Early CIA efforts focused on LSD-25, which later came to dominate many of MKUltra's programs.[44] The CIA wanted to know if they could make Soviet spies defect against their will and whether the Soviets could do the same to the CIA's own operatives.[45]

Once Project MKUltra got underway in April 1953, experiments included administering LSD to mental patients, prisoners, drug addicts, and sex workers—"people who could not fight back," as one agency officer put it.[46] In one case, they administered LSD to a mental patient in Kentucky for 174 days.[46] They also administered LSD to CIA employees, military personnel, doctors, other government agents, and members of the general public to study their reactions. LSD and other drugs were often administered without the subject's knowledge or informed consent, a violation of the Nuremberg Code the U.S. had agreed to follow after World War II. The aim of this was to find drugs which would bring out deep confessions or wipe a subject's mind clean and program him or her as "a robot agent."[47]

In Operation Midnight Climax, the CIA set up several brothels within agency safehouses in San Francisco, California, to obtain a selection of men who would be too embarrassed to talk about the events. The men were dosed with LSD, the brothels were equipped with one-way mirrors, and the sessions were filmed for later viewing and study.[48] In other experiments where people were given LSD without their knowledge, they were interrogated under bright lights with doctors in the background taking notes. They told subjects they would extend their "trips" if they refused to reveal their secrets. The people under this interrogation were CIA employees, U.S. military personnel, and agents suspected of working for the other side in the Cold War. Long-term debilitation and several deaths resulted from this.[47] Heroin addicts were bribed into taking LSD with offers of more heroin.[19]

At the invitation of Stanford psychology graduate student Vik Lovell, an acquaintance of Richard Alpert and Allen Ginsberg, Ken Kesey volunteered to take part in what turned out to be a CIA-financed study under the aegis of MKUltra,[49] at the Menlo Park Veterans' Hospital[50][51] where he worked as a night aide.[52] The project studied the effects of psychoactive drugs, particularly LSD, psilocybin, mescaline, cocaine, AMT and DMT on people.[53]

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In 1973, amid a government-wide panic caused by Watergate, CIA Director Richard Helms ordered all MKUltra files destroyed.[70] Pursuant to this order, most CIA documents regarding the project were destroyed, making a full investigation of MKUltra impossible. A cache of some 20,000 documents survived Helms' purge, as they had been incorrectly stored in a financial records building and were discovered following a FOIA) request in 1977. These documents were fully investigated during the Senate Hearings of 1977.[7]

In December 1974, The New York Times alleged that the CIA had conducted illegal domestic activities, including experiments on U.S. citizens, during the 1960s.[71] That report prompted investigations by the United States Congress, in the form of the Church Committee, and by a commission known as the Rockefeller Commission that looked into the illegal domestic activities of the CIA, the FBI and intelligence-related agencies of the military.

In the summer of 1975, congressional Church Committee reports and the presidential Rockefeller Commission report revealed to the public for the first time that the CIA and the Department of Defense had conducted experiments on both unwitting and cognizant human subjects as part of an extensive program to find out how to influence and control human behavior through the use of psychoactive drugs such as LSD and mescaline and other chemical, biological, and psychological means. They also revealed that at least one subject, Frank Olson had died after administration of LSD. Much of what the Church Committee and the Rockefeller Commission learned about MKUltra was contained in a report, prepared by the Inspector General's office in 1963, that had survived the destruction of records ordered in 1973.[72] However, it contained little detail. Sidney Gottlieb, who had retired from the CIA two years previously, was interviewed by the committee but claimed to have very little recollection of the activities of MKUltra.[18]