Whether you like it or not, vomiting is a very important physiological response that allows the body to expel harmful substances that have been ingested like poisons, dangerous microbes, and foreign bodies, before they can damage other organs. Severe and persistent vomiting however can be a symptom of life-threatening diseases such as liver failure, meningitis or a side effect of medications like chemotherapy agents. While there are multiple medications available for the treatment of nausea and vomiting, they still fall short of meeting expectations in some special cases like treatment-resistant vomiting in chemotherapy patients. Cannabinoids like THC have recently entered clinical practice as promising add-on therapies to solve these unmet medical needs. To learn more about the science behind cannabinoids and their anti-nausea (antiemetic) effects, keep on reading.

Understanding nausea and vomiting

Like any other critical physiological response in the body, vomiting is involuntarily controlled by a region of the brain known as the vomiting centre. It is located in the medulla oblongata which is the lowest section of the brain stem that connects the spinal cord to the rest of the brain stem above. When activated, the vomiting centre signals to different parts of the body like the chest and abdominal muscles to contract in a coordinated manner which leads to a build-up of pressure in the gastrointestinal tract and results in vomiting.

Source: https://nursekey.com/34-drugs-used-to-treat-nausea-and-vomiting/. Accessed online on 12/5/2024.

The vomiting center itself integrates signals from multiple pathways originating at distinct locations both inside the brain and in other organs,^1,2,3,4 namely:

• The chemoreceptor trigger zone (CTZ)
• The vestibular system
• The brain cortex
• The gastrointestinal (GI) tract

As we will discuss further on, antiemetics act by inhibiting the relay of signals from one or more of these pathways to the vomiting centre.

The chemoreceptor trigger zone

The CTZ, also known as the area postrema, is located on the backside of the medulla oblongata close to the vomiting centre, and plays a major role in the regulation of nausea and vomiting. Unlike most other structures in the brain, it lacks a proper blood-brain barrier, meaning that it directly interacts with the bloodstream and its contents. This allows the CTZ to detect toxins and other emetic agents in the blood even if they don’t enter the brain. The cells within the CTZ have multiple receptors through which they recognise emetic substances, the most important being D2 (dopamine receptor), 5-HT3 (serotonin receptor), and NK-1 (substance P receptor). When activated, the CTZ directly sends out signals to the vomiting centre, thus inducing a vomiting reflex.¹

The vestibular system

The vestibular system is located in the inner ear and detects changes in balance and motion. It sends out signals of sensory mismatch to the vomiting centre whenever there is a discrepancy between expected motion and actual motion. For instance, when we read a book in a moving car, our eyes detect that we are in a still position, while the inner ear detects motion. This mismatch activates the vomiting centre, leading to nausea and vomiting - commonly known as motion sickness. Other conditions that damage the inner ear can cause nausea and vomiting, including labyrinthitis (inflammation of the inner ear) and Meniere’s disease (excessive buildup of fluid inside the inner ear). The cells of the vestibular system contain receptors which trigger a vomiting response when activated. These include M1 (muscarinic acetylcholine receptor) and H1 (histamine receptor).²

The brain cortex

The brain cortex encompasses multiple higher brain regions which have a complex and not yet understood role in the regulation of physiological processes like vomiting. However, we know for certain that the brain cortex integrates and relays complex sensory information and emotional responses towards the vomiting centre. That’s why nausea and vomiting can be caused by experiencing intense disgusting smells, sights, tastes, or emotional distress. The brain cortex, being the super complex organ it is, integrates all the information it has previously come into contact with and is able to activate the vomiting center even without a stimulus being present. That’s why some people can get nauseous just by thinking of something unpleasant like cancer patients anticipating their next chemotherapy cycle.³

The gastrointestinal tract

The gastrointestinal (GI) tract plays a major gatekeeping role in the process of vomiting. Emetic substances usually cause vomiting before they can enter the bloodstream to activate any of the aforementioned pathways. The upper GI tract, mainly the throat and oesophagus, are rich in specialised sensory neurons known as mechanoreceptors, which when stimulated by mechanical irritation activate the vagus nerve that sends out an excitatory signal directly to the vomiting centre, leading to nausea and vomiting. This is the infamous gag reflex which plays an important role in the prevention of choking when swallowing foreign bodies. Meanwhile, the lower GI tract, which is made up of the intestines, is rich in chemical sensors known as enterochromaffin cells. When a toxic substance such as a chemotherapy drug comes into contact with these cells, they release serotonin, which binds to 5-HT3 receptors on nearby branches of the vagus nerve and sends a signal to the vomiting centre.⁴

Current antiemetic drugs

Before discussing cannabinoids and their anti-nausea effects, let’s first see what the classical antiemetic agents are:

• Antihistamines (diphenhydramine) or more precisely H1 receptor inverse agonists reduce the activity of H1 receptors in the vestibular system. They are used for the prevention and treatment of motion sickness and other vestibular conditions⁵
• Antimuscarinics (scopolamine) inhibit M1 receptors in the vestibular system and are used to treat nausea and vomiting associated with vestibular conditions as well⁵
• Antidopaminergics (metoclopramide, domperidone, prochlorperazine) inhibit D2 receptors in the CTZ. Metoclopramide and domperidone are widely used to treat nausea and vomiting caused by various factors. Phenothiazines like prochlorperazine (drugs also used for psychotic disorders) on the other hand are generally used for more severe cases, due to greater side effects⁵
• NK receptor inhibitors (aprepitant and fosaprepitant) inhibit NK-1 receptors in the CTZ. They are widely used for the treatment of vomiting induced by chemotherapy (see below)⁵
• Setrons or 5-HT3 receptor inhibitors (ondansetron, dolasetron, granisetron) inhibit 5-HT3 serotonin receptors both in the peripheral nervous system located in the intestines, and the CTZ in the central nervous system. Like the NK receptor inhibitors, they are widely used in chemotherapy patients⁵
• Glucocorticoids (dexamethasone) are used in combination with other medications, primarily in the treatment of nausea and vomiting caused by chemotherapy. Their mechanism has not been fully established yet⁵
• Anxiolytics (alprazolam), although not a typical class of anti-nausea medications, act by inhibiting signal transmission in the central nervous system, including the response to any stimuli sent from the brain cortex to the vomiting centre. Benzodiazepines are the most frequently used anxiolytics in the management of nausea and vomiting, sometimes combined with conventional antiemetics like metoclopramide^6,7

The antiemetic effect of drugs largely depends on the anatomical localisation of their target – whether it is surrounded by the blood-brain barrier or not – and on the physicochemical properties of the drug itself. Usually, drugs need to have small lipophilic molecules to cross the blood-brain barrier and reach most areas of the brain like the vestibular system and the vomiting centre. This is why only some M1 and H1 inhibitors exert an anti-nausea effect, while others don’t – the antihistamine diphenhydramine is more lipophilic and has a strong anti-nausea effect, while the more hydrophilic desloratadine crosses the blood-brain barrier to a limited extend and has practically no anti-nausea effect. On the other hand, D2 inhibitors target the CTZ, which is outside the blood-brain barrier. This allows for antidopaminergics with larger, more hydrophilic molecules to exert an anti-nausea effect. Finally, the 5-HT3 inhibitors primarily target peripheral neurons in the intestines, which are also outside the blood-brain barrier. Cannabinoids have small lipophilic molecules, meaning that they can cross the blood-brain barrier and may target multiple organ sites at once, like the vomiting center and CTZ, but also peripheral organs like the intestines.⁸

A lasting problem: Chemotherapy-Induced Nausea and Vomiting (CINV)

CINV is one of the most distressing side effects of chemotherapy, significantly affecting patients’ quality of life and adherence to therapy. CINV deserves special attention given how it encompasses all previously discussed signalling pathways and requires a complex therapeutic approach. CINV can be classified into five distinct types based on onset and underlying causes:⁹

• Acute CINV: Occurring within the first 24 of chemotherapy. It is primarily caused by acute damage of enterochromaffin cells by chemotherapy drugs and is 5-HT3 receptor-mediated
• Delayed CINV: Manifests later than 24 hours after therapy, usually between 48-72 hours. It is predominantly mediated by overstimulation of the vomiting centre by the CTZ and is NK-1 receptor-mediated
• Anticipatory CINV: A psychological response to previously administered cycles of chemotherapy. It is commonly triggered by sights, smells or even just mere thoughts associated with chemotherapy, and primarily involves the brain cortex

Medical professionals must keep in mind the emetogenic risk of medications used for chemotherapy, the response to treatment of each patient individually, and the available treatment options. Usually, chemotherapy patients are prophylactically treated with a combination of multiple agents that can prevent acute, delayed and anticipatory CINV altogether. For instance, a 5-HT3 inhibitor, combined with an NK-1 inhibitor and a glucocorticoid, is the standard antiemetic protocol for patients treated with high emetogenic chemotherapy regimens.

• Breakthrough CINV: An unexpected onset of nausea and vomiting within 5 days of the chemotherapy cycle. Rescue medications are acutely administered to limit its progression
• Refractory CINV: When CINV does not respond to anti-nausea treatment at all, despite maximum anti-nausea treatment being employed. Additional medications are usually administered to overcome refractory CINV

Where do cannabinoids come in?

Throughout the last few years, cannabinoids have undergone rigorous research uncovering their potential use in the treatment of many diseases with unmet medical needs, like cancer, epilepsy, and vomiting. Cannabinoids are bioactive compounds that are produced by the Cannabis plant. The two most well-known cannabinoids are delta-9-tetrahydrocannabinol (delta-9-THC), commonly known as THC and cannabidiol, commonly known as CBD. Both THC and CBD bind to multiple receptors and enzymes in the human body, comprising the so-called endocannabinoid system. The most notable receptors of the endocannabinoid system are the cannabinoid CB1 and CB2 receptors. CB1 is widely spread throughout the nervous system, while CB2 receptors are mostly found on immune cells, and are expressed by nerve cells mainly during inflammation. THC has been shown to bind to CB1 receptors in the CTZ, vomiting centre and peripheral neurons in the intestines, thus inhibiting emetic signals.⁸ CB2 receptors on the other hand may also have a certain role in the anti-nausea effects of Cannabis and cannabinoids, but it is still understudied.¹⁰ 

A synthetic variant of THC known as dronabinol is currently used for the treatment of treatment-resistant CINV. Another synthetic cannabinoid used for treatment-resistant CINV is nabilone, which chemically resembles THC.^11,12 In a randomised controlled trial, dronabinol has been shown to significantly improve antiemetic response in patients with CINV when combined with conventional antiemetics such as ondansetron.¹³ In another randomised clinical trial, dronabinol compared to placebo led to improvement in appetite and weight gain, as well as decreased nausea.¹¹ 

Currently, the American Society of Clinical Oncology (ASCO) recommends both dronabinol and nabilone together with other medications as treatment options for patients on chemotherapy experiencing insufficient control over their nausea and vomiting symptoms.¹⁴ On the other hand, the Multinational Association of Supportive Care in Cancer (MASCC) and European Society of Medical Oncology (ESMO) have still not considered cannabinoids as an option for patients with CINV, due to legal restrictions on Cannabis and cannabinoid use in most European countries.¹⁵

Summary

Cannabinoids may have the potential to help with the management of complex cases of CINV and improve patient well-being and adherence to chemotherapy. However, there is still a need to generate additional high-quality evidence supporting cannabinoids for CINV. The current legal restrictions surrounding Cannabis and cannabinoids remain a major barrier to their widespread use in clinical practice for CINV, as well as other conditions such as anxiety and anorexia.