Michael E. Thase, MD, of the University of Pennsylvania

Michael E. Thase, MD

Maintenance Dosing, Safety Shape GH001 Outlook, With Michael E. Thase, MD

In the third part of an interview discussing phase 2b findings of inhaled mebufotenin (GH001) for 

, Michael E. Thase, MD, from the Perelman School of Medicine at the University of Pennsylvania, emphasized the importance of maintenance strategies, safety considerations, and future research priorities following rapid antidepressant effects observed in the randomized trial.

“Retreatment will be a reality for most people who have a benefit… I’m telling people, I think it’s going to be every 6 weeks in standard of care,” Thase told 

The double-blind phase 2b study of 81 patients demonstrated significant improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) scores at day 8 with GH001 versus placebo (least squares mean difference, −15.5; 

 < .001), with remission achieved in 57.5% of treated patients and none receiving placebo. However, durability data from the 6-month extension suggested many patients required additional dosing to maintain benefit.

Thase noted that the risk of relapse clustered early after response. The most vulnerable patients began to show symptom worsening within the first month, with a second group relapsing between months 1 and 2. On average, retreatment occurred approximately 6 weeks after the initial treatment, with additional retreatments distributed over the subsequent 4 months. Overall, roughly 90% of patients required ≥ 1 retreatment within 6 months, and individuals who initially responded typically received about 3 retreatments.

He suggested clinicians anticipate intermittent maintenance dosing, potentially every 6 to 8 weeks, while acknowledging variability. Thase also highlighted a potential role for relapse-prevention–oriented psychotherapy during the maintenance phase, hypothesizing that combining circuit “resetting” effects of psychedelics with structured psychotherapy may reduce retreatment frequency and associated costs.

Regarding safety, Thase reported no severe adverse psychoactive experiences among the 81 treated participants. No patients discontinued due to the intensity of effects, though he cautioned that rare “bad trips” may emerge in larger populations. Supportive clinical monitoring during administration may help patients tolerate transient experiences. He also referenced emerging compounds targeting similar serotonergic pathways without hallucinogenic effects.

Looking ahead, Thase identified replication of efficacy as the primary research priority, followed by optimization of long-term dosing strategies. He noted no evidence of dose tolerance in extension data. He concluded by emphasizing caution pending phase 3 trials, particularly those including US sites, stating that “a sufficient level of caution skepticism” remains appropriate while further data are generated.

“This is a project I've been involved with from the beginning, and so it started one day in early 2020, right at the beginning of the pandemic. We couldn't get this done in the US,” Thase said. “[The] next phase will definitely involve US participation…I really want to wait and see…what happens in phase 3 when we get the big US studies [on] how this will look. My final caveat is that there's a lot of work yet to be done.”

 of the interview with Thase on the lack of a placebo response and the clinical advantages of GH001, respectively.

Relevant disclosures for Thase include Otsuka Pharmaceutical, Janssen Scientific Affairs, E.R. Squibb & Sons, Eli Lilly and Company, H. Lundbeck A S, Boehringer Ingelheim International GmbH, and ITI, Inc. (d/b/a Intra-Cellular Therapies, Inc.).

Cubala WJ, Bajbouj M, Bauer M, et al. GH001 vs Placebo in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. 

Videos

In part 3 of an interview, Michael E. Thase, MD, discusses retreatment timing, safety monitoring, and research priorities following phase 2b GH001 data.

Single-Day GH001 for TRD Shows Rapid Response, With Michael E. Thase, PhD

A single-day dose of inhaled mebufotenin (GH001), a psychedelic-based intervention, demonstrated rapid and clinically meaningful improvements in depressive symptoms among adults with 

, a new phase 2b study showed. GH001 improved depression severity within 1 week.

Rapid-acting treatments, including neuromodulation and glutamatergic agents, have expanded the therapeutic landscape of TRD. Yet, these treatments often require repeated visits and prolonged monitoring. The GH001 individualized dosing approach, allowing up to 3 escalating doses administered on a single day, was designed to optimize response while minimizing treatment burden.

“An 8-hour visit really taxes your clinical space,” said Michael E. Thase, MD, from the Perelman School of Medicine at the University of Pennsylvania. “It is true that you might have a dosing space for the first hour or 2 where it's more medical and then a recovery room area for the subsequent 4 to 6 hours…but you do have to have staff available, even if you're not emphasizing the psychotherapeutic aspects of a psychedelic experience. In the GH study, we had kindly professional people who prepared the patients for the treatment, who were there with the patient when they had the treatment and [the]… debriefing…we did not attempt to involve the patient's recollection of their experience with any kind of growth-oriented psychotherapy.”

Thase said when you add the psychotherapy component, you need more space and need to spend more money on a psychotherapist. Without psychotherapy, it is more scalable for practices to treat patients with GH001.

“The GH001 is taken through a warm, aerosolized inhalation, and so it is not excessively medical,” he continued. “You don’t need a nurse or a physician because you're giving a controlled substance. It’s not the same thing as putting an IV in. It has about the same medical complexity as intranasal esketamine.”

Intranasal esketamine requires a patient to stay in the clinic for 2 hours post-administration. The required observation period for GH001, if any, would be determined after the FDA reviews phase 3 data.

“That's several years from now, at the soonest,” he said.

In the randomized, double-blind phase 2b trial, 81 adults with TRD were assigned to individualized GH001 dosing (6 mg, 12 mg, and 18 mg) or placebo. The primary endpoint—change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 8—favored GH001, with a least squares mean difference of −15.5 points (

 <.001) and a large effect size. Remission at day 8 occurred in 57.5% of GH001-treated participants compared with none receiving placebo, corresponding to a number needed to treat of 2. Investigators also observed improvements in anxiety, global illness severity, and quality-of-life measures.

The individualized dosing strategy permitted escalation at 1-hour intervals when tolerated and when peak psychoactive effects were not achieved. Median psychoactive effects lasted approximately 9 to 14 minutes, depending on dose. Most patients were discharge-ready approximately 1 hour after dosing, suggesting compatibility with outpatient care workflows.

The safety profile observed in the trial was consistent with prior psychedelic research. Treatment-emergent adverse events occurred in 72.5% of GH001-treated participants, most commonly nausea, salivary hypersecretion, and paresthesia. All events were mild or moderate, and no serious adverse events, discontinuations, or clinically significant changes in vital signs were reported. No treatment-emergent suicidal behavior occurred.

Durability findings from the 6-month open-label extension suggested that many responders required intermittent retreatment. Median time to first retreatment was approximately 6 weeks, and most patients who achieved remission after initial dosing maintained remission with infrequent additional treatments. These findings indicate potential for periodic maintenance rather than continuous therapy.

Thase highlighted the potential role of GH001 in patients who have not responded to multiple pharmacologic classes. He emphasized that rapid onset may allow clinicians to determine effectiveness within days, which may be particularly valuable in urgent clinical scenarios.

“We did not have anybody who didn't really respond and then slowly got better,” Thase said. “People were either better [or not], and it was clear at the end of a week that they got a good response. Knowing for certain if the treatment is going to be valuable quickly is a real advantage.”

Part 1 of the interview with Thase can be viewed 

An interview with Thase explores rapid antidepressant effects and real-world considerations for single-day individualized GH001 dosing in TRD.


Single-Day GH001 Produces Rapid Remission in TRD, With Michael E. Thase, MD

A single-day, individualized dosing regimen of inhaled mebufotenin (GH001) was associated with rapid and substantial reductions in depressive symptoms among adults with 

, with more than half of treated patients achieving remission by day 8.

In an interview with HCPLive, Michael E. Thase, MD, from the Perelman School of Medicine at the University of Pennsylvania, provided a clinical perspective on the magnitude of effect and considerations for interpreting the findings.

In the randomized, double-blind phase 2b trial of 81 patients, participants were assigned 1:1 to GH001 (n = 40) or placebo (n = 41) and received up to 3 escalating inhaled doses (6 mg, 12 mg, and 18 mg) within a single day. The primary endpoint, which was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 8, favored GH001, with a least squares mean difference of −15.5 points compared with placebo (

 < .001; effect size, −2.0). Remission (MADRS ≤10) occurred in 57.5% of patients in the GH001 group versus 0% in the placebo group, corresponding to a number needed to treat of 2. Response rates were 60.0% and 0%, respectively.

“The effect size is the effect of the active treatment divided by the effect of the inactive treatment,” Thase explained. “When the placebo has little effect, you can have a very large effect size. A little more than half of the patients who received…GH001 got substantially better quickly, and no one in the placebo group [did]. The fact that it's about [a] 55% rapid remission is a wonderful thing.”

He added that while the observed remission rate is clinically meaningful, placebo response rates are likely to increase in larger phase 3 trials.

The study’s design may have contributed to the lack of placebo response. GH001 produces a short-duration psychoactive experience, with a median duration of approximately 9 to 14 minutes across doses, allowing for repeated dosing within a single treatment session. Patients who did not achieve a sufficient psychoactive effect were eligible for up to 2 additional doses at 1-hour intervals. All placebo-treated participants received 3 administrations without meaningful psychoactive effects.

“If you got randomized to placebo…you got 3 duds,” Thase said. “You had 3 times the chance to say, ‘hey, this isn't the real thing.’ I don’t think that 50 plus percent remission rate is just a glorified placebo response, but I do think that the 0% absence of real benefit in the placebo arm reflects the fact that folks were expecting a psychedelic experience. By the end of that long morning, they deduce that they lost the coin flip in this study.”

He described this as functional unblinding, a recognized challenge in psychedelic trials, particularly when subjective effects are closely linked to therapeutic outcomes. The US Food & Drug Administration (FDA) brought up this concern with psychedelics during the advisory committee meeting for MDMA-assisted therapy to treat PTSD.

To reduce bias, efficacy assessments were conducted by independent raters who were not involved in treatment administration and were unaware of patients’ subjective experiences.

 Patients were instructed not to disclose details of their psychoactive response. Despite these measures, Thase acknowledged the limitations of maintaining blinding in this context and noted that regulators have raised similar concerns in prior evaluations of psychedelic therapies.

Beyond the double-blind phase, all 41 placebo non-responders received GH001 in the open-label extension and demonstrated response rates comparable to those initially assigned to active treatment, according to Thase.

“That kind of internal replication within a study is really reassuring that there’s something substantial here,” he said.

Secondary endpoints also favored GH001, with improvements observed in anxiety symptoms, global illness severity, and quality of life measures by day 8. The treatment was generally well tolerated. Treatment-emergent adverse events occurred in 72.5% of patients receiving GH001 and 7.3% receiving placebo, with nausea, salivary hypersecretion, and paresthesia among the most frequently reported events. All adverse events were mild or moderate, and no serious adverse events, discontinuations, or deaths were reported.

Follow-up data from the 6-month extension phase suggest that remission can be maintained with intermittent retreatment. Among patients who achieved remission at day 8, 87% remained in remission at 6 months, typically with limited additional dosing.

For clinicians, Thase emphasized focusing on the observed remission rate rather than the magnitude of the effect size alone.

“A rapid 50-plus percent remission rate is a really good thing,” he said. “Let's hope that…[a] positive result is confirmed in phase 3.”

Kunzmann K. FDA Psychopharmacologic Advisory Committee Votes Against Supporting Effectiveness of MDMA for PTSD. HCPLive. Published on June 4, 2024. Accessed on March 31, 2026. 

https://www.hcplive.com/view/live-updates-fda-psychopharmacologic-advisory-committee-meeting-mdma-ptsd

Inhaled GH001 achieved 57.5% remission by day 8 in TRD with a large effect size vs placebo; Thase discusses interpretation, unblinding, and phase 3 implications.

Lumateperone Shows Broad Symptom Benefit for MDD, With Michael E. Thase, MD

New analyses of adjunctive lumateperone (CAPLYTA) move beyond remission rates to address questions clinicians routinely face regarding symptom-specific benefits, long-term safety, and where the medication may fit in the adjunctive treatment strategy for 

, according to Michael E. Thase, MD, of the University of Pennsylvania.

“To make a long story short, the improvement is consistent across all of the symptoms,” Thase told 

. “The least improvement was seen on the suicide item, but that's not because it doesn't reduce suicidal ideation. It's because… It's not a good idea to have such a patient in a placebo-controlled trial in which they might not get an active medicine for 6 or 8 weeks. So, I would look at that as not a meaningful finding. And even on that item, there was improvement. It just wasn't nominally quite as much [of an] improvement. So, benefit is broad. It's across symptom domains. It includes relief of anxiety and anxious arousal. It includes improvement of sleep…[and] improvement in life satisfaction.”

 approved lumateperone as an adjunctive treatment for MDD, announced by Johnson & Johnson on November 6, 2025.

Since then, investigators conducted further research on remission rates and the safety of lumateperone for this treatment indication.

The analyses pooled short-term data from multiple randomized, placebo-controlled trials in patients with MDD who had an inadequate response to antidepressant therapy (ADT).

 In these studies, lumateperone 42 mg plus ADT significantly improved Montgomery–Åsberg Depression Rating Scale (MADRS) remission rates by day 43 compared with placebo plus ADT (25.5% vs 13.6%;

 <.0001). Complete remission, reflecting near-total symptom resolution, occurred in 10.6% of lumateperone-treated patients versus 5.6% of placebo-treated patients (

 <.01), demonstrating meaningful early symptom improvement in this difficult-to-treat population.

Long-term outcomes from a separate trial and open-label extension showed that 44.1% of patients achieved complete remission, and 65.4% reached remission at some point during the study. Subgroup analyses indicated that these benefits were consistent across age, baseline disease severity, and concomitant antidepressant type.

Beyond overall MADRS improvement, lumateperone demonstrated efficacy across individual symptom domains. Thase noted that all 10 MADRS items—including mood, sleep disturbance, anxiety, and hedonic capacity—showed improvement. Sleep and anxiety improvements were particularly relevant given their contribution to functional impairment and relapse risk. Additional measures outside the MADRS, including life satisfaction and standard anxiety scales, further supported the medication’s broad multidimensional impact.

Long-term tolerability was also favorable. Six-month follow-up revealed minimal weight gain, low rates of sexual dysfunction, and few neurologic adverse effects, such as akathisia or extrapyramidal symptoms. Thase emphasized that these findings support the safety of continued treatment.

“It's one thing not to have weight gain over six weeks. It's another not to have meaningful weight gain over six months,” Thase said. “The 6-month data are very reassuring about the safety profile of this medication.”

Given these results, lumateperone could be considered after failure of a second antidepressant trial, and future evidence may support its evaluation earlier in the adjunctive sequence. Remaining questions focus on very long-term outcomes, particularly tardive dyskinesia, though real-world experience in bipolar depression suggests a very low risk.

“I've been excited about this medication since I don't treat very many people with schizophrenia. When I began to see this used for treatment of bipolar depression, I couldn't wait to have it approved for adjunctive therapy for people with non bipolar depression, because I knew that it had a really good, favorable profile and that it helped a meaningful proportion of patients. So I just want to say I'm delighted that we have it available, and I look forward to having broader use of it than I've had previously.

Thase M. Adjunctive Lumateperone Improves Remission Rates in MDD, With Michael E. Thase, MD. HCPLive. Published on January 19, 2026. Accessed on January 19, 2026. 

https://www.hcplive.com/view/adjunctive-lumateperone-improves-remission-rates-mdd-michael-e-thase-md

FDA approval of CAPLYTA® (lumateperone) has the potential to reset treatment expectations, offering hope for remission in adults with major depressive disorder. JNJ.com. Published November 6, 2025. Accessed on January 19, 2026. 

https://www.jnj.com/media-center/press-releases/fda-approval-of-caplyta-lumateperone-has-the-potential-to-reset-treatment-expectations-offering-hope-for-remission-in-adults-with-major-depressive-disorder

Adjunctive lumateperone 42 mg improves remission, relieves anxiety and sleep symptoms, and shows sustained safety in patients with treatment-resistant MDD.

Michael E. Thase, MD

Articles