Article

A single psilocybin dose is associated with long-term increased mindfulness, preceded by a proportional change in neocortical 5-HT2A receptor binding

Authors:
  • Center for Integrated Molecular Brain Imaging
  • Copenhagen University and Rigshospitalet
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Abstract

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.

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... The mechanisms by which psychedelics confer benefits to well-being share overlap with how nature relatedness and nature contact yield benefits. Psychedelics have been associated with eliciting sustained increases in mindfulness-related capacities (Madsen et al., 2020;Murphy-Beiner and Soar, 2020;Sampedro et al., 2017;Soler et al., 2018;Uthaug et al., 2019), facilitating enhanced connectedness, empathy and unitive states (Carhart-Harris et al., 2018b;Forstmann et al., 2020;Griffiths et al., 2018;Mason et al., 2019;Noorani et al., 2018;Pokorny et al., 2017;van Mulukom et al., 2020;Watts et al., 2017) and eliciting awe (Griffiths et al., 2006;Hendricks, 2018;Noorani et al., 2018;Richards et al., 1977;Watts et al., 2017). Psychedelics have also been found to increase openness to experience in an enduring way (Barrett et al., 2020;Erritzoe et al., 2018;Lebedev et al., 2016;MacLean et al., 2011;Madsen et al., 2020). ...
... Psychedelics have been associated with eliciting sustained increases in mindfulness-related capacities (Madsen et al., 2020;Murphy-Beiner and Soar, 2020;Sampedro et al., 2017;Soler et al., 2018;Uthaug et al., 2019), facilitating enhanced connectedness, empathy and unitive states (Carhart-Harris et al., 2018b;Forstmann et al., 2020;Griffiths et al., 2018;Mason et al., 2019;Noorani et al., 2018;Pokorny et al., 2017;van Mulukom et al., 2020;Watts et al., 2017) and eliciting awe (Griffiths et al., 2006;Hendricks, 2018;Noorani et al., 2018;Richards et al., 1977;Watts et al., 2017). Psychedelics have also been found to increase openness to experience in an enduring way (Barrett et al., 2020;Erritzoe et al., 2018;Lebedev et al., 2016;MacLean et al., 2011;Madsen et al., 2020). ...
... Mindfulness has been defined as 'being attentive to and aware of what is taking place in the present' (Brown and Ryan, 2003: 822). Psychedelics can foster enduring increases in measures of mindfulness-related capacities (Madsen et al., 2020;Murphy-Beiner and Soar, 2020;Sampedro et al., 2017;Soler et al., 2018;Uthaug et al., 2019), even when used outside the context of a mindfulness meditation practice. Cultivating mindfulness also enhances qualities of the acute psychedelic experience, in addition to the long-term psychological benefits obtained from psychedelic use Smigielski et al., 2019a). ...
Article
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Therapeutic psychedelic administration and contact with nature have been associated with the same psychological mechanisms: decreased rumination and negative affect, enhanced psychological connectedness and mindfulness-related capacities, and heightened states of awe and transcendent experiences, all processes linked to improvements in mental health amongst clinical and healthy populations. Nature-based settings can have inherently psychologically soothing properties which may complement all stages of psychedelic therapy (mainly preparation and integration) whilst potentiating increases in nature relatedness, with associated psychological benefits. Maximising enhancement of nature relatedness through therapeutic psychedelic administration may constitute an independent and complementary pathway towards improvements in mental health that can be elicited by psychedelics.
... Mindfulness techniques are associated with improvements in mental health, depression, anxiety, stress, and pain management (Marchand, 2012). Mindfulness-related capacities can be increased by psychedelics, including psilocybin (Madsen et al., 2020), ayahuasca (Murphy-Beiner & Soar, 2020;Sampedro et al., 2017), and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) (Uthaug et al., 2019). Remarkably, mindfulness increases seem to facilitate the therapeutic action of psychedelics in mood and substance use disorders (Mian, Altman, & Earleywine, 2020;Walsh & Thiessen, 2018;Watts, Day, Krzanowski, Nutt, & Carhart-Harris, 2017). ...
... In contrast to previous findings, LSD did not increase mindfulness. This might be explained by previous studies assessing mindfulness in naturalistic settings (Murphy-Beiner & Soar, 2020;Smigielski et al., 2019;Soler et al., 2018Soler et al., , 2016Uthaug et al., 2019) or with baseline comparisons (Madsen et al., 2020;Sampedro et al., 2017), allowing for setting or placebo effects which fundamentally influence psychedelic experiences (Olson, Suissa-Rocheleau, Lifshitz, Raz, & Veissière, 2020). Moreover, our study applied no mindfulness-enhancing procedures, but assessed spontaneous changes. ...
... Contrastingly, mindfulness changes were correlated with mystical experiences and ego-dissolution, positively in the short term and negatively in the mid-term. Similarly, previous findings reported positive relationships between ayahuascainduced ego-dissolution and sub-acute mindfulness (Uthaug et al., 2018) and negative relationships between psilocybin-related effects and long-term mindfulness (Madsen et al., 2020). Overall, these results might indicate that psychedelic experiences facilitate spontaneous mindfulness in the short term but hinder it in the long term. ...
Article
Background For a century, psychedelics have been investigated as models of psychosis for demonstrating phenomenological similarities with psychotic experiences and as therapeutic models for treating depression, anxiety, and substance use disorders. This study sought to explore this paradoxical relationship connecting key parameters of the psychotic experience, psychotherapy, and psychedelic experience. Methods In a randomized, double-blind, placebo-controlled, crossover design, 24 healthy volunteers received 50 μg d -lysergic acid diethylamide (LSD) or inactive placebo. Psychotic experience was assessed by aberrant salience (Aberrant Salience Inventory, ASI), therapeutic potential by suggestibility (Creative Imagination Scale, CIS) and mindfulness (Five Facet Mindfulness Questionnaire, FFMQ; Mindful Attention Awareness Scale, MAAS; Experiences Questionnaire, EQ), and psychedelic experience by four questionnaires (Altered State of Consciousness Questionnaire, ASC; Mystical Experiences Questionnaire, MEQ; Challenging Experiences Questionnaire, CEQ; Ego-Dissolution Inventory, EDI). Relationships between LSD-induced effects were examined. Results LSD induced psychedelic experiences, including alteration of consciousness, mystical experiences, ego-dissolution, and mildly challenging experiences, increased aberrant salience and suggestibility, but not mindfulness. LSD-induced aberrant salience correlated highly with complex imagery, mystical experiences, and ego-dissolution. LSD-induced suggestibility correlated with no other effects. Individual mindfulness changes correlated with aspects of aberrant salience and psychedelic experience. Conclusions The LSD state resembles a psychotic experience and offers a tool for healing. The link between psychosis model and therapeutic model seems to lie in mystical experiences. The results point to the importance of meaning attribution for the LSD psychosis model and indicate that psychedelic-assisted therapy might benefit from therapeutic suggestions fostering mystical experiences.
... Although it remains to be seen whether the mechanisms described here lead to clinical improvement in humans, preclinical data on 5-HT 2A R agonist effects on learning and memory, Fig. 1 A diagram of three converging pathways that may be responsible for induced neural plasticity, potentially resulting in lasting beneficial effects following psychedelic administration: 5-HT 2A R upregulation of neocortical BDNF, amplification of AMPA receptor activity resulting in downstream activation of mTOR, and upregulated Arc protein expression combined with the observed neurological, antidepressant, and anxiolytic effects of psychedelics discussed below, present a compelling rationale for targeted investigation of 5-HT 2A R agonist effects in patients with AD. Psychoplastogenic effects could present a potential mechanism to slow or reverse atrophy in key brain regions affected by AD and could be studied after chronic low-dose or one or more high-dose psychedelic administration sessions in AD patients using pre-and postneuroimaging and neuropsychological testing, parallel to research in healthy volunteers described in more detail below (Madsen et al. 2020). Similarly, preclinical findings on 5-HT 2A R mediated reductions in Aβ levels (Yuede et al. 2021) could be studied in clinical trials administering classic psychedelics to early-stage AD patients and assessing longitudinal impact on Aβ, cognitive function, and disease progression, providing another possible, complementary therapeutic mechanism for advancing AD treatment. ...
... Increased Wellbeing and Life Satisfaction A growing body of work has shown sustained well-being benefits after classic psychedelic administration across diverse samples, from healthy volunteers and older long-term AIDS survivors (Anderson et al. 2020) to people with a range of health conditions including cancer-related distress Swift et al. 2017), alcohol dependence (Bogenschutz et al. 2018), nicotine dependence (Noorani et al. 2018), and major depression (Watts et al. 2017). In many cases, such persisting effects are correlated with enduring personality changes such as increased openness, as well as increased life satisfaction and overall well-being (Erritzoe et al. 2018;Griffiths et al. 2008;MacLean et al. 2011;Madsen et al. 2020;Schmid and Liechti 2018;Smigielski et al. 2019a). Although the mechanisms for post-acute alterations in personality, behavior, and well-being are still under investigation, they have been linked to acute psychoactive drug effects that include a sense of insight and meaning (Erritzoe et al. 2018;Griffiths et al. 2008;Smigielski et al. 2019a), spiritual or mystical-type effects characterized by a sense of oneness MacLean et al. 2011;Schmid and Liechti 2018), and changes in 5-HT 2A R binding (Madsen et al. 2020) and brain network functional connectivity (Barrett et al. 2020a;Sampedro et al. 2017;Smigielski et al. 2019b). ...
... In many cases, such persisting effects are correlated with enduring personality changes such as increased openness, as well as increased life satisfaction and overall well-being (Erritzoe et al. 2018;Griffiths et al. 2008;MacLean et al. 2011;Madsen et al. 2020;Schmid and Liechti 2018;Smigielski et al. 2019a). Although the mechanisms for post-acute alterations in personality, behavior, and well-being are still under investigation, they have been linked to acute psychoactive drug effects that include a sense of insight and meaning (Erritzoe et al. 2018;Griffiths et al. 2008;Smigielski et al. 2019a), spiritual or mystical-type effects characterized by a sense of oneness MacLean et al. 2011;Schmid and Liechti 2018), and changes in 5-HT 2A R binding (Madsen et al. 2020) and brain network functional connectivity (Barrett et al. 2020a;Sampedro et al. 2017;Smigielski et al. 2019b). That classic psychedelics have shown these persisting benefits across such a wide range of individuals provides good impetus to study them in patients with AD who are known to suffer from substantial decrements to quality of life overall (Karttunen et al. 2011;Shin et al. 2005). ...
Article
Serotonin 2A receptor (5-HT2AR) agonist "classic psychedelics" are drawing increasing interest as potential mental health treatments. Recent work suggests psychedelics can exert persisting anxiolytic and antidepressant effects lasting up to several months after a single administration. Data indicate acute subjective drug effects as important psychological factors involved in observed therapeutic benefits. Additionally, animal models have shown an important role for 5-HT2AR agonists in modulating learning and memory function with relevance for Alzheimer's Disease (AD) and related dementias. A number of biological mechanisms of action are under investigation to elucidate 5-HT2AR agonists' therapeutic potential, including enhanced neuroplasticity, anti-inflammatory effects, and alterations in brain functional connectivity. These diverse lines of research are reviewed here along with a discussion of AD pathophysiology and neuropsychiatric symptoms to highlight classic psychedelics as potential novel pharmacotherapies for patients with AD. Human clinical research suggests a possible role for high-dose psychedelic administration in symptomatic treatment of depressed mood and anxiety in early-stage AD. Preclinical data indicate a potential for low- or high-dose psychedelic treatment regimens to slow or reverse brain atrophy, enhance cognitive function, and slow progression of AD. In conclusion, rationale and potential approaches for preliminary research with psychedelics in patients with AD are presented, and ramifications of this line of investigation for development of novel AD treatments are discussed.
... Persistent changes in personality and mood have also been observed in healthy volunteers following a single medium-to-high dose of psilocybin. These include, for example, increases in personality traits openness and extraversion, decreases in neuroticism and increases in mindful awareness (Erritzoe et al., 2018;MacLean et al., 2011;Madsen et al., 2020). These therapeutic and personality effects appear to persist for at least months, and in some cases have been reported to last more than a year (Gasser et al., 2014;Johnson et al., 2017;MacLean et al., 2011). ...
... The medicalisation of psychedelic drugs is expanding rapidly despite a limited understanding of the neurobiology underpinning therapeutic effects. Psychological theories of psychedelic therapy, such as reduced negative affect , increased mindfulness (Madsen et al., 2020;Murphy-Beiner and Soar, 2020;Smigielski et al., 2019), increased cognitive flexibility (Murphy-Beiner and Soar, 2020) and reduced experiential avoidance (Zeifman et al., 2020) have been proposed, as well as increased acceptance and processing of traumatic autobiographical memories (Sloshower et al., 2020), but these have no current grounding in neurobiology. Thus, in order to maximise psilocybin's safety and efficacy as a potential therapeutic, it is important to investigate mechanisms by which psilocybin exerts its effects. ...
... The psychoactive effects of psilocybin stem from agonism at the serotonin 2A receptor (5-HT2AR) (Vollenweider et al., 1998). Positron emission tomography (PET) with the radiotracer [ 11 C]Cimbi-36 enables the quantification of brain 5-HT2AR levels in humans in vivo, which has been previously associated with aspects of the psychedelic experience (Ettrup et al., , 2016Finnema et al., 2014;Madsen et al., 2020;Stenbaek et al., 2020). Combining [ 11 C]Cimbi-36 PET with RSFC would provide insight into the neuromolecular mechanisms associated with psychedelic effects on brain connectivity. ...
Article
Full-text available
Background Psilocybin is a psychedelic drug that has shown lasting positive effects on clinical symptoms and self-reported well-being following a single dose. There has been little research into the long-term effects of psilocybin on brain connectivity in humans. Aim Evaluate changes in resting-state functional connectivity (RSFC) at 1 week and 3 months after one psilocybin dose in 10 healthy psychedelic-naïve volunteers and explore associations between change in RSFC and related measures. Methods Participants received 0.2–0.3 mg/kg psilocybin in a controlled setting. Participants completed resting-state functional magnetic resonance imaging (fMRI) scans at baseline, 1-week and 3-month post-administration and [11C]Cimbi-36 PET scans at baseline and 1 week. We examined changes in within-network, between-network and region-to-region RSFC. We explored associations between changes in RSFC and psilocybin-induced phenomenology as well as changes in psychological measures and neocortex serotonin 2A receptor binding. Results Psilocybin was well tolerated and produced positive changes in well-being. At 1 week only, executive control network (ECN) RSFC was significantly decreased (Cohen’s d = −1.73, pFWE = 0.010). We observed no other significant changes in RSFC at 1 week or 3 months, nor changes in region-to-region RSFC. Exploratory analyses indicated that decreased ECN RSFC at 1 week predicted increased mindfulness at 3 months ( r = −0.65). Conclusions These findings in a small cohort indicate that psilocybin affects ECN function within the psychedelic ‘afterglow’ period. Our findings implicate ECN modulation as mediating psilocybin-induced, long-lasting increases in mindfulness. Although our findings implicate a neural pathway mediating lasting psilocybin effects, it is notable that changes in neuroimaging measures at 3 months, when personality changes are observed, remain to be identified.
... Persistent changes in personality and mood have also been observed in healthy volunteers following a single medium-to-high dose of psilocybin. These include, for example, increases in personality traits openness and extraversion, decreases in neuroticism and increases in mindful awareness (MacLean, Johnson and Griffiths, 2011;Erritzoe et al., 2018;Madsen et al., 2020). These therapeutic and personality effects appear to persist for at least months and in some cases have been reported to last more than a year (MacLean, Johnson and Griffiths, 2011;Gasser et al., 2014;Johnson, Garcia-Romeu and Griffiths, 2017). ...
... The medicalisation of psychedelic drugs is expanding rapidly despite a limited understanding of the neurobiology underpinning therapeutic effects. Psychological theories of psychedelic therapy such as reduced negative affect (Barrett et al., 2020), increased mindfulness (Smigielski et al., 2019;Madsen et al., 2020;Murphy-Beiner and Soar, 2020), increased cognitive flexibility (Murphy-Beiner and Soar, 2020) and reduced experiential avoidance (Zeifman et al., 2020) have been proposed, as well as increased acceptance and processing of traumatic autobiographical memories (Sloshower et al., 2020), but these have no current grounding in neurobiology. Thus, in order to maximise psilocybin's safety and efficacy as a potential therapeutic, it is important to investigate mechanisms by which psilocybin exerts its effects. ...
... Lastly, in an exploratory analysis we assessed correlations between network RSFC change and variables associated with increased well-being. These included personality measures, well-being and mindfulness, which we recently showed were altered three-months after psilocybin, as well as correlated with change in neocortex 5-HT2A binding (Madsen et al., 2020). Additionally, baseline neocortex 5-HT2A binding was related to the temporal character of the psychedelic experience (Stenbaek et al., 2020). ...
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Background Psilocybin is a psychedelic drug that has shown lasting positive effects on clinical symptoms and self-reported well-being following a single dose. There has been little research into the long-term effects of psilocybin on brain connectivity in humans. Aims Evaluate changes in resting-state functional connectivity (RSFC) at one-week and three-months after one psilocybin dose in 10 healthy psychedelic-naïve volunteers and explore associations between change in RSFC and related measures. Methods Participants received 0.2-0.3 mg/kg psilocybin in a controlled setting. Participants completed resting-state fMRI scans at baseline, one-week and three-months post-administration and [ ¹¹ C]Cimbi-36 PET scans at baseline and one-week. We examined changes in within-network, between-network and region-to-region RSFC. We explored associations between changes in RSFC and psilocybin-induced phenomenology as well as changes in psychological measures and neocortex serotonin 2A receptor binding. Results Psilocybin was well tolerated and produced positive changes in well-being. At one-week only, executive control network (ECN) RSFC was significantly decreased (Cohen’s d=-1.73, p FWE =0.010). We observed no other significant changes in RSFC at one-week or three-months, nor changes in region-to-region RSFC. Exploratory analyses indicated that decreased ECN RSFC at one-week predicted increased mindfulness at three-months (r =-0.65). Conclusions These findings in a small cohort indicate that psilocybin affects ECN function within the psychedelic “afterglow” period. Our findings implicate ECN modulation as mediating psilocybin-induced, long-lasting increases in mindfulness. Although our findings implicate a neural pathway mediating lasting psilocybin effects, it is notable that changes in neuroimaging measures at three-months, when personality changes are observed, remain to be identified.
... Persistent changes in personality and mood have also been observed in healthy volunteers following a single medium-to-high dose of psilocybin. These include, for example, increases in personality traits openness and extraversion, decreases in neuroticism and increases in mindful awareness (Erritzoe et al., 2018;MacLean et al., 2011;Madsen et al., 2020). These therapeutic and personality effects appear to persist for at least months, and in some cases have been reported to last more than a year (Gasser et al., 2014;Johnson et al., 2017;MacLean et al., 2011). ...
... The medicalisation of psychedelic drugs is expanding rapidly despite a limited understanding of the neurobiology underpinning therapeutic effects. Psychological theories of psychedelic therapy, such as reduced negative affect , increased mindfulness (Madsen et al., 2020;Murphy-Beiner and Soar, 2020;Smigielski et al., 2019), increased cognitive flexibility (Murphy-Beiner and Soar, 2020) and reduced experiential avoidance (Zeifman et al., 2020) have been proposed, as well as increased acceptance and processing of traumatic autobiographical memories (Sloshower et al., 2020), but these have no current grounding in neurobiology. Thus, in order to maximise psilocybin's safety and efficacy as a potential therapeutic, it is important to investigate mechanisms by which psilocybin exerts its effects. ...
... The psychoactive effects of psilocybin stem from agonism at the serotonin 2A receptor (5-HT2AR) (Vollenweider et al., 1998). Positron emission tomography (PET) with the radiotracer [ 11 C]Cimbi-36 enables the quantification of brain 5-HT2AR levels in humans in vivo, which has been previously associated with aspects of the psychedelic experience (Ettrup et al., , 2016Finnema et al., 2014;Madsen et al., 2020;Stenbaek et al., 2020). Combining [ 11 C]Cimbi-36 PET with RSFC would provide insight into the neuromolecular mechanisms associated with psychedelic effects on brain connectivity. ...
... This finding would be further strengthened by a similar observation with the NEO PI-R (Costa and McCrae, 1992), which is among the most well-validated and broadly applied questionnaires for quantifying personality traits across research frameworks. Intriguingly, recent studies have reported that psilocybin (psychoactive component in 'magic mushrooms') both affects resting-state functional connectivity, including decreased DMN (Carhart-Harris et al., 2012), and increases Openness (MacLean et al., 2011;Carhart-Harris et al., 2016;Madsen et al., 2020). ...
... The negative association between DMN functional connectivity and Openness is convergent with serotonin psychedelic studies reporting decreased resting-state functional connectivity with DMN regions (Carhart-Harris et al., 2012;Smigielski et al., 2019) and increased Openness (MacLean et al., 2011;Erritzoe et al., 2019;Madsen et al., 2020). The above-mentioned studies are consistent with a model wherein Openness is negatively associated with DMN and we speculate that environmental factors such as serotonin psychedelics may translate an individual's position along the axis of this association. ...
Article
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Evaluating associations between the five-factor personality domains and resting-state functional connectivity networks (e.g., default mode network, DMN) highlights distributed neurobiological systems linked to behaviorally relevant phenotypes. Establishing these associations can highlight a potential underlying role for these neural pathways in related clinical illness and treatment response. Here we examined associations between within- and between-network resting-state functional connectivity with functional magnetic resonance imaging (fMRI) and the five-factor personality domains: Openness to experience (Openness), Extraversion, Neuroticism, Agreeableness and Conscientiousness. We included data from 470 resting-state scan sessions and personality assessments in 295 healthy participants. Within- and between-network functional connectivity from 32 a priori defined regions was computed across seven resting-state networks. The association between functional connectivity and personality traits was assessed using generalized least squares. Within-network DMN functional connectivity was significantly negatively associated with trait Openness (regression coefficient= -0.0010; [95% CI] = [-0.0017, -0.0003]; pFWER = 0.033), seemingly driven by association with the Fantasy subfacet. Trait Extraversion was significantly negatively associated with functional connectivity between the visual and dorsal attention networks and positively associated with functional connectivity between the frontoparietal and language networks. Our findings provide evidence that resting-state DMN is associated with trait Openness and gives insight into personality neuroscience.
... In a subset of this cohort, individuals also reported on externally validated positive changes in attitudes, mood, and behavior 14 months later, with the ascending dose sequence showing greater positive effects [4] and this has since been replicated in several studies [5], including a large web-based study involving different psychedelics [6]. The observation of long-lasting effects on Openness after a single dose of psilocybin in healthy individuals has subsequently been replicated in, e.g., [7]. Compared with placebo, psilocybin also enhances mindfulness and improves psychosocial functioning at 3-4-month follow-up [8]. ...
... In other words, are the psychedelic recreational users more prone to use psychedelics because of their lower 5-HT2AR, or does the 5-HT2AR downregulate in response to use of psychedelics? There is some data to support the latter: A single psilocybin dose leads to increased mindfulness as measured 3 months later, preceded by a proportional relative decrease in neocortical 5-HT2A receptor binding [7]. ...
Article
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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.
... Hallucinogenic compounds induce signaling, antidepressant and anxiolytic effects (Magalhaes et al., 2010;Yang et al., 2019;Fuentes et al., 2020;Madsen et al., 2020) SERT Polymorphisms confer small risk increase, binding availability elevated ...
... The 5-HT 2A receptor is also a promising target for hallucinogenic therapeutic agents aimed at reducing depression and anxiety. 5-HT 2A is potently activated by the hallucinogens lysergic acid diethylamide (LSD) and psilocybin (Almaula et al., 1996;López-Giménez and González-Maeso, 2017), which are emerging as effective antidepressant and anxiolytic treatments in recent clinical trials (Fuentes et al., 2020;Madsen et al., 2020) ( Figure 1B). Further exploration of the therapeutic benefits of activated 5-HT 2A signaling as a target of depression and anxiety is thus warranted. ...
Article
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Depression and anxiety are common, debilitating psychiatric conditions affecting millions of people throughout the world. Current treatments revolve around selective serotonin reuptake inhibitors (SSRIs), yet these drugs are only moderately effective at relieving depression. Moreover, up to 30% of sufferers are SSRI non-responders. Endocytosis, the process by which plasma membrane and extracellular constituents are internalized into the cell, plays a central role in the regulation of serotonin (5-hydroxytryptophan, 5-HT) signaling, SSRI function and depression and anxiety pathogenesis. Despite their therapeutic potential, surprisingly little is known about the endocytosis of the serotonin receptors (5-HT receptors) or the serotonin transporter (SERT). A subset of 5-HT receptors are endocytosed by clathrin-mediated endocytosis following serotonin binding, while for the majority of 5-HT receptors the endocytic regulation is not known. SERT internalizes serotonin from the extracellular space into the cell to limit the availability of serotonin for receptor binding and signaling. Endocytosis of SERT reduces serotonin uptake, facilitating serotonin signaling. SSRIs predominantly inhibit SERT, preventing serotonin uptake to enhance 5-HT receptor signaling, while hallucinogenic compounds directly activate specific 5-HT receptors, altering their interaction with endocytic adaptor proteins to induce alternate signaling outcomes. Further, multiple polymorphisms and transcriptional/proteomic alterations have been linked to depression, anxiety, and SSRI non-response. In this review, we detail the endocytic regulation of 5-HT receptors and SERT and outline how SSRIs and hallucinogenic compounds modulate serotonin signaling through endocytosis. Finally, we will examine the deregulated proteomes in depression and anxiety and link these with 5-HT receptor and SERT endocytosis. Ultimately, in attempting to integrate the current studies on the cellular biology of depression and anxiety, we propose that endocytosis is an important factor in the cellular basis of depression and anxiety. We will highlight how a thorough understanding 5-HT receptor and SERT endocytosis is integral to understanding the biological basis of depression and anxiety, and to facilitate the development of a next generation of specific, efficacious antidepressant treatments.
... Psilocybin can induce profound ASC, comprising personally meaningful and spiritually significant mystical-type experiences (Griffiths et al., 2006Pahnke, 1963). The quality of the experience seems to be associated with positive changes in mood, attitude and behaviour in healthy individuals (Griffiths et al., 2006(Griffiths et al., , 2018MacLean et al., 2011;Madsen et al., 2020;Studerus et al., 2011), and therapeutic outcomes in patients with alcohol use disorder (Bogenschutz et al., 2015), nicotine use disorder (Garcia-Romeu et al., 2015;Johnson et al., 2014Johnson et al., , 2017, major depression (Carhart-Harris et al., 2016Davis et al., 2020;Roseman et al., 2018) and cancer-related psychiatric distress (Agin-Liebes et al., 2020;Griffiths et al., 2016;Grob et al., 2011;Ross et al., 2016). While it is of particular interest for future investigations to know how psilocybin dose relates to the phenomenological quality of the ASC, no doseresponse meta-analysis has been reported with regards to psychoactive properties. ...
... Hallucinogennaïve study participants reported slightly more Visionary Restructuralization, Disembodiment, and Changed Meaning of Percepts compared with experienced psilocybin users (Metzner et al., 1965;Studerus et al., 2012). Further, differences in individual pharmacokinetics were reported in terms of plasma psilocin levels and 5-HT2AR occupancy, which were found to correlate with the overall subjective experience (Brown et al., 2017;Hasler et al., 2004;Lindenblatt et al., 1998;Madsen et al., 2020). Finally, brain structure metrics have been reported to correlate with experiences, that is, a correlation of the thickness of the rostral anterior cingulate and subscales of 5D-ASC dimension Oceanic Boundlessness (Lewis et al., 2020). ...
Article
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Background: Psilocybin is the psychoactive component in Psilocybe mushrooms ('magic mushrooms'). Whether and how the quality of the psilocybin-induced experience might mediate beneficial health outcomes is currently under investigation, for example, in therapeutic applications. However, to date, no meta-analysis has investigated the dose-dependency of subjective experiences across available studies. Aim: Establishing dose-response relationships of the subjective experiences induced by psilocybin in healthy study participants and a comparison of patient groups. Method: We applied a linear meta-regression approach, based on the robust variance estimation framework, to obtain linear dose-response relationship estimates on questionnaire ratings after oral psilocybin administration. Data were obtained from the Altered States Database, which contains data extracted from MEDLINE-listed journal articles that used standardized and validated questionnaires: the Altered States of Consciousness Rating Scale, the Mystical Experience Questionnaire and the Hallucinogen Rating Scale. Results: Psilocybin dose positively correlated with ratings on most factors and scales, mainly those referring to perceptual alterations and positively experienced ego dissolution. Measures referring to challenging experiences exhibited small effects and were barely modulated by dose. Conclusion: Psilocybin intensified almost all characteristics of altered states of consciousness assessed with the given questionnaires. Because subjective experiences are not only determined by dose, but also by individual and environmental factors, the results may only apply to controlled laboratory experiments and not to recreational use. This paper may serve as a general literature citation for the use of psilocybin in experimental and clinical research, to compare expected and observed subjective experiences.
... These experiences are persistent and strong enough to stimulate motivation to overcome the addiction. Recent studies using magnetic resonance imaging and positron emission tomography have investigated the ability of psilocybin to modulate functional brain connectivity and suggest that psilocybin induces time-dependent changes with long-lasting effects in cerebral functions [116][117][118] . How these changes can contribute to the therapeutic effects of psilocybin should be considered in future research. ...
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Substance use disorder (SUD) is a global public health concern that affects millions of people worldwide. Considering current research, addiction has been noted as the last stage of a chronic disease that may impair brain reward circuit responses and affects personal and social life. Treatments for SUD face challenges including availability and limited pharmacological response, often resulting in low retention of patients. A growing number of studies from the 'psychedelic renaissance' have highlighted the therapeutic potential of psychedelics for several psychiatric disorders, including SUD. In this non-systematic review we discuss past and current clinical and observational studies with classic (LSD, DMT, psilocybin and mescaline) and non-classic (ibogaine, ketamine, MDMA, salvinorin A and THC) psychedelics for the treatment of SUD published until December 2021. Although results are still inconclusive for LSD, DMT, mescaline, MDMA and Salvinorin A, in general, the literature presents moderate evidence on the controlled use of psilocybin and ketamine for Alcohol Use Disorder, ketamine for management of opiate and alcohol withdrawal, and THC preparations for reducing withdrawal symptoms in Cannabis and possibly in Opioid Use Disorder. Importantly, studies suggest that psychedelics should be more effective when employed as an adjunct therapy. Extensive research is warranted to further elucidate the role of psychedelics in the treatment of SUD.
... Long-term increases in mindfulness following a single dose of psilocybin in ten psilocybin-naïve participants persisted for at least 3 months, even without explicit mindfulness training. This increase in mindfulness may represent a key mechanism of psilocybin therapy (Madsen et al., 2020). Perceptual and qualitative changes regarding intra-and interpersonal consciousness and perceived mindfulness capacities have also been reported by clients who have received SAPT. ...
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The present narrative review is the first in a series of reviews about the appropriate conduct in substance-assisted psychotherapy (SAPT). It outlines a current perspective onpreconditions and theoretical knowledge that have been identified as valuable in the literaturefor appropriate therapeutic conduct in SAPT. In this context, considerations regarding ethics and the spiritual emphasis of the therapeutic approaches are discussed. Further, current methods, models, and concepts of psychological mechanism of action and therapeutic effects of SAPT are summarized, and similarities between models, approaches, and potential mediators for therapeutic effects are outlined. It is argued that a critical assessment of the literature might indicate that the therapeutic effect of SAPT may be mediated by intra- and interpersonal variables within the therapeutic context rather than specific therapeutic models per se. The review provides a basis for the development and adaptation of future investigations, therapeutic models, training programs for therapists, and those interested in the therapeutic potential of SAPT. Limitations and future directions for research are discussed.
... Moreover, the study highlighted a correlation between subjective effects induced by psilocybin and both 5-HT2A receptor occupancy and plasma psilocin levels [59]. Two PET studies performed in healthy volunteers using the 5-HT2A receptor agonist radioligand [11C]-Cimbi-36 have also shown that, after psilocybin administration, individual brain 5-HT2A receptor binding predicted subjective temporal and mystical effects [60], mindfulness and openness [61]. ...
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Psychedelics extracted by plants have been used in religious, spiritual and mystic practices for millennia. In 1957, Dr. Hofmann have identified and synthesized the prodrug psilocybin, a substance present in more than 200 species of psychedelic mushrooms. Although the limitations related to the scientific design of many studies, clinical observations performed during the 1950s and the 1960s have shown a potential therapeutic effect of psilocybin in patients affected by depressive symptoms, anxiety, and conversion disorder. Psilocybin was classed as a schedule I substance in 1970, but the fascination for psychedelics remained almost unchanged over time promoting a new scientific interest starting from the 1990s. Recent studies provided further evidences supporting the suggestive hypothesis of a therapeutic use of psilocybin for treating various psychiatric disorders including: pathological anxiety, mood depressive disorder and addiction.
... … These experiences were rated as among the most personally meaningful and spiritually significant life=me experiences, with moderate to strong persis=ng posi=ve changes in life sa=sfac=on, purpose, and meaning adributed to these experiences". A long-term increase in mindfulness is also noted (Madsen et al. 2020). ...
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This work, presents a minimal augmentation of physical cosmology to admit conscious volition acting on the physical world, invoking a biologically, psychically and cosmologically symbiotic universe, which resolves the central enigma of existential cosmology – the nature and role of subjective experience – thus providing a direct solution to the "hard problem of consciousness" and the problem of autonomous volitional will. This is essential for human ability to consciously affect the physical world, personal responsibility and scientific consistency with criminal and civil law on intent. The cosmology is thus entirely consistent with quantum cosmology and empirical neuroscience. Where it differs, is in refuting the assumption of causal closure in the brain which is scientifically unprovable in the quantum universe. Occam's razor then cuts in favour of the empirical experience of subjective conscious volition over the physical universe, confirmed by veridical perception of our own volition, eliminating pure materialism as inconsistent. Section one formulates a Darwinian pan-psychic cosmology, resolving the hard problem of consciousness and the central enigmas of existential cosmology, and eschatology. The symbiotic cosmology involves complementarity between the physical universe and the "mind at large", which is manifest in primitive forms in quantum uncertainty, edge-of-chaos dynamics, biogenesis, and procaryote excitability. Attentive consciousness emerged in a discrete transition accompanying the endosymbiosis between archaea and bacteria to form the eucaryotes, encapsulated in cellular consciousness in the excitable eucaryote cell mediated by social signalling molecules, later resulting in multi-celled organisms in the conscious brain as a coupled neuronal system, utilising the same palette of signalling molecules. The symbiosis in eucaryotes extends to sexuality as polarised genetic co-evolution and symbiosis with endogenous transposable elements comprising half the human genome. This extends to biospheric symbiosis in which survival of the "fittest" by natural and sexual selection is actually survival of the most successful co-symbionts because, whether parasites, hosts, predators or prey, their individual survival is mediated by the overall survival dynamics of the biosphere as a whole avoiding boom and bust to achieve climax diversity. It then overviews cultural traditions and current research into psychedelics. Because natural analogues of neurotransmitters in living species have proved capable of precipitating ego-dissolution and reversion to "primary consciousness", these gain a significance in consciousness research complementary to that of the LHC in cosmological physics. This process has pivotal importance for avoiding humanity causing a mass extinction of biodiversity and possibly our own demise, instead becoming able to fulfil our responsibilities as guardians of the unfolding of sentient consciousness on evolutionary and cosmological time scales. The panpsychic aspect invokes a deep relationship with animism as the founding cosmological view of Homo sapiens which later evolved to become the world religious traditions. Affirming subjectively conscious physical volition, via quantum indeterminate brain states, is the only point of divergence from the standard scientific world view, with all other aspects, especially the cosmology's evolutionary basis, following core scientific principles. Nevertheless its implications are radically transformative because (a) it opens the entire subjective realm of conscious cosmology to exploration and pivotally, (b) it invokes biospheric symbiosis as the climax cosmological condition of perennial survival in the universe, without which humanity will suffer a Fermi paradox extinction, through evolutionary and/or cultural instability. Biospheric symbiosis is the climax evolutionary manifestation of Symbiotic Existential CosmologThis work, presents a minimal augmentation of physical cosmology to admit conscious volition acting on the physical world, invoking a biologically, psychically and cosmologically symbiotic universe, which resolves the central enigma of existential cosmology – the nature and role of subjective experience – thus providing a direct solution to the "hard problem of consciousness" and the problem of autonomous volitional will. This is essential for human ability to consciously affect the physical world, personal responsibility and scientific consistency with criminal and civil law on intent. The cosmology is thus entirely consistent with quantum cosmology and empirical neuroscience. Where it differs, is in refuting the assumption of causal closure in the brain which is scientifically unprovable in the quantum universe. Occam's razor then cuts in favour of the empirical experience of subjective conscious volition over the physical universe, confirmed by veridical perception of our own volition, eliminating pure materialism as inconsistent. Section one formulates a Darwinian pan-psychic cosmology, resolving the hard problem of consciousness and the central enigmas of existential cosmology, and eschatology. The symbiotic cosmology involves complementarity between the physical universe and the "mind at large", which is manifest in primitive forms in quantum uncertainty, edge-of-chaos dynamics, biogenesis, and procaryote excitability. Attentive consciousness emerged in a discrete transition accompanying the endosymbiosis between archaea and bacteria to form the eucaryotes, encapsulated in cellular consciousness in the excitable eucaryote cell mediated by social signalling molecules, later resulting in multi-celled organisms in the conscious brain as a coupled neuronal system, utilising the same palette of signalling molecules. The symbiosis in eucaryotes extends to sexuality as polarised genetic co-evolution and symbiosis with endogenous transposable elements comprising half the human genome. This extends to biospheric symbiosis in which survival of the "fittest" by natural and sexual selection is actually survival of the most successful co-symbionts because, whether parasites, hosts, predators or prey, their individual survival is mediated by the overall survival dynamics of the biosphere as a whole avoiding boom and bust to achieve climax diversity. It then overviews cultural traditions and current research into psychedelics. Because natural analogues of neurotransmitters in living species have proved capable of precipitating ego-dissolution and reversion to "primary consciousness", these gain a significance in consciousness research complementary to that of the LHC in cosmological physics. This process has pivotal importance for avoiding humanity causing a mass extinction of biodiversity and possibly our own demise, instead becoming able to fulfil our responsibilities as guardians of the unfolding of sentient consciousness on evolutionary and cosmological time scales. The panpsychic aspect invokes a deep relationship with animism as the founding cosmological view of Homo sapiens which later evolved to become the world religious traditions. Affirming subjectively conscious physical volition, via quantum indeterminate brain states, is the only point of divergence from the standard scientific world view, with all other aspects, especially the cosmology's evolutionary basis, following core scientific principles. Nevertheless its implications are radically transformative because (a) it opens the entire subjective realm of conscious cosmology to exploration and pivotally, (b) it invokes biospheric symbiosis as the climax cosmological condition of perennial survival in the universe, without which humanity will suffer a Fermi paradox extinction, through evolutionary and/or cultural instability. Biospheric symbiosis is the climax evolutionary manifestation of Symbiotic Existential Cosmology. To fully cover all aspects of the evolutionary process leading to humanity's cultural explosion, the current edition fully expands the cosmology into an extended evolutionary synthesis, including gene-culture co-evolution, evolution of the human genome, sexuality and language and the impact of cultural evolution on societies, institutions, religions and world political responses to the existential crisis we all face. Social processes, including prescriptive religions, have brought about a paradigm of patriarchal dominance over woman and nature that has exacerbated the way technological civilisation and corporate processes, lacking a genetically stable paradigm, have caused sweeping deleterious impacts to the biosphere through human niche construction by agriculture, farming and urbanisation, causing habitat destruction and species extinction; energy resource demands, leading to climate and biodiversity crisis; and nationalistic militarisation, conducive to nuclear holocaust, so that gene-culture-biodiversity coevolution has become a sine qua non for human survival. Section two discusses the tragic consequences of failing to address naturalistic cosmological reality in the monotheistic religious tradition. Section three covers biocrisis, climate crisis nuclear holocaust and other existential threat to humanity and the diversity of life.y. To fully cover all aspects of the evolutionary process leading to humanity's cultural explosion, the current edition fully expands the cosmology into an extended evolutionary synthesis, including gene-culture co-evolution, evolution of the human genome, sexuality and language and the impact of cultural evolution on societies, institutions, religions and world political responses to the existential crisis we all face. Social processes, including prescriptive religions, have brought about a paradigm of patriarchal dominance over woman and nature that has exacerbated the way technological civilisation and corporate processes, lacking a genetically stable paradigm, have caused sweeping deleterious impacts to the biosphere through human niche construction by agriculture, farming and urbanisation, causing habitat destruction and species extinction; energy resource demands, leading to climate and biodiversity crisis; and nationalistic militarisation, conducive to nuclear holocaust, so that gene-culture-biodiversity coevolution has become a sine qua non for human survival. Section two discusses the tragic consequences of failing to address naturalistic cosmological reality in the monotheistic religious tradition. Section three covers biocrisis, climate crisis nuclear holocaust and other existential threat to humanity and the diversity of life.
... This may, in turn, have wider benefits to society and the global environment. [192][193][194][195][196] 2. ...
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The psychedelic effects of some plants and fungi have been known and deliberately exploited by humans for thousands of years. Fungi, particularly mushrooms, are the principal source of naturally occurring psychedelics. The mushroom extract, psilocybin has historically been used as a psychedelic agent for religious and spiritual ceremonies, as well as a therapeutic option for neuropsychiatric conditions. Psychedelic use was largely associated with the “hippie” counterculture movement, which, in turn, resulted in a growing, and still lingering, negative stigmatization for psychedelics. As a result, in 1970, the U.S. government rescheduled psychedelics as Schedule 1 drugs, ultimately ending scientific research on psychedelics. This prohibition on psychedelic drug research significantly delayed advances in medical knowledge on the therapeutic uses of agents such as psilocybin. A 2004 pilot study from the University of California, Los Angeles, exploring the potential of psilocybin treatment in patients with advanced-stage cancer managed to reignite interest and significantly renewed efforts in psilocybin research, heralding a new age in exploration for psychedelic therapy. Since then, significant advances have been made in characterizing the chemical properties of psilocybin as well as its therapeutic uses. This review will explore the potential of psilocybin in the treatment of neuropsychiatry-related conditions, examining recent advances as well as current research. This is not a systematic review.
... Psilocybin-occasioned increases in mindfulness have recently been found to correlate negatively with changes in 5-HT 2A R binding from pre-to post-psilocybin administration, suggesting potential biological and psychological therapeutic mechanisms of psilocybin (Madsen et al., 2020). BMI, a measure closely related to body weight, has shown positive associations with 5-HT 2A R binding in the cortex, but no relationship to tobacco or alcohol use (Erritzoe et al., 2009), highlighting the complex Tables SC and SD). ...
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Background Growing evidence suggests psilocybin, a naturally occurring psychedelic, is a safe and promising pharmacotherapy for treatment of mood and substance use disorders when administered as part of a structured intervention. In most trials to date, psilocybin dose has been administered on a weight-adjusted basis rather than the more convenient procedure of administering a fixed dose. Aims The present post hoc analyses sought to determine whether the subjective effects of psilocybin are affected by body weight when psilocybin is administered on a weight-adjusted basis and when psilocybin is administered as a fixed dose. Methods We analyzed acute subjective drug effects (mystical, challenging, and intensity) associated with therapeutic outcomes from ten previous studies (total N = 288) in which psilocybin was administered in the range 20 to 30 mg/70 kg (inclusive). Separate multivariate regression analyses examined the relationships between demographic variables including body weight and subjective effects in participants receiving 20 mg/70 kg ( n = 120), participants receiving 30 mg/70 kg ( n = 182), and participants whose weight-adjusted dose was about 25 mg (to approximate the fixed dose that is currently being evaluated in registration trials for major depressive disorder) ( n = 103). Results In the 20 mg/70 kg and 30 mg/70 kg weight-adjusted groups, and in the fixed dose group, no significant associations were found between subjective effects and demographic variables including body weight or sex. Across a wide range of body weights (49 to 113 kg) the present results showed no evidence that body weight affected subjective effects of psilocybin. Conclusions These results suggest that the convenience and lower cost of administering psilocybin as a fixed dose outweigh any potential advantage of weight-adjusted dosing.
... Psilocybin has also been associated with positive outcomes in healthy individuals. For example, a recent study by Madsen et al., 2020 found that a single dose of psilocybin had long lasting beneficial effects on mood, personality, and mindfulness in healthy volunteers. Additionally, Mason et al. (2019) found that a single administration of psilocybin in a social retreat setting may be associated with sub-acute enhancement of creative thinking, empathy, and subjective well-being. ...
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This article reports on the experiences of four healthy individuals who attended a legal psilocybin truffle retreat in the Netherlands. The study employed a qualitative phenomenological approach, using semi-structured interviews to gain an understanding of participants' psilocybin experiences and their after-effects. The experiential themes that emerged from these case studies closely match themes that have been identified in previous studies of psilocybin, including variability of the experience, the presence of mystical-type features, significant changes to subjective sense of self, and a generalized sense of connectedness. Participants framed their narrative accounts around moments of key insight, and these insights were related to a sense of connection: to self, others, and to a broader relational ontology. Embodiment, currently an understudied topic in psychedelic research, also emerged as a theme. The case studies presented here provide preliminary evidence to suggest that for healthy individuals in a well-controlled and supportive retreat setting, a high dose of psilocybin can lead to enduring positive after-effects that last up to twelve months.
... For example, psychedelics without MM have been found to increase facets of trait mindfulness, such as heightened present-moment awareness, increased ability to articulate momentary experience, and the capacities of nonjudgement and nonreactivity. 17,29,31,32 In addition, acute psychedelic effects include decreased self-referential thinking, 40,52 increased decentering, 17 feelings of interpersonal connectedness, 53 and non-dual experience, 18 each also associated with prolonged meditation. ...
Article
Psychedelic and mindfulness interventions have been shown to improve mental ill-health and wellbeing, with a range of clinical processes and effects in common. However, each appear to contain specific challenges in the context of mental health treatment. In this Perspective, we focus on a set of distinct affordances, “useful differences”, within psychedelic and mindfulness interventions that might address common challenges within the other intervention. Accordingly, we propose a set of applied synergies, indicating specific ways in which these two promising interventions might be combined for greater benefit. Metaphorically, on the journey toward mental health and wellbeing, we propose that psychedelic treatments may serve the role of Compass (initiating, motivating, and steering the course of mindfulness practice), with mindfulness interventions serving the role of Vehicle (integrating, deepening, generalizing, and maintaining the novel perspectives and motivation instigated by psychedelic experience). We outline a set of testable hypotheses and future research associated with the synergistic action of psychedelic and mindfulness interventions toward improved clinical outcomes.
... One consequence of the psychedelic renaissance is that the putative connection between psychedelics and meditation has now been subjected to rigorous quantitative investigation. Studies using such instruments as the FFMQ and the EQ have found that a single carefully conducted psychedelic experience, or very few such experiences, can significantly increase mindfulnessrelated capacities-that is, capacities for decentering, non-judging, and so on-for weeks or months (Mian et al. 2020, Murphy-Beiner and Soar 2020, Soler et al. 2016, Sampedro et al. 2017, Uthaug et al. 2018, Madsen et al. 2020, González et al. 2020). This coheres with findings that psychedelic experiences can durably increase psychological flexibility, a construct that is closely related to decentering (Davis et al. 2020, Watts andLuoma 2020). ...
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Psychedelic ingestion and meditative practice are both ancient methods for altering consciousness that became widely known in Western society in the second half of the 20th century. Do the similarities begin and end there, or do these methods – as many have claimed over the years – share some deeper common elements? In this chapter I take a neurophilosophical approach to this question and argue that there are, indeed, deeper commonalities. Recent empirical studies show that psychedelics and meditation modulate overlapping brain networks involved in the sense of self, salience, and attention; moreover, psychedelics can occasion lasting increases in “mindfulness-related capacities” for taking a non-reactive stance on one’s inner experience (e.g. Sampedro et al. 2017). The self-binding theory of psychedelic ego dissolution (Letheby and Gerrans 2017) offers a plausible explanation of these findings: by disrupting self-related beliefs implemented in high-level cortical networks, both psychedelics and meditation can “unbind” mental contents from one’s self-model, moving these contents along the continuum from phenomenal transparency to opacity (cf. Metzinger 2003). In other words, both psychedelics and meditation can expose and weaken our foundational beliefs about our own identity, allowing us to disidentify with these beliefs and see them as “just thoughts”. There are connections between these ideas and recent arguments suggesting that psychedelic use may have epistemic benefits consistent with philosophical naturalism (Letheby 2015, 2016, 2019). I conclude with a proposal: these connections may help in thinking about the putative epistemic benefits of meditation practice from a naturalistic perspective.
... The psychedelic compound psilocybin potently induces an altered state of consciousness and is emerging as a promising novel therapeutic, showing long-lasting beneficial effects with fast onset after a single dose both in healthy individuals ( Griffiths et al., 2018Maclean et al., 2011 ;Madsen et al., 2020 ) and in patients with depression, anxiety and addiction ( Bogenschutz et al., 2015 ;Carhart-Harris et al., 2021, 2016aDavis et al., 2020 ;Griffiths et al., 2016 ;Grob et al., 2011 ;Johnson et al., 2014 ;Ross et al., 2016 ). Our lab recently showed that plasma level of psilocybin's active metabolite psilocin is tightly coupled to both cerebral 5-HT2AR occupancy and the psychedelic experience ( Madsen et al., 2019 ), that psilocybin induces considerable 5-HT2AR occupancy in the pig ( Donovan et al., 2021 ), and that baseline cerebral 5-HT2AR binding correlates with subjective effects of psilocybin . ...
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The emerging novel therapeutic psilocybin produces psychedelic effects via engagement of cerebral serotonergic targets by psilocin (active metabolite). The serotonin 2A receptor critically mediates these effects by altering distributed neural processes that manifest as increased entropy, reduced functional connectivity (FC) within discrete brain networks (i.e., reduced integrity) and increased FC between networks (i.e., reduced segregation). Reduced integrity of the default mode network (DMN) is proposed to play a particularly prominent role in psychedelic phenomenology, including perceived ego-dissolution. Here, we investigate the effects of a psychoactive oral dose of psilocybin (0.2-0.3 mg/kg) on plasma psilocin level (PPL), subjective drug intensity (SDI) and their association in fifteen healthy individuals. We further evaluate associations between these measures and resting-state FC, measured with functional magnetic resonance imaging, acquired over the course of five hours after psilocybin administration. We show that PPL and SDI correlate negatively with measures of network integrity (including DMN) and segregation, both spatially constrained and unconstrained. We also find that the executive control network and dorsal attention network desegregate, increasing connectivity with other networks and throughout the brain as a function of PPL and SDI. These findings provide direct evidence that psilocin critically shapes the time course and magnitude of changes in the cerebral functional architecture and subjective experience following psilocybin administration. Our findings provide novel insight into the neurobiological mechanisms underlying profound perceptual experiences evoked by this emerging transnosological therapeutic and implicate the expression of network integrity and segregation in the psychedelic experience and consciousness.
... Psilozibinaren kontsumoak eragiten dituen onura psikologikoak behin eta berriro frogatu dira boluntario osasuntsuekin egindako ikerlanetan (39,40,41). Eragindako efektu psikologikoen artean afektu positiboen areagotzea eta negatiboen murriztea, esperientzia espiritual-mistikoak, esangura pertsonal handiko bizipenak, jarrera-aldaketa positiboak, gogo-aldartearen eta bizi-kalitatearen hobekuntza dira aipagarrienak. ...
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Depresioa gaixotasun psikiatriko ohikoenen artean dago, eta haren intzidentziaren gorakada etengabea da. Depresioaren jatorria eta mekanismo etiologikoak azaltzen dituzten hainbat teoria garatu diren arren, gaixotasunaren oinarri neurobiologikoaren alderdi asko ezezagunak dira oraindik. Hipotesi esanguratsuenak depresioaren teoria monoaminergikoa, neurotrofikoa eta neuroinflamatorioa dira, eta horien eta beste batzuen jatorria, ebidentziak eta xehetasunak aditzera ematen dira berrikuspen honetan. Iraganean depresioa tratatzeko farmakoen aurkikuntza zorizkoa izan da, eta haien ekintza-mekanismoen ikerketak gaixotasunean ageri diren nahasmendu neurobiologikoei buruzko ezagutza eman digu. Azken hamarkadetan, aldiz, paradigma aldatu da, eta tratamendu berriak depresioaren etiopatogeniaren ituetan oinarritzen hasi dira. Patologiaren tratamendu farmakologikoaren oinarrian antidepresibo klasikoak daude. Duela hamarkada ugari aurkitu ziren, eta geroztik erabili dira: monoaminooxidasaren inhibitzaileak, antidepresibo triziklikoak eta monoaminen birxurgapenaren inhibitzaileak. Trazodona eta mirtazapina antidepresiboak, profil farmakodinamiko konplexuagokoak, urte batzuk geroago garatu ziren. Farmako talde horien eragin desiragaitz ohikoak ekiditeko eta tratamenduaren eraginkortasuna hobetzeko xedez ekintza-mekanismo alternatiboak esploratu dira, eta ikerketa horietatik sortu dira, esate baterako, agomelatina, tianeptina eta bortioxetina. Horien eraginkortasuna eta erabilera oso mugatuak dira, dena den. Ketamina, aldiz, denbora laburrean depresioaren tratamenduaren iraultza abian jarri duen substantzia izan da, sintomen hobekuntza nabarmena eta azkarra erakutsi duelako entsegu anitzetan, segurtasun eta tolerantzia egokiarekin batera. Azkenik, nabarmentzekoak dira substantzia haluzinogenoak, depresioaren eta beste gaixotasun psikiatrikoen tratamendurako erakutsi duten potentzial izugarriari esker. Depresioari dagokionez, psilozibina da psikodelikoen artean azpimarragarriena: paziente deprimituen hobekuntza azkarra eta iraunkorra eragiten badu ere, haren mekanismo antidepresiboak ezezagunak dira, eta horiek argitzeko entseguak ikerketaren gailurrean daude egun.
... However, a significant negative correlation between changes in 5-HT2A levels and mindfulness across individuals was reported. The authors concluded that changes in 5-HT2A levels are likely variable across individuals, but that those changes might still be relevant for long-term psychological or clinical effects of psychedelics [100]. The long-term effects of psychedelics on other receptor systems are currently poorly understood. ...
Article
Classical psychedelics, primarily psilocybin and lysergic acid diethylamide (LSD), have been used and extensively studied in Western medicine as part of substance-assisted psychotherapy in the 1950s and 1960s. Modern clinical research is currently gaining momentum and provides new evidence for the safety and efficacy of classical psychedelics (primarily psilocybin, but also LSD and ayahuasca) in the treatment of different psychiatric conditions, including substance use and mood disorders. In this review article, we outline common pathological mechanisms of substance use disorders (SUD) and unipolar depression. Next, the current literature on the effects of psychedelics is summarized in order to generate hypotheses regarding their potential therapeutic mechanisms of action in treating these psychiatric conditions. Finally, we review and discuss clinical trials published since 2011 investigating the effects of psychedelics in SUD and depression. While results from those modern clinical trials are promising, most of them do not meet the methodological requirements to allow firm conclusions on the clinical efficacy of psychedelics. Larger, blinded, randomized controlled trials (RCT) with clearly defined patient groups and well-defined primary endpoints are needed. Additionally, the therapeutic mechanisms of classical psychedelics are currently unknown. This review presents hypotheses derived from preclinical and human studies that need to be tested in future trials to better understand the clinical potential of psychedelic substances in modern psychiatry.
... Such skills might include experiential acceptance and mindfulness. Open-label psilocybin and ayahuasca increase trait mindfulness even with no specific mindfulness training [67,68]. Qualitative reports suggest greater emotional acceptance [60]. ...
Article
Psychedelics have shown great promise in modern clinical trials for treating various psychiatric conditions. As a transdiagnostic treatment that exerts its effects through subjective experiences that leave enduring effects, it is akin to psychotherapy. To date, there has been insufficient discussion of how psychedelic therapy is similar to and different from conventional psychotherapy. In this article, we review the shared features of effective conventional psychotherapies and situate therapeutic psychedelic effects within those. We then discuss how psychedelic drug effects might amplify conventional psychotherapeutic processes—particularly via effects on meaning and relationship—as well as features that make psychedelic treatment unique. Taking into account shared features of conventional psychotherapies and unique psychedelic drug effects, we create a framework for understanding why psychedelics are likely to be effective with very diverse types of psychotherapies. We also review the formal psychotherapies that have been adjunctively included in modern psychedelic trials and extend the understanding of psychedelics as psychotherapy towards implications for clinical ethics and trial design. We aim to provide some common conceptual vocabulary that can be used to frame therapeutic psychedelic effects beyond the confines of any one specific modality.
... decreased 5-HT2AR expression). Indeed, agonist-induced downregulation of the 5-HT2AR is entirely consistent with this principle (Bull et al., 2004;Erritzoe et al., 2011;Muguruza et al., 2014;Reneman et al., 2002; also see Madsen et al., 2020). From a neurodevelopmental perspective, we must also acknowledge that hyperactivation of 5-HT2ARs coinciding with childhood stress or chronic drug-use could negatively affect neurodevelopmental processes. ...
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This paper introduces a new construct, the ‘pivotal mental state’, which is defined as a hyper-plastic state aiding rapid and deep learning that can mediate psychological transformation. We believe this new construct bears relevance to a broad range of psychological and psychiatric phenomena. We argue that pivotal mental states serve an important evolutionary function, that is, to aid psychological transformation when actual or perceived environmental pressures demand this. We cite evidence that chronic stress and neurotic traits are primers for a pivotal mental state, whereas acute stress can be a trigger. Inspired by research with serotonin 2A receptor agonist psychedelics, we highlight how activity at this particular receptor can robustly and reliably induce pivotal mental states, but we argue that the capacity for pivotal mental states is an inherent property of the human brain itself. Moreover, we hypothesize that serotonergic psychedelics hijack a system that has evolved to mediate rapid and deep learning when its need is sensed. We cite a breadth of evidences linking stress via a variety of inducers, with an upregulated serotonin 2A receptor system (e.g. upregulated availability of and/or binding to the receptor) and acute stress with 5-HT release, which we argue can activate this primed system to induce a pivotal mental state. The pivotal mental state model is multi-level, linking a specific molecular gateway (increased serotonin 2A receptor signaling) with the inception of a hyper-plastic brain and mind state, enhanced rate of associative learning and the potential mediation of a psychological transformation.
... Meanwhile, all remaining compounds with the exception of NEH and MOPPP, bound to the receptor with less affinity similar to MDMA (Ki ≥ 10 μM). Interestingly, most compounds did not interact with the 5-HT2A receptor which is the responsible target site for the associated psychedelic effects induced by classical psychedelic substances like LSD or psilocybin [45][46][47][48]. Only α-PPP, 4-MePPP, MPHP, and MDPPP bound to the 5-HT2A receptor in the low micromolar range (Ki ≤ 10 μM) similar to the prototypical entactogen MDMA, which also produces psychedelic-like effects in users [49,50]. ...
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Pyrovalerone cathinones are potent psychoactive substances that possess a pyrrolidine moiety. Pyrovalerone-type novel psychoactive substances (NPS) are continuously detected but their pharmacology and toxicology are largely unknown. We assessed several pyrovalerone and related cathinone derivatives at the human norepinephrine (NET), dopamine (DAT), and serotonin (SERT) uptake transporters using HEK293 cells overexpressing each respective transporter. We examined the transporter-mediated monoamine efflux in preloaded cells. The receptor binding and activation potency was also assessed at the 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptors. All pyrovalerone cathinones were potent DAT (IC50 = 0.02–8.7 μM) and NET inhibitors (IC50 = 0.03–4.6 μM), and exhibited no SERT activity at concentrations < 10 μM. None of the compounds induced monoamine efflux. NEH was a potent DAT/NET inhibitor (IC50 = 0.17–0.18 μM). 4F-PBP and NEH exhibited a high selectivity for the DAT (DAT/SERT ratio = 264–356). Extension of the alkyl chain enhanced NET and DAT inhibition potency, while presence of a 3,4-methylenedioxy moiety increased SERT inhibition potency. Most compounds did not exhibit any relevant activity at other monoamine receptors. In conclusion, 4F-PBP and NEH were selective DAT/NET inhibitors indicating that these substances likely produce strong psychostimulant effects and have a high abuse liability.
... SPs are also unique with regard to the temporal dynamics of their effects, where acute (psychedelic states), subacute ("afterglow" phenomena), and long-term effects can be distinguished (Majić et al., 2015). Additionally, SPs have been associated with persisting changes in traits such as openness to experience, neuroticism, mindfulness, and optimism (Carhart-Harris et al., 2016;Erritzoe et al., 2018;Griffiths et al., 2018;Polito and Stevenson, 2019;Madsen et al., 2020). However, SP use has also been reported to exhibit prolonged negative consequences. ...
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Background: Serotonergic psychedelics (SPs) like LSD, psilocybin, DMT, and mescaline are a heterogeneous group of substances that share agonism at 5-HT 2a receptors. Besides the ability of these substances to facilitate profoundly altered states of consciousness, persisting psychological effects have been reported after single administrations, which outlast the acute psychedelic effects. In this review and meta-analysis, we investigated if repeated SP use associates with a characteristic neuropsychological profile indicating persisting effects on neuropsychological function. Methods: We conducted a systematic review of studies investigating the neuropsychological performance in SP users, searching studies in Medline, Web of Science, embase, ClinicalTrials.gov, and EudraCT. Studies were included if they reported at least one neuropsychological measurement in users of SPs. Studies comparing SP users and non-users that reported mean scores and standard deviations were included in an exploratory meta-analysis. Results: 13 studies (N 539) published between 1969 and 2020 were included in this systematic review. Overall, we found that only three SPs were specifically investigated: ayahuasca (6 studies, n 343), LSD (5 studies, n 135), and peyote (1 study, n 61). However, heterogeneity of the methodological quality was high across studies, with matching problems representing the most important limitation. Across all SPs, no uniform pattern of neuropsychological impairment was identified. Rather, the individual SPs seemed to be associated with distinct neuropsychological profiles. For instance, one study (n 42) found LSD users to perform worse in trials A and B of the Trail-Making task, whereas meta-analytic assessment (5 studies, n 352) of eleven individual neuropsychological measures indicated a better performance of ayahuasca users in the Stroop incongruent task (p 0.03) and no differences in the others (all p > 0.05). Conclusion: The majority of the included studies were not completely successful in controlling for confounders such as differences in non-psychedelic substance use between SP-users and non-users. Our analysis suggests that LSD, ayahuasca and peyote may have different neuropsychological consequences associated with their use. While LSD users showed reduced executive functioning and peyote users showed no differences across domains, there is some evidence that ayahuasca use is associated with increased executive functioning.
... It is still unclear to what extent neurobiological mechanisms or the psychological experience of an altered state of consciousness, involving personally meaningful and spiritually significant mystical-type experiences, are responsible for the positive therapeutic effects. Quality experiences are associated with positive changes in mood, attitude, and behaviour in healthy individuals (Studerus et al., 2011;Griffiths et al., 2018;Madsen et al., 2020), as well as with positive therapeutic outcomes in patients with alcohol dependence (Bogenschutz et al., 2015), tobacco addiction (Garcia-Romeu et al., 2015), obsessivecompulsive disorder (Moreno et al., 2006), treatment-resistant depression (TRD) , and cancer-related psychiatric disorder (Agin-Liebes et al., 2020). ...
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Classical psychedelics represent a family of psychoactive substances with structural similarities to serotonin and affinity for serotonin receptors. A growing number of studies have found that psychedelics can be effective in treating various psychiatric conditions, including post-traumatic stress disorder, major depressive disorder, anxiety, and substance use disorders. Mental health disorders are extremely prevalent in the general population constituting a major problem for the public health. There are a wide variety of interventions for mental health disorders, including pharmacological therapies and psychotherapies, however, treatment resistance still remains a particular challenge in this field, and relapse rates are also quite high. In recent years, psychedelics have become one of the promising new tools for the treatment of mental health disorders. In this review, we will discuss the three classic serotonergic naturally occurring psychedelics, psilocybin, ibogaine, and N, N-dimethyltryptamine, focusing on their pharmacological properties and clinical potential. The purpose of this article is to provide a focused review of the most relevant research into the therapeutic potential of these substances and their possible integration as alternative or adjuvant options to existing pharmacological and psychological therapies.
... After all, state openness seems to contribute to a positive psychedelic experience in a similar way as the traits openness, acceptance or absorption (Aday et al., 2021). Recent research further confirms that a single psilocybin intake is associated with long-term increases in the personality trait of openness and seems to indicate increased mindfulness as well (MacLean et al., 2011;Madsen et al., 2020). ...
Thesis
It is widely acknowledged that an open character or attitude is vital for having a meaningful and transformative psychedelic experience. Studies further indicate that a mindful and open state of mind paves way for so-called mystical experiences which in turn are predicting positive outcomes regarding mental health. This study further examined the role of openness as a state and trait variable in predicting the degree of experienced mystical states and the levels of acute well-being, using pooled data from 3 trials studying the acute effects of the substances lysergic acid diethylamide (LSD) and psilocybin in two distinct doses each (n = 60). Correlational and regression analyses have shown that the personality trait of openness (NEO-FFI) and its subscales or facets were significantly associated with experienced openness during the psychedelic peak phases in all examined substances and doses (r = 0.35 − 0.62). They also show that an early state of openness between ingestion and onset of substance effects leads to higher levels of mystical states (r = 0.37 − 0.54). Multiple regression analyses show that these mystical experiences have a significant effect on well-being 24 hours after ingestion, in all but the high-dose psilocybin condition. Also, the personality trait of openness to experience has been identified to moderate this relationship significantly and positively (p = 0.034 − 0.025). Further coincidental findings revolve around the timepoint and amplitude of the peak psychedelic phase, which both seem to correlate with certain personality facets of openness to experience. Findings from this thesis can provide information that may have implications for the integration of mindfulness-based therapy models, such as the psychological flexibility model, into psychedelic experiences and their research. Future use cases may also include the prediction of the course and nature of acute psychedelic experiences by means of personality screening.
... Given its potential anti-compulsive properties, herein we focus exclusively on psilocybin, which clinical trial research has demonstrated can be delivered safely. Multiple controlled studies in healthy volunteers have found that moderate-to-high doses of psilocybin are safe and well-tolerated, with no serious and lasting adverse effects and some evidence suggesting psychological benefits (Carhart-Harris et al., 2012;Griffiths et al., 2006Griffiths et al., , 2011Griffiths et al., , 2017Madsen et al., 2020;Nicholas et al., 2018;Smigielski et al., 2019;Vollenweider et al., 1997). Due to a growing body of literature (Carhart-Harris et al., 2016, 2017Erritzoe et al., 2018;Roseman et al., 2018;Stroud et al., 2018;Watts et al., 2017), psilocybin-assisted psychotherapy for treatment-resistant depression was granted breakthrough therapy status by the Food and Drug Administration in 2018, and later, for major depressive disorder (Nichols, 2020). ...
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In this opinion piece we propose the investigation of psychedelic-assisted psychotherapy for the treatment of body dysmorphic disorder (BDD). BDD is a psychiatric disorder characterised by appearance-based preoccupations and accompanying compulsions. While safe and effective treatments for BDD exist, non-response and relapse rates remain high. Therefore, there is a need to investigate promising new treatment options for this highly debilitating condition. Preliminary evidence suggests safety, feasibility, and potential efficacy of psychedelic treatments in disorders that share similar psychopathological mechanisms with BDD. Drawing on this evidence, as well as on relevant qualitative reports and theoretical proposals, we argue that it would be worthwhile to conduct a phase 2a study aimed at assessing the safety and feasibility of psychedelic-assisted psychotherapy in BDD. We also offer some suggestions for how future research ought to proceed.
... Psychedelics may yield more enduring effects to creativity and cognition. They have been shown to increase the personality traits openness to experience and absorption in an enduring way Erritzoe et al., 2018;Lebedev et al., 2016;Madsen et al., 2020;MacLean et al., 2011;Netzband et al., 2020). Openness has a positive association with cognitive ability, fluid intelligence (associated with the ability to think abstractly and solve problems) and permeability to new ideas and experiences (Austin et al., 2002;DeYoung et al., 2005;Moutafi et al., 2003;Rammstedt et al. 2016;Zeidner & Matthews, 2000). ...
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Creativity, that is the creation of ideas or objects considered both novel and valuable, is among the most important and highly valued of human traits, and a fundamental aspect of the sciences. Dreams and hypnagogic states have been highly influential in promoting scientific creativity and insight, contributing to some important scientific breakthroughs. Phenomenologically, the latter states of consciousness share a great deal of overlap with the psychedelic state, which has also been associated with facilitating scientific creativity on occasion. The current article proposes that the dream, hypnagogic and psychedelic states share common features that make them conducive to supporting some aspects of scientific creativity and examines the putative underlying neurophenomenological and cognitive processes involved. In addition , some notable occurrences of scientific insights that have emerged from these types of altered states are reviewed and shared common features are presented, providing a ground for future research. The psychedelic state may have its own characteristic features making it amenable to creativity enhancement, such as brain hyperconnectivity, meta-cognitive awareness, access to a more dependable and sustained altered state experience, and potential for eliciting sustained shifts in trait openness. The contextual factors which may contribute to enhancement of scientific creativity and insight will be evaluated. While research in this area is limited, further work to elucidate how psychedelics may best contribute to scientific creativity enhancement is warranted.
... Preliminary evidence from the last 15 years suggest that psilocybin has a rapid and potent positive treatment effect in affective and addictive disorders (Moreno et al., 2006;Grob et al., 2011;Bogenschutz et al., 2015;Griffiths et al., 2016;Ross et al., 2016;Johnson et al., 2017;Carhart-Harris et al., 2018;Garcia-Romeu et al., 2019;Anderson et al., 2020;Davis et al., 2020;Carhart-Harris et al., 2021). In healthy individuals and patients, psilocybin has been associated with long-lasting positive psychological effects and self-reported positive changes in mood, behaviour Barrett et al., 2020) and personality (e.g., increased openness; (MacLean et al., 2011;Erritzoe et al., 2018;Schmid and Liechti, 2018;Madsen et al., 2020;Kettner et al., 2021), while no association with persisting effects on cognition has been observed (Rucker et al., 2021). ...
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Psychedelic drugs such as psilocybin have shown substantial promise for the treatment of several psychiatric conditions including mood and addictive disorders. They also have the remarkable property of producing persisting positive psychological changes in healthy volunteers for at least several months. In this study (NCT03289949), 35 medium-high doses of psilocybin were administered to 28 healthy volunteers (12 females). By the end of the dosing day, participants reported the intensity of their acute experience using the 30-item Mystical Experience Questionnaire (MEQ) and an open-form qualitative report from home. Persisting psychological effects attributed to the psilocybin experience were measured using the Persisting Effects Questionnaire (PEQ) 3-months after administration. Using a linear latent-variable model we show that the MEQ total score is positively associated with the later emergence of positive PEQ effects ( p = 3 × 10 ⁻⁵ ). Moreover, the MEQ subscales “Positive Mood” ( p corr = 4.1 × 10 ⁻⁴ ) and “Mysticality” ( p corr = 2.0 × 10 ⁻⁴ ) are associated with positive PEQ whereas the subscales “Transcendence of Time and Space” ( p corr = 0.38) and “Ineffability” ( p corr = 0.45) are not. Using natural language pre-processing, we provide the first qualitative descriptions of the “Complete Mystical Experience” induced by orally administered psilocybin in healthy volunteers, revealing themes such as a sense of connection with the Universe, familial love, and the experience of profound beauty. Combining qualitative and quantitative methods, this paper expands understanding of the acute psilocybin induced experience in healthy volunteers and suggests an importance of the type of experience in predicting lasting positive effects.
... Moreover, the study highlighted a correlation between subjective effects induced by psilocybin, 5-HT2A receptor occupancy, and plasma psilocin levels [60]. In two PET studies performed on healthy volunteers using the 5-HT2A receptor agonist radioligand [11C]-Cimbi-36, after psilocybin administration, individual brain 5-HT2A receptor-binding predicted subjective mystical effects [61], mindfulness, and openness [62]. ...
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Psychedelics extracted from plants have been used in religious, spiritual, and mystic practices for millennia. In 1957, Dr. Hofmann identified and synthesized the prodrug psilocybin, a substance present in more than 200 species of psychedelic mushrooms. Although there were limitations related to the scientific design of many studies, clinical observations performed during the 1950s and 1960s showed a potential therapeutic effect of psilocybin for patients affected by depressive symptoms, anxiety, and conversion disorder. Psilocybin was classed as a schedule I substance in 1970, but the fascination with psychedelics has remained almost unchanged over time, promoting a new scientific interest starting in the 1990s. Recent studies have provided further evidence supporting the suggestive hypothesis of the therapeutic use of psilocybin for treating various psychiatric disorders, including pathological anxiety, mood depressive disorder, and addiction.
... In terms of other personality traits, data suggests that psychedelics may increase openness (44,(162)(163)(164). Moreover, higher baseline scores in the personality trait of absorption (focused attention) (45,46) and openness may be useful predictors of a therapeutic psychedelic experience, reportedly linked to increases in brain entropy as measured by fMRI (and experiences of "ego-dissolution") (165), though 5-HT2AR binding did not appear to correlate with variations in openness (166,167), highlighting the individual variability in 5-HT2AR levels after psilocybin and the complex relationship with subjective changes. ...
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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.
... Through stimulation of the serotonin 2A receptor , psilocin, the neuroactive metabolite of psilocybin, potently and acutely induces an altered state of consciousness [9][10][11][12] . Psilocybin also induces rapid and lasting positive effects on mood, well-being, and personality 1,[13][14][15] . These intriguing effects precipitate the need to resolve associated and perhaps mediating neurobiological mechanisms. ...
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Background Psilocin, the neuroactive metabolite of psilocybin, is a serotonergic psychedelic that induces an acute altered state of consciousness, evokes lasting changes in mood and personality in healthy individuals, and has potential as an antidepressant treatment. Examining the acute effects of psilocin on resting-state dynamic functional connectivity implicates network-level connectivity motifs that may underlie acute and lasting behavioral and clinical effects. Aim Evaluate the association between resting-state dynamic functional connectivity (dFC) characteristics and plasma psilocin level (PPL) and subjective drug intensity (SDI) before and right after intake of a psychedelic dose of psilocybin in healthy humans. Methods Fifteen healthy individuals completed the study. Before and at multiple time points after psilocybin intake, we acquired 10-minute resting-state blood-oxygen-level-dependent functional magnetic resonance imaging scans. Leading Eigenvector Dynamics Analysis (LEiDA) and diametrical clustering were applied to estimate discrete, sequentially active brain states. We evaluated associations between the fractional occurrence of brain states during a scan session and PPL and SDI using linear mixed-effects models. We examined associations between brain state dwell time and PPL and SDI using frailty Cox proportional hazards survival analysis. Results Fractional occurrences for two brain states characterized by lateral frontoparietal and medial fronto-parietal-cingulate coherence were statistically significantly negatively associated with PPL and SDI. Dwell time for these brain states was negatively associated with SDI and, to a lesser extent, PPL. Conversely, fractional occurrence and dwell time of a fully connected brain state was positively associated with PPL and SDI. Conclusion Our findings suggest that the acute perceptual psychedelic effects induced by psilocybin may stem from drug-level associated decreases in the occurrence and duration of lateral and medial frontoparietal connectivity motifs in exchange for increases in a uniform connectivity structure. We apply and argue for a modified approach to modeling eigenvectors produced by LEiDA that more fully acknowledges their underlying structure. Together these findings contribute to a more comprehensive neurobiological framework underlying acute effects of serotonergic psychedelics. Clinical Trial Registration NCT03289949
... However, divergent results were reported for personality change after psychedelic admission. For example, psilocybin increased openness, but did not influence neuroticism, extraversion, agreeableness, or conscientiousness in healthy participants post-acutely (MacLean et al. 2011;Madsen et al. 2020). Similarly, patients with treatment resistant depression showed increased openness, but also increased extraversion and decreased neuroticism following psilocybin sessions (Erritzoe et al. 2018). ...
Article
Substance use disorders (SUD) represent a significant public health issue with a high need for novel and efficacious treatment options. In light of this high unmet need, recent results reporting beneficial outcomes of psychedelic-assisted therapy in SUD are particularly relevant. However, several questions remain with regard to this treatment approach. The clinical mechanisms of action of psychedelic substances in the treatment of SUD are not well understood. Closing this knowledge gap is critical to inform and optimize the psychotherapeutic embedding of the acute substance administration. In this chapter, we discuss potential mechanisms that have implications on psychotherapeutic approaches including induced neuroplasticity, alterations in brain network connectivity, reward and emotion processing, social connectedness, insight, and mystical experiences. Furthermore, we outline considerations and approaches that leverage these mechanisms in order to optimize the therapeutic embedding by maximizing synergy between substance effects and psychotherapy. Understanding the mechanisms of action, developing psychotherapeutic approaches accordingly, and evaluating their synergistic efficacy in scientific studies will be critical to advance the framework of psychedelic-assisted therapy for addiction, create evidence-based approaches, and achieve the best treatment outcome for patients with SUD.
... The most relevant evidence to the present study is located in the personality literature. Eleven studies have prospectively examined long-term psychedelic-induced change in personality (e.g., MacLean et al., 2011;Madsen et al., 2020). Of these studies, five have shown evidence of adaptive change in Neuroticism or convergent constructs [e.g., Temperament and Character Inventory Harm Avoidance (characterized by worry)] (e.g., Barbosa et al., 2009;Erritzoe et al., 2018). ...
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The present study examines prospective changes in personality traits relevant to social functioning as well as perceived social connectedness in relation to the naturalistic use of psychedelic compounds in an online volunteer sample. The study also examined the degree to which demographic characteristics, social setting, baseline personality, and acute subjective factors (e.g., emotional breakthrough experiences) influenced trajectories of personality and perceived social connectedness. Participants recruited online completed self-report measures of personality and social connectedness at three timepoints (baseline, 2weeks post-experience, 4weeks post-experience). Linear mixed models were used to examine changes in outcomes and the moderation of these outcomes by covariates. The most substantive changes were reductions in the personality domains Neuroticism, and increases in Agreeableness and social connectedness. Notably, reductions in Neuroticism and increases in Agreeableness covaried over time, which may be suggestive of common processes involving emotion regulation. Preliminary evidence was found for a specific effect on a component of Agreeableness involving a critical and quarrelsome interpersonal style. Although moderation by demographic characteristics, social setting, baseline personality, and acute factors generally found limited support, baseline standing on Neuroticism, perspective taking, and social connectedness showed tentative signs of amplifying adaptive effects on each trait, respectively. Our findings hold implications for the potential use of psychedelics for treating interpersonal elements of personality pathology as well as loneliness.
... Moreover, there could be yet unknown risks from psilocybin acting in peripheral tissues, as 5HT 2A and other receptors are also expressed there. Concerning overdose, due to its pharmacodynamic profile, psilocybin overdose and dependence are also unlikely because tolerance builds up quickly due to the rapid receptor desensitization [129,163]. ...
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The available interventions for people who are at risk of suicide have limited efficacy. Recently, research on new mental health treatments has started to consider psychedelic compounds, particularly psilocybin, a molecule with a few thousand years of history of use in human societies. The possible effects of psilocybin on suicidal ideation and behaviors have not been specifically studied yet; however, the current knowledge on the suicidal process and the available data on es/ketamine suggest that psylocibin could be used to modulate the thoughts and behavioral patterns in individu- als who are at risk of suicidal behaviors. Here, we summarize the available evidence on the possible mechanisms underlying psilocybin positive effects on suicide risk. Major pathways related to suicidal behaviors that might be modulated by psylocibin include serotonin receptors. Specifically, psylocibin directly stimulates the serotonin 2A receptor (5HT2A), targeting the inflammatory and oxidative stress pathways and leading to a rapid increase in brain plasticity and inflammation suppression and increases in cognitive flexibility, spirituality, and empathy. We also present preliminary epidemio- logical data and provide a rationale for studying psilocybin in individuals with suicidal ideation or who are at risk of suicidal behaviors. This review presents a framework to understand the basis for psilocybin use in individuals who are at risk of suicidal behaviors and calls for clinical studies.
... Vyhledávali jsme randomizované kontrolované studie, které sledovaly účinek různých terapeutických nebo intervenčních programů nezaměřených primárně na rozvíjení všímavosti (non-MBIs) na změnu úrovně všímavosti po absolvování těchto programů. Do výběru jsme tedy nezařadili studie, v nichž byl posuzován pouze některý program založený na všímavosti a ke srovnání byla využita buď čekací listina, nebo sku-4 Pro zajímavost uveďme, že existují i studie, které dokládají nárůst všímavosti po jednorázovém užití psychedelik (Madsen et al., 2020;Soler et al., 2016). 5 Tato metaanalýza obsahuje pouze 2 studie, které uvedli rovněž Xia et al. (2019). ...
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Objectives: The aim of this meta-analysis was to investigate if mindfulness is developed in some therapy or intervention programs, that are not explicitly focused on its development. Method: Randomized controlled trials were searched from Scopus database that investigated the effect of non-mindfulness-based therapy or intervention programs on the levels of mindfulness. The search was limited to studies which have used the Five Facet Mindfulness Questionnaire for measuring mindfulness. Results: A total of 24 trials met inclusion criteria. Among the assessed programs, two had large effects for change in mindfulness (0,8 ˂ d), seven had medium effects (0,5 ˂ d ˂ 0,8), ten had small effects (0,2 ˂ d ˂ 0,5) and five had either no effect or negative effect (d ˂ 0,2). The weighted mean of effect sizes of all 24 programs on mindfulness development was d = 0,41. Conclusion: Many non-mindfulness-based therapy or intervention programs do have an effect on the increase of mindfulness.
... Changes in perspective described by contributors were often galvanized during the acute psychedelic experience, and often persisted for 2+ months. This is consistent with existing psychedelic data suggesting transdiagnostically significant longterm outcomes in openness (115), attitude (116), personality (117), depression and anxiety (86,118) reported for months to years (119) following treatment. PPI discussions did not include assessment of specific personality traits. ...
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Background: Chronic Pain is among the leading causes of disability worldwide with up to 60% of patients suffering from comorbid depression. Psychedelic-assisted therapy has recently been found effective in treating a host of mental health issues including depression and has historically been found to be useful in treating pain. Reports of self-medication for chronic pain using psychedelic drugs have been widely documented, with anecdotal evidence indicating widespread success in a range of pathologies. Aims: In preparation for an upcoming trial, to better understand how those with lived experience of chronic pain self-medicate with psychedelic drugs, and to establish, in detail, their therapeutic protocols and practices for success. Methods: As part of patient-involvement (PI) for an upcoming trial in this population, 11 individuals who reported self-medicating with psychedelic drugs took part in a 1-h semi-structured discussion, which was then transcribed and thematically analyzed. Results: Across a range of psychedelic substances and doses, reported pain scores improved substantially during and after psychedelic experiences. Two processes, Positive Reframing and Somatic Presence, were reliably identified as playing a role in improvements in mental wellbeing, relationship with pain, and physical (dis)comfort. Inclusion of other strategies such as mindfulness, breathwork, and movement were also widely reported. Due to the data's subjective nature, this paper is vulnerable to bias and makes no claims on causality or generalisability. Together, these results have been used to inform study design for a forthcoming trial. Conclusion: This pre-trial PI work gives us confidence to test psychedelic therapy for chronic pain in a forthcoming controlled trial. The results presented here will be instrumental in improving our ability to meet the needs of future study participants.
... However, this downregulation of 5-HT 2A density by psilocybin does not appear to be a lasting effect. In a recent PET study on healthy volunteers, the 5-HT 2A binding of psilocybin one week after administration did not differ significantly from that of the baseline [47]. Similar effects were observed in an animal model. ...
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There has recently been a renewal of interest in psychedelic research on the use of psilocybin in psychiatric treatment and, in particular, for the treatment of major depressive disorder (MDD). Several state-of-the-art studies have provided new insight into the mechanisms of action of psilocybin and its therapeutic potential. Nevertheless, many questions remain unanswered. With this review, we provide an overview of the current state of research on the potential mechanisms of psilocybin, its antidepressant potential, and the associated risks and adverse effects, to provide an update on a controversial topic discussed in psychopharmacology. A database search was conducted in Medline including articles on psilocybin over the period of the last 20 years. Despite the promising progress in understanding the mechanisms of psilocybin, the exact antidepressive mechanism and the role of the psychedelic experience remain elusive. The studies included in this review found high treatment effect sizes for psilocybin as an antidepressant. However, the results must be regarded as preliminary due to several limitations. Although the current studies observed no severe adverse events, several questions regarding safety and utility remain and must be subject of future research.
Article
Basic pain research has shed light on key cellular and molecular mechanisms underlying nociceptive and phenomenological aspects of pain. Despite these advances, [[we still yearn for] the discovery of novel therapeutic strategies to address the unmet needs of about 70% of chronic neuropathic pain patients whose pain fails to respond to opioids as well as to other conventional analgesic agents. Importantly, a substantial body of clinical observations over the past decade cumulatively suggests that the psychedelic class of drugs may possess heuristic value for understanding and treating chronic pain conditions. The present review presents a theoretical framework for hitherto insufficiently understood neuroscience-based mechanisms of psychedelics’ potential analgesic effects. To that end, searches of PubMed-indexed journals were performed using the following Medical Subject Headings' terms: pain, analgesia, inflammatory, brain connectivity, ketamine, psilocybin, functional imaging, and dendrites. Recursive sets of scientific and clinical evidence extracted from this literature review were summarized within the following key areas: (1) studies employing psychedelics for alleviation of physical and emotional pain; (2) potential neuro-restorative effects of psychedelics to remediate the impaired connectivity underlying the dissociation between pain-related conscious states/cognitions and the subcortical activity/function leading to the eventual chronicity through immediate and long-term effects on dentritic plasticity; (3) anti-neuroinflammatory and pro-immunomodulatory actions of psychedelics as the may pertain to the role of these factors in the pathogenesis of neuropathic pain; (4) safety, legal, and ethical consideration inherent in psychedelics’ pharmacotherapy. In addition to direct beneficial effects in terms of reduction of pain and suffering, psychedelics’ inclusion in the analgesic armamentarium will contribute to deeper and more sophisticated insights not only into pain syndromes but also into frequently comorbid psychiatric condition associated with emotional pain, e.g., depressive and anxiety disorders. Further inquiry is clearly warranted into the above areas that have potential to evolve into further elucidate the mechanisms of chronic pain and affective disorders, and lead to the development of innovative, safe, and more efficacious neurobiologically-based therapeutic approaches.
Article
After decades of stagnation, research on psychedelic substances (such as lysergic acid diethylamide [LSD], psilocybin, or N,N-dimethyltryptamine [DMT]) has experienced a renaissance over the last 10 years, with various major research programs being conducted across Europe and the United States. This research primarily investigates the potential of psychedelics in the treatment of mental health disorders, their short- and long-term effects on recreational users, and the neurological and cognitive processes responsible for their effects. The present review provides a concise summary of the most recent insights gained from this research. We briefly outline the history of psychedelic research, the objective and subjective effects caused by these substances, the prevalence and socio-psychological correlates of their use, as well as their potential for harm. Subsequently, we review empirical research on the beneficial effects of psychedelics in clinical samples, focusing on their efficacy in the treatment of major depression, anxiety, and substance use disorders, and discuss research on the proposed neural and cognitive mechanisms behind these effects. We then review research on their effects on healthy subjects, focusing on psychological well-being as well as changes in personality, nature-relatedness, and creativity. Finally, we review empirical evidence regarding the long-term effects of single experiences with psychedelics and conclude with a summary and outlook.
Article
Obsessive-compulsive disorder (OCD) is a highly prevalent and disabling condition for which currently available treatments are insufficiently effective and alternatives merit priority attention. Psilocybin may represent a safe and effective avenue for treatment of individuals affected by this condition. In this chapter we briefly introduce OCD symptoms, epidemiology, as well as relevant hypotheses on the mechanism of disease that may inform treatment interventions. We briefly describe currently available treatments, mechanisms of action, and efficacy limitations, as preamble to the potential use of psilocybin and perhaps similar compounds in the treatment of OCD and related conditions. Although much is reviewed throughout this book about the mechanisms of action of psychedelic agents, a focused discussion of psilocybin effects as they pertain to OCD is also included. Our experience with incidental observation, prospective research, and current explorations of psilocybin in OCD are also described.
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In this précis I summarise the main ideas of my book Philosophy of Psychedelics . The book discusses philosophical issues arising from the therapeutic use of classic psychedelic drugs such as psilocybin and LSD. The book is organised around what I call the Comforting Delusion Objection to psychedelic therapy: the concern that this novel and promising treatment relies essentially on the induction of non-naturalistic metaphysical beliefs, rendering it epistemically (and perhaps, therefore, ethically) objectionable. In the book I develop a new response to this Objection which involves showing that a popular conception of psychedelics as agents of insight and spirituality is both consistent with a naturalistic worldview and plausible in light of current scientific knowledge. Exotic metaphysical ideas do sometimes come up, but they are not, on closer inspection, the central driver of change in psychedelic therapy. Psychedelics cause therapeutic benefits by altering the sense of self, and changing how people relate to their own minds and lives--not by changing their beliefs about the ultimate nature of reality. Thus, an "Entheogenic Conception" of psychedelics as agents of insight and spirituality can be reconciled with naturalism (the philosophical position that the natural world is all there is). Controlled psychedelic use can lead to genuine forms of knowledge gain and spiritual growth--even if no Cosmic Consciousness or divine Reality exists.
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The emerging novel therapeutic psilocybin produces psychedelic effects via engagement of cerebral serotonergic targets by psilocin (active metabolite). The serotonin 2A receptor critically mediates these effects by altering distributed neural processes that manifest as increased entropy, reduced functional connectivity (FC) within discrete brain networks (i.e., reduced integrity) and increased FC between networks (i.e., reduced segregation). Reduced integrity of the default mode network (DMN) is proposed to play a particularly prominent role in psychedelic phenomenology, including perceived ego-dissolution. Here, we investigate the effects of a psychoactive peroral dose of psilocybin (0.2–0.3 mg/kg) on plasma psilocin level (PPL), subjective drug intensity (SDI) and their association in fifteen healthy individuals. We further evaluate associations between these measures and resting-state FC, measured with functional magnetic resonance imaging, acquired over the course of five hours after psilocybin administration. We show that PPL and SDI correlate negatively with measures of network integrity (including DMN) and segregation, both spatially constrained and unconstrained. We also find that the executive control network and dorsal attention network desegregate, increasing connectivity with other networks and throughout the brain as a function of PPL and SDI. These findings provide direct evidence that psilocin critically shapes the time course and magnitude of changes in the cerebral functional architecture and subjective experience following psilocybin administration. Our findings provide novel insight into the neurobiological mechanisms underlying profound perceptual experiences evoked by this emerging transnosological therapeutic and implicate the expression of network integrity and segregation in the psychedelic experience and consciousness.
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Clinical research into serotonergic psychedelics is expanding rapidly, showing promising efficacy across myriad disorders. Resting-state functional magnetic resonance imaging (rs-fMRI) is a commonly used strategy to identify psychedelic-induced changes in neural pathways in clinical and healthy populations. Here we, a large group of psychedelic imaging researchers, review the 42 research articles published to date, based on the 17 unique studies evaluating psychedelic effects on rs-fMRI, focusing on methodological variation. Prominently, we observe that nearly all studies vary in data processing and analysis methodology, two datasets are the foundation of over half of the published literature, and there is lexical ambiguity in common outcome metric terminology. We offer guidelines for future studies that encourage coherence in the field. Psychedelic rs-fMRI will benefit from the development of novel methods that expand our understanding of the brain mechanisms mediating its intriguing effects; yet, this field is at a crossroads where we must also consider the critical importance of consistency and replicability to effectively converge on stable representations of the neural effects of psychedelics.
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While anecdotal reports claim that psychedelic microdosing reduces anxiety and mood symptoms, evidence supporting these claims is scarce. This cross-sectional study investigated the association between microdosing and trait anxiety. Furthermore, it was investigated if trait mindfulness mediated this association. Participants completed anonymous online questionnaires and were divided into three groups: current microdosers (n = 186), former microdosers (n = 77) and microdosing-naïve controls (n = 234). Trait anxiety and trait mindfulness were measured using the State-Trait Anxiety Inventory - Trait subscale (STAI-T) and the 15-item Five-Facet Mindfulness Questionnaire (FFMQ-15) respectively. Current and former microdosers reported lower STAI-T scores compared to microdosing-naïve controls. Furthermore, associations of current and former microdosing with trait anxiety were mediated by trait mindfulness, with small effects of FFMQ-15 Total, Non-judging and Non-reactivity scores. However, in an exploratory analysis, all associations between microdosing and STAI-T scores became non-significant when participants with previous macrodose experience (n = 386) were excluded. Our findings suggest that RCT<apos;>s are warranted to test causal hypotheses concerning the effects of microdosing and the role of trait mindfulness in the effects of microdosing, while controlling for previous macrodose experience.
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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.
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Background Psilocybin is a serotonergic psychedelic with psychoactive effects mediated by serotonin 2A receptor (5-HT2AR) activation. It produces an acute psychedelic altered state of consciousness with a unique phenomenology that can be temporally characterized by three intensity phases: onset of psychoactive effect, a peak plateau and return to normal consciousness. Aims We evaluated whether pre-drug brain 5-HT2AR binding predicted the three phases of psilocybin subjective drug intensity (SDI) and retrospective self-report of mystical type experiences in healthy individuals. Method Sixteen participants completed a pre-drug [ ¹¹ C]Cimbi-36 positron emission tomography scan to assess 5-HT2AR binding. On a separate day, participants completed a single psilocybin session (oral dose range 0.2–0.3 mg/kg), during which SDI was assessed every 20 min. The Mystical Experience Questionnaire (MEQ) was completed at the end of the session. The three SDI phases were modelled using segmented linear regressions. We evaluated the associations between neocortex 5-HT2AR binding and SDI/MEQ outcomes using linear regression models. Results Neocortex 5-HT2AR was statistically significantly negatively associated with peak plateau duration and positively with time to return to normal waking consciousness. It was also statistically significantly negatively associated with MEQ total score. Conclusion This is the first study to investigate how individual brain 5-HT2AR binding predicts subjective effects of a single dose of psilocybin. Our findings reinforce the role of cerebral 5-HT2AR in shaping the temporal and mystical features of the psychedelic experience. Future studies should examine whether individual brain levels of 5-HT2AR have an impact on therapeutic outcomes in clinical studies.
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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.
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The main psychedelic component of magic mushrooms is psilocybin, which shows promise as a treatment for depression and other mental disorders. Psychedelic effects are believed to emerge through stimulation of serotonin 2A receptors (5-HT2ARs) by psilocybin’s active metabolite, psilocin. We here report for the first time the relationship between intensity of psychedelic effects, cerebral 5-HT2AR occupancy and plasma levels of psilocin in humans. Eight healthy volunteers underwent positron emission tomography (PET) scans with the 5-HT2AR agonist radioligand [11C]Cimbi-36: one at baseline and one or two additional scans on the same day after a single oral intake of psilocybin (3–30 mg). 5-HT2AR occupancy was calculated as the percent change in cerebral 5-HT2AR binding relative to baseline. Subjective psychedelic intensity and plasma psilocin levels were measured during the scans. Relations between subjective intensity, 5-HT2AR occupancy, and plasma psilocin levels were modeled using non-linear regression. Psilocybin intake resulted in dose-related 5-HT2AR occupancies up to 72%; plasma psilocin levels and 5-HT2AR occupancy conformed to a single-site binding model. Subjective intensity was correlated with both 5-HT2AR occupancy and psilocin levels as well as questionnaire scores. We report for the first time that intake of psilocybin leads to significant 5-HT2AR occupancy in the human brain, and that both psilocin plasma levels and 5-HT2AR occupancy are closely associated with subjective intensity ratings, strongly supporting that stimulation of 5-HT2AR is a key determinant for the psychedelic experience. Important for clinical studies, psilocin time-concentration curves varied but psilocin levels were closely associated with psychedelic experience.
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The Five Factor Mindfulness Questionnaire (FFMQ) measures 5 factor-analytically derived mindfulness aspects (Observe, Describe, Non-Judgment, Non-Reactivity, and Acting with Awareness) and is commonly used as an indicator of mindfulness in population surveys and studies of mindfulness-based interventions (MBI). Outside MBI, FFMQ scores are hypothesized to reflect relatively stable human dispositions of importance to psychological health. However, the long-term test–retest reliability of FFMQ scores is virtually untested and it remains unknown whether FFMQ scores predict psychological health after controlling for standardized socioeconomic status classifications. First, we focused on psychometric validation of the FFMQ translated to Danish in a randomly invited healthy and nonmeditating adult community sample (N = 490). Confirmatory factor analyses primarily supported a four-factor construct excluding the Observe facet. The four-factor model showed adequate composite reliability, convergent validity and satisfactory-excellent internal consistency, Cronbach αs = .72–.91. Structural equation modeling revealed that FFMQ Total scores were positively related to income and socioeconomic status but independently predicted psychological distress and mental health scores, respectively, after controlling for age, gender, body mass index, socioeconomic job classification, stressful life events, and social desirability, β = −.24–.29, ps < .001. Second, FFMQ scores showed adequate short-term (two weeks) test–retest reliability among 99 healthy university students, Spearman’s ρs ≥ .82. Finally, all FFMQ mean scores showed satisfactory test–retest reliability across a long-term (six months) interval (N = 407), intraclass correlation coefficients ≥.74. We recommend the Danish FFMQ for further use. The Observe facet should be interpreted with caution. Remaining FFMQ facet scores comprise an internally consistent four-dimensional construct reflecting long-term-reliable human dispositions of independent significance for predicting mental health.
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Objective To explore whether psilocybin with psychological support modulates personality parameters in patients suffering from treatment‐resistant depression (TRD). Method Twenty patients with moderate or severe, unipolar, TRD received oral psilocybin (10 and 25 mg, one week apart) in a supportive setting. Personality was assessed at baseline and at 3‐month follow‐up using the Revised NEO Personality Inventory (NEO‐PI‐R), the subjective psilocybin experience with Altered State of Consciousness (ASC) scale, and depressive symptoms with QIDS‐SR16. Results Neuroticism scores significantly decreased while Extraversion increased following psilocybin therapy. These changes were in the direction of the normative NEO‐PI‐R data and were both predicted, in an exploratory analysis, by the degree of insightfulness experienced during the psilocybin session. Openness scores also significantly increased following psilocybin, whereas Conscientiousness showed trend‐level increases, and Agreeableness did not change. Conclusion Our observation of changes in personality measures after psilocybin therapy was mostly consistent with reports of personality change in relation to conventional antidepressant treatment, although the pronounced increases in Extraversion and Openness might constitute an effect more specific to psychedelic therapy. This needs further exploration in future controlled studies, as do the brain mechanisms of postpsychedelic personality change.
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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.
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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
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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.
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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
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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.
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Aims: The experience of a compromised sense of “self”, termed ego-dissolution, is a key feature of the psychedelic experience. This study aimed to validate the Ego-Dissolution Inventory (EDI), a new 8-item self-report scale designed to measure ego-dissolution. Additionally, we aimed to investigate the specificity of the relationship between psychedelics and ego-dissolution. Method: Sixteen items relating to altered ego-consciousness were included in an internet questionnaire; eight relating to the experience of ego-dissolution (comprising the EDI), and eight relating to the antithetical experience of increased self-assuredness, termed ego-inflation. Items were rated using a visual analog scale. Participants answered the questionnaire for experiences with classical psychedelic drugs, cocaine and/or alcohol. They also answered the seven questions from the Mystical Experiences Questionnaire (MEQ) relating to the experience of unity with one’s surroundings. Results: Six hundred and ninety-one participants completed the questionnaire, providing data for 1828 drug experiences (1043 psychedelics, 377 cocaine, 408 alcohol). Exploratory factor analysis demonstrated that the eight EDI items loaded exclusively onto a single common factor, which was orthogonal to a second factor comprised of the items relating to ego-inflation (rho = −0.110), demonstrating discriminant validity. The EDI correlated strongly with the MEQ-derived measure of unitive experience (rho = 0.735), demonstrating convergent validity. EDI internal consistency was excellent (Cronbach’s alpha 0.93). Three analyses confirmed the specificity of ego-dissolution for experiences occasioned by psychedelic drugs. Firstly, EDI score correlated with drug-dose for psychedelic drugs (rho = 0.371), but not for cocaine (rho = 0.115) or alcohol (rho = −0.055). Secondly, the linear regression line relating the subjective intensity of the experience to ego-dissolution was significantly steeper for psychedelics (unstandardized regression coefficient = 0.701) compared with cocaine (0.135) or alcohol (0.144). Ego-inflation, by contrast, was specifically associated with cocaine experiences. Finally, a binary Support Vector Machine classifier identified experiences occasioned by psychedelic drugs vs. cocaine or alcohol with over 85% accuracy using ratings of ego-dissolution and ego-inflation alone. Conclusion: Our results demonstrate the psychometric structure, internal consistency and construct validity of the EDI. Moreover, we demonstrate the close relationship between ego-dissolution and the psychedelic experience. The EDI will facilitate the study of the neuronal correlates of ego-dissolution, which is relevant for psychedelic-assisted psychotherapy and our understanding of psychosis.
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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.
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The Mindful Attention Awareness Scale (MAAS) measures perceived degree of inattentiveness in different contexts and is often used as a reversed indicator of mindfulness. MAAS is hypothesized to reflect a psychological trait or disposition when used outside attentional training contexts, but the long-term test-retest reliability of MAAS scores is virtually untested. It is unknown whether MAAS predicts psychological health after controlling for standardized socioeconomic status classifications. First, MAAS translated to Danish was validated psychometrically within a randomly invited healthy adult community sample (N = 490). Factor analysis confirmed that MAAS scores quantified a unifactorial construct of excellent composite reliability and consistent convergent validity. Structural equation modeling revealed that MAAS scores contributed independently to predicting psychological distress and mental health, after controlling for age, gender, income, socioeconomic occupational class, stressful life events, and social desirability (β = 0.32-.42, ps < .001). Second, MAAS scores showed satisfactory short-term test-retest reliability in 100 retested healthy university students. Finally, MAAS sample mean scores as well as individuals' scores demonstrated satisfactory test-retest reliability across a 6 months interval in the adult community (retested N = 407), intraclass correlations ≥ .74. MAAS scores displayed significantly stronger long-term test-retest reliability than scores measuring psychological distress (z = 2.78, p = .005). Test-retest reliability estimates did not differ within demographic and socioeconomic strata. Scores on the Danish MAAS were psychometrically validated in healthy adults. MAAS's inattentiveness scores reflected a unidimensional construct, long-term reliable disposition, and a factor of independent significance for predicting psychological health. (PsycINFO Database Record
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Background: Ayahuasca is a psychotropic plant tea used for ritual purposes by the indigenous populations of the Amazon. In the last two decades, its use has expanded worldwide. The tea contains the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT), plus β-carboline alkaloids with monoamine-oxidase-inhibiting properties. Acute administration induces an introspective dream-like experience characterized by visions and autobiographic and emotional memories. Studies of long-term users have suggested its therapeutic potential, reporting that its use has helped individuals abandon the consumption of addictive drugs. Furthermore, recent open-label studies in patients with treatment-resistant depression found that a single ayahuasca dose induced a rapid antidepressant effect that was maintained weeks after administration. Here, we conducted an exploratory study of the psychological mechanisms that could underlie the beneficial effects of ayahuasca. Methods: We assessed a group of 25 individuals before and 24 h after an ayahuasca session using two instruments designed to measure mindfulness capacities: The Five Facets Mindfulness Questionnaire (FFMQ) and the Experiences Questionnaire (EQ). Results: Ayahuasca intake led to significant increases in two facets of the FFMQ indicating a reduction in judgmental processing of experiences and in inner reactivity. It also led to a significant increase in decentering ability as measured by the EQ. These changes are classic goals of conventional mindfulness training, and the scores obtained are in the range of those observed after extensive mindfulness practice. Conclusions: The present findings support the claim that ayahuasca has therapeutic potential and suggest that this potential is due to an increase in mindfulness capacities.
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The 30-item revised Mystical Experience Questionnaire (MEQ30) was previously developed within an online survey of mystical-type experiences occasioned by psilocybin-containing mushrooms. The rated experiences occurred on average eight years before completion of the questionnaire. The current paper validates the MEQ30 using data from experimental studies with controlled doses of psilocybin. Data were pooled and analyzed from five laboratory experiments in which participants (n=184) received a moderate to high oral dose of psilocybin (at least 20 mg/70 kg). Results of confirmatory factor analysis demonstrate the reliability and internal validity of the MEQ30. Structural equation models demonstrate the external and convergent validity of the MEQ30 by showing that latent variable scores on the MEQ30 positively predict persisting change in attitudes, behavior, and well-being attributed to experiences with psilocybin while controlling for the contribution of the participant-rated intensity of drug effects. These findings support the use of the MEQ30 as an efficient measure of individual mystical experiences. A method to score a "complete mystical experience" that was used in previous versions of the mystical experience questionnaire is validated in the MEQ30, and a stand-alone version of the MEQ30 is provided for use in future research.
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Perturbing a system and observing the consequences is a classic scientific strategy for understanding a phenomenon. Psychedelic drugs perturb consciousness in a marked and novel way and thus are powerful tools for studying its mechanisms. In the present analysis, we measured changes in resting-state functional connectivity (RSFC) between a standard template of different independent components analysis (ICA)-derived resting state networks (RSNs) under the influence of two different psychoactive drugs, the stimulant/psychedelic hybrid, MDMA, and the classic psychedelic, psilocybin. Both were given in placebo-controlled designs and produced marked subjective effects, although reports of more profound changes in consciousness were given after psilocybin. Between-network RSFC was generally increased under psilocybin, implying that networks become less differentiated from each other in the psychedelic state. Decreased RSFC between visual and sensorimotor RSNs was also observed. MDMA had a notably less marked effect on between-network RSFC, implying that the extensive changes observed under psilocybin may be exclusive to classic psychedelic drugs and related to their especially profound effects on consciousness. The novel analytical approach applied here may be applied to other altered states of consciousness to improve our characterization of different conscious states and ultimately advance our understanding of the brain mechanisms underlying them.
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BACKGROUND: The amygdala is a key structure in serotonergic emotion-processing circuits. In healthy volunteers, acute administration of the serotonin 1A/2A/2C receptor agonist psilocybin reduces neural responses to negative stimuli and induces mood changes toward positive states. However, it is little-known whether psilocybin reduces amygdala reactivity to negative stimuli and whether any change in amygdala reactivity is related to mood change. METHODS: This study assessed the effects of acute administration of the hallucinogen psilocybin (.16 mg/kg) versus placebo on amygdala reactivity to negative stimuli in 25 healthy volunteers using blood oxygen level-dependent functional magnetic resonance imaging. Mood changes were assessed using the Positive and Negative Affect Schedule and the state portion of the State-Trait Anxiety Inventory. A double-blind, randomized, cross-over design was used with volunteers counterbalanced to receive psilocybin and placebo in two separate sessions at least 14 days apart. RESULTS: Amygdala reactivity to negative and neutral stimuli was lower after psilocybin administration than after placebo administration. The psilocybin-induced attenuation of right amygdala reactivity in response to negative stimuli was related to the psilocybin-induced increase in positive mood state. CONCLUSIONS: These results demonstrate that acute treatment with psilocybin decreased amygdala reactivity during emotion processing and that this was associated with an increase of positive mood in healthy volunteers. These findings may be relevant to the normalization of amygdala hyperactivity and negative mood states in patients with major depression.
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