The History of Psychedelics

In their joint 2021 Sana Symposium session, Psych Congress Steering Committee Members, Charles Raison, MD, Mary Sue and Mike Shannon Chair for Healthy Minds, Children, and Families, Madison, Wisconsin, and Andrew Penn, MS, PMHNP, associate clinical professor at the University of California, San Francisco and attending nurse practitioner at San Francisco Veterans Administration Hospital, discuss a brief history of psychedelics. In their session, they dive into indigenous origins of psychedelic use, key events in traditional and contemporary uses, and the historical development of ketamine, MDMA, and psilocybin.

Read the transcript:

Charles Raison:  Hey, I'm Chuck Raison and our talk today is, "How do we get here? A brief history of psychedelics."

On the next slide, we can see our disclosures. One of the unusual things I want to add to the disclosure actually, Andrew and I were talking about that this morning is that we owe so much to the indigenous communities in regards to psychedelics.

I really wanted to acknowledge that. I'm talking to you from Madison, Wisconsin, which is uncited Ho-Chunk territory. There's my other disclosures.

I'm really fortunate to be doing this with Andrew Penn, who has as anybody who's been in the Psych Congress family knows has been so involved in teaching mental health in general, but who was so far ahead of the curve in understanding the importance that psychedelics were likely to have to our work. Talking about it, like a light and wilderness, but almost 10 years ago.

Andrew, I'm so glad we're doing this together. You have such a depth of expertise on the history of these substances. Let me turn it over to you.

Andrew Penn:  Thanks, Chuck. I appreciate that. It's a lot of fun to be doing this with you. I am coming to you from unceded Ramaytush Ohlone land, which is now known as San Francisco.

If you're not familiar with this practice of acknowledging the land on which people are coming from, the reason why this matters, at least particularly in this subject, is that across the globe, humans have had relationships with plants, fungi, and in the case of alcohol, with yeast that have allowed them to change their consciousness.

Whether that's ayahuasca in South America or kava in the South Pacific, cannabis in Hindu Kush, or peyote in North America, human beings have long had this complex relationship with nature.

While some of these plants and fungi have been used as intoxicants, more often these substances are sacraments. They're used to strengthen communities. They're used to heal illness and to help people feel in communion with the divine.

The idea of taking them out of their original cultural context and reducing them down to their essential ingredients and calling them drugs to occasion a particular effect is the kind of extraction that has characterized colonialism.

I want to recognize, as a White male descendant of one of those colonial nations, that me delivering a subject that has largely been the domain of Indigenous cultures should be met with a degree of suspicion.

I want to do better with this. I hope that you'll participate in our Q&A, to that extent, so we can broaden our extent knowledge.

The history of psychedelics, for many people, begins in the 1960s with the invention of LSD by John Lennon. No, I'm kidding. To a lot of people, that is the thought, that this is when this began.

The modern history of psychedelics began some 20 years before that when this gentleman, Albert Hofmann, synthesized LSD while working for the Sandoz Corporation in Switzerland. That was in 1938. It was not until 5 years later that he accidentally ingested some, and then had a famous bizarre bicycle ride home, which we'll talk about.

A lot of people forget that in psychiatry, there was this period of serious research that went on for about 15 to 20 years, in which it said that there's about 1000 papers came out of that time in several international conferences.

Many people are only familiar with LSD and other psychedelics as being lumped in with drugs of abuse, as they were called, in the Controlled Substances Act of 1970, which was signed by Richard Nixon. He called drugs public enemy number one and declared the war on drugs, which was carried forth by subsequent administrations.

As I've heard it said recently, the war on drugs has lost and drugs are suing for peace. In the last 25 years, there's been this real thrust of serious research into these compounds, which we'll talk about a little more in here.

I think it's important to acknowledge that this has all happened at a time while the war on drugs has continued, and many people have spent time in prison for altering their consciousness. This history, as you see, each of these dots represents 10 years of time. That this goes back much further than this.

This is Maria Sabina. Obviously, this is a more recent picture from the 1960s, I believe. She was the person who introduced psilocybin to North America. She's a Mazatec medicine woman or a curandera. There are records of psilocybin being used well before that the Spaniards acknowledged it.

They were very fearful of it. They thought it was part of paganism and worked very hard to stamp it out. This tradition goes back in Mesoamerica probably at least 1000 years, if not longer. Then, we go even further back. Now, going further back into ancient Greece.

This last year, there has been a fascinating book published called "The Immortality Key," talking about how the Eleusinian mysteries of ancient Greece were likely, in part, fueled by psychedelic plants and fungi. Even further back than this.

Going back 6 to 9000 years. It's thought that there is evidence of peyote use in North America going back about 5800 years. Anywhere between 6 to 9000 years in North Africa. There is cave painting evidence. The illustration on the right is a cave drawing in what is now Algeria of what appears to be a shamanic character with psilocybin mushrooms emerging from his hands.

Point here is that we have been altering our consciousness for a long time. What we often call the psychedelic period is only a very small portion of known history. Chuck, going to pass it over to you.

Charles:  That's right. Thanks, Andrew.

Next slide.

It's an interesting thing. Why would a plant go to all the trouble? In the case of a molecule called 5-Meo-DMT, why would a toad go to all the trouble of synthesizing these chemicals? We don't know.

Best thought is that often, these chemicals are synthesized as a deterrent against being eaten in unwelcome circumstances. Just to make a point, this is interesting, Andrew. This is not unusual. This is not unique to psychedelic substances or the plants that produce them.

Vegetables. Many of the benefits, many of the nutrients we get from vegetables are poisons. They're things that the plants produce to try to control being eaten. It ties into this idea that I'm interested in about adaptive stressors. That sometimes we benefit, as beings, from a little bit of substances that in larger doses, can be toxic or problematic.

The fact that plants produce these compounds that have this effect on us. It's not surprising that they may have initially evolved as deterrents.

Although there have been some theories that maybe humans co-evolved with psychedelic substances and enhanced our consciousness. The standard brand's evolutionary understanding would be that we are we unexpected end hosts for these plants, in terms of taking them. They didn't evolve to be eaten by us.

It is a very, very fortunate historical accident that we've discovered that they have these properties. Of course, once that discovery is made, then they have this profound effect on individual humans. From that, have this potential to have profound effects on cultures, which we're going to talk about.

Next slide.

Certainly, this is the case in pre-Columbian and North and South America. There's just increasing evidence that indeed, mushrooms and cactus plants played really major roles in a wide range of cultures. From the large-scale cultures of Mexico and South America, down to the smaller scale cultures of places like where you and I grew up.

Andrew, you're lucky to live in San Francisco. I'm a California exile. The use of psychedelic substances was hugely important in indigenous groups in central California, where I come from. They didn't have a wide selection. They had Datura, which is a very problematic cholinergic agent.

They felt so strongly about the use of these agents that one of the things that some of the groups would do at puberty initiation would be to have the young people lay down naked on top of these large anthills, and have their bodies covered with ants. We don't know exactly chemically what it was. This was done to do psychedelic experiences.

Again, widespread use in the new world in pre-Columbian times, again, pointing to the fact that the use of these agents was widespread in human history. It's ancient. Really, in many ways, we are very, very recent interlopers into this space. Andrew, back to you.

Andrew:  This idea of asking patients about their inner world sounds weird. We talk about this in psychedelic work of engaging an inner healer. This is not a new idea.

In addition to these being religious sacraments, as they often were thought to put people in communion with the divine, there's a history of medicine when working with mental maladies asking people to examine their inner worlds.

In ancient Greece, Asclepius was the God of healing. Asclepions were hospitals. This is the ruin of the Asclepion in Bergama, Turkey, where I went a couple of years ago and poked around. It's a rather amazing place. These are some photographs from what remains there.

This idea of engaging your inner world be that dreams or visions, is newer than 2500 years ago. If you think to our more contemporary colleagues, Freud and Jung, this was a significant part of their practice. This isn't anything new for our field of psychiatry, although we've gotten away from it in the last 30 years or so with biological psychiatry.

For the rest of this talk, we're going to focus on what is often referred to as the modern era of psychedelics. Exists starting after 1943. That period went from 1943 to 1970, when the controlled substance act was signed by Nixon.

The early signs of a thaw was, I would say, 1986, when Rick Doblin, one of our fellow presenters, founded the Multidisciplinary Association for Psychedelic Studies. With what was a rather bold and maybe unrealistic vision at that time, at the height of the war on drugs, to make MDMA a prescription medicine.

It wasn't until 1994 when Rick Strassman published the first paper in the modern era on DMT that this contemporary psychedelic renaissance, as it's sometimes called, began. Interestingly, if we bring that forward a day, both of these periods of time have been 27 years long, which I think is fascinating.

I think a lot of times we think that this modern era is fairly nascent and that the previous era went on for decades. In reality, there are now equal periods of time. This is fascinating. It's important to talk about LSD in this modern history because this is often pegged as a starting point.

Again, this is Albert Hoffman. He was a chemist working for the Swiss drug company Sandoz. He was investigating ergotamines as potential precursors to drugs that they then called analeptics. Analeptics were respiratory and cardiac stimulants.

He was working with the rye ergot fungus, and synthesized, accidentally, something called LSD-25, lysergic acid diethylamide. It's a curiosity that we still use the S for sour in German. LAD would be the chemical name for it. It was not until 5 years later.

He synthesized this in 1938. In 1943, it said that he accidentally ingested some in his laboratory and began to feel very strange. He didn't particularly like the feeling. As an empiric scientist, he wanted to understand this better.

Three days later, on April 19th, 1943, he purposely took 250 µm, which he thought would be a very small amount, and began to feel very strange again. Was accompanied by his 21-year-old lab assistant, Susi Ramstein, who stayed with him as he rode his bicycle home, what became known later as bicycle day.

Arguably, she was—not arguably—she was the first psychedelic guide. It was 2 weeks later that she also tried this new compound and became the first woman to ever ingest a modern psychedelic compound.

When he went home, he reported that the experience was at first frightening. Then later, he began to experience kaleidoscopic, fantastic images surged in on me, alternating variegated opening and then closing themselves in circles and spirals.

He discovered this drug, which Sandoz said, "Well, this is very interesting, but we're not sure what to do with it." They marketed it as something called Delysid. They said, "We will give a sample of this to any responsible physician with the request that they report back what they did with it."

Many psychiatrists around the world took them up on this. You have to remember, this is well before prohibition. This is well before the youth culture got hands on it. People like Roland Sanderson, pictured here in the UK, was using it in psychotherapy.

This is Humphry Osmond, who was in Saskatchewan, Canada, who was working with people with what we have now called alcohol use disorder, along with a nurse named Kay Parley, who is still alive. She's 98 years old and has written about her experiences as working with patients being treated with LSD.

Also, people such as Stan Grof, who was trained in Czechoslovakia, but came to Johns Hopkins in 1967. Worked with people like Bill Richards and Walter Pahnke on studies at Spring Grove, Maryland. You have to also remember that before this drug ended up in youth culture, the literature was already interested in it.

This is Aldous Huxley, the British writer, perhaps most famously known for "Brave New World," his dystopian novel. He was introduced to mescaline by Humphrey Osmond in 1953, and a year later, to LSD, also by Humphry Osmond in Los Angeles.

He wrote about his mescaline experience in the 1954 book, "The Doors of Perception." If you're familiar with the 1960s rock group The Doors, this is where they got their name from. This is also the reason why I got interested in psychedelics because I read this book when I was 16. I found it absolutely fascinating.

It was a correspondence between Huxley and Osmond that coined the term psychedelic. The letter that is often quoted was that Osmond said, "To fathom hell or soar angelic, just take a pinch of a psychedelic."

Huxley's last book, "Island," which was written the year before he died, was about a fictional island society, where an unnamed, clearly psychedelic compound named moksha was used, much in the same way that Chuck described the ant ceremonies of Central California. It was used as part of initiation rites, it was used at death, and it was used to solve challenging problems.

Huxley, as a footnote on this, died from laryngeal cancer the same day that Kennedy was killed. He asked his wife in his dying moments to inject him with LSD. He went out of this world tripping.

It was also at the same time that the CIA began its famous MK Ultra operations, where they were seeking mind control or incapacitation agents, and went on, very unethically, to expose many people to compounds, such as LSD, to study their effects.

It was Ken Kesey, who later went on to become a Merry Prankster and the author of "The Electric Acid Kool-Aid Test," who was working at the VA hospital in Menlo Park, California, who was a subject in one of these MK Ultra studies and was exposed to LSD.

It was also around this time that Bill W, the founder of Alcoholics Anonymous, had an LSD experience that was given to him by Betty Eisner. Which he said was similar to the Belladonna experience that he had in the 1930s, which was given to him as an attempt to cure his alcoholism. Very interesting preyouth culture period.

Chuck, you want to talk about what happened next?

Charles:  Yeah. One of the interesting things about things in this universe seems to be that opposites often engender each other. Jung coined the term enantiodromia to get at this idea that one extreme often gives rise to the other, right, Andrew?

This is the ultimate example of that. You got the CIA thinking, "Wow. These agents can be used for mind control to bring people in line." You let the genie out of the bottle, and you'd get these completely unpredictable effects.

In this case, it was very much the opposite effect, where these agents became, in many ways, synonymous with resistance to the ethos of the 1950s.

These 2 gentlemen are often considered to be the heroes or the demons or the villains of this particular narrative. They look like perfectly respectable gentlemen, and they were. On the left is Timothy Leary. On the right is Richard Alpert. They were psychologists and researchers at Harvard.

As you were saying, Andrew, there was all sorts of studying of these agents going on. Leary, he was a serious psychologist. He'd done some serious work.

He was well respected but had a different take on psychedelics, and, of course, over time, and Nixon said he was public enemy number one, eventually became this voice for turn on, tune in, and drop out and had this vision, in fact, that psychedelics would be transformational for society.

Remember, in these years, these are the years that Vietnam is heating up. There's this increasing dichotomy between these older World War II–inspired ways of looking at the world and the youth, which were, at this moment, everything was opening up and had this very, very different vision of nonviolence, world peace.

Let me move to the next one. This goes to our buddy Ram Dass, doesn't it. This is really interesting. The gentleman on the right in the top picture is the gentleman on the right in the bottom picture. This is Leary and Richard Alpert.

Alpert, in fact, went to India and met a guy named Baba Neem Karoli, who was a mystic and had this unbelievably profound experience. As you know, Andrew, I was lucky. Because of some of the work I've done in psychedelics, I was able to spend a couple of days with Ram Dass a few years ago, before he passed. He was a profound human being.

He had a critique of psychedelics, and it was an interesting experience sitting with him because we wanted to engage with him on psychedelics. His position on these agents were hugely useful, but you always come back to your typical self in ways that are frustrating. It frustrated him, so he turned to the spiritual path.

These 2 men, in their different ways, diverged, and you can see the currents of the '60s in them. Leary goes on to then become this emblem of the protest against Vietnam, civil disobedience, eventually, Nixon.

Ram Dass goes this other way, be here now, and gives birth to the new age movement, gives birth to a lot of the spirituality in the '70s, or certainly at least articulating those things.

Then there's the music. It's interesting. I was just reading this morning about LSD. Paul McCartney says, "Don't overestimate the effect that LSD had on our music."

There is no doubt there's been a great deal that, especially LSD but psychedelics in general, changed how music was understood. During psychedelic experiences, music can often be extremely evocative and powerful.

People began to try to create music that got at some of that. "In-A-Gadda-Da-Vida, baby," man, you can hear that shift that psychedelics would drive in the popular culture.

Andrew:  Chuck, I always thought that "Lucy in the Sky with Diamonds" was a reference to LSD, but apparently Lennon denied that. He said...

Charles:  He denied it. He said it was from his kid Julian.

Andrew:  "Alice in Wonderland," yeah, but he said "Tomorrow Never Knows" on "Revolver" is from the "The Tibetan Book of the Dead" that Leary and Alpert wrote after they were fired from Harvard.

Charles:  Exactly. Interestingly, of course, then they went off to Millbrook to do their work.

You and I were talking before we started recording this. I had met Nixon. My dad, we were journalists, he put me on the couch and he said, "Nixon is going to walk right through here."

Charles:  He walked right up. I hopped up, "Oh, Mr. Nixon." I can still see him. He's much better looking in person, actually. One of his more dubious, as you alluded to, decisions was to enact this war on drugs. Of course, his downfall was the end of this era that's on this slide, but one of his enduring legacies was the war on drugs.

Interestingly, the research on psychedelics, I think, is contributing to a current reevaluation of that stance on drugs in general, certainly, on psychedelic agents.

The huge difference between your slide and this slide, and Leary and Alpert did such a great picture with their ties on. This is what happened through those years. When these agents got out of the lab and out of the clinic in this way, they set off a reaction that closed them down. That's the next part of the story, I think, in part.

Andrew:  We're going to talk about ketamine next. To try and do the history of psychedelics in 35 minutes is an unenviable task.

Charles:  ...challenge.

Andrew:  I want to shift gears a little bit and talk about ketamine. We're going to have content on ketamine in this conference. Ketamine has an interesting history because it's not a plant-derived drug. It is a pharmaceutical drug.

It was created by Parke-Davis as an alternative to phencyclidine, also known as PCP, which was also a surgical anesthetic, even though it has a rather sordid history as a street drug. PCP had problems with emergence delirium as an anesthetic.

They created ketamine, which has a similar structure, as you can see there, and works on the same site in the NMDA receptor, which is known as the PCP site. It was safe enough that because it preserved airway function that it could be trialed out in Vietnam as a battlefield drug.

Soldiers were given morphine and ketamine to be able to administer to wounded fellow soldiers to help with their evacuation. It went on to be used largely as an anesthetic and commonly used in veterinary medicine. This is probably where it gets the nickname as a horse tranquilizer, which is probably not well earned. Also, interestingly, in pediatrics.

The reason for this, again, airway preservation and short-acting duration. You can reset a broken arm. The kid will be back to normal in an hour or two. You can send him home. It went on for a couple of decades without anybody appreciating that it had a place in psychiatry.

It did get diverted into the rave scene as a club drug. That was often veterinary ketamine that would be the liquid would be taken, dried out on a hot plate, and then it could be insufflated. That went on. That's probably where it got the name Special K from.

It wasn't until 2000 when Robert Berman and his group at Yale published the first antidepressant study. This is an interesting study because it set out trying to make a psychosis model. I'm aware that my slides are oddly numbered here. You're not imagining things.

Charles:  That's the psychedelic way, though.

Andrew:  This is the embedded psychedelic...

Charles:  It's not linear, man. It's not linear.

Andrew:  That's right. You can eat this presentation when you're done with it.

They were looking to see if they could make a chemical model of psychosis for purposes of studying. What they found was it had this rapidly antidepressant effect within a few hours to a day or so that wore off after a week to two. Sometimes less, sometimes more.

This sparked a lot of interest in a number of papers and replications in both unipolar and bipolar depression. Let's see what number comes up next. We're back to 4. Ketamine never got an FDA approval for depression.

As you probably are aware, most people don't bother spending a lot of money to get a generic drug reapproved for something. It got used off-label all over the place in these ketamine infusion clinics. Often run, interestingly, not by psychiatry, but by anesthesiology, who definitely saw an opportunity for procedural treatment.

Then, in 2018, the FDA approved esketamine, which is the left-handed enantiomer of racemic ketamine, as a rapidly acting antidepressant delivered in an intern nasal spray. Jokingly, often said because psychiatrists don't know how to start IVs. That has had a place now as a rapidly acting antidepressant for the last couple of years.

There's a couple different ways of looking at ketamine. Ketamine infusion model is often done half a milligram per kilogram over 40 minutes. It's often not a robustly psychedelic experience. Some people do have some psychedelic experiences. It's interesting, the makers of esketamine referred to it as dissociative effects, which I think is curious.

Regardless, the journey is more thought of as a side effect. The psychedelic model of using ketamine is more akin to the psychedelic-assisted therapy model, which you're going to hear a lot about over the next couple of days.

This is, as you can see, usually, you're attended to this. The patient is attended by 1 or 2 therapists who have done preparatory and integrative work afterwards.

As you can see, this person is sitting on a couch with headphones and eyeshades on, with their attention directed inward. When ketamine is used in this way, typically, oftentimes, it will be started with a sublingual dose. Then, as the person becomes more conversant in that state, we'll go to an IM push.

In this case, it's much akin to the psychedelic model. The journey is of the interest. A person who deserves a lot of credit for pushing this idea long before it was popular is Dr Raquel Bennett, who founded the Korea Institute here in my neighborhood and has done a yeoman's work of talking about ketamine as a therapeutic.

Then, finally, before I turn this back over to Chuck to talk about psilocybin, which is in his wheelhouse, I want to talk about methylenedioxymethamphetamine or MDMA. This is a drug that was patented by Merck in 1912. They called it methylsafrilamin.

It was never thought to be a drug by itself. It was a drug in a sequence. They were investigating drugs for treating hemorrhage. It was not tested on humans. Nobody knew it was psychoactive.

There was a drug called methylenedioxyamphetamine that was marketed as a diet drug by Smith, Kline, and French in the 1960s, and was also investigated by MK Ultra as an incapacitation agent. Often, there's this misunderstanding that MDMA was created as a diet drug. That's not true.

It sat in obscurity until the 1970s when this gentleman, Sasha Alexander Shulgin, who had made his career working as a chemist for Dow, he created a biodegradable insecticide called Zectran. Which was so popular and so successful that they basically gave him free rein to tinker around and play with chemicals and see what he could come up with.

His backyard hobby was working with phenylethylamines and tryptamines, which are the backbones for psychedelic drugs. He was a classic empiricist scientist. He would make a small tweak on the molecule and then try very small doses on himself. He took copious notes.

If he thought the effect was useful, he would share it with a small group of friends, including his wife, Ann, who is pictured here. They wrote a couple large volumes, "PiHKAL" and "TiHKAL," in which all these experiences and drugs are the formulations for the drugs are preserved.

He had a colleague named Leo Zeff, who was a therapist, who had done a little bit of work with LSD-assisted therapy in the pre-prohibition era, who was working as a couples' therapist in the San Francisco Bay Area.

When he synthesized MDMA, he said, "This is interesting, because it seems to have this capacity for deepening empathy." He thought this might be useful in psychotherapy. Around 1976, he shared this drug with Leo Zeff, who created an anagram. He called it Adam because he thought it returned you back to this primordial state of almost childlike wonder.

People like George Greer, who are using it in psychotherapy, called it empathy. It wasn't until the early 1980s when...Remember, this didn't become a schedule 1 drug until 1985, where this got out into the nightclub scene.

There was some very interesting history about this. Dallas-Fort Worth, interestingly, you could buy this over the counter at bars. There was a large trade in Texas of MDMA. It got out into the nascent rave culture at that time.

You have to remember, this is the middle of the height of the drug war. Reagan's America. Crack cocaine is in "Time Magazine." White powders, people didn't understand the difference between them. The DEA said, "We're going to put this on schedule 1." They did that.

I'm sure Rick Doblin will probably talk about how they did that against the advice of a lot of the psychiatry community who saw its potential effects. Nevertheless, it was put on schedule 1 in 1985.

Rick Doblin goes on to found MAPS in 1986, with the goal of creating the knowledge base that would support an FDA indication for this as a prescribable medicine.

With the help of many people, but spearheaded by Annie and Michael Mithoefer, as the primary investigators in the first studies, began to create the evidence base for this as prescribable and effective treatment for PTSD when supported by psychotherapy. That effort is now in late Phase III and is probably looking at FDA approval if all continues to go well, around 2023.

Chuck, and back to you.

Charles:  MDMA is probably in the lead of agents that are most likely to get FDA approval. Psilocybin, I think, is certainly coming up galloping on its heels. Let's talk about the history of psilocybin.

It's pretty clear that when the Spaniards blew up the culture in Mexico, the Mesoamerican culture, that they recognized that mushroom rights, mushroom use was widespread, powerful part of the culture. It was suppressed and advantaged.

It is amazing to me that all the way into the mid-20th century, people thought it was a myth. They didn't believe it. They couldn't find any evidence for it. There were some folks that identified some psilocybin mushrooms in the '30s, but nothing much came of it.

Where it broke into the Western consciousness, with the ground being prepared by the prior development of LSD, was when a gentleman named Gordon Wasson, who was an executive in New York City, went down to what led to Jimenez in Oaxaca. Had an exposure to psilocybin in a healing ceremony by this curandera that you mentioned, Maria Sabina.

Interestingly, Gordon Wasson's the name that people remember. It was his wife, Valentino Wasson, who was an obsessed genius of mycology. She wrote one of the greatest...There's only 512 copies, apparently, that ever existed, but the Uber text of all texts about mushrooms.

She's the one that got Gordon, the guy we can see here, interested. They wrote a couple of articles. The big one was an article in "Life Magazine." It had a major impact on the culture. It was one of those taboo moments. Next.

Partly because, of course, of this amazing experience she wrote about and partly because it's like an Indiana Jones mystery, oh, my God. It turns out these things have been used for hundreds of years in underground since the Spanish conquest.

Here's our buddy Albert Hoffman again, who was a big player in his early days. He was able to synthesize psilocybin, which is the active ingredient in terms of psychedelic effects in the psilocybe mushrooms. This occurred in 1958. He interacted with Wasson a lot.

Then much like with the Delysid, Sandoz, once again, markets psilocybin as Indocybin. It was on the market from about '61 to '65, so not as long a period. If you dig into the research literature from the '60s and the late '50s, the vast bulk of the work was done with LSD. People did studies with psilocybin, but it was much less frequent.

We've alluded to the fact that 27 years ago this modern era began. One of the linchpins of the institution of that modern era was the founding of Heffter Research Institute in 1996.

A number of people, George Greer, David Nichols, others that were interested in this area and wanted to research got together and put together what was really a very small society where they met, they shared projects and they fundraised.

Those were lean years because there was no way to get any type of government funding for this. They were able to begin set stage and launch what has become now this literally multi, multimillion-dollar industry that's emerged in psychedelics in the last few years.

A key moment in all this. A friend of mine, who actually I'm going to see later today, use this on institutes having the groundbreaking ceremony. Bob Jesse had been a VP at Oracle and deeply believed that these agents had the capacity to offer promise as transformative elements for society, that they could be integrated in society into nondogmatic spiritual ways.

He founded a group called the Council on Spiritual Practices and held a legendary meeting in the history of psychedelics at Esalen around the same time, 1996. Convened folks from FDA, from DEA, religious scholars, and they decided that they were going to pursue active research in psychedelics.

They chose psilocybin and they have asked different people that tell you different reasons. The classic reason was three letters. They would say, "It's not LSD." It doesn't have the same cultural baggage.

I know Bob Jesse also was interested in this molecule precisely because it was available in nature and so harder to patent, harder to control in a purely pharmaceutical way. He had much more of an appreciation for the potential of these plant medicines as plant medicines.

One of the things that Bob decided was they needed to find a top-drawer, squeaky clean researcher who had real pedigree in drugs of abuse and pharmacology. They hit upon a lovely, brilliant gentleman named Roland Griffiths, who was a professor at Hopkins, who had had his life transformed by meditation practices.

He had a sense of the transformative potential of altered states of consciousness. He began, starting in the first years of the 21st century, a very cautious, strategic research program looking at psilocybin.

With him here, he's the white-haired gentleman in the middle, to his left, Matt Johnson is the next generation coming out of Hopkins, has been so important, especially for the substance abuse work, and Mary Cosimano, who has been this astounding guide.

They began publishing a series of papers in healthy normals, showing that psilocybin induced powerful experiences that people actually prized for significant lengths of time. They found some evidence that the psychedelic experiences with psilocybin might change people's personality. Make them more open to new experiences.

Next slide, we could get the next thing.

Then the first clinical studies began in the mid-2000s. Francisco Moreno at University of Arizona looked at psilocybin, without a lot of therapeutic support, for OCD, found a signal. Charles Grob at UCLA published the first trial in cancer, small trial, suggesting it had benefit.

Around the same time, with a lot of support from the Beckley Foundation, Robin Carhart-Harris, David Nutt, Roz Watts began to do clinical and more translational basic science studies to look at what do psychedelics do in the brain that might account for their therapeutic effects, along with the folks at both Hopkins.

We'll talk about it in a second, NYU, showed that these things have antidepressant potential.

Usona, for which I serve as the director of clinical and transformational research, was founded in 2014 with the goal of getting FDA approval for psilocybin for major depression.

Compass Pathways, a commercial entity, was founded in 2016 with the goal of getting FDA approval and European approval for psilocybin in treatment-resistant depression with Bill Linton and George Goldsmith, the leaders of those efforts.

Landmark cancer studies, published in 2016, one from Hopkins and one from NYU, Steve Ross, Tony Bossis, Jeff Guss, showing that a single treatment with psilocybin produced remission rates in depression and anxiety of 70% at 6 months after a single treatment.

Suggesting that these agents were especially powerful, perhaps, for these psychiatric conditions that are framed by existential problems and other problems that these profound psychedelic experiences sometimes address.

Based on these data and based on the gestalt of the field, breakthrough therapy, which is a very special designation given by the FDA for potential treatments that show remarkable promise in unmet medical needs, has been granted.

Usona got the breakthrough therapy in 2019 for psilocybin for major depression, and Compass Pathways got breakthrough therapy in 2018 for treatment-resistant depression.

Then, of course, we've been talking about the pharmacologic activity, but there's also been a lot of advocacy. One of the most interesting was the bill passed in Oregon in 2020 that in 2 years would allow the use of psilocybin with licensed clinicians in very constrained settings.

This is another very novel way that these agents are beginning to come into not just the culture but into clinical practice.

Andrew, I think that's it. We're out of time.

Andrew:  We are, yeah. This is a whirlwind tour.

Charles:  I was talking fast there at the end.

Andrew:  I remember one of my teachers, Bill Richards, said, "Sometimes a psychedelic experience is like roller skating through the Louvre. It takes some time to integrate it because you saw so much." Our audience might need a bit of time to digest this, but I do look forward to getting to answer a few questions after this. Thanks, Chuck.

Charles:  Absolutely. Thanks, Andrew.