DMT Shows Promising Results in Phase II Depression Trial, Offering Shorter Alternative to Traditional Psychedelic Therapy

A synthetic form of dimethyltryptamine—the psychoactive compound found in the Amazonian ceremonial brew ayahuasca—has demonstrated meaningful antidepressant effects in a small but carefully designed clinical trial, adding to the growing body of evidence that psychedelic-assisted therapy may offer new pathways for treating depression.

The phase II study, published February 25 in Nature Medicine, tracked 34 participants over two weeks after receiving either a single intravenous dose of DMT or placebo, all accompanied by structured psychotherapeutic support. Those who received the active compound showed significantly greater reductions in depressive symptoms compared to the placebo group, with the therapeutic effects persisting beyond the drug's immediate 30-minute experiential window.

The research, led by Dr. David Erritzoe at Imperial College London's Centre for Psychedelic Research and sponsored by the pharmaceutical company Small Pharma (now Cybin UK), represents one of the first controlled trials to isolate DMT's therapeutic potential outside its traditional ceremonial context.

A Condensed Psychedelic Experience

Unlike ayahuasca ceremonies that can last hours and often induce nausea and vomiting, the DMT formulation used in this trial produces an intense but brief psychedelic state lasting approximately 30 minutes when administered intravenously. Participants described profound perceptual shifts, emotional processing, and introspective experiences compressed into this window—followed by a relatively rapid return to baseline consciousness.

This shorter timeline distinguishes DMT from other psychedelics currently in clinical development. Psilocybin sessions typically last four to six hours, while MDMA-assisted therapy involves three eight-hour sessions spread over weeks. The condensed DMT experience could potentially make psychedelic therapy more practical and accessible, though researchers emphasize that brevity alone doesn't necessarily mean superiority.

"There's still more to do, but it's promising," said Tommaso Barba, a PhD candidate at Imperial College London and one of the study's authors. He cautioned that while the results are encouraging, the trial was small and preliminary—a Phase II study designed primarily to test feasibility and gather initial efficacy signals rather than provide definitive proof of effectiveness.

The trial enrolled 17 participants who received DMT and 17 who received placebo. All participants had moderate to severe depression and had not responded adequately to at least one previous antidepressant medication. Beyond the drug or placebo injection itself, every participant received identical psychotherapeutic support: preparatory sessions before the dosing day to establish trust and set expectations, continuous therapeutic presence during the psychedelic experience, and integration sessions afterward to help process insights and translate them into behavioral or cognitive changes.

This therapeutic framework reflects an emerging consensus among psychedelic researchers: these compounds are not standalone treatments but catalysts that require skilled psychological support to maximize benefit and minimize risk.

The Role of Therapy in Psychedelic Treatment

Barba emphasized that the improvements participants experienced came not from DMT alone but from the intersection of the psychedelic experience and ongoing therapeutic work. The drug, he explained, can act as a psychological catalyst—helping people recognize patterns, access difficult emotions, or see their circumstances from new perspectives—but lasting change requires sustained effort.

"It can act as a catalyst," Barba said, "because it can help people understand changes they need to make in their mentality or in their life." He noted that improvement often stems from both the DMT session and "capacity to make uncomfortable decisions over time."

For example, if a DMT-assisted therapy session helps someone realize their job is contributing significantly to their depression, the insight alone won't resolve the problem. Actually changing jobs—or setting boundaries, seeking different roles, or addressing workplace dynamics—requires subsequent action that happens outside the psychedelic experience itself.

This mirrors the traditional ayahuasca context, where the psychedelic brew is embedded within broader ceremonial structures, community support, and spiritual frameworks that help participants make meaning of their experiences. While the clinical trial replaced shamanic ritual with contemporary psychotherapy, the underlying principle remains: psychedelics open doors, but people must choose to walk through them.

From Ceremonial Practice to Clinical Setting

DMT occurs naturally in various plants and is traditionally consumed as part of ayahuasca, a tea brewed from plants that contain both DMT and monoamine oxidase inhibitors (MAOIs). The MAOIs prevent the body from rapidly breaking down DMT, extending its effects and allowing it to be orally active. Traditional ayahuasca ceremonies can last several hours and often involve purging—vomiting that some practitioners view as spiritually and emotionally cathartic.

The synthetic DMT used in this trial bypasses the digestive system entirely through intravenous administration, avoiding the nausea while producing a more concentrated experiential arc. Whether something therapeutically valuable is lost by removing the purging component remains an open question.

Dr. Daniel Perkins, a senior research fellow at the University of Melbourne's Psychedelics Research and Therapeutics Unit, noted that while some people report psychological benefit from the vomiting experience during ayahuasca ceremonies—particularly when it coincides with processing trauma—research hasn't found significant overall outcome differences between those who purge and those who don't.

"In our research, people do report that vomiting can have quite psychologically, emotionally cathartic effects," Perkins explained. However, "we couldn't really see that it made that much difference between people who'd reported vomiting versus people that it hadn't" when looking at therapeutic outcomes.

This suggests that while the purging may enhance the subjective experience for some individuals, the core therapeutic mechanisms may lie elsewhere—perhaps in DMT's neurobiological effects, the introspective state it produces, or the interaction between these factors and therapeutic support.

The Broader Psychedelic Therapy Landscape

The DMT trial adds to an expanding portfolio of research investigating psychedelics for mental health conditions. The U.S. Food and Drug Administration approved Spravato (esketamine) in 2019, a ketamine-derived nasal spray for treatment-resistant depression that represented the first psychedelic-adjacent therapy to receive regulatory approval.

Psilocybin, the psychoactive component in "magic mushrooms," has advanced to Phase III trials for major depressive disorder and treatment-resistant depression, with companies like Compass Pathways leading large-scale studies. The FDA granted psilocybin "breakthrough therapy" designation in 2018 for its potential in treating depression, a status intended to expedite development and review.

MDMA-assisted therapy for post-traumatic stress disorder appeared poised for approval in 2024, but the FDA declined to approve the application from Lykos Therapeutics, citing concerns about trial design, data reliability, and ethical issues related to therapist-patient boundaries during treatment. That setback highlighted both the promise and challenges facing psychedelic therapy development.

Perkins noted that DMT and psilocybin may have advantages over MDMA for certain applications. Research suggests these classic psychedelics can provide therapeutic benefits even outside formal clinical settings—naturalistic use studies have found associations between psilocybin use and improvements in well-being and mental health. In contrast, recreational MDMA use doesn't show similar evidence of inherent mental health benefits.

Additionally, MDMA's tendency to increase feelings of emotional closeness and physical touch can create ethical complications in therapeutic settings, potentially blurring professional boundaries between patients and therapists. DMT and psilocybin don't produce similar effects, which may make them safer choices for psychedelic-assisted therapy protocols.

Regulatory and Practical Challenges Ahead

Despite promising research findings, significant hurdles remain before DMT therapy—or any psychedelic-assisted treatment—becomes widely available. The FDA regulates drugs, not therapies, which creates inherent tension for treatments where the therapeutic protocol is arguably as important as the compound itself.

Pharmaceutical companies face financial pressure to simplify treatment protocols to make them more scalable and profitable. The DMT therapy tested in this trial requires intravenous administration in a clinical setting with trained therapists present for several hours—a model far more resource-intensive than dispensing pills or even administering a nasal spray like Spravato.

Whether insurance companies will cover multi-hour therapeutic sessions, how many therapists can be trained to provide this specialized care, and whether the treatment can be delivered equitably across different socioeconomic groups remain open questions. There's also the simple reality that not everyone wants an intense, potentially uncomfortable psychedelic experience, regardless of its therapeutic potential.

The Phase II trial published in Nature used carefully screened participants who underwent medical and psychiatric evaluation to rule out contraindications. They were prepared for what to expect, consented to a challenging experience, and received extensive support. Translating this model to routine clinical practice—where patient populations are more diverse, resources more limited, and quality control harder to maintain—will require solving substantial logistical and regulatory problems.

Not a Quick Fix

One important nuance that quantitative data struggles to capture, Barba noted, is that DMT should not be understood as a rapid solution to depression in the way an antidepressant pill might be conceptualized. The psychedelic experience can catalyze insight and shift perspective, but the therapeutic benefit unfolds over time through continued psychological work and life changes.

This aligns with what many clinicians and researchers in the field emphasize: psychedelics are tools, not cures. They can disrupt entrenched patterns of thought and emotion, create opportunities for new understanding, and reduce the psychological rigidity that characterizes many mental health conditions. But whether those opportunities translate into lasting wellbeing depends on what happens in the days, weeks, and months after the psychedelic session.

Some participants in psychedelic trials report immediate relief that gradually fades. Others describe delayed effects that emerge as they integrate insights over time. Many note that the experience prompted difficult realizations about relationships, careers, or life choices that required uncomfortable action to address. The drug opens a door; whether therapeutic benefit follows depends on whether someone walks through it—and what they find on the other side.

What Comes Next

Before DMT therapy can progress toward potential FDA approval, larger Phase III trials will need to demonstrate consistent efficacy across diverse populations, establish optimal dosing protocols, clarify which patient populations benefit most, and identify safety concerns that might emerge with broader use.

Researchers will also need to better understand DMT's mechanisms of action. Does it work primarily through immediate neurobiological effects on serotonin receptors and neural plasticity? Do the subjective psychedelic experiences themselves—the visions, emotional breakthroughs, and shifts in consciousness—contribute independently to therapeutic benefit? Or is the effect entirely dependent on the interaction between the drug and the therapeutic relationship?

These questions have practical implications. If the psychedelic experience itself is essential to the therapeutic effect, simplified protocols or attempts to minimize the experiential component could undermine efficacy. If the drug's neurobiological effects are what matter most, future developments might focus on compounds that produce similar brain changes with less intense subjective effects.

For now, the Phase II results published in Nature add one more data point suggesting that psychedelic-assisted therapy deserves serious scientific investigation as a potential treatment for depression—a condition that affects hundreds of millions of people worldwide and for which current treatments often provide insufficient relief.

The path from promising Phase II data to approved therapy remains long and uncertain. But for the field of psychedelic research, gradually rebuilding credibility through careful, well-designed studies after decades of regulatory prohibition, each successful trial represents meaningful progress.