Chemotherapy-induced nausea and vomiting (CINV) is the one of the most serious, unpleasant and even severe adverse effects of cancer treatment. Based on the emetogenic potential, chemotherapeutic drugs are classified as high, moderate or low-risk drugs. However, the risk of developing CINV is anywhere between 70% – 80% in cancer patients. Chemotherapy-administered cancer patients are more prone to nausea than vomiting, which is poorly treated by anti-emetic drugs.
CINV interferes with the patient’s treatment compliance or adherence, with increased incidences of depression, distress or anxiety, and impaired quality of life. CINV increases the use of healthcare resources, and also the economic burden of patients and caregivers.
CINV pathogenesis involves a complex network of anatomical, neurological, neurotransmitters and respective receptors. The vomiting process is coordinated by the medulla oblongata, the chemoreceptor trigger zone located in the floor of the fourth ventricle, vagal nerve and enterochromaffin cells (EC) in the gastrointestinal tract. The higher centre plays a critical role in the receiving and processing of emetic stimuli, and sending the efferent signals to various organs including the GI tract, resulting in nausea and vomiting.
Cytotoxic chemotherapeutic drugs degrade EC lining in the GI mucosa, resulting in the generation of free radicals that signal the serotonin release from ECs. The neurotransmitter chemically induces the vagal nerve, and signals the brain to initiate emesis. Depending on the involvement of other chemicals, such as Substance P, the duration of CINV may persist.
Some patient-specific risk factors, such as female gender, history of alcohol use, young age and previous exposure to chemotherapy, are known to increase the risk of CINV.
Prevention of CINV is ideal; however, in the case of onset, it is critical to treat or minimize the symptoms. Conventionally, CINV is treated with anti-emetic drugs, such as dolasetron, palonosetron, ondansetron, granisetron, fosaprepitant, metoclopramide and haloperidol, and sometimes with steroids like dexamethasone. However, the risk versus the benefit of co-administering steroids is questionable. Depending on the onset of CINV, the treatment itself and the treatment duration varies between patients.
Cannabinoids and 5-HT3 receptors
5-HT3 receptors are a group of ligand-gated ion channels involved in pain processing, mood disorders, analgesia, drug abuse and emesis. As 5-HT3 receptors have been implicated in the pathophysiology of emesis and nociception, antagonizing these receptors may treat vomiting and pain. In the pathophysiological process, the endocannabinoid system plays a key role in the emetic response and analgesia (CB receptor-independent) via modulation of 5-HT3 receptors. Cannabinoids have been reported to prevent CINV by acting in the central CB1 receptors, and inhibiting release of pro-emetic chemicals, such as dopamine and serotonin.
The anti-emetic use of cannabinoids dates back to 1985. Later on, the United States Food and Drug Administration approved synthetic cannabinoids for the management of CINV. Among the cannabinoids, delta-9-tetrahydrocannabinol remains the preferred choice for treatment of CINV and cancer-related symptoms – including pain. In cell culture studies, THC directly inhibited the functions of 5-HT3A receptors, which might have a therapeutic role in CINV.
THC has been shown to effectively inhibit 5-HT3 receptors as a non-competitive antagonist and might contribute to therapeutic benefits in emesis and pain symptoms. However, THC has been the second choice of cannabinoids, considering the psychoactive effects.
CBD has also been shown to be effective against pain and emesis, considering the non-CB1 receptor-dependent action of THC. The anti-emetic effect of CBD is attributed to partial inhibition of 5-HT3 receptors. Like THC, the potential inhibition of 5-HT3 receptors by CBD is independent of CB1 receptors, possibly due to the acceleration of receptor desensitization. Desensitization plays an important role in the efficacy of synaptic transmission of certain signals including emetic signals and regulation of neuronal excitability. The degree of 5-HT3 receptor desensitization directly influences the cannabinoids’ ability of receptor inhibition. Meaning, the magnitude of cannabinoid-mediated receptor blocking greatly depends on the receptor desensitization by THC and CBD.
Desensitization kinetics of 5-HT3 receptors has been shown to be altered by CBD and THC without altering activation kinetics. THC does not alter the binding of other 5-HT3 receptor antagonists, therefore the receptor biology and kinetics appear to be complex in nature. At least by partial inhibition, CBD and THC accelerate the rate of receptor desensitization, which regulates the channels (open and desensitization state).
These studies have shown that CBD inhibited 5-HT3 receptors in a dose-dependent manner, but also by an apparent non-competitive mechanism related to 5-HT3 receptor inhibition. However, the complete underlying mechanisms of CBD-induced 5-HT3 receptor inhibition are unknown. Studies have shown that CBD-mediated 5-HT3 receptor inhibition might be mediated by endogenous cannabinoids and capsaicin receptors due to non-involvement of other receptors. Similarly, endocannabinoids – such as anandamide – have been shown to accelerate desensitization of 5-HT3 receptors and nACh receptors, etc.
However, the inhibiting potential of THC and CBD greatly varies and depends on receptor density and other factors regulating the 5-HT3 receptors, present at the cell membrane surface. The expression of 5-HT3 receptors depends on the circulatory level of serotonin, which also influences the sensitivity of 5-HT3 receptors to cannabinoids. This is why THC and CBD exhibit partial inhibition and their anti-emetic potential might be moderate.
Compared to psychoactive THC, the non-psychoactive nature of CBD makes it a preferable choice for almost all age groups.
Treating CINV with cannabinoids
Systemic review studies of at least 23 randomized controlled studies have found that cannabinoids may be beneficial for the treatment of refractory CINV. Further, there were no treatment outcome differences between various treatment groups. However, the study researchers were unable to provide recommendations due to various study bias (low to moderate) in the reviewed studies.
According to a review study that analyzed 30 randomized clinical trials, the cannabinoids treatment was found to be more effective than other conventional treatments for CINV. Cannabinoids completely alleviated the symptoms of CINV in the first 24 hours of chemotherapy and reportedly provided better treatment outcomes. Additionally, the occurrence of moderate adverse events was also reported.
In pediatric cancer patients, CINV and related clinical conditions remains a significant problem despite anti-emetic drug treatments. Requirement of an optimal anti-emetic regimen to improve the symptoms and also the quality of life is critical. Review of 34 randomized controlled studies that investigated several anti-emetics found that a combination of 5-HT3 antagonists with steroids was more effective than older anti-emetic drugs. Cannabinoids were also found to be effective, but reportedly caused frequent side effects.
A review study that compiled several state-run clinical trials on medical cannabis concluded that smoking marijuana before and/or after chemotherapy dramatically relieved CINV by 70-100%, compared to 79-88% in oral THC capsule-administered patients. However, almost all the cannabis smokers reported a ‘high effect’ and sedation.
Medical cannabis as a treatment for CINV has not been investigated enough in clinical trials to compare the benefits with conventional anti-emetic drugs, and it remains controversial. Although not approved by the NCCN for CINV, patients are showing interest in using medical marijuana for emesis treatment. After widespread legalization of medical cannabis for various illnesses, including cancer, investigating the safety and efficacy in this patient population might be worth trying.