26 September 2025

Escaping the Mental Health Silo


Transdiagnostic Potential of Psychedelic Medicines

By: Court Wing, Co-Founder, Psychedelics & Pain Association; Founder & CEO, REMAP Therapeutics

MAPS Bulletin: Volume XXXIV

ABout the author - 926 Bulletin (2)

After 20 years, multiple surgeries, and countless pill bottles, Lynn Watkins, a retired US JAG officer-judge, had little hope of walking again without debilitating pain. Only through completing a protocol of 3 varying doses of psilocybin coupled with neuromodulatory exercises did she finally find relief. Her pain, caused by severe complex regional pain syndrome (CRPS), was complicated by trauma and adverse childhood experiences. Her psychedelic journeys touched on all aspects of her pain, from the psychological identification as a person with unrelenting pain, to the actual mechanics of her gait and mobility, all within each session.

Lynn’s story brings into reality the growing body of evidence pointing to the broader, transdiagnostic, potential of psychedelic medicines. For decades, studies, case reports, and patient accounts have suggested that psychedelics may relieve chronic pain, neurodegenerative illnesses, and other debilitating physical conditions, with results that are often just as striking as what is seen in the mental health realm.

Psychedelics work through multiple mechanisms—serotonergic, glutamatergic, anti-inflammatory, and neuroplastic pathways that sit at the foundation of core bodily functions. Our growing understanding of psychedelic mechanisms of action and the multiple proposed models for how psychedelics create change, explain why people are experiencing relief across a wide range of conditions and the resurgence of research into psychedelics for physical and neurological health.

Diverse Conditions Showing Signal

Psychedelic compounds have been shown to be remarkably effective for some of the worst pain conditions known to medicine, and there is strong, emergent signal for other challenging physical conditions. Here is a snapshot of where science is showing that psychedelics may be beneficial treatments outside of mental health:

The above conditions are not traditionally seen as having common etiologies, and clearly have vastly differing disease manifestations — yet early evidence indicates that psychedelics may be useful treatments for all of them. To highlight how unusual this is, every condition listed above has shown symptom improvement, or even resolution, with psilocybin alone. Further, a variety of other psychedelics have demonstrated unique efficacy for these conditions, like LSD, DMT, ibogaine, and MDMA. Why this striking, transdiagnostic overlap? The answer may lie in the core disease processes that are shared across these conditions —  e.g., inflammation, sensitization of peripheral nerves and pain processing pathways within the spine and brain, degenerative changes to the nervous system, and atrophy of brain structures themselves. 

When a single medicine demonstrates therapeutic effect across seemingly unrelated conditions by targeting the underlying biological pathways that drive them, we call that transdiagnostic—effective against, and sometimes even revealing, the shared causes of multiple diagnoses. While transdiagnostic is most often used to describe psychiatric comorbidities (e.g., depression accompanying anxiety disorder), the term has much broader, and quite useful, applicability. In the case of psychedelics for the treatment of complex pain and other physical conditions, these compounds reveal themselves as thoroughly transdiagnostic. Psychedelics offer a unique opportunity to expand the use of this term into the realm of whole-body medicine, reminding us that these are not single-factor drugs, but multifaceted agents capable of addressing suffering at its systemic roots.

Mechanisms of Action

Psychedelics have multiple targets within the human nervous and immune systems, and may have direct effectiveness on multiple contributors to pathological conditions, mental and physical, including: 

  • Psychological reframing: how one perceives their circumstances, their internal resources, and how information is processed between key brain networks.
  • Structural neuroplasticity: promoting the restoration of nerve trunks, branches, and synaptic connections, locally and in broader networks, influencing how adaptive they are to changing internal and external environments.
  • Anti-inflammatory: effects that reduce damaging inflammatory immune responses to illness or injury that have become chronic and cause damage to the tissues throughout the body, joints, organs, and nerves.
  • Descending inhibition: In the same way that psychedelics can inhibit maladaptive negative thought-loops in depression and PTSD, psychedelics also show evidence of inhibiting nerve sensation that the brain can interpret as pain, which can result in direct reductions in pain levels.
  • Cortical reorganization: when noxious nerve signals become chronic, pain perceptions become a malfunctioning, entrenched response, changing the brain’s healthy default adaptability to often hypersensitized, negative perceptions. Psychedelics reorganize these networks back to more neutral, efficient, and effective assessments of both internal and external environments.

There are multiple models within research about the mechanisms behind the above compelling changes within the nervous system. Some camps believe this is largely due to increased cognitive flexibility, working on the brain’s organization of incoming and outgoing information, its responses, and perceptions. Others think of it as an almost chemotherapeutic approach, where these medicines improve the nerve structures themselves, restoring some of what has been lost to dysfunction or disease, and reducing the inflammatory burden that directly interferes with nerve and immune functions. Further, some researchers believe that psychedelics may audit maladaptive changes to gene expression as a result of various life experiences, like childhood trauma. In this line of thinking, psychedelics may allow for gene encoding that encourages a less threatened response, reducing a predisposition towards illness and/or psychiatric conditions caused by a genetic bias towards “fight or flight.”

Psychedelics & Pain Symposium 2025

The REMAP Therapeutics’ Psychedelics & Pain Symposium, co-presented by PPA, highlights the emerging field of psychedelic transdiagnostic potential.

Recordings will be available for purchase in October 2025

New Indications & Transdiagnostic Dialogue at PS25

In June, the Psychedelics & Pain Association held a groundbreaking panel discussion, “Expanding the Lens: Mechanisms, Models & Modes – Transdiagnostic Potential of Psychedelic Medicines,” at MAPS’ Psychedelic Science Conference in Denver, giving a literal stage to the dynamic discussion of psychedelic transdiagnostic potential. Three top researchers, each following different lines of investigation into the mechanisms behind psychedelics’ effectiveness for a growing variety of conditions, joined us onstage:

  • Dr. Robin Carhart-Harris, known for his investigations into how psychedelics improve depression and similar mental health conditions in what is called computational neurology or hierarchical predictive processing, a.k.a., how the brain processes, sorts, and evaluates information.
  • Dr. Charles Nichols, considered the world’s top expert on psychedelics’ anti-inflammatory properties as well as their potential to improve structural neuroplasticity, creating avenues of restoration in compromised brain structures and neural pathways, aiding in a return to healthy default functioning.
  • Dr. Candace Lewis, investigating how psychedelics may improve or even reverse traumatic gene expression, epigenetics, restoring healthy encoding into how our genes respond to the environment and circumstances.

In describing the framework behind his REBUS model of psychedelic activity or “RElaxed Beliefs Under pSychedelics” in treating conditions like depression or fibromyalgia, creating rapid changes in patients’ symptom burdens, Dr. Carhart-Harris shared: 

“The REBUS model is inspired by a dominant model in cognitive neuroscience psychiatry, called hierarchical predictive processing. This says we experience the world through internal predictive models of our environment & how we make meaning of our experiences. REBUS says that psychedelics modulate the strength of encoding of internal predictive models – they dial these down.”

Psychedelics can create changes in how our internal predictive models “frame” our environment and personal circumstances, downregulating overly alarming predictions that can negatively bias one’s nervous system toward perceiving incoming information and/or sensation as threatening, dangerous – or painful. This allows people to move on from reflexively negative expectations to more neutral evaluations and the development of internal resources. Relevant to this discussion, and expanding from the typical mental health frame, maladaptive predictions are often the cause behind complex chronic pain, the body sensing danger or injury long past initial injury, tissue damage, or nervous system assault.  

Dr. Lewis shared an emerging view in her lab’s research: if traumatic experiences can drive long-lasting negative neuroplastic changes, as seen in PTSD, then psychedelics such as MDMA may be capable of inducing comparable neuroplasticity that results in durable, positive psychological outcomes.

In speaking to the potential mechanisms behind this, she stated:

“There’s been a deep disconnect not only in psychedelic science but across neuroscience and psychology, that the psychological is different than the brain or the biological – and they’re not. They influence each other. We have a large body of literature showing that feelings and experiences of psychological disconnection lead to widespread biological disruption via epigenetic mechanisms. Everything from decreased neuroplasticity, chronic inflammation, dysregulated stress physiology, and altered neurocircuits underlying mood, reward, and cognition can be traced back to stressful experiences altering epigenetic regulation. Is it possible that psychedelics, both their pharmacological actions and their induced psychological states, lead to symptom reduction through similar epigenetic modifications? Our research of both animal and human models with psilocybin, MDMA, and ketamine show epigenetic modifications, similar to how gene expression changes as a result of early life adversity.”

Dr. Nichols’ work has revealed that psychedelics are potent anti-inflammatories, with some compounds 700-800 times more effective than corticosteroids, even at sub-psychoactive doses. He hypothesizes that this potent anti-inflammatory action allows for structural neuroplasticity to thrive and encourages a healthy gene expression. In discussing how these properties can produce lasting improvements in conditions like depression or potentially chronic pain, he shared:

“Our work with animals in a depressed state, shows that psychedelics lead to a 2-week period with a burst of synaptic plasticity and the ability to get out of the rut. By manipulating the environment of these animals during these 2 weeks, we can create an anti-depressant effect that persists 3-4 months later. There is an epigenetic activation of key molecules that facilitates this neurotransmission. So that when we’re looking four months, five months after a single treatment with psilocybin, these animals are still acting like normal, non-depressed, non-stressed animals. We have evidence for epigenetic modifications in our anti-inflammatory models, so it could be that different psychedelics may be targeting different epigenetic markers to produce these long-lasting effects.”

When asked what was the least understood aspect of their research, their answers were revealing. Dr. Lewis offered:

“While a lot of media attention has focused on transgenerational epigenetic effects, the majority of epigenetic research really is about the single organism – within their own lifespan. I find the study of epigenetics to be so groundbreaking to understand how psychedelics can make changes to gene expression similar to a wide range of life experiences.”

Dr. Nichols concluded with: 

“What’s really amazing is that the behavioral effects and potencies of psychedelics don’t match up with their anti-inflammatory effect. For example, LSD is a really bad anti-inflammatory, but it’s a really good, potent psychedelic. We’re looking at the signaling pathways now, and we know that the signaling that leads to behavioral effects, are not the primary pathways involved in the anti-inflammatory effect. I’m exploring why some psychedelics are so potently anti-inflammatory, while others aren’t anti-inflammatory at all. This is the conundrum that faces me every day.”

In closing, Dr. Carhart-Harris offered:

“There is a parallelism between mind and body. As a philosophical perspective, you might call that dual aspect “monism” or “property dualism.” It’s recognizing that mind and body are different in how we experience them, how they look and feel to us. This is relevant because changes in the mind can causally influence changes in the body. This is very relevant to psychedelic therapy work and physical disorders like fibromyalgia syndrome.”

A crucial takeaway from this complex discussion is that no single model fully explains psychedelic action; taken together, they reveal a picture of medicines capable of driving biological changes across both physiological and psychological domains. Where the models converge, we see strong evidence for their therapeutic potential; where they diverge, we uncover new questions and avenues for discovery.

Looking ahead, the challenge is not only to deepen our scientific understanding but also to translate it into practice. Integrating psychedelics into patient-centered care models means building pathways where research, policy, and clinical innovation meet, so that people living with pain, neurological injury, or other debilitating conditions have access to safe, effective, and whole-person treatments.

Court Wing

Court Wing is the Founder and CEO of REMAP Therapeutics and Co-Founder & Research Lead of the Psychedelics & Pain Association. With over 30 years of experience, Court has helped thousands overcome injury through the use of applied neurophysiology. In 2020, Court participated in NYU’s trial of psilocybin for Major Depressive Disorder. By the end of his dosing day, Court achieved full remission from depression AND relief from chronic pain. With his background in neuromodulatory approaches for pain and performance, he realized psychedelics could revolutionize chronic pain treatment, and REMAP Therapeutics was born. REMAP is devoted to formal psychedelic rehabilitation for treating chronic pain, neurodegenerative, and other physical conditions.

Court Wing

 

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