Neuroleptic Malignant Syndrome (NMS) is a well‐known side effect of potentially all antipsychotics, as antagonism of dopamine receptors lead to drops in neurotransmitter activity within dopaminergic pathways. ¹ It has a textbook triad of fever, muscle rigidity, and altered mental status (AMS), but in clinical practice, the majority of cases actually present heterogeneously. ² Similarly, synthetic cannabinoids (SC) possess a widely varying drug profile, due to the vast number of derivatives sold. In recent years, SC have become increasingly popular due to their lower cost, easy obtainability and non‐detectability on traditional drug screens. ³ This is of increasing concern, due to their vastly more unpredictable, severe side‐effects compared to cannabis‐ zero fatalities have been seen with cannabis toxicity, while many have been reported due to SC. Psychiatrically, SC has been show to drastically exacerbate certain conditions including schizophrenia, anxiety, and bipolar disorder. For psychosis in particular, it has been shown that SC use serves as an agonist at cannabinoid type‐1 receptors in the brain, leading to acute increases in dopamine. ⁴

NMS and SC use can present very similarly, including increases in CPK, agitation, rigidity, altered mental status, fever etc. ¹ , ⁴ For our patient, both likely played a role but which contributed more? It is impossible to tell‐ the former is a clinical diagnosis while SC toxicity cannot be definitively measured. ⁴ Regardless, generalizable takeaways can be made. All patients who require antipsychotics (for bipolar disorder, psychosis etc.) should be screened for concurrent SC use. SC use can precipitate muscle injury, leading to elevations in CPK and consequently rhabdomyolysis. We posit this may lead to lowering the threshold for developing NMS following antipsychotic usage, but even if it does not, combining both will almost certainly lead to worse muscle injury. ⁵ Instead, benzodiazepines and non‐dopamine acting drugs should be used unless otherwise necessary. Furthermore, for patients who use synthetic cannabinoids, physical restraints should be minimized, as immobilization drastically increases risk of muscle injury. Both of these points are currently not well‐emphasized in the existing literature, but our experience managing patients who present with SC use in an urban, inner‐city hospital points towards this being especially important. Many of our patients who present following SC use have acute psychiatric symptoms (aggression, agitation, altered mental status etc.) that require sedation for both their own safety and that of our staff. Choosing the correct form of management is key to reducing their length of stay and morbidity/mortality. We believe that the increasing ubiquity of synthetic cannabinoids, combined with their potential for adverse reactions with existing medications, highlights the need for further molecular research in this area.