Because I used a voluntary identification card database as a proxy for all medical marijuana users in California, many approximations may be under estimated. While there was some evidence of a substitution effect between alcohol and medical marijuana from the arrest data, the true effect could be much larger. This would justify why in previous studies, there has been stronger evidence of substitution effects. It was particularly interesting that there was no evidence of a substitution effect between marijuana and narcotics. Because the proxy for narcotics use was arrest rates, it is possible that the actual substitution effect could not be observed. Many users who substitute narcotics for medical marijuana are originally prescribed a legal amount of prescription-drugs, thus having no reason for an arrest to take place. It is also possible that many medical marijuana cardholders do not use for medical purposes and the actual medical users did not identify themselves in this database. While this proxy is not definitive of all effects that marijuana has on society, it offers insight on the true impact that marijuana use can have on crime and substance use. An improvement of this study would be to use data from states that have passed recreational marijuana laws and comparing it to those who have not. However, at the moment we can use this analysis to better understand how the current marijuana laws affect California. Significant changes have taken place in the policy landscape surrounding cannabis legalization, production, pipp racking system and use around the globe and across the United States. Over the last couple of decades, 35 states and the District of Columbia have legalized cannabis for medical conditions; of these, 15 states and the District of Columbia have also legalized adult use of cannabis.
These landmark changes in policy have impacted cannabis use patterns and the perceived levels of risk. However, despite this changing landscape, evidence regarding the short- and long-term health effects of cannabis use remains inconclusive. Several research studies have examined cannabis use in many forms, however, often these research conclusions are not appropriately translated and/or communicated to policy makers, health-care providers, state health officials, and other stakeholders who have been charged with influencing and enacting policies, procedures, and laws related to cannabis use . Other relevant challenges include the availability of cannabinoid-based study medications, federal regulations, and other constraints associated with clinical trials. Oncologists frequently discuss the clinical use of cannabis with their patients although most feel they lack an adequate knowledge base to advise effectively . The National Academies of Sciences, Engineering and Medicine’s report on the Health Effects of Cannabis and Cannabinoids found strong evidence in support of the use of cannabinoids for chemotherapy-induced nausea and vomiting as well as pain . Despite those findings, many oncologists prefer to recommend approved pharmaceuticals with larger bodies of supporting evidence. Increasingly patients are hearing of people healing their malignancies with highly concentrated cannabis oils . Although there is a significant body of preclinical evidence suggesting anticancer effects of cannabinoids, translation to clinical benefit has not yet occurred. Hence, oncologists and cancer researchers are likely to be particularly interested in seeing cannabis research advance. This review highlights challenges and barriers to cannabis and cannabinoid research from the perspectives of administrators from the National Institute on Drug Abuse, National Institutes of Health ; the US Food and Drug Administration ; and clinical researchers. Barriers specifically to studying cannabis, cannabinoids, and cancer are emphasized.Federal restrictions on clinical cannabis research result from its legal status as defined by the Controlled Substances Act [CSA ] and international treaties. However, federal and state laws conflict, with diverse state regulations allowing personal possession and recreational and medical use.
Laws and regulations on federal cannabinoid research have been changing recently, and more changes are expected . Cannabis remains a federal schedule I controlled substance. Schedule I substances include those determined to have high potential for abuse, no currently accepted medical use, and a lack of accepted safety for use under medical supervision. Additionally, the 1961 Single Convention on Narcotic Drugs makes it illegal to grow, possess, or distribute cannabis except under strict conditions. One of those restrictions is that nations may designate a single source of research marijuana. NIDA has served as the single source in the United States since 1968. However, because of a recent re-interpretation of the Single Convention requirements, the DEA recently published a new rule that will potentially allow the approval of additional growers and producers of cannabis for research . Currently, an estimated 41 applications are pending. Conflicting federal and state cannabis regulations hinder research in several ways, including the inability of researchers to access products that are legal in their state, a lack of standardization and quality control of cannabis and cannabis-derived products within and across states, and no national oversight of this standardization and quality control or the industry.The administrative challenges for cannabinoid research include the single domestic source requirement for cannabis, complex and lengthy registration processes, and schedule I classification of nonintoxicating cannabis components such as CBD. Scientific challenges include the complexity of cannabis plants ; difficulty in designing blinded, controlled studies ; and the inability to study products available from dispensaries in states where they exist. Researchers who order cannabis from NIDA for human research in the United States must obtain FDA Investigational New Drug authorization, DEA schedule I registration, and institutional review board approval.
Despite misconceptions, NIDA has no role in determining qualifications. If researchers receive FDA, DEA, and IRB approval, NIDA fulfills orders for cigarettes and bulk cannabis in various THC and CBD concentrations, plus placebos. NIDA’s research cannabis is consistent, reproducible, pesticide free, and herbicide free. Although the cannabis provided by NIDA tracks the average THC potency of the cannabis generally available, NIDA does recognize the need for greater varieties of products, including improved placebos and more formulations , a larger range of potencies, and variable terpene content .There is broad public interest in expanding the availability of cannabis-based products for both medical and non-medical use. In responding to this demand, the mission of the FDA is focused on advancing public health by overseeing the investigation, approval, and production of safe, effective, and high-quality medical products, including those that are synthesized chemically or derived from the cannabis plant. As described above, the Agricultural Improvement Act of 2018 had an important impact on the FDA’s actions in this area. Importantly, the Farm Bill stipulates that the FDA’s authorities under the Federal Food, Drug, and Cosmetic Act are unchanged, so that hemp-based drug products will be subject to the same authorities and requirements as any other drug product. To date, the consequences of FDA regulation of cannabis and cannabinoids, including hemp, pipp vertical racks include the approval of 4 drug products. Three of these products are synthetic THC or similar to THC and are approved to treat nausea from cancerchemotherapy. The fourth product, Epidiolex, is made from highly purified CBD from cannabis. It is approved for certain rare seizure disorders and, more recently, for tuberous sclerosis complex. The marketing approval of Epidiolex, particularly in light of the DEA’s placement of FDA-approved CBD-containing products in schedule V according to the CSA , shows that the clinical development of cannabis-derived medicines derives from the concerted evolution of biomedical knowledge and regulatory flexibility. Beyond the 4 FDA approvals mentioned above, the agency has more generally performed a scientific assessment of cannabis-derived CBD and concluded that, although CBD is psychoactive, it does not have the same abuse potential as THC . In addition to reviewing marketing applications for drugs and their indications, the FDA also regulates clinical studies with cannabis and cannabinoids. For these avenues of research, the investigator submits an Investigational New Drug application to the FDA for review. The application includes a detailed description of the study protocol and information about the investigational drug, including a summary of previous human experience with the investigational drug; animal pharmacology and toxicology; chemistry, manufacturing, and controls information on the investigational drug; and evidence that it was manufactured according to current good manufacturing practices . Given that state legalization may have facilitated the municipal sale and use of many new cannabis-derived products around the United States, it is important for investigators to be aware of FDA regulations before engaging in clinical studies with cannabis and cannabinoids. As the FDA works to regulate cannabis-derived products appropriately, there is a great deal that is unknown about CBD, and even less is known about the dozens of cannabinoids and other compounds present in cannabis extracts.
For example, little is known about the effects of long-term human use of CBD and the impact of CBD in susceptible populations: children, pregnant women, and the elderly. Based on data from the drug development program for Epidiolex and from the published literature, there are known toxicities of concern related to CBD use . For example, there are signals of potential liver injury, potential male reproductive toxicity, and clinically important drug-drug interactions. We do not know exactly how serious these signals are, and it is important that we continue efforts to assess them. Going forward, we also need to identify ways of answering the many remaining questions about the safety of CBD, as well as the many other compounds found in cannabis. With so much yet to be learned, the FDA is committed to supporting scientific cannabinoid research and development. To support human drug development of cannabis and cannabis-derived compounds, the FDA has created several resources to aide investigators as they develop their clinical studies and use real-world data to fill the scientific gaps of knowledge. Some examples of these resources include information about the conduct of clinical studies and how to request formal meetings , considerations for using botanicals , a frequently asked questions website , recently released draft guidance about manufacturing cannabis-derived drugs , and the newly published FDA Voices Blog . The FDA’s research agenda is aimed at supporting studies to develop the data that is needed to understand how cannabinoids can be used safely in drug products and other consumer goods, such as dietary supplements, cosmetics, and pet foods. The FDA also is exploring policy options to enable broader availability of safe, effective, and high-quality cannabinoid products. There is substantial interest in US Congress legislation, and the FDA is actively offering assistance to state and nongovernmental partners in understanding the evolving cannabinoid landscape. The FDA also continues to take enforcement actions whenever violative marketing of cannabinoid products is identified. For example, during the COVID-19 pandemic, the FDA had to take action in multiple instances where makers of CBD products made antiviral, curative claims despite the lack of any supporting evidence on their safety or efficacy. In summary, the FDA has a well-defined and multifaceted role in the cannabinoid space. Its role has been strengthened and clarified in some respects through recent activities on the legislative level. Most importantly, the FDA continues to support the scientific assessment of cannabis-derived compounds. Because of broad interest in expanding the availability of these products, the FDA is considering many different regulatory options for responding to this interest, always informed by our commitment to protect patients and advance our national public health interests.The clinical researcher striving to respond to public health priorities related to the surge in cannabis and cannabinoid use is met with a number of regulatory hurdles. With rapid expansion of new products, novel methods of use, and growing populations using these products for medical indications or for non-medical use, these restrictions are a major contributing factor to the limited data published addressing the most urgent issues. Apart from questions on the potential effectiveness of products on the market for certain indications, a more immediate concern relates to the safety of these products. There are increasingly popular product categories and modes of delivery that are available for purchase in state-regulated dispensaries that have yet to be tested under controlled conditions. Some of these products are hypothesized to have potentially significant negative effects, such as high-potency extracts geared toward delivering efficient intoxicating effects, as well as products such as specific minor cannabinoids and terpenes that, based on preclinical literature, may be safe but have yet to be assessed in humans. In an effort to elucidate both the safety and the potential therapeutic uses of these products for a range of indications for which they are already approved in an overwhelming majority of the United States, researchers must work tirelessly through institutional, regulatory, funding, and drug supply hurdles, all of which significantly influence the scientific impact, public health relevancy, and efficiency of investigations.