A magazine for friends of the Warren Alpert Medical School of Brown University.

Stirring the Pot


What do we really know about medical marijuana?

Ellen Smith P’05 thought her doctor was crazy.

Two years earlier, he’d finally put a name to the source of the pain that had plagued her for 54 years: Ehlers-Danlos syndrome, a connective tissue disorder that stretches her ligaments and tendons and leaves her prone to frequent subluxations.

They’d tried to alleviate the pain with pharmaceutical painkillers, with no luck—Smith can’t metabolize them. She underwent 22 surgeries. As the pain progressively worsened, she had to give up her career as a middle school history teacher, and quit swimming. She spent four years in a wheelchair. She barely slept.

In 2006, Rhode Island legalized medical marijuana. Smith’s physician thought it might help. She’d smoked pot in college, “and I hated the feeling,” she says. “But here’s a doctor saying, go try this because there is nothing else to give you for pain.”

So she tried it. “The next thing I knew, it was morning,” she says. “I slept the entire night.”

Weeding out the truth

Marijuana didn’t cure Smith, but it changed her life. Now 65, she rarely needs her wheelchair anymore. She sleeps most nights, and most days the only drug in her system is a low dose of cannabis, delivered in an olive oil infusion that she cooks herself, in her kitchen. Holding up the bottle, she says, “This is what keeps me alive.”

More than 1 million Americans are legal medical marijuana patients. The drug has been said to work for just about any condition you can think of, from cancer and HIV/AIDS to glaucoma to Alzheimer’s. The growing body of anecdotal evidence has persuaded more than three-quarters of the public, and nearly half of US states and the District of Columbia, that cannabis is a legitimate medical treatment and should be legal.

But physicians considering it for their patients have few peer-reviewed studies or clinical trials to guide their decisions. That’s because marijuana’s classification by the US Drug Enforcement Agency as a Schedule I substance—meaning it has “a high potential for abuse” and “no currently accepted medical treatment use”—discourages scientists, who must endure a lengthy federal approval process to conduct research, and then struggle to get funding, a legal supply of the drug, and, finally, patients for their studies.

In March, a bipartisan group of US senators introduced a bill that would reclassify marijuana as Schedule II, grouping it with cocaine and oxycodone, and lowering the barrier for research. It’s a move that both supporters and opponents say is long overdue.

“Whenever you choose a therapy, you choose it based on risks and benefits,” says Professor of Medicine Peter Friedmann, MD, MPH, who directs the Brown/Rhode Island Hospital Fellowship in Addiction Medicine. “The benefits [of marijuana]are unknown, and the risks are known. … There are people who believe it works for them, but we really don’t have the studies to show if that is an effective therapy.” By rescheduling cannabis, he says, “we would be able to do those kind of studies.”

James Crowley, MD, professor emeritus of medicine and a retired hematologist-oncologist, is more direct. “The Schedule I designation has been deadly,” he says. “In the future people may well say, ‘Do you know at one time this lifesaving drug was illegal?’”

What are they smoking?

Over the decades there has been lots of federally funded research on marijuana, but most of it has focused on negative effects, among them addiction, abnormal brain development, and mental illness, especially among people who began using in adolescence. That intrinsic bias bothers many scientists, perhaps even some at the National Institute on Drug Abuse; in a 2014 paper in the New England Journal of Medicine, NIDA authors noted that most studies focused on heavy, long-term users and that confounding factors, such as concurrent use of other drugs, “detract from our ability to establish causality.” The authors continued, “There is also a need to improve our understanding of how to harness the potential medical benefits of the marijuana plant without exposing people who are sick to its intrinsic risks.”

It’s only within the past 50 years that we’ve begun to understand marijuana’s physiology and why it affects humans and other animals the way it does. The two species used recreationally and medicinally—Cannabis sativa and C. indica—produce hundreds of chemical compounds, more than 80 of which are cannabinoids, which appear to play a role in the plant’s self-defense. In the early 1960s the Israeli chemist Raphael Mechoulam, PhD, sometimes called “the father of marijuana research,” identified the two most abundant cannabinoids: tetrahydrocannabinol (THC), which is responsible for marijuana’s psychotropic properties; and cannabidiol (CBD), its principle non-psychoactive compound.

It took another quarter-century for researchers to figure out that animals have our own, endogenous cannabinoids. Like neurotransmitters, endocannabinoids have receptors throughout the brain and nervous system. But, whereas the brain uses neurotransmitters to send messages to postsynaptic neurons—I’m cold, I’m hot, that hurts—and trigger a reaction—shiver, sweat, flinch—endocannabinoids are produced on demand, when those messages are received, and travel “upstream” to the presynaptic neuron, where their receptors are located. This serves to moderate the body’s initial reaction to a stimulus—dulling pain to tolerable levels, for example.

The elucidation of the endocannabinoid system “has been wonderful to watch from the perspective of a GP who’s been recommending [marijuana]to patients since the ’70s,” says Jeffrey Hergenrather MD’75, the president of the Society of Cannabis Clinicians. “It has this modulating role, this way of helping us to eat, sleep, relax, forget, and protect—all the things we need to do to stay healthy and centered.” He recalls reading the scant medical literature about marijuana while he was at Brown, and “marveling at the polarization and inconsistencies” in the findings. Early in his practice, Hergenrather says, he had patients who swore cannabis helped them with myriad ailments, from pain to seizures, and he gave his tacit blessing.

THC and CBD indeed can have beneficial effects when they bind to humans’ cannabinoid receptors, moderating pain as well as anxiety and nausea, and stimulating appetite. But that’s not all they do, of course. THC, in particular, overwhelms the endocannabinoid system, dampening too many processes in sometimes adverse ways. Judgment, reaction time, and coordination may be impaired; users may experience panic or paranoia.

Effects on the memory are a larger concern, especially among adolescents, as the endocannabinoid system appears to play an important role in brain development. “Repeated cannabis use with high THC appears to affect the formation of the prefrontal cortex, the stress response systems, and dopamine neural activity, probably through impairment of the connectivity of neurons,” says Jeffrey Hunt, MD, professor of psychiatry and human behavior. Furthermore, he adds, “the earlier you use, the more risk you have to become addicted.”

Right now doctors considering medical marijuana for their patients must balance concerns about these adverse effects with anecdotal evidence and their own observations. Most of the physicians interviewed for this article reported decidedly mixed results using cannabis for nausea. Crowley says marijuana helped some of his patients cope with the anxiety of living with cancer; Hergenrather says he’s seen it alleviate symptoms of Crohn’s disease and of Alzheimer’s, and that it may have shrunk a child’s glioma. Stories of epileptic kids whose seizures have slowed or ceased with cannabis treatment have become staples in the popular media, from National Geographic to Wired to CNN.

But few high-quality clinical trials of medical marijuana have been done in the US. Better established research programs exist elsewhere in the world, notably Israel and Europe, yet worldwide, the most conclusive evidence supports its use only for pain and complications related to multiple sclerosis. Studies on glaucoma, nausea, appetite stimulation, insomnia, and Tourette syndrome have been less clear; its effectiveness treating pediatric seizure disorders is unproved.

Thomas Trikalinos, MD, PhD, director of the Center for Evidence-Based Medicine in the Brown School of Public Health, says drug research is needed to “disentangle the signal from the noise.” The “gold standard” for addressing causal questions, such as whether medical marijuana works, is randomized trials, with enough people to achieve statistically significant results, he says. When those aren’t possible, observational studies may take their place—but those findings may be difficult to interpret. “Some may self-select to take medical marijuana; others may be more resistant,” he says. “Those who self-select may have a more severe disease and have tried everything, or may like to experiment.” So it’s hard to tease out whether different outcomes are due to the treatment, or the patients themselves.

“Let’s assume medical marijuana works to alleviate pain in people with chronic pain who have tried several treatments and not responded. So do you recommend everyone take it? Hardly,” Trikalinos says. Though some people swear cannabis works for them, at this point their results are subjective. “But if you are in pain,” he says, “a subjective outcome is the most important outcome.”

Learning curve

Ellen Smith insists that visitors go down to the basement ahead of her. “I’m slow,” she says, as she folds down the seat of her stair lift. “It’s embarrassing.”

As a registered caregiver for five other Rhode Island patients, Smith grows marijuana in the basement of her North Scituate home, where she and her husband, Stuart, have lived since 1992 and raised four sons. After riding down the stairs, Smith leads the way to the first of two warm, bright, aromatic rooms, where she clones, nurtures, and harvests 15 varieties of cannabis; another door leads to a greenhouse, where the plants grow taller than her. Back upstairs, she concentrates the dried flowers into tinctures, salves, lozenges, and oils, tailored to each patient’s needs, including her own.

Smith grows so many different plants, and offers it in so many different forms, because marijuana affects each person in different ways, she says. “You can’t tell someone with MS, ‘this is the strain that works for you.’ It just doesn’t work that way,” Smith says. “It’s not like going to a pharmacy and one size fits all.”

Fifteen strains of marijuana are but a fraction of the hundreds out there, created through selective breeding and hybridization of the two species, Cannabis sativa and C. indica. Each species has different effects, on nausea, suppressed appetite, pain, and other conditions, as do the plant’s two most abundant compounds, THC and CBD; furthermore some people don’t want to get high. Finding the strain that works for each patient is an art, though some in the field are trying to make it a science.

The Thomas C. Slater Compassion Center in Providence is one of Rhode Island’s three state-regulated dispensaries. A former US Postal Service processing center, only the letters “TCS” on one side of the beige, low-slung building distinguish it from its similarly drab neighbors on a busy industrial stretch north of downtown. After passing through security, where a guard checks identification and medical marijuana cards, patients walk by a display with the requisite Bob Marley, John Lennon, and pot leaf images into a cavernous space that’s more hip lounge than waiting room: exposed brick, sleek stainless steel counters, paper lanterns, and comfortable chairs.

The patients, for the most part, look like any you’d see standing in line at Walgreen’s; behind the counter, the patient advisers may fit certain stereotypes in their appearance—dreadlocks, tattoos—but they try to offer the same discretion and assistance that a customer of any commercial pharmacy would expect. “The patient advisers do a really good job of pointing people in the right direction,” says Melissa Bouchard, the Slater Center’s patient outreach coordinator. They keep files for each patient, and use the data they amass as well as any available studies to make their recommendations. It can be a slow and sometimes frustrating process, Bouchard admits. “It’s trial and error at first to find the strains that work,” she says.

The Slater Center offers about 50 different strains, and each is clearly marked, on acrylic display shelves in the waiting room, with the percentages of C. sativaC. indica, THC, and CBD. Steve Doyle, the director of cultivation, says cloning and consistent growing methods help ensure consistent products. Still, “it’s not a widget on a production line. It’s a living plant,” he says. An outside laboratory confirms each product’s contents.

As for determining dosage, caregivers tell patients to start “low and slow,” Bouchard says. “We want them to build a tolerance so they don’t have an adverse reaction.” Advisers help guide patients toward the most effective products, Bouchard says, but ultimately they “have to find what works for them.” Smith says, “You really have to be your own doctor on this. You really have to be your own pharmacist.”

It’s a statement that makes some health professionals cringe; but Daniel Harrop, MBA ’76 MD’79 RES’83 acknowledges parallels to his psychiatry practice in Providence. “The dosage range [of pharmaceuticals]is incredible as well,” he says. “There are people who need one-quarter mg of Xanax a day, there are people who need 8 mg a day, and both seem to work. … But we’re able to do that because it’s legal and people can pick it up at the pharmacy and know they’re getting the legal stuff.” Harrop says he’s “on the fence” about the therapeutic benefits of cannabis, but because of the compassion centers, “I’d be a little more at ease writing a medical marijuana prescription because now I would know the stuff is clean and there is some investigational research into its contents.”

Discomfort with marijuana’s quasi-legal status, concerns about side effects, and uncertainty about the contents of some products deter many patients and physicians. But putting it in pill form may not be the answer. The FDA has approved two drugs synthesized from THC, dronabinol (Marinol) and nabilone, to treat nausea and suppressed appetite; though they show some promise for chemotherapy and AIDS patients for whom other drugs have failed, they were “superseded almost right away by better agents,” says Crowley, who prescribed Marinol when it was first introduced, in the 1980s. A UK firm has developed an antiepileptic for children that is 98-percent pure CBD; clinical trials, which are ongoing, suggest just moderate improvement.

Some researchers suspect that the hundreds of compounds in cannabis work together in what is called the entourage effect. “The whole is greater than the sum of its parts,” Hergenrather says. “I think there’s such a variability in the genome of the cannabinoid receptors and the way they work, and what’s nice for one person won’t be nice for another. … It would be wonderful to get a closer look at these things, but the feds won’t let us.”

If the laws governing marijuana research ease up, the Slater Center is ready to collaborate. “We’re this little petri dish of patients coming here,” says Christopher Reilly, the center’s spokesman. “We have data on who comes here, what they use, what their symptoms are.” But they can offer only anecdotal evidence to guide their patients. “We need studies to show how this is all working, to corroborate the work we do,” Bouchard says.

Clear the air

The recreational use of marijuana is now legal in four states and decriminalized in many others, and more than half of the public supports legalization. That the popularization of pot as medicine may have eased the path for recreational weed does not sit well with some MDs. In an editorial in the Journal of the American Medical Association in June, the authors wrote, “if the states’ initiative to legalize medical marijuana is merely a veiled step toward allowing access to recreational marijuana, then the medical community should be left out of the process, and instead marijuana should be decriminalized.” Harrop, who has seen many more patients struggle with the effects of criminal marijuana convictions than with the effects of the drug, says, “It would be better to have recreational marijuana than to adulterate the medical system.”

Most people can drink alcohol responsibly, and most should be able to use marijuana responsibly, too, says John Femino ’71 MD’76, the medical director of Meadows Edge Recovery Center in North Kingstown, RI. But at least 10 percent of the population, when exposed to any drug, including alcohol, will have problems, he says. “I’m not a prohibitionist,” Femino says. “But people are missing the big point. I’ve practiced addiction medicine for almost 40 years. If we focus our energy on ‘is the drug safe?’, we can never get to the key question, which is, ‘safe for whom?’”

Research, Femino says, needs to focus not only on whether, how, and for what conditions medical marijuana works, but also on its safety for individual patients. He’s concerned about interactions with other drugs, such as opiates, and about patients with substance abuse histories. Several states authorize medical marijuana for post-traumatic stress disorder, even though no research yet supports its use, and since many patients with PTSD have addiction issues, he says, “it’s exactly the opposite treatment you want to do.” And Femino worries about the safety and variability of a natural product, even one grown organically, in controlled conditions. The development of morphine from opium was “a godsend,” he says. “The history of medicine is to get away from natural products because they’re so darn dangerous.”

Hergenrather, who has been approving medical marijuana for patients since its legalization in California, in 1996, says unscrupulous suppliers put patients at risk with tainted, mislabeled, and potentially harmful products. “There is a role for the government in helping to create a path for quality medicines that are organically produced, with certain known, measured amounts of [its active ingredients], so you have a product that is clean and you know what you’re getting,” he says. “We owe it to the public to have clean, measured medicine.”

Many physicians have patients who, as Harrop says, “swear by” medical cannabis; but, being scientists, they want to wait and see what the science says. While the cart may be before the horse, as the JAMA authors opined, the horse is very much out of the barn. “No one can stop the use of medical marijuana, so what we should do is try to understand exactly what we know at this point and do a systematic appraisal,” Trikalinos says. “We should not leave this to experimentation. … Advocacy can help move the conversation forward, but it also hurts it if it is thought of as a miracle drug that doesn’t need research or scrutiny.”


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