Common wisdom in the psychedelic literature suggests that early controlled trials of psychedelic therapy were methodologically flawed. In this review we challenge this view and discuss 11 controlled studies that were conducted in the United States and Canada between 1965 and 1977 to evaluate psychedelic (peak) therapy for individuals suffering from alcohol and opioid use disorder and psychoneuroses. We provide a narrative review of the designs, methods, settings, treatment issues and results and show that these studies already adhered quite well to the regulatory and evidentiary standards of their time. These early psychedelic trials tried to effectively address common methodological problems that still threaten the validity of contemporary psychedelic clinical trials (e.g., regarding blinding and active control conditions). Our review indicates that despite a significant heterogeneity in the methods and research designs, most early controlled studies converge on the same conclusion: there are no durable improvements in the condition of patients treated with psychedelic therapy beyond a few weeks. We discuss implications for contemporary psychedelic science in terms of (a) patient selection (i.e., better prospects for non-chronic conditions), (b) the problems with a single-sided focus on mystical experiences as the primary mechanism of action, (c) the positive afterglow as a therapeutic window of opportunity and (d) the need for a strong psychotherapeutic framework to induce sustained therapeutic effects.

IntroductionDream-like and psychedelic experiences often display internally illogical structures. Recent theories propose that these experiences function as “spontaneous offline simulations” related to specific brain processes. This study investigates whether such perceived illogicality reflects a distinct, premodern mode of cognition—commonly referred to as “mythic” cognition—rather than a cognitive deficit.MethodsThirty-one participants underwent four 90-minute flotation REST (Restricted Environmental Stimulation Technique) sessions designed to induce altered, dream-like states. After each session, participants completed the Phenomenology of Consciousness Inventory (PCI) and additional questions targeting features associated with mythic cognition.ResultsParticipants showed significant phenomenological shifts toward experiences characteristic of mythic cognition. Specifically, their altered states during flotation exhibited ontological parallels with mythic conceptions of space, time, and substance.DiscussionThe findings support the hypothesis that the perceived illogicality in altered states arises from a distinct cognitive framework rather than from deficits.

The authors offer a model for curriculum for education and training in substance-assisted psychotherapy (SAP), that is, psychedelic, psycholytic, and entactogen/MDMA (3,4-methylenedioxymethamphetamine)-assisted psychotherapy, addressing both the detailed contents of training and the question of experiential training. All authors of this model have an abiding interest and extensive experience in both the theory and practical aspects of SAP and questions relating to training. The model curriculum has been written through an international consensus building process and represents a consensus statement about the topic. The model includes an enumeration of theoretical themes and topics, which we suggest for inclusion in an SAP curriculum. The practical part of the curriculum includes experiential training with the following components: (1) apprenticeship observation: learning from observing experienced therapists, (2) ongoing clinical supervision: conducting treatment under direct supervision of experienced SAP therapists, and (3) a proposal for the inclusion of self-experiences for the trainees. Other parts address the use of peer supervision and conventional supervision. The authors are aware of the abiding need for respect of intercultural differences. We are conscious that the proposed model is one largely adapted to western industrialized countries with established graduate level education and training procedures for psychotherapists. However, the model curriculum includes teachings about the use of related substances and treatment techniques in indigenous cultures and traditions. This curriculum model may be valuable to psychedelic researchers, those endeavoring to train therapists for research studies, and those preparing for the clinical work to follow, once SAP is conducted outside of research settings.

ZUSAMMENFASSUNGHanscarl Leuner (1919–1996) gilt aufgrund seines wissenschaftlichen und organisatorischen Engagements als die zentrale Figur der Psycholytischen Therapie in Europa. Die Psycholytische Therapie versucht mithilfe geringer Dosen von Halluzinogenen wie LSD oder Psilocybin Abwehrstrukturen zu lockern und dadurch einen erweiterten Zugang zu unbewussten Konflikten und Seeleninhalten zu gewinnen. Leuner hat mit seinen Forschungen die Grundlagen dieser vor allem in Europa beforschten und verbreiteten Therapie erarbeitet.Im Unterschied zur Psychedelischen Therapie, die auf 1–2 hochdosierte Sitzungen mit mystischem Verbundenheitserleben abhebt, nutzt die Psycholytische Therapie deutlich mehr Substanzapplikationen (5–25), die stets in eine Langzeitpsychotherapie eingebettet sind. Zentral ist die Arbeit an persönlichen Themen, sowohl im veränderten Bewusstseinszustand als auch in den psychotherapeutischen Sitzungen. Dieser Artikel umreißt die Grundzüge der Psycholytischen Therapie und stellt die Forschungsergebnisse Leuners zu den Grundlagen der Psycholytischen Therapie dar.

The emergence of a so-called psychedelic renaissance has been proposed to characterize the revival of research into (psycho-)therapies using psychedelic drugs. In Europe, the most widespread approach employed in the 1960s and 1970s that involved the use of drugs like LSD and psilocybin as an adjunct to psychotherapy was named according to its main theoretical framework, that is, psychoanalysis as psycholytic therapy (psycholysis). Psycholytic therapy involves the use of serial low-dose sessions embedded in conventional long-term psychotherapy. However, this approach seems to be neglected today in favor of the psychedelic peak therapy paradigm with the use of just one or two high dose sessions to induce symptom reduction and personality transformation with a minimum time of psychotherapy. A review of the history and activities of the European Medical Society for Psycholytic Therapy (EPT) shows that it was a significant institution at the time. The EPT was founded as a professional society in 1965 aiming to coordinate European efforts of LSD therapists and enable professional exchange to further the development of psycholytic therapy. It also aimed to disseminate psycholytic therapy as an innovative treatment, and encourage international cooperation to develop standards of therapy and training. Up to now, there is virtually nothing available in the literature about the EPT and its activities. The author reconstructs the history and activities of the EPT based on unique archival resources to learn from past experiences and to help inspire the development of standards for treatment and training in the future.

Abstract This book is intended to provide an overview of the complex and dispersed history of MDMA, in the hope of making it more intelligible. In respect of the period up until the late 1980s, the book focuses on what was happening in Europe and the United States as other countries were not significant in this timeframe. This book does not describe the history of an illegal drug only as it is perceived in the public mind, but also in terms of the research into it, the political responses to it, its spread, and its medical use. It follows the early pharmaceutical history of MDMA shortly after the turn of the twentieth century, its researched military potential, and its early use in psychotherapy, followed by its distribution as a recreational drug and its spread throughout Europe and the United States and other parts of the world. Later chapters focus on the debate about its potential toxicity, its worldwide distribution as a dance drug since the 1990s, and the most recent research on MDMA and its therapeutic potentials. The history of MDMA is characterized by a range of parallel developments occurring at different levels and their many interactions. It is more of a mosaic than a linear story and cannot be described in terms of a simple narrative. This book tries to bring these multiple narratives and levels of its history and their complex interactions together in order to produce a coherent mosaic

The acute psychoactive, autonomic, and endocrine effects of the new psychoactive substance (NPS) 5,6-methylenedioxy-2-aminoindane (MDAI; 3.0 mg/kg, range 180-228 mg) were investigated in six healthy volunteers (four males, two females) in a non-blinded fashion without placebo. Subjective, cardiovascular, and endocrine responses were compared with two different doses of 3,4-methylenedioxymethamphetamine (MDMA) (75 mg and 125 mg) described in previously published placebo-controlled studies, which used identical outcome measures including Visual Analogue Scales (VAS), the Adjective Mood Rating Scale (AMRS), and the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale. MDAI was well tolerated and produced subjective effects comparable with those of 125 mg MDMA. MDAI increased blood pressure similar to 125 mg MDMA but did not increase heart rate or body temperature. MDAI increased cortisol and prolactin levels and could be detected in serum about 20 min post ingestion and remained detectable at least for 4 days. In urine, MDAI was detectable over a period of at least 6 days. Further clinical investigations are warranted to assess whether MDAI could serve as drug with medicinal properties.

Subject Cognition and Behavioural Neuroscience History of Neuroscience Collection: Oxford Scholarship Online

Abstract From 1977, MDMA was used in psychotherapy by a handful of psychiatrists and psychotherapists. They found it to be an ideal aid to psychotherapy as it does not affect ego-functions to the same extent as other psychedelic drugs. Its main effect seemed to be suppression of the fear response, allowing patients the opportunity to observe and reprocess painful memories. Another application was found in couple therapy, as it enables couples to communicate without their usual anxiety-driven limitations. At first, the therapists were eager to keep the substance secret, being afraid it might, as a psychotherapeutic drug, end up having the same fate as LSD. However, their research into its psychotherapeutic utility was broad-based and covered a few hundred patients, apparently with some success. The chapter describes the initial history of the therapeutic use of MDMA, and the people and organizations involved with it. To illustrate its early therapeutic use, five therapists and their work are described in more detail. When the therapists became aware that MDMA might be scheduled, they organized a small conference on its therapeutic use and a psychophysiological study to show its physiological safety. A description of the fate of the research protocols submitted to the Food and Drug Administration (FDA) after its scheduling completes the picture.

Abstract This chapter covers the history of research and events related to the possible toxicity of MDMA, from the first cases of death involving MDMA and early toxicological research through to studies on its neurotoxicity in humans. It also provides some of the background stories behind the research and the debate about MDMA’s possible toxicity. Some ‘anti-Ecstasy campaigns’ related to the toxicity debate are also described. Complex issues and research related to the toxicity question are presented. Some early studies were obviously biased by compromised research methodologies. This is illustrated by the scandal surrounding a Johns Hopkins University researcher who, in 2000, claimed that MDMA could cause Parkinson’s disease; it was later discovered that he accidentally administered methamphetamine, instead of MDMA, to his experimental monkeys. When research on possible toxicological consequences of recreational MDMA began in earnest, a lot of studies were conducted internationally about possible changes in the brain and the long-term consequences for cognitive functions. Some of the more important, sometimes biased, studies and their implications are presented and discussed. A study undertaken with Mormon subjects, who had consumed MDMA, but no other drugs, showed that if MDMA is used alone, it has no long-term effects on cognition. The use of research results in anti-Ecstasy campaigns are described.

Abstract The association between drugs and dancing extends back to ancient times. Parallels can be seen between spontaneous medieval ‘dance epidemics’ and contemporary use of MDMA at dance parties. As a forerunner, MDA was used at dance parties in the late 1960s. However, it was only when the MDMA enthusiast Michael Clegg began to sell MDMA in parts of the Texas night-life scene that the synergy of MDMA and dancing spontaneously arose around 1983, which led to the rapid distribution of MDMA as a ‘dance drug’. From 1985 onwards, MDMA enjoyed a new career as a dance drug and found its way to Europe via the dance scene on the Spanish island of Ibiza: Ibiza dance parties were visited by some prominent disc jockeys from the UK, who became enthusiastic MDMA aficionados and launched the first MDMA-fuelled dance parties in London. The Netherlands, with its more tolerant drug policy and international trade through its capital Amsterdam, also became a distribution hub. The evolution of musical styles related to MDMA-fuelled dance parties are outlined, together with the more important events surrounding them, and descriptions of the experiences of ravers, both positive and negative, are also presented.

Abstract This chapter provides an overview of the early history of the molecule MDMA, which was first synthesized by the pharmaceutical company Merck, in search of a synthesis of the blood-clotting agent hydrastinine. As the original synthesis of hydrastinine had already been patented by another company, Merck needed to find an alternative synthesis. After a few failed attempts, the company’s chemists developed a rather complicated synthesis to circumvent the patent. Their new synthesis produced MDMA as an intermediate. Although it had no medical significance itself, Merck’s chemists subsequently resynthesized MDA a few times for specific purposes and conducted animal experiments, without, however, discovering its effects on humans. Two myths about the origin of MDMA often encountered in the literature—that the prominent German chemist Fritz Haber first synthesized MDMA whilst working on his dissertation, and that MDMA had been developed and tested as an appetite suppressant—are discussed and shown to be false.

Lysergic acid diethylamide (LSD) and similar psychoactive drugs have been used in psychotherapy since 1949, when the first clinical study with lower-dose LSD showed therapeutically relevant effects. This caused an intense interest among psychotherapists and researchers, alike, on an international scale. In 1960, the use of serial lower-dose LSD/psilocybin sessions in a psychoanalytical framework, which was dominant at the time, was named "psycholytic therapy". Psycholytic therapy was usually conducted in clinical environments, on both an inpatient and outpatient basis. Psycholytic therapy was developed and established over a 15-year period on the European continent, where it was used at 30 clinical treatment centers and by more than 100 outpatient psychotherapists. Psycholytic approaches were employed minimally in North America, where the psychedelic approach (use of one or two high-dose sessions for "personality-transforming mystical experiences") became the dominant method in use. The leading figure in psycholytic therapy was Professor Hanscarl Leuner in Germany, who laid the ground with his uniquely fine grained analysis of the LSD reaction in a 1962 monograph. He was central in establishing and distributing psycholytic therapy in Europe and abroad. The article provides comprehensive background information and outlines the essential features of psycholytic therapy. Evidence for the efficacy of psycholytic therapy is reviewed and a case for the inclusion of the psycholytic approach in the field of substance-assisted psychotherapy is made.

Ketamine and its (S)-enantiomer show distinct psychological effects that are investigated in psychiatric research. Its antidepressant activity may depend on the extent and quality of these psychological effects which may greatly differ between the enantiomers. Previous data indicate that the (S)-ketamine isomer is a more potent anesthetic than (R)ketamine. In contrast, in subanesthetic doses (R)-ketamine seems to elicit fewer dissociative and psychotomimetic effects compared to (S)-ketamine. In this randomized double-blind placebo-controlled trial the effects of (R/S)-ketamine and (S)-ketamine on standardized neuropsychological and psychopathological measures were compared. After an initial bolus equipotent subanesthetic doses of (R/S )and (S)-ketamine or placebo were given by continuous intravenous infusion to three groups of 10 healthy male volunteers each (n = 30). (R/S)-Ketamine and (S)-ketamine produced significant psychopathology and neurocognitive impairment compared to placebo. No significant differences were found between (R/S)-ketamine and (S)-ketamine. (S)-Ketamine administration did not result in reduced psychopathological symptomatology compared to (R/S)-ketamine as suggested by previous studies. However, this study revealed a somewhat more "negatively experienced" psychopathology with (S)-ketamine, which opens questions about potential "protective effects" associated with the (R)-enantiomer against some psychotomimetic effects induced by the (S)-enantiomer. As the antidepressant effect of ketamine might depend on a pleasant experience of altered consciousness and perceptions and avoidance of anxiety, the ideal ketamine composition to treat depression should include (R)-ketamine. Moreover, since preclinical data indicate that (R)-ketamine is a more potent and longer acting antidepressant compared to (S)-ketamine and (R/S)-ketamine, randomized controlled trials on (R)-ketamine and comparative studies with (S)-ketamine and (R/S)-ketamine are eagerly awaited. (C) 2021 Elsevier B.V. and ECNP. All rights reserved.

Lysergic acid diethylamide (LSD) is a prototypical serotonergic psychedelic drug and the subject of many clinical investigations. In recent years, a range of lysergamides has emerged with the production of some being inspired by the existing scientific literature. Others, for example various 1-acyl substituted lysergamides, did not exist before their appearance as research chemicals. 1-Cylopropanoyl-LSD (1CP-LSD) has recently emerged as a new addition to the group of lysergamide-based designer drugs and is believed to be psychoactive in humans. In this investigation, 1CP-LSD was subjected to detailed analytical characterizations including various mass spectrometry (MS) platforms, gas and liquid chromatography, nuclear magnetic resonance spectroscopy, solid phase and GC condensed phase infrared spectroscopy. Analysis by GC–MS also revealed the detection of artificially induced degradation products. Incubation of 1CP-LSD with human serum led to the formation of LSD, indicating that it may act as a prodrug for LSD in vivo, similar to other 1-acyl substituted lysergamides. The analysis of blotters and pellets is also included. 1CP-LSD also induces the head-twitch response (HTR) in C57BL/6 J mice, indicating that it produces an LSD-like behavioural profile. 1CP-LSD induced the HTR with an ED 50 = 430.0 nmol/kg which was comparable to 1P-LSD (ED 50 = 349.6 nmol/kg) investigated previously. Clinical studies are required to determine the potency and profile of the effects produced by 1CP-LSD in humans.

1-Propanoyl-lysergic acid diethylamide (1P-LSD) appeared as a non-controlled alternative to LSD a few years ago. Although evidence is beginning to emerge from in vitro and animal studies that 1P-LSD might serve as a prodrug for LSD, an equivalent evaluation in humans is unavailable. Controlled oral and intravenous self-administrations of 100 μg 1P-LSD hemitartrate are reported in two human volunteers followed by analyses of urine and serum samples using a fully validated LC-MS/MS method. Psychometric evaluations included assessment of selected subjective drug effects and administration of the Five-Dimensions of Altered States of Consciousness rating scale (5D-ASC). In serum and urine, oral administrations of 1P-LSD only led to the detection of LSD reflecting biphasic elimination with a terminal elimination half-life of approx. t1/2 = 6.4 h. 1P-LSD could be detected for only up to 4.16 h in serum and 2.7 h in urine following intravenous administration, whereas LSD was detected in all serum samples (last sampling after approx. 24 h) and up to 80 h in urine. LSD showed first order elimination kinetics with an approx. t1/2 = 5.7 h, whereas 1P-LSD showed a rapid decrease in concentration within the first hour followed by a slower decrease, most probably due to hydrolysis. The bioavailability of LSD after oral ingestion of 1P-LSD was close to 100%. The psychosensory effects of 1P-LSD and their time course were comparable to those seen after uptake of LSD in other studies which further supports the prodrug hypothesis. The 5D-ASC scores were higher after oral compared with intravenous administration of 1P-LSD.

There are few medications with demonstrated efficacy for the treatment of posttraumatic stress disorder (PTSD). Treatment guidelines have unequivocally designated psychotherapy as a first line treatment for PTSD. Yet, even after psychotherapy, PTSD often remains a chronic illness, with high rates of psychiatric and medical comorbidity. Meanwhile, the search for and development of drugs with new mechanisms of action has stalled. Therefore, there is an urgent need to explore not just novel compounds but novel approaches for the treatment of PTSD. A promising new approach involves the use of psychedelic drugs. Within the past few years, 2 psychedelics have received breakthrough designations for psychiatric indications from the US Food and Drug Administration, and several psychedelics are currently being investigated for the treatment of PTSD. This review discusses 4 types of compounds: 3,4-methylenedioxymethamphetamine, ketamine, classical psychedelics (e.g., psilocybin and lysergic acid diethylamide), and cannabinoids. We describe the therapeutic rationale, the setting in which they are being administered, and their current state of evidence in the treatment of PTSD. Each compound provides unique qualities for the treatment of PTSD, from their use to rapidly target symptoms to their use as adjuncts to facilitate psychotherapeutic treatments. Several questions are formulated that outline an agenda for future research.

A variety of hallucinogens of the lysergamide type has emerged on the drug market in recent years and one such uncontrolled derivative of lysergic acid diethylamide (LSD) is 1-propionyl-LSD (1P-LSD). Due to the high potency of LSD and some of its derivatives (common doses: 50-200 mu g), sensitive methods are required for the analysis of biological samples such as serum and urine. The occurrence of an intoxication case required the development of a fully validated, highly sensitive method for the quantification of 1P-LSD and LSD in urine and serum using LC-MS/MS. Given that LSD is unstable in biological samples when exposed to light or elevated temperatures, we also conducted stability tests for 1P-LSD in urine and serum under different storage conditions. The validation results revealed that the analysis method was accurate and precise with good linearity over a wide calibration range (0.015-0.4 ng mL(-1)). The limit of detection (LOD) and the lower limit of quantification (LLOQ) of 1P-LSD and LSD in serum and urine were 0.005 ng mL(-1) and 0.015 ng mL(-1), respectively. The stability tests showed no major degradation of 1P-LSD in urine and serum stored at -20 degrees C, 5 degrees C or at room temperature for up to five days, regardless of protection from light. However, LSD was detected in all samples stored at room temperature showing a temperature-dependent hydrolysis of 1P-LSD to LSD to some extent (up to 21% in serum). Serum samples were particularly prone to hydrolysis possibly due to enzymatically catalyzed reactions. The addition of sodium fluoride prevented the enzymatic formation of LSD. The method was applied to samples obtained from the intoxication case involving 1P-LSD. The analysis uncovered 0.51 ng mL(-1) LSD in urine and 3.4 ng mL(-1) LSD in serum, whereas 1P-LSD remained undetected. So far pharmacokinetic data of 1P-LSD is missing, but with respect to the results of our stability tests and the investigated case rapid hydrolysis to LSD in-vivo seems more likely than instabilities of 1P-LSD in urine and serum samples. (C) 2019 Elsevier B.V. All rights reserved.

Aims This heuristic study reports observations on the phenomenology of ayahuasca experiences of nine foreign tourist participants of an ayahuasca retreat in Peru. Methods Narrative interviews, reflecting individual experiences after ayahuasca “night ceremony,” have been analyzed by qualitative content analysis using a data-driven strategy in order to extract themes and categories inherent in the interviews. Previously, a demographic questionnaire was given. The dose–response connection was uncontrolled, which is typical for this naturalistic setting. Results The typical structure of spontaneously reported experiences includes: personal preparation, physical symptoms, visual phenomena, cognitive and emotional phenomena, reactions of the individual within the psychedelic “world” as well as within ordinary reality, and appraisal to the process. Emotional reactions were subsumed under pleasant (psychotherapeutic “target emotions” and hedonistic emotions) and unpleasant emotions. For a majority, the presence of psychotherapeutic target emotions seemed to involve the presence of unpleasant emotions in the same session – possibly as transitional emotional states. Conclusions This suggests that psychodynamic processes, for example, possible activation of emotional conflicts – can take place spontaneously, during ayahuasca intake in this particular setting. Some participants attributed symbolic meaning to the visionary content, which was more likely to take place in psychotherapeutically motivated clients. The specific setting influence as well as corresponding expectations of the participants in native wisdom could have considerable influence on experiences and interpretations, such as communication with entities as well as receiving personal teachings.