Psychedelics: A Reemerging Treatment for Behavioral Health Conditions

Podcast Transcript

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD:

Although early research suggested the therapeutic potential of psychedelics, the substances were banned in the early 1970s, effectively halting further investigation for decades. In recent years, however, psychedelics have reemerged as a promising treatment for various behavioral health diagnoses such as addiction, depression, anxiety and post-traumatic stress disorder. In today's episode, we're discussing the current state of psychedelics research and what could be next for the field.

I'm your host, Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. I'm very pleased to have Dr. Brian Barnett join me for today's conversation. Dr. Barnett is a psychiatrist in the Center for Behavioral Health within Cleveland Clinic's Neurological Institute. Brian, welcome to Neuro Pathways.

Brian Barnett, MD:

Thanks for having me on the show, Glen.

Glen Stevens, DO, PhD:

So, Brian, as an introduction, tell us a little bit about your background and how you found your way to the Cleveland Clinic.

Brian Barnett, MD:

Sure. So I did my psychiatry training at Massachusetts General Hospital and from there, I stayed on an additional year in the Partners Healthcare System in Boston, which also includes Brigham and Women's and McLean Hospital, and I did an addiction psychiatry fellowship. I moved to Cleveland afterwards and completed a fellowship in forensic psychiatry before coming to the clinic. And so I've been at the clinic now going into my fourth year.

Glen Stevens, DO, PhD:

Excellent. Well, welcome. We're happy to have you on board.

So psychedelic is a term that was coined in the 1950s by psychiatrist Humphry Osmond and literally means mind-altering. I was born in the fifties, raised in the sixties and seventies, and of course the name most associated with the psychedelics at that time is Tim Leary, who some consider the father of the psychedelic drugs. And his famous saying was turn on, tune in, drop out, a real counterculture attitude that the establishment really didn't care for. And I guess not surprising that this class of medications disappeared for 50 years.

But in 2020, Oregon became the first state to legalize psilocybin, or what we used to call magic mushrooms. So clearly, a reemergence of these medications. So if you could give us an overview of what's currently going on in psychedelic research and what drugs are getting the most attention and why.

Brian Barnett, MD:

Sure. So there is certainly a lot going on in the world of psychedelic research now. You mentioned Timothy Leary, who's definitely a polarizing figure in the field. On the one hand, he gave us the concept of set and setting for psychedelics, which is very important.

And so set is the mindset that you go into when you're having a psychedelic experience. And so people can get very different things from these drugs. If you're going into it expecting that you're going to have a good time at a party with friends, I can certainly do that. But if you are going into it with therapeutic intent and in an appropriate setting for that, a therapeutic setting, then you can often get benefits that look like they could last for a year or even longer for some patients.

But then on the other hand, Timothy Leary was definitely prodding the establishment and created a lot of controversy and almost certainly contributed to psychedelics getting banned. And so that's why he's such a polarizing figure. But since that time, a lot has changed.

Psychedelic therapeutic research really got off the ground again in 2006 at Johns Hopkins when they published a study looking at the impact of mystical experiences occasioned by psilocybin use, and Hopkins has been at the forefront of this work since then. They now have a dedicated psychedelic research center and have done many of the pivotal trials in the field along with other institutions such as New York University and UCLA. And this work is starting to spread to other institutions now. There's a lot of industry interest.

I would say the psychedelic that's gotten the most attention thus far is psilocybin, and that's where most of the contemporary studies have been done. And so recently, there have been studies demonstrating efficacy for depression as well as psychological distress associated with cancer and alcohol use disorder.

There's also growing interest in LSD. So LSD is the psychedelic that had the most research done on it in the fifties. In the fifties, the regulations were looser, and so there were actually psychiatrists treating patients with LSD-assisted therapy. And we have studies from back then showing that it looked to be very effective for alcohol use disorder, cancer-related distress.

And unfortunately, the first decade or so after LSD was discovered by Albert Hofmann, psychiatry didn't know what to do with this drug and so it was used as a way to possibly experience what it's like to be schizophrenic. And so psychiatrists in training would take LSD to try to get a better sense of what a psychotic experience might look like. And now in retrospect, we know that psychedelics are not good models for psychosis. If you're looking at that from a pharmacological perspective, something like PCP or ketamine would be closer to the psychosis that patients with schizophrenia experience.

And so by the time psychiatry figured out that there were therapeutic effects from psychedelics, the patent had expired for LSD and so there was really no way to, at least at that time, get it over the line with the FDA for an indication. Now, there are companies that are interested in this that are doing unique formulations that are allowing them patent protection who are hoping to get these medications approved by the FDA.

And then finally, besides LSD, there's a lot of interest in shorter acting psychedelics such as dimethyltryptamine and 5-MeO-DMT, which lasts less than an hour and would be much more convenient for the psychiatrist's schedule since we typically see patients for a half hour or an hour. That's a lot more manageable than LSD, which lasts for 12 hours. Psilocybin can last up to eight hours, and so there's a real rush in the field to start looking at shorter-acting psychedelics for their therapeutic potential now.

Glen Stevens, DO, PhD:

Yeah, certainly LSD been around for a long time. I think Hoffmann synthesized it back in 1938, so that's a long time for sure.

You touched on a little bit, but how well do we understand the mechanism of action of these drugs? Do you want to go through any of that for us?

Brian Barnett, MD:

Yeah, sure. I can talk about some of that. So I'll say in general in psychiatry, we don't know a lot about how many of our treatments work. We have inklings here and there from different types of studies, but it looks like the primary mechanism at the neuronal level is that psychedelics activate the serotonin two a pathway, so 5-HT2A. That pathway is involved in a number of areas including learning, memory, pain perception, sleep-wake cycle, but those receptors are most concentrated in what are called the higher-order association areas of the brain. So those are the parts of the brain that really integrate incoming sensory information, and it looks like psychedelics really allow more sensory input to come into the brain. They peel back the control over the thalamus of sensory input data, and so allow more sensory data to come in, which overloads the brain and causes different areas that don't normally talk to each other to speak to each other and connect.

And so that's why sometimes people can get what's called synesthesia when they take a psychedelic, experiencing sound as colors and things like that. And from a different perspective, it looks like after you take a psychedelic, they induce pretty long-lasting periods of neuroplasticity, where the brain is more flexible, it's able to reorganize synaptic connections, and you can really adjust your perspective on things, see life from a different point of view, learn new ways of coping with stress. So we think that period afterwards for several weeks, maybe even several months, is really where a lot of the benefit comes from because patients can really engage in therapy at that point, and therapy can be catalyzed.

Glen Stevens, DO, PhD:

Great. You've broached this a little bit, but the potential applications of the psychedelics in the therapeutic space, can you expound on that a little bit? And in that regard, safety concerns, who's most likely to benefit, who would you consider treating.

Brian Barnett, MD:

So right now, I would say depending on the psychedelic, the most attention is on PTSD and depression. So MDMA, which I didn't mention before, is at the forefront of psychedelic research, and so there's some debate about whether MDMA is truly a psychedelic because it has a different mechanism and the experience is different than the classic psychedelics. But MDMA seems to be really useful for bringing patients into the moment and allowing them to discuss and relive trauma in a way where they are able to process it and able to get closer to it. So it looks like it's a real catalyst for trauma-focused therapy.

There's an organization called the Multidisciplinary Association for Psychedelic Studies that has been doing clinical trials using MDMA to treat post-traumatic stress disorder, and they have just completed their final phase III trial for that. So it looks like MDMA for post-traumatic stress disorder could be approved in 2024.

So a couple years behind that in the pipeline is psilocybin. So there's a company called COMPASS Pathways that is currently starting phase III trials of psilocybin for treatment-resistant depression. So it's looking like that could be approved somewhere around 2025, 2026. So these treatments definitely are not far off.

And then there are a variety of other companies and investigator-initiated studies at academic institutions looking at psychedelic treatments for a variety of other indications. There's a company called MindMed that we're working with that's looking at LSD for generalized anxiety disorder. And then there's been recent work out of NYU looking at psilocybin for alcohol use disorder. So there are many different indications that are being explored right now.

You mentioned safety concerns. Just to talk a little bit about how these are used and if they are FDA approved, how they will be administered, so we don't foresee a model where patients would ever actually be given a prescription for a psychedelic to take home on their own. So this goes back to setting that I mentioned. To really get the therapeutic benefit, you need to be in a therapeutic setting. You really need to be able to trust the people around you and fully let yourself go within a psychedelic experience.

And so right now, the model that the FDA is requiring is that two therapists or two monitors are with the patient at all times. This way, the patient can feel safe and get fully immersed in the experience. And the medical application is very different and takes place in a very structured setting in a room that's decorated to look like a living room with... It's painted with soothing colors. It has artwork that can calm the patient if they're having a hard time, because the reality of this work is that people can have challenging experiences. Psychedelics can bring up memories that have not been at the forefront of the mind for a long time. Sometimes, they can bring up distressing content, anxiety-provoking content, and that's really the role of the therapist or the monitors there to get involved if patients are having those experiences. And so they can do breathing exercises with the patients or give them things to distract themselves and move past that so they can continue to benefit from the positive aspects of the psychedelic experience.

And the groups that we see having the most risk with psychedelics are people with schizophrenia or other psychotic disorders and, to a lesser degree, patients with bipolar disorder because there is the possibility that psychedelics can induce mania in those people. So at this point, we don't see psychedelics as a treatment for psychotic disorders, and we want to avoid them in those patients. And in the clinical trials, people are excluded who have those diagnoses and even if they have close family members who have them.

Glen Stevens, DO, PhD:

So, Brian, if someone was going to be admitted for a trial of medication, what's the time period that they'd need to be observed for? I'm sure it's quite variable depending on the patient, but is this 24, 48, a week, two weeks?

Brian Barnett, MD:

So it's typically just while the drug has psychoactive effect and a little bit of time after it's worn off to make sure that the patient is stable and meeting criteria to go home. But in terms of medium-length psychedelics such as psilocybin or MDMA, that would be something on the order of six to eight hours, whereas the clinical trials with LSD, the FDA is requiring that patients be monitored for 12 hours since it lasts so much longer.

Glen Stevens, DO, PhD:

And use in suicidal patients?

Brian Barnett, MD:

Currently, patients who have active suicidal thoughts or recent suicidality are being excluded from these trials. I think that's an interesting and open question in the field right now.

In the past, there were a lot of concerns raised in the media that psychedelics could cause suicidality. When we look at large-scale population studies now, there tend to be no associations found between suicidality within the past year and psychedelic use, with one exception being LSD. There have been some studies finding associations with suicidality there. And we don't know if that's because patients who have been struggling with severe depression and suicidality are self-medicating with the LSD or if it actually is an effect of the LSD in some vulnerable patients. But there's certainly a lot of caution around suicidality at this point because these can be intense experiences. And right now, I think the field's just trying to get its footing to figure out which patients, using a very conservative point of view, can we use these in. And then as we gather more data and more experience with these drugs, then potentially we could use them in patients who have more severe disorders, who might have suicidality, things like that. But I think the field is approaching this issue very cautiously.

Glen Stevens, DO, PhD:

And what about any assistance we get from other countries? Are there countries in Europe that have much more liberal policies that have been using these medications, that are currently actively using these medications or no?

Brian Barnett, MD:

So there has been a lot of ongoing work in Europe. Switzerland, it seems like they never stopped doing psychedelic research there, although most of the work there had been around things like neuroimaging. Fewer clinical trials, although that that's changing now. But we have a lot of very rich data on neuroimaging studies in psychedelics from Switzerland.And then Imperial College in the United Kingdom has done a lot of the groundbreaking work on psychedelics for a variety of things including neuroimaging, but also for depression. So Europe is certainly contributing a lot to the field as well. And I know that in some cases in Switzerland, clinicians who had a special license were able in the past to use LSD in rare circumstances.

Glen Stevens, DO, PhD:

And are the drugs all given orally, or are some of them IV?

Brian Barnett, MD:

So right now, the contenders at the forefront of regulatory approval are orally based. However, there are companies now that are doing phase I and phase II trials of intravenous, fast-acting psychedelics as well.

Glen Stevens, DO, PhD:

And what about scheduling? Does there need to be a change in schedule of these drugs in order to move forward and be able to utilize them?

Brian Barnett, MD:

So I think this is a complicated area as well. It seems like if a psychedelic in its pure form is approved by the FDA as a medication, the DEA would have to reschedule it at that point because it no longer meets schedule I requirements, with schedule Is being drugs with high abuse potential and no therapeutic potential. However, we have seen approval of medications in the past where the FDA did not reschedule according to that guideline.

So an example there would be dronabinol, which is a marijuana derivative, and cannabidiol in the form of Epidiolex. So both of those are FDA-approved medications that are derived from marijuana, but the DEA did not reschedule marijuana after those were approved. I think the issue there is that marijuana contains many psychoactive substances, and so those were individual substances within marijuana. So with psychedelics, it would be different.

If psilocybin was approved, that's pure psilocybin. There are no other potential compounds in it. It's not that they would be approving magic mushrooms, which do have other compounds. And if LSD were approved, that would be pure LSD. So I do think that we will see these drugs be rescheduled once they are approved by the FDA. However, if they're not, then I could see particular products that have been approved by the FDA given a different schedule by the DEA.

Glen Stevens, DO, PhD:

And are you seeing patients coming in and asking for these treatments?

Brian Barnett, MD:

We are. I would say over the last few years, there's certainly been an uptick in patients who are asking about these, calling us, asking about whether clinical trials are available. And so there's certainly a lot of interest among the patient population.

Glen Stevens, DO, PhD:

And will this be limited to those 18 years of age and over?

Brian Barnett, MD:

Yes. Currently, the clinical trials are only in adults. I think at some point we can expect to see clinical trials looking at adolescents who have severe mental illness that could benefit. But right now, most of the work that I'm aware of is in adults.

Glen Stevens, DO, PhD:

And you've touched on some of this, but major challenges facing the field. How do you see it?

Brian Barnett, MD:

I think the biggest one is probably regulation. So it takes a lot of work to get these studies off the ground because of the DEA regulations. If a drug is schedule I, you have to apply for a special license as a physician to be able to dispense that drug. The drug has to have special storage conditions. It has to be in a room that has multiple locks either inside a large safe inside that room or refrigerator that's bolted to the floor. Pharmacies at academic medical institutions will often not manage the drugs and so as the investigator, you have to manage the drug yourself, including things like monitoring the temperature of the refrigerator where it's stored, keeping logs to make sure that nothing has been taken.

And so that presents considerable challenges for researchers who are looking to get into this area because you also have to have dedicated space, which is often hard to find in hospitals to store the drugs. And so there are groups now that are lobbying Congress to try to if they're not going to immediately reschedule these drugs, to at least create some sort of separate pathway to make working with them easier in academic settings.

Glen Stevens, DO, PhD:

And are you seeing patients using this more, less, same recreationally?

Brian Barnett, MD:

I would say mostly, we have seen upticks in patients using magic mushrooms on their own. There's a lot of microdosing going on. I think data are very conflicted on whether microdosing works.

So microdosing is when you take small doses of a psychedelic that should not alter your perception in any way, and there are various books out there and protocols that people use where they say this helps their depression. However, when you look at studies comparing this to placebo, it doesn't look like it's any better than placebo, which really makes it seem like you need the full psychedelic experience to get the benefit, which often involves a mystical experience where people are experiencing oneness with the universe or feel like they are experiencing God. And that can be a very transformative experience for people.

So I'm pretty skeptical about microdosing. I think it is something worth researching, but we are seeing a lot of patients doing that on their own.

Glen Stevens, DO, PhD:

Any other unmet opportunities that you're seeing out there that we're not looking at that'd be worthwhile to look at?

Brian Barnett, MD:

I think it's going to be interesting to see what neurology does with psychedelics because we are seeing some use by neurology. So for example, there's a study study right now going on at University of California at San Diego where they're using psilocybin to help people with phantom limb syndrome and using mirrors to help relieve the symptoms of that. There's also interest given neuroplasticity and possibly using psychedelics to either treat or possibly prevent dementia. And so I'm seeing more articles coming out about that. And then finally, I would say the world of chronic pain is starting to get interested in this as well, because there are cases of patients who report that their pain is alleviated after a psychedelic experience.

Glen Stevens, DO, PhD:

Excellent. Areas of interest in psychedelics that we haven't covered that you think would be helpful to our audience?

Brian Barnett, MD:

One of the most interesting areas is personality disorder. So personality disorder is something that we struggle with a lot in psychiatry. The ones that most frequently come to our attention are borderline personality disorder, where patients really struggle with having a fully-formed sense of themself. They often have a lot of conflict in their relationships and can find it hard to sustain long, healthy relationships in their life. And they often experience a dysphoria that is similar to depression, but not exactly the same. We don't really have medications that treat this disorder very well. We do know that there are effective therapies, such as dialectical behavior therapy, but often for many patients that's not enough, or they can't get access to it because it is a highly specialized therapy that's largely just available on the coasts in the United States where there's more psychiatric infrastructure.

So there have been studies showing psychedelics can possibly change domains of personality, including openness to new experience, and these are small studies and still certainly a lot of work to be done here. I think that's one area that's starting to get more attention because we don't have as much to offer those patients as we do patients who have mood disorders or anxiety disorders. And so it would be wonderful if we could use psychedelics to help patients with personality disorders and also patients with antisocial personality disorders.

So these are patients who commit crimes, who are in prison, who do things that are very extreme, often in and out of the criminal justice system, and there's really not much treatment for them. This is something that's often not viewed through the lens of psychiatric treatment. But in terms of societal benefit, if we could get treatment for those people that would help change the structure of their personality and keep them from committing crimes and going back into the criminal justice system, there could be significant benefit for the population as a whole.

And so there was some work on this in the fifties and sixties. Timothy Leary did do a study where they used, I can't remember, I believe it was psilocybin to look at recidivism in a prison population. And it looked like it was useful, but now there are questions about whether Leary faked the data. And so we're just not sure how much we can trust that, but it was a very unique idea. And there are population level studies now showing that people who have been to jail or prison who've had a psychedelic experience have less recidivism. And so these are very intriguing lines of inquiry that I hope to see the field jump into in the next few years.

Glen Stevens, DO, PhD:

And what about abuse risk with these medications? I mean, if I get this altering experience, I really like it, do I need to keep getting it?

Brian Barnett, MD:

I think that's a really important question. So I've done some survey work with psychiatrists in the US about their thoughts on psychedelics, their knowledge on psychedelics. And as a field, it looks like we really overestimate the risk of abuse or addiction to psychedelics. These are probably the least addictive psychoactive compounds that we have, and so it's extremely rare to see patients who get addicted to psychedelics.

It's not impossible. I've seen probably a handful of cases over the last 10 years, but those tend to be people who have what used to be called polysubstance abuse, so people who are addicted to many different things and find some sort of pleasure or comfort in multiple types of drugs. So it's very rare to see somebody who is addicted to a psychedelic alone.

Now, that's not to say that it's not something that we're worrying about because as use goes up, you would expect to encounter more cases of that. But just in terms of intrinsic addictive potential, psychedelics are very low compared to other psychoactive substances, and some of that is the way that they behave at the neuronal level. So they tend to stimulate the 5-HT2C receptor, which looks like it reduces addictive potential.

And so psychedelics are actually being used to treat addictions, including there are studies right now looking at opioid use disorder, methamphetamine use disorder and alcohol use disorder. And so it looks like not only are they not really addictive themselves, but they could be powerful for stopping addiction to other substances.

Glen Stevens, DO, PhD:

So, Brian, how should physicians talk to patients about psychedelic use?

Brian Barnett, MD:

I think this is a really important question because surveys are showing that psychedelic use is going up across the US right now, and it's clear that many patients are in severe distress and they don't want to wait until there's FDA approval, and so they're seeking out these experiences on their own. Patients will, if they feel comfortable with their physician, they will ask about this. I actually had a patient yesterday who has severe depression. He's responding well to his medication, but he asked me whether it be okay to use mushrooms with his medication. And I told him that for his particular medication, it could actually have a serious interaction, and I would recommend that he avoid using mushrooms altogether. But I think it's important that we give patients factual, accurate information, not that we're condoning use, but that we are accepting that people will do this on their own because there are real risks with psychedelics.

Patients who have bipolar disorder can be launched in a mania and have to be hospitalized. I've seen that when I've been working on the inpatient unit. There have been patients who have gone to South America for ayahuasca retreats, and ayahuasca contains a monoamine oxidase inhibitor which can interact with other antidepressants, such as SSRIs, and can actually be fatal. And so there are reports of people who have died during those retreats, and it looks like it was probably due to interactions with their medications and the MAOI and ayahuasca. And so we need to be honest with patients about these risks and just help them make the most informed decisions with the caveat that we're not able to recommend these ourselves because these are not approved treatments yet.

Glen Stevens, DO, PhD:

Well, that was very insightful conversation, Brian. Thank you for joining us today, and appreciate your time.

Brian Barnett, MD:

Thank you.

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