Welcome to The Undark Podcast, which will deliver — once a month from September to May — a feature-length exploration of a single topic at the intersection of science and society. In this episode, join science journalist Bradley van Paridon and podcast host Lydia Chain as they explore the neuroscience of psychedelic-assisted therapy, and what it will take to establish the treatment as acceptable and clinically proven to help conditions like depression.
David Nutt: In a space of 10 years, we’ve gone from pictures in a brain image to kind of revolution in psychiatry. And that is a, that is a powerful example of how medicine and science should work together.
Bradley van Paridon: That’s David Nutt, a psychiatrist and professor of neuropsychopharmacology at Imperial College London. He and his colleagues at The Center for Psychedelic Research at Imperial College are among a growing number of therapists and academics who believe that psychedelic drugs are a potential new treatment option for mental health conditions like depression.
David Nutt: The big challenge now is to roll it out so that all the millions of patients around the world who might benefit will get it.
Bradley van Paridon: The details however, of exactly if, when, where, and how this roll out will take place remain to be seen.
Lydia Chain: This is the Undark Podcast, I’m Lydia Chain.
Research into using psychedelic drugs like LSD and psilocybin to treat mental health conditions is rapidly advancing, with a dozen clinical trials in 2021 alone. Paired with the movement to decriminalize or legalize these substances in many places, most recently in Oregon, the idea of bringing psychedelic drugs into the therapist’s office is becoming more mainstream.
But there’s still a lot for researchers and mental health practitioners to figure out, from finding the most effective ways to run a psychedelic-assisted therapy session, to navigating regulatory approval and insurance barriers, to actually recruiting and training therapists in the new methods. Bradley van Paridon has the story.
Nicolas Langlitz: There was a pretty significant amount of psychedelic research in the 1950s, which were also known as the golden age of psychopharmacology.
Bradley van Paridon: That’s Nicolas Langlitz. He studies the anthropology of science and medicine at the New School for Social Research in New York, including the history of research with psychedelic drugs. He says back in the early 60s that research was drastically curbed by new regulations surrounding the use of experimental drugs.
Nicolas Langlitz: The first step towards a more strict regulation had a lot to do with, in my eyes, very legitimate concerns about the way in which drugs, all sorts of drugs, were used by doctors and pharmaceutical industry.
Bradley van Paridon: This led to countries establishing frameworks whereby drug manufacturers are required to prove scientifically that medications are both safe and effective.
Nicolas Langlitz: And then at the end of the 1960s, there was a second more severe crackdown on psychedelic research associated with the prohibition of psychedelics. That really killed off work on human subjects.
Bradley van Paridon: But since the 90s, he says a combination of factors have reopened the conversation. One of them is a leap in basic neuroscience research about the brain and consciousness.
Nicolas Langlitz: The neurosciences are making a lot of headway now. So here are these drugs and we can use them to better understand the brain. And you know, there, there was some red tape of course, but by and large, regulators were willing to listen.
Bradley van Paridon: Decreases in social stigma helped, too. There’s also been a rise in mental health conditions such as depression and post-traumatic stress disorder and new conversations about the limitations of conventional treatment.
Andrea Jungaberle: We really have a worldwide mental health emergency and blunt tools. What we’re working with in psychiatry and psychosomatic medicine and psychotherapy is not working for everybody. So, we need new therapies.
Bradley van Paridon: That’s Andrea Jungaberle, the medical director of OVID Health Systems, a clinic in Berlin offering medical training and ketamine-assisted psychotherapy. It’s also part of a network of academics and doctors performing research and clinical trials in psychedelic-assisted therapy. Many experts agree traditional therapy doesn’t work for everyone. Plus, the discovery of new pharmaceuticals to treat conditions like depression has stalled.
Nicolas Langlitz: You know, if you look at the substances that have come out since the 1980s or even 1970s, most of them were me-too drugs. There were no major breakthroughs.
Bradley van Paridon: Me-too drugs are copies of existing drugs that are slightly altered chemically but still achieve the same effect. Today, there are many versions of selective serotonin reuptake inhibitors, commonly known as SSRIs, and they are the main class of drug prescribed to treat depression. These, like other anti-depressants or anti-psychotic medications, work via their chemical interaction with the brain. To relieve symptoms, a patient takes it routinely.
Nicolas Langlitz: So, if you have a depression, you take an antidepressant and you take it every day. Uh, if you suffer from schizophrenia, you take an anti-psychotic and you take it every day over a very long period, potentially over your lifetime. So, so these are really drugs for life.
Bradley van Paridon: He says this is quite different from how psychedelics are used. Instead, patients take the psychedelic in order to open them up to other types of psychological therapy. Here again is David Nutt.
David Nutt: It’s not just therapy and it’s not just the drug. We think it’s the two together produce that sort of optimal cocktail of, um, of change and facilitation of insights, which lead to improvements in the long-term.
Bradley van Paridon: This field contains people like Nutt, who focus on understanding how psychedelics work in the brain, but also clinicians and practitioners who are attempting to sort out the details of how the therapy component should work. And both are working within a complicated legal and regulatory landscape. Right now, here is how this kind of therapy is believed to work.
Psychedelics, unlike SSRIs, dramatically alter the user’s state of consciousness and perception for a period of time. And while there can be some mood enhancement, according to Nutt, in depressed people this is usually not the case.
David Nutt: Depressed people, when they have, you know, they go into a psychedelic experience, it can be really challenging. We must dismiss this idea that people are coming out of their depression because they’re having a fun trip. They rarely have fun. Mostly it’s painful, difficult, because you basically, the drug breaks down the barriers that they put up to stop remembering the horrible things in their lives.
Bradley van Paridon: The idea is that this altered state, plus some therapeutic guidance, provides a new perspective for patients to view themselves or to work through trauma. Nutt and his colleagues have discovered a clue as to why the psychedelic experience may be specifically suited for this purpose by using MRIs to look at changes in brain networks during and after a psilocybin trip — psilocybin being the psychoactive molecule found in several types of mushrooms, known more widely as magic mushrooms.
David Nutt: But one of the networks, which is very powerfully disrupted, is the network which drives depression. And you’d never have guessed that until you’ve done the study. But when you did this study, you could see that this network was completely fragmented.
Bradley van Paridon: Nutt and colleagues saw that after the session, the brain is in a particularly flexible and receptive state, which they also believe assists the psychotherapy work.
David Nutt: For a few days afterwards, people are in a state of what we call after glow. The brain is perfectly positioned to do really high-quality psychotherapeutic work. The brain is much more flexible and, uh, and reactive in the, uh, the early days after a trip.
Bradley van Paridon: The imaging data may help explain why psychedelics could improve therapy but Nutt and others still firmly believe that the benefits aren’t from the drug alone. And as more places loosen their drug laws, like in Oregon, he says patients may hear about this kind of therapy and want to start trying it, presenting a challenge to local therapists.
David Nutt: The bans on the mushroom have been lifted, uh, with a view to facilitating access to, um, psilocybin or magic mushroom therapy in the next two years. The challenge for Oregon, as I see it is how are we going to roll out a therapy that, um, that might be taken up by hundreds of thousands of people.
Bradley van Paridon: Nutt says there aren’t enough therapists with training in psychedelic-assisted therapy to meet that potential need. Furthermore, it isn’t yet clear which of the many schools of therapy works best with psychedelics. Nutt says even without psychedelics, its challenging to show one therapy style is better than another.
David Nutt: Let’s face it, you know, we’ve been doing controlled trials and psychotherapy for 50 years and it’s proved there are very, very few studies which have compared head-to-head two therapies and shown that one’s better than the other. It’s really difficult to do.
Bradley van Paridon: This is because therapy is dependent on each patient’s individual experience, mindset, brain chemistry, and so on. Here is Janis Phelps, a clinical psychologist and the founder and director of the Center for Psychedelic Therapies and Research at the California Institute of Integral Studies.
Janis Phelps: In psychiatry and psychology, the almost infinite number of variables, only some of which are measurable, are impacting everything we study in mental health, so it’s very, very difficult.
Bradley van Paridon: But she says there are some key components shared by many schools of therapy that are associated with positive outcomes.
Janis Phelps: We know a lot about the effectiveness and the correlations of variables to outcome in clinical studies. Invariably, they are the trustworthiness of the therapist, the strength of the therapeutic alliance, the clarity of the goals of therapy as agreed upon by the therapist and the client, the expectancies of the client for either a negative or a positive outcome, the commitment of the client for the work — those kinds of things we know about, a lot. All these variables have been studied and there’s data for it. We don’t have the data specifically for those variables with psychedelic-assisted therapy yet but we do have clinical data from the last hundred years.
Bradley van Paridon: Phelps says these variables don’t change when working with psychedelics. Based on this knowledge about therapy in general and the clinical experiences and observations of psychedelic research, she developed the first accredited training program for those who want to deliver psychedelic-assisted therapy.
Janis Phelps: So, we’ve applied our clinical understanding, our training with Indigenous peoples who have been doing this work for millennia, as well as observations in the last couple decades of the treatment that’s been done with psilocybin, DMT, LSD, and MDMA.
Bradley van Paridon: She says some therapy models appear to work particularly well when coupled with psychedelics. For instance, in client centered therapy, the clients are given space to explore the thoughts and moods that arise. Therapists are present after the trip during that receptive, flexible after glow phase, for a process called integration, to help the client make their own sense of the experience.
Janis Phelps: Some therapists will be more directive, most will be non-directive and do nudging of the client toward a certain “Aha, well, what, what if we looked at it from this point of view for a second, does that help you get some more understanding.”
Other treatments in medicine have involved integration in everything from surgery to patient education, a clinician or a technician is always checking in with the patient.
This is much more nuanced for us, this integration, since the psychedelic-assisted session affects the person somatically, emotionally, cognitively, et cetera. So, there’s a lot going on, a lot getting stirred up in the sessions and it’s imperative to have integration.
Bradley van Paridon: This model is emerging as one good approach to work with psychedelics, but Phelps believes it won’t be the only one that arises as psychedelics are rescheduled and decriminalized.
Janis Phelps: Uh, therapists have a lot of leeway on how to do this work, or will have a lot of leeway after the rescheduling happens. Right now, the protocols are very oriented toward, typically, the non-directive humanistic approach, but I see that changing dramatically as we open up into further research.
Bradley van Paridon: Because psychedelics remain regulated or illegal in many places, researchers are focusing on showing medical, regulatory and scientific institutions what they already believe to be true, that this is a revolution in psychiatry, that it works, and that it should be made available to those who need it.
Nicolas Langlitz: So the revival of psychedelic research has been based on mainstreaming. That is to say, reintroducing these substances into mainstream neuroscience and into mainstream clinical psychiatry. And that means you have to play by the book.
Bradley van Paridon: The book, however, has very strict rules. Regulatory agencies like the Food and Drug Administration, or the FDA, in America and their equivalents in other countries often require that experimental drugs be proven in a randomized controlled trial, or RCT, to provide better outcomes than placebo before they can be marketed and administered in a health care setting. This poses a problem for psychedelic-assisted therapy, says Jungaberle.
Andrea Jungaberle: This is actually problematic because our modern RCTs are not designed to do what we try to do. They are, all the trials happening now, are essentially drug testing trials. They’re not comparative psychotherapy trials.
Bradley van Paridon: An RCT is designed to control for as many variables as possible to prove the effect is the result of the drug or intervention, not something else. But as Phelps described earlier, mental health and therapies treating mental conditions have a lot of variables, and that’s before psychedelics are added.
Andrea Jungaberle: So, what we’re proving now is that this substance combined with psychotherapy is beneficial, but we don’t have any body of evidence if, for example, psychedelics plus classic depth psychology therapy is better than the psychoactive substance, the psychedelic substances plus cognitive behavioral therapy.
Bradley van Paridon: Right now, most trials are designed to test one psychedelic in combination with one style of therapy, usually something resembling the non-directive approach described by Phelps. And these are expensive. The cost for more trials, testing more variables, such as different forms of therapy in combinations with different drugs or different sized doses is too great for a field that mostly relies on private money. Here is Phelps.
Janis Phelps: This research is all funded by foundations and private donors, and the money has by and large been going to getting the research done in the phases of the drug development. It’ll be exciting to see people start to study that, um, as we get more funding.
Bradley van Paridon: Issues with funding aside, another challenge with these drug trials is a variety of factors that influence the placebo effect — the phenomenon of patients getting better because they expected to rather than the actual treatment. For one, treating patients with the non-directive approach that appears to maximise the psychedelic experience for therapy influences what is known as set and setting. Here is Ido Hartogsohn, a psychedelic researcher at Bar-Ilan University in Israel. His work explores historical, sociological and cultural aspects of the psychedelic experience and in particular the concept of set and setting.
Ido Hartogsohn: And really there’s a great variety of experiences with psychedelics ranging from, um, mystical experiences to creative experiences, therapeutic experiences, but also experiences of going insane or something that resembles psychosis in a way. It can go in so many directions and that all depends on the set and the setting.
Bradley van Paridon: Set and setting are terms that emerged out of the early psychedelic work to describe the factors other than the drug’s chemical influence on the brain that shape the experience. Set reflects internal factors: a person’s intentions, expectations, mood, and personality. Setting covers external factors, like the physical, social, and cultural environment in which the drug is taken. One ready example of this is music, as Langlitz points out.
Nicolas Langlitz: You know anyone who is taking a psychedelic can very well imagine that there is a huge difference between what you experience if you listen to Arvo Pärt’s mystic minimalism, or if you would listen to some death metal, right.
Bradley van Paridon: There are a few things that are generally conducive to a good session, mainly anxiety reducers like soft lighting, freedom to move, and comfortable furniture, and creating these conditions for patients is part of the therapy model. But as Hartogsohn explains, by manipulating the set and setting to produce a more positive outcome, it becomes difficult to say whether the psychedelic alone is providing the benefit. In other words, would patients see the same benefit taking a psychedelic in a different environment?
Ido Hartogsohn: Placebo in most of pharmaceutical research, it’s a concept of what you want to get out of the picture. Once you use set and setting to shape the experience, then you very naturally augment placebo. These kinds of ideas can be considered controversial to people working from within the more conventional placebo framework that would say, well then you, you get a result, that’s not really about what psilocybin or what, does, or what LSD does. You’re getting a result of what they’re doing with all of this other stuff.
Bradley van Paridon: According to Mitul Mehta, a professor of neuroimaging and psychopharmacology at Kings College London, there are other methodological challenges the field will need to address. One is blinding — RCTs require that neither the patient nor the therapist will know if they’ve actually gotten the drug.
Mitul Mehta: Psychedelics are a fantastic example, of the difficulty with blinding. A psychedelic drug given at the doses that are being used in these trials will, what we call, self un-blind. That is, the person and the researcher will know exactly what has been administered because these drugs have profound and hopefully important effects, which are really easily observed. So, there’s plenty of room for expectation to play a role here.
Bradley van Paridon: There are also concerns surrounding the level of hype and positive media attention this work is currently receiving and how this too may influence the expectation and the set and setting for patients in the trials. Here again is Langlitz.
Nicolas Langlitz: At the moment, we get a lot of media reporting about these drugs that tends to be highly optimistic and that, that frames them in a, in a, in a good light, you know, maybe in an overly optimistic light. And so, you know, what, what do these expectations do to what people experience?
Bradley van Paridon: For some, like James Coyne, a former clinical psychologist and professor emeritus at the University of Pennsylvania, the issue of hype is vital, and he questions some of the close relationships of pop culture, wellness figures like podcaster Tim Ferriss and the research community.
James Coyne: So he’s kind of a hype guy and you don’t want him promoting your anti-depressant trial. He is listed as one of the funders of the trial on the recent JAMA paper and he appears in the, in their press releases, talking it up. Wonderful experience. You know, if this were a treatment for schizophrenia, you would, you wouldn’t allow that.
Bradley van Paridon: According to Coyne all of this hype can easily influence the types of people who volunteer for trials and what their expectations of the experience are.
James Coyne: They’re going to come to the drug trial for the wrong reasons. They may even exaggerate their levels of depression to make sure they qualify. So, then you set them up for a bigger effect than they would get in the normal circumstances. That happens a lot in normal volunteer trials.
Bradley van Paridon: We reached out to Ferriss for comment, but did not receive a response. Despite these challenges, psychedelic-assisted therapy is moving through the approval process. For example, the FDA granted breakthrough treatment therapy status for the use of psilocybin to treat depression in 2018 to the life sciences company Compass Pathways and in 2019 to the non-profit Usona Institute. This status helps fast track further clinical trials but as Jungaberle explains, gaining approval has potential downsides too. For example, regulators can decide that only the exact model used in the trials will get approved, meaning if the model tested was expensive, the cost of treatment will also be high.
Andrea Jungaberle: The regulations may be, yes, you can do psilocybin therapy, but it has to have, let’s say three preparatory sessions, two psilocybin sessions and then three interview, uh, integrative sessions. And you can’t do any other model. This might be unaccessible for patients who can’t afford to pay two professionals for a full day to sit their session. This should be accessible for the patients who need it. And people with mental disorders are rarely rich.
Bradley van Paridon: Along with cost of the approved therapy, the cultural context or packaging in which therapy is offered by the clinics gaining approval might also limit the types of patients they can ultimately reach. Here is Langlitz with an example.
Nicolas Langlitz: If psychedelic treatments of depression, as one of the most widespread psychiatric conditions, turn out to be highly effective, and every hospital starts adopting them, I wouldn’t assume that, you know, the same settings would be implemented in hospitals in New York and in Kentucky, right. You will just have very different patients and, you know, if you’re living in a community that has problems with the local school teaching yoga, uh, you probably don’t want to be treated with, you know, in an Amazonian shamanic manner at your hospital.
Bradley van Paridon: Many of these questions will remain unanswered until laws change or the first approvals are granted. In the meantime, Phelps believes they can prepare by promoting safety and education.
Janis Phelps: So, in order to enhance the public good and increase public safety, it’s incumbent upon those of us who can do it to do public education so people have the wherewithal and the information they need to use these safely.
Bradley van Paridon: Jungaberle agrees and is co-founder of a non-profit called The MIND Foundation that offers integration workshops for people looking to make sense of their past psychedelic experiences and which has just launched its own training program for therapists.
Andrea Jungaberle: We don’t want to train people for the underground. We’re strictly against that. We’re trying to stay within the legal framework. Bypassing is easy, but we have given ourselves the task to change the system. And this is slow. This is tedious, and it sometimes is annoying, but we want to give people the chance to already practice these things without breaking the law.
Bradley van Paridon: When it comes to training, Phelps’ program limits enrollment to those with prior experience with therapy but aims to diversify where that experience comes from in order to meet the variety of contexts, she believes, this therapy will be offered.
Janis Phelps: The typical professional who comes into the program is a licensed medical professional, primarily doctors and nurses and medical mental health professionals who have an MA or a Ph.D. or clergy who could be an ordained clergy person or a commission chaplain. So the clergy will be particularly useful and helpful in working with people who are in palliative care situations or hospice or people going through deep bereavement and loss of people through death. And the therapists and the medical professionals will be working in hospitals and community mental health clinics, or free-standing private practice clinics, and able to serve people in those areas.
Bradley van Paridon: Jungaberle adds that on top of experience with therapy, experience with some kind of altered state is also important.
Andrea Jungaberle: In a team of two therapists, there should be at least one person who knows their way around altered states of consciousness, but they don’t necessarily have to be induced by a substance. There are profound ways of experiencing altered states of consciousness in meditation, in breath work, in trance journeys, whatever.
Bradley van Paridon: The MIND curriculum has students familiarize themselves with these states using techniques like breathwork, mediation, and ketamine therapy sessions, which are legal in Germany where MIND is located. They are also working on getting approval for therapists to use psilocybin as well. But she stresses that a substance induced experience is not necessary and won’t make you a great therapist.
Andrea Jungaberle: And it’s also not the best point of reference to say, okay, we only want people in those studies who have, let’s say 200 plus psychedelics experiences. Well, they, they’re good at using drugs themselves or using substances themselves, this doesn’t necessarily qualify them for anything.
Bradley van Paridon: Importantly she says, people wishing to work in this field need to be open to new experiences, viewpoints, and ways of achieving those beyond psychedelics.
Andrea Jungaberle: I think curiosity and mental flexibility to also be open to things you don’t understand. One fallacy you have when you have your own experiences is that you assume that the other person’s experience is like your experience. And also look into other methods to achieve those things. Just because you’ve dropped acid a hundred times that doesn’t make you a Johns Hopkins graduate. You know, sorry, it’s just not true.
Lydia Chain: Hi Brad, thanks so much for joining me!
Bradley van Paridon: Thank you.
Lydia Chain: In your piece, Mehta points out one of the difficulties with setting up a drug trial for psychedelic-assisted therapy, and that’s that the drugs have such recognizable effects that it could be difficult to make sure the patient and therapist don’t know if they’ve been given the real drug or the placebo. Are there any ways around that conundrum?
Bradley van Paridon: Yeah, so researchers have been trying to play with what they’re calling active placebos. So that’s giving those in the control group a substance that induces some kind of physical effect to mask the fact that they didn’t get the psychedelic. So, for example in one study with ayahuasca, which is a potent psychedelic drink, they brewed up a control drink that was similar in taste, color, smell and it even caused some gastro-intestinal symptoms that are common to ayahuasca like nausea and diarrhea.
For trials with psilocybin, this is a little more difficult because you can’t, it’s not a drink, you don’t have these physical cues — the smell and the taste. Researchers are trying things like niacin – so, a drug that will give you a bit of flushing, a little redness in the face, some kind of physical effect that will limit the ability of the participant to say whether they got the psychedelic or not and that’s going to hopefully dampen down their expectations both positive or negative.
So, research like this will help tease out how context and expectation affects these trials and it will help clinicians in the future to minimize those effects in the trials.
Lydia Chain: There’s two threads in your piece here, the first being how practitioners are reacting to legalization, and then also how they are pushing for medical recognition. Can you elaborate on how they’re grappling with that, especially in the context of things getting shut down in the 60s?
Bradley van Paridon: Yeah, the argument for the medical route versus complete legalization is kind of twofold. First, even if your ultimate goal is legalization, and that’s what you believe, the argument becomes let’s start with the people who need it. Let’s start with the people who are in need and let’s start with a project that we think we can prove and push forward and then go from there. And there’s an example of this with marijuana. Where medicalization led the way and arguably helped push forward legalization. But as we pointed out in the piece, this could reduce access for people. And that’s not just financially. You could imagine a scenario where people don’t have access to a doctor, or good access to medical services, or they come from a community that’s not overly trusting of the medical community.
And next is a safety issue which kind of presents a paradox because one of the arguments being used to help approvals is that these compounds are safe, they are safer than the current drugs, there’s less side effects etc. But yet we’re saying they’re not safe enough for you take on your own. So while there is less physical side effects — you can’t really OD on a psychedelic — there are reports of people having long lasting psychological effects and there’s warnings for people who have family history of mental conditions like schizophrenia and others to not take these substances. And ultimately, I think the research community is a little worried about getting shut down. That if there’s some bad press about people having bad trips, politicians and the public will get gun shy and we could end up in a situation like the 60s.
Lydia Chain: Bradley van Paridon is a Canadian freelance science journalist and podcaster based in Marburg, Germany. Our theme music is by the Undark team and additional music in today’s episode is by Kevin MacLeod at Incompetech. I’m your host Lydia Chain. See you next month.