Synthetic Cannabinoids are a street drug that is widely attainable and cheap compared to natural cannabis, and has variable potency and unpredictable effects with no commercially available diagnostic test to confirm its presence. Similar to natural cannabis, Synthetic Cannabinoid intoxication can present in several ways with the most common emergency room presentations to be of neurologic and psychiatric manifestation. The respiratory depressive effect of Synthetic Cannabinoids has not been well documented in medical literature. We report four patients admitted in the Intensive Care Unit with acute respiratory failure necessitating endotracheal intubation after use of Synthetic Cannabinoid. All patients had a reversal of respiratory failure in less than 24 h, three patients had a complicated course due to aspiration pneumonia. All four patients exhibited aggressive behavior, with two of them diagnosed with Bipolar Disorder and Cocaine Use Disorder. The effect of Synthetic Cannabinoids in peripheral receptors such as chemoreceptors and baroreceptors can increase bronchial airway resistance. It is postulated that CB1 receptor stimulation could be one of the possible mechanisms of synthetic cannabinoid-induced respiratory depression. Chemical gases released after its inhalation may also cause damage to the bronchiolar epithelium and has the potential to disrupt the protective surfactant layer in the alveoli, which then could interfere with effective gas exchange leading to hypoxia and acidosis. The stimulation of CB1 receptors have a series of downstream signaling effects in the G protein-coupled pathway and mitogen-activated protein kinase (MAPK) pathway, causing suppression of both excitatory and inhibitory neuronal activity. The aforementioned molecular changes in the central nervous system after CB1 receptor stimulation could impact respiration. The use of Synthetic Cannabinoids can cause respiratory depression in individuals without an underlying pulmonary disease and adds to the growing number of literature about the presentation and debilitating adverse events from its consumption. Although there is no specific toxidrome associated with it, clinicians should have a high index of suspicion with its use especially in patients presenting with a history of drug overdose.