Some drugs with depressant properties on the peripheral nervous system have been examined for depressant effects on the reticular activating system of the cat. Large doses of nicotine, or of the anti-nicotinic agents dihydro-beta-erythroidine and mecamylamine, failed to depress the reticular activating system; non-quaternary drugs with anti-muscarinic properties, such as atropine and hyoscine, depressed it readily. Hyoscine was the most potent depressant tested and its effects could be antagonized by physostigmine. In contradistinction, depression of the reticular activating system with pentobarbitone was not antagonized by physostigmine. Lignocaine was a weak depressant of the reticular activating system, and the possibility that this might be due to a central anti-muscarinic action is discussed. Adrenergic blocking drugs, such as dihydroergotamine, phenoxybenzamine or choline 2:6-xylyl ether, did not appear to depress the reticular activating system: the significance of this is discussed. It was concluded that the hypothetical cholinergic transmitter, acting somewhere within the reticular activating system, displayed actions analogous to the muscarinic, and not to the nicotinic, actions of acetylcholine.