Inside the Fascinating World of Marijuana Research

The following is an excerpt from a new book by Alyson Martin and Nushin Rashidian titled A New Leaf: The End of Cannabis Prohibition (The New Press, 2013). 

Cultivation of cannabis is illegal in Mississippi. After a typical raid, officers weigh the plants, sometimes roots and all. That water- and dirt-soaked weight is used to decide charges, which are heavy themselves and can involve felony counts and tens of thousands of dollars in fines. But in Oxford, Mississippi, there’s an exception to this rule.

Most students at the University of Mississippi probably don’t realize that just past a road called Confederate Drive and the Ole Miss Softball Complex, cannabis is grown right under their noses. And that’s the point. The Coy W. Waller Laboratory Complex is tucked away from student foot traffic. There, within concrete walls—and, some years, in a nearby field guarded by barbed-wire fences and a watchtower—grows the only federally legal cannabis in the United States as part of the federal government’s cannabis research program.

Inside, on first glance, the complex fits in on a typical college campus. In one room of the low building, a black and white bong decorated with a dragon design graces a bookshelf. An issue of High Times rests on a table in another. In a room at the end of a hall, a researcher sits near a Volcano vaporizer, a grinder, a scale, and bags of cannabis, watching and mocking a YouTube video for a pocket vaporizer. Much in the facility would look familiar to grower, too: a poster with the steps for making an extract; trash cans labeled “regular garbage only” and “marijuana trash only”; plants trimmed down to the buds under intense grow lights; some seedlings small enough for an herb garden and others the size of an office plant; a box of Miracle-Gro; watering cans.

Just about everything else here would bring a cannabis enthusiast to tears. Boxes upon boxes of DEA-confiscated cannabis, mementos of many growers’ worst days, await the gas chromatography machine for a potency test. A cabinet museum displays hashish and cannabis seized as long ago as the 1970s, anywhere from Humboldt to Miami. Freezer vaults with steering wheel–sized handles house hundreds of seeds Americans will never plant and barrels of ground cannabis for joints they will never smoke—because, outside of this facility, none of this is federally legal. The differences between cannabis in this facility’s grow rooms, a dispensary in California, or a basement in the Midwest start and end with its legality.

* * *

The genus Cannabis L. includes the species Cannabis sativa L. and the subspecies sativa and indica. The strength of the stalk of a cannabis plant depends on the particular plant’s size and need for support; some grow wide while others tower over the farmer. The leaves form different shapes, but they always bear some resemblance to an outstretched hand. On some plants the leaves are spindly, like thin Grinchy fingers; these are the sativa variety. Other plants have fatter leaves; generally, these are indicas. At the joint of these leaves is an inflorescence, commonly called a bud. These dense clusters may appear dusted in a white or amber confection—the sticky trichomes from which the plant’s resins are released. (These trichomes contain the therapeutic components of the plant.)

Anyone who steps into a grow room and is overwhelmed by light, sugary, citrus scents or deep, spicy, earthy smells has encountered terpenes. “It’s the same thing that’s responsible for the smell of tomatoes and peppers and pine and roses and geranium and oregano,” said Mahmoud ElSohly, director of the federal Marijuana Project in Mississippi, overseen by the National Institute on Drug Abuse (NIDA) since 1968. Due to this large group of essential oil components, dried buds can smell like fuel (the “diesels”), banana bread (in the case of banana kush), honey, tobacco, chocolate, bubble gum, black licorice, and so on. The terpene limonene, for example, generates the citrusy smell of some cannabis buds and is also present in lemon rinds; alpha-pinene (α-pinene) is found in both buds and pine trees. While terpenes have nothing to do with potency, what one ultimately experiences is rooted in a complex blend of odors that the cannabis plant emits based on the terpenes within. Some find these aromas enjoyable; others think they stink.

For a century, this fragrant flowering shrub has lived at the center of passions and politics. One ongoing debate seeks to resolve whether cannabis is a medicine. Twenty states and Washington, D.C., nearly half the country, have passed laws that allow their residents to consume whole plant cannabis for approved medical conditions. The federal government disagrees, maintaining that cannabis is not a medicine and is illegal for that and all other purposes. The cannabis at the federal research farm is grown not as medicine, but for medicine—a nebulous but crucial distinction that defines the discord between the state and federal stances toward this plant.

* * *

The role of cannabis in medicine extends much further back in time than the half century the U.S. government has operated this farm. It’s challenging to pin the exact origin of cannabis use, but archaeologists have traced it as far back as the Neolithic period (4000 B.C.) in China. According to ancient records, cannabis was used as a therapy for various diseases in the Roman Empire, as well as across Africa and the Middle East. Modern exploration of medical cannabis picked up in the early nineteenth century, when doctors began to identify the plant’s therapeutic potential. William O’Shaughnessy, an Irish physician whose name remains synonymous with the origins of Western medical cannabis, published his findings after years of practicing medicine and surveying cannabis use in India.

In his 1843 report in Provincial Medical Journal and Retrospect of the Medical Sciences, O’Shaughnessy observed that cannabis acted as an effective appetite stimulant when taken in small doses and as a sedative in larger doses. In a test, O’Shaughnessy gave a cannabis solution (“one grain of the resin of hemp”) to three patients with rheumatism. Two hours later, he noted the following effects:

At four, p.m., it was reported that one was becoming very talkative, was singing songs, calling loudly for an extra supply of food, and declaring himself in perfect health. The other two patients remained unaffected.

At six, p.m., I received a report to the same effect, but stating that the first patient was now falling asleep.

At eight, p.m., I was alarmed by an emergent note from Nobinchunder Mitter, the clinical clerk on duty, desiring my immediate attendance at the hospital, as the patient’s symptoms were very peculiar and formidable. I went to the hospital without delay, and found him lying on his cot quite insensible, but breathing with perfect regularity, his pulse and skin natural, and the pupils freely contractile on the approach of light.

This patient was in a cannabis coma, which is about as harmful as a food coma. While this is technically an overdose, cannabis has no toxicity so there’s no risk of death. The patient’s limbs were moved in every direction, but he remained unresponsive. His story has a happy ending: within an hour, he was more alert, and within two, he was “perfectly well and excessively hungry.”

In each of O’Shaughnessy’s patients, the cannabis somehow alleviated the pain associated with rheumatism. O’Shaughnessy concluded, “My object is to have it extensively and exactly tested without favor or prejudice, for the experience of four years has established the conviction in my mind, that we possess no remedy at all equal to this in anti-convulsive and anti-neuralgic power.”

Due in part to O’Shaughnessy’s work, cannabis extracts and tinctures became a new therapeutic medicine used throughout Europe and, eventually, the United States. One tiny bottle from the late 1800s read, “100 gelatine-coated pills: extract cannabis.” Its contents were prepared by McKesson & Robbins, manufacturing chemists based in New York.

Medical cannabis went on to be listed in the U.S. Pharmacopeia for almost one hundred years before its removal, in 1941, due to rampant misconceptions about the plant’s dangers. Even after that point, however, the intrigue surrounding cannabis’s medicinal properties didn’t wane.

Cannabinoid science, the study of the active compounds in cannabis, was born in the late 1930s. The plant is thought to contain more than one hundred cannabinoids, but the exact number is unknown, as is the biological activity of each compound and which cannabinoids come from which strains. American scientist Roger Adams and British scientist Alex Todd in 1940 first isolated cannabidiol (CBD), one of the most common cannabinoids found in the plant. Cannabinoid science then accelerated when Raphael Mechoulam, now a professor of medicinal chemistry and natural products at the Hebrew University of Jerusalem, re-isolated CBD and elucidated its structure in 1963. Tetrahydrocannabinol (THC), the foremost cannabinoid and the only one known today to be psychoactive, was isolated and synthesized by Mechoulam and Yechiel Gaoni in 1964, when the team also partially synthesized CBD.

The isolated and examined compounds of cannabis were instrumental in advancing knowledge about the plant’s therapeutic value. At the time, and until recently, researchers were most interested in THC, even though CBD also had promise, partly because of its abundance in the plant and effect on humans. Published articles in the 1970s reported that THC warded off nausea associated with cancer treatments. In 1980, the Food and Drug Administration (FDA) approved the National Cancer Institute to give oral synthetic THC to cancer patients undergoing chemotherapy. The program’s participants reported mixed results: most felt some anti-emetic relief, but some also said they experienced undesired side effects, like confusion or dizziness. In 1985, the FDA approved Unimed Pharmaceuticals’s Marinol capsules (synthetic THC) for cancer patients to manage the nausea associated with chemotherapy; several years later it was approved to help AIDS patients gain weight. The modern pharmaceuticalization of cannabis was under way.

But Marinol was a forerunner medicine with an unsuitable delivery method that contained only the psychoactive cannabinoid THC, to the discomfort of some patients. Patients have stated a preference for inhaled whole plant cannabis, rather than swallowing a capsule and waiting thirty minutes or more for the anti-emetic to kick in. A patient on the verge of vomiting can typically take one or two puffs from a joint, pipe, or vaporizer and the feeling will wash away. Unlike Marinol, the cannabis plant also  provides a complete cocktail of psychoactive and non-psychoactive therapeutic cannabinoids that work in synergy. Perhaps the best measure of Marinol’s efficacy has been the introduction of laws in twenty states and Washington, D.C., to legalize the whole plant as medicine.

While the effects and uses of THC were explored, why and how it and other cannabinoids worked remained unknown until Allyn Howlett, PhD, now a professor at Wake Forest School of Medicine, first discovered a cannabinoid receptor in the brain. In the early 1980s, Howlett came across a Pfizer report on cannabinoids and pain. When the company dropped the project, Howlett contacted Pfizer to ask if it would donate its compounds so she could pick up the research. (This was back before researchers and academic institutions were encouraged to patent their work and profit from it.) Pfizer agreed and provided Howlett with an array of about sixty different compounds to test. At the time, researchers using THC in animal and human studies tended to think of it like alcohol. THC is a lipid-soluble compound, so it was hypothesized that it would penetrate plasma membranes and act like an anesthetic or perturb different kinds of proteins, as alcohol would. In those cases, neurons just stop communicating with each other, and that is when sedation and pain alleviation kick in.

After testing how cells in tissue cultures responded to THC, however, Howlett sensed another possibility. She thought there might be a system of receptors in cell membranes within the human body that, like mailboxes, would be able to receive “messages” in the form of cannabinoids. When present, THC would be brought into the cell and cause a reaction. Howlett’s research led her, in the late 1980s, to discover a receptor in the brain to which THC binds. “When we discovered there was a receptor, of course it was very exciting because I think that lent some legitimacy to these kinds of compounds as actual medicinal compounds. It means that the body has a system that works through these kinds of receptors,” Howlett said. “A lot more researchers became interested. It could explain a lot of things that were going on in different areas of the brain.”

Daniele Piomelli, professor of anatomy and neurobiology at the University of California–Irvine, described a desert surrounding cannabinoid-based research after Mechoulam’s discovery of THC—and a subsequent “boom” after Howlett found the cannabinoid receptor. The reason? More was understood about the mysterious plant’s behavior in the body. “People had the weirdest ideas as to how THC worked. They thought it was a kind of soap—like a detergent that interacted with membranes and caused membranes to change their property, and this somehow changed the activity of the neurons. But in reality, things don’t happen like this in nature. They never do,” Piomelli said of the years before Howlett’s breakthrough.

The two primary receptors—CB1 and CB2, as they later became named—can be thought of as cannabinoid-binding targets found from head to toe in the immune, central, and peripheral nervous systems. Some cannabinoids, like THC, behave like Velcro on these sites; others, like CBD, don’t adhere as well. CB1 exists in great abundance in brain and neural cells, while CB2 receptors are found in the immune system. Researchers are also beginning to find both receptors in organs and tissues through- out the body, and they are trying to understand what those messages say in each cell type.

But what use is a mailbox without any mail? The discovery of receptors indicated the strong likelihood that an endogenous ligand, or naturally occurring binding molecule, must also exist to be sent to the receptors upon demand. William Devane, one of Howlett’s students, went to Israel to work with Mechoulam. There, in late 1992, they discovered the human body’s own production of a cannabinoid—an endocannabinoid. They called this endocannabinoid anandamide, a name derived from the Sanskrit word for bliss. This was fitting because anandamide works through the same pathways that offer feelings of security, comfort, or happiness that cause humans to seek social interaction, cozy homes, and sex. The purpose of those good feelings is to keep the species strong. A second  endocannabinoid—with a less memorable name, 2-arachidonylglycerol (2-AG)—was also discovered. The network became known as the endocannabinoid system.

This system of receptors and endocannabinoids is present from before birth and acts as a motherboard to help the body control mood and appetite, for example. According to a 2010 report from the Center for Medicinal Cannabis Research at the University of California, San Diego, the endocannabinoid system is “implicated in nervous system excitability, movement, analgesia, neuroprotection, and feeding behaviors, including newborn suckling.” At any given time, the system is at work; receptors are activated by either the body’s own production of endocannabinoids or by cannabinoids like THC or CBD. Endocannabinoids are fascinating modulators that work like a dimmer switch for bio-regulation. Anandamide and 2-AG operate “on demand”: they are produced and released when the body needs them, perhaps during times of emotional stress.

In an article published in June 2000 in Trends in Pharmacological Sciences, a group of researchers, including Piomelli, noted, “It would be surprising if such a prominent signaling system, which gives every indication of serving key physiological functions in the CNS [central nervous system] and in peripheral tissues, will fail to prompt the development of new medicines in the not too distant future.” The study of the endocannabinoid system continues to be a pioneering field. And without the cannabis plant as a guide, it is likely that researchers still would not know about this vital human system.



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