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The Potential Role of Psychedelic Drugs in Mental Health Care of the Future
Abstract
Serotonergic psychedelics such as psilocybin, lysergic acid diethylamide (LSD), or dimethyltryptamine (DMT), as well as psychoactive drugs that trigger phenomenologically- related experiences like 3,4-methylenedioxymethamphetamine (MDMA) and ketamine, belong to the most promising treatment approaches in contemporary psychiatry. Psychedelic-assisted psychotherapy is not only a new treatment paradigm in psychopharmacology, but it also requires a redefinition of psychotherapeutic processes and the contextualization of psychopharmacological interventions within a new treatment infrastructure. Crucial for future practice and research in the field are (1) informed patient referral and co-treatment practices, (2) screening (e. g., choosing the right patients for these therapies), (3) the dosing preparation sessions, (4) the assisted dosing sessions as well as after-care procedures such as (5) psychological integration and (6) supporting the development of structured patient communities. Definition of future treatment delivery infrastructures and requirements for therapist training are further challenges for research and practice. Finally, the implementation of psychedelic-assisted psychotherapy in routine mental health care must be embedded into public communication about the potential and risks of these innovative therapeutic approaches. This paper provides a synopsis of challenges for practitioners, researchers, and regulators to be addressed in the approval processes of psychedelics.
Publication History
Received: 15 February 2021
Received: 06 April 2021
Accepted: 13 April 2021
Publication Date:
12 May 2021 (online)
© 2021. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
... Over the past two decades, there has been a notable resurgence of interest in psychedelic use, often referred to as the 'psychedelic renaissance' [1]. Psychedelic or psychedelic-like substances include psilocybin (found in magic mushrooms), lysergic acid diethylamide (LSD) and 3,4-methylenedioxymethamphetamine (MDMA). ...
... Overall, evidence provides support for the safety and efficacy of psychedelics within therapeutic contexts [6,7], a practice known as psychedelic-assisted therapy (PAT). PAT typically involves one to three high-dose psychedelic sessions under controlled conditions alongside a course of specialised psychotherapy that aims to optimise safety, tolerability and therapeutic effectiveness [1,[7][8][9]. ...
... Some participants suggested that these reduced psychological barriers to treatment could facilitate rapid therapeutic benefits compared to other available treatment options, reflected in recent literature [1,7]. This was perceived to help individuals with long-term mental health conditions transition out of the mental health system. ...
Introduction
This study explores the attitudes of psychologists towards psychedelics and psychedelic‐assisted therapy (PAT) following the world‐first regulatory changes in 2023 in Australia which permitted psilocybin and 3,4‐methylenedioxy‐methamphetamine (MDMA) to be used in clinical services.
Methods
A purposive sample of 20 Australian psychologists was recruited using snowball sampling. Semi‐structured interviews were conducted which explored participants' attitudes, knowledge and concerns about PAT. Data were coded and analysed to identify and develop theme categories.
Results
Most psychologists exhibited positive attitudes towards psychedelics and their therapeutic potential, viewing them as promising for addressing chronic mental health conditions like depression. However, there was a notable concern regarding the limited evidence on efficacy and potential adverse experiences, as well as the complexity of the individualised treatment protocol. Despite enthusiasm, many psychologists had limited detailed knowledge about the interventions themselves. The need for comprehensive education and training programs, including exposure to psychedelic experiences and credible higher education institutions, was emphasised to ensure competence in administering PAT.
Discussion and Conclusions
Psychologists displayed notably positive attitudes towards PAT, likely reflecting both shifting perceptions of psychedelics and self‐selection bias within the sample. Despite this optimism, concerns were raised about psychiatric risks and the necessity for comprehensive and reputable training and supervision. The cohort showed openness to both novel treatments and innovative training methods, underscoring the importance of enhancing educational frameworks to ensure effective implementation of PAT.
... The prevailing biological paradigm understands pathological changes in neurotransmission as the cause of these disorders (Köhler, 2019, p. 14), which can be balanced through continuous medication. However, a portion of those affected does not respond adequately to pharmacological treatment, and an even larger portion does not achieve temporary or permanent reduction of symptoms (Gründer & Jungaberle, 2021). Passie (2020, p. 27) speaks of a "crisis of psychopharmacology," which has led to the rediscovery of the use of psychoactive substances in psychotherapy, bringing hope to research. ...
... For several years now, psychotropic substances such as psilocybin and MDMA (3,4methylenedioxymethamphetamine) have been experiencing a renaissance in clinical research (e.g., Carhart-Harris et al., 2016a;Griffiths et al., 2006;Grob et al., 2011;Mitchell et al., 2021;Mithoefer et al., 2011;. These groups of substances promise rapid symptom reduction even in severely ill individuals, and it seems that these effects are long-lasting (Gründer & Jungaberle, 2021). The model of substance-assisted psychotherapy (SPT) combines psychopharmacotherapy and psychotherapy. ...
... The FDA and EMA usually require two phase III studies for approval (Doblin & Davis, 2008). The research on the use of the substance psilocybin in psychotherapy is in phase II, meaning an early stage of the approval process (Gründer & Jungaberle, 2021). The approval process can be accelerated, as the psychotherapy of major depression and TRD with psilocybin received "breakthrough therapy" status in 2020. ...
... While personal experiences could aid empathy during patient sessions, their significance is debated and needs further exploration. Training programs may acknowledge their value while aiming to balance their role, aligning psychedelic therapists' skills with broader psychotherapy research [56]. ...
... A key emphasis in training is on integration skills, facilitating patients' incorporation of psychedelic experiences into daily life. Combining third-wave cognitive-behavioral therapies with psychedelic treatments appears promising in connecting extraordinary experiences with practical, real-life changes [56]. ...
Background
Recent years show an exponential increased interest (“renaissance”) in the use of psychedelics for the treatment of mental disorders and broader. Some of these treatments, such as psilocybin for depression, are in the process of formal regulation by regulatory bodies in the US (FDA) and Europe (EMA), and as such on the brink of real-world implementation. In the slipstream of these developments increasing commercial initiatives are taking shape. The European Psychiatric Association (EPA) acknowledges both the therapeutic potential of psychedelic substances and the challenges for both research and clinical implementation. Steps need to be taken toward a well-balanced policy based upon sound scientific evidence and research, aiming at safe, ethical responsible integration of psychedelic therapy available for all patients who can potentially benefit.
Methods
In this EPA policy paper, we highlight the potential benefits, and also the challenges of psychedelic treatments, which can be relevant for the future real-world implementation of these treatments.
Results
In addition to an overview of the current evidence and hypotheses of working mechanisms of psychedelic treatment, this policy paper specifically highlights the importance of the psychosocial components of the treatment as well as the ethical and professional aspects playing a role in real-world implementation.
Conclusions
Four recommendations are formulated for further research and clinical implementation.
... As a result, drugs such as psilocybin continue to be listed as non-marketable narcotics according to the German narcotics law. Classic psychedelics, including tryptamines such as psilocybin, can induce profound changes of perception, emotional experience, and consciousness (17). Pharmacologically, they share a high binding affinity and (partial) agonistic effect on serotonin 5-HT2A receptors, which is responsible for their specific psychedelic effects such as increased sensory perception, ego-dissolution, and intense emotions, also known as "psychedelic experience" (18). ...
... Natural psychedelic substances have been used by indigenous cultures in psychospiritual and medical rituals for millennia. They are still used today as intoxicants for recreational consumption (17). ...
... We have argued previously that treatment with a psychedelic drug is characterised by some fundamental differences compared with classic treatment with an antidepressant. 47 These differences include variation in treatment regimen and conceptualisation, interactions between patients and therapists, and various psychological dimensions (eg, emotions, cognition, behaviour, and perception). Psychedelics evoke various specific and often strongly immersive patient experiences (eg, intense emotions and experiences of connectedness, awe, ego dissolution, and psychological insight), which seem to be related to both short-term and long-term outcomes. ...
... Among other requirements, this framework should include clinicians who are comprehensively trained to conduct psychotherapy, that is, to create contextual conditions that are conducive to therapeutic experiences and that support patients in translating such experiences into sustainable real-life change. 47,54,55 These ethical obligations apply, in our view, regardless of whether they are recognised by regulators. Nevertheless, adherence to corresponding minimum standards can only be ensured if regulators formally acknowledge that treatment with psychedelics is psychotherapy. ...
Treatment of psychiatric disorders with psychedelic substances represents one of the most promising current treatment approaches in psychiatry. Since its inception in the 1950s, therapy with psychedelics has been conceptualised as psychedelic-assisted psychotherapy—ie, a form of psychotherapy that uses the profound biological effects of this class of substances as a catalyst for changing thinking, emotions, and behaviour. In this view, the psychotherapy component of the treatment is considered as being of the utmost importance for both the safety and efficacy of the therapy. This conceptualisation has been challenged by the idea that the latest clinical studies suggest that the potential therapeutic effects of psychedelics must be attributed solely to the substance itself, with no role for psychotherapy. Here, accompaniment by therapists is understood as mere psychological support, to maintain the safety of the substance administration. In this Personal View, we contrast these two views and argue that the characterisation of treatment with psychedelics as a biological intervention (with psychological support as a purely safety-related component) represents an outdated and reductionistic dualism that has dominated psychiatric treatment and research for far too long. This discussion has important implications for the study and the regulation of these compounds.
... Se zavedením psychedelické terapie do systému péče o duševní zdraví ( jak psychoterapie, tak psychiatrie) se pojí řada výzev. 55,230 Zvláštní pozornost si zaslouží etické aspekty pojící se s tímto novým typem léčby, lišícím se svým mechanismem účinku od konvenční psychofarmakologické léčby. 231 Nezdravotnické specializované služby Tento model představuje možnost podstoupit kontrolovanou psychedelickou zkušenost ve speciálních nezdravotnických centrech pod dohledem vyškolených průvodců a za použití přírodních i syntetických substancí poskytovaných certifikovanými výrobci a pěstiteli. ...
... Ve světě dochází na základě odborného konsenzu o nízké rizikovosti psychedelických látek a důkazů o jejich terapeutickém potenciálu k zavádění různých modelů jejich terapeutického využití v souladu s legislativou daných států, a to jak v kontextu zdravotnických, tak nezdravotnických služeb. Se zavedením psychedelické terapie do systému péče o duševní zdraví se však pojí řada výzev, 55,230 zvláštní pozornost si zaslouží související etické aspekty. 231 Vzdělávání odborníků a metodická podpora Pro vznik kvalitních služeb pro uživatele psychedelik je nezbytné poskytnout jejich pracovníkům příležitost k adekvátnímu specializovanému a akreditovanému vzdělávání v dané problematice, které dnes v ČR až na spíše ojedinělé semináře a kurzy stále chybí. ...
Tato publikace představuje komplexní úvod do problematiky a dosud první souhrnný přehled situace v oblasti fenoménu užívání psychedelik v České republice, shrnující výsledky výzkumného projektu Aplikace výzkumných metod při tvorbě návrhu systému služeb pro uživatele psychedelických látek realizovaného v letech 2019–2021 v Národním ústavu duševního zdraví a spolufinancovaného se státní podporou Technologické agentury České republiky.
This publication is a comprehensive introduction to the phenomenon
and so far the first complex overview of the situation in the field
of psychedelics use in the Czech Republic, summarizing the results
of the research project Application of Research Methods in Creating
a Design of a System of Services for Users of Psychedelics (hereinafter referred to as National Psychedelic Research) implemented
in 2019–2021 at the National Institute of Mental Health.
... Auf jeden Fall gilt es, ethische Standards und Leitlinien für den verantwortungsvollen Umgang mit den Substanzen zu entwickeln, sollten sie Einzug in die klinische Arbeit erhalten [63]. ...
... Grundsätzlich gilt es, für die Behandlung belastbare Standards mit Qualitätskriterien zu erarbeiten, welche aber auch Flexibilität für die individuellen Patientenbedürfnisse bietet [63]. dabei ist auch auf die Qualität und Zertifizierung der Weiterbildung für die klinischen Anwender zu achten. ...
Zusammenfassung
In den letzten Jahren erlebte die klinische Forschung zur therapeutischen Wirksamkeit von Psychedelika eine Art Renaissance. Der aktuelle Stand wissenschaftlicher Erkenntnisse zur Wirksamkeit bei verschiedenen psychiatrischen Indikationen, wie auch die bereits unter bestimmten Voraussetzungen genehmigungsfähige Anwendung einiger psychedelischer Substanzen in der klinischen Praxis in manchen Ländern der Welt, legen die Möglichkeit einer zukünftigen Anwendung im klinischen Setting auch in Deutschland nahe. Dabei steht das Feld noch vor großen Herausforderungen inklusive der Notwendigkeit einer kritischen Gestaltung der Rahmenbedingungen für einen möglichen klinischen Einsatz. In diesem Artikel wird auf die historischen Hintergründe der klinischen Anwendung von Psychedelika eingegangen, um dann Aspekte wie Psychophänomenologie, Wirkmodelle, mögliche Indikationen und Pharmakosicherheit zu beleuchten. Anschließend wird der aktuelle Stand der Forschung und auch der Organisation von Fachgesellschaften in Deutschland im historischen und internationalen Kontext betrachtet, wie auch kritische Aspekte und noch zu klärende Fragen in dem Themenfeld.
... The wider acceptance and de-stigmatisation of psychedelics 1 is allowing researchers to investigate their potential for the treatment of psychopathology (Marks and Cohen, 2021;Dos Santos, 2020). A growing amount of experimental evidence suggests that psychedelics could eventually become a breakthrough new treatment paradigm in psychiatric, social, and palliative care (Enos, 2022;Gründer, 2021;Gründer and Jungaberle, 2021;Hutchison and Bressi, 2021), although the approach is not without risks or critique (Hall, 2022;Johnstad, 2021). One important property of psychedelics is their low addictive properties and other physical side-effects. ...
... With professional guidance, meditation may be a useful supplement to the psychological integration process (Villamil et al. 2019;Travis et al. 2018;Craven, 1989). Indeed, as we shall discuss below, integration is considered by many to be a critical component of safe and effective psychedelic therapy (Gründer and Jungaberle, 2021;Watts and Luoma, 2020;, safe-guarding against the risks associated with psychological destabilisation and exploiting its potential benefits. ...
There is growing evidence for the safety and efficacy of psychedelic therapy in mental health care. What is less understood however, is how psychedelics act to yield therapeutic results. In this paper we propose that psychedelics act as destabilisers — both in a psychological and a neurophysiological sense. Our proposed framework builds on the ‘entropic brain’ hypothesis, according to which psychedelics increase the entropy of spontaneous cortical activity and, in parallel, the richness or depth of content of psychological experience. The so-called ‘RElaxed Beliefs Under pSychedelics’ (REBUS) model is a predictive-coding inspired extension to this hypothesis, which states that psychedelics’ entropic action is paralleled by a relaxation of prior assumptions. Here we adopt a complex systems theory (CST) perspective, proposing that psychedelics act as destabilisers of excessively reinforced fixed points — or ‘attractors’ — which translates as the breaking of excessively reinforced or overweighted patterns of thinking or behaving. Our CST approach explains how psychedelic-induced increases in brain entropy destabilise neurophysiological set-points that are synonymous with overweighted priors, thereby augmenting and enriching the account given by REBUS. We believe that this perspective helps inspire conceptualisations of psychedelic psychotherapy — bearing relevance both to the peak psychedelic experience and subsequent sub-acute period of potential recovery. We discuss implications for risk mitigation and treatment optimization in psychedelic medicine.
... During preparation, risk of harm can be minimised by offering potential check-ups by a medical professional to avoid any issues caused by pre-existing conditions (see Gründer & Jungaberle, 2021). ...
A burgeoning evidence base demonstrates the therapeutic potential of psychedelics. Grounded in a review of existing literature and drawing on assumptions from coaching psychology and positive psychology, this paper argues that psychedelic experiences, beyond their potential to treat disease and disorder, hold promising potential to foster growth, learning, and wellbeing for non-clinical populations, and that coaching can offer effective, safe, and ethical support. Through identifying positive psychological themes in research and highlighting shared motivations to seek coaching and psychedelics, this paper builds the case for psychedelics-assisted coaching, offers a framework for practice, and discusses ethical concerns and future research.
... Arzneimittel aus der Substanzklasse Psychedelika wie Psilocybin nähern sich mit in den nächsten Jahren erwartetem Abschluss von Phase-III-Studien einer Zulassung im Arzneimittelmarkt [13]. Klinische Studien mit Psilocybin in Kombination mit Psychotherapie zeigen vielversprechende Ergebnisse für die Behandlung von Depressionen, Angststörungen und Substanzgebrauchsstörungen [1,6,[10][11][12]16]. Aufgrund der auffälligen subjektiven Wirkung von Psilocybin ist eine Verblindung in diesen klinischen Studien allerdings nicht vollständig zu erreichen [25,27], was eine eingeschränkte Beurteilbarkeit Placebo-kontrollierter Studien zufolge hat. ...
Zusammenfassung
Hintergrund
Klinische Studien mit Psilocybin in Kombination mit Psychotherapie zeigen vielversprechende Ergebnisse bei der Behandlung verschiedener psychischer Störungen. In der Ärzte- und Psychotherapeutenschaft sowie unter Patient:innen bestehen auch Unwissen, Ablehnung und Vorurteile gegenüber dieser neuen Therapieform. Ziel dieser Studie war es, einen möglichst repräsentativen Eindruck vom Informationsstand und der Einstellung zur Implementation psilocybin-assistierter Therapie (PAT) unter Expert:innen für psychische Gesundheit sowie Patient:innen und der Allgemeinbevölkerung zu erheben.
Methodik
Mittels einer Onlineumfrage wurden Informationen zu Einstellungen und Kenntnisstand von 1456 Teilnehmenden, darunter Ärzt:innen, Psychotherapeut:innen und Patient:innen, erfasst sowie Effekte der experimentellen Gabe von Informationen zu Potenzialen und Risiken getestet. Ergebnisse wurden mittels Varianzanalysen und Regressionsmodellen ermittelt.
Ergebnisse
Regressionsanalysen zeigten, dass ein höherer Kenntnisscore und selbsteingeschätzter Kenntnisstand, eigene Behandlungserfahrung, aber auch eigene Erfahrung mit Psychedelika positivere Einstellungen bezüglich der Einführung von PAT vorhersagten ( F [8, 1447] = 154,646, p < 0,001, R ² = 0,39). Die Vermittlung von Informationen über die Potenziale von PAT führte dann zu einer höheren Akzeptanz, wenn diese mit Informationen über deren Risiken kombiniert wurden.
Diskussion
Die Ergebnisse zeigen, dass Teilnehmende einer Einführung psilocybin-assistierter Therapie optimistisch gegenüberstehen. Der Zusammenhang zwischen Wissen und Akzeptanz wurde bestätigt. Dass die Vermittlung ausgeglichener Informationen zu höherer Akzeptanz führt, sollte bei der Aufklärung und Berichterstattung über PAT berücksichtigt werden.
... B. in der Behandlung von therapieresistenten Depressionen. Ein besonderer Aspekt ist hier vor allem die besondere Kombination von Pharmakotherapie mit Psychotherapie, die das subjektive Erleben und die persönliche Erfahrung der Erkrankung wieder mehr in den Fokus der neurobiologischen Behandlung stellt (Gründer & Jungaberle, 2021). Auch die zugrundeliegenden psychologischen Mechanismen scheinen grundsätzlich andere als die der klassischen Antidepressiva zu sein. ...
... To guarantee the safe and responsible clinical application of psychedelics, rigorous ethical and practical standards must be developed and widely disseminated to align with the profound effects these compounds can have on individuals. One solution could be to plan and implement standardised training for psychotherapists who will conduct psychedelic therapy (Gründer & Jungaberle, 2021), while another could be to resort to therapy models already in use in practice, which we know to be safe and effective (although based on a different type of evidence than that required for a drug), in line with the precautionary principle. We will see that our case study belongs to the latter type. ...
The resurgence of interest in psychedelic substances for psychiatric treatment has sparked both excitement and scepticism within the scientific community. This paper addresses the moralisation and hype surrounding psychedelic therapies. Through a systematic review of the literature and a detailed case study, we illustrate that the therapeutic effect of psychedelics is not solely pharmacological but is instead facilitated by their ability to enhance psychotherapy. The paper explores the historical context of psychedelics in psychiatry , their mechanism of action, and evidence of their efficacy in treating depression. We highlight the necessity of integrating psychedelics with psychotherapeutic interventions and emphasise the importance of methodological rigour and ethical standards in psychedelic research and practice. By presenting an informed understanding of psy-chedelic treatments, we advocate for their consideration as legitimate alternatives alongside traditional therapies, offering a potential paradigm shift in psychiatric care. ARTICLE HISTORY
... It is necessary to develop new approaches to reduce the limitations of current treatments and to provide more effective treatment. For this reason, with increasing interest, psychedelic substances are showing promise in therapeutic use in the treatment of psychiatric diseases, especially depression, by offering a new generation approach (Grunder & Jungaberle, 2021). ...
Psychoactive substances obtained from botanicals have been applied for a wide variety of purposes in the rituals of different cultures for thousands of years. Classical psychedelics from N,N′‐dimethyltryptamine, psilocybin, mescaline and various lysergamides cause specific alterations in perception, emotion and cognition by acting through serotonin 5‐HT 2A receptor activation. Lysergic acid diethylamide, the first famous breakthrough in the field, was discovered by chance by Albert Hoffman in the Zurich Sandoz laboratory in 1943, and studies on its psychoactive effects began to take place in the literature. Studies in this area were blocked after the legislation controlling the use and research of psychedelic drugs came into force in 1967, but since the 1990s, it has started to be a matter of scientific curiosity again by various research groups. In particular, with the crucial reports of psychotherapy‐assisted psilocybin applications for life‐threatening cancer‐related anxiety and depression, a new avenues have been opened in the treatment of psychiatric diseases such as treatment‐resistant depression and substance addictions. An increasing number of studies show that psychedelics have a very promising potential in the treatment of neuropsychiatric diseases where the desired efficiency cannot be achieved with conventional treatment methods. In this context, we discuss psychedelic therapy, encompassing its historical development, therapeutic applications and potential treatment effects—especially in depression, trauma disorders and substance use disorders—within the framework of ethical considerations.
... W ährend es in den letzten Jahren in der psychiatrischen Pharmakotherapie, vor allem im Bereich der Antidepressiva, kaum Innovationen gegeben hat, scheinen psychedelische Substanzen eine Perspektive für einen neuen therapeutischen Ansatz darzustellen. Diese heutzutage primär aus dem illegalen Freizeitkonsum bekannten Substanzen wurden bereits zu Beginn ihrer Entdeckung in den westli-chen Gesellschaften der 1940er-bis 1960er-Jahre in einem therapeutischen Rahmen an zehntausenden Patientinnen und Patienten erforscht und genutzt, bevor sie für die klinische Anwendung verboten wurden [1]. ...
... The increasing societal acceptance and stigmatization of psychedelic (for a classification and characterization of psychedelics, see Kelmendi et al. 2022) substances have opened up novel avenues of scientific inquiry into their potential therapeutic applications for psychopathology (Dos Santos et al. 2020, Marks andCohen 2021). Emerging experimental data suggest that psychedelics could potentially serve as a transformative new treatment paradigm for psychiatric, social, and palliative care (Byock 2018a, Gründer 2021, Gründer and Jungaberle 2021, Hutchison and Bressi 2021, Enos 2022, albeit with attendant risks and critique (Johnstad 2021, Hall 2022. A salient advantage of psychedelics is their relatively low potential for addiction and physical side effects, rendering them potentially superior to several current pharmacological treatments for mental health care (Read and Williams 2018, Davies et al. 2019, Jauhar et al. 2019, Guy et al. 2020, Lewis 2021. ...
Recent research has demonstrated the potential of psychedelic therapy for mental health care. However, the psychological experience underlying its therapeutic effects remains poorly understood. This paper proposes a framework that suggests psychedelics act as destabilizers, both psychologically and neurophysiologically. Drawing on the ‘entropic brain’ hypothesis and the ‘RElaxed Beliefs Under pSychedelics’ model, this paper focuses on the richness of psychological experience. Through a complex systems theory perspective, we suggest that psychedelics destabilize fixed points or attractors, breaking reinforced patterns of thinking and behaving. Our approach explains how psychedelic-induced increases in brain entropy destabilize neurophysiological set points and lead to new conceptualizations of psychedelic psychotherapy. These insights have important implications for risk mitigation and treatment optimization in psychedelic medicine, both during the peak psychedelic experience and during the subacute period of potential recovery.
... Burgeoning evidence suggests that psychedelic medications may represent breakthrough treatments for numerous mental health disorders (34)(35)(36). (R,S)-Ketamine (ketamine), a dissociative anesthetic with psychedelic properties, reduces symptoms of depression, PTSD, and suicidality when administered at subanesthetic doses (25,(37)(38)(39)(40). Extensive research has been published on the pharmacokinetics, pharmacodynamics, and cognitive effects of ketamine (40)(41)(42)(43). A wide array of subjective rating scales, cognitive tasks, patient interviews, clinical assessments, and brain imaging techniques have been used to study the effects of ketamine on cognition, dissociation, concentration, verbal fluency, motor coordination, mood, memory, and perception during or shortly after ketamine infusions (44)(45)(46)(47)(48)(49). ...
Suicide is the most common cause of death in male resident physicians and the second most common cause of death in resident physicians overall. Physicians also experience high rates of major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and burnout. These conditions frequently develop during medical school, and threaten not only physicians but the patients they care for. A 30-year-old medical student presented to our clinic with a history of treatment-resistant depression (TRD), generalized anxiety disorder (GAD), PTSD, and 5 years of daily suicidal ideation. Previous treatments included therapy, lifestyle modifications, and various combinations of six antidepressants. These interventions had little effect on the patient’s mental health. The patient was treated at our clinic with an 8-month regimen of IV ketamine infusions and ketamine-assisted psychotherapy (KAP). The patient achieved remission from suicidality and PTSD within 1 month; and TRD and GAD within 7 months. The patient’s Patient Health Questionnaire (PHQ-9) score decreased from 25 (severe depression) to 1 (not depressed). These findings suggest that ketamine and KAP may represent effective interventions for mental health applications in healthcare professionals. The patient made the unique decision to attempt to type narrative journals during four of his ketamine infusions (doses ranged from 1.8 to 2.1 mg/kg/h IV). The patient successfully typed detailed journals throughout each 1-h ketamine infusion. To our knowledge, these journals represent the first independently typed, first-person, real-time narratives of ketamine-induced non ordinary states of consciousness. The transcripts of these journals may provide useful insights for clinicians, particularly in the context of KAP.
... Defining such processes in clear terms and providing theory-based research instruments for measuring them are necessary steps toward overcoming what has been referred to as "psychedelic exceptionalism" and establishing a demystified scientific understanding of the psychedelic state and its transformative potential (Johnson, 2021;Sanders and Zijlmans, 2021). Such an understanding is not a mere academic issue but has important implications regarding the question how psychedelic-assisted therapies should be delivered and how therapists should be trained (Gründer and Jungaberle, 2021). The model presented here, if further supported by prospective-longitudinal studies in the context of clinical trials, could be well-suited for informing answers to these questions since it builds on empirically well-established general psychotherapeutic change mechanisms that are straightforwardly related to therapeutic methods and competencies (Grawe, 1997; for a recent argument in favor of applying the "common factors" view to psychedelic therapy, see Nayak and Johnson, 2020). ...
Background:
Many benefits and some harms associated with psychedelic use could be attributable to these drugs’ acceptance/avoidance-promoting effects and corresponding changes in psychological flexibility. Underlying psychological mechanisms are insufficiently understood.
Aim:
The purpose of this study was the validation of a psychological model of acceptance/avoidance-promoting psychedelic experiences, which included the development of a theory-based self-report instrument: the Acceptance/Avoidance-Promoting Experiences Questionnaire (APEQ). Its two main scales, acceptance-related experience (ACE) and avoidance-related experience (AVE), represent the theorized model’s core constructs. We aimed to test the model’s central assumptions of complementarity (ACE and AVE may occur alternatingly but not simultaneously, and are therefore empirically independent), intertwinedness (subaspects within ACE and AVE are mutually contingent and therefore highly inter-correlated), context-dependence (ACE and AVE depend on context factors) and interaction (longer-term outcomes depend on the interplay between ACE and AVE).
Method:
A bilingual retrospective online survey including 997 English- and 836 German-speaking participants. Each participant reported on one psychedelic experience occasioned by lysergic acid diethylamide (LSD), psilocybin, mescaline, or ayahuasca.
Results:
Whereas ACE and AVE were found to be relatively independent aspects of participants’ reported psychedelic experiences (complementarity), their subaspects were mostly distinguishable but strongly correlated among each other (intertwinedness). Therapeutic, escapist, and hedonic use motives were differentially associated with ACE and AVE (context-dependence), which were in turn associated with retrospective changes in psychological flexibility following participants’ reported experiences. The positive association between ACE and increased psychological flexibility was significantly moderated by AVE (interaction).
Conclusion:
These results provide an initial validation of the APEQ and its underlying theoretical model, suggesting the two can help clarify the psychological mechanisms of psychedelic-induced benefits and harms. Both should be further investigated in prospective-longitudinal and clinical studies.
... Classical psychedelicsa group of serotonin 2A receptor (5-HT2AR) agonists, including lysergic acid diethylamide (LSD) and psilocybinrepresent one of the most innovative and promising treatment approaches in contemporary psychiatric research (Gründer, 2021;Gründer and Jungaberle, 2021;Mertens and Preller, 2021). For example, recent studies have demonstrated efficacy and safety of psilocybin in depression including treatment-resistant depression (TRD) (Carhart-Harris et al., 2016, 2021Davis et al., 2021), and substance use disorders including nicotine (Johnson et al., 2017), and alcohol dependence (Bogenschutz et al., 2015) with large effect sizes. ...
Psychedelics such as psilocybin have recently gained remarkable interest in both the specialist literature and the lay press because studies suggest that these substances may have great therapeutic potential in various psychiatric disorders, including major depression. However, clinical trials with psychedelic drugs pose particular methodological challenges to researchers, some of which differ considerably from those with other psychotropic drugs. These include the problem of successful blinding, which can hardly be guaranteed in clinical trials with psychedelic substances and – directly related – the high risk of expectation bias and nocebo effects. Some of these challenges are being addressed in the given clinical trial on the efficacy and safety of psilocybin in treatment-resistant major depression. It is a phase II randomized, double-blind, active placebo-controlled parallel group trial with 144 patients. The rationale, the study design, and the core features of the study are presented here. The trial (EPIsoDE trial; EudraCT number: 2019-003984-24; NCT04670081) is funded by the German Federal Ministry of Education and Research (BMBF 01EN2006A/B).
... As described in the present review, several clinical trials have shown the efficacy of psilocybin and ayahuasca for TRD. Most psychedelics, including psilocybin and ayahuasca, are 5-HT 2A receptor agonists, which are thought to mediate their psychedelic and hallucinogenic effects [54,55]. Psychedelic compounds may induce brain-derived neurotrophic factor-mediated AMPAR potentiation and enhancement of neural plasticity [56,57], possibly resulting in antidepressant effects. ...
Introduction There is an imminent need for faster-acting and more effective antidepressants beyond the monoaminergic hypothesis.
Methods We systematically searched the US Clinical Trials registry for antidepressant compounds with completed phase II and III trials. Compounds that demonstrated significant superiority over placebo in the primary outcome measure in the latest phase of phase II and III trials were identified. The collateral information was gathered via a PubMed search and press releases.
Results Nine compounds were identified. AXS-05 (a combination of dextromethorphan and bupropion) and ansofaxine hydrochloride showed a positive result over placebo in a phase III study for major depressive disorder or treatment-resistant depression. MIJ821, nitrous oxide, psilocybin, ayahuasca, facial injection of botulinum toxin A, prasterone, and casopitant demonstrated at least one positive result in phase II trials. Ayahuasca showed a greater response rate than placebo at week one, indicating the rapid antidepressant effect.
Discussion These new compounds with novel mechanisms of action are expected to provide a greater variety of treatment options for depression if preliminary positive results are confirmed.
... Classical psychedelicsa group of serotonin 2A receptor (5-HT2AR) agonists, including lysergic acid diethylamide (LSD) and psilocybinrepresent one of the most innovative and promising treatment approaches in contemporary psychiatric research (Gründer, 2021;Gründer and Jungaberle, 2021;Mertens and Preller, 2021). For example, recent studies have demonstrated efficacy and safety of psilocybin in depression including treatment-resistant depression (TRD) (Carhart-Harris et al., 2016, 2021Davis et al., 2021), and substance use disorders including nicotine (Johnson et al., 2017), and alcohol dependence (Bogenschutz et al., 2015) with large effect sizes. ...
... Psychological risks (15)(16)(17) include susceptibility to psychotic or manic episodes, trauma associated with difficult experiences, and rebound reactions of depression or anxiety. Negative emotional responses generally resolve with appropriate preparation and post-session support. ...
Research exploring the potential of psychedelic-assisted therapies to treat a range of mental illnesses is flourishing, after the problematic sociopolitical history of psychedelics led to the shutdown of clinical research for almost 40 years. Encouraged by positive results, clinicians and patients are now hopeful that further interruptions to research will be avoided, so that the early promise of these therapies might be fulfilled. At this early stage of renewed interest, researchers are understandably focusing more on clinical trials to investigate safety and efficacy, than on longer-term goals such as progression to community practice. Looking to identify and avoid potential pitfalls on the path to community clinics, the authors, a group of Australian clinicians and researchers, met to discuss possible obstacles. Five broad categories of challenge were identified: 1) inherent risks; 2) poor clinical practice; 3) inadequate infrastructure; 4) problematic perceptions; and 5) divisive relationships and fractionation of the field. Our analysis led us to propose some strategies, including public sector support of research and training to establish best practice and optimize translation, and funding to address issues of equitable access to treatment. Above all, we believe that strategic planning and professional cohesion will be crucial for success. Accordingly, our key recommendation is the establishment of a multidisciplinary advisory body, broadly endorsed and representing all major stakeholders, to guide policy and implementation of psychedelic-assisted therapies in Australia. Although these challenges and strategies are framed within the Australian context, we sense that they may generalize to other parts of the world. Wherever they apply, we believe that anticipation of potential difficulties, and creative responses to address them, will be important to avoid roadblocks in the future and keep the “psychedelic renaissance” on track.
... Many social, political, and cultural questions are affected by this enculturation. The challenges of how psychedelics could be implement-ed in a future mental health care system are discussed by Gründer and Jungaberle [8]. ...
The renaissance of psychedelics has accelerated further over the past year. At least that’s true if you follow the public press. The New York Times recently titled “The Psychedelic Revolution Is Coming. Psychiatry May Never Be the Same.” on its front page 1.
Zusammenfassung
Der Einsatz von Psychedelika in Psychiatrie und Psychotherapie wird vertieft wissenschaftlich untersucht, national wie international zunehmend fachlich und gesellschaftlich diskutiert sowie international bereits teilweise klinisch praktiziert. Der Artikel bietet eine kurze Standortbestimmung auch hinsichtlich Evidenzlage, kritischer klinischer Fragen und Risiken. Rechtliche, ethische und ökonomische Aspekte werden beleuchtet, therapeutische Qualifikationen möglicher Anwender werden diskutiert und es wird unter Benennung noch aktueller Herausforderungen auf eine mögliche klinisch-psychiatrische Einbettung eingegangen. Insgesamt wird besprochen, unter welchen Voraussetzungen in der Anwendung von Psychedelika ein gewisses Potenzial hinsichtlich Erweiterung des Behandlungsspektrums psychischer Erkrankungen liegen könnte, insb. angesichts auch unter derzeitigen Methoden häufig therapieresistenter und chronischer Verläufe. Auf jeden Fall wären wesentliche grundsätzliche Fragen vor einer eventuellen Einführung zu klären.
ZUSAMMENFASSUNG
In 11 Fokusgruppeninterviews diskutierten 31 Teilnehmende, gegliedert in die Zielgruppen Ärzte, Psychotherapeuten und (Ex-)Patienten ihre Einstellungen, Wünsche und Bedenken in Bezug auf die mögliche Einführung psychedelischer Therapien in das deutsche Gesundheitssystem. Folgende Themenbereiche wurden besprochen: Risiken und Potenziale psychedelischer Therapien; Erwartungen und Wünsche; Zulassung, Regulation und Zugänglichkeit; therapeutische Begleitung psychedelischer Therapien; Ausbildung zur Durchführung psychedelischer Therapien; Rahmenbedingungen und Durchführung psychedelischer Therapien; Sicherheitsvorkehrungen; vermutete Wirkfaktoren psychedelischer Therapien und Befürchtungen und Bedenken. Die Teilnehmenden äußerten sich größtenteils optimistisch und wünschten sich eine patientennahme und risikominimierende Regulierung psychedelischer Therapien.
The evaluation of the therapy of psychiatric illnesses with serotonergic drugs or classical psychedelics, such as psilocybin or lysergic acid diethylamide (LSD) has experienced a renaissance for ca. 10 years. Although the results of larger studies particularly on depression and substance use disorders are very promising, there are methodological and regulatory questions: how can psychedelics be tested according to modern methodological standards, when blinding in randomized clinical studies is practically impossible? Is it a “biological” therapy, which only needs psychological support for ensuring the safety of the patient, or a pharmacologically augmented psychotherapy? Can the therapy with psychedelics be sufficiently described at all with the two categories of pharmacotherapy and psychotherapy or must especially here a cultural anthropological descriptive dimension be introduced? This article gives a review of the state of the art against the background of these questions.
Psychedelische Substanzen haben sich über die letzten Jahre überraschend zu neuen Hoffnungsträgern für eine Verbesserung des Therapieerfolgs in der Behandlung verschiedener psychischer Erkrankungen entwickelt. Auslöser für die Renaissance psychedelischer Therapien waren nicht allein pharmakologische Innovationen der letzten Jahre, sondern auch eine steigende Ratlosigkeit angesichts unbefriedigender Therapieergebnisse und Nebenwirkungen in Langzeittherapien, insbesondere bei schweren und rezidivierenden depressiven Erkrankungen. Studien der letzten Jahre zeigten erste, vielversprechende Behandlungserfolge psychedelischer Therapien bei Depressionen, aber auch bei Angst- und Zwangserkrankungen, Abhängigkeitserkrankungen, sowie in der Verbesserung des psychischen Zustands bei terminalen somatischen Erkrankungen.
Psychedelic microdosing describes the ingestion of near-threshold perceptible doses of classic psychedelic substances. Anecdotal reports and observational studies suggest that microdosing may promote positive mood and well-being, but recent placebo-controlled studies failed to find compelling evidence for this. The present study collected web-based mental health and related data using a prospective (before, during and after) design. Individuals planning a weekly microdosing regimen completed surveys at strategic timepoints, spanning a core four-week test period. Eighty-one participants completed the primary study endpoint. Results revealed increased self-reported psychological well-being, emotional stability and reductions in state anxiety and depressive symptoms at the four-week primary endpoint, plus increases in psychological resilience, social connectedness, agreeableness, nature relatedness and aspects of psychological flexibility. However, positive expectancy scores at baseline predicted subsequent improvements in well-being, suggestive of a significant placebo response. This study highlights a role for positive expectancy in predicting positive outcomes following psychedelic microdosing and cautions against zealous inferences on its putative therapeutic value.
Classic psychedelics produce altered states of consciousness that individuals often interpret as meaningful experiences. Across a number of human studies, when the participant-rated intensity of the overall drug effects are statistically controlled for, certain subjective effects predict therapeutic and other desirable outcomes. Underlying neurobiological mechanisms are likely necessary but not sufficient to confer full and enduring beneficial effects. We propose that the subjective effects of psychedelics are necessary for their enduring beneficial effects and that these subjective effects account for the majority of their benefit.
Public and scientific interest into psychedelic drugs has grown steadily over much of the last two decades, before an
exponential increase in recent years. We contend that 2019, in particular, involved myriad notable changes in the
science, industry, and deregulation of psychedelic drugs. However, it is becoming increasingly difficult for professionals
to keep up-to-date on these advancements given the rapid growth of the field. Further, broad contemporary synopses
are critical in maintaining records in the history of science. To address these concerns, this article synthesizes the
significant number of scientific, business, and regulatory changes related to psychedelic drugs which occurred in 2019.
Establishment of psychedelic research centers, novel applications of the drugs, and international expansion of the field in
2019 seemed to solidify psychedelic research’s place in science. Additionally, many in the business and pharmaceutical
industries stimulated considerable investment and innovation in psychedelics for the first time. In the US, successful
decriminalization efforts and endorsements by eminent political figures, such as Alexandria Ocasio-Cortez, Andrew
Yang, and the heads of the NIH and FDA, in 2019 were representative of unprecedented regulatory changes.
Collectively, this article serves as a succinct summary of the changes psychedelic drugs made across various levels of
society in 2019—by coalescing emerging research themes, industrial innovations, and attitude shifts.
There is a popular interest in microdosing with psychedelics such as LSD. This practice of using one-tenth of a full psychedelic dose according to a specific dosing schedule, anecdotally enhances mood and performance. Nonetheless, controlled research on the efficacy of microdosing is scarce. The main objective of the present dose-finding study was to determine the minimal dose of LSD needed to affect mood and cognition. A placebo-controlled within-subject study including 24 healthy participants, was conducted to assess the acute effects of three LSD doses (5, 10, and 20 mcg) on measures of cognition, mood, and subjective experience, up until 6 h after administration. Cognition and subjective experience were assessed using the Psychomotor Vigilance Task, Digit Symbol Substitution Test, Cognitive Control Task, Profile of Mood States, and 5-Dimensional Altered States of Consciousness rating scale. LSD showed positive effects in the majority of observations by increasing positive mood (20 mcg), friendliness (5, 20 mcg), arousal (5 mcg), and decreasing attentional lapses (5, 20 mcg). Negative effects manifested as an increase in confusion (20 mcg) and anxiety (5, 20 mcg). Psychedelic-induced changes in waking consciousness were also present (10, 20 mcg). Overall, the present study demonstrated selective, beneficial effects of low doses of LSD on mood and cognition in the majority of observations. The minimal LSD dose at which subjective and performance effects are notable is 5 mcg and the most apparent effects were visible after 20 mcg.
Renewed interest in the use of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances. After a hiatus of about 50 years, state-of-the art studies have recently begun to close important knowledge gaps by elucidating the mechanisms of action of psychedelics with regard to their effects on receptor subsystems, systems-level brain activity and connectivity, and cognitive and emotional processing. In addition, functional studies have shown that changes in self-experience, emotional processing and social cognition may contribute to the potential therapeutic effects of psychedelics. These discoveries provide a scientific road map for the investigation and application of psychedelic substances in psychiatry.
Introduction
Interest in the use of psychedelic substances for the treatment of mental disorders is increasing. Processes that may affect therapeutic change are not yet fully understood. Qualitative research methods are increasingly used to examine patient accounts; however, currently, no systematic review exists that synthesizes these findings in relation to the use of psychedelics for the treatment of mental disorders.
Objective
To provide an overview of salient themes in patient experiences of psychedelic treatments for mental disorders, presenting both common and diverging elements in patients’ accounts, and elucidating how these affect the treatment process.
Methods
We systematically searched the PubMed, MEDLINE, PsycINFO, and Embase databases for English-language qualitative literature without time limitations. Inclusion criteria were qualitative research design; peer-reviewed studies; based on verbalized patient utterances; and a level of abstraction or analysis of the results. Thematic synthesis was used to analyze and synthesize results across studies. A critical appraisal of study quality and methodological rigor was conducted using the Critical Appraisal Skills Programme (CASP).
Results
Fifteen research articles, comprising 178 patient experiences, were included. Studies exhibited a broad heterogeneity in terms of substance, mental disorder, treatment context, and qualitative methodology. Substances included psilocybin, lysergic acid diethylamide (LSD), ibogaine, ayahuasca, ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Disorders included anxiety, depression, eating disorders, post-traumatic stress disorder, and substance use disorders. While the included compounds were heterogeneous in pharmacology and treatment contexts, patients reported largely comparable experiences across disorders, which included phenomenological analogous effects, perspectives on the intervention, therapeutic processes and treatment outcomes. Comparable therapeutic processes included insights, altered self-perception, increased connectedness, transcendental experiences, and an expanded emotional spectrum, which patients reported contributed to clinically and personally relevant responses.
Conclusions
This review demonstrates how qualitative research of psychedelic treatments can contribute to distinguishing specific features of specific substances, and carry otherwise undiscovered implications for the treatment of specific psychiatric disorders.
Psychedelic drugs and virtual reality (VR) each have the capacity to disrupt the rigidity and limitations of typical conscious experience. This article delineates the parallels among psychedelic and VR states as well as their potential synergistic applications in clinical and recreational settings. Findings indicate that, individually, psychedelics and VR are used in analogous ways to alter sensory experience and evoke awe. They are also both used in tandem with traditional therapies to treat a variety of mood disorders; their shared capacity to transiently alter perspective and disrupt rigid patterns of mental experience may underly their analogous and transdiagnostic therapeutic uses. In terms of their combined applications, a number of recreational users currently utilize psychedelics and VR together to enhance their experience. We propose that VR may be a useful tool for preparing hallucinogen-naïve participants in clinical trials for the sensory distortions experienced in psychedelic states. Given the critical role of “setting” in psychedelic treatment outcomes, we also detail how VR could be used to optimize the environment in psychedelic sessions. Finally, we provide considerations for future studies and detail how advancements in psychedelic and VR research can inform one another. Collectively, this article outlines a number of connections between psychedelics and VR, and, more broadly, is representative of growing scientific interest into the interactions among technology, psychopharmacology, and mental health.
The efficacy of psychedelic-assisted therapies for mental disorders has been attributed to the lasting change from experiential avoidance to acceptance that these treatments appear to facilitate. This article presents a conceptual model that specifies potential psychological mechanisms underlying such change, and that shows substantial parallels between psychedelic therapy and cognitive behavioral therapy: We propose that in the carefully controlled context of psychedelic therapy as applied in contemporary clinical research, psychedelic-induced belief relaxation can increase motivation for acceptance via operant conditioning, thus engendering episodes of relatively avoidance-free exposure to greatly intensified private events. Under these unique learning conditions, relaxed avoidance-related beliefs can be exposed to corrective information and become revised accordingly, which may explain long-term increases in acceptance and corresponding reductions in psychopathology. Open research questions and implications for clinical practice are discussed.
Rationale
The regular consumption of very small doses of psychedelic drugs (known as microdosing) has been a source of growing media and community attention in recent years. However, there is currently limited clinical and social research evidence on the potential role of microdosing as therapies for mental and substance use disorders.
Objectives
This paper examined subjective experiences of microdosing psychedelics to improve mental health or to cease or reduce substance use, and examined sociodemographic and other covariates of perceived improvements in mental health that individuals attributed to microdosing.
Methods
An international online survey was conducted in 2018 and examined people’s experiences of using psychedelics for self-reported therapeutic or enhancement purposes. This paper focuses on 1102 respondents who reported current or past experience of psychedelic microdosing.
Results
Twenty-one percent of respondents reported primarily microdosing as a therapy for depression, 7% for anxiety, 9% for other mental disorders and 2% for substance use cessation or reduction. Forty-four percent of respondents perceived that their mental health was “much better” as a consequence of microdosing. In a multivariate analysis, perceived improvements in mental health from microdosing were associated with a range of variables including gender, education, microdosing duration and motivations, and recent use of larger psychedelic doses.
Conclusions
Given the promising findings of clinical trials of standard psychedelic doses as mental health therapies, clinical microdosing research is needed to determine its potential role in psychiatric treatment, and ongoing social research to better understand the use of microdosing as self-managed mental health and substance use therapies.
After two decades of quiescence, clinical psychedelic research re-started in the 1990s and is rapidly accelerating. Early evidence for effectiveness is promising, but understanding of the psychological processes of change underlying observed benefits is limited. This paper outlines contextual behavioral science (CBS) as an ideal framework for understanding psychedelic experiences and the psychological processes of change involved in psychedelic assisted therapy. This paper argues that CBS-based therapies, such as Acceptance and Commitment Therapy (ACT), can contribute to deepening and maintaining the often profound acute effects of psychedelics. The paper begins by briefly outlining the current state of clinical psychedelic research. It then progresses to outlining why CBS may be uniquely positioned to potentially increase the efficacy of psychedelic-assisted therapy, how this scientific model fits with existing data on psychedelic-assisted therapy, as well as with leading neuroscientific theories such as the entropic brain theory. Finally, it concludes by suggesting avenues for future research on how CBS could contribute to psychedelic science, and vice versa.
Background
Posttraumatic stress disorder is a prevalent mental health condition with substantial impact on daily functioning that lacks sufficient treatment options. Here we evaluate six phase 2 trials in a pooled analysis to determine the study design for phase 3 trials of MDMA-assisted psychotherapy for PTSD.
Methods
Six randomized, double-blind, controlled clinical trials at five study sites were conducted from April 2004 to February 2017. Active doses of MDMA (75–125 mg, n = 72) or placebo/control doses (0–40 mg, n = 31) were administered to individuals with PTSD during manualized psychotherapy sessions in two or three 8-h sessions spaced a month apart. Three non-drug 90-min therapy sessions preceded the first MDMA exposure, and three to four followed each experimental session.
Results
After two blinded experimental sessions, the active group had significantly greater reductions in CAPS-IV total scores from baseline than the control group [MMRM estimated mean difference (SE) between groups − 22.0 (5.17), P < 0.001]. The between-group Cohen’s d effect size was 0.8, indicating a large treatment effect. After two experimental sessions, more participants in the active group (54.2%) did not meet CAPS-IV PTSD diagnostic criteria than the control group (22.6%). Depression symptom improvement on the BDI-II was greatest for the active group compared to the control group, although only trended towards significant group differences [MMRM, estimated mean difference (SE) between groups − 6.0 (3.03), P = 0.053]. All doses of MDMA were well tolerated, with some expected reactions occurring at greater frequency for the active MDMA group during experimental sessions and the 7 days following.
Conclusions
MDMA-assisted psychotherapy was efficacious and well tolerated in a large sample of adults with PTSD. These studies supported expansion into phase 3 trials and led to FDA granting Breakthrough Therapy designation for this promising treatment.
Trial registration
ClinicalTrials.gov Identifier: NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610.
Background:
Psychedelic therapy is gaining recognition and the nature of the psychedelic experience itself has been found to mediate subsequent long-term psychological changes. Much emphasis has been placed on the occurrence of mystical-type experiences in determining long-term responses to psychedelics yet here we demonstrate the importance of another component, namely: emotional breakthrough.
Methods:
Three hundred and seventy-nine participants completed online surveys before and after a planned psychedelic experience. Items pertaining to emotional breakthrough were completed one day after the psychedelic experience, as were items comprising the already validated Mystical Experience Questionnaire and the Challenging Experience Questionnaire. Emotional breakthrough, Mystical Experience Questionnaire and Challenging Experience Questionnaire scores were used to predict changes in well-being (Warwick-Edinburgh Mental Wellbeing Scale) in a subsample of 75 participants with low well-being baseline scores (⩽45).
Results:
Factor analyses revealed six emotional breakthrough items with high internal consistency (Cronbach’s alpha=0.932) and supported our prior hypothesis that emotional breakthrough is a distinct component of the psychedelic experience. Emotional breakthrough scores behaved dose-dependently, and were higher if the psychedelic was taken with therapeutic planning and intent. Emotional breakthrough, Mystical Experience Questionnaire and Challenging Experience Questionnaire scores combined, significantly predicted subsequent changes in well-being (r=0.45, p=0.0005, n=75), with each scale contributing significant predictive value. Emotional breakthrough and Mystical Experience Questionnaire scores predicted increases in well-being and Challenging Experience Questionnaire scores predicted less increases.
Conclusions:
Here we validate a six-item ‘Emotional Breakthrough Inventory’. Emotional breakthrough is an important and distinct component of the acute psychedelic experience that appears to be a key mediator of subsequent longer-term psychological changes. Implications for psychedelic therapy are discussed.
The paucity of medications with novel mechanisms for the treatment of mental illnesses combined with the delayed response to currently available medications has led to great excitement about the potential therapeutic utility of previously demonized drugs, which offer the hope of generating rapid symptom reductions in some of the sickest patients. Within the past 2 years, the US Food and Drug Administration approved esketamine for treatment-resistant depression and 2 compounds that are still on the US Drug Enforcement Administration’s most restrictive schedule, 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin, have received breakthrough therapy designation. If these latter drugs are approved, they will require a new mental health care infrastructure that is capable of administering powerful psychoactive substances while simultaneously incorporating appropriate psychotherapeutic support. The sheer prevalence of the conditions these drugs are meant to treat (depression and posttraumatic stress disorder among other emerging indications) will mean that clinicians will have to deal with safety issues, including appropriate patient selection, substance abuse potential, and emergent psychiatric and medical crises. These considerations justify investment in elucidating the detailed neural mechanisms by which these drugs work so that we might better control their safety and efficacy while simultaneously developing better treatments with fewer adverse effects.
Contemporary research with classic psychedelic drugs (e.g., lysergic acid diethylamide (LSD) and psilocybin) is indebted to the twentieth-century researchers and clinicians who generated valuable clinical knowledge of these substances through experimentation. Several recent reviews that highlight the contributions of this early literature have focused on psychedelic-assisted individual psychotherapy modalities. None have attempted to systematically identify and compile experimental studies of psychedelic-assisted group therapy. In therapeutic settings, psychedelics were often used to enhance group therapy for a variety of populations and clinical indications. We report on the results of a systematic review of the published literature in English and Spanish on psychedelic-assisted group therapies. Publications are characterized by their clinical approach, experimental method, and clinical outcomes. Given the renewed interest in the clinical use of psychedelic medicines, this review aims to stimulate hypotheses to be tested in future research on psychedelic-assisted psychotherapy, group process, and interpersonal functioning.
The main psychedelic component of magic mushrooms is psilocybin, which shows promise as a treatment for depression and other mental disorders. Psychedelic effects are believed to emerge through stimulation of serotonin 2A receptors (5-HT2ARs) by psilocybin’s active metabolite, psilocin. We here report for the first time the relationship between intensity of psychedelic effects, cerebral 5-HT2AR occupancy and plasma levels of psilocin in humans. Eight healthy volunteers underwent positron emission tomography (PET) scans with the 5-HT2AR agonist radioligand [11C]Cimbi-36: one at baseline and one or two additional scans on the same day after a single oral intake of psilocybin (3–30 mg). 5-HT2AR occupancy was calculated as the percent change in cerebral 5-HT2AR binding relative to baseline. Subjective psychedelic intensity and plasma psilocin levels were measured during the scans. Relations between subjective intensity, 5-HT2AR occupancy, and plasma psilocin levels were modeled using non-linear regression. Psilocybin intake resulted in dose-related 5-HT2AR occupancies up to 72%; plasma psilocin levels and 5-HT2AR occupancy conformed to a single-site binding model. Subjective intensity was correlated with both 5-HT2AR occupancy and psilocin levels as well as questionnaire scores. We report for the first time that intake of psilocybin leads to significant 5-HT2AR occupancy in the human brain, and that both psilocin plasma levels and 5-HT2AR occupancy are closely associated with subjective intensity ratings, strongly supporting that stimulation of 5-HT2AR is a key determinant for the psychedelic experience. Important for clinical studies, psilocin time-concentration curves varied but psilocin levels were closely associated with psychedelic experience.
This narrative review examines evidence related to the potential for third wave behaviour
therapies to serve as adjuncts to psychedelic-assisted therapy. It identifies shared theoretical foundations for both approaches, and notes enhanced mindfulness, decentering, emotion regulation, and distress tolerance as common mechanisms of action. It also identifies potential targets for which both approaches have demonstrated therapeutic potential, including problematic substance use, self-directed and other-directed violence, and mood disorders. Based on these commonalities, there is a call for research on the potential integration of psychedelic-assisted therapy and third wave behaviour therapies including Dialectical Behaviour Therapy, Acceptance and Commitment Therapy, and Mindfulness Based Cognitive Therapy.
Clinical research on psychedelic-assisted psychotherapy is rapidly advancing in the USA, with two drugs, psilocybin and MDMA, progressing through a structure of FDA-approved trials on a trajectory toward Drug Enforcement Agency rescheduling for therapeutic use. Researcher’s and clinician’s personal use of psychedelics was cited as a potential confound in psychedelic research studies conducted in the 1950s and 1960s, a concern which contributed to the cessation of this research for some 20 years. Currently, there is no empirical research on personal use of psychedelics by current academic researchers and clinicians; its influence is undocumented, unknown, and undertheorized. This paper explores the history of personal use of psychedelics by clinicians and researchers, the potential impact of personal use on psychedelic-assisted psychotherapy and research, and the rationale for opening an academic discussion and program of research to investigate the role of personal use. We propose that there are factors unique to psychedelic-assisted therapy such that training for it cannot neatly fit into the framework of modern psychopharmacology training, nor be fully analogous to psychotherapy training in contemporary psychological and psychiatric settings. We argue that scientific exploration of the influence of therapists’ first-hand experience of psychedelics on psychedelic-assisted therapy outcomes is feasible, timely, and necessary for the future of clinical research.
How do psychedelic drugs produce their characteristic range of acute effects in perception, emotion, cognition, and sense of self? How do these effects relate to the clinical efficacy of psychedelic-assisted therapies? Efforts to understand psychedelic phenomena date back more than a century in Western science. In this article I review theories of psychedelic drug effects and highlight key concepts which have endured over the last 125 years of psychedelic science. First, I describe the subjective phenomenology of acute psychedelic effects using the best available data. Next, I review late 19th-century and early 20th-century theories—model psychoses theory, filtration theory, and psychoanalytic theory—and highlight their shared features. I then briefly review recent findings on the neuropharmacology and neurophysiology of psychedelic drugs in humans. Finally, I describe recent theories of psychedelic drug effects which leverage 21st-century cognitive neuroscience frameworks—entropic brain theory, integrated information theory, and predictive processing—and point out key shared features that link back to earlier theories. I identify an abstract principle which cuts across many theories past and present: psychedelic drugs perturb universal brain processes that normally serve to constrain neural systems central to perception, emotion, cognition, and sense of self. I conclude that making an explicit effort to investigate the principles and mechanisms of psychedelic drug effects is a uniquely powerful way to iteratively develop and test unifying theories of brain function.
Psychedelic drugs are making waves as modern trials support their therapeutic potential and various media continue to pique public interest. In this opinion piece, we draw attention to a long-recognised component of the psychedelic treatment model, namely ‘set’ and ‘setting’ – subsumed here under the umbrella term ‘context’. We highlight: (a) the pharmacological mechanisms of classic psychedelics (5-HT2A receptor agonism and associated plasticity) that we believe render their effects exceptionally sensitive to context, (b) a study design for testing assumptions regarding positive interactions between psychedelics and context, and (c) new findings from our group regarding contextual determinants of the quality of a psychedelic experience and how acute experience predicts subsequent long-term mental health outcomes. We hope that this article can: (a) inform on good practice in psychedelic research, (b) provide a roadmap for optimising treatment models, and (c) help tackle unhelpful stigma still surrounding these compounds, while developing an evidence base for long-held assumptions about the critical importance of context in relation to psychedelic use that can help minimise harms and maximise potential benefits.
Research since the 1950s has shown that psychedelic-assisted psychotherapy has had significant positive effects in reductions of specific clinical symptoms and increases in quality of life as measured on a variety of indices. The intensity of focus on evidence-based outcomes, however, has resulted in a paucity of active discussions and research on the core competencies of the therapists themselves. The context of the history of psychedelic research reveals how this neglect of therapist variables occurred. With current discussions of Phase 3 and expanded access research programs for psilocybin-assisted and MDMA-assisted psychotherapies, there will be a great need for competent therapists trained in this clinical specialty. This is particularly the case if less restricted, legal medical use is approved within the next 6 to 10 years. This article is the first review and compilation of psychedelic therapist competencies derived from the psychedelic literature. These six therapist competencies are empathetic abiding presence; trust enhancement; spiritual intelligence; knowledge of the physical and psychological effects of psychedelics; therapist self-awareness and ethical integrity; and proficiency in complementary techniques. A further contribution of this review is a delineation of the 12 fundamental curricular domains of study for the training and development of these therapist competencies. As current legal restrictions evolve, aspects of these training guidelines will develop accordingly.
A growing body of research suggests that traumatic events lead to persisting personality change characterized by increased neuroticism. Relevantly, enduring improvements in Post-Traumatic Stress Disorder (PTSD) symptoms have been found in response to 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy. There is evidence that lasting changes in the personality feature of “openness” occur in response to hallucinogens, and that this may potentially act as a therapeutic mechanism of change. The present study investigated whether heightened Openness and decreased Neuroticism served as a mechanism of change within a randomized trial of MDMA-assisted psychotherapy for chronic, treatment-resistant PTSD. The Clinician-Administered PTSD Scale (CAPS) Global Scores and NEO PI-R Personality Inventory (NEO) Openness and Neuroticism Scales served as outcome measures. Results indicated that changes in Openness but not Neuroticism played a moderating role in the relationship between reduced PTSD symptoms and MDMA treatment. Following MDMA-assisted psychotherapy, increased Openness and decreased Neuroticism when comparing baseline personality traits with long-term follow-up traits also were found. These preliminary findings suggest that the effect of MDMA-assisted psychotherapy extends beyond specific PTSD symptomatology and fundamentally alters personality structure, resulting in long-term persisting personality change. Results are discussed in terms of possible mechanisms of psychotherapeutic change.
There is converging evidence that high doses of hallucinogenic drugs can produce significant alterations of self-experience, described as the dissolution of the sense of self and the loss of boundaries between self and world. This article discusses the relevance of this phenomenon, known as “drug-induced ego dissolution (DIED)”, for cognitive neuroscience, psychology and philosophy of mind. Data from self-report questionnaires suggest that three neuropharmacological classes of drugs can induce ego dissolution: classical psychedelics, dissociative anesthetics and agonists of the kappa opioid receptor (KOR). While these substances act on different neurotransmitter receptors, they all produce strong subjective effects that can be compared to the symptoms of acute psychosis, including ego dissolution. It has been suggested that neuroimaging of DIED can indirectly shed light on the neural correlates of the self. While this line of inquiry is promising, its results must be interpreted with caution. First, neural correlates of ego dissolution might reveal the necessary neurophysiological conditions for the maintenance of the sense of self, but it is more doubtful that this method can reveal its minimally sufficient conditions. Second, it is necessary to define the relevant notion of self at play in the phenomenon of DIED. This article suggests that DIED consists in the disruption of subpersonal processes underlying the “minimal” or “embodied” self, i.e., the basic experience of being a self rooted in multimodal integration of self-related stimuli. This hypothesis is consistent with Bayesian models of phenomenal selfhood, according to which the subjective structure of conscious experience ultimately results from the optimization of predictions in perception and action. Finally, it is argued that DIED is also of particular interest for philosophy of mind. On the one hand, it challenges theories according to which consciousness always involves self-awareness. On the other hand, it suggests that ordinary conscious experience might involve a minimal kind of self-awareness rooted in multisensory processing, which is what appears to fade away during DIED.
The psychological mechanisms of action involved in psilocybin-assisted psychotherapy are not yet well understood. Despite a resurgence of quantitative research regarding psilocybin, the current study is the first qualitative study of participant experiences in psilocybin-assisted psychotherapy. Semistructured interviews were carried out with 13 adult participants aged 22 to 69 years (M = 50 years) with clinically elevated anxiety associated with a cancer diagnosis. Participants received a moderate dose of psilocybin and adjunctive psychotherapy with an emphasis on the process of meaning-making. Verbatim transcribed interviews were analyzed by a five-member research team using interpretative phenomenological analysis. General themes found in all or nearly all transcripts included relational embeddedness, emotional range, the role of music as conveyor of experience, meaningful visual phenomena, wisdom lessons, revised life priorities, and a desire to repeat the psilocybin experience. Typical themes found in the majority of transcripts included the following: exalted feelings of joy, bliss, and love; embodiment; ineffability; alterations to identity; a movement from feelings of separateness to interconnectedness; experiences of transient psychological distress; the appearance of loved ones as guiding spirits; and sharing the experience with loved ones posttreatment. Variant themes found in a minority of participant transcripts include lasting changes to sense of identity, synesthesia experiences, catharsis of powerful emotion, improved relationships after treatment, surrender or “letting go,” forgiveness, and a continued struggle to integrate experience. The findings support the conclusion that psilocybin-assisted psychotherapy may provide an effective treatment for psychological distress in cancer patients. Implications for theory and treatment are discussed.
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 day 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.Neuropsychopharmacology accepted article preview online, 27 April 2017. doi:10.1038/npp.2017.86.
The Internationalization of Ayahuasca is composed of 27 articles (almost 500 pages)
and is divided in three parts: “Ayahuasca in South America and the world”, “About medical,
psychological and pharmacological Issues: is the use of ayahuasca safe?” and “The expansion
of the use of Ayahuasca and the establishment of a global debate on ethics and legalization”.
The book brings together the work of scholars from different countries and academic
disciplines to offer a comprehensive view of the globalization of this Amazonian brew. It presents
a rich array of reflections on the complex implications of this expansion, ranging from
health, spiritual and human rights impacts on individuals, to legal and policy impacts on governments.
As ayahuasca drinking becomes an increasingly established practice beyond the
Amazon in the early 21st century, Labate and Jungaberle have put together a collection that is
an unprecedented contribution to a growing field of research. It is a must-read for people interested
in the present and future of ayahuasca, as well as in spirituality, ethnobotany, social
science theory, contemporary religious and ritual studies, therapeutic potentials of psychedelics,
and international drug policy. (Kenneth W. Tupper, Ph.D.)
Selective serotonin reuptake inhibitors (SSRIs) represent the most common treatment for major depression. However, their efficacy is variable and incomplete. In order to elucidate the cause of such incomplete efficacy, we explored the hypothesis positing that SSRIs may not affect mood per se but, by enhancing neural plasticity, render the individual more susceptible to the influence of the environment. Consequently, SSRI administration in a favorable environment promotes a reduction of symptoms, whereas in a stressful environment leads to a worse prognosis. To test such hypothesis, we exposed C57BL/6 mice to chronic stress in order to induce a depression-like phenotype and, subsequently, to fluoxetine treatment (21 days), while being exposed to either an enriched or a stressful condition. We measured the most commonly investigated molecular, cellular and behavioral endophenotypes of depression and SSRI outcome, including depression-like behavior, neurogenesis, brain-derived neurotrophic factor levels, hypothalamic–pituitary–adrenal axis activity and long-term potentiation. Results showed that, in line with our hypothesis, the endophenotypes investigated were affected by the treatment according to the quality of the living environment. In particular, mice treated with fluoxetine in an enriched condition overall improved their depression-like phenotype compared with controls, whereas those treated in a stressful condition showed a distinct worsening. Our findings suggest that the effects of SSRI on the depression-like phenotype is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions.
A double-blind, randomized, active placebo-controlled pilot study was conducted to examine safety and efficacy of lysergic acid diethylamide (LSD)-assisted psychotherapy in 12 patients with anxiety associated with life-threatening diseases. Treatment included drug-free psychotherapy sessions supplemented by two LSD-assisted psychotherapy sessions 2 to 3 weeks apart. The participants received either 200 μg of LSD (n = 8) or 20 μg of LSD with an open-label crossover to 200 μg of LSD after the initial blinded treatment was unmasked (n = 4). At the 2-month follow-up, positive trends were found via the State-Trait Anxiety Inventory (STAI) in reductions in trait anxiety (p = 0.033) with an effect size of 1.1, and state anxiety was significantly reduced (p = 0.021) with an effect size of 1.2, with no acute or chronic adverse effects persisting beyond 1 day after treatment or treatment-related serious adverse events. STAI reductions were sustained for 12 months. These results indicate that when administered safely in a methodologically rigorous medically supervised psychotherapeutic setting, LSD can reduce anxiety, suggesting that larger controlled studies are warranted.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
Although psilocybin has been used for centuries for religious purposes, little is known scientifically about its acute and persisting effects.
This double-blind study evaluated the acute and longer-term psychological effects of a high dose of psilocybin relative to a comparison compound administered under comfortable, supportive conditions.
The participants were hallucinogen-naïve adults reporting regular participation in religious or spiritual activities. Two or three sessions were conducted at 2-month intervals. Thirty volunteers received orally administered psilocybin (30 mg/70 kg) and methylphenidate hydrochloride (40 mg/70 kg) in counterbalanced order. To obscure the study design, six additional volunteers received methylphenidate in the first two sessions and unblinded psilocybin in a third session. The 8-h sessions were conducted individually. Volunteers were encouraged to close their eyes and direct their attention inward. Study monitors rated volunteers' behavior during sessions. Volunteers completed questionnaires assessing drug effects and mystical experience immediately after and 2 months after sessions. Community observers rated changes in the volunteer's attitudes and behavior.
Psilocybin produced a range of acute perceptual changes, subjective experiences, and labile moods including anxiety. Psilocybin also increased measures of mystical experience. At 2 months, the volunteers rated the psilocybin experience as having substantial personal meaning and spiritual significance and attributed to the experience sustained positive changes in attitudes and behavior consistent with changes rated by community observers.
When administered under supportive conditions, psilocybin occasioned experiences similar to spontaneously occurring mystical experiences. The ability to occasion such experiences prospectively will allow rigorous scientific investigations of their causes and consequences.
The “Generic Model of Psychotherapy” was initially presented 25 years ago (Orlinsky & Howard, 1984) and was conceived as a transtheoretical frame for integrating the varied empirical findings of hundreds of studies relating therapeutic process to outcome that had appeared during the previous 3 decades into a coherent body of knowledge (Orlinsky & Howard, 1986). This article briefly reviews the conceptual model as an integrative metatheory for research and practice and traces its continued growth based on subsequent innovations in process–outcome research, reflections on the human contexts of psychotherapy, and current limitations in the field of psychotherapy research. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
This paper addresses the question of what happens to consciousness under the influence of psychedelic drugs—specifically of psilocybin, or “magic” mushrooms— and performs a Foucauldian discourse analysis upon the answers that have been variously proposed. Predominant societally legitimated answers (the pathological, psychological, and prohibition discourses) are those that, in Foucault's sense, are imposed from the outside as “scientific classifications,” that is, they are based upon observations of the effects of mushrooms on others. By contrast, a series of resistive discourses (the recreational, psychedelic, entheogenic, and animistic discourses) have been constructed in opposition, as a means of making sense of the subjective experience of taking mushrooms. When critiqued, only the animistic discourse— the belief that mushrooms occasion encounters with discarnate spirit entities, or animaphany—transgresses a fundamental societal boundary. In the West, to believe in the existence of spirits is to risk being labeled “mad,” and as such the phenomenon of mushroom-induced animaphany goes largely ignored. It nevertheless remains a phenomenon in need of further scholarly research.
Classical psychedelics, primarily psilocybin and lysergic acid diethylamide (LSD), have been used and extensively studied in Western medicine as part of substance-assisted psychotherapy in the 1950s and 1960s. Modern clinical research is currently gaining momentum and provides new evidence for the safety and efficacy of classical psychedelics (primarily psilocybin, but also LSD and ayahuasca) in the treatment of different psychiatric conditions, including substance use and mood disorders.
In this review article, we outline common pathological mechanisms of substance use disorders (SUD) and unipolar depression. Next, the current literature on the effects of psychedelics is summarized in order to generate hypotheses regarding their potential therapeutic mechanisms of action in treating these psychiatric conditions. Finally, we review and discuss clinical trials published since 2011 investigating the effects of psychedelics in SUD and depression.
While results from those modern clinical trials are promising, most of them do not meet the methodological requirements to allow firm conclusions on the clinical efficacy of psychedelics. Larger, blinded, randomized controlled trials (RCT) with clearly defined patient groups and well-defined primary endpoints are needed. Additionally, the therapeutic mechanisms of classical psychedelics are currently unknown. This review presents hypotheses derived from preclinical and human studies that need to be tested in future trials to better understand the clinical potential of psychedelic substances in modern psychiatry.
Initial interest in the value of psychedelic drugs (“psychotomimetics”) in psychiatry began in the early 20th century, with explorations of the possibility that mescaline or peyote could produce psychosis-like effects. Over time, interest was focused on whether the effects of psychedelics could inform as to the underlying basis for psychiatric disorders. As research continued, and especially after the discovery of LSD in 1943, increasing interest in a role for psychedelics as adjuncts to psychotherapy began to evolve and became the major focus of work with psychedelics up to the present day.
Psychedelics have shown great promise in modern clinical trials for treating various psychiatric conditions. As a transdiagnostic treatment that exerts its effects through subjective experiences that leave enduring effects, it is akin to psychotherapy. To date, there has been insufficient discussion of how psychedelic therapy is similar to and different from conventional psychotherapy. In this article, we review the shared features of effective conventional psychotherapies and situate therapeutic psychedelic effects within those. We then discuss how psychedelic drug effects might amplify conventional psychotherapeutic processes—particularly via effects on meaning and relationship—as well as features that make psychedelic treatment unique. Taking into account shared features of conventional psychotherapies and unique psychedelic drug effects, we create a framework for understanding why psychedelics are likely to be effective with very diverse types of psychotherapies. We also review the formal psychotherapies that have been adjunctively included in modern psychedelic trials and extend the understanding of psychedelics as psychotherapy towards implications for clinical ethics and trial design. We aim to provide some common conceptual vocabulary that can be used to frame therapeutic psychedelic effects beyond the confines of any one specific modality.
Psychedelics represent one of the most promising classes of experimental medicines for the treatment of neuropsychiatric disorders due to their ability to promote neural plasticity and produce both rapid and sustained therapeutic effects following a single administration. Conventional wisdom holds that peak mystical experiences induced by psychedelics are a critical component of their therapeutic mechanisms of action, though evidence supporting that claim is largely correlational. Here, I present data suggesting that the subjective effects induced by psychedelics may not be necessary to produce long-lasting changes in mood and behavior. Understanding the role of subjective effects in the therapeutic mechanisms of psychedelics will have important implications for both basic neuroscience and for increasing patient access to the next generation of medicines developed as a result of psychedelic research.
Research into the basic effects and therapeutic applications of psychedelic drugs has grown considerably in recent years. Yet, pressing questions remain regarding the substances’ lasting effects. Although individual studies have begun monitoring sustained changes, no study to-date has synthesized this information. Therefore, this systematic review aims to fill this important gap in the literature by synthesizing results from 34 contemporary experimental studies which included classic psychedelics, human subjects, and follow-up latencies of at least two weeks. The bulk of this work was published in the last five years, with psilocybin being the most frequently administered drug. Enduring changes in personality/attitudes, depression, spirituality, anxiety, wellbeing, substance misuse, meditative practices, and mindfulness were documented. Mystical experiences, connectedness, emotional breakthrough, and increased neural entropy were related to these long-term changes in psychological functioning. Finally, with proper screening, preparation, supervision, and integration, limited aversive side effects were noted by study participants. Future researchers should focus on including larger and more diverse samples, lengthier longitudinal designs, stronger control conditions, and standardized dosages.
Humans have used serotonergic hallucinogens (i.e. psychedelics) for spiritual, ceremonial, and recreational purposes for thousands of years, but their administration as part of a structured therapeutic intervention is still a relatively novel practice within Western medical and psychological frameworks. In the mid-20th century, considerable advances were made in developing therapeutic approaches integrating administration of low (psycholytic) and high (psychedelic) doses of serotonergic hallucinogens for treatment of a variety of conditions, often incorporating psychoanalytic concepts prevalent at that time. This work contributed seminal insights regarding how these substances may be employed with efficacy and safety in targeted therapeutic interventions, including the importance of optimizing set (frame of mind) and setting (therapeutic environment). More recently, clinical and pharmacological research has revisited the effects and therapeutic potential of psychedelics utilizing a variety of approaches. The current article provides an overview of past and present models of psychedelic therapy, and discusses important considerations for future interventions incorporating the use of psychedelics in research and clinical practice.
Purpose of review:
Psychedelics are reawakening interest from psychiatry, cognitive neuroscience and the general public with impressive outcomes in small-scale clinical trials, intriguing human brain imaging work and high-impact journalism.
Recent findings:
This brief opinion piece offers a perspective on how psychedelics work in the brain that may help contextualize these developments. It attempts to link various scales of action, from the molecular (serotonin 2A receptor agonism) through to the anatomical and functional (heightened plasticity) and up to the dynamic (increased brain entropy), systems level (network disintegration and desegregation) and experiential.
Summary:
It is proposed that psychedelics initiate a cascade of neurobiological changes that manifest at multiple scales and ultimately culminate in the relaxation of high-level beliefs. The purpose of psychedelic therapy is to harness the opportunity afforded by this belief-relaxation to achieve a healthy revision of pathological beliefs.
‘Rat Park’ is the name given to a series of studies undertaken in the late 1970s by Bruce K. Alexander and colleagues. They found that rats housed in enriched environments consumed less morphine solution than those in isolated cages, when rats were pre‐exposed to morphine, naïve to morphine, and whether they had spent their early life in isolation or in enriched housing. The measured conclusions from the authors at the time have become somewhat lost in translation.
Serotonergic psychedelics act as agonists at cortical 5-HT2Areceptors and seem to induce personality changes. We conducted a systematic review of studies assessing the effects of these drugs on personality. Papers published from 1985 to 2016 were included from PubMed, LILACS, and SciELO databases. Three hundred and sixty-nine studies were identified, and 18 were included. Specific personality traits, such as Absorption and Self-Transcendence, seem to influence the effects of psychedelics, and psychedelic drug users and nonusers appear to differ in some personality traits. Psychedelics administered in controlled settings may induce personality changes, such as increased Openness and Self-Transcendence. Increases in global brain entropy induced by acute psychedelic administration predicted changes in Openness, and Self-Transcendence was negatively correlated with cortical thinning of the posterior cingulate cortex in long-term religious ayahuasca users. Acute and long-term use of psychedelics is associated with personality changes that appear to be modulated by 5-HT2Areceptors. These changes seem to induce therapeutic effects that should be further explored in randomized controlled studies.
Zusammenfassung
Hintergrund Der Einsatz von serotonergen Halluzinogenen (Psychedelika) wie Lysergsäure-Diethylamid (LSD) und Psilocybin und Entaktogenen wie 3,4-Methylendioxymethamphetamin (MDMA) im Rahmen von Psychotherapie ist in den letzten Jahren wieder zunehmend ins Licht des wissenschaftlichen Interesses gerückt. Die vorliegende Arbeit fasst die aktuelle Evidenz zur substanzunterstützten Psychotherapie mit serotonergen Psychoaktiva zusammen.
Methode Eine selektive Literaturrecherche erfolgte in PubMed und der Cochrane Library, wobei nach Studien gesucht wurde, in denen der Einsatz von serotonergen Psychoaktiva in der Psychotherapie seit 2000 untersucht wurde.
Ergebnisse Es fanden sich Studien für die folgenden Behandlungsindikationen: Alkoholabhängigkeit (LSD und Psilocybin), Nikotinabhängigkeit (Psilocybin), Behandlung von Angst und Depression bei lebensbedrohlicher körperlicher Erkrankung (LSD und Psilocybin), Zwangsstörungen (Psilocybin), therapieresistente Major Depression (Psilocybin) und posttraumatische Belastungsstörung (MDMA).
Diskussion Abhängigkeitserkrankungen, posttraumatische Belastungsstörung sowie Angst und Depression bei lebensbedrohlicher körperlicher Erkrankung stellen derzeit die am besten evaluierten Indikationen für die substanzunterstützte Psychotherapie mit serotonergen Psychoaktiva dar. Bisher zeigten sich Hinweise für eine Wirksamkeit bei relativ guter Verträglichkeit. Weitere Studien sind erforderlich, um einzuschätzen, ob diese Substanzen in Zukunft in der Behandlung bestimmter therapieresistenter psychischer Erkrankungen eine Option darstellen können.
Most currently available antidepressants target monoamine neurotransmitter function. However, a purely neurotransmitter-based explanation for antidepressant drug action is challenged by the delayed clinical onset of most agents and the need to explain how neurochemical changes reverse the many different symptoms of depression. Novel approaches to understanding of antidepressant drug action include a focus on early changes in emotional and social processing and the role of neural plasticity. In this Review, we discuss the ways in which these two different theories reflect different or complementary approaches, and how they might be integrated to offer novel solutions for people with depression. We consider the predictions made by these mechanistic approaches for the stratification and development of new therapeutics for depression, and the next steps that need to be made to facilitate this translation of science to the clinic.
Set and setting is a term which refers to the psychological, social, and cultural parameters which shape the response to psychedelic drugs. The concept is considered fundamental to psychedelic research and has also been used to describe nonpharmacological factors which shape the effects of other agents such as alcohol, heroin, amphetamines, or cocaine. This paper reviews the history and evolution of the concept of set and setting from the 19th-century Parisian Club des Hashischins, through to 1950s psychotomimetic research on nondrug determinants of psychopharmacology, the use of extra-drug techniques by psychedelic therapists of the 1950s, and the invention of the concept of set and setting by Leary. Later developments and expansions on the concept of set and setting are discussed, and the term of collective set and setting is suggested as a theoretical tool to describe the social forces which shape individual set and setting situations. The concept of set and setting, it is argued, is crucial not only for psychedelic research but also for advancing drug research and developing more effective drug policy.
Background:
A recent open-label pilot study (N = 15) found that two to three moderate to high doses (20 and 30 mg/70 kg) of the serotonin 2A receptor agonist, psilocybin, in combination with cognitive behavioral therapy (CBT) for smoking cessation, resulted in substantially higher 6-month smoking abstinence rates than are typically observed with other medications or CBT alone.
Objectives:
To assess long-term effects of a psilocybin-facilitated smoking cessation program at ≥12 months after psilocybin administration.
Methods:
The present report describes biologically verified smoking abstinence outcomes of the previous pilot study at ≥12 months, and related data on subjective effects of psilocybin.
Results:
All 15 participants completed a 12-month follow-up, and 12 (80%) returned for a long-term (≥16 months) follow-up, with a mean interval of 30 months (range = 16-57 months) between target-quit date (i.e., first psilocybin session) and long-term follow-up. At 12-month follow-up, 10 participants (67%) were confirmed as smoking abstinent. At long-term follow-up, nine participants (60%) were confirmed as smoking abstinent. At 12-month follow-up 13 participants (86.7%) rated their psilocybin experiences among the five most personally meaningful and spiritually significant experiences of their lives.
Conclusion:
These results suggest that in the context of a structured treatment program, psilocybin holds considerable promise in promoting long-term smoking abstinence. The present study adds to recent and historical evidence suggesting high success rates when using classic psychedelics in the treatment of addiction. Further research investigating psilocybin-facilitated treatment of substance use disorders is warranted.
Health-related psychedelic research should focus on helping us flourish, not just remedying ill-health or addiction. We don’t know enough about how psychedelics could enhance human flourishing. Factors promoting health-through-flourishing include finding meaning in life, spiritual practices, comfortable levels of social bonds, emotionally/physically satisfying sex in a long-term monogamous relationship and control over one’s daily life. Psychedelic research could find more. Neuroscience anchors psychedelic research into disease and disorder, e.g. addiction, PSTD, migraine, anxiety, pain etc. Neurophenomenological psychedelics research could illuminate relationships between health, ASC/NOSCs and cognitive liberty to promote human flourishing. If we accept the self as an epiphenomenon of subsystems within the brain, we ‘know’ ‘unconsciously’, but are not aware of, many things which affect our lives profoundly. These include control over identifying, remembering and forgetting our states of mind and how to move between them. A prerequisite for integrated investigations into ASC/NOSCs is the establishment of a taxonomic knowledge base which lists, categorises and characterises ASC/NOSCs to enable us to choose specific states of mind and move securely among them. Or, in other words, to enable us to exercise our cognitive liberty safely. I believe that human health and flourishing would be enhanced were we able to direct our states of being by consciously choosing them. Given the promise of mindfulness techniques to enhance our health, happiness and spiritual growth, constructing both personal and generic classifications of salient ASC/NOSCs makes sense. Laws need to change. The neuroscience of pleasure, love, spirituality, decision-making, pattern recognition and location of meaning should inform health-enhancing psychedelic research while promoting flourishing through cognitive liberty. As part of cognitive liberty, our end-of-life choices should include how we die. In other words, our idea of the good death should include access to psychedelics. Dying high is increasingly likely to become a popular choice as baby boomers age and place their economic clout behind the reform of end-of-life laws as well as drug laws. Achieving such crucial legal changes depends partly on the ability to produce research to anchor evidence based law and policy. Research into psychedelics, ASC/NOSCs and the neurobiology of the dying process is essential.
In this chapter, I would like to discuss the discovery and development of the centrally acting 1,4-benzodiazepines which started with the synthesis and pharmacological evaluation of a compound which is the active ingredient of Librium and is now known by the generic name chlordiazepoxide.