Psychedelics, Psychoplastogens, Microdosing, Mental Health, Brain Chemistry, Creating Novel Drugs | David Olson | #46

Short Summary: The science of psychedelics and neuroplasticity with Dr. David Olson.

About the guest: David Olson, PhD is a chemist and associate professor at UC Davis. His lab pioneers research on advancing non-hallucinogenic psychedelic analogs for therapeutic use.

Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and everyone on YouTube. Partial versions are available elsewhere. Transcript and other information on Substack.

Episode Summary: Dr. David Olson discusses his lab’s research on psychoplastogens, small molecules that enhance brain plasticity to treat conditions like depression and addiction, focusing on compounds like Ibogaine. He explains how modifying molecular structures can reduce harmful effects while retaining therapeutic benefits, delves into the mechanisms of neuroplasticity, and explores the potential for non-hallucinogenic psychedelics to offer scalable mental health treatments. The conversation also covers the broader implications of psychedelic research for understanding brain function.

Key Takeaways:

* “Psychoplastogens” are compounds that promote brain plasticity, potentially treating disorders like depression by regrowing neural connections in the prefrontal cortex.

* Olson’s lab modified Ibogaine to reduce cardiotoxicity while maintaining its anti-addictive and antidepressant effects, tested in mouse models.

* According to Olson, the hallucinogenic effects of psychedelics may not be essential for therapeutic benefits; non-hallucinogenic therapeutic drugs could be developed.

* A single high dose of psychedelics may be more effective and safer than microdosing, which could lead to adverse effects like heart issues or neuronal retraction.

* Psychedelics activate a feedback loop involving BDNF and mTOR, enabling long-lasting neural changes even with brief exposure.

* Peripheral effects of psychedelics, like anti-inflammatory properties, could lead to treatments for conditions such as asthma or autoimmune diseases.

Related episode:

* M&M #121: Psychedelics, Metaplasticity, Critical Periods, Social Learning, Psilocybin, LSD, MDMA, Ketamine, Ibogaine & Neuroscience | Gül Dölen

*Not medical advice.

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* Episode transcript below.

Episode Chapters:

00:00:00 Intro00:04:13 David Olson’s Background00:11:00 Medicinal Chemistry and Drug Modification00:16:03 Ibogaine and Its Properties00:21:54 Psychoplastogens and Neuroplasticity00:26:51 Testing Hallucinogenic Potential00:34:41 Hallucinogenic vs. Non-Hallucinogenic Therapies00:42:08 Scalability and Passive Treatments00:50:14 Future Research Directions00:56:22 Microdosing Risks01:02:21 Peripheral Effects of Psychedelics01:04:13 Final Thoughts and Field Support

Full AI-generated transcript below. Beware of typos & mistranslations!

Nick Jikomes 4:13

Can you start off by just telling everyone who you are and what your background is? Scientifically, sure? So I'm an associate professor at the University of California, Davis in the department of chemistry in the Department of Biochemistry and Molecular Medicine, and I'd say 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,

David Olson 4:45

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, this a lab that's very well known for taking traditional toxins.

Nick Jikomes 0:26

Welcome to the mind and matter podcast. I'm your host, NICK JIKOMES, and today I'm speaking with Dr David Olson. David is an associate professor of chemistry, biochemistry and neuroscience at the University of California Davis. His lab studies a class of compounds called psychoplasty genes, which are small molecules capable of promoting neuroplasticity in the brain. His lab is on the cutting edge when it comes to understanding the mechanisms by which psychedelics and other psychoactive drugs work in the brain. And we spent most of our conversation discussing this research. We touched on everything from the latest research from his lab, including things related to the drug Ibogaine, to new tools they are developing and using to understand these drugs and how they work, to the question of whether it's likely that we'll actually be able to produce non hallucinogenic drug variants of classic psychedelics, which are capable of eliciting therapeutic mental health outcomes, but without triggering psychedelic states of consciousness. We touched on a variety of things related to those areas. My conversation with David got cut a little short for scheduling reasons, but his lab is doing a lot of fascinating, fascinating research in this area, and there will likely be several major discoveries coming from his lab in the next few months. So I hope, I hope to have him back on the podcast at some point in the coming year. As always, if you enjoy the content of this podcast, please do like, share or subscribe. You can subscribe to the video version on YouTube. You could subscribe to my free weekly science newsletter, mind and matter on sub stack. That's Mind and Matter dot sub stack.com, you can also sign up for the paid newsletter, which gets early access to episodes of the podcast, as well as some other content that you can't find elsewhere. You can also just tell people about the podcast, if you enjoy the content here, and you just tell one or two people about the podcast and why you like it, that can actually be very effective at getting more listeners. This episode is supported in part by athletic greens, their main product, AG, one is a comprehensive and convenient daily nutrition product containing 75 vitamins, minerals and whole food sourced ingredients with less than one gram of sugar per serving, no nasty chemicals or artificial anything. It's gluten and dairy free and compatible with paleo, vegan, vegetarian and ketogenic diets. Ag one is a quick and convenient way to supplement your diet to help ensure your body is getting the nutrients it needs. It comes in powder form, and you can mix it in water and drink it, or you can put it into a smoothie or a shake or something like that. I mix it into water and drink it with the first meal of each day, and it's super convenient. If you go to Athletic greens.com/mind, and matter, Athletic Greens will give you a free one year supply of vitamin D and five free travel packs with your first purchase. Their vitamin D product comes in tincture form, so you just take one drop each day. A large fraction of the population is actually vitamin D deficient, especially in winter months, when we get less sun exposure. And vitamin D is super important for the proper function of the immune system and for a variety of other things. And there's even evidence indicating that vitamin D deficiency is correlated with more severe cases of COVID 19 in those who get infected every time I go into the doctor each year for a checkup, I'm always told that vitamin D deficiency is very common and I should be supplementing on a daily basis. So visit Athletic greens.com/minded, matter, or click the link in the episode description, you'll get a free one year supply of vitamin D with your first purchase. Today's show is brought to you in part by dosist, an all natural cannabis company specializing in dose controlled cannabis products made with plant based ingredients. To learn more about dosist their products and where they are available, please visit their website through the link in the episode description, and with that, here's my conversation with David Olson. You

David Olson, thank you for joining

Speaker 1 5:00

Like Saxo toxin, tetrodotoxin, 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 at 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 independent career at UC Davis in 2015 and my academic lab, it, you know, 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 neurobiologists, 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.

Nick Jikomes 5:53

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 how that process works? So you mentioned something called tetrodotoxin. 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?

Speaker 1 6:18

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 developed new reactions, 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 we're actually modifying toxins like saxitoxin and tetrodotoxin. And, you know, those molecules come from a couple of different places, but tetrodotoxin 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 tetrodotoxin 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 my good friend John Mulcahy and and my former boss Justin Dubois, they started a company called site one therapeutics, and they're trying to use these toxins to treat to treat neuropathic pain.

Nick Jikomes 8:06

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 tetrodotoxin, 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

Speaker 1 8:30

in Well, first we need to separate this completely. Like tetrodotoxin, saxitoxin, these are super water soluble compounds. They don't cross the blood brain barrier. These are not acting as central, essentially acting agents. They're working in the periphery, affecting neurons in the spinal cord and other parts of the body, but not necessarily in the brain. What I focus on now my academic lab are molecules that work centrally. 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 pretty simple. Actually, if you think about a drug, 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 that drugs are interacting with?

Speaker 1 9:56

I mean, it depends drug to drug. Case. By case. But you know, most CNS active drugs exhibit very robust, diverse polypharmacology, 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 undesired targets, or off targets, as we would call them, are in the periphery. So for instance, in the case of psychedelics, a very common off target protein would be the five HT 2b receptor in the heart. This is known to cause cardiac valvuopathy, 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 HT to be receptors in the heart, just to avoid that kind of peripheral complication I

Nick Jikomes 11:00

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 at on some of those might lead to a beneficial outcome, the action that it leads that has on 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 of 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 and tune the functional effects of the drug.

Nick Jikomes 11:48

So you mentioned that some psychedelics bind to this receptor called Five, HD, 2b, 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, 5h 2t, 2b Can you elaborate on why it's of concern here? And maybe, what are some of the compounds that are known to activate it?

Speaker 1 12:21

So, it's a related receptor to the five HT to 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. The five HT two a receptor, you know, even in the gut and in immune cells. But when we think about it in terms of its effects on the hallucinogenic effects of psychedelics, we're talking about five HT two A receptors in the brain. Five HT 2b 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 these that obviously are undesired.

Nick Jikomes 13:10

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

Speaker 1 13:13

the heart is not functioning properly, so at least heart issues. Now there, you know, there are other, receptors, ion channels in the heart that are very common, off target effects for a lot of drugs, particularly greasy amines like psychedelics, and one common one is the herd channel. So herd 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, and several people have died after taking Ibogaine due to cardiac arrhythmias.

Nick Jikomes 13:50

Are there any other psychedelic drugs that people may have heard of that have this effect on the five ht, 2b receptors in the heart?

Speaker 1 13:59

Yeah, most of them. I think, you know, salicin, LSD, you know, I think they all have, you know, high affinity and efficacy for five ht, Qb, but

Nick Jikomes 14:09

so, 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?

Speaker 1 14:25

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 some indigenous populations in Africa. But you know, Ibogaine has been, you know, the effects of Ibogaine have been known for quite some time. In particular, at higher doses, it seems to have, you know, via. Anecdotal reports in open label clinical trials, I should say there's nothing 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, IBM 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 cardio toxicity that I mentioned, but also, you know, some some hallucinogenic effects at high

Nick Jikomes 15:41

doses. And traditionally, how is that consumed? How did people actually take that? Yeah,

Speaker 1 15:48

there. It's found primarily in the Root Bark of this, this plant, Taverna, 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 I

Nick Jikomes 16:03

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

David Olson 16:20

guys, the cardio tax issue for Ibogaine comes from the ion channel, the herd channel. That's the primary issue of that. Yep,

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. So it's

Speaker 1 16:39

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 would be better to be able to synthesize it de novo. And so we took Ibogaine and we 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 at that that herd channel that I was telling you about, and by chopping off a lot of the grease, we were able to reduce its potency on herd, pretty substantially, reduce its cardiotoxicity, but we found that it still was a pretty effective anti addictive compound, and 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 anti things, you know, in cells, one of the things that we really look for when trying to identify new antidepressants is we we focus on molecules that are really good at promoting structural neuroplasticity and cortical neurons. And so I probably should take a step back and describe why we care about that first, before we get into 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 the stress related neuropsychiatric disease, I'm talking about things like depression, PTSD and substance use disorder, and a 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 time scale 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. Are a 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 antidepressant compounds, and we started calling these molecules cycloplastigns, 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 and rodents, but what there are, are a whole bunch of tasks 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 21:54

I see. So whether it's depression or many other neuropsychiatric 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 psychoplasty genes 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 gene? You mentioned ketamine? What are some of the other ones that we know about that you've looked at in the

David Olson 22:34

lab? So in 2018 our group published a paper demonstrating that most of the serotonergic psychedelics are very good psychopathogens from a variety of different chemical classes. We're talking ergolines like LSD, tryptamines like Dimethyltryptamine, five Meo, DMT, silacin, amphetamines like DOI even, even compounds like MDMA, from the intactogen family. And then there are a few others that are kind of outside, you know, the typical psychedelic sphere. There are delirians 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. So there's a lot, 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 psychopathogens 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 drugs. 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 and. And 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 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. And mTOR is involved in the production of all of the proteins that you need for neuroplasticity. They 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 plastic effect where these cortical neurons 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 traditional way to do this is with something called drug discrimination, and it works very well if you say you have, you know, a drug like 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 rat gets really good, adds this task. And so in a way, you know, you're asking it a question every time you give it a new drug is, do you think you've got LSD, or do you think you got saline then after you train 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 lever, 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, silence 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 they have these head twitches, and that gives you a really nice predictive assay for hallucinogenic potential in people. And Adam Halberstadt group did some really beautiful work just published recently, where they demonstrated that there was almost perfect correlation between human hallucinogenic potency and potency in this head Twitch response assay. And so I, in my opinion, the head Twitch response assay is probably the most predictive in vivo assay that we have for hallucinogenic potential in 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, that'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? But 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 rodent, it doesn't cross the blood brain barrier, therefore you get no response, and so 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 Lin Tien just recently, and we published a paper about a new biosensor that we call cyclade. And cyclite 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 two, 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 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 HT 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 is this so the five issue 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 as 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 32:13

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 agonists, molecules that will activate the receptor, that will not produce hallucinations. A really great example is a molecule called liceride that people have known about for many, many years. It is an agonist of the two a receptor, but it's 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 we can think about, at least, there's, there's many, many outcomes from from turning on, if you will, the five HD, two receptor one outcome, though, are potential hallucinogenic effects. And a second outcome is the ability to promote cortical neuron growth, or neuroplasticity. And so our group has found is that there are some molecules that will bind to the five HT 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 dissociations 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 plastic genetic 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, sort 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? 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. It 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 hallucinogenic side of things. There are some people who believe that 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 seemed 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 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 an 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, what 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 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 it'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 and 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 their in clinic administration. If you remove the hallucinogenic 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 a 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, do you want? You want to jump in there? Yeah, I

Nick Jikomes 38:28

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, 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 39:19

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, and 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 these 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 of it as major depression, maybe there's really five or 10 or 15 sort of subtypes of that, and each one will respond differently to a different kind of a 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?

Speaker 1 41:24

Well, I think that that is very, very possible. There definitely is a spectrum for every single neuropsychiatric disease. And what 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 the frontier in in translational neuroscience research right now. And so we'll see where it goes. But I think that that is, is very, very possible.

Nick Jikomes 41:55

And so what, what gives you the 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 42:08

Yeah. So, 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, 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 administered 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. It 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 psychotherapy. Now the other the other reason goes back to preclinical 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 looked 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 we're 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

changes. 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 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 it 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. I think

David Olson 44:44

that's possible, um, I wouldn't call it necessarily a loosening, though. I think that, 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. So in 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 a point to a paper that we published with my my collaborator, y's Whoa, in molecular psychiatry. And this is a drug that we call Taberna. It's it's an analog of of both Ibogaine and five Meo DMT, it's a non hallucinogenic cycle, plastic gene. 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 parvalium and positive interneuron 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 regr