Cesamet is a synthetic cannabinoid that is thought to trigger its effects by activating the endocannabinoid receptors, CB1 and CB2, which are present in the human body.^1-4 These receptors are involved in regulating nausea and vomiting. Because of this neuromodulation, the mechanism of action for Cesamet is significantly different from conventional antiemetics. Cesamet has a long duration of action, which allows for less frequent dosing, typically twice-daily.¹

Recent evidence suggests that Cesamet acts as a neuromodulator via agonist action on cannabinoid CB1 receptors,^3,5 which are ubiquitous in the central nervous system,^6,7 and serve to modulate neuronal signaling.⁵ Cesamet also acts as a CB2 agonist, primarily on immune cells in the periphery.^3,5 However, effective control of chemotherapy-induced nausea and vomiting occurs mainly through direct and selective activation of presynaptic CB1 receptors in the brain.^2,8-10 Exogenous cannabinoids (e.g., Cesamet) are thought to mimic or enhance the natural functions of the innate or endogenous cannabinoids,⁷ which act in reverse from classical neurotransmitters and serve as retrograde synaptic messengers.¹⁰

Neuromodulation in the Forebrain and Brainstem Emetic Circuitry May Underlie the Therapeutic Effects of Cesamet

Nausea and emesis (vomiting) are produced by excitation of one or a combination of triggers located in the gastrointestinal (GI) tract, brainstem, and higher cortical and limbic centers.⁸ The antiemetic action of Cesamet may be mediated by agonist action on CB1 receptors within the forebrain, causing inhibition of the brainstem emetic circuitry through descending connections, or within the brainstem emetic circuitry itself.¹³ Specific brain regions^8,9 implicated include:

• The dorsal vagal complex (DVC) in the brainstem emetic circuitry, and in particular, the nucleus of the solitary tract (NTS) within the DVC.⁸ The NTS receives information about blood-borne emetics (such as cytotoxic drugs) via chemosensitive neurons in the area postrema, known as the ‘chemoreceptor trigger zone.’⁸

• Higher cortical and limbic regions influence the brainstem emetic circuitry and can powerfully stimulate or suppress nausea and vomiting.¹⁴

Important Safety Information¹

Cesamet, a synthetic cannabinoid similar to the active ingredient found in naturally occurring Cannabis sativa L. [Marijuana; delta-9-tetrahydrocannabinol (delta-9-THC)], is contraindicated in any patient who has a history of hypersensitivity to any cannabinoid. Patients receiving treatment with Cesamet should be specifically warned not to drive, operate machinery, or engage in any hazardous activity while receiving Cesamet. During controlled clinical trials of Cesamet, virtually all patients experienced at least one adverse reaction. The most commonly encountered events were drowsiness, vertigo, dry mouth, euphoria (feeling “high”), ataxia, headache, and concentration difficulties. Cesamet should not be taken with alcohol, sedatives, hypnotics, or other psychoactive substances because these substances can potentiate the central nervous system (CNS) effects of nabilone. Since Cesamet can elevate supine and standing heart rates and cause postural hypotension, it should be used with caution in the elderly, and in patients with hypertension or heart disease. Cesamet should also be used with caution in patients with current or previous psychiatric disorders, (including manic depressive illness, depression, and schizophrenia) as the symptoms of these disease states may be unmasked by the use of cannabinoids. Cesamet should be used with caution in individuals receiving concomitant therapy with sedatives, hypnotics, or other psychoactive drugs because of the potential for additive or synergistic CNS effects. Cesamet should be used with caution in patients with a history of substance abuse, including alcohol abuse or dependence and marijuana use, since Cesamet contains a similar active compound to marijuana. Cesamet should be used with caution in pregnant patients, nursing mothers, or pediatric patients because it has not been studied in these patient populations.

References

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