With many cannabis products but limited research, ‘education warranted’ for entire oncology workforce
Marijuana use for medical purposes, including control of cancer-associated symptoms, has gained traction over the past decade, achieving legal status in most states.
However, when it comes to amassing a meaningful evidence base and overcoming persistent stigmas, its legitimacy has not entirely caught up with its legality.
Moreover, medical marijuana continues to be illegal at the federal level and is classified as a Schedule I drug, a designation given to drugs or other substances that have “a high chance of being abused or causing addiction,” according to a definition on the NCI website. Experts said the federal restriction creates a catch-22 in which more data is needed to justify medical cannabis’ evidence-based use as the government restricts studies needed to acquire this data.
“Schedule I drugs are considered to have a high potential for abuse with no accepted medical use and cannabis doesn’t fit into that,” Diana M. Martinez, MD, a professor of psychiatry at Columbia University Medical Center who specializes in addiction research, said in an interview with Healio | HemOnc Today. “In fact, it could be argued that practically every Schedule I drug doesn’t fit into that, except heroin. The scheduling of drugs was done in 1971. We know a lot more now, but there haven’t been significant changes. If you want to research medicinal cannabis it doesn’t matter what state you live in, you must abide by federal law when getting approval for your Schedule I studies. This is tough because it requires a special license from the DEA.”
Meanwhile, changes to the 2018 Farm Bill legalized the use of hemp containing less than 0.3% THC. This means that cannabidiol, or CBD — which has been the subject of much preclinical cancer research — is now legal provided it is produced in accordance with the Farm Bill.
Since that change, a seemingly endless proliferation of CBD products has become available, backed by dubious claims and questionable regulatory practices.
“The change to the Farm Bill moved CBD out from the Schedule I category,” Martinez said. “If you read the letter of the law of the Farm Bill, it’s questionable as to whether or not CBD sales are OK. However, it seems unlikely that the federal government, the Department of Justice, is going to step in to enforce that.”
Healio | HemOnc Today spoke with oncologists and other experts about FDA-approved cannabis products, laws that impede large-scale cannabis research and why patients with cancer may be reluctant to participate in such studies, and the need to educate the oncology workforce on medical cannabis so clinicians can engage in informed discussions with patients regarding its use.
Approved cannabis products
The FDA has approved certain synthetic THC and CBD products for various medical indications. The THC analogue dronabinol is approved to treat weight loss and anorexia among patients with HIV, as well as chemotherapy-induced nausea and vomiting, whereas nabilone (Cesamet, Mylan) is indicated for relief of chemotherapy-induced nausea and vomiting and cannabidiol (Epidiolex, GW Pharmaceuticals) is approved for use in managing childhood epilepsy syndromes.
“The most well-known synthetic version of cannabis is Marinol [a brand of dronabinol],” Brooke Worster, MD, medical director of supportive medicine at Sidney Kimmel Cancer Center and Jefferson Health program director of cannabis medicine, said in an interview with Healio | HemOnc Today. “It is a synthetic Delta-9 THC, so it is one kind of different phytochemicals that are in the cannabis plant. The issue is that unopposed Delta-9 THC has the highest risk for adverse effects. It’s not entirely a bad thing, it’s just usually not well-tolerated, and it’s in fixed doses, so either you benefit from it or you don’t.”
According to Donald I. Abrams, MD, cancer and integrative medicine specialist and professor emeritus of medicine at UCSF Osher Center for Integrative Health, much of the existing data on medical cannabis pertains to these derivatives, not the botanical form.
“Until very recently, because marijuana is a Schedule I drug, the only legal source of cannabis for research was the National Institute on Drug Abuse [NIDA],” Abrams said in an interview with Healio | HemOnc Today. “NIDA has a congressional mandate that they can only study substances of abuse as substances of abuse. So, if you want to study potential therapeutic benefits of cannabis against pain in patients with cancer, for example, you must use NIDA cannabis, but they cannot fund such a study. That’s part of why there is such a dearth in the medical literature.”
Another cannabis product, nabiximols (Sativex, GW Pharmaceuticals), is a one-to-one whole plant extract approved in Canada as an adjunctive treatment for cancer pain in adults. It is not currently FDA approved for any indication.
Trial accrual a challenge
Legal and regulatory hurdles may not be the only obstacles to large-scale cannabis research. Patients themselves have shown reluctance to enroll.
Abrams said he tried to conduct two clinical trials of inhaled cannabis among patients with cancer. The first, conducted at San Francisco General Hospital, began concurrently with a similar trial Abrams conducted among patients with HIV-related peripheral neuropathy.
“They were both going to be 16-person pilots followed by randomized, placebo-controlled trials, if the plots showed potential for benefit,” he said. “The HIV study enrolled 16 patients in the pilot and 23 patients in the randomized controlled trial. I enrolled three patients in the cancer study.”
To improve accrual, Abrams expanded the inclusion criteria from breast and prostate cancer with pain from bone metastases to any cancer, any pain.
“We still didn’t enroll patients, and we had our funding taken away,” he said.
The second trial, a cannabinoid/opioid interaction study, aimed to assess the safety of cannabinoids among patients with cancer on sustained-release morphine or sustained-release oxycodone. Although he interviewed 213 patients, he enrolled only one. This led Abrams to talk with a medical sociologist about the possibility of studying why patients with cancer in San Francisco were reluctant to enroll in cannabis clinical trials.
One of his nurse experts in symptom management offered a possible explanation.
“All of my studies have been done in our inpatient unit, and our nurse investigator said, ‘Donald, patients with cancer do not want to spend days in the hospital that are not necessary, because they feel they’re going to be paying their debt later on,’” he said. “Also, I live in San Francisco, where patients have had access to medicinal cannabis since 1996. They might not want to participate in a trial where they will get what they consider to be an inferior-quality product or possibly be randomized to placebo.”
One of the only cannabis products that has been studied in large, placebo-controlled trials is nabiximols, which has been the focus of several such studies, Abrams said.
“GW Pharmaceuticals did a number of larger, placebo-controlled studies in patients with cancer pain, and from a meta-analysis of these studies, it doesn’t seem to work,” Abrams said. “In fact, in their most recent, large international study in [patients with cancer] with pain, the only people who seemed to have a benefit vs. placebo were patients under the age of 65 [years]. That’s part of why it isn’t approved in the U.S.”
Another major impediment to prescribed medical marijuana use among patients with cancer is hesitancy to discuss the subject with their physicians.
In a survey study of 612 Americans with breast cancer, 42% reported use of cannabis for symptom management during cancer treatment, but only 39% of cannabis users consulted their physicians on the topic, with many opting instead to look to friends or the internet for information.
The first author of that study, Marisa C. Weiss, MD, director of breast radiation oncology and breast health outreach at Lankenau Medical Center in Wynnewood, Pennsylvania, said there are various reasons why patients with breast cancer may be reluctant to discuss cannabis with their physicians.
“Generally. people with breast cancer are risk-averse; they are women with a median age of 52 [years], and they are seeking cannabis to manage symptoms or side effects of treatment,” Weiss told Healio | HemOnc Today. “Their intention is not to get high, and they don’t want to get into trouble, since marijuana is illegal at the federal level.”
She said this illegal status is not irrelevant, especially for those with jobs that prohibit any marijuana use.
“There are certain professions where a person is not allowed to use [cannabis] at all,” Weiss said. “For example, if a patient is a corrections officer or a school bus driver, or is in the military, there is zero tolerance for any use.”
The persistent stigma around marijuana use may also lead patients to fear judgment from their physicians.
“They don’t want anyone to think badly of them if they’re using it,” she said. “They also know it’s unlikely that the doctor is going to know very much about it. So, the risk of exposure doesn’t feel worth it, because they don’t expect to get any valuable information from their doctors about it.”
Weiss said lack of knowledge on the part of clinicians is a significant contributor to patient hesitancy in discussing medical marijuana with their physicians.
“Of the 39% of the people in our study who did have a conversation with their doctors, most of those people were disappointed in that conversation, because physicians don’t really know much about medical marijuana,” she said. “People preferred to get information from websites, family or friends, or the pharmacist at the dispensary. Only 4% of the people who sought information thought their doctor would be a useful source of information.”
This disconnect can lead to potentially dangerous effects in patients, including interactions with other drugs the patient is taking or misattribution of certain cannabis-related effects to the cancer treatment itself.
“Hyperemesis syndrome, which is characterized by excessive vomiting, can be caused by excessive use of cannabis and can only be treated by stopping all cannabis,” she said. “However, if the doctor doesn’t know about the cannabis, they might think this vomiting is caused by the chemotherapy, and they might reduce or suspend treatment. Or the patient might use more cannabis because they think the vomiting is from the chemotherapy.”
Additionally, patients and clinicians might also assume that cannabis-induced confusion or forgetfulness is actually “chemo brain.” Weiss urged patients not to assume that cannabis is benign simply because it is a “natural” remedy.
“People perceive cannabis to be safe. They think, ‘It’s natural,’” Weiss said. “The reality is that there is a lot of junk that can get into cannabis, like heavy metals or pesticides, mold or other chemicals. Not only that, there is no standard of labeling.”
Systems that enable patients to choose their own products and decide their own dosing also could increase risk for cannabis use disorder.
A study by Gilman and colleagues of 186 adults in the Greater Boston area showed obtaining a medical marijuana card for chronic pain, insomnia, anxiety or depression led to “rapid onset” of cannabis use disorder. The results, published in JAMA Network Open, also showed no significant association between owning a medical marijuana card and improvements in pain, anxiety or depressive symptoms.
CBD products vs. THC
Since the legalization of hemp under the 2018 Farm Bill, CBD products have become ubiquitous and are marketed for a wide range of uses. Claims around CBD products have included tumor shrinkage in patients with cancer.
“This all stems from laboratory-based studies on animal models or cellular models,” Worster said. “This happens all the time, where people get very excited by something that has been seen in a Petri dish.”
In the in vitro studies, researchers applied CBD to tumor cell lines and reported that in certain cells, it reduced the doubling time and appeared to slow tumor growth, Worster said.
“We’ve seen this happen all the time, though,” she added. “Then it doesn’t bear out. But those claims get blown up and are reported in the lay press and put out there on websites and blogs.”
Abrams noted that unlike THC, CBD does not bind to the brain’s densely populated cannabinoid receptor.
“In preclinical rodent glioma models, THC binds to this receptor and induces the cancer cells to undergo apoptosis. It’s also been demonstrated that cannabinoids, especially THC, inhibit VEGF, which is basically what bevacizumab [Avastin, Genentech] does,” he said. “CBD doesn’t bind with that receptor. In fact, it’s an antagonist in that it’s called a negative allosteric modulator; it changes the shape of the CB1 receptor. Also, when people take THC by mouth, it goes through the liver and gets converted into an even more psychoactive metabolite. CBD works on the enzyme system in the liver to block that transformation. It diminishes the high effect of THC, but I believe it diminishes the therapeutic benefit of the cannabis, as well.”
CBD has shown some promise in alleviating anxiety, Abrams said.
In a randomized study of 24 treatment-naive individuals with social anxiety disorder, Bergamaschi and colleagues found CBD dosed at 600 mg was more effective than placebo in reducing anxiety induced by a simulated public speaking test.
A study presented at last year’s virtual Anxiety and Depression Association of America conference showed patients with moderate to severe anxiety who used a CBD sublingual product over 4 weeks had significant decreases in anxiety, ranging from 70% to 83% according to various measures, as well as depression (77.93% decrease on the Beck Depression Inventory and 63.67% decrease on the Profile of Mood States: Total Mood Disturbance).
“If anything, CBD may decrease anxiety, and if something decreases anxiety, I consider it to be psychoactive,” Abrams said. “However, it doesn’t get you high, and I think that is part of the reason people prefer it.”
‘Think a bit differently’
Although many oncologists would like to see cannabis rescheduled and subsequent large-scale research into its use, Worster maintains researchers and clinicians should adjust their thinking on the topic.
“I think a schedule change will make things easier, but I think we also have to think a bit differently about this substance than we do about a traditional prescription therapeutic,” she said. “This is a plant, and depending on what strain you get, there are different compositions of various phytochemicals. So, going through it with a fine-toothed comb and getting every granular detail in terms of outcomes is going to be difficult.”
She said although continued research can be valuable to the future of medical cannabis, it is also important to recognize that attempting to regulate it as a pharmaceutical product could be problematic.
“We need to continue to build bodies of evidence about where it is helpful and where it isn’t, but also acknowledge that people are going to do what they’re going to do,” she said. “And we, as a medical community, need to educate ourselves better so we can have good conversations with patients about this.”
Worster said she believes that when it comes to resistance on the part of clinicians to recommend cannabis to their patients, ingrained personal beliefs are likely as much of a factor as the current dearth of evidence.
“When we look at clinicians’ attitudes toward cannabis, much of this is shaped more by the kind of things they’ve historically learned in the public sphere, rather than by educational, medically-based material,” she said. “So, whether a clinician is comfortable recommending it or not has more to do with personal beliefs than knowledge set.”
She said it is important to educate the current oncology workforce, many of whom grew up with strong anti-drug messaging from the Nixon and Reagan administrations.
“I think universal education is warranted. It’s not just physicians — it’s nurses, social workers, people who work in dispensaries,” she said. “People are desperate for guidance, and they’ll take it from whomever they are talking to. So, this needs to happen across the board.”
Abrams has found a way to bridge the communication gap between physicians and patients seeking cannabis during cancer treatment. He was approached by two PharmD graduates from University of California, San Francisco, inquiring about opening a dispensary. It turned out to be prohibitively expensive, so the pharmacists tried another plan.
“They ended up opening a concierge cannabis platform, where I give my patients their email or their website and they connect with them,” he said. “The pharmacists find out what the patients have, their diagnosis, what meds they are on, and what they’re trying to treat. Then, they recommend a potentially useful tincture. My patients love it, especially my older patients who don’t want to go into a dispensary.”
Worster said it would also serve clinicians well to stop viewing cannabis as a pharmaceutical product destined for traditional FDA approval.
“We should try to think of it either as a botanical product that has, increasingly, some different FDA considerations, or as a homeopathic/alternative medication that is just never going to become FDA approved,” she said. “This at least gives us the vocabulary to talk about what components are known and what to look out for. That’s one of the ways we can think about it, because if we keep trying to jam it down the same drug development pathway, it’s never going to get there.”
- Bergamaschi MM, et al. Neuropsychopharmacology. 2011;doi:10.1038/npp.2011.6.
- Gruber S. Cannabis, anxiety and depression: Cause for pause or peace of mind? Presented at: The Anxiety and Depression Association of America Annual Conference; Mar. 18-19, 2021 (virtual meeting).
- Hinz B, et al. Br J Pharmacol. 2019;doi:10.1111/bph.14426.
- NCBI.gov: The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Available at: www.ncbi.nlm.nih.gov/books/NBK425763/. Accessed March 25, 2022.
- NCI. Schedule I drug. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/schedule-i-drug. Accessed March 29, 2022.
- Weiss MC, et al. Cancer. 2021;doi:10.1002/cncr.33906.
For more information:
- Donald I. Abrams, MD, can be reached at UCSF Osher Center for Integrative Health, 1545 Divisadero St., 4th Floor, San Francisco, CA 94115; email: firstname.lastname@example.org.
- Diana M. Martinez, MD, can be reached at Columbia University Department of Psychiatry, 1051 Riverside Drive, New York, NY 10032; email: email@example.com.
- Marisa C. Weiss, MD, can be reached at Lankenau Cancer Center, 100 E. Lancaster Ave., Wynnewood, PA 19096; email: firstname.lastname@example.org.
- Brooke Worster, MD, can be reached at Thomas Jefferson University Hospital, 1015 Walnut St., Philadelphia, PA 19107; email: email@example.com.
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