0:00
Optimal minimal.
Search this video
0:02
At this altitude, I can run flat out for a half mile before my hands start shaking.
0:06
Can I ask you a personal question?
0:08
Now, what seems like a perfect time?
0:10
What if I cybernetic organism living tissue over metal endoskeleton?
0:20
[music] Hello, boys and girls.
0:24
This is Tim Ferris and welcome to a very bucolic episode.
0:28
that I'm sitting outside with the birds and the bees, the flowers and the trees of the Tim Ferrris show where it is my job to interview worldclass performers or worldclass experts, people who are in the top of their fields.
0:39
And this episode is a panel.
0:42
The panel relates to psychedelic science and it was recorded at the 2019 Milin Institute global conference and this particular panel was standing room only.
0:54
There were several hundred seats all filled and then the entire room was surrounded by people standing which was really surprising and also encouraging to me because this is a conference comprised of primarily investors many of the best investors and uh certainly most lauded and uh objectively in many respects successful CEOs in the world very very unusual uh to to see that type of crowd in that room.
1:27
And a few notes before we jump into it.
1:31
It was a fantastic experience.
1:33
Uh a lot more to share another time on that.
1:34
Uh we have a number of different types of participants in the panel.
1:40
We have incredible scientists, we have investors and we also have writers who have experimented with micro doing.
1:47
And there are a few visuals that are referenced in the beginning, a number of slides that are presented.
1:56
You don't really need the slides to understand what is being said.
2:00
Uh, and I'm a nerd for the science.
2:00
Uh, you will be able to find those slides and links to the studies at tim.
2:08
blog/mpodcast with all of the other links to everything mentioned in this episode. So, if you go to tim.
2:13
blog/mpodcast and search psychedelic, uh, you will certainly be able to find this episode.
2:20
and find all of the visual references.
2:22
But you do not need them to get the gist of what is being said in the first say 9 and a half minutes.
2:27
If you want to skip directly to a firsterson description of micro doing what that is like or what it can be like I should say and certainly not recommending that you do anything that breaks the law wherever you happen to be.
2:44
Color within the lines would be my recommendation.
2:46
But if you are curious nonetheless forformational purposes what such an experience is like that comes up around 9 minutes and 30 seconds in.
2:57
And without further ado because I do make make because I do make [laughter] for [ __ ] sake I do make much ado about uh my introductions.
3:10
Please enjoy this very wide-ranging and detailed conversation about psychedelics and psychedelic science.
3:21
Thanks for coming everyone.
3:21
I'll keep my introductory remarks pretty short, but I'd like to begin with a show of hands.
3:28
How many people here know someone who is depressed despite the fact that they take anti-depressants? Anyone? All right.
3:36
How many people have anyone in their lives affected by addiction?
3:40
alcohol, opiate or otherwise. All right. All right.
3:44
So, the entire audience for both questions.
3:48
Uh, lest we start on a complete downer, let me give an inspirational story.
3:50
And it relates to Katherine McCormack, a name not many people know.
3:55
I'd recommend that everyone look her up on Wikipedia.
3:59
She was born in 1875 in Michigan.
4:01
She was educated at MIT as an undergrad where she lobbyed the administration to change a requirement that women wear hats with feathers because they were a fire hazard in labs. She said very true. So they changed that.
4:16
Uh she also inherited a good portion of the international harvester fortune and in 1953 she met a man named Gregory Pinkis who was developing an oral contraceptive.
4:28
he had lost his funding because his backers didn't see any profit in sight and over the subsequent years pretty much single-handedly financed that development and in 1957 the FDA approved the pill for menstrual disorders.
4:42
So that was sort of the strategic first indication and then later we know what happened.
4:49
And the reason I bring this up is that in total she provided $2 million of funding.
4:54
In today's dollars, it's around 23 million over many years.
4:56
And it was an uncrowded bet through which she was able to completely bend the arc of history.
5:04
And uh I will give some disclosures now.
5:06
So in 2015, I stopped all my early stage tech investing and redirected almost my entire focus to psychedelic science uh for reasons that I think will become clear in this conversation and have been very involved with both Hopkins and Imperial uh which has been incredibly gratifying.
5:23
So with that, let me introduce our panelists.
5:25
We have Christian Angormayer, founder of Apyron Investment Group.
5:30
We have [snorts] Robin Carheart Harris, head of psychedelic research, center of psychedelic research, department of brain sciences, Imperial College London.
5:37
Matthew Johnson, associate professor, department of psychiatry and behavioral sciences, John's uh Johns Hopkins University School of Medicine.
5:44
And I Waldman, author of A Really Good Day, subtitle, how micro doing a mega difference in my mood, my marriage, and my life.
5:51
So, let's begin, Matt, with uh some of your slides.
5:57
If we can bring those up and I'll let you take it from here. Sure. Slide three.
6:01
So, really important before we get into the meat of some of our other conversation is to let you know that we've been ahead as a field in terms of understanding, being very clear about the risks. There are downsides.
6:16
So, you ask any Jedi Knight about the Force, they're going to tell you in addition to knowing the good side, you need to be aware of the dark side and how to keep it at bay.
6:25
Same thing with psychedelics.
6:27
The so-called bad trip is real.
6:29
There are other risks as well, but we published a paper over a decade ago that has now essentially become the bible of how to uh conduct these studies.
6:39
It's been used by institutional review boards at a growing number of universities.
6:43
And I was at the FDA last week.
6:46
They are using these guidelines to evaluate novel protocols.
6:48
recently published another paper um assessing the abuse liability and risks of psilocybin and thoroughly reviewing the scientific literature and suggesting that if psilocybin which is the active agent and so-called magic mushrooms if it's approved ultimately through phase three trials as a medicine that it belongs in schedule 4 based on the data rather than schedule one.
7:14
So we're aware of the risks, we're paving the way, we've analyzed the data.
7:18
Um, in terms of some of the now we've got the the dark side out of the way, what's the light side?
7:25
We can look at some of the efficacy data very quickly.
7:27
So, next slide number four, please.
7:30
We published the largest a couple years ago, the largest study examining psilocybin in the treatment of depression and anxiety associated with a serious life-threatening cancer diagnosis.
7:45
These are people that are freaked out because they're going to die.
7:49
Um, and this is essentially like the addiction work is picking up on older threads of research largely done with LSD back in the 60s.
7:56
You can I'll tell you briefly about our our results here on the right looking our at depression results on the left and then anxiety um results in the right panel.
8:12
the leftmost uh points on those figures under baseline.
8:15
That's those are the high levels that people had when they came into the into the trial.
8:19
And trust me, this is a clinically severe level of depression and anxiety.
8:26
Post one, the next time point on both panels, the red group has received a high dose of psilocybin.
8:34
This is not a micro dose.
8:36
This is a very large overwhelming dose.
8:39
something you don't want to be at a concert on.
8:41
You see a huge reduction into the non-clinical realm.
8:44
I mean, these people are not having problems at those lower levels uh around eight on the scale.
8:54
You do see a good reduction in the people in the blue group and that's a group that to this point has essentially received a placebo.
9:00
actually is a very small dose that you could call micro dose in this trial really just designed to serve as the comparison condition essentially a placebo.
9:13
So that's probably due to the very careful preparation the rapport building and also some of the so-called placebo effect at the next time point post two that's a month after they've re everyone has received the high dose.
9:26
So the people who had gotten the trivial dose in the first round, they have now also received a high dose.
9:33
Now they have dramatically decreased their depression and anxiety just like the group that got it a couple months before.
9:40
And then the really mind-blowing thing on the last point in both panels is at six months you see sustained reductions in depression and anxiety 6 months after treatment from a single highdose session.
9:55
And so in terms of depression, there's understandably a lot of excitement around ketamine which is recently approved for the treatment of depression in that it has immediate anti-depressant effects that last one to 3 weeks which is wonderful.
10:11
Get ready because we might be at an even higher plateau when it comes to sustained effects with psilocybin.
10:18
Um so I'll jump to the the the next slide.
10:24
these along the addiction angle.
10:24
We decided to do something novel that wasn't done in the '60s.
10:30
One of the interesting things is it appears that this isn't just specific to one drug or another like methadone for opioids or nicotine replacement for smoking.
10:38
But the anti-addiction effects of psychedelics seem to be broad-based.
10:44
They get to the psychological meat of addiction.
10:46
So why wouldn't it work for tobacco smoking?
10:49
People have tried to quit smoking.
10:51
We ran a small open label pilot.
10:53
We had dramatically uh impressive results.
10:57
Um at six months we found that 80% of participants were biologically confirmed as smokefree breath samples, urine samples.
11:07
You know, we trust people, but we verify.
11:09
Um those results held up to to 67% at a year and 60% at an average of 2 and 1/2 years after their after their uh target quit date.
11:25
And in this study they had three psilocybin sessions most participants just to tell you how impressive these results are.
11:31
The best medications we have um such as verinicquin which is chantics gets up into the range at 6 months at about 35%.
11:39
nicotine replacement anywhere depending on the study between 10% and 25%.
11:48
It was an open label study so we have to be cautious.
11:51
The the real question is is does this warrant followup and the answer to that is absolutely and so we're in the middle of that randomized trial at this point.
11:59
So this is just a taste of a a number of trials that have gone on in the field that are telling the same story that the earlier era of research from the 50s through the 70s showed that there is huge potential of these psychedelics in treating a number of psychiatric disorders. Thank you Matt.
12:16
Uh I let's jump to you uh because I'd like to contrast or maybe not contrast but add to the scientific discussion the personal discussion and and your experience.
12:27
Could you talk to how you ended up micro doing?
12:30
What micro doing is and what effect it had?
12:32
That's a very big question, but I'll I'll let you.
12:37
So micro doing is the practice of taking a subperceptual dose of a psychedelic drug.
12:43
I mean, you can micro dose anything, but in this case, we're talking about psychedelics.
12:45
So when I say subperceptual, I mean you do not trip.
12:50
You do not have a hallucinatory experience.
12:53
You see no kaleidoscopic colors.
12:53
The idea is to take a do dose that you cannot perceive of any effects but that there is something going on metabolically.
13:04
So um I was experiencing serious depression and uh I had not I had been on SSRIs, I had been on mood stabilizers, I had been on various medications and they weren't working effectively and so I decided to try micro doing.
13:20
I had been a a professor at UC Berkeley's law school and taught a seminar called the legal and social implications of the war on drugs during the course of which I read the psilocybin research.
13:30
I read the research that you know from the very from the 1930s on through the present day research.
13:37
Um and um I was I you know made sure that what I was doing was safe.
13:43
I made sure that the drugs that I was taking were pure.
13:45
That is the most important issue.
13:48
when drugs um are illegal, you have no guarantee that what you get when you buy from the illegal market is actually what you think you're getting.
13:55
And I embarked on a 30-day experiment micro doing with LSD.
13:57
So, what I did was I took a 110th of a dose.
14:04
If you want to say have a hallucinatory experience at Burning Man, you're going to take somewhere between 100 and 200 micrograms.
14:11
LSD is a very potent drug, so we're not talking milligrams, we're talking micrograms.
14:15
I took 10 micrograms and I took it every three days and the effect was profound.
14:21
So the first day I had been in a suicidal intractable anhidonic depression for what seemed like forever because when you're depressed you have very little capacity to remember when you weren't depressed.
14:36
And the first day I took the drug, I swallowed it early in the morning because LSD is activating and I didn't want to inter interfere with my sleep. and nothing happened.
14:45
So, I thought, "All right, well, this was a bust."
14:47
And I got to work and about after about 40 minutes or so, I looked out my window and my dogwood tree was in bloom.
14:56
And I had this thought, "Oh, look. The dogwood is in bloom. It's so beautiful."
15:02
Now, it wasn't like the petals were bursting into color and taking off butterflies in the sky, but I had been unable to appreciate beauty for months.
15:13
And I saw it and I understood it was beautiful and it made me feel happy.
15:18
And that was an experience that was really mind-boggling.
15:22
Over the course of the next period that I was taking LSD micro doses, it wasn't like every day was a really good day, but many days were really good days.
15:32
And um my set point of depression dramatically changed.
15:36
Um my productivity I wasn't in it for mind enhancement for productivity enhancement but my productivity changed dramatically.
15:47
The book that you can buy afterwards at the bookstore was the first draft of that was written in a month.
15:52
Now I've done that before in periods of hypomomania but I had never done that in a period of productive calm flow.
16:02
Um, so, uh, I became convinced at the end of this experiment that this was a drug that had all the therapeutic benefits that are promised by SSRIs.
16:14
But I often say that if those anti-depressant commercials showed a fat person lying in bed not having sex, that would be a more accurate assessment of their effects than a happy lady skipping through a field of flowers.
16:26
And I was a happy lady skipping through a field of flowers.
16:31
[laughter] Yeah, that's great.
16:36
That that image is messing up my segue. Uh, but thank you.
16:40
[laughter] The microgram mig difference is very important.
16:45
So, please take close note of that.
16:47
Uh Robin, let's jump to you next because uh I really want to get your perspective on plausible mechanisms, plausible explanations for how these compounds do what they do because it's not as though at least in the way they're currently administered in most cases they're sitting in your system saturating your system for say 6 months after the sessation of smoking.
17:14
uh could you talk to based on our current understanding based on your current research what is happening and uh maybe you could also touch on the the entropic brain. Sure. Okay.
17:25
So the first thing to say is that these compounds are working on the serotonin system uh an important um brain chemical that modulates a range of different important uh psychological functions.
17:38
you know, uh, mood especially, but also, uh, cognition and states of consciousness.
17:43
And it's a particular aspect of the serotonin system that psychedelics work on a particular receptor subtype.
17:49
It's called the serotonin 2a receptor.
17:51
And we know from a a a broad range of different evidences that this receptor is involved in um you could um uh uh summarize it as adaptability, flexibility, plasticity.
18:06
Um there are a lot of these receptors in the cortex, an aspect of of of brain that humans have so much of.
18:16
And um so stimulating these 2A receptors appears to um at a higher level have an interesting effect on the um regularity and the quality of brain activity.
18:29
So we can characterize conscious states uh in a way an analogous to um to waves.
18:34
Uh when we record brain activity it it it's very rhythmic.
18:40
Um, and as our conscious states change, that rhythmicity changes as we fall asleep.
18:46
Uh, or if we're knocked out with an anesthetic or we suffer some kind of brain injury, you'll see that um brain activity um starts to look like sort of slow rollers on a on an ocean.
18:59
And um related to that, the the richness of conscious experience drops away.
19:05
It's very predictable, very steady.
19:07
There's not much going on.
19:07
We know if we look at normal waking consciousness that the waves look very different.
19:13
You know, they're much more rapid.
19:14
There's there's much more richness going on.
19:16
What we've discovered with psychedelics is that that richness is enhanced further.
19:21
And that was quite an interesting and novel discovery to our knowledge.
19:25
um there hasn't been a state of consciousness found that shows that increase in the richness uh or complexity of brain activity above the level of normal waking consciousness.
19:39
That's a very mechanistic take on things.
19:41
Um uh another way to to look at this that's a way of characterizing the acute experience.
19:47
Another thing to emphasize tying this in with the therapeutic work is that the quality of the experience that people have under psychedelics appears to predict very reliably the therapeutic uh outcomes.
20:03
And so, you know, these really amazing findings that the drug is well washed out of the body and yet people months on from these isolated experiences are reporting improvements in psychological well-being, drops in uh depression and such like.
20:18
So what's going on there?
20:18
So just quite briefly to talk about the therapeutic mechanisms and perhaps slightly frame it in a in a slightly more um sort of human and and psychological way.
20:28
We can think of a range of different um expressions of mental suffering as being um underpinned by um biases and beliefs.
20:37
Whether it's in depression with negative cognitive biases, we think we are worthless and life is pointless or it's eating disorders where we think we're ugly or overweight or obsessive compulsive disorder with those stampedin habits.
20:55
Um and so um there is this kind of commonality this transdiagnostic commonality that that um that seems to relate to a very range of broad range of different um psychological disorders.
21:12
And what psychedelics seem to do acutely during the experience itself is they seem to relax beliefs and open a window for change for revision.
21:21
And if that opportunity is seized with the right kind of um psychological support, then you can work towards cultivating the a healthy revision of these pathological beliefs and habits. Thank you.
21:36
And it's worth noting also for people who aren't familiar that if if we're talking about [snorts] psilocybin, which in the case of studies is synthesized, it's been used in the form of slocity mushrooms by for instance indigenous populations including the mazetex in Mexico for thousands of years.
21:52
one could argue very very effectively.
21:54
So the there there's a good question.
21:56
We're not going to dive into it right now, but as to why almost every civilization accepting a few in Antarctica have used psychedelic compounds uh and uh certainly for rights of passage, but also with an objective along the lines of these enduring effects that you talk about.
22:13
Uh Christian, let's let's talk about investment in this space and and why you're involved.
22:19
Uh I know that you uh based on our conversation certainly have very sincere interest in making these compounds more widely available to people who are suffering and your biotech company a Thai life sciences is currently one of the largest investors globally aiming to bring some of these psychedelics including psilocybin back into the legal realm.
22:40
What prompted that and uh how are you thinking about approaching it? Um, okay.
22:45
Let's start because you're many investors. Um, I'm a super coward.
22:50
Um, until five years ago, I'm I'm not exaggerating.
22:53
I have never drank alcohol in my whole life.
22:55
And I come from Bavaria in Germany where this is like cultural uh actually appropriate uh to do so, but I I didn't because I was super I was a weird kid.
23:04
So, I I was super worried that my brain cells could die.
23:09
Um, and um so I didn't drink alcohol.
23:12
I've never smoked a cigarette.
23:13
I've never smoked a joint.
23:13
I've not never done anything else.
23:14
till like round about six years ago some very very trusted friends uh tried to convince me of magic mushrooms and I was like you're clearly insane.
23:23
Yeah, I'm never ever going to do that.
23:25
Um till but then they told me a lot about it actually what what Matt and Robin said and and I do invest a lot in biotech actually biotech is how I started my career.
23:35
I founded a biotech company.
23:37
So I was very inclined to read all the data and the data is very compelling.
23:40
So ultimately a year later I gave in.
23:43
It was um to uh to say that as well it was a a jurisdiction where it's legal um and it was under uh a very guided and very u well setup protected uh session with a great guide and um it was the single most meaningful thing I've ever done and experienced in my whole life. Full stop there.
24:05
Nothing comes close to it.
24:08
comes close to it. and uh which is by the way in a lot of studies uh I think it's a John Hopkins study where I think it was twothird of the people rank it among the five most meaningful uh events in their life among birth of a child
24:23
death of a parent and I think oneird roundabout ranks it among the the single most meaningful thing so because I'm an entrepreneur um uh I came out of the trip um the first thing I did I called my parents um um because um Yeah, I realized how much I love them and I never say it. Um, and uh, the second
24:41
Um, and uh, the second thing is was like this should be experienced by more people.
24:46
Um and I do think that the only way to do it when we have a lot of we have a lot of anecdotal experience like myself and like I have a lot of let's call it basic research but uh unfortunately never these drugs these various drugs have been brought to the FDA or in Europe it's called EMA sort of life cycle or sort of cycle how to approve any normal other drug you want to use for for medical purposes.
25:13
So I was like okay this should be done. Is anybody doing that?
25:18
And so I'm [clears throat] embarked on that trip in in a figuratively word um and um uh and met great people like George uh who founded Compass um who had the similar thoughts that this should become a medical drug mainly for the treating for treating depression and then other mental uh health issues. Uh this is where we are. Compass is in phase 2b.
25:38
where we are. Compass is in phase 2b. Um I'm also back the company which is bringing our ketamine hopefully uh on the market which is a sort of sub form um of ketamine also for the treatment of depression and we're looking on other um psychedelics or wider mental health drugs because I think if you look at the numbers and again investors are very numbers driven the whole mental health
26:03
area and not just talking about psychedelics but as well has completely more or less neglected been neglected over the last 30 years because it was sort of um com the mind is a complicated thing and I pharma companies biotech companies thought okay let's focus on cancer let's focus on the more tangible illnesses and also to be fair um depression our view on depression and
26:29
and mental health has changed over the last decades like 50 years ago what we now call a depression people would have said go on with your life go to the gym train a little bit get well yeah uh when when people came back from the second world war and were showing symptoms what we now would call post-traumatic stress disorder people said hey get on yeah so I think the the the the few on mental
26:54
health has changed over the last 20 years uh but also I think we live in a world where mental health is becoming a problem because our world where we live in is very bad for our minds especially for young people if you look at Instagram whatever yeah that whole sort of way we live and we have started living the last 10 20 years I think is very very bad for for the state of our mind. Yeah. And this is why the numbers Yeah.
27:17
And this is why the numbers rise.
27:19
We have 320 million people suffering uh from depression and these are just the official numbers and most probably the the how you say the gray number um is is much higher.
27:29
It became if you count sort of the side effects like people not showing up at work and stuff like that it became the single most costly illness um in the western world and for like 20 30 years there has been no innovation and all the drugs which are on the market are not curing but numbing it. Yeah.
27:50
And again, let's go back to something personal like if if if a person gets very depressive because somebody loved one dies, you don't want to take Prozac and Prozac tells you you don't care about the death.
28:02
You want to sort of dissolve it and solve it in a in a different way.
28:06
And I think this is where psychedelics have a very uh promising path to be a very valuable drug. Thank you.
28:16
And we're not going to probably talk about it very specifically today, but the efficacy of MDMA for post-traumatic stress disorder is is worth looking into uh and is is really remarkable.
28:26
Both MDMA and psilocybin now have uh breakthrough therapy designation by the FDA uh which is remarkable.
28:32
And if you look at the graphs, you look at the data uh for changes in PTSD severity from severe or extreme symptoms to asymptomatic, they look very similar to the smoking sessation graphs. It's it's incredible.
28:48
MAPS is an organization doing great work there.
28:50
Um um Tim, can I add a point to that?
28:54
Is the um it's somewhat ironic that I'm the resident drug user because like you Christian, I don't do drugs other than these. I don't smoke.
29:00
I don't like to smoke weed.
29:03
Sometimes I take CBD because you know you can't get a macho without it nowadays.
29:08
Um but uh uh I don't like to experience any hu I I I like my mind to be sharp at all times.
29:15
But um uh because I was teaching the one of the first sort of people who popularized MDMMA, Sasha Schulen, a chemist in Berkeley, used to lecture to my class and Sasha and his wife an who is a therapist convinced me to um try MDMA which is ecstasy with my husband as a tool of marital therapy.
29:36
And we've done it every couple of years since.
29:39
We have the strongest marriage of anyone I know.
29:44
We're sort of famous among our friends for having an incredibly strong solid marriage.
29:49
And I do actually we have four kids. We have a lot of stress.
29:51
Um but the what MDMA does and why it's relevant I think to PTSD is it somehow and these guys can probably talk more accurately to it.
30:04
It disconnects the the emotional experience from the memory which allows you to um deal with the trauma of memory without the intense overwhelming emotion negative emotional content.
30:13
So in the context of something that isn't PTSD but rather like the you know mundane PTSD of a long marriage um it allows you to talk about your issues but from a place of connection and love.
30:30
So every couple of years we spend 6 hours talking about everything that has come up for us from a place of absolute love and commitment and that sustains that one experience will sustain for as long as 2 years. It's really remarkable. Thank you.
30:49
Yeah, it's not to delve too much into any current use.
30:52
We wouldn't want to implicate anyone.
30:53
Uh but MDMA is worth taking a very close look at.
30:57
uh there are risks associated associated with some like LSD. Yeah.
31:02
So there are some risks associated with these compounds. These are not panaceas.
31:05
They are very effective or appear to be for certain conditions.
31:08
MDMA has certain uh say cardiac risk in some patients for instance since it is uh what is it methyl dioxy methamphetamine um there is that u I might be getting the chemical name wrong but uh then you have risks with say certain other promising psychedelics
31:25
ibeane for potentially opiate addiction which I want to ask you about uh not specific to ibeane you have in the case of ketamine some addictive potential which I've certainly seen and even experienced psychonauts so you have to be careful with how administered. But
31:37
But the I won't talk too much about this, but the toxicity profile of many of the classic psychedelics like psilocybin is is remarkably um appealing.
31:51
Um, so would you mind uh Matt just speaking to the the toxicity or potential toxicity of says psilocybin and also could you could you speak to uh based on what you've seen with tobacco and other forms of addiction uh if you think there might be applications to say opiate or opioid addiction. Sure.
32:13
So for toxicity we can start at the physiological level.
32:20
This is true for psilocybin, LSD, dimethylryptoamine or DMT which is in Iawaska.
32:28
There is no known lethal overdose.
32:28
No dose at which there's any observable organ damage.
32:35
No, not even a potential mechanism for neurotoxicity.
32:41
Um, that's pretty freakish. Cannabis is similar.
32:45
You'd be hardressed to find anything sold over the counter um at CVS, Walgreens that you could say this about.
32:53
You can't say it about caffeine, aspirin, most drugs.
32:54
You can't just take 10 times an effective dose and expect to live or to be undamaged.
33:00
So, remarkably, freakishly robustly uh safe at the physiological level.
33:07
I would never say any drug is safe period.
33:08
It demand it it it depends on what area of risk you're talking about.
33:13
Um so these are very in at sufficient doses um profoundly conscious altering drugs very intoxicating if you will.
33:26
When you see harms they fall into a couple of categories.
33:30
One that's applicable to anybody that takes a high enough dose is what people out there call the bad trip.
33:39
In clinical research, we refer to these as clinical experiences as as challenging, I'm sorry, challenging experiences because in fact, they can be very um helpful themselves going through extremely difficult experiences.
33:52
Nonetheless, we try to minimize them.
33:54
But out there in the wild, so to speak, recreational use or what have you, um and it's certainly a small minority, but sometimes um a an overwhelming anxious state can lead to dangerous behavior.
34:06
someone panics, they run into traffic.
34:09
You know, it was overplayed in the propaganda of the late60s, but falling from heights. Um, it has happened.
34:16
They're very intoxicating drugs.
34:16
Far more people have fallen from heights when they're drunk, but nonetheless, it has it happens.
34:22
So, um, in terms of public health, this ranks lowest amongst all the other major legal and illegal drugs, but nonetheless, there is a risk there.
34:32
So nice thing is you can squarely address that in clinical research and potential clinical use um through preparation and monitoring.
34:39
It's never it's not take two and call me in the morning follow-up care.
34:43
Um the other major area of risk with these classic psychedelics is only applicable to a small percent one or two% of the population who have active psychotic disorders such as schizophrenia or a strong signal for that predisposition.
35:02
And many of the kind of urban legends we may be aware of of folks that took too much of a trip and they never came back.
35:09
It seems very convincing that those folks had a predisposition at least such as you might be familiar with Sid Barrett, the original singer of Pink Floyd.
35:18
Um it and in the earlier era of clinical research with LSD with thousands and thousands of participants, the only people that had prolonged psychiatric reactions beyond the time course of the drug uh were those individuals with that psychotic predisposition.
35:37
It's also very fortunate like the bad trip side that we can squarely address this in clinical research and eventual clinical use.
35:44
Um there are extremely reliable psychiatric structured screenings that can identify pe that small percentage of the population that has this risk and then it does modestly raise blood pressure.
35:55
Um so we can't uh run people through the research who are at an extremely high level of cardiac risk.
36:04
I mean these are the same folks that might have a cardiac event if they go up several flights of stairs.
36:08
Nonetheless, that's a real thing.
36:08
Um and uh also in the area of risk, we we documented some systematic effects in increasing the chances of a headache within the day following use.
36:18
Typically not in the severe category, nothing that we would think would prevent people from um using it uh clinically.
36:26
There's a very rare thing called hallucinogen um uh persisting perceptual disorder. Extremely rare.
36:36
It tends to be well it's all the data show that it is exclusively associated with recreational use where there's typically multiple drugs including alcohol used and there may be a predisposition there.
36:48
It's never been observed in any of the thousands of participants in the older studies or the current studies.
36:55
Um uh so and what I'm referring to are you've heard of the term flashback and that can mean many things but that what this refers to is having persisting perceptual abnormalities that severely hampen the uh uh quality of life and they're very distressing for individuals.
37:15
And it it seems to be that that's it's probably related to a neurological susceptibility where other events, not only psychedelic drugs, but other medications, other events could probably cause the same same thing.
37:27
But you might have heard of that that sort of rounds out the entire sphere of of risk known risks. Thank you.
37:33
And what about uh applications to say opiate opioid, right?
37:38
And just if I could I'll add just a quick personal note.
37:40
So my cousin by marriage uh he had a hereditary disposition to schizophrenia and really abused LSD all throughout high school and college and it would seem that it expedited the onset of symptoms of schizophrenia although very likely that he was headed there already.
37:58
It just hastened the path.
38:00
So I've seen that firsthand.
38:02
Um, and now on the flip side, I've also seen incredible abuse uh on a personal level that is representative of of I suppose a sort of pandemic level problem in opiate abuse.
38:15
So my best friend on Long Island died of fentanyl overdose.
38:17
My aunt died of percoet plus alcohol not too long ago.
38:22
So this is something that's touched a lot of lives in this room.
38:24
Are there any potential uh applications you think or or research worth doing that would look at psychedelics and something like opiate or opioid addiction? Absolutely.
38:36
It's a very promising area.
38:38
There was one study published in the early '7s using LSD with heroin addicted individuals.
38:43
Um there was, you know, we needed to do follow-up, but that was right at the point in society where the rug was pulled out from this research and the research wasn't allowed anymore.
38:53
But nonetheless, there was a a a good initial signal of long-term success.
38:55
And that's part of this formula that I was describing earlier, this picture of broad applicability to treat addiction of various types.
39:07
My colleague Peter Hendricks at University of Alabama Birmingham is is showing initial positive results in treating cocaine addiction.
39:16
Um so opioids um is is an extremely promising um area something that we want to look at.
39:24
Um it's an extremely promising area um particularly in the midst of what's called the opioid crisis and especially since opioid addiction is resistant to treatment.
39:35
Um, you know, we have medicationass assisted treatments now that are more effective at keeping people off o sort of resolving opioid cris problems, but without medicationass assisted treatment, opioids, you know, this the traditional treatments that we think of like narcotics anonymous, they are grossly ineffective.
39:55
So, um, our current opioid crisis will not resolve without wholesale accessibility of medication assisted treatments.
40:04
And I believe without really evaluating the potential of psychedelic drugs.
40:08
Um which is why I actually hope that this crisis might enhance our receptivity to de taking um psychedelics down from schedule one which means that there are the most criminal drugs.
40:23
There is no a schedule drug mean drug schedule one drug means there's no medical use and it's the most illegal drug down to schedule four.
40:34
So what kind of what other drugs do you think of that we could analogize that are on schedule 4?
40:40
Oh, many of the benzoazipines and the sleeping aids are in schedule 4.
40:45
Let me let me jump to Robin for a second because I think that that we we can we can talk about perhaps the broad applicability and perhaps some current diagnostic problems that we may have in psychiatry.
41:01
uh because if you look in the DSM and we could talk to all sorts of people who have previously been uh sort of at the head of mental health to Tom Insulin others uh where you have these disorders these psychiatric disorders so-called disorders that are very cleanly separate
41:19
right you have anorexia nervosa anorexia has the [clears throat] highest mortality rate of any psychiatric disorder then you have OCD then you have this then you have that they're all very much side note Uh could you speak to the explain what the default mode network is if that's possible? Uh just speak to that because
41:36
Uh just speak to that because part of what is um fascinating to me personally is that if we kind of zoom out to 30,000 ft as you mentioned earlier you have this kind of you have conditions associated with hyper rigidity and then you have conditions associated over here OCD anorexia etc.
41:53
these kind of compulsive behavioral or thought patterns and then on the other side you have this hyper fluidity which can be problematic like schizophrenia, right?
42:00
Could but could you speak to um maybe explain for folks if possible the the current thinking around the default mode network? Uh sure. Yeah.
42:09
I mean schizophrenia also it does have that kind of chaotic component to it but it also has a rigidity to it as well if you think of uh fixed uh delusions.
42:19
Um and so um this is a remarkable thing that gets kind of glossed over in psychiatry that uh these diagnostic categories while they're there really to aid the clinician. Um uh that's one view.
42:34
Another view is that they're aiding something else.
42:37
Perhaps drug discovery and uh and such like and perhaps to some extent a myth that there are these crisp uh distinctions that have crisp underlying biomarkers that following the the classical biomedical model, we can come in with a magic bullet and and solve uh solve the situation.
42:58
And and if that was true, then we wouldn't be seeing the the mental health crisis that we're seeing at the moment.
43:04
prescription rates of psychiatric medications are going up at record levels.
43:08
Yet, we're not chipping into the problem.
43:09
So, you know, we do need some kind of major paradigm shifting uh uh event here, a kind of black swan event that that that really changes things.
43:20
And uh you know, I think our collective view is that psychedelics, psychedelic therapy is is that it's this hybrid model that's not just a drug treatment.
43:30
It's more holistic than that.
43:32
It's about managing context.
43:32
Uh giving a drug that produces this suppleness of mind and then managing context to try and move people out of the kind of you know entrenched ways of thinking and and um behaving uh into something um broader and more open.
43:49
So the default mode network uh um is uh in a sense you could say it's the most um it's the strongest candidate that we have in the brain for what you might call the biological substrate of the self or the ego.
44:04
Um it's a system that engages when we disengage so to speak.
44:10
Well, we disengage from attentive focus, but we enter a kind of daydreamy, you know, uh internal uh imaginative state.
44:18
Um but uh this is very much tied in with with self and and the narratives that we build about who we are that we start to believe in the kind of absolute way that guides and drives our behavior. But can be so narrowing.
44:38
you know, ego sees narrow and short.
44:41
Uh, and what you see under psychedelics is that this network breaks down.
44:46
It literally, albeit temporarily, disintegrates and people see broad um and uh they see the bigger picture analogous to the so-called overview effect, you know, that astronauts have described when they uh are up in space.
45:03
uh are up in space. they look look back at the whole of the earth and then they can put things in perspective and think you know why was I squabbbling with my uh wife or my work colleague um and and you know it's about seeing that that bigger picture so here you know we've
45:19
got this opportunity through brain imaging to start to put a bit of meat on the bone you know to uh help um you know lift the lid on this black box that's the brain uh and start to show people that this isn't magic it might feel like magic psychedelic therapy, but it rests very firmly on nature, on biology. Um,
45:36
Um, and I think it's useful to to add that to the conversation and help kind of ground the conversation about uh about psychedelic therapy. Yeah.
45:48
So, one point because both Ayel and u and Robin just touched something important where I disagree with and agree with Robin that most psychedelics, it's not true for all of them, but are a very holistic treatment.
46:02
So partly the setting and the guide and however you experience is equally important.
46:07
So why this is my opinion especially for example on on magic mushrooms that yes they should be available as a medical treatment but not over the counter.
46:15
over the counter. This is nothing somebody should do alone especially when you're depressed and by the way we all I think one risk is that most people very passionately like all of us talking about psychedelics we're not depressed
46:29
and it's a different experience when while when you read observations of of treatments of depressed people they might go through a let's call it katarsis or to a a challenging they might have a challenging trip nevertheless the trip is healing them and and the guide is very important. So
46:45
So this is why I just want to add that yeah uh I personally think yes it should be available as a medical drug.
46:51
is what we're working on.
46:52
But uh it should be available under professional care like with psychiatrist or in clinics u but not over the counter definitely not over the counter.
47:03
I you know I agree with you entirely.
47:05
You know in my book I have a whole sort of chapter about paradigms for decriminalization.
47:11
And you know my ideal paradigm for for psychedelic decriminalization would be for lack of a better word the psychedelic spa where you would check in and get that buttressing because in all drug experiences but particularly in psychedelics the set and setting as you say are critical.
47:26
Set is what you bring to the experience and setting is the setting in which you experience it.
47:31
So like you know the Canyon Ranch of psychedelics with with you know licensed trained support team.
47:39
I'm not sure you have to be a therapist per se but someone with experience and training in supporting an individual.
47:45
Ideally with preparation both before and after which is not to say that I think all people um require that but that is that is much more likely to engender a positive response.
47:59
An interesting number is the Netherlands. It is legal.
48:00
You can access psilocybin, magic mushrooms in the Netherlands legally in coffee shops.
48:05
And the Netherlands have the same mental health crisis than every other country in the world.
48:13
So just the fact that psychedelics are available, yeah, unfortunately do not change um the mental health crisis.
48:20
mental health crisis. is really like the professional and if I experience it with people like I would look at my parents or or or friends who have depression they're not making that leap they rather go to their doctor because they trust them and then the doctor should be the one who's also uh administering that so I'd like to touch on something you said uh actually but that we've sort of
48:43
covered uh in a few different ways but offer a a framing that I think is is helpful and that is that rather than think of good or bad trip, think of safe or unsafe trip because the in in many cases the the difficult experiences are when you see the truths you'd prefer not to see and you look at the behaviors that may be in your blind spot and that can be very uncomfortable. Uh as in the
49:08
Uh as in the case when a smoker's like, "Wow, that's disgusting.
49:12
I saw that I'm killing myself."
49:13
And they have to look at that hard truth.
49:14
Difficult but safe and that depends a lot on the context.
49:18
and the [music] providers and and so on.
49:20
U question for you Christian, how do you think about creating business models around compounds that can be so effective with a single dose or two doses because I know you want this to be available to a great number of people that requires a sustainable model of some type and there are many different ways to approach it.
49:42
You know, MAPS has one with say a BC Corp that does drug development.
49:46
Then there are for-profit [music] options.
49:47
Uh, how do you look out for temptations like taking something that is so effective with one or two doses and create creating something that requires a maintenance dose multiple times a week?
49:58
Is it the therapeutic wrapper that kind of spa element and context around which you build a business?
50:04
How how do you think about that?
50:06
Well, first um and meaning that sounds maybe cheesy or I would say in English, but like uh if you're investing in biotech, you really want to make a difference because I do other tech investments and I'm always very happy about biotech because if you succeed in uh bringing a drug to market, you really make a a difference in the world.
50:25
So, so I think it's not I think this is a little bit the the myth that everybody thinks biotech investors are like evilly plotting um how to make the most out of it.
50:35
At least this is not how I think about it.
50:37
Like we want to cure people.
50:40
Um and and hopefully we're going to make that happen.
50:42
Um second, the market is so huge, meaning I I said we have 320 million people and most and the number is rising and I think there are more people who are not diagnosed.
50:51
So so even if and I would be very very happy if it's a single dose psilocybin which is uh which is helping those people.
50:58
Even if that's the case, the market is is huge. Yeah.
51:02
Then you have the the side business models or the as as said the spas and the the the clinics you can build up. Yeah.
51:10
Because it is all about the holistic um thing and and then even and we don't know yet meaning for a lot of things we also have to say like we have very good indications but we don't know yet what is the right dose.
51:22
This is for example what compass is is trying to figure out at the moment. And it might be Yeah.
51:28
And I'm not saying that because it should be like commercially but it might be that you say oh if somebody was depressed you should do it every year again. We don't know yet.
51:36
We try to figure that out. Yeah.
51:37
But there is enough business uh and I think in general like even if you go aside and look at meditation app like calm for example like I think the the whole mental well-being like treating people who are ill have mental [clears throat] health health issues but also keeping people healthy yeah in our current environment and and this will get worse.
52:00
My personal theory is that that our brain uh has like an an inbuilt actually resilience or like a immune system which is based on faith um love and uh and purpose.
52:13
And if you look what our world is happening, we take these three things away.
52:16
Communities are dissolving, families are dissolving.
52:18
So you have cheesy said a little bit less love in the world. Yeah. Yeah.
52:22
Then most people know that the world will look so different in 20 years that uh that they don't have a purpose anymore.
52:29
The bus driver knows that in 20 years most likely his bus will be driven by an artificial intelligence. Yeah.
52:34
And uh and then we have a dramatic loss of faith in every sense like religion and in in any spiritual dimension and it all will make people more depressive.
52:43
So swinly said the market is growing.
52:46
So I'm not worried about uh about uh how often you have to take it. Okay, thanks.
52:54
The market is growing for better, for worse.
52:56
[laughter] Uh, Matt, I'd like I'd like to come to you.
53:00
First, I'll just I'll I'll make another personal note uh and um try not to directly implicate myself here, but so my family has uh a on both sides quite a bit of severe depression.
53:14
And I would say every 6 months or so as an adult, I've had a major depressive episode.
53:20
Almost killed myself when I was in undergrad at Princeton.
53:21
and I've written about that if you guys want to check it out.
53:24
Uh in the last 5 years I haven't had a single major depressive episode and here we are on this panel.
53:31
I'll let you guys draw your conclusions.
53:33
Uh not to say that that is going to be true 100% of the time, but given the fact that [clears throat] in one could argue that there have been incredible advances scientifically in cardiology and neurology and all these various fields and then you look at psychiatry
53:48
and there's been very little I mean aside from SSRI some time ago and now ketamine which is very interesting I think for uh acute suicidal ideiation and chronic pain especially uh but there's there's very little that has happened and um so I'm I'm very very vested in this space. Matt, the reason I
54:03
Matt, the reason I wanted to come to you next is that you mentioned schedule one and schedule 4.
54:08
Uh, one question that people might have on their minds is, well, wait a second.
54:11
If these are so great, if they have such low toxicity, how did they end up in a category schedule one, which is no known medical application, high potential for abuse, among other things, which of course based on the data I disagree with, but like how did that happen and how do we get out of that?
54:25
And I'll just say one more thing cuz we're running short on time, which is, you know, my not so secret agenda is to set the conditions over the next 3 to 5 years with private philanthropy and so on, so that I can then work separately to try along with other people to help get federal funding for this stuff, which is not currently forthcoming.
54:43
Um, so how did we get to this very difficult and expensive position of operating from schedule one and how do we potentially get out?
54:53
Yeah, this the quick answer is that psych it was really because of the association with the counterculture and everything associated with it in the late '60s early '7s.
55:03
And I would say that that the culture was essentially traumatized from um that kind of early introduction of psychedelics and and and there were casualties when they were used broadly.
55:23
There were also plenty of people said it changed their lives for the better and they're still here to to talk about that.
55:29
Um, but this this came about right at the time when the federal framework for controlling uh scheduled drugs, the controlled substances act was being developed and um there is no there's some flaws in that system.
55:43
There is no category for example of having um no accepted medical use but mild to moderate abuse potential.
55:53
um you know, you jump from uh having no accepted medical use and high potential for abuse in schedule one to schedule two, something like cocaine or methamphetamine, which are schedule two, um as as having uh high high potential for abuse, but um some accepted medical uh value and those two drugs are used uh medically and are approved.
56:18
Um so there's really no framework.
56:20
Now you know psilocybin the language is important here.
56:24
It we squarely know at every level of science the the effects in the messolyic brain structures involving dopamine the epidemiology reliable animal models of reward.
56:34
We know that these aren't drugs of addiction solidly.
56:38
Um but they are they can be drugs of abuse and that simply means used in a way that can can harm you or the people around you.
56:48
So, you know, couple teen teenagers go out driving on mushrooms. That's abuse.
56:52
Or you get into a pattern that interferes with your family relationships, etc.
56:56
Um, so they really don't belong.
57:00
And the again, the controlled substances act is is rather ambiguous.
57:04
You know, they refer to abuse potential, which can include addiction potential, but also other risks. So, they do have risks.
57:10
You could argue they have, you know, these classic psychedelics, mild abuse potential.
57:17
Um but the other side of that is there's there's no accepted medical value.
57:22
Um when the Controlled Substances Act was originally um uh adopted, it wasn't clear what that really meant and through judicial precedent it became solidified that that what that means is FDA approval for an indication.
57:37
So that's where we're at now.
57:40
So until one of these drug until psilocybin is approved for an indication, it's going to by definition remain in schedule one.
57:49
What are the most promising indications currently or those that are furthest along based on the data?
57:54
Um the most promising indication would be depression and anxiety.
57:59
You could call it psychiatric distress associated with a life-threatening cancer diagnosis.
58:05
That's what the most modern uh most uh advanced research with psilocybin as a therapeutic has been focused on.
58:12
There's three randomized studies in that category.
58:16
And then secondary to that sort of as a class are um psilocybin and the treatment of of uh smoking sessation as a smoking sensation medication. I showed you some data. Treatment of alcoholism.
58:31
uh a colleague Mike Bogen shoots at NYU has done some great work with that and and then Robin's published work on depression outside of cancer.
58:38
So all of those those three things have been those are published results with open label non-randomized pilot studies.
58:49
So they all look very promising but they haven't um gone the published data hasn't reached that level of you know large randomized trials yet.
58:57
All of these disorders are associated with being stuck in a narrowed mental and behavioral repertoire.
59:03
And as Robin suggested, I think that's why we're seeing efficacy with these nominally different disorders.
59:08
Psychedelics have a way to blast one out of that narrowed mental repertoire. Thank you.
59:15
Uh I where would you hope what would you hope this uh this field that is broadly speaking psychedelics to look like a few years from now?
59:24
Do you have anywhere you'd like to see it?
59:29
Well, you know, um, because I I went I was a lawyer and I I was a criminal law professor and so I think through this criminal justice lens and I remember a period where decriminalization of marijuana seemed incomprehensible.
59:41
When we first started working um and I was working with the Drug Policy Alliance on state initiatives to decriminalize marijuana, it seemed um remotely possible that in some very liberal states you might have a medical model and absolutely impossible that you would ever have a recreational model.
1:00:00
And I don't know about you guys, but I've been to these pot clubs which are like apple stores and the bud tenders are, you know, showing you weed that in my lifetime as a teenager in New Jersey, I never saw anything approaching.
1:00:17
So there is a kind of there there the shift is possible.
1:00:20
I think we could see a medicalized model specifically for psilocybin.
1:00:26
The reason that this research is happening in psilocybin and not LSD is because of the sort of fear associated with LSD but they operate wouldn't you say Matt almost identically in the brain.
1:00:37
So I think we will see over the course of the next decade a and maybe even less uh a shift to a medical approach maybe maybe changing the schedule or maybe on a statewide basis having the as we did with marijuana.
1:00:53
Marijuana is still schedule one federally.
1:00:54
It's still a crime federally, but we have different models state by state.
1:00:58
Um, and uh, I think that we are a long way from a decriminalization model for other for drugs generally, but I do think psychedelics because of the research that these gentlemen are doing does have great potential for medical applicability.
1:01:15
And I actually think what can drive that more effectively than anything else are the individuals in this room and others like this, which is why I'm speaking to you and I imagine that's why Tim is here as well and maybe the rest of the panel because what we need is a model of investment and corporate pressure to change laws.
1:01:33
I mean, that's the way it works in America.
1:01:38
When there is a wave of uh of capitalist interest, it's a lot easier for laws to change. So, we are up on time.
1:01:48
Closing comments real quickly. Check out the research.
1:01:53
This these are not panaceas, but they are the most exciting thing that I've been focused on for the last several years. It's worth looking at.
1:01:58
You have a chance if you're interested in being on the playing field at having a Katherine McCormick level of impact. It's a big deal.
1:02:07
Uh so please take a look check out everybody on the panel and uh I Ayella and I will be doing book signing over there.
1:02:16
There a couple of chapters in Tools of Titans on the psychedelic stuff as well and uh thank you all for coming and ladies lady and gentlemen. Thank you for coming.
1:02:29
Hey guys, this is Tim again.
1:02:29
Just a few more things before you take off.
1:02:31
Number one, [music] this is Five Bullet Friday.
1:02:34
Do you want to get a short email from me?
1:02:37
Would you enjoy getting a short email from me every Friday that provides a little morsel of fun for the weekend?
1:02:43
And Five Bullet Friday is a very short email where I share the coolest things I've found or that I've been pondering over the week.
1:02:52
That could include favorite new albums that I've discovered.
1:02:54
[music] It could include gizmos and gadgets and all sorts of weird [ __ ] that I've somehow dug up in the the world of the esoteric as I do.
1:03:02
It could include favorite [music] articles that I've read and that I've shared with my close friends, for instance. And it's very short.
1:03:11
It's just [music] a little tiny bite of goodness before you head off for the weekend.
1:03:16
So, if you want to [music] receive that, check it out. Just go to 4hourweek. com. That's 4hourweek. com all spelled out.
1:03:23
[music] And just drop in your email and you will get the very next one.
1:03:27
And if you sign up, I hope you enjoy it.