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Despite a conflicted regulatory landscape, support for medical marijuana is growing amid increasing evidence of potential benefits This is Part 2 of a 2-part series on the potential harm and benefit of cannabis hey call it the “pain cart.” The unassuming piece of equipment at the Centre for Human Drug Research, a nonprofit organization associated with Leiden University in the Netherlands, can create and measure various types of pain inflicted on volunteers. One might be exposed to small electric shocks, another to heat or the extreme cold of an ice bucket. Kari Franson, PharmD, PhD, and colleagues at the center systematically studied the effects of cannabis and purified delta-9-tetrahydrocannabinol (THC), its best-known constituent, in lessening such pain. Although the drug’s pharmacological effects roughly equaled the analgesic properties of the capsaicin

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compound in chili peppers, they found that THC lagged behind nonsteroidal antiinflammatory drugs such as ibuprofen and was far outpaced by opioids. However, given the recent turmoil concerning opioid addiction and lethal overdoses, some scientists suggest that cannabis may still carry an advantage. “It may be less effective, but may be a less dangerous drug,” says Dr. Franson, now associate dean of professional education at the Skaggs School of Pharmacy at the University of Colorado in Aurora. Despite large gaps in knowledge regarding marijuana’s potential benefits and side effects, most researchers agree that the drug and its principal chemicals, or cannabinoids, have shown at least some use in reducing pain, alleviating nausea and vomiting, and stimulating appetite. “Both cannabis and cannabi-

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Hints of Headway?

Hints of Headway?

noid pharmaceuticals can be helpful for a number of problems, including many affecting patients with cancer,” concludes a recent review in CA: A Cancer Journal for Clinicians.1 Other scientists are investigating the drug’s role in treating muscle tremors and spasticity related to diseases such as multiple sclerosis and epilepsy, and in fighting certain forms of cancer. However, few potential therapies have provoked as much public and political controversy. Although laws permitting medical marijuana have now passed in 23 US states and the District of Columbia, cannabis is still classified by the federal government as an illegal Schedule I controlled substance, meaning that it has “no currently accepted medical use” and a “high potential for abuse.” Nevertheless, the US Food and Drug Administration has approved 2 synthetic compounds based on THC, nabilone and dronabinol, for the treatment of chemotherapy-induced nausea and vomiting. Some research suggests that smoked or inhaled cannabis is similarly effective. “Quite frankly, the inhaled cannabis was either equivalent or better than what used to be the old-fashioned antinausea drugs,” Dr. Franson says. Within the past few years, she says, newer antiemetics given intravenously after chemotherapy have surpassed the effectiveness of THC-based products. However, unlike cannabis, as Dr. Franson and other researchers have pointed out, intravenous drugs cannot be readministered at home and a patient with severe nausea may not be able to tolerate an oral antiemetic. The Center for Medicinal Cannabis Research (CMCR) at the University of California at San Diego is among the few cannabis-specific research centers in the world. Since 2000, the CMCR has studied the effectiveness of cannabinoids on 2 other conditions: severe muscle spasm in patients with multiple sclerosis and peripheral neuropathy. During a public forum on marijuana legalization hosted by the Harvard School of Public Health in October 2014, Igor Grant, MD, director of the CMCR, said he and his colleagues found that smoked or inhaled cannabis could “substantially” reduce peripheral neuropathic pain.

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Medical Marijuana:

By Bryn Nelson, PhD Edited By Terence J. Colgan, MD

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Hints of Headway?

The effectiveness was comparable to that of existing drugs, he said, and in some studies provided further benefit when added to a treatment regimen. Cannabis also proved effective against multiple sclerosis–linked spasticity, Dr. Grant said, adding that studies by other groups suggest that a lesser-known component called cannabidiol (CBD) may help treat children with intractable epilepsy. “It’s not a panacea, but it’s something that needs to be researched,” he said.

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Building Evidence, Gradual Thaw Canada and the United Kingdom have approved an oral spray called nabiximols, which delivers a nearly 1:1 ratio of THC and CBD, for treating muscle spasticity. The drug is available in the United States only through clinical trials, but its early promise has helped focus more attention on CBD; researchers are investigating whether it also might help to reduce tremors related to Parkinson disease. Perhaps more surprisingly, multiple groups are examining whether cannabis may directly inhibit tumors. In a recent study in the Journal of Biological Chemistry, for example, scientists from Spain and the United Kingdom induced tumors in mice and then treated the animals with THC. The research identified 2 receptors on the surface of cancerous cells that appeared to modulate THC’s observed antitumor effects and, as such, “may constitute new targets for therapeutic intervention in oncology,” the authors concluded.2 A separate study by researchers at St. George’s, University of London found that THC and CBD partially shrank glioma tumors in mice, which was similar to the effects of radiation alone.3 Treatment with all 3, however, led to a “drastic” reduction that left some of the brain tumors nearly undetectable. Wai Liu, PhD, study coauthor and senior research fellow in the university’s Institute of Infection and Immunity, says the dramatic results suggest that THC and CBD in a 1:1 ratio can somehow enhance the antitumor activity of radiation. “It’s really quite exciting,” Dr. Liu says. “This whole idea that you need different ratios of THC to CBD is something that people are really just appreciating.” The mechanism underlying this joint action remains unknown, but one hypothesis

“Since [cannabis or cannabinoids] are medicine, they should be dispensed by pharmacies or some other means that are well regulated, where the patients know really what they’re getting and doctors know what they’re prescribing.” —Igor Grant, MD posits that the cannabinoids prime cancer cells to commit suicide via apoptosis when exposed to radiation. Other trials in the United Kingdom are testing nabiximols in patients with gliomas in combination with the chemotherapy drug temozolomide. Dr. Liu says his group’s data suggest that a cannabinoid-irradiation clinical trial may prove useful as well, although he acknowledges that using pure THC extract in such a trial would be “incredibly difficult” given the current prohibition of cannabis in the United Kingdom. “If I was to call the cannabinoids ‘Wai’s drug’ and the word ‘cannabis’ wasn’t mentioned, would it be more acceptable?” he asks. Most researchers agree that far more research must be conducted before they can gauge the extent of marijuana’s medicinal value. Nevertheless, several have begun speaking out more forcefully against restrictions such as the US government’s Schedule I classification of the drug. “Scheduling means at the moment marijuana resides with heroin and other terribly dangerous drugs with the addi-

tional statement that it has no medical value,” Dr. Grant said at the Harvard forum. “That’s just not true.” A 2013 poll in the New England Journal of Medicine suggested that an increasing number of physicians share his assessment. The survey of 1446 physicians from 72 countries found that 76% approved of using marijuana for medical purposes.4 What accounted for the surprisingly strong support? “Physicians in favor of medicinal marijuana often focused on our responsibility as caregivers to alleviate suffering,” the poll authors write. Although many clinicians have long complained about limited access to research-grade cannabis from the National Institute on Drug Abuse (NIDA), which is the sole provider for all US trials, some scientists say NIDA has significantly increased production in recent months. According to NIDA officials, the sole grow site at the University of Mississippi is also cultivating marijuana with varying concentrations of THC and CBD to anticipate research needs. “The research environment is improving very slowly,” Dr. Franson says. With the gradual thaw in regulations, researchers are also setting their sights on oversight and quality control issues: if cannabis or cannabinoids are to be tested and used as medicinal drugs, they should be treated as such. “We would not go to a flea market or a farmer’s market to buy penicillin,” Dr. Grant said. “We wouldn’t know what was in there. And similarly, since these are medicine, they should be dispensed by pharmacies or some other means that are well regulated, where the patients know really what they’re getting and doctors know what they’re prescribing.” References 1. Kramer JL. Medical marijuana for cancer [published online ahead of print December 10, 2014]. CA Cancer J Clin. doi: 10.3322/caac.21260. 2. Moreno E, Andradas C, Medrano M, et al. Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling. J Biol Chem. 2014;289:2196021972. 3. Scott KA, Dalgleish AG, Liu WM. The combination of cannabidiol and 69-tetrahydrocannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model. Mol Cancer Ther. 2014;13:2955-2967. 4. Adler JN, Colbert JA. Clinical decisions. Medical use of marijuana–polling results. N Engl J Med. 2013;368:e30. DOI: 10.1002/cncy.21524

Content in this section does not reflect any official policy or medical opinion of the American Cancer Society or of the publisher unless otherwise noted. © American Cancer Society, 2015.

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Medical marijuana: hints of headway? Despite a conflicted regulatory landscape, support for medical marijuana is growing amid increasing evidence of potential benefits.

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