FDA’s Initial Draft Guidance on Clinical Trials with Psychedelic Drugs

The U.S. Food and Drug Administration released a new draft guidance for researchers looking into psychedelic medicines to potentially treat medical illnesses, such as psychiatric or substance use disorders, highlighting important factors. This is the first FDA draft guidance offering industry advice on planning clinical trials for psychedelic medications.

In recent years, there has been an increase in interest in the medicinal potential of psychedelic substances. For usage in the prospective therapy of ailments like depression, post-traumatic stress disorder, substance use disorders, and other illnesses, they are now being evaluated. However, some particular difficulties must be carefully considered when developing clinical investigations to assess the security and efficiency of these substances.

What is the purpose of this draft guidance? 

The draft guidance was created to offer suggestions to researchers as they make psychedelic-containing drugs about study design and other factors. The term “psychedelics” in the draft guidance refers to “classic psychedelics,” which are typically understood to be substances that affect the brain’s serotonin system, like psilocybin and lysergic acid diethylamide (LSD), as well as “entactogens” or “empathogens,” like methylenedioxymethamphetamine (MDMA).

What does the psychedelics draft guidance address?

The document outlines fundamental factors to remember during drug development, such as trial conduct, data collection, subject safety, and prerequisites for new medication applications. For instance, psychedelic substances may have psychoactive effects such as hallucinations, changes in mood and cognition. Because of this, there is a chance that these pharmaceuticals will be abused, a drug safety concern that needs to be carefully considered, and adequate safety precautions must be put in place to prevent misuse during clinical development. The proposed guidance adds that activities connected to investigations under an Investigational New Drug Application for psychedelics currently Schedule I controlled substances must adhere to appropriate Drug Enforcement Administration regulatory standards.

The same level of evidence is required to prove the efficacy of psychedelic medications for all other drugs. However, clinical studies are to be regarded as adequate and well-controlled. In that case, there may be particular factors that investigators need to consider while organizing those trials. The draft guidance also covers the need to characterize dose response, the longevity of any treatment impact, safety monitoring issues, and psychotherapy’s role in creating psychedelic drugs. 

What is the FDA considering in this draft guidance?

In the sections below, we list general factors for drug development programs assessing the therapeutic potential of psychedelic substances by discipline. Sponsors should involve divisions early in drug development; the Agency is open to exploring various techniques to address these problems.

Chemistry, Manufacturing, and Controls

• Chemistry data submitted by a sponsor to FDA may be proprietary.
• If using plant material, algae, macroscopic fungi, or a combination of these, the investigational product may be considered a botanical.
•  Although some psychedelic compounds are derived from plants or fungi, drug products that are genetically modified; produced by fermentation of yeast, bacteria, or plant cells; or highly purified substances from naturally occurring sources are not considered botanicals for purposes of this document.
• Drugs must be manufactured in compliance with current good manufacturing practice 89 (CGMP) under section 501(a)(2)(b) of the FDA Act.

Nonclinical

• An IND must include adequate information about pharmacological and toxicological studies of the drug based on which the sponsor has concluded it is reasonably safe.
• Because psychedelic drugs have serotonin (5-HT) activity, a thorough evaluation of 136 binding to 5-HT receptor subtypes should be conducted.
• Nonclinical studies to support chronic or chronic-intermittent dosing should be provided if the treatment effect is not durable and repeat dosing is expected.
•  Because psychedelic drugs have serotonin (5-HT) activity, a thorough evaluation of binding to 5-HT receptor subtypes should be conducted.

Clinical Pharmacology

The following are some known pharmacodynamic interactions to take into account:

• The effects of psychedelic substances may be lessened by long-term usage of monoamine oxidase inhibitors or selective serotonin reuptake inhibitors.
• Acute use of monoamine oxidase inhibitors or selective serotonin reuptake inhibitors, as well as chronic use of tricyclic antidepressants or lithium, may intensify the effects of psychedelics.
• Most psychedelic substances’ dose-response relationships are not well understood. 

Sponsors must take the necessary action to describe the dose-response relationship for safety and efficacy. 

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