While practicing in Hartford, Conn., in 1844, Wells noted the pain-killing properties of nitrous oxide (“laughing gas”) during a laughing-gas road show and thereafter used it in performing painless dental operations. He was allowed to demonstrate the method at the Massachusetts General Hospital in January 1845, but when the patient proved unresponsive to the gas, Wells was exposed to ridicule.

After William Morton, a dental surgeon and Wells's former partner, successfully demonstrated ether anesthesia in October 1846, Wells began extensive self-experimentation with nitrous oxide, ether, chloroform, and other chemicals to ascertain their comparative anesthetic properties. His personality radically altered by frequent inhalation of chemical vapours, he was jailed in New York City for throwing acid at passersby. There, in a jail cell, he took his own life while the Paris Medical Society was publicly acclaiming him the discoverer of anesthetic gases.