For nearly as long as the federal government has classified marijuana as a Schedule I controlled substance, the Food and Drug Administration (FDA) has been evaluating applications from researchers seeking to develop therapeutic drugs from the plant. In a pair of newly published documents, the agency looks back on more than half a century of investigational cannabis-based drugs and offers its perspective of what the future of drug development might hold.
That includes studying a broader range of methods of consuming marijuana such as edibles as well as investigating lesser-known cannabinoids and other components like terpenes.
Over the past 50 years, FDA has evaluated more than 800 investigational new drug applications (INDs) involving cannabis and cannabis-derived products (CCDPs), agency officials said in both a blog post and an article in the journal Exploration of Medicine. That period has seen profound changes in product form factors, cultural views and the legal landscape around cannabis—all of which have been felt at FDA.
What began as a trickle of applications soon after the passage of the federal Controlled Substances Act (CSA) in 1970 has become a deluge in recent years, authors said, as more states legalize the drug for medical and adult use. The past decade alone has brought a “nearly identical” number of cannabis-related drug applications as the previous 40 years combined, for example, and currently the agency is considering than 150 active INDs involving cannabis-based drugs and related synthetics.
As times have changed, FDA has stepped up its guidance for would-be cannabis researchers and drugmakers. In 2016 it published a guidance document on botanical drug development, and early this year the agency released a separate guidance document outlining the unique considerations around hemp and marijuana.
“The FDA continues to support robust scientific research needed to develop new drugs from cannabis,” agency authors wrote in the Exploration of Medicine article, “and is committed to supporting the development of these new drugs through the IND and drug approval processes.”
INDs have typically focused on four major clinical areas over the years, FDA said. The bulk of them (53 percent) center on addiction and pain medicine, while 19 percent involve neurology, 14 percent involve immunology and inflammation and 9 percent involve psychiatry.
Product form factors have also changed radically since evaluations of cannabis-based drugs began. Early on, in the 1970s, INDs were mostly around smokable forms of marijuana, FDA said. But as more types of products have been developed—fueled in part by state-level legalization—the agency has received more drug applications around oral, vapor and infused-food products like baked goods and sweets.
“The past 10 years have brought a proliferation of new product types proposed for use in human clinical trials as well as an increase in applications,” the journal article says. “Other oral product types began to be proposed for clinical trials in the 1990s and 2000s, but inhalation via cigarette remained the primary [route of administration] studied. However, in the 2010s the variety of product types dramatically expanded in clinical trials to include a wider array of oral product types and other ROAs. Broadly, the product types proposed for use included baked goods, botanical extracts, capsules and tablets, oils, purified (or semi-purified) extracts, sweets (e.g., candies), tinctures, and vaporized products (e.g., vapes).”
The shift in form factors, FDA notes, is largely the result of cannabis consumers themselves. “The emergence of interest in studying these various ROAs under clinical trials is likely due to changes in the cannabis consumer in the United States,” authors wrote. “In recent years, consumers have transitioned from exclusively smoking dried cannabis flower to consuming other non-flower forms, such as edibles.”
Amid the changes, FDA authors said that challenges remain around developing cannabis-related drugs for clinical trials, especially around safety and the unknown qualities of lesser-known chemicals.
“These research challenges include, but are not limited to, absent and/or inadequate quality and manufacturing information, unknown safety profiles and unknown benefits/risks for emerging compounds [e.g., hexahydrocannabinol (HHC), THC acetate (THC-O)], and the complex matrix effects on testing of final product formulations,” the journal article says.
Nevertheless, the authors note that the broadening of form factors being studied “correlates with the drug approvals “correlates with the drug approvals of Syndros (2016) and Epidiolex (2018), which are both oral formulations. This expansion also tracks with the increased availability of products in the state-level marketplace, along with the passage of the Agricultural Improvement Act (i.e., the Farm Bill) on December 20, 2018.”
In FDA’s blog post about the past 50 years of evaluating cannabis-based drugs, authors say they “expect there will be new increased interest in clinical research to study CCDPs.”
In addition to new products and form factors, they also expect “the use of newly identified or less common cannabinoids, as well as other components of the cannabis plant, such as terpenes.”
FDA recognizes the uniqueness of CCDPs and botanical drug research, the post says, and the agency “will continue to support sound, scientifically based research into the therapeutic uses of CCDPs and will work with companies interested in bringing safe, effective, and quality drugs to market through our drug development and approval process.”
Despite the shifting legal landscape and growing diversity of product types, research into cannabis remains difficult as the result of its Schedule I status as well as laws specifically limiting study into marijuana.
Nora Volkow, director of the National Institute on Drug Abuse (NIDA) has repeatedly said that marijuana’s Schedule I status inhibits research into the drug due to additional registrations and other onerous administrative requirements. Other federal agencies, including the National Center for Complementary and Integrative Health, have similarly blamed federal prohibition for stymying cannabis research.
Changes are coming, albeit slowly. Last year, DEA finally ended a longstanding monopoly on marijuana manufacturing for research purposes domestically. The agency noted it’s also implementing rules to streamline cannabis access for scientists following the enactment of a cannabis research bill late last year.
DEA is also currently carrying out a review of marijuana’s CSA scheduling status after receiving a recommendation from the Department of Health and Human Services (HHS) to move marijuana from Schedule I to Schedule III.
DEA has touted its Schedule I drug production quotas as evidence that is supports rigorous research into the substances, but it’s faced criticism from advocates and scientists over actions that are viewed as antithetical to promoting studies.
The agency recently retreated on a proposed ban on psychedelic compounds that scientists say have research value.
Meanwhile, the substances MDMA and psilocybin have been granted breakthrough drug status and could be considered for possible FDA approval in the coming year.
In September, two Republican senators previewed legislation they said would prevent FDA from federally legalizing marijuana without congressional approval.
FDA has approved a small number of cannabis-derived medications and similar synthetics, but the agency generally does not approve holistic or plant-based medicines. If marijuana was rescheduled, as HHS has proposed following a scientific reviewed directed by President Joe Biden, it would remain federally illegal except for medical use with a prescription from a doctor.
Meanwhile, on the House side, a top Democrat reintroduced a bill to federally legalize, tax and regulate marijuana in September, with provisions to expunge prior cannabis convictions.
As for CBD—one of the few parts of the cannabis plant no longer scheduled under the CSA—FDA has been slow to issue rules following Congress’s legalization of the cannabinoid through the 2018 farm bill. FDA said it carried out a comprehensive review before reaching the conclusion, in January, that it couldn’t effectively regulate the complex market.
The resulting uncertainty is widely blamed as a primary driver of the hemp industry’s recent economic woes. It’s also led to confusion within the marketplace as businesses continue to sell a widening variety of cannabis products, including intoxicating cannabinoids such as delta-8 THC, without meaningful oversight.
In response to the ongoing inaction, bipartisan congressional lawmakers have introduced legislation to fill the regulatory gap and provide for the lawful marketing of CBD as food items or dietary supplements. A recent House subcommittee hearing specifically focused on the impact of the lack of FDA rules, and a separate pair of bicameral health committees has solicited expert input on the issue as they consider potential legislative fixes.
State marijuana regulators, as well as hemp industry associations, are among those who responded to the House and Senate committee requests for information. And while there was some disagreement about the scope of FDA’s current regulatory authority, they largely agreed that Congress needs to take a more holistic approach to the issue and consider rules for all hemp-derived cannabinoids, including delta-8 THC.
House Oversight Committee Chairman James Comer (R-KY) said in April that his panel would be launching an investigation into FDA’s CBD review. He requested that the agency turn over documents related to its decision not to regulated the cannabinoid. Even before the agency made that decision, the congressman expressed his intent to address the lack of rules.
The agency did separately receive some bipartisan praise earlier this year for releasing first-ever guidance on developing psychedelic medicines. (Full Story)