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Ep #33 Transcript | David Nichols: LSD, Mescaline, MDMA, DMT, Medicinal Chemistry & Psychedelics

Full episode transcript (beware of typos!) below:

Nick Jikomes

Professor David Nichols, thank you for joining me.

David Nichols 3:30

Today. Happy to be here.

Nick Jikomes 3:32

Can you tell everyone briefly who you are and what you've studied throughout your career at a high level?

David Nichols 3:41

So I was a professor at Purdue University until 2012. I was here 38 years. I taught graduate students and undergraduates and pharmacy school. I started my graduate research in 1969, the University of Iowa and I actually worked on psychedelics for my PhD, what were called psychometrics then, and then evolved to be hallucinogens, and now, I think are more properly called psychedelics. And I continued working on those when I went to Purdue, I got research grants to study those as well as some other areas. And pretty much was an academic scientist. With a major theme being psychedelics, chemistry and pharmacology of second delegations. I had another program that ran for about the same length of time looking at dopamine D one agonist, which would be for treatment of Parkinson's or for schizophrenia. And then for 10 or 12 years, I had another grant to study MDMA and similar agents. And in 1993, I started to have to research institute I founded it to get money from philanthropists to fund clinical studies in psychedelic so we funded sort of the first clinical studies to psychedelics in this modern world. We call it modern era.

Nick Jikomes 5:03

So, in terms of scientists who studied psychedelics in the lab, you have had, I think, one of the longest careers of anyone, you've probably put more years into this than just about any other scientist, is that right? That's probably true. And it's interesting to me that not only you've been doing it for so long, but you were doing this at sort of peak drug war. So what was it? Like? What was it like just getting all the licenses you need to to actually do this work?

David Nichols 5:32

So the Controlled Substances Act was passed in 1970. And I was a graduate student then, so I was working on psychedelics. And then when the Controlled Substances Act was passed, I thought, well, you know, I'll just enjoy my graduate career. Because there's probably no chance I'll be able to get a job during that afterward. And when I started looking for positions, I really had two alternatives at that point, one was to work on oral contraceptives for a company back East. And the other was to take an academic position. And I didn't know too much about academic positions about I knew about industry. And but I didn't know in academic positions, you could work on your own projects. And if you could get them funded. So that attracted me. And I went to Purdue University in 1974.

Nick Jikomes 6:31

So during your time at Purdue, I believe your lab, among other things, was actually synthesizing LSD. Is that correct?

David Nichols 6:40

Yes, we had. We had colonies of rats trained to recognize the the drug effects of many drugs, but LSD was one and we we used LSD trained rats for a number of our study. So every year, we made 100 150 milligrams of LSD, which we use because we had a colony of 12 to 14 rats that would be injected almost on a daily basis with LSD. So, yes.

Nick Jikomes 7:06

So one thing I wanted to ask you about LSD is if you could just walk everyone through what exactly it is chemically, what it looks like, and where it comes from, what what is the sort of natural origin of the precursors of this and how is it made, generally speaking,

David Nichols 7:25

originally, it was obtained from infected rye grains, they would get infected with the ergot fungus or gut or gut will produce these dark kernels that are called ergot, that are a sort of dormant form of the ergot fungus. And those, they're called they're dark black things are called sclerotia. They if you look at a stock of rye or some grain, if it's been infected with our Godfather, this, you'll see these not all of them, but some of them, they won't look like grains so much as enlarged dark black grains kind of. And in the Middle Ages, you had scourges of ergotism. The ergot fungus produces what are called ergot alkaloids. And in the Oregon fungus, if you eat bread that's contaminated with our gut, it will cause the blood vessels in your fingers and toes to constrict, among other things. And if you if you continue eating that bread and you poison yourself, what happens is your toes and fingers take on a Blackburne appearance and fall off. So and there's a lot of pain associated with that. So it was a scourge throughout the Middle Ages, like 40,000 people died of ergot poisoning. So Sandoz laboratories in Basel, Switzerland, had been working on ergot. So you can extract the alkaloids out and there are a number of alkaloids that occur that are produced by the ergot fungus. So Albert Hoffman, whose PhD work was to determine the structure of Titan, which is the exoskeleton on lobsters and insects and so forth. That's what he did for his PhD. And then he was recruited to go to to Santos and work. And he worked on a number of projects, but at a certain point, he went to the Research Director and wanted to work on the ergot fungus. So he made quite a few derivatives of these ergot compounds. It's hard for me to explain what it is but it's a are gods are built on what would be called an Ergoline nucleus. So he could see the structure. You have four rings that are fused together. And then at one position, you have a carboxylic acid function coming off and that can be converted into to a number of different kinds of emits, so lysergic acid diethylamide. You take Lysergic acid and coupled with dye ethyl amine, and you get a diaphragm emitted this what's called the eight position. So there was a compound known as core amine or a calf amide, which was a respiratory stimulant. And Hoffman apparently made LSD because Nick FMI recording has a diaphragm in it, it's a, it's a nicotine amine. And so like the nicotine derivative that has a diaphragm attached to it. So he thought if he made an ergo, amid, like the gap in my head, that what he would get is a very potent respiratory stimulant. And, of course, that he didn't, that is what happened, he got a very potent compound, but it wasn't a respiratory stimulus kind of amazing. That's the story of the discovery. That's kind of interesting. Because he made LSD in 1938. First, he made a whole series of compounds. Many says he was sitting down eating his lunch, five years later, 1943 I think he even said he had a cucumber sandwich or something like that. Anyway, he was sitting there thinking and pharmacology department had told him that LSD did not look very promising in their models, they had mostly mouse models where they give the drug to a mouse and see what happened. So he thought, you know, maybe they miss something. So he synthesized another sample with the idea, he would send it back down to the pharmacology department. And in industry, if you make a compound and the pharmacologist evaluate it, and they don't find anything interesting, and they tell you, this is an interesting, it's very rare that you would make another sample and go back and tell it pharmacologist, you know, I think I screwed something up. You must have missed something. Once you do this, again, he said he had was translated from German and peculiar presentiment. So like he had a gut feeling basically, that they had missed something. Well, he didn't even get to send it down to pharmacology department, because somehow in preparation of the sample on a Friday, in April 1943, to 16th of April,

he started having visions, seeing kaleidoscopic patterns, feeling very strange, went home early from work, and tried to think about what he had worked with, that might have caused that the only new chemical he worked with versus LSD 25 was the 25th. In the series of compounds he made, I don't know how many made maybe 80 or so. So he went back on Monday, and took me took an amount of weight and put into a solution so that he took 250 micrograms. Thinking that this would be an amount that really wouldn't have any effect, because it was such a tiny amount. 1/4 of a milligram. But, of course, 250 micrograms is a pretty hefty dose for most people. So that was the point at which he said, Okay, it's the LSD. And then he gave it to colleagues, they didn't they didn't believe him, the head of research didn't believe me. So there's nothing that potent. So they tried it, they would they didn't want to take 250 micrograms. So they took 80 micrograms. But that was still enough of a dose for them to realize, you know, this is this is what it is. So chemically, there are four rings fused together, it's sensitive to light to ultraviolet light, if you take a solution of LSD, and put it in a window where there's sunlight, it'll destroy it all in about an hour. So it is what it is a very sensitive molecule sensitive to light heat and acid conditions. But no, does it cover enough of it?

Nick Jikomes 13:43

Yes. So to summarize some of that, basically LSD, the the molecule, it is bigger and more complex than other psychedelics like psilocybin say, Yes, it's very potent. What is Why is it so potent and long lasting?

David Nichols 14:01

Well, we're not really sure. But when we published the crystal structure of LSD, in the serotonin to be receptor in 2017, Brian Roth is the lab director. And so we published this structure we had known from when I was still at Purdue before I retired, that there's a piece of the receptor so this receptor threads back and forth, in the neuronal membrane, inside outside, inside outside, there are seven Hela C's packed together. And so obviously, if you have something coming up and it goes back down, there's a loop between that so there's a piece of receptor protein that hooks the top of helix four to the top of helix five and it has a residue there a leucine residue, which is a hydrophobic amino acid is leucine 229 is in that loop. And we had shown previously that we thought that was important residue for binding When you when you use a computer to dock LSD and the receptor, the de F amid was projecting up toward the extracellular part of the receptor for that extra layer loop was. So it turns out that if you do that receptor kinetics with LSD in the receptor that's got that leucine to 29. It takes several hours for LSD to cooperate with the receptor. And it takes even longer for it to come back out of the receptor. So if you have a receptor preparation, typically it would be like a cellular preparation and as the serotonin to a receptor, expressed in you incubated with tritium labeled radioactive LSD. And then you can take aliquot out and you can determine how much is in the receptor, how much is in the solution. So it takes three hours or so at 37 degrees Celsius, to equilibrate. And then if you wash off the receptor and put fresh buffer with no radioactive LSD and, and then take aliquot out, you can see it coming back out of the receptor, and it takes six to eight hours to come back out of the receptor. So what do we did, we were pretty sure that leucine 229 was important. So we mutated the receptor, we made immune receptor, we converted that leucine 229 into an alanine. alanine is just a very small amino acid with a single methyl group. And when you we did that LSD got into the receptor very fast, came back out very fast. So what we think is that that the fact that LSD gets essentially trapped in receptor by this loop gets trapped in a receptor, we think that's what holds it in there. And if you think about blood, having LSD and and circulating past those receptors, a little bit gets in the receptor every time the blood goes by, so slowly accumulates in the receptor. And then, once the LSD is cleared from your blood, then the LSD has a lot of trouble coming back out. So it has to do with actually the shape of the receptor. And the fact that once LSD gets in there, the receptor kind of locks it into traps and inside. So we think that's part of the explanation as to why it's so potent and long lasting.

Nick Jikomes 17:11

And my understanding is you've actually created and work with LSD analogues, and some of them are very commonly used in experimental settings that are actually even more potent. I think one of them is DOI what so what does that compound

David Nichols 17:24

but DUI is a it's actually a substituted amphetamine more related to mescaline. Among among the LSD analogues, we made a compound called LS Z, which showed up as a recreational, chemical or research chemical, where we change the diaphragm and part of LSD into a four membered ring with two methyl groups onto so it's kind of a locked diaphragm. And that's about as potent as LSD. And then we also LSD has an a methyl group attached to us nitrogen. So we replaced that with an ethyl and an allele. And those compounds are a little more potent than LSD itself. We haven't published much on the EFA compound. But it turns out that the fo compound is actually a better stimulator the serotonin to a receptor than then is LSD. Well, if you go to end so if you go to Arrowood there accounts there are people who have taken F lead, which is what we call it, our lead was the Elio and LSC. Those are those got out his research chemicals and people took him so there are reports of those on airway and

Nick Jikomes 18:32

what is airway? Can you explain that for people

David Nichols 18:36

that was a site set up by a couple called Earth they call themselves Earth and fire air with that's obviously not the real name, but that's what everyone calls them Earth and fire. And so it's an it's a digital source where people put the their drug experiences, so you can go and look, they're called the air with volts, singer, the air with volts. And you can find all kinds of self reports of people who have taken various kinds of drugs and posted them on Arrowood. So it's, you know, they're they're anecdotal reports. But still, when there's no scientific data on these, you can go and say, well, this compound looks interesting, or this compound wasn't terrible compound or whatever.

Nick Jikomes 19:21

It's a very interesting website. It's very much in the spirit, I think of Alexander Shogun. Could you explain for people who Alexander Shogun was and what your relationship with him was?

David Nichols 19:32

So Alexander, or Sasha Shogun, which is what a lot of his friends called him. He was a biochemist, who did his PhD in natural products chemistry, and then went to work for Dow Chemical. And then he parted ways with Dow Chemical. And they're very stories about why why and how that happened, but he was an only child and and his parents left him the house that they they lived in when they passed. Because it the farm in Berkeley is actually Walnut Creek, California. So there was an old barn behind that house that burned down in the barn had a concrete block foundation. So he put a roof on top of it and converted into a chemical synthesis lab. So he worked there from the late 60s Up until he passed away, I don't remember when it was, it's been five or six years ago, maybe. And he was he would make compounds in the lab and test them on himself, he would start at low doses and then increase the doses. And then if it had any kind of a psychedelic effect, or anything that he thought was interesting, he would give it to his wife and, and she would take it in, he knew sort of knew their sensitivity through these things. And then if she thought it was an interesting compound, he had a group of friends who lived in the area, and they would get together occasionally, and he would those small up with his new molecule he'd made. So he has two books, one is called Pico, pH K, which stands for phenethylamines, I've known and loved and another one called Te Ka th, Al tryptamines. I've known and look and what they are pico ism, first half of it's a big thick book, the first half of it isn't a sort of autobiography of the two of them. And the second half of the book is a compendium of all the molecules that they made and tested on themselves with in with their friends. So it listed it lists doses that were found to be effective and compounds, the general type of psychological effect that they had. And so those are really peak Caliente collar. It's sort of a summary of his life work making these compounds, and in testing on himself, and then his friends. So it's, it's a useful source. I mean, not not many people would want to do something like that. But it's useful when you're trying to do work. For example, when we were trying to validate by rat models, we could take a compound that he'd made that said, it's active at such and such a dose, we could give that to the rats and see how they respond. So it was a, it was a way to point us in the direction of compounds that were most interesting, I would say

Nick Jikomes 22:28

he's got these two volumes, one of them focus on this class of compounds called phenethylamines. The other one focuses on tryptamines starting with phenethylamines Can you just explain to people what what kind of drug phenethylamine is and what are some of the more well known examples of medicinal, medicinal, interesting phenethylamines

David Nichols 22:49

phenethylamines are the simplest kinds of structures of psychedelics. And probably the prototype in that class is mescaline. I don't know how conversant you're listeners are in chemistry but mescaline has a single aromatic ring or we call it a benzene ring or phenol ring and has three methoxy groups attached to it to CH three attached to an oxygen then attached to the ring there are three of them a three, four and five positions. And then it has a side chain that comes off at what would be the one position so two carbon side chain two carbons with an NH two and amino group on the very end. So mescaline is produced naturally by the peyote cactus and other southern South America cacti, where people have cut those cacti up and boil them and use them for for a psychedelic effect. Peyote is used by the Native American churches, their sacraments and they have protection of the Constitution to use peyote. So they'll have ceremonies for wedding some celebrations of life. They'll get together roadmap leave, this will lead the ceremony and they will pass around and they will chew peyote buttons are a tea that's been made from peyote buttons. Pay it's the pity buttons or the cut off tops of the cactus. So they'll take those so that's the simplest molecule in the phenethylamines. And it's dose as a hydrochloride as sulfate salt would be between 250 Maybe 350 milligrams. It's probably the least potent of the psychedelics, but you can modify it and the reason Sasha I did so much work on it. It's very easy to modify. So we could change the positions of the methoxy groups on the aromatic ring on the benzene ring. We can add we can add another carbon to the side chain and alpha methyl make it like an amphetamine so it didn't break down very easily. And you can get some comments pens that are quite potent, so, doi that you mentioned earlier on the aromatic ring whereas mescaline is a three, four or five trying methoxy. doi is a two five done methoxy with an iron inanimate, the four position and it's quite potent whereas mescaline 250 to 350 milligrams, a DOI would be in the order of a couple, or two or three milligrams to have a similar kind of effect. Most of the phenethylamines are probably not as Sasha would have called them sparkly as mescaline. mescaline has produces a lot of visuals and a lot of interesting. Visual visual, so I hesitate to call hallucinations but visual abstractions and colorful patterns that would would go in tune with the music if you were listening to record or something like that. Some of the more potent ones don't really do that they they produce a CNS effect. They stimulate you to keep you awake and have some psychedelic effect, but they're not as dramatic in terms of their effects as something like mescaline.

Nick Jikomes 26:12

What about MDMA does MDMA fall into this general class?

David Nichols 26:16

MDMA is a phenethylamine. We could call it a substitute Amphetamine is three, four methylene Doxie methamphetamine. So in the aromatic ring instead of three meth oxys, like mescaline, you get two oxygens hooked together with a ch two and that's called a methylene deoxy in the three four positions. And then it's got an alpha methyl and sidechain like an amphetamine and it also has an N methyl attached to the nitrogen. And the N methyl destroys. For the most part, it's an actual psychedelic activity in play in terms of classical psychedelics. Classical psychedelics work by stimulating and activating a type of brain receptor called the serotonin to a receptor. MDMA works differently. It works more like amphetamine or methamphetamine in that. You have monoamine transporters and the presynaptic terminals of your brain neurons. And when they release a transmitter like serotonin or norepinephrine, you have transporters that clear the synapse and pump it neurochemical back into the presynaptic neuron. So it recycles so can be used again. So MDMA works by causing the release of serotonin, norepinephrine and dopamine. So it's a monoamine releaser, rather than a direct stimulate other receptor, like classical psychedelics like LSD, or psilocybin or mescaline would

Nick Jikomes 27:42

be I see. Now, can you talk a little bit about what is actually scientifically known about, say, the neurotoxicity of MDMA?

David Nichols 27:54

So if you give very large doses of MDMA to rats, what happens is if you look at them, and they have to be fairly large doses, and usually they're repeated. If you look at the brains and analyze the brains of those rats, for neurochemical content, what you find out is that serotonin levels are depleted. It's been shown that the presynaptic serotonin terminals are destroyed in those experiments. It's not clear exactly how that happens. We did a lot of work looking at the so called neurotoxicity. And MDMA releases serotonin, dopamine and norepinephrine. Serotonin is not replenished as easily as dopamine and norepinephrine. Ah. So the studies that we did suggested that MDMA was very potent in releasing serotonin from serotonin neurons, but also and the serotonin just diffused away, but also it produced a lot of dopamine in the brains of rats. And the dopamine is actually a substrate for the serotonin transporter. So you get the serotonin neuron releases all the serotonin and it's pretty much empty and then, and then you have dopamine floats by and the serotonin transporter pulls the dopamine inside the serotonin neuron. And actually, as your body temperature increases, we publish one experiment that showed that the serotonin transporter actually prefers to pump dopamine hit body temperature goes up. So if you have people that are dancing and overheating, their serotonin terminals prefer to pump dopamine and dopamine is a fairly toxic neuro chemical. And in dopamine neurons, there are a number of components that prevent the dopamine from destroying the dopamine neurons, ascorbic acid and superoxide dismutase There are three different enzymes in there that will break the dopamine down and prevent it from killing the neuron. But when it gets into the serotonin neurons, there are no none of those protective mechanisms protect against the toxicity of dopamine. So that's what we proposed is that the dopamine was pumped into serotonin neurons, where it caused damage to the neurons through pre radicals that were formed. And that would be compatible with the fact that you don't see the cell bodies destroyed by the MDMA, you see, the neuron terminals destroyed, and it kind of burns back from there toward the cell body, but doesn't kill the cell bodies. But in the rats, you don't really see any sequelae to that. In humans, in humans who have used large and repetitive doses. There, there are some indications that they may have some deficits in their memory. But it's not really clear, in general, my opinion, and I think most of people who are using MDMA for therapy feel like, you know, one or two treatments with MDMA over a period of months or years is not going to cause that kind of toxicity. You really have to hammer people with large doses in hot spaces and dancing and repeatedly taking it. So it's really abuse of MDMA that would lead to toxic effects.

Nick Jikomes 31:22

So this other volume that Shogun wrote, tea call is all about tryptamines. And so tryptamines include other psychedelics that people are familiar with, can you just describe at the level of the chemistry what the difference between a tryptamine and a phenethylamine is.

David Nichols 31:38

So in all of these compounds, you essentially have an aromatic system, two carbons removed from a nitrogen so in mescaline you have a 345 trauma, Flexi benzene, and a two carbon piece with a nitrogen, a tryptamine, has a two as a two ring fused system called an endo as a six membered ring fuse to five membered nitrogen containing green. And it's the basis for serotonin, for example, it also then has a two carbon piece attached to a nitrogen. And for most of the tryptamines psilocin DMT. The nitrogen has two methyl groups on it. So with mescaline, you just have NH two, it's just a single primary mean, with most of the tryptamines. And that wouldn't good LSE, actually, which is a special case of a tryptamine. You have two alkyl groups attached to it. So it's a tertiary amine. But they still have this aromatic system, two carbons away from a basic nitrogen. And that's kind of the template for all the things interactive monoamine receptors.

Nick Jikomes 32:44

I did want to ask you about DMT I think it was correct me if I'm wrong, but I think it was you and maybe Charles who wrote some kind of review paper, looking at DMT facts and myths. And DMT is super interesting at the level of the chemistry at the level of the effects. But it also seems to be one where many myths or sort of half truths have permeated throughout the internet. And so can you just give people a short background of DMT, the basics of DMT what it is and what we know about it? And I do have a few questions that I wanted to ask you that I see people saying a lot online.

David Nichols 33:24

So I was invited to a breakin convention meeting, and I think it was 2017. And they came contacted me and he said we were going to have a session on DMT as a neurotransmitter. And I said why don't believe it is so you don't want me? So no, that's why we put you there because the other people gonna say yes, then we want your opinion. So I gave the talk. And I had a lot of colleagues afterward come up and say, You should publish that because this is out of control. Everybody's talking about DMT Strassman had made a suggestion, I think that DMT might be produced by the pineal gland when people were born and when they died. So I wrote a paper which was published, peer reviewed. And I said, this is just really not possible. The pineal gland is 180 milligrams. To get in that intoxication with DMT, you need to produce about 25 milligrams, and this night, it's just not possible. And that's not its principal, its principal function is produce melatonin, which regulates the diurnal cycle, and it doesn't make that much melatonin. So there, this idea that there's an endogenous psychedelic, has really stirred up a lot of people's passions. Oh, yeah. It's it's a psychedelic quite as a human body make it why is it there? Well, turns out DMT is made by lots of things, including lots of plants. And it's a component of the cerebral spinal fluid in lots of mammalian species. I think it just air because there's an enzyme methylated and it's a byproduct. But they've come back and there was another paper by Dean. And now in 2019, which you may be referring to my son, I wrote a response to that and said, you know, this is just crazy thinking. But it's such a popular meme, you know, this DMT is a really powerful substance. Well, it's powerful in the sense of what it does when you smoke, or given intravenous amount. But the amount it takes to do that is fairly substantial. And there's no evidence, you know, and they've gone in with, they've looked at micro dialysis in brains of rats, and they can detect trace amounts of DMT. And they can detect lots of things. But they're, that's what they're looking for. It's, you know, they're convinced that DMT is doing something. And so they're trying to prove how it's there and why it's there. And when it's doing, I just don't, I just don't think it is, from a pharmacology point of view, biochemical point of view. There's no reason why it should be produced there. And it's not produced in sufficient amounts. So then people say, Well, you know, what about the lungs is one of the the methylation enzymes is a Hindle amine and methyl transferase sign and T, say, Well, there's a bunch of that in lungs, why isn't produced in lungs, what's what's what was its function being you know, we're not listening all the time. Hello, but when we die, or when we have a near death experience, and I pointed out you don't need to invoke DMT because when you have a lot of stress, you have this whole endorphin system, you have endorphin itself, which activates kappa receptors, Cap receptors in the same receptors and Salvadoran accent. And I said, you and even in the papers, or they talked about killing these rats, by suffocation and looking at the production of these compounds. When you're stressed, all kinds of things are produced, it's a whole soup of neuro chemicals, or, you know, you're killing the animal, and everything's going awry. So you're gonna pick DMT out when you get all these other things. And endorphins are much more potent than DMT, you know that endorphins produce psychoactive effects and people. So there's just in my opinion, there's just no reason to really look at it other than it's kind of a cute hypothesis. It but you know, plants don't hallucinate plants produce it. So I just think it's a, I just think it's a metabolic byproduct.

Nick Jikomes 37:23

So to summarize, there's no known physiological function of DMT. In the mammalian nervous system in the mammalian body, it's probably not produced at physiologically relevant levels. And the only time that they've seen sort of elevated levels was in the study that we're referring to by Strassman others, but the elevated levels of DMT they found those but everything was sort of elevated, because that's just what happens when you kill an animal like that.

David Nichols 37:54

They they said it's a brainstorm of neuro chemicals. So it's everything has been with serotonin, dopamine, everything's been released. So why why pick out DMT? Because, you know, it's activating a serotonin receptor, if you have massive, massive serotonin produced, why would it select a tiny amount of DMT to produce an effect when it's being flooded with serotonin? So it just doesn't seem logical to me, there are people that argue with me because they, you know, they're committed to the belief that DMT is there. It's important, but I just don't think it is there's no evidence for it.

Nick Jikomes 38:29

Is there anything interesting about DMT? Medicinal that's known as there any interesting potential there?

David Nichols 38:37

There are some studies I think David Olson did the person's showing when he gave DMT to rats, or mice, I can't remember what it was that it stimulated. synaptogenesis stimulated neurite outgrowth. So there are I know, there are companies now that are 600 companies now trying to make money on psychedelics that are looking at DMT as a possible antidepressant. I don't know, you know, how they're going to do it, whether it's going to be by injection or what but I mean, there's some evidence that all these psychedelics have some effect on synaptogenesis under either Genesis DMT apparently does that it's very short acting. So from a clinical perspective, I guess you could argue that if you were going to treat people for depression, and it worked, you could put them in there and you could give them some intravenous DMT. And the effect would last 15 or 20 minutes, and then it would be over. So you wouldn't have to spend hours and hours and hours like you would with LSD or mescaline. So, I think it may have some therapeutic value, but it's an it's a weird compound.

Nick Jikomes 39:49

Now somewhat related, so so there's this big push to create psychedelic or psychedelic derived medicines right now. A lot of it has to do with the potential for Treating neuropsychiatric disorders that we have struggled to treat new ways for a while, including depression. And there does seem to be this common thread of you know, psilocybin and other compounds are inducing synaptogenesis, spine agenesis, that increased level of plasticity plausibly has something to do with the enhanced efficacy of say therapy that goes, that goes along with that plasticity that helps treat the condition. But, you know, as you mentioned, for something like psilocybin or LSD, or DMT, there's the hallucinogenic effects for something like psilocybin or LSD, those are gonna last for hours. And so clinically, it's it's sort of difficult to work with those compounds in that way, just because you have the hallucination, hallucinogenic effects, and you have to be committed to this hours long event that you're going to participate in. So DMT is interesting, because it's short acting in that way. But there's a big push to create non hallucinogenic psychedelics. Now. Can you comment on whether you think that's plausible? Has anyone created such a compound yet? That's interesting. And is there any reason to believe that the actual psychedelic component of these experiences might be important for something like severe depression, say?

David Nichols 41:17

So my thought on, there's been a lot of debate about whether or not you need the mystical, transcendent experience. If you if you look at the stuff that Robin card, or card Harris has published about brain dynamics and resetting brain dynamics, I think that the psychedelic effects are a biomarker, if you will, or behavioral outcome of the reset mechanism that's taking place. So how can you increase global communications in the brain and reset your brain networks without having some kind of behavioral output. So I don't think that the secondary effects, per se, are what produces a change, but they're a marker of the underlying biochemistry, that's leading to the change. So that's kind of the way I see that. And so from that point of view, I don't know if you can, you know, obviously, if you came up with something that worked like an SSRI, a standard ated, depressant, those have some antidepressant effects. It may well be that if you think of all the people who suffer from depression, that you could give him a pill. Or maybe it would cure him of depression. But I think when you start talking about some other indications, you know, end of life, that people are treated with psychedelics, at end of life, they have a whole process where they go through mentally, and look at their life and what they've done and their relationships with their siblings and significant others. And I think that's part of the process of them coming to grips with the fact that they're dying. And I just don't think you can give those people a pill. And that will have the same effect. I think the same thing is true for addictions, alcohol or substance use disorders, that people that have those they'll look at when they started abusing, when did they start their addiction? What's kept him from what's kept him doing it, we know where their family things have happened, where their family events, bad marriages, what, and I think there's a need to to really cogitate and look at that. And that to some extent is what happens in the integration phase after the drug has worn off, where then you go back and most people that are doing this therapy feel like the integration phase is very important to tie those ends back together. So, you know, in some cases, you know, there's a story, there was a case report by Brandenburg Vanguard, Scandinavian psychiatrists years ago, a person who had severe obsessive compulsive disorder to the extent that he became completely disabled, he couldn't go to work anymore, he get up in the morning, he would spend four hours washing his hands and if somebody flushed the toilet, you have to go wash his hands, this extreme fear of contamination. And this was a 10 year follow up this person was given LSD think once a month for 15 months, without any therapy at all. And completely recovered. His these people said he had a better personality after that he never had before, was poor, went back to his job was promoted. So this was a 10 year follow up and they said, you know, we did no therapy, this guy completely was healed by you know, periodic doses of LSD. So there's a case where he didn't really need therapy, but it was, you know, years worth of whatever he was, you know, going through his mind without what's happening. So I think it kind of depends, you know, with MDMA, which is not a classical psychedelic, you're talking about people who've been traumatized, either physical violence or rape or things like that, or wartime trauma, and the in that case, You really don't, the person really isn't isolated, you talk to the person, the idea is to get them to separate the memory of the event from the effect of components so they could see it, but it doesn't come into their lives like it like it does before the treatment. And there's where, you know, you just can't get a pill and make that happen that requires some verbal therapy. So I think it depends, I think there are cases here, maybe an endogenous depression, where they use a Prozac or an SSRI. Now, it may be that you could have a pill that would do that without any psychedelic effects. I'm not sure what the mechanism of action would be. But I don't know if you can stimulate that receptor without producing psychedelic effects because of where it is and the importance of its function.

Nick Jikomes 45:44

Okay, so it's fair to say that, we don't know if you could create such a drug, but you would not bank on it.

David Nichols 45:51

I wouldn't invest a lot of money in a company trying to do that. Yeah, maybe you know, and there's a company trying to do that, but they may be able to come up with something that's an antidepressant for endogenous depression. But I don't think it's going to have the, the widespread value of treating other substance use disorder and end of life and things like that. I don't, I don't think it would have the value that a psychedelic has all the all the mainstream medical people, me, I mean, they're saying how, you know, nobody wants to have hallucinations. So we got to cut the period short, and make it so they come in and come back out really quickly. And they don't spend a lot of time there. But if you talk to people that are given a psychedelic, in most cases, I found that very rewarding experience. I'm not sure you really want to say, well, this is an important, make the assumption that people don't want to have that experience. I think many people want to have that experience.

Nick Jikomes 46:49

Yeah, I talked to a man named John cost accomplice on the podcast who did three doses of psilocybin to treat severe alcoholism. And he said, literally, after the first dose, he had never had a drink again, after six years. But when he describes it, it's very clear that, you know, he was rewarded by the bit when he describes the visions he had, it was clear that they were meaningful. And they were part of that process, when he describes the integration, the whole thing, like there's no way that he would have elected to give that component up.

David Nichols 47:19

And I think that's true. I mean, especially if you're talking to people, and in life cancer patients, I mean, they haven't experienced that, that gives them a new perspective, they lose their fear of death. And that's one of the oldest those studies of cancer patients go back into the 1960s. In Springboro. Hospital, there's no reason there's no way those people would give that experience up. So I think people that say, Well, you know, there's a big need for compounds that don't produce that experience. I would temper that argument by saying, I'm not sure that's really true. There may be like I said, endogenous depression, where people would just take a pill, and maybe it better like, you know, what we have now, but in these other situations with addiction and end of life and some of these other things, I think that that the integration and the perspective that the game, under the influence of like substance is important to the overall therapy.

Nick Jikomes 48:15

What is your general take on the phenomenon of micro dosing psychedelics, that's become very popular people, you know, on the one hand, you can take a dose that's low enough that you can still feel it, it's still doing something even though it's not a full hallucinatory experience. On the other hand, you know, when I, you know, this has become very trendy, and it almost seems like it's flirting with homeopathy at some point where people are bragging about how low of a dose they're taking, do you think it's plausible that you could take a reasonably low dose of something like psilocybin say, and you're not going to have full blown hallucinations, but there is some sort of potential efficacy there for for something.

David Nichols 48:53

So we have not seen a randomized controlled trial to prove that micro dosing does anything. LSD gets into the receptor and stays there for a long time, I could believe that maybe 20 to 25 micrograms of LSD might have a physiological effect, low doses of psilocybin, it doesn't get caught in a receptor, like that. So I, I'm, frankly, antagonistic to the concept that that does anything. It certainly has become a powerful meme. And everybody's talking about it. And just but, you know, it's there's, you know, the placebo effect is really powerful. And I think for most of these is probably a placebo effect. You think it's going to do something so it does something by micro dosing mushrooms, I feel so much better now. Well, is there a way to verify that? So until somebody actually runs a trial that's controlled randomized, placebo controlled? I'm going to withhold my judgment

Nick Jikomes 49:59

I spoke with Brian Roth one of one of my early episodes on the podcast. And I believe you mentioned that. So technically, you've retired from from your lab. But now you're in his lab actually doing still doing research. Is that accurate?

David Nichols 50:13

Right, I've done some research there. And then I still, I go join his group meetings, and have comments from time to time. I'm waiting on some chemicals to come in to finish the last project. And they've been ordered backordered forever. But I was more active for a while. But now as time is going on, I mean, I, I retired in 2012. And I've been going into Brian's lab for Well, seven or eight years, that's longer than took me to do my PhD and postdoc put together. So it's like, I want to write some books. I had a chance to write books. But yeah, I haven't I haven't completely withdrawn from the field entirely. What, what do you want to write about? Well, I, someone told me, I should write my memoirs. And I thought, No, nobody's gonna be interested. And then my oldest son said, yeah, people would be interested to hear about you. So maybe, I have years of correspondence with Sasha Shogun. And I thought of a book called Conversations with Sacha where I pulled out a little nuggets from our correspondents. And then I have a science fiction book that I'm, I have the idea for that I'm

Nick Jikomes 51:21

working on. Interesting, interesting. What, what do you think is most exciting right now in the research world with respect to psychedelics for you personally,

David Nichols 51:32

I think, in general, structural biology, the strides that they've made now, and being able to identify, you know, active and active and inactive receptors, Brad Ross lab is, he is, like I said, How many structures you'd have you haven't published, I asked him this a couple weeks ago, he said, I think we have about 30. So he has active and inactive structures and structures, he's doing a whole big project now on looking at different psychedelics, looking at which receptors they bind to, and don't bind to, to, for the first time establish a big library of data for what these compounds do, I think they activate the serotonin to a receptor that may be necessary, but maybe not sufficient. I don't know, there hasn't been a psychedelic that lacks, for example, all the psychedelics activate the serotonin, to a and to C receptors, to a certain extent to B, B to C, and to C receptors, and we activate and functionally, they oppose the activation of serotonin to a receptors. So what happens if you make a selective, highly selective serotonin to a receptor ligand that doesn't activate the to see receptor, so it may be possible to come up with better therapeutics that are more specific for just activating the serotonin to a receptor. So the idea of that, and also looking at some of these structures, which largely have not been published yet, that bias lab is working on seeing, like, why this compound is active? And this one isn't? What's the difference in the way they change the shape of the receptor? The FMO lecker level, I think, is a really exciting stuff.

Nick Jikomes 53:15

Is that potentially what you just mentioned about activating multiple receptors simultaneously? Could you imagine that say the difference between the effects of DMT and psilocybin might be because we know one has slightly higher or lower affinity for the to see receptor or something like that? How, how would you generally think about the difference in the effects for these things, even though they're all to a receptor agonists?

David Nichols 53:39

It could be I would, I would tend to focus a bit on the serotonin one a receptor. If you do animal studies with five methoxy DMT, quote, unquote, Tobin, the effect is primarily mediated in rodents through activation, etc, one a receptor. So all the tryptamines activate the one a receptor, but the phenethylamines don't. So no one is really dissected out and said, you know, to what extent is the one a receptor important for the psychopharmacology of the tryptamines, that's something that hasn't been really teased out yet. And I think would be interesting. Those, if you look at what these the targets that they hit, it's really to A to C, a little to B sometimes, and for tryptamines, and one a. But right now, in the lab, they're screening these receptors where they have relatively low affinity. If you look at mescaline, mescaline doesn't have very high affinity for the serotonin to a receptor, but doses 300 milligrams essentially. So it takes a lot when you get a dose that large, there may well be some other receptors that are involved that nobody has really looked at before. A mescaline is unique in that respect. So there's still still a bit to be done. You know, actually quite a bit but

Nick Jikomes 55:00

Just in the last few minutes we have, do you have any final thoughts you want to leave people with about psychedelic research in general.

David Nichols 55:09

Um, I think with respect to psychedelic research, the big thing that sticks in everybody's mind is the fact that this research we're doing now has been stalled for about 50 years, because of the drug war, which was never really legitimate to begin from. According to John Ehrlichman, it was to keep people from voting. And the fact that these might be breakthrough therapies for depression, anxiety, end of life distress, and alcohol and substance use disorders, we probably could have had these, we wouldn't have as much information about the underlying mechanisms like the brain dynamics and brain entropy for the robin, or Harris has been talking about, we might not have the mechanistic stuff, but this could have been used in the 60s. I mean, they were using LSD to treat cancer patients in the 60s, and then everything just got shut down. This is just an example of how damaging politics can be when it gets involved in legitimate scientific research. So that's a message that everyone should realize, and and people are still, even today, they're afraid of psychedelics, because of all the stuff they've heard in the past, but it'll liquefy your spinal cord, and it'll cause mutations and your babies will be mutated. A lot of people still have those ideas, especially the older generation, people, my age, unfortunately, are not really up on what these things actually do and what they could be for. So I think in the next couple years, it's going to be interesting to watch the sociological and cultural aspects of this play up.

Nick Jikomes 56:57

Do you think there's any risk that we have some kind of backlash, just with the prominence culturally that psychedelics are, are coming back to and the level of popularity and the level of interest that there is just generally speaking? Yeah, I

David Nichols 57:12

think there is That danger. I mean, in the 60s, according to John Ehrlichman, it was all the hippies smoking marijuana and using LSD. And according to Ehrlichman, they knew they couldn't keep them from using the drugs, but they could keep them from voting by arresting him for using drugs, and then they would have the felony conviction, and they wouldn't be able to vote. So they were a they were anti establishment. So the original basis for, you know, the illegality, the drug war was because they were anti establishment. I mean, even marijuana with the marijuana tax act in 1937, under Harry Anslinger. That was, that was Congress's sold a bill of goods on that, by being told that Mexican laborers are coming across the border with marijuana given to white women and raping them and killing them. You know, it's like, Oh, my God, everybody's freaking out. We can't have this. So the politics need to be taken out of it. Fortunately, it's being taken out. But we still worry about, you know, decriminalization in in Oregon. So I support decriminalization, I told people that I don't think if you're in your house using a psychedelic in a sacramental spiritual way, the police don't have any right to come in and arrest you for using a psychedelic. But I don't think they should be available over the counter. They're not benign, they can damage some people. So this whole thing has to get sorted out. And we're not there yet. But I think we're moving in a positive direction. I know. The fact that so many scientists and medical institutions are doing the research, I think is is going to prevent it from becoming too crazy. Like we saw in the 60s where it was just everybody was taken, there was no controls. So

Nick Jikomes 59:07

Well, Professor Nichols, thank you for your time and your knowledge and for what it's worth. If you ever get around to publishing those letters with Sacha, I'll definitely buy a copy.

David Nichols 59:15

I think a lot of people want copies of that. So I just have to find the time

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