Advancing Our Understanding of Cannabis-based Cure

The Progress

Cannabis has existed for centuries, but it is only since the 1990’s, with the discovery of the Endocannabinoid system in the human body, that we first started recognizing the medical and therapeutic benefits of cannabis in palliative care and the treatment of arthritis, epilepsy, pain management, and even complex diseases like cancer.

Raphael Mechoulam, a researcher at Hebrew University, Israel and a leading pioneer in cannabis research, co-discovered the endocannabinoid system in 1992, the largest receptor system in the human body and also discovered that the human brain produces its own cannabinoids — compounds that stimulate the body's receptor system.

Since then, in the past twenty years, research has progressed at a jaw dropping pace across the globe, offering new insights and revolutionizing our understanding of how cannabis interacts with the human body. Over 10,000 scientific studies on cannabis have been conducted globally which concretely support the proposed medical and therapeutic benefits while more research and clinical data is needed for complex diseases.

It was in 1996 that California became the first US state to pass the medicinal cannabis legislation paving the way for today's 33 states, including the District of Columbia to legalize medical cannabis. During the same time, several countries including Canada, Netherlands, Israel, Uruguay, and Australia have legalized the use of cannabis for medicinal purposes. Today, roughly 147 million people across the globe (around 25 million in the US), use medical marijuana for effective relief of various ailments, including AIDS, Multiple Sclerosis, Crohn’s disease, side effects from cancer treatment and Parkinson’s. Experts believe these numbers will grow exponentially in the coming years.

Currently, there are over 110 clinical trials involving cannabis underway in Israel, more than any other country in the world.

Meanwhile, the Australian Government has committed millions of dollars towards clinical trials to evaluate the safety and effectiveness of cannabis medicine in providing relief from the symptoms of serious conditions. Several clinical trials are currently underway investigating the potential of cannabis medicine to treat epilepsy, improve appetite in adult palliative care patients with advanced cancer and prevent chemotherapy-induced nausea and vomiting in adult patients. Additionally, the world’s first trial to treat brain cancer with medical cannabis was also launched in Australia.

In the United States, federal agencies are becoming more open to medical marijuana research than they have been in the past. The DEA has increased the amount of cannabis that can be grown for medical studies, and the FDA now says that it's helping states conduct clinical trials to determine the safety and efficacy of cannabis. That could present a big shift from decades of restrictions that delayed and halted research. Even though the NIH has been funding cannabis research projects, only a small portion of their funding went to researching the medicinal properties of cannabis while the rest went into addiction.

In June 2018, the Food and Drug Administration (FDA) granted approval of the first cannabis-based drug called Epidiolex to GW Pharmaceuticals for the treatment of seizures associated with Dravet and Lennox-Gastaut syndromes. The FDA’s approval of Epidiolex represents two major milestones. First, a cannabis-derived product was accorded an “accepted medical use” in the United States, despite DEA’s Schedule 1 criteria. Second, it signaled a shift in the industry’s ability to perform cannabis clinical research which would allow pharmaceutical companies to investigate the medicinal benefits of cannabis and its byproducts through clinical research.

In September 2018, the House Judiciary Committee approved legislation designed to facilitate increased, federally-approved, research into the potential medical benefits of marijuana. The Medical Cannabis Research Act of 2018 (H.R. 5634), which was originally introduced by Rep. Matt Gaetz (R-FL) and had 40 cosponsors, passed in a voice vote. In addition, bill H.R 2020 is pending in the senate that will try to remove cannabis from a schedule 1 drug to schedule 3, which would open the floodgate to research.

While Epidiolex is the first FDA-approved drug directly derived from cannabis, it is not the first cannabis-based drug that has been approved in the United States. Three other commercially available drugs Marinol, Syndros, and Cesamet which contain synthetic versions of cannabinoids (as opposed to cannabinoids derived directly from the cannabis plant) were approved by the FDA. These drugs contain a synthetic version of THC called Dronabinol and Nabilone. All three drugs are approved for adults in the treatment of nausea and vomiting associated with chemotherapy, while Marinol and Syndros are also indicated for the treatment of anorexia in individuals with AIDS.

There are also several drugs currently in development that contain synthetic cannabinoids. Zynerba Pharmaceuticals is conducting Phase II trials with a gel formulation for the transdermal delivery of CBD to treat neuropsychiatric disorders, such as Fragile X Syndrome. A THC pro-drug patch is also undergoing clinical trials for the treatment of Tourette Syndrome. In addition, Corbus Pharmaceuticals is currently conducting Phase II trials with Lenabasum (ajulemic acid), a THC-mimetic drug, for the treatment of rare inflammatory diseases, such as systemic sclerosis, cystic fibrosis, and dermatomyotisis.

Increasing anecdotal and clinical study reports of potential benefit, advances in understanding of the endocannabinoid signaling system, and growing public acceptance for the use of cannabis in selected patients upon the advice of their physicians, is driving renewed and significant interest among researchers. Scientists are working to confirm the existence of other cannabinoid receptors and to study the therapeutic potential of over 80 medically significant cannabis compounds. This work could reveal a wide range of potential therapeutic uses for cannabis, from those diseases impacting the CNS, like Attention Deficit Hyperactivity Disorder (ADHD), to inflammatory and autoimmune diseases like Crohn’s disease.

World class universities are opening doors to cannabis research. UCLA has started The UCLA Cannabis Research Initiative (UCLA-CRI) which is one of the first academic programs in the world dedicated to the study of cannabis. The UCLA CRI is supported by the UCLA Semel Institute for Neuroscience and Human Behavior and the UCLA Brain Research Institute. University of San Diego has launched the Center of Medical Cannabis Research (CMCR) which is in the forefront of Cannabis based studies. They co-ordinate with different federal organizations like NIDA, FDA, DEA, NIH and HHS. Colorado State University has established the Institute of Cannabis Research to conduct scientific and medicinal research on the benefits and risks associated with cannabis. Colleges and universities such as Harvard, University of Denver, Vanderbilt University, Ohio State University, and Northern Michigan University have started either courses or degrees on marijuana policies and law.

Challenges: The Path Forward

Several challenges remain in the clinical research of medical cannabis including the safety and efficacy of future cannabis medical products. Daner’s Hope Foundation believes that the path forward to overcome these challenges can be addressed by setting the right standards for prescription, dosage, delivery mechanisms, and product labelling achieved through high quality clinical research and human clinical trials. This requires tremendous amounts of private and public funding.

Setting The Standards

While we have achieved a lot in the last two decades in terms of research and discovery, we're still far from fully understanding how the Endocannabinoid System and its receptors work and even further from understanding all of the compounds in cannabis and how they activate different physiological reactions through the receptors. Millions of people are using different types of cannabis products, different strains, different concentrations, all consumed in different ways for supposedly different therapeutic purposes. Who is going to set the standards for how these products are used? Standards can only be established when we have enough data to understand how cannabis interacts with the human body at the cellular level through different delivery systems.

Establishing Safety And Efficacy

Most existing data on the therapeutic effects of cannabis comes from preclinical trials which may show promise in animals or tissue cultures, but it cannot be presumed to produce the same results in humans. Before a drug may be prescribed for human consumption, extensive research and testing, including clinical trials, must be undertaken to establish its safety and efficacy. This research also provides physicians with critical information for the use of a medication including when to prescribe the drug, in what dosage, and what its benefits, risks and possible side effects are. This information does not yet exist for cannabis.

Cannabis is a complex botanical plant containing over 750 different cannabinoids and other compounds. Such botanical products like cannabis made from leaves, roots, stems, seeds, pollen or any other part of a plant pose a unique challenge of maintaining lot-to-lot consistency. In addition, a wide range of THC and CBD concentrations in different cannabis products challenge the assessment of its therapeutic efficacy. To objectively evaluate the effects of cannabis, and for manufacturers to demonstrate that they are able to consistently manufacture a high-quality drug, patients need to be provided with controlled levels of cannabinoids (e.g. the ratio of THC to CBD) derived from a source with reproducible methods of production. Only by systematic evaluation of known doses of pure or purified compounds or extracts, and possibly by designing more effective variants, can the field advance without compromising the rigors of the modern drug approval processes. So far, a safe therapeutic window for cannabis has not been established.

Another important consideration is the need to develop a safe, alternative cannabinoid delivery systems to consistently provide a given dose of a drug. A few clinical trials in cannabis have identified problems associated with inconsistent dosing through smoking cannabis. Therefore, the purpose of the clinical trials should not be to develop cannabis as a licensed drug but rather to serve as a first step toward the development of non-smoked rapid-onset cannabinoid delivery systems.

Whole Plant versus Isolated Compounds

Establishing cannabis as a pharmaceutical grade medicine will depend on our ability to draw a distinction between the uses of the whole cannabis plant as a medicine versus its isolated components, the specific cannabinoids and their synthetic derivatives. While popular theory suggests that the whole plant provides an “entourage” effect (combining the effects of other cannabinoids like terpenes and flavonoids), isolated cannabinoids may provide more reliable effects than crude plant mixtures. In controlled clinical trials with cannabis, THC or CBD levels are usually the only composition of matter reported. These two cannabinoids produce distinct, and in some cases, opposite effects, a relationship that underscores the need to isolate individual cannabinoids and investigate them separately.

Ability of Big Pharma to Jump into the Research

So far, in the United States, the big pharmaceutical companies have not been enthusiastic about applied research on cannabis. Primarily because the legal ambiguity around cannabis and the difficulty of filing and enforcing patents on a plant and its compounds that has existed forever. These limitations have also forced US pharma companies to find creative ways to get around federal restrictions in order to obtain premium-grade cannabis for research.

Many pharmas have turned their attention to countries such as Canada and Israel, which have more lenient medical cannabis laws. Seven out of the top cannabis patent holders in Canada are pharmaceutical companies. Multinational pharmaceutical firm Johnson & Johnson recently accepted two medical cannabis businesses, Avicanna and Vapium Medical, into its Canadian JLabs Innovation network. The partnership gives cannabis companies access to lab space and a chance to analyze and consult with top scientists and researchers. Tilray, one of the largest producers of cannabis in Canada, partnered with Sandoz, a unit of the world’s largest pharmaceutical company Novartis, to manufacture and distribute cannabis based non-smokable medical products such as sprays, patches and gel caps to physicians and hospitals in ten different countries.

In the US, as and when the cannabis laws become clearer and cannabis is moved out of a Schedule I drug, we will see a huge influx of research funding by pharmaceutical companies and possibly pharmaceutical grade cannabis medicines being launched by these companies.