What chemotherapy-induced nausea is
Chemotherapy-induced nausea and vomiting (CINV) is one of the most common and distressing side effects of cancer chemotherapy. It can occur in the hours after treatment (acute CINV) or in the days that follow (delayed CINV). Some people also experience anticipatory nausea, triggered by the sights, smells, or settings associated with previous chemotherapy sessions, before a treatment cycle even begins.
The severity of CINV depends on the specific chemotherapy drugs used, their doses, and individual patient factors. Uncontrolled nausea and vomiting can lead to dehydration, electrolyte imbalances, malnutrition, weight loss, damage to the oesophagus, and reduced quality of life. In severe cases, it can cause people to delay or refuse potentially life-prolonging chemotherapy.
Modern antiemetic regimens, including serotonin (5-HT3) receptor antagonists such as ondansetron, neurokinin-1 (NK1) receptor antagonists such as aprepitant, and corticosteroids such as dexamethasone, have substantially reduced the prevalence of CINV. However, some people continue to experience nausea and vomiting despite these treatments. This is sometimes described as breakthrough or refractory CINV.
Cannabis research on Chemotherapy-induced nausea
Two synthetic cannabinoid medicines, nabilone and dronabinol (synthetic THC), are licensed in the UK for the treatment of CINV that has not responded to conventional antiemetics. Both products are oral capsules. They are positioned as third-line treatments, used when first-line and second-line antiemetics have not provided sufficient control.
A 2015 systematic review and meta-analysis by Whiting and colleagues, published in JAMA, included 3 RCTs of cannabinoids for CINV. The pooled analysis found a complete nausea and vomiting response rate of 47 per cent with cannabinoids compared with 20 per cent with placebo (odds ratio 3.82, 95% CI 1.55 to 9.42). The review rated the quality of this evidence as low.
A 2016 systematic review of systematic reviews by Schussel and colleagues assessed the totality of published review-level evidence for cannabinoids in CINV. The authors concluded that cannabinoids cannot be recommended as first- or second-line therapy for CINV. The review noted that some clinical guidelines position pharmaceutical cannabinoids as third-line treatment for breakthrough nausea and vomiting when standard antiemetics have failed.
The original RCTs establishing nabilone as an antiemetic were conducted in the late 1970s and 1980s. A 1980 double-blind RCT by Steele and colleagues compared nabilone with prochlorperazine for chemotherapy-induced emesis and found nabilone produced a significantly greater antiemetic response. A 1987 double-blind crossover trial by Chan and colleagues studied nabilone versus prochlorperazine in children receiving cancer chemotherapy and reported that nabilone was the more effective antiemetic. These trials were small by modern standards — 37 and 30 participants, respectively — and were conducted before the introduction of modern 5-HT3 antagonist antiemetics, which have since become the standard of care.
No RCT has compared nabilone or dronabinol directly against ondansetron or aprepitant for CINV. The existing trial evidence primarily compares cannabinoids with placebo or with older antiemetics such as prochlorperazine and metoclopramide.
A 2018 retrospective multicentre review by Polito and colleagues examined nabilone for acute chemotherapy-induced vomiting prophylaxis in paediatric patients. This was a retrospective chart review, not a prospective RCT, and its findings reflect clinical practice patterns rather than controlled experimental conditions.
Compounds studied for Chemotherapy-induced nausea
THC is the active component of both dronabinol (synthetic THC) and nabilone (a synthetic THC analogue). CB1 receptors in the brainstem, particularly in the dorsal vagal complex, are involved in the regulation of nausea and vomiting. The antiemetic effect observed in RCTs was studied in the context of synthetic oral THC preparations, not inhaled or vaporised cannabis. See THC.
CBD has not been directly studied for CINV in human RCTs. Its interactions with serotonin receptors have been proposed as a mechanism that may influence nausea signalling, but this is laboratory and animal research. See CBD.
CBG has been examined in laboratory research for its receptor interactions at CB1 and CB2. No human RCT has tested CBG for CINV. See CBG.
CBN is a degradation product of THC. Limited laboratory research exists on its receptor binding, but no human RCT has examined CBN for nausea or vomiting. See CBN.
Limonene has been studied in limited animal research for effects on gastric motility. No human RCT has tested isolated limonene for CINV outcomes. See limonene.
Caryophyllene interacts with CB2 receptors and has been examined in animal models of gastrointestinal inflammation. Human trial data for caryophyllene in nausea or vomiting are absent. See beta-caryophyllene.
Pinene has been studied in cell and animal models for anti-inflammatory properties. No human clinical trial has tested isolated pinene for CINV. See pinene.
Limits of the evidence for Chemotherapy-induced nausea
The systematic review-level evidence for cannabinoids in CINV is rated as low quality. The RCTs that established nabilone and dronabinol as antiemetics were conducted decades ago with small sample sizes and used comparator drugs that are no longer standard first-line treatments.
No RCT has compared a cannabinoid directly against a modern 5-HT3 antagonist such as ondansetron. It is not possible to determine from the existing evidence whether cannabinoids are as effective as, more effective than, or less effective than the antiemetics that currently form the standard of care.
The evidence is for synthetic oral THC preparations, not for cannabis flower, cannabis oil, or vaporised cannabis. An RCT of nabilone capsules does not provide evidence about inhaled cannabis for CINV.
The trials measured nausea and vomiting as outcomes. They did not establish that cannabinoids improve cancer outcomes, extend survival, or enhance the efficacy of chemotherapy.
No RCT has tested cannabis-based medicines for anticipatory nausea, which has a different underlying mechanism from acute or delayed CINV.
Sources
1. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015;313(24):2456-2473. doi:10.1001/jama.2015.6358. PMID: 26103030. Study record
2. Schussel V, Kenzo L, Santos A, et al. Cannabinoids for chemotherapy-induced nausea and vomiting — a systematic review of systematic reviews. BMC Cancer. 2016;16:44. doi:10.1186/s12885-016-2536-9. PMID: 26787227. Study record
3. Steele N, Gralla RJ, Braun DW Jr, Young CW. Double-blind comparison of the antiemetic effects of nabilone and prochlorperazine on chemotherapy-induced emesis. Cancer Treat Rep. 1980;64(2-3):219-224. PMID: 6250699. Study record
4. Chan HS, Correia JA, MacLeod SM. Nabilone versus prochlorperazine for control of cancer chemotherapy-induced emesis in children: a double-blind, crossover trial. Pediatrics. 1987;79(6):946-952. PMID: 3035479. Study record
