Numerous food and drug combinations, also ‘legal highs’, may precipitate serotonin syndrome, yet it appears to be rarely diagnosed. This may be explained by diagnostic overshadowing when physical symptoms are misattributed to mental illness. Some symptoms of serotonin syndrome (agitation, tremor and rigidity) overlap with presentations in mental illness. Diagnostic confusion may occur in patients receiving polypharmacy, those receiving medications with previously unknown serotonergic properties or where unforeseen drug interactions occur. Acute medical presentations with hyperthermia and clonus should prompt holistic review to exclude other possible aetiologies. Discontinuation of the suspected agent may avert an array of possible serious outcomes.