you say so, for example, if you have a drug that's got effects that are desirable and beneficial in some way, and effects that are undesirable? How do you think about those in terms of say the receptors the drugs are interacting with?

David Olson 9:56

I mean, it depends drug to drug case. By case, but you know, most CNS active drugs exhibits very robust, diverse poly pharmacology, meaning that they hit lots of different receptors. And sometimes there are off target receptors that give rise to the deleterious effects or the undesired effects. And then you can basically design a molecule that won't bind to those but still binds to your intended target. That's very common, especially when some of your your undesired targets or off targets, as we would call them are in the periphery. So for instance, in the case of psychedelics are very common off target. Protein would be the five HTT to B receptor in the heart. This is known to cause cardiac apathy. And so if you're designing a new version of a psychedelic or something similar to it, you probably want to try to avoid activating five HTTP headers in the heart, just to to avoid that kind of peripheral complication.

Nick Jikomes 11:00

I see. So So a way of thinking about this would be, you've got some chemical, you've got some molecule, it's got some kind of structure, that molecule will very often bind to a large or relatively large number of receptors throughout the brain and or body. And the action that it has add on some of those might lead to a beneficial outcome, the action that it leads that has, others might have a deleterious or bad outcome. And literally what you can do as a chemist in a lab like yours, is chop off or change pieces, that molecule to retain some of those beneficial interactions, but get rid of some of the ones that might be problematic.

David Olson 11:39

That's right, I mean, molecular structure dictates function. And so if you have the ability to change molecular structure, you can tweak in tune the functional effects of the drug.

Nick Jikomes 11:49

So you mentioned that some psychedelics binds to this receptor called Five HT to B. Now, on this podcast, we've talked with a number of experts on psychedelics and typically there you talk about the so called psychedelic receptor five HT to a the particular serotonin receptor that underlies a lot of the hallucinogenic effects. So what is this other receptor five, H two, T two B, can you elaborate on why it's of concern here, and maybe what are some of the compounds that are known to activate it?

David Olson 12:21

So it's a related receptor to the five HTT A, it's very similar in structure, but it's found in a different location in the body. So whereas five HT to a is primer, primarily expressed, on layer five pyramidal neurons in the cortex of the brain, it's it's found everywhere in the body in the five HTT to a receptor, you know, even in the gut and an immune cells. But when we think about it, in terms of its effects on the hallucinogenic effects of psychedelics, we're talking about five HTT to a receptors in the brain, five HT to B receptors do not have high brain expression, and they're mainly expressed in the heart and they can impact you know, the functioning of those heart cells and lead to to value off with ease, that obviously are undesired.

Nick Jikomes 13:10

What does that mean? Basically, that word value apathy,

David Olson 13:14

the heart The heart is not functioning properly. heart issues now there you know, there are other you know, receptors, ion channels in the heart that are very common off target effects for a lot of drugs particularly greasy and means like psychedelics and one common one is the hurt channel. So her channel is an ion channel that's found in the heart and can lead to cardiac arrhythmias and this is particularly problematic with a molecule like Ibogaine, Ibogaine is known to inhibit her channels in several people have died after taking Ibogaine due to you know, cardiac arrhythmias.

Nick Jikomes 13:51

Are there any other psychedelic drugs that people may have heard of that have this effect on the five HT to be receptors in the heart? Yeah, most

David Olson 13:59

of them I think, you know, psilocybin LSD I think they all have you know, high affinity and efficacy for five HTTP

Nick Jikomes 14:09

but so um, so you mentioned Ibogaine, can you before we sort of get into the specifics of the research that you've done? Can you give people some background here? What is Ibogaine? Where is it found naturally? And what is its traditional use?

David Olson 14:26

Sure, Ibogaine is a psychoactive natural product. It's actually found in a whole bunch of plants all over the world. But most people know it from a shrub in West Africa. So what is it used traditionally? I mean, I think it's used for you know, ritualistic purposes in, in some indigenous populations in Africa. But, you know, I began has been, you know, the effects of Ibogaine had been known for quite some time. In particular, at higher doses, it seems to have you know, Vietnam anecdotal reports and open label clinical trials I should say there's nothing you know more substantial than that. Those studies seem to suggest that Ibogaine might have some anti addictive properties. There's been some reports that a single administration of Ibogaine can keep heroin addicts drug free for up to six months. And then with a second additional dose, they can be drug free for up to you know, up to three years in some cases. And actually Ibogaine was sold as an antidepressant in France for many years before it was pulled from the market due to its adverse effects, the adverse effects being you know, things like this cardiotoxicity that I mentioned, but also, you know, some some hallucinogenic effects at high doses.

Nick Jikomes 15:43

And traditionally, how's that consumed? How do people actually take that?

David Olson 15:48

Yeah, there it's found primarily in the Root Bark of this, this plant cover Anantha Boga and so I think people will grind it up and consume it, consume it like that, like a lot of, you know, plant material.

Nick Jikomes 16:03

I see. And so it's it's got these interesting potential therapeutic properties, but it's also got these potentially undesirable properties, especially this cardiotoxicity that it can have via this other serotonin receptor. So the approach that

David Olson 16:20

you guys cardiotoxicity for Ibogaine comes from the ion channel, the herb channel, that's the primary issue that

Nick Jikomes 16:25

I see. And so you guys have done some interesting research on this. And can you describe the basic approach for people you took the Ibogaine molecule, and then you modified it and did some interesting tests on it?

David Olson 16:40

So it's very similar to what I was describing before we you know, Ibogaine is a complex natural product, it's big. And it's hard to synthesize actually, there are no de novo total syntheses of Ibogaine, that would produce the drug and quantities necessary for like human clinical trials. And so to get our hands on it, like you need to extract it from the natural sources, which is problematic for a whole bunch of reasons, including, you know, the environmental effects, but also getting like high drug, you know, purity for, you know, medicinal grade compounds and be better to be able to synthesize it to novo. And so we took Ibogaine, and we said, we simply started chopping it up, we started removing different parts of the molecule to see how that would impact you know, its functional effects, particularly its effects that that that herb channel that I was telling you about. And by chopping off a lot of the grease, we were able to reduce its potency and hurt pretty substantially reduce its cardiotoxicity. But we found that it still was a pretty effective, anti addictive compound, it also seemed to have antidepressant effects as well.

Nick Jikomes 17:52

And then how do you actually test something like that in mouse models? How do you test that something has anti addictive properties?

David Olson 18:01

So the ante did things that we did you know, in cells, one of the things that we really look for when trying to identify new antidepressants is we we focus on fossil fuels that are really good at promoting structural neuroplasticity in cortical neurons. And so I probably should take a step back and describe why we care about that first, before we get into, you know, the in vivo effects of these drugs. So something that's really important to remember is that a hallmark of all stress related neuropsychiatric diseases and many other brain disorders. But with a stress related neuropsychiatric disease, I'm talking about things like depression, PTSD, and substance use disorder. And the hallmark of all of those illnesses is really the atrophy of neurons in a part of the brain called the prefrontal cortex. So the neurons actually physically shrivel up. And so if you think of a neuron, like a tree, you know, the branches would be the dendrites, and the leaves would be the synapses. And in many of these illnesses, the leaves fall off, and the branches get pruned. And that's problematic, because that impairs the ability of the cortex to communicate with other parts of the brain. And normally, the PFC talks to a whole bunch of other subcortical regions that regulate things like motivation, fear, reward mood. And so by restoring the ability of the PFC to effectively communicate with other parts of the brain, that's how we can produce really good antidepressants. And it turns out that every single antidepressant that we know of has the ability to regrow these these critical neurons, they just do so on a timescale that correlates with our therapeutic efficacy. So something like a traditional SSRI, we know that those drugs take weeks to months to demonstrate any efficacy in the clinic. And it turns out, it also takes them weeks to months of chronic administration to regrow those critical neurons. Now something like ketamine or psychedelic, those drugs are really good at regrowing these neurons very quickly. And they can do this within 24 hours in vivo and the effects are relatively long lasting after a single administration. And so one of the things that we look for in anti depressant compounds, and we started calling these molecules psycho passagens, is the ability to promote cortical neuron growth very robustly. And so in the case of these these Ibogaine derivatives that we're talking about, we screen them in some cellular assays looking for structural neuroplasticity. So we basically grew up neurons in a dish, added compounds and look for phenotypic changes in structure. So we can do some microscopy and look for changes in dendritic branching dendritic spine growth, things like that synaptogenesis. From there, of course, we move on to in vivo studies. And these are primarily done in rodent models. And we can look inside the brains of rodents to look for the same physical structural changes. And from there, we can perform some behavioral tests. Now, I should emphasize that, you know, rodents are not people. And there is no one test that recapitulates the complexity of a human neuropsychiatric disease in rodents. But what there are, are a whole bunch of tests that kind of give you an idea of circuit readouts. And so as I was mentioning, before, our goal really has been able has been to, to alter the function of those PFC neurons, we know that they play a critical role in depression. And we know that there are certain circuits in the mouse brain that produce certain behavioral effects. And so we can use those as readouts of of activating the appropriate antidepressant like circuits.

Nick Jikomes 21:55

I see. So whether it's depression or many other neuro psychiatric conditions, a core feature of what happens in the brain, typically, is you get a literal physical atrophy of connections between certain neurons, particularly those in the prefrontal cortex. And these drugs that you're interested in, that you're calling psycho plastic surgeons are just any drug that's good at regrowing some of those physical connections in those types of neurons. That's right. So what are some, you mentioned some, but what are what are some of the prominent examples of a psycho plastic gin? You mentioned ketamine, what are some of the other ones that we know about that you've looked at in the lab?

David Olson 22:35

So, in 2018, our group published a paper demonstrating that most of the serotonergic psychedelics are very good cycled passages from a variety of different chemical classes. We're talking Ergoline, like LSD tryptamines, like Dimethyltryptamine, five Meo DMT, psilocybin and Fetta means like DOI even even compounds like MDMA, from the entactogenic family. And then there are a few others that are kind of outside, you know, the typical psychedelic sphere. There are delirious like scopolamine seems to be pretty good at promoting cortical neuron growth. You mentioned ketamine, and there are a few others that are interesting, that are just completely outside the realm of psychoactive drugs. You know, I'm not sure if your listeners would really care about some of those. There's a lot of talk about a lot of different types of drugs, there's a fair amount so that you know, there's a certain biochemical pathways that lead to this neuronal growth. And you can, you can activate this biochemical pathway in a few different ways. And so you can imagine that there's different classes of drugs that produce the same phenotype, the structural neuronal growth. And of course, our lab is is heavily invested in trying to identify, you know, non hallucinogenic, psycho passagens as potentially scalable treatments for a lot of neuropsychiatric disease.

Nick Jikomes 24:01

So so you've got a variety of drugs that are somewhat diverse, relatively diverse, meaning like they probably activate, they don't activate the same, each one is not activating the same set of receptors. Nonetheless, they have some kind of convergent effect in terms of what's happening to cells after they're doing whatever they're doing as individual drugs. You mentioned convergence onto this particular pathway. Can you dwell on that for a minute, what is this pathway and what's the difference between like a cellular signal transduction pathway inside of a cell versus a receptor that is being bound to

David Olson 24:36

so receptors are the actual physical targets for the drug, so the drug will bind to a receptor, but once it binds to the receptor, it'll induce a conformational change in that protein that will allow it to couple to other signal transducers, other molecules that will carry that signal down further that ultimately leads to the final product, in this case, cortical neuron growth. So you're right, there are a whole bunch of different receptors that can ultimately turn on the cortical neuron growth. But the downstream pathway that seems to be really critical, involves, you know, we still don't know all of the details of this and this is a major focus of our group is to understand the the molecular and biochemical mechanisms that you know, by which these drugs can produce this effect. But there's a couple of proteins that we know are really critical. One is this protein called track B. It is the high affinity target for brain derived neurotrophic factor. And all the neuroscientists listening in the audience are all well aware of BDNF. BDNF is probably one of the most well known proteins that induce neuronal growth. So track B seems to be really critical in this pathway. And then another kinase that is really important is this molecule mTOR. An mTOR is involved in the production of all of the proteins that you need for neuroplasticity, they are the structural proteins that allow the skeleton, the cytoskeleton of the cell to change so that you can actually induce, you know, new growth, and also the ion channels that are really necessary for transferring these electrical signals between between neurons.

Nick Jikomes 26:24

Okay, so you've, you've created this, you've created a new drug. So you take Ibogaine, you chop off a piece of it, and it retains its ability to tap into that cellular pathway. And you still get this psycho clastogenic effect where these cortical neurons can can grow new connections. It gets rid of some of its undesirable effects. How do you test for things like hallucinogenic potential in a mouse?

David Olson 26:51

Yeah, so when we started the Ibogaine work, the only way to really well, there's a couple of ways to do it. But there's one that's a little easier than the other. So I'd say the, the traditional way to do this is with something called drug discrimination, and it worked very well. If you say you have, you know, a drug like V, and you're looking for drugs like LSD. And you want to ask the question, Does this produce a similar effect as LSD and the way this works is, you would typically train a rodent, usually, it's a rat, to press one lever, if you give it LSD and press a different lever, if you give it let's say, saline. And then after a while, the racket is really good at this task. And so in a way, you know, you're you're asking a question every time you give it a new drug, do you think you got LSD? Or do you think you got saline, then after you trained it up, you give them a novel compound, something they'd never seen before. And if they press the LSD lever, then you can assume that the drug produces LSD like effects. And if they press the saline lover, then you can assume that it doesn't produce LSD like effects. That's not typically how we have looked at these compounds, because that is incredibly labor intensive, and very costly, and time consuming. And so there's another assay in rodents called the mouse head Twitch response assay, and this is particularly in mice. And it's a behavioral phenotype that is very characteristic of serotonergic psychedelics like five Meo DMT, LSD, psilocybin and others. If you administer one of these drugs to to a mouse, there will be this very rapid rotational movement of the head. And you can simply quantify the number of times that they they have these head twitches. And that gives you a really nice predictive assay for hallucinogenic potential and people and Adam Halvor stats group did some really beautiful work just published recently, where they demonstrated that there was almost perfect correlation between human who was energetic potency and potency in this head Twitch response assay. And so, in my opinion, the head Twitch response assay is probably the most predictive in vivo assays that we have for hallucinogenic potential and people. Now, you know, the head switch response assay is really great from that perspective, but it's problematic for a couple of other reasons. Number one, it's involves a lot of animals. And so we always try to reduce the number of animals that we use in research. And because it involves a lot of animals, you can't really do high throughput drug discovery with it, you can't test very many compounds. And so if you want to make lots of structural changes, test lots of molecules, there's not really an ideal assay for that. Plus, every time you put one of these compounds into an animal, you have to think about pharmacokinetics. That's something that most people don't think about. When they think about drug discovery. There's two things you have to worry about. Number one, you have to worry about efficacy does Does the drug turn on the pathways that you care about the number two, you have to determine does the drug actually get to the target. And you know, all the targets that we care about are in the brain. So they have to cross the blood brain barrier, which is very challenging. So you might have a drug that has really great efficacy, you put it into the road, and it doesn't cross the blood brain barrier, therefore, you get no response and see if that doesn't really help you to develop better drugs. And so it'd be better if we could do a cellular assay for hallucinogenic potential. And that's where I teamed up with my colleague Lintian. Just recently, we published a paper about a new bio sensor that we call psych light. And psych light is actually a genetically encoded fluorescent protein that can predict the hallucinogenic potential of a molecule just in a dish. And so the idea was really simple. We just took the serotonin to a receptor, which is the target of psychedelics and is responsible for their hallucinogenic effects. We lopped off the intracellular part of that protein, and we fused on this this other fluorescent protein. And so when a molecule binds to the receptor, it'll induce a conformational change in that fluorescent protein on the intracellular side of the receptor. And agonists like LSD and in five Meo DMT, they'll turn on the sensor and non hallucinogenic compounds either won't turn on the sensor, or they'll actually turn off the sensor.

Nick Jikomes 31:34

So basically, you take the five HTT to a receptor itself, you modify it, you staple this other fluorescent protein thing to it. And now when a drug activates that receptor, it causes this thing to light up, and you can see that happen. Right? So, um, is this so the 5g to a receptor? Is it necessarily true that a drug that activates that will have a hallucinogenic effect? Or is it possible to activate it without that effect? In other words, should we think of the hallucinogenic effect is being synonymous with activation of this receptor? Or if there's something more particular about the specific way that some drugs activate it?

David Olson 32:14

Yeah, I definitely think it's the latter. It's the way that some drugs activate it. So we actually know that there are, quote, unquote, agonist molecules that will activate the receptor that will not produce hallucinations. A really great example is a molecule called glyceride that people have known about for many, many years. It is a is an agonist of the to a receptor, but is non hallucinogenic. And so this is where I think pharmacology gets really, really interesting, because it's not as simple as like one receptor, one functional output. There's a concept known as functional selectivity or biased agonism, which, you know, to summarize it is you can have a molecule bind to a receptor, but you can get differential functional responses. And so in the case of

after, we can think about at least there's there's many, many outcomes from from turning on, if you will, the five HTT to a receptor outcome, the or potential hallucinogenic effects. And a second outcome is the ability to promote cortical neuron growth or neuroplasticity. And so what our group has found is that there are some molecules that will bind to the five HTT to a receptor and turn on cortical neuron growth only and not produce hallucinogenic effects. And then there are molecules like LSD and five Meo DMT. That do both.

Nick Jikomes 33:37

I see. So this, this makes perfect sense. You guys have sort of dissected this down to the molecular level, and you find the associations like this. And so it makes sense that that one would then conclude, well, it should be possible to engineer drugs such that they have this desirable, psycho pathogenic effect that's going to be useful for psychiatric applications, but they don't have these hallucinogenic effects. Now, the and ultimately, this is an empirical question that relates to this question in psychedelic medicine of whether or not the psychedelic effects per se, the hallucinatory component is actually important for some of the therapeutic outcomes that we've seen in humans so far. So I think I can imagine your perspective on that. Can you kind of summarize the two perspectives on that right now? What are some of the arguments in favor of the hallucinogenic component in humans being important for therapeutic outcomes? At least their magnitude and duration? And, and what are some of the counter arguments to that and where do you think this will go in the next, you know, 234 years?

David Olson 34:41

Sure. So first, I you know, I want to I want to start off by saying this is not an either or story. It's not, you know, either it's hallucinogenic or non hallucinogenic. I don't think that's true at all. I think that these kind of first generation hallucinogenic molecules absolutely could have benefit in the clinic, and I think patients will be helped by them. And so I'll try to summarize some of the arguments. On the the hallucinogenic side of things, or some people who believe that the the hallucinogenic or the subjective effects of these drugs, particularly their ability to induce mystical type experiences are critical for these molecules to produce their therapeutic effects. And that's, that's, that's one hypothesis. I think that the, the evidence in support of that really has been that there's been a correlation between mystical type experiences and the therapeutic efficacy seen in several several trials so far. But from my perspective, you know, correlation does not imply causation. And so we need to be very careful about assuming that the hallucinogenic effects or the the mystical type experiences, I should be careful on the wording that I use here are absolutely essential for therapeutic the therapeutic effects of psychedelics now, on one hand, I think that it's very possible that these effects could be beneficial for a subset of patients. And as to why I'm not really sure, maybe it's because they facilitate insight into a patient's disease, maybe they help to promote it interaction between the patient and the therapist, maybe it's an enhanced placebo effect, I don't know. But I do think that some patients will benefit from this approach. Now, from my perspective, when I've really been concerned about has been scalability. And as it stands, now, psychedelic assisted psychotherapy is not a very scalable treatment, you have to go in to the to the clinic, to prepare yourself for, you know, your experience, then if you're taking something like psilocybin, you're going to be in the clinic with a couple of healthcare professionals for many hours, to just to monitor you to make sure that you're safe. And then there's integration therapy after that. And, and that is just not a model, it's going to be amenable to treating the number of patients that really suffer from these disorders. And I think that's something that is really important to remember is that one in five people will suffer from a neuropsychiatric disease at some point in their lifetime, we're talking about a billion people. And so how sad would it be if if the only way that patients could benefit from psychedelic medicine was through this this in clinic administration experience. And so one of the questions that our group was trying to address is whether or not we could get any therapeutic benefit from these drugs by removing, you know, their hallucinogenic effects, which is really what necessitates there in clinic administration, if you remove the loosened genic effects, presumably you could have take home therapeutics that a patient could, you know, go to the local pharmacy, pick it up, bring it home, put it in their medicine cabinet, just like they would a lot of other drugs. And in that way, you could reach a larger number of patients. Go ahead, you want you want to jump in there. Yeah,

Nick Jikomes 38:28

I want to, I'd like to dwell on this for a minute. So let's let's just take something like major depressive disorder as an example. So around the scalability issue, all of that makes sense. Obviously, if something necessitates you being in the clinic to have, you know, a six hour psychedelic trip, and two people have to watch you, etc, etc, that's that is very unscalable literally takes hours of time per patient, you can basically only do one patient at a time. It's just a lot of human hours that go into that, sort of the opposite extreme of that would be a drug that we might describe as entirely passive. So you know, the pill that you could take home and take that didn't even require therapy? How do you think that's at all plausible that there could be a drug that one takes that treats severe, major depressive disorder, that doesn't even require you to have therapy in conjunction with taking it?

David Olson 39:20

I do. And so, you know, when I, so something I will say is that if you add psychotherapy to pretty much any medicine, you will get enhanced results, you'll get better results. And I mean, I think that's probably true for your for your diabetes medicine. And so some patients will absolutely need therapy. And that's why I think in some cases, people might need this this mystical type experience plus therapy to get better. And so I kind of think of it as you know, a tiered approach. And so if you could have a scalable drug that the vast majority of people could take at home, and let's say that you could treat 80% of those people, I mean, that would be incredible. And then the next 20% that are treatment resistant to that, that therapy, then maybe they need to combine it with with psychotherapy. Now, again, if you have a take home medicine, you can start doing psychotherapy over zoom, we know that telemedicine has been greatly, you know, improved due to COVID. And so that would, again, be a way to increase the scalability. And then for the next subset of patients where maybe that doesn't work, either, and they need the mystical type experience, that that should still be available to them.

Nick Jikomes 40:37

And do you think, you know, when you think about something, we'll just continue using depression as an example. I don't remember all the specific statistics, but we know that SSRIs work for some number of people, a significant proportion of people, but not everyone. Do you think that you know, for the psychiatric conditions, that our knowledge is just not fine grained enough in terms of the specific phenotypes that are causing these conditions such that, you know, instead of thinking about as major depression, maybe there's really five or 10, or 15, sort of subtypes of that in each one will respond differently to a different kind of drug? Do you think that's maybe kind of what's going on with some of these psychiatric conditions? And we just haven't discovered all of the drugs that treat these different sub phenotypes.

David Olson 41:24

Why I think that that is very, very possible there. There definitely is a spectrum for every single neuropsychiatric disease, and when I'm very hopeful, is that we're going to be able to use translatable biomarkers to really do personalized medicine, and really find people who are likely to respond to, you know, a particular type of medicine and those who aren't. That is, you know, kind of the frontier in in translational neuroscience research right now. And so we'll see where it goes. But I think that that is very, very possible.

Nick Jikomes 41:56

And so what gives you that optimism that there could be drugs that are are these sort of completely passive drugs that have very good effects, but don't require any, any psychotherapy. Yeah. Any any of that?

David Olson 42:09

Yeah. So a couple of cases. So, you know, so first, there's even some suggestion that psychedelics may not need, you know, psychotherapy to be associated with them. For instance, you know, ketamine right now, I know it's not a traditional psychedelic compound, but it does produce mystical type experiences. And some people have argued that that correlates with therapeutic efficacy. Ketamine is administer without psychotherapy, now you go into the clinic, you receive your infusion, and you leave. And ketamine is really good at promoting cortical neuron growth. And so again, in some cases like that might be sufficient for some patients, and might not be sufficient for all patients, but for some patients, definitely. And so that's one of the reasons that I think that you don't necessarily need the the psychotherapy. Now. The other the other reason goes back to pre clinical research, when I originally started this work, I, I had the hypothesis that you absolutely needed training, that you give a drug, it would put the brain in a plastic state, you would then give some kind of training. And then that's how you would rewire neural circuitry. And I and I do think that that works really well, it works exceptionally well. And you will get more robust responses if you if you do that. But then we started doing experiments where we just gave drug. And even with just the drug, we were getting these really kind of long lasting behavioral effects after a single administration. This is not like an SSRI, we have to give it every day for three weeks, in order to see efficacy, we gave one dose and then look two weeks later, and we would see a behavioral change. And I think that really comes down to the circuits that are involved. And we found that based on the genetic localization of kind of the receptors that were impacting, we get certain enhancements of certain circuits in the brain. And that kind of specific rewiring leads to long lasting behavioral

Nick Jikomes 44:03

change. I mean, the way that I would start to think about that, I mean, that's super interesting, because I would generally have the same line of thinking that you described that you originally had that the plasticity is permissive, but it needs to be directed with with training in some way. Now, do you think it's possible that or how do you think about this? You know, are there some circuits in the brain that have intrinsic characteristics where you know, there's almost probably like an attractor state for the types of dynamics that circuit wants to feel, then you can get off track. But if you just sort of loosen things up and create some sort of permissive signal, it will tend to fall back into this into this particular pattern that it's maybe genetically predisposed to have.

David Olson 44:44

I think that's possible. I wouldn't call it necessarily a loosening though. I think that's, I think that that's, you know, what you hear a lot of times is like psychedelics, you know, shake the snow globe and mix it all up and then it kind of all falls back into place as it as it should. My mind it really has more to do with, you know, the genetic localization of the targets. And like I said, you know, the dysfunction of those layer five pyramidal neurons in the cortex, we know is a hallmark of a whole bunch of neuropsychiatric diseases. And so if you can give a drug that completely restores that structure and function, then it's not surprising that it produces kind of lasting behavioral changes. And actually, I'll point to a paper that we published with my my collaborator, ease Whoa, in molecular psychiatry, and this is a drug that we call tabernacle log it's it's an analog of of both Ibogaine and five Meo DMT. It's a non hallucinogenic cycle. Passagen. But we did something really interesting. We're talking about, like, with no training, single administration of a drug, we, you know, gave the animals unpredictable, mild stress, which tends to result in a whole bunch of behavioral deficits, it causes anxiety phenotypes, it causes depression, like phenotypes, it causes a cortical neuron atrophy. It causes dysfunction of parvalbumin Positive inter neuron function, it causes deficits and calcium dynamics in the brain. And we gave one dose of the drug. And then we didn't do anything else, no training, waited 24 hours, a time period when the drug was completely cleared from the body. And then we looked and all of those things were fixed. The dendritic spines were had regrown, the parvalbumin positive inter neuron function was restored, the calcium dynamics restored and all of the behavioral effects were restored. And so I really think that there's there's constant communication between cell types in the brain. And so if you can restore a critical neuron, the function of a critical neuron, like layer five pyramidal neuron, the cortex, I think it has the ability to communicate with its partners, and and help to restore their function as well and globally and globally heal damaged circuits.

Nick Jikomes 46:56

I see. So this is super interesting. Here's the question I have. And maybe it'll clarify something that we were mentioning earlier, when we talk about these layer five pyramidal neurons in the frontal cortex that are so important for things like depression and other psychiatric conditions. When we talk about them, atrophying, do we mean that the cells actually die? Or do we simply mean that some of the connections are lost and what the structure doing is restoring those connections?

David Olson 47:23

Yeah, in the case of the neuropsychiatric disease is not really cell death, it is really physical atrophy. So the the processes are shrinking, those dendritic spines are getting cold, and synapses are being lost, but those can can be regrown and restore. Now I'll point to a really interesting preclinical study that my, my colleague, Connor Liston performed, you know, related to ketamine, its effects. And so one of the big questions is always about causality, right, like, what is causally important for the sustained effects of these drugs. And for a long time, you know, we had, you know, hypothesize that the structural plasticity is really critical to the lasting effects of the drugs. But really, it was just correlation. You know, we knew that, you know, structural plasticity correlated really, really well, with therapeutic effects, like I mentioned, the traditional antidepressants, they take a really long time to do structural plasticity, they take a long time to have therapeutic efficacy as well ketamine, it, you know, can increase dendritic spine density within 24 hours, and that lasts about a week, and that correlates perfectly with its therapeutic effects in humans. Psilocybin seems to be able to promote spine growth for much longer. I mean, Alex Kwan had a really beautiful study, recently demonstrating that it lasts for about a month. And that seems to be roughly kind of how long it lasts in humans too. So all this is still correlation of this point. And then Connor did something really clever. Connor would induce depression depressive like phenotypes in a rodent. And he would use a genetic constructs to also then he used to present like phenotypes, gave ketamine and then regrow the regrew those dendritic spines. And then he used the genetic construct to specifically photo ablate. The newly formed dendritic spines only not everything else, just the new ones. And when he did that, the long lasting effects completely gone. So you get ketamine, the spines grow, you get an effect, you get ketamine, the spines grow you photo ablate those spines, there's no antidepressant effects anymore, which does suggest that structural plasticity Yes, sir. Structural plasticity is causally related to the lasting effects of cabinet.

Nick Jikomes 49:43

Gotcha. Wow, that makes sense. So that's, that's a really cool experiment. So you guys have the precision now that you can go in and literally get basically choose which synapses in an animal that you want to get rid of. Right. Interesting. So what do you are there any interesting is Must be some interesting experiments or problems that you're working on now, what's what's on the horizon?

David Olson 50:04

Oh, geez, I mean, we only have a couple hours buddy.

Nick Jikomes 50:10

Pick pick, let's pick one or two and just kind of define the problem space for people.

David Olson 50:15

I mean, think about this. We, you know, of course, we're trying to develop new molecules based on I'll say that we're, we've got better versions of I think of every major psychedelic scaffold, and so be that. I mean, we've reported on kind of a Boga compounds, there's tryptamine compounds, amphetamine compounds are going compounds that we're really, really excited about. So hopefully, that will be coming up soon. But what I think I'm most excited about is a lot of our mechanistic studies. And how it is that you can produce non hallucinogenic psycho pathogens and have them modify circuits relevant to neuropsychiatric disorders, that hopefully will be coming out in a series of papers pretty soon, but I think that that's really, really interesting. The the pharmacology is, is surprising, I'd say that. And then, you know, lots of other lots of other projects on the horizon. Um, I don't really know where that where to begin with that.

Nick Jikomes 51:17

What do you think about the so so it's intriguing that let's just take some of the classic psychedelics as an example, more or less, all of them seem to have the psycho plastic genic effect. But some of them, you know, only last for a few minutes, in terms of you know, before the body is able to metabolize them DMT would be an example, some of them last for many hours. Why is there anything interesting going on there? Can you can you? Do you think you can have drugs that are really only active in the body for a few minutes, but they do have this full sort of psycho plastic genic effect? Or do you require to sit there for longer?

David Olson 51:50

No, that's one of the first questions that we tried to address. And we published this work in ACS pharmacology and Translational Science, just a year or so ago, we had the same thought, I mean, something that really kind of intrigued me about psychedelics, in general, is that like, these molecules get into the brain, they get out of the brain, and then they produce these really lasting effects on neuronal structure and function. And so I didn't really quite understand how that was, and what like, what is the kind of timeframe How long do they need to stimulate the receptors for and so we did an experiment, where we started to just, you know, give very short pulses of the drug. And so we started with, let's give the drug for three days and see, you know, how much the neurons grow, then let's let's give the drug for a day, then let's give the drug for an hour, then let's get the drug for just 15 minutes, and see how long to see if the neurons grow. And it turns out that even with those really, really short pulses of stimulation, you can get really profound effects on neuronal structure. And it turns out that the reason for that is we think that these compounds turn on an auto regulatory feedback loop in the brain, what it's like flipping us like a light switch, as long as you turn it on. What happens is mTOR, which I mentioned was that downstream kinase, which is really critical for producing all of the structural and functional proteins that you need for plasticity. And for also turns out turns out to produce brain derived neurotrophic factor, BDNF. So then you start increasing the amount of BDNF, BDNF, and that can then bind to the track B receptor, and the track B receptor can turn on mTOR. And then this process can can happen as positive autoregulatory feedback loop exactly how long it happens. And what turns it off, we're not entirely sure. But it's really unique case for a drug to be able to just get it into the brain and get it out of the brain. Normally, what you're trying to do as a medicinal chemist is to have high brain exposure, you want a drug that gets in there and stays there for a really long time, so that you're activating the receptor for a long period of time. But of course, doing that usually results in drugs that have a lot of undesired off target effects, because they're sitting around in the body for longer. But if you have a drug that gets in, flips the light switch and then gets out, you can minimize those off target safety effects and produce something potentially that is more better tolerated.

Nick Jikomes 54:18

I see. So it sounds like I was going to ask but it sounds like you know, this, this self self reinforcing loop that can get activated, almost like a light switch, as you mentioned, we don't know what actually turns it off. So for example, on someone with depression, you know, you would imagine that maybe maybe this pathway was on or activated in some way, and then something shuts it off. So that's still a mystery.

David Olson 54:40

It's still a mystery, but I think it's probably homeostatic plasticity. So neurons have some really tightly controlled mechanisms to make sure they're not firing too much or too little. They're kind of at the Goldilocks state. And so if you're really kind of like low and you're not very happy and you give a drug that produces this growth, then eventually the neuron is Gotta have a mechanism by which to go, okay, that's too much growth. I don't want to be overexcited. Because if you stimulate neurons too much, then they'll die. Because, you know, it's just metabolically very taxing for them.

Nick Jikomes 55:12

So So that brings me to a related question, which is, plasticity is not always a good thing. So you can't have too much plasticity, if too many connections screw that would actually become toxic for the cell.

David Olson 55:23

Yeah, so one thing that we we we found actually in rodents that I think was really interesting. So there's a lot of people, you know, talk about psychedelic micro dosing and the potential for this or lack thereof. Something about micro dosing that concerns me is the constant stimulation, you're stimulating the brain every couple of days. And when we so we did two studies in a rodent, with Dimethyltryptamine, a very rapidly acting quickly eliminated psychedelic drug. If you give one single high dose of Dimethyltryptamine, you get robust cortical neuron growth. If you give a low dose of DMT, every three days for, you know, a couple of months, you actually see the opposite. You see cortical neuron retraction. And we really think that's because you're over stimulating the cells and you're getting this homeostatic plasticity, the cells are intentionally, you know, calling the synapse, the synapses in dendritic spines, so that they don't get overexcited and die.

Nick Jikomes 56:23

Interesting. So you're giving a sub hallucinogenic dose when you do that,

David Olson 56:28

correct. But the the dose is still sufficient turn on the pathway.

Nick Jikomes 56:32

I see. Interesting. So. So in this micro dosing experiment, you the opposite outcome, you get a retraction in the neurons when you're giving things day by day by day.

David Olson 56:43

So in my opinion, I think that psychedelic medicine is probably going to be more effective with a single high dose of the compounds rather than a whole bunch of, you know, small doses.

Nick Jikomes 56:54

Interesting. Well, that's actually good news in some ways, right. So to the extent that that type of treatment is good, at least for some people, it's, it's obviously less unscalable, if you need one mega dose rather than, you know, a number of them

David Olson 57:09

100%. And in the case of of using the traditional hallucinogenic psychedelics, like I mentioned, they do hit the five HT two B receptor. And if you're just agonizing the to B receptor, once, probably not that big a deal. But if your micro dosing and you're taking a drug every day, for every couple of days, every third day for weeks, then you really got to worry about problems in the heart.

Nick Jikomes 57:32

Interesting. So that'll be something to watch out for. Because that is something that I think is happening more and more, you're seeing a lot of products in the what you would probably call the gray market, depending on where you're at in the country, where you know, people are meant to eat one or two gummies of something containing psilocybin or LSD every day.

David Olson 57:50

Yeah, I think that, you know, counter intuitively microdosing might be more dangerous than a single high administration of the compounds.

Nick Jikomes 57:57

Interesting. I've never actually heard that articulated before. Um, so in the time we have left, why don't we Why don't we discuss something a little bit different? Are there any other you know, so who are the other labs that are doing interesting work that you're following, that people might go check out that are doing things in the general area that you're doing, but not quite the same stuff?

David Olson 58:21

So, you know, I'll say that I think that's the field is growing. You know, and when I started my academic career, are very few labs looking at like the basic mechanisms of psychedelics. Unfortunately, that is starting to change. There are a lot more groups doing this now. And so I'll name a few. I'll try to go from west to east so I can make sure I don't forget anybody. One of the first person that comes to mind is Boris Heifetz. I'm actually collaborating with Boris, Boris has done a lot of work on, you know, the effects of MDMA, the mechanisms of MDMA and very interested in kind of brain mapping. And you know, Boris, and I have a couple of really interesting collaborations going on now. So hopefully, something will come with that soon. Down in Santa Cruz, ease Whoa, is one of my good friends. And he has been on several of the papers with us. She's an expert in two photon microscopy, in vivo imaging. And so I'm very happy to say that she just got her schedule on license, and now she can start doing some more studies on psychedelics, so you can expect that coming out from her more in San Diego. You know, there's Adam Halberstadt has been doing this for many, many years, particularly behavioral neuropharmacology, you know, looking at the effects of different structurally modified psychedelics in things like the head Twitch response asset. They move over, there's John McCorvey and in Wisconsin who is doing a lot of receptor pharmacology and signaling and trying to understand how these molecules differentially impact, you know, biochemical pathways. My good collaborator Jamie Peters at University of Colorado. She is very interested in trying to understand how psychedelics and related compounds might be anti addictive medicines. She's doing a lot of really interesting work there. Let's keep moving over. Of course, Alex Klein, who was at Yale, who will be moving to Cornell pretty soon has been doing a lot of two photon in vivo imaging, he had a really nice paper in neuron showing the psilocybin promoted dendritic spine growth for a very long period of time for at least a month. Of course, there's there's Brian Ross, who's doing lots of really great structural biology work to try to understand how psychedelics differentially differentially activate the five HTT to a receptor and other GPCRs. And I think Brian's group is also trying to develop some of these non hallucinogenic analogues of psychedelics for for treating brain disorders. I know I'm forgetting so many other people, gold Dolan is doing some really nice stuff at Hopkins, who she knows she's really interested in the social, pro social effects of a lot of these compounds. I'm trying to think of mainly the people that are on the kind of preclinical mechanistic side of things. Oh, in terms of pharmacology, Oh, I almost forgot Javier Gonzalez myself, Javier was one of the people that really inspired me to get into this field. He's really studied a lot of the molecular interactions of the five HTT a receptor and how there's this differential signaling, you know, this idea of functional selectivity of the to a receptor, you know, was really pioneered in large part by a lot of Javi errs work. There's Chuck Nichols LSU. He's doing a lot of great work on inflammatory processes related to psychedelics. Of course, Chuck's dad Dave Nichols was, I think, probably my scientific hero. You know, Dave was a medicinal chemists, that was really trying to understand how the structure of psychedelics impacts their function. And if it wasn't for Dave, I wouldn't be here today. I think reading his papers as a graduate student really inspired me to get into this field. And then there's Delabar Psalmists, at Columbia, who is making a whole bunch of analogs of Ibogaine and no, sorry, I don't want to forget anybody.

Nick Jikomes 1:02:22

Yeah, so there's a lot, which is good. So there's a lot going on. One of the things that I think is interesting, that gets less attention, I think, just because, you know, the nature of these, when you talk about psychedelics, people think about the the mental effects they tend to have, and then you start talking about all the psychiatric applications. One of the things that I think is super interesting is some of the, some of the other kinds of effects that might be here. So things that are happening in the periphery, like, like anti inflammatory effects, what are some of those non brain effects that are super interesting that people are trying to understand?

David Olson 1:02:56

Yeah, so the serotonin to a receptor is, it's one of my favourite G protein coupled receptors, because it's everywhere. And it's involved in a lot of different things, and, you know, being expressed on immune cells, both in the periphery, and in the central nervous system, there's to a receptors on microglia. And so something that my group is very interested in is looking at the effects of psychedelics related molecules on neuro inflammation. But in the periphery. You know, Chuck's shown a lot of a lot of examples of these compounds having anti inflammatory effects. And so, you know, could they have some potential for treating peripheral disorders, asthma, autoimmune diseases, I mean, I think this is really, really interesting, you can imagine, it'd be pretty easy to make a, it's hard to get a drug into the brain, but it's a lot easier to keep it out of the brain. And so you can probably make some peripherally localized versions of psychedelics to have some anti inflammatory effects in the periphery.

Nick Jikomes 1:03:59

Interesting. Well, David, I want to thank you for your time, and I don't want to take too much more. Are there any final thoughts you want to leave people with just on the general field and what they should look out for or anything interesting that you think is coming up?

David Olson 1:04:13

Um, I just want to encourage people to keep supporting this field, I think that it's, you know, an incredible group of researchers. It's a pretty tight knit group, and I hope it continues to grow. And I think we just all need to kind of be supportive of each other because at the end of the day, I think that everyone in this field just really wants what's best for patients. And I think a lot of different approaches are going to be important and we should be supportive of people, you know, looking at at all options. But yeah, I think that's that's probably it. I'm very happy that the field is where it is today. When I started how I was given a lot of advice to not propose, you know, my proposals when I went on the job market were related to psychedelics, and people told me that Like, you're never going to get a job at a big university. And so I'm very happy that the tides are changing and that now, you know, my trainees that are going out for jobs now they have no qualms about having proposals related to psychedelics, and I'm, you know, hearing from the younger generation that are wanting to get into this field. Oh, and related to that I should put a plug, I'm hiring two postdoctoral positions to understand the the mechanisms of psychedelic so if you're interested, please contact me.

Nick Jikomes 1:05:29

So so what what just one last question, I guess. So when, you know, when you were on the job market, and you have these proposals, you're getting advice not to move in that direction? What made you do it anyway?

David Olson 1:05:42

It's too compelling not to. I think that, you know, there's a lot of people that are really suffering from these brain disorders, like I said, one in five people, and looking at all the data that had been coming out of some really, you know, really incredible pioneering work from people like Ron Griffiths and Matt Johnson and others. It just, it seemed too compelling not to pursue this because there was the translational value, the ability to help people was really, really huge. And on a basic science side, in my opinion, you know, psychedelics are among the most powerful drugs that impact the human brain. And the only way we'll have a full understanding of how the brain works is if we understand how psychedelics do what they do, and so, just decided to go for it.

Nick Jikomes 1:06:29

Alright, well, David Olson, thank you for your time. Thank you.

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