Dr. Charles Nichols: When I was a kid, I wanted to be a rock and roll star in a rock and roll band, and then got interested in science, and I had no intention of actually going into this field. When I was in Purdue University as an undergraduate, I studied bacteria and bacterial phosphatases, and I found that really interesting, and when I went to graduate school, still didn't know what I wanted to do, but I knew the kind of research that my father did with serotonin in pharmacology, and my mother was a pharmacologist.

So, maybe I wanted to distance myself somewhat from pharmacology because both my parents were pharmacologists, and I went into fruit fly genetics, and I studied the neurogenetics of how fruit fly eyes developed for my PhD dissertation, and then I never wanted to see another fruit fly again after I got my PhD.

Jesse Lawler: Yeah, you've seen one fruit fly form, you've seen them all.

Dr. Charles Nichols: Oh, yes. If there is a fruit fly hell, I know where I will be going. But, I wanted to do something more interesting for my post-doctoral work, and I wanted to do something in mammalian systems and behavior. So, I looked around a little bit, interviewed in a lab doing some dopamine pharmacology, and just on a random happenstance, I happened to see an advertisement for a laboratory at Vanderbilt University to study the molecular genetics of serotonin system, and it was an investigator, Elaine Sanders-Bush, who my father had collaborated with, and I knew the type of work that she did with serotonin, and I thought, "Oh, that could be interesting." So, I sent her an email if she was interested in having me interview for a post-doc, and she contacted me back saying, "Well, I'm sorry. I don't know why I was listed on there. The position's not available. I don't have any funding for it." So, that was that.

Then, it was about a month later, I got an email out of the blue from Elaine saying that if I was still interested, she'd love to have me down for an interview. So, I went down, I interviewed. She is a pioneer in the study of serotonin-2 receptors and had done a lot of work with psychedelics in the '80s, and was really instrumental in identifying a lot of the early signaling pathways from the receptor, and she had this project in mind to look at the genetic effects of psychedelics. We called them hallucinogens at the time in the brain, and she wanted somebody to come to the lab who is an expert in genetics to, really, look at the brains of rats given LSD to see how it affects gene expression. I thought, "Oh, that's really interesting. That's cool."

I accepted the position, moved to Nashville, and it was a couple weeks into my post-doc when she came up to me, and you have to know Elaine. She is a very red-headed firecracker lady with a Southern drawl. She came up and said, "I was looking at your CV again. I see that you were with Purdue, and I know a Dave Nichols at Purdue. Do you know him?" and I said, "Yeah, he's my dad," and she just went, "Ah!" and laughed, and from then on, she called me Dave in the lab.

That's kind of how I got into the field. It was really not intended at all, and just through happenstance that I happened to see this ad, and that she had called me back, and for whatever reasons that may be, I've now been in the field for 20 years now.

Jesse: One of the things that seems most interesting about psychedelics is the potency at really small microgram level amounts, and yet they're having effects on serotonin receptors. What does this say about the potency of serotonin itself? I mean, is it like serotonin but a bazillion times more potent, or is serotonin itself just an extremely potent molecule within the brain?

Dr. Charles Nichols: There are differences. Serotonin, itself, will bind to, in mammals, at least 14 known receptor targets, and its affinity, or stickiness, for each of these is vastly different, where for some receptors, you have to have a lot of serotonin, other receptors, just a little bit to activate them. The serotonin-2 receptor, serotonin is fairly potent at it, but there's a key difference between serotonin and psychedelics, and when you activate the receptor with serotonin, even the high levels of serotonin, you don't get psychedelic effects. So, you can artificially increase the amount of serotonin in the person or an animal, and it's not psychedelic. It has these other effects that are known as a serotonin syndrome, and some people will get that if they, say, overdose on an SSRI and they're taking, maybe, monoamine oxidase, but they're very different symptoms.

Jesse: Syndrome never sounds good, so I assume there's negative consequences there. What actually happens?

Dr. Charles Nichols: There's hypothermia, the body heats up, tachycardia, there's a lot of physiological effects. Not many people will die from it. They feel so horrible they'll go to the emergency room and there's classic hallmark symptoms of serotonin syndrome, and so they just basically wait it out and they recover. With psychedelics, it's not that they're more potent or less potent as the receptors in serotonin, but they activate the serotonin receptor differently. So, when serotonin binds, it causes this cascade of enzyme activation downstream, particular sets of enzymes that ultimately will change how that neuron is firing in the brain network. What psychedelics do is we believe that they recruit different enzyme cascades in serotonin that lead to both the psychedelic effects and the anti-inflammatory effects.

Jesse: That might be kind of a good segue into your work looking at the anti-inflammatory effects of psychedelics, which I think is something that we can safely assume most people will not have heard anything about. How did this come to your attention? What made you look in this direction at all?

Dr. Charles Nichols: It was really an accidental discovery. I had recently established my laboratory here at the university, and we were looking to identify some cell culture assays that we could look at the gene expression response to psychedelics like LSD and DOI, because one of my main interests is to identify these different enzymes from the activated receptor with psychedelics and serotonin, and it's kind of a hassle to always have to treat an animal and take the brain out and analyze it, so we wanted to find some tissue culture models that we could do in Petri dishes, and we looked at a lot of different assays to see if we could find one that psychedelics had an influence on, and one of them was brought to my lab by my post-doctoral researcher at the time, being new, it had experience studying atherosclerosis, and blood vessel cultures in the Petri dish.

We took this assay, we put in this molecule that causes inflammation, and then we added the DOI to it, and much to my surprise, we very potently blocked the inflammation produced by this molecule called tumor necrosis factor alpha. At first, I thought that the doses were wrong, things were not right. So, he repeated it again, hot a beautiful dose response curve, I did it, and then I finally convinced myself that we were really on to something here.

It was first in muscle cells from aortas that we looked at, and from that, we looked at different types of cells, and different psychedelics, and found that they were all anti-inflammatory, even LSD, which was the least potent anti-inflammatory that we found was still as potent as a typical corticosteroid at its receptor target.

Jesse: That's interesting that LSD was the least potent, given its sort of famous levels of potency for psychological effects.

Dr. Charles Nichols: Right, and since then, we've looked at several different structures to try to identify what the pathways are, and I've convinced myself that the psychedelic behavioral pathway is different than the anti-inflammatory pathway because we don't really see a correlation between the potencies of psychedelics in humans to produce the psychoactive effects, and the potency of the drugs and animal models to treat inflammatory disorders.

Jesse: Inflammation is there for a good reason. If you have an acute injury, it's very, very helpful. But, of course, one of the problems with everyday life nowadays is that people often live in constant low-grade levels of inflammation that never fully goes away. What do you see with these anti-inflammatory effects as potential therapeutic options?

Dr. Charles Nichols: What we sort of have envisioned as a therapy is that the really ultra-low doses that we're using, in some cases, we predict about 100 times less than we would need to just get a minimal behavioral effect that it's not going to be engaging the receptors enough to have any pathology, but there will be sort of this low-level counteraction against inflammation, and diseases like rheumatoid arthritis, asthma, depression, potentially even diabetes and metabolic disorder that we have some data for that just really involve this chronic, persistent, low-level inflammation, I think, that this will be really effective as a therapy for.

Jesse: This would be a totally sub-perceptual dose range, so for example, somebody micro-dosing mushrooms might be a way to accomplish this?

Dr. Charles Nichols: That could be one way to put it. It would really depend on the molecule. With something like LSD, I think you're going to be in the same range of perceptual as anti-inflammatory, but some molecules like DOI, which are 100 times more potent, for reasons we don't yet understand, I think, are going to represent the best candidates because they're really not going to have any behavioral effects at all that are noticeable.

Jesse: DOI isn't one that we've discussed before on this show. Can you define that, because I think a lot of people probably won't have heard of that one?

Dr. Charles Nichols: Right. DOI is a chemical that, overall in structure, is related to mescaline in that it's a phenethylamine. So, it's related to amphetamine in structure, and it was first synthesized by Sasha Shulgin back in the 1970s, and it's similar to the street drug that was called STP back in the 1960s. We call that one DOM, and this is DOI where it has an iodine instead of a methyl group, but it's closely related to amphetamine, but it's not an amphetamine. It doesn't have any dopamine behaviors or components that it mediates.

One of the reasons that it's not really widely-known, or say, abused recreationally is that, in humans, it's a 24 to 30-hour trip. It's not something for the casual user to, say, go to a concert, and take some DOI and come down two to three days later.

One of the great uses for it is that it's the only selective drug that only targets the serotonin-2 receptor, that something like LSD will hit eight, 10 different receptors, psilocybin will hit five, six, seven different receptors, and DOI is only specific for the 5-HT2 receptors, the target of the psychedelics. So, it's the most widely used chemical reagent that us pharmacologists can use to study the 5-HT2 receptors apart from all the others, and that's why we use that instead of, say, LSD, because it gives a much, much cleaner result in the experiments.

Jesse: What is the difference in the half-life or binding times for the different chemicals within the receptors? Is it just sort of the chemical stickiness of a given compound in a different receptor, and that's why mushrooms might have a six to eight-hour perceptual timeline, whereas LSD is longer and DOI is much longer than that?

Dr. Charles Nichols: That's been a mystery as why LSD lasts eight to 12 hours, when pharmacologically, it's a really poor ligand. It doesn't bind to the receptors tightly as the others, it doesn't activate it as much. There was a recent publication from a couple months ago that showed that there's a little lid on the top of the receptor that traps the LSD molecule in there, so it doesn't come off of the receptor. And because it sticks on there, it keeps signaling, it keeps the receptor active longer than, say, something like psilocybin, which is going to go into the receptor, activate it, and pop back out, it's not going to be stuck in there. So, that could be one of the basis for why LSD lasts for so long and psilocybin doesn't.

For DOI, that hasn't been looked at yet. Some of the other things to take into account, our metabolism, that different classes are metabolized by somewhat different enzymes and can last longer. The half-life for DOI, subcutaneously in a rodent, is about five hours. So, if you inject it, it lasts about 90 minutes. If you put psilocybin or LSD into a mouse, the half-life is only 10 minutes, because it just gets metabolized. So, you can have variability in the human populations as well, depending on how active their metabolic systems are. So, it's a combination of how active is a person metabolizing the drug and its stickiness to the receptor, and then how well it's activating the receptor.

Jesse: Is there anything that a person can do to loose these molecules from your receptors quicker if you want to. If you need to pull the ripcord and get out of a psychedelic trip more quickly, is there anything other than waiting it out?

Dr. Charles Nichols: It's not like you can go for a jog and you get rid of all the LSD in your body, now. So, there are a couple of different enzymes: monoamine oxidases, which are free-floating enzymes, there are enzymes called P450s that reside in the liver that are responsible for the detoxification of most chemicals in the body that also metabolize, and drug-drug interactions are usually one drug can either upregulate or downregulate the expression or activity of one of these P450s.

A good example of that is, say, coating. There are people who metabolize coating very poorly, and those that metabolize it very rapidly into the active drug, morphine, based upon the nature of their P450 metabolic enzyme. You could conceivably figure out what would upregulate a metabolic enzyme and eat that food or take that drug, and then if you took the corresponding psychedelic that was metabolized by that, you would metabolize it faster. But, we don't know which ones metabolize the psychedelics. Those studies haven't been done yet.

Jesse: To get back to the therapeutic uses for the anti-inflammatory effects, where are things at in the potential drug discovery or therapeutic recommendations? I suffer from allergies. In certain parts of the year, I had asthma as a kid. So, my ears definitely perk up when I hear about anything that could dampen down a body's response like that.

Dr. Charles Nichols: We have some intellectual property and patents that have been issued and applied for regarding several aspects of inflammation in the serotonin-2 receptor activation. In the asthma studies, we've found that we can both prevent the development of allergic asthma and rescue asthma that's already present. We're now working towards developing a clinical trial protocol to, hopefully within the year or so, test DOI in a small cohort of human asthma patients for efficacy, and that's kind of our goal within the next year to have that data to demonstrate proof of principle in humans.

Jesse: Do you see any potential roadblocks or do you think that this will work? Is there cause for optimism?

Dr. Charles Nichols: I think there's a lot of cause for optimism. The one main potential roadblock is that the road to market is littered with thousands of drugs that were successful in curing diseases in rodents, but not humans. So, it's really can we make the leap from rodent to humans, because all the anti-inflammatory effects that we've looked at, we've found, for diabetes, metabolic disorder, high cholesterol, asthma, inflammatory bowel, there's efficacy in both rats and mice in tissue cultures of rats and mice. So, it works great. I have no doubt, if we wanted to cure these diseases, guinea pigs, it would be awesome.

But, can we make the leap to humans? That's the big unknown, and I'm fairly optimistic that we can because in a couple of the cell lines that we've tested, they've been human cells, and we've shown that the anti-inflammatory effects are there in human cells. So, I'm fairly optimistic on that, and just from anecdotally, I, as you can imagine, get all sorts of emails from people that have read my work from all walks of life, and I have several anecdotal reports of people who have conveyed to me their experience with their inflammatory conditions, and after using psychedelics, that it will go into remission or be treated better than the therapy that they're taking.

In some cases, the therapy is not working, and they'll say, "I've tried to use it in this way, and I'm symptom-free for a month or two, and it's wonderful." So, I have several anecdotal reports, although those have to be taken with several grains of salt, but I'm really optimistic.

Jesse: One question that comes to mind is people have been doing psychedelics for a long time, and people have had inflammatory issues for that entire time, are we just noticing this now? Even anecdotally, if there were really something there that where there's smoke, there's fire, we would have maybe been seeing the smoke signals before now.

Dr. Charles Nichols: Yeah. I think a lot of what I'll receive, for example, would be an email from somebody who says, "You know what? I always noticed that whenever I took mushrooms that my asthma seemed to get better for a week or two or something like that." So, I think it's been there, but it's been written off by the people who have noticed it, and people don't use psychedelics on a daily basis.

Jesse: It's unfortunate too because, when you hear something from somebody that's talking about, "Well, I did some psychedelics," and the easy, dismissive thing to say is, "Well, that person was tripping out. Of course, they thought 'fill in the blank'."

Dr. Charles Nichols: Right. So, you had these people who used them not on the daily basis or a therapeutic basis, but maybe once a year, twice a year, they go to a concert or something and, "Oh, my asthma got better for a couple weeks," and they just write it off. So, I think there's been a low-level signal that just really hasn't been picked up on. I think the therapeutic strategy going forward is going to be, really, these low-dose therapies on a regular basis for these long-lasting effects.

Jesse: What does that mean for a compound that's been synthesized like DOI? I don't know what university Sasha Shulgin was at when he created that originally, but as far as something like this entering the big pharmaceutical pipeline of being a prescribable drug, what happens? What are the intellectual property ramifications?

Dr. Charles Nichols: With DOI, it's different than most drugs. Most drugs are made in a university, the IP is filed under the structure of them, and then they go to market, and they make their money. DOI was synthesized by Sasha when he essentially was working out of his laboratory at his farm. So, it's been in the public domain for the last 40 years or so, so it's not a patentable thing in terms of structure. But, the normal pipeline would be to demonstrate safety and efficacy, to get FDA-approval. To demonstrate safety, we have to do several experiments in rodents, increasing the dose, finding out what the toxic dose is, how it's affecting the different tissues. So, we have to put DOI through the same rigorous preclinical testing that any other drug would have to go through.

Psilocybin did not really have to go through that because it had been used for centuries by indigenous populations and have a demonstrated safety profile. So, they are able to do that with psilocybin, but with DOI, we're currently in the process of doing those types of experiments to get the FDA-approval to take it into humans.

Jesse: I'm always fascinated with the concept of the pharmaceutical index, which is a term I try to throw in every five or 10 podcast episodes just because I think it's one that most people haven't heard of, but it's such a valuable thing to be aware of of like that ratio between an effective dose and a lethal dose, and I know that it's something incredibly high, and psilocybin is like 300 to 1 or something.

Dr. Charles Nichols: Oh, yeah.

Jesse: What do you see is the pharmaceutical index in some of these other psychedelic compounds?

Dr. Charles Nichols: I think we're looking at two different indexes. One is sort of the LD50, half the people die, and that's huge for these drugs.

Jesse: It would be like you would have to eat a garbage bag of mushrooms.

Dr. Charles Nichols: Yeah, yeah. You could take massive amounts, and you're not going to be doing any physical harm to your brain or your body. People have, in the past, anecdotally, accidentally sniffed a line of LSD thinking it was cocaine or something like that, and they go unconscious, sometimes, for several days, but they recover, and it's not toxic at that level. I think, in humans, you'd have to really work hard to get a toxic, lethal dose of most of these types of drugs. The different one being the one that's now known as a 25I or N-Bomb, that does have toxicity associated with it.

But, all of the others, that's not really an issue. What is the issue is what's the dose of where you're starting to get perceptual changes. The therapeutic index that we're working with with DOI and these other drugs is what's the maximum dose isn't going to kill you, but when are you going to start hallucinating. So, that's what we're in the process of identifying now for DOI and a couple other of those chemicals.

There is already an FDA-approved psychedelic drug on the market called Lorcaserin that is marketed as a selective serotonin to see agonist, but it's not very selective. And if you take just a little bit more than prescribed, in humans, there is a paper that they had people who were experienced on LSD and heroin, multi-drug users, and they gave them Belviq, and at about three to four times the normal dose, it was producing a full-on acid trip. So, there is an FDA-approved psychedelic on the market with a much lower and narrower therapeutic index based upon the behaviors, and I think DOI would be on the market. So, I think that elephant is out of the room now.

Jesse: That is a little known fact. It hasn't made it out to circulation much.

Dr. Charles Nichols: I used to get questions all the time. You think the FDA will approve a psychedelic, and they've already done that.

Jesse: How widely-prescribed is that compound? Is that something that sees the light of day a lot?

Dr. Charles Nichols: It is for, essentially, morbidly obese individuals that is effective in suppressing the appetite for people not to eat as much, and it's effective in about half the population probably due to metabolic genetics where they lose a significant amount of body mass, of BMI, and they will maintain that through activation of the 2C receptors. But, its activation of the 2C receptors has been shown to also produce anxieties. So, the psychedelic trip that these human subjects in their research study had was unpleasant, and for them, it was psychedelic and psychoactive, but it was very unpleasant. So, I think it's a combination of your activating the C receptor and bringing in anxiety with the A receptor for the psychedelic effects, and they just don't want to take it again. So, it's not got a reputation for being a trip that you would want to have.

Jesse: It's self-reinforcing in not wanting to take too much of a dose, which is probably a very good thing as far as not getting prescription users into trouble and also getting doctors more comfortable in actually prescribing these sorts of compounds. How have you found the general political climate in doing these sorts of studies? Have you been getting the evil eye? Is there still a taboo?

Dr. Charles Nichols: When I first got into this field 20 years ago, my father told me it's the kiss of death. If you go into the field of psychedelics, that's it. Nobody will find you, you won't be taken seriously. But, I did it anyway, and I think it's the approach that I've taken to study molecular mechanisms, what's going on, and how these drugs activate the receptor in the brain because, to me, it's fascinating that you can activate these receptors and have people report that they're in a different reality. I think that they're really fundamental to our understanding of consciousness and mental disorders that change our consciousness.

So, I've approached it, really, from that level, and I've been successful with NIH funding to understand, really, the biology of the serotonin-2 receptors and its relationship to normal cognitive processes, and by extension, developing therapies to treat diseases are similar to some of the effects of psychedelics like schizophrenia.

I've had a lot of funding from NIH to study that, and then when we discovered the anti-inflammatory effects, it's novel because we're not inducing these CNS effects, and it's in the periphery. So, I've had success from several different funding agencies, NIH included, some small foundations as well that aren't dedicated to studying psychedelics, like MAPS or Hefter.

Scientifically, I think it's been not as difficult as I originally thought it was going to be because of the questions that I've been trying to study and answer.

Jesse: For the anti-inflammatory effects, it seems like such a wide swath of society is affected by something that falls under that umbrella. Do you have any numbers there as far as what proportion of the population deals with inflammation issues?

Dr. Charles Nichols: Well, the leading cause of death in this country, one of the leading cause, if not the, is cardiovascular disease, atherosclerosis, coronary artery disease, diabetes, metabolic disorder. If you have, say, 200 million adults, 100 million who are affected who could potentially benefit, that's 30 to 50 percent of the adult population, which is a huge number, and we've got animal data for each of those indications that this therapy might be successful.

I think that the anti-inflammatory effects are also relevant to the antidepressant effects that have been seen in the clinical trials, and that's one of the things that we're starting to look at now in some animal models.

Jesse: Can you dig into that one a bit? I would love to hear about the potential crossover between the psychological effects and the anti-inflammatory effects, how those tie together.

Dr. Charles Nichols: I think, in depression, there's a large percentage of people who are depressed that have inflammation associated with the depression. So, that's been a really hot topic in our pharmacology. The last seven to eight years has been neuroinflammation as related to depression, bipolar disorder, schizophrenia, that these people have activated microglia in the brain, which are the responsiveness cells to inflammation. There's increased inflammatory markers. The brains of these patients look inflamed, and so the theory has been if we could treat the inflammation, then we can alleviate the depression. So, there have been several clinical trials using anti-inflammatories to treat depression, and they've shown that.

For example, depressed patients who show inflammation in the brain before taking a selective serotonin reuptake inhibitor like Prozac, after they have been treated and their depression goes away, the inflammation goes away as well. So, it's still kind of a chicken and an egg.

Jesse: Yeah, sort of a vicious cycle there.

Dr. Charles Nichols: Right. So, my current hypothesis is that the psilocybin in the clinical trials is having an anti-inflammatory effect within the brain that, when somebody goes into these trials, they're depressed, they take the psilocybin, they have their mystical experience that Roland Griffiths has spoken about, that seems to be integral to them recovering from the depression.

But then, ketamine does the same thing. That treatment-resistant depression, you give the patients ketamine, they're better, but only for a couple of weeks. Why is that, where psilocybin seems to be effective for a year, a year and a half out without really any decrease after a single dose? So, what I think, it's that mystical experience that you're having, regardless if it's ketamine or psilocybin is getting you out of the depression.

But, unlike ketamine, with psilocybin, you're treating any underlying neuroinflammations. So, you're normalizing the inflammation and the brain doesn't get sucked back into that depressive state after a few weeks. I think that it's a really integral part of the antidepressant effects of psilocybin, but that's something that we have to validate experimentally.

Jesse: The problem is sort of try to dissect what's actually happening there, since these compounds are affecting both psychologically levers and neurophysiological levers.

Dr. Charles Nichols: Right, and if we could separate out the inflammation from the psychedelic effects, which I believe we will be able to sooner than later, and if you give a psychedelic non-anti-inflammatory versus a psychedelic anti-inflammatory, and then look to see, in head-to-head trials, which one will be more effective than the other, and I would predict that the psychedelic anti-inflammatory is the one that will be effective one year out, two years out, whereas the non-anti-inflammatory psychedelic may only be effective for a few weeks.

Jesse: Is that a study that you're actually planning to conduct sometime in the reasonably near future?

Dr. Charles Nichols: I would hope so. We are actively dissecting out the pathways of these different classes to try to identify the psychedelic anti-inflammatory versus the psychedelic non-anti-inflammatory and vice-versa combination. So, hopefully, within the next couple years, we'll be able to test some of these hypotheses.

That's one advantage to having a chemist in the family. I'm fortunate enough to be able to have a large library to test the structure, function, and activity of these molecules, basically, at will without having to sort of say, "Well, what happens if we have this molecule and we remove this?" We don't have to go out and get it made because I've already got it.

Jesse: Early in the conversation, we were talking just a bit about the epigenetic changes that can happen from psychedelics use. It's funny, though. The first thing that I really remember hearing about psychedelics was Nancy Reagan-era scare tactics, "They'll screw up your genes," this idea that psychedelics had actual germ line changes, which of course, isn't really what happens, but epigenetic changes are happening all the time. What do we know about the epigenetic changes that come along with psychedelics exposure?

Dr. Charles Nichols: We've looked at chronic and acute. I'm not going to go into the chronic too much. That's a model of psychosis that my father developed where you give LSD every other day to rats, and after three months, they essentially go crazy, and it's all in the timing. It's every other day. If we do it every day or every third day, it doesn't work. But, every other day, and it's only with LSD. It's not with any of the other psychedelics.

Jesse: And they never bounce back from it?

Dr. Charles Nichols: No, they don't. We stop the drug and they stay crazy.

Jesse: What defines a crazy rat, by the way? If you met a rat, how would you know he's crazy?

Dr. Charles Nichols: Very aggressive, hyperactive, they startle a lot, we try to pick them up, they jump, they try to bite. Normal rats, they don't really do that. They're very friendly. But, they had all the similar symptoms that if you give a rat high doses of methamphetamine, it acts very similar. And when we looked at the brains of those rats, we found that there's a very significant enrichment of genes that are implicated in the schizophrenia and bipolar disorder that were just regulated. So, that was a sort of moderate-low chronic every other day for three months.

Jesse: That's fascinating that it was not every day, and it was not every third day, but something about hitting that exact ratio of days.

Dr. Charles Nichols: Right, and that's not how people normally take these medications, but it was following on some observations that my father had made on his rats over several years, and lately, we've been looking at more of whether the effects of a single acute dose, and we've looked at DOI and LSD, and we've been treating the animals, and then 45 minutes later, dissecting out the brain, and we've figured out how to sort out the different cell types from one another, and we've identified that there are about 5% of the brain neurons that are directly responding to psychedelics, that most of them don't respond, it's about 5%, and we've been able to purify out this 5% of neurons, and I call them the trigger population that the 5% of neurons that activate directly with psychedelics, that their activation then sort of propagates the signal to the rest of the brain.

Jesse: Are these 5% localized in any particular brain areas?

Dr. Charles Nichols: They are localized to a few different brain areas to the medial prefrontal cortex, we see a lot of the activated neurons, and we also see a lot of them in a structure called the claustrum. The claustrum is one of the most highly interconnected brain areas, but it's also not studied very well because it's very hard to get to. It's like a little ribbon that runs from the front to the back of your brain that's connected to almost every structure.

We see a high level of activation in that structure in the medial prefrontal cortex, which is sort of the executive part of your brain that most of your cognitive abilities reside in, and we've been able to look at those 5% trigger population neurons and do gene expression profiling on them, and see that there are a lot of early responsive genes that become activated, there are some circadian rhythm genes that become activated.

But, how they're activated at the genetic level changes from one brain region to another. So, when we compare what would otherwise be the same neuron type from the medial prefrontal cortex to the somatosensory cortex, which is responsible for movement, they're activated differently. Different types of cells are activated, and the types of cells that are activated have different genetic responses, and that was something that wasn't really known before.

I think that may help to explain some of the connectivity data that the Imperial Group and the UK is seeing, that you're strengthening some connections, and weakening other connections, but overall, increasing connectivity that, within the different brain areas, we're affecting these cells at the molecular and the genetic level differently. So, you can't really look at it as this brain area's becoming more active in talking with this one, but within that brain area, you're getting cells that are excitatory and cells that are repressive, both becoming activated in somewhat different balances. So, you look below the surface, it gets even more complicated and more questions come up.

Jesse: Does there seem to be consistency, maybe, between people or even between the same person on multiple doses as to these levels of activation, or is there somewhat of pulling the lever on a slot machine and you get different activations every time?

Dr. Charles Nichols: I think that gets back to the old adage of set and setting that the state of your brain is really, at any given time, defined by your mood, your setting, where you are. So, the actual state of your brain is going to be different from, say, one use to another use, and that, I think, underlies a lot of the variability of why one experience, say you're at a Grateful Dead show, is going to be different than you're at your grandmother's funeral if you're taking LSD or something like that, because the states of your brain before are going to be somewhat different because of the activity, the inputs coming in.

Jesse: And how long do these induced epigenetic changes seem to actually last? How long do they persist? I assume beyond the actual period of psychedelic effects and perceptual changes?

Dr. Charles Nichols: For the chronic studies, where we gave them LSD for three months, we did the gene expression studies four weeks or one month after the final LSD dose, and the changes were really profound at that point. So, I think that, within that model system, the changes are fairly stable and persistent. We haven't looked at the length of the changes in the acute studies. We've looked to five hours out. Most of the genes are back to baseline level by five hours, but there's some that are still maximally induced at five hours.

So, it could be that somebody takes a single dose, they're inducing a lot of genes, changing the function of the brain cells, and then after the course of the trip, the genes go back to normal, for the most part. But, there's a few genes that are still not back to normal that are giving a slight change to the brain neurons and how they're functioning. So, if they take another dose, say, a day, or two, or three days later, they're sort of bootstrapping on that and recruiting additional genes.

Jesse: I forget whose study it was, but the finding that psychedelics are, I think, still the only known way of reliably changing one of the five basic personality characteristics, and it increases openness.

Dr. Charles Nichols: Right. I think a lot of those studies have been out of the Franz Vollenweider's group in Basel. In Switzerland, they've been doing a lot of studies on personality with that. But, yeah, that could be that maybe some of the genes, after even a single dose, they might permanently be altered, and we can't say that they're not, and that's at the expression level, and we're just now beginning to look at epigenetic changes and chromatin structure to see if those are really playing an issue or not, but it's quite possible that certain genes come on after a single dose and just don't go off again, and that could be underlying some of the positive therapeutic effects.

Jesse: Do you suspect that you'll see those sorts of persistent changes even in the ultra-low doses that might be used for anti-inflammatory effects?

Dr. Charles Nichols: I think they're engaging two different systems, and you need more of the drug to engage the psychedelic system than the anti-inflammatory system. So, the low-dose anti-inflammatory, I don't predict, will be associated with these CNS gene expression changes, but the experiments just haven't been done yet.