Perspectives

Psychedelics in Drug Development and Regulatory Considerations Part I: Benefit-Risk

The systematic study of psychedelics in drug development programs is a relatively recent phenomenon with psychedelics currently under evaluation in clinical trials for the treatment of anxiety, depression, bipolar disorder, epilepsy, obesity, and substance addiction. Such clinical studies are essential in determining the safety and efficacy of these therapies within medically supervised contexts.

Nonmedical use of psychedelics can cause acute anxiety or panic reaction in response, often referred to as a “bad trip”, along with physical harm to the users including toxicity.

Long term use of classic hallucinogens, including lysergic acid diethylamide (LSD), mescaline, and psilocybin, is known to cause persistent psychosis and hallucinogen persisting perception disorder (HPPD). The challenge for regulators is to balance the known risks of nonmedical use with the potential therapeutic benefits of psychedelic therapy in a manner that safely facilitates the conduct of clinical trials and eventual drug approval.

For Sponsors, understanding this benefit-risk framework is essential for effective and fruitful communication with global health authorities at all stages of psychedelic drug development.

It is important to note that all benefit-risk frameworks are dynamic. They attempt to represent what is known broadly about a given mechanism of action within the context of a specific development program and patient population. When knowledge about a specific mechanism of action is extensive and controversial, challenges in clinical development increase, and it becomes critical for pharmaceutical sponsors to understand and prepare for them. In the spirit of fostering this preparation, a summary of regulatory challenges unique to psychedelics in drug development is provided below.

Current Regulations in Core Regions

The Health Canada Special Access Program permits health care practitioners to request access to drugs that have shown promise in clinical trials or been approved in other countries, but that have not yet been authorized for sale in Canada. Magic mushrooms, psilocybin, and psilocin are illegal to produce, sell, or possess without a license or exemption.

For all clinical trial applications involving psychedelic drugs, therapists must be properly trained must be properly trained on evidence-informed protocols for psychedelic-assisted psychotherapy and be licensed to provide psychotherapy by a regulatory body (if applicable in their jurisdiction).

The Therapeutic Goods Administration (TGA) reclassified psilocybin and methyl-enedioxy-methamphetamine (MDMA) from Schedule 9 (prohibited substances) to Schedule 8 (controlled drugs) in 2023. The TGA also introduced the Authorized Prescriber Scheme, which enables authorized psychiatrists with experience relevant to the specific condition and clinical use of psychedelic therapies to prescribe unregistered drugs, including psilocybin and MDMA, for patients with specific treatment-resistant conditions: Psilocybin can be prescribed for treatment-resistant depression, while MDMA can be prescribed for PTSD.

The European Medical Association (EMA) held a multi-stakeholder workshop in April 2024 to establish regulatory guidelines for the development and therapeutic use of psychedelic substances in Europe. The workshop aimed to discuss the development and therapeutic use of psychedelic substances to address unmet needs in mental health, to define the safe and effective use of psychedelics in drug development, and to identify regulatory challenges associated with the development and evaluation of psychedelic medicines.

In the US, the proposed Breakthrough Therapies Act, reintroduced in 2023, aims to reduce regulatory hurdles in compassionate use and research by providing access to heavily restricted substances in Schedule I of the Controlled Substances Act. Breakthrough therapies are defined as those that exhibit significant improvement compared to currently available therapies and this act will enable the Drug Enforcement Agency (DEA) to allow reclassification and transfer of breakthrough therapies involving Schedule I substances such as MDMA and psilocybin to Schedule II. There is ongoing clinical trial investigation and discussion on greater patient access in the psychedelic drug development space.

A Comparison of guidelines on clinical trials for psychedelics

FDA Guidelines

The latest FDA guidance on “Psychedelic Drugs: Considerations for Clinical Investigations” under an investigational new drug application (IND) and academic studies discusses the following:

Sponsors should explore specific listed drug-‑drug and drug-disease interactions and dose responses in any clinical pharmacology testing. Currently, FDA recommends that Sponsors exclude subjects with preexisting valvulopathy or pulmonary hypertension from multiple-dose studies of drugs with this mechanism until the risk of cardiac valve stiffening with 5-HT2B agonists can be better characterized.
Abuse potential assessment: Sponsors should closely assess the abuse potential of drug product under development.
- - Data from abuse potential assessments and proposal for drug scheduling under the Controlled Substances Act are required to be included in a new drug application submission.
  - Psychedelic drugs that are Schedule I controlled substances must comply with the applicable DEA regulations.
  - Sponsors are encouraged to discuss their plans for an abuse potential assessment with the FDA early in the IND stage of drug development.
  - An assessment of the potential for physical dependence with a psychedelic drug may be appropriate as part of the abuse potential assessment, depending on the proposed conditions of use for which the drug is being studied (e.g., acute intermittent use versus prolonged continuous use).
  - For more information on abuse potential assessment, Sponsors are encouraged to refer to the guidance “Assessment of Abuse Potential of Drugs”

The FDA indicated that the substantial evidence standard for establishing effectiveness of psychedelic drugs is similar to that for other drugs. However, the agency also acknowledged that Sponsors should consider the unique characteristics of psychedelics when designing clinical trials.
- - Adequate and well-controlled clinical studies are generally required to meet the substantial evidence standard to establish effectiveness in a marketing application. However, these studies pose a challenge in psychedelic drug development as use of a placebo is not advisable. Agency recommendations for controls include subperceptual doses of a psychedelic drug or other psychoactive drugs that mimic some aspects of the psychedelic experience, etc.
  - Complementary trial designs across phases 2 and 3 could address different challenges, e.g., a trial using a low, middle, and high dose without a placebo could be paired with a placebo-controlled trial.
  - Many of the psychedelic drug development programs involve administering the investigational drug and then engaging in psychological support or psychotherapy either while the subject is experiencing the acute effects of the drug or in a subsequent session. As psychotherapeutic interventions have the potential to increase expectancy and performance biases, a factorial design may be useful for characterizing the separate contributions of drug and psychotherapy to any observed treatment response.
  - FDA may place an IND under hold if the agency feels that there are substantial risks to human participants. Hence, safety monitoring by two appropriately qualified monitors, such as someone with a qualification in psychotherapy and another with experience in a mental health care setting, are recommended.
  - For drugs that have been shown to have functional activity at the 5-HT2B receptor, like selective serotonin reuptake inhibitors (SSRI), baseline and follow-up echocardiograms to assess valve structure and function and pulmonary artery pressures are recommended, especially if the drug is indicated for long term use.
  - Sponsors should address how adverse events or serious risks are mitigated during the clinical studies and if similar strategies can be implemented post marketing.
  - FDA may consider the public health effects of the drug as part of the overall benefit-risk assessment. Public health effects of the drug include its potential effect on risks that are related to nonmedical use, substance use disorder, accidental exposure, and overdose for patients and nonpatients.

EMA Guidelines

While the European Medicines Agency has not released a guidance on psychedelics at the time of this blog post, the September 2023 draft guideline on clinical investigation of medicinal products in the treatment of depression provides some insight into their thinking on this topic. The guideline acknowledges the research and development of psychedelics for the treatment of depression, it highlights challenges in clinical development such as:

The use of placebo/appropriate comparator is difficult due to altering of brain function while using psychedelics.
Risk of unblinding and expectancy bias: Positive expectancy might lead to overestimation bias while disappointment with treatment (negative expectancy) might lead to symptom worsening or safety issues (nocebo effect). Use of substances with different mechanisms of action but similar effects have been recommended along with the use of independent and blinded external raters to mitigate the effects.
The dose-relationship is difficult to characterize because of many factors, including:
- Variance in the characteristics of acute psychedelic experience and associated clinical improvement.
- The need for individualized dosing due to individual variability in drug metabolism, age, sex, or personality traits.
Maintenance of effect and need for recurrent dosing.
The ability to change perception of reality, addiction potential, suicide potential, hypertension, and drug-drug interactions all require assessment. Hence, psychedelics must be administered in a controlled environment. The guideline emphasizes the need for specific considerations in the development of psychedelics, including the use of validated assessment tools, the importance of monitoring suicidal thoughts and behavior, and the need for studies on efficacy and safety in special populations. The guideline suggests starting clinical investigations in a more severely affected population, such as patients with treatment-resistant depression.
Monotherapy with psychedelics may not be always feasible. In these studies, monotherapy means psychedelic therapy with no associated psychotherapy. While employing associated psychotherapy, the process must conclusively prove that the effects seen are not due to psychotherapy but due to psychedelics. Hence, the duration, type, and frequency of psychotherapy needs to be standardized for an accurate assessment.

Psychedelic drug development is fraught with challenges in clinical trial design, safety monitoring, regulatory agency interactions, and extensive trial documentation.

Stay tuned for our next blog post on the changing lexicon of psychedelics in drug development, as global health authorities and regulatory agencies in the pharmaceutical industry are familiar with the importance of terminology and are starting to recognize the stigma and negative bias related with the terms “abuse” and “addiction.” This shift in lexicon to new terms such as “substance use disorder” and “nonmedical use” has implications for prescription information and labelling for drugs that have central nervous system activity.

At MMS, we have a team of industry experts, including clinical scientists, regulatory strategists, and pharmacovigilance experts, with extensive experience that can help Sponsors address challenges in psychedelic drug development.

For questions on this and other Psychedelics services, please click here and we will connect you with the appropriate expert.