Arizona State University Investigates Psychedelic Therapy and Neuroplasticity for Mental Health Treatment
Standard treatments for depression and post-traumatic stress disorder (PTSD) leave a significant portion of patients without relief. Approximately 30% of people diagnosed with depression do not respond to first-line medications or therapy. For those suffering from PTSD, the non-response rates climb even higher, reaching up to 40% for medications and 50% for cognitive behavioral therapy. These statistics highlight a critical gap in mental health care across the USA. To address this unmet need, researchers are turning their attention to a class of compounds that were previously restricted by federal regulations. Arizona State University is now leading a major federally funded initiative to examine how psychedelic therapy can promote neuroplasticity and provide alternative pathways for mental health recovery.
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The Challenge of Treatment-Resistant Mental Health Conditions
When standard interventions fail, patients and clinicians are left with few clinically proven alternatives. Selective serotonin reuptake inhibitors (SSRIs) and traditional talk therapies remain the cornerstones of psychiatric care, but their limitations are well-documented. Treatment-resistant conditions often become chronic, leading to prolonged suffering, decreased quality of life, and increased healthcare costs. The biological mechanisms underlying these resistant conditions are complex, involving genetic predispositions, environmental factors, and deep-rooted neural pathways that do not readily respond to conventional pharmacology.
For decades, researchers suspected that mind-altering compounds could offer benefits where standard treatments failed. Substances such as MDMA, ketamine, and psilocybin showed early promise in clinical settings. However, the Controlled Substances Act of 1970 classified these compounds as having a high potential for abuse and no accepted medical use. This classification effectively halted mainstream research, confining studies to a small number of tightly controlled trials. Today, the landscape is shifting. Federal agencies are now funding multimillion-dollar efforts to explore these compounds, moving the field from preliminary safety checks into rigorous, data-driven scientific inquiry.
Understanding Psychoplastogens and Neuroplasticity
At the center of this new wave of research is the concept of neuroplasticity. Neuroplasticity refers to the brain’s ability to reorganize itself by forming new neural connections throughout life. In the context of mental health, impaired neuroplasticity is often associated with depression and trauma, where the brain becomes rigidly locked into negative thought patterns and stress responses.
The compounds being studied by Arizona State University researchers—including psilocybin, LSD, MDMA, and ketamine—are broadly defined as psychoplastogens. Despite belonging to different pharmacological classes, these substances share a critical commonality: they induce structural changes in neurons and synapses. Candace Lewis, the principal investigator on the project and an assistant professor with a dual appointment in the School of Life Sciences and the Department of Psychology, explains that these structural changes directly increase the biological mechanism of learning. Providing a brain with heightened neuroplasticity during a therapeutic experience creates an optimal window for patients to process trauma, alter destructive behaviors, and establish healthier cognitive patterns.
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The MONRA Project: A Multi-Omic Approach to Psychedelic Therapy
To systematically evaluate the efficacy and mechanisms of psychedelic therapy, the Advanced Research Projects Agency for Health (ARPA-H) has awarded a $4 million grant to Arizona State University. The funding supports the Multi-Omic Neuroplastogen Response Atlas, or MONRA. This project represents a significant methodological advancement in psychiatric research. Instead of relying solely on self-reported patient surveys or basic clinical observations, the MONRA project integrates biological and behavioral data collected from multiple clinical trials involving psychoplastogens.
The goal of the MONRA dataset is to build predictive models that can accurately identify which patients are most likely to benefit from specific treatments, which individuals might be at risk for adverse effects, and how long the therapeutic effects will last. This move toward precision psychiatry is essential for the safe integration of psychedelic therapy into mainstream medical practice across the USA.
Integrating Genomics, Epigenomics, and Proteomics
Build a comprehensive biological profile requires looking at the body from multiple molecular perspectives. The ASU team is integrating several layers of biological measurements into ongoing clinical trials conducted with partners such as the U.S. Department of Veterans Affairs, Definium Therapeutics, and Sunstone Therapies.
Genomics provides a baseline by examining the inherited genes that influence how an individual metabolizes certain compounds and regulates mood. Epigenomics adds a dynamic layer, examining how life experiences influence gene activity. Lewis describes epigenomics as a dynamic molecular map of what a body has been through, shaped by stress, trauma, nutrition, and other environmental factors. By understanding a patient’s epigenomic profile, researchers can see how trauma has physically altered gene expression over time. Finally, proteomics measures the proteins circulating through the body, offering a real-time snapshot of cellular processes and inflammation. Combining these three omic layers allows researchers to identify distinct biological signatures that correlate with therapeutic success or failure.
Artificial Intelligence and Speech Analysis in Mental Health
Biological data alone does not paint the complete picture of a patient’s mental state. The MONRA project also incorporates advanced artificial intelligence and multimodal machine learning to analyze behavioral data. Visar Berisha, associate dean of research and commercialization, and Asif Salekin, an assistant professor, both from the Ira A. Fulton Schools of Engineering, are leading the AI integration.
A particularly innovative aspect of this research is the use of digital speech biomarkers, spearheaded by Julie Liss, vice dean and professor in the College of Health Solutions. Speech is a complex motor and cognitive function that is highly sensitive to changes in mental health. Machine learning algorithms can identify subtle, imperceptible patterns in language—such as changes in lexical diversity, pause duration, pitch variability, and syntax complexity. These acoustic and linguistic markers can reveal changes in cognitive load, emotional state, and psychological resilience that a patient or clinician might not consciously notice. By correlating speech analysis data with multi-omic profiles, the ASU team is creating a highly nuanced, multimodal dataset.
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Building Predictive Models for Personalized Care
The ultimate objective of synthesizing these massive datasets is to develop predictive models that bring personalized medicine to psychiatry. Currently, prescribing psychiatric medication often involves a trial-and-error process. A patient may try multiple medications over several months before finding one that works, all while enduring side effects and continued suffering. Psychedelic therapy carries its own risks and requires significant clinical resources, making the trial-and-error approach unsustainable and potentially unsafe.
By analyzing the genomic, epigenomic, proteomic, and behavioral data collected through MONRA, researchers hope to establish clear parameters for treatment matching. Lewis notes that with sufficient data, clinicians could eventually analyze a patient’s genetics and epigenetics to determine if they are an ideal candidate for a specific compound like psilocybin, or if another substance like MDMA might yield better results. This level of precision would minimize risks, optimize therapeutic outcomes, and drastically reduce the time patients spend searching for effective relief.
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Federal Support and the Future of Mental Health Research in the USA
The ARPA-H award signals a broader institutional shift in how the USA approaches psychedelic science. Early clinical trials in this field focused primarily on demonstrating basic safety and efficacy to satisfy the U.S. Food and Drug Administration. As federal interest and funding have expanded, the scientific community can now interrogate deeper, more complex questions about why these treatments work on a biological level.
Dr. Holly Lisanby, founding dean of the John Shufeldt School of Medicine and Medical Engineering and a co-investigator on the project, emphasizes that this collaborative effort represents ASU at its best. Bringing together expertise from neuroscience, psychiatry, engineering, artificial intelligence, genomics, and clinical translational research breaks down traditional academic silos. This convergence of medicine and engineering is increasingly viewed as the future of healthcare innovation.
As the MONRA project progresses over the coming years, its findings will likely influence clinical trial designs, regulatory frameworks, and eventual treatment protocols for psychedelic therapy. For the millions of individuals in the USA living with treatment-resistant depression and PTSD, this research offers a concrete foundation for future therapies that address the root biological and cognitive mechanisms of their conditions.
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