Cannabinoids against nausea and vomiting during chemotherapy (CINV)

CINV-Nausées et Vomissements

Chemotherapy is one of the central pillars of cancer therapy, along with radiotherapy and surgery. The drugs used, so-called cytostatics or chemotherapeutics, fight malignant tumours, attack cancer cells and prevent them from multiplying. However, chemotherapeutic agents do not only damage tumour cells but also healthy cells, which can lead to numerous side effects, such as nausea and vomiting. Cannabinoids play an important role in combating these extremely debilitating complaints.

Nausea and vomiting – side effects of chemotherapy

One of the most common side effects of chemotherapy, and the one most feared by cancer patients, is nausea and vomiting (CINV). The symptoms can be so severe that some patients stop the therapy, thus jeopardising the success of the treatment. For this reason, anti-nausea drugs – so-called antiemetics – are an integral part of chemotherapy. CINV is the abbreviation for chemotherapy-induced nausea and vomiting.

According to estimates by the Robert Koch Institute, approximately 500,000 people are newly diagnosed with cancer in Germany every year. The trend is rising due to the increasing ageing of the population. In women, breast cancer is the most common diagnosis, in men prostate cancer [1].

Acute vomiting can now be treated well thanks to highly effective serotonin antagonists and other antiemetics. Nausea and delayed vomiting are more difficult to treat. Cannabinoids can be a useful additional therapy option here.

Frequency and risk of nausea and vomiting during chemotherapy

The severity and duration of nausea and vomiting depend on the cancer drug, the dosage, concomitant medications and individual risk factors of the patient. Basically, the treatment of nausea depends on the emetogenic effect of the cytostatic drug, i.e. the ability of the chemotherapeutic drug to cause nausea.

Risk of CINV if no antiemetic is taken

  • High emetogenic chemotherapy: more than 90%
  • Moderate emetogenic chemotherapy: 30-90%
  • Low emetogenic chemotherapy: 10%
  • Minimal emetogenic chemotherapy: less than 10%

Antiemetic therapy can help in this case. However, despite optimal treatment, 20-30% of cancer patients experience vomiting and 40-50% experience nausea [2].

Classification of CINV

Depending on the time of chemotherapy when the symptoms appear, three forms are distinguished:

  • Acute vomiting starts within 24 hours after the start of chemotherapy.
  • Delayed vomiting does not occur until more than 24 hours after the start of chemotherapy. However, the symptoms can last up to five days.
  • Anticipatory vomiting (“learned vomiting”) occurs before the cytostatic drug is administered. It is triggered by external factors. For some people, the frightening environment of the hospital or the memory of discomfort from previous chemotherapy – combined with negative expectations – is enough to trigger nausea [3].

Symptoms of CINV include nausea, retching and vomiting. According to international guidelines of the Common Terminology Criteria for Adverse Events (CTCAE), a distinction is made between five degrees of severity [3]:

Severity Nausea Vomiting
0 none none
1 mild mild 1-2 times per day
2 moderate medium 3-5 times per day
3 severe severe 6 times a day or more
4 life-threatening life-threatening

Why does chemotherapy-induced vomiting occur?

The two hormones serotonin and substance P are involved in the development of CINV. Serotonin plays the main role in acute vomiting. Here, so-called enterochromaffin cells (EC cells) in the gastrointestinal tract are stimulated by the cancer drugs. These cells normally recognise aromatic substances from food and then secrete serotonin to promote digestion [4]. Chemotherapy releases a massive amount of serotonin. This binds to serotonin receptors (5-HT3 receptors) in the gut. The body relays the signal to the vomiting centre – with the result that the affected person vomits.

Delayed vomiting is triggered by the messenger substance P. Chemotherapeutic drugs stimulate the release of the hormone in the central and peripheral nervous system. Substance P attaches itself to neurokinin receptors and leads to delayed vomiting that lasts for several days [5].

Other receptors that play a role in nausea are histamine receptors, dopamine receptors and muscarinic and cannabinoid receptors.

Therapy of chemotherapy-induced vomiting

Anti-emetic drugs are an integral part of cancer therapy. They work best if they are taken prophylactically. If they are only used when vomiting occurs acutely, the drugs are often barely effective.

Effective anti-emetic therapy – from the very first chemotherapy – is important to prevent the development of anticipatory vomiting [3]. Depending on how much the respective chemotherapy can cause nausea, and depending on the symptoms, different drug groups are used. These can also be combined with each other:

  • Serotonin receptor blockers (5-HT3 antagonists): The serotonin antagonists include, for example, the drug ondansetron. They inhibit the serotonin receptors both in the intestine and in the vomiting centre. Serotonin released by enterochromaffin cells can therefore no longer bind, causing the vomiting reflex to stop. They work best in acute vomiting.
  • Neurokinin 1 receptor blockers (NK1 antagonists): The active ingredient aprepitant is used for delayed vomiting. This prevents the hormone substance P from binding to its receptors.
  • Corticosteroids: The active substance dexamethasone is used most often. They are usually combined with antiemetics from other drug groups to combat acute and delayed vomiting more effectively [5].

If patients continue to suffer from nausea and vomiting despite taking serotonin blockers, neurokinin blockers and corticosteroids, additional drugs are prescribed:

  • Dopamine D2 receptor blockers (e.g. metoclopramide): Metoclopramide is approved for delayed vomiting after chemotherapy.
  • Histamine 1-receptor blockers (e.g. dimenhydrinate): Antihistamines block the effect of the hormone histamine, which plays a role in many causes of nausea.
  • Benzodiazepines (e.g. lorazepam): Benzodiazepines have an anxiety-relieving effect and can therefore be used alongside behavioural therapy for anticipatory vomiting. However, they have a high dependence potential [3].

What else can people do to improve their symptoms?

  • Rest and relaxation: Some patients find relaxation exercises helpful. If nausea occurs, breathing in and out several times or fresh air can do good.
  • Acupressure for nausea: Some people get relief by pressing on a specific spot on the inside of the forearm.
  • Diet: It is not a good idea for cancer patients to force themselves to eat. It is best to eat according to appetite. Eating several small portions of food throughout the day is usually easier on the stomach than eating a few large portions. Ginger is an effective home remedy for nausea and, especially in the form of tea, can also help to adjust the fluid balance.
  • Drinking: Drinking plenty of fluids is important to compensate for the fluids lost during vomiting. Melissa tea is easy to digest and has a calming effect.
  • Oral care: Persistent vomiting not only causes an unpleasant taste in the mouth, but the stomach acid can also attack teeth and the mucous membranes of the mouth. The remedy is to rinse the mouth or brush the teeth [6].

Cannabinoids for nausea and vomiting during chemotherapy

Medical cannabis can alleviate some of the most common symptoms associated with cancer and its treatment. Many patients struggle not only with CINV, but also with loss of appetite, severe pain and other symptoms. Cannabinoids can therefore combat various symptoms and thus improve the quality of life of those affected. However, the current evidence for the different symptoms is very mixed [7].

Mechanism of action of THC and CBD against CINV

Both cannabidiol (CBD) and tetrahydrocannabinol (THC) relieve nausea and vomiting, especially during chemotherapy. These cannabinoids have the ability to inhibit serotonin release by enterochromaffin cells in the small intestine.

Although many studies have explored the effect of tetrahydrocannabinol in relation to nausea and vomiting, questions still remain. Since cannabidiol also has an antiemetic effect, but does not trigger any psychotropic effects, CBD is becoming the focus of research as an antiemetic [8].

Nabilone against CINV

Since 2017, nabilone capsules (Canemes ®) have been available in Germany for the treatment of therapy-resistant nausea and vomiting during chemotherapy. It has been approved in the USA since 1985. A controlled study of 38 people in 1986 demonstrated the superiority of nabilone over domperidone in relieving vomiting. Sufferers reported reduced nausea and increased appetite with nabilone. However, cannabinoid therapy was associated with more side effects [9].

Almost half of affected people report relief

In a 2015 review and meta-analysis, researchers analysed 79 randomised controlled trials on the use of medical cannabis for CINV and other conditions (chronic pain, appetite stimulation in HIV/AIDS, spasticity, Tourette’s syndrome, sleep disorders, psychosis, anxiety disorders, glaucoma). In total, the data of 6,462 patients were evaluated. Different cannabinoid drugs were used: cannabidiol, dronabinol, nabilone and Sativex®.

The results showed that when taking cannabinoids, 47 percent of the study participants experienced significant relief from nausea and vomiting. In the placebo group, only 20 percent of people reported improvement. However, taking cannabinoids was associated with an increased risk of temporary side effects, such as dizziness, dry mouth or drowsiness. The scientific team notes that the evidence base for CINV is currently weak. The evidence is better for chronic pain and spasticity [10][11].

83% of patients prefer THC/CBD on top of existing medication

A recent study from the University of Sydney is currently investigating the efficacy of a THC/CBD extract in capsule form in cancer patients with CINV who experience nausea and vomiting despite taking standard anti-emetic medication.

The 2020 study involved 81 cancer patients who had three consecutive cycles of chemotherapy. In the cannabinoid group, participants took THC/CBD capsules for six days in addition to standard therapy. The first use was the day before the first administration of the cancer drug. The placebo group took a placebo. In the next chemotherapy cycle, the groups were switched, which is why this study design is also called a cross-over study. In the third and last therapy cycle, the participants now had the choice between cannabinoid and placebo.

Eighty-three percent of those affected preferred the treatment with THC and CBD, although about one third complained of mild side effects. A quarter (25%) reported a significant reduction in their symptoms compared to 14 percent who took a placebo. To further investigate the effectiveness, the research team is planning another randomised controlled trial. This time, the 170 patients will receive either THC/CBD capsules or placebo over three cycles of chemotherapy [12].

Conclusion

The current studies show that cannabinoids can be an effective add-on therapy to established antiemetics. THC seems to be a strong anti-emetic and thus interesting especially in severe cases of CINV. CBD also seems to be effective against nausea. However, there is still a lot of research to be done, as the study situation is thin so far. Future research with larger numbers of people aims to compare cannabinoids with a placebo as an add-on therapy.

Sources:

[1]         Krebs in Deutschland für 2015/2016. 12. Ausgabe. Robert Koch-Institut (Hrsg) und die Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. (Hrsg). Berlin, 2019

[2]        The effect of guideline-consistent antiemetic therapy on chemotherapy-induced nausea and vomiting (CINV): the Pan European Emesis Registry (PEER) Aapro, M. et al. Annals of Oncology, Volume 23, Issue 8, 1986 – 1992

[3]        Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): Supportive Therapie bei onkologischen PatientInnen – Langversion 1.3, 2020, AWMF Registernummer: 032/054OL, https://www.leitlinienprogramm onkologie.de/leitlinien/supportive-therapie/

[4]        Braun T, Voland P, Kunz L, Prinz C, Gratzl M. Enterochromaffin cells of the human gut: sensors for spices and odorants. Gastroenterology. 2007 May;132(5):1890-901. doi: 10.1053/j.gastro.2007.02.036. Epub 2007 Feb 21. PMID: 17484882.

[5]        Overview of Chemotherapy-Induced Nausea and Vomiting and Evidence-Based Therapies October 2, 2017 Nelly Adel, PharmD, BCOP, BCPS Supplements and Featured Publications, Managed Care Considerations in Chemotherapy-Induced Nausea and Vomiting, Volume 23, Issue 14

[6]       Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): Supportive Therapie – Vorbeugung und Behandlung von Nebenwirkungen einer Krebsbehandlung – Patientenleitlinie, 2018 AWMF Registernummer: 032/054OL, https://www.leitlinienprogramm onkologie.de/leitlinien/supportive-therapie/

[7]        Kleckner AS, Kleckner IR, Kamen CS, Tejani MA, Janelsins MC, Morrow GR, Peppone LJ. Opportunities for cannabis in supportive care in cancer. Ther Adv Med Oncol. 2019 Aug 1;11:1758835919866362. doi: 10.1177/1758835919866362. PMID: 31413731; PMCID: PMC6676264.

[8]        Mortimer TL, Mabin T, Engelbrecht AM. Cannabinoids: the lows and the highs of chemotherapy-induced nausea and vomiting. Future Oncol. 2019 Mar;15(9):1035-1049. doi: 10.2217/fon-2018-0530. Epub 2019 Feb 5. PMID: 30720344.

[9]        Pomeroy, M., Fennelly, J.J. & Towers, M. Prospective randomized double-blind trial of nabilone versus domperidone in the treatment of cytotoxic-induced emesis. Cancer Chemother. Pharmacol. 17, 285–288 (1986). https://doi.org/10.1007/BF00256701

[10]      Sulcova A. Pharmacodynamics of cannabinoids. Arch Pharm Pharma Sci. 2019; 3: 011-018. DOI: 10.29328/journal.apps.1001013

[11]      Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015 Jun 23-30;313(24):2456-73. doi: 10.1001/jama.2015.6358. Erratum in: JAMA. 2015 Aug 4;314(5):520. Erratum in: JAMA. 2015 Aug 25;314(8):837. Erratum in: JAMA. 2015 Dec 1;314(21):2308. Erratum in: JAMA. 2016 Apr 12;315(14):1522. PMID: 26103030.

[12]      Grimison P, Mersiades A, Kirby A, Lintzeris N, Morton R, Haber P, Olver I, Walsh A, McGregor I, Cheung Y, Tognela A, Hahn C, Briscoe K, Aghmesheh M, Fox P, Abdi E, Clarke S, Della-Fiorentina S, Shannon J, Gedye C, Begbie S, Simes J, Stockler M. Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial. Ann Oncol. 2020 Nov;31(11):1553-1560. doi: 10.1016/j.annonc.2020.07.020. Epub 2020 Aug 13. PMID: 32801017.

[13]      Rock EM, Parker LA. Cannabinoids As Potential Treatment for Chemotherapy-Induced Nausea and Vomiting. Front Pharmacol. 2016;7:221. Published 2016 Jul 26. doi:10.3389/fphar.2016.00221

About Alexandra

Alexandra Latour verfügt über langjähre Erfahrungen als Autorin im medizinischen Bereich. Ab dem Jahr 2017 hat sie sich als Medical Writer auf das Thema Cannabis als Medizin spezialisiert und war für Leafly Deutschland tätig.

Leave a Reply

Your email address will not be published.