An Interview with Dave Nichols|
Dr. Dave talks about Heffter, new super-potent compounds, and how to train drug savvy rats.
You started work with psychotropics or psychotomimetics thirty years ago the Summer of Love. How was your decision influenced?
Well, that was of course in the mid- to late 1960s. There were some number of people at the University of Cincinnati and the University of Kentucky who were in small enclaves, I suppose. Maybe there were a few small groups. So I knew about psychedelics, but in the Midwest, it wasn't really a big thing. It was more academic curiosity. Not many people in my circle of friends knew very much about them. I was sort of considered the scientific wizard and so I would keep up with the literature and tell them what was happening. They'd say, "Dave, did you ever hear of this thing?" and I'd say, "Oh, yes, that's such and so and thus and so." I was sort of a resource for questions.
So your interest in psychotropics is older than your research in them?
Yes, it would probably go back to at least three or four years before I actually went to graduate school.
Did your interest stem from personal experience?
Well, from people I knew.
So how would you compare the climate in psychedelic research at that time to today? Do you think you can describe how it evolved during all this time?
In the beginning, of course, they were called psychotomimetics. The government really got interested in where LSD was coming from I think in 1965 or thereabouts. The rumors were that the communists had infiltrated universities and were putting these drugs in, and so I believe a lot of resources were mobilized to find out what were the sources. Teams went into a lot of universities to find out where the drugs were coming from, who was supplying them, what their sources were, before they concluded that it really wasn't a big organized conspiracy. But I think there was a lot of hysteria. You can't separate that time from what was going on socially in the country. There were protests and a tremendous amount of turmoil over the Viet Nam war. Even the music was reflecting protest. A whole generational protest against the parents was happening. You added the drugs in, and it was a fairly chaotic time. So there was a lot of interest in how psychedelic drugs worked. It was much more difficult in the midwest to get information some of the writings that Leary and earlier people had done those weren't readily available like they were on the west coast, for example. But there was a lot of interest, a lot of concern over the use, and of course the government was putting out a lot of stories as much as they could about the dangers of these drugs, and why you shouldn't use them, that they would damage your chromosomes, and various sorts of things. So it was much more hysterical. I think funding for research was probably more plentiful, because politics drove the funding in the area of drug abuse. So it was much easier to get funding. But as that tapered off, and the use of psychedelics sort of dropped off, maybe in the early 1970s, the scientists who had been working in that area got out. It was much more difficult to do clinical studies, so no clinical studies were occurring, and you had a period in the early to mid 1970s where a lot of clinical investigators did retrospectives, wrote up, "Well, this is what we did, and this is what we found, but we can't do it anymore, and hopefully somebody will be able to do it some day," and it was sort of a eulogy for psychedelic research. But I guess I was tenacious and just kept doing it. Gradually everybody just sort of disappeared from the field, except for a very few.
How would you describe your role today in academia, as a chemist and a pharmacologist, and also as part of the psychedelic movement?
My perspective has changed over these thirty years as well. In the beginning it was more a curiosity about how these worked and what we could understand about the structures and so forth. My interest was more focused toward why people use these substances. I really didn't focus my attention so much on the positive aspects. But within the last decade, I guess I've thought a lot more about it. Imagine and I've used this analogy with people I've talked to before so maybe you've heard this, but I'll tell this story. Imagine all the things that can change your life. You might fall in love, you might get married, have a child, get a divorce, or a parent dies, a sibling dies, a child dies. Or you take a dose of LSD. How is that possible? What's the substrate in the brain that such a relatively small number of molecules can permanently transform the way that you see and appreciate life and your role in it? That became a really interesting question. I began to sense, I think, the deeper implications of how these drugs could work. And now, of course, they're finding that the receptors that psychedelics stimulate the serotonin 2A receptors are very dense in the cortex, that they're probably involved in cognitive processing sort of doing the number crunching in the cortex. One fallout of that is interest in new antipsychotic drugs that block serotonin 2A receptors. So I think these receptors and it's not surprising if you really think about it these receptors are fundamentally much more important in defining who we are and how we really see things than people have formerly thought. I think people who took these drugs, or people who did clinical studies with these drugs, always believed that they had some deep, profound importance, but I think a lot of that belief was just blown off by the drug abuse establishment, in a propaganda effort to try and shut off all use of these drugs. But in fact, I think that these drugs stimulate parts of the brain that are very important, extremely important, that we should be interested in, in terms of how we process sensory information and normal cognition and a lot of very fundamental human mental feats.
You mentioned antipsychotic drugs that act at the same sites as psychotropic agents do. Do you see now that drug companies have become more interested in your research than they used to be?
They're more interested in receptor antagonists for that receptor. There are some companies who are actually interested in serotonin 2A agonists now, more related to understanding how they affect cognitive function, because we have Alzheimer's, senile dementia, and lots of disorders where in fact if the idea that these are mind-expanding drugs if that were true in some sense, then you may be able to develop drugs that would stimulate these receptors and actually produce enhanced cognition. I think the possibilities are there. They've been so heavily obscured by the drug abuse propaganda that it has been difficult for a lot of people to see.
Perhaps I am over-estimating this a bit, but I feel that over the last few years, since drugs like Viagra and Prozac came onto the market, new pharmacueticals are not so much about treating an illness but about enhancing the quality of life. If you push this a little bit further, the drug companies could tap the vast resources of people who are not ill but only want to feel better do you think that the drug companies could become allies of the psychedelic movement? Do you think any change is on the way in that respect?
I think there will have to be some change. When we have effective drugs to treat all the major illnesses, then you have people who enter into middle age or late middle age who can't remember faces and names anymore, who forget telephone numbers, who really cannot do mental feats like they could when they were younger. I see no inherent evil in developing drugs for those people. In the past, the problem has been that drugs were only developed for pathological conditions where you could identify specific problems that you had to fix. But I think the drug companies will eventually see the other possibilities. There is a huge market for cognitive activators, certainly among late middle aged and geriatric people. The companies are only looking at drugs to treat Alzheimer's and various types of dementia. But that's just the first step. I think that once you discover how to enhance cognition in Alzheimer's, what's to prevent you from enhancing cognition in someone who doesn't have Alzheimer's, but who maybe can't remember telephone numbers or can't connect faces to names? I think that will come. There is the demand for it. You could probably talk to the average man on the street anywhere in the world who was having problems with his memory at any age and say, "Do you think it would be an evil thing for a drug company to develop a drug that you could take that would enable you to have the kind of memory you had when you were twenty years old?" I mean, nobody will turn down a drug like that. And the drug companies know that.
Sure. I had more in mind a drug that simply enhances your mood, your perception of life or your joy in life something like that.
Well, I think things will happen in steps. I don't think there will be anything dramatic. The shift that you saw with Prozac being used in people who clearly did not suffer from profound depression and the use of Viagra in people whose lives were normal in other ways, I think you'll see other incremental changes. I think drugs to treat cognitive deficits will probably come along next. And there'll be a big debate about whether they should be given to college students to help them study for exams. So you'll have this series of debates as new drugs are discovered. There is a Calvinist notion in U.S. society that you are born with all the mental tools you need, so that if the quality of your life is not what it should be, then too bad. Those are the cards that God dealt you and you should just play them. I think that we are going to have to enter into that debate, because I suspect that there are a lot of people in the world today who suffer from a sort of vague sense of anhedonia. They see other people who really enjoy things, who say things like, "What a great meal, what a beautiful picture, what a wonderful concert" but they say, "Yeah, yeah, you know, it was ok." I mean, why shouldn't those people be able to experience those things at the same level? So we have this sort of Calvinist doctrine now that says, "I'm sorry, that's just the way you are, you're not going to be able to appreciate these great works of art and great works of music." I think the debate will come at some point. I don't know when it will be. I don't think it will be very soon, but I think a debate will come eventually. Those drugs will become available. They may only be on specific occasions. You might not be able to take them all the time, but you might be able to get something akin to a prescription go to a doctor and say, "I'm going to go to the symphony on Friday, and I really don't like symphonies, but I would like to take this symphony-enhancer drug that I've read about so that I can appreciate it." And whoever the shaman or psychiatrist is at that point in our culture that is dispensing things will give you that and you'll go and just have a wonderful time at the symphony.
You think that is going to happen?
Oh yes. But the question is when. It just doesn't make sense to operate forever under this kind of Calvinist, suffering doctrine. If you see people who go to an opera and the singer is singing something really emotional, and tears just run down this person's cheek, and for them it's just such a wonderful thing, someone else will sit there, watching and think, "What's her problem? I mean, she's obviously getting a lot of this opera, but it doesn't affect me that way." The person who doesn't feel to that depth is being deprived in a certain way, I think, of the emotion that the author of that opera intended to convey to the audience. When Beethoven wrote a symphony, presumably he felt tremendous passion when he wrote that symphony, and that's the passion he wanted to convey to the audience. If you're not feeling that passion, it seems to me you're not in touch with the true Beethoven, right? I mean that's what I would say. And if you can't experience that passion, if you're not in touch with the true Beethoven, why shouldn't you be allowed to have the experience that he intended to create and convey? Those things have to come. To me, there's a sort of moral rightness in everybody being able to experience things like that. The same thing for works of art, or music, or anything. All people have the right to experience what the artist tried to communicate. But I think it will be a long time. Certainly not in my lifetime, who knows, maybe in my grandchildren's lifetime. We have so many things now, but especially I think in the United States, even though there is a lot of talk about freedom, freedom doesn't extend to changing the state of your mind through mind-altering substances. That's something that's related to the drug war. I don't see that changing until there's a fundamental paradigm shift in society, until they recognize that some of that thinking is associated with notions of good and evil that have been brought forth from Calvinist and Puritan ideas from the last century and before. Thinking seems so heavily influenced by that now. I think it's going to take a while before the perspectives change. But I think change has to come.
One way to bring this change would surely be to educate the population more and to do more research in this field. One organization that does this is the Heffter Institute, which you co-founded. Tell us about what your motivations have been in founding and working with the Heffter Institute and if you are happy with the progress made so far.
Well, progress has been much slower than I had fantasized. I am happy that we are still growing after five years, but we're also still a young organization. We just got some people on board recently, and a fund-raiser who looks to be quite good. Some things that we're trying to do haven't actually crystallized. I'm convinced that once we actually start doing some clinical studies and getting results, more people will get excited about what we're doing.
What inspired you to create the Heffter Institute?
I really had the idea for the Heffter Institute probably in the mid-1970s, after I had finished my post-doctoral work. I became aware of the work that was done with terminal patients at Spring Grove, and by Stan Grof, and I was really impressed by some of that. I talked to colleagues of mine at the time about the possibility of doing research like that in the future and that was when the drug war was really heating up. It wasn't called a drug war, but was really a pretty vigorous, intense campaign to shut down the use of psychedelics. We had many discussions where my colleagues would say, "Well, the government is never going to fund that stuff, forget it, it's on the way out." And I would come back with, "Yes, but there must be lots of people who have had these experiences who recognize their intrinsic value who would fund it privately. We just need to find someone to do that, and then we would work through the normal regulatory authorities, write the protocols, and get this work done." And this was back in the time when I envisioned that an investment of a million dollars would give you enough income that you could do everything that you wanted to do. So that has been quite a while ago. Periodically I would meet with friends and I'd say, "Gee, I sure wish someone would set up an institute like that, I think it would be really interesting, all kinds of things could be done that we can't do now, and maybe it would be a new paradigm for psychiatry, and you could have this whole branch of psychiatry that dealt with these drugs and treated patients who can't be treated now by conventional psychotherapy and psychoanalysis, all the things that people imagine work and don't work very well." Then they would say to me, "Well, why don't you do it?" And I'd say, "I don't have an M.D. degree, so I can't do it, and what's the point if you can't work with humans?" I kept waiting for someone to do something like that, but it just never happened. So it has been close to ten years now 1990 or 1991 and I was sitting around one day, thinking these kinds of thoughts and I realized that I could be sixty-five or seventy years old, sitting in my rocking chair, still wishing that someone would start it. And I thought, well, let's just find some people who are interested and just go ahead and do it. So I contacted some physicians mostly physicians I knew at that time – some other PhDs, and we had discussions along these lines at meetings, and just basically decided to do it. I think it's a critical thing to do, because I believe right now there is a sort of window of opportunity. There are a few people around who still believe that these drugs can play an important role in therapy, and I think that in fifteen or twenty years, most of those people are going to be gone. And then what will exist are old anecdotal accounts, and paperback books that you buy in used book stores, and a few aficionados who may be still experimenting a little bit, but I think the great knowledge base that still exists now will be evaporated. And then I believe it will be much more difficult to actually bring these drugs back into the mainstream.
My basic angle has been to go back to the medical model. A lot of people disagree with that. They think physicians and organized medicine are the least well equipped to handle psychedelics. But frankly, looking at the regulatory structure in the United States, I think it's the only way it can happen in this country and probably in most places, to come back through the psychiatry establishment to show that these things can be used in a psychiatric context and hope that as the culture evolves, eventually psychiatrists who use these kinds of medicines in their practice become very skilled and recognize other kinds of applications, so that at some point in the future, the average guy who feels like he isn't enjoying life very much, and Prozac isn't working for him, can go into the psychiatrist, explain his problem, and the psychiatrist or shaman whatever that person is called at that time can say, "Well, perhaps some sort of psychedelic session will help you get through some of these issues, and help you see some joy in life." So I see it as an evolutionary process. Heffter is, I hope, just the beginning of trying to bring it in through the medical establishment into mainstream medicine, with the idea that the value of psychedelics, assuming it exists, will become evident and that the evolutionary process will continue until eventually they're integrated fully into medicine and are no longer drugs of whatever you want to call them anathema.
In your own words, what is the objective of Heffter?
The mission statement is to foster and encourage and support high quality scientific research that uses psychedelic agents as primary tools in that research.
We support both basic as well as clinical research. I personally think it's very important to do a clinical study fairly soon that demonstrates efficacy. We know what you can do on the basic science side, we know some of the things you can do. And of course, many of us have been doing research pre-clinical and basic research for a long time. But really, it is important to demonstrate that these drugs can be used in a clinical setting, and can be useful for something, documented statistically, that they have a specific effect. I think it's important to establish that as a foundation before moving on the clinical side.
The Heffter Institute also has a publication, the Heffter Review. Number One is out, Number Two is in the making, I understand. Do you have any ambitions to develop this further than just a publication for the Heffter Institute, to establish it as one of the scientific journals one would find in most scientific libraries and make it an open forum for every researcher in this field and not only for Heffter fellows?
I frankly haven't thought much about the evolution of the journal. The Heffter Institute itself has plans to develop handbooks for the use of psychedelics handbooks that would be useful in designing clinical protocols, etc. We actually have an outline to do that in our five-year plan that would make these more accessible to other researchers. Certainly, if we are able to get things moving in a big way, do a clinical study and demonstrate efficacy and move into some second or third studies and really get a lot of interest going, such that other investigators started looking at psychedelics as a viable research option, I could see the Review evolving into something that would be a means for reporting the results of those investigators. I haven't really thought about the Review in that context yet, but certainly that would be a good way for it to go.
Are you familiar with other journals, such as amateur journals that feature ambitious amateur research, like the German Integration, or the Italian one, Eleusis? Do you know them?
I've seen those.
Is that a direction you'd like to see the Heffter Review going?
One of the things we try to fairly and consistently do is maintain a standard for the Heffter that really kept it allied as much as possible with mainstream forces. Even on our web site, we've had a lot of people with alternative web sites write to us and say, "Gee, we'd love it if you would link to us." We'd look at their site and see it's an interesting and popular site with a lot of anecdotal reports and discussion of spiritual transformation and what not. We generally have not linked to those sites. My feeling is, and it's because of the way the drug war has really skewed the view of many people, that in order to have any chance of success in the United States in developing clinical protocols, and doing research that is viewed as being legitimate, we have to maintain as much as possible a sort of squeaky-clean image if I can use that term. I think it's certainly true in the United States that it's important to do that. Otherwise what happens is, the people in the regulatory agencies that you would have to deal with the Drug Enforcement Administration, or the National Institute on Drug Abuse, places like that will look at you like a bunch of weirdos and won't take you seriously, and they'll throw roadblocks up for you. So our whole sort of focus has been to bring in high-quality people. Our Board of Advisors includes some really outstanding academic and clinical researchers who have good, solid reputations as far as that goes, and it has been our hope to maintain that. A lot of those publications are very interesting to read, and I read articles in some of them from time to time, but we've really tried to keep Heffter much to the consternation of some of the people involved in those other publications as mainstream as we could so that we could forge needed alliances with regulatory agencies and public officials in order to bring about the transformation in psychiatry that we believe should occur.
The work with Heffter and your academic work as well demands that you stay in touch with other researchers. How would you describe the loose community of researchers in this field today? Is there a network? Do people know each other and talk to each other?
I would say that there is a reasonably good network between most of the main players. And of course, there aren't that many people who are major players right now. I think there is a good network of people who have done this work and email has really facilitated that. The Heffter board members get queries all the time. One person then sends it to everybody on the Board. A lot of times those people send it to people they know who have an expertise or interest. And before long you have an answer, or some kind of consensus. A lot of people have sent questions through the Heffter web page asking about the effect of a particular drug, or a relative who has had some sort of an adverse reaction and is being treated in such-and-such a way, and is this the way it should be done, or questions about whether they should take certain drugs, and so forth. I think we serve as a good source of information for a lot of people. We've had hundreds of questions. I get a lot of questions from people who are interested in entering a research career in this field, and we have dialogues with them about the best way to do that, is it something that's feasible for them, are they interested in going into medicine, or are they interested in experimental psychology, and so forth. I've had two inquiries from people in the last month asking the same sort of questions: "How can I get into this field?" or "What are my opportunities?" So I think there is sort of a nucleus of major players and it networks out through newsgroups and use-groups, and so forth, and I think the connections are reasonably good.
Before email, you obviously had to rely on the classic things. In the interview in the last issue of TRP (Spring '99), Terence McKenna mentions the Esalen conferences as at that time a very fruitful source of getting together and to know each other. How did you experience that?
Those were very interesting conferences. I went to a couple at Esalen. Remembering that I am in the Midwest, prior to email, I mean, where there wasn't much going on, those conferences put me in contact with a lot of the people on the west coast who had been involved in earlier work and a lot of personal experimentation. It showed me up front a side of the research that I hadn't actually seen first hand before. It was interesting to listen to those people's experiences and their ideas and so forth. I can't say that those meetings had a real impact on the direction of my research. It didn't really contribute anything beyond the fact that listening to some of these people's stories made me become more convinced that these drugs were important. I met psychiatrists at Esalen, for example, who had been using MDMA in their therapy. I knew a little bit about MDMA, but hadn't talked to anyone first-hand who had actually used it in therapy. You would talk to some of these therapists, and they'd say, "This is really amazing. Let me tell the story of this patient I had..." So hearing these stories first hand really gave me much more of a sense that these things really do have value. It's not just something you read about. You hear psychiatrists giving very impressive first-hand information, so there was value in that.
So you are obviously really interested in seeing these substances back in human trials, and some research has been done lately, like Strassman's work with DMT and, I think, with psilocybin. You are also working with MDMA right now and Richard Yensen´s work with LSD has been started.
No, I don't think he is working with LSD yet. But there are two other clinical groups
No, I thought... Didn't you actually provide the material for his work?
We did package the LSD into sealed unit doses, but as far as I know, he has not gotten approval to actually do the experiments that he wants to do.
So it has been delayed or denied?
I think it's viewed as being postponed. There are a couple of other groups that are also working with MDMA, more in just basic research. There is a group at Wayne State
And they are in clinical trials as well?
Yes. A drug abuse research unit at Wayne State and also at the University of California-San Francisco. Reese Jones is the project director at San Francisco, but they're not doing anything related to therapeutic work. They're looking more at basic things, such as the mechanism of action, what are the behavioral effects, the effects on blood pressure, and so forth.
And then there's Evgeny Krupitzky, who does work with ketamine.
In Russia. Right. He's using ketamine to treat alcoholism and heroin addiction. He has some interesting and encouraging results. We'll have to wait and see the long-term follow-ups and how effective it ultimately turns out to be, but that's very interesting work, with ketamine.
And do you think to get substances like that into clinical trials that it is easier or more difficult in the U.S. compared to the rest of the world?
I think it is more difficult in the United States. By far.
So you would expect more research in foreign countries.
In Germany at Aachen, there's Dr. Gouzoulis, who has a funded research project looking at mescaline, MDE, and amphetamine. She is trying, I think, to pick out elements of drug-induced experience that may in some ways parallel what happens in psychosis. This idea of psychotomimetics was for her and Dr. Leo Hermle, another investigator at Gottingen, sort of a model paradigm that they were using. There is another fellow in Germany, at Ulm, named Dr. Manfred Spitzer, who has done some really elegant work with PET imaging and psilocybin. He was at Heidelberg, but has recently moved to Ulm. In the process of moving, of course, his research program has been more or less delayed, but I would expect that he'll probably start working again. He was doing some really creative things, looking at the effects of psilocybin on cognitive processing. Of course, in Switzerland, Dr. Franz Vollenweider is probably the most prolific clinical researcher with these drugs today. I think in every case they haven't had the difficulty getting the drugs and getting the permission that you have in the United States. It's just incredibly difficult to get permission in the United States. Rick Strassman spent a couple of years in dialog back and forth with the FDA in order to get a study approved and was really very tenacious and very persistent. He had some things going for him in terms of DMT having been studied in humans before. It had been speculated that it might be an endogenous psychotogen, might be produced within the body, that there were mechanisms such as monoamine oxidase within the body to degrade it quickly, and it was short acting. He had a lot of things going for him in terms of selecting that particular drug to work with, and it still took him years to get the study going.
According to an interview with him in an earlier issue of TRP he thinks that getting research with psychedelics approved now is easier, that he was the first one to break the resistance after a long time. Do you agree?
He was the first to do it, he showed it could be done. To some extent I think it was also related to personnel and some administrative changes at FDA. I don't believe it's quite as easy now as when he did it. There was a particular individual at FDA then who worked with him. The FDA had a lot of projects that were on hold and they met and decided that if studies were well designed there was no reason that they should remain indefinitely on hold. Strassman has to be given credit for being the first one to show it could be done because for so many years people would just routinely say, "You can never get these into humans the government will never allow you to do studies in humans." I met countless numbers of people and I'd say, "If you work and if you're qualified, you can do it," and they'd say, "Oh, no, no, no, no, you can never get them into humans." Strassman demonstrated that wasn't true by saying, yes, if you are qualified, if you have the academic credentials, if you've got a well-designed protocol and if you are willing to jump through all the hoops you can do these studies.
Yes, but Richard Yensen is still waiting. His study with LSD is ready to go and has been for two years.
You have to consider what the FDA and the DEA are looking for. Strassman was an Associate Professor of Psychiatry at the University of New Mexico who had an experienced staff of people there who had helped design his protocols. He had a support team there that was going to take measurements and draw blood samples. He had the whole structural setting of a hospital as a back up and infrastructure. Richard Yensen has the Orenda Institute, which I understand is within his personal residence. It doesn't have the infrastructure of a hospital, he's not in an academic research department, and he doesn't have all the other tangibles that you find in a research institute. I think the regulatory people look at Richard and look at the structure / infrastructure, the support staff, clinical experience, and so forth. A lot of factors come into it other than just the fact that you are tenacious and work hard. You have to consider who the people are in the government agencies that you're dealing with. They may see themselves as trying to prevent some kind of public relations disaster.
So that supports you trying to maintain such high standards at Heffter.
Exactly. You have to.
Let's talk about your research. There was an article in the first Heffter Review and of course in the Journal of Medicinal Chemistry about these new, extremely potent phenethylamines you came along with. Can you tell us about that?
Most of the phenethylamine psychedelics are very flexible, floppy molecules. We have essentially tried to constrain portions of those molecules into particular shapes with the idea that when these things bind to their brain receptors, if we could lock them into the same shape that the receptor had, their potency would increase, and that would give us some idea of what the shape was, much in the way to use a simple analogy that you might start grinding on blank keys and sticking them into a lock and trying to turn it, then grinding them some more until you finally find one that turns the lock. It is sort of the same kind of idea, except we were locking parts of the molecule. We had played around with the two-carbon side chain and locked it into a lot of different shapes. Some years ago we started to lock the methoxy groups in 2C-B or DOB and found that there were particular orientations that they had to be in to have the most potency. And that defined the shape that they had when they bound to the brain serotonin receptors. That increased the potency. Then I had a student working with me on his PhD Matt Parker and he was talking to someone in another research group who was making aromatic compounds and realized that what we had in some of the rigid compounds we'd made with the methoxys locked was the possibility of converting them into completely aromatic compounds. So he took some of these precursors and made them completely aromatic with three flat rings. When we tested them they proved to be extremely potent in the animal models and had extremely high potency at the receptors. In fact, as far as we know, in the models we have, in the animal models and the receptor binding assays, those are the most potent drugs in binding to these particular types of brain receptors that have ever been discovered.
Are they more potent than LSD, which was the so-far unmatched standard?
Yes. If you actually look at the ability of LSD to bind to the serotonin 2A receptor, which is the presumed brain target, LSD isn't actually quite as potent as things like DOB or DOI. They are slightly more potent. But in terms of the animal model, when you look at the whole animal, LSD was far more potent than any of the simple phenethylamines. We think there is possibly some sort of interaction in the brain between the different things that LSD does that amplifys its potency beyond what you would predict just from its ability to bind to serotonin receptors. When we tested these rigid phenethylamines in rats, they turned out to be more potent than LSD. That is the first example of phenethylamine compounds that we've tested in our animal model which actually were more potent than LSD. They are also tremendously more potent in receptor binding than LSD, about a hundred times more potent. In rats, of course, the increase in potency is not as great. It's maybe two- or three-fold more. But still, to find a very simple amine that has such high affinity tells you it is binding and activating that receptor very well.
You mentioned lysergamides. What are the recent developments there? LSD is fifty years old.
We did some early work where we played with the methyl group on the nitrogen of LSD and replaced it with propyl, ethyl, and allyl. All those compounds were at least as potent or even more so than LSD. But that wasn't really exciting, because it kind of made sense from what we knew about what the receptors were looking for. We have focused most of our attention on the diethylamide, because the potency of LSD is so exquisitely dependent on what that amide is. We've made a lot of compounds that we haven't even published data on. We have receptor binding or rat assays, and I think it won't be too long before we write some sort of review and summarize everything we know. We have some new compounds now where we've also used this rigid analog approach to constrain the diethylamide into different orientations. We know from our receptor binding data that one of those orientations is much more potent than the others. We will be in the process of getting further biological data on those in the near future. I think that will be very important work because in that paper we will define what the shape of those two ethyl groups is when LSD actually binds to its receptors, or the key receptor that the rats are responding to, at least. LSD binds to a large number of receptors, not just serotonin 2A receptors. One of the things we're hoping is that by constraining the diethyl groups into these differing orientations, these molecules, three different rigid LSD analogs, may bind to subsets of the total set of receptors that LSD binds to. That may give us a better clue as to why LSD is so potent, beyond what you'd predict from the binding to serotonin 2A receptors. I'm really hoping that those will be key compounds. When we write that paper, we'll probably put some other compounds in and follow it up with some of the things we haven't published, really try to define the nature of that part of the binding site in the receptor, and some of the other receptors, dopamine receptors, and some of the other serotonin receptors. I think that's really an interesting area to look at. We've done some work already with another serotonin receptor called the 5HT1A receptor. LSD binds to that receptor as well, as do things like DMT and psilocin. And we know that receptor has a very different shape around the amide group than the serotonin 2A receptor. So we think we might be able to target lysergamides to different kinds of receptors by very carefully tailoring the nature of what's attached at that location of the molecule.
You have already done a very good job of tuning the potency of the molecules. Would that be a step toward tuning the effects?
Well, I think it would certainly be interesting if you could ever do clinical studies on these molecules. You have a molecule like LSD that binds to fifteen receptors and has a certain qualitative effect, then you somehow parse that into three molecules that all have a subset of the receptor actions of the parent molecule. Now if you can do clinical studies I think you're going to be able to relate some of the clinical effects to those specific receptors. The analogy I use is having a series of simultaneous equations with X unknowns. With LSD you've never had that possibility before. You've had this unique potent agent that binds to all these different receptors. The only way it was discovered that the serotonin 2A receptor was a target was by having other classes of psychedelics, the phenethylamines and tryptamines, and the only thing they had in common with LSD was binding to the serotonin 2A receptor. So in a sense, you had a series with those. But still, when you go back to LSD it's a unique compound which has unique properties, and we still don't have other examples to really be able to pin down what effect LSD has at all these other receptors. We are hoping that by playing with the amide function we can develop a series of compounds that will really help us to understand the importance of that particular part of the molecule in targeting different receptors and subsequently in producing different behavioral effects.
You already mentioned animal models and the rat studies. Unfortunately, you can't go into human trials. Or perhaps you don't want to go with every compound into human trials. But you test them somehow. How does this work?
What we use is probably, in my opinion, the best assay that you can use in a laboratory outside of a primate or a human. Essentially what you do and the rats are not mistreated at all, so it's not stressful you put the rat into a chamber. It's just a small cubicle that has two little bars protruding on one wall, one on the right side of the wall and one on the left side of the wall. In between the two bars is a little opening that delivers a food pellet. Essentially what you do is put the rat in and let him wander around. He eventually learns that if he presses the bars little food pellets appear in the opening. Once he learns that if he presses a bar he gets this reward then you shape his behavior. You turn on only one lever so it activates the food pellet delivery only when the rat has been given a particular drug or not been given a drug. For example, suppose we put the rat in the box on Monday and we don't give him any drug at all, or we give him an injection of just saline or placebo. We turn on the left lever. Now the rat presses the left lever and gets his food reward. If he pushes the right lever nothing happens. We put him in on Tuesday, and we give him an injection of LSD. But now, we turn on the right lever. So he only gets a pellet when he presses the right lever. If he presses the left lever, nothing happens. It's actually done over a period of two to three months, and by a variation of that procedure, you teach the rat that if he has received no drug, he presses the left lever. If he has received LSD, he presses the right lever. It's called two-lever drug discrimination.
That must be pretty laborious.
Yes. In the beginning you have to teach the rats how to press the lever and then you have to couple the lever-pressing with particular drug treatments. We also train some of the rats to press the right lever if they're given LSD and some to press the left lever if they're given LSD, so you don't have the possibility of a sort of "handedness" in rats, that rats might always press with the right paw if they've been given LSD, or whatever. It's all computer-controlled. The computer knows which rat is trained on what drug and which lever he should press, and it keeps track of all the presses. So on any given day, once we have these rats trained, if we give a rat LSD and put him into the box, in fifteen minutes he may press the correct lever two or three thousand times.
Just one rat? So often?
Yes. It's unbelievable. They just press and press and press.
Do they eat that much?
No, they can't eat that much. What happens, actually, to save money, and because they press so many times, they only get a food pellet every fifty times they press. So the rat has to press the lever fifty times. He hears the click, he gets the food pellet. We don't give them all the food that they want to eat. We give them enough food so that they're maintained at about 80% of the weight that they would have if they could just eat all the food they want. So when they go in the chamber they're always a little bit hungry for a snack. These pellets have a high carbohydrate content, so they're kind of like rat candies. So, when they go in the box, they know if they press the correct lever fifty times they'll get a little rat candy. So they start pressing. We've trained rats not only on LSD but on other drugs as well LSD, MDMA, DOI, and amphetamine. And the beauty of this assay is the rat only responds to the drug he was trained on. So if we have rats that were trained to respond to LSD, if we give those rats amphetamine they respond as if they were given no drug at all. So the rat either says it was like the training drug or it wasn't like the training drug. "You gave me LSD," or "you didn't give me LSD." It's a great assay.
So that's your way of testing the drugs.
So the rat thinks this is LSD-like or MDMA-like?
Exactly. The rat tells us if he thinks he was given LSD or not. And what we do then is we test a large number of rats. We have anywhere from twelve to fifteen rats and we start giving them different doses of drug. We find the dose at which all of the rats say, "You didn't give me LSD," and the dose at which all the rats say, "You gave me LSD," and then we find the dose at which half of the rats say, "You gave me LSD," and half the rats say "You didn't give me LSD," so it's sort of intermediate. Then by using that dose response it's called a dose response curve, which tells us what percentage of the rats think it's LSD depending upon the dose that allows us to estimate the potency of any new compound relative to LSD.
So the animals don't die during the assays?
Oh no. We avoid doses that are toxic. Because we have so much invested in these rats, we try to be very careful. The rats cost us a lot to maintain. We pay more to maintain the rats than it would cost for them to live in a hotel. For rats, it's pretty expensive. By the time you have all the costs in housing, plus two to three months of training, and then after you train them, calibrating them to make sure they're working correctly and giving the kind of numbers that you expect, by the time you do all that plus the time of the personnel to do all the training, each of those rats is very precious. For the woman who is my research associate, each of the rats has its own personal name and she talks to them. She treats these animals almost like little people. So we really treat them pretty carefully. It's rare that we ever give a rat something that's toxic. We usually have a good idea before hand of whether it should be toxic because of the kinds of compounds we work with. In fifteen years I can't remember if we ever lost a rat to an overdose, but if we did it was a real accident. I know when a rat gets sick or dies because my research associate gets pretty upset, because she's the one who trains them.
As sophisticated as this behavioral model seems to be, whatever happened to self-administration? Albert Hofmann did it fifty years ago and if he had not done it, we would perhaps not know about LSD and its effects. And of course, Sasha Shulgin did it and wrote two books about it. So why is this no longer acceptable?
Self-experimentation has gone the way of the five-cent cigar. I think Shulgin was probably the last in the tradition. Science in general had a long history of chemists tasting compounds. That was sort of a traditional thing that was done. After the drugs became popular in the 1960s, I think the use of drugs was somehow defined as immoral. It really has become a sort of de facto definition of drugs, that using them is somehow inherently immoral. Self-experimentation, while it would only seem to involve risk to the experimenter, I think has been defined in a larger context as somehow something very bad. I think that came with the whole drug war, the anti-drug thing, or maybe it even preceded it. You had such an over-reaction that no use of a drug was tolerable, that it's criminal. If you talk to a lot of people today about Albert Hofmann taking 250 micrograms of LSD on purpose they say, "Oh my God, it's unbelievable, why did they let him do that?" That would not be tolerated at a company today. If you discovered a drug like LSD through a self-experiment today, while working at a modern pharmaceutical company, you would lose your job.
But he didn't know what he was up to.
No, but after he did it he still gave it to Dr. Stoll and other officials in the company and they all took it and agreed it was really remarkable. And they gave it to other people. There wasn't this sudden, "Oh, my God, this is horrible stuff, we can't let anyone know, no, we'd never take it." It was a completely different philosophy than you would see today. I believe that if you discovered a drug today that was as profound as LSD the company would probably keep it under wraps because they wouldn't want anyone to know that one of their scientists had deliberately taken it. You'd probably never even hear about it. So I think things are not going to change in the foreseeable future, but I believe that Shulgin is right. I think he is right you have the right to do with your body as you see fit if you don't become a burden to society. I think a trained scientist, a pharmacologist, working within a series of compounds as he did, generally knows the risks of other types of toxicity. These compounds are pretty much known not to be cancer-causing. They are known not to cause cardiovascular damage, and not to damage organ systems. The only risk was basically psychological. That was a risk he assumed. I don't see that as immoral or evil. Certainly there were people who defined it that way, and when he wrote his books they were aghast that he would put that out. They thought it was just horrible. I don't see it that way. But in fact, I couldn't do it here. I'd lose my job. People who do research legitimately would lose their jobs. They'd say you were setting a bad example, or "sending the wrong message."
How about this researcher Gordon Alles?
The double conscious technique?
Yes. Who was this guy?
Gordon Alles was a pioneer psychopharmacologist. He may have been the one who discovered amphetamine, but he discovered many amphetamine analogs. He was the first person, I believe, to report on the effects of MDA.
Yes. There was one of those symposia, maybe in the fifties, and I don't have it on my shelf but I've read it, where he described the effects of MDA. He was sitting in an office, way up in a building, and he could hear people talking down on the street that normally he couldn't hear. And he could hear their conversation. He saw these wisp-like smoke rings that were materializing in thin air. He actually first described the effects of MDA and he tested many compounds on himself. I think that may be the model that Shulgin has referred to as the double conscious technique. The double blind technique is where neither the subject nor the researcher knows which drug is being given to the patient. But Gordon Alles called it the double conscious technique because he said, "I not only gave it to myself, but I know what it was, too," something like that. So it's kind of humorous.
One recent event where a drug that originally stemmed from your lab caused a lot of trouble, in fact tragedy, was when 4-methylthioamphetamine hit the streets. The pills were marketed as "flatliners."
Yes, MTA. I think that Sasha Shulgin knew that people watched the literature for papers that had him as an author, and a lot of the things he made may have shown up in different places. And this is something he and I talked about. I never had really thought that much about people watching the things that my laboratory did, although I'm sure there must have been people, and that is a good example of it. When we developed methylthioamphetamine, we were looking for serotonin-releasing agents. It had become pretty clear by that point in time that drugs that had an effect like MDMA not only had to release serotonin but also had to release dopamine and had an effect on catecholamine systems. Methylthio-amphetamine didn't have any effects like that. It was a very specific serotonin-releasing agent. We thought it might actually have some uses as an antidepressant because it was so specific in its effect. We published papers on it including one showing that it did have an effect similar to the SSRI class of serotonin uptake re-inhibitors that are used now as antidepressants, like Prozac. It had that effect. But in one of the papers we published, we reported that in rats trained to recognize MDMA in the drug discrimination model that I talked about, when we gave rats methylthioamphetamine, they responded like they had been given MDMA. Rats will do that, because the feature of MDMA that they pick up on is the serotonin release. They don't also recognize the dopamine release. Rats only respond to one component of the drug that you give them. They can't recognize multiple components. Evidently someone saw that paper and said, "Hmm. MTA is a drug that the rats recognize as being like MDMA. Let's make a bunch of it." So they evidently put this material out in 125 mg tablets and sold it. I don't know how many deaths there were, but certainly at least a couple that I heard about. My impression is that these people died because they took these tablets and not much happened, and so they took more and not much happened, and then they took even more. The problem with methylthioamphetamine is it doesn't just release serotonin, but subsequent to some of the papers we published we found that it also inhibits monoamine oxidase A, which is the enzyme that destroys serotonin. So MTA is a drug that is releasing serotonin from neuron endings, but it's also inhibiting the enzyme that would destroy all that excess serotonin. What happens is you get these incredibly high levels of extracellular serotonin, and I think that's what led to the fatal reactions. These people had huge amounts of serotonin being released in the brain and their cardiovascular systems.
What do you think about those who brought it on the market and who produced it and who sold it? Were they just not thinking at all, or are they are just mean assholes?
I think they were pretty irresponsible and they were looking for a quick way to make some money. Obviously these people who made it hadn't taken it themselves or they would have realized it really didn't do anything. And if it doesn't do anything until you take six or seven tablets why didn't they manufacture tablets that had 600 mg or 700 mg in them? I don't completely understand it. I think the idea of putting a drug out without knowing what its effects are is just totally irresponsible. There are some drugs that are available on the recreational market, like 2C-B and DOB, but those have been used for so many years and for so long that the toxic effects are generally recognized, and those things are seen to be relatively innocuous. But new drugs to come out and just make thousands of tablets of something for which there is only one or two reports in the literature on rats and no toxicology I think is totally irresponsible. We're fortunate that only a few people died. I mean you really don't know what will happen. When you're doing something like that, when you've found some compound that's been reported in a publication and it talks about rats and you have one or two papers that talk only about a few kinds of assays, if that drug would produce some sort of extreme cardiovascular toxicity, or would produce liver failure, or kidney failure, and you sell tens of thousands of the tablets, suddenly the hospitals are deluged with 5,000 people with kidney failure after a rave and they don't know what's happening, I mean, the tragedy could have been enormous. That's why I say we are lucky that only a few people died. I think the potential for tragedy was enormous there with a compound that had no history at all.
Do events like this hurt your research or what you want to accomplish at Heffter? In a way that it harms even more the public opinion about drugs?
Oh, of course. Because now people can say, "Well, here's another recreational drug, and see, it kills people. These things are dangerous. We know they're dangerous. We've been saying that they're dangerous and nobody listens to us and now we have two more dead people three more dead people who took this drug. Won't these people ever learn? Of course it hurts research.
Part of the reason why these new drugs are on the market, in my opinion, is because drugs that are comparably safe, like 2C-B, have been banned in the first place. Would you agree? In the Netherlands, 2C-B was scheduled only two years ago, or something like that. With that drug readily available, I don't think there would have been a problem with MTA.
You can get into very tricky debates here because I think you could make the legitimate argument for most drugs that the proscription or banning of drugs that are relatively safe almost invariably leads to the availability of higher-potency, more dangerous drugs. If the drugs were in some way more available or accessible then the users might be satisfied with those drugs, but when proscription occurs and of course, this is the whole problem with the criminal approach to drug use invariably you create worse problems. You see that with almost every situation where you proscribe a drug. So sure, if you make it difficult to get things like 2C-B, or even LSD, which is not a toxic drug in terms of organ systems if you make these drugs unavailable and completely shut them down or as much as you can – then you create opportunities for people to bring out things that are not scheduled. "This is a new legal high, this is a new brain drug, this is a new drug for raves" and so you create opportunities for things that in some cases could be much more dangerous than the drugs they had controlled in the first place. I don't know how you enter that debate, because the people who control things are always going to say, "Well, we have to control these things, we have to proscribe them. People take them at their own risk." And even if you say, "Well, what you're doing is creating opportunities for people to produce drugs that are even more dangerous," their response is, "Well, we'll just have to catch them when they do it."
Have you heard that they are producing a sublingual salvinorin tablet?
Yes, that's true. And some folks tried to market an instant pharmahuasca tablet, with 5-methoxy-DMT and harmine in it.
As an unscheduled, not explicitly scheduled substance.
Here, too. Of course, it is covered by the Analogs Act.
Right. The United States has the Controlled Substances Analogs bill, which covers virtually anything that comes out as a recreational drug.
Yes, but are you aware of any lawsuit where anybody has actually been accused and has been sent to jail or whatever according to this Analogs Act law? As far as I know it has never been applied. Am I wrong?
I haven't followed that law closely. I know that the Analogs bill has been brought to bear in a couple of cases, but I haven't really followed the law to know how many. Certainly, with any new drugs that come out that is going to be the case. The DEA will prosecute. If you have a 5-methoxy-DMT and harmaline combination that people were taking, if it becomes popular the DEA will say it's an analog of DMT and something else and they will use that. I mean, there's no doubt in my mind. In Europe, if they still must explicitly schedule any drug that is proscribed, it may be more difficult. But I think even there, in England, they went through PIHKAL and picked out every drug in the book and made a listing, and said, "We propose to schedule everything that's in PIHKAL."
That's funny. But it's kind of tragic in the way the book itself provided the list of chemicals.
It gave them things to watch out for.
Do you follow the medical marijuana movement at all? Have you entered that discussion?
I haven't really done any work on marijuana. The Heffter Institute has essentially decided that we're not gong to enter that debate at all. It's just simply too controversial. The marijuana laws represent a political position the governmental authorities. There have already been hearings a few years ago by Judge Francis Young, and he ruled that marijuana should be moved to Schedule 2 and the DEA said, "We're not going to do it." This debate has been going on since Harry Anslinger first pushed the scheduling of marijuana back in the late 1930s. It is really a political football. I think the people who advocate medical marijuana have legitimate concerns. There is evidence that marijuana is medically effective. And if people having chemotherapy want to smoke marijuana instead of taking commercial drugs, I think it should be their right. We see the health food movement and the nutriceuticals movement, and nobody's concerned about any of that. Marijuana is a natural plant. I personally don't see why it should not be available for medical uses, but of course it is a political thing. The government has spent millions of dollars on drug campaigns, has spent years and years trying to convince everybody that marijuana is a great evil and the gateway to every kind of possible sin imaginable. They're not about to back off unless they're challenged vigorously in some court of law. I don't really know what will happen. But Heffter is basically disassociated from that because of the political controversy. That's an issue and a debate we just haven't gotten into.
In the beginning of our interview, you talked about how the government really panicked about psychedelics in the late 60s and all the propaganda that was put out at that time that LSD alters your genes, alters your brain, that you'll never have the same brain chemistry after you have taken a hit of LSD I can still hear these opinions today from otherwise reasonably well-informed people who are in other ways open-minded, but when it comes to these topics you can hear them repeating the most ridiculous government propaganda. Why do you think the whole issue is so emotionally charged, and what do you think should be done about it?
Most of the propaganda has been disseminated by the government through the media. People in general tend to believe things the government says. There hasn't been any campaign to educate people with respect to the medical value of these drugs. I gave a seminar to a group of retired people some years ago middle-class, retired people who were most probably conservative in their political views and I talked about the use of LSD to treat terminal patients. They had never heard anything like that before. They couldn't believe it. And they were very interested to hear about how LSD had been used for that and was effective in 60 to 70% of those patients. They asked me why did it work, and we got a very lively discussion going where they were genuinely interested. And they said, "Well, we've never heard this before." Whenever you have a war, you have to really demonize the enemy. You demonize Saddam Hussein. You demonize Slobodan Milosevic. You demonize drugs. They can have no redeeming qualities. In order to fight a war, the enemy can have no redeeming qualities. If they do, then you might have to hold back, and not use the most powerful weapons possibleyou might have to have some compassion, but you can't wage a war if you have any compassion for the enemy. You have to kill, to completely destroy the enemy. So you have to demonize things. And I think drugs have been demonized to the fullest extent possible by society. But the social aspects cannot be overlooked. During the 60s, during Viet Nam, there was a tremendous social upheaval in the United States that didn't occur in other countries. I think LSD is associated with that in the minds of many of the older people in the population. The hippies were associated with drugs and anti-war protests. So there is a whole mindset that sort of sticks it all together. Many of the people in authority positions can't think about LSD without thinking about hippies occupying university administration buildings and hippies burning flags and hippies tearing up their draft cards. So I believe there is a kind of gut reaction to drugs that transcends the pure fact of the existence of the drugs themselves.
Do you see a chance that if you came up with a new substance without a scary history like LSD that you can separate the perception of this drug, the impressions you make with this drug on public opinion, from those of LSD?
I think if you do it carefully, it's possible. I think the Heffter Institute wants to try to do something like that. Certainly we've gotten signals from some people who are in positions of authority in other countries that if we could develop a drug th
Tags : psychedelic
Rating : Teen - Drugs
Posted on: 2003-12-02 00:00:00