Stay up to date on the latest research in psychedelic medicine

Every month, around 100 new studies on psychedelics are published, adding to what we know about these substances. To help clinicians and practitioners stay up-to-date with the most important findings, the Psychedelic Provider Network has teamed up with Blossom to review the latest studies.

May 2025 Research Summary

To keep clinicians and practitioners informed about the most relevant developments, the Psychedelic Provider Network and Blossom have reviewed the latest psychedelic research from April 2025. From over 159 new studies this month, we’ve highlighted three particularly important findings with direct implications for clinical practice.

First, we will examine two economic analyses of ketamine for treatment-resistant depression. One is a cost-utility analysis comparing subcutaneous ketamine to an active control, and the other is a simulation study modeling the broader economic impact of expanded access to intravenous ketamine versus ECT. Next, we will assess the safety profile of esketamine through two distinct reports: a pharmacovigilance analysis using European data to identify common adverse reactions and explore potential suicidality signals, and a Phase III long-term extension study evaluating its continued safety and efficacy. Finally, we will look at a secondary analysis of a randomized controlled trial that investigated how psilocybin-assisted therapy and escitalopram treatment differentially affect brain responsiveness to emotional stimuli in patients with major depressive disorder.

These studies offer practical insights into the economic viability, safety considerations, and distinct mechanisms of action of these treatments. The findings presented are intended to support clinicians and practitioners in their ongoing work with psychedelic medicines. We will now examine each topic in more detail.

Economic Viability of Ketamine for Treatment-Resistant Depression

Understanding the economic implications of ketamine treatments for treatment-resistant depression (TRD) is increasingly important as these therapies become more widespread. This month, two studies provide valuable insights into the cost-effectiveness and broader economic implications of ketamine. The first is a cost-utility analysis of subcutaneous ketamine from the KADS trial, and the second is a simulation modeling the effects of expanded intravenous ketamine access in the United States. These analyses provide data that can help clinicians and healthcare systems evaluate the financial aspects of offering ketamine.

The KADS study conducted a cost-utility analysis in conjunction with a randomized controlled trial involving 174 participants with TRD. The trial compared subcutaneous ketamine (up to 63mg/70kg, twice weekly for four weeks) against midazolam, an active control. From a health sector perspective, when the costs associated with administering the midazolam (such as drug and monitoring costs) were included in the comparison, ketamine was found to be dominant, meaning it was both more effective and less costly. Specifically, ketamine treatment resulted in higher Quality-Adjusted Life Years (QALYs) and had a 90% probability of being cost-effective at a willingness-to-pay threshold of A$50,000 per QALY gained over 8 weeks.

However, the economic picture shifted when the costs of the midazolam active control arm were excluded, a scenario intended to represent ketamine being added to standard care without a directly comparable active intervention. In this conservative scenario, subcutaneous ketamine was no longer considered cost-effective from the health sector perspective. From a broader societal perspective, which included patient travel, carer time, and productivity losses, ketamine was not found to be cost-effective in either base-case scenario in this specific trial. 

This highlights for practitioners that the perceived cost-effectiveness can heavily depend on the comparator chosen and the specific costs included in the analysis. The study also noted that factors like shorter nursing supervision or using wholesale drug prices could improve ketamine's economic profile.

Complementing this trial-based analysis, a population-level Markov simulation study modeled the economic impacts of expanded access to intravenous ketamine versus electroconvulsive therapy (ECT) for TRD over five years in the U.S. The model, which began with an initial cohort of 350,000 eligible patients and added 11,296 new patients annually, projected significant societal savings if access to ketamine were expanded. 

Annually, this expansion was estimated to save $828.2 million at a societal level. These savings were distributed as $95.3 million for patients (primarily through reduced treatment and healthcare costs, and less time lost for recovery) and $743.7 million for payers. This aligns with findings from a January 2025 study, which showed esketamine nasal spray led to lower acute care healthcare resource use and costs compared to ECT for MDD patients with acute suicidal ideation.

Assessing the Safety Profile of Esketamine

As esketamine (Spravato) continues to be used for TRD, clinicians need to understand its long-term safety, including rare or delayed side effects. This month, two studies provide important insights into this topic: one examined real-world side effect reports from Europe, and the other followed patients for a prolonged period after clinical trials. These reports provide different perspectives on esketamine safety, utilizing both real-world data and controlled study environments.

The first study examined 751 safety reports regarding esketamine nasal spray submitted to a European database between 2019 and late 2024. The most common side effects reported were high blood pressure (15.4%) and feeling disconnected from reality (15%). While most reports came from women, high blood pressure and completed suicide were reported more often in men. Serious side effects made up 35% of all reports, with mental health problems being the most common type. For clinicians, these real-world findings confirm the known immediate side effects of esketamine and identify which patients may be more susceptible to certain reactions.

One important finding from this European analysis was about suicide risk. The study compared esketamine to two common antidepressants: fluoxetine and venlafaxine. The results suggested esketamine might have a higher risk of suicidal thoughts and actions. Specifically, suicidal thoughts were reported about 3 times more often compared to fluoxetine and 5 times more often compared to venlafaxine. Completed suicide was reported even more frequently, about 8 times more than fluoxetine and 11 times more than venlafaxine. While this type of data can't prove that esketamine directly causes these problems due to limitations like reporting bias, these warning signs suggest doctors should carefully monitor patients taking esketamine, especially those who have had suicidal thoughts before.

The second study, reporting on the SUSTAIN-3 trial, was a long-term follow-up study with 1,148 adults with treatment-resistant depression who had been in previous esketamine trials. Participants received flexible doses of nasal esketamine (28mg, 56mg, or 84mg) along with a regular antidepressant pill, with some patients continuing treatment for up to 6.5 years. In this controlled study setting, esketamine was generally well-tolerated. The most common side effects were headache, dizziness, nausea, feeling disconnected, and sleepiness, which usually went away on the same day as treatment. Serious side effects happened in 19% of participants, but only about 2% were considered likely related to esketamine. Importantly, researchers found no evidence of new safety problems, mental decline, or major organ damage with long-term use.

Psilocybin and Emotional Responsiveness in Depression

A common observation in patients taking SSRIs for depression is something often called "emotional blunting," where people report feeling less intense positive and negative emotions. Psychedelic therapy, on the other hand, is often linked to reports of increased emotional connection and processing. A follow-up analysis of a well-known study directly comparing psilocybin therapy with the SSRI escitalopram provides brain data that supports these different experiences.

This brain imaging study looked at how the brain responds to emotional faces in 59 patients with moderate-to-severe depression. One group received two 25mg doses of psilocybin, while the other group received daily escitalopram for six weeks plus two inactive doses (1mg) of psilocybin. Both groups received the same psychological support. Brain activity was measured before treatment and at a 6-week follow-up, which was three weeks after the second psilocybin session.

The results showed a significant difference between the two treatments in how brain responses to emotional faces changed over time. Specifically, the escitalopram group showed a clear reduction in brain responses to all types of emotional faces (fearful, happy, and neutral) in several brain regions at the 6-week follow-up. This reduction was especially noticeable in the amygdala's response to fearful faces. In contrast, the psilocybin group showed no such reduction; in fact, there was a slight increase in responsiveness in some areas, particularly to neutral faces.

These results suggest that while both treatments led to improvements in depression symptoms (though the main study did not show psilocybin was better than escitalopram), their impact on emotional processing in the brain appears different. The reduced emotional responsiveness seen in the escitalopram group matches previous research and common reports of emotional blunting with SSRIs. Psilocybin therapy, despite also helping depression symptoms, did not produce this dampening effect on emotional brain responses. 

For clinicians, these findings offer a potential brain-based explanation for the different experiences reported by patients undergoing these treatments. The lack of emotional blunting with psilocybin may be a desirable feature for some patients, particularly those who find the side effect of dulled emotions with SSRIs problematic. This finding aligns with earlier research from the same trial, which suggested that reductions in avoiding uncomfortable thoughts and feelings contributed to the improvements observed in the psilocybin group. Similarly, another brain imaging study in patients with alcohol problems found that psilocybin was linked to brain changes suggesting improved emotional control and goal-directed behavior in response to emotional and alcohol-related triggers.

While this study provides valuable insights, it is a follow-up analysis with a relatively small sample size for brain imaging research. The timing of the post-treatment scan (three weeks after the final psilocybin dose) captures medium-term effects, and more research is needed to understand longer-term impacts on emotional processing. Nonetheless, these results add to our understanding that psilocybin therapy may offer a different path to recovery from depression, one that potentially preserves or even enhances emotional responsiveness, contrasting with the emotional dampening often seen with SSRI treatment.

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May 2025 in Psychedelic Research

May 2025 brought important research for clinicians working with ketamine and psilocybin. Economic studies of ketamine for treatment-resistant depression showed mixed results. Injectable ketamine can be cost-effective from a healthcare perspective, especially when compared to other treatments; however, its broader value to society and its added benefits when combined with standard care remain less clear. A separate study projected significant savings for society and insurers if intravenous ketamine became more widely available as an alternative to ECT, highlighting its potential economic benefits if insurance policies were to support it.