Led by David E. Olson, director of the Institute for Psychedelics and Neurotherapeutics and a professor of chemistry and of biochemistry and molecular medicine at UC Davis, the team approached LSD not as an untouchable chemical monument but as an engineering problem. LSD’s core structure, known as the ergoline scaffold, consists of four fused ring-like shapes that form the molecule’s rigid backbone. That complexity has long been both the source of LSD’s remarkable pharmacology and the bane of medicinal chemists hoping to improve upon it. “We’ve known the structure of LSD for a long time, but the complexity of its core has really limited our ability to engineer optimized drugs based on its structure,” Olson explained. “If you can only modify a couple of spots, you’re limited in what you can do.” With so few chemically addressable positions on the fused ring system, researchers have historically been stuck tweaking the periphery of the molecule rather than interrogating its architectural logic.

The conceptual breakthrough of the new study lies in its willingness to ask a deceptively simple question: what happens if you start deleting rings? Olson framed the ergoline core as a molecular hybrid of the two great families of psychedelic compounds — the tryptamine family, which includes psilocybin and DMT, and the phenethylamine family, which includes mescaline and MDMA. “If you take those structures and overlap them, they basically produce LSD,” he noted. “The big question is, which one of those is more important for the hallucinogenic effects of LSD?” The molecule, in other words, wears the chemical fingerprints of both lineages simultaneously, and no one had definitively established which contribution mattered most for the psychedelic experience — and, by extension, whether the two could be separated.

The answer turned out to be the phenethylamine-like traits. When the researchers surgically removed the tryptamine-like portions of the molecule, the resulting simplified analogues retained their ability to stimulate the 5-HT2A serotonin receptor — the receptor widely regarded as the primary driver of psychedelic hallucinations. But when other segments of the ergoline scaffold were removed, a striking and clinically valuable trade-off emerged: hallucinogenic activity diminished, and so did cardiotoxicity. That toxicity is mediated by the 5-HT2B receptor, whose chronic activation is associated with potentially fatal cardiac valvulopathy — the same liability that has doomed several once-promising drug candidates, including the fenfluramine component of the notorious fen-phen weight-loss combination. Any psychedelic-inspired medicine intended for repeated, long-term dosing must therefore steer clear of 5-HT2B, and the UC Davis strategy offered a systematic route to doing exactly that.

To map the functional landscape of the ergoline scaffold in full, the team synthesized nine modified versions of LSD’s core, each representing a different degree of molecular deconstruction. The work is a tour de force of synthetic chemistry, because stripping rings from a fused polycyclic system while preserving receptor-binding geometry is far harder than it might sound. Each deletion changes the molecule’s shape, rigidity, and electronic distribution, all of which influence how it docks into serotonin receptors. Among the nine analogues, two compounds emerged with substantially improved safety profiles — reduced hallucinogenic potential paired with reduced cardiotoxicity. The researchers named them UCD0094 and UCD0076, and both now stand as proof that LSD’s therapeutic signal can be uncoupled from its psychedelic noise.

The second compound delivered an even more surprising twist. UCD0076 displayed a strong preference for binding the 5-HT2C receptor, a serotonin receptor subtype that has attracted growing pharmaceutical interest for reasons that have nothing to do with psychedelia. When the compound was tested in standard mouse behavioral assays, it produced antipsychotic-like effects rather than psychedelic ones. “It’s interesting that you could take LSD’s structure, chop off a part of it and you’re left with a molecule that is fundamentally antipsychotic,” Olson said. He pointed out that compounds activating 5-HT2C receptors are currently being explored as treatments not only for schizophrenia but also for epilepsy and substance use disorders. “This is a great starting point for those conditions.” The irony is hard to miss: a molecule distilled from one of the most famously hallucinogenic substances on Earth may point the way toward drugs designed to quell psychosis, not provoke it.

The broader context for this work is the intense scientific and commercial race to harness psychedelics for psychiatry. A wide range of neuropsychiatric and neurodegenerative diseases — depression, anxiety, PTSD, and others — are characterized by the withering of neural connections, and psychedelics have shown a remarkable ability to spur the growth of neurons and strengthen the connections between them, a process Olson and others refer to as psychoplastogenic or neuroplastic effects. The obstacle has always been the hallucinations. Classic psychedelics like LSD and psilocybin produce profound subjective experiences that require supervised clinical sessions, driving up the cost, complexity, and regulatory burden of therapy. The holy grail of the field is a non-hallucinogenic compound that preserves the neural-repair benefits — a goal this deconstruction strategy brings measurably closer.

That is what makes the “molecular autopsy” approach so consequential for drug discovery. Rather than accepting LSD as an indivisible gift from nature, the UC Davis team treated it as a puzzle to be solved, testing hypotheses about structure-function relationships that had remained speculative for decades. “We found that when you start deleting portions of LSD’s molecular structure, you can retain some properties and eliminate others,” Olson said. “By systematically deleting these rings, we can figure out what rings are important for what effects.” The method generalizes: the same systematic deconstruction logic could now be applied to other complex natural-product psychedelics, such as ibogaine or salvinorin A, whose formidable molecular architecture has similarly resisted optimization. In effect, the study converts LSD from a single, pharmacologically messy endpoint into a family of chemically tractable launchpads.

For the pharmaceutical industry, the practical implications are immediate. Simplified analogues like UCD0094 and UCD0076 are smaller, more synthetically accessible molecules than LSD itself, meaning they can be manufactured, modified, and patented with far greater ease. Their defined receptor-selectivity profiles — retaining activity at 5-HT2A while shedding 5-HT2B in one case, or pivoting entirely toward 5-HT2C in the other — give medicinal chemists precisely the kind of structure-activity data needed to begin iterative optimization. A 5-HT2C agonist derived from LSD, for example, would enter a therapeutic space where selectivity is everything: the receptor is implicated in appetite regulation, mood, and impulse control, and untoward activity at 5-HT2A or 5-HT2B has historically limited candidate drugs. Starting from a deconstructed psychedelic offers a pharmacological foundation that conventional medicinal chemistry might never have reached on its own.

The study also carries a symbolic weight for a field still fighting for scientific legitimacy. For half a century, research on LSD was effectively frozen by restrictive drug policies, and only in recent years has the molecule been examined with modern tools of pharmacology, receptor structural biology, and behavioral neuroscience. The UC Davis findings demonstrate that LSD is not merely a relic of the 1960s counterculture but a rich chemical resource whose full therapeutic potential may still be hiding in its substructures. The deconstruction revealed that the molecule’s celebrated psychedelic identity and its medicinally useful properties are not inextricably fused — they are separable, and once separated, each can be pursued on its own terms.

Funding for the research came from the National Institutes of Health, the National Science Foundation, the Camille and Henry Dreyfus Foundation, and the Pershing Square Foundation — a mix of federal agencies and private philanthropy that reflects the unusual position psychedelic science now occupies: rigorous academic chemistry aimed at one of the most commercially and clinically dynamic frontiers in medicine. Whether UCD0094, UCD0076, or their descendants ultimately reach the clinic remains to be seen; both compounds will need extensive preclinical safety testing, optimization of pharmacokinetics, and eventually carefully designed human trials. But the conceptual achievement is already secure. By taking LSD apart ring by ring, the UC Davis team has shown that the road to safer, more targeted neurotherapeutics may run straight through the wreckage of the most famous psychedelic molecule ever synthesized — and that what remains after the autopsy may be more valuable than the original.

The therapeutic use of psychedelics is far from new. Between the 1950s and early 1970s, over 40,000 participants took part in clinical studies exploring psychedelics’ promise for treating a range of psychiatric disorders, amassing a substantial corpus of research—over 1,000 published articles—that is virtually forgotten today. Dr. Ross emphasizes that this significant body of knowledge disappeared from psychiatric curricula and clinical practice following the Controlled Substances Act of 1970, which criminalized these compounds and effectively stymied research. This historical oversight, he explains, led to a profound gap in psychiatric education, leaving an entire generation of clinicians unaware of psychedelics’ therapeutic potential.

Dr. Ross’s NYU Psychedelic Research Group, founded in 2006, aimed to revive and expand this promising domain. Among his most notable studies is the landmark 2016 randomized controlled trial that examined psilocybin-assisted psychotherapy for patients with advanced cancer suffering from anxiety, depression, and existential distress. This trial was groundbreaking not only for its scientific rigor but also for its profound findings: a single psilocybin session, when combined with supportive psychotherapy, yielded rapid, sustained alleviation of psychological symptoms. The results resonated widely, captivating public and scientific audiences alike, and earning front-page coverage in the New York Times.

What made these findings particularly remarkable was the speed and durability of clinical improvement observed after just one dose of psilocybin. Unlike conventional psychiatric medications—which typically require daily administration over extended periods—psilocybin induced profound transformations in mood, anxiety, and existential well-being within hours that persisted for months. Approximately 75% of participants rated their psychedelic experience as one of the most meaningful and memorable of their lives, underscoring the depth of the intervention’s impact. These findings challenge prevailing paradigms in psychiatry by suggesting that a small number of psychedelic-assisted sessions may catalyze long-lasting changes in brain and mind.

Building on the success of cancer-related distress studies, Dr. Ross expanded his investigations into other difficult-to-treat psychiatric conditions. Notably, his 2022 JAMA Psychiatry-published clinical trial explored psilocybin-assisted psychotherapy for alcohol use disorder. This study revealed significant reductions in heavy drinking days following just two psilocybin sessions combined with psychotherapy, effects that persisted over an eight-month follow-up period. Such findings open promising avenues for addictions treatment, a notoriously challenging field where existing pharmacological and behavioral interventions often yield limited success rates.

The mechanisms underlying these sustained therapeutic effects remain an active area of inquiry. Neurobiological studies suggest that psychedelics like psilocybin modulate the brain’s default mode network (DMN)—a set of interconnected regions implicated in self-referential thought and rumination. Psilocybin appears to transiently disrupt rigid DMN activity, promoting neural plasticity and heightened emotional processing that may facilitate the psychological breakthroughs observed in therapy. Additionally, psychedelics induce profound alterations in consciousness, fostering experiences of ego dissolution, interconnectedness, and meaning that may underpin the rapid and enduring clinical benefits.

Dr. Ross’s research portfolio also includes recent work on major depressive disorder (MDD). As senior author of a phase 2 multi-center clinical trial published in JAMA in 2023, he reported that a single dose of psilocybin-assisted psychotherapy elicited rapid, clinically significant, and sustained reductions in depressive symptoms. These data reinforce the potential for psychedelic therapies to complement or even supplant traditional antidepressants, which often require weeks to months to yield partial relief and carry burdensome side effect profiles.

Currently, Dr. Ross is spearheading the largest NIH-funded clinical trial of psilocybin therapy aimed at alleviating emotional and spiritual distress in cancer patients. This landmark funding marks a pivotal moment in the field, representing the first major NIH grant awarded to psychedelic research in more than 50 years. The study seeks not only to replicate earlier promising findings but also to establish a regulatory foundation for integrating psilocybin therapy into mainstream oncological and palliative care settings.

Furthermore, Dr. Ross is pioneering explorations of psychedelic therapy’s applicability beyond psychiatric diagnoses, including potential uses in treating chronic pain and addressing fear of cancer recurrence in early-stage breast cancer patients. These expansions reflect a broader conceptual evolution, wherein psychedelics are not merely repositioned as mental health agents but as modulators of complex biopsychosocial suffering patterns that span psychiatry, oncology, and pain medicine.

Despite his groundbreaking advances, Dr. Ross acknowledges the professional challenges that accompanied his commitment to psychedelic research. When he embarked on this path, several mentors cautioned him that his focus on psychedelics could derail his career, labeling the area a “road to nowhere.” Nevertheless, his perseverance highlights the importance of intellectual courage and resilience in the face of entrenched scientific skepticism and regulatory hurdles.

The ongoing mainstreaming of psychedelic therapies poses significant implications for healthcare systems. Integration into cancer centers, addiction treatment facilities, and palliative programs would necessitate new clinical infrastructures, including specialized training for therapists, development of ethical guidelines, and frameworks to ensure patient safety and accessibility. Dr. Ross’s work not only advances the scientific basis of these therapies but also illuminates the systemic changes required to translate research discoveries into widespread clinical practice.

Stephen Ross’s contributions exemplify the reawakening of psychedelic medicine as a frontier in mental health and broader medical care. His work, blending clinical acumen, rigorous trials, and compassionate application, redefines the potential for psychedelics to address some of the most intractable psychiatric and medical conditions. As regulatory landscapes evolve and public acceptance grows, his research paves the way for a paradigm shift that could reshape psychiatry and oncology, bringing hope and healing through experiences “hidden in plain sight” for decades.

Subject of Research: People

Article Title: Stephen Ross: Psychedelic-assisted therapies for difficult-to-treat psychiatric and medical disorders

News Publication Date: 10-Jun-2025

Web References:
http://dx.doi.org/10.61373/pp025k.0017

Image Credits: Stephen Ross, MD

Keywords: Psychedelic medicine, psilocybin, psychiatric disorders, cancer-related distress, psychedelic-assisted psychotherapy, substance use disorder, major depressive disorder, neurobiology, default mode network, clinical trials, NIH-funded research, psychedelic therapy integration

Psychedelic substances have been shown to hold significant promise for treating a range of mental health disorders, including post-traumatic stress disorder (PTSD), depression, and anxiety, particularly in cases where traditional medications have failed. However, one persistent challenge has been the inconsistent results observed across clinical trials, which often arise because the therapeutic outcome is profoundly shaped by factors beyond the drug dose itself. Researchers have come to acknowledge that the "set and setting" — a person’s mindset, the environment, and the therapeutic context — are not merely background variables but central components that significantly influence the psychedelic experience’s trajectory and outcome.

In order to better capture and account for this complexity, a collaborative international study led by teams from McGill University, Imperial College London, and the University of Exeter convened a diverse panel of 89 experts from 17 different countries. Using a rigorous Delphi consensus methodology, the researchers engaged in multiple rounds of systematic discussion and feedback. This iterative process culminated in the formulation of the Reporting of Setting in Psychedelic Clinical Trials (ReSPCT) guidelines, which define a comprehensive 30-item checklist that specifies the psychosocial factors deemed most critical to report in psychedelic trials.

The publication of these guidelines, recently featured in the prestigious journal Nature Medicine, marks the first global consensus to formally document how researchers should evaluate and communicate the context in which psychedelics are administered. Unlike traditional pharmacological research, which typically strives to control for or eliminate environmental variables, the ReSPCT guidelines acknowledge that the psychedelic experience is intrinsically contextual. Variables such as the therapeutic setting’s physical attributes, the relational dynamics between therapist and patient, the participant’s expectations and mood, as well as ancillary elements like music and sensory stimuli must be systematically assessed to better understand treatment efficacy.

Co-lead author Chloé Pronovost-Morgan, affiliated with McGill University and Imperial College London, explained that two studies using the same psychedelic compound at identical dosages may yield wildly different outcomes if the surrounding context varies. This revelation challenges decades-old paradigms in psychopharmacology, demanding a more nuanced approach that integrates psychosocial variables as active components of the treatment rather than noise to be minimized. The ReSPCT checklist provides a practical tool to uniformly capture these complex variables, enabling more robust cross-study comparisons and meta-analyses.

Leor Roseman from the University of Exeter emphasized the transformative potential of these guidelines in the clinical research landscape. Unlike typical psychiatric medications, whose mechanisms and effects may be more pharmacologically straightforward, psychedelics operate through intricate interactions between neurobiology and subjective experience—a process deeply interwoven with the psychological and environmental setting. Establishing standardized criteria for reporting these contextual factors will therefore facilitate a clearer understanding of how and why these substances work, fostering reproducibility and confidence among the scientific and regulatory communities.

Beyond the laboratory, the absence of standardized reporting has tangible consequences for patients and public health policy. This became starkly evident when the U.S. Food and Drug Administration recently rejected approval for MDMA-assisted therapy for PTSD, citing inconsistent and incomplete data reporting as significant barriers. This regulatory setback underscored the pressing need for rigorous, universally accepted guidelines to elevate the level of evidence and build trust among approval bodies.

Kyle Greenway, Assistant Professor at McGill’s Division of Social and Transcultural Psychiatry and co-senior author, highlighted the broader implications for societal and clinical advancement. With an urgent demand for novel treatments for mental health conditions that have resisted conventional approaches, the ReSPCT guidelines represent a crucial bridge. By standardizing how researchers capture the therapeutic milieu, the work aims to unlock clearer pathways to delivering safe, effective psychedelic therapies to patients who desperately need them.

Complementing this effort, the research team plans to host an intensive three-day workshop in October, sponsored by McGill’s Healthy Brains, Healthy Lives initiative. This assembly of leading psychedelic scientists and neuroscientists will delve into practical strategies for integrating the guidelines into ongoing and future research, as well as explore how clinical protocols can evolve to align with these reporting standards. Such initiatives are expected to catalyze a more cohesive and transparent global psychedelic research community.

The importance of these guidelines cannot be overstated in the broader context of a rapidly shifting psychedelic research landscape, which straddles scientific innovation and regulatory scrutiny. For decades, the tendency has been to isolate pharmacological variables in controlled environments, yet psychedelic medicine demands a multidisciplinary and multi-dimensional approach. The ReSPCT consensus breaks new ground by marrying the rigors of clinical science with a deep appreciation of the human experience’s complexity inherent in psychedelic therapy.

As the psychedelic renaissance continues to expand, these guidelines offer a timely intervention to mitigate replication issues, improve trial design, and facilitate meta-analyses that offer generalized insights rather than fragmented case studies. They may also provide essential guidance for training clinicians and designing therapeutic environments optimized for efficacy and safety. This represents a maturation of the field, underscoring an emerging paradigm where context is not peripheral but central to psychedelic medicine.

Ultimately, the ReSPCT guidelines embody a critical shift toward evidence-based standardization that respects the unique characteristics of psychedelic treatment. By promoting transparency and comprehensive reporting of setting-related variables, this framework promises to accelerate the translation of promising research into tangible mental health solutions worldwide. As a new gold standard, it aims to unify a fragmented research landscape and pave the way for psychedelic therapies to fulfill their vast potential.

This progress offers hope not just for the scientific community but for millions suffering from mental illnesses that defy current treatments. By arming clinical investigators with tools to rigorously document what happens within the therapy room and beyond, the ReSPCT guidelines elevate the credibility and impact of psychedelic science. With continued collaboration and refinement, these advances signal the dawn of a new era in psychiatry—one where context and chemistry harmonize to unlock profound healing.

Subject of Research: People
Article Title: The Reporting of Setting in Psychedelic Clinical Trials (ReSPCT) Guidelines : An international Delphi consensus study
News Publication Date: 3-Jun-2025
Web References: https://respctguidelines.com/
References: Pronovost-Morgan, C., Greenway, K., Roseman, L. (2025). The Reporting of Setting in Psychedelic Clinical Trials (ReSPCT) Guidelines: An international Delphi consensus study. Nature Medicine. https://www.nature.com/articles/s41591-025-03685-9
Keywords: Clinical research, Psychedelic therapy, MDMA, Psilocybin, Mental health, PTSD, Psychiatry, Research guidelines