Psychedelic drug

• 1. Introduction

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  Psychedelic drugs have shaped medicine, culture, and human consciousness for thousands of years. The earliest archaeological evidence of their use by humans dates back roughly 10,000 years. Long before a Swiss chemist accidentally discovered LSD in 1943, indigenous peoples across the Americas, Africa, and beyond were drinking ayahuasca brews, eating psilocybin mushrooms, and chewing peyote buttons to commune with what they understood as the spirit world. Then, within a single generation in the mid-20th century, these ancient substances crashed into Western science, politics, and popular culture at once. How did molecules from fungi and cacti become the subject of CIA mind-control research, Harvard firings, Bicycle Day celebrations, and now FDA breakthrough therapy designations? That is the story of psychedelics.

• 2. Ancient Roots

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  Peyote has been used for several thousand years in the Rio Grande Valley by native tribes as an entheogen. In the Andean region of South America, the San Pedro cactus has a similarly deep history, with archaeological evidence tracing use back two thousand years through the Moche, Nazca, and Chavín cultures. When the Spanish arrived and the Roman Catholic church attempted to suppress its use, they failed. The cactus acquired the name "San Pedro" based on the belief that just as Saint Peter holds the keys to heaven, the effects of the cactus allow users "to reach heaven while still on earth." In 2022, the Peruvian Ministry of Culture declared the traditional use of the San Pedro cactus in northern Peru as cultural heritage.

  The Mazatec people of Oaxaca, Mexico used psilocybe mushrooms in ceremonies that Spanish explorers observed as early as 1519 with the arrival of Hernán Cortés. Spanish ethnographer Bernardino de Sahagún traveled to Mexico in 1529 and documented the practice. The DMT-containing brew ayahuasca anchored spiritual and physical healing practices in the Amazon basin, particularly in Peru. Even a psychedelic lichen of eastern Ecuador, Dictyonema huaorani, reportedly containing both 5-MeO-DMT and psilocybin, was used by witches and sorcerers in some traditions.

  These were not merely recreational rituals. Indigenous cultures in South America tended to use psychedelics for divination. Users sought to identify diseases and their causes, locate lost objects, and understand afflictions in ways that conventional medicine could not explain. The kykeon of the Eleusinian Mysteries in Ancient Greece may also have been a psychedelic, possibly derived from ergot or psilocybin-containing mushrooms, though this remains debated.

• 3. Western Discovery

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  American physician John Raleigh Briggs, living in Texas, learned of peyote from Native Americans and Mexicans who told him it produced "beautiful visions" and transported users into the "spirit world". He obtained mescal buttons from Mexico and published a journal article about trying a very low dose in May 1887. The article was read by George Davis of Parke, Davis and Company, who obtained the buttons from Briggs in June 1887. Parke-Davis attempted to market peyote as a cardiac stimulant but met with little success.

  German pharmacologist Louis Lewin obtained mescal buttons from Parke-Davis that same year and began studying them. The first known published description of a full hallucinogenic peyote experience came from American neurologist Silas Weir Mitchell in December 1896. His account prompted the chemist Arthur Heffter to isolate and personally ingest mescaline from peyote in 1897, confirming its effects with the pure compound. Austrian chemist Ernst Späth synthesized mescaline for the first time in 1919, and German pharmaceutical company Merck began distributing pharmaceutical mescaline the following year.

  German psychiatrist Kurt Beringer, a student of Lewin and an acquaintance of Hermann Hesse and Carl Jung, became known as the father of psychedelic psychiatry. He conducted mescaline experiments in more than 60 people starting in 1921 and published his monograph Der Meskalinrausch (Mescaline Intoxication) in 1927. Mescaline is sometimes called the "first psychedelic" because it was the first to be fully characterized by Western science. The word "psychedelic" itself, meaning "mind-manifesting", was coined by English psychiatrist Humphry Osmond in 1956, in correspondence with writer Aldous Huxley, who had tried mescaline in 1953 and described the experience in his 1954 book The Doors of Perception.

• 4. Hofmann and the Bicycle

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  In 1938, Swiss chemist Albert Hofmann, working at Sandoz Laboratories, synthesized lysergic acid diethylamide (LSD) while developing oxytocic drugs derived from ergot. The compound was set aside and stored for five years. In 1943, Hofmann returned to it, and minute amounts absorbed through his skin accidentally triggered its hallucinogenic effects. Three days later, on April 19, he conducted a deliberate self-experiment. That date became the psychedelic holiday known as Bicycle Day, commemorating his bicycle ride home while under the drug's full effect.

  Hofmann later described the morning after that first full experience in his 1980 book LSD: My Problem Child: "Exhausted, I then slept, to awake next morning refreshed, with a clear head, though still somewhat tired physically. A sensation of well-being and renewed life flowed through me. Breakfast tasted delicious and gave me extraordinary pleasure. When I later walked out into the garden, in which the sun shone now after a spring rain, everything glistened and sparkled in a fresh light. The world was as if newly created. All my senses vibrated in a condition of highest sensitivity, which persisted for the entire day."

  Sandoz Laboratories began distributing LSD for research purposes under the brand name Delysid in 1949. Hofmann continued contributing to psychedelic science; he identified psilocybin as the active constituent of the mushrooms collected during Gordon and Valentina Wasson's 1957 expedition to Mexico, and developed a chemical synthesis for it in 1958. During a speech on his 100th birthday in 2006, Hofmann said of LSD: "It gave me an inner joy, an open mindedness, a gratefulness, open eyes and an internal sensitivity for the miracles of creation."

• 5. The Mushroom Hunters

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  R. Gordon Wasson and Valentina Wasson were an amateur couple of ethnomycologists who in 1952 learned from the published work of American ethnobotanist Richard Evans Schultes about the ritual use of hallucinogenic mushrooms in 16th-century Mexico. They made several trips to Mexico in search of them. In mid-1955, the pair participated in a mushroom ceremony with Mazatec curandera Maria Sabina in Huautla de Jiménez, Oaxaca. Gordon Wasson published his account in an article titled "Seeking the Magic Mushroom" for Life magazine in 1957; Valentina Wasson published hers as "I Ate the Sacred Mushroom" in This Week magazine that same year.

  A second expedition in 1957, joined by French mycologist Roger Heim, produced mushroom samples that Heim identified as belonging to the genus Psilocybe and sent to Hofmann for analysis. Hofmann identified psilocybin as the active constituent in 1958, and Sandoz Pharmaceuticals began distributing psilocybin tablets under the brand name Indocybin in 1960.

  The story of teonanacatl, as the Mazatec called the mushrooms, had reached Harvard before the Wassons. Austrian anthropologist and ethnobotanist Blas Pablo Reko had written of its use in Oaxaca in 1919 and sent specimens to Swedish anthropologist Henry Wassén in 1937. Those samples eventually arrived at Harvard under the attention of Schultes, but they had decomposed too badly to be identified. Before Wassén obtained specimens around 1936, the existence of teonanacatl as a real hallucinogenic mushroom was disputed and even denied. It took a combination of indigenous knowledge, amateur passion, and laboratory chemistry to finally bring psilocybin to Western science.

• 6. Research, Prohibition, and the CIA

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  Extensive clinical research in the 1950s and 1960s focused almost exclusively on LSD, mescaline, and psilocybin. Harvard psychologists Timothy Leary and Richard Alpert began studying LSD and psilocybin in the early 1960s and were fired from the university in 1963. Sandoz Laboratories ceased distribution of Delysid in 1965. By the end of the 1960s, psychedelic clinical research throughout the world had largely ceased, and the substances became controlled internationally in the 1960s and 1970s.

  What the public did not know at the time was that the United States government had been conducting its own research. In the 1940s through the 1970s, the CIA ran Project MKUltra and the U.S. Army ran research at Edgewood Arsenal, both investigating psychedelics as potential mind-control and truth-serum agents. These programs were later revealed but had operated in parallel to the legitimate clinical science of that era.

  Alexander Shulgin, an American chemist at Dow Chemical Company who tried mescaline by 1960, redirected his entire career after that experience. It has been described as "the most consequential mescaline trip of the sixties". Starting in the 1960s, Shulgin synthesized and documented hundreds of novel synthetic psychedelics and entactogens, publishing them in scientific papers and in the books PiHKAL (1991) and TiHKAL (1997). When MDMA was outlawed in the mid-1980s, Rick Doblin founded the Multidisciplinary Association for Psychedelic Studies (MAPS) in 1986 to push for psychedelics as medicines.

• 7. How They Work

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  Classic psychedelics produce their effects by binding to and activating the serotonin 5-HT2A receptor in the brain. There is a very strong correlation between 5-HT2A receptor affinity and hallucinogenic potency in humans, and the intensity of effects is directly correlated with receptor occupancy as measured with positron emission tomography imaging. Blocking that receptor with drugs like ketanserin or risperidone can abolish hallucinogenic effects entirely.

  Czech psychiatrist Stanislav Grof studied the effects of psychedelics like LSD early in his career and described the experience as commonly including "complex revelatory insights into the nature of existence... typically accompanied by a sense of certainty that this knowledge is ultimately more relevant and 'real' than the perceptions and beliefs we share in everyday life." Luis Luna describes psychedelic experiences as having a gnosis-like quality that offer "learning experiences that elevate consciousness and can make a profound contribution to personal development."

  The phenomenon of ego dissolution, one of the most striking features of a high-dose experience, correlates with desynchronization of the default mode network, a collection of brain areas that constructs our sense of space, time, and self. Visual hallucinations correlate separately with disruption in the visual cortex. At lower doses, experiences include warping of surfaces, intense colors not previously encountered, and repetitive geometric shapes. At higher doses, users may experience synesthesia, a perception of additional spatial or temporal dimensions, or complete detachment from reality.

  DMT is particularly notable in this regard. When inhaled, its onset is measured in seconds and its effects in minutes, producing a hallucinatory state often characterized by hyperbolic geometry and encounters with what users describe as entities. Users have also reported communicating with these entities. Ayahuasca, the oral form, typically lasts four to six hours, because harmine and harmaline in the brew act as MAO inhibitors that prevent DMT from being broken down in the digestive system.

• 8. Medicine, Risk, and Revival

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  A 2022 survey by YouGov found that 28% of Americans had used a psychedelic at some point in their life. A June 2024 report by the RAND Corporation indicated that psilocybin mushrooms are currently the most widely used psychedelic among U.S. adults, with 3.1% of adults reporting psilocybin use in the past year and about 12% reporting lifetime use.

  The U.S. Food and Drug Administration has granted breakthrough therapy status to psilocybin therapy for both treatment-resistant depression and major depressive disorder, which expedites its path toward formal approval. As of 2021, several countries including Australia, Switzerland, Canada, and Israel have legally approved or permitted psilocybin and LSD in certain treatment programs under special access arrangements.

  Psychedelic therapy differs from conventional psychiatric medication in a fundamental way. Where standard medications are taken daily without supervision, contemporary psychedelic therapy administers the drug in a single session, sometimes up to three sessions, in a therapeutic context. The patient wears eyeshades and listens to music. The therapeutic team prepares the patient beforehand and helps integrate insights afterward. Ira Byock wrote in 2018 in the Journal of Palliative Medicine that psilocybin is safe when administered to a properly screened patient supervised by a qualified professional with appropriate set and setting, but called for an "abundance of caution" in the absence of those conditions.

  Risks do exist. A 2023 international survey found that 14% of respondents felt more anxious for an extended period following ingestion. In a survey of 608 people who reported post-psychedelic difficulties, one third said the difficulties lasted longer than a year and one fifth said they lasted longer than three years. The most commonly reported difficulties included anxiety, derealization, social isolation, and existential confusion. A very rapid tolerance, known as tachyphylaxis, also develops with repeated use. By the second day with LSD in one study, there was already a 50% decrease in psychoactive effects, and after three to four days of repeated use, effects are nearly absent. Psychedelic microdosing practices, which have become more widespread in the 21st century, may likewise be subject to this tolerance mechanism, potentially limiting the long-term benefits some practitioners claim.