This is, to our knowledge, the first study specifically dealing with the GI symptoms of SC use in an acute setting. Among symptomatic SC users presenting to the ED, 38% had GI manifestations and abdominal pain was reported by of those with GI symptoms. Still, the clinical presentation, laboratory results, and imaging findings ranged in severity among these patients. Most patients had only mild abdominal pain, while others had severe elevations of serum lactate with one patient having suffered an intestinal perforation. Nevertheless, the vast majority of patients (20/21) had a complete resolution of abdominal pain and normalization of serum lactate levels within a few hours of presentation.

When comparing the differences between the patients with GI symptoms and those without, there were no statistically significant differences in their prognoses, clinical severity, or laboratory values. Lack of significant difference may have been due to their low numbers. However, the patients with GI manifestations had higher lactate levels likely caused by the intestinal involvement and more patients with severe leukocytosis. The mechanism causing the varied effects of SC on the GI tract is unclear, but may be related to a previously reported effect of THC and cannabidiol on CBr1 and CBr2, which influence GI function, motility, and sensation [14, 16]. Our study suggests that SC GI symptoms are unpredictable and can vary from minimal, or no symptoms to intestinal perforation and death [15]. This varied GI response to SC may be due to the varying potency of SC, especially with the development of new ultra-potent SC that may impact the GI tract more than regular cannabis [17]. Others have suggested that the variability of SC on the GI tract may be due to adulterants added to the compounds (such as caffeine, nicotine, and tramadol), which can contribute to clinical effects and toxicity [18, 19].

An additional proposed mechanism of SC induced GI symptoms may involve vascular spasm. SC have been shown to rapidly alter neurotransmitter release from nerve terminals, thereby potently activating vascular smooth muscle cells, potentially resulting in vascular spasm. Rose et al. reported two cases of subarachnoid hemorrhage following SC consumption and used digital subtraction angiography to confirm transient vasospasm [20]. Moreover, Mir et al. reported two patients with ST-elevation MI following SC use with subsequent normal coronary angiography [21]. These reports imply that SC causes vasospasm in other organs without solid evidence regarding the GI tract. The low proportion of abnormal imaging in patients with severe abdominal pain, as in our study, supports the vasospasm hypothesis as vasospasm is reversible, and no vascular pathological findings were demonstrated. This assumption is less established and controversial.

Currently, with the increasing prevalence of cannabis use by the public, there is extensive awareness among clinicians of the GI symptoms related to cannabis use, including abdominal pain and vomiting [22]. However, SC related GI symptoms have been less frequently discussed. Nausea and vomiting and abdominal pain are frequent features of SC presentations [7, 23]. Treatment is mostly symptomatic, and involves intravenous hydration, and the use of anti-emetics [13, 24]. In other cases, treatment requires the use of sedatives and antipsychotics [13] The lack of identifiable SC in the toxicology screening in routine use make the diagnosis of SC related GI symptoms difficult.

One limitation of our study is a lack of diagnostic serum and urine analytical studies to diagnose objective SC use, a challenge noted in many SC cohorts. As in many hospitals, the availability of gas chromatography and mass spectrometry testing in the acute setting is lacking, and similar to other studies in this field. We currently rely on patient and/or family reported history. A second limitation of our study is that patients presenting with SC use often have a concomitant drug intoxication, such as amphetamines and cannabis, which can also impact GI symptoms in a similar manner although not in the same rates of GI involvement compared to SC. A third limitation is the lack of autopsy and post mortem imaging aside from one post mortem CT. Notwithstanding these limitations, we present the first cohort of patients presenting with various GI symptoms and SC use in the acute setting. This can help to raise awareness and potentially guide future studies to evaluate the mechanisms of SC GI involvement, including the hypothesis that transient arterial vasospasm causes the acute GI symptoms. GI consequences occurring with SC use are often short-lived and resolve quickly, although in certain instances these can be life-threatening (e.g. intestinal perforation; as demonstrated by one case in this cohort).

Our findings have a number of implications on the treatment of SC related intoxication. First, they emphasize that awareness of the breadth of clinical presentations and GI signs/symptoms common to SC intoxication is important for healthcare providers treating these patients. This is particularly important when practicing in areas where there is a high prevalence of SC use. As SC use is not associated with a well-defined toxidrome, some clinicians are less confident in managing their acute toxicity [25]. Second, clinicians should be aware of the range, and dynamic nature of SC related GI manifestations. Initial bouts of abdominal pain, nausea and emesis could well develop into fatal mesenteric ischemia, which necessitates surgical intervention. Although SC toxicity appears to be involved in the suppression of symptoms of intestinal ischemia or may even exacerbate existing ischemia, it is not possible with current evidence to ascertain that it is the cause of ischemia. However, the fact that our study did not demonstrate significant differences in GI involved biomarkers and non-GI involved cases of SC consumption suggests that clinicians should be overtly attentive to the challenge of identifying at-risk patients. Hence, our study may aid in helping recognize further complications of SC use to facilitate the diagnosis of intoxications, and their treatment.

Better analytical testing and drug confirmation techniques are needed along with prevention of SC use via counseling in at-risk populations is vital to reduce public health implications and morbidity from SC use.