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Post-acute psychological effects of classical serotonergic psychedelics: A systematic review and meta-analysis
Abstract
Background:
Scientific interest in the therapeutic effects of classical psychedelics has increased in the past two decades. The psychological effects of these substances outside the period of acute intoxication have not been fully characterized. This study aimed to: (1) quantify the effects of psilocybin, ayahuasca, and lysergic acid diethylamide (LSD) on psychological outcomes in the post-acute period; (2) test moderators of these effects; and (3) evaluate adverse effects and risk of bias.
Methods:
We conducted a systematic review and meta-analysis of experimental studies (single-group pre-post or randomized controlled trials) that involved administration of psilocybin, ayahuasca, or LSD to clinical or non-clinical samples and assessed psychological outcomes ⩾24 h post-administration. Effects were summarized by study design, timepoint, and outcome domain.
Results:
A total of 34 studies (24 unique samples, n = 549, mean longest follow-up = 55.34 weeks) were included. Classical psychedelics showed significant within-group pre-post and between-group placebo-controlled effects on a range of outcomes including targeted symptoms within psychiatric samples, negative and positive affect-related measures, social outcomes, and existential/spiritual outcomes, with large between-group effect in these domains (Hedges' gs = 0.84 to 1.08). Moderator tests suggest some effects may be larger in clinical samples. Evidence of effects on big five personality traits and mindfulness was weak. There was no evidence of post-acute adverse effects.
Conclusions:
High risk of bias in several domains, heterogeneity across studies, and indications of publication bias for some models highlight the need for careful, large-scale, placebo-controlled randomized trials.
... Research on the therapeutic effects of meditation practices, while well established, is still ongoing, and in the case of psychedelic use, it is nascent. Nevertheless, recent systematic reviews and meta-analyses suggest that both meditation practice and psychedelic use may be beneficial for a range of psychological symptoms [11][12][13][14][15]. ...
... One potential reason that psychedelics may positively enhance the potential impact of meditation practice on psychological outcomes is that psychedelic use itself may increase one's levels of mindfulness [13,19,33]. Mindfulness is a semantically ambiguous construct with a rich conceptual history [34][35][36][37][38]. ...
... Several studies have investigated mindfulness in the context of psychedelic use. For instance, there is some indication that following psychedelic use, participants may experience greater mindfulness and related capacities including decentering for weeks or even months following initial use [13,[46][47][48][49][50]. Furthermore, psychedelic-induced mystical experiences which occasion changes in perception and cognition share similarities to experiences associated with advanced meditative states [27,51]. ...
Introduction
Meditation practice and psychedelic use have attracted increasing attention in the public sphere and scientific research. Both methods induce non-ordinary states of consciousness that may have significant therapeutic benefits. Thus, there is growing scientific interest in potential synergies between psychedelic use and meditation practice with some research suggesting that psychedelics may benefit meditation practice. The present study examined individual, psychedelic-related, and meditation-related factors to determine under what conditions meditators perceive psychedelic use as beneficial for their meditation practice.
Method
Participants (N = 863) who had reported psychedelic use and a regular meditation practice (at least 3 times per week during the last 12 months) were included in the study. To accommodate a large number of variables, machine learning (i.e., elastic net, random forest) was used to analyze the data.
Results
Most participants (n = 634, 73.5%) found psychedelic use to have a positive influence on their quality of meditation. Twenty-eight variables showed significant zero-order associations with perceived benefits even following a correction. Elastic net had the best performance (R² = .266) and was used to identify the most important features. Across 53 variables, the model found that greater use of psychedelics, intention setting during psychedelic use, agreeableness, and exposure to N,N-Dimethyltryptamine (N,N-DMT) were most likely to be associated with the perception that psychedelics benefit meditation practice. The results were consistent across several different approaches used to identify the most important variables (i.e., Shapley values, feature ablation).
Discussion
Results suggest that most meditators found psychedelic use to have a positive influence on their meditation practice, with: 1) regularity of psychedelic use, 2) the setting of intentions for psychedelic use, 3) having an agreeable personality, and 4) reported use of N,N-DMT being the most likely predictors of perceiving psychedelic use as beneficial. Longitudinal designs and randomized trials manipulating psychedelic use are needed to establish causality.
... Research on the therapeutic effects of meditation practices, while well established, is still ongoing, and in the case of psychedelic use, it is nascent. Nevertheless, recent systematic reviews and meta-analyses suggest that both meditation practice and psychedelic use may be beneficial for a range of psychological symptoms (10)(11)(12)(13)(14). ...
... One potential reason that psychedelics may positively enhance the potential impact of meditation practice on psychological outcomes is that psychedelic use itself may increase one's levels of mindfulness (12,18,31). Mindfulness is a semantically ambiguous construct with a rich conceptual history (32)(33)(34)(35)(36). ...
... Several studies have investigated mindfulness in the context of psychedelic use. For instance, there is some indication that following psychedelic use, participants may experience greater mindfulness and related capacities including decentering for weeks or even months following initial use (12,(44)(45)(46)(47)(48). Furthermore, psychedelic-induced mystical experiences which occasion changes in perception and cognition share similarities to experiences associated with advanced meditative states (26,49). ...
Introduction: Meditation practice and psychedelic use have attracted increasing attention in the public sphere and scientific research. Both methods induce non-ordinary states of consciousness that may have significant therapeutic benefits. Thus, there is growing scientific interest in potential synergies between psychedelic use and meditation practice with some research suggesting that psychedelics may benefit meditation practice. The present study examined individual, psychedelic-related, and meditation-related factors to determine under what conditions meditators perceive psychedelic use as beneficial for their meditation practice.
Method: Participants (N = 863) who had reported psychedelic use and a regular meditation practice (at least 3 times per week during the last 12 months) were included in the study. To accommodate a large number of variables, machine learning (i.e., elastic net, random forest) was used to analyze the data.
Results: Most participants (n = 634, 73.5%) found psychedelic use to have a positive influence on their quality of meditation. Twenty-eight variables showed significant zero-order associations with perceived benefits even following a correction. Elastic net had the best performance (R2 = .266) and was used to identify the most important features. Across 53 variables, the model found that greater use of psychedelics, intention setting during psychedelic use, agreeableness, and exposure to N,N-Dimethyltryptamine (N,N-DMT) were most likely to be associated with the perception that psychedelics benefit meditation practice. The results were consistent across several different approaches used to identify the most important variables (i.e., Shapley values, feature ablation).
Discussion: Results suggest that most meditators found psychedelic use to have a positive influence on their meditation practice, with: 1) regularity of psychedelic use, 2) the setting of intentions for psychedelic use, 3) having an agreeable personality, and 4) reported use of N,N-DMT being the most likely predictors of perceiving psychedelic use as beneficial. Longitudinal designs and randomized trials manipulating psychedelic use are needed to establish causality.
... After decades of prohibition and suppressed research on psychedelics, a new resurgence of psychedelic research is occurring [11]. Over the past few years, the number of publications on psychedelics has increased dramatically (Figure 1), including a growing number of clinical studies demonstrating the promising therapeutic potential of psychedelics for treating a broad range of conditions [2,[12][13][14][15], such as major depressive disorder [5,[16][17][18][19][20], anxiety or depression due to a life-threatening diagnosis [21][22][23], and substance use disorders [24]. for depression. ...
... In recent years, the therapeutic effects of psychedelics have been investigated for multiple mental health conditions, and public interest in the potential benefits of psychedelics has grown. While these results are promising, more research is required to more precisely identify the factors that foster positive therapeutic outcomes from psychedelic-assisted therapy [1][2][3]. Despite the preliminary nature of the research quantifying the risks and benefits of psychedelics, this field has attracted a substantial amount of hype or attention, coinciding with inflated expectations, echoing the hype around mindfulness-based interventions that occurred a few years ago (i.e., in an article called "Mind the Hype" [4], and benefits of psychedelics, this field has attracted a substantial amount of hype or attention, coinciding with inflated expectations, echoing the hype around mindfulnessbased interventions that occurred a few years ago (i.e., in an article called "Mind the Hype" [4], which we directly acknowledge in the title of the present article). ...
... After decades of prohibition and suppressed research on psychedelics, a new resurgence of psychedelic research is occurring [11]. Over the past few years, the number of publications on psychedelics has increased dramatically (Figure 1), including a growing number of clinical studies demonstrating the promising therapeutic potential of psychedelics for treating a broad range of conditions [2,[12][13][14][15], such as major depressive disorder [5,[16][17][18][19][20], anxiety or depression due to a life-threatening diagnosis [21][22][23], and substance use disorders [24]. The representation of psychedelics in public media has moved from alarmism about their risks (for the past several decades) to hyping their potential benefits (in just the past few years). ...
Rationale: Psychedelic research re-emerged from a period of suppression into the so-called psychedelic renaissance. In parallel, most media reporting has shifted from the overstatement of the risks of psychedelics to overly positive hype. As the empirical evidence is more equivocal than frequently portrayed, the conclusions about the effectiveness of psychedelics should be considered preliminary. Poor science communication about psychedelics’ therapeutic potential may lead potential participants or patients to feel misled and policy decisions to be misinformed. An evidence-informed characterization of their risks and benefits is needed. Objectives: This article assesses the state of psychedelic research for treating depression and the effect sizes of psychedelics on therapeutic outcomes, the risk of bias, and the prevalence of adverse effects. We review research on the risks and benefits of psychedelics and discuss how the following depression treatments have shown decreasing effect sizes over time: (1) cognitive behavioral therapy, (2) mindfulness interventions, (3) selective serotonin reuptake inhibitors, and (4) ketamine. We speculate that a similar trend may occur for psychedelic treatments. Results and conclusions: It is likely that larger and better-controlled psychedelic trials will demonstrate smaller effect sizes that are more comparable to other conventional and emerging treatments for mood disorders. Clear science communication is critical for setting public expectations and psychedelic policy. With this evidence-based assessment, we aim to cut through the misinformation about the benefits, risks, and future prospects of psychedelic treatments.
... In the following sub-sections, we present an overview of the safety considerations for certain substances for which we were able to find more robust information. Goldberg et al. (2020) conducted a systematic review of psychological outcomes in the postacute phase (>24 hours) after administration of psilocybin, LSD, or ayahuasca in both clinical and non-clinical (i.e. healthy) samples. ...
... 34 studies were included in the review, half of which used single-group pre-post designs (50.0%), while 16.7% were within-group RCTs and 33.3% were between-group RCTs. The majority of these studies investigated psilocybin (58.3%), 25% investigated ayahuasca, and 16.7% investigated LSD (Goldberg et al., 2020). Most studies (54.2%) included a follow-up assessment occurring on average at 5.54 weeks post-treatment. ...
... Two potential sources of correctable bias are attrition and selective reporting. Selective reporting bias was commonly rated as unclear, in part due to difficulty in assessing whether the reported outcomes were planned (Goldberg et al., 2020). ...
A rapid review synthesizing published research on the possible therapeutic applications of psychedelics.
... Psychedelics have been categorized as meaning-response magnifiers enhancing the effects of placebo and set and setting (Hartogsohn, 2017(Hartogsohn, , 2018 and have been found to enhance suggestibility in human subjects (R. L. Carhart- Harris et al., 2015;Schindler et al., 2018) Individuals who regularly consume ayahuasca in a ritual setting score higher on scales measuring positive self and decentering (Franquesa et al., 2018). Participants report being more spiritual after psilocybin administration (Goldberg et al., 2020), and demonstrate increased cognitive and neural flexibility (Doss, Považan, et al., 2021). Measurable increases in traits of openness and extroversion have been documented during this time, alongside numerical decreases in neuroticism; however, strongest improvements have been found in the trait of conscientiousness MacLean et al., 2011). ...
... Further, reductions in negative affect and increases in positive mood underlie reductions in rumination, and improvements in self-compassion and self-forgiveness have been noticed and may be key therapeutic effects. Administration of serotonergic psychedelics is associated with long-term improvements in mood, attitude, and well-being Goldberg et al., 2020; R. ...
... While much has been made of the entropy under psychedelics, there is limited research into the post-session afterglow stage of heightened neuroplasticity and improved affect (Doss, Považan, et al., 2021;Goldberg et al., 2020;Majić et al., 2015;Sampedro et al., 2017), a period thought to last at least to 4 weeks . This proposed model of psychedelic action views psychedelics as catalysts to change, and heavily weighs the activities and processes which occur in the days to weeks following the psychedelic experience. ...
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Abstract
Psilocybin is a psychedelic compound of interest to clinicians, researchers and the general public for its unique effects on perception, cognition and emotion. Fifteen years of clinical trials, reviewed here using the scoping review method of knowledge synthesis , provide evidence for the safety and therapeutic efficacy of psilocybin when combined with psychological supports. A similar review of more than 50 years of research on non-human animals shows the safety of psilocybin and demonstrates persisting positive effects of psilocybin on self-regulation. To provide context to these scoping reviews, I conducted a detailed literature review and a separate narrative review on the neuroscience of psilocybin, with a marked interest in the dynamics of neuroplasticity and how habits of self-regulation are formed, revised and updated. While my working hypothesis considered mystical states as the mechanism of therapeutic action underlying psilocybin’s apparent benefits, the evidence was stronger to support a revised hypothesis: that psilocybin improves self-regulation. It does so by disrupting habit, potentiating new learning and promoting improvements to health behaviours. I offer here a novel contribution to the literature: a time-based Transition State Model of Psychedelic Effect which views psilocybin as a catalyst to improved flexibility of thought and behaviour. Psilocybin appears to attenuate or loosen the effects of past conditioning which appear as habits and which have become hard-wired into brain networks. This learning model heavily weights the activities undertaken in the days and weeks following psilocybin administration, providing a basis for psilocybin-assisted therapies to leverage this critical period for improvements to health behaviours.
... Acute intoxication with tryptamines can result in various effects, primarily affecting perception, cognition, and physiological functions [78,111]. Individuals experiencing tryptamine intoxication may encounter visual hallucinations (which can be vivid, colorful, and highly realistic, creating an altered visual experience), de-personalization (a sense of detachment or disconnection from oneself), and alterations in sensory perception (involving heightened sensitivity to sensory stimuli, where sounds, colors, textures, and tastes may become intensified or distorted) [78,112]. In addition to perceptual effects, acute tryptamine intoxication can lead to various physiological symptoms. ...
... In addition to perceptual effects, acute tryptamine intoxication can lead to various physiological symptoms. Anxiety (marked by feelings of unease, worry, or fear), increased blood pressure (potentially straining the cardiovascular system), headaches (contribute to the overall discomfort experienced during acute intoxication), and nausea, often accompanied by a feeling of queasiness or the urge to vomit, can also be present [112]. A meta-analysis study analyzed the post-acute psychological effects of psychedelics, and no evidence that these increase the risk for adverse effects was obtained [112]. ...
... Anxiety (marked by feelings of unease, worry, or fear), increased blood pressure (potentially straining the cardiovascular system), headaches (contribute to the overall discomfort experienced during acute intoxication), and nausea, often accompanied by a feeling of queasiness or the urge to vomit, can also be present [112]. A meta-analysis study analyzed the post-acute psychological effects of psychedelics, and no evidence that these increase the risk for adverse effects was obtained [112]. The use of hallucinogens can trigger episodes of schizophrenia and lead to profound alteration of the consumer's behavior. ...
Aim:
Drug abuse and addiction are major public health concerns, with millions of people worldwide affected by the negative consequences of drug use. To better understand this complex issue, a review was conducted to examine the mechanisms of action and effects of drugs of abuse, including their acute and chronic effects, the symptoms of abstinence syndrome, as well as their cardiovascular impacts.
Methods:
The analyzed data were obtained after surveying an electronic database, namely PubMed, with no time limit, grey literature sources, and reference lists of relevant articles.
Results:
The review highlights the different categories of drugs of abuse, such as opioids, stimulants, depressants, hallucinogens, and cannabis, and discusses the specific ways that each drug affects the brain and body. Additionally, the review explores the short-term and long-term effects of drug abuse on the body and mind, including changes in brain structure and function, physical health problems, and mental health issues, such as depression and anxiety. In addition, the review explores the effects of drug abuse on cardiovascular health, focusing on electrocardiogram changes. Moreover, the analysis of relevant literature also highlighted possible genetic susceptibility in various addictions. Furthermore, the review delves into the withdrawal symptoms that occur when someone stops using drugs of abuse after a period of chronic use.
Conclusion:
Overall, this review provides a comprehensive overview of the current state of knowledge on drug abuse and addiction. The findings of this review can inform the development of evidence-based prevention and intervention strategies to address this critical public health issue.
... Despite gaining momentum in recent years psyche delic AE assessment still suffers from several method ological limitations (many of which mirror issues previously noted in meditation research: . These methodological issues include the fol lowing: (1) the use of passive monitoring, which relies upon participants to spontaneously report adverse events to research staff, and has been estimated to undercount adverse event incidence by up to 20fold depending on context (Kramer, 1981) when compared to criteriabased assessment; (2) imprecise or incon sistent definitions of AEs, resulting in unstandardized and heterogenous measures; (3) a lack of longterm monitoring; (4) use of analytical strategies (e.g., group averages) that obscure extreme scores; and (5) a lack of rigorously designed and validated measures of adverse effects (Aday et al., 2020;Breeksema et al., 2022;Goldberg et al., 2020;Schlag et al., 2022;Hinkle et al., 2024). Most psychedelic studies have queried only a limited set of longterm negative effects, such as fear, anxiety, paranoia, and depression (Carbonaro et al., 2016;Johnstad, 2021;Raison et al., 2023), and a detailed, comprehensive study on the phenomenol ogy of enduring psychedelicrelated AEs has yet to be conducted. ...
... Changes that may be innocuous in the short term, such as alterations to sleep architecture, as have been observed in meditation and psy chedelics (Dudysová et al., 2020;Evens et al., 2023), may constitute AEs if they contribute to enduring dif ficulties. Few studies of psychedelics have followups of more than one year (Aday et al., 2020;Goldberg et al., 2020), although some research has found that nearly 1 in 10 individuals who had challenging psilo cybin experiences reported psychological symptoms that lasted one year or longer, with 8% seeking pro fessional treatment (Carbonaro et al., 2016). Gathering detailed information on the enduring impacts of psychedelicrelated AEs on functioning and other important outcomes (e.g. ...
... More recently, the term "psychedelics" has also been used to refer to non-serotonergic substances such as ketamine and 3,4-methylenedioxymethamphetamine (MDMA). It has been suggested that psychedelics may have therapeutic potential for a variety of mental pathologies (Andersen et al. 2021;Goldberg et al. 2020;Luoma et al. 2020) such as drug dependence and eating disorders. In non-clinical settings, psychedelics are also associated with enduring benefits, such as increased well-being and life satisfaction (Griffiths et al. 2008) and improved sleep, diet, and exercise (Teixeira et al., 2022). ...
... Third, many variables previously identified as pertinent to psychedelic-use outcomes were not included in the current study, such as the variables of type and dose of psychedelic used (Goldberg et al. 2020), features of the physical and social environment ("setting") (Aday et al. 2021), and naive use versus repeat use (Grob and Grigsby 2021). ...
Interest in psychedelics and their possible therapeutic potential has been growing. Metaphysical belief theory asserts that these benefits stem from the adoption of comforting supernatural beliefs following a mystical experience. By contrast, predictive self-binding theory suggests that the beneficial outcomes of psychedelics are primarily driven by psychological insights. The present study tests these competing models of psychedelic benefits. We conducted a quantitative content analysis on unsolicited self-reports of psychedelic users available on Erowid.org, to examine the potential relations between psychological insight, ego dissolution, therapeutic intent, altered metaphysical belief, and enduring health outcomes. We randomly selected, coded, and analyzed two hundred forty psychedelic experience reports from the website. Path analysis using structural equation modeling showed that psychological insight, not metaphysical beliefs, uniquely predicted beneficial outcomes. Moreover, beneficial outcomes’ positive relation to ego dissolution and therapeutic intent was fully mediated by psychological insight. These findings support the predictive self-binding model over the metaphysical belief model.
... Taken together, most compelling evidence indicates benefits in a range of psychopathologies, while preliminary evidence hints towards effects on cardiovascular, metabolic, neurological and immunological pathologies. A meta-analysis and review on adverse events of serotonergic psychedelics found a very low occurrence of serious adverse effects (e.g., psychotic episodes), especially in modern clinical trials that exclude patients with predispositions for psychotic illnesses (Goldberg et al., 2020;Schlag et al., 2022). Commonly observed are transient adverse events such as headache, anxiety, nausea and increased blood pressure (Goldberg et al., 2020;Schlag et al., 2022). ...
... A meta-analysis and review on adverse events of serotonergic psychedelics found a very low occurrence of serious adverse effects (e.g., psychotic episodes), especially in modern clinical trials that exclude patients with predispositions for psychotic illnesses (Goldberg et al., 2020;Schlag et al., 2022). Commonly observed are transient adverse events such as headache, anxiety, nausea and increased blood pressure (Goldberg et al., 2020;Schlag et al., 2022). ...
The use of serotonergic psychedelics has gained increasing attention in research, clinical practice and society. Growing evidence suggests fast-acting, transdiagnostic health benefits of these 5-hydroxytryptamine 2A receptor agonists. Here, we provide a brief overview of their benefits for psychological, cardiovascular, metabolic, neurodegenerative, and immunological pathologies. We then review their effect on mitochondria including mitochondrial biogenesis, functioning and transport. Mitochondrial dysregulation is a transdiagnostic mechanism that contributes to the aforementioned pathologies. Hence, we postulate that psychedelic-induced effects on mitochondria partially underlie their transdiagnostic benefits. Based on this assumption, we propose new treatment indications for psychedelics and that the health benefits induced by psychedelics depend on patient-specific mitochondrial dysregulation.
... Moreover, previous research suggests that classic psychedelics have immunomodulatory and anti-inflammatory properties [25][26][27], low physiological toxicity [22,28], and appears safe in clinical trials, at least when potential risk populations are screened out [17,29]. Recent clinical trials also suggest that classic psychedelics may be effective in the treatment of various psychiatric disorders, when administered by health professionals in a safe and supportive setting [30][31][32][33][34][35][36]. ...
... Indirectly, the acute transcendent experience occasioned by classic psychedelics may induce long-term behavior changes towards a healthy lifestyle [44][45][46] that contribute to better physical as well as mental health. Direct mechanisms that could influence overall health involve improvements on a range of mental health indices such as psychological distress, depression and anxiety [17,[29][30][31][32][33][34][35]. Classic psychedelics may also influence factors concerned with positive psychology, such as mindfulness, feelings of purpose and prosociality [50,51], which not only influence mental but also physical health [52][53][54]. ...
Objectives:
Absenteeism from work due to illness, and related costs, has increased steadily during the past decades. In recent years, there has been a reemergence of research on the therapeutic effects of classic psychedelics showing associations with both physical and mental health. However, the association between classic psychedelics and sick leave remains unknown. The aim of this study is to investigate the association between lifetime classic psychedelic use and sick leave in the past 30 days among adults in the United States (N = 407,717), using data from the National Survey on Drug Use and Health (2005-2019), weighted to be representative of the US adult population.
Methods:
The primary analysis was conducted using multiple linear regression, controlling for sociodemographic characteristics, risky behavior, and use of other substances.
Results:
There was a significant and negative association between lifetime classic psychedelic use and sick leave in the past 30 days (B = -0.09, p < 0.01) when adjusting for all control variables.
Conclusion:
These findings suggest that classic psychedelics could potentially lead to reduced sick leave and associated costs in the general population, but more research is needed to investigate potential causal pathways of classic psychedelics on sick leave and evaluate possible mechanisms.
... Papers published until 16 December 2015 were extracted from a previous systematic review on human studies with ayahuasca [8]. Furthermore, we have also searched for more recent articles in newer systematic reviews and meta-analyses [6,[44][45][46]. Finally, we searched the PubMed database from December 2015 until January 2022 with the following string: '(ayahuasca OR DMT OR dimethyltryptamine) AND (randomized OR placebo OR blind)') to acquire any other recent experiments that fitted our inclusion criteria. ...
... Lastly, it is also known that the serotoninergic system is involved in the etiology of pain and some types of headaches [56], with selective 5-HT 1B/D serotonin agonists being approved medications for the treatment of migraines [57]. At the current state of psychedelic substances research, all these AEs are expected and are known to occur with the consumption of ayahuasca and other related substances such as psilocybin and LSD [7,45] (see also our review on the safety of LSD and psilocybin in the context of depression in this Special Issue). ...
Introduction:
Ayahuasca is a psychedelic brew originally used by indigenous tribes from the Amazon Rainforest and in religious rituals. Pre-clinical and observational studies have demonstrated its possible potential as an antidepressant, and open and placebo-controlled clinical trials corroborated these results. For it to become an approved treatment for depression, its safety and tolerability need to be assessed and documented.
Areas covered:
We have gathered data regarding occurrence of adverse events (AEs) in all reported randomized, placebo-controlled trials with healthy and clinical populations involving ayahuasca administration (n = 108 ayahuasca administrations). We systematically categorized these results, recorded their prevalence and discussed the possible mechanisms related to their emergence.
Expert opinion:
: There were no reports of serious AEs, indicating a relative safety of ayahuasca administration in controlled settings. Most common AEs related to ayahuasca administration included nausea, vomiting, headaches and transient increases in cardiovascular measurements. Ayahuasca research is still in its infancy, especially concerning the absence of large and robust clinical trials to verify its antidepressant effects. Dose standardization, legal prohibition of the possession of its alkaloids and how traditional communities will be compensated if ayahuasca becomes an approved medicine are the biggest obstacles to overcome for its future use in the therapeutic context.
... Several meta-analyses have explored the putative role of psychedelics in the management of mental disorders. However, these studies included both healthy participants and patients with a variety of mental disorders, such as depression and/or anxiety, post-traumatic stress disorder, cancer-related mood disorders, and even pain [10][11][12][13][14][15][16]. These meta-analyses suggested that psychedelics exert antidepressant effects, that they are pleiotropic compounds, and that combining all serotonergic psychedelics may not be methodologically appropriate [17]. ...
... We systematically searched the MEDLINE, Cochrane Central Register of Controlled Trials, Embase, and PsycINFO databases from the time of their inception until 27 January 2021 to identify all clinical trials reporting the efficacy of psilocybin in the management of depressive symptoms. Further studies were identified by manually searching the reference lists of eligible studies, as well as those included in previous meta-analyses [10][11][12][13][14][15][16]. Supplementary File S1 presents the details of the search strategy. ...
We examined the cardiovascular safety, acceptability, and trajectory of the antidepressant effects of psilocybin after single- or two-dose administration. Four major electronic databases were systematically searched. Data were pooled using a multivariate random-effects meta-analysis. Primary outcomes were changes in depressive symptoms. Secondary outcomes were cardiovascular safety and acceptability. Ten studies were included. The estimated effect sizes (standardized mean difference (SMD) with 95% confidence intervals) for psilocybin were −0.75 (−1.15 to −0.35) on day 1, −1.74 (−2.15 to −1.32) at 1 week, −1.35 (−1.77 to −0.93) at 1 month, −0.91 (−1.31 to −0.51) at 3 months, and −1.12 (−1.56 to −0.68) at 6 months. Higher doses and two sessions of psilocybin treatment were significantly associated with superior antidepressant effects. The all-cause discontinuation and heart rate after psilocybin administration were comparable to placebo; meanwhile, psilocybin increased systolic and diastolic blood pressure by 19.00 mmHg and 8.66 mmHg, respectively. There were no significant differences between SMD derived from placebo-controlled trials compared to those from pre–post changes and SMD in randomized controlled trials (RCTs) compared to those in non-RCTs. The present study demonstrates that single- or two-dose psilocybin administration has rapid and sustained antidepressant effects for up to 6 months, with favorable cardiovascular safety and acceptability.
... One of the biases mentioned in the literature is "selective reporting bias" as it is often unclear due to challenges in determining whether the reported outcomes were pre-planned [36]. Also, the self-selection bias is often highlighted in psychedelic research, posing challenges for representative ethnic and demographic sampling in mental health research, contributing to healthcare disparities [35]. ...
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.
... Some evidence suggests that psilocybin may have long-lasting effects on some personality traits, personal values, and attitudes. 205 . Although most subjects describe these changes as positive, 33 patients should be informed of these possible effects before consenting to PT. ...
Psilocybin therapy has recently emerged as a promising new treatment for depression and other mental health disorders. This chapter summarizes the most recent data on its safety and efficacy. The delivery of psilocybin therapy and its subjective effects are also presented. Furthermore, this chapter outlines our current understanding of psilocybin’s pharmacology and neurobiological effects. Other similar psychedelic substances with encouraging therapeutic potential are briefly presented.
... Two contemporary population surveys (Johansen & Krebs, 2015;Krebs & Johansen, 2013) found no evidence that recreational use of psychedelics was associated with increased rates of poor mental health, as indexed in various ways. Similarly, a 2020 meta-analysis of 24 studies that examined post-acute effects of psilocybin, ayahuasca and LSD given in clinical or experimental settings (Goldberg et al., 2020) found no evidence of any more than transient adverse effects. Our findings, whilst not directly comparable in terms of methodology, paint a different picture: psychedelic drugs, even when taken only one or a few times, can be followed by major psychiatric adverse events. ...
Background
Psychedelic drugs are a focus of interest in the treatment of depression and other disorders but there are longstanding concerns about possible adverse psychiatric consequences. Because the relevant literature is largely informal, the seriousness of these risks is difficult to evaluate.
Methods
Searches were made for case reports of schizophrenia-spectrum, affective or other psychiatric disorders after use of psychedelic drugs. Case reports of flashbacks were also searched for. Individuals with recent use of other drugs (apart from cannabis and alcohol) and/or a previous history of major psychiatric disorder were excluded. Symptoms were tabulated using the Syndrome Check List of the Present State Examination (PSE-9).
Results
We found 17 case reports of schizophrenia spectrum disorder, 17 of affective disorder (depression, mania, or both), 3 cases of anxiety, 1 of depersonalization, and 1 of unclassifiable illness. The states could develop after a single use of the drug (5/17 schizophrenia; 6/17 affective disorder), and duration was highly variable. Recovery was the rule in cases of affective disorder but not in schizophrenia spectrum disorder. Twelve of 29 cases of flashbacks showed psychiatric symptomatology definitely outlasting the attacks, mainly anxiety (5 cases) and depression (8 cases). Flashback symptoms resolved within twelve months in approximately half of the cases but in a few persisted for years.
Conclusions
Reliable descriptions of schizophrenia spectrum disorder and major affective disorder after psychedelic drug use disorder exist but are relatively uncommon. Flashbacks are sometimes but not always associated with psychiatric symptomatology, mainly anxiety or depression.
... Meditation has been shown to improve mental health and psychological well-being across a multitude of randomized controlled studies (Goldberg et al., 2018;Rose et al., 2020). Similarly, expanding research on psychedelics provides growing evidence of their promising therapeutic potential for treating a broad range of mental health conditions (Andersen et al., 2021;Goldberg et al., 2020;Hadar et al., 2022;Lawrence et al., 2021;Romeo et al., 2020). ...
Background
In recent years, both meditation and psychedelics have attracted rapidly increasing scientific interest. While the current state of evidence suggests the promising potential of psychedelics, such as psilocybin, to enhance meditative training, it remains equivocal whether these effects are specifically bound to psilocybin or if other classical psychedelics might show synergistic effects with meditation practice. One particularly promising candidate is N,N-dimethyltryptamine (DMT), an active ingredient of ayahuasca.
Aim
This study aims to investigate the effect of the psychedelic substance DMT, combined with the monoamine oxidase inhibitor harmine ( DMT-harmine), on meditative states, compared to meditation with a placebo.
Method
Forty experienced meditators (18 females and 22 males) participated in a double-blind, placebo-controlled study over a 3-day meditation retreat, receiving either placebo or DMT-harmine. Participants’ levels of mindfulness, compassion, insight, and transcendence were assessed before, during, and after the meditation group retreat, using psychometric questionnaires.
Results
Compared to meditation with a placebo, meditators who received DMT and harmine self-attributed greater levels of mystical-type experiences, non-dual awareness, and emotional breakthrough during the acute substance effects and, when corrected for baseline differences, greater psychological insight 1 day later. Mindfulness and compassion were not significantly different in the DMT-harmine group compared to placebo. At 1-month follow-up, the meditators who received DMT and harmine rated their experience as significantly more personally meaningful, spiritually significant, and well-being-enhancing than the meditators who received placebo.
Conclusion
Investigating the impact of DMT-harmine on meditators in a naturalistic mindfulness group retreat, this placebo-controlled study highlights the specific effects of psychedelics during meditation.
Trial registration
ClinicalTrials.gov identifier NCT05780216.
... Indeed, findings from metaanalysis indicate that effect sizes associated with these therapies are larger than those associated with typical psychopharmacological or psychotherapy interventions for a range of mental health conditions 1 . This is particularly evident in meta-analyses that have looked at the effects of psychedelic-assisted treatment to address (1) anxiety and depression in the context of life-threatening illness, (2) anxiety in autistic adults, and (3) post-traumatic stress disorder (PTSD) and suicidality [1][2][3][4][5][6][7] . These analyses also find little evidence of post-acute adverse effects. ...
... To date, five randomized clinical trials have examined LSD and psilocybin to treat mood and anxiety symptoms related to a life-threatening illness [17,45,46,47,48]; three placebocontrolled trials have examined psilocybin in the treatment of major depression (MDD) [16, 49,50]; and one placebocontrolled trial examined ayahuasca for treatment-resistant depression [51] -all of which had outcomes supporting the efficacy of psychedelics. Looking more broadly at the persisting effects of psychedelics on affect, a meta-analysis evaluated 24 experimental studies which did not include the controlled major depression trials described above [52]. Among the 8 studies reporting between-group effects on positive and negative affect (6 studies, n = 82), effect size estimates were 0.89 and 0.87 (Hedges' g), respectively. ...
Purpose of review
This article utilizes a pre-existing framework in the field of addiction to comprehensively capture the effects of classic psychedelics (psilocybin, lysergic acid diethylamide, dimethyltryptamine, and mescaline) for the treatment of alcohol use disorder (AUD).
Recent findings
Basic science, preclinical, and clinical studies support the influence of psychedelics on all 3 core domains of addiction, comprising negative emotionality (including depression and anxiety), incentive salience (including craving and compulsive use) and executive functioning (including impulsivity and cognitive flexibility). However, systematic investigation using objective measures to evaluate these domains in AUD is needed.
Summary
We close by discussing limitations and challenges in the field of psychedelic science, and propose future research directions to advance our understanding of the psychological and neurobiological basis of clinical improvement. Conceptualizing future research under this 3-domain framework may assist the refinement of psychedelic-assisted treatments and the development of personalized medicine approaches for AUD.
... Psychedelische Substanzen sind bekannt für ihre Fähigkeit, ein breites Spektrum an akuten Effekten hervorzurufen, welche die Wahrnehmung, Kognitionen und Emotionen tiefgreifend beeinflussen können. Jenseits der akuten psychedelischen Erfahrung sind diese Substanzen jedoch auch mit einem Spektrum an postakuten Effekten verbunden, die für Tage, Wochen und manchmal Monate nach der Einnahme einer Substanz anhalten können [2,3]. Dieser Artikel bietet einen Überblick über diese postakuten Effekte, die von vorwiegend als angenehm erlebten psychedelischen "Afterglow"-Erfahrungen bis hin zu länger anhaltenden Komplikationen reichen, die in seltenen Fällen eine psychiatrisch-psychotherapeutische Versorgung erforderlich machen können. ...
ZUSAMMENFASSUNG
Klassische Psychedelika wie Psilocybin oder Lysergsäurediethylamid (LSD) werden seit einigen Jahren wieder als Mittel für die Behandlung psychiatrischer Störungen untersucht. Nach dem Abklingen der akuten psychedelischen Effekte werden typischerweise postakute Effekte beobachtet, die eine entscheidende Rolle für den Einsatz dieser Substanzen als mögliche Therapeutika spielen und sich in subakute und Langzeiteffekte unterteilen lassen. Subakute Effekte umfassen u. a. das psychedelische „Afterglow“-Phänomen, das sich in Wohlbefinden, Gefühlen von Leichtigkeit, einer tieferen Verbundenheit mit sich und einer erhöhten Offenheit für zwischenmenschliche Begegnungen sowie einer Abnahme repetitiver Grübelschleifen äußert. Andererseits können in dieser Zeit aber auch Komplikationen auftreten. So werden in den Tagen nach der Einnahme häufig Kopfschmerzen beschrieben sowie seltener depressive und Angstsymptome, Schlafstörungen, dissoziative Symptome und visuelle Wahrnehmungsstörungen sowie psychotische Syndrome. In manchen Fällen können diese Komplikationen in anhaltende psychische Störungen übergehen, die eine psychiatrisch-psychotherapeutische Versorgung erforderlich machen.
... Evidence for the treatment efficacy of psychedelics in depression is shown in Supplementary Table S4 (124,(266)(267)(268)(269)(270)(271)(272)(273)(274)(275)(276)(277)(278), summaries are shown in Table 2. (282) The use of psychedelics to treat depression is different from the use of most pharmacological agents and is differentiated. An important factor to consider with psychedelic use is the primacy of the experience. ...
Antidepressants are among the most used medications in the US, with significant deleterious effects on people’s well-being. At any given time, depression impacts approximately 1 in 10 Americans, causing wide and broad societal costs. Interest is developing for non-pharmacological treatments and preventative measures. We summarize the literature on non-invasive dietary and lifestyle approaches for treating depression, including recent work with the psychedelic treatment of depression. This review aims to inform future research and treatment programs for depression. This review provides an evidentiary summary of integrative therapeutic approaches for depression.
... The psychological effects of psychedelics are theorized to intervene on core domains of AUD. Within the negative emotionality domain, a growing number of studies suggest psychedelics increase positive mood and decrease negative mood and neuroticism in healthy and clinical populations 25,26 . Within the incentive salience domain, increases in the personality traits openness and conscientiousness have been observed following psilocybin treatment 26,27 . ...
This pilot study investigated psilocybin-induced changes in neural reactivity to alcohol and emotional cues in patients with alcohol use disorder (AUD). Participants were recruited from a phase II, randomized, double-blind, placebo-controlled clinical trial investigating psilocybin-assisted therapy (PAT) for the treatment of AUD (NCT02061293). Eleven adult patients completed task-based blood oxygen dependent functional magnetic resonance imaging (fMRI) approximately 3 days before and 2 days after receiving 25 mg of psilocybin (n = 5) or 50 mg of diphenhydramine (n = 6). Visual alcohol and emotionally valanced (positive, negative, or neutral) stimuli were presented in block design. Across both alcohol and emotional cues, psilocybin increased activity in the medial and lateral prefrontal cortex (PFC) and left caudate, and decreased activity in the insular, motor, temporal, parietal, and occipital cortices, and cerebellum. Unique to negative cues, psilocybin increased supramarginal gyrus activity; unique to positive cues, psilocybin increased right hippocampus activity and decreased left hippocampus activity. Greater PFC and caudate engagement and concomitant insula, motor, and cerebellar disengagement suggests enhanced goal-directed action, improved emotional regulation, and diminished craving. The robust changes in brain activity observed in this pilot study warrant larger neuroimaging studies to elucidate neural mechanisms of PAT.
Trial registration: NCT02061293.
... Recently, both observational studies and clinical trials have yielded interesting results: (a) psychedelics substantially improve therapeutic outcomes in various mental disorders [12,30,31]; (b) psychedelics improve well-being [32][33][34]; (c) the meaningfulness of psychedelic experiences predicts therapeutic outcomes [35][36][37]; (d) set variables such as personality traits and pre-session state of mind predict qualities of the psychedelic experience [32,38]; and (e) setting conditions predict meaningfulness of psychedelic experiences and therapeutic outcomes [32,39,40]. ...
Free E-Print available here: https://www.tandfonline.com/eprint/CYSUD5IQWXNZUVQAEYIC/full?target=10.1080/17512433.2023.2295997
Background:
In psychedelic therapy, the importance of set and setting is a fundamental but under-researched assumption. The aim of this study is to correlate variables of set (psychedelic use motivation) and setting (psychedelic use location and type of companion) with psychopathology, wellbeing and personality variables.
Research design and methods:
A sample of 1022 participants of the Spanish-speaking population was collected through an online survey. A novel instrument, the Psychedelic Use Scale (PUS), was developed to measure substance use variables of LSD, mescaline, psilocybin, DMT, 5-Meo-DMT, ketamine, Salvia divinorum, ibogaine and MDMA. Various personality, well-being and psychopathology instruments were implemented to measure outcome variables.
Results:
Growth motivations, natural settings and presence of significant others predicted less psychopathology, greater wellbeing and meaningfulness of psychedelic experiences, whereas problematic motivations predicted greater psychopathology, lower wellbeing and did not predict meaningfulness of psychedelic experiences.
Conclusions:
Based on these results, we suggest experimental hypotheses for future clinical trials and longitudinal studies with potential clinical implications.
... Several reviews and meta-analyses of PAP for depression have been previously completed based on small initial pilot trials (Galvão-Coelho et al., 2021;Goldberg et al., 2020;Reiff et al., 2020;Romeo, Karila, Martelli, & Benyamina, 2020). ...
... Along with nicotine and cannabis, psychedelic drug use, on the other hand, has been linked to openness 8,9,31,32 , a personality trait tied to non-conformity and liberalism 33,34 . In most population studies probing these links, it is challenging, if not impossible, to deduce causal relationships between personality structure and patterns of drug use; that is, whether a drug induces a personality change or whether a particular personality structure predisposes an individual to prefer a certain type of drug. ...
Previous research has suggested that classical psychedelics can foster significant and enduring changes in personality traits and subjective wellbeing. Despite the lack of evidence for adverse effects on mental health stemming from psychedelic use, concerns persist regarding the capacity of these substances to modulate information processing and attitudes towards factual data. The aim of the present study was to investigate the propensity for accepting alternative facts and the general treatment of knowledge within a sample of 392 participants, 233 of whom reported at least a single incidence of psychedelic use in their lifetime. To do this, we leveraged step-wise methods of linear modelling investigating effects of demographics, psychiatric conditions and concomitant drug use. Our findings revealed a moderate positive association between psychedelic use and beliefs in alternative facts, as well as the specific belief that facts are politically influenced. However, no links were found for favouring intuition over evidence when confirming facts. Among other investigated drugs, only alcohol was negatively associated with beliefs in alternative facts. Taken together, our results support the link between psychedelic use and non-conformist thinking styles, which can be attributed to the psychological effects of the drugs themselves, but may also mirror a common trait related to unconventional beliefs and illicit substance use.
... Other cohort studies have found positive relationships between lifetime use of hallucinogens and mental health 27,32,47,48 , and negative relationships between hallucinogenic drug use and suicidality 26,49 and violence 50,51 . Additionally, there are numerous published manuscripts reporting the positive effects of hallucinogens on mental health in clinical settings (for reviews, see Goldberg et al. 52 ; Luoma et al. 53 ; and Yu et al. 54 ) and in ceremonies where hallucinogens were administered 15,20,[55][56][57] . Lastly, cross-sectional studies comparing regular hallucinogen users with non-users have found an absence of neuropsychiatric impairments in the former, with users reporting better scores than non-users on some measures 31,[58][59][60][61] . ...
The COVID-19 pandemic has had a devastating impact on the health and wellbeing of the global population. This paper presents the results of a longitudinal transcultural study that was begun at the peak of the pandemic (in April, 2020). An online survey was used to collect data from English-, Spanish-, and Portuguese-speaking participants. The survey collected information about sociodemographics, lifestyle activities, COVID-19-related circumstances, and drug use (with an emphasis on hallucinogenic drugs), as well as involving psychometric questionnaires. Users of hallucinogenic drugs had higher psychological well-being and lower scores on psychopathology scales, both at baseline and during follow-ups. This difference was larger when users were distinguished by frequency of use, as regular users scored higher on psychological well-being and lower on psychopathology scales. Subjects with more psychological distress had lower scores for all scales of post-traumatic growth, but if they were regular hallucinogens users, they had higher scores for post-traumatic growth. When comparing the results between cultural contexts, heterogeneous results were obtained. There were more English-speaking regular users of hallucinogenic drugs. Further research should analyse the potential role of hallucinogens in large-scale catastrophes, with a special focus on post-traumatic growth.
... Moreover, openness to experience is a personality trait that may be increased following psychedelic use, suggesting an underlying synergy between the benefits of openness and the effects of psychedelics (Maclean et al., 2011). It should be noted, however, that this effect may be small (Goldberg et al., 2020). Although distinct concepts, openness and acceptance can work together, being open to experiences can help facilitate acceptance. ...
Objectives
The mindfulness-informed intervention that has so far received the most attention as an adjunct to psychedelic-assisted psychotherapy is Acceptance and Commitment Therapy (ACT), but little remains known about potential synergies between psychedelic-assisted psychotherapy and mindfulness-based interventions such as Mindfulness-Based Cognitive Therapy (MBCT). This paper examines and evaluates the therapeutic compatibility of MBCT with psychedelic-assisted psychotherapy, and their potential synergies.
Methods
This study represents a narrative review of the current literature on psychedelic-assisted psychotherapy and MBCT.
Results
We demonstrate how MBCT targets core processes including acceptance, being present, concentration, decentering and embracing difficulties — and outline why strengthening these capacities with systematic meditation training may prove invaluable during the preparation, dosing and integration phases of psychedelic-assisted psychotherapy.
Conclusions
MBCT’s emphasis on systematic training in mindfulness meditation and fostering nonjudgmental presence aligns well with the states of consciousness induced by psychedelics, highlighting its potential to enhance various stages of both the psychedelic experience and subsequent integration. By equipping individuals with effective mindfulness and cognitive restructuring techniques, MBCT may offer advantages beyond those provided by ACT, such as the ability to skillfully navigate and manage challenging experiences that can emerge during different phases of the psychedelic experience and integration. This suggests that MBCT’s unique approach may complement psychedelic-assisted psychotherapy in ways that ACT may not fully address, particularly in the context of handling challenging experiences.
... Clinical trials have been conducted on classical psychedelics for indications of alcohol use disorder (Bogenschutz et al., 2015), obsessive-compulsive disorder (OCD; Moreno et al., 2006), nicotine dependence (smoking) (Johnson et al., 2014), anxiety and depression in life-threatening illness, and major depression disorder (Carhart-Harris et al., 2016, 2021Davis et al., 2021;Griffiths et al., 2006;Grob et al., 2011;Ross et al., 2016). Most trials have published promising and profound results, as have systematic reviews and meta-analyses (Galvão-Coelho et al., 2021;Goldberg et al., 2020aGoldberg et al., , 2020b;Li et al., 2022;Luoma et al., 2020;Vargas et al., 2020;Yu et al., 2021Yu et al., , 2022. ...
Background:
The classical psychedelics, psilocybin, peyote, ayahuasca/N,N-dimethyltryptamine, and lysergic acid diethylamide are considered promising new treatments for psychiatric illnesses, such as depression, anxiety, addiction, and obsessive-compulsive disorders. However, their profound and characteristic subjective effects raise concern for distinctive biases in randomized clinical trials.
Methods:
We performed a systematic literature search to identify all clinical trials on classical psychedelics with patient populations to examine descriptive data and determine the risk of bias. Two independent reviewers searched three databases (PubMed, Embase, and APA PsycNet) and extracted information on study design, study population, use of active or inactive placebo, dropouts, evaluation of blinding of intervention, and reporting of expectancy and therapeutic alliance.
Results:
We included 10 papers reporting on 10 unique trials. The trials generally included populations that were predominantly white and highly educated. The trials had small samples and considerable dropout. Blinding was either unsuccessful or not reported regardless of type of placebo. Few trials published protocols, statistical analysis plans (SAPs), and outcomes relating to psychotherapy fidelity. All trials but one were rated as high risk of bias.
Conclusion:
Successful blinding of intervention is a significant challenge in this field. To better accommodate this, we suggest that future trials use a parallel-group design and utilize an active placebo on a psychedelic-naïve population. Future trials should publish trial protocol and SAPs, use clinician-rated outcomes accessed by a blinded rater, evaluate blinding of intervention, and consider measuring expectancy and therapeutic fidelity.
... One recent meta-analysis focused on postacute psychological effects, reporting large effect sizes on a range of outcomes, including targeted symptoms within psychiatric samples, negative and positive affect-related measures, social outcomes, and existential/spiritual outcomes. 16 However, this work combined subacute with long-term effects, preventing conclusions restricted to effects specific to the subacute period. As previous reports on the subacute psychedelic afterglow emphasize its transient nature, subacute and long-term effects may differ in quantity and/or quality. ...
Background
Classic serotonergic psychedelics have anecdotally been reported to show a characteristic pattern of subacute effects that persist after the acute effects of the substance have subsided. These transient effects, sometimes labeled as the ‘psychedelic afterglow’, have been suggested to be associated with enhanced effectiveness of psychotherapeutic interventions in the subacute period.
Objectives
This systematic review provides an overview of subacute effects of psychedelics.
Methods
Electronic databases (MEDLINE, Web of Science Core Collection) were searched for studies that assessed the effects of psychedelics (LSD, psilocybin, DMT, 5-MeO-DMT, mescaline, or ayahuasca) on psychological outcome measures and subacute adverse effects in human adults between 1950 and August 2021, occurring between 1 day and 1 month after drug use.
Results
Forty-eight studies including a total number of 1,774 participants were eligible for review. Taken together, the following subacute effects were observed: reductions in different psychopathological symptoms; increases in wellbeing, mood, mindfulness, social measures, spirituality, and positive behavioral changes; mixed changes in personality/values/attitudes, and creativity/flexibility. Subacute adverse effects comprised a wide range of complaints, including headaches, sleep disturbances, and individual cases of increased psychological distress.
Discussion
Results support narrative reports of a subacute psychedelic ‘afterglow’ phenomenon comprising potentially beneficial changes in the perception of self, others, and the environment. Subacute adverse events were mild to severe, and no serious adverse events were reported. Many studies, however, lacked a standardized assessment of adverse effects. Future studies are needed to investigate the role of possible moderator variables and to reveal if and how positive effects from the subacute window may consolidate into long-term mental health benefits.
... It is also not surprising that many of our participants had misconceptions about which substances are psychedelics. A survey of college students' attitudes on hallucinogens showed that a majority of them thought that hallucinogens cause addiction 30 , even though their dependency potential is generally known to be low [35][36][37][38] . Poor general knowledge on psychedelics is understandable, as psychedelic research has only recently experienced revival and the information on these topics is slowly reaching the mainstream 3,39 . ...
Although there is research interest to assess attitudes on psychedelics, no validated instrument exists for this purpose. We aimed to develop and examine the psychometric properties of the Attitudes on Psychedelics Questionnaire (APQ) in a sample of the Croatian general population. A cross-sectional, web-based survey among the general population was conducted on 1153 participants (62.1% female, 77.7% with a graduate or high school degree, 15.1% health care workers). We assessed participants’ ability to recognize psychedelic substances using a short knowledge test. The APQ consists of 20 items with four sub-scales: Legal Use of Psychedelics, Effects of Psychedelics, Risk Assessment of Psychedelics, and Openness to Psychedelics. This model demonstrated best fit in a confirmatory factor analysis. Total scale reliability was excellent (McDonald’s ω = 0.949, 95% CI = 0.944–0.953). A strong correlation with a similar unvalidated measure (r = 0.885, P < 0.001) demonstrated convergent validity. We observed an association between attitudes and knowledge on psychedelics (r = 0.494, P < 0.001). Younger age, male gender, and lower educational status were associated with higher APQ scores. The APQ is valid, reliable, and could be applied in assessing educational interventions, patients’ treatment outcomes, and the attitudes of different groups of experts. We encourage further validation of the APQ in English.
... While a state of mindfulness can be cultivated through dedicated practice or psychological therapy, this may be further facilitated through use of psychedelic substances. A more recent review and meta-analysis by Goldberg et al. (2020) also supports the hypothesis that psychedelics increase mindfulness, however, there are currently no systematic reviews examining the link between psychedelic use and its effect on facets or characteristics of mindfulness. Previous narrative reviews have emphasised the importance of integration of mindfulness interventions and psychedelics (Payne, Chambers, & Liknaitzky, 2021;Walsh & Thiessen, 2018). ...
Background and aims
The benefits of classic serotonergic psychedelics (e.g. psilocybin, LSD, DMT, ayahuasca) are becoming more widely known with the resurgence in research in the past decade. Furthermore, the benefits of mindfulness are well documented. However, no systematic reviews have examined linkage of mindfulness and psychedelics use. The aim of this systematic review is to explore the link between psychedelics and characteristics of mindfulness.
Methods
We conducted a systematic search across multiple databases, inclusive of grey literature and backwards/forward-citation tracking, on the 18 January 2021. The search strategy included terms relating to mindfulness and psychedelics, with no restriction on clinical or non-clinical conditions. Study quality was assessed. An exploratory random-effects meta-analysis was conducted on pre-post mindfulness data relative to psychedelic ingestion.
Results
Of 1805 studies screened, 13 were included in the systematic review. There was substantial variability in participant characteristics, psychedelic administration method and measurement of mindfulness. The ingestion of psychedelics is associated with an increase in mindfulness, specifically relating to domains of acceptance, which encompasses non-judgement of inner experience and non-reactivity. The meta-analysis of a subset of studies (N = 6) showed small effects overall relative to ayahuasca ingestion, increasing mindfulness facets of non-judgement of inner experience and non-reactivity, as well as acting with awareness.
Conclusions
Further methodologically robust research is needed to elucidate the relationship between psychedelics and mindfulness. However, mindfulness and specific facets relating to acceptance have been shown to increase following ingestion of psychedelics in a number of studies.
... [1][2][3][4][5][6][7][8] Although the mechanisms of psychedelic-assisted treatments remain unclear, the action of these drugs at the serotonin 2A receptor and downstream effects on neurotransmission, intracellular signaling, epigenetics, and gene expression appear to enhance plasticity at multiple levels, including neuronal structure, neural networks, cognition, affect, and behavior. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] However, some clinically relevant effects may be independent of serotonin 2A receptor activation. 24,25 Moreover, the direction and magnitude of change observed in a therapeutic context can be influenced by the subjective experience under the influence of the drug [26][27][28][29] and by contextual factors, including concomitant psychotherapy. ...
Importance:
Although classic psychedelic medications have shown promise in the treatment of alcohol use disorder (AUD), the efficacy of psilocybin remains unknown.
Objective:
To evaluate whether 2 administrations of high-dose psilocybin improve the percentage of heavy drinking days in patients with AUD undergoing psychotherapy relative to outcomes observed with active placebo medication and psychotherapy.
Design, setting, and participants:
In this double-blind randomized clinical trial, participants were offered 12 weeks of manualized psychotherapy and were randomly assigned to receive psilocybin vs diphenhydramine during 2 day-long medication sessions at weeks 4 and 8. Outcomes were assessed over the 32-week double-blind period following the first dose of study medication. The study was conducted at 2 academic centers in the US. Participants were recruited from the community between March 12, 2014, and March 19, 2020. Adults aged 25 to 65 years with a DSM-IV diagnosis of alcohol dependence and at least 4 heavy drinking days during the 30 days prior to screening were included. Exclusion criteria included major psychiatric and drug use disorders, hallucinogen use, medical conditions that contraindicated the study medications, use of exclusionary medications, and current treatment for AUD.
Interventions:
Study medications were psilocybin, 25 mg/70 kg, vs diphenhydramine, 50 mg (first session), and psilocybin, 25-40 mg/70 kg, vs diphenhydramine, 50-100 mg (second session). Psychotherapy included motivational enhancement therapy and cognitive behavioral therapy.
Main outcomes and measures:
The primary outcome was percentage of heavy drinking days, assessed using a timeline followback interview, contrasted between groups over the 32-week period following the first administration of study medication using multivariate repeated-measures analysis of variance.
Results:
A total of 95 participants (mean [SD] age, 46 [12] years; 42 [44.2%] female) were randomized (49 to psilocybin and 46 to diphenhydramine). One participant (1.1%) was American Indian/Alaska Native, 5 (5.3%) were Black, 16 (16.8%) were Hispanic, and 75 (78.9%) were non-Hispanic White. Of the 95 randomized participants, 93 received at least 1 dose of study medication and were included in the primary outcome analysis. Percentage of heavy drinking days during the 32-week double-blind period was 9.7% for the psilocybin group and 23.6% for the diphenhydramine group, a mean difference of 13.9%; (95% CI, 3.0-24.7; F1,86 = 6.43; P = .01). Mean daily alcohol consumption (number of standard drinks per day) was also lower in the psilocybin group. There were no serious adverse events among participants who received psilocybin.
Conclusions and relevance:
Psilocybin administered in combination with psychotherapy produced robust decreases in percentage of heavy drinking days over and above those produced by active placebo and psychotherapy. These results provide support for further study of psilocybin-assisted treatment for AUD.
Trial registration:
ClinicalTrials.gov Identifier: NCT02061293.
... These psychoactive compounds, which exert effects through agonist activity at the serotonin 2A receptor, have recently received renewed scientific attention . The clinical research to date has been limited in the number of studies and the size of samples (Goldberg et al., 2020), but the evidence suggests that classic psychedelics, delivered in conjunction with therapy, may be particularly effective in the treatment of internalizing disorders . For example, a recent double-blind randomized, controlled trial found that psilocybin-assisted therapy was at least as effective as an active control condition (escitalopram) in reducing depressive symptoms among patients with moderate-to-severe major depressive disorder . ...
Objectives
Previous studies have reported links between classic psychedelic use and seizures, but little remains known about prevalence and potential risk factors of classic psychedelic-related seizures.
Methods
Using a sample representative of the US adult population with regard to sex, age, and ethnicity (N = 2822), this study examined the prevalence and potential risk factors of classic psychedelic-related seizures, in a subsample of respondents who reported lifetime classic psychedelic use (n = 613).
Results
Among those who reported lifetime classic psychedelic use, 1.5 % reported classic psychedelic-related seizures, a statistic that comports with the prevalence of epilepsy in the US population. Among those who reported seizures while using a classic psychedelic, almost half reported co-use of antidepressants, mood stabilizers, or opioid replacement therapies at the time of the seizures. Notably, classic psychedelic-related seizures were more commonly reported in certain respondents, especially those with a personal or family history of epilepsy.
Conclusions
These results suggest that classic psychedelic use could increase the risk of seizures in certain populations, particularly those with a personal or family history of epilepsy.
... While a wide variety of psychedelic molecules are found in the natural world, these molecules are related chemically and the vast majority are Trp derivatives (Fig. 5). Further, the subjective effects of these agents on the conscious state are primarily mediated through the activation of the neurotransmission system centered around the Trp-derivative serotonin with particular action at 5-HT2A receptors [205,206]. The most commonly used psychedelics include: psilocybin, a prodrug of psilocin found in psilocybin mushrooms, "magic mushrooms"; lysergic acid diethylamide (LSD) found in fungus (Claviceps); DMT (N,N-dimethyltryptamine, found in many plants' extracts (including ayahuasca); bufotenin (N,Dimethyl-5-hydroxytryptamine) and O-methylbufotenin (5-MeO-DMT) found in mushrooms, plants, toads' skin and venom of (Bufogenus); and ibogaine and harmine found in a number of plants [207]. ...
Sunlight held the key to the origin of life on Earth. The earliest life forms, cyanobacteria, captured the sunlight to generate energy through photosynthesis. Life on Earth evolved in accordance with the circadian rhythms tied to sensitivity to sunlight patterns. A unique feature of cyanobacterial photosynthetic proteins and circadian rhythms' molecules, and later of nearly all photon-sensing molecules throughout evolution, is that the aromatic amino acid tryptophan (Trp) resides at the center of light-harvesting active sites. In this perspective, I review the literature and integrate evidence from different scientific fields to explore the role Trp plays in photon-sensing capabilities of living organisms through its resonance delocalization of π-electrons. The observations presented here are the product of apparently unrelated phenomena throughout evolution, but nevertheless share consistent patterns of photon-sensing by Trp-containing and Trp-derived molecules. I posit the unique capacity to transfer electrons during photosynthesis in the earliest life forms is conferred to Trp due to its aromaticity. I propose this ability evolved to assume more complex functions, serving as a host for mechanisms underlying mental aptitudes – a concept which provides a theoretical basis for defining the neural correlates of consciousness. The argument made here is that Trp aromaticity may have allowed for the inception of the mechanistic building blocks used to fabricate complexity in higher forms of life. More specifically, Trp aromatic non-locality may have acted as a catalyst for the emergence of consciousness by instigating long-range synchronization and stabilizing the large-scale coherence of neural networks, which mediate functional brain activity. The concepts proposed in this perspective provide a conceptual foundation to encourage further interdisciplinary dialogue aimed at examining and defining the role of aromaticity (beyond Trp) in the emergence of life and consciousness.
... The field of psychedelic research is particularly prone to suffer from inability to appropriate blinding and by study participants often being biased towards use of psychedelics. The psychological effects of psychedelics in healthy controls and patient groups were recently assessed in a systematic review and meta-analysis [13] which also identified the need for careful, large-scale, placebo-controlled randomized trials. ...
The serotonergic classical psychedelics include compounds that primarily activate the brain’s serotonin 2 A receptor (5-HT2AR), such as LSD, psilocybin, and DMT (ayahuasca). The acute effects of these compounds are well-known as are their ability to increase the emotional state both in healthy people and in those with neuropsychiatric disorders. In particular psilocybin, the psychoactive constituent in “magic mushrooms”, has shown great potential for treatment of anxiety and depression. A unique and compelling feature of psychedelics is that intake of just a single psychedelic dose is associated with long-lasting effects. This includes effects on personality, e.g., higher openness, and amelioration of depressive symptoms. This review focuses on these stunning effects and summarizes our current knowledge on which behavioral, biochemical, neuroimaging, and electrophysiological data support that the intriguing effects of psychedelics on the human brain and mind are based on neural plasticity. The review also points to so far understudied areas and suggests research questions to be addressed in future studies which potentially can help to understand the intriguing long-term effects after intake of a single (or a few) psychedelic doses.
... Die Pilotstudie aus Yale war der Ausgangspunkt für eine Vielzahl größerer und später auch placebokontrollierter Studien, die zur Entwicklung und Zulassung von Esketamin führten. In diesem Kontext entstand in der Folge auch der Begriff "Schnell wirksame Antidepressiva" ("rapidly acting antidepressants", RAAD; [2] [3,4]. ...
... There has been a dramatic reemergence of research into the therapeutic effects of psychedelics over the past decades. Although experimental studies remain few in number and limited in sample size, the available evidence suggests psychedelics may hold therapeutic potential, particularly in the context of psychiatric disorders (Goldberg et al. 2020;Romeo et al. 2020;Sessa 2018). This research has mainly focused on classic psychedelics, which commonly refers to psychoactive substances known to act as agonists principally at serotonin 2A receptors (Nutt and Carhart-Harris 2021). ...
There are neurophysiological and phenomenological overlaps between psychedelic and meditative states, but there is little evidence on how exposure to psychedelics might be associated with meditation-related variables. We assessed lifetime classic psychedelic use, ego dissolution during one’s most intense experience using a classic psychedelic, and exposure to meditation in a representative sample (n = 953) of American adults. Those who reported experience with meditation were invited to complete a follow-up survey (n = 536, 92.1% response rate) measuring meditation-related variables. Models controlled for a range of potential confounds. Exposure to meditation was associated with lifetime classic psychedelic use and ego dissolution in covariate-adjusted models. In addition, among meditators, greater ego dissolution was associated with more frequent meditation practice. Both lifetime classic psychedelic use and ego dissolution were associated with enlightenment as motivation to practice meditation as well as lower likelihood of overall perceived barriers to meditation practice. Ego dissolution was positively associated with finding meditation more effective. Neither lifetime classic psychedelic use nor ego dissolution was associated with greater likelihood of meditation-related adverse effects. Taken together, results support potential synergy between psychedelics and meditation, but randomized controlled trials are necessary to establish safety and evaluate potential causal relationships.
... Some of the most important evidence for the operation of psychedelics on the NVS unsurprisingly comes from studies in depression. Pre-modern studies conducted during the 1950-60's first indicated a role of psychedelic therapy for depression and anxiety symptoms (76), which aligns with modern-era studies (77)(78)(79). The initial double-blind, randomized, placebo-controlled clinical studies in the modernera of psychedelic therapy (psilocybin) showed an immediate and sustained antidepressant and anxiolytic effect in people Frontiers in Psychiatry | www.frontiersin.org ...
Accumulating clinical evidence shows that psychedelic therapy, by synergistically combining psychopharmacology and psychological support, offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and/or maladaptive habitual patterns of emotion, cognition and behavior, notably, depression (MDD), treatment resistant depression (TRD) and addiction disorders, but perhaps also anxiety disorders, obsessive-compulsive disorder (OCD), Post-Traumatic Stress Disorder (PTSD) and eating disorders. Despite the emergent transdiagnostic evidence, the specific clinical dimensions that psychedelics are efficacious for, and associated underlying neurobiological pathways, remain to be well-characterized. To this end, this review focuses on pre-clinical and clinical evidence of the acute and sustained therapeutic potential of psychedelic therapy in the context of a transdiagnostic dimensional systems framework. Focusing on the Research Domain Criteria (RDoC) as a template, we will describe the multimodal mechanisms underlying the transdiagnostic therapeutic effects of psychedelic therapy, traversing molecular, cellular and network levels. These levels will be mapped to the RDoC constructs of negative and positive valence systems, arousal regulation, social processing, cognitive and sensorimotor systems. In summarizing this literature and framing it transdiagnostically, we hope we can assist the field in moving toward a mechanistic understanding of how psychedelics work for patients and eventually toward a precise-personalized psychedelic therapy paradigm.
... 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.
... Winkelman and Sessa's (2019) edited volume contains reviews of clinical evidence showing the therapeutic effectiveness of psychedelics in the treatment of various health conditions, including anxiety, trauma, treatmentresistant depression, as well as personality, inflammatory, and autoimmune conditions (also see Szabo, 2019; Thompson and Szabo, 2020). The immersive experiences engendered by high doses of psychedelics are often attributed deep personal meaning, and a growing body of theoretical and empirical work shows they can have persisting beneficial effects on well-being and psychosocial functioning (Kuypers et al., 2016;Sweat et al., 2016;Bouso et al., 2018;Haijen et al., 2018;Carhart-Harris and Friston, 2019;Kuypers, 2019;Mason et al., 2019Mason et al., , 2021Barrett et al., 2020;Girn et al., 2020;Goldberg et al., 2020b;Yaden and Griffiths, 2020). There are also hints that lifetime psychedelic use is associated with markers of physical health (self-reported overall health, body mass index, and heart condition and/or cancer in the past 12 months: Simonsson et al., 2021). ...
Our hominin ancestors inevitably encountered and likely ingested psychedelic mushrooms throughout their evolutionary history. This assertion is supported by current understanding of: early hominins’ paleodiet and paleoecology; primate phylogeny of mycophagical and self-medicative behaviors; and the biogeography of psilocybin-containing fungi. These lines of evidence indicate mushrooms (including bioactive species) have been a relevant resource since the Pliocene, when hominins intensified exploitation of forest floor foods. Psilocybin and similar psychedelics that primarily target the serotonin 2A receptor subtype stimulate an active coping strategy response that may provide an enhanced capacity for adaptive changes through a flexible and associative mode of cognition. Such psychedelics also alter emotional processing, self-regulation, and social behavior, often having enduring effects on individual and group well-being and sociality. A homeostatic and drug instrumentalization perspective suggests that incidental inclusion of psychedelics in the diet of hominins, and their eventual addition to rituals and institutions of early humans could have conferred selective advantages. Hominin evolution occurred in an ever-changing, and at times quickly changing, environmental landscape and entailed advancement into a socio-cognitive niche, i.e., the development of a socially interdependent lifeway based on reasoning, cooperative communication, and social learning. In this context, psychedelics’ effects in enhancing sociality, imagination, eloquence, and suggestibility may have increased adaptability and fitness. We present interdisciplinary evidence for a model of psychedelic instrumentalization focused on four interrelated instrumentalization goals: management of psychological distress and treatment of health problems; enhanced social interaction and interpersonal relations; facilitation of collective ritual and religious activities; and enhanced group decision-making. The socio-cognitive niche was simultaneously a selection pressure and an adaptive response, and was partially constructed by hominins through their activities and their choices. Therefore, the evolutionary scenario put forward suggests that integration of psilocybin into ancient diet, communal practice, and proto-religious activity may have enhanced hominin response to the socio-cognitive niche, while also aiding in its creation. In particular, the interpersonal and prosocial effects of psilocybin may have mediated the expansion of social bonding mechanisms such as laughter, music, storytelling, and religion, imposing a systematic bias on the selective environment that favored selection for prosociality in our lineage.
Much of the world's landmass is already known. Deep sea and outer space are beyond most people's reach. It feels like there are fewer places left to discover. Psychedelics, on the other hand, reveal worlds that remain largely obscure. Altered states offer modern, 21st-century audiences boundless opportunities to explore what a human being can experience. In this book, I show you how to become a capable discovery-maker, sample-collecting naturalist, and rational thinker of visionary phenomena.
In the same way European explorers left their shores 500 years ago in search of spice routes by using technologies to get to the other side of the world, you can use psychedelics to get to the other side of ordinary perception and back. Knowing how to gather data, conduct experiments, and make contact with the locals will equip you to chip away at the mystery. You will learn conceptual tools to shape your new mindset, taking an active, rather than passive, role.
If you ever wanted to make more sense of your experiences, now is the time. Find out how you can become part of the Psychedelic Age of Discovery.
Following a decades-long decline in psychedelic research resulting from social, political, and legislative factors, there has been greatly renewed interest in these compounds' ability to treat psychiatric disorders. Classic psychedelics, encompassing both natural and synthetic psychoactive compounds, are characterized by their action as agonists or partial agonists of serotonin 5-hydroxytryptamine 2A receptors. In this comprehensive review, we summarize the latest clinical trials of classic psychedelics on depression and anxiety, attending to the patient demographics and methodology of each study. Overall, studies published since 2020 affirm the potential for classic psychedelics to treat major depressive disorder, treatment-resistant depression, bipolar II, and anxiety-spectrum disorders. However, findings are limited by short follow-up durations and nonstandard dosing and study designs. Given that many of the studies identified were post hoc analyses or follow-up studies from a select few parent studies, it is recommended that more original research be undertaken, with more diverse and larger sample sizes, standardized methodologies including blinding assessment, and long-term follow-up to identify duration of benefits and adverse reactions. It is also important to consider the role of psychological support and the therapeutic alliance in the psychedelic treatment of psychiatric disorders.
After being outlawed in 1970, psychedelics have reemerged in the consciousness of Western society in the form of the so-called psychedelic renaissance. This has led to widespread interest in psychedelic compounds being used for recreation, treatment of mental illness and addiction, and even the so-called “enhancement” of individuals and society. This renewed interest in psychedelics has resulted in seemingly endless publications in both the popular and the academic press, including authors from fields as diverse as philosophy, theology, pharmacology, neuroscience, and clinical medicine. A common thread in this developing literature is the claim that psychedelic compounds mediate their reported benefits by inducing the so-called psychedelic mystical experience (PME). The nature of PME is hotly debated, with some claiming that it is entirely psychological and others proposing that it involves contact with extramental reality. This raises a number of important questions for Catholics, especially whether PME should be considered properly “mystical,” how PME compares with traditionally understood Catholic mysticism, and whether, and if so under what conditions, psychedelics could be licitly used by the Catholic faithful. This paper is an attempt to begin the process of reconciling empiric scientific data regarding psychedelics generally, and PME specifically, with Catholic philosophical and theological considerations, with the goal of both providing recommendations regarding the licitness of the use of psychedelic compounds and inviting conversation about this important and challenging topic.
Summary
Over the past 20 years, there has been a renewed interest in of psychedelics. Many articles have been published extoling the benefits of psychedelics, including for the treatment of mental illness and addiction, recreation, and “enhancement” of individuals and society. A common claim is that the benefits of psychedelics are a result of the psychedelic mystical experience (PME). This paper considers both the use of psychedelics and PME from the perspective of Catholic theology, provides recommendations about their use for the Catholic faithful, and invites further conversation about this important and challenging topic.
Short Summary
This paper considers challenges posed by psychedelics, considers licitness of use, and calls for further discussion.
Psychedelics are psychoactive substances that receive renewed interest from science and society. Increasing empirical evidence shows that the effects of psychedelics are associated with alterations in biochemical processes, brain activity, and lived experience. Still, how these different levels relate remains subject to debate. The current literature presents two influential views on the relationship between the psychedelic molecule, neural events, and experience: The integration view and the pluralistic view. The main aim of this article is to contribute a promising complementary view by re-evaluating the psychedelic molecule-brain-experience relationship from an enactive perspective. We approach this aim via the following main research questions: (1) What is the causal relationship between the psychedelic drug and brain activity? (2) What is the causal relationship between brain activity and the psychedelic experience? In exploring the first research question, we apply the concept of autonomy to the psychedelic molecule-brain relationship. In exploring the second research question, we apply the concept of dynamic co-emergence to the psychedelic brain-experience relationship. Addressing these two research questions from an enactive position offers a perspective that emphasizes interdependence and circular causality on multiple levels. This enactive perspective not only supports the pluralistic view but enriches it through a principled account of how multi-layered processes come to interact. This renders the enactive view a promising contribution to questions around causality in the therapeutic effects of psychedelics with important implications for psychedelic therapy and psychedelic research.
In this thesis, the author investigates the therapeutic potential of psychedelics through literature analysis. First, he places psychedelics in a historical context and presents the current legal regime. Through the presentation of the psychedelic experience through aspects of safety, physiological effects, neurobiological effects and psychological effects, the author answers the question of how, if at all, psychedelics work in combination with psychotherapy. In the discussion, the author notes that psychedelics: (a) create new connections between different centers in the brain; (b) release high-level beliefs of the default brain network, (c) reduce normal ego functions, (d) enhance feelings of connection with others, nature and self and lead from avoidance of emotions to acceptance; (e) affect the personality structure.
Introduction:
A limited number of preliminary open-label (n = 3) and placebo-controlled clinical trials (n = 5) have suggested psilocybin and LSD as potential rapid antidepressants. In this context, there is a growing need to verify and document their safety and tolerability as therapeutic agents, discuss the challenges associated with their administration, and develop safety protocols for their use as next-generation therapeutic agents.
Areas covered:
We have analyzed all randomized, double-blind, and controlled trials that assessed the antidepressant effects of psilocybin and LSD in clinical populations to date, taking special attention to adverse events (AEs) related to their use. Prevalence, significance, and mechanisms of action related to AEs were systematically extracted, analyzed, and discussed.
Expert opinion:
There were no serious AEs related to psilocybin and LSD administration. Most AEs were expected, manageable, and transient. Nevertheless, safety and tolerability concerns regarding some effects, such as dissociation, paranoia, and confusion, remain. Thus, randomized controlled trials with bigger samples are warranted to confirm their therapeutic effects and further investigate their safety and tolerability.
Mystical experiences triggered by psychedelic drugs predict symptom reduction in various psychiatric disorders, and increased well-being in healthy individuals. This work aimed at validating a French version of a tool used to measure mystical experiences: the Revised Mystical Experience Questionnaire-30 items (MEQ30). Construct validity, internal consistencies, concurrent, discriminant, and predictive validities of the French MEQ30 were examined using data about the most significant psychedelic experience of 320 French individuals. Results showed that the original four-factor (i.e., mystical, positive mood, transcendence, and ineffability) structure fit the data best, with good to excellent statistical indices. Total French MEQ30 score was strongly associated with subjective ratings of the mystical (i.e., mystical, spiritual, or religious, and personally significant) and drug intensity-related qualities of the experience, but not with non-mystical (i.e., fun, inebriating, and easy) qualities. Moreover, French MEQ30 score was a significant predictor of subjective positive changes in psychological well-being, relations with self and others, feeling of proximity or connection with nature, and creativity, whereas drug intensity-related and non-mystical qualities of the experience were not, or were only weakly associated with such changes. This French version of the MEQ30 seems to be an appropriate tool for measuring mystical experiences among French speaking individuals.
After a two-decade hiatus in which research on psychedelics was essentially halted, placebo-controlled clinical trials of psychedelic-assisted therapy for mental health conditions have begun to be published. We identified nine randomized, placebo-controlled clinical trials of psychedelic-assisted therapy published since 1994. Studies examined psilocybin, LSD (lysergic acid diethylamide), ayahuasca (which contains a combination of N,N-dimethyltryptamine and harmala monoamine oxidase inhibitor alkaloids), and MDMA (3,4-methylenedioxymethamphetamine). We compared the standardized mean difference between the experimental and placebo control group at the primary endpoint. Results indicated a significant mean between-groups effect size of 1.21 (Hedges g), which is larger than the typical effect size found in trials of psychopharmacological or psychotherapy interventions. For the three studies that maintained a placebo control through a follow-up assessment, effects were generally maintained at follow-up. Overall, analyses support the efficacy of psychedelic-assisted therapy across four mental health conditions-post-traumatic stress disorder, anxiety/depression associated with a life-threatening illness, unipolar depression, and social anxiety among autistic adults. While study quality was high, we identify several areas for improvement regarding the conduct and reporting of trials. Larger trials with more diverse samples are needed to examine possible moderators and mediators of effects, and to establish whether effects are maintained over time.
Psilocybin is a classic psychedelic compound that may have efficacy for the treatment of mood and substance use disorders. Acute psilocybin effects include reduced negative mood, increased positive mood, and reduced amygdala response to negative affective stimuli. However, no study has investigated the long-term, enduring impact of psilocybin on negative affect and associated brain function. Twelve healthy volunteers (7F/5M) completed an open-label pilot study including assessments 1-day before, 1-week after, and 1-month after receiving a 25 mg/70 kg dose of psilocybin to test the hypothesis that psilocybin administration leads to enduring changes in affect and neural correlates of affect. One-week post-psilocybin, negative affect and amygdala response to facial affect stimuli were reduced, whereas positive affect and dorsal lateral prefrontal and medial orbitofrontal cortex responses to emotionally-conflicting stimuli were increased. One-month post-psilocybin, negative affective and amygdala response to facial affect stimuli returned to baseline levels while positive affect remained elevated, and trait anxiety was reduced. Finally, the number of significant resting-state functional connections across the brain increased from baseline to 1-week and 1-month post-psilocybin. These preliminary findings suggest that psilocybin may increase emotional and brain plasticity, and the reported findings support the hypothesis that negative affect may be a therapeutic target for psilocybin.
The current meta-analysis examined the effects of psilocybin in combination with behavioral interventions on anxiety and depression in samples with elevated symptoms. Across four studies (one uncontrolled; three randomized, placebo-controlled; N = 117), within-group pre-post and pre-follow-up effects on anxiety and depression were large (Hedges' gs=1.16 to 1.47) and statistically significant. Across three placebo-controlled studies, pre-post placebo-controlled effects were also large (gs = 0.82 to 0.83) and statistically significant. No serious adverse events were reported. Limitations include the small number of studies and risk for bias within studies. Results tentatively support future research on psilocybin for the treatment of anxiety and depression.
Meditation and psychedelics have played key roles in humankind’s search for self-transcendence and personal change. However, neither their possible synergistic effects, nor related state and trait predictors have been experimentally studied. To elucidate these issues, we administered double-blind the model psychedelic drug psilocybin (315 μg/kg PO) or placebo to meditators (n = 39) during a 5-day mindfulness group retreat. Psilocybin increased meditation depth and incidence of positively experienced self-dissolution along the perception-hallucination continuum, without concomitant anxiety. Openness, optimism, and emotional reappraisal were predictors of the acute response. Compared with placebo, psilocybin enhanced post-intervention mindfulness and produced larger positive changes in psychosocial functioning at a 4-month follow-up, which were corroborated by external ratings, and associated with magnitude of acute self-dissolution experience. Meditation seems to enhance psilocybin’s positive effects while counteracting possible dysphoric responses. These findings highlight the interactions between non-pharmacological and pharmacological factors, and the role of emotion/attention regulation in shaping the experiential quality of psychedelic states, as well as the experience of selflessness as a modulator of behavior and attitudes. A better comprehension of mechanisms underlying most beneficial psychedelic experiences may guide therapeutic interventions across numerous mental conditions in the form of psychedelic-assisted applications.
This book serves as an accessible introduction into how meta-analyses can be conducted in R. Essential steps for meta-analysis are covered, including pooling of outcome measures, forest plots, heterogeneity diagnostics, subgroup analyses, meta-regression, methods to control for publication bias, risk of bias assessments and plotting tools.
Advanced, but highly relevant topics such as network meta-analysis, multi-/three-level meta-analyses, Bayesian meta-analysis approaches, SEM meta-analysis are also covered.
The programming and statistical background covered in the book are kept at a non-expert level. A print version of this book has been published with Chapman & Hall/CRC Press (Taylor & Francis). The complete book can be accessed online: https://bookdown.org/MathiasHarrer/Doing_Meta_Analysis_in_R/.
Modern sophisticated archeometric instruments are increasingly capable of detecting the presence of psychoactive plant sources in archeological contexts, testifying the antiquity of humanity’s search for altered states of consciousness. The purpose of this article is to provide a general picture of these findings, covering the main psychoactive plant sources of the world, and identifying the most ancient dates so far evidenced by archeology. This review is based on the archeological literature identifying the presence of psychoactive plant sources, relying on original research documents. The research produced two main results: (a) a systematization of the types of archeological evidence that testify the relationship between Homo sapiens and these psychoactive sources, subdivided into direct evidence (i.e., material findings, chemical, and genetic) and indirect evidence (i.e., anthropophysical, iconographic, literary, and paraphernalia); and (b) producing a list of the earliest known dates of the relationship of H. sapiens with the main psychoactive plant sources. There appears to be a general diffusion of the use of plant drugs from at least the Neolithic period (for the Old World) and the pre-Formative period (for the Americas). These dates should not to be understood as the first use of these materials, instead they refer to the oldest dates currently determined by either direct or indirect archeological evidence. Several of these dates are likely to be modified back in time by future excavations and finds.
Background: Evidence suggests that classical psychedelics can promote enduring changes in personality, attitudes and optimism, as well as improvements in mental health outcomes.
Aim: To investigate the effects of a composite intervention, involving psilocybin, on pessimism biases in patients with treatment-resistant depression (TRD).
Methods: Patients with TRD (n = 15) and matched, untreated non-depressed controls (n = 15) performed the Prediction Of Future Life Events (POFLE) task. The POFLE task requires participants to predict the likelihood of certain life events occurring within a 30-day period, after which the actual rate of event occurrence is reported; this gives an index of potential pessimism versus optimism bias. Psilocybin was administered in two oral dosing sessions (10 and 25 mg) one week apart. Main outcome measures were collected at baseline and one week after the second dosing session.
Results: Patients showed a significant pessimism bias at baseline [t(14) = -3.260, p = 0.006; 95% CI (-0.16, -0.03), g = 1.1] which was related to the severity of their depressive symptoms (rs = -0.55, p = 0.017). One week after psilocybin treatment, this bias was significantly decreased [t(14) = -2.714, p = 0.017; 95% CI (-0.21, -0.02), g = 0.7] and depressive symptoms were greatly improved [t(14) = 7.900, p < 0.001; 95% CI (16.17, 28.23), g = 1.9]; moreover, the magnitude of change in both variables was significantly correlated (r = -0.57, p = 0.014). Importantly, post treatment, patients became significantly more accurate at predicting the occurrence of future life events [t(14) = 1.857, p = 0.042; 95% CI (-0.01, 0.12), g = 0.6] whereas no such change was observed in the control subjects.
Conclusion: These findings suggest that psilocybin with psychological support might correct pessimism biases in TRD, enabling a more positive and accurate outlook.
Introduction: Mood, anxiety, and substance use disorders are among the most prevalent psychiatric disorders in the population. Although several pharmacological treatments are available, they are not effective for a significant proportion of patients and are associated with several adverse reactions. Therefore, new treatments should be explored. Recent with serotonergic hallucinogens/psychedelics including ayahuasca, psilocybin and lysergic acid diethylamide (LSD) suggest that these drugs have anxiolytic, antidepressive, and antiaddictive effects.
Areas Covered: A systematic review of systematic reviews assessing the efficacy, safety, and tolerability of serotonergic hallucinogens/psychedelic was performed using the PubMed data base until 11 April 2018. Systematic reviews with or without meta-analysis were analyzed, but only reviews that described at least one randomized controlled trial (RCT) were included.
Expert Commentary: Psilocybin and LSD reduced anxiety and depression in cancer patients and symptoms of alcohol and tobacco dependence, and ayahuasca reduced depression symptoms in treatment-resistant depression. Although the results are promising, several studies were open-label and only few were RCTs, and most had small sample sizes and a short duration. Single or few doses of these drugs seem to be well tolerated, but long-term studies are lacking. New RCTs with bigger samples and longer duration are needed to replicate these findings.
Background:
Despite renewed interest in studying the safety and efficacy of psychedelic-assisted psychotherapy for the treatment of psychological disorders, the enrollment of racially diverse participants and the unique presentation of psychopathology in this population has not been a focus of this potentially ground-breaking area of research. In 1993, the United States National Institutes of Health issued a mandate that funded research must include participants of color and proposals must include methods for achieving diverse samples.
Methods:
A methodological search of psychedelic studies from 1993 to 2017 was conducted to evaluate ethnoracial differences in inclusion and effective methods of recruiting peopple of color.
Results:
Of the 18 studies that met full criteria (n = 282 participants), 82.3% of the participants were non-Hispanic White, 2.5% were African-American, 2.1% were of Latino origin, 1.8% were of Asian origin, 4.6% were of indigenous origin, 4.6% were of mixed race, 1.8% identified their race as "other," and the ethnicity of 8.2% of participants was unknown. There were no significant differences in recruitment methodologies between those studies that had higher (> 20%) rates of inclusion.
Conclusions:
As minorities are greatly underrepresented in psychedelic medicine studies, reported treatment outcomes may not generalize to all ethnic and cultural groups. Inclusion of minorities in futures studies and improved recruitment strategies are necessary to better understand the efficacy of psychedelic-assisted psychotherapy in people of color and provide all with equal opportunities for involvement in this potentially promising treatment paradigm.
Mental disorders are rising while development of novel psychiatric medications is declining. This stall in innovation has also been linked with intense debates on the current diagnostics and explanations for mental disorders, together constituting a paradigmatic crisis. A radical innovation is psychedelic-assisted psychotherapy (PAP): professionally supervised use of ketamine, MDMA, psilocybin, LSD and ibogaine as part of elaborated psychotherapy programs. Clinical results so far have shown safety and efficacy, even for “treatment resistant” conditions, and thus deserve increasing attention from medical, psychological and psychiatric professionals. But more than novel treatments, the PAP model also has important consequences for the diagnostics and explanation axis of the psychiatric crisis, challenging the discrete nosological entities and advancing novel explanations for mental disorders and their treatment, in a model considerate of social and cultural factors, including adversities, trauma, and the therapeutic potential of some non-ordinary states of consciousness.
Background:
Recent open-label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression.
Methods:
To test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. We assessed changes in depression severity with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days after dosing.
Results:
We observed significant antidepressant effects of ayahuasca when compared with placebo at all-time points. MADRS scores were significantly lower in the ayahuasca group compared with placebo at D1 and D2 (p = 0.04), and at D7 (p < 0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen's d = 0.84; D2: Cohen's d = 0.84; D7: Cohen's d = 1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64% v. 27%; p = 0.04). Remission rate showed a trend toward significance at D7 (36% v. 7%, p = 0.054).
Conclusions:
To our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression. This study is registered at http://clinicaltrials.gov (NCT02914769).
Aim:
The aim of the current study was to investigate the relationship between escalating higher doses of psilocybin and the potential psilocybin occasioned positive subjective effects.
Methods:
Healthy participants ( n=12) were given three escalating doses of oral psilocybin (0.3 mg/kg; 0.45 mg/kg; 0.6 mg/kg) or (18.8-36.6 mg; 27.1-54.0 mg; 36.3-59.2 mg) a minimum of four weeks apart in a supervised setting. Blood and urine samples, vital signs, and electrocardiograms were obtained. Subjective effects were assessed using the Mystical Experience Questionnaire and Persisting Effects Questionnaire.
Results:
There was a significant linear dose-related response in Mystical Experience Questionnaire total score and the transcendence of time and space subscale, but not in the rate of a complete mystical experience. There was also a significant difference between dose 3 compared to dose 1 on the transcendence of time and space subscale, while no dose-related differences were found for Mystical Experience Questionnaire total scores or rate of a mystical experience. Persisting Effects Questionnaire positive composite scores 30 days after completion of the last dose were significantly higher than negative composite scores. Persisting Effects Questionnaire results revealed a moderate increase in sense of well-being or life satisfaction on average that was associated with the maximum Mystical Experience Questionnaire total score. Pharmacokinetic measures were associated with dose but not with Mystical Experience Questionnaire total scores or rate of a mystical experience.
Conclusions:
High doses of psilocybin elicited subjective effects at least as strong as the lower doses and resulted in positive persisting subjective effects 30 days after, indicating that a complete mystical experience was not a prerequisite for positive outcomes.
Background: The therapeutic effects of the Amazonian plant tea ayahuasca may relate to its ability to enhance mindfulness capacities. Ayahuasca induces a modified state of awareness through the combined action of its active principles: the psychedelic N,N-dimethyltryptamine (DMT) and a series of centrally acting β-carbolines, mainly harmine and tetrahydroharmine. To better understand the therapeutic potential of ayahuasca, here we compared the impact on mindfulness capacities induced by two independent interventions: (a) participation in four ayahuasca sessions without any specific purpose related to improving mindfulness capacities; and (b) participation in a standard mindfulness training course: 8 weeks mindfulness-based stress reduction (MBSR), with the specific goal of improving these skills.
Methods: Participants of two independent groups completed two self-report instruments: The Five Facet Mindfulness Questionnaire (FFMQ) and the Experiences Questionnaire (EQ). The MINDSENS Composite Index was also calculated, including those EQ and FFMQ items that have proven to be the most sensitive to meditation practice. Group A (n = 10) was assessed before and after the last of four closely spaced consecutive ayahuasca sessions. Group B (n = 10) was assessed before and after completion of a standard 8-week MBSR course.
Results: MBSR training led to greater increases in overall mindfulness scores after the 8-week period. MBSR but not ayahuasca led to increases in the MINDSENS Composite Index. However, the ayahuasca sessions induced comparable increases in the Non-Judging subscale of the FFMQ, specifically measuring “acceptance.” Improving this capacity allows for a more detached and less judgmental stance toward potentially distressing thoughts and emotions.
Results: The present findings suggest that a small number of ayahuasca sessions can be as effective at improving acceptance as more lengthy and costly interventions. Future studies should address the benefits of combining ayahuasca administration with mindfulness-based interventions. This will allow us to investigate if ayahuasca will improve the outcome of psychotherapeutic interventions.
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.
Rationale:
Previous research suggests that classical psychedelic compounds can induce lasting changes in personality traits, attitudes and beliefs in both healthy subjects and patient populations.
Aim:
Here we sought to investigate the effects of psilocybin on nature relatedness and libertarian-authoritarian political perspective in patients with treatment-resistant depression (TRD).
Methods:
This open-label pilot study with a mixed-model design studied the effects of psilocybin on measures of nature relatedness and libertarian-authoritarian political perspective in patients with moderate to severe TRD ( n=7) versus age-matched non-treated healthy control subjects ( n=7). Psilocybin was administered in two oral dosing sessions (10 mg and 25 mg) 1 week apart. Main outcome measures were collected 1 week and 7-12 months after the second dosing session. Nature relatedness and libertarian-authoritarian political perspective were assessed using the Nature Relatedness Scale (NR-6) and Political Perspective Questionnaire (PPQ-5), respectively.
Results:
Nature relatedness significantly increased ( t(6)=-4.242, p=0.003) and authoritarianism significantly decreased ( t(6)=2.120, p=0.039) for the patients 1 week after the dosing sessions. At 7-12 months post-dosing, nature relatedness remained significantly increased ( t(5)=-2.707, p=0.021) and authoritarianism remained decreased at trend level ( t(5)=-1.811, p=0.065). No differences were found on either measure for the non-treated healthy control subjects.
Conclusions:
This pilot study suggests that psilocybin with psychological support might produce lasting changes in attitudes and beliefs. Although it would be premature to infer causality from this small study, the possibility of drug-induced changes in belief systems seems sufficiently intriguing and timely to deserve further investigation.
Human research with hallucinogens such as lysergic acid diethylamide (LSD) has been ongoing in the USA since 1949. During the 1960s, LSD was investigated for a variety of psychiatric indications, including the following: as an aid in treatment of schizophrenia; as a means of creating a “model psychosis”; as a direct antidepressant; and as an adjunct to psychotherapy. Studies with all drugs, including LSD, have always been conducted under federal regulatory controls, including the 1938 Food Drug and Cosmetic Act (FDCA; which ensured the safety of drugs) and the 1962 Kefauver-Harris Amendments to the FDCA (which described appropriate scientific methodology and ensured drug efficacy). This paper details how the 1962 Amendments introduced numerous safety and efficacy requirements that must be in satisfied during clinical drug research—and how human studies conducted with LSD in the 1960s struggled with their fulfillment. Information is provided from Senate hearings, case law, and interviews with key investigators. Examples are also drawn from scientific papers and symposia published during and since that period, with a focus on information from clinical studies conducted with LSD by psychiatrist Albert Kurland at the Spring Grove State Hospital, near Baltimore, MD. While Kurland largely conformed with these new regulations, other investigators often fell short of complying with scientific standards and federal requirements. Thus, the human hallucinogen studies of the 1960s are best understood as providing pilot data on safety and efficacy, as well as testable hypotheses for current hallucinogen studies conducted under modern scientific and regulatory standards.
Rationale:
Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy.
Objectives:
Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression.
Methods:
Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure.
Results:
Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen's d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen's d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience.
Conclusions:
Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.
Rationale:
Depressed patients robustly exhibit affective biases in emotional processing which are altered by SSRIs and predict clinical outcome.
Objectives:
The objective of this study is to investigate whether psilocybin, recently shown to rapidly improve mood in treatment-resistant depression (TRD), alters patients' emotional processing biases.
Methods:
Seventeen patients with treatment-resistant depression completed a dynamic emotional face recognition task at baseline and 1 month later after two doses of psilocybin with psychological support. Sixteen controls completed the emotional recognition task over the same time frame but did not receive psilocybin.
Results:
We found evidence for a group × time interaction on speed of emotion recognition (p = .035). At baseline, patients were slower at recognising facial emotions compared with controls (p < .001). After psilocybin, this difference was remediated (p = .208). Emotion recognition was faster at follow-up compared with baseline in patients (p = .004, d = .876) but not controls (p = .263, d = .302). In patients, this change was significantly correlated with a reduction in anhedonia over the same time period (r = .640, p = .010).
Conclusions:
Psilocybin with psychological support appears to improve processing of emotional faces in treatment-resistant depression, and this correlates with reduced anhedonia. Placebo-controlled studies are warranted to follow up these preliminary findings.
Psilocybin can occasion mystical-type experiences with participant-attributed increases in well-being. However, little research has examined enduring changes in traits. This study administered psilocybin to participants who undertook a program of meditation/spiritual practices. Healthy participants were randomized to three groups (25 each): (1) very low-dose (1 mg/70 kg on sessions 1 and 2) with moderate-level (“standard”) support for spiritual-practice (LD-SS); (2) high-dose (20 and 30 mg/70 kg on sessions 1 and 2, respectively) with standard support (HD-SS); and (3) high-dose (20 and 30 mg/70kg on sessions 1 and 2, respectively) with high support for spiritual practice (HD-HS). Psilocybin was administered double-blind and instructions to participants/staff minimized expectancy confounds. Psilocybin was administered 1 and 2 months after spiritual-practice initiation. Outcomes at 6 months included rates of spiritual practice and persisting effects of psilocybin. Compared with low-dose, high-dose psilocybin produced greater acute and persisting effects. At 6 months, compared with LD-SS, both high-dose groups showed large significant positive changes on longitudinal measures of interpersonal closeness, gratitude, life meaning/purpose, forgiveness, death transcendence, daily spiritual experiences, religious faith and coping, and community observer ratings. Determinants of enduring effects were psilocybin-occasioned mystical-type experience and rates of meditation/spiritual practices. Psilocybin can occasion enduring trait-level increases in prosocial attitudes/behaviors and in healthy psychological functioning.
Trial Registration
ClinicalTrials.gov Identifier NCT00802282
RationaleLysergic acid diethylamide (LSD) and other serotonergic hallucinogens can induce profound alterations of consciousness and mystical-type experiences, with reportedly long-lasting effects on subjective well-being and personality. Methods
We investigated the lasting effects of a single dose of LSD (200 μg) that was administered in a laboratory setting in 16 healthy participants. The following outcome measures were assessed before and 1 and 12 months after LSD administration: Persisting Effects Questionnaire (PEQ), Mysticism Scale (MS), Death Transcendence Scale (DTS), NEO-Five Factor Inventory (NEO-FFI), and State-Trait Anxiety Inventory (STAI). ResultsOn the PEQ, positive attitudes about life and/or self, positive mood changes, altruistic/positive social effects, positive behavioral changes, and well-being/life satisfaction significantly increased at 1 and 12 months and were subjectively attributed by the subjects to the LSD experience. Five-Dimensions of Altered States of Consciousness (5D-ASC) total scores, reflecting acutely induced alterations in consciousness, and Mystical Experience Questionnaire (MEQ30) total scores correlated with changes in well-being/life satisfaction 12 months after LSD administration. No changes in negative attitudes, negative mood, antisocial/negative social effects, or negative behavior were attributed to the LSD experience. After 12 months, 10 of 14 participants rated their LSD experience as among the top 10 most meaningful experiences in their lives. Five participants rated the LSD experience among the five most spiritually meaningful experiences in their lives. On the MS and DTS, ratings of mystical experiences significantly increased 1 and 12 months after LSD administration compared with the pre-LSD screening. No relevant changes in personality measures were found. Conclusions
In healthy research subjects, the administration of a single dose of LSD (200 μg) in a safe setting was subjectively considered a personally meaningful experience that had long-lasting subjective positive effects. Trial registrationRegistration identification number: NCT01878942.
Background:
Ayahuasca is a plant tea containing the psychedelic 5-HT2A agonist N,N-dimethyltryptamine (DMT) and harmala monoamine-oxidase inhibitors. Acute administration leads to neurophysiological modifications in brain regions of the default mode network (DMN), purportedly through a glutamatergic mechanism. Post-acutely, ayahuasca potentiates mindfulness capacities in volunteers, and induces rapid and sustained antidepressant effects in treatment-resistant patients. However, the mechanisms underlying these fast and maintained effects are poorly understood. Here we investigated in an open-label uncontrolled study in sixteen healthy volunteers ayahuasca-induced post-acute neurometabolic and connectivity modifications, and their association with mindfulness measures.
Methods:
Using 1H-magnetic resonance spectroscopy (MRS) and functional connectivity, we compared baseline and post-acute neurometabolites and seed-to-voxel connectivity in the posterior (PCC) and anterior (ACC) cingulate cortex after a single ayahuasca dose.
Results:
MRS showed post-acute reductions in Glx (glutamate+glutamine), creatine and NAA-NAAG (N-acetylaspartate+N-acetylaspartylglutamate) in the PCC. Connectivity was increased between the PCC and the ACC, and between the ACC and limbic structures in the right medial temporal lobe (MTL). Glx reductions correlated with increases in the "Non-Judging" subscale of the Five Facets Mindfulness Questionnaire. Increased ACC-MTL connectivity correlated with increased scores on the Self-Compassion questionnaire. Post-acute neural changes predicted sustained elevations in "Non-Judging" two months later.
Conclusions:
These results support the involvement of glutamate neurotransmission in the effects of psychedelics in humans. They further suggest that neurometabolic changes in the PCC, a key region within the DMN, and increased connectivity between the ACC and MTL structures involved in emotion and memory, potentially underlie the post-acute psychological effects of ayahuasca.
The Open Science Framework (OSF) is a free, open source,r esearch workflow web application developed and maintained by the Center for Open Science (COS).
Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes.
Trial Registration
ClinicalTrials.gov identifier: NCT00465595
Background:
Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression.
Methods:
In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks.
Results:
Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60-80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression.
Conclusions:
In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress.
Trial registration:
ClinicalTrials.gov Identifier: NCT00957359.
Background:
Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression.
Methods:
In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin's effects. Patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797.
Findings:
Psilocybin's acute psychedelic effects typically became detectable 30-60 min after dosing, peaked 2-3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0-1 scale) was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week (mean QIDS difference -11·8, 95% CI -9·15 to -14·35, p=0·002, Hedges' g=3·1) and 3 months (-9·2, 95% CI -5·69 to -12·71, p=0·003, Hedges' g=2) after high-dose treatment. Marked and sustained improvements in anxiety and anhedonia were also noted.
Interpretation:
This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach.
Funding:
Medical Research Council.
The relationship between humans and psychoactive substances can be traced back over millennia. This paper aims to provide a comprehensive overview of the consumption of drug plants and fermented beverages in prehistoric times by drawing upon some archaeological examples worldwide that illustrate the early use of these substances. The archaeological evidence of psychoactive substances is assessed in the light of some indicators that should be taken into consideration when examining this type of data.
Background
Psychedelic drugs have shown an efficacy in some psychiatric disorders and have an original mechanism of action with a 5-HT 2A agonism.
Aim
The aim of this meta-analysis was to assess by a quantitative analysis the putative efficacy of psychedelic drugs on depressive symptoms and to investigate the kinetic of this efficacy.
Methods
We searched the MEDLINE and PsycINFO databases through April 2019, without limits on year of publication. Means and standard deviations were extracted to calculate standardized mean differences (SMD). Scores of depressive symptoms were compared with baseline scores at days 7, 14, and 21; weeks 4–5 and 6–8; and months 3 and 6.
Results
Eight studies were included in this meta-analysis. A significant decrease of depressive symptoms was found from day 1 ( n = 5 studies; SMD = ‒1.4, 95% confidence interval (CI): ‒2.33 to ‒0.48, p = 0.003) to 6 months ( n = 4 studies; SMD = ‒1.07, 95% CI: ‒1.44 to ‒0.7, p < 0.001) after psychedelic sessions. No serious adverse effect was reported in all included studies. A transient increase of the heart rate, blood systolic, and diastolic pressure were found after psychedelics compared with placebo.
Conclusion
This meta-analysis shows that psychedelic treatments were safe and could contribute to a rapid improvement of depressive symptoms.
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.
A single dose of the serotonin 2A receptor (5-HT2AR) agonist psilocybin can have long-lasting beneficial effects on mood, personality, and potentially on mindfulness, but underlying mechanisms are unknown. Here, we for the first time conduct a study that assesses psilocybin effects on cerebral 5-HT2AR binding with [¹¹C]Cimbi-36 positron emission tomography (PET) imaging and on personality and mindfulness. Ten healthy and psychedelic-naïve volunteers underwent PET neuroimaging of 5-HT2AR at baseline (BL) and one week (1W) after a single oral dose of psilocybin (0.2–0.3 mg/kg). Personality (NEO PI-R) and mindfulness (MAAS) questionnaires were completed at BL and at three-months follow-up (3M). Paired t-tests revealed statistically significant increases in personality Openness (puncorrected = 0.04, mean change [95%CI]: 4.2[0.4;∞]), which was hypothesized a priori to increase, and mindfulness (pFWER = 0.02, mean change [95%CI]: 0.5 [0.2;0.7]). Although 5-HT2AR binding at 1W versus BL was similar across individuals (puncorrected = 0.8, mean change [95%CI]: 0.007 [−0.04;0.06]), a post hoc linear regression analysis showed that change in mindfulness and 5-HT2AR correlated negatively (β [95%CI] = −5.0 [−9.0; −0.9], pFWER= 0.046). In conclusion, we confirm that psilocybin intake is associated with long-term increases in Openness and – as a novel finding – mindfulness, which may be a key element of psilocybin therapy. Cerebral 5-HT2AR binding did not change across individuals but the negative association between changes in 5-HT2AR binding and mindfulness suggests that individual change in 5-HT2AR levels after psilocybin is variable and represents a potential mechanism influencing long-term effects of psilocybin on mindfulness.
Objective:
The authors provide an evidenced-based summary of the literature on the clinical application of psychedelic drugs in psychiatric disorders.
Methods:
Searches of PubMed and PsycINFO via Ovid were conducted for articles in English, in peer-reviewed journals, reporting on "psilocybin," "lysergic acid diethylamide," "LSD," "ayahuasca," "3,4-methylenedioxymethamphetamine," and "MDMA," in human subjects, published between 2007 and July 1, 2019. A total of 1,603 articles were identified and screened. Articles that did not contain the terms "clinical trial," "therapy," or "imaging" in the title or abstract were filtered out. The 161 remaining articles were reviewed by two or more authors. The authors identified 14 articles reporting on well-designed clinical trials investigating the efficacy of lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), psilocybin, and ayahuasca for the treatment of mood and anxiety disorders, trauma and stress-related disorders, and substance-related and addictive disorders as well as in end-of-life care.
Results:
The most significant database exists for MDMA and psilocybin, which have been designated by the U.S. Food and Drug Administration (FDA) as "breakthrough therapies" for posttraumatic stress disorder (PTSD) and treatment-resistant depression, respectively. The research on LSD and ayahuasca is observational, but available evidence suggests that these agents may have therapeutic effects in specific psychiatric disorders.
Conclusions:
Randomized clinical trials support the efficacy of MDMA in the treatment of PTSD and psilocybin in the treatment of depression and cancer-related anxiety. The research to support the use of LSD and ayahuasca in the treatment of psychiatric disorders is preliminary, although promising. Overall, the database is insufficient for FDA approval of any psychedelic compound for routine clinical use in psychiatric disorders at this time, but continued research on the efficacy of psychedelics for the treatment of psychiatric disorders is warranted.
Background:
Depression and anxiety are prevalent psychiatric disorders that carry significant morbidity. Pharmacological and psychosocial interventions are used to manage these conditions, but their efficacy is limited. Recent interest into the use of psychedelic-assisted therapy using ayahuasca, psilocybin or lysergic acid diethylamide (LSD) may be a promising alternative for patients unresponsive to traditional treatments. This review aims to determine the efficacy and tolerability of psychedelics in the management of resistant depression.
Methods:
Clinical trials investigating psychedelics in patients with depression and/or anxiety were searched via MEDLINE, EMBASE and PsychINFO. Efficacy was assessed by measuring symptom improvement from baseline, and tolerability was evaluated by noting the incidence and type of adverse effects reported. Risk of bias was assessed.
Results:
Seven studies, with 130 patients, were analysed in this review. Three were conducted in patients with depression, two in patients with anxiety and two in patients with both. In a supportive setting, ayahuasca, psilocybin, and LSD consistently produced immediate and significant anti-depressant and anxiolytic effects that were endured for several months. Psychedelics were well-tolerated. The most common adverse effects were transient anxiety, short-lived headaches, nausea and mild increases in heart rate and blood pressure.
Limitations:
At present, the number of studies on this subject is very limited; and the number of participating patients within these is also limited as the treatment under investigations is a relatively novel concept.
Conclusions:
Though further evidence is required, psychedelics appear to be effective in significantly reducing symptoms of depression and anxiety and are well-tolerated.
Background:
Numerous anecdotal reports suggest that repeated use of very low doses of lysergic acid diethylamide (LSD), known as microdosing, improves mood and cognitive function. These effects are consistent both with the known actions of LSD on serotonin receptors and with limited evidence that higher doses of LSD (100-200 μg) positively bias emotion processing. Yet, the effects of such subthreshold doses of LSD have not been tested in a controlled laboratory setting. As a first step, we examined the effects of single very low doses of LSD (0-26 μg) on mood and behavior in healthy volunteers under double-blind conditions.
Methods:
Healthy young adults (N = 20) attended 4 laboratory sessions during which they received 0 (placebo), 6.5, 13, or 26 μg of LSD in randomized order at 1-week intervals. During expected peak drug effect, they completed mood questionnaires and behavioral tasks assessing emotion processing and cognition. Cardiovascular measures and body temperature were also assessed.
Results:
LSD produced dose-related subjective effects across the 3 doses (6.5, 13, and 26 μg). At the highest dose, the drug also increased ratings of vigor and slightly decreased positivity ratings of images with positive emotional content. Other mood measures, cognition, and physiological measures were unaffected.
Conclusions:
Single microdoses of LSD produced orderly dose-related subjective effects in healthy volunteers. These findings indicate that a threshold dose of 13 μg of LSD might be used safely in an investigation of repeated administrations. It remains to be determined whether the drug improves mood or cognition in individuals with symptoms of depression.
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.
Cancer is highly prevalent and one of the leading causes of global morbidity and mortality. Psychological and existential suffering is common in cancer patients, associated with poor psychiatric and medical outcomes. Promising early-phase clinical research (1960s to early 1970s) suggested a therapeutic signal for serotoninergic psychedelics (e.g. psilocybin, LSD) in treating cancer-related psychiatric distress. After several decades of quiescence, research on psychedelic-assisted therapy to treat psychiatric disorders in cancer patients has resumed within the last 2 decades in the US and Europe. This review article is based on a systematic search of clinical trials from 1960–2018 researching the therapeutic use of psychedelic treatment in patients with serious or terminal illnesses and related psychiatric illness. The search found 10 eligible clinical trials, with a total of 445 participants, with the vast majority of the patients having advanced or terminal cancer diagnoses. Six open label trials, published between 1964 and 1980 (n = 341), suggested that psychedelic therapy (mostly with LSD) may improve cancer-related depression, anxiety, and fear of death. Four RCTs trials were published between 2011 and 2016 (n = 104), mostly with psilocybin treatment (n = 92), and demonstrated that psychedelic-assisted treatment can produce rapid, robust, and sustained improvements in cancer-related psychological and existential distress.
Background:
Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder.
Methods:
We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291.
Findings:
We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89-2·41) for amitriptyline and 1·37 (1·16-1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72-0·97) and fluoxetine (0·88, 0·80-0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01-1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43-0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30-2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.
Interpretation:
All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.
Funding:
National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.
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.
Meta-analysis of psychotherapy intervention research normally examines differences between treatment groups and some form of comparison group (e.g., wait list control; alternative treatment group). The effect of treatment is normally quantified as a standardized mean difference (SMD). We describe procedures for computing unbiased estimates of the population SMD from sample data (e.g., group Ms and SDs), and provide guidance about a number of complications that may arise related to effect size computation. These complications include (a) incomplete data in research reports; (b) use of baseline data in computing SMDs and estimating the population standard deviation (σ); (c) combining effect size data from studies using different research designs; and (d) appropriate techniques for analysis of data from studies providing multiple estimates of the effect of interest (i.e., dependent effect sizes).
Clinical or Methodological Significance of this article: Meta-analysis is a set of techniques for producing valid summaries of existing research. The initial computational step for meta-analyses of research on intervention outcomes involves computing an effect size quantifying the change attributable to the intervention. We discuss common issues in the computation of effect sizes and provide recommended procedures to address them.
Anxiety and depression are some of the most common psychiatric symptoms of patients suffering with life-threatening diseases, often associated with a low quality of life and a poor overall prognosis. 5-HT2A-receptor agonists (serotonergic hallucinogens, ‘psychedelics’) like lysergic acid diethylamide (LSD) and psilocybin were first investigated as therapeutic agents in the 1960s. Recently, after a long hiatus period of regulatory obstacles, interest in the clinical use of these substances has resumed. The current article provides a systematic review of studies investigating psychedelics in the treatment of symptoms of existential distress in life-threatening diseases across different periods of research, highlighting how underlying concepts have developed over time. A systematic search for clinical trials from 1960 to 2017 revealed 11 eligible clinical trials involving a total number of N = 445 participants, of which 7 trials investigated the use of lysergic acid diethylamide (LSD) (N = 323), 3 trials investigated the use of psilocybin (N = 92), and one trial investigated the use of dipropyltryptamine (DPT) (N = 30). The 4 more recent randomized controlled trials (RCTs) (N = 104) showed a significantly higher methodological quality than studies carried out in the 1960s and 1970s. Evidence supports that patients with life threatening diseases associated with symptoms of depression and anxiety benefit from the anxiolytic and antidepressant properties of serotonergic hallucinogens. Some studies anecdotally reported improvements in patients´ quality of life and reduced fear of death. Moreover, low rates of side effects were reported in studies that adhered to safety guidelines. Further studies are needed to determine how these results can be transferred into clinical practice.
A core aspect of the human self is the attribution of personal relevance to everyday stimuli enabling us to experience our environment as meaningful [1]. However, abnormalities in the attribution of personal relevance to sensory experiences are also critical features of many psychiatric disorders [2, 3]. Despite their clinical relevance, the neurochemical and anatomical substrates enabling meaningful experiences are largely unknown. Therefore, we investigated the neuropharmacology of personal relevance processing in humans by combining fMRI and the administration of the mixed serotonin (5-HT) and dopamine receptor (R) agonist lysergic acid diethylamide (LSD), well known to alter the subjective meaning of percepts, with and without pretreatment with the 5-HT2AR antagonist ketanserin. General subjective LSD effects were fully blocked by ketanserin. In addition, ketanserin inhibited the LSD-induced attribution of personal relevance to previously meaningless stimuli and modulated the processing of meaningful stimuli in cortical midline structures. These findings point to the crucial role of the 5-HT2AR subtype and cortical midline regions in the generation and attribution of personal relevance. Our results thus increase our mechanistic understanding of personal relevance processing and reveal potential targets for the treatment of psychiatric illnesses characterized by alterations in personal relevance attribution.
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.
Background:
Lysergic acid diethylamide (LSD) is a potent serotonergic hallucinogen or psychedelic that modulates consciousness in a marked and novel way. This study sought to examine the acute and mid-term psychological effects of LSD in a controlled study.
Method:
A total of 20 healthy volunteers participated in this within-subjects study. Participants received LSD (75 µg, intravenously) on one occasion and placebo (saline, intravenously) on another, in a balanced order, with at least 2 weeks separating sessions. Acute subjective effects were measured using the Altered States of Consciousness questionnaire and the Psychotomimetic States Inventory (PSI). A measure of optimism (the Revised Life Orientation Test), the Revised NEO Personality Inventory, and the Peter's Delusions Inventory were issued at baseline and 2 weeks after each session.
Results:
LSD produced robust psychological effects; including heightened mood but also high scores on the PSI, an index of psychosis-like symptoms. Increased optimism and trait openness were observed 2 weeks after LSD (and not placebo) and there were no changes in delusional thinking.
Conclusions:
The present findings reinforce the view that psychedelics elicit psychosis-like symptoms acutely yet improve psychological wellbeing in the mid to long term. It is proposed that acute alterations in mood are secondary to a more fundamental modulation in the quality of cognition, and that increased cognitive flexibility subsequent to serotonin 2A receptor (5-HT2AR) stimulation promotes emotional lability during intoxication and leaves a residue of 'loosened cognition' in the mid to long term that is conducive to improved psychological wellbeing.
This study reports 3-year outcomes for clients who had been treated in the five outpatient sites of Project MATCH, a multisite clinical trial designed to test a priori client treatment matching hypotheses. The main purpose of this study was to characterize the status of the matching hypotheses at the 3-year follow-up. This entailed investigating which matching findings were sustained or even strengthened across the 3-year study period, and whether any hypotheses that were not supported earlier eventually emerged at 3 years, or conversely, whether matching findings discerned earlier dissipated at this later time. This research also examines the prognostic effects of the client matching attributes, characterizes the overall outcomes at 37 to 39 months, and explores differential effects of the three treatments at extended follow-up. With regard to the matching effects, client anger demonstrated the most consistent interaction in the trial, with significant matching effects evident at both the 1-year and 3-year follow- ups. As predicted, clients high in anger fared better in Motivational Enhancement Therapy (MET) than in the other two MATCH treatments: Cognitive- Behavioral Therapy (CBT) and Twelve-Step Facilitation (TSF). Among subjects in the highest third of the anger variable, clients treated in MET had on average 76.4% abstinent days, whereas their counterparts in the other two treatments (CBT and TSF) had on average 66% abstinent days. Conversely, clients low in anger performed better after treatment in CBT and TSF than in MET. Significant matching effects for the support for drinking variable emerged in the 3-year outcome analysis, such that clients whose social networks were more supportive of drinking derived greater benefit from TSF treatment than from MET. Among subjects in the highest third of the support for drinking variable, TSF participants were abstinent 16.1% more days than MET participants. At the lower end of this variable, difference in percent days abstinent between MET and TSF was 3%, with MET clients having more abstinent days. A significant matching effect for psychiatric severity that appeared in the first year posttreatment was not observed after 3 years. Of the 21 client attributes used in testing the matching hypotheses, 11 had prognostic value at 3 years. Among these, readiness-to-change and self- efficacy emerged as the strongest predictors of long-term drinking outcome. With regard to the overall outcomes, the reductions in drinking that were observed in the first year after treatment were sustained over the 3-year follow-up period: almost 30% of the subjects were totally abstinent in months 37 to 39, whereas those who did report drinking nevertheless remained abstinent an average of two-thirds of the time. As in the 1-year follow-up, there were few differences among the three treatments, although TSF continued to show a possible slight advantage.
Ayahuasca is an Amazonian botanical hallucinogenic brew which contains dimethyltryptamine, a 5-HT2A receptor agonist, and harmine, a monoamine-oxidase A inhibitor. Our group recently reported that ayahuasca administration was associated with fast-acting antidepressive effects in 6 depressive patients. The objective of the present work was to assess the antidepressive potentials of ayahuasca in a bigger sample and to investigate its effects on regional cerebral blood flow. In an open-label trial conducted in an inpatient psychiatric unit, 17 patients with recurrent depression received an oral dose of ayahuasca (2.2 mL/kg) and were evaluated with the Hamilton Rating Scale for Depression, the Montgomery-Åsberg Depression Rating Scale, the Brief Psychiatric Rating Scale, the Young Mania Rating Scale, and the Clinician Administered Dissociative States Scale during acute ayahuasca effects and 1, 7, 14, and 21 days after drug intake. Blood perfusion was assessed eight hours after drug administration by means of single photon emission tomography. Ayahuasca administration was associated with increased psychoactivity (Clinician Administered Dissociative States Scale) and significant score decreases in depression-related scales (Hamilton Rating Scale for Depression, Montgomery-Åsberg Depression Rating Scale, Brief Psychiatric Rating Scale) from 80 minutes to day 21. Increased blood perfusion in the left nucleus accumbens, right insula and left subgenual area, brain regions implicated in the regulation of mood and emotions, were observed after ayahuasca intake. Ayahuasca was well tolerated. Vomiting was the only adverse effect recorded, being reported by 47% of the volunteers. Our results suggest that ayahuasca may have fast-acting and sustained antidepressive properties. These results should be replicated in randomized, double-blind, placebo-controlled trials.