When medical cannabis laws made their debut in the latter half of the 1990s, they were intended to protect cancer patients from prosecution. These patients found a medication that combatted the harsh, nauseating side effects of chemotherapy, and though cannabis’ efficacy was largely anecdotal at the time, we can now look at the science of cannabinoids to better understand why it works to suppress nausea and vomiting.
What is CINV and how is it treated?
Overpowering. That’s how cancer patients describe the onslaught that occurs within the first 24 hours after starting chemotherapy. Certainly patients fear the hair loss, but the most dreaded side effect is the extreme bouts of nausea and vomiting (called emesis). This isn’t just regular nausea–chemotherapy-induced nausea and vomiting (CINV) is severe and usually occurs right away, with a peak window of 6-24+ hours after treatment.
Traditional pharmaceuticals are used as anti-nausea (anti-emetic) therapies to prevent or minimize CINV. Dexamethasone, a corticosteroid prescribed for inflammatory conditions, is most commonly prescribed; as it turns out, it is also very effective in treating CINV. Serotonin receptor agonists called 5-HT3 (ondansetron, palonosetron, and aprepitant) have been effective when used with dexamethasone. Even antihistamines, antidepressants and anticonvulsants have been tried.
But what happens if these drugs don’t alleviate symptoms? Many chemotherapy patients don’t respond to traditional drugs and report that they can leave them feeling more drugged, more lethargic, and even delusional.
Cannabinoids have shown success in treating the symptoms of CINV. Two medicines, nabilone and dronabinol, are orally-administered synthetic cannabinoids (not to be confused with synthetic cannabis like K2 and Spice). The two are slightly different variations of delta-9-tetrahydrocannibinol (Δ9-THC), which naturally occurs in a cannabis plant. Dronabinol is marketed as Marinol from the US-based Banner Pharmacaps, and nabilone is sold as Cesamet by the Canadian company Valeant Pharmaceuticals International. Both are available in oral and inhaled solutions, and both have been approved for treatment of CINV.
Doctors will usually prescribe traditional medications first, but then try Marinol or Cesamet for patients who don’t respond to other pharmaceuticals.
Research on synthetic cannabinoids for nausea relief
In 1985, dronabinol and nabilone were both approved by the FDA for treatment of CINV. Since then, nearly 30 clinical trials have been conducted and show that synthetic cannabinoids are superior to traditional dopamine receptor antagonist medications for CINV.
Specifically, several clinical trials (1975-1996) involved 1,366 patients. Sixteen trials studied nabilone, and thirteen trials studied dronabinol. Placebos were used, and metoclopramide was used as a control. Cannabinoids alleviated CINV more effectively than either metoclopromide or placebos in all trials.
With synthetic cannabinoids, patients reported beneficial effects such as euphoria, but they also noted negative side effects like drowsiness, depression, drops in blood pressure, and even hallucinations and paranoia. For some patients, the side effects were so intolerable that they dropped out of the studies.
Scientists are also running trials in which the synthetics are used in conjunction with traditional pharmaceuticals, like the addition of dronabinol to dexamethasone. Various studies show a dramatic reduction in emesis, but some of the adverse side effects of the synthetic cannabinoids are still present, albeit less severe than previous studies.
A typical dronabinol dosage is 5mg taken 3 to 4 times daily; for nabilone, a 1-2mg dose is typically taken twice daily. Both are usually given about 1 to 3 hours prior to the start of chemotherapy.
Surprisingly, the medical community still considers these synthetic cannabinoids to be a controversial treatment, despite being approved by the FDA more than 20 years ago. Nabilone and dronabinol are still not as well-studied in clinical trials as their traditional counterparts. Although there is anecdotal evidence regarding drug combinations, very few studies have been designed to look CINV solutions involving a formulation of cannabis and other drugs.
How do cannabinoids work to prevent nausea?
Nabilone and dronabinol work by blocking the binding of serotonin and dopamine, both of which are associated with CINV, at receptor sites. Some of the body’s endocannabinoid receptors exist within emetic reflex pathways, making them a promising target for managing CINV. The dorsal vagal complex (DVC) in the brainstem is the overall regulator of emesis (nausea/vomiting), and it is responsible for communication between signals in the blood (like chemotherapy) and the nerve cells that initiate emesis. The DVC and gastrointestinal tract have endocannabinoid receptors, and all have shown to exhibit anti-emetic responses when the receptors are activated by Δ9-THC.
Natural cannabis and nausea treatment
According to the National Cancer Institute, as of April 2017, only 10 human trials have studied the effect of inhaled cannabis for treatment of CINV. In some cases, inhaled cannabis was used because dronabinol failed. One trial found that inhaled cannabis was effective for patients who received high doses of methotrexate.
Natural cannabis can also be used for all types of nausea, not just CINV. Most evidence has come from strains containing some degree of THC. The therapeutic outcomes, of course, depend on the THC concentration. Other formulations involve THC and cannabidiol (CBD) in different ratios. Cannabis strains are specifically grown to have different ratios/concentrations to achieve a particular pharmacologic effect.
CBD is non-intoxicating, and although research has only been done in animals, several animal studies have shown it to be effective at reducing nausea. Rats and mice don’t vomit in response to a toxin, so other species such as cats and ferrets must be studied. However, it’s possible to determine the degree of nausea in rats by studying the conditioned gaping response.
In a 2012 rat study published in the British Journal of Pharmacology, CBD was found to be effective on nicotine-induced nausea. Other animal studies found that low doses of CBD were effective in several types of induced vomiting and anticipatory vomiting, but so far it has not been effective on nausea and vomiting induced by motion sickness.
Many people have started using CBD to treat nausea and vomiting, based on preliminary results showing that CBD activates a neurotransmitter that decreases the sensation of nausea. More research—to identify appropriate combinations, dosages, and drug interactions—is needed for both natural and synthetic cannabinoids used for CINV as well as other types of nausea.
Unfortunately, natural cannabis is not yet a part of the global standard Clinical Practice Guidelines for Oncology, and in the US, because medical marijuana is still illegal at the federal level, researchers remain somewhat reluctant to register studies on clnicaltrials.gov. The recourse patients have is to pursue nausea treatment options in states that have approved medical cannabis use.
