Isaacs’ syndrome (IS) is an autoimmunological hyperexcitability syndrome of the peripheral motor nerves, manifesting with progressive muscle stiffness, involuntary continuous muscle twitching, muscle pain and cramping, sweating, and decreased reflexes. We report a 31-yearold man who was suffering from muscle twitches and stiffness in lower extremities and previously diagnosed with IS in his age of 16 through electrophysiological studies and the shown presence of autoantibodies against voltage-gated potassium channels. Without any adherence to the prescribed treatment, he had been using synthetic cannabinoids and opioids for 10 years. He admitted lessened complaints by using them. Current literature offered cannabinoid receptor agonists not only for symptomatic relief in IS, but also potential modulator effects on both potassium channels and autoimmunity. Opioids were also recognized with their analgesic and antispastic effects in the management of IS. This report aimed to discuss possible medicinal effects and therapeutic mechanisms of aforementioned psychoactive molecules on the symptomatology of IS.