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A single psilocybin dose is associated with long-term increased mindfulness, preceded by a proportional change in neocortical 5-HT2A receptor binding
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.
... Six of the studies employed the Persistent Effects Questionnaire (PEQ) as the main outcome measure related to well-being (Griffiths et al., 2006(Griffiths et al., , 2011(Griffiths et al., , 2018Madsen et al., 2020;Nicholas et al., 2018). This instrument contains subscales about positive changes in mood, social effects, and attitudes about life and oneself. ...
... Personally significant changes to health and well-being due to behavioural lifestyle changes, an increased sense of self-love, self-acceptance, selfconfidence, positive emotions, an increased interest in spirituality and improved interpersonal connection Madsen et al. (2020) Open label, withinsubject study self-acceptance (e.g., "your self-confidence/self-assurance has increased"), and positive social effects include questions related to positive relationships (e.g., "you have a more positive relationship with others"). The PEQ also contains a final item that asks participants on a 7-point Likert scale whether they believe that the experience of using psilocybin and the contemplation about the experience led to changes in their current sense of personal well-being or life satisfaction. ...
... The PEQ also contains a final item that asks participants on a 7-point Likert scale whether they believe that the experience of using psilocybin and the contemplation about the experience led to changes in their current sense of personal well-being or life satisfaction. In one study using the PEQ, this item was not reported (Madsen et al., 2020). Three other studies also examined life satisfaction. ...
Background and aims
This scoping review employed a multifaceted conceptualization of well-being to examine how psilocybin use affects well-being and related sub-concepts in healthy individuals. It investigated which factors influence the relationship between psilocybin use and well-being, what research protocols have been employed, and what underlying mechanisms have been proposed in existing studies.
Methods
A comprehensive literature search in line with the PRISMA guidelines was conducted. Scopus, PubMed, PsycINFO, Web of Science, and Google Scholar were searched for peer-reviewed articles about psilocybin and well-being in healthy populations.
Results
Studies were heterogeneous in regard to study objectives, study design, study procedure, sample size and psilocybin dosage. In all studies, psilocybin use led to positive well-being-related outcomes for the majority of participants. Facets of well-being positively affected by psilocybin use in this review were self-acceptance, positive relationships, and meaning/purpose in life.
Conclusions
This scoping review provided preliminary evidence for the beneficial effects of psilocybin on well-being and related sub-concepts such as self-acceptance, positive relationships, and meaning/purpose in life in healthy individuals. Ego-dissolution, unity, connectedness, and mystical-type experiences are interrelated concepts that seem to be crucial for explaining such positive well-being-related effects of psilocybin. Under conducive conditions, the use of psilocybin may contribute to healthy functioning, through broad and sustained improvements in a variety of well-being concepts. Due to the heterogeneous nature of the studies, more definite conclusions require further research with a rigorous and homogeneous design.
... Psilocybin was purchased by RS from Dr. Martin Kuchar, Forensic Laboratory of Biologically Active Compounds, Department of Chemistry of Natural Compounds, University of Chemistry and Technology Prague, Prague, Czech Republic. The validity of psilocybin produced by this laboratory was demonstrated in clinical studies showing acute psychedelic and long-term clinical effects and effects in PET neuroimaging in healthy individuals [21][22][23][24][25][26][27][28], as well as in animal studies [29,30]. Doses of psilocybin (5 mg/kg and 20 mg/kg) were chosen according to Jefsen et al. (2021) [31]. ...
... Another study reported that a single dose of psilocybin 1 mg/kg induces long-lasting antidepressant effects in rats [10]. The doses of psilocybin used in our study (5 mg/kg and 20 mg/ kg) are much higher than those having an antidepressant effect in animal models [10] and those used in clinical studies in humans, where the weight-adjusted dose of psilocybin ranges from 0.025 mg/kg to 0.42 mg/kg [11,14,[21][22][23]25]. Clinical studies reported that psilocybin in doses of around 0.2-0.3 ...
... Clinical studies reported that psilocybin in doses of around 0.2-0.3 mg/kg per os induces in healthy individuals acute subjective psychedelic effects such as altered state of consciousness, dissolution of ego and personhood, mystical experience, disembodiment, changed perception of time and space, audio-visual synesthesiae, positive mood, blissful state, reduction of sense of self and of the border between self and the external world, as well as long-term effects like increase in openness to new experiences and mindfulness, positive changes in mood, behavior and personality, increased cognitive flexibility [21,23,25]. A dose of 1 mg/kg psilocybin in Sprague-Dawley rats is equivalent to 0.16 mg/kg in humans [37]. ...
S-ketamine, a N-methyl-D-aspartate receptor (NMDAR) antagonist, and psilocybin, a 5-hydroxy-tryptamine (serotonin) 2A receptor (5-HT2AR) agonist, are reported as effective rapid-acting antidepressants. Both compounds increase glutamate signalling and evoke cortical hyperexcitation. S-ketamine induces neurotoxicity especially in the retrosplenial cortex (Olney’s lesions). Whether psilocybin produces similar neurotoxic effects has so far not been investigated. We performed an immunohistochemical whole-brain mapping for heat shock protein 70 (HSP70) in rats treated with psilocybin, S-ketamine, and MK-801. In contrast to S-ketamine- and MK-801-treated animals, we did not detect any HSP70-positive neurons in retrosplenial cortex of rats treated with psilocybin. Our results suggest that psilocybin might be safer for clinical use compared to S-ketamine regarding neuronal damage.
... Over the past decade, psilocybin has emerged as a promising therapeutic for several hard-to-treat neuropsychiatric disorders, including Major Depressive Disorder [1,2], end-of-life anxiety [3], addiction [4], and Obsessive-Compulsive Disorder [5]. In healthy individuals, psilocybin has been shown to increase well-being [6], the core personality trait openness [7], and mindfulness [8]. Interestingly, the above changes appear to have a rapid onset and persist well beyond the acute pharmacological actions. ...
... Mechanisms thought to mediate these lasting effects of psilocybin include changes in distributed brain function, assessed with resting-state connectivity [9], modulation of brain serotonin (5-HT) 2A receptor (5-HT 2A R) binding [8] and the acute subjective experience [10]. Recently, anti-inflammatory action within the central nervous system has been proposed as a complementary mechanism that may contribute to the observed lasting therapeutic effects of psilocybin [11,12]. ...
... Sixteen healthy participants were recruited through an online survey (demographics are shown in Table 1). Data acquired from these participants were also included in previously published neuroimaging studies unrelated to the topic of this paper, including data from positron emission tomography (PET) and functional magnetic resonance imaging [8,16,[34][35][36]. After receiving a detailed description of the study, participants provided written informed consent and subsequently underwent a screening interview and a medical examination. ...
Rationale
Psilocybin is a serotonergic psychedelic that has gained prominent attention recently as a potential therapeutic for neuropsychiatric disorders including Major Depressive Disorder. Pre-clinical and initial studies in humans suggest that serotonin 2A receptor agonists, including serotonergic psychedelics, have anti-inflammatory effects. This may contribute to its therapeutic effects as previous studies indicate a link between neuropsychiatric disorders and inflammatory processes. However, the effect of psilocybin on biomarkers of inflammation has not been evaluated in humans.
Objectives
Investigate the effect of a single dose of psilocybin on peripheral biomarkers of inflammation in healthy humans.
Methods
Blood samples were collected from 16 healthy participants before and one day after the administration of a single oral dose of psilocybin (mean dose: 0.22mg/kg) and subsequently analyzed for concentrations of high-sensitivity C-reactive protein (hsCRP), tumor-necrosis-factor (TNF) and soluble urokinase plasminogen activator receptor (suPAR). Change in inflammatory markers was evaluated using a paired t-test where p < 0.05 was considered statistically significant.
Results
We did not observe statistically significant changes in any of the above biomarkers of inflammation (all Cohen's d ≤ 0.31; all p ≥ 0.23).
Conclusions
Our data do not support that a single dose of psilocybin reduces biomarkers of inflammation in healthy individuals one day after administration. Nevertheless, we suggest that future studies consider additional markers of inflammation, including markers of neuroinflammation, and evaluate potential anti-inflammatory effects of psilocybin therapy in clinical cohorts where more prominent effects may be observable.
... The searches identified a total of 1805 records from databases and other sources with a total of 13 studies meeting inclusion criteria (Domínguez-Clavé et al., 2019;Madsen et al., 2020;Mian, Altman, & Earleywine, 2019;Murphy-Beiner & Soar, 2020;Polito & Stevenson, 2019;Sampedro et al., 2017;Smigielski et al., 2019;Soler et al., 2016Soler et al., , 2018Thomas et al., 2013;Uthaug et al., 2018Uthaug et al., , 2019Uthaug et al., , 2020. Figure 1 shows the full screening process including reasons for exclusion of articles. Table 1 shows the characteristics of all included studies. ...
... Table 1 shows the characteristics of all included studies. Substances studied were ayahuasca -8 (Domínguez-Clavé et al., 2019;Mian et al., 2019;Murphy-Beiner & Soar, 2020;Sampedro et al., 2017;Soler et al., 2016Soler et al., , 2018Thomas et al., 2013;Uthaug et al., 2018), psilocybin -2 (Madsen et al., 2020;Smigielski et al., 2019), 5-MeO-DMT -2 (Uthaug et al., 2019(Uthaug et al., , 2020, and mixed serotonergic psychedelics (LSD, Psilocybin, Mescaline, other) -1 (Polito & Stevenson, 2019). Eleven of the included studies were pre-post intervention design with no control group (Domínguez-Clavé et al., 2019;Madsen et al., 2020;Murphy-Beiner & Soar, 2020;Polito & Stevenson, 2019;Sampedro et al., 2017;Soler et al., 2016Soler et al., , 2018Thomas et al., 2013;Uthaug et al., 2018Uthaug et al., , 2020Uthaug et al., , 2019. ...
... Substances studied were ayahuasca -8 (Domínguez-Clavé et al., 2019;Mian et al., 2019;Murphy-Beiner & Soar, 2020;Sampedro et al., 2017;Soler et al., 2016Soler et al., , 2018Thomas et al., 2013;Uthaug et al., 2018), psilocybin -2 (Madsen et al., 2020;Smigielski et al., 2019), 5-MeO-DMT -2 (Uthaug et al., 2019(Uthaug et al., , 2020, and mixed serotonergic psychedelics (LSD, Psilocybin, Mescaline, other) -1 (Polito & Stevenson, 2019). Eleven of the included studies were pre-post intervention design with no control group (Domínguez-Clavé et al., 2019;Madsen et al., 2020;Murphy-Beiner & Soar, 2020;Polito & Stevenson, 2019;Sampedro et al., 2017;Soler et al., 2016Soler et al., , 2018Thomas et al., 2013;Uthaug et al., 2018Uthaug et al., , 2020Uthaug et al., , 2019. The two remaining studies were a cross-sectional survey (Mian et al., 2019) and a randomised controlled trial (Smigielski et al., 2019). ...
Background and aims
The benefits of classic serotonergic psychedelics (e.g. psilocybin, LSD, DMT, ayahuasca) are becoming more widely known with the resurgence in research in the past decade. Furthermore, the benefits of mindfulness are well documented. However, no systematic reviews have examined linkage of mindfulness and psychedelics use. The aim of this systematic review is to explore the link between psychedelics and characteristics of mindfulness.
Methods
We conducted a systematic search across multiple databases, inclusive of grey literature and backwards/forward-citation tracking, on the 18 January 2021. The search strategy included terms relating to mindfulness and psychedelics, with no restriction on clinical or non-clinical conditions. Study quality was assessed. An exploratory random-effects meta-analysis was conducted on pre-post mindfulness data relative to psychedelic ingestion.
Results
Of 1805 studies screened, 13 were included in the systematic review. There was substantial variability in participant characteristics, psychedelic administration method and measurement of mindfulness. The ingestion of psychedelics is associated with an increase in mindfulness, specifically relating to domains of acceptance, which encompasses non-judgement of inner experience and non-reactivity. The meta-analysis of a subset of studies ( N = 6) showed small effects overall relative to ayahuasca ingestion, increasing mindfulness facets of non-judgement of inner experience and non-reactivity, as well as acting with awareness.
Conclusions
Further methodologically robust research is needed to elucidate the relationship between psychedelics and mindfulness. However, mindfulness and specific facets relating to acceptance have been shown to increase following ingestion of psychedelics in a number of studies.
... Multiple clinical trials have investigated the effectivity of psychedelic-assisted psychotherapy and found promising results for the treatment of anxiety in patients with life threatening diseases (Gasser et al. 2014;Griffiths et al. 2016;Grob et al. 2011;Ross et al. 2016) and treatment resistant depression , 2016Osório et al. 2015). In addition, psychedelic use is associated with positive personality change (Dressler, Bright, and Polito 2021;MacLean, Johnson, and Griffiths 2011) and mindfulness (Madsen et al. 2020;Soler et al. 2016;Uthaug et al. 2019) in healthy individuals. While multiple studies have demonstrated the physiological safety and low abuse potential of macrodoses Johnson et al. 2018;Moreno et al. 2006), they are not without risks. ...
... As macrodoses have been found to be effective in the treatment of anxiety (Gasser et al. 2014;Griffiths et al. 2016;Grob et al. 2011;Ross et al. 2016) and treatment resistant depression , 2016Osório et al. 2015), and some early reports suggest the same for microdosing (Hutten et al. 2019;Johnstad 2018), the first aim of this study was to investigate if current microdosers report lower trait anxiety compared to microdosing-naïve controls. In addition, as macrodose effects are often long-term Gasser et al. 2014;Griffiths et al. 2016;Grob et al. 2011;Ross et al. 2016) and may include changes in relatively stable traits such as openness and neuroticism (Dressler, Bright, and Polito 2021;MacLean, Johnson, and Griffiths 2011) and mindfulness (Madsen et al. 2020;Soler et al. 2016;Uthaug et al. 2019), the second aim of this study was to investigate if former microdosers also report lower trait anxiety compared to microdosing-naïve controls. ...
... In addition, changes in the DMN have been found in long-term MM practitioners (Brewer et al. 2011). As MM and psychedelic states show similarities in associated outcomes (Bohlmeijer et al. 2010;Eberth and Sedlmeier 2012;Hofmann et al. 2010), phenomenology (Berkovich-Ohana and Glicksohn 2017; Griffiths et al. 2011;Hanley, Nakamura, and Garland 2018;Liechti, Dolder, and Schmid 2017;Nour et al. 2016;Reavley and Pallant 2009;Russ and Elliott 2017) and neural correlates (Carhart-Harris et al. 2012;Fox et al. 2016;Palhano-Fontes et al. 2015), and as macrodoses have been associated with increased mindfulness (Madsen et al. 2020;Soler et al. 2016;Uthaug et al. 2019), the third aim of this study was to investigate if trait mindfulness mediates the association between microdosing and trait anxiety. ...
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.
... Beyond these limitations, the results of this study seem to concur with the evidence found in the field of studies on psychedelics, where positive effects are indicated in traits related to empathy, sociability, a feeling of connection, openness to experience and spiritual acceptance Dolder et al., 2016;Erritzoe et al., 2018;Hysek et al., 2014;Kettner et al., 2021;Lebedev et al., 2016;Lerner & Lyvers, 2006;MacLean et al., 2011;Madsen et al., 2020;Pokorny et al., 2017;Schmid & Liechti, 2018;Watts et al., 2017). The case of ayahuasca seems to be no exception, with quantitative and qualitative studies showing potential effects on social personality traits and effects at existential and spiritual levels (Apud, 2019;Argento et al., 2019;Kavenská & Simonová, 2015;Kjellgren et al., 2009;Netzband et al., 2020;Trichter et al., 2009). ...
... Más allá de estas limitaciones, los resultados del presente trabajo parecen ir en consonancia con la evidencia encontrada en el campo de estudios sobre psicodélicos, donde se señalan efectos positivos en rasgos relacionados con la empatía, sociabilidad, el sentimiento de conexión, la apertura a la experiencia y la espiritualidad Dolder et al., 2016;Erritzoe et al., 2018;Hysek et al., 2014;Kettner et al., 2021;Lebedev et al., 2016;Lerner & Lyvers, 2006;MacLean et al., 2011;Madsen et al., 2020;Pokorny et al., 2017;Schmid & Liechti, 2018;Watts et al., 2017). El caso de la ayahuasca parece no ser la excepción, con estudios cuantitativos y cualitativos que marcan potenciales efectos en rasgos sociales de la personalidad, y efectos a nivel de creencias existenciales y espirituales (Apud, 2019;Argento et al., 2019;Kavenská & Simonová, 2015;Kjellgren et al., 2009;Netzband et al., 2020;Trichter et al., 2009). ...
The current article is a systematic review and meta-analysis of cross-sectional studies that assess personality traits of long-term participants in ayahuasca rituals. An electronic search was conducted in the SCOPUS, PubMed and Web of Science databases. The systematic review included six final articles. In the metaanalysis, long-term ayahuasca participants, when compared with control groups, obtained: (i) lower significant scores for Harm Avoidance (g = −0.51), Anticipatory Worry (g = −0.56), Fear of Uncertainty (g = −0.27), Shyness with strangers (g = −0.41), Fatigability (g = −0.28) and Purposefulness (g = −0.27); (ii) higher significant scores for Reward Dependence (g = 0.34), Attachment (g = 0.40), Helpfulness (g = 0.38), Self-Transcendence (g = 0.91), Transpersonal Identification (g = 0.68) and Spiritual Acceptance (g = 1.02). The results show a ‘social’ and ‘spiritual’ profile for longterm ayahuasca participants that seems to concur with evidence from other psychedelic studies.
... This suggests a broadening of thought-action repertoire, as openness to experience is related to the tendency to seek out novel information and activities (Costa and McCrae, 2010). Classic psychedelics have been shown to increase mindfulness capabilities (Soler et al., 2016;Sampedro et al., 2017;Uthaug et al., 2019;Madsen et al., 2020;Murphy-Beiner and Soar, 2020;Mans et al., 2021) and absorption (Barrett et al., 2020a), where mindfulness is defined as an "attentiveness and non-judgmental acceptance of present-moment experience" (Bishop et al., 2004), resulting in a broadening of awareness (Garland et al., 2015;Garland and Fredrickson, 2019), and absorption is the predisposition to have one's attention fully present to an experience to the extent that awareness of the self is reduced (Tellegen and Atkinson, 1974). Both findings suggest a broadening of attentional scope. ...
... Some initial work suggested that decreases in DMN connectivity during the acute effects of classic psychedelics are a key contributor to the experience of ego dissolution (Carhart-Harris et al., 2012Kometer et al., 2015); decreases in DMN integrity during the acute effects of classic psychedelics are a frequently reported finding (Viol et al., 2017;M€ uller and Borgwardt, 2019;Madsen et al., 2020Madsen et al., , 2021Mason et al., 2021). However, similar alterations in DMN integrity have also been noted in substances with a range of subjective effects, including MDMA (M€ uller et al., 2021) and salvinorin A (a j-opiate receptor agonist) (Doss et al., 2020). ...
The extremes of human experiences, such as those occasioned by classic psychedelics and psychosis, provide a rich contrast for understanding how components of these experiences impact well-being. In recent years, research has suggested that classic psychedelics display the potential to promote positive enduring psychologic and behavioral changes in clinical and nonclinical populations. Paradoxically, classic psychedelics have been described as psychotomimetics. This review offers a putative solution to this paradox by providing a theory of how classic psychedelics often facilitate persistent increases in well-being, whereas psychosis leads down a "darker" path. This will be done by providing an overview of the overlap between the states (i.e., entropic processing) and their core differences (i.e., self-focus). In brief, entropic processing can be defined as an enhanced overall attentional scope and decreased predictability in processing stimuli facilitating a hyperassociative style of thinking. However, the outcomes of entropic states vary depending on level of self-focus, or the degree to which the associations and information being processed are evaluated in a self-referential manner. We also describe potential points of overlap with less extreme experiences, such as creative thinking and positive emotion-induction. Self-entropic broadening theory offers a heuristically valuable perspective on classic psychedelics and their lasting effects and relation to other states by creating a novel synthesis of contemporary theories in psychology. SIGNIFICANCE STATEMENT: Self-entropic broadening theory provides a novel theory examining the psychedelic-psychotomimetic paradox, or how classic psychedelics can be therapeutic, yet mimic symptoms of psychosis. It also posits a framework for understanding the transdiagnostic applicability of classic psychedelics. We hope this model invigorates the field to provide more rigorous comparisons between classic psychedelic-induced states and psychosis and further examinations of how classic psychedelics facilitate long-term change. As a more psychedelic future of psychiatry appears imminent, a model that addresses these long-standing questions is crucial.
... A further psychological process which may be of particular salience when discussing therapeutic efficacy for anxiety, and which psychedelics have been repeatedly found to enhance, are mindfulness capacities (10,22,23,(42)(43)(44)(45)(46). Mindfulness has been described as "paying attention in a particular way: on purpose, in the present moment, and non-judgmentally" (47). ...
... Usually when taking conventional anxiolytics the treatment duration will vary but might extend over months (5,6). For psychedelics, persisting effects on personality or wellbeing can be found up to 12 months after a single dose administration (25), whereas increased mindfulness capacities have been found to persist up to 3 months (43). It has been suggested by some studies that the intensity or quality of the psychedelic experience determines the treatment outcome (52)(53)(54). ...
Anxiety disorders are the most common type of psychiatric disorders among Western countries. Evidence-based treatment modalities including pharmacological and cognitive-behavioral therapy result in deficient treatment responses. Historical and recent research suggests psychedelic drugs may be efficacious in alleviating anxiety-related symptoms among healthy and clinical populations. The main aim of the present study was investigation of the effects of psilocybin-containing truffles, when taken in a supportive group setting, on ratings of state and trait anxiety across self-reported healthy volunteers. Attendees of psilocybin ceremonies were asked to complete a test battery at three separate occasions: before the ceremony (baseline), the morning after, and 1 week after the ceremony. The test battery included questionnaires assessing state and trait anxiety (State-Trait Anxiety Inventory), mindfulness capacities (Five Facet Mindfulness Questionnaire), and personality (Big Five Inventory). Additionally, the psychedelic experience was quantified with the Persisting Effects Questionnaire and the Ego Dissolution Inventory. The total amount of psilocybin-containing truffles consumed by each participant was recorded, and a sample of the truffles was analyzed to determine psilocin concentrations. Fifty-two attendees (males = 25; females = 25; others = 2) completed parts of the baseline assessment, 46 (males = 21; females = 24; others = 1) completed assessments the morning after the ceremony, and 23 (males = 10; females = 13) completed assessments at the 1-week follow-up. Average psilocin consumption across individuals was 27.1 mg. The morning after the ceremony, we observed medium reductions in anxiety measures (both state and trait) compared to baseline (d¯ = 6.4; p < 0.001 and d¯ = 6; p = 0.014, respectively), which persisted over a 1-week period post-ceremony (d¯ = 6.7; p = 0.001 and d¯ = 8.6; p = 0.004, respectively). At 1 week post-ceremony, the non-judging facet of the mindfulness scale was increased (d¯ = 1.5; p = 0.03), while the personality trait neuroticism decreased (d¯ = 5.2; p = 0.005), when compared to baseline. Additionally, we found ratings of ego dissolution (mean: 59.7, SD: 28.3) and changes in neuroticism to be the strongest predictors of reductions in state and trait anxiety, respectively. In sum, results suggest rapid and persisting (up to 1 week) anxiolytic effects in individuals with sub-clinical anxiety symptoms, which are related to the acute experience of ego dissolution, as well as lasting changes in trait neuroticism. Results also add support to the feasibility and potential efficacy of group sessions with psychedelics. To understand whether these effects extend to wider populations suffering from heightened anxiety, and the mechanisms involved, further experimental research is needed.
... 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]. ...
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.
... Another recent study demonstrated an improvement in cognitive exibility in patients with MDD after treatment with psilocybin 32 . Enduring changes in personality, especially decreases in neuroticism [33][34][35][36][37] and increases in openness 38-40 as well as increases in mindfulness 39 , have been reported after administration of classic hallucinogens. These cognitive and personality changes may be associated with psychological insights 5 and changes in psychological exibility 7 that have been proposed to mediate enduring therapeutic effects of hallucinogens. ...
... Given that we explicitly matched groups on psychiatric diagnosis, and the majority of individuals in both groups did not have a diagnosis, we are unable to make any statements regarding the effects of lifetime use of a hallucinogen on psychopathology (though others have done so 118,170 ). However, our ndings are consistent with previous studies suggesting that hallucinogens may confer cognitive bene t 32,78,79,135,171 and increase openness 21,[38][39][40]105,172,173 . While we were interested in directly assessing the association between personality and cognitive ability scores and white matter integrity, some of these relationships were di cult to interpret. ...
Recent research has demonstrated potential therapeutic effects of hallucinogens, but little is known regarding enduring effects of hallucinogens on human brain structure. Preclinical findings suggest micro-scale structural neuroplastic changes after hallucinogen administration. The current study sought to investigate the association between hallucinogen use, macroscale brain structure, personality, cognitive ability, and illicit drug use in a naturalistic sample. Data from 53 subjects reporting ever having used hallucinogens and 53 approximately hallucinogen-naïve matched controls were drawn from the Nathan Kline Institute-Rockland Sample database. Participants had completed diffusion tensor imaging, psychological, behavioral, and psychiatric assessments. Groups were compared on measures of personality, cognitive ability, history of illicit drug use, and the density of white matter tracts determined from probabilistic tractography. Hallucinogen users reported greater lifetime use of illicit drugs than controls and scored higher on measures of openness to new experiences and cognitive ability. Hallucinogen users also had greater density of structural connectivity in white matter tracts that are thought to support cognition, emotion, and creativity. These findings are consistent with reports that hallucinogen use may lead to shifts in personality as well as multiple cognitive domains. These novel findings provide clues to potential neural mechanisms underlying therapeutic effects of hallucinogens.
... Studies showed that similarly to MM, acute effects of psychedelics include non-dual experiences [54] and elevated interpersonal connectedness [55]. Moreover, psychedelics have been found to increase trait mindfulness, and the skills of nonjudgement, compassion and non-reactivity [56,57]. ...
There has been increasing scientific and clinical interest in studying psychedelic and meditation-based interventions in recent years, both in the context of improving mental health and as tools for understanding the mind. Several authors suggest neurophysiological and phenomenological parallels and overlaps between psychedelic and meditative states and suggest synergistic effects of both methods. Both psychedelic-assisted therapy and meditation training in the form of mindfulness-based interventions have been experimentally validated with moderate to large effects as alternative treatments for a variety of mental health problems, including depression, addictions, and anxiety disorders. Both demonstrated significant post-acute and long-term decreases in clinical symptoms and enhancements in well-being in healthy participants, in addition. Postulated shared salutogenic mechanisms, include, among others the ability to alter self-consciousness, present-moment awareness and antidepressant action via corresponding neuromodulatory effects. These shared mechanisms between mindfulness training and psychedelic intervention have led to scientists theorizing, and recently demonstrating, positive synergistic effects when both are used in combination. Research findings suggest that these two approaches can complement each other, enhancing the positive effects of both interventions. However, more theoretical accounts and methodologically sound research are needed before they can be extended into clinical practice. The current review aims to discuss the theoretical rationale of combining psychedelics with mindfulness training, including the predictive coding framework as well as research findings regarding synergies and commonalities between mindfulness training and psychedelic intervention. In addition, suggestions how to combine the two modalities are provided.
... Downstream effects of psilocybin were evaluated previously using PET ligands such as [11C]raclopride, to evaluate changes in dopamine release [37] and [18F]fluorodeoxyglucose PET [38] to evaluate changes in glycolysis and brain metabolism. A recent study examined the relationship between 5-HT2AR binding with PET and long-term changes in personality factors [39], and the same team also reported neocortical 5-HT2AR binding to be negatively associated with peak plateau duration of the psilocybin experience [40]. PET investigations have also helped understand long-term effects on serotonin brain markers, such as serotonin transporters and 5-HT2A receptors, following different degrees of recreational use of MDMA and psychedelics [41]. ...
Psychedelic therapy (PT) is an emerging paradigm with great transdiagnostic potential for treating psychiatric disorders, including depression, addiction, post-traumatic stress disorder, and potentially others. ‘Classic’ serotonergic psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), which have a key locus of action at the 5-HT2A receptor, form the main focus of this movement, but substances including ketamine, 3,4-Methylenedioxymethamphetamine (MDMA) and ibogaine also hold promise. The modern phase of development of these treatment modalities in the early 21st century has occurred concurrently with the wider use of advanced human neuroscientific research methods; principally neuroimaging. This can potentially enable assessment of drug and therapy brain effects with greater precision and quantification than any previous novel development in psychiatric pharmacology. We outline the major trends in existing data and suggest the modern development of PT has benefitted greatly from the use of neuroimaging. Important gaps in existing knowledge are identified, namely: the relationship between acute drug effects and longer-term (clinically-relevant) effects, the precise characterisation of effects at the 5-HT2A receptor and relationships with functional/clinical effects, and the possible impact of these compounds on neuroplasticity. A road-map for future research is laid out, outlining clinical studies which will directly address these three questions, principally using combined Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) methods, plus other adjunct techniques. Multimodal (PET/MRI) studies using modern PET techniques such as the 5-HT2A-selective ligand [11 C]Cimbi-36 (and other ligands sensitive to neuroplasticity changes) alongside MRI measures of brain function would provide a ‘molecular-functional-clinical bridge’ in understanding. Such results would help to resolve some of these questions and provide a firmer foundation for the ongoing development of PT.
... Psilocybin is a nonselective serotonin receptor agonist that can alter individuals' perceptions, moods, and cognitive processes (Nichols and Barker 2016). Termed a "classic psychedelic", psilocybin has been found to be associated with positive, long-term effects on healthy individuals' mindfulness (Madsen et al. 2020;McCulloch et al. 2021), connectedness (Lutkajtis 2021;Studerus et al. 2010), and ties to nature (Kettner et al. 2019). Although this research is in a nascent stage, each of these long-term effects offers a unique mechanism of action by which psilocybin could potentially decrease individuals' willingness to allocate their finite time to their employer. ...
Despite the recent and sharp rise in psychedelic research, few studies have investigated how classic psychedelic use relates to employees' work-related outcomes. This is surprising given that the increased use, decriminalization, and legalization of classic psychedelics in the United States (U.S.) has the potential to impact both employees and their organizations. Addressing this gap, the current study explores how employees' lifetime psilocybin use relates to the amount of overtime they work, thereby offering insight into what current trends in psilocybin use could mean for businesses. Using pooled, cross-sectional data from the National Survey on Drug Use and Health (2002-2014) on 217,963 adults employed in the U.S. full-time, this study tests whether lifetime psilocybin use is associated with employees' number of overtime hours worked in the past week. After adjusting for sociodemographics and other substance use, a significant negative association is found between employees' lifetime psilocybin use and the amount of overtime they reported working. Specifically, the findings suggest that lifetime psilocybin use in the U.S. full-time working population is associated with an estimated 44,348,400 fewer overtime hours worked per year and may help explain recent findings linking employees' lifetime psilocybin use to a reduction in sick leave taken.
... Madsen [27] disclosed a robust positive correlation between psilocybin, mood, and heightened states of mindfulness. The research shows that 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. ...
Nature created a mushroom-based compound known as psilocybin that can biochemically alter perception and affect mental anguish. Medical research shows that psilocybin activates the brain, engendering new cognition and awareness. Although psilocybin usage dates to ancient times, its contemporary medical usefulness is still in its infancy. This review discusses a potential breakthrough in natural medicine; psilocybin-based therapy may be a life-changing experience bringing hope to many suffering from mental anguish based on emotional and physical pain
... Adaptive changes in neuroticism, introversion, and openness are additionally supported by other areas of psychedelic research. For example, despite lacking formal therapeutic interventions, controlled laboratory studies, involving supportive monitoring from clinicians, have observed increases in openness in healthy subjects (Barrett & Griffiths, 2017;Carhart-Harris et al., 2016b;Griffiths et al., 2018;MacLean, Johnson, & Griffiths, 2011;Madsen et al., 2020). More mixed findings of increased conscientiousness and agreeableness have additionally been reported (Barrett & Griffiths, 2017;Schmid & Liechti, 2018). ...
Background:
Psilocybin Therapy (PT) is being increasingly studied as a psychiatric intervention. Personality relates to mental health and can be used to probe the nature of PT's therapeutic action.
Methods:
In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, over a core 6-week trial period. Five-Factor model personality domains, Big Five Aspect Scale Openness aspects, Absorption, and Impulsivity were measured at Baseline, Week 6, and Month 6 follow-up.
Results:
PT was associated with decreases in neuroticism (B = -0.63), introversion (B = -0.38), disagreeableness (B = -0.47), impulsivity (B = -0.40), and increases in absorption (B = 0.32), conscientiousness (B = 0.30), and openness (B = 0.23) at week 6, with neuroticism (B = -0.47) and agreeableness (B = 0.41) remaining decreased at month 6. Escitalopram was associated with decreases in neuroticism (B = -0.38), disagreeableness (B = -0.26), impulsivity (B = -0.35), and increases in openness (B = 0.28) and conscientiousness (B = 0.22) at week 6, with neuroticism (B = -0.46) remaining decreased at month 6. No significant between-condition differences were observed.
Conclusions:
Personality changes across both conditions were in a direction consistent with improved mental health. With the possible exception of trait absorption, there were no compelling between-condition differences warranting conclusions regarding a selective action of PT (v. escitalopram) on personality; however, post-escitalopram changes in personality were significantly moderated by pre-trial positive expectancy for escitalopram, whereas expectancy did not moderate response to PT.
... Generally, our findings are in line with anecdotes about individuals becoming more engaged and interested in aesthetic experiences after psychedelic use and expand upon earlier studies that used less refined measures of aesthetic experience (e.g., MacGlothin et al., 1967;Studerus et al., 2011). Given that openness to experience has been associated with enhanced aesthetic experience (Fayn et al., 2015;Silvia et al., 2015;Swami & Furnham, 2014), and that psychedelics have been shown to increase openness across a number of studies Erritzoe et al., 2018;Griffiths et al., 2018;MacLean et al., 2011;Madsen et al., 2020), it is possible that changes in openness may account for increases in aesthetic experience after psychedelic use. Silvia et al. (2015) suggested that openness to experience, although not generally seen as an emotional trait, is a propensity for awe-like experiences that include expanding one's typical ways of thinking about oneself and the world, and this lends itself to deeper aesthetic experiences. ...
Psychedelic drugs are currently being investigated for their potential to facilitate a variety of long-lasting psychological changes. One area of psychological functioning that has yet to be systematically investigated in psychedelic research regards aesthetic experiences. This is surprising given the notable acute changes in perception induced by the drugs as well as the wealth of anecdotal reports of individuals reporting increased engagement in aesthetic experiences after psychedelic use. The current study was designed to address this gap in the literature by administering a validated measure of aesthetic experience one-week before, one-week after, and one-month after participants (N = 54) attended an ayahuasca retreat center. Participants also completed surveys indexing the extent to which they endorsed mystical-type experiences, awe, and ego dissolution during their ayahuasca sessions to identify potential predictors of long-term change. We found that compared to baseline, participants exhibited increased levels of aesthetic experience at both follow-ups. Measures of acute drug effects did not predict changes in aesthetic experience. Although the study was limited by an open-label design, the results support anecdotal reports regarding changes in aesthetic experience after psychedelic use and provide important groundwork for future study.
... The study's findings suggest that lifetime use of classic psychedelics, specifically indoleamines, is positively associated with the psychological distress of unemployment for job seekers, without affecting the psychological distress of employed individuals. One reason why classic psychedelics may alter an individual's response to stressful or uncertain life phases (e.g., unemployment) is because these psychoactive substances have been found to have long-term effects on mindfulness (Madsen et al., 2020;McCulloch et al., 2021). Defined as "receptive attention to and awareness of present events and experience" (Brown, Ryan, & Creswell, 2007;p. ...
Background
Despite recent research linking lifetime classic psychedelic use to positive mental health outcomes, little work has explored the role played by classic psychedelics in healthy users' ability to cope with ordinary, yet stressful, life situations.
Aims
This study begins to fill this gap by exploring whether lifetime classic psychedelic use is associated with attenuated or exacerbated psychological distress in unemployed job seekers.
Methods
Drawing on openly-available data from the National Survey on Drug Use and Health (2013–2019) on 208,136 adults in the United States, this study tests whether lifetime classic psychedelic use interacts with employment status to predict differences in respondents' psychological distress experienced in the last 30 days.
Results
After adjusting for sociodemographics, health factors, and other substance use, unemployed job seekers with lifetime classic psychedelic use are found to report greater psychological distress relative to unemployed job seekers without lifetime psychedelic use. No differences in psychological distress based on lifetime classic psychedelic use were found in employed individuals.
Conclusion
This study suggests that lifetime classic psychedelic use (of indoleamines specifically) may exacerbate stressful phases of life and provides context to previous studies linking lifetime classic psychedelic use to predominantly positive mental health outcomes in healthy populations.
Declaration of interest/funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Furthermore, the author declares that there is no conflict of interest.
... [9] Studies of psilocybin in healthy volunteers have shown increases in positive or prosocial personality traits such as openness and extraversion and mindfulness, with these changes potentially persisting for months after ingestion. [10][11][12] Studies of the effect of psilocybin on depression and other stress related neuropsychiatric disorders have seen positive results. A phase II randomised control trial (RCT) compared psilocybin with escitalopram. ...
Classic psychedelics such as psilocybin, ketamine and lysergic acid diethylamide (LSD) are 5HT2A serotonin receptor agonists that produce individualised subjective affects. Today, public interest in psychedelic medicine has reached a fervour but the evidence for clinical benefit still lags. Psilocybin and psilocin are tryptophan based alkaloids found worldwide in mushrooms of the genera Psilocybe, Panaeolus, Conocybe, Gymnopilus, Stropharia, Pluteus and Panaeolina. This review addresses the current evidence base for psilocybin as a clinical medicine, the general chemistry and proposed mechanism of its therapeutic effect and future research directions for psilocybin based therapies.
... Although this presents regulation of 5HT2AR as a compelling mechanism, 5HT2AR availability returns to baseline a few days after psychedelic intervention in preclinical studies, which speaks against this effect as a mediator of lasting change (Buckholtz et al., 1990;Raval et al., 2021). PET studies in humans could not identify a reliable trend regarding neocortical 5HT2AR availability, although individual-specific relationships between 5HT2AR regulation and therapeutic outcomes were implied by Erritzoe et al. (2011) and Madsen et al. (2020). Further studies are necessary to evaluate the role of 5HT2AR modulation in therapeutic effects of psychedelics and explore alternative mechanisms besides downregulation, such as redistribution within the cell. ...
The potential of psychedelics to persistently treat substance use disorders is known since the 1960s. However, the biological mechanisms responsible for their therapeutic effects have not yet been fully elucidated. While it is known that serotonergic hallucinogens induce changes in gene expression and neuroplasticity, particularly in prefrontal regions, theories on how specifically this counteracts the alterations that occur in neuronal circuitry throughout the course of addiction are largely unknown. This narrative mini-review endeavors to synthesize well-established knowledge from addiction research with findings and theories regarding the neurobiological effects of psychedelics to give an overview of the potential mechanisms that underlie the treatment of substance use disorders with classical hallucinogenic compounds and point out gaps in the current understanding.
... However, LSD is an atypical psychedelic compound as it also exerts pleiotropic actions, especially on the 5-HT 1A subtype (8)(9)(10), at doses inducing psychoactive effects. Non-invasive neuroimaging offers the opportunity to investigate the modulation of psychedelic drugs on brain hemodynamics (11)(12)(13)(14)(15)(16)(17). Functional Magnetic Resonance Imaging (fMRI) studies have shown that LSD generates a significant increase in between-network cortico-cortical functional connections (18,19). ...
Background:
Lysergic acid diethylamide (LSD) is an atypical psychedelic compound exerting its effects through pleiotropic actions, mainly involving 1A/2A serotoninergic (5-HT) receptor subtypes. However, the mechanisms by which LSD promotes a reorganization of the brain's functional activity and connectivity are still partially unknown.
Methods:
Our study analyzed resting-state functional magnetic resonance imaging (rs-fMRI) data acquired from fifteen healthy volunteers undergoing LSD acute intake. A voxel-wise analysis investigated the alterations of the brain's intrinsic functional connectivity and local signal amplitude induced by LSD or by a placebo. Quantitative comparisons assessed the spatial overlap between these two indices of functional reorganization and the topography of receptor expression obtained from a publicly available collection of in-vivo, whole-brain atlases. Finally, linear regression models explored the relationships between changes in rs-fMRI and behavioral aspects of the psychedelic experience.
Results:
LSD elicited modifications of the cortical functional architecture that spatially overlapped with the distribution of serotoninergic receptors. Local signal amplitude and functional connectivity increased in regions belonging to the default mode and attention networks associated with high expression of 5-HT2A receptors. These functional changes correlate with the occurrence of simple and complex visual hallucinations. At the same time, a decrease in local signal amplitude and intrinsic connectivity was observed in limbic areas, which are dense with 5-HT1A receptors.
Conclusions:
This study provides new insights into the neural processes underlying the brain network reconfiguration induced by LSD. It also identifies a topographical relationship between opposite effects on brain functioning and the spatial distribution of different 5-HT receptors.
... This is supported by qualitative research by Amada et al. (2020), where multiple reports of psychedelic experiences mention decentring (or metacognitive awareness) as a mechanism for gaining insights. Furthermore, studies have suggested that psychedelics enhance mindfulness post-acutely (Qiu & Minda, 2021;Madsen et al, 2020;Soler et al., 2016;Sampedro et al., 2017) and users have also reported amplified mindfulness acutely (Watts et al, 2017;Belser et al, 2017;Amada et al, 2020) which lends some additional support to the link between mindfulness and insight. ...
Occasionally, a solution or idea arrives as a sudden understanding - an insight. Insight has been considered an "extra" ingredient of creative thinking and problem-solving. Here we propose that insight is central in seemingly distinct areas of research. Drawing on literature from a variety of fields, we show that besides being commonly studied in problem-solving literature, insight is also a core component in psychotherapy and meditation, a key process underlying the emergence of delusions in schizophrenia, and a factor in the therapeutic effects of psychedelics. In each case, we discuss the event of insight and its prerequisites and consequences. We review evidence for the commonalities and differences between the fields and discuss their relevance for capturing the essence of the insight phenomenon. The goal of this integrative review is to bridge the gap between the different views and inspire interdisciplinary research efforts for understanding this central process of human cognition.
... The following findings replicate those of previous research, showing psychedelics associated with: greater self-transcendence 17,19 , greater mindfulness 61,104,135,147,152 , greater self-compassion 135,153 , greater positive affect 84,141 , greater perceived health 8 , greater life satisfaction 24 , greater meaning in life 59,76 , less anxiety 63 , and depression 55,57 , and decreased levels of perceived physical pain 7,171 . All our findings align with previous research, whose reported findings were all replicated in the same direction. ...
Classical psychedelics appear efficacious in improving psychological well-being in randomized clinical trials, but their effects in the population at large are relatively unknown. In the present paper, which includes three studies conducted by online survey with a collective 3,157 participants, classical psychedelic users showed greater psychological strengths and well-being, and lower levels of distress, after controlling for demographic variables, respondents’ beliefs about the potential benefits of psychedelics, and their use of other psychoactive drugs. These benefits contrast with patterns for cannabis and alcohol users, both of whom showed comparatively maladaptive profiles. Reported relationships between psychedelic use and the combined index of psychological strengths was fully mediated by self-transcendence. We show an effect of motivation for psychedelic use, where those who reported a ‘growth’ motivation showed the most robustly adaptive psychological profile. Psychedelic users reported more lifetime meditation experience, and within psychedelic users, greater frequency of use correlated with greater hours of lifetime seated meditation practice. Meditation experience did not account for the differences in strengths, well-being, and distress. In these studies, psychedelic users showed an adaptive psychological pattern on a wider array of strengths than previously studied, which were not attributable to several salient covariates. While causality cannot be inferred from this study, findings align with and advance past research which provides evidence for the potential benefits associated with psychedelics.
... In particular, studies suggest that psychedelics may be an effective treatment for a variety of clinical issues, including treatment-resistant depression , cancer-related distress Ross et al., 2016), obsessive compulsive disorder (Moreno et al., 2006), substance use disorders (Bogenschutz et al., 2015(Bogenschutz et al., , 2018Johnson, Garcia-Romeu, & Griffiths, 2017), eating disorders (Spriggs, Kettner, & Carhart-Harris, 2020), and neurodegenerative disorders (Saeger & Olson, 2021). Psychedelics have also been posited to promote healthy lifestyle changes (Lutkajtis, 2021;Madsen et al., 2020;Teixeira et al., 2022), increase nature-relatedness (Lyons & Carhart-Harris, 2018) and foster environmental virtues (Kirkham & Letheby, 2022). Additionally, Gandy, Bonnelle, Jacobs, and Luke (2022) argue that psychedelics might act as potential catalysts of scientific creativity and insight. ...
This article reports on integration challenges that were experienced by nine individuals who attended a three-day legal psilocybin truffle retreat in the Netherlands. The study employed a qualitative phenomenological approach, using semi-structured interviews to gain an understanding of participants' ( n = 30) psilocybin experiences and their after-effects. While the study did not actively seek to measure integration issues or unexpected side effects, nine out of thirty participants (30%) spontaneously reported a post-experience integration challenge. These challenges included: mood fluctuations, ‘post-ecstatic blues’, disconnection from community, re-experiencing symptoms, spiritual bypass and perceived lack of support. Integration challenges were transient; they occurred immediately after the psilocybin experience (once the main psychedelic effects had worn off) and in the days and weeks following the retreat, and resolved with time. Integration challenges were also correlated with positive after-effects including long-term remission of significant health conditions. The experiences related in this article align with existing literature that describes the ‘spiritual emergency’ phenomenon; that is, the potential challenges that can arise after ecstatic experiences and how these challenges may be integral to the transformative potential of such experiences. We discuss the implications for psychedelic integration and harm reduction practices and for future psychedelic research.
... The related psychological construct of decentering is also a potentially important variable explaining the beneficial effects of psychedelic experiences (Soler et al., 2016). Emerging research suggest that the use of classic psychedelics may be associated with increased trait mindfulness (Franquesa et al., 2018;Madsen et al., 2020;Sampedro et al., 2017). Specifically, significant increases in nonreactivity and nonjudgment of internal experiences (two central aspects of trait and state mindfulness; Baer et al., 2008) and decentering are reported after episodes of psychedelic use (Murphy-Beiner & Soar, 2020;Soler et al., 2016;Uthaug et al., 2018). ...
Similarities between meditative and psychedelic states have long been recognized. Recently, parallels in the psychological mechanisms mediating the beneficial effects of mindfulness and psychedelic treatments—as well as their potential therapeutic complementarity—have been noted. However, empirical research in this area remains limited. Here, we explore the naturalistic use of meditation practices among psychedelic users recruited outside of treatment/retreat or research settings. Participants with ≥1 psychedelic drug experience(s) were included in an online survey. The majority (n = 875; 66.5%) indicated that they engaged in meditation, 39.4% (n = 345) of whom had combined psychedelic use with meditation practices on ≥1 occasion. The majority (74.2%; n = 256) provided written accounts describing their experiences of “psychedelic–meditation,” which were the basis for the present thematic analytic study. Six overarching themes were identified: (1) Compatibility Between Psychedelic and Meditative States; (2) Enhancement of the Meditative and Psychedelic Experience; (3) Beneficial Changes in Relating to the Internal and External World (encompassing acceptance, connection, peacefulness, and transformation); (4) Negative Effects of Combined Use; (5) Meditation as a Preparatory and Navigational Tool; and (6) Contextual Considerations (including reflections upon, and practical advice about, combining meditation and psychedelics). Participants’ experiences appear to support recent empirical and theoretical work on the parallels and complementarity between psychedelic drug effects and meditation. The findings identify facilitating conditions for combining psychedelics with meditation, which may have implications for their combined therapeutic use. For example, the use of meditation techniques might represent a “psychedelic-sparing” strategy, potentially enabling therapeutically important psychedelic effects to emerge at lower doses.
... Experiences of increased relaxation (e.g., feeling calm and grounded) among individuals with BD reported here suggest similar psilocybin effects as reported elsewhere. Psilocybin therapy has been associated with reduced distress, anxiety, and depression [25, [70][71][72], as well as increased mindfulness [73], which all could have contributed to improved relaxation and sleep in our population. ...
Objectives
People with bipolar disorder (BD) spend more time depressed than manic/hypomanic, and depression is associated with greater impairments in psychosocial functioning and quality of life than mania/hypomania. Emerging evidence suggests psilocybin, the psychoactive compound in “magic mushrooms,” is a promising treatment for unipolar depression. Clinical trials of psilocybin therapy have excluded people with BD as a precaution against possible adverse effects (e.g., mania). Our study centered the experiences of adults living with BD who consumed psilocybin-containing mushrooms, and aimed to (1) understand its subjective impacts on BD symptoms, (2) deepen understanding of Phase I survey results, and (3) elucidate specific contextual factors associated with adverse reactions in naturalistic settings.
Methods
Following an international survey (Phase I), follow-up interviews were conducted with 15 respondents (Phase II) to further understand psilocybin use among adults with BD. As part of a larger mixed-methods explanatory sequential design study, reflexive thematic analysis was used to elaborate findings.
Results
Three major themes containing sub-themes were developed. (1) Mental Health Improvements: (1.1) decreased impact and severity of depression, (1.2) increased emotion processing, (1.3) development of new perspectives, and (1.4) greater relaxation and sleep. (2) Undesired Mental Health Impacts: (2.1) changes in sleep, (2.2) increased mania severity, (2.3) hospitalization, and (2.4) distressing sensory experiences. (3) Salient Contextual Factors for psilocybin use included: (3.1) poly-substance use and psilocybin dose, (3.2) solo versus social experiences, and (3.3) pre-psilocybin sleep deprivation.
Conclusion
Our findings demonstrate both benefits and risks of psilocybin use in this population. Carefully designed clinical trials focused on safety and preliminary efficacy are warranted.
... Psilocybin is a psychedelic compound that has gained significant interest over the last decade with promising evidence for therapeutic efficacy in treating several neurological and neuropsychiatric disorders, Through stimulation of the serotonin 2A receptor (5-HT2AR), psilocin, the neuroactive metabolite of psilocybin, potently and acutely induces an altered state of consciousness ( Griffiths et al., 2006 ;Hasler et al., 2004 ;Madsen et al., 2019 ;Stenbaek et al., 2021 ). Psilocybin also induces rapid and lasting positive effects on mood, well-being, and personality Erritzoe et al., 2018 ;MacLean et al., 2011 ;Madsen et al., 2020 ). These intriguing effects precipitate the need to resolve associated and perhaps mediating neurobiological mechanisms. ...
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 time-varying functional connectivity implicates network-level connectivity motifs that may underlie acute and lasting behavioral and clinical effects.
Aim
Evaluate the association between resting-state time-varying functional connectivity (tvFC) 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 partly associated with motion 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. 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.
... 51 These approaches are believed to work in synergy with the effects of psilocybin 47 48 51-53 and are employed to promote motivation for change, openness and psychological flexibility, 54 skills for navigating altered states of consciousness and mindful awareness of the present moment. 55 Elements from MI and ACT are integrated as they both rest on the foundation of an egalitarian relationship between patient and therapist, and emphasise the value of the client's experience in contributing the change process. 56 Here, MI will be particularly useful in resolving ambivalence and help the patients become more aware of their intentions before the treatment. ...
Introduction:
Alcohol use disorder is a difficult-to-treat psychiatric disorder and a major burden on public health. Existing treatment efficacy is moderate, and relapse rates are high. Preliminary findings suggest that psilocybin, a psychedelic compound, can safely and reliably occasion highly meaningful experiences that may spur a positive change in drinking behaviour when administered in a therapeutic context. However, the efficacy of a single psilocybin administration and its potential neurobiological underpinnings still remain unknown.
Methods and analysis:
To establish efficacy, we will investigate the effects of psilocybin-assisted therapy versus placebo in a randomised, double-blinded, placebo-controlled 12-week clinical trial. Ninety treatment-seeking patients, aged 20-70 years, diagnosed with alcohol use disorder will be recruited from the community via advertisement and referrals from general practitioners or specialised treatment units. The psilocybin or placebo will be administered in accordance with a protocol for psychological support before, during and after the dosing. Outcome assessments will be carried out 1, 4, 8 and 12 weeks postdosing. The primary outcome is reduction in the percentage of heavy drinking days from baseline to follow-up at 12 weeks. Key secondary outcomes are as follows: (1) total alcohol consumption, (2) phosphatidyl-ethanol, an objective biomarker for alcohol, (3) plasma psilocin, the active metabolite, to establish a possible therapeutic range, (4) the acute subjective drug experience as a possible predictor of treatment outcome and (5) neuronal response to alcohol cues and cognitive flexibility within corticostriatal pathways by use of functional MR brain imaging 1-week postdosing.
Ethics and dissemination:
Ethical approval has been obtained from the Committee on Health Research Ethics of the Capital Region of Denmark (H-20043832). All patients will be provided oral and written information about the trial before screening. The study results will be disseminated by peer-review publications and conference presentations.
Trial registration number:
EudraCT 2020-000829-55 and NCT05416229.
... A.E. Calder and G. Hasler circuits originating in the PFC [141,142], and ayahuasca and psilocybin have been shown to promote certain aspects of cognitive flexibility [143][144][145][146][147]. Regular ayahuasca users additionally perform better on tests of behavioral inhibition, cognitive flexibility, working memory, and executive functioning [147]. Ayahuasca and psilocybin have also been shown to increase mindfulness, one form of attentional regulation for which the PFC, but also the ACC is essential [13,58,143,[148][149][150]. It is possible that dendritic growth in PFC and ACC neurons is responsible for these effects [59]. ...
Classic psychedelics, such as LSD, psilocybin, and the DMT-containing beverage ayahuasca, show some potential to treat depression, anxiety, and addiction. Importantly, clinical improvements can last for months or years after treatment. It has been theorized that these long-term improvements arise because psychedelics rapidly and lastingly stimulate neuroplasticity. The focus of this review is on answering specific questions about the effects of psychedelics on neuroplasticity. Firstly, we review the evidence that psychedelics promote neuroplasticity and examine the cellular and molecular mechanisms behind the effects of different psychedelics on different aspects of neuroplasticity, including dendritogenesis, synaptogenesis, neurogenesis, and expression of plasticity-related genes (e.g., brain-derived neurotrophic factor and immediate early genes). We then examine where in the brain psychedelics promote neuroplasticity, particularly discussing the prefrontal cortex and hippocampus. We also examine what doses are required to produce this effect (e.g., hallucinogenic doses vs. “microdoses”), and how long purported changes in neuroplasticity last. Finally, we discuss the likely consequences of psychedelics’ effects on neuroplasticity for both patients and healthy people, and we identify important research questions that would further scientific understanding of psychedelics’ effects on neuroplasticity and its potential clinical applications.
... For example, social cognitive interventions such as social skills training helps teach individuals how to interact with peers by providing explicit instructions and opportunities to develop or improve social interaction, social performance, and interpersonal skills and has been effective in schizophrenia and ASD [226][227][228][229]. Administering social cognitive interventions with recoveryoriented individual and group therapy that targets dysfunctional socialization attitudes or behaviours [230][231][232] could have further benefits than psychotherapy alone. Proof-of-concept pharmacotherapy-aided approaches have been extended to other practices such as mindfulness as well with promising results [233][234][235]. In addition, aerobic exercise has pro-social cognitive effects [236] and music therapy activates cortical regions and improves social cognition and behaviour in children with ASD and might be usefully combined with social cognitive interventions [237][238][239][240]. ...
Social behaviour is an essential component of human life and deficits in social function are seen across multiple psychiatric conditions with high morbidity. However, there are currently no FDA-approved treatments for social dysfunction. Since social cognition and behaviour rely on multiple signalling processes acting in concert across various neural networks, treatments aimed at social function may inherently require a combinatorial approach. Here, we describe the social neurobiology of the oxytocin and endocannabinoid signalling systems as well as translational evidence for their use in treating symptoms in the social domain. We leverage this systems neurobiology to propose a network-based framework that involves pharmacology, psychotherapy, non-invasive brain stimulation and social skills training to combinatorially target trans-diagnostic social impairment. Lastly, we discuss the combined use of oxytocin and endocannabinoids within our proposed framework as an illustrative strategy to treat specific aspects of social function. Using this framework provides a roadmap for actionable treatment strategies for neuropsychiatric social impairment.
This article is part of the theme issue ‘Interplays between oxytocin and other neuromodulators in shaping complex social behaviours’.
... 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. ...
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.
... 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). ...
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.
... In an extension of this study, Mertens et al. (2019) explained that changes in the functional connectivity between the amygdala and ventromedial prefrontal cortex are the proof of the revival of emotional responsiveness after psychedelic therapy. In a support of this finding, another group of researchers reported that psilocybin therapy affected the change in patients' mindfulness and openness based on the individual change in 5-HT2AR (serotonin receptor) (Madsen et al., 2020). According to the authors, this might represent the possible mechanism of psilocybin's long-term positive effects. ...
Mushrooms have been used in traditional medicine for centuries, although only relatively recently they have become a subject of intensive studies as a source of potential drugs and products that could be used in the treatment of many disorders. Mushroom-forming fungi are shown to produce a vast number of unique metabolites that exhibit various biological effects; these include polysaccharides, terpenoids, polyketides, and amino compounds. The most studied use of mushrooms is for cancer treatment; mushrooms are a source of both compounds with direct antitumor effect, as well as immunomodulating polysaccharides (particularly β-glucans), which have been shown to stimulate the host's immune system and immunological response to cancer cells. Glucan-based mushroom products, such as lentinan from Lentinula edodes and PSK from Trametes versicolor, are clinically proven to be beneficial in the treatment of certain cancer types. Mushrooms are also known to be a source of potent cytotoxic compounds, such are illudins, clitocine, and ganoderic acids. As microbial resistance to antibiotics is becoming more and more prevalent, mushrooms are seen as a good source of new classes of compounds with antimicrobial activity, some of which, such as pleuromutilin, have led to the synthesis of new drugs that have been recently approved for use in humans. Psychedelic mushrooms and psilocybin have also been studied as breakthrough therapies for depression. Mushroom consumption has been associated with beneficial effects on sugar and lipid metabolism, which led to increased interest in research of mushroom product use in the treatment of metabolic disorders. Although mushrooms are often presumed to be a rich source of certain compounds with vitamin activity, this may not be the case. However, mushroom production can be manipulated to obtain higher yields of physiologically active compounds, such as vitamin D.
... 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). ...
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). ...
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.
... Small clinical trials over the past 15 years with psilocybin and ayahuasca provide intriguing preliminary evidence for efficacy in treating major depressive disorder (including otherwise treatmentresistant individuals) , 2018Davis et al., 2020;de Osório et al., 2015;Palhano-Fontes et al., 2019), obsessive compulsive disorder (Moreno et al., 2006), smoking addiction (Johnson et al., 2017), alcohol abuse (Bogenschutz et al., 2015), demoralisation (Anderson et al., 2020), and depressive and anxiety symptoms associated with diagnosis of life-threatening diseases (Gasser et al., 2015(Gasser et al., , 2014Griffiths et al., 2016;Grob et al., 2011;Ross et al., 2016). Remarkably, there is also preliminary clinical evidence that psychedelics can produce lasting positive psychological effects in healthy individuals (Barrett et al., 2020a;Griffiths et al., 2011;Kettner et al., 2021;MacLean and Griffiths, 2013;Madsen et al., 2020;Stenbaek et al., 2020;Uthaug et al., 2019Uthaug et al., , 2018. ...
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.
... Other measures quantify the capacities to be aware of mental events, such as thoughts, feelings, and perceptions, as they happen, and to adopt a nonjudgemental or non-reactive stance towards them. Several studies have found that a single psychedelic experience, without any accompanying mindfulness training, can increase these mindfulness-related capacities for anywhere from one week to three months (Heuschkel & Kuypers, 2020;Madsen et al., 2020). In some cases, these increases have been found to correlate with therapeutic effects, such as reductions in psychiatric symptoms (González et al., 2020;Mian et al., 2020). ...
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” (serotonergic) 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. I begin the précis by summarizing material from chapters two and three of the book, which review evidence for the therapeutic efficacy of psychedelics, and the facts about their clinical use that prompt the Comforting Delusion Objection. I then summarize materials from chapters four and five of the book, which argue that psychedelic therapy works neither by experience-independent processes of neuroplasticity, nor by inducing non-naturalistic metaphysical ideations, but by altering mental representations of the self. Next, I summarise the specific, speculative account of how this might work that is developed in chapters six and seven of the book. This account is based on the predictive processing theory of brain function and the self-binding theory of self-representation. Chapters eight and nine of the book argue, on the basis of this account, that psychedelic therapy can have significant epistemic and spiritual benefits that are compatible with a naturalistic worldview. I summarize this material, and then, finally, the overall conclusions about psychedelic therapy drawn in the tenth and final chapter of the book.
... 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). ...
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.
Psilocybin is the main psychoactive compound found in hallucinogenic/magic mushrooms and can bind to both serotonergic and tropomyosin receptor kinase b (TrkB) receptors. Psilocybin has begun to show efficacy for a range of neuropsychiatric conditions, including treatment‐resistant depression and anxiety disorders; however, neurobiological mechanisms are still being elucidated. Clinical research has found that psilocybin can alter functional connectivity patterns in human brains, which is often associated with therapeutic outcomes. However, preclinical research affords the opportunity to assess the potential cellular mechanisms by which psilocybin may exert its therapeutic effects. Preclinical rodent models can also facilitate a more tightly controlled experimental context and minimise placebo effects. Furthermore, where there is a rationale, preclinical researchers can investigate psilocybin administration in neuropsychiatric conditions that have not yet been researched clinically. As a result, we have systematically reviewed the knowledge base, identifying 82 preclinical studies which were screened based on specific criteria. This resulted in the exclusion of 44 articles, with 34 articles being included in the main review and another 2 articles included as Supporting Information materials. We found that psilocybin shows promise as a lead candidate molecule for treating a variety of neuropsychiatric conditions, albeit showing the most efficacy for depression. We discuss the experimental findings, and identify possible mechanisms whereby psilocybin could invoke therapeutic changes. Furthermore, we critically evaluate the between‐study heterogeneity and possible future research avenues. Our review suggests that preclinical rodent models can provide valid and translatable tools for researching novel psilocybin‐induced molecular and cellular mechanisms, and therapeutic outcomes.
Introduction: The classic psychedelic psilocybin, found in some mushroom species, has received renewed interest in clinical research, showing potential mental health benefits in preliminary trials. Naturalistic use of psilocybin outside of research settings has increased in recent years, though data on the public health impact of such use remain limited.
Methods: This prospective, longitudinal study comprised six sequential automated web-based surveys that collected data from adults planning to take psilocybin outside clinical research: at time of consent, 2 weeks before, the day before, 1–3 days after, 2–4 weeks after, and 2–3 months after psilocybin use.
Results: A sample of 2,833 respondents completed all baseline assessments approximately 2 weeks before psilocybin use, 1,182 completed the 2–4 week post-use survey, and 657 completed the final follow-up survey 2–3 months after psilocybin use. Participants were primarily college-educated White men residing in the United States with a prior history of psychedelic use; mean age = 40 years. Participants primarily used dried psilocybin mushrooms (mean dose = 3.1 grams) for “self-exploration” purposes. Prospective longitudinal data collected before and after a planned psilocybin experience on average showed persisting reductions in anxiety, depression, and alcohol misuse, increased cognitive flexibility, emotion regulation, spiritual wellbeing, and extraversion, and reduced neuroticism and burnout after psilocybin use. However, a minority of participants (11% at 2–4 weeks and 7% at 2–3 months) reported persisting negative effects after psilocybin use (e.g., mood fluctuations, depressive symptoms).
Discussion: Results from this study, the largest prospective survey of naturalistic psilocybin use to date, support the potential for psilocybin to produce lasting improvements in mental health symptoms and general wellbeing.
The serotonin 2A receptor (5HT 2A R) and personality factors indexing stress coping mechanisms are implicated in the pathophysiology of depression. Cross-sectional studies performed in individuals with high familial risk for depression suggest that the coupling between 5-HT 2A R and the inward-directed facets of neuroticism may be associated with a risk for depression. This study aimed to build a risk model for first-episode depression in healthy individuals based on serotonergic and personality biomarkers and utilizing up to 19 years of longitudinal data on depression. Such a model could have potential implications for identifying high-risk individuals for early preventative interventions. In this study, 131 healthy volunteers completed an [ ¹⁸ F]altanserin positron emission tomography scan to measure 5-HT 2A R binding and personality assessment of neuroticism, as part of research studies conducted between 2000-2008. Following study participation, information on future diagnoses of depression was obtained until 2019 from the Danish National Health Registers. Cause-specific Cox regression was used to investigate the hypothesis that neocortical 5-HT 2A R binding in interaction with the inward-directed facets of neuroticism (neuroticism inward ) would be associated with a risk of developing depression. The study found a significant positive interaction between neocortical 5HT 2A R binding and neuroticism inward (p=0.018) such that individuals with high 5-HT 2A R binding and high neuroticism inward scores had the highest risk for developing depression. In conclusion, the study provides a novel risk model for first-episode depression. Healthy individuals who have the personality phenotype of high neuroticism inward along with the serotonergic phenotype of high 5-HT 2A R binding may be at the greatest risk for developing depression in the future.
Eine erfolgreiche Therapie psychischer Störungen ist angesichts des häufig vorhandenen Leidensdrucks der Betroffenen sehr wichtig. Da anerkannte pharmazeutische und psychotherapeutische Ansätze leider nicht für alle Patient:innen zur erwünschten Besserung ihres Leidens führen, findet intensive Forschung zu ergänzenden oder alternativen Behandlungsmethoden statt. Besonders vielversprechend zeigte sich zuletzt die Psilocybin-gestützte Psychotherapie, die in den USA deshalb für klinische Studien mit größeren Stichproben als bisher zugelassen wurde. Psilocybin gehört zu den Psychedelika und beeinflusst in seiner Wirkung das psychische Erleben. Bei der gestützten Therapie wird Psilocybin in kontrollierten Dosen unter medizinischer Aufsicht verabreicht. In den bisher durchgeführten Studien konnten bereits nach einer, bis wenigen Einnahmen längerfristige positive Effekte in Hinblick auf die jeweiligen Störungsbilder gezeigt werden. Um ein besseres Verständnis der potenziellen therapeutischen Mechanismen zu ermöglichen, sollen in diesem Artikel zunächst Erkenntnisse zur Wirkweise von Psilocybin auf neurobiologischer und psychologischer Ebene vorgestellt werden. Anschließend soll die Analyse der bisher durchgeführten klinischen Studien mit einer Anwendung von Psilocybin bei Patient:innen helfen, das Potential der Psilocybin-gestützten Psychotherapie für verschiedene Störungsbilder besser einschätzen zu können.
Psychedelic drugs are currently being investigated for their potential to facilitate a variety of long-lasting psychological changes. One area of psychological functioning that has yet to be systematically investigated in psychedelic research regards aesthetic experiences. This is surprising given the notable acute changes in perception induced by the drugs as well as the wealth of anecdotal reports of individuals reporting increased engagement in aesthetic experiences after psychedelic use. The current study was designed to address this gap in the literature by administering a validated measure of aesthetic experience one-week before, one-week after, and one-month after participants (N = 54) attended an ayahuasca retreat center. Participants also completed surveys indexing the extent to which they endorsed mystical-type experiences, awe, and ego dissolution during their ayahuasca sessions to identify potential predictors of long-term change. We found that compared to baseline, participants exhibited increased levels of aesthetic experience at both follow-ups. Measures of acute drug effects did not predict changes in aesthetic experience. Although the study was limited by an open-label design, the results support anecdotal reports regarding changes in aesthetic experience after psychedelic use and provide important groundwork for future study.
This article assesses the right to privacy as a ground for challenging the constitutionality of the criminalisation of psilocybin mushrooms. In doing so, it discusses the right to privacy as found in section 14 of the Constitution of the Republic of South Africa, 1996 (Constitution). Drawing on Constitutional Court case law, the article argues that the right to privacy is a fundamental right that deserves paramount protection, even in instances where individuals engage in illicit activities within the confines of their personal realm of privacy. Accordingly, the prohibiting laws, notably the Drugs and Drug Trafficking Act 140 of 1992 and the Medicines and Related Substances Act 101 of 1965, do prima facie limit an individual's right to privacy, and therefore an analysis in terms of section 36 of the Constitution is necessary. A section-36 limitations analysis is accordingly presented, through which it is concluded that the nature and importance of the limited right outweighs the importance and purpose of the criminalisation. This paper argues that the current articles of legislation, which criminalise psilocybin mushrooms, are not justifiable, in that they unjustifiably limit the right to privacy. As such, the criminalisation of psilocybin mushrooms falls short of the standards implemented in section 36 of the Constitution and is concluded to be unconstitutional.
Background: The research for underlying mechanisms of psychedelic experiences continues. In addition to the established concept of peak experience, which encompasses various aspects of positive experience, insight is receiving increasing attention as a possible mechanism of psychedelic interventions. Potential synergies with mindfulness-based therapy components are part of current scientific discussion, including the relevance of a mindfulness-based preparation phase for psychedelic experiences. Objective: The aim of this study was to differentiate aspects of psychedelic experiences more precisely to gain a greater understanding of possible underlying mechanisms. Furthermore, this study investigated the prediction of psychedelic experiences through mindfulness practice and its potentially associated skills: absorption and mindfulness. Methods: A retrospective online survey was conducted, 209 subjects were asked about various aspects of their last psychedelic experience that had happened in the last twelve months and the persisting changes through the experience. In addition, mindfulness practice prior to the experience in question, mindfulness and absorption were assessed. The resulting data was analysed through structural equation modelling. Results: absorption indirectly predicted persisting positive changes via aspects of positive experience and insight. Direct effects of mindfulness and absorption emerged when predicting persisting negative changes; in addition, an indirect effect of mindfulness was mediated by the occurrence of challenging experiences and an indirect effect of absorption was mediated by insight. Conclusions: We conclude that insight during the psychedelic experience represents a significant predictor of persisting positive and negative changes, thus providing clues to an underlying mechanism of psychedelic interventions. Absorption appears to facilitate deeper immersion, thereby increasing the positive potential of the psychedelic experience, while also representing a risk factor for persisting negative changes. Mindfulness seems to reduce persistent negative changes; this relationship is explained in part by a reduced occurence of challenging experiences.
Recent studies have demonstrated the promise of psilocybin therapies in creating positive changes for those with poor mental health across multiple diagnostic categories, including major depressive disorder (MDD), end-of-life anxiety, and obsessive-compulsive disorder (OCD). While there may be a large population that is eligible to participate in psilocybin therapy based on psychiatric diagnosis and medical clearance, little attention has been given to intrapersonal and interpersonal factors that might influence patient's readiness (i.e., eligibility and capacity) for psychedelic interventions. This paper proposes that readiness assessment includes both intrapersonal and interpersonal factors in order to improve safety, patient care, and treatment outcomes. While at the present time a reliable and valid instrument has not been developed, we propose that three specific areas of focus - patient presentation, therapeutic alliance, and patient safety - may be used to establish a patient's readiness for psilocybin therapy, thus increasing therapy optimization and personalization.
In this paper, we present the development of the Altered States Database (ASDB), an open-science project based on a systematic literature review. The ASDB contains psychometric questionnaire data on subjective experiences of altered states of consciousness (ASC) induced by pharmacological and non-pharmacological methods. The systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Scientific journal articles were identified through PubMed and Web of Science. We included studies that examined ASC using the following validated questionnaires: Altered States of Consciousness Rating Scale (APZ, 5D-ASC, 11-ASC), Phenomenology of Consciousness Inventory (PCI), Hallucinogen Rating Scale (HRS), or Mystical Experience Questionnaire (MEQ30). The systematic review resulted in the inclusion of a total of 165 journal articles, whereof questionnaire data was extracted and is now available on the Open Science Framework (OSF) website (https://osf.io/8mbru) and on the ASDB website (http://alteredstatesdb.org), where questionnaire data can be easily retrieved and visualized. This data allows the calculation of comparable psychometric values of ASC experiences and of dose-response relationships of substances inducing ASC.
Background
Psilocybin-induced mystical-type experiences are associated with lasting positive psychological outcomes. Recent studies indicate that trait mindfulness is increased 3 months after psilocybin intake, preceded by decreases in neocortical serotonin 2A receptor (5-HT 2A R) binding. However, the association between psilocybin-induced mystical-type experiences and subsequent changes in trait mindfulness remains unexplored, as does the association between pre-drug trait mindfulness and 5-HT 2A R binding in the healthy brain.
Aim
We evaluated whether psilocybin induced lasting increases in trait mindfulness in healthy volunteers, and whether the mystical-type experience was associated with this increase. We further examined the association between pre-drug trait mindfulness and 5-HT 2A R binding in neocortex and selected frontolimbic regions.
Materials and methods
Forty-six medium-high dose psilocybin sessions were conducted in 39 healthy individuals. The mystical-type experience was measured with the Mystical Experience Questionnaire (MEQ) at the end of the session. Trait mindfulness was measured using the Mindful Attention and Awareness Scale (MAAS) at baseline and 3 months after the psilocybin session. Thirty-two of the participants completed pre-drug [ ¹¹ C]-Cimbi-36 positron emission tomography (PET) to assess 5-HT 2A R binding in neocortex and, post-hoc , in the frontolimbic regions amygdala, frontal cortex, and anterior cingulate cortex.
Results
The MAAS score was significantly increased at 3-month follow-up ( p = 3.24 × 10 –6 ), a change positively associated with the MEQ score ( p = 0.035). Although the association between pre-drug MAAS score and neocortex 5-HT 2A R binding was not significant ( p = 0.24), post-hoc analyses revealed a significant negative association between MAAS and right amygdala 5-HT 2A R binding (p FWER = 0.008).
Conclusion
We here show that lasting changes in trait mindfulness following psilocybin administration are positively associated with intensity of the mystical-type experience, suggesting that the acute phenomenology of psilocybin facilitates a shift in awareness conducive for mindful living. We furthermore show that higher pre-drug trait mindfulness is associated with reduced 5-HT 2A R binding in the right amygdala.
Lifetime psychedelic substance use has previously been linked to nature relatedness and pro-environmental behaviour. Yet, participants’ responses to the self-report measures in these studies may have been affected by stereotypical associations or confirmation bias. We therefore re-examined this link by measuring three pro-environmental dependent variables: nature relatedness, concerns about climate change, and objective knowledge about climate change. Additionally assessing lifetime experience with 30 psychoactive substances, we collected an international convenience sample for an online survey ( n = 641), Controlling for age, educational attainment, and covariation in substance use indicators, psychedelic use (primarily the use of psilocybin) predicted objective knowledge about climate change directly, and indirectly via nature relatedness. Further, it predicted concern about climate change indirectly via nature relatedness. The results suggest that the relationship of psychedelics with pro-environmental variables is not due to psychological biases, but manifests in variables as diverse as emotional affinity towards nature as well as knowledge about climate change.
Psilocybin is a psychedelic substance approaching clinical use. The drug has long-lasting effects after single or multiple administrations and enhances structural plasticity in the brain. Little is known if the plasticity inducing effects of psilocybin could be timed to other treatments and promote a larger effect. We investigated the effect of psilocybin on cultured mouse hippocampal neurons, examining the plasticity promoting effects from 5 min to 72 h post-treatment. We found robust effects on pre- and postsynaptic (Piccolo and Homer1) protein expression 1-3 h following treatment. Presynaptic Synapsin-1 expression mirrored these findings, with peak expression 72 h post-treatment. Our studies suggest psilocybin opens a window of plasticity that rapidly normalizes. As psilocybin has been shown to have an effect treating diseases (e.g. depression and cluster headache) linked with inflammation, we used an immortalized microglia cell line (IMG) to demonstrate its anti-inflammatory effects against a lipopolysaccharide (LPS) challenge (we show reduced tumor necrosis factor-alpha (TNF-α) secretion). Altogether, our studies show discrete and acute cell type specific effects of psilocybin that provides insight into its mechanisms of action and potential therapeutic value.
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.
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.
Recent research found lasting increases in personality trait Openness in healthy individuals and patients after administration of the serotonin 2A receptor (5‐HT2AR) agonist psilocybin. However, no studies have investigated whether 5‐HT2AR availability as imaged using positron emission tomography (PET) is associated with this trait. In 159 healthy individuals (53 females), the association between 5‐HT2AR binding in neocortex imaged with [18F]altanserin or [11C]Cimbi‐36 PET and personality trait Openness was investigated using linear regression models. In these models the influence of sex on the association was also investigated. Trait Openness was assessed with the NEO Personality Inventory‐Revised. No significant associations between neocortical 5‐HT2AR binding and trait Openness were found for [18F]altanserin (p = 0.5) or [11C]Cimbi‐36 (p = 0.8). Pooling the data in a combined model did not substantially change our results (p = 0.4). No significant interactions with sex were found (p > 0.35). Our results indicate that differences in 5‐HT2AR availability are not related to variations in trait Openness in healthy individuals. Although stimulation of the 5‐HT2AR with compounds such as psilocybin may contribute to long‐term changes in trait Openness, there is no evidence in favor of an association between 5‐HT2AR and trait Openness.
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.
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.
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.
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
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.
Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes.
Trial Registration
ClinicalTrials.gov identifier: NCT00465595
Background:
Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression.
Methods:
In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks.
Results:
Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60-80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression.
Conclusions:
In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress.
Trial registration:
ClinicalTrials.gov Identifier: NCT00957359.
Significance statement:
We present a high-resolution PET and MR-based human brain atlas of important serotonin receptors and the transporter. The regional PET-derived binding measures correlate strongly with the corresponding autoradiography protein levels. The strong correlation enables the transformation of the PET-derived human brain atlas into a protein density map of the 5-HT system. Next, we compared the regional receptor/transporter protein densities to mRNA levels, and uncovered unique associations between protein expression and density at high detail. This new in vivo neuroimaging atlas of the 5-HT system does not only provide insight in the human brain's regional protein synthesis, transport and density, but also represents a valuable source of information for the neuroscience community as a comparative instrument to assess brain disorders.
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.
Background:
Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression.
Methods:
In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin's effects. Patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797.
Findings:
Psilocybin's acute psychedelic effects typically became detectable 30-60 min after dosing, peaked 2-3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0-1 scale) was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week (mean QIDS difference -11·8, 95% CI -9·15 to -14·35, p=0·002, Hedges' g=3·1) and 3 months (-9·2, 95% CI -5·69 to -12·71, p=0·003, Hedges' g=2) after high-dose treatment. Marked and sustained improvements in anxiety and anhedonia were also noted.
Interpretation:
This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach.
Funding:
Medical Research Council.
The 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
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.
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.
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.
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.
[(11)C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT2A) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [(11)C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT2A receptors with [(11)C]Cimbi-36 PET. The two-tissue compartment model using arterial input measurements provided the most optimal quantification of cerebral [(11)C]Cimbi-36 binding. Reference tissue modeling was feasible as it induced a negative but predictable bias in [(11)C]Cimbi-36 PET outcome measures. In five subjects, pretreatment with the 5-HT2A receptor antagonist ketanserin before a second PET scan significantly decreased [(11)C]Cimbi-36 binding in all cortical regions with no effects in cerebellum. These results confirm that [(11)C]Cimbi-36 binding is selective for 5-HT2A receptors in the cerebral cortex and that cerebellum is an appropriate reference tissue for quantification of 5-HT2A receptors in the human brain. Thus, we here describe [(11)C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT2A receptors in the human brain.Journal of Cerebral Blood Flow & Metabolism advance online publication, 30 April 2014; doi:10.1038/jcbfm.2014.68.
The serotonin 5-HT2A receptor is a primary target of psychedelic hallucinogens such as lysergic acid diethylamine, mescaline and psilocybin, which reproduce some of the core symptoms of schizophrenia. An incompletely resolved paradox is that only some 5-HT2A receptor agonists exhibit hallucinogenic activity, whereas structurally related agonists with comparable affinity and activity lack such a psychoactive activity. Using a strategy combining stable isotope labeling by amino acids in cell culture and enrichment of peptide samples in phosphorylated peptides by hydrophilic interaction liquid chromatography followed by immobilized metal affinity chromatography, we compared the phosphoproteome in HEK-293 cells transiently expressing the 5-HT2A receptor and exposed to either vehicle or the synthetic hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) or the non-hallucinogenic 5-HT2A agonist lisuride. Among the 5,995 identified phosphorylated peptides, 16 sites were differentially phosphorylated upon exposure of cells to DOI vs. lisuride. These include a serine (Ser280) located in the third intracellular loop of the receptor, a region important for desensitization. Specific phosphorylation of Ser280 by hallucinogens compared with non-hallucinogenic agonists was further validated by quantitative mass spectrometry on purified receptor and by using a phosphosite specific antibody. Administration of DOI, but not lisuride, to mice also enhanced 5-HT2A receptor phosphorylation at Ser280 in prefrontal cortex. Moreover, hallucinogens induced less pronounced desensitization of receptor-operated signaling in HEK-293 cells and neurons than exposure to non-hallucinogenic agonists. Mutation of Ser280 into aspartate (to mimic phosphorylation) reduced receptor desensitization by non-hallucinogenic agonists, while its mutation to alanine increased the ability of hallucinogens to desensitize the receptor. This study reveals biased phosphorylation of 5-HT2A receptor by hallucinogenic vs. non-hallucinogenic agonists, which underlies their distinct capacity to desensitize the receptor.