The Therapeutic Potential of Psychedelics; NYAS at South By Southwest 2022

Modern research on psychedelics is turning the “turn-on, tune-in, and drop-out” culture of the 1960’s upside down. What was once considered a recreational activity is now an evidence-based treatment for psychiatric illnesses such as depression, PTSD, and addiction. An expert panel—curated and presented by the New York Academy of Sciences—drew a 1,500+ audience to the mainstage of the March 2022 South By Southwest Conference, to forecast what’s next for the 21st century renaissance of psychedelic medicine. Here, we capture highlights of their conversation on this new era in psychiatry.

Brooke Grindlinger, PhD, introducing the Academy’s panel discussion

Rewiring the Engine That Is Your Brain

Classic psychedelics are a structurally diverse set of compounds that, when administered in humans, produce a unique profile of changes in thoughts, perceptions, and emotions. These often include profound changes in a sense of meaning, and even in one’s understanding of reality. The latest fundamental research and clinical studies of psychedelic treatment are just beginning to reveal the complex neural mechanisms at the root of these experiences, and demonstrate utility as a treatment modality for psychiatric diseases, most notably for depression and addiction.

“When you have a chronic mental illness, like depression, that takes a toll on the brain,” opened the panel’s moderator, John Krystal, MD, Chair of the Department of Psychiatry at Yale University and Chief of Psychiatry and Behavioral Health at Yale-New Haven Hospital. “Synaptic connections—the structural connections to the place where one neuron communicates with another neuron—can be shown to be reduced in certain parts of the brain. What was first shown with ketamine—the only psychedelic drug that’s actually licensed for use as a medicine—and now has been shown with other psychedelic drugs, is that these parts of the brain can regrow those structural places of communication with synapses.”

John Krystal, MD

“That's a very different idea about how a therapeutic drug might work from the way that we used to think about how antidepressants might work,” Krystal continued, referencing how popular antidepressants, like Prozac, are believed to achieve their effects by normalizing an imbalance in the levels of serotonin in the brain—the messenger chemical that carries signals between nerve cells. “Now, in this generation of [psychedelic] medications, we're talking about drugs that restore functional capacities and structural foundations for communication in the brain, and thereby produce perhaps a more profound and hopefully more lasting kind of change,” Krystal explained.

Beyond observing these lasting changes to the architecture of the neuron, “we know which areas of the brain are activated and which areas of the brain are deactivated acutely with these compounds,” stated fellow panelist Roland Griffiths, PhD, Professor in the Departments of Psychiatry and Neurosciences and Director of the Center for Psychedelic and Consciousness Research at the Johns Hopkins University School of Medicine. “Parts of the brain that normally don't talk to one another light up. There's not just chaos, there's organization there, and it's led to this idea of ‘resetting’ the brain. The idea is, the brain has been rewired in some fundamental way at that level.”

A Therapeutic Coat of Many Colors

To date, two companies—COMPASS Pathways and the Usona Institute—have received breakthrough therapy status from the U.S. Food and Drug Administration to explore their psilocybin (the active ingredient in magic mushrooms) therapy for treatment-resistant depression or major depressive illness. According to Griffiths, COMPASS just reported “a large trial of 230-plus people comparing different doses of psilocybin for treatment-resistant depression, and they're showing it was well tolerated [and with a] 24% treatment response at 12 weeks.” Treatment response, Griffiths clarified, indicates “a greater than 50% drop in some established measure of depression.” A separate trial for major depressive disorder, ran by Griffiths, showed “a 75% response rate at 12 months, which is really quite notable…but, we're seeing a lot of variability in terms of the magnitude of effects and the duration of effects across these trials,” Griffiths reflected. “Now, that may be because treatment-resistant depression is altogether a different beast than major depressive disorder, but… it could have a lot to do with the therapy, the therapeutic package, the context. So, there's a lot that we don't know. But all these trials are pointing in the same direction, and that is toward an efficacy signal.”

Roland Griffiths, PhD

While the primary target of recent clinical trials with psychedelic therapy has been depression, Griffiths also spoke of other studies at Johns Hopkins on addiction: “We have some incredibly positive preliminary data on using psilocybin as a treatment for smoking cessation. An initial, open label trial [led by Matthew W. Johnson, PhD], showed 80% abstinence at six months…[and] 60% after two and a half years.” He continued with excitement, “if you know anything about the addiction literature, that's just astounding.” Griffiths commented that the results of ongoing efficacy trials—comparing the efficacy of nicotine replacement therapy versus a psychedelic treatment—also look quite promising. Acknowledging the fast-growing psychedelics research output of other academic research groups, Griffiths referenced additional studies in the field showing positive effects: psilocybin for the treatment of alcoholism, led by Michael Bogenschutz, MD, at New York University, and for cocaine-related substance abuse disorder, led by Peter Hendricks, PhD, at the University of Alabama at Birmingham. Griffiths paused to observe: “Isn't it remarkable that a single treatment could target these very different addictions? The addiction field is ripe and ready to go.”

Fellow panelist, entrepreneur and psychedelics research philanthropist, Tim Ferriss, interjected: “What fascinates me, in addition to many other things about psychedelics as a class of possible therapeutics, is that they not only seem to have fascinating effects on these [brain] structures, these fundamental building blocks of your mental health, but also seem to have a lasting effect on rewriting [one’s] narratives and beliefs—the content that drives a lot of our behaviors, whether that's OCD thought patterns, anorexia nervosa, chronic depression or addiction.”  Ferriss continued, “how can something you take only twice have this extended effect, when the half-life of these drugs is on the order of hours? It's part of the reason this science excites me so much—it brings up many more interesting questions in each subsequent study.”

Tim Ferriss

The User Experience

A number of people who have received therapy with the psychedelic ketamine have described the feeling of their depression, or the burden of their depression, just melting away. Ferriss, who jokingly referred to himself as the “muggle” of the panel as a lay person deeply interested in this research, spoke candidly of his personal exploration of the effects of psychedelics on his own mental health. “My first experiences, and I should note unsupervised, were in college," he said. "On average, I was experiencing two to three extended, debilitating, depressive episodes per year. It's hereditary, I've seen it throughout my family, and it really was, and had been, a crippling experience. With my first [psychedelic] exposure—keeping in mind, no prep, no integration—I nonetheless experienced this afterglow effect, where I did not experience depressive symptoms for anywhere from three to six months. A feeling of unity and connection with people around me, the things around me. I didn't really think about the depression. The nature around me acted as a sort of countervailing force against this repetitive egocentric fixation that I had up to that point. I wasn't perseverating on my problems and how I was broken.” Griffiths was quick to validate Ferriss’ personal experience with observations from clinical studies: “Psychedelics appear to be changing the narrative structure of how someone understands themselves, their lives, their worldview.”

Panelist Rosalind Watts, PhD, a former Clinical Lead of the Psilocybin for Depression trial at Imperial College London, and now a consultant therapist, reflected on two key themes she observed emerging from psychedelic therapy studies that she led for individuals with treatment-resistant depression: “The first was that people describe going from disconnection to connection. They described that in depression they just felt, it wasn't so much that they were sad all the time, it was much more that they were numb and disconnected from themselves, from their bodies, from the world around them. They felt that they were trapped in a prison in their minds. After the psychedelic experience, it was like they went from being stuck ‘up here’ [motioning to her head] to this process of expansion where they could connect with their senses, their bodies, and the world around them.

Rosalind Watts, PhD

Watts continued, “Three to six months, I would say, was the average amount of time that people felt this process of expansion and connection. And then it did tend to retract again after that amount of time. The second theme they described was they went from avoidance of emotion to acceptance of emotion. There was this ability to engage with emotions that had been repressed for a long period of time. So, in the months afterwards, people often felt quite destabilized, quite raw, processing trauma. And if they had good integration therapy, it was something they were able to process.”

Tour Guide Required

Ferriss likened the psychedelic experience to getting on a trapeze: “You want to set up the safety net before you get on.” This safety net—a therapist-guided process consisting of preparation, supervised sessions, and post-treatment integration—"is essential to an effective patient experience,” said Watts. She continued, “[it’s] a process of therapy with two therapists, escorting [the patient] on a journey with two days of music, meditation, and care, compassion, and time. It's not just about the dose of the drug, it's also about the care and the container.”

“One of the things that doesn't often get discussed is how absolutely terrifying psychedelic experiences can be,” commented Watts. “They can be really wonderful, but they can be incredibly scary. It's so hard to put into words, but the visceral pain and grief that people can come into contact with, autobiographical grief, ancestral grief…this kind of huge void of deep suffering of the whole world. It's a lot for people to cope with. When they're in the container of the trial, where they have therapists around them, and all the support, they can feel that is contained and held. But then the trial ends quite abruptly and then they go home, they go back to their community and then they're left with this sometimes-called ‘ontological shock’, which is like your world view has suddenly been turned on its head. You go back into the world. Your brain has been rewired, potentially, and you are a bit reset…you're thin skinned, sometimes your senses are more intense and sensitive, and you are often just feeling quite destabilized. Psychedelics have the power to disrupt. It's opening Pandora's box sometimes. And what we don't have in our society are the structures and the lineage to deal with these things.” Griffiths noted with concern, “with regards to psychedelics, and really any intervention, we need to think about a long-term course of treatment. These episodes of treatment have to be embedded in a natural arc of treatment because it's really the whole treatment that's therapeutic, not just the one part of it. That’s really important, and another other reason why recreational use of a psychedelic drug not embedded in this arc misses the point, and may produce more risk than benefit, for some. We have an awful lot to learn about how these interventions can be used, and in which populations or sub-populations they are most efficacious.”

Following these observations, Watts has developed the ACER model (Accept, Connect, Embody, Restore), supplementing psychedelic therapy with a year-long integration program. “There is so much more work needing to be done on integration. The psychedelic experience itself is studied a lot, but people in the days and months and years after their psychedelic experience need lots of support.” Watts went further, noting that even among healthcare professionals there is “not yet a common understanding of psychedelic work. The healing modalities that have been the gold standard [such as antidepressants or talking therapy], are about fixing it, healing it, and numbing it…or correcting your negative biases and thinking more positively. Let’s fix that.“

Can There Be Reward Without Risk?

Despite their enthusiasm and excitement for this field of research and therapy, the panelists pivoted, to explore what Krystal called “the shadow side and the difficulties.” In some studies, but not all, a small percentage of participants have reported, even a year after the psychedelic experience, that they were having some kind of psychological condition for which they were in treatment. “We are also concerned about precipitation of enduring psychotic illness in people who are predisposed to that,” said Griffiths. “These drugs are very popular within the age frame in which the probability of the emergence of schizophrenia is most probable. So, a concern is people [who are] potentially preschizophrenic are going to get a high dose and maybe this is enough to push them over. That's irreversible, you don't come out of schizophrenia once you have that diagnosis,” he warned. In terms of using so-called magic mushrooms, “the potency of psilocybin, even within a species of mushrooms, can vary over a ten-fold range. Most people don't assay what they're taking, so there are lots of unknowns here that can contribute to difficult experiences,” said Griffiths. Ferriss expanded: “Treat these things with incredible caution, because they can be a catalyst and they create this amplification within a window of plasticity. You're warming up the Play-Doh that is your brain and your psyche. And depending on who's playing with it, depending on the inputs, you're not guaranteed to have a better output by the end of it.”

Left to right: Brooke Grindlinger, PhD; Roland Griffiths, PhD; Rosalind Watts, PhD; John Krystal, MD; Tim Ferriss

While the conversation centered mostly on the participant experience within a carefully monitored clinical trial environment, the panel could not ignore the risks of recreational psychedelics use. “I ended up taking a 10-year hiatus from any psychedelics,” admitted Ferriss, as he went on to solemnly describe almost being hit by a car while in the throes of an unsupervised psychedelic experience. “Risk is involved when you don't have guardrails, trained professionals.” Griffiths cautioned, “the most frequent kind of adverse effect that we worry about, and it doesn't occur in clinical trials, but it certainly occurs recreationally, is people engaging in dangerous behavior while they're in the streets. We are going to see deaths, suicides, and homicides attributed to psychedelics.”

Pharma Tunes in to the Potential of Psychedelics

Despite the challenges facing the field of psychedelic medicine, Krystal closed the discussion with a positive outlook: “It’s a remarkable time for [psychedelic] treatment, but it's also a remarkable time in the pharmaceutical industry around drug development in the psychedelic space. There are a large number of new companies that are springing up. Many of them are [trying] to design drugs that capture the clinical benefit of the psychedelic drugs without producing the ‘trip’, if you will.” Griffiths—quick to not throw out the baby with the bathwater— mused: “There may be something that can be captured that's therapeutically useful in developing a compound that doesn't produce any phenomenology, but the meaning-making that comes out of these experiences all relates to the subjective effects…the narrative structure of how someone experiences the world, sees themselves, and then proceeds forward in time. You're not going to have that in absence of the phenomenology.”

Time, and the data, will tell.

Watch the full South By Southwest panel discussion, Psychedelics for Therapeutics and Well-being:

Therapy photo courtesy: Center for Psychedelic & Consciousness Research Other photos: Ana Karotkin ©NYAS

Further Reading and Listening:

Psychedelics to Treat Depression and Psychiatric Disorders
New York Academy of Sciences, 2021 June 1