The history of LSD begins in 1938, when Swiss chemist Albert Hofmann synthesized lysergic acid diethylamide, a semisynthetic derivative of ergot.
By Manuel Villaescusa
The psychoactive potential of LSD was not discovered until 1943, when Hofmann accidentally absorbed a microscopic dose through his skin, noticing its profound alterations of consciousness. This led Hofmann to self-administer a dose of 250 micrograms, discovering that LSD was the most potent psychoactive compound known to humankind, active in fractions of a milligram. From the first scientific paper published in 1947 on the effects of LSD in humans by Walter Stoll (son of the director of Sandoz, the pharmaceutical company where Hofmann worked and which marketed the substance under the brand name Delysid) until 1966, when the United States government declared LSD devoid of scientific value and banned further research (1), more than two thousand papers were published on the drug—making it arguably the single most studied substance over those two decades. In psychopharmacology, this research helped catalyze the modern neurochemical revolution, shifting psychiatry from a discipline dominated by psychoanalysis toward today’s biochemical understanding of the brain and its pharmacological treatments. According to psychiatrist J. Halpern, LSD research fostered a deeper understanding of the neurotransmitter serotonin, as both share a remarkably similar molecular structure. This paved the way toward grasping serotonin’s role in depression and developing modern selective serotonin reuptake inhibitors. Alongside these developments, LSD spurred new models of psychotherapy. Three primary paradigms emerged: the psychotomimetic, the psycholytic, and the psychedelic.
1 – For an analysis of the political motivations behind this prohibition, see A. Escohotado’s General History of Drugs, Espasa Publishing.
The Psychotomimetic Model
The first paradigm to emerge was the psychotomimetic model. Proponents believed the LSD experience closely mirrored the psychotic delusions seen in schizophrenia and paranoia, hence the term (psychotomimetic: mimicking psychosis). This model offered two main avenues of inquiry. On one hand, psychiatrists could ingest the compound in a controlled setting to experience the delusional worlds of their patients firsthand, enhancing their clinical empathy and insight. On the other hand, administering the compound to healthy volunteers was thought to produce a time-limited “model psychosis” that could be investigated to better understand mental illness. This model soon revealed its shortcomings as the clear differences between LSD-induced states and organic psychotic delirium became increasingly obvious. Sandoz distributed generous samples to psychiatrists, framing it as an educational tool for clinical training. Yet the psychotomimetic model also yielded intriguing findings, such as those made by Humphrey Osmond, a British psychiatrist based in Canada researching the serotonergic system and its potential role in schizophrenia. Osmond viewed LSD as an invaluable tool for studying psychosis and testing his hypothesis that an endogenous neurotoxin or an imbalance between adrenaline and serotonin might trigger the disorder. While serving as clinical director of an addiction facility in Saskatchewan, he designed an experimental treatment that involved giving alcoholics a high dose of LSD to simulate an episode of delirium tremens (1). Like many psychiatrists, Osmond had observed that patients who survived delirium tremens often emerged with improved motivation to stay sober. His hypothesis was that an LSD experience could achieve this outcome artificially. The results were paradoxical: a substantial percentage did achieve lasting sobriety and behavioral change after a single session. However, this was not because they had endured the horrors of delirium tremens, but because they had undergone an epiphaneia, an intuitive realization of the underlying nature of reality through
1 – Delirium tremens is a severe state of confusion and autonomic hyperactivity caused by alcohol withdrawal, often involving terrifying hallucinations, tactile sensations of insects crawling under the skin, and potentially fatal complications.
direct engagement with a spiritual dimension—an experience that fundamentally reorganized how they perceived themselves and the world around them. Recognizing the therapeutic power of these transformative states, Osmond abandoned the psychotomimetic framework and set out to formulate the psychedelic model (“mind-manifesting,” a term he coined himself).
The Psychedelic Model
LSD was no longer viewed as a delirium-inducing agent, but rather as a catalyst capable of inducing altered states of consciousness akin to those reported by mystics across spiritual traditions—states that often prompted profound therapeutic breakthroughs. Rather than psychotomimetic, LSD was now regarded as mysticomimetic. This approach gained widespread traction among American psychiatrists and psychotherapists, producing remarkable outcomes in numerous patients (1). Among these practitioners, two stood out for the breadth and originality of their work: Czech psychiatrist Stanislav Grof and Mexican psychiatrist Salvador Roquet. Although foreign-born, both worked in the United States and exerted a substantial influence on the American clinical landscape.
Stan Grof and Basic Perinatal Matrices
Originally trained in psychoanalysis, Stan Grof began working with LSD in Prague during the late 1950s before continuing his clinical career in the United States, where he remains active today. Drawing on thousands of sessions, Grof formulated a cartography of the psyche that accounts for perinatal development and the transpersonal dimension of consciousness. Based on observations of high-dose LSD sessions, Grof categorized deep psychic material into four distinct experiential clusters corresponding to the phases of biological birth, which he termed basic perinatal matrices (BPM).
1 – One of the most famous examples was actor Cary Grant, who overcame severe chronic alcoholism through therapeutic LSD sessions and became an outspoken public advocate for the compound in Hollywood circles.
The first group corresponds to the intrauterine state prior to labor (BPM I). If gestation was undisturbed, this phase manifests as oceanic bliss, boundless expanses, and celestial realms. If gestation was fraught, patients might experience apocalyptic waters, feelings of poisoning, impending doom, or encounters with demonic entities. The second group (BPM II) aligns with the onset of uterine contractions while the cervix remains closed. This phase of maternal antagonism involves sensations of being trapped, swallowed, or crushed, severe claustrophobia, and descents into subterranean hells or the realm of death. Subjects often endure absolute existential despair with no discernible way out. The third matrix (BPM III) corresponds to the stage where the cervix dilates and contractions propel the fetus through the birth canal. This synergistic struggle often surfaces as intense battles, bloody violence, orgiastic themes, torture, or human sacrifice. Subjects encounter surging sexual energy, agonizing pressure, and intense pain intertwined with ecstasy—a visceral confrontation between life and death. The fourth and final matrix (BPM IV) corresponds to birth itself: the final emergence and separation from the mother. The existential struggle resolves into feelings of liberation, radiant light, expansive love, and forgiveness. It represents the death-rebirth archetype central to psychedelic experiences and ancient rites of passage alike.
According to Grof, systematically processing and integrating these perinatal layers over the course of treatment allows patients to resolve deep neuroses until sessions culminate primarily in experiences of transcendence and integration, signaling therapeutic completion. When LSD was outlawed for clinical practice and research, Grof developed holotropic breathwork—a drug-free modality utilizing hyperventilation and evocative music to access non-ordinary states of consciousness, a technique he continued to refine over subsequent decades.
Salvador Roquet’s Psychosynthesis
Another pioneering figure in psychedelic therapy was Mexican psychiatrist Salvador Roquet. Introduced to indigenous entheogenic practices by traditional healers, including the renowned Mazatec curandera María Sabina, Roquet sought to adapt these ancient methods to modern psychiatry. In his words, his mission was “to harness the extraordinarily rich ethnobotanical heritage of my country, assimilating and integrating millennia-old indigenous practices into modern psychiatric science, with the respect both deserve.” Alongside regional sacred plants (psilocybin mushrooms, peyote, morning glory seeds, datura), he incorporated LSD, MDMA, and ketamine into his work. Roquet developed an approach that leveraged the deep suggestibility induced by visionary substances to deliberately dismantle neurotic ego structures, providing an opening for healthier, more adaptive reintegration. His technique differed sharply from Grof’s. Where Grof favored soothing, supportive music to nurture blissful and mystical states, Roquet employed deliberate sensory overload: multiple projectors flashing emotionally charged imagery, competing sound systems blasting discordant audio, and rapid, unpredictable sensory shifts. This intentional disruption aimed to break through rigid psychological defenses so patients could achieve a higher-order emotional reorganization free from fear. Despite these methodological contrasts, both clinicians shared the fundamental goal of facilitating an ego-death and rebirth process, allowing individuals to transcend rigid defense mechanisms and cultivate deeper empathy and connection. Between his first sessions in 1967 and the closure of his clinic by Mexican authorities in 1974, Roquet conducted 720 group sessions involving over 1,700 patients, reporting favorable outcomes in 85% of cases—an exceptionally high success rate in psychiatric practice. Following allegations of having induced psychosis in four patients (charges he steadfastly denied), Roquet was imprisoned for nine months and released only after intense advocacy from American psychiatric colleagues and former patients. He was never able to resume his psychedelic practice openly.
The Psycholytic Model
While the high-dose psychedelic model gained traction in North America, European clinicians developed an alternative paradigm known as psycholytic. therapy. Rather than administering large psychedelic doses (250–1500 µg) across a handful of sessions, psycholytic practitioners used low to moderate doses (75–150 µg) over dozens of consecutive meetings. The objective was to dissolve (psycholytic: psyche-loosening) psychological defenses, easing access to repressed traumatic memories, clarifying unconscious conflicts, and intensifying transference processes (1) within the therapeutic alliance. Psycholytic therapy functioned essentially as an adjunct to psychodynamic work—psychoanalysis amplified by chemistry. One of its foremost architects was German psychiatrist Hans Carl Leuner, who grounded his practice in psychoanalytic principles while utilizing low-dose LSD states characterized by heightened emotional receptivity and symbolic visualization. When clinical LSD was prohibited, Leuner adapted his methodology by developing drug-free hypnotic and imagery techniques. His method, known as Guided Affective Imagery (katathym-imaginative psychotherapy), remains widely practiced in Germany and directly reflects his clinical discoveries with visionary substances.
Conclusions
Across these varying frameworks, LSD therapy showed notable therapeutic promise in diverse applications: alcoholism, depression, end-of-life existential distress, personal growth, creative problem-solving, mystical experience, prisoner rehabilitation, neuroses in individual and group settings,
1 – Transference: a psychoanalytic phenomenon in which a patient unconsciously redirects emotions and expectations rooted in early childhood figures (such as parents) onto the therapist.
sexual dysfunctions, and psychosomatic disorders. Administered to tens of thousands of individuals, the compound proved remarkably safe when delivered in supportive environments with thorough preparation. However, early studies often suffered from methodological shortcomings typical of mid-century psychiatry, leaving much of that historical literature suggestive rather than definitive by modern standards. Methodological reviews have highlighted the limitations of these early trials (e.g., Doblin, 2004). Yet while the substance’s low physiological toxicity and lack of addictive potential have long been documented, rigorous modern research into its therapeutic profile was largely halted. Questionable political choices brought promising scientific inquiry to a standstill. Decades of punitive drug policies have caused undeniable social harm, compounding the very problems they claimed to resolve. Today, four decades after that shutdown, research into visionary substances is experiencing a cautious renaissance. Regulatory bodies are evaluating formal protocols for psilocybin and MDMA. While clinical approvals for LSD have lagged behind other psychedelics, shifting attitudes at regulatory agencies (1) suggest a slow emergence from this prolonged hiatus. American psychiatrist Richard Yensen was the last scientist granted permission to administer LSD to human subjects and may well be among the first to resume that work. Protocols exploring LSD for end-of-life distress aim to alleviate psychological and existential suffering, helping patients confront terminal illness with greater equanimity.
Consider how biological sciences would have fared had the microscope been banned for forty years, or how medicine would look had antibiotics been outlawed. That is precisely the sentiment shared by clinicians and researchers who never lost sight of these compounds’ profound therapeutic potential, despite decades of stigma. There is a sensible middle path between the
(1) DEA: Drug Enforcement Administration, the federal agency responsible for enforcing controlled substances laws in the United States.
punitive prohibition that categorically dismisses any therapeutic utility and the utopian excesses of the hippie counterculture, which hailed psychedelics as instantaneous panaceas. That middle ground is cognitive liberty and rigorous scientific inquiry: the freedom to systematically investigate how these substances interact with human consciousness, resuming the interrupted path toward understanding their true therapeutic value.
