Psilocybin therapy involves more than the compound itself, and a new research initiative at the University of Southern California is investigating the effects of combining psilocybin with structured mental training.

A team from the Keck School of Medicine of USC, working with the USC Dornsife Brain and Creativity Institute and the USC Norris Comprehensive Cancer Center, has begun the university’s first clinical trial of psychedelic therapy. The study will examine whether structured mindfulness meditation can boost the effects of psilocybin, the active ingredient in psychedelic mushrooms, on mental well-being and cognitive performance.

Funding for the trial comes from ARPA-H’s EVIDENT initiative, a federal program designed to accelerate the development of rapid-acting treatments for mental and behavioral health conditions. The study will investigate whether adding mindfulness training to psilocybin-assisted therapy yields outcomes distinct from those of psilocybin-assisted therapy alone.

A Schedule 1 Drug With a Breakthrough Label

Although the Controlled Substances Act still classifies psilocybin as a Schedule I substance, the FDA has granted it a breakthrough therapy designation for major depressive disorder and treatment-resistant depression. In clinical settings, psilocybin has shown promise in treating these conditions, and other studies suggest it may also help with addiction.

Psilocybin alters a person’s perception, mood, and thought processes, and can influence how individuals experience their senses and their sense of time and space. With therapeutic support, people often report emotionally meaningful or spiritual experiences during these altered states.

Testing Whether Mental Training Changes the Outcome

About 72 middle-aged adults from the Los Angeles area will take part in the study. All participants will have no psychiatric or medical conditions and no previous experience with either psychedelics or meditation. Researchers will assign participants to one of two groups: one will receive supervised psilocybin alone, while the other will receive psilocybin alongside an eight-week mindfulness training program designed to build attention and focus through structured meditation.

The study is based on the hypothesis that mindfulness training, which has demonstrated mental and physical health benefits independently, may enhance the effects of psilocybin-assisted therapy when used together.

“Mindfulness meditation practice provides people with the tools to deconstruct unhelpful narratives, a process that may be amplified by psilocybin-assisted therapy,” said Rael Cahn, MD, PhD, director of the USC Center for Mindfulness Science and the study’s co-lead. The trial, he said, is meant to clarify how combining the two approaches “may enhance both the potential immediate and longer-term effects of psychedelic medicine.”

An Unusually Deep Data Set

The team will collect extensive biological, neurological, and psychological data from participants throughout the study. Participants will undergo EEG scans, brain MRI and fMRI imaging, and provide saliva, blood, and stool samples. Researchers will administer psychological and cognitive assessments before and after treatment and will survey participants again at three, six, and twelve months.

The team will use the data to track changes across psychological, cognitive, neurological, and biological measures, including well-being, spirituality, brain activity, and markers of inflammation and brain health. The open-label design means both participants and researchers are aware of group assignments, which allows for more comprehensive data collection at the expense of some blinding rigor.

Through the EVIDENT initiative, researchers will contribute anonymized trial results to a national repository. The resource will help researchers identify broader patterns in rapid-acting mental health treatments.

“Psilocybin-assisted therapy has the potential to revolutionize how we approach mental health research,” said Caryn Lerman, PhD, director of the USC Norris Comprehensive Cancer Center and the study’s other co-lead. Beyond addiction, she said, there’s growing evidence the treatment could improve “quality of life and emotional well-being for people facing serious illness and end-of-life challenges.”

A Test Case for the Next Wave of Psychedelic Medicine

If mindfulness training is shown to enhance the effects of psilocybin therapy, future protocols for psychedelic treatment may incorporate mental training as an additional component of treatment. Regardless of the outcome, the study will generate one of the most detailed biological and psychological datasets from a psilocybin trial to date.

Whether mindfulness ultimately amplifies psilocybin’s effects remains an open question. By tracking participants’ brains, biology, and psychological well-being over the course of a year, the USC team hopes to generate some of the clearest data yet on how mindset and psychedelic medicine interact.

Austin Burgess is a writer and researcher with a background in sales, marketing, and data analytics. He holds an MBA, a Bachelor of Science in Business Administration, and a data analytics certification. His work focuses on breaking scientific developments, with an emphasis on emerging biology, cognitive neuroscience, and archaeological discoveries.

Researchers may have stumbled on a completely unknown pathway.

In the literature related to the powerful entheogen dimethyltriptamine (DMT), it is often reported that individuals claim to have had encounters with what they perceived as non-human entities during their DMT experiences. Descriptions related to these powerful visionary experiences range from what some describe as insect-like forms and machine-like intelligences, to what some describe as conscious entities associated with intricate geometries.

For years, many researchers have regarded these reports purely as hallucinations generated by the human brain while under the influence of the psychedelic compound. However, past studies have never directly tested whether these reported entities could represent something other than internally generated hallucinations.

Now, a recent preprint paper outlines a path toward testing this assumption experimentally.

A collaborative team from the Trace Institute and the nonprofit Noonautics has released a preprint titled Traces of the Other –Are DMT Entities Real? DMT Phenomenology in the Framework of Conscious Realism. The study presents a mathematical framework for understanding the human psychedelic experience and outlines experiments designed to test its primary hypothesis.

The research was led by Professor Emeritus Donald Hoffman, founder of the Trace Institute, and Dr. Andrew Gallimore, a neurobiologist and pharmacologist at the Okinawa Institute of Science and Technology and head of Noonautics. The preprint is currently awaiting peer review.

A Problem With a Default Answer

According to some figures, as many as 45% of the individuals who take a sufficient dose of DMT report experiences involving non-human beings. People describe these entities as intelligent and autonomous, and report similar experiences across different cultures and backgrounds.

Typical hallucinations tend to draw on material from memory, such as familiar faces, animals, or places. By contrast, encounters with other humans appear in less than 5% of DMT encounters.

The authors of the new preprint study argue that these reports are difficult to reconcile with conventional accounts of pure hallucination and that the consistency of reports regardless of culture, location, belief systems, and other factors warrants deeper investigation. 

A Framework Built on Conscious Realism

The project draws on Hoffman’s theory of conscious realism, which proposes that interacting conscious agents fundamentally constitute reality. In this framework, the physical world as humans perceive it functions more like a user interface than a direct view of objective reality. According to this theory, conscious agents of varying levels of complexity may exist beyond what humans normally perceive and go unnoticed in everyday life.

The researchers propose that DMT changes the perceptual interface, allowing consciousness to access regions where normal perceptual constraints are absent. In these regions, it may be possible to detect traces of other conscious agents. Hoffman says the project “will provide a new framework for exploring the effects of psychoactive substances such as DMT on the structure and function of spacetime.”

The Protocol That Makes Testing Possible

Testing these ideas has become possible due to past work involving technical development by Gallimore and researcher Rick Strassman. Typically, a DMT experience lasts only three to five minutes, which is not long enough for structured experiments. The extended-state DMT protocol, called DMTx, uses a controlled intravenous infusion to maintain a stable experience for up to an hour, allowing researchers to adjust the dosage as required.

That controllable window makes experimentation possible. “With a theoretical foundation for the highly unusual state of consciousness induced by DMT, we can test these theories experimentally,” Gallimore says.

Experiments Built to Fail

The proposed experiments are designed so that if the external-agent hypothesis is incorrect, the results will be negative. In one protocol, a computer in a sealed room randomly displays either blue or yellow, and a subject under DMTx attempts to learn the hidden color by interacting with an entity. Another experiment involves two isolated subjects under DMTx who try to transmit a random word to each other through a shared entity, a process that would be difficult to explain solely in terms of internal brain mechanisms.

The researchers acknowledge several limitations. Cooperation from entities cannot be guaranteed, results depend on subjective reports, and expectation bias is difficult to rule out. The preprint continues to treat the hallucination model as the default explanation for these entities. What distinguishes this work is that the hypothesis is now formulated in a way that allows for experimental testing.

“This collaboration is a first step to a mathematics of altered states of consciousness and, ultimately, for engineering our perceptual interface to expand our view of reality,” Gallimore says.

Hoffman and Gallimore will discuss the research publicly on Saturday, June 13, 2026, at the Lighthouse Campus at the historic Venice Beach Post Office in Los Angeles, with video to follow on YouTube.

Austin Burgess is a writer and researcher with a background in sales, marketing, and data analytics. He holds an MBA, a Bachelor of Science in Business Administration, and a data analytics certification. His work focuses on breaking scientific developments, with an emphasis on emerging biology, cognitive neuroscience, and archaeological discoveries.