Cannabis is of extraordinary cultural importance as it is the most commonly used illicit drug worldwide and ranks on the third place of recreational drugs behind alcohol and tobacco [9]. Every year about 130–230 million people use cannabis as a recreational drug [10] whereupon the percentage of legal and medical use is rising since a strong legalization movement has been established in people and governments of several countries over the last few years. It is therefore crucial to have solid evidence based information about all its possible health risks. There are many well explored short- and long-term side effects such as changes in mood, impaired memory, impaired attention, depression anxiety, and its correlation with schizophrenia [1, 2, 11].

The exact mechanisms of how and by which receptors the effects of THC are mediated in the human body are not yet completely understood. There are two main G-protein coupled receptors: the CB1 and CB2 receptor. The CB1 receptor is found in the central and peripheral nervous system, for example, in the hippocampus, the basal ganglia, and the cerebellum as well as in the enteric nervous system, and plays a neuromodulator role [12]. We know less about the CB2 receptor which is found primarily in immune cells and seems to have immunomodulatory effects [4, 13]. THC modulates the hypothalamus-pituitary axis by a diminution of secretion of anterior pituitary hormones like prolactin, growth hormone, thyroid hormone, or gonadotropin as well as an augmentation of corticotropin secretions [13]. These changes in the hypothalamus-pituitary-adrenal axis might also implicate changes in the thermoregulation. In a mouse model a decrease in body temperature has been described after the administration of THC [14] which might be an approach to a possible explanation of the compulsive bathing behavior in CHS patients.

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. THC is lipophilic and accumulates in body fat, which serves as a long-term storage and probably liberates THC due to lipolysis in times of food deprivation and stress [13]. This might be one of the key aspects in the development of the CHS considering that mostly long-term users are concerned. However, since only a very small percentage of long-term cannabis consumers develop a CHS we need to identify risk factors for the development. Galli et al. proposed that the genetic polymorphisms in the cytochrome P450 enzymes and resulting in these possible excessive levels of emetogenic cannabinoid metabolites might be the cause [13].

Another important aspect is the quality of THC as a partial agonist on cannabinoid CB1 receptors. In case of chronic use and high tissue concentrations the antagonist nature of THC may emerge and induce a sudden withdrawal [16]. A sudden cessation from prolonged cannabis use might induce hyperemesis as already stated by Allen et al. in 2004 [5]. A downregulation of receptor density and desensitization of transduction mechanisms (tolerance) which can rapidly develop in case of chronic use [17] can also induce the transformation of THC from a partial agonist to an antagonist on CB1 receptors.

Eventually THC delays gastric emptying through the CB1 receptors found on the gastrointestinal system [18]. This effect has proven to be resistant to the development of tolerance [19].

Given the high prevalence of chronic cannabis abuse we presume that the syndrome is often underdiagnosed or misdiagnosed as cyclic vomiting or psychogenic vomiting. Further studies are warranted to better understand the pathophysiology and to identify risk factors as well as to validate the diagnostic criteria. Meanwhile, clinicians must evoke this diagnosis to avoid extensive workup and sometimes even futile surgery. Many of these patients relapse upon resuming cannabis because of their perception that it will have beneficial effects on nausea. Patient education should therefore be provided with emphasis on the paradoxical nature of the symptoms of CHS.