Years of Safety Data: What Long-term Esketamine Research Tells Us About Psychedelic Medicine
The Safety Question That Matters Most
When people consider psychedelic therapy for treatment-resistant depression, anxiety, or other mental health conditions, one question consistently rises above all others: "Is it safe?" This concern is entirely understandable, given the decades of stigma surrounding psychedelic substances and the limited long-term safety data available for most psychedelic medicines [1]. While short-term studies have generally shown favorable safety profiles for psychedelic therapies, the question of what happens with extended use has remained largely unanswered—until now. The SUSTAIN-3 study of intranasal esketamine represents a landmark in psychedelic medicine research, providing unprecedented long-term safety data from nearly 1,200 patients followed for an average of over three and a half years [1]. This massive dataset offers the most comprehensive picture available of what happens when people use psychedelic medicine over extended periods, providing crucial insights that extend beyond esketamine to inform our understanding of psychedelic medicine safety more broadly. The findings from this study offer significant reassurance for people considering psychedelic therapy while also highlighting the importance of proper medical supervision and monitoring.
Understanding the safety profile of long-term psychedelic medicine use is particularly important as these treatments move from experimental research settings into mainstream medical practice. Regulatory agencies, healthcare providers, patients, and families all need reliable information about the risks and benefits of extended psychedelic therapy to make informed decisions about treatment [1]. The esketamine safety data provides a crucial foundation for these discussions and helps establish the evidence base needed for the responsible integration of psychedelic medicine into standard healthcare.
Understanding Treatment-Resistant Depression
Treatment-resistant depression (TRD) affects millions of people worldwide and represents one of the most challenging conditions in all of medicine. By definition, TRD occurs when someone has not responded adequately to at least two different antidepressant treatments of adequate dose and duration [1]. People with TRD often experience severe, persistent symptoms that significantly impair their ability to work, maintain relationships, and enjoy life, despite trying multiple conventional treatments including various medications and psychotherapy approaches. The statistics surrounding TRD are sobering and help explain why innovative treatments like esketamine are so desperately needed. Even among people with TRD who initially respond to treatment, approximately 70% will relapse within six months, creating a cycle of hope and disappointment that can be devastating for patients and families [1]. The suicide risk in TRD is substantially higher than in non-treatment-resistant depression, making the development of effective long-term treatments a matter of life and death for many people.
Traditional antidepressant medications work primarily through the serotonin, norepinephrine, or dopamine systems, but these approaches often prove inadequate for people with TRD. The limited effectiveness of conventional treatments in TRD has led researchers to explore novel mechanisms of action, including the NMDA receptor antagonism that underlies esketamine's antidepressant effects [1]. This different mechanism of action helps explain why esketamine can be effective even in people who haven't responded to multiple other antidepressants. The chronic nature of TRD means that effective treatments need to be not only powerful but also safe for long-term use. Unlike acute medical conditions that might be treated with intensive but brief interventions, TRD often requires ongoing treatment for months or years to maintain remission and prevent relapse [1]. This reality makes long-term safety data absolutely crucial for any treatment intended for TRD, as the benefits of treatment must be weighed against the cumulative risks of extended use.
The burden of TRD extends far beyond the individual patient to affect families, healthcare systems, and society as a whole. People with TRD often require frequent hospitalizations, emergency department visits, and intensive mental health services, creating substantial healthcare costs [1]. The disability associated with TRD also results in lost productivity and reduced quality of life that affects not only patients but also their loved ones and communities. Effective long-term treatments for TRD therefore have the potential to provide benefits that extend far beyond symptom reduction to include improved functioning and reduced healthcare utilization.
The SUSTAIN-3 Study: Unprecedented Safety Data
The SUSTAIN-3 study represents the largest and longest follow-up study of any psychedelic medicine to date, providing safety and efficacy data from 1,148 patients with treatment-resistant depression who received esketamine nasal spray for an average of 42.9 months [1]. This massive undertaking, conducted from June 2016 to December 2022, accumulated an unprecedented 3,777 cumulative patient-years of exposure data—far exceeding the safety database for any other psychedelic medicine and rivaling the long-term safety data available for many conventional psychiatric medications. The study design allowed for flexible, individualized dosing that reflects real-world clinical practice rather than the rigid protocols typical of clinical trials. Participants could receive esketamine twice weekly during induction phases and then transition to individualized maintenance schedules ranging from weekly to every four weeks, depending on their individual response and clinical needs [1]. This flexible approach provides safety data that is more relevant to actual clinical practice than studies using fixed dosing schedules that may not reflect how the medication would be used in real-world settings. The primary finding of the SUSTAIN-3 study—that no new safety signals were identified during long-term treatment—represents a remarkable achievement in psychedelic medicine research. After nearly 4,000 patient-years of exposure, researchers found no unexpected safety concerns or previously unknown adverse effects [1]. This finding provides substantial reassurance about the long-term safety of esketamine and, by extension, suggests that psychedelic medicines may have more favorable long-term safety profiles than many people have assumed.
The most common adverse events reported in SUSTAIN-3 were generally mild to moderate and consistent with the known effects of esketamine. Headache was the most frequently reported side effect, occurring in 36.9% of participants, followed by dizziness (33.9%), nausea (33.6%), dissociation (25.5%), nasopharyngitis (23.8%), somnolence (23.1%), dysgeusia or altered taste (20.2%), and back pain (20.0%) [1]. Importantly, these side effects were generally transient and manageable, and the rates did not increase over time, suggesting that tolerance or accumulation of adverse effects does not occur with long-term use.
The discontinuation rates in SUSTAIN-3 provide additional evidence of the treatment's tolerability and effectiveness. Only 5.3% of participants discontinued treatment due to lack of efficacy, and 6.4% discontinued due to adverse events [1]. These low discontinuation rates are particularly impressive given the long duration of the study and the severity of the patient population, suggesting that esketamine remains both effective and well-tolerated even with extended use. Mortality data from the study, while sobering, provides important context about the risks and benefits of long-term esketamine treatment. Nine participants died during the study period, with causes including COVID-19 (3 deaths), pneumonia (2 deaths), and one death each from completed suicide, myocardial infarction, multiple injuries, and unknown cause [1]. While any death in a clinical study is tragic, the overall mortality rate was lower than would be expected in a population with severe treatment-resistant depression, suggesting that effective treatment may actually reduce mortality risk in this vulnerable population.
Real-World Treatment Experience
The effectiveness data from SUSTAIN-3 demonstrates that esketamine's antidepressant benefits are not only sustained over time but actually improve for many patients with continued treatment. During the induction phase, participants showed a mean reduction of 12.8 points on the Montgomery-Åsberg Depression Rating Scale (MADRS), a substantial improvement that was maintained throughout the optimization and maintenance phases [1]. This sustained effectiveness is particularly important for TRD, where maintaining remission over time is often more challenging than achieving initial response.
The remission rates observed in SUSTAIN-3 provide compelling evidence of esketamine's long-term effectiveness. While 35.6% of participants achieved remission at the end of the induction phase, this rate increased to 48.5% at week 112 and 49.6% at the optimization/maintenance endpoint [1]. This pattern of increasing remission rates over time suggests that some patients continue to improve with extended treatment, challenging the assumption that maximum benefits are achieved quickly and then plateau. The flexible dosing approach used in SUSTAIN-3 allowed clinicians to optimize treatment for individual patients based on their response and tolerability. During the optimization and maintenance phases, dosing frequency was adjusted based on depression severity and individual patient needs, with some patients receiving weekly treatments while others were maintained on every-other-week or monthly schedules [1]. This individualized approach reflects real-world clinical practice and demonstrates that esketamine can be effectively tailored to meet diverse patient needs.
Quality of life improvements observed in SUSTAIN-3 extend beyond symptom reduction to include meaningful changes in functioning and well-being. Participants reported improvements in their ability to work, maintain relationships, and engage in activities they had previously found difficult or impossible due to their depression [1]. These functional improvements are particularly important for people with TRD, who often experience significant disability even when their mood symptoms are partially controlled. The real-world effectiveness demonstrated in SUSTAIN-3 is particularly impressive given the severity of the patient population. All participants had treatment-resistant depression by definition, meaning they had failed to respond to multiple previous treatments [1]. The fact that nearly half of these patients achieved remission with esketamine treatment represents a major advance in the treatment of this challenging condition and provides hope for people who have not found relief with conventional approaches.
Cognitive Safety: Protecting Mental Function
One of the most important findings from long-term esketamine research relates to cognitive safety—the question of whether extended use of psychedelic medicine might impair thinking, memory, or other mental functions. A detailed study by Sobreiro and colleagues specifically examined cognitive outcomes in eight patients with treatment-resistant depression who received esketamine nasal spray for six months, using comprehensive neuropsychological testing to assess multiple domains of cognitive function [2]. The results provide reassuring evidence that long-term esketamine treatment not only avoids cognitive impairment but may actually improve certain aspects of mental function.
The cognitive assessment battery used in the study included tests of attention, memory, executive function, working memory, set-shifting, and inhibitory control—all areas that are often impaired in depression and that could potentially be affected by psychedelic medicine use [2]. Rather than showing the cognitive decline that some critics of psychedelic medicine have feared, participants demonstrated improvements in multiple cognitive domains over the course of treatment. These improvements included enhanced attention, better memory performance, and improved executive functions including working memory, set-shifting, and inhibitory control. The timeline of cognitive improvements observed in the study provides insights into how esketamine affects mental function over time. Most cognitive improvements were apparent by the three-month assessment point, but some effects, particularly improvements in working memory and set-shifting, became significant only at the six-month endpoint [2]. This pattern suggests that some cognitive benefits of esketamine treatment may continue to develop over time, providing additional rationale for long-term treatment in appropriate patients.
Importantly, the cognitive improvements observed in the study were correlated with improvements in depression severity, suggesting that better cognitive function may be a direct result of more effective depression treatment rather than a separate effect of esketamine [2]. This finding is consistent with research showing that depression itself impairs cognitive function, and that effective treatment of depression often leads to cognitive improvements. The fact that no cognitive tests showed worsening performance over the six-month treatment period provides strong evidence against concerns about cognitive toxicity from long-term esketamine use. The cognitive safety findings from esketamine research have important implications for other psychedelic medicines as well. While different psychedelic substances have different mechanisms of action and safety profiles, the demonstration that one psychedelic medicine can be used safely over extended periods without cognitive impairment provides a valuable precedent [2]. This evidence may help address concerns about cognitive safety that have been barriers to the development and acceptance of other psychedelic therapies.
Implications for Future Psychedelic Medicine
The safety and effectiveness data from long-term esketamine research provides a roadmap for the development and regulation of other psychedelic medicines. The SUSTAIN-3 study demonstrates that it is possible to conduct large-scale, long-term safety studies of psychedelic medicines, providing the type of comprehensive safety data that regulatory agencies require for approval [1]. This precedent may accelerate the development of other psychedelic therapies by showing that the safety studies needed for regulatory approval are feasible and can be conducted with appropriate scientific rigor. The flexible dosing approach validated in SUSTAIN-3 may inform treatment protocols for other psychedelic medicines. Rather than using fixed dosing schedules, the esketamine research demonstrates the value of individualized treatment approaches that can be adjusted based on patient response and tolerability [1]. This personalized medicine approach may be particularly important for psychedelic therapies, where individual responses can vary significantly and where the goal is to optimize both effectiveness and tolerability for each patient.
The integration of psychedelic medicine into mainstream healthcare, as demonstrated by the esketamine approval and clinical implementation, provides a model for how other psychedelic therapies might be introduced into medical practice. The esketamine experience shows the importance of specialized training for healthcare providers, appropriate clinical settings, and robust safety monitoring systems [1]. These lessons learned from esketamine implementation can help ensure that future psychedelic medicines are introduced safely and effectively into clinical practice. The regulatory pathway established for esketamine may also facilitate the approval of other psychedelic medicines. Regulatory agencies now have experience reviewing psychedelic medicine applications and have established precedents for the types of safety and efficacy data required for approval [1]. This regulatory experience may lead to more efficient review processes for future psychedelic therapies and clearer guidance for companies developing these treatments.
The success of esketamine in treating treatment-resistant depression has also helped change perceptions about psychedelic medicine among healthcare providers, patients, and the general public. The demonstration that a psychedelic medicine can be safely and effectively integrated into mainstream medical practice has reduced stigma and increased acceptance of psychedelic therapies more broadly [1]. This changing perception may facilitate research funding, clinical adoption, and patient access for other psychedelic medicines as they become available.
Making Informed Treatment Decisions
The extensive safety data from esketamine research provides valuable information for people considering psychedelic therapy, but it's important to understand both what this data does and doesn't tell us about psychedelic medicine safety more broadly. While esketamine's safety profile is reassuring, different psychedelic substances have different mechanisms of action, dosing requirements, and potential side effects [1]. The safety of esketamine doesn't automatically guarantee the safety of other psychedelic medicines, though it does provide encouraging evidence about the general feasibility of safe long-term psychedelic treatment. For people with treatment-resistant depression specifically, the esketamine data provides strong evidence for both safety and effectiveness that can inform treatment decisions. The combination of substantial efficacy data and comprehensive long-term safety information makes esketamine a well-supported treatment option for people who haven't responded to conventional antidepressants [1]. However, esketamine treatment requires specialized medical supervision and is typically reserved for people who have tried and failed multiple other treatments.
The importance of working with qualified healthcare providers cannot be overstated when considering any psychedelic medicine treatment. The safety demonstrated in clinical studies like SUSTAIN-3 was achieved in the context of careful medical supervision, appropriate patient selection, and comprehensive monitoring [1]. Attempting to replicate these benefits outside of proper medical supervision could result in very different safety and effectiveness outcomes. Realistic expectations are crucial when considering psychedelic medicine treatment. While the results from esketamine research are encouraging, not everyone will respond to treatment, and even those who do respond may experience side effects or require ongoing monitoring [2]. Understanding both the potential benefits and limitations of psychedelic medicine can help people make informed decisions about whether these treatments are appropriate for their individual situations.
The decision to pursue psychedelic medicine treatment should be made in the context of a comprehensive treatment plan that may include other interventions such as psychotherapy, lifestyle modifications, and social support. While psychedelic medicines like esketamine can be highly effective, they are typically most beneficial when used as part of a broader approach to mental health treatment [1]. Working with healthcare providers to develop comprehensive treatment plans can help maximize the benefits of psychedelic medicine while minimizing risks and addressing all aspects of mental health and well-being.
References
[1] Zaki, N., Chen, L., Lane, R., Doherty, T., Drevets, W. C., Morrison, R. L., Sanacora, G., Wilkinson, S. T., Young, A. H., Lacerda, A. L. T., et al. (2025). Safety and Efficacy with Esketamine in Treatment-Resistant Depression: Long-Term Extension Study. International Journal of Neuropsychopharmacology, pyaf027. https://doi.org/10.1093/ijnp/pyaf027
[2] Sobreiro, M. F. M., Silveira, P. S. P., Cavenaghi, V. B., da Costa, L. P., de Souza, B. P. F., Takahashi, R. E. S., Starek, R. V. M., Siqueira, J. O., & Fraguas, R. (2025). Long-Term Cognitive Outcomes of Esketamine Nasal Spray in Treatment-Resistant Depression: A Preliminary Report. Pharmaceuticals, 18(2), 173. https://www.mdpi.com/1424-8247/18/2/173
Disclaimer: Psychedelic Assisted Psychotherapy has not been approved by any regulatory agencies in the United States, and the safety and efficacy are still not formally established at the time of this writing.