Neuroimaging in psychedelic drug development: past, present, and future.

Psychedelic therapy (PT) is an emerging paradigm with great transdiagnostic potential for treating psychiatric disorders, including depression, addiction, post-traumatic stress disorder, and potentially others. 'Classic' serotonergic psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), which have a key locus of action at the 5-HT2A receptor, form the main focus of this movement, but substances including ketamine, 3,4-Methylenedioxymethamphetamine (MDMA) and ibogaine also hold promise. The modern phase of development of these treatment modalities in the early 21st century has occurred concurrently with the wider use of advanced human neuroscientific research methods; principally neuroimaging. This can potentially enable assessment of drug and therapy brain effects with greater precision and quantification than any previous novel development in psychiatric pharmacology. We outline the major trends in existing data and suggest the modern development of PT has benefitted greatly from the use of neuroimaging. Important gaps in existing knowledge are identified, namely: the relationship between acute drug effects and longer-term (clinically-relevant) effects, the precise characterisation of effects at the 5-HT2A receptor and relationships with functional/clinical effects, and the possible impact of these compounds on neuroplasticity. A road-map for future research is laid out, outlining clinical studies which will directly address these three questions, principally using combined Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) methods, plus other adjunct techniques. Multimodal (PET/MRI) studies using modern PET techniques such as the 5-HT2A-selective ligand [11 C]Cimbi-36 (and other ligands sensitive to neuroplasticity changes) alongside MRI measures of brain function would provide a 'molecular-functional-clinical bridge' in understanding. Such results would help to resolve some of these questions and provide a firmer foundation for the ongoing development of PT.

Supporting the Patient on LSD Day.

Editor's note: From its first issue in 1900 through to the present day, AJN has unparalleled archives detailing nurses' work and lives over more than a century. These articles not only chronicle nursing's growth as a profession within the context of the events of the day, but also reveal prevailing societal attitudes about women, health care, and human rights. Today's nursing school curricula rarely include nursing's history, but it's a history worth knowing. To this end, From the AJN Archives highlights articles selected to fit today's topics and times. During the 1960s, the therapeutic effects of lysergic acid diethylamide (LSD) were studied in psychiatric clinical settings. In this February 1964 article, nurse Kay Parley writes enthusiastically about this work at one such research hospital. She describes the benefits of LSD therapy for patients with alcoholism, as well as the richness of the experience for the nurse who guides the patient through treatment. "No role is so welcomed on our psychiatric unit than that of 'sitting' with a patient during LSD therapy." Parley vividly describes the nurse's role in these treatments. Her own long hospitalization for "manic-depressive psychosis" and treatment with LSD undoubtedly framed her approach to this therapy. Today there is renewed interest in the therapeutic use of psychoactive substances such as LSD. Penn and colleagues provide an update in "Psychedelic-Assisted Therapy" in this issue.-Betsy Todd, MPH, RN.

A dangerous method? Psychedelic therapy at Modum Bad, Norway, 1961-76.

After many years of disregard, the use of psychedelic drugs in psychiatric treatment has re-emerged in recent years. The prospect that psychedelics may again be integrated into mainstream psychiatry has aroused interest in long-forgotten research and experience from the previous phase of psychedelic therapy, which lasted from the late 1940s to the 1970s. This article will discuss one large-scale psychedelic therapy programme at Modum Bad Nervesanatorium, a psychiatric clinic which treated 379 inpatients with psychedelic drugs during the years 1961-76. The psychiatrists there initially regarded the psychedelic treatment as efficacious and without serious negative reactions, but reports of long-term harm have since surfaced. This article discusses how insights from Modum Bad might benefit the new generation of psychedelic treatment efforts.

Psychedelic crossings: American mental health and LSD in the 1970s.

This article places a spotlight on lysergic acid diethylamide (LSD) and American mental health in the 1970s, an era in which psychedelic science was far from settled and researchers continued to push the limits of regulation, resist change and attempt to revolutionise the mental health market-place. The following pages reveal some of the connections between mental health, LSD and the wider setting, avoiding both ascension and declension narratives. We offer a renewed approach to a substance, LSD, which bridged the gap between biomedical understandings of 'health' and 'cure' and the subjective needs of the individual. Garnering much attention, much like today, LSD created a cross-over point that brought together the humanities and arts, social sciences, health policy, medical education, patient experience and the public at large. It also divided opinion. This study draws on archival materials, medical literature and popular culture to understand the dynamics of psychedelic crossings as a means of engendering a fresh approach to cultural and countercultural-based healthcare during the 1970s.

The Past and Future of Psychedelic Science: An Introduction to This Issue.

Psychedelic plants and fungi have been used in indigenous medicinal traditions for millennia. Modern psychedelic research began when Albert Hofmann first synthesized lysergic acid diethylamide (LSD-25) in 1938. Five years later, became the first person to ingest LSD. Hofmann was unaware of the significance of his actions, and the effects they would set in motion. After a burgeoning period of scientific and cultural exploration in the1950s and '60s, psychedelic research was slowed to a near halt. Throughout the 1970s and '80s governmental interventions severely hampered global psychedelic research, despite evidence of the limited medical risks and therapeutic potential of psychedelics. After decades of persistent education and advocacy, rigorous research employing psychedelics as tools of discovery and healing are abundant today. Studies are taking place in research institutions and in private practice sites supported by non-profit and for-profit organizations, as well as individual investigators. This research includes clinical trials with MDMA-assisted therapy for the treatment of PTSD, alcoholism, and social anxiety, and psilocybin clinical studies for depression and addiction, as well as the ability of psychedelics to catalyze spiritual or mystical experiences and inspire creativity, and into the neuroscientific understanding the effects of psychedelic substances on our nervous system.

Psychedelics and Dying Care: A Historical Look at the Relationship between Psychedelics and Palliative Care.

This article examines the historical relationship between psychedelics and palliative care. Historians have contributed to a growing field of studies about how psychedelics have been used in the past, but much of that scholarship focused on interrogating questions of legitimacy or proving that psychedelics had therapeutic potential. Palliative care had not yet developed as medical sub-specialty, more often leaving dying care on the margins of modern, pharmaceutical-based treatments. As psychedelic researchers in the 1950s began exploring different applications for psychoactive substances such as LSD and mescaline, however, dying care came into clearer focus as a potential avenue for psychedelics. Before that application gained momentum in clinical or philosophical discussions, psychedelics were criminalized and some of those early discussions were lost. This article looks back at historical discussions about LSD's potential for easing the anxiety associated with dying, and considers how those early conversations might offer insights into today's more articulated discussions about psychedelics in palliative care.

Beyond LSD: A Broader Psychedelic Zeitgeist during the Early to Mid-20th Century.

During the 1950s and 1960s, there was a tremendous surge in research into the effects of psychedelic drugs. When discussing this period of research, the discovery of the psychoactive properties of LSD in 1943 is often presented as the main, and sometimes only, driving force of the boom in research. This "Great Person," or "Great Chemical," historiographical lens fails to acknowledge other factors that were fundamental in setting the stage for the research. In particular, other psychedelic drugs, such as mescaline, were already being probed for their uses in psychotherapy and as models for psychosis before the effects of LSD had been discovered. Psilocybin and other classical psychedelics had also been discovered by Western researchers around the same time as the synthesis of LSD. Additionally, many of the dominant zeitgeists (e.g., pharmacological, psychoanalytic, and humanistic) in psychology during this period were congruent with psychedelic research. This article argues that while the discovery of LSD may have been a catalyst for psychedelic research in the 1950s and '60s, there was a broader psychedelic zeitgeist that deserves acknowledgement for setting the stage.

Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD).

Lysergic acid diethylamide (LSD) is one of the most potent psychoactive agents known, producing dramatic alterations of consciousness after submilligram (≥20 µg) oral doses. Following the accidental discovery of its potent psychoactive effects in 1943, it was supplied by Sandoz Laboratories as an experimental drug that might be useful as an adjunct for psychotherapy, or to give psychiatrists insight into the mental processes in their patients. The finding of serotonin in the mammalian brain in 1953, and its structural resemblance to LSD, quickly led to ideas that serotonin in the brain might be involved in mental disorders, initiating rapid research interest in the neurochemistry of serotonin. LSD proved to be physiologically very safe and nonaddictive, with a very low incidence of adverse events when used in controlled experiments. Widely hailed by psychiatry as a breakthrough in the 1950s and early 1960s, clinical research with LSD ended by about 1970, when it was formally placed into Schedule 1 of the Controlled Substances Act of 1970 following its growing popularity as a recreational drug. Within the past 5 years, clinical research with LSD has begun in Europe, but there has been none in the United States. LSD is proving to be a powerful tool to help understand brain dynamics when combined with modern brain imaging methods. It remains to be seen whether therapeutic value for LSD can be confirmed in controlled clinical trials, but promising results have been obtained in small pilot trials of depression, anxiety, and addictions using psilocybin, a related psychedelic molecule.

LSD experiments by the United States Army.

Extensive LSD testing was conducted by the US Army at Edgewood Arsenal and other locations from 1955 to 1967. A number of different reports have been produced describing the health effects of this testing, including the Veterans Health Initiative Report in 2003. By and large, these reports gloss over and minimize the short and long-term side effects and complications of this testing. However, the reports themselves document frequent, severe complications of the LSD. These side effects were regarded by the Army as having been directly caused by the LSD exposure. In view of the current resurgence of interest in hallucinogens within psychiatry, the sanitized version of the effects of LSD exposure on US soldiers needs to be replaced with a more accurate account.

Modern Clinical Research on LSD.

All modern clinical studies using the classic hallucinogen lysergic acid diethylamide (LSD) in healthy subjects or patients in the last 25 years are reviewed herein. There were five recent studies in healthy participants and one in patients. In a controlled setting, LSD acutely induced bliss, audiovisual synesthesia, altered meaning of perceptions, derealization, depersonalization, and mystical experiences. These subjective effects of LSD were mediated by the 5-HT2A receptor. LSD increased feelings of closeness to others, openness, trust, and suggestibility. LSD impaired the recognition of sad and fearful faces, reduced left amygdala reactivity to fearful faces, and enhanced emotional empathy. LSD increased the emotional response to music and the meaning of music. LSD acutely produced deficits in sensorimotor gating, similar to observations in schizophrenia. LSD had weak autonomic stimulant effects and elevated plasma cortisol, prolactin, and oxytocin levels. Resting-state functional magnetic resonance studies showed that LSD acutely reduced the integrity of functional brain networks and increased connectivity between networks that normally are more dissociated. LSD increased functional thalamocortical connectivity and functional connectivity of the primary visual cortex with other brain areas. The latter effect was correlated with subjective hallucinations. LSD acutely induced global increases in brain entropy that were associated with greater trait openness 14 days later. In patients with anxiety associated with life-threatening disease, anxiety was reduced for 2 months after two doses of LSD. In medical settings, no complications of LSD administration were observed. These data should contribute to further investigations of the therapeutic potential of LSD in psychiatry.

"Ethics and Clinical Research" in Biographical Perspective.

Henry K. Beecher (1904-1976) played an important role in the development of bioethics. His 1966 article "Ethics and Clinical Research" in the New England Journal of Medicine intensified concern about the welfare of patients participating in clinical research, and his leadership in the 1968 Harvard Ad Hoc Committee on Brain Death redefined the determination of death. Beecher deserves, and even demands, explanation and explication. This essay offers a biographical perspective on the Harvard professor. In addition to his early life and education in both Kansas and Boston, the essay explores how Beecher's experiences in World War II and in the new geopolitical realities of the Cold War shaped his views about the ethical dilemmas of clinical research.

Prohibited or regulated? LSD psychotherapy and the United States Food and Drug Administration.

Over the 1950s and early 1960s, the use of the hallucinogenic drug lysergic acid diethylamide (LSD) to facilitate psychotherapy was a promising field of psychiatric research in the USA. However, during the 1960s, research began to decline, before coming to a complete halt in the mid-1970s. This has commonly been explained through the increase in prohibitive federal regulations during the 1960s that aimed to curb the growing recreational use of the drug. However, closely examining the Food and Drug Administration's regulation of LSD research in the 1960s will reveal that not only was LSD research never prohibited, but that the administration supported research to a greater degree than has been recognized. Instead, the decline in research reflected more complex changes in the regulation of pharmaceutical research and development.

Neurotoxicity and LSD treatment: a follow-up study of 151 patients in Denmark.

LSD was introduced in psychiatry in the 1950s. Between 1960 and 1973, nearly 400 patients were treated with LSD in Denmark. By 1964, one homicide, two suicides and four suicide attempts had been reported. In 1986 the Danish LSD Damages Law was passed after complaints by only one patient. According to the Law, all 154 applicants received financial compensation for LSD-inflicted harm. The Danish State Archives has preserved the case material of 151 of the 154 applicants. Most of the patients suffered from severe side effects of the LSD treatment many years afterwards. In particular, two-thirds of the patients had flashbacks. With the recent interest in LSD therapy, we should consider the neurotoxic potential of LSD.

Humphry Fortescue Osmond (1917-2004), a radical and conventional psychiatrist: The transcendent years.

This article describes the life and work of the psychiatrist Humphry Osmond who pursued a radical path as a psychiatrist while he remained within the establishment. To the public mind however, he is best known as the man who introduced Aldous Huxley to mescaline and coined the iconic word psychedelic. From an early stage of his career, Henry Osmond embraced new ideas to break the nexus in psychiatry at a time when neither biological nor psychoanalytic treatments were shown to have much benefit. To do this, he joined the radical social experiment in health in the Canadian province of Saskatchewan where he initiated a range of innovations that attracted international attention, as well as controversy over his espousal of the use of hallucinogens better to understand the experiences of psychotic patients.

From Hofmann to the Haight Ashbury, and into the future: the past and potential of lysergic acid diethlyamide.

Since the discovery of its psychedelic properties in 1943, lysergic acid diethylamide (LSD) has been explored by psychiatric/therapeutic researchers, military/intelligence agencies, and a significant portion of the general population. Promising early research was halted by LSD's placement as a Schedule I drug in the early 1970s. The U.S. Army and CIA dropped their research after finding it unreliable for their purposes. NSDUH estimates that more than 22 million (9.1% of the population) have used LSD at least once in their lives. Recently, researchers have been investigating the therapeutic use of LSD and other psychedelics for end-of-life anxiety, post-traumatic stress disorder (PTSD), cancer, and addiction treatment. Adverse psychedelic reactions can be managed using talkdown techniques developed and in use since the 1960s.

[The substance experience, a history of LSD]. / The substance ou l'histoire mouvementée du LSD.

This article reviews the recent knowledge on LSD stemming from various disciplines among which pharmacology, sociology and epidemiology. The d-lysergic acid diethylamide (LSD) is a particularly powerful hallucinogenic substance. It produces distortions and hearing, visual and tactile hallucinations. Rarely used (only 1.7% of people aged 15-64 years old have tried it in their lifetime), this very powerful drug generates a strong apprehension within the general population, but the ethnographical studies show that its image seems rather good among illicit drug users. This representation relies both on the proper effects of this substance and also on the history of LSD very closely linked to the counterculture characteristic of the years 1960-1970.