INTRO
[00:00:00]
MUSIC
Dr. Richard Friedman: There's evidence that humans have experimented with psychedelics for, you know, thousands of years.
This is Dr. Richard Friedman, Clinical Psychiatrist at NewYork-Presbyterian and Weill Cornell Medicine.
Dr. Richard Friedman: And then, jumping ahead a few thousand years, when Albert Hoffman, the Swiss chemist, was actually experimenting to try to synthesize new drugs to treat migraine headaches. And he must have accidentally ingested some of it because he described this hallucinogenic experience, you know, heightened sense of the universe, bright colors, shapes that were shifting. And he didn't realize it at the time, he synthesized LSD.
That was back in 1938. Just a few decades later, psychedelics swept through the counterculture and into the public eye. Young people and artists experimented with these compounds – and were met with legal backlash.
Dr. Richard Friedman: They became classified [01:00] early on, you know, in the ‘70s as drugs that had no medical applications whatsoever. And although they held therapeutic promise, it really wasn't until recently that the field even started to think, maybe we should study them and subject them to the same kind of critical scientific study as we do with every other form of treatment that we use.
MUSIC out
Studies that examine the therapeutic applications of psychedelics are gaining momentum and showing promise.
THEME
And the need now is greater than ever, given the worsening mental health epidemic, and because many of today’s standard forms of treatment don’t work for everyone.
Dr. Richard Friedman: A fairly sizable percent of people who have mood disorders like major depression either don't respond fully or don't respond at all to conventional drugs that we have.
Psychedelic compounds might provide relief for these patients. But there are still a lot of unanswered questions about how to responsibly study them, and eventually use them [02:00] to treat patients with a range of mental disorders.
I'm Erin Welsh and this is Advances in Care, a podcast about groundbreaking developments in modern medicine.
In today's episode, two NewYork-Presbyterian psychiatrists from Columbia and Weill Cornell Medicine share a detailed perspective of how psychedelic compounds work in the brain compared to standard medications, what makes these mechanisms so novel, and what clinical trials have revealed about the promise of psychedelic therapy so far.
THEME out
________________________________________
DR. FRIEDMAN
Dr. Freidman typically treats patients with disorders like major depression, chronic depression, and addiction. Patients with these conditions usually take serotonin-based anti-depressant therapies like SSRIs and SNRIs. But not all patients respond to them.
Dr. Richard Friedman: If you took a hundred people with major depression and randomly gave them any of the antidepressants that we have, [03:00] about a third of them will respond well, about a third of them will have a partial response, meaning 50 percent or a little less, and about a third of them will have no response. And if you keep repeating this experiment over and over, with each successive group that doesn't respond, you'll end up with about 25 percent of your original sample that has an inadequate response to conventional drugs.
Erin: That's a substantial amount of people that we're missing.
Dr. Richard Friedman: Yes, considering that, you know, the lifetime prevalence of major depression is about 17, 18 percent in the United States. You're talking about a quarter of that sample.
That’s over 15 million people. So why aren't these patients responding? Dr. Friedman thinks that in many cases, it might have something to do with the way that SSRIs and SNRIs work. Both types of drugs flood the brain with serotonin, which ultimately helps with mood regulation.
But they take a long time to get those levels up, and they have side effects [04:00] like weight gain and sexual dysfunction. And oftentimes, the serotonin-reuptake mechanism that helps patients' mental state improve just stops working after a while. Psychedelics, on the other hand, have a pretty different mechanism.
MUSIC in
Dr. Richard Friedman: Psychedelics don't actually increase the amount of serotonin in the brain. There are specific stimulators at one subtype of a serotonin receptor called the serotonin 2A receptor. And there's something very special about this receptor.
The serotonin 2A receptor is located in the prefrontal cortex. It sits right behind your forehead and handles everything to do with planning, abstract and critical thinking, self awareness, and more.
Dr. Richard Friedman: It appears these drugs, once they stimulate the serotonin receptor, set off a cascade of events that end up with one particular outcome, which is it quiets the default mode network of the brain. [05:00]
The default mode network, or DMN, is a group of interconnected brain regions that are active when a person’s focus is less on things outside of themselves, and more zoomed into their inner thoughts and feelings –
Dr. Richard Friedman: When you are lying still, for example, and thinking about yourself, and your mind is wandering and you're thinking about your life, or you're wondering about the future, your default mode network is on. It's active. But when you're engaged with the outside world, let's say you start to do a math problem, or you start to read something, or you're working on something, your default mode network shuts off, meaning you're not aware so much about yourself. You're focused on outside things.
Psychedelics dial that default mode network down.
MUSIC out
Dr. Richard Friedman: It produces this state in which your attention is not focused so much on yourself, the so-called egoless state, you're focused on other things. It could be the world outside, the beauty of a flower, the color of the sky, a problem that's outside yourself.
Shifting that focus outward [06:00] can stop the rumination and thought loops that characterize psychiatric disorders like depression, anxiety, and OCD.
Erin: So SSRIs and SNRIs do not have this effect. They don't shut off this network.
Dr. Richard Friedman: Exactly. In fact, we don't know of any drug that does that. SSRIs, SNRIs, all the traditional antidepressants that we use also are drugs that will enhance neuroplasticity, but they do it slowly and less powerfully over the course of four to six weeks, let's say.
But with a compound like psilocybin, for example –
Dr. Richard Friedman: What you see with one exposure of psilocybin is that neurons start to become more densely connected and sprout little dendrites which allow them to connect with one another. They are what we call rapid-acting neuroplastic agents. They bring about synaptic changes in neurogenesis very quickly, within hours. And this is the molecular basis for learning and for memory in the right regions of the brain [07:00] and is thought to underlie some of the therapeutic effect of these drugs and why they work so quickly.
Sounds promising, right? So why not give these drugs to patients instead of SSRIs? Well, while the adverse effects of taking an SSRI are fairly benign – possible weight gain, the chance that the drug won’t work for you – taking a psychedelic can be very risky for some people.
Dr. Richard Friedman: The side effects from psychedelics that we are concerned about in a small percent of people who will get exposed are psychotic-like experiences. That the trip itself, the transcendent experience, produces insights that one has about oneself, memories, real or fantasized, both, that can be very upsetting and that are hard to contain.
MUSIC in
So how can we harness the therapeutic advantages of psychedelics without causing these extreme adverse effects? For most promising drugs, the obvious answer is to learn about how to administer them [08:00] through rigorous clinical study.
Dr. Richard Friedman: The gold standard for testing whether a drug is useful and safe is a randomized clinical trial in which the drug that you want to study or the therapy you want to study has a control, a placebo. Psychiatric illnesses like depression and anxiety have high placebo response rates. And so, if you want to answer the question, “Is the drug making someone better or is hope, a placebo response, making you better?” You need a placebo control.
But psychedelics pose a unique challenge to traditional research methods.
Dr. Richard Friedman: The key problem in studying psychedelics is there's no way to be blind.
Researchers try to solve the placebo problem by giving the control group benzodiazepines or niacin instead. But a trip is a pretty distinct experience – patients might see patterns or colors, feel a deeper connection to the universe, or experience synesthesia. That’s when stimulation of one sensory pathway creates sensations [09:00] in another sensory pathway. So for example, hearing a certain sound that makes one see certain colors.
Dr. Richard Friedman: If you get a psychedelic, you know you're getting a psychedelic. More than 95 percent of people in clinical trials with psychedelics can identify correctly that they were given a psychedelic. So that's a problem.
MUSIC out
________________________________________
DR. HELLERSTEIN
But researchers are trying to tackle this problem to unlock the benefits of psychedelic therapy. Recently, a team led by Dr. David Hellerstein, Research Psychiatrist at NewYork-Presbyterian and Columbia, took a novel approach by implementing a smaller placebo dose of psilocybin.
The study examined patients with Treatment Resistant Depression – a major depressive disorder that doesn’t respond to standard antidepressant medications or to psychotherapy.
Dr. David Hellerstein: As a psychiatrist seeing people for medication treatments of their depression, I want them to have a good placebo response and a good medication response, because why not?
Dr. Hellerstein and his team [10:00] worked with a synthetic form of psilocybin in a large, randomized, controlled, double-blind study. It involved 233 subjects at 20 different sites in 10 countries. It was a phase 2B study, which in FDA terms means that it was about finding the right dose to achieve the best treatment effects with minimal risk.
Dr. David Hellerstein: The design was, there were three different doses of psilocybin: 1 milligram, 10 milligrams, and 25 milligrams. So you're trying to find, like, what's the right amount? So that was a really interesting thing because, for one thing, we could honestly tell our participants everybody's getting some psilocybin, we just didn't know how much.
Ingesting just a little bit of psilocybin can still produce some mildly hallucinogenic sensations.
MUSIC in
Patients in Dr. Hellerstein’s study took their dose and remained under surveillance for up to 8 hours. Three weeks later, they were examined for a response – an improvement in their depression symptoms. They were then monitored for up to [11:00] 12 weeks after that initial dose to see if they maintained that response.
Dr. David Hellerstein: Interestingly, the effect of the medicine became apparent the day after dosing, but then up through week 12 there was clearly benefit of the different doses. And at the end of the day, the 10 and 1 looked pretty similar and the 25 showed more of an effect.
Erin: That's after just one dose and that's 12 weeks later.
Dr. David Hellerstein: Right, so, that comes back to me, what is this really interesting mystery, and the more I talk to neuroscientists and neuroimagers the less I understand how that would happen. Why is that one exposure could have such a lasting effect long after the drug has vanished from the body? And that's kind of cool. It's kind of scary, but it's something that is worthy of further investigation.
Mystery aside, the results of the trial [12:00] not only identified an effective dose of synthetic psilocybin, they also substantiated a method of blind study design for psychedelic compounds.
MUSIC out
For Dr. Hellerstein, the curiosity surrounding what psychedelics are doing in the brain are a synthesis of three main areas of psychiatry – psychoanalysis, the DSM, and neuroscience.
Dr. David Hellerstein: To me, the psychedelics connect all those eras of psychiatry because clearly there's a neuroscience component because they're having this rapid, profound, and somehow mysteriously lasting effect on brain networks and connectivity and nerve cell growth. But they can be used for many different disorders – depression, anxiety disorders, OCD, addiction.
And then the psychoanalytic piece is really interesting because when people use these drugs, they re-experience these major, very profoundly affecting life experiences. So their traumas, [13:00] their losses, their deaths, their people they miss, their fantasies, they re-experience it in a very powerful way. So it sort of connects to the feeling of you must uncover things and reveal things and work things through, which was from the days of psychoanalysis.
That's why therapy in tandem with psychedelic consumption is so important. Because, as Dr. Hellerstein mentioned, there are so many complicated psychiatric disorders that could potentially be treated with these compounds. Psilocybin and treatment resistant depression is just one example.
He and his colleagues are actually preparing for a study of MDMA on PTSD patients. Specifically combat veterans, who are a vulnerable group with high mortality, and often experience both substance abuse issues and problems connecting socially.
MUSIC in
Dr. David Hellerstein: We're really interested with MDMA, which is called ecstasy for a reason. There's logic to why we would want to use MDMA for PTSD [14:00] and trauma because it makes people more socially connected during the dosing session and maybe opens them up.
MDMA is different from psilocybin and other psychedelic compounds like LSD in that it acts as both a stimulant and a mild psychedelic.
Surprisingly enough, these compounds don't only show promise for psychiatric disorders. Their neuroplastic effects might prove beneficial for patients with other types of illnesses that have a psychiatric connection. For example, Dr. Hellerstein is also developing a study to use DMT – a very strong psychedelic that can be found in a variety of plants – to treat patients with long COVID. These patients often have long-lasting symptoms that can be neurological, cardiological, and psychological, too.
Dr. David Hellerstein: It's going to be focused primarily on people who have a psychological or psychiatric component to their long COVID. The thought, I guess, would be that there's some [15:00] kind of stuckness of circuits. Kind of adverse plasticity or impairment of plasticity, and that the medical and psychiatric state that the person is in is somehow reinforced in this kind of stuck way. And then if you can kind of shake things up, you can essentially allow the person to heal.
While all of this sounds quite promising, Dr. Hellerstein acknowledges that application of these compounds isn't without its risks.
MUSIC out
Dr. David Hellerstein: I think we've got to keep in mind that the first honeymoon of psychedelics ended really badly, and so we don't want the second one to end that way. We want to come out with good knowledge, safe treatments, identify risks who's vulnerable for becoming psychotic or suicidal. We want to know, do they need extra support? Should they just not take these drugs?
These are all crucial questions for psychiatric patients and the physicians who treat them. And they are precisely the questions that Dr. Hellerstein and his team are working to answer [16:00] through these rigorous, well-designed trials.
Dr. David Hellerstein: So we want to really have good guardrails and safety and figure out what's best for whom, which gets back to, how do clinical trial researchers try to work? That's a model that I think is robust and makes a lot of sense. And it's one part of the big tent for psychedelics, but I think it's a really essential one.
________________________________________
OUTRO
MUSIC in
As that research continues, it's going to be critical for the next generation of psychiatric professionals to keep an open – but reasonably skeptical – frame of mind when it comes to psychedelics, as they potentially become more commonplace treatment options. This is something that Dr. Friedman thinks about as he instructs psychiatric residents.
Dr. Richard Friedman: I try to instill in them a desire for, you know, unquenchable learning. The half life of knowledge in the field can be short, science thrives on replication, so you want to see interesting things replicated in order to really believe in them. And that, you know, you have to be a lifelong learner. [17:00]
And you have to be aware that there are new therapeutics that are constantly being investigated and tested. And you have to come to this with an open, but critical, skeptical mind. We talk about what the history is and what is known. And then we talk about the methodologic problems in current clinical trials, the ways the studies are designed, and what's around the corner.
MUSIC out
Both Dr. Friedman and Dr. Hellerstein are optimistic about how NewYork-Presbyterian, Columbia, and Weill Cornell Medicine will shepherd in this new era of psychiatry.
Dr. David Hellerstein: We're hopeful, if you think going forward, that our expertise in doing psychedelic assisted psychotherapy, we have a cohort of really wonderful therapists, as these drugs move toward approval will lead toward increased expertise and then provision of clinical care amongst people who have really good experience and can help train other clinicians.
THEME
Dr. David Hellerstein: If these things do indeed come into [18:00] a state of being FDA approved, then there's going to be a need to provide them safely, ethically, have well trained physicians that are prescribing them, administering them, and having really top notch psychotherapists who can help people deal with the powerful challenges of the psychedelic experience.
Thank you so much to Dr. Richard Friedman and Dr. David Hellerstein for taking the time to speak to me about the emerging field of psychedelic therapy, and how NewYork-Presbyterian, Columbia, and Weill Cornell Medicine are shaping the future of psychiatric care.
I’m Erin Welsh.
Advances in Care is a production of NewYork-Presbyterian Hospital. As a reminder, the views shared on this podcast solely reflect the expertise and experience of our guests. To listen to more episodes of Advances in Care, be sure to follow and subscribe on Apple Podcasts, Spotify, or wherever you get your podcasts. And to learn more about the latest medical innovations [19:00] from the pioneering physicians at NewYork-Presbyterian, go to nyp.org/advances.
