Mechanisms of Broad-Spectrum Antiemetic Efficacy of Cannabinoids against Chemotherapy-Induced Acute and Delayed Vomiting

Abstract

Chemotherapy-induced nausea and vomiting (CINV) is a complex pathophysiological condition and consists of two phases. The conventional CINV neurotransmitter hypothesis suggests that the immediate phase is mainly due to release of serotonin (5-HT) from the enterochromaffin cells in the gastrointestinal tract (GIT), while the delayed phase is a consequence of release of substance P (SP) in the brainstem. However, more recent findings argue against this simplistic neurotransmitter and anatomical view of CINV. Revision of the hypothesis advocates a more complex, differential and overlapping involvement of several emetic neurotransmitters/modulators (e.g. dopamine, serotonin, substance P, prostaglandins and related arachidonic acid derived metabolites) in both phases of emesis occurring concomitantly in the brainstem and in the GIT enteric nervous system (ENS) [1]. No single antiemetic is currently available to completely prevent both phases of CINV. The standard antiemetic regimens include a 5-HT3 antagonist plus dexamethasone for the prevention of acute emetic phase, combined with an NK1 receptor antagonist (e.g. aprepitant) for the delayed phase. Although NK1 antagonists behave in animals as broad-spectrum antiemetics against different emetogens including cisplatin-induced acute and delayed vomiting, by themselves they are not very effective against CINV in cancer patients. Cannabinoids such as Δ9-THC also behave as broad-spectrum antiemetics against diverse emetic stimuli as well as being effective against both phases of CINV in animals and patients. Potential side effects may limit the clinical utility of direct-acting cannabinoid agonists which could be avoided by the use of corresponding indirect-acting agonists. Cannabinoids (both phyto-derived and synthetic) behave as agonist antiemetics via the activation of cannabinoid CB1 receptors in both the brainstem and the ENS emetic loci. An endocannabinoid antiemetic tone may exist since inverse CB1 agonists (but not the corresponding silent antagonists) cause nausea and vomiting.

Cannabinoid Hyperemesis Syndrome: A Case Report of Cyclic Severe Hyperemesis and Abdominal Pain with Long-Term Cannabis Use

“…The antiemetic effect of cannabis is mediated by an activation of CB-1 receptors in the brainstem and the enteric nervous system [15]. We still lack understanding of how a paradoxical hyperemetic effect can develop in long-term users, although several hypotheses were established during the last years.…”

Klinischer Einsatz von Cannabinoiden

“…CINV ist ein komplexes Geschehen, das sowohl auf peripheren als auch auf zentralen Mechanismen beruht. Zu den involvierten Modulatoren und Neurotransmittern zählen Dopamin, Serotonin, Substanz P, Prostaglandine und andere Metaboliten des Arachidonsäurezyklus [5]. Serotonin ist dabei ein bedeutender Mediator der sofortigen Emesis, also innerhalb von 24 Stunden nach Applikation der Chemotherapie.…”

“…Bei der späten Emesis, also innerhalb von 2 -7 Tagen nach Chemotherapie, spielt vor allem Substanz P eine Rolle. Dementsprechend setzt sich das Standard-Behandlungsregime aus Kortikosteroiden und einem Serotonin-Rezeptor-Antagonisten für die frühe Phase der Emesis und einem Neurokinin-Rezeptor-Antagonisten für die späte Phase zusammen [5]. Die Wirksamkeit der Cannabinoide bei CINV wird unter anderem über zentrale CB1-Rezep-toren vermittelt, wobei proemetische Effekte unterbunden werden.…”

“…Die Wirksamkeit der Cannabinoide bei CINV wird unter anderem über zentrale CB1-Rezep-toren vermittelt, wobei proemetische Effekte unterbunden werden. Dies geschieht beispielsweise durch eine Verringerung der Freisetzung von Serotonin und Substanz P. Es wird vermutet, dass eine über periphere CB1-Rezeptoren vermittelte Reduktion der Magen-Darm-Peristaltik eine Rolle spielt [5,6].…”

The successful use of dronabinol for failure to thrive secondary to intestinal dysmotility

“…It is frequently used off-label for anorexia and nausea of other etiologies, but there is a dearth of literature supporting its efficacy in those settings. Its anti-emetic mechanism of action is not completely understood, although, it is thought to act both centrally and peripherally [13,14] . Data suggest that it may slow gastric emptying and increase colonic compliance in humans [15,16] .…”