Flashback: psychiatric experimentation with LSD in historical perspective.

In the popular mind, d-lysergic acid diethylamide (LSD) research in psychiatry has long been associated with the CIA-funded experiments conducted by Ewen Cameron at the Allen Memorial Institute in Montreal, Quebec. Despite this reputation, a host of medical researchers in the post World War II era explored LSD for its potential therapeutic value. Some of the most widespread trials in the Western world occurred in Saskatchewan, under the direction of psychiatrists Humphry Osmond (in Weyburn) and Abram Hoffer (in Saskatoon). These medical researchers were first drawn to LSD because of its ability to produce a "model psychosis." Their experiments with the drug that Osmond was to famously describe as a "psychedelic" led them to hypothesize and promote the biochemical nature of schizophrenia. This brief paper examines the early trials in Saskatchewan, drawing on hospital records, interviews with former research subjects, and the private papers of Hoffer and Osmond. It demonstrates that, far from being fringe medical research, these LSD trials represented a fruitful, and indeed encouraging, branch of psychiatric research occurring alongside more famous and successful trials of the first generation of psychopharmacological agents, such as chlropromazine and imipramine. Ultimately, these LSD experiments failed for 2 reasons, one scientific and the other cultural. First, in the 1950s and early 1960s, the scientific parameters of clinical trials shifted to necessitate randomized controlled trials, which the Saskatchewan researchers had failed to construct. Second, as LSD became increasingly associated with student riots, antiwar demonstrations, and the counterculture, governments intervened to criminalize the drug, restricting and then terminating formal medical research into its potential therapeutic effects.     

Utiliser les psychédéliques pour « guérir » des adolescents homosexuels ? Essai de thérapie de conversion,France, 1960

Between 1960 and 1962, a children's judge placed two French adolescents in a psychiatric hospital in Alsace. Described as “delinquent sexual perverts”, Michel, 15, and Bernard, 18, were in fact two young homosexuals. However, at the time, homosexuality was considered a psychiatric disorder that should be “cured”. With this in mind, psychiatrists set up shock or disgust therapies to push patients to become heterosexual. In this hospital, the chief doctor tested two new substances on them: mescaline and LSD. Injected in very high doses, the idea was to cause a powerful psychological shock in the hope of changing the adolescents’ sexual orientation. This type of placement as well as the treatment inflicted were then common (lobotomies or electroshocks were part of the “therapeutic” possibilities to “cure” homosexuality). Two aspects of these experiments are however particularly original: on the one hand, the use of substances such as mescaline and LSD, on the other hand, the very type of “therapy” implemented. It would thus seem, in the current state of knowledge on the use of LSD and mescaline in psychiatric therapy, that these experiences were isolated facts: the literature remains silent on the subject of the use of mescaline to “cure” homosexuality, and the few known therapies carried out using LSD were offered to adults and above all volunteers. Finally, these therapeutic methods were the opposite: psychotherapies in which particular attention was paid to patients and their well-being in the United States or in England and “psychic shocks” in Alsace. This hospital is the only French example of an attempt to “treat” homosexuality using psychedelics. The use of these substances by the French team therefore began in 1960; it involved administering mescaline or LSD in high doses (an exceptional characteristic in Europe where psychiatrists were in favor of therapy with low doses known as “psycholytic”) and in injections, ranging from 200 to 1200 mg for mescaline and for LSD from 100 to 800 micrograms. By way of comparison, a recreational dose is 300 to 500 mg for mescaline and 100 micrograms for LSD, administered orally. In order to create “psychic shock”, the effects of the substances were immediately stopped by the injection of chlorpromazine, a powerful neuroleptic. The authors noted that for all patients, “two modes of behavior are common: stupor and agitation”. They sometimes tore their sheets or pajamas or grabbed the examiner, asking for support. The sessions were linked: in 118 days, Bernard would undergo 16 of these sessions, one every 7 days on average. Michel, during one of the sessions, felt like he had been killed by his psychiatrists. Neither would subsequently become heterosexual. Elsewhere in the world, other forms of LSD conversion therapy have emerged. However, these were benevolent psychotherapies; the product was not injected but taken orally (therefore with more progressive effects), and the approach was not the same. Thus, acceptance of their homosexuality by patients was considered as desirable an option for therapists as was conversion to heterosexuality. For French practitioners, on the contrary, “healing” was the only objective. This article will highlight a double French specificity in the use of psychedelics: first, the refusal to introduce the new method of administering these substances, called “set and setting”, theorized from the late 1950s in Anglo-Saxon countries, and yet known and discussed by French experimenters. Then, it will show the use of these substances in shock therapy, particularly in the treatment of homosexuality.     

Editors’ Introduction and Review: An Appraisal of Surprise: Tracing the Threads That Stitch It Together

Though the scientific study of surprise dates back to Darwin ( 1872 ), there was an upsurge in interest beginning in the 1960s and 70s, and this has continued to the present. Recent developments have shed much light on the cognitive mechanisms and consequences of surprise, but research has often been siloed within sub‐areas of Cognitive Science. A central challenge for research on surprise is, therefore, to connect various research programs around their overlapping foci. This issue has its roots in a symposium on surprise, entitled “Triangulating Surprise: Expectations, Uncertainty, and Making Sense,” at the 36th Annual Conference of the Cognitive Science Society (Quebec City, July 2014). Building on the interdisciplinary conversations that started at the symposium, this issue aims to draw attention to some promising empirical and modeling results and their theoretical implications. The present paper sets the stage for the issue by presenting a historical summary, discussing contrasting definitions of surprise, and then by tracing major threads that run through both this issue and the larger literature on surprise. Our aim is to develop broader, shared understandings of the main insights, theories, and findings regarding surprise, with a view to supporting future integration and progress.     

CNS drug development: Part II: Advances from the 1960s to the 1990s

This column is the second in a series on central nervous system (CNS) drug development. The goal of this series is to explain to practicing clinicians how drugs are developed and why CNS drug development is at an important juncture involving both significant challenges and opportunities. This column (Part 2) reviews the history of CNS drug development from the 1960s to the 1990s. During the 1960s, researchers acquired a much clearer understanding of basic CNS pharmacology (e.g., biogenic amine transmitter systems in the brain) and developed the first animal models of psychiatric illness that could be used to test potential psychiatric medications. During the 1970s, drug development scientists used their expanded understanding of receptor binding affinity and the theories and techniques developed in the 1950s and 1960s to produce new CNS-active medications. They did this by adding or reducing affinities for certain regulatory proteins (e.g., receptors) to increase positive effects and/or minimize adverse effects. The development of newer antipsychotics and antidepressants is discussed to illustrate this process. The next column in this series will review CNS drug development during the first decade of the 21st century and discuss what directions we can expect the field to take in the next 10 to 20 years.     

The content of hippocampal “replay”

One of the most striking features of the hippocampal network is its ability to self‐generate neuronal sequences representing temporally compressed, spatially coherent paths. These brief events, often termed “replay” in the scientific literature, are largely confined to non‐exploratory states such as sleep or quiet rest. Early studies examining the content of replay noted a strong correlation between the encoded spatial information and the animal's prior behavior; thus, replay was initially hypothesized to play a role in memory formation and/or systems‐level consolidation via “off‐line” reactivation of previous experiences. However, recent findings indicate that replay may also serve as a memory retrieval mechanism to guide future behavior or may be an incidental reflection of pre‐existing network assemblies. Here, I will review what is known regarding the content of replay events and their correlation with past and future actions, and I will discuss how this knowledge might inform or constrain models which seek to explain the circuit‐level mechanisms underlying these events and their role in mnemonic processes.     

Phencyclidine: pharmacologic and clinical review

Phencyclidine (PCP), discovered in Germany during the 1920s, has become over the past four decades the number one drug of abuse in the United States. While briefly showing promise as being the "ultimate" anasthetic agent during the late 1950s, it very quickly fell into disfavor because of untoward side-effects during post-anesthetic emergence (1960s). Some few years later (1970s), PCP began its ascent in the illicit drug market. PCP is a drug with a broad range of pharmacological activity. It has been implicated as a major cause of psychiatric decompensation and has a number of clinical syndromes described in the literature. In addition, PCP has been shown to cause significant medical morbidity and mortality.     

Substance Use Disorders in Later Life: A Review and Synthesis of the Literature of an Emerging Public Health Concern

Substance use disorders (SUDs) among older persons are among the fastest growing health problems in the United States. The number of older persons is projected to exceed 72.1 million persons by 2030, following a trend of general population growth in the mid-1940s to 1960s. The generation, known as “baby boomers,” who refashioned drug use during their 20–30s, are increasingly continuing drug habits into later life. This review aims to assess the epidemiology, impact, and treatment of geriatric SUDs. Academic databases including PubMed, PsychInfo, Ovid, and Medline, were queried up to December 2018 for terms of “geriatric,” “older,” “elderly,” “substance abuse,” “drug,” “drug use,” “drug abuse,” “drug dependency,” “illicit drugs,” and “geriatric psychiatry.” Articles identified included 17 government documents, 29 studies based upon government documents, 43 studies not related to US government surveys, 19 review articles, 9 commentary pieces, 4 newspaper articles, 2 textbooks, and 1 published abstract. Evaluated studies and documents together suggest that older individuals are using illicit drugs and meeting criteria for SUDs at higher rates than previous geriatric cohorts resulting in substantial negative impacts on medical and psychiatric conditions. These findings represent a novel trend since previous cohorts of older individuals were thought to rarely use illicit substances. Current treatment models are inadequate to address the new wave of older individuals with SUDs. The fields of geriatrics, addiction, and geriatric psychiatry must work together to establish comprehensive care models and treatment modalities for addressing this emerging public health concern.     

The neurobiological mechanisms of physical exercise in methamphetamine addiction

Methamphetamine (METH) is the primary drug within amphetamine‐type stimulants which are the second most abused group of drugs worldwide. There is no pharmacological treatment addressed specifically to METH addiction, and behavioral therapy is shadowed by poor long‐term recovery and relapse. Therefore, novel approaches to manage METH addiction are an urgent need. This review aims to describe the current state of physical exercise use on methamphetamine addiction management. The following searching terms in PubMed were used: (“physical exercise” OR “exercise”) AND “methamphetamine.” Relevant references from key publications and gray literature were also reviewed to identify additional citations for inclusion. Original investigation regarding physical exercise and methamphetamine addiction (clinical data) or neurobiological mechanisms of physical exercise in animal models of methamphetamine administration (preclinical data) was included. Overall, METH users demonstrated improvements, including better fitness and emotional measures, lower relapse rates, and sustained abstinence when compared to nonexercised individuals. The neurobiological mechanisms of physical exercise in METH users seem to reflect an interplay of several agents, including neurochemicals, oxidative stress, neurogenesis, gliogenesis, and blood‐brain barrier as disclosed by preclinical data. Exercise‐based interventions alone or as a conjoint therapy may be a useful tool for managing METH addiction.     

Hans Helmut Kornhuber: Neurologist—Engaged Clinician—Neurophysiologist—Scientist and Humanist

Synopsis 1: This contribution in memoriam Hans Helmut Kornhuber, 1928–2009, Freiburg – Baltimore – Ulm, Chair of Neurology and founding Professor of Neurology of Ulm University was prepared for the “Memorial Symposium – Prof. Hans Helmut Kornhuber” on June 20, 2013 during the 53rd International Neuropsychiatric Pula Congress. It is an attempt to bear in remembrance Hans Helmut Kornhuber's scientific legacy. The aim is to give a review of his immensely broad range of interests. Kornhuber was one of the last shining examples of what has been called “Naturforscher und Arzt”/“Researcher and Physician” in the 19th and early 20th century. Reviewing his scientific oeuvre includes: Kornhuber's early interest in epistemiology and brain function. His work on the sensory systems/perception, conducting many experiments at Baltimore with Mountcastle and his team on skin receptors/tactile sensibility, and also measuring the channel capacity of sensory systems and consciousness. The entire field of Neurology he knew in extenso, there were not many clinicians engaged with such an intensity as Kornhuber with his always up to date and profound knowledge about new developments and therapies in neurology, and he conducted his own research into new therapies with particular emphasis on multiple sclerosis, stroke, dementia, movement disorders, etc. For Psychiatry as well he made important contributions, e.g. the glutamate theory. To Oto-Rhino-Laryngology he contributed a lot, e.g. hand book articles such as ‘Physiology and Clinic of the Vestibular System’. Kornhuber also discovered the eye muscle field in the cerebellum.     

L’émergence des psychothérapies assistées au LSD (1950-1970)

In the early 1950s, a new psychotropic substance appeared in the field of psychiatry, LSD-25. As one of the most studied drugs of the 1950-1970 period, LSD was used in a wide variety of indications. In particular, its effects were quickly considered therapeutic when taken in conjunction with psychotherapy. It was also used to train health care personnel: therapists were recommended to self-experiment with the substance in order to develop empathy towards subjects under the influence of psychedelics, but also towards their psychotic patients in general. LSD was indeed classified as a “psychotomimetic”, i.e. a drug that mimics psychosis. Thus, temporarily experiencing an artificial psychosis was intended to allow caregivers to better manage their patients. These practices led to the development of new concepts to improve LSD-assisted psychotherapy, known as set and setting. From then on, the relationship between therapists and patients was more horizontal: the former had to make sure to create a therapeutic alliance, a secure and reassuring environment for the latter. Two models of psychotherapy were also developed: psycholytic therapy and psychedelic therapy. The first was based on a large number of sessions with increasing, but still medium, doses. The idea was that the patient would gradually discover the effects of the substance, releasing the defense mechanisms in order to accelerate the psychotherapeutic process. This therapeutic model was particularly used in Europe, where many therapists developed it. Psychedelic therapy, on the other hand, involved giving high doses of LSD in order to create a deep and transformative experience in one to three sessions, generating new behaviors. These new kinds of psychotherapies were carried out both in hospitals, in services specially built to implement them and in private psychiatry. This article will present the emergence of this therapeutic model with its different currents, the actors involved in this research at the international level and the problems raised by these new methods which break with traditional practices. It will also indicate the methodological differences between the French practices and the proposals related to set and setting which were elaborated by English, German, Canadian or American therapists.     

LSD alters eyes‐closed functional connectivity within the early visual cortex in a retinotopic fashion

The question of how spatially organized activity in the visual cortex behaves during eyes‐closed, lysergic acid diethylamide (LSD)‐induced “psychedelic imagery” (e.g., visions of geometric patterns and more complex phenomena) has never been empirically addressed, although it has been proposed that under psychedelics, with eyes‐closed, the brain may function “as if” there is visual input when there is none. In this work, resting‐state functional connectivity (RSFC) data was analyzed from 10 healthy subjects under the influence of LSD and, separately, placebo. It was suspected that eyes‐closed psychedelic imagery might involve transient local retinotopic activation, of the sort typically associated with visual stimulation. To test this, it was hypothesized that, under LSD, patches of the visual cortex with congruent retinotopic representations would show greater RSFC than incongruent patches. Using a retinotopic localizer performed during a nondrug baseline condition, nonadjacent patches of V1 and V3 that represent the vertical or the horizontal meridians of the visual field were identified. Subsequently, RSFC between V1 and V3 was measured with respect to these a priori identified patches. Consistent with our prior hypothesis, the difference between RSFC of patches with congruent retinotopic specificity (horizontal–horizontal and vertical–vertical) and those with incongruent specificity (horizontal–vertical and vertical–horizontal) increased significantly under LSD relative to placebo, suggesting that activity within the visual cortex becomes more dependent on its intrinsic retinotopic organization in the drug condition. This result may indicate that under LSD, with eyes‐closed, the early visual system behaves as if it were seeing spatially localized visual inputs. Hum Brain Mapp 37:3031–3040, 2016. © 2016 Wiley Periodicals, Inc .     

Pharmacologic and cellular therapies in the treatment of traumatic spinal cord injuries: A systematic review

ObjectiveThe objective of this review is to synthesize and consolidate the existing literature on the treatment of SCI, focusing on drugs in development and cellular therapeutics, including stem-cell treatments.MethodsStudies were identified through a systemic search of PubMed, Ovid MEDLINE, Embase and the Cochrane database from their respective inceptions through January 1, 2020. We used the keywords “spinal cord injuries”, “therapeutics”, “stem cells”, and “pharmacology.”Study selectionStudies that assessed treatment strategies for SCI were included.Data extraction and synthesisData on SCIs were processed according to the Preferred Reporting Items for Systematic Reviews and meta-Analyses (PRISMA) guidelines.FindingsIn total, 62 articles were found in the literature search and 13 clinical trials were identified and included in this study. This review article discusses the management and treatment of SCI with an emphasis on the pharmacology, molecular approaches, and the use of stem cells. Presently, none of the treatments examined has shown to be clearly effective.ConclusionsPresent management strategies of SCI are focused on improving spinal cord perfusion and decreasing secondary injuries such as hypoxia, inflammation, edema, excitotoxicity and disturbances of ion homeostasis. This review hopes to demonstrate the significant advances made in the field of SCI and the new methodologies and practices being employed by researchers to improve our knowledge of the pathology. Our hope is that by consolidating the past and current research, improvements can be made in the management, treatment, and outcomes for these patients and other who suffer from spinal pathologies.     

Spinal Cord Stimulation Modulates Visceral Nociception and Hyperalgesia via the Spinothalamic Tracts and the Postsynaptic Dorsal Column Pathways: A Literature Review and Hypothesis

Introduction. Early animal and human evidence existed for a postsynaptic dorsal column (PSDC) pathway for visceral nociception that, when lesioned, decreased pain of terminal illness. There have been recent anecdotal reports in the literature that spinal cord stimulation (SCS) reduces pain of visceral nociception. We present here a review of the literature supporting a hypothesis that SCS might work by modulating information through the spinothalamic tracts (STT) and PSDC. Methods. A review of the relevant literature regarding nociception, nociceptive transmission, visceral sensitization, and the “brain‐gut” axis; and SCS was performed as a foundation for this hypothesis. Key words used for this review of databases and nonindexed relevant journals included visceral pain, visceral nociception, visceral hyperalgesia, visceral neuropathic pain, visceral sensitization, “brain‐gut” axis, SCS, PSDC pathway, and STTs. Results. An abundance of both clinical and scientific literature suggests the neuropathic and sensitized nature of chronic visceral nociception. There is also evidence that there may be an interaction between the PSDC pathway and lateral spinothalamic tracts (LSTT) that might be operant in the preclinical and anecdotal clinical evidence that SCS ameliorates the pain of visceral nociception. Conclusions. Chronic visceral nociception may be secondary to visceral sensitization and hyperalgesia and can be affected by the spinal cord and brain, the “brain‐gut” axis. There is preclinical evidence and clinical anecdotes that this nociceptive information is transmitted in the central nervous system through the PSDC pathway and LSTT and that SCS decreases pain of visceral nociception. It may be that SCS works by modulation of the above pathways.     

Embolization-induced angiogenesis in cerebral arteriovenous malformations

Endovascular occlusion of cerebral arteriovenous malformations (AVM) is often utilized as adjunctive therapy in combination with radiosurgery or microsurgery. Evidence supports that partial occlusion of AVM via endovascular embolization leads to increased angiogenesis. This phenomenon may be a contributing factor to the decreased efficacy of AVM radiosurgery following embolization. We review the literature for potential mechanisms of embolization-induced angiogenesis. A comprehensive literature search was performed using PubMed to identify studies that sought to elucidate the pathophysiology behind embolization-induced angiogenesis. The terms “arteriovenous malformation”, “embolization”, and “angiogenesis” were used to search for relevant publications individually and together. Three distinct mechanisms for embolization-induced angiogenesis were described in the literature: (1) hypoxia-mediated angiogenesis, (2) inflammatory-mediated angiogenesis, and (3) hemodynamic-mediated angiogenesis. Embolization-induced angiogenesis of cerebral AVM likely results from a combination of the three aforementioned mechanisms. However, future research is necessary to determine the relative contribution of each individual mechanism to overall post-embolization AVM neovascularization.     

Expérimentations des psychodysleptiques à Sainte-Anne dans les années 1960

The history of neuroleptics is only the emerging part of an iceberg of research, the birth of Psychopharmacology in France, several episodes of which are less known or forgotten. In this article, the author describes the experiments of psychodysleptics (mescaline, LSD25 and psilocybin), from 1950 to 1967, at Hôpital Sainte-Anne in the Department of Psychiatry University of Jean-Delay. These experiments were intended as “clinical trials” aimed at psychological and psychotherapeutic research. This article refers to a period in the history of psychiatry, between the disappearance of classical medical self-experimentation and the birth of Psychopharmacology, between the publication of the Nuremberg Code (1948) and the voting of the law of 31, December 1970, on Addictions.     

A review of disease progression models of Parkinson's disease and applications in clinical trials

Quantitative disease progression models for neurodegenerative disorders are gaining recognition as important tools for drug development and evaluation. In Parkinson's disease (PD), several models have described longitudinal changes in the Unified Parkinson's Disease Rating Scale (UPDRS), one of the most utilized outcome measures for PD trials assessing disease progression. We conducted a literature review to examine the methods and applications of quantitative disease progression modeling for PD using a combination of key words including “Parkinson disease,” “progression,” and “model.” For this review, we focused on models of PD progression quantifying changes in the total UPDRS scores against time. Four different models reporting equations and parameters have been published using linear and nonlinear functions. The reasons for constructing disease progression models of PD thus far have been to quantify disease trajectories of PD patients in active and inactive treatment arms of clinical trials, to quantify and discern symptomatic and disease‐modifying treatment effects, and to demonstrate how model‐based methods may be used to design clinical trials. The historical lack of efficiency of PD clinical trials begs for model‐based simulations in planning for studies that result in more informative conclusions, particularly around disease modification. © 2016 International Parkinson and Movement Disorder Society