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Challenges for Clinical Cannabis and Cannabinoid Research in the United States

Challenges for Clinical Cannabis and Cannabinoid Research in the United States Significant changes have occurred in the policy landscape surrounding cannabis legalization, production, and use around the globe and across the United States. With widespread availability of novel cannabis and cannabis-based products, there is an urgent need to understand their safety and effectiveness for medical indications. Three primary barriers contribute to the dif- ficulty in initiating research geared toward answering the most pressing public health questions: the US regulatory status of cannabis and cannabinoids, sources for cannabis and cannabinoid study medications, and limited funding and resources to support studies. Despite these hurdles, research is rapidly increasing, and recent changes in the United States have paved the way for exciting new work. Here, challenges and barriers to cannabis and cannabinoid research are described from the per- spectives of the National Institute on Drug Abuse, National Institutes of Health; the US Food and Drug Administration; and 2 clinical researchers. Barriers specifically to studying cannabis, cannabinoids, and cancer are emphasized. Significant changes have taken place in the policy landscape influencing and enacting policies, procedures, and laws related surrounding cannabis legalization, production, and use around to cannabis use (2,3). Other relevant challenges include the the globe and across the United States. Over the last couple of availability of cannabinoid-based study medications, federal decades, 35 states and the District of Columbia have legalized regulations, and other constraints associated with clinical trials. cannabis for medical conditions; of these, 15 states and the Oncologists frequently discuss the clinical use of cannabis District of Columbia (1) have also legalized adult use of canna- with their patients although most feel they lack an adequate bis. These landmark changes in policy have impacted cannabis knowledgebase to advise effectively (4). The National Academies of Sciences, Engineering and Medicine’s report on the Health use patterns and the perceived levels of risk. However, despite this changing landscape, evidence regard- Effects of Cannabis and Cannabinoids found strong evidence in sup- ing the short- and long-term health effects of cannabis use port of the use of cannabinoids for chemotherapy-induced nau- remains inconclusive. Several research studies have examined sea and vomiting as well as pain (5). Despite those findings, cannabis use in many forms, however, often these research many oncologists prefer to recommend approved pharmaceuti- conclusions are not appropriately translated and/or communi- cals with larger bodies of supporting evidence. Increasingly cated to policy makers, health-care providers, state health offi- patients are hearing of people healing their malignancies with cials, and other stakeholders who have been charged with highly concentrated cannabis oils (6). Although there is a Received: 21 August 2021; Accepted: 23 August 2021 Published by Oxford University Press 2021. This work is written by US Government employees and is in the public domain in the US. 114 Downloaded from https://academic.oup.com/jncimono/article/2021/58/114/6446199 by DeepDyve user on 16 July 2022 Z. D. Cooper et al. | 115 significant body of preclinical evidence suggesting anticancer immigration status of people convicted of cannabis-related effects of cannabinoids, translation to clinical benefit has not yet offenses; and reviewed sentences and expunged federal canna- occurred. Hence, oncologists and cancer researchers are likely to bis convictions. The US Senate–passed Cannabidiol and be particularly interested in seeing cannabis research advance. Marihuana Research Expansion Act (12) would have removed This review highlights challenges and barriers to cannabis plant-derived and synthetic cannabidiol (CBD) from the CSA schedule, streamlined the process of obtaining DEA registration and cannabinoid research from the perspectives of administra- tors from the National Institute on Drug Abuse, National to conduct research with marijuana, and required the DEA to act on pending applications. As of July 2021, no recent federal Institutes of Health (NIDA/NIH); the US Food and Drug Administration (FDA); and clinical researchers. Barriers specifi- legislation on cannabis has passed both houses of Congress and been signed into law by the president, although many bills have cally to studying cannabis, cannabinoids, and cancer are emphasized. been introduced, and some have passed either the House or the Senate (for updates, see https://www.govtrack.us/congress/ bills/subjects/drug_abuse/1759#sort=-introduced_date&text¼ Current Regulatory Status of Cannabis and cannabis&congress¼__ALL__&terms¼__ALL__&terms2¼__ALL__). Cannabinoids: An Overview Federal restrictions on clinical cannabis research result from its Research Procedures and Barriers: A Single legal status as defined by the Controlled Substances Act [CSA Source for Cannabis (7)] and international treaties. However, federal and state laws conflict, with diverse state regulations allowing personal pos- The administrative challenges for cannabinoid research include session and recreational and medical use. Laws and regulations the single domestic source requirement for cannabis, complex and lengthy registration processes, and schedule I classification on federal cannabinoid research have been changing recently, and more changes are expected (for up-to-date information of nonintoxicating cannabis components such as CBD. from the US Drug Enforcement Administration [DEA], refer to Scientific challenges include the complexity of cannabis plants (containing >100 cannabinoids and other components); diffi- deadiversion.usdoj.gov and the NIDA Drug Supply program at https://www.drugabuse.gov/research/research-data-measures- culty in designing blinded, controlled studies (particularly for driving after drug exposure); and the inability to study products resources/nida-drug-supply-program). Cannabis remains a federal schedule I controlled substance. available from dispensaries in states where they exist. Researchers who order cannabis from NIDA for human re- Schedule I substances include those determined to have high potential for abuse, no currently accepted medical use, and a search in the United States must obtain FDA Investigational New Drug authorization, DEA schedule I registration, and insti- lack of accepted safety for use under medical supervision. Additionally, the 1961 Single Convention on Narcotic Drugs tutional review board (IRB) approval. Despite misconceptions, NIDA has no role in determining qualifications. If researchers makes it illegal to grow, possess, or distribute cannabis except under strict conditions. One of those restrictions is that nations receive FDA, DEA, and IRB approval, NIDA fulfills orders for ciga- rettes and bulk cannabis in various THC and CBD concentra- may designate a single source of research marijuana. NIDA has served as the single source in the United States since 1968. tions, plus placebos. NIDA’s research cannabis is consistent, reproducible, pesticide free, and herbicide free. Although the However, because of a recent re-interpretation of the Single cannabis provided by NIDA tracks the average THC potency of Convention requirements, the DEA recently published a new the cannabis generally available, NIDA does recognize the need rule that will potentially allow the approval of additional for greater varieties of products, including improved placebos growers and producers of cannabis for research (8). Currently, and more formulations (eg, extracts), a larger range of poten- an estimated 41 applications are pending. It is anticipated that cies, and variable terpene content (13). NIDA’s Drug Supply Program will remain one of the licensed producers. Conflicting federal and state cannabis regulations hinder re- Role of the FDA in the Regulation of Cannabis search in several ways, including the inability of researchers to Products access products that are legal in their state, a lack of standardi- zation and quality control of cannabis and cannabis-derived There is broad public interest in expanding the availability of products within and across states, and no national oversight of cannabis-based products for both medical and nonmedical use. this standardization and quality control or the industry. In responding to this demand, the mission of the FDA is focused on advancing public health by overseeing the investigation, ap- proval, and production of safe, effective, and high-quality medi- Recent and Pending Legislative Action cal products, including those that are synthesized chemically or The Agriculture Improvement Act of 2018 [also known as the derived from the cannabis plant. Farm Bill (9)] removed hemp (cannabis containing no more than As described above, the Agricultural Improvement Act of 0.3% on a dry-weight basis) from the CSA schedule and re- 2018 (9) had an important impact on the FDA’s actions in this affirmed the FDA’s regulatory authority for hemp-derived medi- area. Importantly, the Farm Bill stipulates that the FDA’s au- cations, dietary supplements, and food additives (10). thorities under the Federal Food, Drug, and Cosmetic Act are The US House of Representatives–passed Marijuana unchanged, so that hemp-based drug products will be subject to Opportunity Reinvestment and Expungement Act of 2020 (11) the same authorities and requirements as any other drug prod- would have removed cannabis from the CSA schedule; elimi- uct. To date, the consequences of FDA regulation of cannabis nated criminal penalties for its manufacture, distribution, or and cannabinoids, including hemp, include the approval of 4 possession; established a 5% cannabis tax to support War on drug products. Three of these products are synthetic THC or Drugs compensation; protected the federal benefits and similar to THC and are approved to treat nausea from cancer Downloaded from https://academic.oup.com/jncimono/article/2021/58/114/6446199 by DeepDyve user on 16 July 2022 116 | J Natl Cancer Inst Monogr, 2021, Vol. 2021, No. 58 chemotherapy. The fourth product, Epidiolex, is made from substantial interest in US Congress legislation, and the FDA is highly purified CBD from cannabis. It is approved for certain actively offering assistance to state and nongovernmental part- rare seizure disorders and, more recently, for tuberous sclerosis ners in understanding the evolving cannabinoid landscape. The complex. The marketing approval of Epidiolex, particularly in FDA also continues to take enforcement actions whenever vio- light of the DEA’s placement of FDA-approved CBD-containing lative marketing of cannabinoid products is identified. For ex- products in schedule V according to the CSA (14), shows that ample, during the COVID-19 pandemic, the FDA had to take the clinical development of cannabis-derived medicines derives action in multiple instances where makers of CBD products from the concerted evolution of biomedical knowledge and reg- made antiviral, curative claims despite the lack of any support- ulatory flexibility. ing evidence on their safety or efficacy. Beyond the 4 FDA approvals mentioned above, the agency In summary, the FDA has a well-defined and multifaceted has more generally performed a scientific assessment of role in the cannabinoid space. Its role has been strengthened cannabis-derived CBD and concluded that, although CBD is psy- and clarified in some respects through recent activities on the choactive, it does not have the same abuse potential as THC legislative level. Most importantly, the FDA continues to sup- (which remains on schedule I of the CSA) (15). In addition to port the scientific assessment of cannabis-derived compounds. reviewing marketing applications for drugs and their indica- Because of broad interest in expanding the availability of these tions, the FDA also regulates clinical studies with cannabis and products, the FDA is considering many different regulatory cannabinoids. For these avenues of research, the investigator options for responding to this interest, always informed by our submits an Investigational New Drug application to the FDA for commitment to protect patients and advance our national pub- review. The application includes a detailed description of the lic health interests. study protocol and information about the investigational drug, including a summary of previous human experience with the investigational drug; animal pharmacology and toxicology; General Challenges for the Clinical Researcher chemistry, manufacturing, and controls information on the in- The clinical researcher striving to respond to public health pri- vestigational drug; and evidence that it was manufactured orities related to the surge in cannabis and cannabinoid use is according to current good manufacturing practices (16). Given met with a number of regulatory hurdles. With rapid expan- that state legalization may have facilitated the municipal sale sion of new products, novel methods of use, and growing pop- and use of many new cannabis-derived products around the ulations using these products for medical indications or for United States, it is important for investigators to be aware of nonmedical use, these restrictions are a major contributing FDA regulations before engaging in clinical studies with canna- factor to the limited data published addressing the most urgent bis and cannabinoids. issues. Apart from questions on the potential effectiveness of As the FDA works to regulate cannabis-derived products ap- products on the market for certain indications, a more immedi- propriately, there is a great deal that is unknown about CBD, ate concern relates to the safety of these products. There are and even less is known about the dozens of cannabinoids and increasingly popular product categories and modes of delivery other compounds present in cannabis extracts. For example, lit- that are available for purchase in state-regulated dispensaries tle is known about the effects of long-term human use of CBD that have yet to be tested under controlled conditions. Some of and the impact of CBD in susceptible populations: children, these products are hypothesized to have potentially significant pregnant women, and the elderly. Based on data from the drug negative effects, such as high-potency extracts geared toward development program for Epidiolex and from the published lit- delivering efficient intoxicating effects, as well as products erature, there are known toxicities of concern related to CBD such as specific minor cannabinoids and terpenes that, based use (15). For example, there are signals of potential liver injury, on preclinical literature, may be safe but have yet to be potential male reproductive toxicity, and clinically important assessed in humans. In an effort to elucidate both the safety drug-drug interactions. We do not know exactly how serious and the potential therapeutic uses of these products for a these signals are, and it is important that we continue efforts to range of indications for which they are already approved in an assess them. Going forward, we also need to identify ways of overwhelming majority of the United States, researchers must answering the many remaining questions about the safety of work tirelessly through institutional, regulatory, funding, and CBD, as well as the many other compounds found in cannabis. drug supply hurdles, all of which significantly influence the With so much yet to be learned, the FDA is committed to scientific impact, public health relevancy, and efficiency of supporting scientific cannabinoid research and development. investigations. To support human drug development of cannabis and Given the diverse nature of cannabis and cannabinoid re- cannabis-derived compounds, the FDA has created several search, differences in state laws, and varied institutional regula- resources to aide investigators as they develop their clinical tions, every scientist will likely have a unique experience when studies and use real-world data to fill the scientific gaps of initiating cannabis and cannabinoid work. In fact, with rapid knowledge. Some examples of these resources include informa- changes in oversight and regulations, one cannot necessarily tion about the conduct of clinical studies and how to request predict how to navigate regulatory hurdles for future studies formal meetings (16–19), considerations for using botanicals based on one’s own previous experiences. The following ac- (20), a frequently asked questions website (21), recently released count is from personal experience working with cannabis and draft guidance about manufacturing cannabis-derived drugs (22), and the newly published FDA Voices Blog (23). The FDA’s cannabinoids in 2 states and 2 institutions. This account high- lights the arduous path of starting a research program focusing research agenda is aimed at supporting studies to develop the data that is needed to understand how cannabinoids can be on controlled administration of cannabis and cannabinoids in humans and demonstrates that the pathway to embarking on used safely in drug products and other consumer goods, such as dietary supplements, cosmetics, and pet foods. The FDA also is this research is demanding both of the researcher’s time and exploring policy options to enable broader availability of safe, resources. This experience is important to stress as more effective, and high-quality cannabinoid products. There is researchers become interested in delving into this field but are Downloaded from https://academic.oup.com/jncimono/article/2021/58/114/6446199 by DeepDyve user on 16 July 2022 Z. D. Cooper et al. | 117 required to start from scratch to get projects off the ground. Regulatory Approvals. A study assessing the effects of canna- bis and/or cannabinoid administration is required to be submit- Because of the time, expenses, and regulatory knowledge re- ted to and approved by the IRB and the FDA. Protocols quired to get a single study started in this field, researchers will submitted to the IRB must be justified scientifically, meet the frequently opt not to pursue work in this area. Consequently, al- ethical principles of the Belmont Report (27), and include steps though more issues need to be addressed by diverse experts, the to minimize risk. This protocol is also submitted to the FDA as field will likely continue to be limited to those institutions and an Investigational New Drug application alongside detailed in- researchers who have historically pursued this work. formation regarding the chemistry, manufacturing, and control Below is a description of the 3 primary hurdles to conducting data of the agent to be studied as described in Section titled Role cannabis and cannabinoid research in the United States. of the FDA in the Regulation of Cannabis Products. Finally, state reg- Although the US regulatory status of cannabis and cannabi- ulatory approvals must also be obtained. Some states have sep- noids is a US-specific barrier, the other barriers—the paucity of arate controlled substance licensing requirements. For funding available for investigations and the availability of test example, in New York State, the investigator must apply for and medications that can be studied—are global and limit the ex- receive a license from the Bureau of Narcotic Enforcement. pansion of work in the field. Similarly, although some barriers Other states may require that protocols be approved by the state are unique to this field, it should be noted that clinical research board of medical examiners. For example, in the state of in general is difficult and burdensome, regardless of the study California, the Research Advisory Panel of California, under the medication under investigation. However, many hurdles de- state attorney general’s office, reviews and authorizes studies tailed below are unique to studying cannabis and cannabinoids involving schedules I and II substances to ensure the safety and in the United States. These challenges are intertwined with one protection of participating human research subjects, in addition another, creating a situation where overcoming one obstacle to the security provisions in place for the controlled substances requires success in surmounting the others, as depicted in used in the study. This panel also evaluates the scientific valid- Figure 1. ity of the studies. Therefore, studies can be rejected if deemed to “produce conclusions of little scientific value, or would not justify the exposure of California subjects to the risk of US Regulatory Status of Cannabis and Cannabinoids research” (28). If any of these bodies request modifications to As mentioned earlier, the most obvious regulatory hurdle in con- the protocol, amendments must be submitted to and reviewed ducting cannabis and cannabinoid research is the schedule I sta- by the other agencies. This approval process can take several tus of cannabis (with more than 0.3% THC) and specific months even if no modifications are required. cannabinoids. Although there has been movement in the field to Application to the DEA for a schedule I license includes the relax regulations, including the landmark change decontrolling above-mentioned approved regulatory documents; the investi- gator’s qualifications, including a curriculum vitae; a descrip- CBD derived from hemp, many changes have, in fact, made the tion of the research project, including its statement of purpose; regulatory landscape more confusing and difficult to navigate for the name and amount of substances to be used; a description of the researcher. For example, in the case of CBD, according to the and the number of research subjects; drug doses to be adminis- DEA interim final rule that outlines DEA’s amendments to the tered; mode of administration; and the duration of the study. CSAmadebythe AgricultureImprovement Actof 2018(24), prod- Details regarding where the study will be conducted and secu- ucts with CBD specifically derived from the plant that contain less rity provisions for storing the drug must also be included. than 0.3% delta-9-THC are now decontrolled, yet synthetic CBD Finally, an institutional letter of support must be provided, as remains on schedule I according to the CSA. Despite the fact that well as an indication of approved funding provided, if applicable the molecule is the same, its origins define its regulatory standing. (26). Once the application is received, the DEA communicates Another example of these confusing laws relates to the classifica- with the FDA to determine the merits of the study and the qual- tion of delta-9-THC, which has 3 distinct schedules based on the ifications and competency of the submitting investigator, which source of production and the formulation. For example, dronabi- is a process that takes at least 30 days. The local DEA inspector nol, synthetic delta-9-THC, is categorized on 3 different schedules: will then make an appointment to inspect the facility. Security oral capsules of the synthetic delta-9-THC dronabinol (ie, Marinol) issues noted during the inspection need to be resolved before is classified as schedule III, yet the FDA-approved liquid dronabi- the license is granted. nol (Syndros) is schedule II, and dronabinol not packaged accord- Security Requirements for Schedule I Material. Requirements for ing to FDA formulations (ie, active pharmaceutical ingredient) is schedule I drug storage are complicated, and the specifics out- schedule I (25). Currently, all forms of delta-9-THC derived from lined in Title 21 of the Code of Federal Regulations may not real- the cannabis plant (ie, not synthetic) are schedule I. These are a istically correspond to an investigator’s study needs. For few examples of the confusing nature of cannabinoid scheduling example, drugs may be required to be frozen to maintain stabil- that require near mastery to successfully identify whether a pro- ity (26). The Code of Federal Regulations does not provide an ad- posed trial with a potential study medication requires a schedule I equate solution for how this drug should be stored. As such, DEA license. Without proper guidance and support from people in researchers develop ways to maintain the integrity of their drug the field, a researcher is likely to get lost in the regulatory quag- product while still adhering to the DEA code. In general, small mire that is rapidly evolving. amounts of the drug must be stored in a safe or steel cabinet Once it has been determined that the test material is indeed that weighs at least 750 pounds and complies with the following schedule I, the investigator is required to apply and be approved specifications: protected for “30 man-minutes against surrepti- for schedule I registration. Prior to applying for this license, 2 tious entry, 10 man-minutes against forced entry, 20 man- significant milestones must be met: approval of a research pro- hours against lock manipulation, and 20 man-hours against ra- tocol that employs the schedule I substance for which the li- diological techniques.” If the safe or cabinet is not 750 pounds, cense is being sought and identification of a storage facility that it needs to be bolted or cemented to the floor or wall. The safe will meet DEA requirements (26). or steel cabinet should be equipped with an alarm that signals a Downloaded from https://academic.oup.com/jncimono/article/2021/58/114/6446199 by DeepDyve user on 16 July 2022 118 | J Natl Cancer Inst Monogr, 2021, Vol. 2021, No. 58 Figure 1. Primary obstacles in pursuing cannabis and cannabinoid research. Federal regulations, drug source, and funding are significant barriers to conducting canna- bis and cannabinoid research, which can lead to significant delays in study onset. As depicted by the double-headed arrows, these challenges are intertwined with one another, creating a situation where overcoming one obstacle requires success in surmounting the others. IRB ¼ institutional review board; FDA ¼ US Food and Drug Administration. central protection agency, a police agency, or a 24-hour control human study. Therefore, even if cannabis and schedule I canna- station operated by the registrant in the event of an unauthor- binoids shed their classification and are removed from the CSA, ized entry. Guidance for practitioners (clinical researchers) is researchers would still bear the burden of identifying a product modified to state that “Controlled substances listed in Schedule that adheres to the FDA’s Good Manufacturing Practice require- I shall be stored in a securely locked, substantially constructed ments. For example, hemp-derived CBD was recently removed cabinet” (26), however, there is not a detailed account of what from the CSA. This evolution should have improved research in type of safe meets this definition and may be left up to the local this area substantially, yet there are few manufacturers that DEA jurisdiction and agent. The storage facility is required to be make plant-derived CBD according to the FDA’s standards. in a space that is only accessible to a minimum number of spe- When a manufacturer of clinical-grade, hemp-derived CBD is cifically authorized employees. This stipulation requires that identified, the product can only be considered for use if the the institution secure space for the researcher that cannot be manufacturer agrees to provide the materials needed for the accessible to anyone other than the investigator and employees researcher’s FDA Investigational New Drug submission and pro- authorized to have access to the drug. vides enough study drug to cover the needs of the investigation These requirements place a significant burden on the inves- at a cost that is not prohibitively expensive for a typical re- tigator embarking on a path to researching cannabis and canna- search budget. In addition, for a placebo-controlled study, a binoids. The security provisions can only be met with matched placebo is also required, ideally manufactured by the institutional support and commitment and with sufficient company providing the study drug. As such, providing a study funding to establish a secure drug storage area that adheres to drug for clinical trials is time intensive and resource heavy for the DEA’s standards. the manufacturer, and few manufacturers are creating these materials for direct sale to customers and researchers. This presents a conundrum where the types of cannabis products Source of the Study Drug available to the public continue to increase, yet research is lim- ited to only a handful of cannabinoids, modes of delivery, and Whereas the schedule I status of cannabis and many cannabi- noids is a significant barrier to research, identifying a drug for doses. Another issue with respect to feasibility of clinical trials clinical studies continues to be a principal obstacle, regardless with schedule I material is the lack of clear federal guidance on the limitations or restrictions for taking such study medication of the drug’s scheduling status. The challenges related to the across state lines. Researchers would be advised to check with single source of cannabis are outlined earlier in this paper (Section Research Procedures and Barriers: A Single Source for individual state governments if such scenarios are planned. Cannabis). Although the limitations related to a single source of Because of the various scheduling and availability issues of cannabis and cannabinoids, identifying the source of a drug for cannabis is clearly related to its schedule I status, a challenge that is frequently overlooked is identifying sources of any can- a particular study is absolutely integral when developing the nabinoid study drug independent of the drug’s scheduling. protocol and applying for funding (Figure 1). In fact, given the These challenges lie in the issues raised in Section 4.0, address- limitations of study drug availability, a study’s premise, objec- ing the need for a study drug to meet the FDA’s standards for tive, and design are usually crafted based on what is available. Downloaded from https://academic.oup.com/jncimono/article/2021/58/114/6446199 by DeepDyve user on 16 July 2022 Z. D. Cooper et al. | 119 for cannabis and cannabinoid studies is the existing infrastruc- Funding ture needed for this type of research, including institutional The ultimate limitation to research in this field is the availabil- support for this research, investigator expertise, and a schedule ity of funding. As noted before, funding is difficult to obtain for I license, if required for the study medication proposed in the nearly all areas of research, but this is especially true for canna- grant application. As such, to obtain funding, it is optimal for bis and cannabinoid research. Until recently, there were very the researcher to demonstrate experience in the field and have few opportunities to fund research dedicated to the therapeutic the support necessary to have successfully applied for and effects of cannabis and cannabinoids. The NIH Research, obtained a schedule I license. This is nearly impossible for most Condition, and Disease Categorization (29) system tracks expen- new investigators given that obtaining a schedule I license ditures by the NIH institutes. In 2019, the NIH budget for re- requires funding to support 1) the secure drug storage space search projects was approximately $9.6 billion, with an overall and 2) a study that is submitted for IRB, FDA, and state regula- funding rate of 19% (30). Despite laws restricting research, the tory approvals. These mutually dependent conditions create a NIH cannabis and cannabinoid research portfolio is significant situation that shuts out new investigators, especially those and growing and includes the provision of cannabis materials based at institutions that do not have infrastructure in place to for research. The cannabinoid research category includes the support clinical studies with schedule I substances. endocannabinoid system, CBD, and therapeutic cannabinoids. NIH cannabinoid research support increased from $111.3 mil- lion for 285 projects in 2015 to $189 million for 408 projects in Experience of a Clinician-Researcher Studying 2019, with more than a doubling of funds dedicated toward can- the Therapeutic Effects of Cannabis in Cancer nabis and cannabinoid therapeutics from 2015 to 2019, from $21 million to $46.5 million (Table 1), about 0.5% of the overall NIH Embarking on Clinical Cannabis Research: Cannabis in research budget. Of the 27 NIH components, 20 supported some HIV and AIDS cannabinoid research in 2019. NIDA was the primary source of Until recently, NIH did not have pathways specifically dedicated support, with $118.7 million for 258 projects. Noteworthy to provide funds to study the therapeutic effects of cannabis; changes include the National Center for Complementary and however, funds were set aside to investigate the potential ad- Integrative Health research on the potential therapeutic bene- verse effects of the plant. Hence, 25 years ago, to assess whether fits of minor cannabinoids and terpenes and the National cannabis could be useful in patients with AIDS wasting, Donald Cancer Institute workshop and research funds dedicated to can- I. Abrams and colleagues in the Department of Medicine at San nabinoids and cancer. Francisco General Hospital, California, proposed a clinical trial In addition to NIH, additional sources for funding have be- that was funded to primarily determine the safety of adding come available for cannabis and cannabinoid research. For ex- cannabis to HIV protease inhibitors, which also allowed for the ample, in 2000, $3 million per year for 3 years was appropriated potential study of the therapeutic effects of cannabis in this to the California state-funded Center for Medicinal Cannabis population (31–33). Research (CMCR) based at the University of California, San A second study funded by the CMCR 20 years ago sought to Diego, through legislation calling for a research program to determine the effects of inhaled cannabis on neuropathic pain oversee medical research of cannabis and cannabinoids. This in patients with HIV-related peripheral neuropathy. This trial center, now funded by revenue from taxes on adult-use canna- was designed to enroll 16 participants in a pilot phase to assess bis sales, was initially created to conduct and support clinical the activity of inhaled cannabis and calculate the sample size trials on the efficacy of cannabis. The research agenda ex- needed for a follow-up randomized controlled trial if the initial panded to include supporting clinical trials on the efficacy of results were encouraging. The study involved 9-day inpatient cannabis and cannabinoids to determine optimal dosing, tim- stays in the San Francisco General Hospital Clinical Research ing, and modes of administration; comparing the efficacy and Center. Inpatient studies were favored for research involving safety of various delivery methods; assessing the safety and this schedule I substance to ensure that the participants were toxicity of cannabis in the medically ill; and conducting limited using cannabis as described in the study protocol and not di- preclinical studies. Although funding is available only to inves- verting it to family or friends. Participants were not allowed to tigators at institutions based in California, submissions are have visitors or leave the Clinical Research Center ward. To high, with 55 applications received in the past 2 years. Yet, simi- standardize the inhaled dosing, the Foltin uniform puff proce- lar to NIH funding rates, the CMCR awards are very competitive, dure was employed (34). To anchor the participants’ subjective with a 12% funding rate (personal communication with Thomas description of their pain, the heat and capsaicin experimental Marcotte, co-director of the CMCR). The volume of grants sub- pain model was performed to provide a more objective mea- mitted demonstrates the eagerness of researchers to do work in surement. This method involved heating an area of the forearm the field, and the limited success rate exemplifies the difficulty to 40 C and then applying capsaicin cream, creating an area of in obtaining funds. In addition to state-funded research, private allodynia and hypesthesia that was mapped with a brush and a philanthropy and foundation support are other sources for sup- piece of foam while the subject looked off in another direction. porting cannabis and cannabinoid research for specific These areas were measured before and after exposure to the conditions. study drug. The trial was successfully completed with 50 partic- Without funding, it is impossible to cover the expenses asso- ipants enrolled in the randomized trial (35). ciated with the study, among which are personnel, participant expenses, study medication, and the costs to maintain regula- tory approvals and drug storage security (Figure 1). With limited Cannabis and Cancer Research funding opportunities and the highly competitive nature of those that exist, a proposal’s impact and novelty are weighed Simultaneous with funding awarded to assess the effects of alongside the study’s feasibility and potential for success in trial cannabis on HIV neuropathy, the Abrams team was awarded a initiation and completion. A key component of study feasibility CMCR grant to study cannabis in combination with opioids in Downloaded from https://academic.oup.com/jncimono/article/2021/58/114/6446199 by DeepDyve user on 16 July 2022 120 | J Natl Cancer Inst Monogr, 2021, Vol. 2021, No. 58 Table 1. NIH cannabinoid research investment by Research, Condition, and Disease Categorization (RCDC), fiscal years 2015-2019 RCDC category 2015 2016 2017 2018 2019 Cannabinoid $111 275 219 $115 167 703 $139 903 453 $146 551 293 $188 912 542 Cannabidiol $9 035 446 $11 667 081 $15 059 130 $19 397 279 $30 661 833 Endocannabinoid n/a $51 217 092 $62 870 455 $62 628 836 $73 139 271 Therapeutic cannabinoids $21 214 163 $28 174 758 $36 290 698 $37 322 692 $46 461 827 The Research, Condition, and Disease Categorization system tracks National Institutes of Health (NIH) research expenditures year by year in standardized groups de- fined by NIH experts. The cannabinoid research RCDC category is the “master” category for all NIH-supported cannabis research. It includes 3 subsets: cannabidiol, endocannabinoid, and therapeutic cannabinoid research. Individual projects may be included in multiple research categories. For example, a study investigating the potential therapeutic benefits of cannabidiol would be categorized under the cannabinoid, cannabidiol, and therapeutic cannabinoids RCDC categories. Studies investi- gating endogenous cannabinoids would be included in the cannabinoid and endocannabinoid systems RCDC studies. patients with breast and prostate cancer with painful bone me- patients who expressed interest, only 1 had met the eligibility tastases. This study also involved 9-day inpatient stays in the criteria and enrolled in the trial. The most frequent reasons that San Francisco General Hospital Clinical Research Center, and potential participants were deemed ineligible were because most of the study procedures were identical to those used in they were not taking the correct opioid analgesic, or more com- the HIV neuropathy study. However, in the time that it took to monly, they were taking the sustained-release morphine or complete the neuropathy study, only 3 participants enrolled in oxycodone preparations 3 or 4 times a day, which would not al- the cancer pain study. In an effort to increase accrual, eligibility low for the 12-hour opioid kinetics curve desired. Rather than was expanded to include any cancer patient with any pain. forfeit funding because of lack of accrual, the protocol was mod- Ultimately, the funding for the cancer pain study was with- ified after several months to eliminate cancer-related pain as drawn. Barriers to enrollment of cancer patients in this trial an entry criterion and included any participants with any pain were considered. It was suggested that cancer patients may not as long as they took the sustained-release opioid twice a day. be interested in spending unnecessary inpatient time (eg, in the With the expansion of the eligibility criteria beyond cancer Clinical Research Center to participate in a trial). The IRB patients, the study was successfully completed (37). expressed concern about inflicting experimental pain models on cancer patients. In addition, patients in San Francisco have long had access to cannabis without having to consent to a trial Cannabis and Sickle Cell Disease and risk getting randomly assigned to receive a placebo. More recently, a colleague of Dr Abrams, Kalpna Gupta, PhD, In an effort to bypass the need for inpatient Clinical works with transgenic mice with the human sickle hemoglobin Research Center admission, an outpatient study to examine the gene that experience pain. In her laboratory, she found that effects of cannabinoids on delayed chemotherapy-induced nau- cannabinoids ameliorate the chronic hypoxia-reoxygenation - sea and/or vomiting was designed and favorably reviewed for evoked acute pain in the mice. Approximately 8 years ago (ap- funding by the CMCR nearly 2 decades ago. Patients who had experienced delayed nausea after the first cycle of chemother- proximately 2013), she was seeking a collaborator interested in apy were then randomly assigned to receive true cannabis ciga- doing a human proof of principle study to accompany a grant rettes and placebo dronabinol, placebo cigarettes and active that she was submitting to the National Heart, Lung, and Blood dronabinol, or placebo cigarettes and placebo dronabinol. The Institute. Having completed the opioid-cannabinoid pharmaco- target sample size was 81. After enrolling the first 8 patients in kinetic interaction study, the Abrams team felt that a trial in this study, aprepitant was licensed and improved for this pre- sickle cell pain would be easily designed using a similar protocol cise indication. Local oncologists lost interest in referring as most of the participants would be on opioid analgesics. By patients to a trial where a placebo was possible in view of the this time, CBD had come bursting onto the scene as the most fa- new available effective treatment option. Having only enrolled vored cannabinoid. A 4-arm trial was envisioned comparing 10% of the accrual target, trial funding was withdrawn. THC-dominant cannabis, CBD-dominant cannabis, a balanced The question of possible synergy between cannabinoids and blend, and a placebo. However, funding was only available to opioids still loomed as a compelling area of investigation de- support 2 arms, and 1 had to be a placebo. Eager to evaluate a spite the failure of the initial attempt to study it. In an effort to CBD-containing product, the team requested that NIDA provide be sensitive to the potential concerns of cancer patients regard- a balanced strain, and they received a 4.4%THC to 4.9% CBD ing the smoked method of cannabis administration, use of the chemovar. Volcano vaporizer as a smokeless delivery system for cannabis The goal of this inpatient randomized, double-blind, pla- was explored. In healthy volunteers, the dose-dependent sub- cebo-controlled crossover trial was to determine the analgesic jective effects and pharmacokinetics of smoked and vaporized and subjective effects of cannabis in sickle cell patients main- cannabis were compared. Findings demonstrated that vaporiza- tained on opioid analgesics. This study required approvals from tion was a safe and effective delivery system and likely had re- multiple regulatory bodies as described in Section General duced respiratory risk compared with smoked cannabis (36). Challenges for the Clinical Researcher, and more than 1 year The Abrams team then submitted a proposal to NIDA to do a elapsed from the time the protocol was submitted to the IRB for pharmacokinetic interaction study in patients with cancer on approval when enrollment began. Nearly 3 years later, only 23 sustained-release morphine or sustained-released oxycodone of the target 35 patients had completed both arms of the cross- to determine whether it was safe to add vaporized cannabis to over trial; similar to cancer patients, patients with sickle cell the regimen. The study focused on the safety of the drug combi- nation and was quickly funded. After screening 218 cancer disease also found the inpatient component difficult (38). Downloaded from https://academic.oup.com/jncimono/article/2021/58/114/6446199 by DeepDyve user on 16 July 2022 Z. D. Cooper et al. | 121 With so many products available to patients currently, a Notes common questions is, “What is the right ratio of THC: CBD to Role of the funder: Part of this work was supported by the Semel study?” Or, should it be cannabigerol or perhaps cannabinol? Charitable Foundation, which had no role in conceiving or draft- How can an investigator decide what chemovar or mode of de- ing this manuscript. livery should be studied in a prospective clinical trial? It would almost seem that by the time the decision is made, a newer op- Disclosures: The authors have no competing interests in rela- tion may have become most favored in the free market of me- tion to the work described. Over the past 3 years, ZDC has dicinal cannabis products. In summary, cannabis and served as a consultant to GB Sciences and Beckley Canopy cannabinoid research requires navigating many hurdles. The Therapeutics and has served on the scientific advisory board of schedule I status of cannabis creates excessive regulatory hur- FSD Pharma. DIA is a scientific advisor to Cannformatics, dles, and potential participants have increased opportunities to Lumen, and Maui Grown Therapies. The other authors have no access medicinal cannabis and cannabis-derived products with- conflicts of interest to disclose. out participating in a clinical trial. These factors contribute to Author contributions: All authors drafted sections of the text the difficulty in initiating a study and enrolling enough partici- and reviewed the final draft. ZDC edited and compiled the com- pants to successfully complete a trial. plete and final draft. Disclaimers: The views and opinions expressed in this manu- script are those of the authors only and do not necessarily rep- resent the views, official policy, or position of the US Conclusion Department of Health and Human Services or any of its affili- With widespread availability of novel cannabis and cannabis- ated institutions or agencies. based products, there is an urgent need to understand their safety and potential effectiveness for medical indications. Prior presentations: Ideas discussed in this manuscript were Three primary barriers contribute to the difficulty in initiating presented at the 2020 NCI Cannabis, Cannabinoids, and Cancer research geared toward answering the most pressing public Research Symposium. health questions: the US regulatory status of cannabis and can- nabinoids, sources for cannabis and cannabinoid study medica- References tions, and funding to support studies. These barriers are 1. Britannica ProCon. 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Challenges for Clinical Cannabis and Cannabinoid Research in the United States

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Oxford University Press
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Abstract

Significant changes have occurred in the policy landscape surrounding cannabis legalization, production, and use around the globe and across the United States. With widespread availability of novel cannabis and cannabis-based products, there is an urgent need to understand their safety and effectiveness for medical indications. Three primary barriers contribute to the dif- ficulty in initiating research geared toward answering the most pressing public health questions: the US regulatory status of cannabis and cannabinoids, sources for cannabis and cannabinoid study medications, and limited funding and resources to support studies. Despite these hurdles, research is rapidly increasing, and recent changes in the United States have paved the way for exciting new work. Here, challenges and barriers to cannabis and cannabinoid research are described from the per- spectives of the National Institute on Drug Abuse, National Institutes of Health; the US Food and Drug Administration; and 2 clinical researchers. Barriers specifically to studying cannabis, cannabinoids, and cancer are emphasized. Significant changes have taken place in the policy landscape influencing and enacting policies, procedures, and laws related surrounding cannabis legalization, production, and use around to cannabis use (2,3). Other relevant challenges include the the globe and across the United States. Over the last couple of availability of cannabinoid-based study medications, federal decades, 35 states and the District of Columbia have legalized regulations, and other constraints associated with clinical trials. cannabis for medical conditions; of these, 15 states and the Oncologists frequently discuss the clinical use of cannabis District of Columbia (1) have also legalized adult use of canna- with their patients although most feel they lack an adequate bis. These landmark changes in policy have impacted cannabis knowledgebase to advise effectively (4). The National Academies of Sciences, Engineering and Medicine’s report on the Health use patterns and the perceived levels of risk. However, despite this changing landscape, evidence regard- Effects of Cannabis and Cannabinoids found strong evidence in sup- ing the short- and long-term health effects of cannabis use port of the use of cannabinoids for chemotherapy-induced nau- remains inconclusive. Several research studies have examined sea and vomiting as well as pain (5). Despite those findings, cannabis use in many forms, however, often these research many oncologists prefer to recommend approved pharmaceuti- conclusions are not appropriately translated and/or communi- cals with larger bodies of supporting evidence. Increasingly cated to policy makers, health-care providers, state health offi- patients are hearing of people healing their malignancies with cials, and other stakeholders who have been charged with highly concentrated cannabis oils (6). Although there is a Received: 21 August 2021; Accepted: 23 August 2021 Published by Oxford University Press 2021. This work is written by US Government employees and is in the public domain in the US. 114 Downloaded from https://academic.oup.com/jncimono/article/2021/58/114/6446199 by DeepDyve user on 16 July 2022 Z. D. Cooper et al. | 115 significant body of preclinical evidence suggesting anticancer immigration status of people convicted of cannabis-related effects of cannabinoids, translation to clinical benefit has not yet offenses; and reviewed sentences and expunged federal canna- occurred. Hence, oncologists and cancer researchers are likely to bis convictions. The US Senate–passed Cannabidiol and be particularly interested in seeing cannabis research advance. Marihuana Research Expansion Act (12) would have removed This review highlights challenges and barriers to cannabis plant-derived and synthetic cannabidiol (CBD) from the CSA schedule, streamlined the process of obtaining DEA registration and cannabinoid research from the perspectives of administra- tors from the National Institute on Drug Abuse, National to conduct research with marijuana, and required the DEA to act on pending applications. As of July 2021, no recent federal Institutes of Health (NIDA/NIH); the US Food and Drug Administration (FDA); and clinical researchers. Barriers specifi- legislation on cannabis has passed both houses of Congress and been signed into law by the president, although many bills have cally to studying cannabis, cannabinoids, and cancer are emphasized. been introduced, and some have passed either the House or the Senate (for updates, see https://www.govtrack.us/congress/ bills/subjects/drug_abuse/1759#sort=-introduced_date&text¼ Current Regulatory Status of Cannabis and cannabis&congress¼__ALL__&terms¼__ALL__&terms2¼__ALL__). Cannabinoids: An Overview Federal restrictions on clinical cannabis research result from its Research Procedures and Barriers: A Single legal status as defined by the Controlled Substances Act [CSA Source for Cannabis (7)] and international treaties. However, federal and state laws conflict, with diverse state regulations allowing personal pos- The administrative challenges for cannabinoid research include session and recreational and medical use. Laws and regulations the single domestic source requirement for cannabis, complex and lengthy registration processes, and schedule I classification on federal cannabinoid research have been changing recently, and more changes are expected (for up-to-date information of nonintoxicating cannabis components such as CBD. from the US Drug Enforcement Administration [DEA], refer to Scientific challenges include the complexity of cannabis plants (containing >100 cannabinoids and other components); diffi- deadiversion.usdoj.gov and the NIDA Drug Supply program at https://www.drugabuse.gov/research/research-data-measures- culty in designing blinded, controlled studies (particularly for driving after drug exposure); and the inability to study products resources/nida-drug-supply-program). Cannabis remains a federal schedule I controlled substance. available from dispensaries in states where they exist. Researchers who order cannabis from NIDA for human re- Schedule I substances include those determined to have high potential for abuse, no currently accepted medical use, and a search in the United States must obtain FDA Investigational New Drug authorization, DEA schedule I registration, and insti- lack of accepted safety for use under medical supervision. Additionally, the 1961 Single Convention on Narcotic Drugs tutional review board (IRB) approval. Despite misconceptions, NIDA has no role in determining qualifications. If researchers makes it illegal to grow, possess, or distribute cannabis except under strict conditions. One of those restrictions is that nations receive FDA, DEA, and IRB approval, NIDA fulfills orders for ciga- rettes and bulk cannabis in various THC and CBD concentra- may designate a single source of research marijuana. NIDA has served as the single source in the United States since 1968. tions, plus placebos. NIDA’s research cannabis is consistent, reproducible, pesticide free, and herbicide free. Although the However, because of a recent re-interpretation of the Single cannabis provided by NIDA tracks the average THC potency of Convention requirements, the DEA recently published a new the cannabis generally available, NIDA does recognize the need rule that will potentially allow the approval of additional for greater varieties of products, including improved placebos growers and producers of cannabis for research (8). Currently, and more formulations (eg, extracts), a larger range of poten- an estimated 41 applications are pending. It is anticipated that cies, and variable terpene content (13). NIDA’s Drug Supply Program will remain one of the licensed producers. Conflicting federal and state cannabis regulations hinder re- Role of the FDA in the Regulation of Cannabis search in several ways, including the inability of researchers to Products access products that are legal in their state, a lack of standardi- zation and quality control of cannabis and cannabis-derived There is broad public interest in expanding the availability of products within and across states, and no national oversight of cannabis-based products for both medical and nonmedical use. this standardization and quality control or the industry. In responding to this demand, the mission of the FDA is focused on advancing public health by overseeing the investigation, ap- proval, and production of safe, effective, and high-quality medi- Recent and Pending Legislative Action cal products, including those that are synthesized chemically or The Agriculture Improvement Act of 2018 [also known as the derived from the cannabis plant. Farm Bill (9)] removed hemp (cannabis containing no more than As described above, the Agricultural Improvement Act of 0.3% on a dry-weight basis) from the CSA schedule and re- 2018 (9) had an important impact on the FDA’s actions in this affirmed the FDA’s regulatory authority for hemp-derived medi- area. Importantly, the Farm Bill stipulates that the FDA’s au- cations, dietary supplements, and food additives (10). thorities under the Federal Food, Drug, and Cosmetic Act are The US House of Representatives–passed Marijuana unchanged, so that hemp-based drug products will be subject to Opportunity Reinvestment and Expungement Act of 2020 (11) the same authorities and requirements as any other drug prod- would have removed cannabis from the CSA schedule; elimi- uct. To date, the consequences of FDA regulation of cannabis nated criminal penalties for its manufacture, distribution, or and cannabinoids, including hemp, include the approval of 4 possession; established a 5% cannabis tax to support War on drug products. Three of these products are synthetic THC or Drugs compensation; protected the federal benefits and similar to THC and are approved to treat nausea from cancer Downloaded from https://academic.oup.com/jncimono/article/2021/58/114/6446199 by DeepDyve user on 16 July 2022 116 | J Natl Cancer Inst Monogr, 2021, Vol. 2021, No. 58 chemotherapy. The fourth product, Epidiolex, is made from substantial interest in US Congress legislation, and the FDA is highly purified CBD from cannabis. It is approved for certain actively offering assistance to state and nongovernmental part- rare seizure disorders and, more recently, for tuberous sclerosis ners in understanding the evolving cannabinoid landscape. The complex. The marketing approval of Epidiolex, particularly in FDA also continues to take enforcement actions whenever vio- light of the DEA’s placement of FDA-approved CBD-containing lative marketing of cannabinoid products is identified. For ex- products in schedule V according to the CSA (14), shows that ample, during the COVID-19 pandemic, the FDA had to take the clinical development of cannabis-derived medicines derives action in multiple instances where makers of CBD products from the concerted evolution of biomedical knowledge and reg- made antiviral, curative claims despite the lack of any support- ulatory flexibility. ing evidence on their safety or efficacy. Beyond the 4 FDA approvals mentioned above, the agency In summary, the FDA has a well-defined and multifaceted has more generally performed a scientific assessment of role in the cannabinoid space. Its role has been strengthened cannabis-derived CBD and concluded that, although CBD is psy- and clarified in some respects through recent activities on the choactive, it does not have the same abuse potential as THC legislative level. Most importantly, the FDA continues to sup- (which remains on schedule I of the CSA) (15). In addition to port the scientific assessment of cannabis-derived compounds. reviewing marketing applications for drugs and their indica- Because of broad interest in expanding the availability of these tions, the FDA also regulates clinical studies with cannabis and products, the FDA is considering many different regulatory cannabinoids. For these avenues of research, the investigator options for responding to this interest, always informed by our submits an Investigational New Drug application to the FDA for commitment to protect patients and advance our national pub- review. The application includes a detailed description of the lic health interests. study protocol and information about the investigational drug, including a summary of previous human experience with the investigational drug; animal pharmacology and toxicology; General Challenges for the Clinical Researcher chemistry, manufacturing, and controls information on the in- The clinical researcher striving to respond to public health pri- vestigational drug; and evidence that it was manufactured orities related to the surge in cannabis and cannabinoid use is according to current good manufacturing practices (16). Given met with a number of regulatory hurdles. With rapid expan- that state legalization may have facilitated the municipal sale sion of new products, novel methods of use, and growing pop- and use of many new cannabis-derived products around the ulations using these products for medical indications or for United States, it is important for investigators to be aware of nonmedical use, these restrictions are a major contributing FDA regulations before engaging in clinical studies with canna- factor to the limited data published addressing the most urgent bis and cannabinoids. issues. Apart from questions on the potential effectiveness of As the FDA works to regulate cannabis-derived products ap- products on the market for certain indications, a more immedi- propriately, there is a great deal that is unknown about CBD, ate concern relates to the safety of these products. There are and even less is known about the dozens of cannabinoids and increasingly popular product categories and modes of delivery other compounds present in cannabis extracts. For example, lit- that are available for purchase in state-regulated dispensaries tle is known about the effects of long-term human use of CBD that have yet to be tested under controlled conditions. Some of and the impact of CBD in susceptible populations: children, these products are hypothesized to have potentially significant pregnant women, and the elderly. Based on data from the drug negative effects, such as high-potency extracts geared toward development program for Epidiolex and from the published lit- delivering efficient intoxicating effects, as well as products erature, there are known toxicities of concern related to CBD such as specific minor cannabinoids and terpenes that, based use (15). For example, there are signals of potential liver injury, on preclinical literature, may be safe but have yet to be potential male reproductive toxicity, and clinically important assessed in humans. In an effort to elucidate both the safety drug-drug interactions. We do not know exactly how serious and the potential therapeutic uses of these products for a these signals are, and it is important that we continue efforts to range of indications for which they are already approved in an assess them. Going forward, we also need to identify ways of overwhelming majority of the United States, researchers must answering the many remaining questions about the safety of work tirelessly through institutional, regulatory, funding, and CBD, as well as the many other compounds found in cannabis. drug supply hurdles, all of which significantly influence the With so much yet to be learned, the FDA is committed to scientific impact, public health relevancy, and efficiency of supporting scientific cannabinoid research and development. investigations. To support human drug development of cannabis and Given the diverse nature of cannabis and cannabinoid re- cannabis-derived compounds, the FDA has created several search, differences in state laws, and varied institutional regula- resources to aide investigators as they develop their clinical tions, every scientist will likely have a unique experience when studies and use real-world data to fill the scientific gaps of initiating cannabis and cannabinoid work. In fact, with rapid knowledge. Some examples of these resources include informa- changes in oversight and regulations, one cannot necessarily tion about the conduct of clinical studies and how to request predict how to navigate regulatory hurdles for future studies formal meetings (16–19), considerations for using botanicals based on one’s own previous experiences. The following ac- (20), a frequently asked questions website (21), recently released count is from personal experience working with cannabis and draft guidance about manufacturing cannabis-derived drugs (22), and the newly published FDA Voices Blog (23). The FDA’s cannabinoids in 2 states and 2 institutions. This account high- lights the arduous path of starting a research program focusing research agenda is aimed at supporting studies to develop the data that is needed to understand how cannabinoids can be on controlled administration of cannabis and cannabinoids in humans and demonstrates that the pathway to embarking on used safely in drug products and other consumer goods, such as dietary supplements, cosmetics, and pet foods. The FDA also is this research is demanding both of the researcher’s time and exploring policy options to enable broader availability of safe, resources. This experience is important to stress as more effective, and high-quality cannabinoid products. There is researchers become interested in delving into this field but are Downloaded from https://academic.oup.com/jncimono/article/2021/58/114/6446199 by DeepDyve user on 16 July 2022 Z. D. Cooper et al. | 117 required to start from scratch to get projects off the ground. Regulatory Approvals. A study assessing the effects of canna- bis and/or cannabinoid administration is required to be submit- Because of the time, expenses, and regulatory knowledge re- ted to and approved by the IRB and the FDA. Protocols quired to get a single study started in this field, researchers will submitted to the IRB must be justified scientifically, meet the frequently opt not to pursue work in this area. Consequently, al- ethical principles of the Belmont Report (27), and include steps though more issues need to be addressed by diverse experts, the to minimize risk. This protocol is also submitted to the FDA as field will likely continue to be limited to those institutions and an Investigational New Drug application alongside detailed in- researchers who have historically pursued this work. formation regarding the chemistry, manufacturing, and control Below is a description of the 3 primary hurdles to conducting data of the agent to be studied as described in Section titled Role cannabis and cannabinoid research in the United States. of the FDA in the Regulation of Cannabis Products. Finally, state reg- Although the US regulatory status of cannabis and cannabi- ulatory approvals must also be obtained. Some states have sep- noids is a US-specific barrier, the other barriers—the paucity of arate controlled substance licensing requirements. For funding available for investigations and the availability of test example, in New York State, the investigator must apply for and medications that can be studied—are global and limit the ex- receive a license from the Bureau of Narcotic Enforcement. pansion of work in the field. Similarly, although some barriers Other states may require that protocols be approved by the state are unique to this field, it should be noted that clinical research board of medical examiners. For example, in the state of in general is difficult and burdensome, regardless of the study California, the Research Advisory Panel of California, under the medication under investigation. However, many hurdles de- state attorney general’s office, reviews and authorizes studies tailed below are unique to studying cannabis and cannabinoids involving schedules I and II substances to ensure the safety and in the United States. These challenges are intertwined with one protection of participating human research subjects, in addition another, creating a situation where overcoming one obstacle to the security provisions in place for the controlled substances requires success in surmounting the others, as depicted in used in the study. This panel also evaluates the scientific valid- Figure 1. ity of the studies. Therefore, studies can be rejected if deemed to “produce conclusions of little scientific value, or would not justify the exposure of California subjects to the risk of US Regulatory Status of Cannabis and Cannabinoids research” (28). If any of these bodies request modifications to As mentioned earlier, the most obvious regulatory hurdle in con- the protocol, amendments must be submitted to and reviewed ducting cannabis and cannabinoid research is the schedule I sta- by the other agencies. This approval process can take several tus of cannabis (with more than 0.3% THC) and specific months even if no modifications are required. cannabinoids. Although there has been movement in the field to Application to the DEA for a schedule I license includes the relax regulations, including the landmark change decontrolling above-mentioned approved regulatory documents; the investi- gator’s qualifications, including a curriculum vitae; a descrip- CBD derived from hemp, many changes have, in fact, made the tion of the research project, including its statement of purpose; regulatory landscape more confusing and difficult to navigate for the name and amount of substances to be used; a description of the researcher. For example, in the case of CBD, according to the and the number of research subjects; drug doses to be adminis- DEA interim final rule that outlines DEA’s amendments to the tered; mode of administration; and the duration of the study. CSAmadebythe AgricultureImprovement Actof 2018(24), prod- Details regarding where the study will be conducted and secu- ucts with CBD specifically derived from the plant that contain less rity provisions for storing the drug must also be included. than 0.3% delta-9-THC are now decontrolled, yet synthetic CBD Finally, an institutional letter of support must be provided, as remains on schedule I according to the CSA. Despite the fact that well as an indication of approved funding provided, if applicable the molecule is the same, its origins define its regulatory standing. (26). Once the application is received, the DEA communicates Another example of these confusing laws relates to the classifica- with the FDA to determine the merits of the study and the qual- tion of delta-9-THC, which has 3 distinct schedules based on the ifications and competency of the submitting investigator, which source of production and the formulation. For example, dronabi- is a process that takes at least 30 days. The local DEA inspector nol, synthetic delta-9-THC, is categorized on 3 different schedules: will then make an appointment to inspect the facility. Security oral capsules of the synthetic delta-9-THC dronabinol (ie, Marinol) issues noted during the inspection need to be resolved before is classified as schedule III, yet the FDA-approved liquid dronabi- the license is granted. nol (Syndros) is schedule II, and dronabinol not packaged accord- Security Requirements for Schedule I Material. Requirements for ing to FDA formulations (ie, active pharmaceutical ingredient) is schedule I drug storage are complicated, and the specifics out- schedule I (25). Currently, all forms of delta-9-THC derived from lined in Title 21 of the Code of Federal Regulations may not real- the cannabis plant (ie, not synthetic) are schedule I. These are a istically correspond to an investigator’s study needs. For few examples of the confusing nature of cannabinoid scheduling example, drugs may be required to be frozen to maintain stabil- that require near mastery to successfully identify whether a pro- ity (26). The Code of Federal Regulations does not provide an ad- posed trial with a potential study medication requires a schedule I equate solution for how this drug should be stored. As such, DEA license. Without proper guidance and support from people in researchers develop ways to maintain the integrity of their drug the field, a researcher is likely to get lost in the regulatory quag- product while still adhering to the DEA code. In general, small mire that is rapidly evolving. amounts of the drug must be stored in a safe or steel cabinet Once it has been determined that the test material is indeed that weighs at least 750 pounds and complies with the following schedule I, the investigator is required to apply and be approved specifications: protected for “30 man-minutes against surrepti- for schedule I registration. Prior to applying for this license, 2 tious entry, 10 man-minutes against forced entry, 20 man- significant milestones must be met: approval of a research pro- hours against lock manipulation, and 20 man-hours against ra- tocol that employs the schedule I substance for which the li- diological techniques.” If the safe or cabinet is not 750 pounds, cense is being sought and identification of a storage facility that it needs to be bolted or cemented to the floor or wall. The safe will meet DEA requirements (26). or steel cabinet should be equipped with an alarm that signals a Downloaded from https://academic.oup.com/jncimono/article/2021/58/114/6446199 by DeepDyve user on 16 July 2022 118 | J Natl Cancer Inst Monogr, 2021, Vol. 2021, No. 58 Figure 1. Primary obstacles in pursuing cannabis and cannabinoid research. Federal regulations, drug source, and funding are significant barriers to conducting canna- bis and cannabinoid research, which can lead to significant delays in study onset. As depicted by the double-headed arrows, these challenges are intertwined with one another, creating a situation where overcoming one obstacle requires success in surmounting the others. IRB ¼ institutional review board; FDA ¼ US Food and Drug Administration. central protection agency, a police agency, or a 24-hour control human study. Therefore, even if cannabis and schedule I canna- station operated by the registrant in the event of an unauthor- binoids shed their classification and are removed from the CSA, ized entry. Guidance for practitioners (clinical researchers) is researchers would still bear the burden of identifying a product modified to state that “Controlled substances listed in Schedule that adheres to the FDA’s Good Manufacturing Practice require- I shall be stored in a securely locked, substantially constructed ments. For example, hemp-derived CBD was recently removed cabinet” (26), however, there is not a detailed account of what from the CSA. This evolution should have improved research in type of safe meets this definition and may be left up to the local this area substantially, yet there are few manufacturers that DEA jurisdiction and agent. The storage facility is required to be make plant-derived CBD according to the FDA’s standards. in a space that is only accessible to a minimum number of spe- When a manufacturer of clinical-grade, hemp-derived CBD is cifically authorized employees. This stipulation requires that identified, the product can only be considered for use if the the institution secure space for the researcher that cannot be manufacturer agrees to provide the materials needed for the accessible to anyone other than the investigator and employees researcher’s FDA Investigational New Drug submission and pro- authorized to have access to the drug. vides enough study drug to cover the needs of the investigation These requirements place a significant burden on the inves- at a cost that is not prohibitively expensive for a typical re- tigator embarking on a path to researching cannabis and canna- search budget. In addition, for a placebo-controlled study, a binoids. The security provisions can only be met with matched placebo is also required, ideally manufactured by the institutional support and commitment and with sufficient company providing the study drug. As such, providing a study funding to establish a secure drug storage area that adheres to drug for clinical trials is time intensive and resource heavy for the DEA’s standards. the manufacturer, and few manufacturers are creating these materials for direct sale to customers and researchers. This presents a conundrum where the types of cannabis products Source of the Study Drug available to the public continue to increase, yet research is lim- ited to only a handful of cannabinoids, modes of delivery, and Whereas the schedule I status of cannabis and many cannabi- noids is a significant barrier to research, identifying a drug for doses. Another issue with respect to feasibility of clinical trials clinical studies continues to be a principal obstacle, regardless with schedule I material is the lack of clear federal guidance on the limitations or restrictions for taking such study medication of the drug’s scheduling status. The challenges related to the across state lines. Researchers would be advised to check with single source of cannabis are outlined earlier in this paper (Section Research Procedures and Barriers: A Single Source for individual state governments if such scenarios are planned. Cannabis). Although the limitations related to a single source of Because of the various scheduling and availability issues of cannabis and cannabinoids, identifying the source of a drug for cannabis is clearly related to its schedule I status, a challenge that is frequently overlooked is identifying sources of any can- a particular study is absolutely integral when developing the nabinoid study drug independent of the drug’s scheduling. protocol and applying for funding (Figure 1). In fact, given the These challenges lie in the issues raised in Section 4.0, address- limitations of study drug availability, a study’s premise, objec- ing the need for a study drug to meet the FDA’s standards for tive, and design are usually crafted based on what is available. Downloaded from https://academic.oup.com/jncimono/article/2021/58/114/6446199 by DeepDyve user on 16 July 2022 Z. D. Cooper et al. | 119 for cannabis and cannabinoid studies is the existing infrastruc- Funding ture needed for this type of research, including institutional The ultimate limitation to research in this field is the availabil- support for this research, investigator expertise, and a schedule ity of funding. As noted before, funding is difficult to obtain for I license, if required for the study medication proposed in the nearly all areas of research, but this is especially true for canna- grant application. As such, to obtain funding, it is optimal for bis and cannabinoid research. Until recently, there were very the researcher to demonstrate experience in the field and have few opportunities to fund research dedicated to the therapeutic the support necessary to have successfully applied for and effects of cannabis and cannabinoids. The NIH Research, obtained a schedule I license. This is nearly impossible for most Condition, and Disease Categorization (29) system tracks expen- new investigators given that obtaining a schedule I license ditures by the NIH institutes. In 2019, the NIH budget for re- requires funding to support 1) the secure drug storage space search projects was approximately $9.6 billion, with an overall and 2) a study that is submitted for IRB, FDA, and state regula- funding rate of 19% (30). Despite laws restricting research, the tory approvals. These mutually dependent conditions create a NIH cannabis and cannabinoid research portfolio is significant situation that shuts out new investigators, especially those and growing and includes the provision of cannabis materials based at institutions that do not have infrastructure in place to for research. The cannabinoid research category includes the support clinical studies with schedule I substances. endocannabinoid system, CBD, and therapeutic cannabinoids. NIH cannabinoid research support increased from $111.3 mil- lion for 285 projects in 2015 to $189 million for 408 projects in Experience of a Clinician-Researcher Studying 2019, with more than a doubling of funds dedicated toward can- the Therapeutic Effects of Cannabis in Cancer nabis and cannabinoid therapeutics from 2015 to 2019, from $21 million to $46.5 million (Table 1), about 0.5% of the overall NIH Embarking on Clinical Cannabis Research: Cannabis in research budget. Of the 27 NIH components, 20 supported some HIV and AIDS cannabinoid research in 2019. NIDA was the primary source of Until recently, NIH did not have pathways specifically dedicated support, with $118.7 million for 258 projects. Noteworthy to provide funds to study the therapeutic effects of cannabis; changes include the National Center for Complementary and however, funds were set aside to investigate the potential ad- Integrative Health research on the potential therapeutic bene- verse effects of the plant. Hence, 25 years ago, to assess whether fits of minor cannabinoids and terpenes and the National cannabis could be useful in patients with AIDS wasting, Donald Cancer Institute workshop and research funds dedicated to can- I. Abrams and colleagues in the Department of Medicine at San nabinoids and cancer. Francisco General Hospital, California, proposed a clinical trial In addition to NIH, additional sources for funding have be- that was funded to primarily determine the safety of adding come available for cannabis and cannabinoid research. For ex- cannabis to HIV protease inhibitors, which also allowed for the ample, in 2000, $3 million per year for 3 years was appropriated potential study of the therapeutic effects of cannabis in this to the California state-funded Center for Medicinal Cannabis population (31–33). Research (CMCR) based at the University of California, San A second study funded by the CMCR 20 years ago sought to Diego, through legislation calling for a research program to determine the effects of inhaled cannabis on neuropathic pain oversee medical research of cannabis and cannabinoids. This in patients with HIV-related peripheral neuropathy. This trial center, now funded by revenue from taxes on adult-use canna- was designed to enroll 16 participants in a pilot phase to assess bis sales, was initially created to conduct and support clinical the activity of inhaled cannabis and calculate the sample size trials on the efficacy of cannabis. The research agenda ex- needed for a follow-up randomized controlled trial if the initial panded to include supporting clinical trials on the efficacy of results were encouraging. The study involved 9-day inpatient cannabis and cannabinoids to determine optimal dosing, tim- stays in the San Francisco General Hospital Clinical Research ing, and modes of administration; comparing the efficacy and Center. Inpatient studies were favored for research involving safety of various delivery methods; assessing the safety and this schedule I substance to ensure that the participants were toxicity of cannabis in the medically ill; and conducting limited using cannabis as described in the study protocol and not di- preclinical studies. Although funding is available only to inves- verting it to family or friends. Participants were not allowed to tigators at institutions based in California, submissions are have visitors or leave the Clinical Research Center ward. To high, with 55 applications received in the past 2 years. Yet, simi- standardize the inhaled dosing, the Foltin uniform puff proce- lar to NIH funding rates, the CMCR awards are very competitive, dure was employed (34). To anchor the participants’ subjective with a 12% funding rate (personal communication with Thomas description of their pain, the heat and capsaicin experimental Marcotte, co-director of the CMCR). The volume of grants sub- pain model was performed to provide a more objective mea- mitted demonstrates the eagerness of researchers to do work in surement. This method involved heating an area of the forearm the field, and the limited success rate exemplifies the difficulty to 40 C and then applying capsaicin cream, creating an area of in obtaining funds. In addition to state-funded research, private allodynia and hypesthesia that was mapped with a brush and a philanthropy and foundation support are other sources for sup- piece of foam while the subject looked off in another direction. porting cannabis and cannabinoid research for specific These areas were measured before and after exposure to the conditions. study drug. The trial was successfully completed with 50 partic- Without funding, it is impossible to cover the expenses asso- ipants enrolled in the randomized trial (35). ciated with the study, among which are personnel, participant expenses, study medication, and the costs to maintain regula- tory approvals and drug storage security (Figure 1). With limited Cannabis and Cancer Research funding opportunities and the highly competitive nature of those that exist, a proposal’s impact and novelty are weighed Simultaneous with funding awarded to assess the effects of alongside the study’s feasibility and potential for success in trial cannabis on HIV neuropathy, the Abrams team was awarded a initiation and completion. A key component of study feasibility CMCR grant to study cannabis in combination with opioids in Downloaded from https://academic.oup.com/jncimono/article/2021/58/114/6446199 by DeepDyve user on 16 July 2022 120 | J Natl Cancer Inst Monogr, 2021, Vol. 2021, No. 58 Table 1. NIH cannabinoid research investment by Research, Condition, and Disease Categorization (RCDC), fiscal years 2015-2019 RCDC category 2015 2016 2017 2018 2019 Cannabinoid $111 275 219 $115 167 703 $139 903 453 $146 551 293 $188 912 542 Cannabidiol $9 035 446 $11 667 081 $15 059 130 $19 397 279 $30 661 833 Endocannabinoid n/a $51 217 092 $62 870 455 $62 628 836 $73 139 271 Therapeutic cannabinoids $21 214 163 $28 174 758 $36 290 698 $37 322 692 $46 461 827 The Research, Condition, and Disease Categorization system tracks National Institutes of Health (NIH) research expenditures year by year in standardized groups de- fined by NIH experts. The cannabinoid research RCDC category is the “master” category for all NIH-supported cannabis research. It includes 3 subsets: cannabidiol, endocannabinoid, and therapeutic cannabinoid research. Individual projects may be included in multiple research categories. For example, a study investigating the potential therapeutic benefits of cannabidiol would be categorized under the cannabinoid, cannabidiol, and therapeutic cannabinoids RCDC categories. Studies investi- gating endogenous cannabinoids would be included in the cannabinoid and endocannabinoid systems RCDC studies. patients with breast and prostate cancer with painful bone me- patients who expressed interest, only 1 had met the eligibility tastases. This study also involved 9-day inpatient stays in the criteria and enrolled in the trial. The most frequent reasons that San Francisco General Hospital Clinical Research Center, and potential participants were deemed ineligible were because most of the study procedures were identical to those used in they were not taking the correct opioid analgesic, or more com- the HIV neuropathy study. However, in the time that it took to monly, they were taking the sustained-release morphine or complete the neuropathy study, only 3 participants enrolled in oxycodone preparations 3 or 4 times a day, which would not al- the cancer pain study. In an effort to increase accrual, eligibility low for the 12-hour opioid kinetics curve desired. Rather than was expanded to include any cancer patient with any pain. forfeit funding because of lack of accrual, the protocol was mod- Ultimately, the funding for the cancer pain study was with- ified after several months to eliminate cancer-related pain as drawn. Barriers to enrollment of cancer patients in this trial an entry criterion and included any participants with any pain were considered. It was suggested that cancer patients may not as long as they took the sustained-release opioid twice a day. be interested in spending unnecessary inpatient time (eg, in the With the expansion of the eligibility criteria beyond cancer Clinical Research Center to participate in a trial). The IRB patients, the study was successfully completed (37). expressed concern about inflicting experimental pain models on cancer patients. In addition, patients in San Francisco have long had access to cannabis without having to consent to a trial Cannabis and Sickle Cell Disease and risk getting randomly assigned to receive a placebo. More recently, a colleague of Dr Abrams, Kalpna Gupta, PhD, In an effort to bypass the need for inpatient Clinical works with transgenic mice with the human sickle hemoglobin Research Center admission, an outpatient study to examine the gene that experience pain. In her laboratory, she found that effects of cannabinoids on delayed chemotherapy-induced nau- cannabinoids ameliorate the chronic hypoxia-reoxygenation - sea and/or vomiting was designed and favorably reviewed for evoked acute pain in the mice. Approximately 8 years ago (ap- funding by the CMCR nearly 2 decades ago. Patients who had experienced delayed nausea after the first cycle of chemother- proximately 2013), she was seeking a collaborator interested in apy were then randomly assigned to receive true cannabis ciga- doing a human proof of principle study to accompany a grant rettes and placebo dronabinol, placebo cigarettes and active that she was submitting to the National Heart, Lung, and Blood dronabinol, or placebo cigarettes and placebo dronabinol. The Institute. Having completed the opioid-cannabinoid pharmaco- target sample size was 81. After enrolling the first 8 patients in kinetic interaction study, the Abrams team felt that a trial in this study, aprepitant was licensed and improved for this pre- sickle cell pain would be easily designed using a similar protocol cise indication. Local oncologists lost interest in referring as most of the participants would be on opioid analgesics. By patients to a trial where a placebo was possible in view of the this time, CBD had come bursting onto the scene as the most fa- new available effective treatment option. Having only enrolled vored cannabinoid. A 4-arm trial was envisioned comparing 10% of the accrual target, trial funding was withdrawn. THC-dominant cannabis, CBD-dominant cannabis, a balanced The question of possible synergy between cannabinoids and blend, and a placebo. However, funding was only available to opioids still loomed as a compelling area of investigation de- support 2 arms, and 1 had to be a placebo. Eager to evaluate a spite the failure of the initial attempt to study it. In an effort to CBD-containing product, the team requested that NIDA provide be sensitive to the potential concerns of cancer patients regard- a balanced strain, and they received a 4.4%THC to 4.9% CBD ing the smoked method of cannabis administration, use of the chemovar. Volcano vaporizer as a smokeless delivery system for cannabis The goal of this inpatient randomized, double-blind, pla- was explored. In healthy volunteers, the dose-dependent sub- cebo-controlled crossover trial was to determine the analgesic jective effects and pharmacokinetics of smoked and vaporized and subjective effects of cannabis in sickle cell patients main- cannabis were compared. Findings demonstrated that vaporiza- tained on opioid analgesics. This study required approvals from tion was a safe and effective delivery system and likely had re- multiple regulatory bodies as described in Section General duced respiratory risk compared with smoked cannabis (36). Challenges for the Clinical Researcher, and more than 1 year The Abrams team then submitted a proposal to NIDA to do a elapsed from the time the protocol was submitted to the IRB for pharmacokinetic interaction study in patients with cancer on approval when enrollment began. Nearly 3 years later, only 23 sustained-release morphine or sustained-released oxycodone of the target 35 patients had completed both arms of the cross- to determine whether it was safe to add vaporized cannabis to over trial; similar to cancer patients, patients with sickle cell the regimen. The study focused on the safety of the drug combi- nation and was quickly funded. After screening 218 cancer disease also found the inpatient component difficult (38). Downloaded from https://academic.oup.com/jncimono/article/2021/58/114/6446199 by DeepDyve user on 16 July 2022 Z. D. Cooper et al. | 121 With so many products available to patients currently, a Notes common questions is, “What is the right ratio of THC: CBD to Role of the funder: Part of this work was supported by the Semel study?” Or, should it be cannabigerol or perhaps cannabinol? Charitable Foundation, which had no role in conceiving or draft- How can an investigator decide what chemovar or mode of de- ing this manuscript. livery should be studied in a prospective clinical trial? It would almost seem that by the time the decision is made, a newer op- Disclosures: The authors have no competing interests in rela- tion may have become most favored in the free market of me- tion to the work described. Over the past 3 years, ZDC has dicinal cannabis products. In summary, cannabis and served as a consultant to GB Sciences and Beckley Canopy cannabinoid research requires navigating many hurdles. The Therapeutics and has served on the scientific advisory board of schedule I status of cannabis creates excessive regulatory hur- FSD Pharma. DIA is a scientific advisor to Cannformatics, dles, and potential participants have increased opportunities to Lumen, and Maui Grown Therapies. The other authors have no access medicinal cannabis and cannabis-derived products with- conflicts of interest to disclose. out participating in a clinical trial. These factors contribute to Author contributions: All authors drafted sections of the text the difficulty in initiating a study and enrolling enough partici- and reviewed the final draft. ZDC edited and compiled the com- pants to successfully complete a trial. plete and final draft. Disclaimers: The views and opinions expressed in this manu- script are those of the authors only and do not necessarily rep- resent the views, official policy, or position of the US Conclusion Department of Health and Human Services or any of its affili- With widespread availability of novel cannabis and cannabis- ated institutions or agencies. based products, there is an urgent need to understand their safety and potential effectiveness for medical indications. Prior presentations: Ideas discussed in this manuscript were Three primary barriers contribute to the difficulty in initiating presented at the 2020 NCI Cannabis, Cannabinoids, and Cancer research geared toward answering the most pressing public Research Symposium. health questions: the US regulatory status of cannabis and can- nabinoids, sources for cannabis and cannabinoid study medica- References tions, and funding to support studies. These barriers are 1. Britannica ProCon. 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Journal

JNCI Monographs – Oxford University Press

Published: Nov 28, 2021

Keywords: cannabinoids; cannabis; marijuana

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