Interest in the therapeutic potential of psychedelic drugs has a long history across the globe. More recently, pharmaceutical companies, researchers, and academics have been evaluating the transformative potential of psychedelics through the pharmaceutical development pathway. Importantly, the Food, Drug, and Cosmetic Act (FDCA) and the Controlled Substances Act (CSA) can be, and have been, navigated to bring novel products to market, including substances controlled in Schedule I of the CSA, the most restrictive schedule. The draft guidance notes that for psychedelic drugs that are controlled substances, activities associated with investigations under an IND must comply with the applicable CSA statutory provisions and Drug Enforcement Administration (DEA) regulations, including those for research, manufacturing, importation/exportation, handling, and security requirements. For substances in Schedule I, additional DEA consideration of the protocol and registration of the investigator is required. The draft guidance advises sponsors to contact DEA to discuss and ensure compliance with all applicable DEA requirements.

FDA recognizes in new draft guidance that “designing clinical studies to evaluate the safety and effectiveness of these compounds presents a number of unique challenges.” Accordingly, the agency is now offering regulatory compliance recommendations to sponsors developing psychedelic drugs for treatment of a range of medical conditions. The new draft guidance summarizes the following general considerations for drug development programs evaluating the therapeutic potential of psychedelic drugs.

CMC compliance: Botanicals vs. Synthetic and Biotechnology-derived products

For all clinical trials, sponsors must provide sufficient chemistry, manufacturing, and controls (CMC) information to ensure proper identification, quality, purity, and strength of the investigational drug substance and drug product. For research on psychedelic drugs, FDA notes that when using plant material, algae, macroscopic fungi (or a combination of these), the investigational product may be considered a botanical, as that term is defined in the guidance for industry Botanical Drug Development (December 2016).

However, FDA does not consider a drug product a botanical if it genetically modified; produced by fermentation of yeast, bacteria, or plant cells; or highly purified substances from naturally occurring sources. Sponsors of these products should consult the 2000 FDA guidance “Content and Format of INDs for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products,” in order to ensure compliance with the Current Good Manufacturing Practice (CGMP) regulations found in 21 CFR part 211.

Nonclinical studies considerations

Generally, a psychedelic drug’s nonclinical program should follow recommendations outlined in the January 2010 ICH guidance “M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals.” FDA’s draft guidance suggests the following considerations regarding nonclinical studies in the development of psychedelic drugs:

• Human testing. Clinical studies with certain psychedelic drugs may be initiated under an IND in the absence of the typical animal toxicology testing when extensive human exposure and information are available from previously conducted clinical studies and no serious safety concerns were identified. However, these sponsors should plan to conduct nonclinical studies to support further drug development after initiation of the IND unless there are adequate data in the published scientific and medical literature. FDA’s draft guidance notes that psychedelic drugs without a history of adequate clinical exposure should not be tested in humans until safety has been established in nonclinical studies.

• Chronic dosing. Because most of the conditions being studied to date in psychedelic drug development programs are chronic, nonclinical studies should be provided if the treatment effect is not durable and repeat dosing is expected.

• 5-HT receptor subtype research. Because psychedelic drugs have serotonin (5-HT) activity, a thorough evaluation of binding to 5-HT receptor subtypes should be conducted.

Additional research considerations

The draft guidance advises that the pharmacokinetics and/or pharmacodynamics of a psychedelic drug should be adequately characterized both in vitro and in vivo. In addition, sponsors should consider the following clinical pharmacology aspects when developing psychedelic drugs:

• High-fat meal concerns. Sponsors should evaluate the effect of a high-fat meal on the pharmacokinetics of an oral psychedelic drug early in development.

• Drug Interaction. Sponsors should thoroughly evaluate potential drug-drug and drug-disease interactions

• 5-HT2B agonists. FDA recommends that sponsors exclude subjects with preexisting valvulopathy or pulmonary hypertension from multiple-dose studies of drugs with 5-HT2B agonists until this risk can be better characterized.

• Dose-response. The draft guidance highlights the need for psychedelic drug sponsors to carefully characterize the dose-response relationship.

FDA also notes potential pharmacodynamic interactions that should be considered, including the chronic use of selective serotonin reuptake inhibitors or monoamine oxidase inhibitors; and the chronic use of tricyclic antidepressants or lithium and acute use of selective serotonin reuptake inhibitors or monoamine oxidase inhibitors.

Abuse Potential Assessment Considerations

Like all drug products that act on the central nervous system, psychedelic drugs will need to be evaluated for abuse potential during drug development, both to understand and characterize the safety profile of the product and to support the rescheduling evaluation and recommendation. Such considerations are outlined in FDA’s guidance “Assessment of Abuse Potential of Drugs.” FDA’s draft guidance provides the following recommendations for psychedelic drug research:

• Full abuse potential assessment. For those psychedelic drugs that have not been well-characterized in preclinical and clinical studies, sponsors should conduct a full abuse potential assessment prior to an NDA submission. For abuse potential and dependence-related studies that will contribute to the abuse potential assessment, it is generally recommended that these studies be conducted after the therapeutic dose range is determined, which typically occurs when phase 2 clinical studies are completed.

• Human abuse potential studies. Generally, FDA requests a human abuse potential study be conducted when a drug has shown abuse-related signals in animal and/or human studies. The draft guidance notes that such a study may not be scientifically necessary for certain psychedelic drugs to support the abuse potential assessment in an NDA “when the subjective effects predictive of abuse are well characterized from extensive clinical studies and robust epidemiological data exist to demonstrate that individuals are using the psychedelic drug for abuse purposes.”

• Adverse event (AE) safety reporting. The draft guidance states that sponsors of psychedelic drugs should take special care in their evaluation of psychedelic responses that occur during clinical studies, utilizing validated subjective scales and monitoring of abuse-related AEs, such as euphoria, hallucinations, stimulation, and emotional lability. Investigators and session monitors should be trained to record all abuse-related AEs. This may be particularly challenging as abuse-related AEs, including “euphoria, hallucinations, stimulation, and emotional lability,” may also be related to the therapeutic benefits of treatment.

• Physical dependence potential. An assessment of the potential for physical dependence may be appropriate as part of the abuse potential assessment.

Clinical research considerations for psychedelic drugs

FDA’s draft guidance touches on the challenges in conducting adequate and well-controlled studies with psychedelic substances, such as the importance of developing effective controls and assessments to account for placebo effects. The guidance provides the following considerations:

• Placebo alternatives. In the context of psychedelic drug development, the use of a traditional placebo as a control can be problematic for assessing efficacy due to the well-known effects of psychedelic drug treatment. For example, subjects assigned to the treatment arm may be functionally unblinded due to the profound effects of psychedelic substances. Therefore, sponsors may wish to consider an inactive control or alternatives to an inert placebo. Complementary trial designs across phases 2 and 3 may help address placebo-related concerns in psychedelic drug development.

• Blinding. Given special concerns over bias in the study, the use of a blinding questionnaire for both subjects and investigators/raters can be helpful to evaluate the impact of functional unblinding.

• Psychotherapy bias risk. 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; “this additional variable both complicates the assessment of effectiveness and presents a challenge for any future product labeling,” the draft guidance notes, adding that “[p]sychotherapeutic interventions have the potential to increase expectancy and performance biases.” As a result, FDA advises that sponsors should plan to justify the inclusion of a psychotherapy component and describe any trial design elements intended to reduce potential bias or to quantify the contribution of psychotherapy to the overall treatment effect.

• Safety monitoring protocols. FDA cites in the draft guidance special concerns for the safety-monitoring of patients undergoing active treatment with psychedelic drugs. To mitigate this risk, the agency recommends:

  • Two monitors. Observation by two monitors for the duration of the treatment session.

  • Lead monitor training. A health care provider with graduate-level professional training and clinical experience in psychotherapy, licensed to practice independently, serving as the lead monitor.

  • Assistant monitor education. An assistant monitor with a bachelor’s degree and at least 1 year of clinical experience in a licensed mental healthcare setting.

• Informed consent. According to the draft guidance, the clinical research informed consent “should clearly describe that subjects may experience changes in perception, cognition, and judgment that persist for many hours, as well as increased vulnerability and suggestibility during the treatment session.”

FDA is seeking comments on its draft guidance through August 23, 2023. If you may wish to comment on the guidance, or have any questions on psychedelic drug research or clinical trials more generally, you may contact any of the authors of this alert or the Hogan Lovells attorney with whom you generally work.