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Down the Rabbit Hole: Genomics and Psychedelics – Charles Nichols

Charles Nichols is a Professor of Pharmacology at LSU Health Sciences Centre in New Orleans in USA. His main research focus is exploring the effects of psychedelics, particularly in relation to the 5-HT2A receptor, on the body. In recent years, Nichols’ lab has delineated the relationship between psychedelics and its anti-inflammatory properties in mice.

Please note the transcript has been edited for brevity and clarity.

FLG: Hello, everybody, and hello, Charles, thank you so much for joining me today as we go down the rabbit hole and take a look at some of the weird and wonderful ways that genomics is being applied in research. Today, we are going to be looking at how genomics is being applied in relation to psychedelics and research in that area. So, Charles, if you could just introduce yourself and tell us about what you do as well.

Charles: Thank you for speaking with me today, Shannon. I’m Dr. Charles Nichols, Professor of Pharmacology at LSU Health Sciences Centre in New Orleans in USA. I have been studying psychedelics professionally for almost 25 years now, predominantly serotonin 5HT2A receptor function in psychiatric diseases, and more recently as anti-inflammatory targets.

FLG: Would you be able to provide a brief summary of what psychedelics are and what their effects are? What pathways do they work on?

Charles: Psychedelics are a class of drugs that activate what’s called the serotonin 2A receptor in the brain and throughout the rest of the body. But when they activate this target receptor in the brain, it produces sensory distortions, disassociations from reality, the ‘psychedelic trip’. There are magic mushrooms, there is LSD; some of the more infamous psychedelics that are out there. And they are very, very potent and powerful drugs that, due to political considerations in the 1960s/1970s, were made illegal to research through the scheduling drug laws. And so, not much work had been done on them from the 1970s, 1980s and to the 1990s. There were only maybe a handful of people who were doing preclinical work. But now, they’ve really come back as we’re starting to understand some of the potential medicinal roles for psychedelics to treat disorders like depression, drug abuse and inflammatory-related disorders.

FLG: What are some of the social and political issues you mentioned? How have attitudes shifted in more recent years?

Charles: I think a lot of it was in the politics of the 1960s, sort of as a way to control the hippies and the upstarts that were protesting against the government. It was like, ‘Well, we can’t arrest them for protesting, but they’re all using these drugs. So, let’s make these drugs illegal, then we can arrest them.’ And they were seen as dangerous drugs with no real medical value, which led to a halt to just about any research, both the clinical psychology studies, as well as cell culture in vitro animal studies. It became very difficult to get permission from the DEA and the government to do research on these. So, because of that, maybe only five or six people in the world were really able to do any kind of research on these drugs, as initially how are they involved in drug abuse and to show that. But then we began to understand that serotonin and serotonin 2A receptors are really involved in several aspects of mood and cognition and normal brain function.

Then in the 1990s, some clinical studies were performed. There was a study by Rich Strassman using DMT characterising what effects DMT had on people, and he wrote a book about this – DMT: The Spirit Molecule. Charles Grob at UCLA did the first clinical study of using psilocybin to treat end-stage cancer patients and saw some really amazing therapeutic effects there. Then that was followed on by some studies from Johns Hopkins, Roland Griffiths’ lab, showing that a single administration of psilocybin had really long-lasting positive effects. And then they followed that up with studies looking at end of life-associated depression and anxiety at John Hopkins and NYU, and also Imperial College in the UK with Robin Carhart-Harris and David Nutt. So really prestigious research groups then showed that a single treatment with psilocybin had these profound anti-depression-like effects in these resistant patients. Then, popular culture books, for example from Michael Pollan, came out around the same time and now, I think it isn’t so much of a stigma. Back in the 80s, it was ‘Don’t use drugs it is going to fry your brains.’ Now, we understand that once we put some effort into researching them, we understand that there’s some significant medical potential associated with this class of drug, and activation of the target serotonin 2A receptor.  

FLG: What psychedelics are the most studied in a research capacity, and why?

Charles: There are several that are found in nature. The most widely known one in nature is psilocybin, which is in magic mushrooms. There’s also DMT, which is found in ayahuasca brew; it is one the main components there. There’s 5-MeO-DMT, which is in toad secretions. They’ve been used for thousands of years by indigenous populations. Mescaline is in the peyote cactus. But I think the one that was most well-known was LSD. This is derived from ergotamine, which is made by a rye fungus, ergot fungus, and it was used by a lot of the counterculture in the 1950s and 60s. So, most of the research was done with LSD early on. Psilocybin has become more prevalent recently, I think because of the demonstrated safety of it for hundreds, if not thousands, of years in indigenous populations. The psilocybin itself comes from a natural source with very little toxicity associated with it. It’s less of a dirty drug. Psilocybin is only targeting a subset of serotonin receptors, whereas LSD lasts much longer and has effects on other receptors. So, I think the focus recently has been on psilocybin in the clinical therapy setting because of its relative selectiveness for serotonin receptors, and its behavioural effects only last a few hours, 3-4 hours, as opposed to, say, 8-12 hours. Although both LSD and psilocybin have been used in clinical settings, I think the focus really has been on psilocybin.

FLG: Why is studying psychedelics relevant?

Charles: Depression has really been a significant burden to society for decades, especially now with COVID. The rates of depression and psychiatric disorders have really, really gone up recently. There have been no new antidepressants on the market since the 1980s. The last major breakthrough in the pharmacological treatment of depression was essentially Prozac and modulation of serotonin levels in the brain, which have a low efficacy. There’s a high placebo effect. Anti-depressants, in general, in the end help about 30% of the patients who take them. There are resistant populations. And so, with increasing depression by COVID and no new mechanisms, psychedelics appear to be really exciting developments to treat depression. Some of the early clinical data suggests that 70-80% of patients respond to psychedelics, and a single treatment has anti-depressant effects and prevents somebody from relapsing for three to four years. So, it’s really a paradigm change, going from taking a drug every day that maybe only helps 30% of people, to one or two treatments helping 70-80% of the people over several years. It represents a real paradigm shift in psychology.

FLG: Aside from altering mood, are there any other applications of psychedelics? You mentioned earlier its anti-inflammatory effects?

Charles: That is a main discovery from our lab that we’re really trying to develop into therapeutics now. We have discovered in several animal models that psychedelics are really potent anti-inflammatories at sub-behavioural levels. We looked at models of inflammatory bowel, asthma, cardiovascular disease, ocular disease, and it has really potent suppression of a lot of symptoms and pro-inflammatory biomarkers. So, what psychedelics might also represent, at sub-perceptual, non-psychedelic doses, would be potent anti-inflammatories to treat things like inflammatory bowel, asthma, arthritis, diseases like that apart from psychiatric disease. But then there’s a fairly substantial fraction of people with psychiatric disease where neuro-inflammation is involved, for example, schizophrenia, psychosis, even in drug abuse. So not only could the psilocybin be directly affecting neural processes and circuitry to treat things like depression and substance use disorder, but the anti-inflammatory may also be a key factor in treating other diseases.

FLG: In terms of genomics, what are some of the main findings exploring the effects of psychedelics on gene expression changes?

Charles: There’s been a few groups, including mine, that have looked at this. We initially started looking at the effects of LSD and other psychedelics on gene expression using the first-generation Affymetrix arrays, and surprisingly in those first studies, we found that what I would consider a whopping dose of LSD in the rats had a really small effect in the brain at that size. We only were able to identify/verify about 7-10 genes whose expression was significantly differentially changed. We were able to validate, out of, I think, 3 different Affymetrix chips, A, B and one of the other chips we screened. So that was somewhat surprising! But then what we also found is that almost all of the genes had something to do with synaptic plasticity and facilitating how neurons communicate with one another. We saw no genes that were indicative of damage or stress or toxicities. It was really a small collection of genes that were involved in synaptic plasticity. Some other groups also did genomics, RNA-seq and microarrays in mice and identified similar things. We followed up that with looking at persistent effects of LSD in a model of psychosis, where we treated the animals every other day with a low dose, and that essentially makes them go crazy over three months. We were one of the first groups to apply RNA-seq to behavioural changes induced by LSD. And we found that even in the absence of the drug, there were over 700 genes that were significantly differentially expressed by this chronic treatment with LSD. So that shows us that, for better or worse, psychedelics can influence gene expression within the brain. But how it’s influencing it to be potentially therapeutic versus pathological really depends on the dosing.

FLG: You mentioned the long-term effects of some of these drugs. How can other omics technologies, such as epigenomics, provide insight into these effects?

Charles: That’s what one of the main projects in my laboratory is right now. We are trying to identify why a single dose of psilocybin has anti-depressive effects. With ketamine, for example, it’s an anti-depressant but it wears off after about two weeks. With psilocybin in humans, it is demonstrated to last upwards of four years, if not more, for a substantial number of patients. So why is it so long-lasting? We don’t really know that. The first thing that would obviously jump to mind is that there are some epigenetic changes that are occurring. And what we have developed is a rat model where a single administration of psilocybin has very long-lasting persistent anti-depressant effects. So, we’ve taken the brains of these animals and have dissected key brain regions, and we are in the process of preparing RNA to do RNA-seq, to do ATAC-seq, to look at gene expression and epigenetic changes. We are also now considering how can we leverage the single cell RNA sequencing into this pipeline. So, we’ve been looking at that. We’ve developed protocols called neurocytometry that allows us to go into banked fixed brain tissue and sort out individual cell types based on flow cytometry. So, what we’d like to do is see if we can combine that with the single cell techniques to, where we can, get these entire populations of brain cells from fixed brains and do profiling of, say, what’s in the medial prefrontal cortex, and how are we potentially changing the population of maybe microglia between the depressed, the non-depressed, the psilocybin-treated. Also, potentially combining that with the single cell ATAC-seq to look at epigenetic changes and maybe we will get some clues there.

FLG: What are the challenges working with these samples and technologies?

Charles: One is just having a good animal model that I think has good validity construct and predictability. I think with our rat model that we have developed, it’s a stress-based model that’s effective in females. Most of the animal models of depression aren’t effective in females. Depression in the human population is more prevalent in females than males, but most people are studying male animals. So, we’ve got a female depression model that’s based on stress, where a single dose of psilocybin is able to normalise specific brain circuitry function and behaviours. So, I think going in with a good animal model is paramount. The other thing is our process that we developed for neurocytometry. We are able to get single cells from these brains, as opposed to just getting unlabelled nuclei we don’t know what they are for. So, we’re able to put in a flow cytometry step where, maybe, we can select for only neurons or interneurons to do the single cell sequencing to get a little bit better granularity, or detail, than just taking the entire brain as it is. So that’s one of the things that we hope may give us some clues by going in with the target cell population to begin with.

FLG: What other areas are people focusing on?

Charles: One of the other areas in addition to the antidepressant effect of psilocybin is the immune cell function, and how psychedelics are affecting immune cells in our model of asthma. We’re looking at macrophages and T cells. And that’s another area that we want to apply genomics to, is looking at how we are affecting the immune cell landscape within these tissues, for example, the lung, and doing single cell PCR and genomics and single cell ATAC-seq, looking at how psychedelics are affecting, say, Th1 cells or Th2 cells in the lung that’s asthmatic that has been treated with psychedelics or not, towards identifying what the therapeutic mechanism is. The mechanisms right now are unknown, but we do know that we are suppressing cytokine secretion from innate cells, from adaptive cells. We are preventing recruitment of eosinophils and T cells to the lung. But what those mechanisms are and why 5HT2A receptor activation with psychedelics, but not serotonin, is still a mystery. So, I think going in with some of these newer genomic profiling paradigms we can really assess the landscape of what’s happening within these tissues at a detail that we wouldn’t normally be able to.

FLG: Are there many groups working in this space?

Charles: Most of the work is done by clinicians and psychologists and psychiatrists who are looking at depression and substance use and patient response there. There are very few people who are looking at mechanistic aspects of how this is happening. There are a few groups – there’s myself, there is Dr Gonzalez-Maeso, who is at Virginia Commonwealth, who is also doing some genomic studies, and they’ve done some epigenetic studies looking at 5HT2A receptor and psychedelics and schizophrenia. I think actually doing genomics in the field of psychedelics right now, there’s really only about two labs that I can think of. I think it’s difficult to get the necessary permits to get these drugs to do the research. But that’s becoming a little bit easier as more people are coming into the field. I think, still, a lot of it is clinically focused, not so much on the basic science.

FLG: How does your research impact drug development?

Charles: If we can find what the mechanism is, if we do our single cell sequencing, we do our ATAC-seq, we find a collection of genes that are surprisingly differentially regulated with respect to anti-depressant effects, and it turns out that that’s a key mechanism for the anti-depressant effects, then we combine that with our receptor pharmacology drug design and development to try to develop a new class of psychedelics that are activating the receptor, that will preferentially only activate the effector pathways necessary for that therapeutic effect. So, we could conceivably design drugs that only activate these antidepressant pathways, or we could identify drugs that would only activate the pathways leading to anti-inflammatory effects, which I think are probably different. So, we could really tailor new chemical entities and drugs that activate the receptor to only selectively activate whatever that therapeutic pathway is for that disease indication, which would mean less side effects, less behavioural effects for people taking the drug for other indications. Because if you don’t need to hallucinate, why should you hallucinate for therapeutic effects, and we can engineer that out, I believe.

FLG: Is there also a potential of synthetically engineering novel neuropharmaceuticals?

Charles: There is another area. Bryan Roth, who I think is a third laboratory who is working on the molecular biology and receptor pharmacology of psychedelics, not so much the genomics part yet. But he’s been given a $26 million grant by the US army to essentially figure out how to make a non-psychedelic antidepressant. They’re doing a lot of really cool stuff in his lab. But I think it’s having a basic understanding of what pathways are being activated for drug development that is really the direction that it’s going. We have developed some new drugs in my laboratory that are as anti-inflammatory as our prototypical drugs but are less behavioural. So, they’re not making the animals have the hallucinogenic behaviours in typical assays. So rather than having, say, psilocybin that everybody takes – okay, that works, but people are going to have to hallucinate, they’re going to have to be in the clinic for three or four hours. But what if you could make a drug that is just going to be targeting specific pathways that that receptor could possibly activate out of the many that it can, that will just selectively activate whatever it is that’s causing the antidepressant effect or the anti-inflammatory effect. And that could be different between different diseases, like to treat asthma, to treat drug abuse, migraine headaches, might all be a different pathway that this receptor is acting at.

FLG: People often use psychedelics in a recreational capacity. How can we ensure that we can control use? What is microdosing?  

Charles: I think what MAPS (Multidisciplinary Association for Psychedelic Studies) is trying to do with MDMA is to have these treatment therapy centres. It’s really a new paradigm for the FDA and the DEA to consider. But there have been public presentations by both the DEA and FDA, that they’re both amenable to developing psychedelics as therapies. The FDA is on public record in several conferences for saying, ‘Yeah, if you can show that these drugs are safe and effective, we will work with the DEA into revising scheduling laws and coming up with proper regulatory protocols for the use of these drugs’. And the DEA has also said, ‘Yes, show they’re safe and effective and we will work to see how we can make this happen.’ So, I think that as things are progressing, it is really unknown territory that we’re going to have to come up with new treatment strategies, regulatory affairs on how to handle these. I don’t think that you’re going to see a situation where any psychiatrist or physician will just be able to prescribe these drugs. I think there are safety and regulatory issues that need to be taken into account. For example, there are people out there who should not be taking psychedelics, primarily those that have a history of psychosis in their family, that there’s a chance that it could make that worse. So there has to be rigorous screening protocols in place to make sure that only people who are at low risk for making a psychosis worse are getting these therapies. So, what the prescribing laws and everything are, I think, remains to be seen. It is kind of being developed as we go along.

FLG: What do you think the future of this research area will look like?

Charles: The future, I think it’s promising! I know when I got into the field there were maybe half a dozen researchers. My father was one of them and he told me it was going be the kiss of death if I went into this for my career. I ignored his advice! It’s going from where it was with half a dozen people to now so many – there’s hundreds of people and companies that are now in the space. It is kind of like the Wild West. I think there’s going to be a lot of good that comes out of it, a lot of crazy stuff. But I really hope that that the therapeutic potential of these drugs can be vigorously and scientifically vetted to where they are accepted as therapies. I think this is a real possibility in the next 5 to 10 years, that we will see therapy centres with MDMA, with different psychedelics. We will have the proper protocols out there, the treatment centres, and really be able to help people. I think what started for me as a curiosity – how are these drugs working – to now having a real legitimate chance of helping alleviate suffering is a really positive thing!

FLG: Thank you so much for joining me today, Charles, it has been really interesting, and I think this area does not receive a lot of attention and I have definitely learnt some stuff today and I hope others have too! So, thank you so much.

Charles: Thank you!