Introduction: As cannabis use continues to increase in popularity, it is important to investigate how it impacts public health in all sectors of the population, including patients undergoing anesthetic management. This retrospective study focuses on the orthopedic trauma population presenting through an emergency department (ED) and receiving a urine drug screen (UDS) with subsequent urgent surgical intervention. We aimed to evaluate differences in response to general anesthesia in patients with exposure to THC, a major cannabinoid, compared to controls that screened negative for THC. Materials and Methods: All ED visits at UC Irvine, a level 1 trauma center between November 4, 2017 and January 7, 2020, were evaluated in this study. Only adult patients who received a UDS and underwent urgent orthopedic trauma surgery within 48 h of ED visit were included in this study. Additional inclusion criteria required an anesthesia time greater than 1 h as well as anesthesia induction and intubation while in the operating room. Overall, we analyzed a total of 221 adult patients. Discussion: When adjusting for demographic variability, there were statistically significant differences in response to general anesthesia between these two groups. The THC-positive (THC(+)) group was less likely to receive intraoperative vasopressors, had higher mean arterial blood pressure and mean diastolic blood pressure, needed less total fluid input and had a lower overall fluid balance. Chronic exposure to THC has been shown to downregulate cannabinoid 1 receptors and cause alterations in endocannabinoid tone. These are two potential mechanisms by which the THC(+) group in our study may have become more resistant to the typically observed hypotensive effects of general anesthesia. Conclusion: The present study suggests that prior use of cannabis, objectively assessed by urinalysis, results in a decreased need for blood pressure support during general anesthesia. The physiological basis for this phenomenon is unclear, but possible causes might include the downregulation of vascular cannabinoid receptor 1 and/or altered endocannabinoid levels after exposure to cannabis.