Synthetic cannabinoids are heterogeneous biological compounds that act in binding to cannabinoid receptors of psychoactive substrates with a high potency [7,8]. Endocannabinoids are a compound modularity system that is responsible for cell response to various intrinsic and extrinsic stimulants through a complex cascade of gene expression, receptor activation, and enzyme reactions [8]. Exposure to cannabinoids in either synthetic or organic form is associated with physical and psychological factors [8]. Rhabdomyolysis is a disorder that is characterized by muscle injury resulting in the leakage of intracellular myocytes into the extracellular space [9]. The etiology is associated with several factors, including trauma, infection, muscle ischemia, dehydration, exercise, heat stroke, and drug intoxication (cannabinoids, heroin, and cocaine) [7,10]. Drug-induced rhabdomyolysis is divided into primary and secondary myotoxic effects [10]. Rhabdomyolysis usually presents with a wide variety of clinical features ranging from muscle weakness to life-threatening acute renal failure [3]. The classical triad includes skeletal muscle injury, dark urine, and renal dysfunction [10]. However, in drug-induced rhabdomyolysis, subclinical features can present without common features [10]. Studies showed that drugs are the most frequent causative agents, reaching 81% of cases [11].

The pathophysiology of cannabinoids-induced rhabdomyolysis is poorly understood [1]. However, studies suggest that the effect of synthetic cannabinoids is carried out through two receptors, CB1 and CB2. The CB1 receptors are considered the responsive form of the cannabinoid component that activates G-protein coupled receptors in the presynaptic terminal, decreasing the cellular cyclic adenosine monophosphate (cAMP) levels and eliciting a cannabimimetic response [12]. CB2 mainly controls the release of cytokine and the migration of immune cells [12]. However, the binding affinity is greater in CB1 in comparison to CB2 [13]. The impairment in the production of endocannabinoids can dysregulate the CB1 receptor and their signaling pathways, contributing to the irreversible degeneration of skeletal muscle tissue [8]. Another mechanism is the dysregulation of Krebs cycle activation in the mitochondrial membrane, altering the glucose and fatty acid metabolism and affecting the skeletal muscle fibers [8]. Studies also showed that metabolites such as the inhibition of gamma-aminobutyric acid can relatively increase creatinine kinase (CK) levels and result in kidney failure, which can subsequently manifest in the development of rhabdomyolysis [14]. Ronco et al. showed that conventional dialysis techniques can limit the capacity of removing myoglobin from circulation because of molecular properties, solute transport mechanisms, or extracorporeal technical difficulties [14]. Amanollahi et al. reported a study in Iran showed that among 227 poisoned individuals, almost 75.8% of those affected were men. The reason behind this is that women have a higher mitochondrial mass in the skeletal muscle with a greater oxidative phosphorylative capacity, and therefore, greater protection against rhabdomyolysis [7].

Cannabinoids-induced rhabdomyolysis is a diagnosis of exclusion. Furthermore, establishing a high index of suspicion is essential for early identification through a detailed history, clinical evaluation, and laboratory investigations, including negative universal drug screens [1,6]. The management of such cases includes continuous elimination of the exposed drug, infusion of intravenous normal saline early, sufficient volume replenishment, and electrolyte correction. The goal is to cease muscle destruction, resolve metabolic and electrolyte abnormalities, and preserve renal function [5,10]. Paul et al. reported two cases who presented with nausea, vomiting, and generalized fatigue and had elevated CK of 47,000 and 37,000 U/L, respectively. The diagnosis of rhabdomyolysis was made. Accordingly, the patients underwent aggressive hydration and forced diuretics followed by hemodialysis [1]. Strain et al. reported a 26-year-old who presented with weakness and severe muscle pain after exercise, which was suggestive of rhabdomyolysis. Accordingly, the patient underwent aggressive hydration with normal saline [5]. Another study by Adedinsewo et al. reported on patients who ingested cannabinoids and presented with seizures, agitation, and bizarre behavior (Table 3) [6]. In our case, the patient had increased serum CK levels with decreased urine output postoperatively, and it was discovered that he was administering synthetic THC cannabinoids and was intoxicated, which led to the development of rhabdomyolysis. Accordingly, he received aggressive hydration therapy with normal saline and underwent continuous renal replacement therapy (CRRT) and then was shifted to hemodialysis where his creatinine kinase, myoglobin creatinine, and urine output gradually improved.