Ware et al for Supportive Care in Cancer (MASCC), reﬂect the efﬁcacy of aprepitant for prevention of delayed CINV due to highly emetogenic chemotherapy, recommending its use with a cor- ticosteroid and against the use of 5-HT3 receptor antagonists for this purpose (Gralla 2005; Kris et al 2006). Despite the augmentation of antiemetic activity provided by aprepitant, a substantial proportion of patients receiving ﬁrst-line therapy continue to experience persistent delayed CINV. Poli-Bigelli and colleagues reported their efﬁcacy ﬁndings from a clinical trial involving 523 evaluable subjects who were receiving high-dose cisplatin-based chemotherapy (Poli-Bigelli et al 2005). Compared with standard therapy (5-HT3 receptor antagonist and a corticosteroid), the aprepitant-containing regimen (combined with a 5-HT3 receptor antagonist and a corticosteroid) was signiﬁcantly (p 0.001) more effective in achieving complete control, deﬁned as no emesis and no rescue therapy. The investigators’ secondary analyses revealed persistent delayed nausea in nearly half (47%) of the patients, however, and signiﬁcant delayed nausea in more than one of every four patients. Delayed emesis occurred in 28% of patients. Overall, total control was documented in less than half (44%) of patients. Anticipatory nausea and vomiting also represents a sig- niﬁcant problem among cancer patients undergoing chemo- therapy. Although the etiology is likely to be multifactorial, one major cause is thought to be classic or Pavlovian con- ditioning (Stockhorst et al 1993) due to incomplete control of post-treatment nausea (Morrow et al 1998). Anticipatory nausea occurs in 29% of chemotherapy patients, and antici- patory vomiting occurs in 11% of patients about to undergo chemotherapy (Morrow et al 1998; Roscoe et al 2000). Despite improvements in overall CINV with the introduc- tion of 5-HT3 receptor antagonist medications, the incidence of anticipatory nausea and vomiting has remained the same (Morrow et al 1998). The high prevalence of CINV in cancer patients receiving chemotherapy, the burden imposed on patients, and the failure of ﬁrst-line and conventional antiemetic therapies to provide adequate control of nausea and vomiting, particularly delayed events, indicate an ongoing need for additional treatment options. Combining agents with different mechanisms of action (MOA) may be the optimal approach to management of CINV (National Cancer Institute 2006). The use of cannabis to self-treat CINV has been known for several years (Vinciguerra et al 1988), and with recent improvements in our understanding of the physiology underlying cannabis effects, renewed efforts are underway to identify safe and effective pharmaceutical cannabinoids. 100 A recent systematic review found evidence that cannabinoids were a rational option for CINV (Tramér et al 2001). This paper examines the clinical evidence for nabilone, a synthetic cannabinoid recently approved in the United States for the treatment of CINV. Scientiﬁc rationale for the use of the cannabinoids in CINV Since the definitive identification of cannabinoid (CB) receptors in humans, a better understanding of the science behind the effects of exogenous cannabinoids has emerged. Two CB receptors have been identiﬁed in humans (CB1 and CB2) which are recognized exclusively by cannabinoids. (Howlett et al 2002; Martin and Wiley 2004). The CB1 receptor is present in high densities in areas of the central nervous system (CNS), and it is the interaction between nabilone and this receptor and its signaling pathways that appears to be responsible for the antiemetic effects of the agent. Endocannabinoids – endogenous cannabinoid ligands that act on CB receptors – exert complex effects, including the modulation of neurotransmitters known to be involved in CINV (Howlett et al 2002; Martin and Wiley 2004). More speciﬁcally, endocannabinoids activate the pre-synaptic CB1 receptor, inhibiting release of both excitatory and inhibitory neurotransmitters in the CNS and peripheral nervous sys- tem (ie, glutamate and gamma aminobutyric acid [GABA], respectively) (Schlicker and Kathmann 2001; Howlett et al 2002). The effect of endocannabinoids is not solely inhibi- tory in nature; however, as an initial inhibitory effect may trigger increased release of neurotransmitters further along the pathway, thus inhibitory and excitatory effects may be observed. The antiemetic effects of the endocannabinoid system appear to be produced by a multi-step process in which the CB1 ligands act as retrograde synaptic messengers (Diana and Mart 2004). In this “reverse signaling” process, neurotransmitters released from the pre-synaptic neuron activate the post-synaptic receptors. In turn, the activated post-synaptic neuron releases endocannabinoids such as anandamide (Freund et al 2003; Navari 2003; Piomelli 2003) These endogenous CB1 ligands then diffuse back and bind to the pre-synaptic CB1 receptor (Piomelli 2003). Binding of endocannabinoids to the CB1 receptor results in activation of a G-protein leading to a reduction of neurotransmitter release, a process known as depolarization-induced suppression of inhibition (DSI) (Freund et al 2003; Diana and Mart 2004) Several neurotransmitters mediate nausea and vomit- ing, including serotonin, dopamine, GABA, glutamate, Therapeutics and Clinical Risk Management 2008:4(1)