Despite scant research regarding medical use of cannabis, strong popular sentiment is driving legalization of the flowering plant for therapeutic use.
Nearly two decades have passed, but Stacy Sklaver still remembers the overwhelming nausea. Her doctor was treating her breast cancer with a six-month course of the chemotherapies doxorubicin, cyclophosphamide and paclitaxel, and she thought the drugs were more likely to kill her than the disease.
“I remember the stuff was so toxic that nurses wore gloves to prevent it from burning the skin on their hands,” says Sklaver, now 60, who typically became nauseated a couple of days after treatment and got no relief from Zofran (ondansetron), the anti-nausea drug her doctor prescribed. “I remember getting up a couple hours after going to bed and spending four hours or more doubled over my toilet and vomiting.”
That was long before the days of legal medical marijuana, but a friend had read that cannabis could help ease nausea, and her doctor said it might work, so Sklaver decided to give it a try. She now regards that as one of the better decisions in her life.
“It didn’t entirely eliminate the nausea and vomiting, but it got pretty close. I could make myself eat,” says Sklaver, who typically smoked a joint before bed a few times a week during the worst part of each chemotherapy cycle and then gave it up after treatment. “It also eliminated the pain that bad nausea creates in every part of your body. I wasn’t functioning normally because I still had the exhaustion, but at least I wasn’t miserable.”
Sklaver’s experience vividly illustrates the one proven effect of cannabis’s most active ingredient in patients with cancer: controlling nausea and vomiting. Her strong belief that any sick adult should be able to access marijuana legally illustrates why medical marijuana laws have become common in the years since her chemotherapy.
STACY SKLAVER found that cannabis relieved nausea from chemotherapy that prescribed drugs did not.
Thirty-three state legislatures have legalized medical marijuana for a wide variety of conditions, and their counterparts in 13 other states allow its use in limited circumstances. Their actions stem from a growing belief that for patients struggling with symptoms such as pain, anxiety, insomnia and loss of appetite, the positive effects of cannabis outweigh any negatives associated with the drug.
With the exception of data about its anti-nausea and appetite stimulating powers, there is, however, surprisingly little evidence, either positive or negative, regarding the medical uses of cannabis or its active ingredients, collectively known as cannabinoids.
Studies of marijuana are relatively few and weak. It’s next to impossible to conduct large, randomized, controlled trials on a substance that the federal government bans, so the research consists mostly of small, short trials; user surveys; and statistical analysis of information collected for other purposes. It might still be possible to make some broad assertions about medical marijuana if most of those researchers had reached similar conclusions, but they didn’t. Some findings, for example, suggest that whole cannabis or individual cannabinoids control cancer pain about as well as opioids; others find no significant effect on pain.
Currently, patients with cancer have just two thoroughly researched, fully validated options for adding marijuana derivatives to their treatment regimens: the medications Marinol or Syndros (dronabinol) and Cesamet (nabilone). Both are standardized, synthetic oral cannabinoids that have been approved by the Food and Drug Administration (FDA) for treating nausea and vomiting caused by chemotherapy. Patients considering the use of other cannabinoids need to talk to their physicians, read the research, consider other relevant factors (like cost) and make their own decisions.
Those who decide in favor of the drug are not alone. “The rise of medical marijuana is much more of a political and popular movement than a medical movement. No dramatic new research justifies the wave of legislation on this issue. It was popular sentiment,” says Mellar Davis, M.D., who wrote a research review on cannabinoids and cancer treatment for the Journal of the National Comprehensive Cancer Network.
THE SEARCH FOR EVIDENCE
Cannabis is a flowering plant that originated in central Asia. The greatest concentrations of cannabinoids typically occur in the flowers and the resin, a viscous goo the plant secretes. (The substance called marijuana, weed or pot consists of dried flower buds, whereas the substance called hashish consists of resin.) People in far-flung parts of the world have been using cannabis flowers and resin for both recreational and medicinal purposes since early in the human experience. Its use as a medicine likely started in Asia around 500 B.C., according to history.com.
A cannabis plant contains more than 400 chemical entities, including more than 60 cannabinoids. The vast majority of research to date has focused on just two of them: tetrahydrocannabinol (THC) and cannabidiol (CBD). Both THC and CBD contain 30 hydrogen atoms, 21 carbon atoms and two oxygen atoms, but they’re arranged a bit differently, so they bind to different receptors in the body. THC binds directly to cannabinoid receptor 1, which sends signals to the brain, creating the psychoactive effects that are generally described as “getting high.” CBD binds to cannabinoid receptor 2, which does not get users high.
These receptors are there to bind to the natural cannabinoids (similar to plant cannabinoids) that our bodies manufacture. These cannabinoids are among many neurotransmitters (such as dopamine, for instance) made by our brains and other tissues, which bind to receptors and enable different aspects of brain physiology related to mood, emotion and more.
Most studies done on the subject agree that THC significantly reduces nausea, vomiting and weight loss due to chemotherapy and other conditions. The largest of those trials led to the FDA approvals of dronabinol and nabilone. (Dronabinol is identical to the THC in cannabis, although it’s made in a factory rather than extracted from a plant, whereas nabilone is a man-made molecule that acts very much like THC in the body.) An analysis that combined results from 30 trials involving a collective 1,366 patients found that among patients taking chemotherapy, THC better controlled nausea and/or vomiting than the anti-nausea drugs prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone or alizapride.
The evidence that THC can safely reduce cancer-related pain is decidedly more mixed. Positive results include those of an observational study that found significantly less cancer-related pain in 47 nabilone users than in 65 nonusers. A review of nine pain-reduction trials, five of which focused on cancer pain, concluded that THC controlled pain about as well as codeine but noted that depressant effects on the central nervous system often limited the use of THC; the researchers described most of its side effects as “psychotropic.” Other analyses of multiple trials, however, revealed just a small benefit, and THC, used in conjunction with opioids, did no better than placebo and opioids in a trial that randomly assigned 177 opioid-using patients with cancer to take THC, placebo or Sativex (nabiximols), which combines THC and CBD.
Sativex, which is approved in many countries but not the U.S., significantly reduced cancer-related pain in that study, but it’s no magic bullet. Other randomized trials of the drug found few significant benefits for pain stemming from cancer and other conditions in more than 500 patients.
Researchers looking into dronibanol, nabilone and every other form of THC all conclude that it has significant mind-altering properties. Some patients find that these improve mood and spur relaxation. Though there is little evidence of patients becoming addicted to or abusing either FDA-approved drug, these effects come with significant drawbacks: Some patients hate them, they render all users unable to legally drive a car, and they leave some unable to work productively.
None of those downsides come with CBD, which is regulated in many states like a supplement such as echinacea or green tea extract. Would-be users can find dozens of formulations on Amazon.com that are advertised as able to reduce pain or improve sleep, all for under $50. However, as with many other supplements, there is little regulatory oversight to guarantee that the bottles’ contents match their labels, and little scientific evidence supports their efficacy. That may change, however. The FDA recently approved Epidiolex, a pharmaceutical company’s version of CBD, for the treatment of seizures related to two rare conditions. Researchers have also begun to study a range of possible benefits of CBD usage, including pain relief and immunomodulation, but right now, scant published data suggests that isolated CBD can help any of the symptoms associated with cancer.
DOES CANNABIS FIGHT CANCER?
Some preliminary work does suggest that CBD may help stave off some types of cancer. Researchers have found that CBD induces programmed cell death in breast cancer cells cultivated in the lab; inhibits expression of the Id-1 gene, interfering with the proliferation and invasion of breast cancer cells; and protects against induced colon cancer in mice.
Findings from studies of lab samples and animals also showed that CBD and THC can slow the progression of brain tumors called glioblastomas, which have a very high number of cannabinoid receptors. The exact mechanism of tumor growth inhibition is unknown. What’s more, a 2018 study in 23 patients with glioblastoma noted that those who used at least 50 mg of cannabinoids per day for at least a month were more likely than other patients to be alive both one year (80 percent versus 74 percent) and two years (73 percent versus 65 percent) after beginning treatment.
On the other hand, preliminary evidence suggests that cannabis may reduce the efficacy of the immunotherapy Opdivo (nivolumab), so patients need to weigh potential costs and benefits and keep their doctors informed of their choices. Opdivo is approved to treat colorectal cancer and is being tested in glioblastoma and breast cancer in clinical trials.
“I’m continuing to track my two groups of glioblastoma patients, and outcomes among the patients who used the higher doses of cannabinoids continue to be good by the very poor standards of glioblastoma patients,” says Nicholas Blondin, M.D., an assistant professor of clinical neurology at Yale School of Medicine. “Is the data from this small observational study proof of benefit? No, not even close. But I believe it’s definitely interesting enough to justify more research.”
THE CHALLENGES OF STUDYING CANNABIS
Blondin’s study illustrates one way that recent laws allowing the use of medical marijuana increase our ability to research its effects: They provide the chance to observe differences in outcomes among patients who do and don’t seek access to dispensaries. Unfortunately for those who wish to perform cannabis research, state laws don’t eliminate the many remaining obstacles to well-controlled trials. The Drug Enforcement Agency (DEA) still classifies cannabis as a schedule 1 drug — it’s considered to have high potential for abuse but no proven medical uses. As a result, researchers who wish to conduct clinical studies of it must file an investigational new drug application with the FDA, obtain a schedule 1 license from the DEA and get approval from the National Institute on Drug Abuse.
Some researchers work through this process to perform quality studies, but not many. A scholarly article that appeared in 2015, just before CURE®
published its last overview of cannabis in cancer care, sought to round up all the quality research that had been performed on the medical effects of cannabis or natural cannabinoids in human subjects. Its authors scoured 50 years of academic journals and found just two trials that merited inclusion.
In the first study, 50 HIV patients received either three marijuana or three placebo cigarettes daily for five days. (Researchers made the placebos convincing by removing the active ingredients but not the distinctive smell or taste from marijuana.) The actual cannabis reduced the daily pain that patients reported by 34 percent, whereas the placebo reduced pain just 17 percent. For the second study, 39 patients with neuropathic pain took 12 puffs of 1.29 percent vaporized cannabis, 3.53 percent vaporized cannabis or placebo. Both doses of cannabis performed better than placebo and similar to widely used pain medications, but the higher dose produced no better results than the lower dose.
Because of the lack of data and FDA approvals, health insurers generally don’t cover cannabis, even in states where medical marijuana is legal. None of the experts interviewed for this story had heard of a patient getting reimbursed for cannabis expenditures, which are significant. Prices vary by state, but estimates online put the monthly cost of medical marijuana above $200.
Still, neither cost nor uncertainty about effectiveness deters a significant percentage of patients with cancer from using medical marijuana. An anonymous survey of adult patients at a large cancer center in Washington state, where medical marijuana is legal, found that 24 percent of 926 respondents had used cannabis in the past year and that 21 percent of them had used it in the past month. Looking just at active users, 70 percent consumed inhaled cannabis products and 70 percent consumed edibles.
Those patients with cancer who do use medical marijuana seem to be pretty satisfied with it. An analysis of data that providers collected from about 2,970 cancer patients who used medical marijuana between 2015 and 2017 looked at why patients turned to cannabis and found the most common symptoms they hoped to treat were sleep problems (78.4 percent), pain (77.7 percent), weakness (72.7 percent), nausea (64.6 percent) and lack of appetite (48.9 percent). After six months of follow-up, 902 patients had died and 682 had stopped the treatment. Of the remaining 1,211, almost all —96 percent — reported an improvement in whatever condition they were trying to treat with cannabis.
“There are many studies that find benefit, but there are others that find none, and none of it is definitive,” says Donald Abrams, M.D., an oncologist at the University of California, San Francisco who has been studying cannabinoids for more than two decades. “So, if you talk to five different oncologists, you’ll probably hear five different views on medical marijuana, and that will probably be true for some time.”