FDA’s Half-Century Journey in Cannabis Research

The FDA boasts a rich history of scrutinizing clinical research related to cannabis; both marijuana and hemp, as well as cannabis-derived products like cannabidiol (CBD). In October this year, the FDA released their half century documentation on cannabis research relating to drug development.

Since the early 1970s, the FDA has processed over 800 investigational new drug applications (INDs) and pre-IND applications linked to cannabis and cannabis-derived products (CCDP). In the past decade, there has been a noticeable surge in interest in studying CCDPs as potential medical treatments, with double the number of IND and pre-IND applications submitted during this period. Additionally, there has been a notable increase in exploring new forms of cannabis products and methods of administration (ROA) for delivering these drugs into the body.

The roots of this clinical research can be traced back to the enactment of Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970, commonly known as the Controlled Substances Act (CSA). This federal legislation established a comprehensive framework for the regulation of substances based on their potential for abuse, categorizing them into one of five schedules. Notably, certain components of the Cannabis sativa L. plant have been regulated under the CSA since 1970, specifically classified as “Marihuana.”

A recent article published in Open Exploration, titled “A U.S. FDA Perspective on Cannabis Research and Drug Development,” offers a detailed breakdown of CCDP applications received by the FDA over the past five decades. This publication also encapsulates the FDA's experiences, challenges, and provides valuable recommendations and resources for those keen on conducting CCDP clinical research. The article's primary aim is to dispel any misconceptions about the types of CCDP research that the FDA has assessed over the years and to provide insights into the landscape of clinical research concerning CCDPs in the United States. It further serves as a resource for researchers aspiring to create their own CCDP clinical research initiatives. Here are some key highlights from the article:

Cannabis Research & Drug Development

• Pre-INDs and INDs offer a framework for researchers working on new drugs to conduct clinical studies involving human subjects. The FDA reviews proposed research for CCDPs just as it does for any other drug that falls under its regulatory purview.
• Cannabis products are intricate mixtures with multiple active ingredients, often contributing to therapeutic effects. The FDA's review process acknowledges this complexity when assessing whether an IND aligns with the agency's requirements, regardless of the cannabis source or other plant-based products being examined in the trials. Currently, the FDA is reviewing over 150 active INDs dedicated to evaluating CCDPs, including synthetic compounds that mimic the effects of natural substances.
• To date, the FDA has not granted marketing approval for a cannabis-based drug to treat any specific disease or condition. However, clinical investigations into cannabis-derived products have led to the identification of naturally occurring compounds. Notably, in 2018, the FDA approved Epidiolex to treat severe forms of epilepsy, with its active ingredient being cannabidiol (CBD), isolated and highly purified from the cannabis plant. It is essential to distinguish this from the more complex mixtures often present in other CCDPs.

Therapeutic Research Areas

• Nearly every clinical review division within the FDA's Office of New Drugs has received at least one application for a cannabis product (IND or pre-IND). The clinical trials initiated or proposed under these applications span various clinical indications, encompassing a spectrum of formulations, potencies, strengths, and ROAs.
• The majority of CCDP INDs concentrate on four primary therapeutic areas: addiction and pain medicine (53%), neurology (19%), immunology and inflammation (14%), and psychiatry (9%).

Diversification of ROAs

• Over the years, researchers have diversified the routes of administration (ROA) explored in clinical trials. In the 1970s and 1980s, most cannabis trials involved smoking via cigarettes, with a limited range of oral products. In the 1990s and 2000s, the array of oral products expanded, but cigarette inhalation remained predominant. However, in the 2010s, the variety of products under scrutiny expanded dramatically, encompassing baked goods, botanical extracts, capsules, oils, purified extracts, sweets, tinctures, and vaporized products.
• Since 2020, the diversity of ROAs and product types in clinical trials has continued to grow, reflecting shifts in cannabis consumption patterns. In recent years, users have transitioned from predominantly smoking dried cannabis flowers to exploring alternative non-flower forms like edibles.

Guidance Documents for Cannabis Drug Product Research

• The FDA remains committed to facilitating robust scientific research to develop new drugs derived from cannabis. To support this mission, the agency has issued two guidance documents for the industry:
  • Botanical Drug Development (2016): This guidance provides insights into developing botanical drugs, outlining the FDA's thinking regarding growing conditions and manufacturing quality controls for botanical raw materials.
  • Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research (2023): This guidance reflects the FDA's contemporary outlook on clinical research for human drugs containing CCDPs, emphasizing the importance of manufacturing high-quality drugs.

The Future of Cannabis Research and Drug Development

• The FDA anticipates a continued uptick in INDs focused on evaluating CCDPs as medical and non-medical cannabis programs at the state level evolve. This growth may encompass the exploration of newly identified or less common cannabinoids and other cannabis plant components like terpenes. Furthermore, researchers may expand their exploration of edible CCDP product types and novel ROAs.
• Over the span of 50 years, the FDA has accumulated invaluable experience by assessing more than 800 INDs dedicated to cannabis products. The agency acknowledges the unique nature of CCDPs and the technical intricacies associated with botanical drug development and research. It remains steadfast in its support of scientifically sound research into the therapeutic potential of CCDPs and collaborates with companies aiming to bring safe, effective, and high-quality drugs to the market through the FDA's drug development and approval processes.