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Posterior reversible encephalopathy syndrome (PRES) is a neurovascular sequence聽noted in patients with preeclampsia/eclampsia, solid-organ/bone marrow transplantation, and malignant hypertension. The mechanism in which PRES occurs has not yet been determined. It has been hypothesized that it may be related to endothelial cell dysfunction or injury leading to the compromise of the blood-brain barrier. The clinical presentations vary but are similar to symptoms of increased intracranial pressure, such as headache, visual changes, focal neurological deficits, seizures, and altered mental status. Although the pathology suggests reversibility, that is not always the case in which severe ischemic damage has occurred. We present a patient who came to the emergency room with a history of substance abuse and聽tested positive on a urinary toxicology screen for methamphetamine and cocaine. In the US, polysubstance use has been more prevalent in recent years. Furthermore, literature has highlighted the additive effects on one's blood pressure when such drugs are combined. Our patient presented with altered mental status, hypertension, and pinpoint pupils. Over the course of her stay, the patient's mentation slowly improved聽and was able to follow commands intermittently. We believe that this is the first documented case of polysubstance abuse in correlation to PRES. We hypothesize that the mechanism of PRES resulted from the multiplicative effect of several illicit drugs known to cause transient hypertensive episodes and their ability to disrupt the structural proteins imperative for the blood-brain barrier.