Research and Cannabis: Ethical Research in a Changing Regulatory Landscape

California was the first state to legalize medical cannabis with the approval of proposition 215 in 1996¹.  By 2012, when Washington State and Colorado were the first states to legalize recreational use, more than 15 other states had also legalized medical cannabis.  Between 2012 and 2023, one state after another changed their laws to permit the use of cannabis with only 4 states currently considering cannabis fully illegal².

How is Cannabis regulated?

Cannabis, the cannabis sativa plant, has over 80 compounds called cannabinoids. Since 1970, when the Controlled Substances Act was enacted, most uses of whole cannabis plant and cannabiniods (compounds extracted from the plant like THC) have been considered by FDA as schedule I drugs, those without accepted medical use. The use of cannabis and cannabiniods is regulated at the federal level under both the United States Food and Drug Administration (FDA) and the United States Drug Enforcement Administration (DEA).

With the passage of the 2018 Farm Bill³, hemp-derived cannabinoids with no more than 0.3% THC are no longer considered controlled substances under the Controlled substances act⁴.  Hemp and hemp-derived products with greater than 0.3% THC are still classified as schedule I drugs.

Cannabis as a drug

THC (dronabinol) is the active ingredient in the approved drug products, Marinol capsules (and generics) and Syndros oral solution. Dronabinol is used to treat nausea and vomiting caused by chemotherapy in people who have already taken other medications to treat this type of nausea and vomiting without good results. Dronabinol is also used to treat loss of appetite and weight loss in people who have acquired immunodeficiency syndrome (AIDS)⁵.

CBD is the active ingredient in the approved drug product, Epidiolex.  Epidiolex has been approved to treat two different seizure disorders, with the most recent approval in 2020.  Epidiolex does not contain tetrahydrocannabinol (THC) which is the compound in cannabis that produces a euphoric effect.  While Epidiolex has been demonstrated to be effective in controlling seizures, it is not without side effects.  The most common side effects include diarrhea, elevated liver enzymes, decreased appetite, sleepiness, fever, and vomiting⁶.

Once FDA approves a substance as a drug product, that product in any form is by FDA definition a drug, and it can no longer be considered a food product or supplement regardless of the intent of the product.  FDA has therefore concluded that it is a prohibited act to introduce or deliver for introduction into interstate commerce any food (including any animal food or feed) to which THC or CBD has been added⁷.

Cannabis as a supplement

You may have noticed the explosion of CBD wellness products for both humans and animals on store shelves in the last few years.  The consumer market for human CBD wellness products was estimated to reach $4.17 billion in 2022⁸.  It will come as no surprise that with an increase in public interest in the products, research in this area has also expanded.

FDA recently published an opinion regarding cannabidiol products as dietary supplements in response to the growing CBD products market. FDA convened a high-level internal working group to investigate the best regulatory pathway for these types of products⁹.

Between 2019 and 2022, three citizens petitions (Consumer Healthcare Products Association, Citizen Petition from The Council for Responsible Nutrition, and Natural Products Association) were received by FDA and publicly posted.  On the same day FDA published the opinion regarding CBD as dietary supplements, it also published its responses to the three pending petitions.  The petitions have been denied, with FDA recommending congress work with FDA to establish a new regulatory pathway for CBD-containing products that are not intended to be marketed as drugs¹⁰.

Research with cannabis

In December 2022, after being passed by the House and Senate, the Medical Marijuana and Cannabidiol Research Expansion Act¹¹ was signed into law by the President.  This act supports research on cannabis by creating a process for the Attorney General to approve requests to conduct research as long as the research contains provisions to prevent the diversion of cannabis for non-research use.  Additionally, the Act requires the Secretary of the National Institutes of Health and the heads of other relevant Federal agencies to submit a report on the potential therapeutic benefits of marijuana (the flowers from cannabis) and cannabidiol on serious medical conditions, the potential effects of marijuana on developing adolescent brains, cognitive abilities, such as those required to drive a vehicle or operate heavy machinery, and State-level barriers to conducting research on marijuana within one year.  These activities will be conducted via grants, contracts, and cooperative research.  This Act represents a substantial step forward in expanding research on the benefits and risks of using cannabis.

Considerations for IRB review

When the IRB receives a protocol for review, there are two main questions the IRB will ask during its review. 

1. How is this research regulated? 
2. Is the research ethical? 

The IRB will review the protocol, advertising, and other information provided with the submission to arrive at an independent answer to the first question.  One of the most important aspects of this assessment is discriminating between research procedures and procedures that will happen regardless of the research¹². 

Sponsors should ensure that the protocol is clear and consistent via inclusion/exclusion criteria, description of procedures, and risks of the research.  Once the IRB determines which procedures are research procedures, the IRB assesses the regulations under which the research is governed.  If the research involves a test article that is regulated by FDA, the research will need to adhere to FDA regulations for research.  If the research is funded by or conducted at a federal agency, the research will need to adhere to the regulations of that agency.  Additionally, research may be subject to institutional policies and local laws as well.  Many institutions expect all research to follow Common Rule regulations because they receive federal funds. 

Case study 1:

Researchers wish to test participants’ mood and ability to perform cognitive tasks after ingesting gummies containing a cannabis extract. 

1.  Participants are habitual consumers of gummies.
2. The participants purchase and ingesting a gummy before engaging with the research staff.
3. Staff will ask questions about what was ingested, but will not direct or dispense any product.
4. Staff will assess participants’ mood using standard questionnaires and scales, and will direct them to complete a range of cognitive tasks.

Board Review:

The gummy is not a test article, it is not being studied nor directed by the research.  The research is not FDA-regulated.  The board may have safety concerns regarding participants ingesting uncontrolled gummies.  The board may have concerns about consent, privacy, and confidentiality of research data.  The product may be legally sold per local laws but may be considered a controlled substance per federal law.

Case study 2:

Researchers wish to test participants’ mood and ability to perform cognitive tasks after ingesting gummies containing a cannabis extract. 

1. Participants are habitual consumers of gummies.
2. Procedures include research staff dispensing a test article (a gummy containing a cannabis extract enriched for CBD).
3. Staff will assess participants’ mood using standard questionnaires and scales, and will direct them to complete a range of cognitive tasks.

Board Review:

The gummy is a test article and the study is FDA-regulated.  It is being given to participants as a research procedure.  The study will need an IND from FDA.  If the gummy contains over 0.3% by dry weight of THC, it is also regulated by DEA.  In order to study the gummy as a drug, the cannabis will need to be sourced from an approved source.  A list of DEA-authorized growers of Schedule I cannabis is available online¹³.

Ethical issues in research with cannabis containing THC

Because the legal landscape varies widely from state to state and THC-containing cannabis is a federally controlled substance, research participants who report being habitual users may be at legal risk if their identity is disclosed.  Researchers can consider requesting a certificate of confidentiality (CoC).  NIH provides CoC’s for unfunded or unregulated research under certain conditions, and FDA provides them for research conducted under an IND or IDE¹⁴.

Another ethical concern involves impairment.  One of the key components of ethical research is obtaining informed consent from participants.  Some research projects involving use of cannabis, such as in case study 1, could involve seeking consent from individuals who may be impaired at the time consent is sought.  Care must be taken to ensure that the consent process is effective and that participants understand the research and are freely consenting to participate.  Depending on their level of impairment, their ability to understand and make sound decisions could be compromised¹⁵. 

Final thoughts

Despite the regulatory and ethical challenges in conducting research using cannabis, the societal need for this research is compelling.  As more states permit the use of cannabis for medicinal or recreational purposes, understanding both short-term and long-term effects of its use is important for policy, health, and safety.