Treating mental health disorders, such as addiction, depression, schizophrenia or post-traumatic stress disorder (PTSD), has not been as simple as swallowing a pill. The complexity of these disorders, and the factors that give rise to them – experiences of trauma, genetics, neurohormones and brain chemistry, interpersonal relationships, other illnesses (and other medications), and plenty of unknowns – demand a holistic approach to healing. With psychedelic therapies, that means understanding the subjective experiences of patients, and helping to guide them toward an intended outcome, not just during treatment, but before and afterward as well.
Panelists participating in Demy Colton’s virtual salon, Psychedelics Get Serious, emphasized the importance of “set and setting,” which includes a patient’s intentions when coming in for treatment, the location and environment where the treatment takes place, and a therapist’s role in facilitating a positive outcome. “It’s not as simple as a molecule leading to action, which leads to clinical outcomes, which you can see with other medications, especially in infectious diseases or cardiology,” said Adam Gazzaley, a professor of neurology, physiology and psychiatry at the University of California, San Francisco (UCSF), and the founder and executive director of Neuroscape, a research center at UCSF.
With psychedelics, the setting or “contextual influences” are important, including “how you come in with your intentions, or what psychological context you have, or even if you have a mental health condition, what happens during the treatment itself, and then how you integrate and process that [experience] afterwards,” said Gazzaley. “There’s a lot more research [needed] to understand how we can deliver these treatments in the most effective way.”
Measuring Experiences
Effectively measuring the many aspects of set and setting had been difficult, too, and would likely require the use of technology, noted Walter Greenleaf, a neuroscientist and medical technology developer at Stanford University. “We need to dynamically measure to the best we can someone’s mood and emotional state, leveraging what we can with biosensors, and also seeing any behavioral indications that we can get both during the experience and before and after.”
In May, The Multidisciplinary Association for Psychedelic Studies (MAPS), a 501(c)(3) nonprofit organization, published the results of its Phase III trial of MDMA for the treatment of PTSD. The study showed impressive improvement in PTSD symptoms for patients receiving MDMA in conjunction with therapy sessions.
Berra Yazar-Klosinski, chief scientific officer of the MAPS Public Benefit Corporation and deputy director at MAPS, joined the organization in 2010 as a clinical research scientist. She described the ability of MDMA to “trigger signaling cascades that deploy neurohormone effects, specifically around oxytocin and vasopressin, and also cortisol, prolactin and adrenocorticotropic hormone,” which has the effect of “opening up the mind and body to be more susceptible to external factors.” That vulnerability is what makes “set and setting so important,” she said.
Yazar-Klosinski noted that in PTSD, the efficacy measures required by the FDA “are the same measures of efficacy that were in use when Paxil and Zoloft were approved for PTSD, they’ve just gone through a slight update” with the publication of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, or DSM-5. The FDA requirements for psychiatric indications are quite restrictive, and while surrogate endpoints related to genetic or epigenetic changes, for instance, would be useful, they would also require validation. MAPS “doesn’t feel that that that’s really a good use of donor resources.”
Ekaterina Malievskaia, who in 2016 founded Compass Pathways with her husband George Goldsmith and In Vivo 2021 Rising Leader Lars Wilde, said that psychiatric skills currently in practice “were developed in the 1950s and 60s, and they are not optimal for measuring what happens to patients during a [psychedelic] experience.” Compass is developing a synthetic form of psilocybin for treatment-resistant depression, and is conducting a Phase IIb dose finding study. “We’re not convinced that [today’s measurements] adequately reflect the value that is created for patients and perhaps for health systems,” said Malievskaia, adding that patients will sometimes say that the symptoms of depression may come back, but that they do not engage with the symptoms; they coexist with them. “That is very difficult to capture,” she said.
Psychedelic treatments flip the health care model, which has been based on a kind of “saviorism” that looks outward to a drug or a doctor to fix a problem, says Charlie Hartwell, managing partner at Bridge Builders Collaborative, an investment group focused on mindfulness, mental health and digital therapeutics. “With these medicines, we’re actually looking inward, to understand ourselves better, and to be able to permanently transform some of the trauma and behavior which causes suffering in the first place.”
Hartwell expressed concern about the training of practitioners working with psychedelic therapies, and suggested that therapists themselves should have their own experience with the medicines their patients are taking. “If you are going to be present with somebody, for an experience that many people describe as one of the most important experiences of their lives, then it is really important to have done your own personal work as a therapist, but also to experience this medicine so you can be in a better relationship with the person [receiving treatment] and understand what they are going through.” Hartwell acknowledged that “there’s not a legal framework necessarily to do that right now.”
Regulators On The Level
Despite the complexities surrounding psychedelic treatments, which include subjective personal experiences and the need for therapy in concert with treatment, regulators have recognized the stark unmet need in mental health. In 2019, the FDA approved Janssen’s (a Johnson & Johnson company) inhaled version of ketamine, called Spravato (esketamine). (Also see “Psychedelics For CNS Disorders: Understanding The Opportunity” – In Vivo, 9 Sep, 2020.) MAPS’ MDMA product was likely to be the next DEA Schedule 1 substance to receive the FDA’s blessing, ahead of psilocybin, Lars Wilde, president, chief business officer and co-founder of Compass Pathways, told In Vivo (see Exhibit 1).Exhibit 1.
Psychedelic Leaderboard: Front-Runners In The Clinic
| Psychedelic Substance | Development stage | Sponsor company | Indication | Notes |
|---|---|---|---|---|
| ketamine | Approved | Janssen | Treatment-resistant depression, Major depressive disorder with acute suicidal ideation or behavior | Esketamine, the active ingredient in Janssen’s Spravato, is the s-enantiomer of ketamine, which is considered more potent than the ketamine molecule’s mirror image, known as r-ketamine. |
| MDMA | III | MAPS | PTSD | MAPS is also developing MDMA for a number of other indications. The following indications have entered Phase II development: eating disorders, anxiety associated with a life-threatening illness, social anxiety in autistic adults. |
| psilocybin | II | Compass Pathways / Usona Institute | Treatment-resistant depression / Major depressive disorder | Compass developed a synthetic form of psilocybin, and does not use natural extracts from mushrooms. |
| LSD | II | MindMed | Anxiety, cluster headaches, ADHD, undisclosed severe pain indication | In January 2021, MindMed announced a Phase I clinical trial in humans that will combine MDMA with psilocybin. |
| DMT | I/II | GH Research / Small Pharma | Treatment-resistant depression / Major depressive disorder | GH Research developed a proprietary inhalation formulation for use in the administration of its DMT product. |
| ibogaine | I/II | DemeRx | Opioid use disorder | Ibogaine is a naturally occurring psychedelic substance present in certain members of the Apocynaceae family of flowering plants. Ibogaine was first introduced for use as a medical product in France, in the 1930s, under the trade name Lambarene. It was marketed as a physical and mental stimulant, and as an anti-depressant. |
| mescaline | I | MindMed | Health volunteers: study focus on impact of variable doses and the contribution of the 5-HT2A receptor in mescaline-induced alterations of consciousness. | Mescaline, despite a long history of ceremonial and spiritual uses among Native cultures, has very little modern scientific information about its pharmacology or effect on humans. |
New scientific discoveries, in the areas of basic research and early drug development, had piqued the interest of regulators, said Malievskaia. “When we had our very first interaction with the European Medicines Agency, they came armed with bunch of studies; they knew the research and were actively engaged in it.” The same was true in the “12 or 13 countries that we’ve interacted with,” including the FDA, she said. That was partly due to a lack of innovation in psychiatry, and also due to pervasive unmet needs, she said. “Regulators are people too, they have family members who are affected by mental health issues.”
Regulators still struggle to fit holistic treatment approaches, which contain a multitude of variables, into the well-worn assessment models that have been used for decades. “We get this question a lot from regulatory agencies: ‘Why haven’t you tried a two-by-two factorial [trial] design?’ It’s because we think the effects are greater than the sum of their parts,” said Yazar-Klosinski. That is changing, however, as evidenced by new regulatory language. “There is a newly emerging understanding on the part of regulators that psychedelic assisted therapies represent a new category of intervention, which they are calling ‘integrated multimodal therapy,’” Yazar-Klosinski said. “It’s a holistic approach to defining what is going on, as opposed to a reductionistic one.”
Cultural change, too, may be helping to push regulators toward a greater openness regarding psychedelics. “We’ve seen very strongly held conventions, specifically vis-à-vis cannabis, change and the sky has not fallen, society seems to function very well,” said Ronan Levy, co-founder and executive chair at Field Trip, a vertically integrated psychedelics company comprised of Field Trip Health, which is “building the clinical infrastructure to delivery psychedelics at scale,” and a research and development operation currently focused on advancing FT-104, an internally developed (and undisclosed) psychedelic molecule acting on the serotonin 5-HT2A receptor. “People are looking for more holistic, proactive approaches to health care, as opposed to the reactive approach,” said Levy.
Role Of Digital
Digital technology has an important role to play in the eventual approval and use of psychedelics, both as a way to more accurately assess individual patients undergoing treatment, and to help promote positive experiences and improve the effectiveness of medicines. Gazzaley’s research at UCSF served as the basis for what became EndeavorRX, the first video game approved by the FDA as a medical product. He is a co-founder and board member at Akili Interactive, which markets the game. (Also see “Digital Therapeutics Have Arrived But Will Insurers Get On Board?” – In Vivo, 9 Jul, 2020.)
During the panel discussion, Grazzaley said that he became interested not just in video games as an experiential medicine, but also thinking about how psychedelics induce their effects. “Digital technologies can be used to both understand the person and the brain, before, during and after treatment. It’s a way of offering a lot more information,” he said. “On the other side, digital technologies can be used to change context itself. Virtual and sensory immersive experiences – and this is still a research question – may integrate nicely with the psychedelic compounds and the perceptual shifts they are causing.”
Bringing a “digital layer to the therapeutic process,” said Greenleaf, means that “we can also start bringing story, bringing narrative, we can make it a journey. I think it’s more than just a compliment to the therapy with measurements and feedback, it’s also expanding to leverage the ways that people grow and learn.”
At Field Trip, Levy said the company is “taking a big data approach of actually treating people and collecting all of the circumstances and dynamics and who the therapists are, and every piece of data that we can collect around it, trying to generate an understanding through a big data model and machine learning, as opposed to a clinical context.”
More information about a psychedelic experience could eventually lead to better predictions, and a “recipe to create the most meaningful and sustainable outcomes,” said Grazzaley. “We’re very interested in the sensory context: what they see, hear, smell and feel, which is almost completely unexplored in a prospectively design research study.” A deeper understanding of what occurs in the brain during treatment with a psychedelic medicine, and the different levers of sensory experience, could lead to what Grazzaley called a “closed-loop psychedelic treatment.” The implication of such a system would mean that “therapists would have a new set of tools … where they can understand what is happening in the moment to their patients, and then have all these levers of what they can introduce, from smells to music, to help guide a patient most effectively,” he said. “That is the future that we envision.”