Chemotherapy-induced nausea and vomiting (CINV) is one of the most dreaded side effects of cancer treatment (Griffin, Ann Oncol, 1996; Kuchuk, J Clin Oncol, 2013). CINV can be broken down into three categories: acute emesis, which occurs within hours of treatment; delayed emesis, which occurs at least 24 hours after treatment; and anticipatory emesis, which occurs prior to treatment as a conditioned response (Hesketh, NEJM, 2008).
In general, the body regulates nausea and vomiting through a complex network of organs and signaling molecules, that includes the GI tract, the autonomic nervous system, neurotransmitters, and certain regions of the brain (Aapro, Support Care Cancer, 2018). Different chemotherapeutic agents have varying degrees of emetogenicity, or the ability to induce nausea and vomiting, and can trigger emesis in multiple ways.
Current standard of care involves prophylaxis with three to four anti-emetic agents prior to chemotherapy administration, including a 5-HT3 antagonist, neurokinin-1-receptor (NK1R) antagonist, and dexamethasone with or without olanzapine, an atypical antipsychotic (Hesketh, J Clin Oncol, 2017). If breakthrough nausea and/or vomiting occurs, rescue medication can be provided.
Despite the vast number of anti-emetic agents currently available, not all patients achieve adequate control of their CINV. On the contrary, a recent study demonstrated that up to 40% of cancer patients will experience CINV over the course of their disease (Dranitsaris, Ann Oncol, 2017).
Certain types of CINV are better controlled than others. For instance, acute CINV is reported substantially less frequently than delayed CINV in patients receiving the current standard regimen (Escobar, Support Care Cancer, 2015; Grunberg, Cancer 2004), while nausea is perhaps the most poorly controlled symptom (Aapro, Support Care Cancer, 2018). New therapies must be developed to address this high symptomatic burden in cancer patients receiving chemotherapy.
The use of cannabinoids, both natural and synthetic, have been investigated for the treatment of CINV. Two cannabinoids, dronabinol and nabilone, are already FDA-approved for the treatment of CINV. Although these drugs have a demonstrated efficacy, some adverse effects were reported with their use, such as sedation, depression, hallucinations, and paranoia, likely due to the psychoactive properties of THC, from which these compounds are derived (Smith, Cochrane Database Syst Rev, 2015; Tramer, BMJ, 2001). These negative side effects limit their widespread use.
Nonetheless, data from preclinical and early clinical studies suggests that other cannabinoids may be beneficial for the treatment of CINV. THC, CBD, and other endogenous cannabinoids were shown to reduce nausea, both acute and anticipatory, as well as vomiting in multiple animal models (Rock, Front Pharmacol, 2016). CBD acid was also shown to act synergistically with THC, 5-HT3 antagonists, and D2-antagonists to reduce nausea, such that sub-therapeutic doses of all compounds could be used (Rock, Psychopharmacology (Berl), 2015; Rock, Pharmacol Biochem Behav, 2013; Rock, Br J Pharmacol, 2013).
Additionally, in a small randomized, placebo-controlled phase 2 trial, nabiximols, an oromucusal spray with a 1:1 ratio of THC:CBD, protected against delayed CINV in treatment-refractory patients (Duran, Br J Pharmacol, 2010). Taken together, these data suggest that cannabinoids used alone or in combination with other standard of care therapies could meaningfully address some of the gaps in the current management of CINV.