Participants with acute motion sickness did not only show low endocannabinoid signaling, they also demonstrated a massive activation of the hypothalamic-pituitary-adrenal axis. Although one could assume that HPA-axis activation under the conditions of acute motion sickness is simply a non-specific reaction to stress, there is increasing evidence that endocannabinoids provide a tonic and highly specific feedback to control HPA-axis activity. These effects may occur both at a peripheral as well as on a central level where it has been shown that the ECS is a negative regulator of the HPA-axis and that the Tenuifolin levels of 2-AG in the hypothalamus regulate the corticosterone response to stress. In particular, high levels of 2-AG dampen HPA-axis activity whereas a stress associated decline in 2-AG levels reduced activation of CB1-receptors resulting in increased HPA-axis activity. These findings from animal experiments remarkably resemble our observations in humans and give further evidence that a failure to up-regulate and to maintain endocannabinoid signaling during kinetic stimulation may result in both, an increased risk for the development of motion sickness with N&V and a pronounced stress response. An impairment in endocannabinoid signaling may therefore be an important link between stress responsiveness and the development of motion sickness and could represent a neurobiologic mechanism leading to this common disorder. Our findings also suggest that pharmacologic enhancement of endocannabinoid signaling may represent an alternative prophylactic or therapeutic approach for motion sickness in patients who do not respond to currently available treatments. All cells have the capacity to make appropriate Schisandrin-C responses to signals perceived from their environment. Mitogen-activated protein kinases coordinate and execute cellular responses to environmental signals. Upon activation by upstream cues, MAP kinases typically enter the nucleus and activate transcription factors to initiate new gene transcription that is required to execute a sequence of events specified by the cues.