Background: Psychedelic drug development and regulatory context

• A growing body of evidence suggests that psychedelics may provide clinical benefit for certain purposes, especially mental health conditions. Psychedelic drugs primarily influence the way the brain processes the chemical serotonin, which can lead to vivid visions and alterations to a person’s sense of self, according to the National Institutes of Health. Classic psychedelics include serotonergic agonists such as psilocybin (from psychedelic mushrooms) and lysergic acid diethylamide (LSD). Other substances that also typically fall into this category are entactogens or empathogens, such as 3,4-methylenedioxy-methamphetamine (MDMA, or “ecstasy”). However, the road to research for these products is paved with obstacles.
• For example, the actual experience before, during, and after a single dose of a psychedelic substance may significantly alter the participant’s long-term outcomes. Research indicates that the effects from these substances for the treatment of mental health disorders may be both rapid in onset and long-lasting. This suggests that patients may only require a single dose, or few repeat doses, to achieve therapeutic benefit. However, most experts agree that the experience after drug administration, often referred to as “set and setting,” can dramatically affect outcomes. Most research to date has provided doses in a highly controlled, positive environment, often with a licensed mental health practitioner present to help guide the participant through the experience. Many studies have also employed a follow-up session for the participant to discuss their experience with the practitioner. This contrasts dramatically with the experience of using these substances in a home or social setting.

Status check on European psychedelic landscape

• Currently, there is no E.U. psychedelic-specific guidance. As AgencyIQ previously reported, the closest psychedelic-specific regulatory resource is the draft guideline on clinical investigation of medicinal products in the treatment of depression – Revision 3. This draft guideline, which was open for public comments from September 15, 2023, through March 31, 2024, aims to modernize its set of criteria for developing medicines to treat depression since the guideline has not been updated since 2013. Curiously, psychedelics considerations are addressed in only two sub-sections of the methodology section.
• The section on psychedelics clarifies that the EMA’s definition includes “classical hallucinogens,” such as psilocybin, LSD, and mescaline, as well as entactogens like MDMA and dissociative anesthetics such as ketamine and esketamine. The guideline recommends beginning investigation in “a more severely affected population,” such as patients with treatment resistant depression.
• The EMA lays out several challenges in studying psychedelics, including the risk of functional unblinding and difficulty choosing a placebo or comparator, finding an appropriate dose, showing maintenance of effect, and establishing a safe trial environment. Importantly, the draft guideline also addresses the issue of psychological support that ordinarily accompanies administration of psychedelics. Recognizing that extensive pre- and post-administration support, as well as attendance during an hours-long dosing experience, is a customary part of psychedelic administration, the EMA recommends that applicants address these and other issues unique to the drug classes by seeking scientific advice before beginning trials. [ See AgencyIQ’s analysis on EMA’s draft guidance on clinical trials to treat depression].
• Zooming out, the legal classification of psychedelics in the European Medicines Regulatory Network (EMRN) is primarily left to Member States. The legal classification of psychedelics is not within the EMA’s remit. Instead scheduling is dependent on the “ specific substance and the national legislation in each EU Member state.” although most are generally classified as controlled substances and their production and access are often highly restricted. All Member States have signed onto the United Nations Convention on Psychotropic Substances of 1971, which classifies psychedelic drugs as Schedule 1 substances, meaning that there is little to no therapeutic benefit and there is a high potential for abuse. Although the E.U. has adopted some measures to spur Member States to harmonize their approach towards regulating the possession and research use of narcotics, the specifics nonetheless vary from jurisdiction to jurisdiction.
• This legal paradigm often hinders the spread of psychedelic clinical trials but there is still substantial interest in growing their presence. For example, there are pathways for continued research under existing E.U. funding frameworks, such as Horizon Europe and the Innovative Health Initiative. Through these programs, the EMRN has seen a rise in the number of psychedelic clinical trials that address various central nervous system conditions; from February 2023 to April 2024, the number of ongoing psilocybin trials grew from 11 to 19, MDMA trials grew from four to seven, and LSD trials grew from one to three.
• EMA has not offered any more updates guiding psychedelics developers since it released its third revision of the major depressive disorder guideline for public comments. Many of the challenges identified in that document featured prominently in a recent EMA-hosted workshop on regulation of psychedelics, where attendees shared both regulatory challenges and innovative approaches to studying therapies in this area.

An overview of the EMA’s psychedelic workshop

• The EMA recently gathered an array of psychedelic stakeholders to discuss developing psychedelic medicinal products. The April 2024 multi-day workshop showcased presentations and panels from various regulators, trade groups, academics and patient advocates. Notably, in addition to five academic presentations, the workshop featured presentations from the U.S. FDA’s Deputy Center Director for Substance Use and Behavioral Health MARTA SOKOLOWSKA, the Australian Therapeutic Goods Administration’s Chief Medical Officer for its Health Product’s Regulatory Group ROBYN LANGHAM, and the German regulator BfArM’s Head of Neurology, Psychiatry, and Ophthalmology MARION HABERKAMP. (Haberkamp was the chief author of the EMA’s draft guideline for depression treatments.) Additionally, representatives from trade groups and professional societies – like the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the European Psychiatric Association (EPA) – participated in several panels discussions alongside patient advocacy groups like the Psychedelic Participant Advocacy Network (PsyPAN).
• During the workshop, presenters and participants primarily discussed how psychedelic clinical research can fit in the EMA’s existing regulatory guidelines. In addition to highlighting ongoing research, some of the most important regulatory topics covered included study design approaches, accurate evaluation of data, and the role of drug regulation versus clinical regulation, among other topics. To capture the insights from the multiple presentations and discussion, EMA recently shared a report summarizing the major points from the event. The main takeaway from the report is that the EMA recognizes that psychedelics stakeholders still face mighty R&D and legal obstacles but that “ measures can be implemented to mitigate their impact.”
• At a high level, the report highlights psychedelic study design challenges, EMA’s measures to mitigate the challenges, and stakeholder feedback. The opportunities highlighted in the report center around the promise of addressing a prevalent, unmet need and further integrating innovative technology, like using artificial intelligence to “ provide simultaneous translation and text creation while collecting analytics on the data.” However, the report primarily focuses on the factors that are bottlenecking the expansion of psychedelic clinical trials. Among the list of challenges the report outlines, AgencyIQ pulled out three key themes – bias, psychotherapeutic interventions, participant selection – that capture the complexity of the psychedelic landscape.

The problems of functional unblinding and expectancy bias

• Functional unblinding poses a significant study design challenge for sponsors because it blurs the line between comparator and treatment groups. The report notes that properly designed and conducted clinical trials are the gold standard for sponsors to demonstrate a drug’s efficacy and safety and psychedelic drugs are no exception. However, the unique effects of psychedelic products can present a barrier to adequate blinding. Additionally, many patients enrolled in these studies may have preconceived expectations related to the upcoming experience, referred to as response expectancy, leading patients to correctly guess their study arm assignment, either validating expected effects of the study drug or provoking frustration that the perceived therapeutic effects aren’t experienced. Further, psychedelic clinical trials may be more likely to enroll patients who have had previous experience with psychedelics. All of these factors can make it difficult for investigators to achieve the aims of a randomized, double-blind placebo-controlled trial and complicate sponsors’ interpretation of efficacy and safety data.
• The report offers several strategies to mitigate bias in the study design. The report proposes three strategies to mitigate the effect of functional unblinding, including: (1) remote, blinded independent raters (which was used in Janssen-Cilag International NV’s development program for its antidepressant, Spravato [esketamine]); (2) post-participation blinding questionnaires given to both groups to assess the impact of functional unblinding; and (3) administering different dosage levels to “introduce some uncertainty in the treatment allocation.” Additionally, regarding possible solutions, the report also briefly highlighted ongoing clinical trials evaluating the effectiveness of ketamine and midazolam as a comparator to psilocybin for treatment-resistant depression and in cancer patients. Lastly, the report noted that effective blinding is most important when subjective scales are used for assessment; it also may be less critical when the treatment effect is since blinding is “ substantial.”
• Stakeholders were critical of EMA’s proposed mitigating measures. Although stakeholders, such as the European College of Neuropsychopharmacology (ECNP) and the European pharmaceutical trade association EFPIA recognized that the Agency’s outlined blinding measures could be helpful, they countered that the mitigating measures do not overcome a central issue – “ functional unblinding may bias efficacy interpretation.” Further, other representatives from academia and industry questioned whether regulatory agencies place too much emphasis on blinding given that obstacles related to effective blinding are not unique to psychedelics. Additionally, stakeholders from academia, the Psychedelic Access and Research European Alliance (PAREA), and the European Brain Council (EBC) observed that the existing frameworks are designed primarily designed for conventional medicines and proposed that the “ gold standard of randomized controlled trials may not fit psychedelics.”

Psychotherapeutic interventions

• Psychedelic products are often accompanied with some variation of “psychological support or psychotherapy.” The EMA differentiates between these terms, holding that psychological support is focused on ensuring the safety of a patient, such as by “ chaperoning them during active treatment,” while psychotherapy involves an additional “ psychotherapeutic in intervention,” moving beyond safety concerns to integrating the psychotherapy as an integral part of treatment. Despite their differences, these roles are understood to contribute to the “set and setting” of a psychedelic clinical trial (these terms were coined early in the course of psychedelic research to refer to patient mindset and the physical and social environment, respectively). In many trials, both psychological support and psychotherapy have similar baseline frameworks with three stages: (1) offering preparatory sessions prior to administration; (2) administrating the sessions; and (3) following up with a patient to assess their experience and subsequent insights (i.e., integration sessions).
• From the EMA’s perspective, psychological support aimed solely at ensuring patient safety in support of marketing authorization applications (MAAs) for psychedelics can be “ described and standardized” in a clinical trial’s protocol and setting description.
• Conversely, pairing psychotherapy alongside psychedelic administration adds more burden to a sponsor’s study design; the EMA report observed that sponsors would “likely” need to use a factorial study design to assess the relative contributions of psychotherapy and the psychedelic to “ relevant efficacy endpoints.”
• Another wrinkle in adoption of psychotherapy is that regulating the practice of medicine falls outside of the EMA’s remit. The role of a medicinal products regulatory authority like the EMA is to ensure that health care professionals and patients can access safe and effective medical products; however, the role of determining how clinical support (psychological support versus psychotherapy) is integrated into existing clinical practice guidelines or which patients would benefit from a specific type of support does not fall within the EMA’s scope. Accordingly, the agency cannot define an optimal psychotherapy approach, and the EMA noted that the burden of scoping out such an approach should fall onto the professional bodies or learned societies that regulate and guide clinician practice. Additionally, the EMA spotlighted the U.S.’s FDA approach to the issue of medical products vs clinical regulation. According to the FDA, once a psychedelic treatment is available to the public, it does not “ regulate the medical practice that would be applying such treatments.” However, the FDA did note that it has worked with state medical boards on their approach towards regulating psychotherapy in clinical settings where psychedelics are used.
• Stakeholders were divided on the utility of psychological support versus psychotherapy. Overall, stakeholders agreed that adopting a standardized, empirical framework to integrate phycological support or psychotherapy is a challenge for all sponsors. Additionally, representatives from PAREA noted that a patient’s level of support during a psychedelic administration is highly variable and may depend not only on the type of psychedelic, but also on its intended therapeutic indication. However, representatives from EFPIA advocated against the use of psychotherapy in psychedelic clinical trials, since other than MDMA-assisted psychotherapy for PTSD, most drug development programs do not involve this clinical practice and the psychotherapy component may introduce bias in the assessment of the drug’s efficacy. Conversely, representatives from the PsyPAN said that in their experience, most trial participants want (or need) additional therapeutic services to “help them achieve lasting change and prolong response and remission.”
• A possible solution to address the varying levels of patient support, proposed by PAREA and endorsed by PsyPAN, would be to establish a pan-European multidisciplinary advisory board. This group could establish a comprehensive E.U. mental health support framework that recommends models of care, crafts ethical guidelines and sets safety standards.

Participant selection

• Clearly defining comprehensive inclusion and exclusion criteria to select trial participant is difficult given that there are many unknowns. The EMA report explained that to establish a positive benefit-risk balance, sponsors should consider several key factors, such as disease severity, responses to prior treatments(especially for those patients facing treatment resistance), demographics (like age or sex), concomitant medicines and comorbidities.
• However, sponsors may face significant challenges selecting in patient selection: Psychedelic products are often evaluated for severe psychiatric diseases, such as treatment-resistant depression (TRD) and PTSD. Since polypharmacy is common among this category of patients, the report also emphasizes the importance of inclusion and exclusion criteria for patients taking concomitant medicines. Although sponsors are responsible for assessing whether a potential drug-drug interaction could impact the results of their evaluation or cause participants harm, not much is known about how and to what extent psychedelics may interact with other psychiatric medicines. For example, some literature suggests that selective serotonin reuptake inhibitors (SSRIs) may diminish the therapeutic effects of psychedelics, although it does not appear that other medicines have a negative impact on psilocybin.
• The EMA recommends that sponsors focus on selecting s participant population with high, unmet medical needs, to increase the probability of treatment effect. One example of such a group would be patients with TRD. Although studying a broader population is possible, the EMA advises against sponsors taking this approach because generating confirmatory safety and efficacy data may be more challenging. Data could later be applied to a “broader patient population with a less severe disease” and help gain more insight into an optimal treatment paradigm. However, the EMA emphasizes that it is still the responsibility of learned societies to offer treatment guidelines for patient cohorts.
• Discussions from stakeholders emphasized that a lack of understanding of disease burden makes selecting an “ideal” patient cohort a challenging feat, even in a smaller patient group. Although the EMA noted that enrolling patients with a specific, high unmet need will likely yield the best clinical trial data, an industry representative countered that early intervention for a potentially broader patient group is key because “psychiatric diseases such as depression have a higher risk of further episodes.” A clinician also explained that depressive episodes can be neurotoxic and possibly lead to a reduction in volume of the brain’s hippocampus.

A snapshot of global psychedelics regulation

• At the workshop, several global regulators also weighed in on their national efforts to advance the marketing of psychedelic products. The report highlighted presentations by the Australian Therapeutics Goods Administration (TGA), Health Canada and the U.S. FDA sharing timelines of their regulatory work.
• In Australia, certain psychedelics have been rescheduled to allow approved psychiatrists to administer the drug. Prior to 2023, all psychedelics were labeled under Australia’s scheduling policy framework as a schedule 9 “prohibited substance,” meaning that drug was deemed to have “ no therapeutic value” and that the “benefits of use are substantially outweighed by the risks.” However, following a two-year effort where regulators and other government officials weighed the opinions of expert groups, analyzed existing evidence, and sought public consultation, Australia moved to reschedule MDMA and psylocibin to a schedule eight “controlled drug,” still conferring stringent safeguards. Therefore, as of July 1, 2023, patients can be prescribed MDMA and/or psylocibin, in combination with psychotherapy, to manage TRD and PTSD in certain cases. Importantly, this rescheduling did not register MDMA or psylocibin as medicines. Consequently, the TGA developed a mechanism, named the Authorized Prescriber pathway, to allow certain psychiatrists to apply to be able to administer one (or both) of the schedule 8 psychedelic drugs. As of April 16, 2024, there are nine authorized prescribers who can prescribe MDMA for PTSD, or psylocibin for TRD, or both.
• Health Canada’s case study demonstrates how legislative reversals can impact access to psychedelics. From 2013-2021, the Canadian government classified psychedelics as a restricted drug in Part J of the Food and Drug Regulations, meaning that Canda did not recognize any approved medical uses. Health Canada does have a specific pathway – the Special Access Program (SAP) – where restricted or unapproved drugs can be given to patients who have life threatening conditions where “ conventional therapies have failed, are unsuitable or are unavailable”; however, due to regulatory amendments to the Food and Drugs Regulations in 2013, psychedelics were the only the class of drug that could not be requested through the SAP.
• Fast forwarding to 2020, Health Canada moved to amend the Food and Drugs Regulation to once again restore psychedelic drugs’ inclusion in SAP; after a lengthy public consultation period and expert evaluation of more recent psychedelic research, Health Canada ultimately did move MDMA and psilocybin back into SAP. As of January 2022, health care professionals can apply to provide specific patients psychedelic-assisted psychotherapy. Since adopting the amendments to the Food and Drug Regulation, 200 Canadian patients have received psilocybin for either major depressive disorder (MDD) or end-of-life psychological distress, and 40 patients have received MDMA for PTSD, all under SAP. Additionally, Health Canda is working to establish a scientific mental health expert committee to “ examine the Canadian clinical context for treating different mental health conditions.”
• The FDA, and other federal agencies, have been addressing how psychedelics are studied and regulated. In the U.S., nearly all psychedelics are classified as Schedule I drugs under the Controlled Substance Act (CSA), meaning that research programs evaluating these substances are subject to additional oversight from U.S. Drug Enforcement Administration. Also, when a substance is scheduled under the CSA, companies may find it difficult to obtain sufficient supplies to run clinical trials and gather data and evidence to support their marketing efforts. However, in December 2023, the National Defense Authorization Act for Fiscal Year 2024 included a specific mandate that the Department of Defense investigate the therapeutic impact of certain psychedelics on patients with PTSD or traumatic brain injuries.
• Additionally, as AgencyIQ previously reported, the FDA in June 2023 released a draft guidance on development of psychedelic medicines for public comment. Safety and risk mitigation are prominent components of the draft guidance, with discussion on topics ranging from assessing abuse potential, to conducting regular echocardiograms, to requiring study facilitators to have specific training, experience, and credentials. AgencyIQ also reviewed the 223 comments that FDA received; a key takeaway is that there is a large disconnect between the FDA and stakeholders regarding best practices. However, new clinical trial research is still ongoing, especially given that since 2017, some psychedelics under development to treat mental health conditions have been granted breakthrough therapy designation by the FDA.

What’s next

• Despite the fact that the EMA consistently reminded workshop participants that regulating the practice of medicine (such as defining the optimal treatment paradigm regarding psychotherapy) is outside of its remit, stakeholders still sought direction. For example, the European Psychiatric Association (EPA) called for more guidance from the EMA on how to account for factors such as integration sessions in the design of psychedelic clinical trials.
• The current lack of direction on such specifics is compounded by the lack of a specific guideline for development of psychedelic therapies. The most current guidance is the slim section addressing psychedelics within the third revision of EMA’s draft anti-depressant guideline. Additionally, EMA has also not addressed the question of developing psychedelic drugs for any indication other than depression, potentially leaving developers who wish to investigate treatment of PTSD, anxiety, or other psychiatric developers in the dark about key questions such as endpoint selection, study population, trial duration, long-term follow-up, and more.
• Regarding this lack of specific guidelines, the EMA shared that further guidance may be introduced once a “ sufficient evidence base has been established to identify the optimal approach to support drug development and characterize the benefit-risk.” Until this changes, sponsors will likely need to request scientific advice early and consult frequently with regulators throughout their studies.
• The workshop’s inclusion of other leading regulators was noteworthy. Sokolowska, a senior FDA official, attended in-person, continuing a conversation among global regulators about how to address the regulatory challenges of psychedelics as medicinal products. In the fall of 2023, the EMA’s FLORENCE BUTLEN teamed with a representative from U.S. industry to anchor a psychedelics-focused plenary session at the annual Regulatory Affairs Professionals Society (RAPS) Convergence meeting. The issues raised in that session mirrored those in the spring workshop and the recent EMA report, showing that even if global regulators haven’t yet figured out how to resolve some conundrums in psychedelic drug development, they are at least in agreement about where the problems lie.
• In contrast to the situation in Europe, the U.S. has published psychedelic-specific guidance and has several ongoing psychedelic clinical trials. Additionally, the EMA’s report did highlight how the FDA has been communicating with state boards on their regulation of psychotherapy performed concomitantly with psychedelic use. The report considers a slightly different approach that would collaborate with regulators and professional societies to set these parameters and foster pan-European collaboration.
• Additionally, the Australian TGA case study highlights a potentially applicable pathway to better integrate psychotherapy into psychedelic interventions. The TGA also shares the EMA’s and FDA’s view on regulatory remit. However, their case study highlights how a high degree of collaboration between medicines and clinical regulators can help clinicians participate in the development of psychedelic therapies.
• One area that was mentioned throughout many presentations but not prominently featured in the report is the administrative and financial burdens of conducting these clinical trials. Given that psychedelics are not universally legalized, sponsors can have trouble accessing national funds or even the drugs themselves. For example, during PAREA’s presentation on the impact of the E.U.’s legal status on psychedelic R&D, they highlighted a quote from a psychedelic researcher, DAVID NUTT, that underscores the administrative challenges of carrying out a trial: “Our first psilocybin depression trial took 32 months to get permissions to buy and import psilocybin for all largely due to regulations.”
• Additionally, the high cost of these trials was a point that was raised by an industry representative during the European College of Neuropsychopharmacology’s (ENCP) discussion on conducting trials in combination with psychotherapeutic interventions; especially for larger trials, these expenses could represent disincentives for firms to continue investigation of psychedelics. The report did not offer any concrete solutions to these administrative and financial burdens. However, during Haberkamp’s presentation on the European regulatory perspective, she highlighted that in January 2024, the E.U. funded a planned large psychedelic study for patients with incurable diseases, information also reported by our colleagues at POLITICO. This study, set to begin in January 2025, received 6.5 million euros from the E.U.’s Horizon Europe program; it may serve both as an important data generation source and as a regulatory proving ground as Europe finds its way in this complicated field.

Featuring previous research by Chelsey McIntyre and Kari Oakes.

To contact the author of this item, please email Sebastian Godoy ( sgodoy@agencyiq.com)
To contact the editor of this item, please email Kari Oakes ( koakes@agencyiq.com).

Key Documents and Dates

• EMA multi-stakeholder workshop on psychedelics – Towards an EU regulatory framework, April 16 and 17, 2024
• EMA multistakeholder workshop on psychedelics – Workshop report, July 16, 2024