cbd dataDecember 15, 2021
While the FDA appreciates the information and engagement from numerous stakeholders on CBD-related issues, many evidence gaps remain. Filling these gaps will not be a trivial exercise but will require high-quality data analyzed using robust methods. We believe there is an opportunity to develop better sources of RWD to provide incremental improvements in our scientific understanding of the safety profile of CBD in the general population and, potentially, in specific populations.
The FDA has approved one drug, Epidiolex, that contains a highly-purified form of CBD for the treatment of seizures associated with Lennox‑Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC) in people one year of age and older. During review of the marketing application for Epidiolex, the FDA identified certain safety risks, including the potential for liver injury and for adverse reactions caused by the interaction between Epidiolex and other medications. These risks are communicated in the approved labeling for Epidiolex.
For CBD data collection and analysis efforts to have the maximum scientific impact, they should be designed to address the most significant practical and scientific challenges in this area. Below, we highlight challenges in current capabilities for collecting and evaluating CBD-related data and point to a framework for the FDA’s development of research projects that leverage novel data sources and can form the foundation for additional research on the safety profile of CBD products. First, we describe principles that we believe should guide this work.
We know from experience that collaborative projects with researchers across government, academia, and the private sector can stimulate rapid progress in the development of rigorous methods for collecting and analyzing RWD. Most recently, in the context of COVID-19, collaborative research projects between the FDA and outside data experts have focused on using RWD to improve analytical methods and inform the public health response to the pandemic.
As we continue to evaluate the regulatory frameworks that apply to certain cannabis-derived products that are intended for non-drug uses, including whether any new FDA regulations may be warranted, the FDA continues to work actively with drug developers through the investigational new drug, drug review, and drug approval processes. The FDA’s work in this area involves both meetings with drug developers to provide advice that is specific to the development of a proposed product, as well as the development of guidance documents on high-priority regulatory and scientific issues. For example, the FDA recently published a draft guidance “Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research,” which, when final, will represent the agency’s current thinking on sources of cannabis, resources for information on quality considerations, and percent delta-9 THC calculation. The FDA is evaluating comments submitted to the agency regarding this draft guidance.
A Practical Framework for Robust, Collaborative CBD Data Projects to Inform Public Health Decisions.
We believe that ongoing efforts to systematically collect data on the safety and use of CBD are important and we are engaging with stakeholders to advance this work. At the same time, we see a critical opportunity for the FDA to work collaboratively with partners in government, industry, and academia to develop the foundation for more robust CBD data collection and analysis projects.
What follows is a brief overview of our work on CBD and a framework for building a more robust evidentiary foundation to inform public health decisions.
We are encouraged by the many groups that are interested in helping to develop better data on the use and safety of CBD products, but also note that existing efforts generally are not adequate to fill the outstanding knowledge gaps. For example, observational studies that are too small or that do not include techniques to ensure data quality or methodological rigor are of limited use for public health decision making.
It is important to note that there are research questions for which RWD research projects are unlikely to substitute for certain types of traditional studies. We do not expect that analyses of observational data will substitute for other types of studies in certain contexts. For example, appropriately designed animal studies can address toxicological issues that are difficult to study in humans, such as chronic, developmental, and reproductive toxicity.
The FDA at times tests products as part of its compliance and enforcement activities. For example, in connection with several warning letters sent to firms for marketing unapproved new drugs that allegedly contain CBD, the agency tested the cannabinoid content of certain products and many were found to not contain the levels of CBD they claimed to contain. The FDA made the results of such testing publicly available. The FDA also designed surveys of the market and currently is conducting a two-phase marketplace sampling and testing study. The first phase involved a small sampling and analysis study (
Although the 2018 Farm Bill expressly did not change the FDA’s authorities regarding the regulation of CBD and other cannabis derivatives, the fact that these substances are no longer controlled substances has triggered increased interest in and availability of these ingredients for commercial development. Our website provides additional information about the agency’s activities related to CBD. The FDA’s work to develop better information on CBD and on the CBD market has been focused in the following areas: engagement with stakeholders, including on the development of data on CBD use and safety; and, sampling and testing by the FDA of CBD products in the market.
Sampling and testing of marketed CBD products is another way that the FDA has gathered more information about the safety profile of these products. This is an important component of the FDA’s work because little is known about the amounts of CBD and various related cannabinoids, as well as the occurrence of toxic elements, pesticides, other possible chemical contaminants, and adulterants, that may be present in CBD products that are marketed to consumers. We are testing CBD product samples in the following ways:
The FDA evaluates CBD just like any other substance we regulate, under a regulatory framework defined by law and with rigorous scientific evidence as a basis for both our regulatory approach and information we communicate. We’ve consistently communicated concerns and questions regarding the science, safety, and quality of many of these products based on currently available evidence. We still don’t have clear answers to important questions such as what adverse reactions may be associated with CBD products and what risks are associated with the long-term use of CBD products. Better data in these areas are needed for the FDA and other public health agencies to make informed, science-based decisions that impact public health.
Here, we describe a framework for the FDA’s work in the development of research projects that lay the methodological groundwork for high quality RWD science on the safety and use of CBD products. These research projects would be aimed at building upon currently existing independent state and national quality and safety monitoring efforts, observational study data models, and novel data sources to develop more robust capabilities and methods for CBD data collection and analysis.
We see an important public health opportunity in using novel sources of data and rigorous analytical methods to build a more robust base of scientific evidence on the safety profile and use of CBD products. The FDA is uniquely situated to contribute its expertise in evaluating data from different sources to inform regulatory decision-making. We think that real-world data (RWD) on CBD use and safety has a crucial role alongside data from other types of studies to fill in the current gaps in our understanding.
Engagement with Stakeholders on CBD Issues.
However, we strongly believe that RWD, when collected and analyzed using rigorous methods, can be important for moving the science forward—including by aiding hypothesis generation and by refining the design of follow-up studies. For example, RWD may identify new potential adverse events or subpopulations of CBD users that should be the focus of follow-up studies.
Over a short period of time, our society has seen a rapid increase in the interest and availability of cannabidiol (CBD) products and other products derived from cannabis. However, we still have a limited understanding of the safety profile of CBD and many other cannabis-derived compounds, including potential safety risks for people and animals. At the U.S. Food and Drug Administration, we see these knowledge gaps as an opportunity to develop new ways of building the science to inform public health decisions.
In December 2018, a change in the law made the FDA’s work on CBD issues particularly important. The Agriculture Improvement Act of 2018 (also known as the 2018 Farm Bill) removed hemp from the definition of marijuana in the Controlled Substance Act (CSA). This means that cannabis plants and derivatives that contain no more than 0.3 percent delta-9-tetrahydrocannabinol (THC) on a dry weight basis are no longer controlled substances under the CSA. While hemp that meets this definition is no longer controlled under the CSA, FDA-regulated products containing hemp must still meet applicable requirements of the Federal Food, Drug, and Cosmetic (FD&C) Act.
When the 2018 Farm Bill was enacted, we recognized the importance of engaging with the community of stakeholders interested in CBD. We held a public hearing in May 2019 and issued a call to stakeholders to work with the agency to develop high-quality data on CBD. The FDA re-opened the May 2019 public hearing docket, and will keep it open in the future as one mechanism for stakeholders to share data. In July 2020, we gathered stakeholder and industry input regarding the challenges surrounding quality, safety, and monitoring of the current marketplace. We also held a multidisciplinary scientific conference in November 2020 to provide further insight into the scientific evidence supporting the presence or absence of sex and gender differences in use and responses to CBD and other cannabinoids. The FDA also conducts regular listening sessions with stakeholders willing to share their perspective and data with us.
In the coming months, the FDA intends to develop and refine plans for research projects that use the following strategies, among others, to address the gaps in current CBD data research capabilities:
Challenges in current capabilities for collecting data regarding the use and safety of CBD.
FDA continues to be interested in the results of studies designed to address the uncertainties and data gaps related to the safety of cannabidiol (CBD). FDA is aware of ongoing efforts that will help to address some of these gaps, especially as it relates to nonclinical data.
Additional types of studies or surveillance may be useful based on findings. Whether data are useful to inform an assessment of the safety of CBD depends on whether the study is appropriately designed and executed to meet its identified aims. While FDA recognizes that there are many study designs that can be appropriate, ranging from randomized controlled trials conducted in a clinical trial setting to observational studies leveraging real world data, it is important that studies and/or trials be designed in a way that produce data that can inform regulatory decision making. This includes careful consideration of not only study design, but also study endpoints and any statistical considerations. FDA welcomes the opportunity to review and provide feedback on protocols for studies intended to address any of the data gaps identified above.
FDA encourages stakeholders to submit comments, data, and information related to CBD to the public docket, which FDA reopened on March 11, 2020. FDA reopened this docket to provide a public and transparent way for stakeholders to provide new and emerging information to us in real time as it becomes available. In the notice reopening the public docket, FDA outlined areas where data would be useful to inform FDA on the safety of CBD. This notice also includes instructions on how to submit data. For those interested in submitting confidential information, please review the instructions in the notice that specifically address how to submit such data. Those with questions or concerns about data submission, including questions or concerns related to confidentiality, should reach out to FDA at: [email protected]
Clinical Studies 1.
The broad availability of CBD provides an opportunity to establish safety surveillance systems that could capture data about exposure and outcomes related to CBD uses that are not feasible or practical to generate using traditional clinical trials or studies. For example, surveillance could provide data on chronic exposure and vulnerable populations (e.g., children that are exposed either in utero or while very young).
To promote efficient and expeditious development of high-priority data on the safety of CBD, FDA has identified areas where it would be most helpful for clinical data to be generated to further address data gaps related to safety. This includes both specific clinical studies and the development of systematic surveillance. FDA is actively working to address these gaps, with the limited available funds for research, but also seeks collaboration and data from stakeholders.
While much of the data needs expressed above focus specifically on CBD isolated from cannabis, there are also substantial unknowns about other cannabis-derived ingredients, including other isolates and complex extracts that can be slightly different from manufacturer to manufacturer. FDA has issued many guidance documents that describe the toxicological principles to generate important safety data that can be applied to each specific cannabis-derived ingredient that can then form the basis for ensuring products are safe for consumers. 3 These toxicological principles are useful to inform the question of what data FDA is seeking in order to better understand the safety of different cannabis-derived ingredients outside of just CBD.
It is expected that U.S. consumer sales of cannabidiol (CBD) will reach around 1.8 billion U.S. dollars by 2022, which would represent a significant increase from around half a billion U.S. dollars in 2018. Following a similar trajectory, sales of legal cannabis in the U.S. are projected to hit 23 billion U.S. dollars in 2025.
Cannabidiol is a naturally occurring substance found in cannabis. However, CBD does not cause any of the psychoactive effects that come from another active ingredient found in the plant: tetrahydrocannabinol (THC). The health benefits of the plant extract continue to be examined, and the World Health Organization states that CBD exhibits no effects indicative of any abuse or dependence potential. The CBD retail industry is already flourishing, with a wide range of products marketed as treatments for chronic pain, anxiety, and depression.