In contrast to general intensive care units, the neurosciences ICU admits fewer cases of incidental overdoses with illicit or prescribed drugs than cases of adverse drug effects. Overdoses of illicit drugs can be seen in conjunction with traumatic brain injury and anoxic-ischemic injury. In fact, the illegal drug is often the main culprit in the acute brain injury. Alcohol intoxication remains frequent and the intoxication signs depressing brain function may merge with clinical signs of an acute structural brain injury. This chapter discusses toxins causing laboratory abnormalities, first treatment considerations, and antidotes, including commonly used drugs for detoxification. When available, antidotes for toxidromes are provided. The chapter also summarizes the neurology of drug overdose.