Operation Midnight Climax was a Central Intelligence Agency (CIA) sub-project of the illegal Project MKUltra, the CIA mind-control research program that began in the 1950s. It was initially established in 1954 by Sidney Gottlieb and placed under the direction of the Federal Bureau of Narcotics in Boston, Massachusetts with the "Federal Narcotics Agent and CIA consultant" George Hunter White under the pseudonym of Morgan Hall.

Gottlieb was a chemist who was chief of the Chemical Division of the Office of Technical Service of the CIA. He based his plan for MKUltra and Midnight Climax on interrogation method research under Project Artichoke. Unlike Artichoke, Midnight Climax gave Gottlieb permission to test drugs on unknowing citizens, which created the infamous legacy of this operation. Hundreds of federal agents, field operatives, and scientists worked on these programs before they were shut down in the 1960s.

Official results of these experiments were not released, and accounts from supervisors of the experiments give little insight to the findings. George Hunter White, an agent at the Federal Bureau of Narcotics, and Ira "Ike" Feldman, a former military intelligence officer, who oversaw San Francisco experiments, noticed that subjects spoke far more freely when under the influence of a combination of drugs and sex. "No one knows where they [human test subjects] are now, or what effects they may have suffered."

Operation Midnight Climax was launched in 1954 and consisted of a web of CIA-run safehouses in San Francisco at 225c Chestnut Street, San Francisco, CA, in Mill Valley, California, as well as New York City. The safehouses were dramatically scaled back in 1963, following a report by CIA Inspector General John Earman which strongly recommended closing the facility. The San Francisco safehouses were closed in 1965, and the New York City safehouse soon followed in 1966. Operation Midnight Climax and Project MKUltra were considered to be so secretive that few people, even in the highest government positions, knew about Sidney Gottlieb or his connection to the LSD used in the operation.

Operation Midnight Climax was established in order to study the effects of LSD on non-consenting individuals. Prostitutes on the CIA payroll were instructed to lure clients back to the safehouses, where they were surreptitiously plied with a wide range of substances, including LSD, and monitored behind one-way glass. The prostitutes were instructed in the use of post-coital questioning to investigate whether the victims could be convinced to involuntarily reveal secrets. The victims were sometimes fed subliminal messages in attempts to induce them to involuntary actions, including criminal activity such as robbery, assault, and assassination. Many of the CIA operatives involved in the experiments voluntarily indulged in the drugs and prostitutes for recreational purposes. Additionally, information from Wilmington News Journal on October 15, 1978, reports from a FOIA request that, "the spy agency purchased two pounds of Yohimbine hydrochloride... by Dr. Robert V. Lashbrook, the chief aide to Dr. Sidney Gottlieb." The role of Dr. Lashbrook was to, "monitor and approve materials for Operation Midnight Climax."

Senate investigators were told that the goals of these experiments were to study mind control and sexual behavior. More specifically, to learn about the secrets of brainwashing to gain control over enemy spies and protect U.S. agents. Other objectives included finding drugs that could incapacitate entire buildings via poisoned food, which would create "confusion-anxiety-fear," and other symptoms such as headaches and earaches. These drugs could also have amnesia effects, which were intended for use on foreign spies following interrogations and retiring CIA agents. Another aspect they tested was the effect of combining LSD and isolation, where the subjects would be dosed and isolated for months at a time with minimal food and water.

In 1947, the CIA was prohibited on behalf of President Truman, due to fears of political abuse, from spying against American citizens, but these actions contradict the adherence to this prohibition. These acts were illegal and several significant operational techniques were developed in this theater, including extensive research into sexual blackmail, surveillance technology and the possible use of mind-altering drugs in field operations. Furthermore, the CIA operatives in charge of administering these experiments were told by superiors that the results of the experiments would be beneficial to the country. There is currently^[when?] a debate over how ethical White's actions were, with some arguing that if his motive was to legally make people suffer, he was unethical, while others argue that if he believed that the experiments would benefit national security, his actions could be justified. The subjects of Gottlieb's experiments also included mentally disabled children. Operation Midnight Climax was soon expanded, and CIA operatives began dosing people in restaurants, bars, and beaches along with signing up to use the drugs themselves. The extent to which this widespread exposure of the public to mind-altering drugs contributed to the rise of the counter-culture movement in the late 1950s and 1960s is unknown, although Ken Kesey has attributed his role in the genesis of the influential San Francisco Bay Area psychedelic social scene that developed in the 1960s to his participation in Project MKUltra LSD experiments at the Menlo Park, California, VA Hospital.

In 1974, The New York Times journalist Seymour Hersh published a story exposing the CIA's illegal spying on U.S. citizens and how the CIA had conducted non-consensual drug experiments. His report started the lengthy process of bringing long-suppressed details about MKUltra to light. Project MKUltra came to light in the spring of 1977 during a wide-ranging survey of the CIA's Technical Services Division. John K. Vance, a member of the CIA inspector general's staff, discovered that the agency was running a research project that included administering LSD and other drugs to unwilling human subjects. Additionally, several CIA FOIA requests revealed a collection of documents from several news sources in the late 1970s reporting information on Operation Midnight Climax.