The Frontiers of Psychedelic Medicine

The following is Dr. Samoon Ahmad‘s interview with Dr. Stephen Ross regarding the mental health benefits of Psilocybin.

SAMOON AHMAD

To start, could you give me a little bit of an overview about what drew you to psilocybin? What made you so passionate about it? Was there a particular study or anecdotal story that really drove this interest in psilocybin?

Dr. Stephen Ross: Yes. It happened in 2006. It was my sixth year at Bellevue [Hospital]. I had just taken over the leadership of the Substance Abuse Division and I was being supervised by Jeff Guss, who’s a longtime faculty member. One day in supervision he starts talking to me about some conference he’s going to in Switzerland commemorating the discovery of LSD . I was like, ‘What are you talking about? Why would anybody commemorate the discovery of LSD?’ In my psychiatric training and my addiction training, the only thing I learned about psychedelics was that they’re bad, that they cause psychosis or addiction—these sorts of urban legends, in a way. And he said, ‘Well, actually, psychedelics were a big part of psychiatry.’

So, I started looking, and you don’t have to look very far because it’s all kind of hidden in plain sight. There’s this enormous body of research in psychiatry spanning 30 years. You know, LSD was discovered in 1943 by Albert Hoffman, but in the Fifties and Sixties and into the early Seventies there was an enormous body of research in psychiatry, including among some of the top psychiatrist of the day. There were APA conferences dedicated to LSD; it was hailed to be a wonder drug; and it was used in all these clinical indications.

What really got my attention was that the most studied indication with LSD was the treatment of alcoholism. There were thousands of people in clinical trials. There were six randomized control trials that included close to 600 people. What they found was that a single dose of LSD led to improvements in drinking compared to placebo even after six months. I just thought that was fascinating. The other most studied indication for LSD was for the treatment of terminal cancer—specifically psychiatric and existential distress.

I just couldn’t believe that there was this enormous body of research in my own field that I never learned about! I kept thinking, ‘How is this possible?’ And then I realized why it had been suppressed. As an addiction psychiatrist, it all kind of came together for me. You know, you work at Bellevue and with people with addiction, and you realize in general that they are the most marginalized group within medicine. They are very poorly treated.

Why are they poorly treated? Why are they mostly in prison? Why do most psychiatrists and doctors not know about addiction? It was because Richard Nixon declared war on drugs in 1970 and created the Controlled Substances Act. This really strengthened the criminalization of addiction that occurred in this country. [Nixon] was concerned that the American middle-class—you know, wealthier, mostly white people—were doing psychedelics during in the Sixties and not thinking straight—from his perspective—and not wanting to go to Vietnam, so he specifically enacted the Controlled Substances Act to basically stop people from using psychedelics, and what that did was profound. It stopped this very interesting body of research and it created this idea that these drugs are evil.

And that’s what I knew about them [until this time]. All this research within the medical education in psychiatry was so thoroughly suppressed; it was just missing from the history books. And I just thought all this was so fascinating that we decided to form a reading group. We called ourselves the Psychedelic Reading Group at NYU. It me, Jeff Guss, and Tony Bossis.

Tony was a psychologist around the corner from me and he overheard Jeff and I talking one day. He was really interested in psychedelics and had always been. I didn’t have a lifelong interest in psychedelics. I knew something about them growing up in Los Angeles because the whiff of the Sixties was still in the air there, and I knew people who did them, but other than that I didn’t know anything about them, so we formed this reading group, and I heard about a month after we formed the group that psychedelic research had resumed in the US in the late 90s, and that one of the sites was UCLA.

Now, I had gone to UCLA for medical school, and my favorite rotation was at Harbor-UCLA, which is kind of like Bellevue. And though I never met him at the time, there was a guy, Charlie Grob, doing psilocybin research for terminal cancer—studying people who had anxiety, depression, and existential distress—at UCLA.

I was introduced to him when I went to visit my family in late 2006. I went to Harbor and we had like a three-hour lunch. He was Division Chief like me, running their child division, and he’s just this amazing guy who said, ‘This is a really promising part of psychiatry and it’s starting to come back and I’m doing this trial.’ And then he said, ‘Why don’t you do a bigger trial at NYU? My daughter is an NYU student. I love NYU.’

So I said okay, and he gave me his protocol and I looked at and designed a bigger trial than the one at UCLA. This is all late 2006.

So out of nowhere we formed a group, formulated to study, I wrote a protocol, I applied to the Heffter Research Institute for funding, but I was not a researcher. I just had some background in my residency at Columbia. So, I went to John Rotrosen, who became my research mentor, and he said, ‘This is the dumbest idea. It’ll never get funded. It’s going to be impossible. Just, you know, don’t do it.’

So I think I was young enough in my career and naïve enough that…I just thought it was so interesting. I thought, why don’t I just keep going and see how far I can get, and so I just kept putting one foot in front of the other. I applied to the FDA [Food and Drug Administration] to get an investigational new drug license to do it. I was shocked that they gave me the license right away. I then had to go through the Cancer Review Board. They had a hard time with it and they almost killed it, but it eventually squeaked through. It sailed through the IRB [Institutional Review Board]. Then there was the whole part of getting a Schedule 1 license with the DEA [Drug Enforcement Administration]. That was actually not that complicated because I had a very close relationship with the DEA running the Substance Abuse Division, but Bellevue…that’s where it stopped.

You know how much I love Bellevue, but they would not let me do it. The medical directors said, ‘I’m not going let you give LSD to dying Black people in this hospital.’ And I said, ‘First of all, it’s not LSD. And why would you bias against minorities? We should try to do this in particular to help our own patients.’ And he said, ‘You know Bellevue has been in the media for way too long negatively. We’re not going let you do it.’

Now, I thought that was the end of it, but the NYU College of Dentistry reached out to me, and they said they were interested in part because the head of their clinical research center was dying of lung cancer. So we did this study, this psilocybin and cancer study at the Bluestone Center for Clinical Research at the Dental School. At the end of that trial, we designed this psilocybin for alcoholism trial that we’re finishing now, but the dental school said, ‘We can’t have drunk people running around the dental school. You have to do that at Bellevue.’ And I said, ‘But Bellevue don’t doesn’t allow us to do that.’

Turns out after several years and positive media portrayals, Bellevue has accepted me back, and so we now have our psychedelic lab at Bellevue. We have our dosing room and our Clinical and Translational Science Institute at Bellevue; we’re finishing up our alcohol trial at Bellevue; and all our psychedelic research now is happening at Bellevue.

So that’s a longwinded way of saying: 2006 due to this serendipitous interaction with Jeff Guss. That started it all off.

Dr. Ahmad: I want to go back to how you were talking about alcohol and existential distress. In your opinion, are these the primary conditions that you believe psilocybin has the most potential to treat?

Dr. Ross: Well, there are three main areas that are very likely going to get psilocybin rescheduled in the next three to five years. The work we did with cancer patients…Hopkins did a very similar study. Between the two studies there were 80 participants in Phase 2 studies. We published our findings at the end of 2016, and it created a big splash around the country. It was on the front page of the New York Times December 1, 2016. That kind of opened the doors of this research.

From that, I went to the FDA to try to initiate a Phase 3 trial for psilocybin in cancer, but they had a hard time with it. They said, ‘Well, why do it in just cancer? Why not do it in something more broad like major depression?’ So this company formed, one of my donors formed a company, and now they’re in Phase 2 trials for psilocybin and major depression, and we’re part of that at NYU.

I don’t know if it will work for major depression, but it seems promising. That research has to continue. But the work we’re doing with cancer patients…I’m going back to the FDA now to see if we can try again for Phase 3. If that works, that’s going to be the leading edge of moving psilocybin to a prescribable medication.

And then the third thing is psilocybin for alcoholism. Michael Bogenschutz and I are just finishing up a trial in 100 participants with alcohol use disorder. We’re going to publish that in a couple of months, and Michael has taken that to the FDA to initiate a Phase 3 program and is getting positive signals. So I think psilocybin, between cancer-related existential distress, alcoholism, major depression…one of those will get psilocybin very likely…I mean, the trials could fail, but I would doubt it at this point—certainly for cancer and alcohol. We know that there’s a very strong efficacy signal.

So I think that in three to five years, psychiatry will be very different with these drugs available. We have ketamine; I think MDMA will be made available as a treatment for PTSD in about two years; and then psilocybin soon after that. Psychiatry is undergoing this very dramatic transformation with these old banned, psychedelic drugs, that are being repurposed to treat very difficult to treat psychiatric disorders: addiction, terminal cancer distress, PTSD, depression.

Jay Fox: What are your thoughts about potentially treating dissociative identity disorder with psychedelics, either MDMA or maybe psilocybin?

Dr. Ross: I had a discussion with an expert in dissociative identity disorder recently, and I think you could do it with MDMA. I think people that have severe dissociation typically have been traumatized, and there’s a big overlap between PTSD and dissociative phenomena. I think trauma is at the core of dissociative phenomena, and I think you could use MDMA in that regard, but it’s unknown territory. Could it make them worse in some ways?

I don’t think that psilocybin will be helpful for somebody who has dissociative identity disorder, but using MDMA to deal with the trauma, to decrease the dissociation, to me seems like a promising concept.

Dr. Ahmad: Steve, have you found any other classic psychedelics that can produce similar results?

Dr. Ross: In the historical era, LSD was the most studied with a little bit on psilocybin and a little bit on mescaline. I think mescaline is an interesting drug. It’s a phenethylamine. It’s more of an amphetaminergic psychedelic. For the Native American Church, it’s part of their tradition and they have very low rates of alcoholism. The Native American people have among the highest rates of alcoholism, but the Native American Church have almost non-existent rates [of alcoholism]. Some of that could be due to cultural issues, as they prohibit the use of alcohol, but their use of peyote to create these spiritual contexts may be helpful.

So I think mescaline is worth studying as a psychedelic, but, I mean, there’s thousands of psychedelics. Sasha Shulgin synthesized hundreds of thousands of these compounds. There’s so many directions to go with different psychedelics with different psychotherapies for a bunch of psychiatric disorders, but I think doing more work with psilocybin is going to be key, and I do think that LSD therapeutics is around the corner from making a comeback.

I designed a new trial using LSD to treat metastatic cancer pain. This is based on work done in the Fifties and Sixties by a guy, Eric Kast; he was an internist and psychiatrist at the University of Chicago. He didn’t know anything about the psychological effects of LSD; he just ordered some from Sandoz[i] and started giving, like, 100 micrograms to his dying cancer patients in pain without too much preparation or anything and found these astonishing results in over 250 people that he gave it to. They had rapid reductions in pain that lasted several weeks. The patients reported decreased depression, decreased anxiety, and resolution of death anxiety. And that was actually the beginning of the work of psychedelics in terminally ill cancer patients.

So I think that is an interesting area to reprise, both using LSD and to go after a pain indication.

Dr. Ahmad: I’ve read that ayahuasca could be used to treat addiction and provide patients with some mystical experiences. To your knowledge, has there been any kind of clinical study on that preparation or its active ingredient, DMT [N,N-Dimethyltryptamine]?

Dr. Ross: There’s anecdotal evidence that ayahuasca can help addiction, and there are clinics in South America. There’s one called Wasiwaska in Peru where people with addiction come and have an ayahuasca ceremony, but there’s not a formal research program, so I’ve never looked at outcomes. Charles Grob did one of the only ayahuasca studies published in the literature and found that people that used ayahuasca tended to not use drugs, but that was a very small sample.

There’s been some work done at the União do Vegetal, this group in America that uses ayahuasca, and when they do epidemiologic studies of these groups, they have extremely low rates of addiction.[ii] But that gets back to the issue of the Native American church. Is it the psychedelic doing that or is it the cultural community context that’s doing that?

But ayahuasca, I think, should definitely be studied. It’s more complicated because it’s not just one compound. It has the DMT, from Psychotria viridis. Part of that plant has DMT. But then the Banisteriopsis caapi has all these MAO [monoamine oxidase] inhibitors—these harmalines. So, to get the FDA to approve a compound, a plant decoction that has a bunch of different chemicals, that would be quite complex, although there’s a guy, Jordi Riba, in Spain that did get approval. There’s also a group in Brazil that are doing research with ayahuasca. There’s some evidence that ayahuasca helps people with major depression. There’s been some preliminary studies. Someone soon, probably not in the US, will do trials of ayahuasca for addition. I think that’s a promising area.

Dr. Ahmad: What about DMT alone? I’ve read about this so-called “business trip” drug because you get this tremendously intense experience in the shortest period of time? I was intrigued by that.

Dr. Ross: That’s smoked DMT?

Dr. Ahmad: Yes. I was wondering, from your experience, do things have to be taken in a slow, methodical way to get the end results? Is this short-term, intense experience maybe counterproductive in some way? Or is that a question mark and nobody knows?

Dr. Ross: I think the right model is that this is medication-assisted psychotherapy. This is not: You give a patient a drug, and then the drug magically does everything. All our treatments are done with two dyad therapy teams, and there is an enormous amount of preparation before the dosing session. For everyone, we take a very detailed history of their life. We then go into the disease state, like their cancer, and we go into the details of how it’s causing anxiety and depression and existential distress. We then carefully prepare them for the dosing session. We go through the range of experiences with the drugs. We go through how to respond if they’re having a really hard time and they have an anxiety reaction.

On the dosing day, you know, it’s very controlled. There’s a kind of living room in the Clinical Translational Science Institute. We do a little ritual with them ahead of time. We hold hands with them. We have them state their intention for the day. We take their vitals. We make sure they’re ready. We then give them the pill. We turn on preselected music that we play for the whole time. We have them lying supine on the couch. They put eye shades on, they listen to the music, and the default is to focus internally while the two therapists are there to support them.

With psilocybin, it’s a six-hour experience. It comes on gradually, it peaks for about two or three hours, and it comes down gradually. Following the dosing session with the psilocybin, there’s a lot of integrative psychotherapy. I think that arc is much different than if you smoke DMT and you have 10 minutes where you feel you’re transported to another dimension of reality and where, when you come back, it’s hard to make heads or tails of it all.

So I really think that the arc is at the heart of the therapeutic experience. The drug is part of it, but the drug facilitates the psychotherapy as opposed to the model of ketamine for depression, which is that it’s a biological effect that is changing glutamate or BDNF [brain-derived neurotrophic factor]. Our cancer patients, and this is throughout the study, 75% said the experience was the single or top-five most meaningful most spiritual experience of their lives. I think these are highly memorable, difficult, transformative experiences that kind of get people thinking in a different way, and then it’s what happens after that’s key. So, again, I think it’s drugs plus psychotherapy and not just drugs alone.

Dr. Ahmad: That’s very helpful. I think that really clarifies some misconceptions that people may have. I’m just wondering, as you were just talking about experience, are there certain patients who are more responsive to treatment with psychedelics? In other words, are there any particular attributes, like religious devotion, age, gender, that tend to correlate with better or worse therapeutic results?

Dr. Ross: We’ve looked at it. The sample sizes have been too small so far. You really need a much bigger sample to look at for predictive factors of outcome, but in our cancer trial we looked at a couple of things. We looked at gender. We looked at whether somebody had a religious affiliation or was agnostic or atheist. We looked at if they had advanced cancer or less advanced cancer.

None of it was associated with outcome. We thought maybe if somebody had taken psychedelics before and they knew to landscape, maybe that would make them more likely to have a therapeutic effect, but it didn’t matter whether you’d had it hadn’t.

But again, these are small studies. When we do bigger trials like the alcohol trials, which is 100 people, or the new cancer trial, which is 150, those trials are now sufficiently powered to go in and look at some of these things. What does predict who’s going to be a responder or not? And I think that’ll be important information to know in the future.

Dr. Ahmad: For patients who do have a negative experience, what do you do to manage them?

Dr. Ross: We have a whole algorithm to deal with somebody having a difficult psychological experience. Interestingly, psilocybin is extremely safe medically. It’s not associated with organ damage or overdose death. It can cause a mild increase in blood pressure and we measure that a lot, but the main thing is that people can have anxiety reactions or psychotic-like experiences. That’s why we carefully rule out people with psychotic illnesses or a family history [of these illnesses]. We rule out people with severe personality disorders. We also rule out people where there is not a good rapport.

We’re very careful to only go into a dosing session if we feel comfortable. If somebody does have a difficult experience, we’ve rehearsed it ahead of time. ‘If you feel like you’re going crazy and you’re never going to come back, that’s common. If that happens, this is what you should do: Dive into the experience, don’t run away from it. You know, try to go with it and be curious as the first step.’ If they’re still having a hard time, we will then sit them up and we might provide therapeutic touch to them. Somebody may hold their hand or their shoulder and reassure them that they’re under the influence of a drug and that they are going to be okay.

And those are often the therapeutic moments. If someone is having a really hard time and they’re resisting, and we remind them, ‘Go back into it. Don’t be scared. We’ve got you.’ It’s typically those moments that people have these kinds of psychological breakthroughs.

If someone is really having a hard time, though we can give them Valium, but we rarely have to do that—maybe two or three times in 150 patients. If we need to abort experience, there is an antipsychotic you can give them. Psilocybin is a 5-HT2A agonist, and we have Zyprexa, which is a 5-HT2A antagonist. If we give them that, it will essentially stop the experience. I think we’ve done that once.

So that’s the safety algorithm. We go through that with them. We show them that these are the drugs in the room. We tell them, ‘You’re in Bellevue Hospital, the safest place on the planet to have any emergency.’ And after going through all of that, people feel very safe. We’ve never had a serious adverse event in any of our studies, either psychiatrically or medically with psilocybin. If you carefully screen people and prepare them and have skilled therapists, the rates of adverse events are extremely low.

Dr. Ahmad: I’m just curious how do you qualify that level of mystical experience? Do you have any particular questions or surveys or scales?

Dr. Ross: We have a validated scale. It’s called the Mystical Experience Questionnaire. It was actually developed first in the 60s. There was a psychologist, Walter Stace, who was a psychology professor interested in comparative religion and mysticism. He looked at all these different branches of religion and found that throughout the mystical traditions there was a commonality in the way mystical experiences were described. They described, like five or six core elements such as unitary consciousness, paradoxicality, ineffability, being transported to a different dimension of time and space, a sense of deeply felt sacredness, and a sense of awe—these kinds of things.

So he was the first to describe it, and then Walter Pahnke was this really interesting guy. He was a psychiatrist and a divinity graduate at Harvard who did the Good Friday Experiment where he gave psilocybin to divinity students, and Pahnke developed the Mystical Experience Questionnaire for this experiment. The Johns Hopkins team then took that scale and created a modern version of it. They did psychometrics and validated it, and we use this validated scale to measure mystical experience.

What we found in our cancer study, and what a lot of people have found, is that the intensity of these experiences appears to be a causal mediation towards improved anxiety and depression. So, seven hours after they have the experience, we measure the mystical experience. Those that score higher on that scale, that predicts or mediates antidepressant and anxiolytic effects several weeks later. In the bigger trial, we’re going to be able to look at, first of all, is that a real finding? And if it is, what are the subcomponents there that are the more specific therapeutic ingredients? For cancer patients, is that the sense that they have a death experience and they realize that energy is universal and continuous, and that they’re no longer scared of death? Or is it something else that’s going on?

But, yes, there’s a validated scale.

Dr. Ahmad: Do you know if there’s any placebo response in terms of the mystical experience?

Dr. Ross: Yes. In our cancer study, our active placebo was niacin, which is not a great one. It gives you kind of a tingly feeling and it can mimic psilocybin to a very small degree. Still, we had a couple people on niacin have full-blown mystical experiences because, you know, some people are just more suggestible. Some people read about the experiences and they come in with an expectancy set, especially now with the Michael Pollan book. It’s kind of created a problem for us because people come in and they want to have the Michael Pollan mystical experience.[iii] They’re sure that it’ll cure them and they’re often upset if they don’t get that.

So, people can come in and think they’re going to have an experience, get a placebo, and then some do have full mystical experiences. We also found that there were placebo response effects in our cancer trial. The placebo group did have an improvement in depression and anxiety for a day or so, but then they quickly returned to their baseline levels.

But having an active control is hard. To get something that really blinds adequately is hard to do because psilocybin is so unique. We’re still trying to you know perfect that.

Dr. Ahmad: I know you said the effect is around 6 hours, but I’m just wondering about the sense of spiritual awe. How long does that last? Is that in hours, too? Or do you measure it in days or weeks even?

Dr. Ross: Well we ask them to reflect on the experience in total, and the psilocybin takes about an hour or so to come on, and the peak is between one and three hours. It’s typically during that time that people are having these deeply spiritual, transformative experiences. In the last couple of hours, they’re still in that state, but it’s typically in that [previous] period where they have these intense experiences.

Months later, sometimes years, later we ask them to reflect on the experience, and they’re often able to say, precisely, ‘I had this experience. I remember this thing happening and that’s stuck with me to this day. It had a profound effect on me at the time and it still has a profound effect on me. I can remember very clearly when I had that confrontation with cancer’ or ‘When I experienced my death’ or ‘When I came to another insight.’ And that’s why these are so memorable, but they have this kind of spiritual content to them.

Dr. Ahmad: So a lot of your work has been researching psilocybin treatment in terms of end of life care to reduce anxiety and depression among patients who have terminal diseases. Have you found that these spiritual experiences are any more or less pronounced in people who are not struggling with the issue of personal mortality?

Dr. Ross: Well Hopkins did a study they published in 2006. They gave psilocybin to normal volunteers. They didn’t have any psychiatric problems, but these were spiritually oriented people. In that study, they found that three out of four said the psilocybin experience was the singular or among the top-five most spiritual or most meaningful experience of their lives. The Good Friday Experiment was also in “normal” volunteers and divinity students.

Our religious professional trial that we’re doing with Hopkins, these are, again, “normal” volunteers, but they’re rabbis, priests, imams. We’re still analyzing the data, but, just anecdotally, they’ve been some of the most profound experiences I’ve seen. These religious professionals are having really intense spiritual and mystical experiences and they are having, for the most part, a positive impact on their religious practice, and sort of deepening their religion or giving them new insights into the nature of reality and God. So I think that the use in “normal” volunteers is interesting to consider and how it may help people that don’t necessarily have a psychiatric illness, but want to have some kind of spiritual growth.

Dr. Ahmad: You recently published your long-term follow-up study on the treatment of existential distress in patients with life-threatening cancer. Could you share some of your key findings?

Dr. Ross: Yes. The original sample was about 30 and we were able to follow up with about half of them, about 15 or 16, because the other half had died. It was pretty astonishing. Four and a half years after a single dose, we found pretty much what we found one day after giving them the dose. It was that 80% of people were in remission from their depression or anxiety symptoms.

You have to be skeptical that that was due to the single dose psilocybin. First of all, this was a crossover study, so both groups got psilocybin. You don’t have a true control group at this long-term follow-up. We also measured how much aftertreatment they got, and just about everyone had gotten no further psychiatric treatment—no further medications, no further psychotherapy for their cancer. Some people said, ‘Yeah, I still get anxious’ or ‘I actually had to go on a medicine for a while like Zoloft, but that was because I’m anxious about what’s happening politically in this country, but when it comes to my cancer I’m no longer anxious.’

So the qualitative component to it really made me think that this was due to the psilocybin. They clearly were able to attribute it to that, which is pretty remarkable that a drug given once could have effects months to years later.

But, again, you have to be very skeptical of that. To really demonstrate that you need a much bigger study. It needs to be a parallel design. But the idea that people with cancer who have a very bad reaction with it, who feel anxious and depressed and wish they were dead already or that life has no meaning, it appears that psilocybin really works for those people. In the majority of them, it can rapidly transform them out of that state and into a much better orientation to cancer and life, and that it can last for a long time.

Dr. Ahmad: Okay. I just want to shift for a moment. Is there any data or is there anything anecdotally you’ve seen that you can share in terms of the differences in the level of psilocybin’s efficacy depending upon the substance to which the person is addicted?

Dr. Ross: We’re finishing up a trial on psilocybin and alcoholism in about 100 people, and we’ll analyze the data in a month or so. My sense is that it’s going to be a positive trial. It’s going to be helpful compared to placebo. Psilocybin is being studied for tobacco addiction at Johns Hopkins, and they’re finishing up a controlled trial of psilocybin versus nicotine replacement, and we’ll know more there soon, too. Their pilot trial, you know, was like in 12 people, and it astonishing. Like 80% of people after two doses of psilocybin were not smoking at six months. But, again, that was open label. It was very small. We have to see what the control trial shows.

There’s also a trial at the University of Alabama finishing up with the use of psilocybin to treat crack cocaine addiction. We should know in like a year or so about that. There’s now a trial starting up use psilocybin to treat opiate addiction, but that’s in the very early stages.

I think psychedelics can be very helpful for addiction. Certainly that was the most promising area historically, but we’ll have to see the results of all these trials to see how helpful they are for these other disorders. If they are, then they’ll have a huge public health impact. If you think of alcohol, tobacco, and opiates, as well as cocaine…I mean, there’s an enormous negative public health impact of those drugs. Some of them have zero pharmacotherapies like cocaine.

I think if psychedelics are helpful for addiction, it would be very interesting.

Dr. Ahmad: I mean, looking at all of these various trials going on…Are there any directions that you hope the research will take in the future?

Dr. Ross: We’re getting close to forming a Center for Psychedelic Medicine at NYU, and the novel direction we want to go is to use psychedelic therapeutics within medicine and neurology—or at the intersection between psychiatry and medicine. This is an area that is completely new, and this would be for pain disorders. There’s evidence that psychedelics have potent anti-inflammatory properties, so we’re going to be looking at inflammatory conditions like rheumatoid arthritis and some of these kinds of conditions, too. There’s also some evidence that psilocybin is associated with neural regeneration, and there’s some people now thinking of using it for neurodegenerative disorders like Alzheimer’s or Parkinson’s.

But it’s wild to think of utilizing them not for their psychological effects, but for their biological effects. And I think the area that, to me, encapsulates putting all this together would be this use of LSD in metastatic cancer pain. There, LSD may have direct analgesic effects, but it also may indirectly help pain by making depression and anxiety better.

So, yeah, the interface with medicine and neurology, I think, is the newest thing. There’s also this concept of microdosing. Rather than these big macro-doses that cause mystical experiences, how can you leverage things and use them daily? There’s a lot of hype about LSD and psilocybin microdosing, but there’s no data. Those trials are starting. I have another research program with CBD (cannabidiol), and we’re using that daily to treat pain disorders. There’s psychedelics, like bromo-LSD as an example, that don’t cause any psychological effects, but it appears to be helpful for cluster headaches.

So, these kind of non-psychedelic psychedelics are also increasingly being studied.

Dr. Ahmad: You mentioned two of them. Are you conducting any other studies involving psilocybin?

Dr. Ross: We have several full-time studies. We’re finishing up psilocybin for alcoholism. That’s going into a Phase 3. We’re just starting psilocybin and for major depression. That’s a Phase 2. I’m hoping to restart the psilocybin and cancer work soon. We’re finishing up use of psilocybin and religious professionals.

Interestingly, in the age of COVID-19, we’re hoping to move in that direction, as well. I designed a trial using psilocybin to treat frontline healthcare workers—you know, ICU docs, ER docs, nurses, and so on—who have COVID-related anxiety, depression, and existential distress. Depending on getting funding, we may be doing something COVID-related.

Dr. Ahmad: Very interesting. Lastly, I wanted to ask you, do you believe that psilocybin will become more widely available to clinicians and researchers? I’m sort of thinking of the path of marijuana and how long that took to become accepted. Do you think a similar amount of cultural or societal change needs to happen in terms of educating people about psychedelics like psilocybin?

Dr. Ross: I think it’s going to be vital to educate the public. Otherwise, history will repeat itself. When psychedelics came into the view in the Fifties and Sixties, they were hailed as wonder drugs. Then they escaped from the lab and started to be used by the general public, and people realized that these drugs were dangerous. They could make psychotics worse. In unprepared situations, people could inadvertently kill themselves or hurt other people. And then because of that, they were demonized and thoroughly repressed.

Now they’re coming back and it’s like the echoes of history. There’s this exuberance phase and the public is hearing about it through the Pollan book and other sources, and they’re thinking, “My God! This is going to cure me. One or two doses of psilocybin will cure me.’ And then they realize it’s not legal, so then they find it in the underground.

And now you get into dangerous territory. This overexuberance and wanting to just do it yourself sort of thing. It doesn’t work that way. Really, in my opinion, you need skilled therapists and careful safety monitoring. I think if we’re not careful, we can have a cultural backlash again. And I think what we need to do is be very cautious. Continue to do the research, to do good research to see what the data shows and how good or not the effects are, and then educate the public that, yeah, these are new treatments, but they have risks associated with them and they should only be using these kinds of ways. It’s going to take a lot to educate the public, but I think a careful, methodical approach that pays attention to history is the way to go.

Dr. Ahmad: Thanks, Steve, because that is exactly what we’re trying to do. This is not just for clinicians, but more for the general public and education, who will receive a tremendous amount of insight just based on the information that you have given us. I really appreciate your time.

Jay: I had one question. You mentioned psilocybin could be used as an anti-inflammatory. I’m curious, what is the mechanism of action?

Dr. Ross: So the antiinflammation stuff is interesting. It comes from studies of a psychedelic drug called DOI (2,5-Dimethoyx-4-iodoamphetamine) down at LSU by guy named Chuck Nichols. He took rats that had asthma. When you biopsy them before they get the drug, there’s all this inflammation and all these inflammatory cells. When they gave them DOI, one dose of it, a day later they did the biopsies again of the pulmonary tissue, and what they found was remarkable. There was no more inflammation; all the inflammatory cells were gone; the entire inflammatory process was not there.

The mechanism is unclear. Psychedelics exert their psychological effects by activating the serotonin 2A receptor, but how they work as anti-inflammatories is actively being worked on. It definitely appears that they have rapid and sustained anti-inflammatory properties. But, again, there’s a lot more research to be done there to see if that’s true effect, how universal it is, and then what the exact mechanism is.

Dr. Ahmad: I’m wondering, Steve, if these psychedelics can reduce the levels of anxiety and stress? At least theoretically, as we understand that how the stress response system plays a role downward back through the HPA axis (hypothalamic pituitary adrenal axis), and how inflammation and interleukin and cytokine increases in people who have hypercortisolism and extreme HPA axis hyperactivity, could it reduce the type of inflammation associated with these phenomena?

Dr. Ross: I think so. There’s the whole inflammatory hypothesis of depression—that depression is associated with hyperactivation of cytokines and increased inflammation. People with depression have shorter rates of survival compared to people without depression.

We looked at this in cancer. We actually looked at inflammatory and immune markers because cancer-related distress, whether anxiety or depression, is associated with decreased rates of survival, so the implication is that there’s something going on We know that depression, in particular, drives this hyperinflammatory response and decreases immunoresponse, but unfortunately we never got to analyze those samples because of Hurricane Sandy. When Sandy hit Bellevue, our samples were in the Bellevue CTSI (Clinical & Transitional Science Institute) and because all the generators are in the basement, and, as you remember, the lights went out, so we lost our samples. We never we never got to analyze them. It would be really interesting to…and, again, this is, like, you have to be very careful here because there really is no data yet, but some people get really excited that psilocybin will cure cancer—not just cancer anxiety, but that it’ll make their anxiety and depression so much better that their immune system will get better and they’ll fight off the cancer. That’s a real stretch, but you could look at that. You could properly design a trial to actually look at that, and if that were the case, it would be pretty big. But I would think that just improving someone’s state of mind that has cancer is going to have some positive effect on the rate of survival.

Dr. Ahmad: Right. Kim, do you have anything?

Kim: I have a couple of follow-ups that are more conversational because I am more of a layperson than everyone else on this call. First, I’m hearing in the mainstream that microdosing of LSD and psilocybin is becoming much more popular and I’d love to know your thoughts on that as an approach relative to what you’ve been doing through your studies.

Dr. Ross: I recently wrote an article about this. I was invited by the Journal of Psychopharmacology because they did a review article on microdosing, and I wrote like a component to that. Really, in looking at the literature, I think my title was like ‘All Hype, No Data, and the Implications of Microdosing Within Psychiatry.’ It’s funny. My mom, who’s in her seventies, asked me, ‘Do you think I should microdose with LSD?’ And I was like, ‘Mom! What are you talking about?’ And she goes, ‘I hear it’s great. It’s been proven to be great!’

So it just goes to show you that there’s so much out there, and that people think that it’s going to help their creativity and their energy and their sex lives and their sleep and on and on. The reality is we know nothing about microdosing. We don’t know anything about its potential benefits or its potential harms. If you give a psychedelic a lot, it may be harmful. The serotonin 2B receptor that psilocybin also activates is associated with valvulopathy [disease or disorder of the valves of the heart]. That’s associated with, like, the Fen-phen [fenfluramine/phentermine] drug; that was a [serotonin] 2B agonist.[iv] So it may that we find out that microdosing causes cardiac problems, but we just don’t know.

People are now just beginning to look at microdosing in human populations, number one, to take normal volunteers and see what are the psychological effects; and then, right around the corner from that group, there are those starting to design trials for microdosing to see if it can help treat psychiatric disorders like major depression, ADHD, addiction.

With microdosing, we just don’t know. It’s one of these examples of the overexuberance among the public. People think that something is a real thing, they want to try it, and then they get into trouble.

Kim: My next question would be related to the microbiome and also the vagus nerve. What conversations, if any, are you having on that front with respect to your research and your knowledge of psychedelics?

Dr. Ross: No one has looked at that yet, but that is very interesting. The microbiome’s link to disease has only recently come into focus. There’s a guy at NYU, Marty Blazer, who is one of the world experts in this field. But the more people have looked at the microbiome, the more they see that suboptimal gut functioning is associated with mental health—or mental distress. That is an interesting area to think of, you know, what is the link between these billions of bacteria in our guts, our enteric nervous system, and psychiatric illness? How psychedelics interact with all that is completely unknown. How it interacts with the vagus nerve is also unknown.

So, yeah, it would be interesting to see how those different fields can come together, but the microbiome is its own thing in terms of how that may ultimately be helpful in psychiatry. You know, could you do a fecal transplant as a way to help a psychiatric disorder? I mean, that’s a kind of crazy thought.

Kim: My last question has to do with just research in general into fungi. Do you know if any of the big pharmaceutical companies are going into fungi research and how does that affect your research, if at all?

Dr. Ross: There’s a lot of commercial interests in this area now, so I think you’re having a lot of for-profit companies jumping into psychedelic research. For companies that are studying fungi…I mean there’s some work on that. There are some companies that are trying to harness the medicinal properties of fungi. There’s a famous mycologist, Paul Stamets, who is one of the world experts on fungi, and he’s developed all these different fungi for all kinds of things. He’s found that they have antiviral, antimicrobial, and immunomodulating effects. He’s also an expert on psilocybin.

So I think fungi are remarkable compounds. Their evolution is extremely interesting and how they form this mycelial network underground is a remarkable kind of thing. They’re so helpful for the life cycle in so many ways and they produce all these therapeutic chemicals. They also produce deadly ones. If you eat the wrong mushroom, you could be dead.

And what’s interesting is that Oregon, probably this year, will pass the first medical voter referendum psilocybin law. They put it to the voters in Oregon and, similar to what happened in 1996 with cannabis in California, they said, ‘Hey voters, do you think psilocybin should be a medicine?’ And if they say, ‘Yes,’ then psilocybin will be legal on the state level in Oregon to be used by therapists [to treat] patients with psychiatric disorders or for spiritual growth. They’re going to use psilocybin mushrooms, and Paul Stamets is going to supply that program. So that program will be the plants that you eat to have the experience. What we use is a synthetic version.

Dr. Ahmad: I want to thank you for enlightening us. That was a lot and will take a while to digest and go over it, but I really appreciate it.

About Dr. Ahmad

My Wonderful Flight to the Mushroom Planet

 

 

 

[i] Albert Hofmann worked at the pharmaceutical-chemical department of Sandoz when he discovered LSD in 1943. Sandoz continued to produce the compound until 1965.

[ii] The União do Vegetal is a religious movement that was founded in Brazil in the 1960s. The movement has since spread throughout the Americas, including the United States. In 2006, the U.S. Supreme Court unanimously ruled that the group could use ayahuasca as part of their religious ceremonies.

[iii] Michael Pollan’s book, How to Change Your Mind, was published in 2018. It examined the therapeutic use of psychedelics and described some of Dr. Ross’ research. The book was immensely popular.

[iv] This drug combination was introduced in the 1970s, but was pulled from US markets in the 1990s due to the cardiac risks associated with usage.

__________________________________________________________________________________________________

[1] Albert Hofmann worked at the pharmaceutical-chemical department of Sandoz when he discovered LSD in 1943. Sandoz continued to produce the compound until 1965.

[1] The União do Vegetal is a religious movement that was founded in Brazil in the 1960s. The movement has since spread throughout the Americas, including the United States. In 2006, the U.S. Supreme Court unanimously ruled that the group could use ayahuasca as part of their religious ceremonies.

[1] Michael Pollan’s book, How to Change Your Mind, was published in 2018. It examined the therapeutic use of psychedelics and described some of Dr. Ross’ research. The book was immensely popular.

[1] This drug combination was introduced in the 1970s, but was pulled from US markets in the 1990s due to the cardiac risks associated with usage.

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