Cancer and CINV

Evidence-based guidelines

Guidance on the suggested use of medical cannabis for cancer and chemotherapy-induced nausea and vomiting (CINV)

This evidence-based guidance was reviewed and approved on 6/14/2022.

There is substantial evidence to support the conclusion that medical cannabis or cannabinoids are effective for the treatment of cannabis-induced nausea and vomiting.

There is limited evidence to support the conclusion that medical cannabis or cannabinoids may effectively treat pain due to complications from an invading neoplasm. A 2010 randomized double-blinded placebo-controlled study involving 177 patients with inadequately managed cancer pain despite appropriate use of opioids showed that the use of orally-administered chemotype II medical cannabis extract resulted in a significant reduction in pain compared to placebo. Use of chemotype I (THC-predominant) medical cannabis extract with little or no CBD for treating cancer-related pain was not statistically different from the placebo  (Johnson et al., 2010).  

There is insufficient evidence to support or refute the conclusion that medical cannabis or cannabinoids may effectively treat neuropathic pain due to nerve damage from chemotherapy. Although medical cannabis has been shown to be effective in relieving pain due to peripheral neuropathy from other causes, there is only one small crossover placebo-controlled trial involving 16 patients that used nabiximols oral-mucosal spray in the treatment of pain due to peripheral neuropathy caused by chemotherapy. Overall, neuropathic pain scores in this study were not statistically different between active treatment and placebo, but 5 of the 16 patients significantly reduced their reported pain with active treatment. (Lynch et al., 2014). Three phases, 3 randomized, double-blind, placebo-controlled trials examined adjunctive nabiximols spray (27 mg/mL THC: 25 mg/mL CBD starting at 1 spray/day and titrated by 1 spray/day to a maximum of 10 sprays/day) among adults with advanced cancer and chronic pain despite optimal opioid therapy.  These trials did not demonstrate a significant difference in the change in average daily patient-reported pain scores for nabiximols versus placebo. However, 1 trial demonstrated significant improvements in secondary quality-of-life outcomes, and the other 2 trials demonstrated some improvement in patient function, all favoring nabiximols (Fallon et al., 2017; Lichtman et al. 2018). 

There is insufficient evidence to support or refute the conclusion that medical cannabis is effective in treating cancer-associated cachexia (see the persistent nausea, vomiting/cachexia section of the general use guidelines webpage.

There is insufficient evidence to support the conclusion that medical cannabis or cannabinoids are effective or ineffective for treating malignant neoplasms in humans (National Academies of Sciences, Engineering, and Medicine, 2017). There is, however, an increasing body of preclinical in-vitro and animal-model data suggesting the direct anticancer effects of cannabinoids in some types of cancer (Rocha et al., 2014). Accumulating evidence from these in vitro and pre-clinical studies suggests that antineoplastic effects of cannabinoids occur via dysregulation of the endocannabinoid system (Velasco et al., 2016 & Pisanti et al., 2009). 

*Developed using level of evidence categories from the 2017 National Academies of Sciences, Engineering, and Medicine report on cannabis (National Academies of Sciences, Engineering, and Medicine, 2017d).

Elevated levels of endocannabinoids and their receptors (CB1 and CB2) have been observed in several cancers (lymphomas, hepatocellular carcinoma, leukemia, glioma, and pancreatic, prostate, and breast cancers). In some cases, increased expression of the cannabinoid receptors correlated with disease severity (Velasco  et al., 2016).  

The exact mechanism through which cannabinoids exert antineoplastic effects is unknown, but in vitro data suggest cannabinoids induce cancer cell apoptosis  (Velasco et al., 2016). Cannabinoids may also inhibit tumor angiogenesis and limit cancer cell migration and metastasis (Velasco et al., 2016). Cannabidiol has been shown to specifically inhibit cancer cell invasiveness in various preclinical animal models (Velasco et al., 2016). However, caution is advised, as tumor-promoting effects have been described less frequently (Hart et al., 2004 & Cudaback et al., 2010). The reason for this conflict is unknown, but it may be related to the achieved concentration of cannabinoids, the expression level of cannabinoid receptors, or the immunosuppressive effects of cannabinoids (Pisanti et al., 2009 & Hart et al., 2004 & Cudaback et al., 2010).  

Antineoplastic properties of cannabinoids in vitro have typically been observed at very high doses that may not be achieved in clinical practice (Health Canada, 2018).  The efficacy of cannabinoids as antitumor agents has not been sufficiently studied in clinical studies. The limited existing clinical studies of cannabinoids have been for treating recurrent glioblastoma multiforme (GBM), an aggressive primary brain tumor with a poor prognosis (Guzman et al., 2006 & GW Pharmaceuticals, 2017).  

Case reports describing patient-administered inhaled cannabis (among 2 children with pilocytic astrocytomas) or orally administered hemp oil (in 1 child with terminal acute lymphoblastic leukemia (ALL) reported a regression in tumors and reduction in blast cell counts, respectively, during the time period of administration of the cannabinoids (Foroughi et al., 2011 & Singh et al., 2013). In a phase I/II trial involving 9 patients with GBM that had failed standard therapies, including surgery, external-beam radiotherapy, and in 2/9 patients adjuvant chemotherapy, Δ9 THC was administered intracranially directly into the tumor via a catheter that was surgically placed during a second surgery. The THC was infused daily for up to 10 days per cycle, and some patients received multiple cycles (up to 6). Overall, intracranially administered THC was well tolerated; 1 patient had a mild episode of bulimia, hypothermia, and euphoria that resolved. All patients experienced cerebral edema, which is typical after a craniotomy. Median survival was approximately 24 weeks, and 2 patients survived for >1 year (Guzman et al., 2006). Additional studies of cannabis (the nabiximols oromucosal spray, Sativex)  for recurrent or newly diagnosed GBM are underway (GW Pharmaceuticals, 2017).  

NOTE: Open discussion should be encouraged between healthcare providers and patients regarding the potential use of medical cannabis in cancer management, symptoms due to cancer, and side effects of chemotherapy. Some patients may consider the use of cannabis outside of the recommendations of their oncology team (Abrams, 2016). The decision to use cannabis or medical cannabis for the management of chemotherapy side effects, pain, or primary treatment/palliative treatment of a malignant neoplasm should generally be made through consultation with an oncology professional who can explore all potential treatment options with the patient.

There is substantial evidence to support the conclusion that cannabinoids are effective for the treatment of chemotherapy-induced nausea and vomiting (CINV). This is based on supportive findings from good-quality studies with very few or no credible opposing findings.

*Developed using level of evidence categories from the 2017 National Academies of Sciences, Engineering, and Medicine report on cannabis (National Academies of Sciences, Engineering, and Medicine, 2017d).

A 2016 Cochrane review of 23 randomized controlled trials looking at cannabinoids for chemotherapy-induced nausea and vomiting (CINV) found that fewer people who received cannabis-based medicines experienced nausea and vomiting than those who received a placebo (Smith et al., 2015). The proportion of people who experienced nausea and vomiting who received cannabis-based medicines was similar to that of conventional anti-nausea medicines. However, more people experienced side effects on cannabis-based medicines, such as 'feeling high,' dizziness, sedation, and dysphoria, compared with either placebo or other anti-nausea medicines. In cross-over trials where people received cannabis-based and conventional medicines, overall, people preferred the cannabis-based medicines.

Meta-analysis of trials using dronabinol (synthetic THC) suggests that low-moderate dosing of THC (7mg/m2) to prevent CINV may be more effective than higher doses of THC or attempting to treat CINV once it is established (Plasse et al., 1991).

Dronabinol vs. ondansetron

In a study of 61 patients comparing ondansetron to dronabinol in the treatment of CINV, treatment response was similar with dronabinol (54%), ondansetron (58%), and combination therapy (47%) when compared with placebo (20%). Nausea absence was significantly greater in active treatment groups (dronabinol, 71%; ondansetron, 64%; combination therapy, 53%) versus placebo (15%; p < 0.05 vs. placebo for all), but there was no added benefit of combining dronabinol with ondansetron compared with either agent by itself. Nausea intensity and vomiting/retching were lowest in patients treated with dronabinol. Active treatments were well-tolerated (Meiri et al., 2007).

Things to consider prior to recommending medical cannabis for the treatment of CINV:

  1. From a patient's perspective, CINV is one of the more distressing aspects of chemotherapy.
  2. Preventing acute, delayed, and anticipatory CINV is preferable to attempt at treatment.
  3. Oral cannabinoids (dronabinol and nabilone) have been shown to be more effective than placebo in preventing and treating acute and delayed CINV.
  4. Established first-line antiemetic treatment regimens (e.g., 5-HT3 antagonists, neurokinin-1 antagonists, and corticosteroids) for a given chemotherapy intervention should be used unless contraindicated or not tolerated.
  5. Dronabinol or nabilone (oral FDA-approved cannabinoids for the treatment of CINV) can be used as monotherapy or in combination with other antiemetics and have the advantage over medical cannabis of possible insurance coverage.
  6. There is no controlled study of artisanal medical cannabis preparations or inhaled herbal cannabis that shows superiority over current first-line CINV therapies or oral FDA-approved cannabinoids (dronabinol and nabilone). However, observational studies and individual patient experience and anecdotes suggest that some patients may have a beneficial response to inhaled cannabis or orally-ingested or sublingually administered preparations of medical cannabis as the sole treatment or add-on therapy to standard antiemetic therapy in the treatment of CINV (Abrams, 2016).
  7. Some observational data suggest that inhaled cannabis (smoked or vaporized) may be more useful in treating CINV than oral dosage forms of synthetic THC and orally administered medical cannabis extracts (Musty & Rossi, 2001).
  8. Prior patient experience with first-line therapies and inhaled or orally ingested forms of medical cannabis should be taken into consideration when recommending treatment of CINV using medical cannabis.
  9. There are problems with variable absorption and bioavailability with all forms of medical cannabis, especially orally ingested products taken on an empty stomach with no food or taken orally during active nausea and vomiting.
  10. The antiemetic dose-response curve for the use of cannabinoids in the treatment of CINV has not been studied. However, it may not be linear, meaning that dose escalation may or may not result in an improved therapeutic response. In some cases, dose escalation could hypothetically result in worsening symptoms of CINV.
  11. Always check for drug-drug interactions prior to using medical cannabis. THC and CBD can affect serum levels of chemotherapeutic agents and other medications metabolized by several of the cytochrome P450 enzymes. Use a drug interaction checker to check for drug-drug interactions between cannabis and any other medications

Dosing suggestions for treatment of CINV using orally and sublingually administered medical cannabis products:

There are no dose-finding studies to guide the use of oral medical cannabis extracts or inhaled forms of cannabis in the prevention and treatment of CINV. The dose suggestions below are based only on FDA-approved oral dosing recommendations for dronabinol (MARINOL) in treating CINV. Bioavailability and pharmacodynamic effects of orally and sublingually-administered medical cannabis extracts may differ substantially from an orally ingested dose of a single cannabinoid, dronabinol. Because of these variables, the dosing suggestions below may not be appropriate for all patients with CINV:

  1. Start with 5 mg/m2 THC equivalent, administered 1 to 3 hours before the administration of chemotherapy and then every 2 to 4 hours after chemotherapy, for a total of 4 to 6 doses per day.
  2. In elderly patients with unstable vital signs or co-occurring cardiovascular problems, consider initiating THC equivalent at 2.5 mg/m2 once daily, 1 to 3 hours before chemotherapy, to reduce the risk of CNS symptoms and adverse cardiovascular outcomes.
  3. The dosage can be titrated to clinical response during a chemotherapy cycle or subsequent cycles, based upon initial response, as tolerated to achieve a clinical effect in increments of 2.5 mg/m2.
  4. The maximum dosage of THC equivalent should not exceed 15 mg/m2 per dose for 4 to 6 doses per day.
  5. Adverse reactions are dose-related, and psychiatric symptoms increase significantly at higher and maximal dosages.
  6. Monitor patients for adverse reactions and consider decreasing the dose to 2.5 mg once daily, 1 to 3 hours before chemotherapy, to reduce the risk of CNS adverse reactions.

Note: The above dosing suggestions for CINV are above and beyond the conservative recommendation of “start low and go slow” and are more aggressive than those listed in the general dosing guidelines on this website. They are not based on clinical trials using actual medical cannabis preparations. They are intended only to be used as dosing suggestions for treating severe CINV that has not adequately responded to first-line therapies.

These dosing suggestions are based on dronabinol and do not consider variations in bioavailability or any possible additional pharmacodynamic effects or side effects of medical cannabis extracts due to possible therapeutic synergy related to other cannabinoids and terpenoids that may be present in a given oral or sublingual medical cannabis preparation. Although there are no clinical trial results and minimal observational data in humans, preclinical animal data suggest that it is possible that cannabinoids, in addition to decarboxylated Δ-9 THC, may have significant clinical effects on CINV symptoms in humans.

Caution should be exercised when trying to balance the acute need to control symptoms of CINV in a physically compromised individual against the potential for significant side effects associated with higher doses of THC in chemotypes I and II medical cannabis products. In cannabis naïve patients who are elderly or significantly compromised, THC equivalent doses lower than the above suggestions should be considered.

References

  1. Abrams, D. (2016). Integrating cannabis into clinical cancer care. Current Oncology, 23, 8. doi: 10.3747/co.23.3099 
  2. Cudaback, E., Marrs, W., Moeller, T., & Stella, N. (2010). The Expression Level of CB1 and CB2 Receptors Determines Their Efficacy at Inducing Apoptosis in Astrocytomas. PLoS ONE, 5(1). doi: 10.1371/journal.pone.0008702 
  3. Fallon MT, Eberhard AL, McQuad R, et al. Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain  unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies. British Journal of Pain. 2017. 11(3) 119- 133.
  4. Foroughi, M., Hendson, G., Sargent, M. A., & Steinbok, P. (2011). Spontaneous regression of septum pellucidum/forniceal pilocytic astrocytomas—possible  role of Cannabis inhalation. Childs Nervous System, 27(4), 671–679. doi: 10.1007/s00381-011-1410-4  
  5. Guzmán, M., Duarte, M. J., Blázquez, C., Ravina, J., Rosa, M. C., Galve-Roperh,  I., … González-Feria, L. (2006). A pilot clinical study of Δ9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. British Journal of Cancer, 95(2), 197–203. doi: 10.1038/sj.bjc.6603236 6. 
  6. GW Pharmaceuticals: Cannabinoid Research & Medicines. (2017). Retrieved from https://www.gwpharm.com/healthcareprofessionals/research/therapeutic-areas# 
  7. Hart, S., Fischer, O. M., & Ullrich, A. (2004). Cannabinoids Induce Cancer Cell Proliferation via Tumor Necrosis Factor α-Converting Enzyme (TACE/ADAM17)-Mediated Transactivation of the Epidermal Growth Factor  Receptor. Cancer Research, 64(6), 1943–1950. doi: 10.1158/0008-5472.can 03-3720 
  8. Health Canada. (2018). Information for Health Care Professionals - Cannabis (marihuana, marijuana) and the cannabinoids. Retrieved from https://www.canada.ca/en/health-canada/services/drugs-medication/cannabis/information-medical-practitioners/information-health-care-professionals-cannabis-cannabinoids.html
  9. Johnson, J. R., Burnell-Nugent, M., Lossignol, D., Ganae-Motan, E. D., Potts, R., & Fallon, M. T. (2010). Multicenter, Double-Blind, Randomized, Placebo Controlled, Parallel-Group Study of the Efficacy, Safety, and Tolerability of THC:CBD Extract and THC Extract in Patients with Intractable Cancer-Related  Pain. Journal of Pain and Symptom Management, 39(2), 167–179. doi:  10.1016/j.jpainsymman.2009.06.008
  10. Lichtman AH, Lux EA, McQuade R, et al. Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain. Journal of Pain and Symptom Management. 2018. 55 (2) 179-188. 
  11. Lynch, M. E., Cesar-Rittenberg, P., & Hohmann, A. G. (2014). A Double-Blind,  Placebo-Controlled, Crossover Pilot Trial with Extension Using an Oral Mucosal Cannabinoid Extract for Treatment of Chemotherapy-Induced  Neuropathic Pain. Journal of Pain and Symptom Management, 47(1), 166– 173. doi: 10.1016/j.jpainsymman.2013.02.018 
  12. Meiri, E., Jhangiani, H., Vredenburgh, J. J., Barbato, L. M., Carter, F. J., Yang, H.- M., & Baranowski, V. (2007). Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy induced nausea and vomiting. Current Medical Research and Opinion, 23(3),  533–543. doi: 10.1185/030079907x167525 
  13. Musty, R. E., & Rossi, R. (2001). Effects of Smoked Cannabis and Oral δ9- Tetrahydrocannabinol on Nausea and Emesis after Cancer Chemotherapy. Journal of Cannabis Therapeutics, 1(1), 29–56. doi: 10.1300/j175v01n01_03 
  14. Pisanti, S., Malfitano, A. M., Grimaldi, C., Santoro, A., Gazzerro, P., Laezza, C., & Bifulco, M. (2009). Use of cannabinoid receptor agonists in cancer therapy as palliative and curative agents. Best Practice & Research Clinical  Endocrinology & Metabolism, 23(1), 117–131. doi: 10.1016/j.beem.2009.02.001 
  15. Pisanti, S., Malfitano, A. M., Grimaldi, C., Santoro, A., Gazzerro, P., Laezza, C., & Bifulco, M. (2009). Use of cannabinoid receptor agonists in cancer therapy as palliative and curative agents. Best Practice & Research Clinical  Endocrinology & Metabolism, 23(1), 117–131. doi: 10.1016/j.beem.2009.02.001 
  16. Plasse, T. F., Gorter, R. W., Krasnow, S. H., Lane, M., Shepard, K. V., & Wadleigh, R. G. (1991). Recent clinical experience with dronabinol.  Pharmacology Biochemistry and Behavior, 40(3), 695–700. doi: 10.1016/0091- 3057(91)90385-f 
  17. Rocha, F. C. M., Júnior, J. G. D. S., Stefano, S. C., & Silveira, D. X. D. (2014).  Systematic review of the literature on clinical and experimental trials on the antitumor effects of cannabinoids in gliomas. Journal of Neuro-Oncology, 116(1), 11–24. doi: 10.1007/s11060-013-1277-1 
  18. Singh, Y., & Bali, C. (2013). Cannabis Extract Treatment for Terminal Acute Lymphoblastic Leukemia with a Philadelphia Chromosome Mutation. Case Reports in Oncology, 6(3), 585–592. doi: 10.1159/000356446
  19. Smith, L. A., Azariah, F., Lavender, V. T., Stoner, N. S., & Bettiol, S. (2015).  Cannabinoids for nausea and vomiting in adults with cancer receiving  chemotherapy. Cochrane Database of Systematic Reviews. doi: 10.1002/14651858.cd009464.pub2 
  20. The National Academies of Sciences, Engineering, and Medicine. (2017d). The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. doi: https://doi.org/10.17226/24625 
  21. Velasco, G., Hernández-Tiedra, S., Dávila, D., & Lorente, M. (2016). The use of cannabinoids as anticancer agents. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 64, 259–266. doi: 10.1016/j.pnpbp.2015.05.010