The legal landscape surrounding the use of cannabis products, both medically and recreationally, continues to evolve. Although marijuana remains a Schedule I substance under the Controlled Substances Act, the number of states that have passed laws allowing cannabis use has consistently grown, and scientific research into the benefits of cannabis and its molecular components is expanding.
Researchers believe cannabis and the individual group of substances found within the cannabis plant known as cannabinoids both have potential to reduce pain, improve quality of life, provide palliative care benefits, and increase appetite. This makes cannabis products attractive in the hematology space, as so many patients suffer from chronic pain, therapy-related nausea, and loss of appetite.
Despite the potential benefits to patients, there remain several challenges with the use and clinical testing of cannabis and cannabinoids. For example, each state has its own rules for dispensing, so state laws affect the marijuana formulations that physicians and providers are able to offer. This makes it difficult to compare research trials conducted in one state to another or to develop uniform guidelines or conclusions.
As Kalpna Gupta, PhD, a professor of the division of hematology/oncology in the Department of Medicine at UCI Health in California, explained, cannabis is not “one size fits all.”
“It’s not one drug or one component,” she said. “It’s several hundred.”
As the legal landscape changes and cannabis becomes more widely available, more patients are turning to marijuana than ever before. ASH Clinical News spoke with Dr. Gupta and other experts about the number of patients who use it, the benefits and risks associated with cannabis products, and how to talk to patients about marijuana use.
Gone to Pot
ASH Clinical News took a comprehensive look at cannabis in a 2017 feature article, “High Hopes.”1 At the time, 28 states and the District of Columbia had legalized either medical or recreational marijuana. In the five years that have passed, that number has only grown.
As of February 2022, 37 states, four U.S. territories, and the District of Columbia allow medical use of cannabis products, according to the National Conference of State Legislatures.2 As of the end of May, 19 of those states, along with two territories and the District of Columbia, had enacted measures to regulate the recreational use of cannabis as well.
While marijuana remains illegal at the federal level, in 2020, the National Survey on Drug Use and Health found that 17.9% of people ages 12 or older (about 49.6 million people) reported having used cannabis within the preceding 12 months.3 It’s a growing trend that hematologists are also seeing in clinical practice.
“A lot of patients are certainly using,” said Susanna Curtis, MD, an oncologist at Montefiore Medical Center in New York.
Dr. Curtis was one of the authors on a 2018 study,4 which found that 42% of adult patients with sickle cell disease (SCD) who were surveyed reported marijuana use within the previous two years, primarily for medicinal purposes. Similarly, a 2020 survey at Beaumont Hospital in Michigan found that 24.5% of oncology patients surveyed used medical cannabis to treat their symptoms: 81% of patients reported improvements in pain, 77.3% reported improved appetite, 73% reported decreased anxiety, and 54% reported better tolerance to their treatment.5
Defining Medical Cannabis
One of the challenges with the current landscape is that there is no uniform formulation for cannabis products, so comparing medical cannabis is not always an apples-to-apples scenario. The term “cannabis” is used to refer to products derived from the plant Cannabis sativa, according to the National Center for Complementary and Integrative Health.6 It’s believed the cannabis plant is made up of about 540 chemical substances.
One group of substances found within the cannabis plant is known as cannabinoids. The two primary cannabinoids are tetrahydrocannabinol (THC) and cannabidiol (CBD), but more than 100 other cannabinoids have been identified to date. While some formulations may be high in THC, others may have lower amounts of THC and higher quantities of CBD.
“There are so many formulations,” Dr. Gupta said. “Every state has its own approval, and you cannot transfer any medical cannabis from one state to the other, even if you are fully compliant and have NIH [National Institutes of Health] approval; the DEA [U.S. Drug Enforcement Agency] will not allow that.”
Each state also has its own dispensaries that offer their own formulations and products.
While cannabis currently has no accepted medical use on the national level, the U.S. Food and Drug Administration (FDA) has approved two synthetic cannabinoids. Dronabinol is a gelatin capsule containing THC that’s approved to treat nausea and vomiting in patients who are undergoing chemotherapy, and it can also be used to improve appetite in patients with AIDS, according to the American Cancer Society.7 The second synthetic formulation is nabilone, which is said to function much like THC and is used to treat chemotherapy-induced nausea and vomiting when other options have failed.
Cannabis Use in Hematology Settings
The potential benefits of cannabis use in hematology and oncology patients have been documented in a series of emerging studies. After SCD became a qualifying condition for medical marijuana in Connecticut in 2016, Dr. Curtis and colleagues began certifying patients with SCD to obtain medical marijuana through legal routes. While they couldn’t prescribe cannabis in Connecticut, they could certify that a patient had a qualifying condition to obtain medical marijuana, which allowed the patient to take the doctor’s letter to the state to register, get a card, and then use that card at area dispensaries.
Dr. Curtis admitted she would have preferred to be able to prescribe a given dosage and specific product like other medications, but she decided to certify patients after determining that many of them were already using illegal forms of cannabis. She decided it was “harm reductive” to provide her patients with more legal avenues.
“Right now, if 50% of our patients are using this more dangerous, lower quality, illegal form, let’s at least get them something that is regulated [and] is going to be safer,” she said. “Let’s get them access to a non-smokable form.”
Dr. Curtis studied the number of patients who requested certification at an adult SCD center and then evaluated differences between those who jumped through the state’s legal hoops – including paying a $100 annual fee – to gain access to medical marijuana and those who didn’t. She found that of the 52 patients who requested certification, 28 eventually obtained medical marijuana, while another 22 never did.8 Two of the patients who requested certification never received it because of concerns about inappropriate use in their past, according to the study’s authors. The group of patients who did obtain medical marijuana had a decrease in admission rates in the following six months compared with those who never obtained medical marijuana; however, researchers noted no significant changes between the use of acute services or daily opioids.
While Dr. Curtis noted the findings weren’t as strong as a randomized controlled trial would have been, she believes the results “hinted” that medical cannabis “seemed to be making a difference for patients.”
Donald Abrams, MD, a retired integrative oncologist and professor at the University of California, San Francisco, also evaluated the effect of cannabis on patients with SCD and chronic pain in a randomized controlled pilot study.9 Dr. Abrams and colleagues used a cross-over design to compare the use of vaporized cannabis containing 4.4% THC and 4.9% CBD to that of a vaporized cannabis placebo from which the CBD had been extracted. Among the 23 patients who completed both treatment arms, investigators found no significant differences in self-reported pain levels or disease-related symptoms.
“Our findings were a little underwhelming in that there was no statistically significant difference between cannabis and placebo for pain,” Dr. Abrams told ASH Clinical News in 2020,10 “but we know from observational studies that patients with SCD are using cannabis mainly for pain relief.”
The use of cannabis has also been explored for patients with refractory skin graft-versus-host disease (GVHD). While treating a patient who developed GVHD after undergoing hematopoietic cell transplant for T-cell acute lymphoblastic leukemia, Tsiporah B. Shore, MD, of Weill Medical College of Cornell University and New York Presbyterian Hospital, tried prescribing cannabis after she read an Israeli study which found CBD had been effective in treating GVHD.11
Using the Israeli study as her guide, Dr. Shore sent her patient to a leukemia physician who was specially licensed in the state of New York to work with dispensaries. Her colleague was able to secure a prescription for a cannabis product that mimicked the product used in Israel, which had high levels of CBD and low levels of THC. Within two years after transplant, the patient’s skin issues resolved and Dr. Shore submitted a case study to the 2019 American Society of Hematology Annual Meeting documenting the experience.12 However, she had a subsequent patient who wasn’t able to tolerate the sleepiness associated with cannabis and discontinued the treatment.
“After that, there have been several new drugs for [GVHD] in the last couple years that made it such that people would try those new drugs that are approved before they would try something that has not been proved and that isn’t licensed,” she said, adding that now, she typically only considers cannabis for patients who are not responding to other treatments.
The effects of cannabis are also being evaluated in emerging cancer studies, and a small body of research has suggested it could be helpful in treating chemotherapy-induced nausea and vomiting, neuropathic pain, or appetite.7
Damien Hansra, MD, a hematologist and oncologist with Piedmont Healthcare in Georgia, studied the use of dronabinol, the synthetic delta-9-tetrahydrocannabinol, in 16 older patients with hematologic (19%) and oncologic (81%) malignancies13 and found that those taking the drug reported “significant improvements” in appetite, anxiety levels, and quality of life measures.
“I thought it was very positive and meaningful,” Dr. Hansra said, adding that he regularly uses dronabinol in his practice for patients, starting with a low dose of 2.5 mg twice a day and titrating up from there if needed to as high as 10 mg twice daily.
Despite a growing collection of positive results, much of the research done to date lacks the support of large, randomized controlled trials to draw more concrete conclusions about cannabis or synthetic forms of the drug.
“The problem is, there is a clear need for it from the population – there’s a clear demand – but the medical science is not quite there yet,” Dr. Hansra said. “We just need really good quality studies.”
The challenge, according to Dr. Gupta, is getting a DEA license to obtain a Schedule I substance through the federal government remains very difficult, and conducting trials also requires multiple compliances through the state and institution, as well as approval of the study protocol. It can also be a challenge to register patients, who must commit to giving up any extraneous, personal use of cannabis to ensure the study results are valid.
Potential Risks
Medical marijuana has been legalized since 1998 in the state of Washington and its recreational use has been legalized for the past decade. Getting marijuana isn’t a problem for state residents, but Anna Halpern, MD, an assistant professor in the division of hematology at the University of Washington, said it isn’t something she prescribes for her patients.
“I think one of the problems is the marijuana industry is very unregulated. You don’t know what you’re getting, so I would never feel comfortable prescribing it like I would prescribe a drug that is FDA regulated and you know what is in the drug that you’re giving,” Dr. Halpern said.
Research has suggested cannabis use can increase feelings of disorientation, anxiety, vomiting or nausea, and fatigue in the short term. In the long term, evidence suggests cannabis use may also increase depression over time, according to a presentation by Kari L. Franson, PharmD, PhD, BCPP, a professor of clinical pharmacy at the University of Southern California, at the 2022 American College of Physicians Internal Medicine Meeting.14
Dr. Franson pointed to a naturalist study in Canada that showed although 89% of medical cannabis users who tracked symptoms using an app and reported feeling stressed, anxious, or depressed saw a 50% reduction in depression in the short term after 20 minutes of use, their baseline symptoms of depression increased over time during the sessions.14,15
Dr. Hansra said the research on possible interactions or side effects to cannabis is limited, and it is unknown whether it could interfere with the efficacy of chemotherapeutics and chemotherapy drugs.
“We’re in a data-free zone with respect to what it is actually doing, what is the interaction with a variety of chemotherapy drugs, and also of the cancer itself,” he said.
To Inhale or Not To Inhale
Smoking marijuana can also present its own set of challenges. Dr. Halpern treats mostly malignant hematologic disorders like leukemias and high-grade myeloid neoplasms like myelodysplastic syndromes. As a result, her patients tend to be severely immunocompromised and at risk for developing infections. A significant risk her patients face from smoking medical marijuana is developing fungal infections or fungal pneumonias.
“This has been seen particularly in immunocompromised patients because fungal spores can basically grow on the plant and are not easily killed,” she said.
In fact, one study using data from a large health insurance claims database found that patients who used cannabis were 3.5 times more likely to develop a fungal infection than those who did not.16
“If they are using it illegally, there is a concern over smoking it or vaporizing it and then there’s a whole slew of potential complications from smoking tobacco,” Dr. Hansra said. “You can get lung disease, you can get fungal diseases, acute lung toxicity, [and] pneumothorax.”
Dr. Curtis recommends that her patients opt for capsules, edibles, or formulations that are absorbed through mucosal tissues to avoid smoking. In contrast, Dr. Abrams noted inhalation forms like vaporization may provide better control over the onset, depth, and duration of the therapeutic effect.
“When you inhale THC, the peak plasma concentration is reached in 2.5 minutes and then it dissipates over the next 30 minutes, whereas if you take it by mouth it takes 2.5 hours to reach a much lower peak,” he said, adding that oral forms are also metabolized by the liver and often increase the psychoactive effect.
Dr. Abrams said most dispensaries also now offer tinctures or oils to be placed under the tongue, which he thinks are likely the best option. This administration route allows the patient to absorb some of the liquid placed under the tongue, gaining an immediate benefit, while the rest is swallowed.
Establishing a Communication Habit
Regardless of legal status, cannabis use in the U.S. is increasing, which makes it an important conversation to have with patients.
While working with patients with SCD, Dr. Curtis often asks what works for their pain, what doesn’t work, and what treatments they may be taking at home. This line of questioning opens the door to talk about cannabis, the concerns there may be with using cannabis products off the street, and the patient’s habits overall.
Another avenue to open the conversation is during the social history, Dr. Halpern said. During this portion of a visit, she asks about alcohol use, tobacco use, drug use, and then specifically about marijuana and how the patient may be using it.
“I just try to weave it into my history in a very non-judgmental form,” Dr. Halpern added.
She also makes sure to caution patients about marijuana at the end of an appointment, making sure to present information to patients in a factual and straightforward way that highlights the risks to anyone who is immunocompromised.
The Future Ahead
There are still big unanswered questions about medical cannabis, its efficacy, and which patient populations could benefit most.
“It’s a little bit like the wild west right now,” Dr. Hansra said. “There’s no leadership; there’s no guidance.”
Experts hope to see more federal, state, and association guidelines in the years to come to standardize cannabis use, along with more randomized clinical trials to determine who may benefit most from the drug.
Dr. Gupta believes cannabis products need some kind of FDA approval to certify their purity and ensure those using medical cannabis are using authenticated and certified products.
“It will be very hard to come to a uniform conclusion, because we are not using anything uniform,” she said, adding that consensus needs to be reached at the provider, policymaker, and compliance levels.
It seems, at least, that there could be some small steps in the right direction.
Dr. Abrams is currently serving on an American Society of Clinical Oncology committee to develop guidelines for cannabis use.
“If specialty organizations, especially, come up with guidelines, then practitioners are going to feel more confident knowing that these guidelines have been vetted,” he said. “The dream would be that every organization’s guidelines are consistent.”
References
- High Hopes. ASH Clinical News. December 2017.
- National Conference of State Legislatures. State medical cannabis laws. May 27, 2022. Accessed June 13, 2022. https://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx.
- Substance Abuse and Mental Health Services Administration. 2020 National Survey of Drug Use and Health (NSDUH) Releases. Accessed June 13, 2022. https://www.samhsa.gov/data/release/2020-national-survey-drug-use-and-health-nsduh-releases.
- Roberts JD, Spodick J, Cole J, Bozzo J, Curtis S, Forray A. Marijuana use in adults living with sickle cell disease. Cannabis Cannabinoid Res. 2018;3(1):162-165.
- Macari DM, Gbadamosi B, Jaiyesimi I, Gaikazian S. Medical cannabis in cancer patients: a survey of a community hematology oncology population. Am J Clin Oncol. 2020;43(9):636-639.
- National Center for Complementary and Integrative Health. Cannabis (marijuana) and cannabinoids: what you need to know. October 2019. Accessed June 13, 2022. https://www.nccih.nih.gov/health/cannabis-marijuana-and-cannabinoids-what-you-need-to-know.
- American Cancer Society. Marijuana and cancer. August 4, 2020. Accessed June 13, 2022. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/complementary-and-integrative-medicine/marijuana-and-cancer.html.
- Curtis SA, Lew D, Spodick J, Roberts JD. Medical marijuana for sickle cell disease: results of two years of certification in an adult sickle cell center. Blood. 2018;132(Supplement 1):858.
- Abrams DI, Couey P, Dixit N, et al. Effect of inhaled cannabis for pain in adults with sickle cell disease: A randomized clinical trial. JAMA Netw Open. 2020;3(7):e2010874.
- Inhaled vaporized cannabis yields no analgesic benefit in patients with SCD. ASH Clinical News. October 2020.
- Yeshurun M, Shpilberg O, Herscovici C, et al. Cannabidiol for the prevention of graft-versus-host-disease after allogeneic hematopoietic cell transplantation: results of a phase II study. Biol Blood Marrow Transplant. 2015;21(10):1770-1775.
- Shore TB, Ryan JB, Samuel MB. A case report of the benefit of cannabidiol (cannabidiol (CBD)-predominant medical cannabis preparation) in the management of refractory skin graft vs host disease (GVHD). Blood. 2019;134(Supplement 1):5687.
- Hansra DM. Evaluation of safety, efficacy, and other clinical endpoints of delta-9-tetrahydrocannabinol in older patients with hem/onc malignancies. J Clin Oncol. 2017;35(15):e21671.
- Viguers S. ‘There’s a real risk there’: Cannabis use exacerbates depression. April 30, 2022. Accessed June 13, 2022. https://www.healio.com/news/primary-care/20220430/theres-a-real-risk-there-cannabis-use-exacerbates-depression.
- Cuttler C, Spradlin A, McLaughlin RJ. A naturalistic examination of the perceived effects of cannabis on negative affect. J Affect Disord. 2018;235:198-205.
- Benedict K, Thompson GR, Jackson BR. Cannabis use and fungal infections in a commercially insured population, United States, 2016.Emerg Infect Dis. 2020;26(6):1308-1310.
