NIH cannabinoid research support increased from $111.3 million for 285 projects in 2015 to $189 million for 408 projects in 2019, with more than a doubling of funds dedicated toward cannabis and cannabinoid therapeutics from 2015 to 2019, from $21 million to $46.5 million , about 0.5% of the overall NIH research budget. Of the 27 NIH components, 20 supported some cannabinoid research in 2019. NIDA was the primary source of support, with $118.7 million for 258 projects. Noteworthy changes include the National Center for Complementary and Integrative Health research on the potential therapeutic benefits of minor cannabinoids and terpenes and the National Cancer Institute workshop and research funds dedicated to cannabinoids and cancer. In addition to NIH, additional sources for funding have become available for cannabis and cannabinoid research. For example, in 2000, $3 million per year for 3 years was appropriated to the California state-funded Center for Medicinal Cannabis Research based at the University of California, San Diego, through legislation calling for a research program to oversee medical research of cannabis and cannabinoids. This center, now funded by revenue from taxes on adult-use cannabis sales, was initially created to conduct and support clinical trials on the efficacy of cannabis. The research agenda expanded to include supporting clinical trials on the efficacy of cannabis and cannabinoids to determine optimal dosing, timing, and modes of administration; comparing the efficacy and safety of various delivery methods; assessing the safety and toxicity of cannabis in the medically ill; and conducting limited preclinical studies. Although funding is available only to investigators at institutions based in California, submissions are high, vertical growing weed with 55 applications received in the past 2 years. Yet, similar to NIH funding rates, the CMCR awards are very competitive, with a 12% funding rate . The volume of grants submitted demonstrates the eagerness of researchers to do work in the field, and the limited success rate exemplifies the difficulty in obtaining funds. In addition to state-funded research, private philanthropy and foundation support are other sources for supporting cannabis and cannabinoid research for specific conditions.
Without funding, it is impossible to cover the expenses associated with the study, among which are personnel, participant expenses, study medication, and the costs to maintain regulatory approvals and drug storage security . With limited funding opportunities and the highly competitive nature of those that exist, a proposal’s impact and novelty are weighed alongside the study’s feasibility and potential for success in trial initiation and completion. A key component of study feasibility for cannabis and cannabinoid studies is the existing infrastructure needed for this type of research, including institutional support for this research, investigator expertise, and a schedule I license, if required for the study medication proposed in the grant application. As such, to obtain funding, it is optimal for the researcher to demonstrate experience in the field and have the support necessary to have successfully applied for and obtained a schedule I license. This is nearly impossible for most new investigators given that obtaining a schedule I license requires funding to support 1) the secure drug storage space and 2) a study that is submitted for IRB, FDA, and state regulatory approvals. These mutually dependent conditions create a situation that shuts out new investigators, especially those based at institutions that do not have infrastructure in place to support clinical studies with schedule I substances.Until recently, NIH did not have pathways specifically dedicated to provide funds to study the therapeutic effects of cannabis; however, funds were set aside to investigate the potential adverse effects of the plant. Hence, 25 years ago, to assess whether cannabis could be useful in patients with AIDS wasting, Donald I. Abrams and colleagues in the Department of Medicine at San Francisco General Hospital, California, proposed a clinical trial that was funded to primarily determine the safety of adding cannabis to HIV protease inhibitors, which also allowed for the potential study of the therapeutic effects of cannabis in this population .
A second study funded by the CMCR 20 years ago sought to determine the effects of inhaled cannabis on neuropathic pain in patients with HIV-related peripheral neuropathy. This trial was designed to enroll 16 participants in a pilot phase to assess the activity of inhaled cannabis and calculate the sample size needed for a follow-up randomized controlled trial if the initial results were encouraging. The study involved 9-day inpatient stays in the San Francisco General Hospital Clinical Research Center. Inpatient studies were favored for research involving this schedule I substance to ensure that the participants were using cannabis as described in the study protocol and not diverting it to family or friends. Participants were not allowed to have visitors or leave the Clinical Research Center ward. To standardize the inhaled dosing, the Foltin uniform puff procedure was employed . To anchor the participants’ subjective description of their pain, the heat and capsaicin experimental pain model was performed to provide a more objective measurement. This method involved heating an area of the forearm to 40 C and then applying capsaicin cream, creating an area of allodynia and hypesthesia that was mapped with a brush and a piece of foam while the subject looked off in another direction. These areas were measured before and after exposure to the study drug. The trial was successfully completed with 50 participants enrolled in the randomized trial .Simultaneous with funding awarded to assess the effects of cannabis on HIV neuropathy, the Abrams team was awarded a CMCR grant to study cannabis in combination with opioids inpatients with breast and prostate cancer with painful bone metastases. This study also involved 9-day inpatient stays in the San Francisco General Hospital Clinical Research Center, and most of the study procedures were identical to those used in the HIV neuropathy study. However, in the time that it took to complete the neuropathy study, only 3 participants enrolled in the cancer pain study. In an effort to increase accrual, eligibility was expanded to include any cancer patient with any pain. Ultimately, the funding for the cancer pain study was withdrawn. Barriers to enrollment of cancer patients in this trial were considered. It was suggested that cancer patients may not be interested in spending unnecessary inpatient time . The IRB 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 and risk getting randomly assigned to receive a placebo. In an effort to bypass the need for inpatient Clinical Research Center admission, an outpatient study to examine the effects of cannabinoids on delayed chemotherapy-induced nausea and/or vomiting was designed and favorably reviewed for funding by the CMCR nearly 2 decades ago. Patients who had experienced delayed nausea after the first cycle of chemotherapy were then randomly assigned to receive true cannabis cigarettes and placebo dronabinol, placebo cigarettes and active dronabinol, pipp shelving or placebo cigarettes and placebo dronabinol. The target sample size was 81. After enrolling the first 8 patients in this study, aprepitant was licensed and improved for this precise indication. Local oncologists lost interest in referring patients to a trial where a placebo was possible in view of the new available effective treatment option. Having only enrolled 10% of the accrual target, trial funding was withdrawn. The question of possible synergy between cannabinoids and opioids still loomed as a compelling area of investigation despite the failure of the initial attempt to study it. In an effort to be sensitive to the potential concerns of cancer patients regarding the smoked method of cannabis administration, use of the Volcano vaporizer as a smokeless delivery system for cannabis was explored. In healthy volunteers, the dose-dependent subjective effects and pharmacokinetics of smoked and vaporized cannabis were compared.
Findings demonstrated that vaporization was a safe and effective delivery system and likely had reduced respiratory risk compared with smoked cannabis . The Abrams team then submitted a proposal to NIDA to do a pharmacokinetic interaction study in patients with cancer on sustained-release morphine or sustained-released oxycodone to determine whether it was safe to add vaporized cannabis to the regimen. After screening 218 cancer patients who expressed interest, only 1 had met the eligibility criteria and enrolled in the trial. The most frequent reasons that potential participants were deemed ineligible were because they were not taking the correct opioid analgesic, or more commonly, they were taking the sustained-release morphine or oxycodone preparations 3 or 4 times a day, which would not allow for the 12-hour opioid kinetics curve desired. Rather than forfeit funding because of lack of accrual, the protocol was modified after several months to eliminate cancer-related pain as an entry criterion and included any participants with any pain as long as they took the sustained-release opioid twice a day. With the expansion of the eligibility criteria beyond cancer patients, the study was successfully completed .More recently, a colleague of Dr Abrams, Kalpna Gupta, PhD, works with transgenic mice with the human sickle hemoglobin gene that experience pain. In her laboratory, she found that cannabinoids ameliorate the chronic hypoxia-reoxygenation – evoked acute pain in the mice. Approximately 8 years ago , she was seeking a collaborator interested in doing a human proof of principle study to accompany a grant that she was submitting to the National Heart, Lung, and Blood Institute. Having completed the opioid-cannabinoid pharmacokinetic interaction study, the Abrams team felt that a trial in sickle cell pain would be easily designed using a similar protocol as most of the participants would be on opioid analgesics. By this time, CBD had come bursting onto the scene as the most favored cannabinoid. A 4-arm trial was envisioned comparing THC-dominant cannabis, CBD-dominant cannabis, a balanced blend, and a placebo. However, funding was only available to support 2 arms, and 1 had to be a placebo. Eager to evaluate a CBD-containing product, the team requested that NIDA provide a balanced strain, and they received a 4.4%THC to 4.9% CBD chemovar. The goal of this inpatient randomized, double-blind, placebo-controlled crossover trial was to determine the analgesic and subjective effects of cannabis in sickle cell patients maintained on opioid analgesics. This study required approvals from multiple regulatory bodies as described in Section General Challenges for the Clinical Researcher, and more than 1 year elapsed from the time the protocol was submitted to the IRB for approval when enrollment began. Nearly 3 years later, only 23 of the target 35 patients had completed both arms of the crossover trial; similar to cancer patients, patients with sickle cell disease also found the inpatient component difficult .In the early fall of 2018, a minor media storm described a seafood restaurant in Maine that was proposing to expose lobsters to marijuana smoke prior to cooking . At least three testable assertions were made including 1) that some psychoactive constituent of cannabis would be transferred to the lobster via open air respiration , 2) that this would have specific behavioral effects similar to those produced in vertebrates and 3) that the cooking process would remove intoxicating psychoactive constituents from the meat thereby rendering it safe for human consumption. This latter assertion was related to a claim that “a steam as well as a heat process” would bring the lobster to 420 °F , which would presumably require broiling or oven baking in preference to the more typical boiling or steaming cooking method. These assertions lead to at least two key questions. Can air exposure to Δ9-tetrahydrocannabinol , the primary psychoactive constituent of cannabis, produce significant tissue levels of the drug in lobsters? If so, does it have any discernible behavioral effects? Lobsters are aquatic species that respirate via gills located inside their carapace. Lobsters can survive in air for many hours up to a few days, if they are able to keep their gills wet enough to function, but they do go into oxygen debt, e.g. across a 24 h emersion from water . It is unclear if the gill structures would support the uptake of THC that is rendered airborne via smoke particulate or Electronic Drug Delivery System device vapor.