For much of the past, physicians were botanists. Medicinal gardens were the forerunners of Big Pharma, but not all things sprouting from the soil have been favorably received. For years, cannabis and psilocybin have been treated as contraband, not as medicinal agents. On this episode of SoundPractice we will discuss the understudied medicinal benefits of some illegal substances.
This transcript of the discussion has been edited for clarity and length.
Mike Sacopulos: My guest today is Jeffrey Lieberman. Dr. Lieberman is a nationally known psychiatrist and neurobiologist and a bestselling author. His latest book is Malady of the Mind: Schizophrenia and the Path to Prevention. Dr. Lieberman, welcome to SoundPractice.
Jeffrey Lieberman: Thanks very much. Glad to be with you.
Sacopulos: It’s my pleasure. I’ve been looking forward to our discussion. We’re going to be talking about some mindbending medications and substances, and I thought maybe you could give us a little context to frame our discussion.
Lieberman: Right. Well, mindbending is the kind of colloquial term that’s used, but it really refers to what I would call recreational intoxicants. These are psychoactive substances that have been found to provide pleasurable effects, and they’re used for enjoyment in the same way that maybe alcohol is, or nicotine, or caffeine. But their effects are more powerful potentially and also more controversial, as well as, depending on when in time you’re looking at it, illegal, to varying degrees.
These are substances that may have been used variably for therapeutic purposes, but really the broader motivation to make them more widely available, ostensibly through demonstrating what therapeutic benefits they have, is because the public wants them. The challenge, for government in terms of policy, law enforcement, the judicial system and the medical community, scientific community, is to determine what are their risks and benefits.
And that’s what we’re trying to do. The only problem is, we’re accumulating knowledge on what their mechanisms of action are, what they’re really effective for, as opposed to the hype of the claims being made of how they’re beneficial, while the train is leaving the station. Meaning they’re being widely used for various purposes before there’s any proven evidence that they will be effective. And huge amounts of money are being invested and made as a result of it.
We have a convergence of motives and interests that are driving this process. I think what I try to do and what the medical community is trying to do is to be the responsible adults in the social or societal room in informing people about what the real truth of these substances is in terms of what the risks and benefits are. It begins really with cannabis.
Just to describe the menu of these substances, I would consider the recreational intoxicants that are currently in play to be the cannabis products; the ketamine or dissociative pharmacologic substances, which would include phencyclidine, angel dust, or ibogaine; and the psychedelics, the classical psychedelics being substances such as psilocybin, mescaline, LSD, ayahuasca, DMT, and then MDMA, otherwise known as ecstasy. Unfortunately, there’s a lack of rigorous classification or categorization of these substances by many of the proponents of their use — which doesn’t pay attention strictly to the pharmacology.
If you go on the website of what is probably the most influential foundation that’s been promoting the development, legalization, and therapeutic demonstration of their uses, MAPS — the Multidisciplinary Association of Psychedelic Studies, led by Rick Doblin, who is (I don’t know if he’ll consider this an insult or a compliment) a latter-day Timothy Leary type—they’ll consider all these things psychedelics, when that is not the case. Psychedelics are much more precisely defined. These substances historically were used either ritualistically by indigenous peoples or by certain segments of society that were kind of avant-garde, on the cutting edge, such as bohemians, artists, musicians, et cetera.
But then in the 1960s, the counterculture broadened their use, and that’s when the government began to come into action and set down boundaries of what could be used or what couldn’t be used and what was legal or illegal. They did so in a way that was somewhat Draconian, because some of these substances had genuine therapeutic potential, which had not yet been explored. Here I’m referring particularly to the psychedelic drugs. They were throwing the baby out with the bath water. They put such strict restrictions on them that there was really no research activity for 30 years or more. Then in the early 2000s, efforts began to try to reintroduce them, at least for exploring them scientifically for therapeutic use, if not also making them more broadly accessible by decriminalization and then legalization.
From that point on, it was game on, and momentum built. The ways in which they were being commercially developed and marketed increased, the amount of money that flowed into investing in companies and commercializing them increased, and the ways that they were being promulgated and utilized increased. This was really driven by the desire of the population and the population asking for better access, better standardization of quality, rather than going out and buying it on the black market from your local drug dealer.
This demand influenced state legislatures and has resulted in the decriminalization and the legalization of it, in many — I think it’s up to 38 or 40 now — states, at least of cannabis products. The same process follows suit with other types of substances, particularly the psychedelics.
Sacopulos: Well, let’s start with the psychedelics. Probably front and center in my mind there, we’re seeing at least as far as legalization, is psilocybin. From a medical standpoint, what can you tell us about psilocybin’s promise for treating certain mental health disorders?
Lieberman: Well, I’m going to start with a question. This is, “Why psilocybin?” Psychedelics are a very specific type of psychoactive substance, whether it’s naturally occurring like psilocybin does in mushrooms or whether it’s synthesized, such as LSD was. They all have a common pharmacology. They act by binding to the serotonin 2A receptor and acting as a partial agonist. They create a clinical effect that approximates an altered state of consciousness that has mystical properties that many people find extremely illuminating, inspiring, and exciting and enjoyable.
They’re time-limited. The effect can vary from 2 to 4 hours to 8 to 10 hours in duration. There are differences, some differences in the subjective or qualitative nature of the experience among the various psychedelics, mescaline, psilocybin, LSD, the active ingredient within ayahuasca, and DMT. They’re basically producing a similar overall altered state of consciousness with some variation in the nature of that experience — more cerebral, more sensory perceptual, more powerful, more attractable.
Now, these drugs are unique. I mean, there’s no other drug in the pharmacopeia that really comes close to producing the same kind of effects, even though, as I said previously, the classification by some advocates is not very precise. That classification includes substances like ketamine or ecstasy in this group, which they shouldn’t be. It understandably has suggested to scientists and physicians, and particularly to psychiatrists, that this unique effect that they have could be put to therapeutic purposes.
That is exactly what was being done in the 1950s and 1960s, before these drugs were so restricted by the DEA and the government that research stopped all but completely. Since they’ve been rehabilitated and pursued by a variety of companies seeking FDA approval for some therapeutic indication, there’s been a return to research investigation. But it’s not been of the most rigorous type, and it’s not been the way that treatments for other types of ailments are developed. To put it in somewhat derisive terms, it’s amateur hour. And the tells in that regard are twofold. One is that no Big Pharma company is touching it.
These are smaller companies that have sprung up, started largely by true believers who are well-intended, but scientifically naïve — somewhat naive as was Timothy Leary, you could say. There’s an article that I could share with you that was published about three years ago where the authors did a search on NIH Reporter, which lists all the funded, sponsored research by the NIH. At that time there wasn’t even one study in psychedelics that was being funded, meaning that it hadn’t penetrated the academic medical research community. Now there are some, but not nearly enough.
You have this process of trying to develop evidence to get FDA indication for specific uses that’s ongoing and getting close to the finish line, but it still requires a modicum of basic knowledge about the mechanism of action of how these drugs work, and what indications, what ailments they are actually genuinely and definitively effective for.
Also, and this gets back to my opening question, why psilocybin? There’s nothing that provides a rationale for why you would be prioritizing one psychedelic versus another to be used for any given condition, whether it’s depression, whether it’s addiction, whether it’s anxiety. There’s no comparative effectiveness knowledge or data.
What I would say is that we’re at a, I call it a Promethean moment. Prometheus was a human who angered the gods by bringing fire to humans and making it available prematurely and without restriction. It turned out to be both good and bad. It’s good because we cook, we eat food, but it’s bad because it also makes weapons. So he was punished for it. We’re at a Promethean moment. This could be something of tremendous value therapeutically, and not just for treating illnesses, it could be a rite of passage.
Writers such as Aldous Huxley have written about how this, and this is how it’s used in Native American spirituality. Being a good Jewish boy, I became a doctor, but I also had a Bar Mitzvah. Similarly, certain Native American societies utilize psychedelics as a rite of passage to initiate youth into adulthood. So it could be good for humankind, but the way we’re going about it, as I’ve been intimating, is worrisome, because it’s not being done in as rigorous a way as I would like. We’re getting close to the finish line where a couple of the early entrants into the FDA approval process are getting close to being reviewed by the FDA and an advisory group, probably sometime in 2024.
Sacopulos: We saw, starting back in 2019, this effort to decriminalize psilocybin. I believe it started in Denver, Colorado, but then other cities joined in — Oakland, Seattle, Washington, DC — and now we have states that have decriminalized it — Oregon, Colorado.
Lieberman: More than decriminalized, legalized it.
Sacopulos: Right. From a public policy perspective, is this a good idea or really a dangerous trend?
Lieberman: I think it’s probably more the latter than the former. I mean, it’s one thing to have marijuana widely available. It’s another thing to have psychedelics widely available.
I mean, there’s only one FDA-approved indication for cannabis-derived products. And that’s a rare form of epilepsy. Everything else is largely anecdotal or apocryphal. Cannabis dry products are available mainly for people to use recreationally, and that’s not bad. I mean, it’s hard to make a case that smoking pot or using pot is more dangerous than alcohol or tobacco is.
On the other hand, that’s for people at my age who are middle-aged or older. There are vulnerable periods of life where the risks are much higher, and that happens to be youth, meaning adolescence and young adulthood. What’s happening is that with the legalization of cannabis and the commercialization of cannabis, the THC concentration has gone from when I was in college and we would smoke — of course we didn’t inhale — but the naturally grown cannabis had THC concentrations of 2% to maximally 10% — Maui Waui, Vietnamese, et cetera.
Now that it’s been commercialized, you can get oils, you can get gummies, you can get smokable forms. The THC concentration is upward of 80%. What we’re seeing is many more casualties in the emergency rooms of people who are acutely intoxicated. Even worse in individuals who smoke beginning at an early age, chronically — meaning daily, for some years — it can induce an enduring state of psychosis. These are not completely risk-free, and the group that’s most susceptible to the harmful effects are adolescents and young adults.
In terms of psychedelics, what’s happened is that the enthusiasm for them has gotten people to say, “Well, if they produce these amazing unique effects that give me a kind of perspective and experience and way of understanding my life and the world, it must be good for something.” Therefore, even before the data are in from the FDA testing process, there are facilities that are being established and financed to be essentially resorts or spas or clinics for people to have guided psychedelic experiences. Oregon, I think, has been in the lead by having legalized it. And money has been invested in establishing a Canyon Ranch–type facility for having a guided psychedelic experience.
Then the term guided psychedelic experience is a little bit laughable, because sure, you can have somebody with you who is ostensibly a therapist who has some kind of experience and is able to work with people who want to have an intoxicated trip. But there’s no standardized methodology. It’s basically being improvised. The improvised methods may be okay, but that’s not the way medicine should work. There needs to be a standardized methodology that’s applied uniformly after it’s been validated as being helpful.
This is a situation where the train leaves the station while people are still getting on board and the destination is still unknown — the belief in the utility of it is there, but the lack of sufficient knowledge about the dangers or risks is being ignored.
Sacopulos: It does seem to be a dangerous trend. I’m wondering if it is not restricted just to the substances we’re talking about today, Dr. Lieberman. Has there been an impact from the pandemic and from COVID on the overall public’s view and stance on these medications and on the field of medicine in general?
Lieberman: That’s a very good question. I hadn’t really thought about it in that way, but I’m sure that there is because I mean, the trend, I think, had been ongoing. We saw this with autism and the vaxxers, or, rather, the anti-vaxxers. There’s more of a skepticism on the part of the public toward science and mainstream medicine that has emerged in the context of COVID, either because of the isolation people were forced into, or because of the fact that COVID was a brand new infectious pathogen that kept eluding medical science’s ability to identify what mutated forms it would take, leading to the development of iterative types of vaccines that were ostensibly going to be effective, but then weren’t entirely effective.
We saw the same thing with AIDS and HIV, but the skepticism didn’t arise there the way it is now. I think you’re right, the public, coming out of COVID, or at least the initial worst part of the pandemic, has made people less willing to accept what they’re being told by the medical community and the empirically validated evidence about illness treatments that this research community provides. And they are more willing to accept either their own beliefs, or what they hear on the internet or from irresponsible media pundits who are putting out false information.
There’s an erosion of the process of accumulating knowledge, vetting the knowledge, and making that part of the canon of what Western civilization believes. And things that for thousands of years have gone through a rigorous vetting process to establish, and that’s worrisome.
Sacopulos: You alluded to it, I believe, earlier, but as you know, there are ketamine clinics popping up, I believe ostensibly to treat anxiety. Can you give me your thoughts on these clinics? Are they safe for patients?
Lieberman: It’s really shameful and it’s a black mark on, I think, the medical profession how this has become offered promiscuously to people for many more purposes than the evidence has demonstrated. I think what it reflects is the tension.
When you go to medical school, you’re supposedly going into a noble helping profession. You take a Hippocratic oath and you’re supposed to have fidelity to the principles of that and the well-being of your patient. Of course, you’ve got to make a living — no margin, no mission — but the tension between profitability and your sacred responsibility to first do no harm and to try to promote health in individuals who really are suffering, that clearly should take precedence. But sometimes that balance is violated.
Ketamine is a good example. Ketamine is a substance that originated back in the 1960s when a pharmaceutical company in the Midwest was trying to develop a new treatment for, I think, postpartum hemorrhaging. They came up with phencyclidine and — no, it wasn’t for that, they were trying to develop an anesthetic that didn’t produce sedating effects. This drug could, if given in too high a dose — as, unfortunately, Michael Jackson found out — cause respiratory depression and death.
This was a different kind of anesthetic that didn’t work based on sedation. They came up with the concept of a dissociative anesthetic. The first one was phencyclidine, and it worked by binding to one of the glutamate ionotropic receptors. But phencyclidine caused a lot of adverse psychotoxicity, meaning the people who were going to undergo some surgical procedure went crazy when they were given it, and that wasn’t going to work. So they produced a kinder, gentler kind of phencyclidine, ketamine.
Ketamine began to be used as a dissociative anesthetic, meaning that it didn’t put you to sleep, but it put you into a kind of dissociated state of mind so that you were kind of inured to the discomfort you might be experiencing. It came to be used particularly for children and for burn victims. It was just a go-to anesthetic, but then it became a “club drug,” because some people found its effects desirable. It initially was used in that way, but it was then tested in depression. This was kind of a “Hail Mary” type of an experiment. There was no a priori rationale why it would be effective, but it was tested in treatment-resistant depression, and lo and behold, it had a dramatic beneficial effect. Moreover, instead of taking the 7 to 14 days traditional antidepressants need to alleviate symptoms, it did so very rapidly. That was a good thing, and it could be used in severe depression and people who were suicidal.
The field of psychiatry had no procedures, apart from ECT, electroconvulsive therapy. And procedures are among the more lucrative ways in which therapeutics can be administered, as opposed to prescriptions for medications. Finally, psychiatry had a procedure that was less invasive and less controversial than ECT. The use of ketamine in clinics began to proliferate. But it wasn’t being used just by psychiatrists.
I mean, any doctor could do this, and anesthesiologists knew how to do it best, so they could get into this business, but it wasn’t limited to anesthesiologists or psychiatrists. You had a proliferation of clinics; you had more types of specialty doctors getting into it. Then they began using it for a variety of purposes beyond what it was originally tested for, which was severe depression or depression with suicide.
The other thing was that the original data showed how it could be administered acutely and produce a therapeutic effect. But the research had not yet been done to determine the optimal dosing or the best route of administration. Does it need to be repeated? If so, how many times? And then what do you do for maintenance treatment? You had all these questions about the original way in which it was administered — which is the way it’s done in anesthesia, parenterally intravenously by infusion. You can give a bolus or you can infuse it over a period of time. But people began giving it in those ways at different doses. They began giving it intramuscularly, and that wasn’t good.
The other thing that happened was that since ketamine had been an anesthetic for a long time, it wasn’t patent protected. Just using ketamine, even if there may be patents for using it for psychiatric purposes, wasn’t sufficient. The desire by Pharma to get some exclusivity so they could generate more revenue was to find a more practical way to administer it. That’s when Johnson & Johnson Janssen got into lyophilizing it in the form of an inhalant form.
Ketamine has not been a terribly successful drug in terms of the market share. Where the action really has been, and what’s been, I think, really promiscuously overdone, is the number of clinics that have sprung up and the way people are administering ketamine. The clinics themselves are big sources of revenue for the ways that it’s being used. What was the actor’s name from Friends that died recently in Los Angeles? [Editor’s note: Matthew Perry.] That’s a prime example of the risks. Now, that was an extreme example, of course, because his death was because of the combination of drugs he was taking with ketamine.
The other thing that’s worrisome to someone like myself who is very knowledgeable on psychopharmacology and neurobiology is this: with the psychedelic drugs such as LSD and psilocybin, they can be psychologically dangerous for some people, but medically you can’t hurt yourself with them. You can take tons of it and it’s not going to hurt you, for the most part. In fact, there’s a built-in tachyphylaxis if you try and use it repeatedly within too short a period of time.
With ketamine, though, and with the way it works on the NMDA receptor of the glutamate system, you can produce excitotoxicity if it’s used in too high a dose or on a repeated basis, and this can produce organic brain injury. We don’t know what the cumulative effects of it are in people who may resort to using it repeatedly for their psychological symptoms. This is a good example of a drug that has psychoactive properties. Legitimate therapeutic use was found for it. Before the optimal way to utilize it and what other purposes it could be put to were determined, it had already become as common as CVS, or Duane Reade, or Walgreens on every street corner — there are clinics all over the place, and they’re offering it to people in a very unrestricted way.
Sacopulos: I’d like to end our time together with a discussion of cannabis. As a kid who grew up hearing Nancy Reagan tell the country to “just say no,” I’m amazed at where we are today — 38 states have legalized cannabis for medical use, while 24 now permit recreational use. From your position as a psychiatrist, how’s this working out?
Lieberman: I think that the way in which cannabis has been legalized and commercialized is not something I would say is horrific. On the other hand, though, the risks, what the initial incentives or motivations to do it and what the risks are to society by having made it available in the way that it is — that really is not optimal. Just going back to the original way in which society viewed cannabis, which was through the lens of an exaggerated dramatization of its evil powers in such things as the documentary, Reefer Madness, that was vastly overblown and inaccurate.
Because if you say, well, what is the basis for saying that cannabis is any more dangerous than alcohol or tobacco, which are legal? You can’t say it’s worse, because those are things that have caused an untold degree of illness and suffering and cost. By legalizing cannabis, allowing it to be commercialized, it’s led to the production of a different animal than the form that cannabis was used in historically and during the counterculture in the ‘60s and ‘70s. Meaning that when the public indicated its desire to have broader access and use these ruses or these claims, such as therapeutic properties, as justification, state governments saw yielding to public opinion as a way of generating a product that would produce tax revenues. And the business community saw a new industry that could be created.
Tobacco was on the wane because of understandable concerns and all the warnings about health risks. The cannabis industry sprang up overnight. Billions of dollars were poured into it. In the 38 states where it’s legal, you can find more forms in which cannabis products are offered than ever existed before. Moreover, the concentration of the psychoactive component has changed — cannabis is a naturally occurring plant, which has over 100 biochemical constituents, but only two of them have any psychoactive properties, with the main one being THC, tetrahydrocannabinol. Tetrahydrocannabinol in these commercialized forms, as opposed to the naturally grown forms, has multiples of THC concentrations, 80% versus, in the naturally grown forms, maximally 10%. The degree of intoxication is much greater, and that’s led to two consequences that are already apparent.
One is that, just like if you drive when you’re drunk, your risk for an accident is greater. If you drive when you’re stoned on one of these more potent forms of cannabis — well, the accident rate in Colorado, which was one of the first to legalize it, has gone up.
The more worrisome thing for me as a doctor and psychiatrist is we are seeing in the emergency rooms a lot of people coming in with paranoid psychoses that have occurred either while or after they’re intoxicated with cannabis. Even more seriously, people may use cannabis repeatedly over long periods of time — I am talking about daily or multiple times a week or years. They can induce what is basically an enduring psychotic disorder characterized by paranoid perceptions and beliefs and delusions. I call this a phenocopy, a phenocopy of a naturally occurring form of a psychotic disorder. Phenocopy is not as responsive to treatment as idiopathic psychotic disorders, and this is going to increase. It’s already been demonstrated in terms of data.
The last thing I’ll say is that, as you know, many medical conditions are polygenic complex medical disorders: type 2 diabetes, essential hypertension, atherosclerotic heart disease, schizophrenia, bipolar disorder. In other words, these are not monogenic conditions. These are conditions in which you have multiple genes contributing susceptibility in an additive fashion. And when you have a polygenic disorder, you have a risk score, a genetic risk score of your chances of getting it.
It’s not certain, but it’s possible or probable. Let’s say you’ve got a predisposition to type 2 diabetes, but you’re an athlete, you watch your weight, you are very strict about your diet. You may never get diabetes. If you’re a food critic or a chef, your chances of getting it are much more. The same thing, if you have a predisposition to a mental disorder and your lifestyle is such that, despite your genetic risk, other risk factors are not that great, you might never get it. But if you use some pharmacologic provocative agents, such as like cannabis, it’ll trigger it. The end result from both of these phenocopy, as well as pharmacologic triggers, is that the incidence, the population frequency of psychotic disorders is going to increase.
Sacopulos: On that sobering note, thank you. My guest has been Jeffrey Lieberman. Dr. Lieberman is the author of Malady of the Mind: Schizophrenia and the Path to Prevention, which is released in paperback in April of 2024. Dr. Lieberman, thank you so much for being on SoundPractice.
Lieberman: Enjoyed the discussion and happy to talk about this topic.