Steve Levine, MD

COMP360 Psilocybin Shows Rapid, Durable Effect in TRD, With Steve Levine, MD

Following positive topline results from the phase 3 COMP006 trial, 

 spoke with Steve Levine, MD, chief patient officer of Compass Pathways, to contextualize the clinical relevance of COMP360 (synthetic psilocybin) for treatment-resistant 

“One of the most striking things about the data we've just presented from our 05 and 06 studies is the rapidity of onset,” Levine told 

. “In both cases, we were able to detect a clinically and statistically significant difference in MADRS reduction as of day 2, which is the first day after administration of COMP360. That is a rapidity of effect that we've never seen before.”

Levine said the rapid onset may reflect acute, network-level effects mediated through 5-HT2A receptor agonism. He noted that this mechanism appears distinct from those underlying currently available treatments for TRD.

In COMP006, two 25-mg doses of COMP360 administered 3 weeks apart demonstrated a –3.8-point least squares mean difference in Montgomery-Åsberg Depression Rating Scale (MADRS) score at week 6 compared with a 1-mg control (

 <.001). According to Levine, a 3-point MADRS difference is generally considered clinically meaningful in TRD, placing the 3.8-point separation above the accepted threshold for relevance.

He noted that the magnitude of effect is comparable to that observed in pivotal trials of esketamine (Spravato), currently the only FDA-approved medication specifically indicated for TRD. However, whereas esketamine’s approximately 4-point treatment difference was achieved after multiple administrations over 4 weeks, COMP360 demonstrated a similar effect size 6 weeks after a single administration in COMP005 and after 2 administrations in COMP006.

In Part B of COMP005, participants who achieved ≥ 25% reduction in MADRS at week 6 and received a second treatment demonstrated sustained benefit through week 26. Among those with an initial clinically meaningful response who underwent re-treatment, approximately 40% achieved remission. These findings suggest that 1 or 2 administrations may support symptom improvement lasting up to 6 months in responders.

Furthermore, in COMP005, 25% of participants receiving 25 mg achieved a ≥ 25% MADRS reduction versus placebo. In COMP006, 39% reached this threshold after a second administration.

“This is a level of improvement that is very likely to translate into really meaningful benefit for patients, particularly those who have treatment-resistant depression,” Levine said. “Even modest decreases in symptoms can have an outsized impact on the course of their care and the quality of their life.”

A relevant disclosure for Levine includes Janssen Pharmaceuticals, Inc.

Compass Pathways Successfully Achieves Primary Endpoint in Second Phase 3 Trial Evaluating COMP360 Psilocybin for Treatment-Resistant Depression. Compass Pathways. Published on February 17, 2026. Accessed on February 19, 2026. 

https://ir.compasspathways.com/News--Events-/news/news-details/2026/Compass-Pathways-Successfully-Achieves-Primary-Endpoint-in-Second-Phase-3-Trial-Evaluating-COMP360-Psilocybin-for-Treatment-Resistant-Depression/default.aspx

Derman C. COMP360 Psilocybin Meets Primary Endpoint in Second Phase 3 Trial for TRD. HCPLive. Published on February 19, 2026. Accessed on February 20, 2026. 

https://www.hcplive.com/view/comp360-psilocybin-meets-primary-endpoint-second-phase-3-trial-trd

Videos

Levine breaks down Compass Pathways’ phase 3 data on COMP360, highlighting next-day onset and sustained symptom improvement through 26 weeks.

Medical Ethics Unpacked: Organ Donations

the story of a surgeon taking the organs out of Misty Hawkins, who was believed to be dead. She was not. After a surgeon made an incision in the 42-year-old’s chest and sawed through her breastbone, he discovered her beating heart.

Although Hawkins was an extreme case, many surgeons rush to get donor donations, leading to rash decision-making. Several donations come from people who are considered circulatory dead—currently alive, but on life support; doctors deem these patients near death. With circulatory death donations, a doctor can withdraw life support if the relatives agree. Once the person is declared dead, surgeons can take the organs.

, Arthur Caplan, PhD, the founding head of the Division of Medical Ethics at NYU Grossman School of Medicine, joins Dominic Sisti, PhD, from Penn Medicine, and Steve Levine, MD, from COMPASS Pathways, to discuss definitions of brain death, cardiac death, and the ethics surrounding organ transplantations. When are organ transplants ethical?

“People wonder whether we have the right criteria for brain death. Do we know what we're doing? I don't worry about that,” Caplan said. “I think we have very good definitions: totally reversible loss of brain function, no response when you try to breathe on your own.”

Brain death is determined via an apnea test. When people get off the machine and are still not breathing, still have no reflexes, this confirms brain death.

“We know what brain death is,” Caplan continued. “If you’re well-trained, you know what to do.”

What we do not necessarily know is the definition of cardiac death.

“If I wander around the NYU hospital and go floor to floor, and somebody said to me, 'How long do you wait after the heart stops before you declare somebody dead?’ If it's me, an ancient person of maybe less popularity to my colleagues for yelling at them all day long about ethics issues, maybe about 30 seconds,” Caplan said. “If it's a teenager who was just getting into the prime of life, you might try to resuscitate them 6 times, 7 times. If it's a 90-year-old with many comorbidities, and they've already had a resuscitation, you're going to call cardiac death relatively quickly.”

No proper definition of cardiac death creates problems for donations. Some places may wait 2 minutes to see if the heart does anything, while other places may wait 4 minutes.

Caplan added, “Now people are saying, ‘Hey, I think if you froze the body, or cooled the body down and maybe put the heart on a side pump just to keep it oxygenated, you're still dead, because we've called you both cardiac death and brain dead.’ But somebody else is saying, ‘Well, wait a minute, if you got the machine going and the heart is perfused and it's still pumping, then why did you think they were dead?’ The heart still works. And just to make things completely crazy, well, of course, the heart still works. That's why you're going to transplant it.”

Rosenthal BM, Tate J. A Push for More Organ Transplants Is Putting Donors at Risk. 

. https://www.nytimes.com/2025/07/20/us/organ-transplants-donors-alive.html. Published July 20, 2025.

In this episode, Dominic Sisti and Steve Levine discuss dilemmas surrounding donor transplants, brain death, and cardiac death in organ donations.

Medical Ethics Unpacked: Ethical Issues in Organ Transplantation

 Q1/Q2 Psychiatry Updates, with Steve Levine, MD

With the first quarter of the year coming to an end, 

spoke with Steve Levine, MD, from Compass Pathways, for a brief recap of developments in 

 this year and a look ahead at what is coming in quarter 2.

Levine said aside from psychedelics, the pipeline is relatively dry, with several cases of failures and discontinuations. Looking ahead to quarter 2, topline results for several treatments in treatment-resistant depression are expected to be announced.

“Because there are multiple data readouts coming up...clinicians should just be paying attention and reading these studies in detail—or at least to the extent that you know it may be sort of top line results, press release, as opposed to published peer review data,” Levine said.

J&J’s Monotherapy Indication for SPRAVATO

The US Food and Drug Administration (FDA) approved esketamine (SPRAVATO) CIII nasal spray as the first monotherapy for adults with treatment-resistant depression (TRD), announced by Johnson & Johnson on January 21, 2025. The approval of this supplemental new drug application (NDA) was based on a phase 4 randomized, double-blind, multicenter, placebo-controlled study which found esketamine brought a rapid and superior improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at 4 weeks compared with placebo; 22.5% on esketamine vs 7.6% on placebo reached remission (MADRS ≤ 12) at week 4.

Otsuka and Lundbeck’s NDA for Brexpiprazole 

The FDA accepted the sNDA for brexpiprazole alongside sertraline to treat adult PTSD, Otsuka and Lundbeck announced in June 2024. Since then, a phase 3 trial showed brexpiprazole with sertraline significantly reduced PTSD symptoms in 10 days, and Otsuka announced FDA announced plans to host an advisory committee meeting to discuss this decision. The FDA has yet to set a meeting date, but it is anticipated to occur during the first half of 2025. This has pushed back brexpiprazole with sertraline’s original PDUFA target date of February 8, 2025.

Neumora’s Kappa Opioid Receptor, Navacaprant 

Neumora’s kappa opioid antagonist, navacaprant, failed to show efficacy in the phase 3 KOASTAL-1 trial for major depressive disorder. Navacaprant demonstrated no significant difference from placebo in reducing depressive symptoms after 6 weeks of treatment and even led the company’s shares to drop by > 80%.

Discontinued VENTURA Program on Anticaprant for MDD

J&J decided to discontinue their phase 3 VENTURA program after the kappa opioid receptor anticaprant failed to show significant improvements in MDD. However, the company said aticaprant could have potential in other therapeutic areas.

Transcend Therapeutics announced on March 31, 2025, that methylone (TSND-201) signficantly improved PTSD symptoms in the phase 2 IMPACT-1 trial, thus meeting its primary endpoint of significant change from baseline to day 64 in the Clinician-Administered PTSD Scale for DSM05 (CAPS-5) score. This randomized, double-blind, placebo-controlled trial demonstrated patients on methylone had an average CAPS-5 improvement of – 9.64 points on day 64 compared with placebo (-23.28 points vs -13.64 points; P = .0011), with improvement evident on day 10.

COMP360 for Treatment-Resistant Depression

Levine said Compass Pathways will be reporting topline primary endpoint data on COMP360 psilocybin treatment for treatment-resistant depression during the second quarter. The company’s phase 2b trial, conducted across 22 sites in 10 countries across Europe and North America, assessed the safety and efficacy of COMP360 in 3 doses: 1 mg, 10 mg, and 25 mg. Previous findings demonstrated that a single 25 mg dose of COMP360, in combination with psychological support, was linked to a significantly greater reduction in depressive symptoms after 3 weeks (P < .001), with a rapid, durable response for 12 weeks.

Beckley Psytech’s Intranasal 5-MeO-DMT for Treatment-Resistant Depression 

Beckley Psytech, developing a novel formulation of intranasal 5-MeO-DMT for treatment-resistant depression, also anticipates announcing topline results in the second quarter.

Last year, the company announced positive initial data from their open-label phase 2a study of 5-MeO-DMT formulation BPL-003 for treatment-resistant depression, finding that a single dose provides a rapid antidepressant response in 55% of patients the day after dosing. More than half (55%) achieved remission from depression at day 29 and 45% at day 85.

Derman, C. FDA Approves Esketamine as First Monotherapy for Treatment-Resistant Depression. HCPLive. January 21, 2025. 

https://www.hcplive.com/view/fda-approves-esketamine-first-monotherapy-treatment-resistant-depression

Derman, C. Brexpiprazole with Sertraline Significantly Reduces PTSD Symptoms in 10 Days. HCPLive. December 19, 2024. 

https://www.hcplive.com/view/brexpiprazole-sertraline-significantly-reduces-ptsd-symptoms-10-days

Derman, C. FDA Accepts sNDA for Brexpiprazole in Combination with Sertraline for Adult PTSD. HCPLive. June 25, 2025. 

https://www.hcplive.com/view/fda-accepts-snda-for-brexpiprazole-in-combination-with-sertraline-for-adult-ptsd

Otsuka Announces FDA Plans to Host an Advisory Committee Meeting to Discuss the sNDA for Brexpiprazole in Combination with Sertraline for the Treatment of Adults with Post-Traumatic Stress Disorder (PTSD). Otsuka. January 10, 2025. 

https://www.otsuka-us.com/news/otsuka-announces-fda-plans-host-advisory-committee-meeting-discuss-snda-brexpiprazole

Derman, C. Phase 3 KOASTAL-1 Trial Fails to Show Navacaprant Significantly Improves MDD. HCPLive. January 2, 2025. 

https://www.hcplive.com/view/phase-3-koastal-1-trial-fails-show-navacaprant-significantly-improves-mdd

J&J Axes Late-Stage Depression Trial After Underwhelming Efficacy. BioSpace. March 7, 2025. 

https://www.biospace.com/drug-development/j-j-axes-late-stage-depression-trial-after-underwhelming-efficacy

Derman, C. Methylone Shows Rapid PTSD Symptom Improvement in Phase 2 IMPACT-1 Trial. HCPLive. March 31, 2025. 

https://www.hcplive.com/view/methylone-shows-rapid-ptsd-symptom-improvement-in-phase-2-impact-1-trial

https://compasspathways.com/our-work/comp360-psilocybin-treatment-in-trd/

Beckley Psytech announces positive initial data from Phase IIa study of novel 5-MeO-DMT formulation BPL-003 for Treatment Resistant Depression. Beckley Psytech. March 26, 2024. 

https://www.beckleypsytech.com/posts/beckley-psytech-announces-positive-initial-data-from-phase-iia-study-of-bpl-003-for-treatment-resistant-depression

Articles

The first quarter of 2025 in psychiatry saw significant developments, including the FDA's approval of esketamine as a monotherapy for treatment-resistant depression and promising results for brexpiprazole with sertraline in PTSD. However, some trials, like Neumora's navacaprant, failed to show efficacy. Looking ahead, the second quarter anticipates key data releases for treatment-resistant depression, including Compass Pathways' COMP360 psilocybin and Beckley Psytech's intranasal 5-MeO-DMT. These upcoming results could influence future treatment strategies and clinical practices in psychiatry.

HCPLive spoke with Levine about what is moving in the psychiatry pipeline and what is to come.

Q1 and Q2 Psychiatry Updates, with Steve Levine, MD

Medical Ethics Unpacked: Addressing GLP-1 Allocation and Challenges of Equitable Access

Medical Ethics Unpacked: Addressing GLP-1 Allocation 

00:00 Introduction to GLP-1 Agonists and Ethical Considerations

03:38 Current Landscape and Insurance Coverage

06:04 Fair Priority Model and Ethical Principles

13:37 Application of Principles and Tiered Allocation

34:30 Challenges and Objections to the Framework

38:41 Future Considerations and Broader Applications

, hosts Steve Levine, MD, a psychiatrist, and Dominic Sisti, PhD, a bioethicist, are joined by special guest Johan Dellgren, BA, a research fellow at the University of Pennsylvania’s Department of Medical Ethics and Health Policy. Together, they explore the ethical and policy challenges surrounding the allocation of GLP-1 receptor agonists, a class of medications widely recognized for their effectiveness in treating diabetes and obesity.

The conversation addresses the growing demand for GLP-1 drugs such as Ozempic and Wegovy, which have shown profound health benefits but remain costly and in limited supply. Dellgren outlines the complexities of insurance coverage, highlighting disparities in access between private insurers, Medicare, and Medicaid. Some insurers cover these medications as preventive care due to their potential to reduce cardiovascular risks and long-term healthcare costs, but others hesitate due to their high price tags—often exceeding $1,300 per month.

At the core of the discussion is distributive justice: how should these scarce medications be allocated fairly? Dellgren presents a framework known as the 

, developed by Dr. Ezekiel Emanuel and colleagues, which balances multiple ethical principles. The model incorporates 4 key values: maximizing benefit and minimizing harm, ensuring equal moral concern for all individuals, prioritizing the most disadvantaged, and rewarding social contribution.

A key takeaway is the prioritization of GLP-1s for obesity over diabetes, an approach based on potential years of life lost (PYLL). Dellgren explains that long-term obesity significantly shortens lifespan—by as much as 10 to 15 years in some cases. Additionally, prioritizing individuals with severe obesity could help prevent the development of type 2 diabetes and other comorbidities. The model also stratifies patients by age, prioritizing younger individuals to maximize life years saved.

Sisti and Levine challenge Dellgren on objections to the PYLL metric, particularly concerns about its racial neutrality. Dellgren explains that while the model does not explicitly factor in race, it is racism-conscious, ensuring that communities disproportionately affected by obesity and diabetes—often communities of color—are fairly represented through the prioritization of those with the highest PYLL scores.

The discussion expands to the broader implications of GLP-1 access, including the current unjust distribution system, where higher-income individuals and those with comprehensive insurance disproportionately secure these medications, even in cases where clinical need is lower.

Another key ethical issue raised is patient adherence. With limited drug supply, should patients who fail to adhere to treatment lose access in favor of those more likely to benefit? Dellgren notes that some countries, such as Iceland, already incorporate adherence-based criteria into their public insurance coverage, requiring patients to meet specific weight-loss milestones to continue treatment. The conversation also touches on whether drug patents should be suspended to allow generic production and address shortages.

Throughout, Levine, Sisti, and Dellgren emphasize the ethical complexities of rationing high-impact medications and the need for policies that balance medical necessity, social equity, and cost-effectiveness.

Dellgren and colleague’s paper on GLP-1 allocation published in the New England Journal of Medicine can be accessed 

Steve Levine, MD: Chief patient officer at Compass Pathways

Dominic Sisti, PhD: Associate professor in the Department of Medical Ethics & Health Policy and the director of the Scattergood Program for the Applied Ethics of Behavioral Health Care at the University of Pennsylvania

Relevant disclosures for Sisti include Lykos Therapeutics and Tactogen. Relevant disclosures for include Levine include Compass Pathways.

The views and opinions expressed by the hosts and guests are their own and do not necessarily reflect those of 

. This content is intended to encourage thoughtful discussion and does not constitute medical advice or endorsement of any particular position. Listeners are encouraged to approach these subjects with care and consult appropriate resources for further information.

Podcasts

Drs. Levine and Sisti discuss the ethical challenges of GLP-1 drug allocation, exploring fairness, disparities, and policy solutions for obesity and diabetes treatment.