Dole had suffered from complications of a ruptured aorta, family members said.
A clinician at The Rockefeller University, Dole studied a wide range of human biological processes. But it was his pioneering work with methadone that earned the highest accolades.
In 1964, Dole and research partner Dr. Marie Nyswander experimented with shifting addicts from crippling drugs like heroin and morphine to methadone, a synthetic drug far less damaging to the body.
At the time, methadone was known predominantly as a painkiller. First synthesized in the late 1930s, it wasn't widely used because it was highly addictive.
Dole and Nyswander, however, noted that methadone didn't disable its users like heroin or morphine. Methadone satisfied the physical cravings of addiction but didn't make users high or subject them to violent mood swings.
Their studies suggested that addicts could be put on "maintenance" doses of methadone — meaning they would remain physically dependent on the drug but be able to conduct otherwise normal lives. Those findings sparked the creation of hundreds of methadone programs worldwide.
Jules Hirsch, a professor emeritus at Rockefeller who worked with Dole for nearly 50 years, said the research also fostered thinking that drug addiction should be treated as a medical problem, rather than a purely moral one.
Methadone's addictive properties made it a controversial treatment, up to the present day. As recently as 1998, New York Mayor Rudolph Giuliani threatened to do away with city-funded methadone maintenance programs in the city where Dole helped invent them, saying patients were better off abstaining from all drugs.
Hirsch said Dole was always surprised at how methadone persisted as a political issue.
"I think he was sort of perplexed by it, because he saw some of the plain logic of helping people in distress," Hirsch said.
Born in Chicago in 1913, Dole earned degrees from Stanford and Harvard universities before joining the Rockefeller Institute for Medical Research in 1941. During World War II, he was a lieutenant commander at the Naval Medical Research Unit at The Rockefeller Hospital. Nyswander, who became Dole's second wife, died in 1986.
Dole's survivors include his wife, Margaret Dole; three children; and four stepchildren.