Sonnenberg Breaks Down EMERGE Phase 3 Trial Design for DT120 in MDD

John Sonnenberg, PhD, clinical psychologist, founder of the Uptown Research Institute, and faculty at Northwestern University Feinberg School of Medicine, sat down with HCPLive to walk through the design of EMERGE, a phase 3 trial evaluating DT120 (lysergide) ODT 100 µg in adults with major depressive disorder (MDD). The conversation took place before phase 3 topline data were announced; those results are now public, and Sonnenberg has since spoken with HCPLive about them directly.¹ ²

EMERGE, a multicenter, randomized, double-blind, placebo-controlled trial, enrolled 149 adults with DSM-5-confirmed MDD across 20 sites and met its primary endpoint, with a placebo-adjusted MADRS reduction of 8.1 points at week 6 (P <.0001) that was sustained through week 12.¹ The trial also produced a 24% remission rate at week 6, compared with 3% for placebo, and was generally well tolerated, with no serious adverse events or suicidality signals identified.¹

In this Q&A, Sonnenberg details the patient population and inclusion-exclusion criteria, the screening process, what happens during and after a dosing session, and how outcomes were tracked through the 12-week primary endpoint and into the open-label extension—the design choices that ultimately produced the results above.

Addressing Clinician Skepticism About Psychedelic Medicine

HCPLive: What would you want a clinician who's skeptical of psychedelic medicine to understand about where the science actually stands right now?

Sonnenberg: This is being studied as rigorously and as critically as any other psychiatric medication I have ever studied for any indication, whether it's anxiety, depression, bipolar, schizophrenia, [or] PTSD.

The scientists have recognized that there is something special about psychedelics, as opposed to other classes of medications. The pharmaceutical companies I am working with across the board are approaching this as scientists ought to: dispelling the null hypothesis, putting safety signals first, and ensuring that there's a true clinical need being addressed, not just another me-too opportunity.

There's one other thing clinicians might be intrigued by, because I am. Patients who have been exposed to the pharmaceutical-grade LSD we're testing in the Definium studies have shown a pattern where their symptoms have decreased, which isn't unheard of in clinical trials for depression. What I'm seeing that I don't see in other treatments is that patients have a different relationship to the symptoms they have.

The patients may say, "Yeah, I don't sleep well. Yeah, my stomach rumbles. Yeah, I'm just not as bothered by it anymore." So much of psychiatry is focused on this idea that we have to quash the symptoms.

There is this emphasis on trying to regain a stable equilibrium, and I think psychedelics, if they live up to half their promise, will be particularly helpful in letting people feel comfortable with themselves wherever they are on the spectrum from happy to anxious while at the same time allowing them to conquer and quell some of their symptoms. That's fundamentally different from the treatment armament clinicians have at this time.

Phase 3 EMERGE for MDD: Trial Design

HCPLive: Can you walk us through the EMERGE trial design? Specifically, what patient population is being enrolled and what the key inclusion and exclusion criteria are?

Sonnenberg: The 310 study came down to this: these are depressed adults who don't have other primary psychiatric conditions, and they are not treatment-resistant. They have a [current] depressive episode…which doesn't mean they've had a successful treatment in the past; it just means they've had a failed treatment. Their current episode has to be between 2 weeks and 2 years, which is standard inclusion-exclusion criteria for this type of trial.

The one thing that might differ from other standard phase 3 psychiatric depression trials is [that] some other studies have a lower age cutoff, because there are more safety concerns with some of the other medications out there, interestingly enough. The other difference is that we don't want people who've had significant exposure to psychedelics, because they're going to have bias, and we don't want people going in with assumptions about what the experience should or shouldn't be like. While we didn't exclude [people with past psychedelic exposure], [that population] was capped.

EMERGE Screening Process

HCPLive: What does the screening process look like for a patient before they're enrolled?

Sonnenberg: It was very much like another typical psychiatric depression trial. There was about a 30-day screening period, [during which] the patient was evaluated by central raters who worked independently of the site and weren't privy to where the patient was in the site process.

A third party [then] does an independent review to make sure the patient doesn't have a history of treatment resistance or some other hidden psychopathology that would be exclusionary and would muck up the data. Once a patient is identified as appropriate for the study…there's blood work, EKGs, and all the medical parameters done as per FDA [requirements and safety needs].

After about a month of screening, if the patient remains eligible, we do a final [check] to see whether the patient's depression has gone away. If the symptoms are still there and the patient continues to meet criteria, they're then paired with a DSM. This is the dosing session monitor.

EMERGE Dosing Session

HCPLive: What happens on dosing day itself, and what kind of monitoring is built into that visit?

Sonnenberg: There's 2 [DSMs]. One is in the room with the patient at all times, and the other is a backup who can observe from somewhere else in a building through closed caption. A baby monitor is actually what we use.

The patient has the dosing session, [then] comes back the next day. Typically, I meet with them at that time to go over any adverse events and do a general assessment of their well-being, and they also meet with the DSM to process the experience.

They're not there to process symptoms; they're there to process the experience, which could be: “Boy, that was the longest 8 hours.”

EMERGE Primary Endpoint Assessment

HCPLive: How are outcomes measured over the course of the study, and what happens once the primary endpoint window closes?

Sonnenberg: [Patients] come back once a week. I meet with them to make sure they're not having residual symptoms, either from the dosing day or from a change in their depression that would require me or a member of my staff to address.

They [also] have weekly assessments done through independent raters, [who administer the MADRS]. That's done through week 12.

The patient then rolls over into an open-label extension, [which] is their choice, and I also have a say if I don't think it's appropriate for them. In the open-label extension, they come in for assessments and also [complete] some assessments through a phone app. If any of those scores reach a certain level, they come in for an additional assessment through the third-party vendor rater…[who] doesn't know where [the patient is] in the study.

Depending on that score, the patient would then be eligible for redosing. One of the things we've been able to do in the phase 3 studies is examine the process of subsequent dosing over the course of a year, which will help us understand how this medication [should] be used in the clinic setting.

Editor’s note: Reported disclosure for Sonnenberg includes Bristol Myers Squibb Company.

References

1. Definium Therapeutics. Definium Therapeutics. Published June 22, 2026. Accessed June 23, 2026. https://ir.definiumtx.com/news-events/press-releases/detail/232/definium-therapeutics-announces-positive-topline-results-from-phase-3-emerge-study-of-dt120-orally-disintegrating-tablet-odt-in-major-depressive-disorder

2. Sonnenberg J. Emerge Phase 3: DT120 Shows Rapid, Durable Relief in MDD. HCPLive. June 23, 2026. https://www.hcplive.com/view/emerge-phase-3-dt120-rapid-durable-relief-mdd. Accessed July 20, 2026.