Applying the EU Regulatory Framework to Determine the Benefit–Risk Profile of Psychedelics

Abstract

Marketing authorization applications for psychedelics must align with the regulatory requirements and evidentiary standards required for the approval of all medicinal products in the European Union. While medicine regulators recognize the therapeutic potential of psychedelics, their characteristics present methodological challenges that complicate the design and interpretation of pivotal trials intended to assess their benefit–risk profile. This Viewpoint presents the European Medicines Agency’s perspective on the main knowledge gaps that must be addressed to ensure robust evidence generation for regulatory decision-making, as discussed at a multistakeholder workshop convened by the Agency in April 2024. Central among these are issues related to functional unblinding and expectancy and nocebo effects. Furthermore, characteristics of the trial population must be rigorously aligned with those defined in the therapeutic indication to ensure findings are relevant and generalizable. Development programmes should also support the characterization of the dose–response relationship, both in terms of pharmacological effects and the association between the subjective experience and therapeutic response. Moreover, the decision to incorporate either psychological support or psychotherapy in the therapeutic framework has methodological implications for the trial’s design and protocol, as well as the conditions for use, all of which require careful consideration. Additionally, characterization of the safety profile of psychedelics necessitates a multifaceted approach, including adequately powered clinical trials, the use of appropriate controls, the development of robust risk mitigation strategies, the establishment of continuous safety monitoring protocols, and the systematic consideration of ethical implications.

With over one in six people in the European Union (EU) affected, mental health disorders represent a significant public health concern. While conventional pharmacotherapies often yield adequate therapeutic responses, a considerable proportion of patients with mental health disorders exhibit treatment resistance, underscoring an unmet medical need in this population. Furthermore, despite significant advances in understanding the underlying pathophysiology of these disorders, progress in developing novel treatments has been limited.

Against this background there has been a renewed interest in investigating the therapeutic potential of psychedelics for treating mental health disorders. This has led to a significant increase in clinical trials across various regulatory jurisdictions, contributing to a growing body of evidence suggesting that psychedelics could be effective in treating conditions such as treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), substance use disorders, and end-of-life psychological distress.

However, the marketing authorization of psychedelics as medicinal products in the European Union (EU) requires submission of an application that adheres to the evidentiary standards established by the EU medicines regulatory framework. While acknowledging the therapeutic potential of psychedelics, the European Medicines Agency (EMA) also recognizes the unique challenges these substances present in the context of drug development and regulation. To address these challenges and explore how the EU regulatory framework could support development programmes, EMA organized a workshop in April 2024 that convened a diverse group of stakeholders, including healthcare professionals, patient advocates, academic researchers, industry representatives, and international regulatory bodies. This event provided a platform for multidisciplinary, evidence-based discussions on the current state of psychedelic research and regulatory strategies for advancing clinical development.

This Viewpoint outlines the Agency’s perspective on the knowledge gaps that need to be addressed in support of marketing authorization of psychedelic medicines. The main focus of this Viewpoint includes methodological challenges for clinical trials investigating the efficacy and safety of psychedelics, the strategies that can be used to mitigate their effects and the safety considerations that should be integrated in development programmes to support marketing authorization of psychedelics. Additionally, we highlight the various regulatory platforms and support structures provided by EMA that can assist developers in navigating the complex landscape of psychedelic medicine development.

Several additional factors must be considered when establishing a framework to ensure patient access to safe and effective psychedelic medicines in the EU. For instance, determining the cost-effectiveness of these treatments through health technology assessment (HTA) to guide reimbursement strategies by national health systems, securing funding for research, developing consensus regarding the optimal psychotherapeutic component to pair with psychedelics in psychedelic-assisted psychotherapy and overcoming legal obstacles due to their classification as controlled substances. Although these issues are relevant in order to bring an effective psychedelic medicine to the patient, they fall outside the purview of EMA’s mandate and therefore will not be addressed in this Viewpoint.

1. Methodological Challenges

For a medicine to be approved, applicants are required to submit a comprehensive marketing authorization application (MAA). This dossier, which includes quality, non-clinical and clinical data, undergoes rigorous evaluation by regulators to determine if the medicine has a favorable benefit–risk profile.

Marketing authorization applications (MAAs) for psychedelics must align with the requirements and evidentiary standards applicable to all medicines. All clinical trials supporting an EU MAA must comply with ICH guidelines for safety and efficacy. In terms of clinical development, these encompass principles for sound trial planning, such as defining primary and secondary end points, justifying sample sizes, and outlining detailed statistical analysis plans.

However, the characteristics of psychedelics present specific challenges in the design and conduct of clinical trials and in the subsequent interpretation of their results. EMA has provided provisional guidance on these aspects in its updated guideline on the clinical investigation of medicinal products for depression, which now includes considerations for psychedelics. ,

The following subsections highlight these challenges in greater detail and outline strategies to mitigate their impact.

1.1. Functional Unblinding

Routine methods to control bias and maintain blinding in clinical trials include randomization, blinding of treatment allocation and administration, and the inclusion of a control group. However, the nature of psychedelic interventions, the limited understanding of the mechanisms by which agents elicit their therapeutic effect, and a highly informed patient population further complicate the blinding process. In 2024 the US Food and Drug Administration (FDA) noted the impact of functional blinding in the clinical trials submitted as part of a new drug application (NDA) for MDMA-assisted psychotherapy for PTSD, which was subsequently declined. Despite the trial’s double-blind design, approximately 90% of subjects assigned to treatment and 75% assigned to placebo were able to accurately guess their treatment allocation. This underscores the critical need for robust blinding methodologies to mitigate bias and ensure the validity of clinical trial results.

Additional measures are required to mitigate functional unblinding due to the pronounced, salient effects of psychedelics, which are often apparent to both participants and investigators. Developing robust blinding procedures tailored to specific psychedelic compounds and administration methods is crucial for minimizing functional unblinding and ensuring the validity and reliability of the data obtained from these trials. These include the use of:

• 1. blinded or independent centralized raters. This concept is illustrated by the Spravato (esketamine) development program, which provides a useful example of how to separate those who assess outcomes from those who administer treatment. In the short term phase 3 studies submitted as part of the MAA for Spravato, independent, remote (telephone-based) blinded raters assessed outcomes using the Montgomery-Åsberg Depression Rating Scale (MADRS). The MADRS scores were derived from patient interviews conducted by these blinded raters. This methodology was adopted to maintain the integrity of the blinding process due to the dissociative effects of esketamine;
• 2. blinding questionnaires to determine the integrity of blinding. Participants are asked to guess their allocation and specify the cues that influenced their choice, such as perceived efficacy or other factors. Tools such as the Bang Blinding Index (BBI) and the Correct Guess Rate Curve (CGRC) can be employed to quantify the degree to which these guesses deviate from random chance. To maintain the integrity of the blinding process and minimize potential biases, such as response bias, it is important to clarify with whom participants should share their guesses. In order to ensure the objectivity of subject’s responses, the timing of ascertaining this information should be carefully planned, ideally immediately postdosing but prior to outcome assessments or the onset of potential treatment effects. Similar questions can also be posed to the investigators;
• 3. controlled trials administering varying dose levels, such as low or comparative doses. Using a range of doses, or an active placebo, can reduce differences in perception between treatment groups, thereby reducing the likelihood of functional unblinding. This is particularly pertinent for trials using higher doses where functional unblinding is of significant concern. Additionally, employing a dose–response design for phase II studies allows for the assessment of the therapeutic window and the identification of the minimum effective dose. Statistical methods, such as dose–response modeling and mixed-effects regression analysis, can be used to analyze the data and facilitate selection of the target dose.

1.2. Expectancy and Nocebo Effects

Expectancy, both positive and negative, can significantly influence treatment outcomes in psychedelic clinical trials. If blinding is compromised, a pronounced synergistic interaction between expectancy and active response in the treatment group, coupled with a reduced expectancy effect in the control group, may hamper interpretation of the results. The emerging collective perception of psychedelics as valid pharmacological tools for mental health disorders, a phenomenon referred to as the ’Pollan effect’, has catalyzed public interest in their therapeutic benefits. Consequently, it is reasonable to assume that positive expectancy is growing. The integrity of the trial can also be undermined by nocebo effects, particularly if patients harbor fears or misconceptions regarding psychedelic treatments. Nocebo effects may also encompass exacerbation of symptoms due to disappointment from receiving placebo instead of the active treatment, as well as disappointment from not experiencing the expected therapeutic response with active treatment.

Strategies to mitigate expectancy and nocebo effects are inherently related to those which aim to mitigate functional unblinding. However, as expectancy is partially shaped by information that participants internalize regarding treatments, comprehensive informed consent procedures and appropriately trained facilitators can mitigate their impact by managing and setting realistic expectations for patients before, during and after treatment. This is particularly pertinent for psychedelics, as participants may have preconceived assertions of efficacy.

Given the significant impact of expectancy effects, it is worth considering whether treatment expectancy should be systematically assessed. Although rarely done and lacking a consensus on the process, tools such as the Stanford Expectations of Treatment Scale (SETS) or the Credibility/Expectancy Questionnaire (CEQ), could potentially be used. ,, These measures could be applied to participants, therapists, and raters, both at baseline and after dosing.

1.3. Psychological Support versus Psychotherapy

Trial protocols for psychedelic development programmes generally include some form of psychological support or psychotherapy. These two approaches have distinct implications: psychological support in the context of psychedelic treatments typically involves a framework to ensure patient safety, such as chaperoning participants during active treatment, while psychotherapy encompasses additional psychotherapeutic interventions. Both approaches typically adhere to a standardized three-stage framework consisting of preparatory, administration and integration sessions. However, in the context of a MAA, the choice of either psychological support or psychotherapy has significant implications for the trial’s design, protocol and the approved conditions for use.

If psychotherapy is an integral part of treatment, it is essential to determine whether the therapeutic benefits are due to the psychedelic compound, the psychotherapeutic intervention, or any synergistic effect. Trials with a factorial design, such as 2 × 2 or higher-order factorials, could provide a systematic approach to delineate these respective contributions by clearly defining treatment factors and levels.

However, there are several challenges associated with conducting these trials, particularly in relation to ethical considerations and methodological rigor. While use of placebo controls is beneficial for isolating treatment effects, it raises significant ethical concerns, which can in turn limit the feasibility of such trials. Furthermore, factorial trials inherently require large sample sizes. Even moderate interactions between treatment components can significantly dilute the power required to detect individual treatment effects, necessitating a robust sample size to achieve adequate statistical power. Alternative multiarm trial designs may offer more practical and ethically acceptable approaches for evaluating multiple interventions simultaneously.

To accurately assess the magnitude and duration of the therapeutic response for psychedelic-assisted psychotherapy, these trials should ensure that there is consistency in the doses or characteristics (i.e., number and duration) of psychotherapy sessions across all conditions. Further consideration must be given to psychotherapy controls, including the potential impact of expectancy effects.

It is also imperative to demonstrate that therapists, in the case of psychotherapy, or facilitators, in the case of psychological support, adhere to the approach specified in the protocol. If psychotherapy is an integral part of treatment, the protocol should specify methods used to ensure the uniformity of the clinical intervention. This does not preclude the possibility that patients may exhibit personalized responses to treatment which should also be anticipated and accommodated in the study protocol (e.g., alternative treatment pathways and criteria for dropout). For psychological support, protocols should empirically define the minimum parameters necessary to ensure patient safety, such as chaperoning the patient, to facilitate standardization and replicability across trial sites, while avoiding the potential for bias due to an unintended therapeutic intervention.

During the workshop, the integration of artificial intelligence (AI) was also mentioned. While the use of AI in medicines’ development presents risks that should be adequately mitigated, its application in areas such as translation and text analysis, particularly for extracting themes and evaluating protocol fidelity, could be considered. Additionally, the use of adherence instruments, such as the therapist adherence and competence scale (TACS) and the manual adherence measure, was also proposed as a method to systematically verify protocol fidelity.

Consideration should also be given to standardization of other parameters within the physical environment or “setting”, such as the music and setup of the room. During the workshop it was noted that existing evidence indicates that setting can contribute to the therapeutic response. However, further research is required to determine the optimal therapeutic setting.

The use of either psychological support or psychotherapy will guide both the indication and usage instructions in the product label. When a psychedelic is to be used in conjunction with a specific psychotherapy, the indication in the product label must clearly state that the psychedelic is to be administered in the context of specific psychedelic-assisted psychotherapy. Conversely, if the psychedelic is to be administered with psychological support which is aimed at ensuring the safety of patients, the product label must accurately reflect the safety parameters outlined in the trial protocol. It is also important to note that medicines regulators do not regulate psychotherapy.

1.4. Patient Populations

Selecting an appropriate patient population for pivotal trials aimed at supporting a MAA is a critical step in the drug development process. It is essential that the characteristics of the trial population align with the intended patient population specified in the indication of the MAA to ensure findings are both relevant and generalizable to the target population.

To achieve this, inclusion and exclusion criteria for pivotal trials must be meticulously defined based on the characteristics of the intended patient population. This includes clear definitions for parameters and demographics such as disease severity, response to previous treatments (refractoriness), age, concomitant medication and comorbidities.

Regarding disease severity, it is crucial that trial participants meet established diagnostic criteria that confirm a specific severity threshold. This is especially important in development programmes for psychedelics targeting treatment-resistant conditions, where inclusion criteria may require patients to have failed to respond to standard first- or second-line treatments. This level of detail will ultimately be reflected within the approved indication for use. Patients with organ dysfunction or chronic conditions may be excluded from the trial due to concerns related to the risk of adverse reactions arising from comorbidities and concomitant medications. For instance, given the potential for classic psychedelics to induce modest and transient sympathomimetic effects, such as hypertension, uncontrolled hypertension may be considered as an exclusion criterion. Additionally, these criteria should address the use of concomitant medication that could potentially mask a treatment effect and affect the interpretation of the results. Exclusion criteria should also encompass patients for whom the treatment may be contraindicated. For example, exclusion of participants who have a history or family history of psychosis or mania should be considered due to the risk of precipitating or exacerbating these conditions.

Trials that include subjects who have prior experience can lead to a selection of more favorable attitudes, potentially skewing results toward a positive outcome which can impact the trials’ external validity. Furthermore, if patients have difficulty verbalising complex emotions, which may be the case for certain subsets such as those with PTSD and alexithymia, clinicians may be less inclined to refer them for enrolment in trials. This can result in a nonrepresentative sample, thereby compromising the generalizability of the findings. ,

While the potential scope of application for psychedelics could be wide, they cannot be considered a panacea for all conditions. Development programmes should commence in patient populations with a high unmet medical need such as for instance, treatment-resistant depression. These patients have limited treatment options and often encounter persisting symptoms which leads to chronicity of depression. This clinical profile is particularly pertinent when assessing the overall benefit–risk profile of novel interventions. For instance, currently Spravato is the only medicine centrally authorized for treatment-resistant Major Depressive Disorder, highlighting the challenges associated with developing innovative therapies that have novel mechanisms.

Given the novelty associated with psychedelics, a stepwise approach in development might be preferred. If, hypothetically, psychedelics were authorized in a population with an unmet medical need, such as individuals with treatment-resistant depression, the resulting safety data could provide valuable insights that may inform future considerations for expanding their indications to broader patient populations. Nevertheless, diversity is also essential in trials to ensure that findings are generalizable across different demographic groups, including ethnicity, age, sex and socioeconomic background, although conducting such trials in a broader, more heterogeneous patient population in support of an MAA may be more challenging.

The optimal place for psychedelics in contemporary psychiatric treatment paradigms remains uncertain and requires further consideration. If a psychedelic medicinal product is authorized, learned societies will also play a role in determining where these treatments fit in the armamentarium and how they should be integrated in clinical guidelines.

1.5. Dose Response Studies and Maintenance of Effect

Dose–response studies are essential components of drug development programmes, enabling the identification of optimal dosing regimens that ensure both safety and efficacy. For psychedelics, this involves characterization of both subjective experiences and established therapeutic outcomes associated with different doses. However, the dose–response relationship for psychedelics is poorly understood, presenting unique challenges.

While it is hypothesized that the therapeutic effects of psychedelics are linked to the intensity and nature of subjective experiences, the precise relationship remains unclear. Dose-finding studies should aim to characterize the relationship between dose, subjective experience and therapeutic response. Scales and questionnaires such as the 11-Dimensional Altered State of Consciousness (11D-ASC) and the States of Consciousness Questionnaire (SCQ) are often used to evaluate subjective experiences. The validity, specificity and sensitivity of these scales are not well established, and their outcomes do not serve as surrogate markers for therapeutic response. During the workshop, it was proposed that neurobiological changes, such as neuroplasticity and disruption of entrenched cognitive patterns, are key to achieving therapeutic effects, especially in the long term. Neuroimaging techniques, such as fMRI and PET, may provide insights into neural dynamics associated with different doses and help elucidate the neurobiological mechanisms underlying therapeutic effects, thereby complementing data from self-reported scales. For instance, PET imaging could be used to explore the relationship between plasma concentration levels and receptor occupancy.

Durability of response, following the dosing session and during the disease episode itself, also requires further characterization to inform on the need for repeat dosing particularly in the context of development programmes targeting chronic conditions. This should be evaluated in long-term studies to accurately assess the maintenance of the therapeutic effect. Further consideration should also be given to characterization of the durability of response based on neuroplasticity mechanisms.

Psychedelics often exhibit nonlinear dose–response dynamics, complicating the optimization of dosing regimens. One of the primary challenges is the variability in subjective effects across different dose levels. At low doses, psychedelics may not induce significant subjective experiences or therapeutic effects. However, as the dose increases to moderate levels, therapeutic benefits may be apparent. In contrast, high doses may not proportionally enhance therapeutic benefits and can lead to overwhelming subjective experiences or adverse reactions, such as anxiety or paranoia. This nonlinear relationship necessitates a careful balance in dosing to maximize therapeutic outcomes while minimizing adverse effects. For instance, studies on LSD have demonstrated that while subjective effects intensify with increasing doses, the therapeutic window is relatively narrow.

During the workshop, there was discussion on whether the subjective experience is a necessary condition for the treatment effect. If the subjective experience and treatment effect is dissociated, the subjective experience may not form a guidance for dosing.

Another challenge lies in determining whether interindividual variability related to factors such as metabolism, age, sex, genetic differences, prior experience with psychedelics and psychological state impact the subjective experience and dose–response relationship. Factors related to the environmental context may also influence both the subjective experience and the therapeutic outcome, complicating the establishment of a standardized dose–response curve.

2. Safety Considerations

Current data characterizing the safety profile of psychedelics is limited, predominantly derived from small-scale clinical trials or illicit use. Furthermore, their safety profile is influenced by various factors, including the setting, patient population, and context of use.

To enable further characterization for a MAA, comprehensive strategies are required. These include determining suitable sample sizes for trials, implementing appropriate controls, developing robust risk management plans, establishing vigilant monitoring protocols, and addressing ethical considerations.

Larger trials with longer durations are necessary, especially to facilitate characterization of the long-term safety profile. However, requirements for specific MAAs may vary based on the treatment regimen, such as single- or repeat-dosing. For example, guidance for the long-term treatment of nonlife-threatening diseases recommends a total patient exposure of approximately 1,500 individuals, with at least 300 and 100 patients using the medicine for six and 12 months, respectively, prior to approval.

2.1. Systematic Documentation and Collection of Adverse Events

Comprehensive and systematic collection of safety data, both in the context of clinical trials and the postmarketing setting, is also essential to determine the frequency, severity, seriousness, and dose–response of adverse events, including differences across patient subsets such as demographics, comorbidities, and/or concomitant therapies. Investigators must document and report all adverse events which meet the ICH-E2D definition, according to the timelines established in the EU Clinical Trial Regulation, unless otherwise specified in the protocol. Serious, unexpected adverse reactions (SUSARs) require expedited reporting to ensure timely risk assessment and management.

A salient aspect is the requirement for consensus-based guidelines regarding the reporting of adverse events related to subjective experiences, both during and after dosing. While these can be subjective and often open to interpretation, these data are ultimately required to inform patients and healthcare providers on what to expect during active treatment and to mitigate risks. , It is therefore imperative to differentiate between transient psychological effects that may be part of the therapeutic experience and adverse events. While an optimal approach has not been empirically defined, development programmes must carefully consider how these events will be defined, assessed and clearly specify this in the protocol.

Several validated psychometric scales are available to assess and describe subjective experiences, each tailored to distinct dimensions. For instance, the Challenging Experience Questionnaire (CEQ) focuses on negative valence while the Hallucinogen Rating Scale (HRS) evaluates aspects such as somaesthesia, perception and cognition, which may encompass adverse events. However, further collaboration is required to determine how they can be used systematically in trials. Other approaches discussed during the workshop included the necessity for investigators to collect comprehensive information on subjective experiences, irrespective of whether they are considered on-target effects, and categorizing any effects that persist beyond the acute phase or that require intervention as adverse events.

Defining adverse events of special interest (AESIs) is crucial to facilitate enhanced, systematic monitoring and evaluation of specific safety concerns. Although a causal relationship between psychedelics and risks of suicidality and psychosis has not been established, both should be considered AESIs.

2.2. Risk Management Plans

A mandatory requirement for all MAA dossiers is a risk management plan (RMP), which not only facilitates further characterization of the product’s safety profile but also outlines how risks will be proactively managed throughout its lifecycle. The RMP’s safety specification summarizes important identified and potential risks, as well as missing information, associated with a particular product. It is based on data ascertained from sources such as non-clinical and clinical studies, the epidemiology of the indication and the target population, and forms the basis for the pharmacovigilance and risk minimization plans.

The RMP’s pharmacovigilance plan outlines the methods used to facilitate further characterization of safety concerns in the safety specification. While routine pharmacovigilance activities, such as adverse event reporting and signal detection, are applicable to all medicines, additional pharmacovigilance activities, such as post-authorization safety studies, may be required to provide a more comprehensive understanding of specific risks in the safety specification. For Spravato, additional pharmacovigilance activities at the time of approval included post-authorization studies, specifically an open-label long-term extension study and a pregnancy registry. These studies aimed to further characterize important potential risks, including cognitive disorders, memory impairment, interstitial cystitis associated with long-term use, and missing information, specifically use during pregnancy.

The RMP’s risk minimization plan should establish a strategic framework to mitigate risks identified in the safety specification through targeted risk minimization measures (RMMs). It should also consider how best to evaluate the effectiveness of specific RMMs. Routine measures, such as the summary of product characteristics, package leaflet, pack size, labeling and legal status, apply to all medicines. For prescription-only medicines, the legal status may be subject to additional conditions including categorization as medicines available with either a restricted medical prescription or a special medical prescription. Additional risk minimization measures, such as educational materials, controlled access programmes, and controlled distribution systems, may be required to mitigate specific risks and are imposed as a condition of the marketing authorization. For Spravato, aRMMs at the time of approval included educational materials for both patients and healthcare professionals to mitigate important identified risks of drug abuse, transient dissociative states and perceptions disorders, disturbances in consciousness and increased blood pressure. A controlled access programme was also implemented to mitigate the risk of drug abuse, restricting Spravato administration to healthcare settings where patients can self-administer under direct healthcare professional supervision. Additionally, a checklist for administration was introduced to aid healthcare professionals in evaluating patients’ stability following Spravato administration, ensuring safe discharge following treatment. This aRMM was implemented to mitigate the important identified risks of transient dissociative states and perceptions disorders, disturbances in consciousness and increased blood pressure. ,

The pharmacovigilance plan also included surveys for both patients and healthcare professionals to assess the effectiveness of specific additional risk minimization measures (aRMMs).

2.3. Facilitators and Informed Consent

Facilitators who chaperone patients during active treatment play an integral role in safeguarding patients. However, patients may be susceptible to manipulation or exploitation during active treatment due to their vulnerable condition.

Development programmes should therefore ensure robust ethical standards and put strategies in place to mitigate the potential for abuse by facilitators. Several proposals were outlined during the workshop, including the requirement for two facilitators to be present during active treatment and ensuring they are well-trained and possess relevant core competencies. Other proposals included dedicated educational programmes for facilitators, which could be provided as supplemental training to those with a relevant background, as well as adherence instruments to ensure they comply with standardized procedures in the protocol.

Robust informed consent procedures are also crucial due to the risks associated with heightened suggestibility and the unpredictability of subjective effects. In the EU, the approval of informed consent for clinical trials falls within the remit of national ethics committees. Member States have specific requirements for informed consent, which are dependent on national legislation. The concept of informed consent in clinical practice is regulated at the national level by or by codes of deontology for healthcare professionals. Consequently, EMA does not enforce these obligations. However, educational materials, implemented through the RMP, could be used to ensure patients are fully informed of all risks associated with treatment if a psychedelic medicine is authorized.

3. Regulatory Platforms and Support Structures

As noted by EMA experts during the workshop, the optimal approach to support the development of psychedelic medicines and to characterize their benefit–risk profile in specific indications has yet to be empirically defined. Recommendations in existing EU guidelines reflect the current state of knowledge in the field, gathered through procedures such as scientific advice or stakeholder engagement. These guidelines are subject to change and will be updated as new data emerges.

Developers are encouraged to engage with EU regulators at an early stage so that regulatory challenges can be addressed in a way that considers the specific attributes of individual development programmes. Given the aforementioned methodological challenges and complexities associated with the development of safe and effective psychedelic medicines, developers are strongly advised to engage early with EMA. This can be facilitated through the Agency’s scientific advice procedure or protocol assistance, which enables developers to receive feedback on dedicated questions related to their development programme. Scientific advice is prospective in nature and can cover various aspects, including quality, clinical, non-clinical, and methodological issues. Additionally, scientific advice can be revisited and requested at various key points during development, ensuring optimal support for devising the most effective development programme. EMA also provides scientific advice to support the qualification of novel methodologies, such as biomarkers or imaging methods. In this process, the Agency’s committee for human medicines (CHMP) provides an opinion on the regulatory acceptability of a novel method for its intended application.

Developers of psychedelic medicines can also avail of support from the Agency through other scientific and regulatory platforms and tools. For instance, EMA’s Innovation Task Force (ITF) provides a forum for early dialogue with developers of innovative medicines and technologies. This forum facilitates discussions on the scientific, technical, and regulatory aspects of novel therapies, helping to identify potential challenges early in the development trajectory and providing strategic guidance on how they are best addressed.

The Agency’s PRIME (PRIority MEdicines) scheme is designed to enhance support for the development of medicines that target unmet medical needs. Through PRIME, EMA offers early and proactive support to optimize the generation of robust data on a medicine’s benefits and risks, enabling accelerated assessment of MAAs. This scheme includes early appointment of rapporteurs, kick-off meetings with multidisciplinary experts, and iterative scientific advice.

EMA also collaborates with HTA bodies through parallel scientific consultations. This collaboration aims to align evidence requirements and streamline the development process, ensuring that data generated meets the needs of both regulatory and HTA bodies.

The Agency’s small and medium-sized enterprise (SME) office can also provide advice, guidance and assistance to SMEs who intend to develop and market psychedelic medicines in the EU and EEA.

4. Conclusion

As with all medicines, MAAs for psychedelics must comply with the evidentiary standards and requirements established by the EU regulatory framework. The intrinsic characteristics of psychedelics present challenges in designing, conducting, and interpreting trials to characterize their benefit–risk profile. However, measures can be implemented to mitigate these challenges. Knowledge gaps exist in the field, such as how the subjective experience is associated with and affects therapeutic outcomes. These gaps can only be addressed through the generation of reliable and valid data. It is crucial for developers to engage with regulators at an early stage to ensure that data generated meets regulatory expectations and addresses these unique challenges and knowledge gaps. Such engagement also facilitates the development of evidence-based guidelines thereby advancing the development of safe and efficacious psychedelic medicines. Cross-sector and multidisciplinary collaboration is also necessary to establish the optimal treatment paradigm, including the generation of clinical guidelines for psychedelics and relevant standards for healthcare professionals who will be involved in their administration and oversight.

The views expressed in this Viewpoint are the personal views of the author(s) and may not be understood or quoted as being made on behalf of or reflecting the position of the regulatory agency/agencies or organizations with which the author(s) is/are employed/affiliated.

The authors declare no competing financial interest.

Published as part of ACS Pharmacology & Translational Science special issue “Psychedelics and Entactogens”.