LSD & Psychedelic Chemistry – Mushroom Revival

LSD & Psychedelic Chemistry

Lysergic acid diethylamide (LSD) is one of fungi’s most well known chemical analogues. Today we bring you a leading scientist, Dr. David Nichols who speaks to the history, chemistry, legality and so much more of this notable compound. 

 Topics covered:

  • David Nichol’s career pursuing psychedelic pharmacology
  • Patent litigation, especially with psychedelic constituents 
  • Lab testing for new psychedelic analogues in rats
  • Bureaucracy of working with Schedule I substances
  • How to synthesize LSD
  • LSD’s physical characteristics, structure and fluorescence
  • What happens to the LSD molecule when you adjust minute aspects, and what that tells us about itself
  • Structural similarities and differences in an array of psychedelic molecules / chemical ‘templates’ for psychoactive compounds
  • Neuro-mechanics of LSD and other entheogenic compounds
  • Evolution and function of serotonin receptors
  • HPPD: Hallucinogen Persisting Perception Disorder
  • Trepanation: how does it affect neurochemistry, if at all?
  • NBOMes (N-benzyl methoxy): What is it and how does it work?
  • Metabolizing LSD and related compounds
  • Chirality in psychedelics, especially LSD
  • Listener questions

 

Show notes:

Hamilton’s Pharmacopeia feat. Dr. Nichols: https://www.youtube.com/watch?v=7N4VoqeuK3s

Hallucinogens (2004) : https://pubmed.ncbi.nlm.nih.gov/14761703/

DEA 222 - https://dehs.umn.edu/using-dea-form-222-order-controlled-substances

Mapping the Mind Talk: https://www.youtube.com/watch?v=6hfsIbib_50

MAPS Talk: https://www.youtube.com/watch?v=TxjCSKMbZBA

Telluride Keynote presentation: https://www.youtube.com/watch?v=RlDCM5JQzRk

Leo Perutz & the Mystery of St Peter’s Snow: https://www.tandfonline.com/doi/abs/10.2752/175169713X13589680082172

Trepanation articles & video: https://lostmediawiki.com/Heartbeat_in_the_Brain_(partially_found_Amanda_Fielding_trepanation_documentary;_1970)

Downloadable literature: https://drive.google.com/drive/folders/14N9VdXGFlLvjnShYRH2MRurNi54a77Ig?usp=sharing

 

TRANSCRIPT
Transcribed by https://otter.ai ** Subject to error
Alex 0:00
You're listening to the mushroom revival podcast.

Lera 0:13
So on this week's episode, we are talking about LSD. And for anyone listening who may not know we're covering this molecule on a mycology podcast because it is a daughter compound of a special group of fungi. We talked about this fungi in last week's episode, so feel free to check it out. If you are interested in its ecological roots.

Alex 0:32
We are blessed to have yet again another expert who appeared in Hamilton's pharmacopoeia, who was once the only person in the United States allowed to synthesize LSD and has had a really influential role in psychoactive pharmacology. We bring you Dr. David Nichols. So you're a chemist and would be great to give your bio from your perspective of Who are you what cool things have you done in this life?

David 1:01
Okay, I started out in chemical engineering didn't enjoy the math quit after two years, didn't have much money left at home and community University Cincinnati. I went to University of Cincinnati even college to finish my bs took five and a half years, I worked in the Chemical and Biochemical industry. And since they in the daytime during that, that time, I then went to graduate school in 1969. And stumbled upon a guy there named Charlie barf neck, who had not done anything on psychedelics, which is what I wanted to work on, but hadn't been able to find a way to do that. And he started talking about projects he was working on. And he said something that mescaline metabolites and I said, Oh, really, and we had a lengthy discussion and I had a fellowship, so it didn't cost him anything. So I decided to work for him and spend three and a half years doing work on basically mescaline analogs. We call them psychometrics then then after I finished my PhD work, in almost record time, I went over and did a almost two year postdoctoral fellowship in the department of pharmacology. So I had a background in both chemistry and pharmacology. And then went to Purdue University in 1974, as an assistant professor of medicinal chemistry, and stayed there until I retired in 2012. And then, in the latter part of my career at Purdue, I also was named a professor of pharmacology and actually, when I retired at Purdue, I was a distinguished professor of medicinal chemistry, and also the Robert C and Sharla P. Anderson, distinguished chair in pharmacology. So I had did both chemistry and pharmacology and I started working on psychedelics. Like I said, mescaline and Lux when I started Graduate School in 1969. And I continued, I was funded by the National Institute of Drug Abuse for just about 29 years, and was one of my major projects. I also worked for about 10 years on MDMA, and also worked on some analogs of dopamine for treatment of late stage Parkinson's disease, and cognitive activators in schizophrenia. So I had a broad background. And then I also worked as a consultant and an expert in let patent litigation for a number of pharmaceutical companies. So I had a real broad background from a teaching research, I had a number of graduate students and postdocs that worked in my lab, published a couple of 100 papers, more than half on psychedelics. And so that's sort of a general background.

Lera 3:40
So was mescaline, kind of your introduction to psychedelics? What was your perspective going into that? Were you interested? Or was this just something that you were given to in college?

Alex 3:52
This is a great question, because I was I actually spent the first couple years of my life in Cincinnati and it's not, you know, it's it's a hip city, but it's not like some places in California, you know, in the in the 60s, where it's super progressive, so did you in earlier in your life, did you have an introduction to psychopharmacology? Or was this just happenstance, nothing was happening in Cincinnati?

David 4:16
If you know Cincinnati versus Cincinnati, there was a street code Calhoun street, and there were some sort of head shops that were set up there that made Custom Leather work and bongs and things like that. And Cincinnati was very conservative. And when they realized there was kind of a hippie commune in Calhoun Street, up in or in Clifton Avenue, maybe they shut it down. They declared all the shops were fire hazards, and they shut them all down. So there was nothing really in Cincinnati, not much of a music scene. So it was a really conservative place. And I graduated from high school in 1962. And I had several friends that went away to school, University of Kentucky. And as I said, I lived at home because my parents couldn't afford to send me off. So I lived I lived in only community versus Cincinnati. So they came up and visited on weekends because it was about a one hour drive down to Lexington where the University of Kentucky was. And they would be talking about, you know, reefer and LSD and acid and things that I really didn't know anything about, because the newspapers also didn't cover much on the, in the way of the stories. So they were talking about smoking, reefer and amuri, for what's that marijuana and, and then talking about acid and LSD had just hit the campus. And so I got a book, I use book on pharmacology and started reading, because I was concerned that they were going to get it become addicted. And I got a book on pharmacology. And I started reading about marijuana. And I thought, Oh, this stuff is really pretty benign. It doesn't it's not addictive, and it's been known and it's more of a political thing. And then mescaline was something that was fairly easy to synthesize. And I figured out how to do that, and made some samples of mescaline and I actually had taken one or two doses of that at one point in time, but basically, became very interested in the fact that these substances had such powerful effects on the mind and the way you perceive things. And I thought these would be really interesting to work on. And then I started doing some research in the scientific literature and found some papers published by Alexander t Shogun, from Shogun drive in Lafayette, California. And he had published a paper in 1969 called structure activity relationships of one ring psychotic my medics, and it was a summary of all the work he had done, essentially modifying the structure of mescaline. So I knew that paper kind of chapter and verse and I went to University of Iowa, I didn't go there to work for Charlie barf deck, I went there look for work for Joe cannon, because he had been working on some drugs related after pain, which disrupt consciousness pretty dramatically. That was the closest I could get to the field, no one else seemed to be doing any chemistry that I could find. And so I had a fellowship was called in a National Defense Education Act, title for fellowship. At that time, they were promoting STEM education, science, technology, engineering and math. So I had a basically a free ride and that that came with some money for lab supplies and for your mentor. And so Joe cannon told me that even though we corresponded, I could work for anybody I wanted to work for in the department is a very small department. So there were only two other people to interview besides Joe cannon. And so when I interviewed Charlie Birkbeck, he had students working on try and isolate some oral contraceptives from a plant and had another student who's working on some anti inflammatory substances. And he had this other student who was working on these quote unquote, mescaline, metabolites. And mescaline is really not metabolized. And so he started telling me about each of the projects he had. And he talked about the student who was doing the mescaline metabolites. And I knew everything on the subject. So I was kind of finishing his sentences. So he got kind of excited, and I had a fellowship that wouldn't cost him any money for me to work with him. And plus, he gets some money for office supplies, and so forth. So, unbeknownst to me, he was right there in that little department and was just perfect for me. And so he said, Yeah, you can work for me. And because I'd been putting myself through even college and I had worked in industry in Cincinnati for five and a half years, I was used to being very productive. Because industry, you come in at, you know, eight, and you're done at five. So you have to get all your work packed in. In those hours, you can't stay over, you can't work weekends. So to me, graduate school was kind of a breeze. Imagine I went to school every four nights a week for five and a half years taking a full load and evening college to finish my bachelor's degree, working at the daytime, in the daytime. And plus, I had a baby son that was born in 1967. So I had a family. So that was kind of pretty much of us a struggle to keep, you know, burning the candle at both ends. So go into graduate school to me it was kind of like a vacation. I just had to take a couple of courses in chemistry, which I loved, and do some research, which I also loved. So it was just a breeze for me. I just had a lot of fun. And Charlie barf neck, he realized I had a lot of lab experience. And so he basically just let me kind of craft my own project. I go in and say what do you think about this neat sale? Yeah, it looks like a good idea. And then I would do that. I published a lot of papers as a graduate student and really had a lot of fun. It wasn't much of a stress. It was really kind of much more fun than had the previous financial years had been when I was working all day and going to school all night.

Lera 9:48
Yeah, you seem like a true academic Trailblazer in terms of psychoactive pharmacology. And once upon a time you were the only person legally allowed to synthesize LSD. Can you speak to the legal status of this now? And before you were people, where were people getting this? Were they asking Sandoz or another lab.

David 10:10
So I started graduate school in the fall of 1969. And the Controlled Substances Act of 1970 was passed. And so that made everything illegal. And it was kind of funny, because I had made all these mescaline analogues that Sasha Shogun had reported. And we just had them in a drawer. They weren't locked up or anything because they weren't illegal. But we had to get a little permission slip sign, because the ethanol the ethyl alcohol we used in our research was not taxed, because it was a nonprofit institution. And so we could go down to the stockroom and get ethanol as a solvent to use in our chemic chemical reactions. And we had to get these little cards signed to take down to the stockroom. And I mentioned to Charlie burfict glasses that this is funny, I have to get a card signed by fn o and I have this drawer full of mescaline analogues upstairs my lab to just like sitting there. But in graduate school, I didn't have to worry about it so much when I started at Purdue. By then you had to get that you had to get a controlled substances license. So I had to get a license for everything that I worked with. So mescaline and compound called STP, MDA, and ultimately LSD. So you could get the license to do it. And nobody had really worked on LSD for many years, that mescaline and some of the fnf amines like Sasha Shogun had made were fairly easy to make in the lab and just a couple of chemical steps. To make LSD you had to have lysergic acid. So in the very early years, I wrote to the National Institute on Drug Abuse, and they had a drug supply program. And if you were a licensed researcher, they would donate it to you. And so I got some small amount of lysergic acid in the very beginning, from the drug supply program at nyda. Later on, I got donations of five and 25 grams of lysergic acid from colleague who worked at a company in Italy known as farm Italia. But I was allowed to make it because I had a I had a license to use it. And then we had trained colonies of brats that ultimately we used LSD. And so we made, you know, 100 to 200 milligrams of LSD tartrate. Every year for most of the time, I was at Purdue just because we had these train rats. And they were the model we had to use for how these drugs work. We couldn't obviously put in tested in humans like Sasha Shogun had. So we had rats that were trained to recognize the effects of LSD, we had him in a little, what's called an operant chamber that had two little levers in the front that they could press a left lever and a right lever. And if they pressed a coup, what we call the correct lever, they would get a 15 milligram sucrose pellet, basically, or a little rat candy. And so we could train them, it took two or three months to train them. And if we gave them injections of LSD and train them to press the right lever, and when they got LSD, but press the left lever, when they got to CBOE they got very good, they would press the lever in 15 minutes, maybe 1000 1500 times. And we use that then if we made new analogues that we thought were psychedelics, we would inject the rats and see which lever they selected. And if they selected the lever that they've been trained on with LSD, then they basically were telling us I think it gave me LSD. And that's, you know, that's a pale reflection of what LSD does in humans. But with respect to the potency, the amount of took, there was a nice linear correlation between the potency and our rat models that were trained with LSD, and to human doses. And actually, I published a review in 2004, where I think I put that correlation in there was called hallucinogens. Were there any psychoactive compounds that you couldn't synthesize, or either because of legality or you couldn't get the permit, or it was just too complicated, because there was a mixture of ingredients. And then on the flip side, were there any compounds that you made that you thought, you know, and still to this day, you think could be really beneficial, but we're never really pushed out there and used, so any, we could make pretty much anything we wanted to make. And there were no restrictions because they weren't known compounds. Of course, this was before the controlled substances analog bill that was passed around the mid 80s, when MDMA got really popular. But prior to that, the things that we were making, were really not controlled. The things that Sasha Shogun had made weren't really controlled. Some of them were active, we knew which ones were active. We were basically making molecules and then testing him to see whether they were active or not. And all these molecules would have different three dimensional shapes, you know, flat things and round things and twisted things. So we were trying to understand what the this is before anybody really knew what the receptor was. So we were really trying to probe like, imagine if you have a lock, and you don't have a key for it. But you can cut a whole bunch of different keys and put them in the lock and some of them move. So you can tell some of them move some of the tumblers. And another one will move a different set of tumblers and not yet a third key would move a different set of tumblers. And we do that whole thing you find out, okay, if we cut a key that has these notches in the door will open. So it was kind of that's kind of an analogy of what we were trying to do. And we weren't really focused on therapy much at all until I started working with MDMA. And when MDMA got popular, I didn't think it would ever be possible to make into a drug because it had come from the, you know, illicit drug scene. So my goal there was to come up with something like MDMA that had been developed in an academic lab and potentially could be developed as a medicine. And I worked in that for about 10 years didn't really find much that that was like MDMA. And then I quit that work when it became clear that the only thing that the funding agencies wanted to support was understanding why MDMA might be toxic and why it you know, people died if they took large doses of MDMA and danced all night. And in overheated rooms. I wasn't really interested in that I was interested in the neuro chemistry. So I got out of that after about 10 or 12 years of having funding, because I just didn't, wasn't interested in why MDMA was toxic. But we could make pretty much anything we wanted. In fact, I made MDMA for all the phase one and phase two studies and maps carried out I made the high, you know, high purity MDMA for them, made the DMT Fumarate that Rick strassman used in all of his studies, and made his psilocybin that Roland Griffiths at Johns Hopkins used for his first study, and then for his later study and end of life patients. So the synthesis wasn't a problem, I just had to have a permit for anything I was doing. And to get that permit. With a schedule one controlled substance license, you have to specifically list every chemical that you're going to use. You can't just say I'm going to work with psychedelic, so I had 15 different things on that schedule, LSD and mescaline and dlm. And to Cb 15 different things. And once you had the license, if I was working in a collaboration with someone, I could make it for them. So Rick Doblin and maps didn't have anybody to make it, he had checked the price of getting some high quality MDMA because he wanted to develop it as a drug. And he needed to have a large amount to do animal toxicology studies and some early studies. And so he couldn't, he couldn't afford to make it. So he came to me and said, you know, could you make it? I made two kilograms for the cost of the story materials. And I and my graduate students did it, I think it cost him $4,000. And at a recent meeting, he said, he told me that the cost of one kilogram of GMP, MDMA, which has been certified for human use when one kilogram cost him, so our $100,000 so you know, he got quite a deal. And Rick strassman, the same thing happened, you know, I encouraged him, I'd met him earlier. And I encouraged him to do a clinical study with a psychedelic, and he wondered whether he could do it or not necessarily, I think you can, because you're a psychiatrist and a medical school, you just need credentials, because people told us to and told me, You can't do credit mistakes, government won't let you do it. And I just didn't believe that. You know, I thought you just need to have credentials. And the problem was, there wasn't any grants, right? If you worked in the seal, there was no money to do. And so Rick strassman said to me, you know, what, if I get all the approvals, and I get the protocol, and everything's ready to go, and I can't get the DMT. And I told him, I just made this MDMA for Rick Doblin so I can make DMT for you. And that's what happened. He's written about a little bit about the story of height, hurdles he had to jump through. And then he got ready to do it. And then we made the DMT for that. So I enabled most of those early studies, because there was no other way for a Greg to get MDMA or Rick strassman to get DMT or so even psilocybin in quantity sufficient for clinical studies.

Alex 19:14
Like once, once you make it, do you ship it to them? Do you have to have some sort of, you know, person from the DEA, supervise and look over the transaction actually be there in person? I mean, do you have to make it at their lab or debate? How does that work?

David 19:33
So in order to get a schedule, one license, um, you have to have your laboratory and your storage facilities inspected by the DEA. So I had a two inch thick oak door in my office, and inside I had a safe that in addition to being locked also had a one inch steel bar that went down through some loops that were the further doors and It was locked with a key lock. So there was in plus there was another outer door. That was a reception area where a secretary would sit. So there were two oak doors they had to break through again in my office. And then they would have had to take a cutting torch or a hacksaw to hacks off the hat the bar off of my safe, and then break open the safe. So you had to have a level of security. So that had to be approved. So after I made these substances, I stored them in that safe. And so when somebody wanted it, of course, when I first made MDMA, it was the schedule one. So I sent 250 grams to the laboratory that was doing the preclinical toxicology for maps. And then that turned out to be more than enough, and I still had more than one and a half kilos left, which I kept on my safe for a long time. And I sent it to people, once it became schedule one, there's a form called a DEA 222. And that's the form you use to order and to request samples of schedule one substances. So that form has several, I think, two carbon copies under it, you get a stack of those. And if you want to, if you want to get a schedule one substance from somebody, even from an industry that sells itself as a company that sells LSD, for example, you would have to send them your DEA to to to and that list, your name, your your physical address, and also your DEA schedule and registration number, so there's paperwork to do the transfer. So then you would send you in send a request to them, or they send a request to me, then I would fill it out, then I would send it via courier. So you had to see couldn't send it through the mail, I would send it through a courier and then you had to keep copies of the receipts for those transfers, and then send those to the DEA periodically. So there was a control mechanism to see who had requested it when it was sent where it was sent and who received it. So there there is some paperwork now it's worse now than it was and is it in like a stainless steel briefcase with like a handcuff to is read by I'm just trying to think like a courier like what what does that look like? Well, they basically didn't know what was in those. Um, if you send it FedEx or

Alex 22:13
Oh, it was like FedEx. It was not like a private you just Oh, wow. Crazy. Yeah, I was not expecting that at all. Okay.

David 22:22
Yeah. And of course it they required a signature and, and but DEA would send samples to me, you know, if I requested some from DEA would come by FedEx or one of the other couriers. Wow. So it would just be in a bottle that was sealed with the label and usually packed in with you know, plastic wrap or, you know, this, this plastic, spongy peanuts and sealed up and wrapped and just have a label on it. So nobody really knew what was in there. And in most cases, even if it was diverted, it wouldn't be enough to really create a diversion problem. The DEA is mostly concerned about diversion of controlled substance, somebody getting hold on who doesn't right isn't supposed to happen. So imagine, you know, you have to have a schedule and license to work with mescaline. And the dose of mescaline in humans is the hydrochloride. There, sulfate salt would be 200 to 250 milligrams minimum. If you want to work with 50 milligrams, which might be enough to do a number of rad experiments, you still have to have a storage facility, a schedule one license in a DEA inspection, even to work with non abuse, not you know, non trivial or trivial amounts of compounds. So it wasn't really that big of a problem later on. Base, the DEA is to just read your protocols, and then they would approve it. Then they added another layer they brought the FDA in, because then they would ask the FDA, okay, this person wants to work with LSD, do you approve of what they're doing? So then the FDA would have to look at it and say, this looks okay, or this doesn't look okay. And then they would tell the DEA, so it's kind of a paperwork, hassle. And if you want to work with schedule one substances, it's a hassle because, well, you have to have a safe in new in New York University to have to give safe when they work with silver Simon in their end of life studies. And Steve Ross was telling me, they had it in this big safe that weighed 300 pounds. And they had, I think a total of one gram of something like psilocybin, and the DA guy demanded that they take it out of every day and weigh it in the presence of a witness to assure that none had been taken out, which is kind of just really absurd. Yeah. But and then you had to get you to get the license. They had to get the an inspector facilities inspect where you're keeping it. They had to have your CV, they had usually have a letter from the Dean of your school or department. And then you then you request the license, they send the DEA personnel to inspect your lab and your storage area and everything. And then it can still take like six or eight months before they do anything. And I know, I think when Rick strassman applied for his da schedule one to work with psilocybin. It was like six or eight months, and he hadn't heard anything back. And they'd already expected me to add, plied and everything. And he call and they'd say, Oh, the guy who has to sign is out of the office. Yeah, well let him know your code. And this went on for a while, he finally talked to the, I think the President of University of New Mexico where he was, and they called and said, Look, this investigator wants to do the study, we can't get a signature on this approval, and then it came through pretty quickly. And when I know another person who they came and inspected his facility, and he waited six months or so and called and said, you know, what's going on, he said, Oh, we can't find the paperwork, we need to come out and inspect you again. So it's just, you know, a level of incompetence and interference, that just creates obstacles, and keeps people from wanting to work with these, you know, if you're an academic, and you're doing pharmacology, or chemistry, or say pharmacology, and you're in the lab, and you think, boy, you know, I just had this idea for a really cool experiment, we could get this drug and not necessarily a psychedelic, but it was a schedule one, they say, you know, we could do this study in rats or mice. And this might give us some background, we could write a grant, this would be really interesting. And then you say, oh, but we need to schedule one drug to do this. And you go, huh, well, we can't do that. Because we got to go through the paperwork and get the approval and have the get a safe and the whole rigmarole. So people just, they just don't want to do that. Plus, a lot of places have a fee that you have to pay. If you're a not for profit, public institution, usually doesn't cost you but if you're the private university, there's a fee for I think there's a fee for a couple of $100 every year to re register. So it's, it's a disincentive. If you can't just pick something up and do it. You know, it's like, if you're at home one day, and you go, Ash, let's go, let's go take a ride in the park, you know, and go, let's go rent a canoe and paddle out on the lake, you could just do that. But if you're an academic, and you want to work with a controlled substance, and you think, you know, I wonder what what if you can't do it, because you don't have a scheduling license. And then they want to know exactly what you're going to do. So you're going to treat 10 rats, and you're going to give them a 10th of a milligram per kilogram and the rat weighs 250 grams. So that's for rats per kilo. So you need one milligram, a 10th of a milligram for for rats, and you're when you're 16 rats, so you request, you know, six milligrams of LSD plus 10% over for weighing errors and whatever. And so you know, it's just not, that's just not something you can do. You can't just write to a chemical company, like virtually every other chemical intermediate one, say, hey, I need to get 100 milligrams of this stuff, can you send it to me? So it's a disincentive. So not many people wanted to work in that field. Plus, there was no funding for it. It was zero is kind of the kiss of death. Working in that field, my son's a professor at Louisiana State University. And he wrote his first grant up, and it was all about figuring out how LSD works. And this has been like years ago. And I said, Don't send that granted, because nobody cares. Nobody gives a damn how LSD works. If you want to use LSD as a tool to study something, he might have better luck. And, you know, he didn't really have much luck anyway. But, you know, it was, you know, working on psychedelics, for somebody who was a psychologist, or even a clinician, for a long time was just the kiss of death in your academic career, because you won't get any, you won't get grant money. And if you're an academic, and you don't have grant money, you can't find your research. And if you can't find your research, you'll be you won't get tenure, and you'll be looking for another job in five years. So it's kind of you have to be kind of nutty. I mean, I fortunately, was able to get a grant a few years after I got to Purdue, because nobody else is working on psychedelics. And that allowed me to work in that field, you know, and I just kept doing what I'd done as a graduate student and really didn't think a whole lot about it. And there weren't that many hassles until near the end of my career when they started getting more aggressive with their inspections and, you know, beefed up I guess the DEA, I don't know what the drug war.

Lera 28:58
Well, thanks for alluding to the bureaucratic headaches behind the scenes and for synthesizing all these compounds for people to actually do some clinical trials and works. You're primarily known for synthesizing LSD and I'm curious, as a chemist, the first time that you saw LSD, the structure of it, what kind of thoughts came through your mind did that the shape of it allude to anything that you previously knew if you could just describe the experience you had with like actually seeing it for the first time?

David 29:30
Well, of course, I knew about LSD and I knew about its history. And I knew it was a sensitive molecule. And when we decided to make it, the way you purify it is with a technique called column chromatography. And LSD is highly fluorescent. And so you run it down a column of aluminum oxide, and eluted and you turn all the lights out in the room and you use it, use a long wave UV light, if you shine it sort of in the direction and calm, you see this bright blue fluorescent band, which is LSD, coming off the column, and it takes on a big column, it takes several hours to get to come off the column, you just follow it moving down through this column comes off, and then you start collecting the fluorescent liquid that comes out the bottom, and then stripping off the solvent. And the first time I made it, I made the tartrate solid and gave these really beautiful needles of LSD tartrate. And so it was kind of cool to think you know, that I was able to make it because it was a fairly tricky molecule. And we could go around the lab, if we had made solutions over had prepared it or worked on it. You could turn all the lights out and shine the UV light around the laboratory, and you'd see all these little blue fluorescent spots were made, the drop of the solution had splashed out. So it was kind of fun to work with it. later on. I had graduate students who had made some under Mike my direction, I'd say, okay, we need to make some here's the way and I you know, check to make sure that it was all everything was fine. And I had one student Tell me, you know, I don't know how Albert Hoffman really got high the first time in his lab, because we were kind of sloppy when we made it hoping we'd get some solution on our scanners. And I'll get some inner skin. And I had a couple of students that worked with us DNA said we never could that never happened. Yeah, we don't know how Albert Hoffman did that. Because he was such a careful chemist. So that's, that was kind of funny.

Lera 31:22
Do you think there's some doctrine of signature there? I don't know if you've heard of this term before, but it's basically when something in the real world looks like the thing that has action in the body and LSD just being fluorescent and being this psychoactive chemical. It's it's just kind of a cute coincidence, or maybe there's something to the fluorescence, what can you say about that?

David 31:44
Um, so when I was a graduate student, I made a whole bunch of mescaline analogues. And I made an STP, which was a comment a Sasha had made, and it was in the Haight Ashbury area in 1967. And I was doing thin layer chromatography and illuminating the plates with UV light. And I noticed that the DLM had a really bright kind of pinkish blue fluorescence. And so one, the first paper that actually published was a correlation between the fluorescence intensity of a bunch of these compounds, and human activity. So I made DOB, and do M and mescaline. And it was published. And so at that point, we didn't I mean, I didn't understand why the fluorescence could have anything new with activity, but did notice a correlation between fluorescence and in activity in humans. And LSD is by far much more fluorescent than any compound that I had made. So it made sense to me that that high fluorescence was probably related to the the activity of LSD. And there's a double bond in LSD in one position. And if you reduce it, make 910 die hydro LST. The molecule is essentially rendered inactive. It looks chemically, it looks almost the same as LSD. But it's not active, and it loses its fluorescence. So there's just something unique about LSD that it's there lots of things that Neo quinine is fluorescent, but it's not psychoactive. So I don't know that there's any significance in the psycho activity. But it's just, it's just a peculiarity of the molecule. It is highly fluorescent. In many of the early assays to quantify, you know, the amount that was in the solution or for analytical procedures, they actually measured the fluorescence and the fluorescence intensity of LSD as a method for analysis.

Alex 33:48
So obviously, we're super geeks about fungi. And so we're particularly interested in psilocybin and cillessen and LSD, since they're derived from fungi. And we actually just interviewed Dennis McKenna, and we're talking about how beautiful the compound of psilocybin and stillson were, as, as you know, being so close to serotonin and also DMT. And how it's almost like the perfect entheogen it's ready to go, it's ready to be absorbed. Right? And it's it, you don't have to really synthesize it in a lab, it's ready to go in nature. But, you know, on the same school of thought is they're looking at the compounds of, of any fungal psychedelic compounds compared to those from a plant or, you know, a toad or, you know, totally synthesized in a lab. You know, are there any differences or similarities that you see from the fungal derived compounds.

David 34:58
Well with LSD, so psilocybin five methoxy DMT DMT. They all have a tryptamine core in them. That's a it's a two ring system with a six membered ring fused to a five membered ring and then you have two carbons coming off with a basic nitrogen. And some methyl groups attached a dmts seratonin has a hydroxy and the five position sila psilocybin has a an oxygen at the four position with a phosphate but the phosphate is cleaved off in the body really quickly. So silos and the four hydroxy. So it's a four hydroxy dimethyltryptamine. And serotonin is a five hydroxy tryptamine, it doesn't have the day methyls and booth attendant would have to methyls there so it would be kind of the analog but booth attendant doesn't get into the central nervous system. So far as I know, it doesn't seem to have psycho activity. So the endo core goes all looks the same. But when you go to something like mescaline or the non synthetic compounds, when you go beyond mescaline, it's not clear how those actually bind to the serotonin receptor. You know, you can see LSD psilocin, five methoxy DMT. You could imagine that they bind to the serotonin receptor because they look to some extent, like serotonin, LSD is a big, you know, big rigid tryptamine. But it still has, you know, the elements of what you might call serotonin built into the structure when you go to the phenethylamines. And that's what I spend a lot of time trying to do because there were ideas published early on by some really well known chemists, Salma Snyder, for example, who had said that mescaline bound because it adopted is shaped like serotonin, and chemically It was quite unsound. He got it published and think proceeds the National Academy of Sciences, which I just I saw that that Oh my God, this guy doesn't know any chemistry. And of course, he didn't, he was a good pharmacologist, but didn't know any chemistry. But that was completely wrong. And so I spent a lot of time trying to define was there a molecule you could make based on a mescaline core that look in some way like LSD, and that allowed it to bind. And turns out that just not true, they've just bind in completely different ways. There are, you know, there are residues in the serotonin to a receptor that engage the benzene ring of mescaline and also engaged the endo ring, the tryptamines. And, and you know, there's an there's a residue called and a sportaid in the in the in the receptor that interacts with the basic nitrogen. But beyond that, there's no similarities it really the only overall similarity between all of these would be an aromatic system and in mescaline, it could be one benzene ring, and in the tryptamines, it can be this endonuclease, but an aromatic system, two carbons away from a basic nitrogen atom and that's a template that's carried in most of the biogenic amines net and epinephrine, norepinephrine and dopamine, they have that same motif and aromatic ring two carbons away from basic nitrogen. And so of course, the receptors and those transferees have co evolved to be compatible or complimentary to each other. So that's the only common theme that you would see in those but mescaline or DUI or these other molecules, they just don't have any. You don't bear any superficial resemblance to a trip to Maine or to LSD.

Lera 38:21
This might be a dumb question, but do most or all psychedelics bind to the serotonin receptor?

David 38:21
All of the psychedelics the classic psychedelics that we talked about, activate to a more a greater or lesser extent the sickness a receptor called the serotonin to a receptor. They typically also activate another receptor, the serotonin to see receptor and psilocybin five methoxy DMT and LSD also activate the serotonin one a receptor, LSD interacts with a bunch of receptors, not just serotonin receptors, but also some dopamine receptors and alpha receptors. So, but the common theme is, is activation of serotonin to a receptors. And that's been demonstrated in receptor studies in animal studies and in humans, that if you use a drug that blocks that receptor that binds to the serotonin to a receptor, specifically, then the if you event put a psychedelic in there or you give it to an animal or human, it blocks the effect completely that's been demonstrated humans with both psilocybin and with LSD recently, molecule known as key tansen, will block the effects of those drugs. So that's the primary target and that that's a really important, serotonin to a receptor is the most widely expressed G protein coupled receptor in the body. And it does go back into evolutionary history seratonin two receptor similar to the two eight exists in single celled organisms and speedtree be retained all up through evolution. So in our brains, it's in the In the cortex, and the outer layers of the cortex, where it's, it is one of the most important receptors in the brain for cognition, and things like that. So I don't know if I answered your question completely.

Lera 40:14
Yeah it was amazing to learn about how far back that receptor went, all of our ancestors have this.

David 40:21
Yeah, you can think about in evolution, if something works really well, nature usually keeps it. So this receptor must have worked really well in all kinds of organisms, because it was kept up to the present time.

Lera 40:31
Indeed, and I want to revisit your locking key analogy. So if this serotonin to a receptor is the lock, and all of these molecules are different keys, you spoke to how some turn different tumbles than others, do you think or have we found a so called skeleton key or some kind of molecule that will turn all of it and, you know, open up the consciousness to the whatever is behind there.

David 40:58
So it's an interesting phenomena with receptors. The seretonin a receptor is in a big family called G protein coupled receptors, and they represent the targets for about 40% of the market and prescription drugs. So they're really important. And the sick these receptors, we used to think that when a drug bound, it just kind of turned the receptor on. And when the drug left it turned receptor off. That's not actually what happens. These receptors are proteins. I don't know how much biochemistry you know, but they're, the proteins can exist in an alpha helical form. And these G protein coupled receptors, thread back and forth through the membrane seven times. So they're bundles of alpha helixes. And they're flexible. So you normally have thermal motion, just Brownian motion, where they're kind of moving around and wiggling. And they can adopt different low energy shapes, depending on you know, their, their shape. So there are several different shapes they can adopt. And these drugs can stabilize one or more of those. So LSD, serotonin, psilocin, DMT, five, methoxy, DMT, they all activate the serotonin to a receptor, but they don't produce exactly the same shape when they bind. So imagine, if you will, you've got this like a bundle of sticks, like the receptors or alpha helixes bundled together, and you put a you know, a square object down in the top that spreads the sticks out and changes their shape, or you put a round a ball in the top, and that spreads the sticks out and changes their shape. So each of these psychedelics has a different shape. And so when it binds to the receptor, it may activate a different form of a different form or different energy form of the receptor. And what happens is, inside the nerve membrane where the receptor is bound, there are connecting loops because again, these receptor proteins thread inside and outside and inside and outside, go back and forth, like a long snake looping up and down. And so they have connecting pieces at the bottoms. So where helix one comes out the bottom, there's a piece that goes over to the bottom of helix two, he goes up through helix two comes out the top of helix two to the top of helix three, goes down through helix three comes off the bottom of helix three to the bottom of helix four goes up helix four to the top, so forth, so it threads in and out. And then they couldn't connecting loops on the bottom. When you change the shape of that receptor bundle. You change the way they arrange themselves to loops inside the neuron cell change their shape. And their signal generating molecules inside the cell called GTP binding proteins. They bind a substance called either GDP or GTP. And they're hetero trimers. That means they have three different things hooked together. So there's an alpha subunit, a beta subunit, and a gamma subunit. And they're all associated with each other. And they can associate with the interior loop, one of these loops of the receptor and the receptor is activated, those g proteins will dissociate and travel to another part of the membrane and actually generate the signals. So depending on what the drug is that binds, those, there are different g proteins, there are like 15 different g proteins. And depending on what the drug is, they can activate different signaling mechanisms. So although they all activate the to a receptor, the actual signals they generate may be distinct in some way. And that's not really fully been explored yet in the lab, where I'm working now is actually using some fairly comprehensive techniques now, to characterize a large library of different kinds of psychedelics and non psychedelics, looking at which of these g proteins they activate, and what other receptors they activate. So, the activation of the to a receptor may be a necessary, but not sufficient condition for producing the effects that you see with a classical psychedelic. So there may be other side effects, or there may be more anxiety or more kind of paranoia and things like that that would be associated with other other signaling pathways being activated. It's hard to describe that without visually showing it, but I'm trying to give you some idea hope, I hope I did a decent job on that.

Lera 45:38
So I'm imagining since this serotonin to a receptor is in, that's unanimous within animalia. If you were to give them LSD or something, it would bind to that receptor and something would potentially happen. Can you speak to this? Are people considering using psychedelics to test for consciousness? Obviously, the rats expressed some interest in the compounds. But how deep do you think this goes to single celled organisms have an experience? Or do we just have no idea?

David 46:07
We don't really have an idea rats and mice, presumably, they have some kind of consciousness dogs and cats, when they gave LSD to cats, they would go into a rage was a rage response to cats, he put a mouse into a cage with a cat to begin to have an LSD, and the cat would freak out and try to get as far away from the mouse as he could, if you give dogs LSD, they go. And you don't know what's going on in their mind. But the consciousness studies, what's happened with the clinical studies and the resurgence of interest is a lot of them brain imaging, using fMRI bold techniques, or Magneto encephalography, they actually start looking at the currents, the network currents that are produced in the brain. And they're starting to understand a little bit more about consciousness by understanding what parts of the brain psychedelics turn on, and what they do to change the electronic dynamics, if you will, of the brain functional networks. So that's where we're finding the most out about consciousness by giving these drugs to humans, LSD and psilocybin. So Simon, especially, and using brain imaging techniques, and there are a number of papers out published now, looking at what happens to to brain dynamics when you put it put a psychedelic in there. But animals really don't have enough, you know, cognitive abilities, I guess, I mean, Nick, you know, they can choose one lever over another or they can they speed up running around in a cage or in mice, they twitch their heads back and forth. But beyond that, you can't learn much about consciousness from in any animal models that I'm aware of.

Alex 47:51
So I'd love I'd love to kind of dismantle a myth that or, you know, speak some truth on it. But I've heard some stories of people, you know, some old hippies that took a bunch of LSD in the 60s. And there's a rumor that goes around that if you crack your back too hard or something like that, you can get a dose of LSD. And I've heard that you can also test for LSD and a spinal tap. How true is that? Or is it just a fanciful myth? And can you detect it in a hair sample? Like I've heard?

David 48:29
Yeah. First of all, with respect to your spinal fluid, that's complete baloney. After LSD is going from your body after whatever the halflife is, it's all diffuse that there's nothing left there. If you have a flashback, or you know, hppd, you know, hallucinogen persisting persisting perceptual disorder, these are changes that have occurred in the way your brain structure works, but there's no drug left there. And you could analyze, I think you could analyze hair for LSD. But what they typically do, you know, if you analyze for LSD in the urine, or plasma, a lot of times what they actually analyze for is a metabolite in the body, LSD is oxidized in liver, and there's a primary metabolite Oxo LSD that's formed, and they usually analyze for that. But you can detect trace amounts, but typically, you know, they do that for people that are on probation, and they're forbidden to use cocaine or heroin or whatever. Typically, they'll use hair analyses to find out whether somebody has been violating conditions of their patrol parole. I don't recall that I've ever seen anybody rely on the hair test for LSD, but you probably you probably can test it, but it's not there in very large amounts. Obviously, the larger dose of drug you take, the more the more easily you're going to be able to detect it in here.

Alex 49:54
So going on more of a strange topic. Have you heard of trepanation?

David 50:02
Amanda fielding.

Alex 50:03
Exactly, yeah, so she was part of that series that that you were a part of and it blew my mind, literally. And it was the first time I heard of this, this concept. And just diving in more research, it seems to be something that humans have done for a very, very long time all over the globe. And it was interesting, it's, you know, for anyone who doesn't know, it's, it's literally drilling a hole in your skull. And the thought behind it was, I think, back in a day, it was for headaches, or for you know..

David 50:39
It was to allow the evil spirits to get out of your head, if you had a headache or pain, they thought it was from an evil spirit. And so if they made a hole in your skull, the evil spirits could escape.

Alex 50:49
And I think Amanda, dropped LSD through the hole. Is that right?

David 50:56
No, she, she believed that psychedelics work by increasing blood flow to the brain. And she believed that by doing trepanation, you would increase blood flow to the brain, which actually doesn't happen. She did a self trepanation, as you know, and had a video of it, when we first became aware of her at the hefter Institute, back in the 90s, that video was was on and we said, you need to take that video down, people are gonna think you're completely nutty, take that video down, it was really kind of a bloody thing to watch her do that. And there's no evidence that trepanation increases blood flow to the brain, nor that psychedelics work that way. But that was her initial belief. When she started getting involved in this field, she wanted to support studies that proved that increase that psychedelics work by increasing blood flow to the brain. And she funded some studies to try to show that and of course, they didn't show that. But that was her interent entry into the field was this kind of, you know, mystical belief that trepanation would increase blood flow to the brain. And that would increase her level of consciousness. But I don't think there's there's never been a study that's shown that it was just, you know, kind of a thing that she did.

Alex 52:05
Thanks for clarifying that. And it's interesting to show hard science. And I wonder if there any, is anything there? Since it is curious that many different cultures around the world have done it independently. So maybe there is something there, but not sure exactly what it is.

David 52:26
They're mostly primitive cultures that did that, you know, his skulls from South America, for example, some other places where they find they find the cranium, craniums, or skeletons that have holes drilled in heads. And I think the thought was that they didn't have you really didn't have medicine. So if you had a pounding headache, you know, with some demons, and they're really trying to get out really hard. And so let's, let's cut a hole. And those people, those skulls healed over so they know that whoever got trepanation survived the procedure, but it seems to me like it would be really, and I don't know how many of them survived because, you know, infection would be really rampant unless they had some way to prevent it, which they didn't. So I think they were mostly primitive societies. And that was just a belief that she developed.

Lera 53:15
So is there any way to increase the potency of psychedelics to increase the potency? I mean, yeah, hanging upside down consuming vitamin C. I mean, I hear all kinds of like anecdotes.

David 53:26
No, I don't think so. I mean, you're really talking about the amount of drug that's in your body that gets into your brain, and the receptors that it targets there. And it changed that basic fact, by changing vitamins or change in you might change your diet, you might change, you know, the health of your brain physiology. But there's no evidence of anything that works that way. I was in Germany, a meeting some years ago. And this guy came up to me Carlin nerdy guy, and he said he had gotten some supercharged LSD. And I said, supercharged LSD. So yeah, he bought some supercharged LSD. And I think it was on blotters. And I said, So what was it like, Oh, it was really powerful is the best LSD I ever took. And what did they do to supercharge it? And I says, they didn't do anything. You can't supercharge LSD. LSD is a molecule. I said, but your belief, right, that it was supercharged, probably played a role in the effect because you thought, oh, wow, this is the best acid trip I've ever had. Because it was supercharged LSD. So placebo and your own personal beliefs can be very powerful. The placebo effect is really strongly placebos or have really good analgesic pain killing properties. If you give someone who's in pain, a placebo tablet and say, Oh, this is a new pain reliever that's been developed. A significant percentage of people will get pain relief from that. So your belief you know, it's mind over matter. your beliefs can really affect what you perceive

Alex 54:57
Right and I think on a similar vein, you know, one case of people using psychedelics without much knowledge around it, and maybe it causes it to be a little dangerous is is NBOMs. Right? So So that was something that I heard vise cover and I think you had a part in making it. Is that is that right?

David 55:19
Yeah, we I learned from a fella who worked in Ralf Himes laboratory in Germany, he sent me a copy of Ralph Holmes a poster that he'd given at a scientific meeting, and parts of his thesis where he had first developed these n bone compounds, and stumbled on him actually, accidentally, and we had a lab looking at the mechanism of action, we saw that and they're, they're super easy compounds to make. So we made a whole bunch of them. And then did molecular pharmacology, molecular biology, looked at the receptor, where we thought that how they how we thought they bound where they bound, they're very potent. Last year, the lab where I work published a crystal structure of one of the N bombs in the serotonin to a receptor. And they're extremely potent because they push against there's a residue and the receptor, a trip to fan 336. And the end bombs push over against that trip to fan and push it down. And that's one of the mechanisms for activating the serotonin to a receptor is particularly tryptophane as part of what's called a switch mechanism. And so they bind to the receptor just like, you know, DOB or to CB would accept that benzo pushes off into another part of the receptor that pushes this activation switch this tryptophan residue. So they're extremely potent, no one knows why they're toxic. I think probably it's a difference in metabolism, because a lot of people have taken the N bombs but a fair number of people have have died, but not as many as have taken it. And it's been shown that in the liver, there's one of the methoxy groups that's clipped off cleaved off in the liver by an enzyme called a mixed function oxidase. And it's then coupled to glucuronic acid and excrete it. And that that happens really quickly. So if you look at in animal studies, where they've administered these n Bo compounds, printing, you see this glucuronide formed really fast. And what I think is that most people metabolize it quickly, and they don't suffer these, you know, the lethality, but in some people, we know that there's a lot of variability of those enzymes in the liver. And some people don't have the ability to take that methoxy group off. So you have the intact drug molecule. And it hangs around for a long time it gets in the receptor and stays there for a long time. And we think that's somehow related to the toxicity of those substances. Why was the embalm created, he was actually trying to dissect drugs that block that receptor, the serotonin to a receptor. And he was doing studies to figure out what part of that molecule was responsible for blocking the receptor. And he started basically dissecting some known molecules that bound to the receptor, but were inactive. And he got down to this minimal structure, which was an invent the benzo compounds in both compounds, and found out that they were really potent. So he wasn't even looking for these, he was trying to discover the part of these molecules that bound to the receptor and block the effects of psychedelics, not drugs that that actually activated the receptor. So he came at it from a completely unexpected direction and just kind of stumbled on these n benzo compounds. And then, then we picked up on them and published and then of course, they got really popular because everybody started making them. And then because they were so potent, they could put them on bladders. So for a long time, and in some of the areas like in the San Francisco Bay Area, a lot of people were getting bloggers that were called LSD, but they really had inbound compounds.

Lera 58:59
So was the point to create some kind of drug that could bring someone down if they were too high on psychedelics, or like what was the original intention for having this blocker?

David 59:10
In medicinal chemistry there, there's a process you use code structure activity relationship analysis, and that basically means you're trying to understand what about what is about a molecule that makes it active. And in doing that, you modify that molecule by adding new pieces to it or by taking pieces off. And so it's kind of like a big puzzle. And you kind of take pieces off or put pieces on until you find out what's the minimal part of that molecule. So with LSD, LSD is a very complex molecule. But you may be aware that it has a tryptamine fragment inside the structure of LSD. So if we'd never discovered if DMT dimethyltryptamine had never been discovered, someone could take the LSD molecule and start cutting pieces of it off till they got down to the tryptamine part. And they would find out that that was active. And so they would say, well, this trick to me in part is the functional part of LSD. So he was taking drugs that block that receptor and trying to understand what was the minimal part that band. And if you know the minimal part, then you can sort of look at the receptor and say, What are those pieces interacting with in the receptor? So he wasn't necessarily trying to develop a better blocker or an antagonist. He was just trying to understand the structural basis for the ability of those drugs to block that receptor.

Alex 1:00:34
Do you think it's fatal because these chemists are doing that procedure wrong? And they're making something that is not the actual compound and in you know, or using chemicals that are toxic that are getting into the formula? Or do you think it's the actual compound itself? Or how people are ingesting it? I know, I read some people were taking it naturally. And it might be that ingestion that maybe is way too potent, and there, or is it they're taking way too much.

David 1:01:07
There are a lot of variables that I've seen cases of people who died from taking two or three blotters so they were there was a larger dose there. But normally, psychedelics are not lethal. They're not, you know, nobody's died of an LSD overdose really. So that doesn't seem completely reasonable to me that it was just taken two or three. Now there's another case where some people got some powdered in Bo compound, and took too much there was a massive overdose, and that killed us and fell some fellas, I think, in North Dakota. But I think that it the pure molecule, I think it's a failure of some people to metabolize it quickly. And they're the ones that have died. But also, if this stuff is made from China, you know, you don't have the FDA in China, making sure that these compounds meet their standards of purity. So if you get something made offshore, the Chinese make a big batch of it, and maybe it has got some toxic impurity in it. So it could be a toxic impurity could be overdoses, it could be related to people that don't metabolize it efficiently. So I think there are a combination of factors there. And of course, if you, if you insufflated, put it up your nose, then it's going to hit you really fast. And again, then it doesn't go through the liver at all. It goes right into your systemic circulation. And so the liver doesn't have any chance to break it down. So there again, if it's the intact molecule that's toxic, by by blowing some of your nose, then you're avoiding the mechanism that would detoxify it. So any of these things could be involved.

Alex 1:02:47
So moving to DMT, which is a fascinating subject, specifically m, eo eyes, these beta carboline that block the enzyme in the liver that that breaks down DMT. And, and I've heard, you know, we just interviewed Dennis McKenna, and he has a theory that DMT is, although not proven, he thinks it's in pretty much every single plant. Many he said he wouldn't be surprised if it's in every single plant are the beta carboline? Are they just more rare? And it's, you know, that that's why we're not being every time we eat a salad. Yeah, and and why, you know, for Iosco, there's two different plants that have to come together. And you know, what would happen if you you take a beta carboline supplement and went about your day? Would you have more intense dreams when your body naturally produces DMT? or?

David 1:03:48
Yeah, what would happen if you just took the beta carboline as a supplement, to my knowledge, beta karpeles do not have any effect. They were investigated as anti Parkinson drugs, way back maybe in the 30s or 40s, because they blocked the degradation of dopamine. And Parkinson's disease is a deficit of dopamine. So they were trying to increase dopamine levels by taking beta car believes. But as far as I know, beta carboline, you know, you don't produce enough DMT in your body to really have an effect even if you block the breakdown by giving an mo inhibitor. Other ml inhibitors are commercially uses antidepressants. So they were they were first developed, I think probably back in the 50s or 60s. And they they prevent the breakdown of serotonin, dopamine and norepinephrine in the body. And so they're uses antidepressant so beta carboline, might be might have any depressant effects, but you don't have enough DMT in your body for it to build up in effect, any the physiology you'd have to really get you know, I wrote a paper on this, I gave a talk and he said breakin convention. He really needed about a 25 milligram dose of DMT, to have any kind of, you know, have those effects. And you just can't produce that much in your body. It's a big controversy because it's really a popular meme that DMT is produced, you know, at the moment of death, and it's produced when you dream and all these other things. There's no, there's really no evidence for that at all.

Lera 1:05:21
I'm curious if you've ever looked at the mirror images of these molecules and studied various Kairos cities in the psychedelic realm?

David 1:05:29
Yeah, in fact, my first patent was when I was a graduate student, I patented the method to make the the optical isomers of psychedelic amphetamine derivatives like deal. And STP. MDA. Yeah, you know, the body is made of L amino acids, and only l amino acids. And not there's no D amino acids. And so your body is really a big stereo, chemical, everything everything in your body is, you know, is a one type of stereochemistry. So if you imagine, these stereo, these stereo isomers, are kind of like glove. So left handed and right handed glove. And your left hand fits into the left handed glove, but not in to the right handed glove. And so if you think about drug isomers, being like, left and right hands, and the body being just like a left handed glove, owner or there are only right hand and glove only one of your hands will fit is because that all the receptors are made of L amino acids. So all the targets for these drugs are el amino acids. So there is a steric chemical preference LSD has a two steric chemical senators wanted the five position. And it's only the one where the hydrogen is in what would be called the R configuration that's active if you make ns plus LSD if you make minus LSD, and that actually was made by Albert Hoffman at Sandoz in the first method that he used to make LSD. It made it gave a mixture of the plus and minus hella LSD. And they examined the L LSD, and it wasn't active at all, big large molecules that have stereochemistry like that typically, only one of them. There's so many natural products out there that are toxins, and they have specific more than one often 234 stereocenters. And because of the targets in the body are being made of L amino acids, usually only one of those will fit. And of course, the enzymes that the plants use are all l amino acids too. So they're making only one form of these compounds. So the ergot alkaloids only the only the plus or get alkaloids are made by the ergot fungus because their enzymes are all l amino acids. And so they make only one form of the drug.

Lera 1:07:42
Don't drink the mirror milk, right. That was something Lewis Carroll mentioned in his book, Through the Looking Glass, where he stated that Looking Glass milk wouldn't be a good idea because perhaps he was aware of the ambidextrous universe and how like mirror images of compounds can be destructive in our bodies. Because, as you stated, our metabolism is modeled for a handedness within certain compounds. And if you were to give it the mirror image, it either wouldn't bind to those proteins or you know, some some other destructive behavior would unravel. But coming up on our time here. And I want to make sure we get to some listener questions. And our first question is, is LSD difficult to make and how much lab experience does one typically have to have before they have the skills to do it?

David 1:08:38
The trick to making LSD is getting either lysergic acid, or ergotamine, which is a naturally occurring or gut, if you have either one of those, it's pretty easy to make lysergic acid can be coupled with dimethyl amine. And there are now some modern reagents that are really safe and the company goes really fast. So if you could get lysergic acid, you store it in a solvent in the dark, you have to protect it from light because it is sensitive to light. He put it in a solvent like dichloromethane stirred, put in lysergic acid diet for the mean and thrilling there's there's a coupling reagent you can use and reactions done in 15 minutes, and you put into a separatory funnel, wash it with water and evaporate off the solvent and then typically you might purify it over column chromatography. It wouldn't take very extensive equipment to do that. But you would have to have lysergic acid as a starting material. And, you know, but it's, it's you know, it's a one it's really a one step synthesis. If you had ergotamine, you treat her gadimian essentially with lye, you cook it up with lye, and then you that breaks off everything except for the lysergic acid and then you can isolate the lysergic acid that's a little bit messier. Because a 10 lysergic acid in our guts tend to oxidize and turn work in air, etc. But then you purify with column chromatography and a lot of stuff is cleaned up. So it's not that hard. But the issue is getting the story material getting lysergic acid or an ergot. And both of those are watched items. If you try to order a bunch of ergotamine, the DA will probably come knocking on your door, another listener wrote in and he said that after a very large dose, 1000 micrograms of LSD, he felt like he didn't want cigarettes anymore. And I've heard a lot of studies of alcohol addiction with LSD and then cigarette addiction with with psilocybin. Has there been any research with LSD with with cigarette addiction? Not yet, but I think all addictions probably have the same kind of route. There in the early days of LSD research, treating alcoholism was one of the big things were that most attention was focused and actually, and there was a meta analysis done a couple years ago, by a Scandinavian couple, where they went back and did a meta analysis of all the studies that it used LSD to treat alcoholism. And each of the individual studies were not powerful enough, you know, to do to do a study like that you need a lot of you need a lot of subjects, and you need a long follow up time. But they show that there was a significant effect of LSD against alcohol use in those early studies. And they really weren't designed to they would they just gave it to them. And there wasn't really much therapy to go along with it. The studies of nicotine and alcohol use disorders that have been done recently by Matt Johnson, Johns Hopkins and Michael Bogan shoots now at New York University. In those they both have therapy, before and after, and so you really prime people to think about their addiction, you know, to think about their life, why they, why they drink, why they can't stop smoking. And that's part of it. So then you take the psychedelic, and there's some kind of an increased cognitive awareness, something happens. And that's really the task for psychiatry to figure out in the future, how these things actually do what they actually seem to do. So it's a really exciting time. It's 50 years overdue, in my opinion, but at least it's happening now.

Alex 1:12:10
Yeah. And Hamilton Morris's pharmacopoeia, you were featured, there's a section that was kind of sliced in there of him asking you about you having to destroy a lot of the compounds that you made, and asking if that hurt, you know, as an artist to destroy your compounds. And you responded that you had to pour them down the sink with a witness and things like that, what what compounds did you have to destroy and why.

David 1:12:40
So the ones that were scheduled one that I was able to transfer, I transferred to other people who had scheduling licenses for those compounds, and there weren't very many, I had some LSD that I transferred to accompany MDMA, I transferred all two maps. And if there were, there might have been some others. But basically, you they were either burned if they weren't controlled substances, or if they were controlled substances, they had to be washed out of the sink, and someone had to witness you destroying him. So yeah, that was when I retired, I had big libraries of compounds that we'd made over the years that, you know, might have had interesting properties, but they had to go, you know, down down the toilet.

Alex 1:13:26
And what about the procedures are? Are those accessible by people? Can they remake those molecules? Or did you have to destroy those as well? Yeah, we've published all our work. And all the exact synthetic details are in all those publications. So if anybody was interested in anything that we did, yeah, we could. We could have a mate, they could make it.

Lera 1:13:48
From Rachel and Austin, Texas. And she wants to know, how do you feel about putting patents on synthesizer versions of LSD similar to what compass pathways is doing with psilocybin? And if it's used medicinally for trauma, do you? What are your thoughts on the ethics of withholding that part of nature that can help so many people?

David 1:14:09
So the patents follows pretty much the standard pharmaceutical industry, procedures and practices. If you consider that there are literally hundreds of millions of people out there who need treatment for depression, addictions, etc. I'm not sure how you do it without getting funding from investors. And getting funding from investors depends upon you having intellectual property which means a patent. So compass wouldn't have been able to get all the investors they've got without having patents. Now, their patents don't really protect much. In that case. psilocybin can be manufactured by different methods, different polymorphs can be formed. You can make different salts, so I'm not sure that really prevents these substances from being used. I'm not, I don't believe that the compas patent prevents anyone from using psilocybin and LSD, there's only really only one way to make LSD. And it would be very difficult to patent it. And, and even if you did, people could still make it. So I'm not as concerned about patents as some of the people are, who believe that they should be available for anyone to use for, you know, for any reason. So I'm less concerned about whether or not these are these patents are produced, the patents do mean that if there's money to be made, that there will be incentive incentives by these companies to develop more robust procedures, maybe develop even new drugs that are even better than the ones that we have. So money, as you know, drives our capitalist economy. And I think without without the patents, there won't be the investment, oh, this flurry of new companies or something like 600, more than 600 entities trying to make money in this space now. And they're not all going to survive, either a few are going to survive, because they don't understand how much money it costs to do, say, a clinical trial. If someone develops psilocybin analog, and they want to do a clinical trial, the clinical trial is going to cost between 50 and $100 million, where's that money going to come from. And the money comes from investors, who see a company that has a new idea or a new way to use psychedelic therapy. And so they invest because they expect a return on their investment. So it's kind of a complicated issue. It's not just really people planning these things. And so nobody can use them matches, not the situation. So if we really, I think, if we really want these medications and medicines to be used widely, globally, they're almost have to be patents, because patent protection for your product or your approach, really is the thing that attracts investors. And that's the case for every, you know, every publicly owned company in the world and in the United States. So I don't think the patents are keeping these from being developed, but rather, are ensuring that investors will come in and support this because there is a great need for these medicines. And I don't see any way that they're going to get out to people, you can't treat 100 or 200 million people, if you don't have money coming in from somewhere. And you can't just charge the patients, because they don't they're not going to have they're not going to be able to afford the therapy. So it's it's a it's a kind of a touchy and difficult situation. But I'm not that concerned about the patents.

Lera 1:17:47
Thanks for that insight. And I do believe that patents aren't inherently bad. And if it is done by the right person, it can actually be a good thing because they'll protect itself from you know, other people coming in making it restrictive, but some people can patent so nobody else does that. Right. So yeah, I think there's, there's hope to do it the right way.

David 1:18:08
Yeah, I mean, compass tried to patent, you know, the, the comfortable furnishings in the room and the use of eyeshades and earphones, that patent in my opinion will never be awarded, it's because it's in the common it's in, it's in the common public domain. There's prior art out there, you can't patent something that's been known since the 1960s. And everybody uses that. So they've tried to get broader patents, but I don't believe the examiners will allow those patent that those parts of the patents.

Alex 1:18:38
If you could see the future of this industry, or, you know, are there any? Is there any research that you're just dying to see done or do yourself that you think could pave the way for this space?

David 1:18:52
Well, I think the psychedelics are proving to be a very useful tools in understanding brain function and how the brain generates mind. You know, they've had, they have modern imaging techniques now in technology, you know, fMRI and magnetoencephalography, and FM, you know, all these brain imaging techniques, which you can look at a normal brain, or you can look at it diseased brain, and you can see differences, but with the psychedelics, where you have this kind of expansion of awareness, you know, increased level of insights and introspection, and it's activating parts of your brain that normally are not activated. They're able to pick that up with the brain imaging. And so I think, and the real trick is understanding what to look for, and having software that's sophisticated enough to really figure out what's happening there. So in the future, I think they're, first of all, I mean, I think I would accept that we're going to see people treated for depression and anxiety and lots of disorders, some addictions and maybe eating disorders, obsessive compulsive disorder. There are a lot of things where the The dynamics of the brain are disturbed. And I think psychedelics can fix that. And the other side of that coin is that in fixing those problems, coupling that with brain imaging is going to give us a much better insight into how the brain actually works. You know what personality is related to what personality disorders are related to. And it's really going to help us understand fundamentally more about who we are as human beings, and you know why we are the way we are.

Lera 1:20:28
Well, thank you for all the important contributions that you've made. We're so thankful to have gotten the opportunity to speak with you.

Alex 1:20:35
Immense gratitude for David's time, his expertise, his impact on this field. And for all of our beautiful listeners tuning in and trimming in, you can support the show and keep content like this coming by visiting our website, mushroom revival, calm and purchasing any of our products.

Lera 1:20:54
You can also support us by rating and reviewing. These go a long way and we always appreciate feedback to help us improve our content.

Alex 1:21:17
Please keep spreading the spores tell all your friends, your family, your co workers, everybody about mushrooms the show and how they can form a sacred relationship with fungi. And as always, much love and may the spores be with you.