At Mindstates IV, Dr David Nichols, chemist and pharmacologist, professor of medicinal chemistry and molecular pharmacology at Purdue University, proposed a novel alternate reading of Albert Hofmann's famous 1943 "Bicycle Day" and a brief overview of his research.


I'm here to give you a report from the institutional research division of your community. If you pay taxes to the IRS, you support my research to understand how psychedelics affect brain chemistry; thank you.

Since we're just a slight bit past the 60th anniversary of the discovery of LSD, I thought I would have a little audience participation fun, and give you a little insight into how the scientific process works. Because, often times in this community, "scientist" has somewhat of a pejorative connotation. I want to show you how we're not so different, and do a little experiment.

You know the way science works. We make observations, we develop or formulate a hypothesis that is consistent with those observations, and then we attempt to carry out experiments to test the hypothesis. I don't think we'll be able to carry out the experiments to test the hypothesis, but what I want to do is develop a hypothesis today that I think you'll find very interesting. But the first thing we need to know is what kind of a database we're working with. What I'd like you to do is raise your hand if you have read Albert Hofmann's account of the discovery of LSD.

[nearly everyone in the conference hall raises their hand]

Ah, just as I suspected. So we have a good database, and probably an educated database.

What I want to do now is another experiment. I want you to raise your hand and hold it in the air as long as I am stating things that you hold to be true, and when I say something you believe not to be true, then put your hand down.

So, the first thing I'm going to say, if you believe it to be true, raise your hand, and keep it up there until I say something you disagree with.

On April 16, 1943, when Albert Hofmann accidentally ingested LSD, he ingested at least 25 micrograms. Now keep your hand up until I say something you disagree with.

[most people in the audience raise their hands]

On that same date in 1943, Albert Hofmann ingested at least 50 micrograms of LSD.

[a few people put their hands down]

On that same date in 1943, Albert Hofmann ingested at least 75 micrograms.

[several more people put their hands down]

And then again, on that date in 1943, Albert Hofmann ingested at least 100 micrograms.

[more people put their hands down]

On that same date, Albert Hofmann ingested 150 micrograms.

[only a few people still have their hands still up]

Well I think I've already proved the point. I think there's a consensus that Albert Hofmann must have ingested at least 50 to 75 micrograms, and there are people in here who believe he must have ingested 100 or 150 micrograms. Now we've estimated, with this educated database, approximately how much LSD he must have accidentally gotten inside himself.

Now, we'll do the same thing again. In April 1943, after his accidental ingestion, how many people believe that Albert Hofmann would have experienced the effects of LSD for at least 10 hours, based on that dose?

[Several people put their hands up]

Now if we believe he took LSD, and if we believe he took 50 to 75 micrograms -- that's the context -- how many people believe the effects should have lasted at least 8 hours. [many more hands go up] How many believe the effects would have lasted at least 6 hours? [more hands go up] How believe the effects would have lasted at least four hours? [nearly all hands are up at this point]

Now, how many people believe that the effects of a 50-75 microgram dose of LSD would only have lasted two hours? [nearly all hands go down]

We read from his account:
"I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors. After some two hours (emphasis added) this condition faded away." (Hofmann, 1983).

Well now, that was a conundrum for me. I read that and I thought, "gee I'm a scientist, and this doesn't make sense with what I know." And for most of you, I think, that doesn't make sense either. So, the question: how can we formulate a hypothesis consistent with this observation? We need to consider a few things.

We know that Albert originally synthesized LSD in 1938 as part of an ambitious program to make a number of lysergamides. LSD-25 was only the 25th in the series. I actually don't know how many of those compounds he made, but let's assume he only made 30. So we had up to 30 in the series. He may have made many more actually, but at least say 30. And they were all tested; he sent the pharmacology department LSD-25, 24, 23... and so forth. They then say, "LSD-25: not interesting." The assays of that day really didn't provide much information; they were very unsophisticated. But five years later, Albert has a hunch that the pharmacology department missed something on this 25th in the series.

Now that's kind of peculiar. I'm familiar with the drug industry, and I've actually started a small company myself. Imagine you're a musician, and you've created this musical piece. It's really wonderful; it's one of the best pieces you've ever written; you play it for people, they think it's great. And this one artist comes down. He's very creative but he has no musical talent at all, really tone deaf, he listens to your music and he says, "Man that sucks. You missed something. There's something missing." Now you as a musician are probably going to have some sort of a gut reaction to that. And even though the pharmacologist at Sandoz was probably a friend of Albert's, can you imagine this chemist coming down the hall and saying, "You know, I made this compound five years ago, out of this whole series, and there's this one compound, LSD-25, that you said was uninteresting... but you must have missed something. I just have this 'peculiar presentiment,' this strange hunch that you missed something." You're going to look at Albert and say, "You know, really, I'm an expert in pharmacology Albert. We tested it very well."

The Germans and the Swiss are very precise chemists, and pharmacologists, and scientists. There wouldn't have been any question about this being somehow mis-analyzed the first time.

This is another interesting point. Why the 25th? We know that only the 25th in the series was active. Any other compound that he made -- and I've made many of them, we've tested many of them -- none of the others approach LSD, either in its sophistication or in its potency. Only the 25th. And this is unusual. In pharmacology often you have a regular series. If we think of things like DOB, and DOI, there's a kind of regular progression. They all fit into a kind of subgenus. And LSD doesn't. We don't call the other members of the series Albert made as LSD something or other, but if we had LSD-23, 24 and 26, they would all be one-tenth the activity of LSD-25. Peculiar presentiment indeed!

As I've said, Swiss and German chemists have a reputation -- today and back then -- for being absolutely meticulous. If we had gone into Albert's lab at Sandoz in 1943, we would probably have found everything in its place, organized in an obsessively neat manner. No dirty glassware, no trash on the floor, meticulous. How in the world did a meticulous Swiss chemist get 50 to 75 micrograms or more of LSD into his body? We don't know.

Another fact: I've made LSD in my lab on many occasions for research purposes, possibly in not so meticulous a manner as Albert Hofmann. Nothing ever happened. I had several graduate students who made LSD as an intermediate for projects. No accidental ingestion of LSD ever occurred. A technician in my lab makes it routinely because we use it as a drug to train our rats. He's learned by experience that he never gets high, nothing ever happens. And yesterday I was talking to Nick Sand, and Nick said, "I made a solution of LSD in DMSO…" -- DMSO (dimethyl sulfoxide) is a chemical that greatly enhances absorption of other chemicals through the skin -- he says, "…I painted it on my skin. Nothing happened." A concentrated solution and nothing happened! How did this very meticulous Swiss chemist get the LSD into his body? I don't know.

The other fact we need to think about is when Albert was a child, he had a spontaneous mystical experience. Now depending on whether you're a psychologist or a psychiatrist or whatever, we could say that Albert had a predisposition to altered states of consciousness.

So what facts do we know? I'm going to formulate a hypothesis. He took a dose that by your consensus should have lasted certainly more than two hours, but it only lasted two hours. He was a meticulous chemist -- a Swiss chemist. Anyone I know who's worked with LSD -- and Nick Sand painted a solution of it on his arm -- didn't get high. This doesn't make sense. And what is this peculiar presentiment? Why the 25th in the series? Inexplicable! And, he was predisposed to altered states of consciousness.

The only hypothesis I can come up with that's consistent with all of these facts is that on April 16, 1943, Albert Hofmann did not get LSD in his body at all. He had a spontaneous mystical experience!

Now if I were working in the lab with a new chemical, and I started having kaleidoscopic visions of wonderful colors and patterns, my first thought wouldn't be that I was having a spontaneous experience. My first thought would be, "What was that new chemical I was working with? I need to tell Sasha about it." [laughter]

I think that's what happened, that's the hypothesis. We can't test that hypothesis, but when I saw Albert in Basel a couple years ago, I presented that particular hypothesis to him and said, "What do you think?" He said, "It's entirely possible." So, that's our little experiment, and I think most of you really didn't think seriously about the discovery of LSD, but it puts a different light on it.

Now one aside to that we could then bring up is this. If the force that caused him to have this peculiar presentiment -- and very peculiar it is -- is the same force that induced him to have this mystical experience, which caused him to focus on this chemical, we can hope it might happen again.


I can't tell you all the things I do but let me just quickly give you an overview of what a hard scientist so-to-speak does, a reductionist scientist.

I look at how psychedelics affect brain chemistry. We make molecules. We make modified LSD analogues, we have a computer model of the serotonin receptor that's in the brain that we think is a target of these, computer generated that we discovered. We simulate the docking of these molecules to the receptor. We try to understand what are the amino acids in the receptor that interact with the different parts of the molecule. Then we look further in, we say when the molecule docks to the receptor, changes occur in the intercellular biochemistry. We look at the changes, how do those occur. My son who is a PhD in molecular biology doing neuropharmacology work at Vanderbilt has then looked even further and said what does LSD do to genetic regulation. He uses micro-array analysis to look at the gene expression changes following LSD in rats, and has seen changes in expression of 80 different genes. And then we have rat behavior where the rats tell us, "I think you gave me LSD" or "I don't think you gave me LSD." So we start from the design of the molecule, using computers, we synthesize the molecules, we then dock them in the receptor. We're mutating the receptor to change the amino acids so we can see how the complementary amino acids in the receptor modify the interaction with the drug. Then we look at the signaling in the receptor, what signaling pathways are turned on. And then ultimately to genetic regulation, where do protein expression changes occur.

We're looking at all the basic science -- preclinical stuff. I didn't have an MD degree so I couldn't do clinical research. This was sort of disturbing to me, but to get around it I founded the Heffter Research Institute, and they're doing all the clinical work. We're studying psilocybin -- in Zürich we have a clinical facility over there, with Franz Vollenweider. Most people know about the University of Arizona psilocybin study in OCD. Most people know about Charlie Grob's psilocybin study in terminal patients at UCLA. Those are all projects funded by the Heffter Institute.

So, we've translated everything from the basic science on into the clinical. I don't know if we can do a whole lot more. I'm doing as much as I can. We're not doing research with LSD, but I believe within a framework of 5 to 10 years, if we continue on and are successful with our psilocybin research, it will be possible to get protocols approved in the United States. We might start in Europe first but I think it will be possible to reinitiate clinical studies with LSD.