By Lillian Padgitt-Cobb
In 2015, the Oregon SB844 Task Force comprised of scientists, marijuana growers, politicians and drug abuse professionals convened to assess the direction of marijuana research in Oregon. Members faced a daunting task. Since the research typically required to produce and approve a therapeutic agent simply does not exist for marijuana, ensuring safety for users represents a race against time.
One of the scientists appointed to the task force is Jane Ishmael, associate professor in the College of Pharmacy at Oregon State University. Her perspective on marijuana research stems from her expertise with the pharmacology and biochemistry of what scientists call natural products, compounds produced by microbes, plants and animals. Ishmael focuses on how such compounds affect processes occurring in cells. In particular, she studies cell receptors and how natural-product compounds impact the central nervous system.
Such knowledge is critical for Oregon’s marijuana task force. The group was charged with, among other things, reporting on the development of the medical cannabis industry that provides patients with the medical products they use to treat the symptoms of a variety of diseases. The initial task-force conclusions appeared in a 2016 report published by the Oregon Health Authority. Significantly, the report found that research on the health effects of marijuana is lagging and that legal and regulatory hurdles impede its progress.
Ishmael’s research is unrelated to marijuana. She investigates the anticancer activity of naturally occurring, novel compounds discovered in marine environments around the world by Oregon State researchers. She wants to know how these natural products might impact cell growth and death in glioblastoma, a particularly aggressive form of cancer of the central nervous system, and triple-negative breast cancer cells.
In her lab, Ishmael studies compounds that have been isolated from a complex mixture of chemicals and analyzes them for their therapeutic potential. In particular, she studies the mechanism of action (the process by which a compound impacts its biological surroundings) of a chemical known as coibamide A. Oregon State professor Kerry McPhail isolated this compound from a marine cyanobacterium that she first reported in 2008 from the coast of Panama. McPhail and Ishmael have been investigating the capacity of coibamide A to kill cancer cells.
“We know so much less about the chemicals made by marine microorganisms,” says Ishmael. “It’s an area that holds great potential. We get to ask biological questions to determine the usefulness of novel structures, including their impact on cell signaling in human disease.” Their methods are similar to those used for studying the therapeutic potential of marijuana.
Natural Product Medicine
The process of determining which compounds in a mixture have therapeutic potential is complex and can take many years. Natural products have inspired some of our most valued medicines. Notable examples include aspirin, penicillin and morphine. Considering the enormous diversity of novel compounds made by plants and marine organisms, our grasp of the potential of natural product-derived therapies is superficial. Few have been studied thoroughly or even identified.
As an extension of her college teaching, Ishmael conducts continuing education programs to inform health-care providers about what scientists know and don’t know about marijuana biochemistry. In addition to the science, she incorporates guidelines about marijuana use among patients. Medical practitioners are not alone in seeking to learn how to navigate safe marijuana use. There are plenty of people, she says, who simply want to know more about the effects of its myriad cannabinoids, any of the hundreds of compounds produced by marijuana plants that act on human cells.
As the stigma associated with marijuana use slowly dissipates, it’s becoming possible to have open conversations about the plant’s unique properties, safe use and colorful history.
In March, Ishmael participated in an interdisciplinary continuing education event held at the Oregon Health & Science University in Portland. Health-care providers — physicians, dentists, pharmacists and physician assistants — shared their experiences and insights regarding patient marijuana use. Doctors and pharmacists can’t prescribe marijuana because of the requirement that they hold a U.S. Drug Enforcement Administration license. Marijuana remains illegal at the federal level, with a Schedule I classification under the Controlled Substances Act of 1970.
Nevertheless, health-care providers are caring for more patients who use marijuana recreationally, in addition to patients who hold a card from the Oregon Medical Marijuana Program. Conversely, some people who might be eligible to hold a medical marijuana card are opting to obtain marijuana recreationally. The fallout from state legalization in October 2015 is still unfolding.
Involvement in the state task force has inspired Ishmael to stay positive about the future of research in natural product drug development. “We’re studying things we may never have the full answer to, and we might never see the impact on human health,” she says. “But understanding how cell signaling occurs, by using new chemical structures to probe the disease state, might eventually reveal new pathways and connections. We’re really investing in research for the future.”
The Marijuana Pharmacopoeia
Deconstructing a network of compounds in order to parse the contribution of one of them is not a problem unique to marijuana. Plants have evolved tightly woven biochemical networks comprised of compounds and the enzymes that produce them. To study one compound is not necessarily enough to understand what is happening and how or why.
Marijuana contains more than 480 distinct chemical compounds, including both primary and secondary metabolites, which are the intermediate products of chemical reactions. While primary metabolites are required for basic cell functioning and found in all plants, secondary metabolites vary in structure and function across the plant kingdom. They are produced in variable quantities for optimal growth and survival in distinct environments.
Plants experience oxidative stress, exposure to pathogens, UV damage and cell death. All invoke a response through chemical defense. By gathering evidence and modifying hypotheses as new information becomes available, scientists try to make sense of how individual compounds in plants behave in a cooperative constellation.
Since it was first cultivated in Central Asia thousands of years ago, Cannabis sativa has been utilized across the world in agriculture as a source of medicine and fiber for textiles. The species includes marijuana and hemp, which differ only in terms of their tetrahydrocannabinol (THC) content. In order to be classified as hemp, the plant must contain less than 0.3 percent THC by dry weight. Cannabinoids present in the marijuana plant, including THC and cannabidiol (CBD), are among its most studied secondary metabolites, due to their well-documented psychotropic effects, which include the feeling of being high.
Once in the body, foreign cannabinoids compete with cannabinoids that occur naturally in the human body. When they bind to what scientists call endocannabinoid receptors on human cells, these foreign compounds contribute to their well-known effects.
Interest in studying terpenes, another family of marijuana compounds, is gathering momentum. Evidence shows that these chemicals can modulate the effects of cannabinoids. Among the 120 different terpenes that have been identified in marijuana are those that produce its characteristic aroma. Terpenes are also involved in essential plant cell processes, such as photosynthesis and chemical defense against pathogens.
The polypharmacology (the study of how multiple compounds interact to give rise to a unique or enhanced effect) of marijuana remains elusive. Only a few of its most well-known compounds have been investigated rigorously.
What Are Receptors?
The cells of the central nervous system possess the ability to react to changes in their environment by sending and receiving signals in the form of neurotransmitter chemicals. Embedded in the surface of cells are compounds called receptors that bind chemicals such as THC, like a lock to a key. The unique shapes of these molecular combinations ensure that each key will conform only to the binding site of its corresponding lock.
Investigation of the affinity of THC for specific receptors on the cell membrane has helped to demystify the function of the endocannabinoid system. As a result of endocannabinoid related research, deeper clarity into the biology has revealed how it might be possible to design a drug to target these receptors. Scientists have explored the possibility of using endocannabinoid receptors as therapeutic targets in the treatment of disorders such as nerve pain, neurodegenerative diseases, seizures, nausea and glaucoma.
Research into the safety and efficacy of marijuana remains critical as the abundance of active compounds in the plant has changed with long-term breeding strategies over the last several decades. Moreover, marijuana strains are highly varied and contain unpredictable amounts of active compounds, which confounds the comparison of therapeutic effect among users.
Although we have no record of human death resulting from a marijuana overdose, cannabis use disorder can occur. This disorder is characterized by the interference of marijuana in the tasks of daily life, and is accompanied by adverse symptoms.
Note: Lillian Padgitt-Cobb is a Ph.D. student in the Department of Biochemistry and Biophysics. She is also a host of Inspiration Dissemination, a weekly radio show about graduate student research on KBVR.