Systematically Testing the Evidence on Marijuana

Federal law classifies cannabis as a Schedule I Controlled Substance, and the US Department of Veterans Affairs (VA) must follow all federal laws. VHA clinicians may not recommend cannabis or help Veterans get it. Veterans who are in a state’s legal cannabis program are eligible for VA care and services. VA health care practitioners can and do discuss cannabis use with Veterans as part of comprehensive care planning, including adjusting treatment plans as needed. On their website, the VA says:

• Veterans can talk about cannabis use with their VHA providers.
• VHA clinicians may talk about a patient’s cannabis use as it relates to their care, and answer any patient questions on cannabis.
• VHA providers will record cannabis use in the Veteran’s medical record for treatment planning. Information in the medical record is protected under patient privacy and confidentiality laws and regulations.
• VA clinicians may not recommend medical cannabis; VA clinicians may only prescribe medications approved by the US Food and Drug Administration (FDA) for medical use.
• VA clinicians may not complete paperwork or forms Veteran patients need to be in state-approved cannabis programs.
• VA pharmacies may not fill prescriptions for medical cannabis.
• The VA will not pay for medical cannabis prescriptions from any source.
• VA scientists may conduct research on cannabis benefits and risks, and potential for abuse, under regulatory approval.
• Cannabis is prohibited at all VA medical centers.
• Veterans who are VA employees are subject to drug testing under terms of employment.

The full VHA directive (1315) on cannabis can be accessed here: https://www.va.gov/vhapublications/ViewPublication.asp?pub_ID=5711

Source: https://www.publichealth.va.gov/marijuana.asp

Conducting clinical research using cannabis-derived substances labeled as controlled under the Controlled Substances Act (CSA) often involves interacting with multiple federal agencies.

US Food and Drug Administration (FDA):

• To conduct clinical research that can lead to approval of a new drug using materials from plants such as cannabis, researchers need to work with the FDA and submit an Investigational New Drug Application (IND) to the Center for Drug Evaluation and Research (CDER). Researchers are encouraged to contact the relevant CDER review division and CDER’s Botanical Review Team (BRT) to answer questions related to their specific drug development program (https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/cder-offices-and-divisions).
• The FDA encourages researchers to request a Pre-Investigational New Drug (PIND) application meeting to discuss questions related to the development of specific cannabis-derived and cannabis-related drug products.
• If an Investigator is conducting human subjects research with research participants, but not working toward approval of a drug, the investigator must also submit an IND request to FDA (see: https://www.fda.gov/drugs/investigational-new-drug-ind-application/information-sponsor-investigators-submitting-investigational-new-drug-applications-inds)
• In all cases, studies cannot be initiated until 30 days after the date of receipt of the IND by FDA unless the research receives earlier notification by FDA that studies may begin.

Animal research: Researchers planning to develop an animal drug product need to establish an Investigational New Animal Drug (INAD) file with the Center for Veterinary Medicine (CVM) to conduct their research, instead of establishing an IND with CDER

US Drug Enforcement Agency (DEA):

Research of CSA Schedule I drugs require site-specific DEA investigator registration (see: 21 CFR 1301.18). There is an application fee, and renewal is required annually. The registration process can be lengthy, often taking 6 months to a year. For information on how to apply visit:  https://www.deadiversion.usdoj.gov/drugreg/

State or Local Licensure

• Different states and localities (e.g., towns, cities, counties) may require licensure for the storage and distribution of cannabis. For example, California State law requires research conducted in California involving a Schedule I controlled substance receive approval from the California Attorney General’s Office Research Advisory Panel. Please explore state and municipal laws to ensure compliance.

Sources:

• https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process
• https://leginfo.legislature.ca.gov/faces/codes_displaySection.xhtml?sectionNum=11480.&lawCode=HSC

With the exception of hemp, all cannabis or cannabis derivatives with nominal delta-9-tetrahydrocannabinol (THC) levels are controlled substances. The Agriculture Improvement Act of 2018 removed hemp (defined below) from the controls of the Controlled Substances Act (CSA), and there is now a streamlined process for researchers who plan to study hemp. 

Agricultural Improvement Act (2018 to 2023)

Subtitle G—Hemp Production

SEC. 297A. DEFINITIONS. HEMP.—The term ‘hemp’ means the plant Cannabis sativa L. and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a delta-9-tetrahydrocannabinol concentration of not more than 0.3 percent on a dry weight basis. 

Sources:

https://www.congress.gov/115/bills/hr2/BILLS-115hr2enr.pdf

https://www.deadiversion.usdoj.gov/GDP/(DEA-DC-057)(EO-DEA217)_Researchers_Manual_Final_signed.pdf

Yes, the following types of research do not require a DEA Schedule I license:
• Research where the final product under investigation naturally occurs in the cannabis plant and has less than 0.3 percent delta-9-tetrahydrocannabinol (THC), as of DEA Interim Final Rule on August 21, 2020
• Research about cannabis that does not involve the direct use, possession, distribution, or cultivation of cannabis in a research procedure
• Research conducted with parts of the plant not part of the definition of “marihuana” by the Controlled Substances Act (CSA; e.g., the mature stalks of plants)
• Human observational studies where the researchers do not obtain the cannabis used
• Studies that include the drug Epidiolex, which has been approved by the US Food and Drug Administration. Epidiolex is classified under the CSA as a Schedule V drug. Schedule V drugs, substances, or chemicals are defined as drugs with lower potential for abuse than Schedule IV and consist of preparations containing limited quantities of certain narcotics.
Sources:
https://www.deadiversion.usdoj.gov/GDP/(DEA-DC-057)(EO-DEA217)_Researchers_Manual_Final_signed.pdf

https://cannabis.ucdavis.edu/faq

For any clinical research leading to US Food and Drug Administration (FDA) drug approval, researchers must work with the FDA and submit an Investigational New Drug (IND) application to the Center for Drug Evaluation and Research (CDER). As described in the FAQ, “What are the federal steps required to conduct legally approved cannabis research?” the 2018 Farm Bill removed hemp from the Controlled Substances Act (CSA) and streamlined the process for researchers who want to study cannabis or derivatives that fall under the definition of hemp. Hemp refers to the plant Cannabis sativa L. and any part of that plant, including the seeds and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a delta-9-THC concentration of no more than 0.3 percent on a dry weight basis. This includes some forms of CBD.

The FDA published specific information on how investigators can work with them to conduct clinical research using cannabis including step-by-step descriptions of the IND process for cannabis study drugs controlled under schedule I of the CSA (greater than 0.3% THC on a dry weight basis), and for cannabis study drugs containing hemp (no more than 0.3% THC on a dry weight basis). For details, please see “FDA and Cannabis Research and Drug Approval Process.”

Regardless of FDA-approval status, research on cannabis that does not meet the definition of hemp will require:

• Drug Enforcement Agency (DEA) approval. Research of CSA Schedule I drugs requires site-specific DEA investigator registration (see: 21 CFR 1301.18). There is an application fee, and annual renewal is required. The registration process often takes 6 months to a year. For information on how to apply visit: https://www.deadiversion.usdoj.gov/drugreg
• Historically, cannabis was required to come from a National Institute on Drug Abuse (NIDA) provider. DEA is expanding the number of approved providers, but cannabis may still come from its NIDA provider. NIDA requires all researchers who get cannabis through their program show scientific validity and ethical soundness. Researchers must submit a protocol that is reviewed for merit by at least 2 nongovernment scientists. More information is available here: https://www.drugabuse.gov/research/research-data-measures-resources/nida-drug-supply-program.
• DEA has also approved an additional eight growers for purchase of cannabis for research or other licit purposes, which requires a DEA registration to access cannabis. (see:  https://www.deadiversion.usdoj.gov/drugreg/marihuana.htm).

Different states may also require licensing for storage and distribution of cannabis. For example, California State law requires approval from the California Attorney General’s Office Research Advisory Panel for research conducted in California involving a Schedule I controlled substance. Please explore state laws to ensure compliance.

Sources:

https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process

https://www.deadiversion.usdoj.gov/drugreg/

https://www.drugabuse.gov/research/research-data-measures-resources/nida-drug-supply-program

A long-standing source for cannabis for research, under federal law, is through the National Institute on Drug Abuse (NIDA) Drug Supply Program: https://www.drugabuse.gov/research/research-data-measures-resources/nida-drug-supply-program
• NIDA has US Drug Enforcement Agency (DEA) registration to oversee cannabis cultivation for medical research, and contracts with the University of Mississippi to grow cannabis at a secure facility. Varying potencies, compositions, and marijuana-derived compounds are available.
• Due to reinterpretations of the international treaties controlling cannabis production, the DEA is allowing additional growers (beyond the University of Mississippi) to register to produce and distribute cannabis for research purposes. However, companies must provide adequate chemistry, manufacturing, and controls (CMC) information for the Investigational New Drug (IND) application.

• More recently, the DEA has approved eight additional growers. The list can be found can be found at: https://www.deadiversion.usdoj.gov/drugreg/marihuana.htm

As the result of a recent amendment to federal law, hemp (i.e., forms of cannabis with less than 0.3 percent delta-9-tetrahydrocannabinol) no longer require DEA registration to grow or manufacture. The U.S. Department of Agriculture regulates hemp production in the U.S. For more information on hemp production, https://www.ams.usda.gov/rules-regulations/hemp.

Sources:
https://www.drugabuse.gov/research/research-data-measures-resources/nida-drug-supply-program
https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process

Before submitting a research grant, investigators should contact the relevant NIH program official to discuss the relevance of their research to the NIH Institute or Center, as well as the best funding mechanism to support their research. The NIH RePORT (Research Portfolio Online Reporting Tools) website “Matchmaker” module can help find potential NIH program officials and institutes for your research (see https://reporter.nih.gov/).

• NIH also has a website that is updated regularly describing NIH-supported research funding opportunities on cannabis, cannabinoids, and related compounds: https://www.nccih.nih.gov/grants/nih-supported-research-on-cannabis-cannabinoids-and-related-compounds

University investigators should check with their institution’s research pharmacy team prior to developing a proposal to determine their capabilities for involvement in cannabis research. In some states, the investigator must take full responsibility for all aspects of managing the cannabis needed for their study. This requires the study team have Schedule I storage facilities and personnel able to receive, manage, prepare, and dispense products.

You can ask a pharmacy to store cannabis, but some pharmacies may be unable or unwilling to store cannabis. Since 1970, some cultivations and parts of the Cannabis sativa L. plant are controlled under the Controlled Substances Act (CSA; specifically under the drug class “Marihuana,” 21 USC §802[16]). Cannabis is included under Schedule I of the CSA, due to its potential for abuse, primarily related to the psychoactive and intoxicating effects of delta-9-tetrahydrocannabinol, and in absence of an accepted medical use in the US. Because of this classification, and specifically the absence of an accepted medical use, pharmacy representatives may be wary of storing cannabis.

It is likely that special ventilation will be required if participants smoke or vape the drug. This will vary by state and local law. For example, in Minnesota the Clean Indoor Air Act requires any research that allows individuals to smoke marijuana indoors meet the following criteria:
• The study must be peer-reviewed and related to the health effects of smoking
• The study administrator must establish a policy designed to minimize exposure of nonsmokers to smoke
• Written submission to, and written approval of the policy by, the Commissioner of Health is required
• Smoking is only allowed in a designated space that is separated from other areas with a ventilation rate of 60 cubic feet per minute per person
• Signs must be posted at each entrance of the study facility that explain smoking is prohibited, except in designated areas
• Signs must be posted at the entrance of all designated smoking areas saying smoking is permitted or displaying the international symbol indicating smoking is permitted

Of note, some grants will not allow money to go towards renovations, such as those needed to install ventilation systems. Discuss with the research institution ahead of time to determine if renovations will be needed, what the cost will be, and who will be responsible for those costs.

Sources: https://www.health.state.mn.us/communities/environment/air/mciaa/study.html

All substances controlled by the US Drug Enforcement Agency (DEA) must be disposed of through a reverse distributor. A reverse distributor is a DEA-registered entity legally allowed to handle controlled substance disposal. Researchers should also consult with their institution’s Environmental Health and Safety team to determine local disposal requirements.

Sources: https://www.federalregister.gov/documents/2014/09/09/2014-20926/disposal-of-controlled-substances

Nonclinical Research
For nonclinical protocols, investigators may immediately pursue investigator and study site licensure and protocol registration with the US Drug Enforcement Agency (DEA). For more information on the DEA application process visit: https://www.deadiversion.usdoj.gov/drugreg. Nonclinical studies, including studies conducted under an Investigational New Animal Drug (INAD) file established with the Center for Veterinary Medicine (CVM), do not require protocol approval from the US Food and Drug Administration (FDA) before investigators proceed with the registration application to the DEA.

Clinical Research of Cannabis Study Drugs With More Than 0.3 Percent Delta-9-Tetrahydrocannabinol (THC) by Dry Weight:
1. The investigator may obtain a pre-Investigational New Drug (pre-IND) application number through the Center for Drug Evaluation and Research (CDER) review division, to request a pre-IND meeting and receive FDA guidance on research plans and the content required for an IND submission.
For animal drug research, a sponsor may engage with the CVM to establish an INAD file. A pre-IND meeting with the CDER is optional.
2. The sponsor should contact the National Institute on Drug Abuse (NIDA) or other DEA-registered cannabis source to identify available variants, so the required chemistry, manufacturing, and controls (CMC) and botanical raw material (BRM) information can be included in the IND submission or the relevant Drug Master File (DMF) can be referenced (see #4).
Importing products controlled under the Controlled Substance Act are subject to DEA authorization.
3. The sponsor may contact the DEA to discuss Schedule I drug research plans. A DEA inspection may be required for an investigator and study site Schedule I license.
4. If the selected BRM or drug substance manufacturer holds a Drug Master File (DMF), the sponsor must obtain a Letter of Authorization (LOA) to reference CMC and BRM information. Of note, if the investigator manipulates the product after receipt (e.g., turns it into an oral solution) researchers will have to provide stability and contaminant data on the product to the FDA before it can be administered to humans. Researchers will need to find labs that have this capability.

A DMF is a submission to the FDA that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of human study drugs.

If there is no DMF, an IND submission must contain all required CMC data characterizing the study drug and assuring it is safe for use in humans.

5.  The sponsor will send to the FDA a copy of the IND application and clinical protocol, including a copy of the LOA as appropriate.
6.  The FDA will review the submitted IND. The sponsor must wait 30 calendar days after IND submission before initiating any clinical trials, unless the FDA notifies the sponsor that trials may begin sooner or the protocol is put on hold for safety or other concerns. In this latter case, the IND will not be authorized until the sponsor adequately addresses all concerns raised by the FDA.
7.  If the IND is authorized by the FDA as “safe to proceed,” the sponsor will submit their clinical protocol registration application, including referenced IND number, to the DEA to obtain the protocol registration. Once this is received, the sponsor contacts NIDA or another DEA-registered source to obtain the cannabis or cannabis-derived substances, and they can then begin the study.

Clinical Research of Cannabis Study Drugs Containing Hemp or With no More Than 0.3 Percent THC by Dry Weight
1. The sponsor may obtain a pre-IND number through the CDER review division, to request a pre-IND meeting and receive FDA guidance on research plans and the required content for an IND submission. For animal drug research, a sponsor may engage with the CVM to establish an INAD file. A pre-IND meeting with the CDER is optional.
2. Sponsor provides all applicable CMC and BRM information in the IND for FDA review, including information about hemp cultivations being studied.
3. If the hemp manufacturer holds a DMF, the sponsor must obtain a LOA to reference the CMC and BRM information. Alternatively, an IND submission would need to contain all necessary CMC data characterizing their study drug and assuring it is safe for use in humans.
4. The sponsor will send to the FDA a copy of the IND application and clinical protocol, including a copy of the LOA as appropriate.
5. The FDA will review the submitted IND. The sponsor must wait 30 calendar days after submission before initiating any clinical trials (unless the FDA notifies the sponsor that the trials may proceed sooner) or the protocol is put on hold for safety or other concerns. In this latter case, the IND will not be authorized until the sponsor adequately addresses all concerns raised by the FDA.
Sources:
https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process

Most journal publications provide contact information for at least one of the publication authors. Many researchers are willing to assist and provide information to others. If you identify articles with research similar or related to the studies you want to complete, you could reach out to the publication authors and ask for assistance. ClinicalTrials.gov similarly has information about researchers conducting similar studies.

The National Institutes of Health (NIH) RePORT (Research Portfolio Online Reporting Tools) website provides access to a variety of reporting tools. One of the tools available on the RePORT site is the RePORTER (RePORT Expenditures and Results) module. RePORTER is an electronic tool that allows users to search a repository of NIH-funded research projects, which includes the Principal Investigator and their affiliation, and provides access to publications and patents resulting from NIH funding (see https://reporter.nih.gov). In addition the National Institutes on Drug Abuse (NIDA) Drug Supply Program can provide guidance and answers to questions related to cannabis materials (see https://www.drugabuse.gov/research/research-data-measures-resources/nida-drug-supply-program). 

• Updated information about NIH-supported Research funding opportunities on and NIH program officer contacts for research on cannabis, cannabinoids, and related compounds can be found at https://www.nccih.nih.gov/grants/nih-supported-research-on-cannabis-cannabinoids-and-related-compounds.