Interest in psychedelic-assisted therapy (PAT) is surging across research and medical communities, prompting the discussion of policy shifts that reflect growing openness to implementing psychedelics in clinical practice. State-level psychedelic reform in the United States has accelerated since 2019, with legalization projected to reach most states within the next decade if trends follow those of cannabis 1. This transition of PAT from tightly controlled clinical trials to real-world practice raises concerns about how patient screening, treatment setting, and therapist support will be managed outside research environments. Critically, clinicians must be able to ensure that the experiences induced by psychedelics are translated into lasting therapeutic gains in a generalizable and safe manner, while regulatory agencies must establish standards to govern ethical implementation. Anticipating and addressing these challenges with appropriate education, training, and clear guidelines, while maintaining fidelity to protocols developed in research settings, will be essential for the responsible incorporation of PAT into mainstream psychiatry. One of the greatest concerns in the rollout of PAT in clinical practice is the potential loss of rigorous screening and safety monitoring procedures. Clinical trials employ rigid inclusion and exclusion criteria, selecting for individuals most likely to benefit and less likely to experience adverse reactions 2. These trials' protocols rely on comprehensive evaluations, including detailed review of medical histories, physical exams, and in-depth psychiatric interviews to rule out personal or family histories of psychotic or bipolar disorders 3. While such criteria may be overly restrictive and exclude broader patient populations 4, when adhered to and paired with proper therapeutic support and supervision, serious adverse events are rare 3. Maintaining this level of diligence in routine clinical practice will be challenging for many clinics, as the logistical and financial demands of appropriately prescribed and safely administered PAT may increase pressure on clinics to lower standards to increase throughput. A cautionary example can be seen in a subset of for-profit ketamine clinics, which have been reported to advertise benefits beyond the current evidence base and administer doses that exceed established therapeutic ranges with insufficient medical supervision 5, 6. To preserve safety and public trust, clinicians must uphold rigorous screening practices and safety protocols to avoid the dangers of treating patients with high-risk comorbidities, contraindicated medications or medical conditions, or unstable psychosocial situations that predispose them to decompensation. Careful patient selection, medical oversight, and psychological support protect patients from harm and prevent unwanted outcomes that could complicate PAT's integration into mental health care, though these safeguards may also increase cost and limit access. Unlike conventional pharmacotherapies, PAT emphasizes the role of ‘set’ (the patient's mindset, expectations, and intentions) and ‘setting’ (the physical and social environment) in shaping both acute experiences and lasting effects 7. While empirical data directly associating set and setting with improved outcomes remains limited, attention to these factors has been standard across PAT trials, consistent with the hypothesis that serotonin receptor-mediated increases in neuroplasticity also increase sensitivity to environmental context 8. Additionally, qualitative studies consistently suggest that nonpharmacological factors such as psychological preparation, therapeutic rapport, setting, and integration all meaningfully shape participants' experiences and perceived therapeutic benefit 9 and that sterile environments or a lack of rapport with the session monitor can predispose patients to fear and a difficult experience 3, 8, 10. Completely disregarding these insights in favor of cost-reduction and feasibility might reduce treatment efficacy and introduce risk. As PAT moves beyond research settings, standardized training and certification for providers should be established in the same way Good Clinical Practice training is used in research, with the goal of ensuring strong rapport between providers and patients 8. Given the heightened vulnerability and suggestibility that can occur during psychedelic states, it will also be critical to patient safety to determine criteria for who may serve as a session monitor. Requirements for background checks, credentials, and appropriate training can replace the FDA-mandated protections for PAT in research, such as the 2:1 model or live-video monitoring. Further research is needed to define appropriate standards for PAT; however, these standards should be overseen by a designated ethics committee and/or Center of Excellence that provides authoritative oversight and facilitates continued collaboration. The loss of regulation that will naturally occur as PAT is offered beyond highly supervised research environments introduces uncertainty about the nature and adequacy of psychological support that will be provided. Qualitative research on PAT for treatment-resistant depression reveals that patients often anticipate transformative insights, reconnection with suppressed emotions, or vivid visual effects 11. Such expectations may be inflated by media coverage that sensationalizes psychedelics as a cure-all 12, thus promoting unrealistic optimism and reinforcing the need for proper psychoeducation and informed consent. Preparation sessions play a crucial role in educating patients about the potential effects of psychedelics, guiding intention-setting, building trust, and emphasizing that each experience is highly individual and unpredictable. Participants who entered PAT sessions well-informed and with a ‘surrendered’ mindset were better able to navigate difficult moments 13 and were more likely to report a mystical-type experience, which is predictive of long-term benefits 9. The loss of the formal consenting procedures required in clinical research will place added responsibility on clinicians to engage patients in nuanced, evidence-based conversations that openly discuss risks while accurately representing treatment efficacy. Integration, the process of making sense of psychedelic experiences, is often emphasized as being a central component of PAT's therapeutic benefit 9. Typically occurring in one or more therapy sessions shortly after dosing, integration allows patients to reflect, resolve lingering confusion, and translate insights into tangible change 14. Notably, emotionally challenging sessions can be deeply meaningful, but only when sufficiently processed afterward 15. Despite its importance, integration structure and support are often minimal even in clinical trials, with qualitative studies showing participants frequently feel under-supported and left without a clear roadmap once the initial benefits of PAT subside 11. Integration is a structured opportunity to assess for adverse events while facilitating emotional processing in a way that complements the pharmacological effects of psychedelics. Policymakers must decide how to balance access with safety while designing clinical practice guidelines for PAT. The FDA's Risk Evaluation and Mitigation Strategy (REMS) program offers one credible method by requiring additional safeguards for certain medications to ensure that benefits outweigh risks. A REMS for PAT could standardize safety protocols, mandating that psychedelic medications be administered only in certified clinics with appropriate medical and psychological supervision, reducing the likelihood of serious adverse events. A pertinent comparison is Spravato's 2019 approval, which came with a strict REMS to prevent misuse and manage acute risks of the intranasal esketamine spray, such as dissociation, sedation, and suicidal thoughts or behaviors 16. Pharmacists, clinics, and patients must be enrolled in this REMS program to access the medication, and patients are required to remain under direct observation for at least 2 h post esketamine dose, ensuring all dissociative symptoms have resolved 17. Enforcement of a REMS brings significant logistical challenges for expansion of access to PAT, because the safety measures that make it effective (e.g., in-clinic dosing, prolonged patient monitoring, training and certification) also create barriers for both clinics and patients. PAT sessions utilizing psilocybin are extremely resource-intensive, lasting 6–8 h with multiple staff present. Clinics may only be able to treat one patient per day, potentially reducing financial incentive for providers and creating bottlenecks in access. While establishing a REMS for PAT appears practical to protect patients and uphold treatment quality, policymakers must weigh the trade-off between safety and scalability. Ultimately, a REMS for PAT would necessarily include mitigation strategies for immediate risks to patient safety, such as suicidal ideation, psychosis, and hypertensive emergency, and also monitor for the development of hallucinogen persisting perception disorder or other rare adverse outcomes 18. In summary, the emergence of psychedelic-assisted therapy represents an exciting and transformative shift in psychiatry. The realization of its full potential will partially depend on the clinical framework it's delivered in. Safe and effective implementation requires thorough screening practices, a supportive and well-considered treatment environment, and sufficient preparation and integration. At the policy level, regulators must weigh safety and feasibility to inform guidelines, learning from past precedents while tailoring oversight to the distinct features of PAT. Notably, greater flexibility in clinical practice, such as individualizing music and setting, or varying the number of dosing and therapy sessions, may ultimately benefit some patients. This capacity for personalization represents one of the most promising opportunities for PAT beyond research settings and supports a more patient-centered model of care. PAT offers a rare opportunity to reshape mental health care because, unlike most conventional treatments, it combines psychotherapeutic and pharmacological elements and also incorporates meaning-making. Adoption of PAT could catalyze a shift toward a more holistic model of psychiatry that extends beyond symptom management, toward a more dynamic process involving self-discovery, reflection, and inner healing. If successfully and safely implemented, PAT could expand the psychiatric toolkit, offering relief to patients for whom existing treatments fall short. The path forward requires caution, well-considered regulations, and a commitment to uphold the importance of the patient experience. Jessie Kim served as lead author and was the primary person responsible for drafting the manuscript and working with journal reviewers. All three authors contributed to drafting, editing, and revising the manuscript. Dr. Weissman served as the senior author overseeing the project. Dr. Weissman and Jessie Kim have been supported by Compass Pathways through participation as a trial site for clinical research on psilocybin at UC San Diego. The other author declares no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
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