Carhart-Harris, R., Giribaldi, B., Watts, R., Baker-Jones, M., Murphy-Beiner, A., Murphy, R., … Nutt, D. J.. (2021). Trial of Psilocybin versus Escitalopram for Depression. New England Journal of Medicine
Plain numerical DOI: 10.1056/nejmoa2032994
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“Abstract background psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking. methods in a phase 2, double-blin…”
Al-Naggar, R. A., Alshaikhli, H., & Erlam, G.. (2021). Effectiveness of psilocybin on depression: A qualitative study. Electronic Journal of General Medicine
Plain numerical DOI: 10.29333/ejgm/10862
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“Introduction: psilocybin mushroom use is well documented in spiritual and religious ceremonies globally. this drug is now the most popular in europe and the usa. objective: the objective of this study is to explore the experiences and effects of psilocybin on patients with depression and anxiety. method: a qualitative study was conducted interviewing ten participants currently taking psilocybin while experiencing depression and/or anxiety. ethical approval was obtained from the university ethics committee. participants were recruited via social media and groups are known to have used psilocybin for the treatment of anxiety and/or depression. participants were informed of study aims and consent was obtained before interviews commenced. confidentiality was maintained throughout this study. interviews began with informing participants that psilocybin may be effective in the management of depression. initially, information around the way treatment with psilocybin was obtained was sought. this was followed by queries around the effects of the drug in terms of experiences both during and after treatment. finally, participants were asked to outline the positive effects of psilocybin on their lives. results: the data were thematically coded using grounded theory as an underpinning philosophical paradigm. emerging themes included enhancement of smell, vision, hearing, and taste sensations. another theme emerging was the experience of being ‘connected with the universe’ while on the drug. additionally, participants reported a stabilization of mood, an increase in optimism and emotional control, and a healthier emotional connection with others. most also felt an increase in comfort, peace and calmness. another theme that emerged centered on the mechanism of action of psilocybin. participants stated that this substance seemed to ‘make new connections in their brain,’ resulting in new perspectives. some participants felt this resulted in a calming influence on the mind and body. this aligns with research showing that psilocybin works by changing the thinking and improving information processing. conclusion: psilocybin has promising effects on the patients with depression/anxiety even after a single dose. psilocybin is safe but the administration should be guided by a health professional to yield safe and positive outcomes.”
Heuschkel, K., & Kuypers, K. P. C.. (2020). Depression, Mindfulness, and Psilocybin: Possible Complementary Effects of Mindfulness Meditation and Psilocybin in the Treatment of Depression. A Review. Frontiers in Psychiatry
Plain numerical DOI: 10.3389/fpsyt.2020.00224
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“Depression is a major public health problem that affects approximately 4.4% of the global population. since conventional pharmacotherapies and psychotherapies are only partially effective, as demonstrated by the number of patients failing to achieve remission, alternative treatments are needed. mindfulness meditation (mm) and psilocybin represent two promising novel treatments that might even have complementary therapeutic effects when combined. since the current literature is limited to theoretical and empirical underpinnings of either treatment alone, the present review aimed to identify possible complementary effects that may be relevant to the treatment of depression. to that end, the individual effects of mm and psilocybin, and their underlying working mechanisms, were compared on a non-exhaustive selection of six prominent psychological and biological processes that are well known to show impairments in patients suffering from major depression disorder, that is mood, executive functioning, social skills, neuroplasticity, core neural networks, and neuroendocrine and neuroimmunological levels. based on predefined search strings used in two online databases (pubmed and google scholar) 1129 articles were identified. after screening title and abstract for relevance related to the question, 82 articles were retained and 11 were added after reference list search, resulting in 93 articles included in the review. findings show that mm and psilocybin exert similar effects on mood, social skills, and neuroplasticity; different effects were found on executive functioning, neural core networks, and neuroendocrine and neuroimmune system markers. potential mechanisms of mm’s effects are enhanced affective self-regulation through mental strategies, optimization of stress reactivity, and structural and functional adjustments of prefrontal and limbic areas; psilocybin’s effects might be established via attenuation of cognitive associations through deep personal insights, cognitive disinhibition, and global neural network disintegration. it is suggested that, when used in combination, mm and psilocybin could exert complementary effects by potentiating or prolonging mutual positive effects, for example, mm potentially facilitating psilocybin-induced peak experiences. future placebo-controlled double-blind randomized trials focusing on psilocybin-assisted mindfulness-based therapy will provide knowledge about whether the proposed combination of therapies maximizes the…”
Watts, R., Day, C., Krzanowski, J., Nutt, D., & Carhart-Harris, R.. (2017). Patients’ Accounts of Increased “Connectedness” and “Acceptance” After Psilocybin for Treatment-Resistant Depression. Journal of Humanistic Psychology
Plain numerical DOI: 10.1177/0022167817709585
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“Objective: to identify patients’ perceptions of the value of psilocybin as a treatment for depression. method: twenty patients enrolled in an open-label trial of psilocybin for treatment-resistant depression participated in a semistructured interview at 6-month follow-up. thematic analysis was used to identify patients’ experiences of the treatment and how it compared with previous treatments. results: two main change processes were identified in relation to the treatment. the first concerned change from disconnection (from self, others, and world) to connection, and the second concerned change from avoidance (of emotion) to acceptance. a third theme concerned comparison between psilocybin and conventional treatments. patients reported that medications and some short-term talking therapies tended to reinforce their sense of disconnection and avoidance, whereas treatment with psilocybin encouraged connection and acceptance. conclusions: these results suggest that psilocybin treatment for depression may work via paradigmatically novel means, antithetical to antidepressant medications, and some short-term talking therapies.”
Patra, S.. (2016). Return of the psychedelics: Psilocybin for treatment resistant depression. Asian Journal of Psychiatry
Plain numerical DOI: 10.1016/j.ajp.2016.08.010
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“Psilocybin, the clinically most researched classic psychedelic has recently been tested for its safety and efficacy in a clinical population of treatment resistant depression. the efficacy of psilocybin in clinical depression previously demonstrated in the elecrophysiologic and neuroimaging findings as also in neuropsychological assessments is further validated by the findings of this rigorously conducted randomized trial. mechanism of action of psilocybin and efficacy in treatment resistant depression are discussed in this paper. ethical issues of conducting clinical trials with psychedelics are also discussed with particular emphasis on their relative safety and absence of addiction potential. implications of these issues for conduct of larger trials for establishing risk benefit ratio in treatment resistant depression are further suggested.”
Ross, S., Bossis, A., Guss, J., Agin-Liebes, G., Malone, T., Cohen, B., … Schmidt, B. L.. (2016). Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial. Journal of Psychopharmacology
Plain numerical DOI: 10.1177/0269881116675512
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“Background: clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression. methods: in this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. the primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks. results: prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. at the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60-80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. the psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression. conclusions: in conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress. trial registration:
clinicaltrials.gov identifier: nct00957359.”
Carhart-Harris, R. L., Bolstridge, M., Day, C. M. J., Rucker, J., Watts, R., Erritzoe, D. E., … Nutt, D. J.. (2018). Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology
Plain numerical DOI: 10.1007/s00213-017-4771-x
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“Rationale: recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy. objectives: here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression. methods: twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated qids-sr16 as the primary outcome measure. results: treatment was generally well tolerated. relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (cohen’s d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. results remained positive at 3 and 6 months (cohen’s d = 1.5 and 1.4, respectively, both p < 0.001). no patients sought conventional antidepressant treatment within 5 weeks of psilocybin. reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience. conclusions: although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.”
Goldberg, S. B., Pace, B. T., Nicholas, C. R., Raison, C. L., & Hutson, P. R.. (2020). The experimental effects of psilocybin on symptoms of anxiety and depression: A meta-analysis. Psychiatry Research
Plain numerical DOI: 10.1016/j.psychres.2020.112749
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“The current meta-analysis examined the effects of psilocybin in combination with behavioral interventions on anxiety and depression in samples with elevated symptoms. across four studies (one uncontrolled; three randomized, placebo-controlled; n = 117), within-group pre-post and pre-follow-up effects on anxiety and depression were large (hedges’ gs=1.16 to 1.47) and statistically significant. across three placebo-controlled studies, pre-post placebo-controlled effects were also large (gs = 0.82 to 0.83) and statistically significant. no serious adverse events were reported. limitations include the small number of studies and risk for bias within studies. results tentatively support future research on psilocybin for the treatment of anxiety and depression.”
Więckiewicz, G., Stokłosa, I., Piegza, M., Gorczyca, P., & Pudlo, R.. (2021). Lysergic acid diethylamide, psilocybin and dimethyltryptamine in depression treatment: A systematic review. Pharmaceuticals
Plain numerical DOI: 10.3390/ph14080793
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“Despite many different kinds of substances available for depression treatment, depression itself still appears to be a clinical challenge. recently, formerly illicit substances came to scientists’ attention, including lysergic acid diethylamide (lsd), psilocybin and dimethyltryptamine (dmt). some studies suggest that these substances might be effective in depression treatment. the aim of this study was to evaluate the efficiency of lsd, psilocybin and dmt in depression treatment in the light of current medical literature. the authors followed the preferred reporting items for systematic review and meta-analysis (prisma) guidelines for this systematic review. the authors searched the pubmed and cochrane library databases to identify relevant publications. finally, 10 papers were included. most of the selected studies showed significant correlation between psilocybin and dmt use and reduction in depression symptom intensity. by analyzing qualified studies, it can be concluded that psilocybin and dmt could be useful in depression treatment, but further observations are still required.”
Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., … Klinedinst, M. A.. (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of Psychopharmacology
Plain numerical DOI: 10.1177/0269881116675513
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“Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. the effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. this randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. instructions to participants and staff minimized expectancy effects. participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. high-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. at 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. community observer ratings showed corresponding changes. mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes. trial registration
clinicaltrials.gov identifier: nct00465595”
Roseman, L., Demetriou, L., Wall, M. B., Nutt, D. J., & Carhart-Harris, R. L.. (2018). Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression. Neuropharmacology
Plain numerical DOI: 10.1016/j.neuropharm.2017.12.041
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“Recent evidence indicates that psilocybin with psychological support may be effective for treating depression. some studies have found that patients with depression show heightened amygdala responses to fearful faces and there is reliable evidence that treatment with ssris attenuates amygdala responses (ma, 2015). we hypothesised that amygdala responses to emotional faces would be altered post-treatment with psilocybin. in this open-label study, 20 individuals diagnosed with moderate to severe, treatment-resistant depression, underwent two separate dosing sessions with psilocybin. psychological support was provided before, during and after these sessions and 19 completed fmri scans one week prior to the first session and one day after the second and last. neutral, fearful and happy faces were presented in the scanner and analyses focused on the amygdala. group results revealed rapid and enduring improvements in depressive symptoms post psilocybin. increased responses to fearful and happy faces were observed in the right amygdala post-treatment, and right amygdala increases to fearful versus neutral faces were predictive of clinical improvements at 1-week. psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with ssris. this suggests fundamental differences in these treatments’ therapeutic actions, with ssris mitigating negative emotions and psilocybin allowing patients to confront and work through them. based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions. trial registration: isrctn, number isrctn14426797. this article is part of the special issue entitled ‘psychedelics: new doors, altered perceptions’.”
Roseman, L., Nutt, D. J., & Carhart-Harris, R. L.. (2018). Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Frontiers in Pharmacology
Plain numerical DOI: 10.3389/fphar.2017.00974
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“Introduction: it is a basic principle of the ‘psychedelic’ treatment model that the quality of the acute experience mediates long-term improvements in mental health. in the present paper we sought to test this using data from a clinical trial assessing psilocybin for treatment-resistant depression (trd). in line with previous reports, we hypothesized that the occurrence and magnitude of oceanic boundlessness (obn) (sharing features with mystical-type experience) and dread of ego dissolution (ded) (similar to anxiety) would predict long-term positive outcomes, whereas sensory perceptual effects would have negligible predictive value. materials and methods: twenty patients with treatment resistant depression underwent treatment with psilocybin (two separate sessions: 10 and 25 mg psilocybin). the altered states of consciousness (asc) questionnaire was used to assess the quality of experiences in the 25 mg psilocybin session. from the asc, the dimensions obn and ded were used to measure the mystical-type and challenging experiences, respectively. the self-reported quick inventory of depressive symptoms (qids-sr) at 5 weeks served as the endpoint clinical outcome measure, as in later time points some of the subjects had gone on to receive new treatments, thus confounding inferences. in a repeated measure anova, time was the within-subject factor (independent variable), with qids-sr as the within-subject dependent variable in baseline, 1-day, 1-week, 5-weeks. obn and ded were independent variables. obn-by-time and ded-by-time interactions were the primary outcomes of interest. results: for the interaction of obn and ded with time (qids-sr as dependent variable), the main effect and the effects at each time point compared to baseline were all significant (p = 0.002 and p = 0.003, respectively, for main effects), confirming our main hypothesis. furthermore, pearson’s correlation of obn with qids-sr (5 weeks) was specific compared to perceptual dimensions of the asc (p < 0.05). discussion: this report further bolsters the view that the quality of the acute psychedelic experience is a key mediator of long-term changes in mental health. future therapeutic work with psychedelics should recognize the essential importance of quality of experience in determining treatment efficacy and consider ways of enhancing mystical-type experiences and reducing anxiety.”
Carhart-Harris, R. L., Roseman, L., Bolstridge, M., Demetriou, L., Pannekoek, J. N., Wall, M. B., … Nutt, D. J.. (2017). Psilocybin for treatment-resistant depression: FMRI-measured brain mechanisms. Scientific Reports
Plain numerical DOI: 10.1038/s41598-017-13282-7
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“Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. here, cerebral blood flow (cbf) and blood oxygen-level dependent (bold) resting-state functional connectivity (rsfc) were measured with functional magnetic resonance imaging (fmri) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (trd). quality pre and post treatment fmri data were collected from 16 of 19 patients. decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. whole-brain analyses revealed post-treatment decreases in cbf in the temporal cortex, including the amygdala. decreased amygdala cbf correlated with reduced depressive symptoms. focusing on a priori selected circuitry for rsfc analyses, increased rsfc was observed within the default-mode network (dmn) post-treatment. increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex rsfc was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex rsfc. these data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. the post-treatment brain changes are different to previously observed acute effects of psilocybin and other ‘psychedelics’ yet were related to clinical outcomes. a ‘reset’ therapeutic mechanism is proposed.”
NCT03380442. (
2017).
Psilocybin and Depression.
Psilocybin and Depression – Assessing the Long-Term Effects of a Single Administration of Psilocybin on the Psychiatric Symptoms and Brain Activity of Patients With Severe Depression
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“The main aim of the study is to investigate the possible long-term therapeutic effects of psilocybin on the symptoms of severe depression, as well as the brain mechanisms underlying these changes. depression severity is assessed before and after (i.e., 1 week, 3 months and 6 months after) a single dose of psilocybin and compared to respective scores of a group receiving an active placebo, ketamine. brain activity (using functional magnetic resonance imaging) is measured before and one week after drug administration in order to determine whether changes in brain networks related to emotional and self-referential processing correlate with any observed changes in depression scores. further, blood samples will be obtained from the participants and analyzed in order to reveal gene expression and molecular level correlates underlying rapid antidepressant effects, and to identify biomarkers that predict treatment outcome.”
Vargas, A. S., Luís, Â., Barroso, M., Gallardo, E., & Pereira, L.. (2020). Psilocybin as a new approach to treat depression and anxiety in the context of life-threatening diseases-a systematic review and meta-analysis of clinical trials. Biomedicines
Plain numerical DOI: 10.3390/biomedicines8090331
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“Psilocybin is a naturally occurring tryptamine known for its psychedelic properties. recent research indicates that psilocybin may constitute a valid approach to treat depression and anxiety associated to life-threatening diseases. the aim of this work was to perform a systematic review with meta-analysis of clinical trials to assess the therapeutic effects and safety of psilocybin on those medical conditions. the beck depression inventory (bdi) was used to measure the effects in depression and the state-trait anxiety inventory (stai) was used to measure the effects in anxiety. for bdi, 11 effect sizes were considered (92 patients) and the intervention group was significantly favored (wmd = -4.589; 95% ci = -4.207 to -0.971; p-value = 0.002). for stai-trait, 11 effect sizes were considered (92 patients), being the intervention group significantly favored when compared to the control group (wmd = -5.906; 95% ci = -7.852 to -3.960; p-value < 0.001). for stai-state, 9 effect sizes were considered (41 patients) and the intervention group was significantly favored (wmd = -6.032; 95% ci = -8.900 to -3.164; p-value < 0.001). the obtained results are promising and emphasize the importance of psilocybin translational research in the management of symptoms of depression and anxiety, since the compound may be effective in reducing symptoms of depression and anxiety in conditions that are either resistant to conventional pharmacotherapy or for which pharmacologic treatment is not yet approved. moreover, it may be also relevant for first-line treatment, given its safety.”
Tai, S. J., Nielson, E. M., Lennard-Jones, M., Johanna Ajantaival, R. L., Winzer, R., Richards, W. A., … Malievskaia, E.. (2021). Development and Evaluation of a Therapist Training Program for Psilocybin Therapy for Treatment-Resistant Depression in Clinical Research. Frontiers in Psychiatry
Plain numerical DOI: 10.3389/fpsyt.2021.586682
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“Introduction: psychological support throughout psilocybin therapy is mandated by regulators as an essential part of ensuring participants’ physical and psychological safety. there is an increased need for specially trained therapists who can provide high-quality care to participants in clinical studies. this paper describes the development and practical implementation of a therapist training program of psychological support within a current phase iib international, multicenter, randomized controlled study of psilocybin therapy for people experiencing treatment-resistant depression. description of training program: this new and manualized approach, based on current evidence-based psychotherapeutic approaches, was developed in partnership with different mental health researchers, practitioners, and experts; and has been approved by the fda. training consists of four components: an online learning platform; in-person training; applied clinical training; and ongoing individual mentoring and participation in webinars.this paper provides a brief overview of the method of support, the rationale and methodology of the training program, and describes each stage of training. the design and implementation of fidelity procedures are also outlined. lessons learned: as part of the phase iib study of psilocybin therapy for treatment-resistant depression, 65 health care professionals have been fully trained as therapists and assisting therapists, across the us, canada and europe. therapists provided informal feedback on the training program. feedback indicates that the didactic and experiential interactive learning, delivered through a combination of online and in-person teaching, helped therapists build conceptual understanding and skill development in the therapeutic approach. clinical training and engagement in participant care, under the guidance of experienced therapists, were considered the most beneficial and challenging aspects of the training. conclusions: clinical training for therapists is essential for ensuring consistently high-quality psilocybin therapy. development of a rigorous, effective and scalable training methodology has been possible through a process of early, active and ongoing collaborations between mental health experts. to maximize impact and meet phase iii and post-approval need, enhanced online learning and establishing pathways for clinical training are identified as critical points for quality assurance. this will require close public, ac…”
Carhart-Harris, R. L., Bolstridge, M., Rucker, J., Day, C. M. J., Erritzoe, D., Kaelen, M., … Nutt, D. J.. (2016). Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry
Plain numerical DOI: 10.1016/S2215-0366(16)30065-7
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“Background psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression. methods in this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. there was no control group. psychological support was provided before, during, and after each session. the primary outcome measure for feasibility was patient-reported intensity of psilocybin’s effects. patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item quick inventory of depressive symptoms (qids) serving as the primary efficacy outcome. this trial is registered with isrctn, number isrctn14426797. findings psilocybin’s acute psychedelic effects typically became detectable 30–60 min after dosing, peaked 2–3 h after dosing, and subsided to negligible levels at least 6 h after dosing. mean self-rated intensity (on a 0–1 scale) was 0·51 (sd 0·36) for the low-dose session and 0·75 (sd 0·27) for the high-dose session. psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. the adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). relative to baseline, depressive symptoms were markedly reduced 1 week (mean qids difference −11·8, 95% ci −9·15 to −14·35, p=0·002, hedges’ g=3·1) and 3 months (−9·2, 95% ci −5·69 to −12·71, p=0·003, hedges’ g=2) after high-dose treatment. marked and sustained improvements in anxiety and anhedonia were also noted. interpretation this study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeuti…”
Corrigan, A. E., Burchill, E., Pelton, L., Marrocu, A., Mazzoleni, A., & Shackshaft, L.. (2021). Psilocybin: the magic medicine for depression?. BJPsych Open
Plain numerical DOI: 10.1192/bjo.2021.456
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“Aims depression is the single largest contributor to global disability. however, effective treatments are currently lacking, resulting in a significant burden of treatment-resistant depression (trd). psilocybin, a serotonergic psychedelic, found as the active compound in ‘magic mushrooms’, has been proposed as a novel therapeutic avenue for trd. we aimed to evaluate the future feasibility and implications of psilocybin as a new antidepressant therapy. method we reviewed and critically analysed the available literature on the efficacy and safety of psilocybin as a treatment for depression, and the potential pharmacological and psychological mechanisms of the therapeutic benefit. we discussed the relative contributions to this therapeutic effect of the pharmacological drug treatment, placebo effects, and the context and parameters of the psychotherapeutic experience. we reviewed legal, social, and economic barriers to primary research and clinical implementation. result psilocybin in combination with psychotherapy has been shown to be safe and effective in trd. its mechanism of action in trd has not been fully elucidated, however reviewing functional neuroimaging studies demonstrated disparate short and long-term modifications of default mode network connectivity, suggested to represent a ‘reset’ mechanism of acute modular disintegration and subsequent reintegration which restores normal function, reviving emotional responsiveness. research suggests psychedelic treatment induces lasting personality, belief and attitude changes. the psychedelic drug itself, the context of the psychotherapeutic experience, and the post-drug integration therapy all appear to have a significant role. preparation prior to treatment, the environment, context and support during the psychedelic experience itself, and the following long-term integration and support process must be considered. despite novel findings psilocybin is a schedule i drug; this imposes a persisting ethical barrier to clinical use. prohibition of psilocybin results in high costs of drug supply, and potential for harmful drug-seeking behaviours. therefore, complex socio-political factors currently limit wider implementation. conclusion psilocybin in combination with psychotherapy is safe and effective in trd. the interacting and elusive therapeutic mechanisms have implications for clinical implementation. preparation prior to treatment, the physical and social environment in which the…”
Meikle, S. E., Liknaitzky, P., Rossell, S. L., Ross, M., Strauss, N., Thomas, N., … Castle, D. J.. (2020). Psilocybin-assisted therapy for depression: How do we advance the field?. Australian and New Zealand Journal of Psychiatry
Plain numerical DOI: 10.1177/0004867419888575
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“In the quest for new treatment options for depression, attention is being paid to the potential role of psychedelic drugs. psilocybin is of particular interest given its mechanism of action, its benefits in early trials and its relatively low side effects burden. this viewpoint outlines a number of key issues that remain to be elucidated about its potential use in the clinical environment, including clarification of the profile of people most likely to benefit and those who might experience adverse effects, longer-term outcomes and the role of psychotherapeutic input alongside the drug itself. there are also opportunities to understand better, the neurobiology underpinning its effects.”
Daws, R., Timmerman, C., Giribaldi, B., Sexton, J., Erritzoe, D., Roseman, L., … Carhart-Harris, R.. (
2021).
Decreased brain modularity after psilocybin therapy for depression.
PREPRINT (Version 1) Available at Research Square [Https://Doi.Org/10.21203/Rs.3.Rs-513323/V1]
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“Importance psilocybin therapy shows antidepressant potential; our data link its antidepressant effects to decreased brain network modularity post-treatment. objective to assess the sub-acute impact of psilocybin on brain activity in patients with depression. design pre vs post-treatment resting-state functional mri (fmri) was recorded in two trials: 1) open-label treatment-resistant depression (trd) trial with baseline vs 1 day post-treatment fmri (april-2015 to april-2016); 2) two-arm double-blind rct in major depressive disorder (mdd), fmri baseline vs 3 week after psilocybin-therapy or 6 weeks of daily escitalopram (january-2019 to march-2020). setting study visits occurred at the nihr imperial clinical research facility.participants adult male and female patients with trd or mdd. intervention(s) (for clinical trials) or exposure(s) (for observational studies)study 1: two oral doses of psilocybin (10mg and 25mg, fixed order, 7 days apart). fmri was recorded at baseline and one day after the 25mg dose. study 2: either: 2 x 25mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo (‘psilocybin-arm’), or 2 x 1mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram [10-20mg] (‘escitalopram-arm’). fmri was recorded at baseline and 3 weeks after the 2nd psilocybin dose, which was the final day of the 6-week daily capsule ingestion. main outcome(s) and measure(s) beck depression inventory and fmri network modularity. results study 1: in 16 adults (mean age [sd], 42.8 [10.1] years, 4 [25%] female), psilocybin therapy was associated with markedly decreased bdi scores at 1 week (mean difference, -21; 95% ci=[-27.3, -14.7], p<.001) and 6 months (mean difference, -14.19; 95% ci=[-21.3, -7.1], p<.001). decreased network modularity at one day post-treatment correlated with treatment response at 6 months (pearson, 0.64; p=.01). study 2: in 43 adults (42.7 [10.5] years, 14 [33%] female), antidepressant effects favoured the psilocybin-arm at 2 (mean difference, -8.76; 95% ci=[-13.6, -3.9], p=.002) and 6 weeks (mean difference, -8.78; 95% ci=[-15.6, -2.0], p=.01). specific to the psilocybin-arm, improvements at the 6-week primary endpoint correlated with decreased network modularity (pearson, -0.42, p=.025). conclusions and relevance consistent efficacy-related functional brain changes correlating with robust and reliable antidepressant effects across two …”
Mertens, L. J., Wall, M. B., Roseman, L., Demetriou, L., Nutt, D. J., & Carhart-Harris, R. L.. (2020). Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression. Journal of Psychopharmacology
Plain numerical DOI: 10.1177/0269881119895520
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“Background: psilocybin has shown promise as a treatment for depression but its therapeutic mechanisms are not properly understood. in contrast to the presumed actions of antidepressants, we recently found increased amygdala responsiveness to fearful faces one day after open-label treatment with psilocybin (25 mg) in 19 patients with treatment-resistant depression, which correlated with treatment efficacy. aims: aiming to further unravel the therapeutic mechanisms of psilocybin, the present study extends this basic activation analysis. we hypothesised changed amygdala functional connectivity, more precisely decreased amygdala-ventromedial prefrontal cortex functional connectivity, during face processing after treatment with psilocybin. methods: psychophysiological interaction analyses were conducted on functional magnetic resonance imaging data from a classic face/emotion perception task, with the bilateral amygdala and ventromedial prefrontal cortex time-series as physiological regressors. average parameter estimates (beta weights) of significant clusters were correlated with clinical outcomes at one week. results: results showed decreased ventromedial prefrontal cortex-right amygdala functional connectivity during face processing post- (versus pre-) treatment; this decrease was associated with levels of rumination at one week. this effect was driven by connectivity changes in response to fearful and neutral (but not happy) faces. independent whole-brain analyses also revealed a post-treatment increase in functional connectivity between the amygdala and ventromedial prefrontal cortex to occipital-parietal cortices during face processing. conclusion: these results are consistent with the idea that psilocybin therapy revives emotional responsiveness on a neural and psychological level, which may be a key treatment mechanism for psychedelic therapy. future larger placebo-controlled studies are needed to examine the replicability of the current findings.”
Hibicke, M., Landry, A. N., Kramer, H. M., Talman, Z. K., & Nichols, C. D.. (2020). Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression. ACS Applied Materials and Interfaces
Plain numerical DOI: 10.1021/acschemneuro.9b00493
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“Psilocybin shows efficacy to alleviate depression in human clinical trials for six or more months after only one or two treatments. another hallucinogenic drug, esketamine, has recently been u.s. food and drug administration (fda)-approved as a rapid-acting antidepressant. the mechanistic basis for the antidepressant effects of psilocybin and ketamine appear to be conserved. the efficacy of these two medications has not, however, been directly compared either clinically or preclinically. further, whether or not a profound subjective existential experience is necessary for psilocybin to have antidepressant effects is unknown. to address these questions, we tested psilocybin, lysergic acid diethylamide (lsd), and ketamine in a rat model for depression. as in humans, a single administration of psilocybin or lsd produced persistent antidepressant-like effects in our model. in contrast, ketamine produced only a transient antidepressant-like effect. our results indicate that classic psychedelics may have therapeutic efficacy that is more persistent than that of ketamine, and also suggest that a subjective existential experience may not be necessary for therapeutic effects.”
Malone, T. C., Mennenga, S. E., Guss, J., Podrebarac, S. K., Owens, L. T., Bossis, A. P., … Ross, S.. (2018). Individual experiences in four cancer patients following psilocybin-assisted psychotherapy. Frontiers in Pharmacology
Plain numerical DOI: 10.3389/fphar.2018.00256
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“A growing body of evidence shows that existential and spiritual well-being in cancer patients is associated with better medical outcomes, improved quality of life, and serves as a buffer against depression, hopelessness, and desire for hastened death. historical and recent research suggests a role for psilocybin-assisted psychotherapy in treating cancer-related anxiety and depression. a double-blind controlled trial was performed, where 29 patients with cancer-related anxiety and depression were randomly assigned to treatment with single-dose psilocybin (0.3 mg/kg) or niacin in conjunction with psychotherapy. previously published results of this trial demonstrated that, in conjunction with psychotherapy, moderate-dose psilocybin produced rapid, robust, and enduring anxiolytic, and anti-depressant effects. here, we illustrate unique clinical courses described by four participants using quantitative measures of acute and persisting effects of psilocybin, anxiety, depression, quality of life, and spiritual well-being, as well as qualitative interviews, written narratives, and clinician notes. although the content of each psilocybin-assisted experience was unique to each participant, several thematic similarities and differences across the various sessions stood out. these four participants’ personal narratives extended beyond the cancer diagnosis itself, frequently revolving around themes of self-compassion and love, acceptance of death, and memories of past trauma, though the specific details or narrative content differ substantially. the results presented here demonstrate the personalized nature of the subjective experiences elicited through treatment with psilocybin, particularly with respect to the spiritual and/or psychological needs of each patient.”
Li, N. X., Hu, Y. R., Chen, W. N., & Zhang, B.. (2022). Dose effect of psilocybin on primary and secondary depression: a preliminary systematic review and meta-analysis. Journal of Affective Disorders
Plain numerical DOI: 10.1016/j.jad.2021.09.041
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“Background: previous studies have shown that psilocybin has antidepressant effects. in the current study, we aim to explore the dose effects of psilocybin on primary (major depression patients) and secondary depression (depressed cancer patients). methods: published studies concerning psilocybin for depression were retrieved. in accordance with prisma guidelines, 6 databases (pubmed, embase, web of science, cochrane library,
clinicaltrials.gov 2.3 and wanfang database) were searched for research studies published or still in progress from inception to 30 november, 2020, with language restricted to english and chinese. hedges’ g of beck depression inventory (bdi) score changes was calculated as the primary outcome. results: 7 articles were finally included, with a total of 136 participants. in terms of efficacy, hedges’ g was 1.289 (95%ci=[1.020, 1.558], heterogeneity i2=50.995%, p<0.001). as psilocybin dose increases within a certain range, the antidepressive effect declines and then increases, with 30-35 mg/70 kg achieving the optimal therapeutic effect. subgroup analysis suggested that the antidepressive effect of psilocybin was extremely significant at a relatively high dose (30-35mg/70kg: hedges’ g=3.059, 95%ci=[2.269, 3.849], p<0.001), long-term (>1month: hedges’ g=1.123, 95%ci=[0.861, 1.385], p<0.001) and when used in primary depression patients (hedges’ g=2.190, 95%ci=[1.423, 2.957], p<0.001). limitations: only a small number of studies can be identified of variable quality, thus our conclusions remain preliminary. conclusions: our preliminary results have shown that psilocybin exerts a rapid effect in reducing depressive symptom on primary and secondary depression. the optimal dose of psilocybin may be 30-35mg/70kg or higher; future clinical trials are warranted for further evaluation on its effect.”
O’Donnell, K. C., Mennenga, S. E., & Bogenschutz, M. P.. (2019). Psilocybin for depression: Considerations for clinical trial design. Journal of Psychedelic Studies
Plain numerical DOI: 10.1556/2054.2019.026
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“Background and aimsgiven the enormous global burden of depressive illness, there is an urgent need to develop novel and more effective treatments for major depressive disorder (mdd). recent finding…”
Lyons, T., & Carhart-Harris, R. L.. (2018). Increased nature relatedness and decreased authoritarian political views after psilocybin for treatment-resistant depression. Journal of Psychopharmacology
Plain numerical DOI: 10.1177/0269881117748902
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“Rationale: previous research suggests that classical psychedelic compounds can induce lasting changes in personality traits, attitudes and beliefs in both healthy subjects and patient populations. aim: here we sought to investigate the effects of psilocybin on nature relatedness and libertarian–authoritarian political perspective in patients with treatment-resistant depression (trd). methods: this open-label pilot study with a mixed-model design studied the effects of psilocybin on measures of nature relatedness and libertarian–authoritarian political perspective in patients with moderate to severe trd (n=7) versus age-matched non-treated healthy control subjects (n=7). psilocybin was administered in two oral dosing sessions (10 mg and 25 mg) 1 week apart. main outcome measures were collected 1 week and 7–12 months after the second dosing session. nature relatedness and libertarian–authoritarian political perspective were assessed using the nature relatedness scale (nr-6) and political perspective questionnaire (ppq-5), respectively. results: nature relatedness significantly increased (t(6)=−4.242, p=0.003) and authoritarianism significantly decreased (t(6)=2.120, p=0.039) for the patients 1 week after the dosing sessions. at 7–12 months post-dosing, nature relatedness remained significantly increased (t(5)=−2.707, p=0.021) and authoritarianism remained decreased at trend level (t(5)=−1.811, p=0.065). no differences were found on either measure for the non-treated healthy control subjects. conclusions: this pilot study suggests that psilocybin with psychological support might produce lasting changes in attitudes and beliefs. although it would be premature to infer causality from this small study, the possibility of drug-induced changes in belief systems seems sufficiently intriguing and timely to deserve further investigation.”
Nutt, D.. (2019). Psychedelic drugs—a new era in psychiatry?. Dialogues in Clinical Neuroscience
Plain numerical DOI: 10.31887/DCNS.2019.21.2/dnutt
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“This article covers the renaissance of classical psychedelic drugs such as psilocybin and lsd plus 3,4-methylene dioxymethamphetamine (mdma—ecstasy) in psychiatric research. these drugs were used quite extensively before they became prohibited. this ban had little impact on recreational use, but effectively stopped research and clinical treatments, which up to that point had looked very promising in several areas of psychiatry. in the past decade a number of groups have been working to re-evaluate the utility of these substances in medicine. so far highly promising preliminary data have been produced with psilocybin in anxiety, depression, smoking, alcoholism, and with mdma for post-traumatic stress disorder (ptsd) and alcoholism. these findings have led to the european medicines agency approving psilocybin for a phase 3 study in treatment-resistant depression and the food and drug administration for ptsd with mdma. both trials should read out in 2020, and if the results are positive we are likely to see these medicines approved for clinical practice soon afterwards.”
Suppes, T., Lyu, J., & Hambro, B.. (
2019).
Psilocybin in the treatment of depression and anxiety.
Bipolar Disorders
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“We present a targeted literature review examining the use of the psychoactive drug psilocybin in treating mood disorders. psilocybin is currently under investigation globally for its potential use in treating mood disorders. trials in healthy, depressed, and terminally ill patients have yielded significant decreases in anxious and depressive symptoms, as well as reported improvement in quality of life. these early findings suggest the potential for psilocybin as a therapeutic tool in treating depression and anxiety. psilocybin has a low toxicity and a comparatively low potential for harm. studies in healthy controls suggest that the effects of psilocybin may be surprisingly durable with recent studies finding a preponderance of participants reporting improved scores in mood, behavior, attitude regarding coping with death for up to 6 months post-treatment, with no apparent long-term side effects. while early results are promising, there are still relatively few double-blind, placebo-controlled trials of psilocybin in the treatment of depression or anxiety. the following controlled trials have been recently completed in depression: griffiths et al. (2016), ross et al. (2016), and stroud et al. (2017). recent controlled studies focusing on anxiety include: griffiths et al. (2016), ross et al. (2016), and grob et al. (2011). consideration of these recent controlled trials including strengths and limitations, as well as details of the results, will be presented. conclusions of these studies, including potential mediators and moderators will be reviewed. current studies and future directions for future studies of psilocybin will be discussed.”
Lyons, T., & Carhart-Harris, R. L.. (2018). More realistic forecasting of Future Life Events after psilocybin for treatment-resistant depression. Frontiers in Psychology
Plain numerical DOI: 10.3389/fpsyg.2018.01721
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“Background: evidence suggests that classical psychedelics can promote enduring changes in personality, attitudes and optimism, as well as improvements in mental health outcomes. aim: to investigate the effects of a composite intervention, involving psilocybin, on pessimism biases in patients with treatment-resistant depression (trd). methods: patients with trd (n = 15) and matched, untreated non-depressed controls (n = 15) performed the prediction of future life events (pofle) task. the pofle task requires participants to predict the likelihood of certain life events occurring within a 30-day period, after which the actual rate of event occurrence is reported; this gives an index of potential pessimism versus optimism bias. psilocybin was administered in two oral dosing sessions (10 and 25 mg) one week apart. main outcome measures were collected at baseline and one week after the second dosing session. results: patients showed a significant pessimism bias at baseline [t(14) = -3.260, p = 0.006; 95% ci (-0.16, -0.03), g = 1.1] which was related to the severity of their depressive symptoms (rs = -0.55, p = 0.017). one week after psilocybin treatment, this bias was significantly decreased [t(14) = -2.714, p = 0.017; 95% ci (-0.21, -0.02), g = 0.7] and depressive symptoms were greatly improved [t(14) = 7.900, p < 0.001; 95% ci (16.17, 28.23), g = 1.9]; moreover, the magnitude of change in both variables was significantly correlated (r = -0.57, p = 0.014). importantly, post treatment, patients became significantly more accurate at predicting the occurrence of future life events [t(14) = 1.857, p = 0.042; 95% ci (-0.01, 0.12), g = 0.6] whereas no such change was observed in the control subjects. conclusion: these findings suggest that psilocybin with psychological support might correct pessimism biases in trd, enabling a more positive and accurate outlook.”
Psilocybin for Depression. (2021). New England Journal of Medicine
Plain numerical DOI: 10.1056/nejmc2108082
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“To the editor: carhart-harris et al. (april 15 issue)1 hypothesize that ‘equivalent efficacy (primary outcome) is predicted for . . . escitalopram vs. 25 mg psilocybin,’ as stated in section s2.1 i…”
Mahapatra, A., & Gupta, R.. (2017). Role of psilocybin in the treatment of depression. Therapeutic Advances in Psychopharmacology
Plain numerical DOI: 10.1177/2045125316676092
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“ Psilocybin is a naturally occurring alkaloid, pharmacologically similar to the classic hallucinogen lysergic acid diethylamide (lsd). although primarily used as a recreational drug or an entheogen in particular cultural settings, recent population based studies have shown that it does not lead to serious physical or mental health problems or dependent use. in view of recent work demonstrating psilocybin’s potential to increase subjective sense of wellbeing and because of its novel mechanism of 5-ht 2a serotonin receptor agonism, it is being explored for possible therapeutic utility in mood and anxiety disorders. ”
Kelly, J. R., Crockett, M. T., Alexander, L., Haran, M., Baker, A., Burke, L., … O’Keane, V.. (2021). Psychedelic science in post-COVID-19 psychiatry. Irish Journal of Psychological Medicine
Plain numerical DOI: 10.1017/ipm.2020.94
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“The medium-to long-term consequences of covid-19 are not yet known, though an increase in mental health problems are predicted. multidisciplinary strategies across socio-economic and psychological levels may be needed to mitigate the mental health burden of covid-19. preliminary evidence from the rapidly progressing field of psychedelic science shows that psilocybin therapy offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and maladaptive habitual patterns of cognition and behaviour, notably depression, addiction and obsessive compulsive disorder. the compass pathways (compass) phase 2b double-blind trial of psilocybin therapy in antidepressant-free, treatment-resistant depression (trd) is underway to determine the safety, efficacy and optimal dose of psilocybin. results from the imperial college london psilodep-rct comparing the efficacy and mechanisms of action of psilocybin therapy to the selective serotonin reuptake inhibitor (ssri) escitalopram will soon be published. however, the efficacy and safety of psilocybin therapy in conjunction with ssris in trd is not yet known. an additional compass study, with a centre in dublin, will begin to address this question, with potential implications for the future delivery of psilocybin therapy. while at a relatively early stage of clinical development, and notwithstanding the immense challenges of covid-19, psilocybin therapy has the potential to play an important therapeutic role for various psychiatric disorders in post-covid-19 clinical psychiatry. © 2020 the author(s). published by cambridge university press on behalf of the college of psychiatrists of ireland.”
Lyu, J., Hambro, B., & Suppes, T.. (2019). A SYSTEMATIC REVIEW OF PSILOCYBIN IN THE TREATMENT OF DEPRESSION AND ANXIETY. Journal of Affective Disorders
Plain numerical DOI: 10.1016/j.jad.2018.10.335
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“We present a targeted literature review examining the use of the psychoactive drug psilocybin in treating mood disorders. psilocybin is currently under investigation globally for its potential use in treating mood disorders. trials in healthy, depressed, and terminally ill patients have yielded significant decreases in anxious and depressive symptoms, as well as reported improvement in quality of life. these early findings suggest the potential for psilocybin as a therapeutic tool in treating depression and anxiety. psilocybin has a low toxicity and a comparatively low potential for harm. studies in healthy controls suggest that the effects of psilocybin may be surprisingly durable with recent studies finding a preponderance of participants reporting improved scores in mood, behavior, attitude regarding coping with death for up to 6 months post-treatment, with no apparent long-term side effects. while early results are promising, there are still relatively few double-blind, placebo-controlled trials of psilocybin in the treatment of depression or anxiety. the following controlled trials have been recently completed in depression: griffiths et al. (2016), ross et al. (2016), and stroud et al. (2017). recent controlled studies focusing on anxiety include: griffiths et al. (2016), ross et al. (2016), and grob et al. (2011). consideration of these recent controlled trials including strengths and limitations, as well as details of the results, will be presented. conclusions of these studies, including potential mediators and moderators will be reviewed. current studies and future directions for future studies of psilocybin will be discussed.”
Stroud, J. B., Freeman, T. P., Leech, R., Hindocha, C., Lawn, W., Nutt, D. J., … Carhart-Harris, R. L.. (2018). Psilocybin with psychological support improves emotional face recognition in treatment-resistant depression. Psychopharmacology
Plain numerical DOI: 10.1007/s00213-017-4754-y
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“Rationale: depressed patients robustly exhibit affective biases in emotional processing which are altered by ssris and predict clinical outcome. objectives: the objective of this study is to investigate whether psilocybin, recently shown to rapidly improve mood in treatment-resistant depression (trd), alters patients’ emotional processing biases. methods: seventeen patients with treatment-resistant depression completed a dynamic emotional face recognition task at baseline and 1 month later after two doses of psilocybin with psychological support. sixteen controls completed the emotional recognition task over the same time frame but did not receive psilocybin. results: we found evidence for a group × time interaction on speed of emotion recognition (p = .035). at baseline, patients were slower at recognising facial emotions compared with controls (p < .001). after psilocybin, this difference was remediated (p = .208). emotion recognition was faster at follow-up compared with baseline in patients (p = .004, d = .876) but not controls (p = .263, d = .302). in patients, this change was significantly correlated with a reduction in anhedonia over the same time period (r = .640, p = .010). conclusions: psilocybin with psychological support appears to improve processing of emotional faces in treatment-resistant depression, and this correlates with reduced anhedonia. placebo-controlled studies are warranted to follow up these preliminary findings.”
Carrillo, F., Sigman, M., Fernández Slezak, D., Ashton, P., Fitzgerald, L., Stroud, J., … Carhart-Harris, R. L.. (2018). Natural speech algorithm applied to baseline interview data can predict which patients will respond to psilocybin for treatment-resistant depression. Journal of Affective Disorders
Plain numerical DOI: 10.1016/j.jad.2018.01.006
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“Background: natural speech analytics has seen some improvements over recent years, and this has opened a window for objective and quantitative diagnosis in psychiatry. here, we used a machine learning algorithm applied to natural speech to ask whether language properties measured before psilocybin for treatment-resistant can predict for which patients it will be effective and for which it will not. methods: a baseline autobiographical memory interview was conducted and transcribed. patients with treatment-resistant depression received 2 doses of psilocybin, 10 mg and 25 mg, 7 days apart. psychological support was provided before, during and after all dosing sessions. quantitative speech measures were applied to the interview data from 17 patients and 18 untreated age-matched healthy control subjects. a machine learning algorithm was used to classify between controls and patients and predict treatment response. results: speech analytics and machine learning successfully differentiated depressed patients from healthy controls and identified treatment responders from non-responders with a significant level of 85% of accuracy (75% precision). conclusions: automatic natural language analysis was used to predict effective response to treatment with psilocybin, suggesting that these tools offer a highly cost-effective facility for screening individuals for treatment suitability and sensitivity. limitations: the sample size was small and replication is required to strengthen inferences on these results.”
Kaelen, M., Giribaldi, B., Raine, J., Evans, L., Timmerman, C., Rodriguez, N., … Carhart-Harris, R.. (2018). The hidden therapist: evidence for a central role of music in psychedelic therapy. Psychopharmacology
Plain numerical DOI: 10.1007/s00213-017-4820-5
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“Rationale: recent studies have supported the safety and efficacy of psychedelic therapy for mood disorders and addiction. music is considered an important component in the treatment model, but little empirical research has been done to examine the magnitude and nature of its therapeutic role. objectives: the present study assessed the influence of music on the acute experience and clinical outcomes of psychedelic therapy. methods: semi-structured interviews inquired about the different ways in which music influenced the experience of 19 patients undergoing psychedelic therapy with psilocybin for treatment-resistant depression. interpretative phenomenological analysis was applied to the interview data to identify salient themes. in addition, ratings were given for each patient for the extent to which they expressed ‘liking,’ ‘resonance’ (the music being experienced as ‘harmonious’ with the emotional state of the listener), and ‘openness’ (acceptance of the music-evoked experience). results: analyses of the interviews revealed that the music had both ‘welcome’ and ‘unwelcome’ influences on patients’ subjective experiences. welcome influences included the evocation of personally meaningful and therapeutically useful emotion and mental imagery, a sense of guidance, openness, and the promotion of calm and a sense of safety. conversely, unwelcome influences included the evocation of unpleasant emotion and imagery, a sense of being misguided and resistance. correlation analyses showed that patients’ experience of the music was associated with the occurrence of ‘mystical experiences’ and ‘insightfulness.’ crucially, the nature of the music experience was significantly predictive of reductions in depression 1 week after psilocybin, whereas general drug intensity was not. conclusions: this study indicates that music plays a central therapeutic function in psychedelic therapy.”
Johnson, M. W., & Griffiths, R. R.. (2017). Potential Therapeutic Effects of Psilocybin. Neurotherapeutics
Plain numerical DOI: 10.1007/s13311-017-0542-y
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“Psilocybin and other 5-hydroxytryptamine2a agonist classic psychedelics have been used for centuries as sacraments within indigenous cultures. in the mid-twentieth century they were a focus within psychiatry as both probes of brain function and experimental therapeutics. by the late 1960s and early 1970s these scientific inquires fell out of favor because classic psychedelics were being used outside of medical research and in association with the emerging counter culture. however, in the twenty-first century, scientific interest in classic psychedelics has returned and grown as a result of several promising studies, validating earlier research. here, we review therapeutic research on psilocybin, the classic psychedelic that has been the focus of most recent research. for mood and anxiety disorders, three controlled trials have suggested that psilocybin may decrease symptoms of depression and anxiety in the context of cancer-related psychiatric distress for at least 6 months following a single acute administration. a small, open-label study in patients with treatment-resistant depression showed reductions in depression and anxiety symptoms 3 months after two acute doses. for addiction, small, open-label pilot studies have shown promising success rates for both tobacco and alcohol addiction. safety data from these various trials, which involve careful screening, preparation, monitoring, and follow-up, indicate the absence of severe drug-related adverse reactions. modest drug-related adverse effects at the time of medication administration are readily managed. us federal funding has yet to support therapeutic psilocybin research, although such support will be important to thoroughly investigate efficacy, safety, and therapeutic mechanisms.”
Watts, R., & Luoma, J. B.. (2020). The use of the psychological flexibility model to support psychedelic assisted therapy. Journal of Contextual Behavioral Science
Plain numerical DOI: 10.1016/j.jcbs.2019.12.004
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“Psychedelic assisted therapy comprises three stages: preparation, psychedelic session, and integration. preparation is key for maximising the potential of a beneficial psychedelic experience and integration is important for prolonging improvements. the psychological flexibility model (pfm) appears to be a promising one to guide psychedelic preparation and integration. this paper proposes a model that utilises the pfm as informed by a previously published qualitative study of patient accounts of change processes in psilocybin therapy that identified themes of acceptance and connection as associated with positive outcomes. this new model, the ace (accept, connect, embody) model presents the six psychological flexibility processes, renamed and rearranged in an acceptance triad (defusion, present moment focus, willingness) and a connection triad (self as context, values, committed action). this paper describes the ace model and how it is being used in an ongoing trial of psilocybin treatment for major depression. it also describes qualitative evidence supportive of the idea that psychological flexibility may be key to characterizing the processes of change involved in psilocybin assisted therapy for depression. these and other results suggest that psilocybin may be specifically increasing psychological flexibility and point to the possibility that psychotherapy approaches incorporating the pfm may serve as a means to deepen and extend the benefits of psilocybin treatment, thus bridging the experiential gap between a potent inner experience and an outer life better lived.”
Cowen, P.. (2016). Altered states: psilocybin for treatment-resistant depression. The Lancet Psychiatry
Plain numerical DOI: 10.1016/S2215-0366(16)30087-6
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McCorvy, J. D., Olsen, R. H. J., & Roth, B. L.. (2016). Psilocybin for depression and anxiety associated with life-threatening illnesses. Journal of Psychopharmacology
Plain numerical DOI: 10.1177/0269881116675771
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Whelan, A., & Johnson, M. I.. (2018). Lysergic acid diethylamide and psilocybin for the management of patients with persistent pain: a potential role?. Pain Management
Plain numerical DOI: 10.2217/pmt-2017-0068
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“Recently, there has been interest in lysergic acid diethylamide (lsd) and psilocybin for depression, anxiety and fear of death in terminal illness. the aim of this review is to discuss the potential use of lsd and psilocybin for patients with persistent pain. lsd and psilocybin are 5-hydroxytryptamine receptor agonists and may interact with nociceptive and antinociceptive processing. tentative evidence from a systematic review suggests that lsd (7 studies, 323 participants) and psilocybin (3 studies, 92 participants) may be beneficial for depression and anxiety associated with distress in life-threatening diseases. lsd and psilocybin are generally safe if administered by a healthcare professional, although further investigations are needed to assess their utility for patients with persistent pain, especially associated with terminal illness.”
Agin-Liebes, G. I., Malone, T., Yalch, M. M., Mennenga, S. E., Ponté, K. L., Guss, J., … Ross, S.. (2020). Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. Journal of Psychopharmacology
Plain numerical DOI: 10.1177/0269881119897615
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“Background: a recently published randomized controlled trial compared single-dose psilocybin with single-dose niacin in conjunction with psychotherapy in participants with cancer-related psychiatric distress. results suggested that psilocybin-assisted psychotherapy facilitated improvements in psychiatric and existential distress, quality of life, and spiritual well-being up to seven weeks prior to the crossover. at the 6.5-month follow-up, after the crossover, 60–80% of participants continued to meet criteria for clinically significant antidepressant or anxiolytic responses. methods: the present study is a long-term within-subjects follow-up analysis of self-reported symptomatology involving a subset of participants that completed the parent trial. all 16 participants who were still alive were contacted, and 15 participants agreed to participate at an average of 3.2 and 4.5 years following psilocybin administration. results: reductions in anxiety, depression, hopelessness, demoralization, and death anxiety were sustained at the first and second follow-ups. within-group effect sizes were large. at the second (4.5 year) follow-up approximately 60–80% of participants met criteria for clinically significant antidepressant or anxiolytic responses. participants overwhelmingly (71–100%) attributed positive life changes to the psilocybin-assisted therapy experience and rated it among the most personally meaningful and spiritually significant experiences of their lives. conclusion: these findings suggest that psilocybin-assisted psychotherapy holds promise in promoting long-term relief from cancer-related psychiatric distress. limited conclusions, however, can be drawn regarding the efficacy of this therapy due to the crossover design of the parent study. nonetheless, the present study adds to the emerging literature base suggesting that psilocybin-facilitated therapy may enhance the psychological, emotional, and spiritual well-being of patients with life-threatening cancer.”
Savalia, N. K., Shao, L. X., & Kwan, A. C.. (2021). A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics. Trends in Neurosciences
Plain numerical DOI: 10.1016/j.tins.2020.11.008
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“Pilot studies have hinted that serotonergic psychedelics such as psilocybin may relieve depression, and could possibly do so by promoting neural plasticity. intriguingly, another psychotomimetic compound, ketamine, is a fast-acting antidepressant and induces synapse formation. the similarities in behavioral and neural effects have been puzzling because the compounds target distinct molecular receptors in the brain. in this opinion article, we develop a conceptual framework that suggests the actions of ketamine and serotonergic psychedelics may converge at the dendrites, to both enhance and suppress membrane excitability. we speculate that mismatches in the opposing actions on dendritic excitability may relate to these compounds’ cell-type and region selectivity, their moderate range of effects and toxicity, and their plasticity-promoting capacities.”
Carhart-Harris, R. L., & Goodwin, G. M.. (2017). The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology
Plain numerical DOI: 10.1038/npp.2017.84
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“Plant-based psychedelics, such as psilocybin, have an ancient history of medicinal use. after the first english language report on lsd in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. used most notably as aids to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as lsd showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programs. since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with lsd and three separate clinical trials of psilocybin for depressive symptoms. in this circumspective piece, rlc-h and gmg share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.”
Carhart-Harris, R.. (
2015).
Results: Of a multi-modal neuroimaging study of LSD and a psilocybin for treatment-resistant depression clinical trial.
Neuropsychopharmacology
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“Background: our research team have conducted a series of mri and meg studies with the 5ht2a receptor agonist psilocybin in comparison with mdma, an entactogen that releases 5ht. the mri studies of psilocybin (both asl and fmri) revealed unexpected reduction in brain blood flow and a decrease in bold signal (carhart-harris et al 2013 pnas) in high-level cortical regions and the thalamus, with post-hoc analysis showing large increases in brain connectivity between, rather than within, the usual resting state networks (petri et al j roy soc 2014). the cortical psilocybin mri findings were confirmed by a later meg study that revealed a major loss of power in all measured frequency bands (1-100hz) after psilocybin with decreases in alpha power in the posterior cingulate cortex correlating with egodissolution measures (carhart-harris and muthukumaraswamy et al 2013 j neurosci). results from the fmri and meg work suggested psilocybin has antidepressant properties and from these we are now conducting the first study of psilocybin in resistant depression. data from a pilot phase will be ready for the acnp meeting. mdma also decreased blood flow and bold signal but the effects were largely subcortical, particularly in the amygdala, and no psychedelic effects were seen (carhart-harris et al 2014 biol psych). negative memories were attenuated and positive ones enhanced by mdma and these effects were associated with fmri-measured changes in brain activity (carhart-harris et al 2013 int neuropychopharm). lsd is the prototypical hallucinogen, with much greater use than the others in psychiatric and research settings, with over 1000 papers published before it was banned in 1967. since then, and only in the past year, there have been 3 research reports, but none using modern brain imaging methods. methods: over the course of 6 hours, 20 healthy volunteers were scanned sequentially with asl/bold-fmri/ and meg following 75 microgm lsd iv or saline placebo in a crossover design at least 2 weeks apart. subjective ratings of psychedelic experiences were then correlated with the imaging data. twelve patients with resistant depression were treated with two sessions of psilocybin. significant improvements in symptom severity were observed for up to 5 weeks post-treatment, with a far greater before and (1 week) after treatment effect size (cohen’s d = 3.4) than seen with currently available anti-depressant interventions. results: lsd decreased integrity and segregation of brain …”
EUCTR2017-000219-18-GB. (
2018).
Assessing psilocybin as a treatment for depression.
Www.Who.Int/Trialsearch/Trial2.Aspx?TrialID=EUCTR2017-000219-18-GB
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“INTERVENTION: product name: psilocybin product code: na pharmaceutical form: capsule, soft inn or proposed inn: psilocybin cas number: 520‐52‐5 concentration unit: mg milligram(s) concentration type: equal concentration number: 25‐ trade name: escitalopram film‐coated tablets product name: escitalopram film‐coated tablets pharmaceutical form: capsule, hard inn or proposed inn: escitalopram cas number: 219861‐08‐2 current sponsor code: na other descriptive name: s‐(+)‐citalopram oxalate concentration unit: mg milligram(s) concentration type: range concentration number: 10‐20 pharmaceutical form of the placebo: capsule, hard route of administration of the placebo: oral use condition: major depressive disorder ; meddra version: 20.0 level: pt classification code 10057840 term: major depression system organ class: 10037175 ‐ psychiatric disorders ; meddra version: 20.0 level: pt classification code 10057840 term: major depression system organ class: 10037175 ‐ psychiatric disorders therapeutic area: psychiatry and psychology [f] ‐ mental disorders [f03] primary outcome: main objective: how effective is a single dose of psilocybin for major depressive disorder against an an active gold‐standard medical treatment (6‐weeks of escitalopram)? primary end point(s): qids‐16 secondary objective: how do the relevant interventions affect brain activity and can brain measures be used to predict treatment response?; timepoint(s) of evaluation of this end point: baseline and main endpoint = 1 week after the psilocybin dosing session secondary outcome: secondary end point(s): fmri measures ; ; other clinical ratings include:; ; o qids‐16 (daily measure) [82]; o bdi ii (two‐weekly measure) [13]; o ham‐d [14] ; o madrs [34]; o spielberger’s trait anxiety inventory (stai) ‐ trait [15]; o warwick‐edinburgh mental wellbeing scale (wemwbs) [16]; o snaith hamilton anhedonia pleasure scale (shaps) [17]; o life orientation test (lot‐r) [18]; o meaning in life questionnaire (mlq) [19]; o brief resilience scale (brs) [20] ; o dysfunctional attitudes scale (das) [21] ; o 44‐item big five inventory [22]; o peters 21‐item delusional inventory (pdi) [23]; o ease anomalous subjective experience [24]; o ruminative responses scale (rrs) [25]; o white bear suppression inventory (wbsi) [26]; o barrett impulsivity scale (bis) [27]; o brief experiential avoidance questionnaire [28] ; o modified tellegen absoprtion questionnaire (modtas) [29] ; o scale to assess the therapeutic relationship (s…”
Majić, T., Jungaberle, H., Schmidt, T. T., Zeuch, A., Hermle, L., & Gallinat, J.. (2017). Psychotherapy with Adjuvant use of Serotonergic Psychoactive Substances: Possibilities and Challenges. Fortschritte Der Neurologie Psychiatrie
Plain numerical DOI: 10.1055/s-0043-103085
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“Background recently, scientific interest in the therapeutic potential of serotonergic and psilocybin hallucinogens (psychedelics) such as lysergic acid diethylamide (lsd) and entactogens like 3,4-methylendioxymethamphetamine (mdma) within the framework of psychotherapy has resumed. the present article provides an overview on the current evidence on substance-assisted psychotherapy with these substances. method a selective search was carried out in the pubmed and cochrane library including studies investigating the clinical use of serotonergic psychoactive substances since 2000. results studies were found investigating the following indications: alcohol (lsd and psilocybin) and tobacco addiction (psilocybin), anxiety and depression in patients suffering from life-threatening somatic illness (lsd and psilocybin), obsessive-compulsive disorder (ocd) (psilocybin), treatment-resistant major depression (psilocybin), and posttraumatic stress disorder (ptsd) (mdma). discussion substance use disorders, ptsd and anxiety and depression in patients suffering from life-threatening somatic illness belong to the indications with the best evidence for substance-assisted psychotherapy with serotonergic psychoactive agents. to date, studies indicate efficacy and relatively good tolerability. further studies are needed to determine whether these substances may represent suitable and effective treatment options for some treatment-resistant psychiatric disorders in the future.”
Thomas, K., Malcolm, B., & Lastra, D.. (2017). Psilocybin-Assisted Therapy: A Review of a Novel Treatment for Psychiatric Disorders. Journal of Psychoactive Drugs
Plain numerical DOI: 10.1080/02791072.2017.1320734
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“Recent research suggests that functional connectivity changes may be involved in the pathophysiology of psychiatric disorders. hyperconnectivity in the default mode network has been associated with psychopathology, but psychedelic serotonin agonists like psilocybin may profoundly disrupt these dysfunctional neural network circuits and provide a novel treatment for psychiatric disorders. we have reviewed the current literature to investigate the efficacy and safety of psilocybin-assisted therapy for the treatment of psychiatric disorders. there were seven clinical trials that investigated psilocybin-assisted therapy as a treatment for psychiatric disorders related to anxiety, depression, and substance use. all trials demonstrated reductions in psychiatric rating scale scores or increased response and remission rates. there were large effect sizes related to improved depression and anxiety symptoms. psilocybin may also potentially reduce alcohol or tobacco use and increase abstinence rates in addiction, but the benefits of these two trials were less clear due to open-label study designs without statistical analysis. psilocybin-assisted therapy efficacy and safety appear promising, but more robust clinical trials will be required to support fda approval and identify the potential role in clinical psychiatry.”
Erritzoe, D., Roseman, L., Nour, M. M., MacLean, K., Kaelen, M., Nutt, D. J., & Carhart-Harris, R. L.. (2018). Effects of psilocybin therapy on personality structure. Acta Psychiatrica Scandinavica
Plain numerical DOI: 10.1111/acps.12904
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“Objective: to explore whether psilocybin with psychological support modulates personality parameters in patients suffering from treatment-resistant depression (trd). method: twenty patients with moderate or severe, unipolar, trd received oral psilocybin (10 and 25 mg, one week apart) in a supportive setting. personality was assessed at baseline and at 3-month follow-up using the revised neo personality inventory (neo-pi-r), the subjective psilocybin experience with altered state of consciousness (asc) scale, and depressive symptoms with qids-sr16. results: neuroticism scores significantly decreased while extraversion increased following psilocybin therapy. these changes were in the direction of the normative neo-pi-r data and were both predicted, in an exploratory analysis, by the degree of insightfulness experienced during the psilocybin session. openness scores also significantly increased following psilocybin, whereas conscientiousness showed trend-level increases, and agreeableness did not change. conclusion: our observation of changes in personality measures after psilocybin therapy was mostly consistent with reports of personality change in relation to conventional antidepressant treatment, although the pronounced increases in extraversion and openness might constitute an effect more specific to psychedelic therapy. this needs further exploration in future controlled studies, as do the brain mechanisms of postpsychedelic personality change.”
Camile, B.. (
2019).
Psilocybin based therapy for cancer related distress, a systematic review and meta analysis.
ArXiv
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“Background : depression and anxiety are common in patients with cancer, classical antidepressant has no proven efficacy on this type of distress compared to placebo. a psilocybin (serotoninergic hallucinogen) based therapy appear to give promising results among recent studies. aims : to examine if a psilocybin based therapy could be considered for patients with cancer related depression and anxiety and to assume it’s safety. to sum up heffter institute work, as the main institute working on this topic. method : following prisma (preferred reporting items for systematic reviews and meta analyses) guidelines, a systematic review was conducted, for quantitative and qualitative studies about psilocybin for treating cancer related depression and anxiety. pubmed and the heffter institute databases have been reached for this purpose, separating studies in types : qualitative or quantitative. we studied the effects on cancer related depression and anxiety separately and investigated the psychological and neurobiological mechanisms. results : the four studies included a total of 105 randomized patients, meta analysis on depression and anxiety with pooled peto odds ratio showed a significant superiority of psilocybin over placebo. the substance appeared to be safe for this type of patients. surprising psychological mechanisms hypothesis have been found out. conclusion : psilocybin appear to be potentially useful as a treatment for cancer related depression and anxiety. future research should verify these findings on wider population and eventually seek a way to apply therapy to non hospitalized (ambulatory) patients. keywords : psilocybin, depression, anxiety, review, meta-analysis”
Jones, T. K., & Lippmann, S.. (2020). Psilocybin Can Diminish Depression. The Primary Care Companion for CNS Disorders
Plain numerical DOI: 10.4088/PCC.19br02580
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Euctr, G. B.. (
2020).
A Trial of Psilocybin in Clinical Depression Resistant to Standard Treatments.
Libdb.Csu.Edu.Cn:80/Rwt/TCL/Http/P75YPLUYNBYT64LPPE/Trialsearch/Trial2.Aspx?TrialID=EUCTR2018-003573-97-GB
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“INTERVENTION: product name: psilocybin pharmaceutical form: capsule inn or proposed inn: psilocybin cas number: 520‐52‐5 concentration unit: mg milligram(s) concentration type: equal concentration number: 5‐ pharmaceutical form of the placebo: capsule route of administration of the placebo: oral use condition: major depressive disorder ; meddra version: 21.1 level: pt classification code 10057840 term: major depression system organ class: 10037175 ‐ psychiatric disorders therapeutic area: psychiatry and psychology [f] ‐ mental disorders [f03] primary outcome: main objective: to evaluate the feasibility of a randomised, controlled trial design, in which a single dose of psilocybin 25mg po vs placebo, is given to adult participants with treatment resistant major depressive disorder (trd), under psychologically supportive conditions, with 6 weeks of follow up, by measuring recruitment rates, dropout rates and by estimating the variance of the primary outcome measure (madrs) to inform upon the design of a phase 3 trial. primary end point(s): recruitment rates, dropout rates and estimation of the variance of the primary outcome measure (madrs).; ; secondary objective: 1)to assess the clinician‐rated efficacy of psilocybin 25mg compared to placebo via:; a)the change in the madrs total score from baseline to 3 weeks after treatment; b)the proportion of participants who demonstrate a response to treatment( =50% decrease in madrs total score) from baseline to week 3. ; c)proportion of participants in remission( madrs total score =10 at week 3); 2)to assess the participant‐rated efficacy of psilocybin 25mg compared to placebo via:; a)proportion of participants who demonstrate a response to treatment, ( a =50% decrease in qids‐sr‐16 total score) from baseline (v2) to week 3 (v6).; b)proportion of participants in remission, where remission is defined as a qids‐sr‐16 total score =5 at week 3. ; 3)to evaluate the safety and tolerability of psilocybin in participants with trd based on adverse events (aes), changes in vital signs and suicidal ideation/behaviour (measured using the columbia suicide severity rating scale).; timepoint(s) of evaluation of this end point: 3 weeks after dosing secondary outcome: secondary end point(s): 1) the change in the montgomery‐asberg depression rating scale total score from the baseline visit (v2 ‐ 1 day prior to treatment) to week 3 after treatment (v6). ; 2) the proportion of participants who demonstrate a response to treatment, whe…”
S., P.. (
2016).
Return of the psychedelics: Psilocybin for treatment resistant depression.
Asian Journal of Psychiatry
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“Psilocybin, the clinically most researched classic psychedelic has recently been tested for its safety and efficacy in a clinical population of treatment resistant depression. the efficacy of psilocybin in clinical depression previously demonstrated in the elecrophysiologic and neuroimaging findings as also in neuropsychological assessments is further validated by the findings of this rigorously conducted randomized trial. mechanism of action of psilocybin and efficacy in treatment resistant depression are discussed in this paper. ethical issues of conducting clinical trials with psychedelics are also discussed with particular emphasis on their relative safety and absence of addiction potential. implications of these issues for conduct of larger trials for establishing risk benefit ratio in treatment resistant depression are further suggested.
copyright © 2016 elsevier b.v.”
Kelly, J. R., Baker, A., Babiker, M., Burke, L., Brennan, C., & O’keane, V.. (2019). The psychedelic renaissance: The next trip for psychiatry?. Irish Journal of Psychological Medicine
Plain numerical DOI: 10.1017/ipm.2019.39
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“The psychedelic research renaissance is gaining traction. preliminary clinical studies of the hallucinogenic fungi, psilocybin, with psychological support, have indicated improvements in mood, anxiety and quality of life. a seminal, open-label study demonstrated marked reductions in depression symptoms in participants with treatment-resistant depression (trd). the associated neurobiological processes involve alterations in brain connectivity, together with altered amygdala and default mode network activity. at the cellular level, psychedelics promote synaptogenesis and neural plasticity. prompted by the promising preliminary studies, a randomized, double-blind trial has recently been launched across europe and north america to investigate the efficacy of psilocybin in trd. one of these centres is based in ireland – cho area 7 and tallaght university hospital. the outcome of this trial will determine whether psilocybin with psychological support will successfully translate into the psychiatric clinic for the benefit of patients.”
Chahar, D. Y. K.. (2021). Unmet need in depression: Psilocybin, a breakthrough treatment option. International Journal of Advanced Research in Medicine
Plain numerical DOI: 10.22271/27069567.2021.v3.i1f.159
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Silveira, F. M., Mendes, A. P., Santos, M. R. dos, Cerchi, J. R., Umeda, I. T. T., Melo, B. B. de, … Abdalla, D. R.. (2021). Use of alternative therapy with Psilocybin in oncologic patients with depression and/or anxiety disorders – integrative review. Research, Society and Development
Plain numerical DOI: 10.33448/rsd-v10i10.19297
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“Cancer is not limited to the physical dimension, but it also affects the entire biopsychosocial context in which the patient is inserted, making him more susceptible to psychiatric disorders such as depression and anxiety. these often require pharmacological intervention, and the use of psilocybin, a substance found in mushroom species, is one of the alternatives considered today. the present study aims to carry out an integrative review regarding the use of alternative therapies, in this case psilocybin, in cancer patients suffering from anxiety and / or depression disorders. the type of study carried out was an integrative literature review, which was based on a bibliographic survey of texts published between 2010 and 2021 on the pubmed platform. this survey took place between december 2020 and february 2021, with a review of three articles in total. studies show a potential new line of alternative treatment for anxiety and depression in cancer patients, the use of psilocybin. the treatment is done quickly, sustained and lasting, in conjunction with psychotherapy there is improvement in a single dose. all the studies analyzed so far have been shown to be effective for the treatment of anxiety and depression in cancer patients. with this, psilocybin can be an alternative therapy for those patients in psychological distress due to cancer, especially for those who did not obtain a satisfactory response with the use of conventional treatment, allowing that in the future the substance may become a definitive therapeutic modality for patients in psychological distress due to cancer.”
Reiff, C. M., Richman, E. E., Nemeroff, C. B., Carpenter, L. L., Widge, A. S., Rodriguez, C. I., … McDonald, W. M.. (2020). Psychedelics and psychedelic-assisted psychotherapy. American Journal of Psychiatry
Plain numerical DOI: 10.1176/appi.ajp.2019.19010035
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“Objective: the authors provide an evidenced-based summary of the literature on the clinical application of psychedelic drugs in psychiatric disorders. methods: searches of pubmed and psycinfo via ovid were conducted for articles in english, in peer-reviewed journals, reportingon ‘psilocybin,’ ‘lysergic acid diethylamide,’ ‘lsd,’ ‘ayahuasca,’ ‘3,4-methylenedioxymethamphetamine,’ and ‘mdma,’ in human subjects, published between 2007 and july 1, 2019. a total of 1,603 articles were identified and screened. articles that did not contain the terms ‘clinical trial,’ ‘therapy,’ or ‘imaging’ in the title or abstract were filtered out. the 161 remaining articles were reviewed by two or more authors. the authors identified 14 articles reporting on well-designed clinical trials investigating the efficacy of lysergic acid diethylamide (lsd), 3,4-methylenedioxymethamphetamine (mdma), psilocybin, and ayahuasca for the treatment of mood and anxiety disorders, trauma and stress-related disorders, and substancerelated and addictive disorders as well as in end-of-life care. results: the most significant database exists for mdma and psilocybin, which have been designated by the u.s. food and drug administration (fda) as ‘breakthrough therapies’ for posttraumatic stress disorder (ptsd) and treatment-resistant depression, respectively. the research on lsd and ayahuasca is observational, but available evidence suggests that these agents may have therapeutic effects in specific psychiatric disorders. conclusions: randomized clinical trials support the efficacy of mdma in the treatment of ptsd and psilocybin in the treatment of depression and cancer-related anxiety. the research to support the use of lsd and ayahuasca in the treatment of psychiatric disorders is preliminary, although promising. overall, the database is insufficient for fda approval of any psychedelic compound for routine clinical use in psychiatric disorders at this time, but continued research on the efficacy of psychedelics for the treatment of psychiatric disorders is warranted.”
Psiuk, D., Nowak, E., Cholewa, K., Łopuszańska, U., & Samardakiewicz, M.. (2021). The potential role of serotonergic hallucinogens in depression treatment. Life
Plain numerical DOI: 10.3390/life11080765
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“Due to an increasing number of depression diagnoses and limited effective treatments, researchers continue to explore novel therapeutic strategies for this disorder. recently, interest has revolved around the use of serotonergic psychedelics to reduce the symptoms of depression. in this systematic review, we summarize the currently available knowledge on the safety and efficacy of psychedelic substances for the treatment of depression. a literature search of the pubmed/med-line database identified 14 clinical trials from the last 10 years that examined the use of psilocybin, mdma, dmt, or lsd for the treatment of depression symptoms. some psychedelics, especially psilocybin, demonstrated an ability to reduce depressive symptoms as measured by several psychological scales, which was often sustained for months after the last psychedelic session. moreover, one study revealed that psilocybin has comparable efficacy to escitalopram in the treatment of depression. none of the studies reported any serious adverse events associated with psychedelic ad-ministration. the reviewed studies suggest that psychedelics have great potential in depression therapy and, after addressing and overcoming the current study limitations, may be used as a novel method of treating depression in the future.”
de Veen, B. T. H., Schellekens, A. F. A., Verheij, M. M. M., & Homberg, J. R.. (2017). Psilocybin for treating substance use disorders?. Expert Review of Neurotherapeutics
Plain numerical DOI: 10.1080/14737175.2016.1220834
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“Introduction: evidence based treatment for substance use disorders (sud) includes psychotherapy and pharmacotherapy. however, these are only partially effective. hallucinogens, such as psilocybin, may represent potential new treatment options for sud. this review provides a summary of (human) studies on the putative therapeutic effects of psilocybin, and discusses the receptor systems, brain regions and cognitive and emotional processes mediating psilocybin’s effects. psilocybin’s chemical structure is similar to that of serotonin. dysregulations in the serotonin system are associated with alterations in stress hormones, such as cortisol, and mood disorders. after psilocybin administration cortisol levels spike and activate the executive control network, with subsequent increased control over emotional processes, and relief of negative thinking and persistent negative emotions. preliminary data of ongoing alcohol and smoking addiction studies in humans shows promising effects of psilocybin administration on substance use. importantly, psilocybin has a low risk of toxicity and dependence and can be used safely under controlled clinical conditions. areas covered: this paper is a narrative review based on the search terms: psilocybin, substance use disorder, addiction, depression, serotonin. literature on potential efficacy and mechanisms of action of psilocybin in sud is discussed. expert commentary: recent positive findings with psilocybin need confirmation in well-designed placebo controlled randomized trials employing a large sample size.”
Nutt, D.. (2016). Psilocybin for anxiety and depression in cancer care? Lessons from the past and prospects for the future. Journal of Psychopharmacology
Plain numerical DOI: 10.1177/0269881116675754
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Nayak, S. M., Gukasyan, N., Barrett, F. S., Erowid, E., Erowid, F., & Griffiths, R. R.. (2021). Classic Psychedelic Coadministration with Lithium, but Not Lamotrigine, is Associated with Seizures: An Analysis of Online Psychedelic Experience Reports. Pharmacopsychiatry
Plain numerical DOI: 10.1055/a-1524-2794
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“Introduction psychedelics show promise in treating unipolar depression, though patients with bipolar disorder have been excluded from recent psychedelic trials. there is limited information on the use of classic psychedelics (e. g., lsd or psilocybin) in individuals using mood stabilizers to treat bipolar disorder. this is important to know, as individuals with bipolar depression may attempt to treat themselves with psychedelics while on a mood stabilizer, particularly given enthusiastic media reports of the efficacy of psilocybin for depression. methods this study analyzed reports of classic psychedelics administered with mood stabilizers from 3 websites (
erowid.org,
shroomery.org, and
reddit.com). results strikingly, 47% of 62 lithium plus psychedelic reports involved seizures, and an additional 18% resulted in bad trips while none of 34 lamotrigine reports did. further, 39% of lithium reports involved medical attention. most of the lamotrigine reports (65%) but few (8%) of the lithium reports were judged to not affect the psychedelic experience. discussion although further research is needed, we provisionally conclude that psychedelic use may pose a significant seizure risk for patients on lithium.”
Nichols, D. E.. (2020). Psilocybin: from ancient magic to modern medicine. Journal of Antibiotics
Plain numerical DOI: 10.1038/s41429-020-0311-8
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“Psilocybin (4-phosphoryloxy-n,n-dimethyltryptamine) is an indole-based secondary metabolite produced by numerous species of mushrooms. south american aztec indians referred to them as teonanacatl, meaning ‘god’s flesh,’ and they were used in religious and healing rituals. spanish missionaries in the 1500s attempted to destroy all records and evidence of the use of these mushrooms. nevertheless, a 16th century spanish franciscan friar and historian mentioned teonanacatl in his extensive writings, intriguing 20th century ethnopharmacologists and leading to a decades-long search for the identity of teonanacatl. their search ultimately led to a 1957 photo-essay in a popular magazine, describing for the western world the use of these mushrooms. specimens were ultimately obtained, and their active principle identified and chemically synthesized. in the past 10–15 years several fda-approved clinical studies have indicated potential medical value for psilocybin-assisted psychotherapy in treating depression, anxiety, and certain addictions. at present, assuming that the early clinical studies can be validated by larger studies, psilocybin is poised to make a significant impact on treatments available to psychiatric medicine.”
Fricke, J., Lenz, C., Wick, J., Blei, F., & Hoffmeister, D.. (2019). Production Options for Psilocybin: Making of the Magic. Chemistry – A European Journal
Plain numerical DOI: 10.1002/chem.201802758
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“The fungal genus psilocybe and other genera comprise numerous mushroom species that biosynthesize psilocybin (4-phosphoryloxy-n,n-dimethyltryptamine). it represents the prodrug to its dephosphorylated psychotropic analogue, psilocin. the colloquial term ‘magic mushrooms’ for these fungi alludes to their hallucinogenic effects and to their use as recreational drugs. however, clinical trials have recognized psilocybin as a valuable candidate to be developed into a medication against depression and anxiety. we here highlight its recently elucidated biosynthesis, the concurrently developed concept of enzymatic in vitro and heterologous in vivo production, along with previous synthetic routes. the prospect of psilocybin as a promising therapeutic may entail an increased demand, which can be met by biotechnological production. therefore, we also briefly touch on psilocybin’s therapeutic relevance and pharmacology.”
Panels, Mini-Panels and Study Groups. (2015). Neuropsychopharmacology
Plain numerical DOI: 10.1038/npp.2015.324
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“Background: our research team have conducted a series of mri and meg studies with the 5ht2a receptor agonist psilocybin in comparison with mdma, an entactogen that releases 5ht. the mri studies of psilocybin (both asl and fmri) revealed unexpected reduction in brain blood flow and a decrease in bold signal (carhart‐harris et al 2013 pnas) in high‐level cortical regions and the thalamus, with post‐hoc analysis showing large increases in brain connectivity between, rather than within, the usual resting state networks (petri et al j roy soc 2014). the cortical psilocybin mri findings were confirmed by a later meg study that revealed a major loss of power in all measured frequency bands (1‐100hz) after psilocybin with decreases in alpha power in the posterior cingulate cortex correlating with egodissolution measures (carhart‐harris and muthukumaraswamy et al 2013 j neurosci). results from the fmri and meg work suggested psilocybin has antidepressant properties and from these we are now conducting the first study of psilocybin in resistant depression. data from a pilot phase will be ready for the acnp meeting. mdma also decreased blood flow and bold signal but the effects were largely subcortical, particularly in the amygdala, and no psychedelic effects were seen (carhart‐harris et al 2014 biol psych). negative memories were attenuated and positive ones enhanced by mdma and these effects were associated with fmri‐measured changes in brain activity (carhart‐harris et al 2013 int neuropychopharm). lsd is the prototypical hallucinogen, with much greater use than the others in psychiatric and research settings, with over 1000 papers published before it was banned in 1967. since then, and only in the past year, there have been 3 research reports, but none using modern brain imaging methods. methods: over the course of 6 hours, 20 healthy volunteers were scanned sequentially with asl/bold‐fmri/ and meg following 75 microgm lsd iv or saline placebo in a crossover design at least 2 weeks apart. subjective ratings of psychedelic experiences were then correlated with the imaging data. twelve patients with resistant depression were treated with two sessions of psilocybin. significant improvements in symptom severity were observed for up to 5 weeks post‐treatment, with a far greater before and (1 week) after treatment effect size (cohen’s d = 3.4) than seen with currently available anti‐depressant interventions. results: lsd decreased integrity and segregation of brain …”
Study: Psilocybin enhances therapy in patients with major depression. (2021). The Brown University Psychopharmacology Update
Plain numerical DOI: 10.1002/pu.30675
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“Patients with major depressive disorder who received two administrations of the psychedelic psilocybin as part of a psychotherapy regimen saw a rapid and lasting improvement in depression symptoms, a randomized open‐label trial has found. these findings extend results of research that have suggested antidepressant effects for psilocybin in patients with cancer and treatment‐resistant depression, the researchers stated. study results were published online nov. 4, 2020, in jama psychiatry.”
Hesselgrave, N., Troppoli, T. A., Wulff, A. B., Cole, A. B., & Thompson, S. M.. (2021). Harnessing psilocybin: Antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proceedings of the National Academy of Sciences of the United States of America
Plain numerical DOI: 10.1073/pnas.2022489118
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“Depression is a widespread and devastating mental illness and the search for rapid-acting antidepressants remains critical. there is now exciting evidence that the psychedelic compound psilocybin produces not only powerful alterations of consciousness, but also rapid and persistent antidepressant effects. how psilocybin exerts its therapeutic actions is not known, but it is widely presumed that these actions require altered consciousness, which is known to be dependent on serotonin 2a receptor (5-ht2ar) activation. this hypothesis has never been tested, however. we therefore asked whether psilocybin would exert antidepressant-like responses in mice and, if so, whether these responses required 5-ht2ar activation. using chronically stressed male mice, we observed that a single injection of psilocybin reversed anhedonic responses assessed with the sucrose preference and female urine preference tests. the antianhedonic response to psilocybin was accompanied by a strengthening of excitatory synapses in the hippocampus—a characteristic of traditional and fast-acting antidepressants. neither behavioral nor electrophysiological responses to psilocybin were prevented by pretreatment with the 5-ht2a/2c antagonist ketanserin, despite positive evidence of ketanserin’s efficacy. we conclude that psilocybin’s mechanism of antidepressant action can be studied in animal models and suggest that altered perception may not be required for its antidepressant effects. we further suggest that a 5-ht2ar–independent restoration of synaptic strength in cortico-mesolimbic reward circuits may contribute to its antidepressant action. the possibility of combining psychedelic compounds and a 5-ht2ar antagonist offers a potential means to increase their acceptance and clinical utility and should be studied in human depression.”
Jefsen, O., Højgaard, K., Christiansen, S. L., Elfving, B., Nutt, D. J., Wegener, G., & Müller, H. K.. (2019). Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat. Acta Neuropsychiatrica
Plain numerical DOI: 10.1017/neu.2019.15
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“Objective:psilocybin is a serotonin receptor agonist with a therapeutic potential for treatment-resistant depression and other psychiatric illnesses. we investigated whether the administration of psilocybin had an antidepressant-like effect in a rat model of depression.methods:using the flinders sensitive line (fsl) rat model of depression, we assessed the antidepressant-like effect of psilocin and psilocybin, measured as a reduction in immobility time in the forced swim test (fst). we measured locomotor activity in an open field test (oft) to control for stimulant properties of the drugs. we performed a set of experiments to test different doses, treatment paradigms, and timing of the tests in relation to the drug administration.results:psilocin and psilocybin showed no effect on immobility, struggling, or swimming behaviour in the fst and no effect on locomotor activity in the oft. fsl rats did show significantly more immobility than their control strain, the flinders resistant line, as expected.conclusion:psilocin and psilocybin showed no antidepressant-like effect in the fsl rats, despite a positive effect in humans. this suggests that other animal models of depression and other behavioural tests may be more appropriate for translational studies in the effects of psilocybin.”
Kraehenmann, R., Preller, K. H., Scheidegger, M., Pokorny, T., Bosch, O. G., Seifritz, E., & Vollenweider, F. X.. (2015). Psilocybin-induced decrease in amygdala reactivity correlates with enhanced positive mood in healthy volunteers. Biological Psychiatry
Plain numerical DOI: 10.1016/j.biopsych.2014.04.010
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“Background the amygdala is a key structure in serotonergic emotion-processing circuits. in healthy volunteers, acute administration of the serotonin 1a/2a/2c receptor agonist psilocybin reduces neural responses to negative stimuli and induces mood changes toward positive states. however, it is little-known whether psilocybin reduces amygdala reactivity to negative stimuli and whether any change in amygdala reactivity is related to mood change. methods this study assessed the effects of acute administration of the hallucinogen psilocybin (.16 mg/kg) versus placebo on amygdala reactivity to negative stimuli in 25 healthy volunteers using blood oxygen level-dependent functional magnetic resonance imaging. mood changes were assessed using the positive and negative affect schedule and the state portion of the state-trait anxiety inventory. a double-blind, randomized, cross-over design was used with volunteers counterbalanced to receive psilocybin and placebo in two separate sessions at least 14 days apart. results amygdala reactivity to negative and neutral stimuli was lower after psilocybin administration than after placebo administration. the psilocybin-induced attenuation of right amygdala reactivity in response to negative stimuli was related to the psilocybin-induced increase in positive mood state. conclusions these results demonstrate that acute treatment with psilocybin decreased amygdala reactivity during emotion processing and that this was associated with an increase of positive mood in healthy volunteers. these findings may be relevant to the normalization of amygdala hyperactivity and negative mood states in patients with major depression.”
Donovan, L. L., Johansen, J. V., Ros, N. F., Jaberi, E., Linnet, K., Johansen, S. S., … Knudsen, G. M.. (2021). Effects of a single dose of psilocybin on behaviour, brain 5-HT2A receptor occupancy and gene expression in the pig. European Neuropsychopharmacology
Plain numerical DOI: 10.1016/j.euroneuro.2020.11.013
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“Psilocybin has in some studies shown promise as treatment of major depressive disorder and psilocybin therapy was in 2019 twice designated as breakthrough therapy by the u.s. food and drug administration (fda). a very particular feature is that ingestion of just a single dose of psilocybin is associated with lasting changes in personality and mood. the underlying molecular mechanism behind its effect is, however, unknown. in a translational pig model, we here present the effects of a single dose of psilocybin on pig behaviour, receptor occupancy and gene expression in the brain. an acute i.v. injection of 0.08 mg/kg psilocybin to awake female pigs induced characteristic behavioural changes in terms of headshakes, scratching and rubbing, lasting around 20 min. a similar dose was associated with a cerebral 5-ht2a receptor occupancy of 67%, as determined by positron emission tomography, and plasma psilocin levels were comparable to what in humans is associated with an intense psychedelic experience. we found that 19 genes were differentially expressed in prefrontal cortex one day after psilocybin injection, and 3 genes after 1 week. gene set enrichment analysis demonstrated that multiple immunological pathways were regulated 1 week after psilocybin exposure. this provides a framework for future investigations of the lasting molecular mechanisms induced by a single dose of psilocybin. in the light of an ongoing debate as to whether psilocybin is a safe treatment for depression and other mental illnesses, it is reassuring that our data suggest that any effects on gene expression are very modest.”
Fricke, J., Sherwood, A., Kargbo, R., Orry, A., Blei, F., Naschberger, A., … Hoffmeister, D.. (2019). Enzymatic Route toward 6-Methylated Baeocystin and Psilocybin. ChemBioChem
Plain numerical DOI: 10.1002/cbic.201900358
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“Psilocybin and its direct precursor baeocystin are indole alkaloids of psychotropic psilocybe mushrooms. the pharmaceutical interest in psilocybin as a treatment option against depression and anxiety is currently being investigated in advanced clinical trials. here, we report a biocatalytic route to synthesize 6-methylated psilocybin and baeocystin from 4-hydroxy-6-methyl-l-tryptophan, which was decarboxylated and phosphorylated by the psilocybe cubensis biosynthesis enzymes psid and psik. n-methylation was catalyzed by psim. we further present an in silico structural model of psim that revealed a well-conserved sam-binding core along with peripheral nonconserved elements that likely govern substrate preferences.”
Majić, T., Jungaberle, H., Schmidt, T., Zeuch, A., Hermle, L., & Gallinat, J.. (2017). Psychotherapie mit adjuvanter Gabe von serotonergen psychoaktiven Substanzen – Möglichkeiten und Hindernisse. Fortschritte Der Neurologie · Psychiatrie
Plain numerical DOI: 10.1055/s-0043-103085
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“Hintergrund der einsatz von serotonergen halluzinogenen (psychedelika) wie lysergsäure-diethylamid (lsd) und psilocybin und entaktogenen wie 3,4-methylendioxymethamphetamin (mdma) im rahmen von psychotherapie ist in den letzten jahren wieder zunehmend ins licht des wissenschaftlichen interesses gerückt. die vorliegende arbeit fasst die aktuelle evidenz zur substanzunterstützten psychotherapie mit serotonergen psychoaktiva zusammen.methode eine selektive literaturrecherche erfolgte in pubmed und der cochrane library, wobei nach studien gesucht wurde, in denen der einsatz von serotonergen psychoaktiva in der psychotherapie seit 2000 untersucht wurde.ergebnisse es fanden sich studien für die folgenden behandlungsindikationen: alkoholabhängigkeit (lsd und psilocybin), nikotinabhängigkeit (psilocybin), behandlung von angst und depression bei lebensbedrohlicher körperlicher erkrankung (lsd und psilocybin), zwangsstörungen (psilocybin), therapieresistente major depression (psilocybin) und posttraumatische belastungsstörung (mdma).diskussion abhängigkeitserkrankungen, posttraumatische belastungsstörung sowie angst und depression bei lebensbedrohlicher körperlicher erkrankung stellen derzeit die am besten evaluierten indikationen für die substanzunterstützte psychotherapie mit serotonergen psychoaktiva dar. bisher zeigten sich hinweise für eine wirksamkeit bei relativ guter verträglichkeit. weitere studien sind erforderlich, um einzuschätzen, ob diese substanzen in zukunft in der behandlung bestimmter therapieresistenter psychischer erkrankungen eine option darstellen können.”
Saplakoglu, Y.. (
2019).
FDA Calls Psychedelic Psilocybin a “Breakthrough Therapy” for Severe Depression
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“FDA calls psychedelic psilocybin a ‘Breakthrough therapy’ for severe depression”
Germann, C. B.. (2020). The Psilocybin-Telomere Hypothesis: An empirically falsifiable prediction concerning the beneficial neuropsychopharmacological effects of psilocybin on genetic aging. Medical Hypotheses
Plain numerical DOI: 10.1016/j.mehy.2019.109406
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“We introduce a novel hypothesis which states that the therapeutic utilisation of psilocybin has beneficial effects on genetic aging. ex hypothesi, we predict a priori that controlled psilocybin interventions exert quantifiable positive impact on leucocyte telomere length (telomeres are a robust predictor of mortality and multifarious aging-related diseases). our hypothesising follows the popperian logic of scientific discovery, viz., bold (and refutable) conjectures form the very foundation of scientific progress. the ‘psilocybin-telomere hypothesis‘ is formalised as a logically valid deductive (syllogistic) argument and we provide substantial evidence to support the underlying premises. impetus for our theorising derives from a plurality of converging empirical sources indicating that psilocybin has persistent beneficial effects on various aspects of mental health (e.g., in the context of depression, anxiety, ptsd, ocd, addiction, etc.). additional support is based on a large corpus of studies that establish reliable correlations between mental health and telomere attrition (improved mental health is generally correlated with longer telomeres). another pertinent component of our argument is based on recent studies which demonstrate that ‘meditative states of consciousness’ provide beneficial effects on genetic aging. similarly, psilocybin can induce states of consciousness that are neurophysiologically and phenomenologically significantly congruent with meditative states. furthermore, prior research has demonstrated that a single dose of psilocybin can occasion life-changing transformative experiences (≈ 70% of healthy volunteers rate their experience with psilocybin amongst the five personally most meaningful lifetime events, viz., ranked next to giving birth to a child or losing a loved one). we postulate that these profound psychological events leave quantifiable marks at the molecular genetic/epigenetic level. given the ubiquitous availability and cost effectiveness of telomere length assays, we suggest that quantitative telomere analysis should be regularly included in future psilocybin studies as an adjunctive biological marker (i.e., to facilitate scientific consilience via methodological triangulation). in order to substantiate the ‘psilocybin-telomere hypothesis’ potential neuropsychopharmacological, endocrinological, and genetic mechanisms of action are discussed (e.g., hpa-axis reactivity, hippocampal neurogenesis, neurotropic growth factors…”
Galvão-Coelho, N. L., Marx, W., Gonzalez, M., Sinclair, J., de Manincor, M., Perkins, D., & Sarris, J.. (2021). Classic serotonergic psychedelics for mood and depressive symptoms: a meta-analysis of mood disorder patients and healthy participants. Psychopharmacology
Plain numerical DOI: 10.1007/s00213-020-05719-1
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“Rationale: major depressive disorder is one of the leading global causes of disability, for which the classic serotonergic psychedelics have recently reemerged as a potential therapeutic treatment option. objective: we present the first meta-analytic review evaluating the clinical effects of classic serotonergic psychedelics vs placebo for mood state and symptoms of depression in both healthy and clinical populations (separately). results: our search revealed 12 eligible studies (n = 257; 124 healthy participants, and 133 patients with mood disorders), with data from randomized controlled trials involving psilocybin (n = 8), lysergic acid diethylamide ([lsd]; n = 3), and ayahuasca (n = 1). the meta-analyses of acute mood outcomes (3 h to 1 day after treatment) for healthy volunteers and patients revealed improvements with moderate significant effect sizes in favor of psychedelics, as well as for the longer-term (16 to 60 days after treatments) mood state of patients. for patients with mood disorder, significant effect sizes were detected on the acute, medium (2–7 days after treatment), and longer-term outcomes favoring psychedelics on the reduction of depressive symptoms. conclusion: despite the concerns over unblinding and expectancy, the strength of the effect sizes, fast onset, and enduring therapeutic effects of these psychotherapeutic agents encourage further double-blind, placebo-controlled clinical trials assessing them for management of negative mood and depressive symptoms.”
Mason, N. L., Mischler, E., Uthaug, M. V., & Kuypers, K. P. C.. (2019). Sub-Acute Effects of Psilocybin on Empathy, Creative Thinking, and Subjective Well-Being. Journal of Psychoactive Drugs
Plain numerical DOI: 10.1080/02791072.2019.1580804
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“Creative thinking and empathy are crucial for everyday interactions and subjective well-being. this is emphasized by studies showing a reduction in these skills in populations where social interaction and subjective well-being are significantly compromised (e.g., depression). anecdotal reports and recent studies suggest that a single administration of psilocybin can enhance such processes and could therefore be a potential treatment. however, it has yet to be assessed whether effects outlast acute intoxication. the present study aimed to assess the sub-acute effects of psilocybin on creative thinking, empathy, and well-being. participants attending a psilocybin retreat completed tests of creative (convergent and divergent) thinking and empathy, and the satisfaction with life scale on three occasions: before ingesting psilocybin (n = 55), the morning after (n = 50), and seven days after (n = 22). results indicated that psilocybin enhanced divergent thinking and emotional empathy the morning after use. enhancements in convergent thinking, valence-specific emotional empathy, and well-being persisted seven days after use. sub-acute changes in empathy correlated with changes in well-being. the study demonstrates that a single administration of psilocybin in a social setting may be associated with sub-acute enhancement of creative thinking, empathy, and subjective well-being. future research should test whether these effects contribute to the therapeutic effects in clinical populations.”
Shukuroglou, M., Roseman, L., Wall, M., Nutt, D., Carhart-Harris, R., & Kaelen, M.. (
2019).
Changes in music-evoked emotion and ventral-striatum functional connectivity following psilocybin therapy for depression.
Brain and Neuroscience Advances
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“Introduction: there has recently been renewed interest in the therapeutic potential of psychedelic drugs such as psilocybin1. music reliably evokes emotion2, and the ability of psychedelics to enhance music-evoked emotion has been illustrated in the past, where the combination of psychedelics and music enhanced certain subjective experiences thought to be useful in the therapeutic context3. the present investigation sought to examine whether psilocybin therapy for treatment-resistant depression could elicit sustained changes in music-evoked emotion, and in ventral-striatum (vs) functional-connectivity (fc). methods: 19 patients with treatment-resistant depression received a low oral dose (10 mg) of psilocybin on the first session, and a high dose (25 mg) on another session, separated by one week. they underwent functional magnetic resonance imaging (fmri) on two occasions, one week prior to the first session and one day following the second session. during each session, two scans were conducted; one without music, and one with music. subjective ratings were completed after each scan, comprising of a visual analogue scale (vas), and the 21-item geneva emotional music scale (gems). given its role in musical reward, the ventral striatum (vs), specifically the nucleus accumbens (nac), was chosen as region of interest (roi)4, and changes in its functional-connectivity profile were assessed. statistical approach: a two-way repeated measures anova was performed to test for differences between musicand no-music scans (a music-effect), before and after treatment (a treatment-effect) and an interaction-effect for inscanner pleasure ratings. paired two-tailed t tests were then performed to test for significant differences between conditions for the in-scanner ratings, as well as for the gems factors. results and conclusions: results revealed a significant increase in music-evoked emotions following treatment with psilocybin. moreover, decreased nac fc with the default-mode network (dmn) was observed following psilocybin treatment during music listening. these results are consistent with current thinking on the role of psychedelics in enhancing the effects of music-evoked pleasure, and provide new insights into the functional brain changes underlying this. we suggest that nac-dmn connectivity could reflect an inhibitory mechanism for the hedonic experience of music in depression, and that this mechanism is diminished following therapy with psilocybin. (figure prese…”
Higgins, G. A., Carroll, N. K., Brown, M., MacMillan, C., Silenieks, L. B., Thevarkunnel, S., … Sellers, E. M.. (2021). Low Doses of Psilocybin and Ketamine Enhance Motivation and Attention in Poor Performing Rats: Evidence for an Antidepressant Property. Frontiers in Pharmacology
Plain numerical DOI: 10.3389/fphar.2021.640241
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“Long term benefits following short-term administration of high psychedelic doses of serotonergic and dissociative hallucinogens, typified by psilocybin and ketamine respectively, support their potential as treatments for psychiatric conditions such as major depressive disorder. the high psychedelic doses induce perceptual experiences which are associated with therapeutic benefit. there have also been anecdotal reports of these drugs being used at what are colloquially referred to as ‘micro’ doses to improve mood and cognitive function, although currently there are recognized limitations to their clinical and preclinical investigation. in the present studies we have defined a low dose and plasma exposure range in rats for both ketamine (0.3–3 mg/kg [10–73 ng/ml]) and psilocybin/psilocin (0.05–0.1 mg/kg [7–12 ng/ml]), based on studies which identified these as sub-threshold for the induction of behavioral stereotypies. tests of efficacy were focused on depression-related endophenotypes of anhedonia, amotivation and cognitive dysfunction using low performing male long evans rats trained in two food motivated tasks: a progressive ratio (pr) and serial 5-choice (5-csrt) task. both acute doses of ketamine (1–3 mg/kg ip) and psilocybin (0.05–0.1 mg/kg sc) pretreatment increased break point for food (pr task), and improved attentional accuracy and a measure of impulsive action (5-csrt task). in each case, effect size was modest and largely restricted to test subjects characterized as ‘low performing’. furthermore, both drugs showed a similar pattern of effect across both tests. the present studies provide a framework for the future study of ketamine and psilocybin at low doses and plasma exposures, and help to establish the use of these lower concentrations of serotonergic and dissociative hallucinogens both as a valid scientific construct, and as having a therapeutic utility.”
Adams, A. M., Kaplan, N. A., Wei, Z., Brinton, J. D., Monnier, C. S., Enacopol, A. L., … Jones, J. A.. (2019). In vivo production of psilocybin in E. coli. Metabolic Engineering
Plain numerical DOI: 10.1016/j.ymben.2019.09.009
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“Psilocybin, the prodrug of the psychoactive molecule psilocin, has demonstrated promising results in clinical trials for the treatment of addiction, depression, and post-traumatic stress disorder. the development of a psilocybin production platform in a highly engineerable microbe could lead to rapid advances towards the bioproduction of psilocybin for use in ongoing clinical trials. here, we present the development of a modular biosynthetic production platform in the model microbe, escherichia coli. efforts to optimize and improve pathway performance using multiple genetic optimization techniques were evaluated, resulting in a 32-fold improvement in psilocybin titer. further enhancements to this genetically superior strain were achieved through fermentation optimization, ultimately resulting in a fed-batch fermentation study, with a production titer of 1.16 g/l of psilocybin. this is the highest psilocybin titer achieved to date from a recombinant organism and a significant step towards demonstrating the feasibility of industrial production of biologically-derived psilocybin.”
Ross, S., Agin-Liebes, G., Lo, S., Zeifman, R. J., Ghazal, L., Benville, J., … Mennenga, S. E.. (2021). Acute and Sustained Reductions in Loss of Meaning and Suicidal Ideation following Psilocybin-Assisted Psychotherapy for Psychiatric and Existential Distress in Life-Threatening Cancer. ACS Pharmacology and Translational Science
Plain numerical DOI: 10.1021/acsptsci.1c00020
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“People with advanced cancer are at heightened risk of desire for hastened death (dhd), suicidal ideation (si), and completed suicide. loss of meaning (lom), a component of demoralization, can be elevated by a cancer diagnosis and predicts dhd and si in this population. we completed a randomized controlled trial in which psilocybin-assisted psychotherapy (pap) produced rapid and sustained improvements in depression, demoralization, and hopelessness in people with cancer. converging epidemiologic and clinical trial findings suggests a potential antisuicidal effect of this treatment. to probe our hypothesis that pap relieves si through its beneficial impacts on depression and demoralization (lom in particular), we performed secondary analyses assessing within- and between-group differences with regard to lom and an si composite score. among participants with elevated si at baseline, pap was associated with within-group reductions in si that were apparent as early as 8 h and persisted for 6.5 months postdosing. pap also produced large reductions in lom from baseline that were apparent 2 weeks after treatment and remained significant and robust at the 6.5 month and 3.2 and 4.5 year follow-ups. exploratory analyses support our hypothesis and suggest that pap may be an effective antisuicidal intervention following a cancer diagnosis due to its positive impact on hopelessness and demoralization and its effects on meaning-making in particular. these preliminary results implicate psilocybin treatment as a potentially effective alternative to existing antidepressant medications in patients with cancer that are also suicidal, and warrant further investigation in participants with elevated levels of depression and suicidality.”
Nutt, D., Erritzoe, D., & Carhart-Harris, R.. (2020). Psychedelic Psychiatry’s Brave New World. Cell
Plain numerical DOI: 10.1016/j.cell.2020.03.020
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“After a legally mandated, decades-long global arrest of research on psychedelic drugs, investigation of psychedelics in the context of psychiatric disorders is yielding exciting results. outcomes of neuroscience and clinical research into 5-hydroxytryptamine 2a (5-ht2a) receptor agonists, such as psilocybin, show promise for addressing a range of serious disorders, including depression and addiction.”
R., C.-H.. (
2015).
Results: Of a multi-modal neuroimaging study of LSD and a psilocybin for treatment-resistant depression clinical trial.
Neuropsychopharmacology
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“Background: our research team have conducted a series of mri and meg studies with the 5ht2a receptor agonist psilocybin in comparison with mdma, an entactogen that releases 5ht. the mri studies of psilocybin (both asl and fmri) revealed unexpected reduction in brain blood flow and a decrease in bold signal (carhart-harris et al 2013 pnas) in high-level cortical regions and the thalamus, with post-hoc analysis showing large increases in brain connectivity between, rather than within, the usual resting state networks (petri et al j roy soc 2014). the cortical psilocybin mri findings were confirmed by a later meg study that revealed a major loss of power in all measured frequency bands (1-100hz) after psilocybin with decreases in alpha power in the posterior cingulate cortex correlating with egodissolution measures (carhart-harris and muthukumaraswamy et al 2013 j neurosci). results from the fmri and meg work suggested psilocybin has antidepressant properties and from these we are now conducting the first study of psilocybin in resistant depression. data from a pilot phase will be ready for the acnp meeting. mdma also decreased blood flow and bold signal but the effects were largely subcortical, particularly in the amygdala, and no psychedelic effects were seen (carhart-harris et al 2014 biol psych). negative memories were attenuated and positive ones enhanced by mdma and these effects were associated with fmri-measured changes in brain activity (carhart-harris et al 2013 int neuropychopharm). lsd is the prototypical hallucinogen, with much greater use than the others in psychiatric and research settings, with over 1000 papers published before it was banned in 1967. since then, and only in the past year, there have been 3 research reports, but none using modern brain imaging methods. methods: over the course of 6 hours, 20 healthy volunteers were scanned sequentially with asl/bold-fmri/ and meg following 75 microgm lsd iv or saline placebo in a crossover design at least 2 weeks apart. subjective ratings of psychedelic experiences were then correlated with the imaging data. twelve patients with resistant depression were treated with two sessions of psilocybin. significant improvements in symptom severity were observed for up to 5 weeks post-treatment, with a far greater before and (1 week) after treatment effect size (cohen’s d = 3.4) than seen with currently available anti-depressant interventions. results: lsd decreased integrity and segregation of brain …”
Strauss, N.. (2017). Psilocybin-assisted therapy for anxiety and depression: Implications for euthanasia. Medical Journal of Australia
Plain numerical DOI: 10.5694/mja17.00081
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Malone, T., Mennenga, S. E., Ross, S., Bossis, A., Guss, J., Babb, J., … Belser, A.. (
2016).
Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial..
Journal of Psychopharmacology
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“Background: clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression. methods: in this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. the primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks. results: prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. at the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60–80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. the psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression. conclusions: in conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress. trial registration:
clinicaltrials.gov identifier: nct00957359 [abstract from author]”
Bienemann, B., Ruschel, N. S., Campos, M. L., Negreiros, M. A., & Mograbi, D. C.. (2020). Self-reported negative outcomes of psilocybin users: A quantitative textual analysis. PLoS ONE
Plain numerical DOI: 10.1371/journal.pone.0229067
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“Psilocybin, a substance mainly found in mushrooms of the genus psilocybe, has been historically used for ritualistic, recreational and, more recently, medicinal purposes. the scientific literature suggests low toxicity, low risk of addiction, overdose, or other causes of injury commonly caused by substances of abuse, with growing interest in the use of this substance for conditions such as treatment-resistant depression. however, the presence of negative outcomes linked to psilocybin use is not clear yet. the objective of this study is to investigate the negative effects of psilocybin consumption, according to the users’ own perception through self-reports extracted from an online platform. 346 reports were analyzed with the assistance of the iramuteq textual analysis software, adopting the procedures of descending hierarchical classification, correspondence factor analysis and specificities analysis. the text segments were grouped in 4 main clusters, describing thinking distortions, emergencies, perceptual alterations and the administration of the substance. bad trips were more frequent in female users, being associated with thinking distortions. the use of multiple doses of psilocybin in the same session or its combination with other substances was linked to the occurrence of long-term negative outcomes, while the use of mushrooms in single high doses was linked to medical emergencies. these results can be useful for a better understanding of the effects of psilocybin use, guiding harm-reduction initiatives.”
Geiger, H. A., Wurst, M. G., & Daniels, R. N.. (2018). DARK Classics in Chemical Neuroscience: Psilocybin. ACS Chemical Neuroscience
Plain numerical DOI: 10.1021/acschemneuro.8b00186
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“Psilocybin is found in a family of mushrooms commonly known as ‘magic mushrooms’ that have been used throughout history to induce hallucinations. in the late 1950s albert hofmann, of sandoz laboratories, identified and synthesized the psychoactive compounds psilocybin and psilocin which are found in psilocybe mushrooms. psilocybin was marketed by sandoz as indocybin for basic psychopharmacological and therapeutic clinical research. psilocybin saw a rapid rise in popularity during the 1960s and was classed as a schedule i drug in 1970. this led to a significant decrease in psilocybin research. recently, however, preliminary studies with psilocybin have shown promise as potential for the treatment of obsessive compulsive disorder, alcohol addiction, tobacco addiction, and major depressive disorder, and the treatment of depression in terminally ill cancer patients. this review describes in detail the synthesis, metabolism, pharmacology, adverse drug reactions, and importance of psilocybin to neuroscience in the past and present.”
Fricke, J., Kargbo, R., Regestein, L., Lenz, C., Peschel, G., Rosenbaum, M. A., … Hoffmeister, D.. (2020). Scalable Hybrid Synthetic/Biocatalytic Route to Psilocybin. Chemistry – A European Journal
Plain numerical DOI: 10.1002/chem.202000134
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“Psilocybin, the principal indole alkaloid of psilocybe mushrooms, is currently undergoing clinical trials as a medication against treatment-resistant depression and major depressive disorder. the psilocybin supply for pharmaceutical purposes is met by synthetic chemistry. we replaced the problematic phosphorylation step during synthesis with the mushroom kinase psik. this enzyme was biochemically characterized and used to produce one gram of psilocybin from psilocin within 20 minutes. we also describe a pilot-scale protocol for recombinant psik that yielded 150 mg enzyme in active and soluble form. our work consolidates the simplicity of tryptamine chemistry with the specificity and selectivity of enzymatic catalysis and helps provide access to an important drug at potentially reasonable cost.”
Reynolds, C. F.. (2021). Psilocybin-Assisted Supportive Psychotherapy in the Treatment of Major Depression – Quo Vadis?. JAMA Psychiatry
Plain numerical DOI: 10.1001/jamapsychiatry.2020.2901
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Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., … Griffiths, R. R.. (2021). Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry
Plain numerical DOI: 10.1001/jamapsychiatry.2020.3285
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“Importance: major depressive disorder (mdd) is a substantial public health burden, but current treatments have limited effectiveness and adherence. recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression. objective: to investigate the effect of psilocybin therapy in patients with mdd. design, setting, and participants: this randomized, waiting list-controlled clinical trial was conducted at the center for psychedelic and consciousness research at johns hopkins bayview medical center in baltimore, maryland. adults aged 21 to 75 years with an mdd diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. enrollment occurred between august 2017 and april 2019, and the 4-week primary outcome assessments were completed in july 2019. a total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). data analysis was conducted from july 1, 2019, to july 31, 2020, and included participants who completed the intervention (evaluable population). interventions: two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 ml of water) in the context of supportive psychotherapy (approximately 11 hours). participants were randomized to begin treatment immediately or after an 8-week delay. main outcomes and measures: the primary outcome, depression severity was assessed with the grid-hamilton depression rating scale (grid-hamd) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. secondary outcomes included the quick inventory of depressive symptomatology-self rated (qids-sr). results: of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession assessments. this population had a mean (sd) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (sd) baseline grid-hamd score of 22.8 (3.9). the mean (sd) grid-hamd scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment gr…”
dos Santos, R. G., Bouso, J. C., Alcázar-Córcoles, M. Á., & Hallak, J. E. C.. (2018). Efficacy, tolerability, and safety of serotonergic psychedelics for the management of mood, anxiety, and substance-use disorders: a systematic review of systematic reviews. Expert Review of Clinical Pharmacology
Plain numerical DOI: 10.1080/17512433.2018.1511424
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“Introduction: mood, anxiety, and substance-use disorders are among the most prevalent psychiatric disorders in the population. although several pharmacological treatments are available, they are not effective for a significant proportion of patients and are associated with several adverse reactions. therefore, new treatments should be explored. recent studies suggest that serotonergic hallucinogens/psychedelics including ayahuasca, psilocybin, and lysergic acid diethylamide (lsd) have anxiolytic, antidepressive, and antiaddictive effects. areas covered: a systematic review of systematic reviews assessing the efficacy, safety, and tolerability of serotonergic hallucinogens/psychedelic was performed using the pubmed data base until 11 april 2018. systematic reviews with or without meta-analysis were analyzed, but only reviews that described at least one randomized controlled trial (rct) were included. expert commentary: psilocybin and lsd reduced anxiety and depression in cancer patients and symptoms of alcohol and tobacco dependence, and ayahuasca reduced depression symptoms in treatment-resistant depression. although the results are promising, several studies were open label, and only few were rcts, and most had small sample sizes and a short duration. single or few doses of these drugs seem to be well tolerated, but long-term studies are lacking. new rcts with bigger samples and longer duration are needed to replicate these findings.”
Anderson, B. T., Danforth, A., Daroff, P. R., Stauffer, C., Ekman, E., Agin-Liebes, G., … Woolley, J.. (2020). Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study. EClinicalMedicine
Plain numerical DOI: 10.1016/j.eclinm.2020.100538
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“Background: psilocybin therapy has shown promise as a rapid-acting treatment for depression, anxiety, and demoralization in patients with serious medical illness (e.g., cancer) when paired with individual psychotherapy. this study assessed the safety and feasibility of psilocybin-assisted group therapy for demoralization in older long-term aids survivor (oltas) men, a population with a high degree of demoralization and traumatic loss. methods: self-identified gay men oltas with moderate-to-severe demoralization (demoralization scale-ii ≥8) were recruited from the community of a major us city for a single-site open-label study of psilocybin-assisted group therapy comprising 8–10 group therapy visits and one psilocybin administration visit (0·3–0·36 mg/kg po). primary outcomes were rate and severity of adverse events, and participant recruitment and retention. the primary clinical outcome was change in mean demoralization from baseline to end-of-treatment and to 3-month follow-up assessed with a two-way repeated measures anova. trial registration:
clinicaltrials.gov (nct02950467) findings: from 17 july 2017 to 16 january 2019, 18 participants (mean age 59·2 years (sd 4·4)) were enrolled, administered group therapy and psilocybin, and included in intent-to-treat analyses. we detected zero serious adverse reactions and two unexpected adverse reactions to psilocybin; seven participants experienced self-limited, severe expected adverse reactions. we detected a clinically meaningful change in demoralization from baseline to 3-month follow-up (mean difference -5·78 [sd 6·01], ηp2 = 0·47, 90% ci 0·21–0·60). interpretation: we demonstrated the feasibility, relative safety, and potential efficacy of psilocybin-assisted group therapy for demoralization in oltas. groups may be an effective and efficient means of delivering psychotherapy pre- and post-psilocybin to patients with complex medical and psychiatric needs. funding: carey turnbull, heffter research institute, nimh r25 mh060482, nih ul1 tr001872, river styx foundation, saisei foundation, sarlo foundation, stupski foundation, usona institute, us department of veterans affairs (advanced neurosciences fellowship and ik2cx001495).”
C., M., L., M., & C., F.. (
2018).
Psilocybin: Antidepressive, anxiolytic and antiaddictive effects.
European Psychiatry
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“Psilocybin, a psychoactive alkaloid contained in hallucinogenic mushrooms, has recently been tested for its safety and efficacy in clinical populations for the treatment of depression, anxiety disorders and substance dependence. the main objective of this study is to summarize the mechanism of action of psilocybin and its efficacy in the treatment of different psychiatric conditions. we also present the ethical issues concerning psilocybin use in clinical practice and its safety profile. we did a review using the pubmed database with the mesh terms: ‘psilocybin’ and ‘depression’ or ‘anxiety’ or ‘dependence’. we selected clinical trials and reviews published in the last 20 years written in english, portuguese or spanish according to our aims. psilocybin and psilocin (the psychoactive metabolite of psilocybin) are substances with predominant agonist activity on serotonin 5ht2a/c and 5ht1a receptors. psilocybin acts as a hallucinogen and has a profound effect on cognition, perception and emotion, producing transient psychosis-like symptoms. clinical trials showed that the administration of psilocybin resulted in significant reductions in yale- brown obsessive-compulsive scale, in anxiety scores and in tobacco and alcohol craving. the analysis of the psilocybin safety profile showed that it can be safely administered in controlled settings. the evidence overall strongly suggests that psilocybin should be re-examined in modern clinical trials for their use in non-psychotic mental health conditions.”
S., R., A., B., J., G., T., M., S.E., M., K., K., … G., A.-L.. (
2016).
Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial.
Journal of Psychopharmacology
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“Background: clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression. methods: in this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. the primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks. results: prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. at the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60-80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. the psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression. conclusions: in conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress. trial registration:
clinicaltrials.gov identifier: nct00957359.
copyright © the author(s) 2016.”
Kuypers, K. P. C.. (2020). The therapeutic potential of microdosing psychedelics in depression. Therapeutic Advances in Psychopharmacology
Plain numerical DOI: 10.1177/2045125320950567
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“Microdosing psychedelics is the repeated use of small doses of, for example, lysergic acid diethylamide (lsd) and psilocybin, typically for a few weeks. despite the popular and scientific attention in recent years, and claims by users that it has therapeutic value in affective disorders like depression, little scientific knowledge is available to back this. the purpose of this review was to investigate whether there are scientific grounds to state that this practice could be helpful in the treatment of affective disorders, and safe to use repeatedly. to that end, the literature (pubmed, medline) was searched, looking for (controlled) experimental studies with low doses of lsd and/or psilocybin, in healthy volunteers and patient samples. after a selection process and the addition of relevant articles, 14 experimental studies entered this review. findings show that both lsd (10–20 mcg) and psilocybin (<1–3 mg) have subtle (positive) effects on cognitive processes (time perception, convergent and divergent thinking) and brain regions involved in affective processes. besides the pleasant experience, increased anxiety and a cycling pattern of depressive and euphoric mood were also found. with regard to safety, it was demonstrated that low doses are well tolerated (in healthy volunteers) and have no-to-minimal effects on physiological measures. while it is yet unclear whether psychedelic microdosing is of therapeutic value for depression, the aforementioned effects on selective processes suggest that low doses of psychedelics could play a role in depression by inducing some kind of cognitive flexibility, which might lead to decreased rumination. while previous studies were conducted mostly in small samples of healthy volunteers, future placebo-controlled clinical trials in depressed patients are required to understand the therapeutic value of microdosing psychedelics, how this differs from therapy using full psychedelic doses, and whether different psychedelics have different effect patterns. the proposed research will give new insights into the potential of future alternative psychiatric treatment forms that are fiercely needed.”
Stauffer, C. S., Anderson, B. T., Ortigo, K. M., & Woolley, J.. (2021). Psilocybin-Assisted Group Therapy and Attachment: Observed Reduction in Attachment Anxiety and Influences of Attachment Insecurity on the Psilocybin Experience. ACS Pharmacology and Translational Science
Plain numerical DOI: 10.1021/acsptsci.0c00169
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“Attachment insecurity is determined early in life, is a risk factor for psychopathology, and can be measured on two separate continuous dimensions: attachment anxiety and attachment avoidance. therapeutic changes toward more secure attachment correlate with reduction in psychiatric symptoms. psilocybin-assisted psychotherapy has demonstrated promise in the treatment of psychopathology, such as treatment-resistant depression and substance use disorders. we hypothesized that psilocybin-assisted psychotherapy would reduce attachment anxiety and attachment avoidance, thus increasing attachment security. we also hypothesized that baseline measures of attachment insecurity, which can reflect a diminished capacity for trust and exploration, would inform the quality of the psilocybin session. participants were male long-term aids survivors with moderate-severe demoralization (n = 18). using the experiences in close relationships scale, we measured attachment insecurity at baseline as well as immediately, and 3 months, after completion of a brief group therapy course, which included a single midtreatment open-label psilocybin session conducted individually. clinically important aspects of the psilocybin session were assessed using the revised mystical experience questionnaire and the challenging experience questionnaire the day following psilocybin administration. self-reported ratings of attachment anxiety decreased significantly from baseline to 3-months post-intervention, t(16) = -2.2; p = 0.045; drm = 0.45; 95% ci 0.01, 0.87. attachment avoidance did not change significantly. baseline attachment anxiety was strongly correlated with psilocybin-occasioned mystical-type experiences, r(15) = 0.53, p = 0.029, and baseline attachment avoidance was strongly correlated with psilocybin-related challenging experiences, r(16) = 0.62, p = 0.006. these findings have important implications for the general treatment of psychopathology as well as optimizing psilocybin-assisted psychotherapy as a broadly applicable treatment modality.”
Mason, N. L., Kuypers, K. P. C., Müller, F., Reckweg, J., Tse, D. H. Y., Toennes, S. W., … Ramaekers, J. G.. (2020). Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin. Neuropsychopharmacology
Plain numerical DOI: 10.1038/s41386-020-0718-8
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“There is growing interest in the therapeutic utility of psychedelic substances, like psilocybin, for disorders characterized by distortions of the self-experience, like depression. accumulating preclinical evidence emphasizes the role of the glutamate system in the acute action of the drug on brain and behavior; however this has never been tested in humans. following a double-blind, placebo-controlled, parallel group design, we utilized an ultra-high field multimodal brain imaging approach and demonstrated that psilocybin (0.17 mg/kg) induced region-dependent alterations in glutamate, which predicted distortions in the subjective experience of one’s self (ego dissolution). whereas higher levels of medial prefrontal cortical glutamate were associated with negatively experienced ego dissolution, lower levels in hippocampal glutamate were associated with positively experienced ego dissolution. such findings provide further insights into the underlying neurobiological mechanisms of the psychedelic, as well as the baseline, state. importantly, they may also provide a neurochemical basis for therapeutic effects as witnessed in ongoing clinical trials.”
US National Library of Medicine. (
2018).
The Safety and Efficacy of Psilocybin in Participants With Treatment Resistant Depression (P-TRD).
Clinicaltrials.Gov
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“INTERVENTION: product name: psilocybin 5 mg pharmaceutical form: capsule inn or proposed inn: psilocybin cas number: 520‐52‐5 other descriptive name: psilocybin concentration unit: mg milligram(s) concentration type: equal concentration number: 5‐ pharmaceutical form of the placebo: capsule route of administration of the placebo: oral use product name: psilocybin 1 mg pharmaceutical form: capsule inn or proposed inn: psilocybin cas number: 520‐52‐5 other descriptive name: psilocybin concentration unit: mg milligram(s) concentration type: equal concentration number: 1‐ condition: therapeutic area: psychiatry and psychology [f] ‐ mental disorders [f03] treatment‐resistant depression (p‐trd) ; meddra version: 20.0 level: llt classification code 10025454 term: major depressive disorder, recurrent episode system organ class: 100000004873 ; meddra version: 20.0 level: llt classification code 10025463 term: major depressive disorder, single episode system organ class: 100000004873 primary outcome: main objective: the main purpose of period 1 of this study is to allow compass to determine the optimal dose of psilocybin, either 10 mg or 25 mg. the intent of the primary efficacy analysis, which occurs during period 2 of the study, is to demonstrate superiority of the optimal therapeutic dose of psilocybin (10 mg or 25 mg) versus the 1 mg psilocybin via the following objectives:; ; the primary objective of this study is to evaluate the efficacy of psilocybin (25 mg or 10 mg) compared to 1 mg, administered under supportive conditions to adult participants with trd, in improving depressive symptoms, as assessed by the change in the montgomery‐asberg depression rating scale (madrs) total score from baseline. baseline is defined as the assessment score obtained on day ‐1. the primary timepoint is week 3; this variable will be analysed for the change from baseline to weeks 1, 3, 6, and 12. ; primary end point(s): the primary endpoint is the change in madrs total score from baseline (day ‐1) to 3 weeks post‐psilocybin in period 2. secondary objective: to assess the efficacy of psilocybin compared to 1 mg psilocybin on:; ‐ proportion of participants with response defined as a =50% decrease in madrs total score from baseline to week 3. this will also be assessed at weeks 1, 6 and 12. ; ‐ proportion of participants in remission defined as the participants with a madrs total score =10 at week 3. this will also be assessed at weeks 1, 6, and 12. ; ‐ proportion of responding …”
Nutt, D.. (2015). 5HT2a Receptors – a New Target for Depression?. European Psychiatry
Plain numerical DOI: 10.1016/s0924-9338(15)30027-4
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“Cortical 5ht2a receptors are largely expressed in layer 5 pyramidal neurons and appear to play a pivotal role in brain function in that they gate top-down descending inputs to local cortical microcircuits. there is evidence that they may play a role in depression in that the number of these receptors is increased in some people with depression and the augmenting action of atypical antipsychotics in depression is thought to be – at least in part – due to blockade of these receptors. we have explored this possibility by studying the effects of agonists at these receptors – the psychedelic druds psilocybin and lsd. we found they had profound effects to reduce brain activity particularly in regions that higly express the 5ht2a receptor such as the default mode network [dmn]. as this region is overactive in depression this may explain the improvements in mood that users of psychedelic often report. based on these findings a study of psilocybin in resistant depression has been funded by the uk mrc and will start in early 2015.”
Future Paths in Psychopharmacology. (2019). Dialogues in Clinical Neuroscience
Plain numerical DOI: 10.31887/dcns.2019.21.2
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“This article covers the renaissance of classical psychedelic drugs such as psilocybin and lsd plus 3,4-methylene dioxymethamphetamine (mdma-ecstasy) in psychiatric research. these drugs were used quite extensively before they became prohibited. this ban had little impact on recreational use, but effectively stopped research and clinical treatments, which up to that point had looked very promising in several areas of psychiatry. in the past decade a number of groups have been working to re-evaluate the utility of these substances in medicine. so far highly promising preliminary data have been produced with psilocybin in anxiety, depression, smoking, alcoholism, and with mdma for post-traumatic stress disorder (ptsd) and alcoholism. these findings have led to the european medicines agency approving psilocybin for a phase 3 study in treatment-resistant depression and the food and drug administration for ptsd with mdma. both trials should read out in 2020, and if the results are positive we are likely to see these medicines approved for clinical practice soon afterwards.”
Madsen, M. K., Fisher, P. M., Burmester, D., Dyssegaard, A., Stenbæk, D. S., Kristiansen, S., … Knudsen, G. M.. (2019). Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology
Plain numerical DOI: 10.1038/s41386-019-0324-9
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“The main psychedelic component of magic mushrooms is psilocybin, which shows promise as a treatment for depression and other mental disorders. psychedelic effects are believed to emerge through stimulation of serotonin 2a receptors (5-ht2ars) by psilocybin’s active metabolite, psilocin. we here report for the first time the relationship between intensity of psychedelic effects, cerebral 5-ht2ar occupancy and plasma levels of psilocin in humans. eight healthy volunteers underwent positron emission tomography (pet) scans with the 5-ht2ar agonist radioligand [11c]cimbi-36: one at baseline and one or two additional scans on the same day after a single oral intake of psilocybin (3–30 mg). 5-ht2ar occupancy was calculated as the percent change in cerebral 5-ht2ar binding relative to baseline. subjective psychedelic intensity and plasma psilocin levels were measured during the scans. relations between subjective intensity, 5-ht2ar occupancy, and plasma psilocin levels were modeled using non-linear regression. psilocybin intake resulted in dose-related 5-ht2ar occupancies up to 72%; plasma psilocin levels and 5-ht2ar occupancy conformed to a single-site binding model. subjective intensity was correlated with both 5-ht2ar occupancy and psilocin levels as well as questionnaire scores. we report for the first time that intake of psilocybin leads to significant 5-ht2ar occupancy in the human brain, and that both psilocin plasma levels and 5-ht2ar occupancy are closely associated with subjective intensity ratings, strongly supporting that stimulation of 5-ht2ar is a key determinant for the psychedelic experience. important for clinical studies, psilocin time-concentration curves varied but psilocin levels were closely associated with psychedelic experience.”
Swift, T. C., Belser, A. B., Agin-Liebes, G., Devenot, N., Terrana, S., Friedman, H. L., … Ross, S.. (2017). Cancer at the Dinner Table: Experiences of Psilocybin-Assisted Psychotherapy for the Treatment of Cancer-Related Distress. Journal of Humanistic Psychology
Plain numerical DOI: 10.1177/0022167817715966
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“Recent randomized controlled trials of psilocybin-assisted psychotherapy for patients with cancer suggest that this treatment results in large-magnitude reductions in anxiety and depression as well as improvements in attitudes toward disease progression and death, quality of life, and spirituality. to better understand these findings, we sought to identify psychological mechanisms of action using qualitative methods to study patient experiences in psilocybin-assisted psychotherapy. semistructured interviews were conducted with 13 adult participants with clinically elevated anxiety associated with a cancer diagnosis who received a single dose of psilocybin under close clinical supervision. transcribed interviews were analyzed using interpretative phenomenological analysis, which resulted in 10 themes, focused specifically on cancer, death and dying, and healing narratives. participants spoke to the anxiety and trauma related to cancer, and perceived lack of available emotional support. participants described the immersive and distressing effects of the psilocybin session, which led to reconciliations with death, an acknowledgment of cancer’s place in life, and emotional uncoupling from cancer. participants made spiritual or religious interpretations of their experience, and the psilocybin therapy helped facilitate a felt reconnection to life, a reclaiming of presence, and greater confidence in the face of cancer recurrence. implications for theory and clinical treatment are discussed.”
Vitkauskas, M., & Mathuru, A. S.. (2020). Total recall: Lateral habenula and psychedelics in the study of depression and comorbid brain disorders. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms21186525
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“Depression impacts the lives and daily activities of millions globally. research into the neurobiology of lateral habenula circuitry and the use of psychedelics for treating depressive states has emerged in the last decade as new directions to devise interventional strategies and therapies. several clinical trials using deep brain stimulation of the habenula, or using ketamine, and psychedelics that target the serotonergic system such as psilocybin are also underway. the promising early results in these fields require cautious optimism as further evidence from experiments conducted in animal systems in ecologically relevant settings, and a larger number of human studies with improved spatiotemporal neuroimaging, accumulates. designing optimal methods of intervention will also be aided by an improvement in our understanding of the common genetic and molecular factors underlying disorders comorbid with depression, as well as the characterization of psychedelic-induced changes at a molecular level. advances in the use of cerebral organoids offers a new approach for rapid progress towards these goals. here, we review developments in these fast-moving areas of research and discuss potential future directions.”
Kim, K., Che, T., Panova, O., DiBerto, J. F., Lyu, J., Krumm, B. E., … Roth, B. L.. (2020). Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor. Cell
Plain numerical DOI: 10.1016/j.cell.2020.08.024
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“Hallucinogens like lysergic acid diethylamide (lsd), psilocybin, and substituted n-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. how psychedelics mediate their actions—both therapeutic and hallucinogenic—are not understood, although activation of the 5-ht2a serotonin receptor (htr2a) is key. to gain molecular insights into psychedelic actions, we determined the active-state structure of htr2a bound to 25-cn-nboh—a prototypical hallucinogen—in complex with an engineered gαq heterotrimer by cryoelectron microscopy (cryo-em). we also obtained the x-ray crystal structures of htr2a complexed with the arrestin-biased ligand lsd or the inverse agonist methiothepin. comparisons of these structures reveal determinants responsible for htr2a-gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders.”
Shore, R. J., Ioudovski, P., McKeown, S., Dumont, E., & Goldie, C.. (2019). Mapping psilocybin-assisted therapies: A scoping review. MedRxiv
Plain numerical DOI: 10.1101/2019.12.04.19013896
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“We conducted a scoping review on psilocybin-assisted therapy for addiction, depression, anxiety and post-traumatic stress disorder. psilocybin is a naturally-occurring tryptophan derivative found in species of mushroom with psycho-active properties. from 2022 records identified by database searching, 40 publications were included in the qualitative synthesis from which we identified 9 clinical trials with a total of 169 participants. trials used a peak-psychedelic model of therapy, emphasizing inward journey through the use of eyeshades, set musical scores and with medium to high doses of psilocybin. no serious adverse effects were reported; mild adverse effects included transient anxiety, nausea and post-treatment headaches. overall, the 9 trials all demonstrated safety, tolerability and preliminary efficacy in the treatments of obsessive-compulsive disorder, substance use disorder, treatment-resistant unipolar depression, anxiety or depression in patients with life-threatening cancer and demoralization among long-term aids survivors.the literature was found to be early and exploratory, with several limitations: only 5 were randomized controlled trials, small and homogenous patient sample size, difficulties in blinding, and the confounding influence of psychological supports provided. further research is indicated to establish effectiveness for these and other indications, with a more diverse range of patients, and with differing program and dosing modalities. keywords: psilocybin, psychedelic, psychedelic-assisted therapy, scoping review, depression, anxiety, obsessive-compulsive disorder, end-of-life distress, substance use disorder ### competing interest statement the authors have declared no competing interest. ### funding statement none. ### author declarations all relevant ethical guidelines have been followed; any necessary irb and/or ethics committee approvals have been obtained and details of the irb/oversight body are included in the manuscript. yes all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. yes i understand that all clinical trials and any other prospective interventional studies must be registered with an icmje-approved registry, such as
clinicaltrials.gov. i confirm that any such study reported in the manuscript has been registered and the trial registration id is provided (note: if posting a prospective study registered retrospectively, please provide a…”
Kargbo, R. B.. (2020). Psilocybin Therapeutic Research: The Present and Future Paradigm. ACS Medicinal Chemistry Letters
Plain numerical DOI: 10.1021/acsmedchemlett.0c00048
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“Psilocybin, an active component in ‘magic mushroom’, may have the potential to meet the therapeutic needs for a number of indications without the addictiveness and overdose risk of other mind-altering drugs, such as cocaine, heroin, alcohol, methamphetamine, and so forth. the need for new therapies is urgent because addiction, overdose, and suicide deaths have risen throughout the united states and around the world. anecdotal and contemporary pharmacological reports have provided some indication about the therapeutic use of psilocybin for the treatment of mental health disorders such as major depressive disorder and addiction disorders. in this viewpoint, i summarize the current state of psilocybin therapeutic research and attempt to provide some insight into future directions on which the scientific community may wish to focus.”
Johnson, M. W., Hendricks, P. S., Barrett, F. S., & Griffiths, R. R.. (2019). Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharmacology and Therapeutics
Plain numerical DOI: 10.1016/j.pharmthera.2018.11.010
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“The purpose of this paper is to provide an integrative review and offer novel insights regarding human research with classic psychedelics (classic hallucinogens), which are serotonin 2a receptor (5-ht2ar)agonists such as lysergic acid diethylamide (lsd), mescaline, and psilocybin. classic psychedelics have been administered as sacraments since ancient times. they were of prominent interest within psychiatry and neuroscience in the 1950s to 1960s, and during this time contributed to the emergence of the field of molecular neuroscience. promising results were reported for treatment of both end-of-life psychological distress and addiction, and classic psychedelics served as tools for studying the neurobiological bases of psychological disorders. moreover, classic psychedelics were shown to occasion mystical experiences, which are subjective experiences reported throughout different cultures and religions involving a strong sense of unity, among other characteristics. however, the recreational use of classic psychedelics and their association with the counterculture prompted an end to human research with classic psychedelics in the early 1970s. we provide the most comprehensive review of epidemiological studies of classic psychedelics to date. notable among these are a number of studies that have suggested the possibility that nonmedical naturalistic (non-laboratory)use of classic psychedelics is associated with positive mental health and prosocial outcomes, although it is clear that some individuals are harmed by classic psychedelics in non-supervised settings. we then review recent therapeutic studies suggesting efficacy in treating psychological distress associated with life-threatening diseases, treating depression, and treating nicotine and alcohol addictions. we also describe the construct of mystical experience, and provide a comprehensive review of modern studies investigating classic psychedelic-occasioned mystical experiences and their consequences. these studies have shown classic psychedelics to fairly reliably occasion mystical experiences. moreover, classic-psychedelic-occasioned mystical experiences are associated with improved psychological outcomes in both healthy volunteer and patient populations. finally, we review neuroimaging studies that suggest neurobiological mechanisms of classic psychedelics. these studies have also broadened our understanding of the brain, the serotonin system, and the neurobiological basis of consciousness. overa…”
R.L., C.-H., M., B. B., J., R., C.M.J., D., D., E., M., K., … DJ, N.. (
2016).
Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study..
The Lancet. Psychiatry
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“Background psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression. methods in this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. there was no control group. psychological support was provided before, during, and after each session. the primary outcome measure for feasibility was patient-reported intensity of psilocybin’s effects. patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item quick inventory of depressive symptoms (qids) serving as the primary efficacy outcome. this trial is registered with isrctn, number isrctn14426797. findings psilocybin’s acute psychedelic effects typically became detectable 30-60 min after dosing, peaked 2-3 h after dosing, and subsided to negligible levels at least 6 h after dosing. mean self-rated intensity (on a 0-1 scale) was 0.51 (sd 0.36) for the low-dose session and 0.75 (sd 0.27) for the high-dose session. psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. the adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). relative to baseline, depressive symptoms were markedly reduced 1 week (mean qids difference -11.8, 95% ci -9.15 to -14.35, p=0.002, hedges’ g=3.1) and 3 months (-9.2, 95% ci -5.69 to -12.71, p=0.003, hedges’ g=2) after high-dose treatment. marked and sustained improvements in anxiety and anhedonia were also noted. interpretation this study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeuti…”
Jefsen, O. H., Elfving, B., Wegener, G., & Müller, H. K.. (2021). Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin. Journal of Psychopharmacology
Plain numerical DOI: 10.1177/0269881120959614
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“Background: psilocybin is a serotonergic psychedelic found in ‘magic mushrooms’ with a putative therapeutic potential for treatment-resistant depression, anxiety, obsessive-compulsive disorder, and addiction. in rodents, psilocybin acutely induces plasticity-related immediate early genes in cortical tissue; however, studies into the effects on subcortical regions, of different doses, and the subsequent translation of corresponding proteins are lacking. methods: we examined the acute effects of a single administration of psilocybin (0.5–20 mg/kg) on the expression of selected genes in the prefrontal cortex and hippocampus. in total, 46 target genes and eight reference genes were assessed using real-time quantitative polymerase chain reaction. corresponding protein levels of the three most commonly regulated genes were assessed using western blotting. results: in the prefrontal cortex, psilocybin increased the expression of cebpb, c-fos, dups1, fosb, junb, iκβ-α, nr4a1, p11, psd95, and sgk1, and decreased the expression of clk1. in the hippocampus, psilocybin strongly increased the expression of arrdc2, dusp1, iκβ-α, and sgk1 in a dose-dependent manner, and decreased the expression of arc, clk1, egr2, and ptgs2. protein levels of sgk1, dusp1, and iκβ-α showed only partial agreement with transcriptional patterns, stressing the importance of assessing downstream translation when investigating rapid gene responses. conclusion: the present study demonstrates that psilocybin rapidly induces gene expression related to neuroplasticity, biased towards the prefrontal cortex, compared to the hippocampus. our findings provide further evidence for the rapid plasticity-promoting effects of psilocybin.”
L., R., D.J., N., R.L., C.-H., L., D., & M.B., W.. (
2018).
Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression.
Neuropharmacology
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“Recent evidence indicates that psilocybin with psychological support may be effective for treating depression. some studies have found that patients with depression show heightened amygdala responses to fearful faces and there is reliable evidence that treatment with ssris attenuates amygdala responses (ma, 2015). we hypothesised that amygdala responses to emotional faces would be altered post-treatment with psilocybin. in this open-label study, 20 individuals diagnosed with moderate to severe, treatment-resistant depression, underwent two separate dosing sessions with psilocybin. psychological support was provided before, during and after these sessions and 19 completed fmri scans one week prior to the first session and one day after the second and last. neutral, fearful and happy faces were presented in the scanner and analyses focused on the amygdala. group results revealed rapid and enduring improvements in depressive symptoms post psilocybin. increased responses to fearful and happy faces were observed in the right amygdala post-treatment, and right amygdala increases to fearful versus neutral faces were predictive of clinical improvements at 1-week. psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with ssris. this suggests fundamental differences in these treatments’ therapeutic actions, with ssris mitigating negative emotions and psilocybin allowing patients to confront and work through them. based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions. trial registration: isrctn, number isrctn14426797. this article is part of the special issue entitled ‘psychedelics: new doors, altered perceptions’.
copyright © 2018 the authors”
Doblin, R. E., Christiansen, M., Jerome, L., & Burge, B.. (2019). The Past and Future of Psychedelic Science: An Introduction to This Issue. Journal of Psychoactive Drugs
Plain numerical DOI: 10.1080/02791072.2019.1606472
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“Psychedelic plants and fungi have been used in indigenous medicinal traditions for millennia. modern psychedelic research began when albert hofmann first synthesized lysergic acid diethylamide (lsd-25) in 1938. five years later, became the first person to ingest lsd. hofmann was unaware of the significance of his actions, and the effects they would set in motion. after a burgeoning period of scientific and cultural exploration in the1950s and ‘60s, psychedelic research was slowed to a near halt. throughout the 1970s and ‘80s governmental interventions severely hampered global psychedelic research, despite evidence of the limited medical risks and therapeutic potential of psychedelics. after decades of persistent education and advocacy, rigorous research employing psychedelics as tools of discovery and healing are abundant today. studies are taking place in research institutions and in private practice sites supported by non-profit and for-profit organizations, as well as individual investigators. this research includes clinical trials with mdma-assisted therapy for the treatment of ptsd, alcoholism, and social anxiety, and psilocybin clinical studies for depression and addiction, as well as the ability of psychedelics to catalyze spiritual or mystical experiences and inspire creativity, and into the neuroscientific understanding the effects of psychedelic substances on our nervous system.”
A., W., & M.I., J.. (
2018).
Lysergic acid diethylamide and psilocybin for the management of patients with persistent pain: A potential role?.
Pain Management
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“Recently, there has been interest in lysergic acid diethylamide (lsd) and psilocybin for depression, anxiety and fear of death in terminal illness. the aim of this review is to discuss the potential use of lsd and psilocybin for patients with persistent pain. lsd and psilocybin are 5-hydroxytryptamine receptor agonists and may interact with nociceptive and antinociceptive processing. tentative evidence from a systematic review suggests that lsd (7 studies, 323 participants) and psilocybin (3 studies, 92 participants) may be beneficial for depression and anxiety associated with distress in life-threatening diseases. lsd and psilocybin are generally safe if administered by a healthcare professional, although further investigations are needed to assess their utility for patients with persistent pain, especially associated with terminal illness.
copyright © 2018 future medicine ltd.”
Begola, M. J., & Schillerstrom, J. E.. (2019). Hallucinogens and their therapeutic use: A literature review. Journal of Psychiatric Practice
Plain numerical DOI: 10.1097/PRA.0000000000000409
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“The exploration of possible therapeutic benefits of hallucinogenic substances has undergone a revitalization in the past decade. this literature review investigated the published literature regarding the psychotherapeutic uses of hallucinogens in psychiatric disorders. the results showed that a variety of substances have been evaluated in the treatment of psychiatric disorders, including ayahuasca, ibogaine, ketamine, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, and psilocybin. the conditions treated ranged from depression to autism, with the largest volume of research dedicated to substance use disorders. the majority of studies that were reviewed demonstrated significant associations with improvement in the conditions investigated. however, it was difficult to draw definitive conclusions as most studies suffered from small sample sizes, inconsistent measures, and poor study design. to properly assess the risks and potential benefits of hallucinogens in psychiatric treatment, there is a need for well designed, standardized studies that demonstrate the impact of hallucinogenic substances on psychiatric conditions.”
Grob, C. S., Danforth, A. L., Chopra, G. S., Hagerty, M., McKay, C. R., Halberstad, A. L., & Greer, G. R.. (2011). Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Archives of General Psychiatry
Plain numerical DOI: 10.1001/archgenpsychiatry.2010.116
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“Context: researchers conducted extensive investigations of hallucinogens in the 1950s and 1960s. by the early 1970s, however, political and cultural pressures forced the cessation of all projects. this investigation reexamines a potentially promising clinical application of hallucinogens in the treatment of anxiety reactive to advanced- stage cancer. objective: to explore the safety and efficacy of psilocybin in patients with advanced-stage cancer and reactive anxiety. design: a double-blind, placebo-controlled study of patients with advanced-stage cancer and anxiety, with subjects acting as their own control, using a moderate dose (0.2 mg/kg) of psilocybin. setting: a clinical research unit within a large public sector academic medical center. participants: twelve adults with advanced-stage cancer and anxiety. main outcome measures: in addition to monitoring safety and subjective experience before and during experimental treatment sessions, follow-up data including results from the beck depression inventory, profile of mood states, and state-trait anxiety inventory were collected unblinded for 6 months after treatment. results: safe physiological and psychological responses were documented during treatment sessions. there were no clinically significant adverse events with psilocybin. the state-trait anxiety inventory trait anxiety subscale demonstrated a significant reduction in anxiety at 1 and 3 months after treatment. the beck depression inventory revealed an improvement of mood that reached significance at 6 months; the profile ofmoodstates identified mood improvement after treatment with psilocybin that approached but did not reach significance. conclusions: this study established the feasibility and safety of administering moderate doses of psilocybin to patients with advanced-stage cancer and anxiety. some of the data revealed a positive trend toward improved mood and anxiety. these results support the need for more research in this long-neglected field. © 2011 american medical association. all rights reserved.”
Corrigan, K., Haran, M., McCandliss, C., McManus, R., Cleary, S., Trant, R., … Kelly, J. R.. (2021). Psychedelic perceptions: mental health service user attitudes to psilocybin therapy. Irish Journal of Medical Science
Plain numerical DOI: 10.1007/s11845-021-02668-2
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“Introduction: despite the rapid advance of psychedelic science and possible translation of psychedelic therapy into the psychiatric clinic, very little is known about mental health service user attitudes. objectives: to explore mental health service user attitudes to psychedelics and psilocybin therapy. methods: a questionnaire capturing demographics, diagnoses, previous psychedelic and other drug use, and attitudes to psychedelics and psilocybin therapy was distributed to mental health service users. results: ninety-nine participants completed the survey (52% female, mean age 42 years). the majority (72%) supported further research, with 59% supporting psilocybin as a medical treatment. a total of 27% previously used recreational psilocybin, with a male preponderance (p = 0.01). younger age groups, those with previous psychedelic experience, and those with non-religious beliefs were more likely to have favourable attitudes towards psilocybin. a total of 55% of the total sample would accept as a treatment if doctor recommended, whereas 20% would not. fewer people with depression/anxiety had used recreational psychedelics (p = 0.03) but were more likely to support government funded studies (p = 0.02). a minority (5%) of people with conditions (psychosis and bipolar disorder) that could be exacerbated by psilocybin thought it would be useful for them. one fifth of the total sample viewed psychedelics as addictive and unsafe even under medical supervision. concerns included fear of adverse effects, lack of knowledge, insufficient research, illegality, and relapse if medications were discontinued. conclusions: the majority supported further research into psilocybin therapy. younger people, those with previous recreational psychedelic experience, and those with non-religious beliefs were more likely to have favourable attitudes towards psilocybin therapy.”
Dydak, K., Śliwińska-Mossoń, M., & Milnerowicz, H.. (2016). Psilocybin as an alternative medicine for patients suffering from depression. Psychiatria i Psychologia Kliniczna
Plain numerical DOI: 10.15557/pipk.2016.0023
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“© medical communications sp. z o.o. psilocybin is a psychodysleptic substance of natural origin present in the psilocybe type mushrooms. psychodysleptics are psychoactive substances which strongly affect the perception, mood and cognitive processes of a human. the mind-altering operation of psilocybin is based on stimulating the serotoninergic receptors, which leads to the increase in the concentration of serotonin in the brain and contributes to the intensification of the sensorimotor activity and perception. the effect of the operation of psilocybin on the human body are various changes in behaviour – frequent euphoria, cheerfulness, the feeling of lightness and unity with the surrounding world. additionally, psilocybin causes perception modification not imitating reality, often mistaken for hallucinations. the operation of psilocybin may be compared to the operation of lsd (lysergic acid diethylamide), yet many times weaker. psilocybin may be found on the list of intoxicants in the i-p group, namely substances with no medical applications and with a high potential of overusing, which are excluded from the pharmaceutical trade and may be used solely for scientific purposes. however, the properties of psilocybin make it possible to consider its use in medicine. ailments, in which the use of this substance brings measurable effects, include depression. studies conducted on volunteers show that psilocybin may be a good alternative to the currently available antidepressants – its effectiveness was observed and very low toxicity confirmed.”
Johnson, M. W., Griffiths, R. R., Hendricks, P. S., & Henningfield, J. E.. (2018). The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act. Neuropharmacology
Plain numerical DOI: 10.1016/j.neuropharm.2018.05.012
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“This review assesses the abuse potential of medically-administered psilocybin, following the structure of the 8 factors of the us controlled substances act (csa). research suggests the potential safety and efficacy of psilocybin in treating cancer-related psychiatric distress and substance use disorders, setting the occasion for this review. a more extensive assessment of abuse potential according to an 8-factor analysis would eventually be required to guide appropriate schedule placement. psilocybin, like other 5-ht2a agonist classic psychedelics, has limited reinforcing effects, supporting marginal, transient non-human self-administration. nonetheless, mushrooms with variable psilocybin content are used illicitly, with a few lifetime use occasions being normative among users. potential harms include dangerous behavior in unprepared, unsupervised users, and exacerbation of mental illness in those with or predisposed to psychotic disorders. however, scope of use and associated harms are low compared to prototypical abused drugs, and the medical model addresses these concerns with dose control, patient screening, preparation and follow-up, and session supervision in a medical facility. conclusions: (1) psilocybin has an abuse potential appropriate for csa scheduling if approved as medicine; (2) psilocybin can provide therapeutic benefits that may support the development of an approvable new drug application (nda) but further studies are required which this review describes; (3) adverse effects of medical psilocybin are manageable when administered according to risk management approaches; and (4) although further study is required, this review suggests that placement in schedule iv may be appropriate if a psilocybin-containing medicine is approved. this article is part of the special issue entitled ‘psychedelics: new doors, altered perceptions’.”
Ross, S.. (2018). Therapeutic use of classic psychedelics to treat cancer-related psychiatric distress. International Review of Psychiatry
Plain numerical DOI: 10.1080/09540261.2018.1482261
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“Cancer is highly prevalent and one of the leading causes of global morbidity and mortality. psychological and existential suffering is common in cancer patients, associated with poor psychiatric and medical outcomes. promising early-phase clinical research (1960s to early 1970s) suggested a therapeutic signal for serotoninergic psychedelics (e.g. psilocybin, lsd) in treating cancer-related psychiatric distress. after several decades of quiescence, research on psychedelic-assisted therapy to treat psychiatric disorders in cancer patients has resumed within the last 2 decades in the us and europe. this review article is based on a systematic search of clinical trials from 1960–2018 researching the therapeutic use of psychedelic treatment in patients with serious or terminal illnesses and related psychiatric illness. the search found 10 eligible clinical trials, with a total of 445 participants, with the vast majority of the patients having advanced or terminal cancer diagnoses. six open label trials, published between 1964 and 1980 (n = 341), suggested that psychedelic therapy (mostly with lsd) may improve cancer-related depression, anxiety, and fear of death. four rcts trials were published between 2011 and 2016 (n = 104), mostly with psilocybin treatment (n = 92), and demonstrated that psychedelic-assisted treatment can produce rapid, robust, and sustained improvements in cancer-related psychological and existential distress.”
Kringelbach, M. L., Cruzat, J., Cabral, J., Knudsen, G. M., Carhart-Harris, R., Whybrow, P. C., … Deco, G.. (2020). Dynamic coupling of whole-brain neuronal and neurotransmitter systems. Proceedings of the National Academy of Sciences of the United States of America
Plain numerical DOI: 10.1073/pnas.1921475117
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“Remarkable progress has come from whole-brain models linking anatomy and function. paradoxically, it is not clear how a neuronal dynamical system running in the fixed human anatomical connectome can give rise to the rich changes in the functional repertoire associated with human brain function, which is impossible to explain through long-term plasticity. neuromodulation evolved to allow for such flexibility by dynamically updating the effectivity of the fixed anatomical connectivity. here, we introduce a theoretical framework modeling the dynamical mutual coupling between the neuronal and neurotransmitter systems. we demonstrate that this framework is crucial to advance our understanding of whole-brain dynamics by bidirectional coupling of the two systems through combining multimodal neuroimaging data (diffusion magnetic resonance imaging [dmri], functional magnetic resonance imaging [fmri], and positron electron tomography [pet]) to explain the functional effects of specific serotoninergic receptor (5-ht2ar) stimulation with psilocybin in healthy humans. this advance provides an understanding of why psilocybin is showing considerable promise as a therapeutic intervention for neuropsychiatric disorders including depression, anxiety, and addiction. overall, these insights demonstrate that the whole-brain mutual coupling between the neuronal and the neurotransmission systems is essential for understanding the remarkable flexibility of human brain function despite having to rely on fixed anatomical connectivity.”
Barbara Geller, M.. (
2017).
Can Psilocybin Treat Severe Depression?.
NEJM Journal Watch
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“In 1970, the fda categorized psilocybin as a schedule 1 drug, largely because of its recreational uses, which include inducing spirituality and”
Muttoni, S., Ardissino, M., & John, C.. (2019). Classical psychedelics for the treatment of depression and anxiety: A systematic review. Journal of Affective Disorders
Plain numerical DOI: 10.1016/j.jad.2019.07.076
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“Background: depression and anxiety are prevalent psychiatric disorders that carry significant morbidity. pharmacological and psychosocial interventions are used to manage these conditions, but their efficacy is limited. recent interest into the use of psychedelic-assisted therapy using ayahuasca, psilocybin or lysergic acid diethylamide (lsd) may be a promising alternative for patients unresponsive to traditional treatments. this review aims to determine the efficacy and tolerability of psychedelics in the management of resistant depression. methods: clinical trials investigating psychedelics in patients with depression and/or anxiety were searched via medline, embase and psychinfo. efficacy was assessed by measuring symptom improvement from baseline, and tolerability was evaluated by noting the incidence and type of adverse effects reported. risk of bias was assessed. results: seven studies, with 130 patients, were analysed in this review. three were conducted in patients with depression, two in patients with anxiety and two in patients with both. in a supportive setting, ayahuasca, psilocybin, and lsd consistently produced immediate and significant anti-depressant and anxiolytic effects that were endured for several months. psychedelics were well-tolerated. the most common adverse effects were transient anxiety, short-lived headaches, nausea and mild increases in heart rate and blood pressure. limitations: at present, the number of studies on this subject is very limited; and the number of participating patients within these is also limited as the treatment under investigations is a relatively novel concept. conclusions: though further evidence is required, psychedelics appear to be effective in significantly reducing symptoms of depression and anxiety and are well-tolerated.”
ACTRN12619001225101. (
2019).
Psilocybin-assisted psychotherapy for the treatment of depression and anxiety associated with life-threatening illness.
Www.Who.Int/Trialsearch/Trial2.Aspx?TrialID=ACTRN12619001225101
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“INTERVENTION: psilocybin assisted psychotherapy the study aim is to investigate the efficacy of psilocybin plus psychotherapy (before during and after the psilocybin dose sessions) in the treatment of depression and/or anxiety associated with having a terminal illness ‐materials used ‐ 25 mg psilocybin (active dose) ‐ oral capsule, single dose supervised administration with drug packaging return ‐ 100mg niacin (active placebo) ‐ oral capsule, single dose supervised administration 11 sessions of psychotherapy (including two dose days) will take place across the two parts of the study preparatory psychotherapy ‐ 3 sessions before dose 1 integrative/preparatory psychotherapy ‐ 3 sessions after dose 1 and before dose 2 integrative psychotherapy ‐ 3 session post dose 2 psychotherapy session frequency varies ‐ initially, the first 3 psychotherapy sessions and dose day occur within the first 14 days of baseline and another session occurs the day following the first dose. following this, psychotherapy occurs approximately every 3rd week until the second dose, and again every 3 weeks following the second dose ‐ if additional sessions are required, this is arranged and documented. **there is a psychotherapy session the day before each dose day to ensure that the participant is adequately prepared, and another psychotherapy session the day after the dose session to ensure the participant has an opportunity to integrate their experiences. part 1 = rct (baseline ‐ 6‐7 weeks post dose one) dose day 1 = either 25mg psilocybin or 100mg niacin (active placebo) part 2 = open label (commences 6‐7 weeks following dose 1 which is at the same time as the completion of the rct arm‐ participants are followed up for 26 weeks post dose 2/open label dose) dose day 2 = psilocybin 25mg for all participants. follow‐up continues to 26 weeks weeks post dose two. the psychotherapy component is largely informed by meaning centred psychother condition: cancer ‐ any cancer depression in terminal illness (any palliative condition including malignant and non‐malignant terminal illnesses);anxiety in terminal illness (any palliative condition including malignant and non‐malignan terminal illnesses); ; depression in terminal illness (any palliative condition including malignant and non‐malignant terminal illnesses) ; anxiety in terminal illness (any palliative condition including malignant and non‐malignan terminal illnesses) mental health ‐ anxiety mental health ‐ depression primary outcome: …”
Rößler, A.. (
2020).
Psilocybin wirksam bei Major Depression.
Pharmazeutische Zeitung
Barnby, J. M., & Mehta, M. A.. (2018). Psilocybin and mental health-don’t lose control. Frontiers in Psychiatry
Plain numerical DOI: 10.3389/fpsyt.2018.00293
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Nichols, D. E.. (2014). The Heffter Research Institute: Past and Hopeful Future. Journal of Psychoactive Drugs
Plain numerical DOI: 10.1080/02791072.2014.873688
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“This essay describes the founding of the heffter research institute in 1993 and its development up to the present. the institute is the only scientific research organization dedicated to scientific research into the medical value of psychedelics, and it has particularly focused on the use of psilocybin. the first clinical treatment study was of the value of psilocybin in obsessive-compulsive disorder. next was a ucla study of psilocybin to treat end-of-life distress in end-stage cancer patients. while that study was ongoing, a trial was started at johns hopkins university (jhu) to study the efficacy of psilocybin in treating anxiety and depression resulting from a cancer diagnosis. following the successful completion of the ucla project, a larger study was started at new york university, which is near completion. a pilot study of the value of psilocybin in treating alcoholism at the university of new mexico also is nearing completion, with a larger two-site study being planned. other studies underway involve the use of psilocybin in a smoking cessation program and a study of the effects of psilocybin in long-term meditators, both at jhu. the institute is now planning for a phase 3 clinical trial of psilocybin to treat distress in end-stage cancer patients. © taylor & francis group, llc.”
R.L., C.-H., M., B. B., C.M.J., D., J., R., R., W., D.E., E., … Nutt, D. J.. (
2018).
Psilocybin with psychological support for treatment-resistant depression: six-month follow-up.
Psychopharmacology
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“RATIONALERecent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy.objectiveshere, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression.methodstwenty 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.resultstreatment 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.conclusionsalthough 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.”
Lowe, H., Toyang, N., Steele, B., Valentine, H., Grant, J., Ali, A., … Gordon, L.. (2021). The therapeutic potential of psilocybin. Molecules
Plain numerical DOI: 10.3390/molecules26102948
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“The psychedelic effects of some plants and fungi have been known and deliberately ex-ploited by humans for thousands of years. fungi, particularly mushrooms, are the principal source of naturally occurring psychedelics. the mushroom extract, psilocybin has historically been used as a psychedelic agent for religious and spiritual ceremonies, as well as a therapeutic option for neuropsychiatric conditions. psychedelic use was largely associated with the ‘hippie’ counterculture movement, which, in turn, resulted in a growing, and still lingering, negative stigmatization for psychedelics. as a result, in 1970, the u.s. government rescheduled psychedelics as schedule 1 drugs, ultimately ending scientific research on psychedelics. this prohibition on psychedelic drug research significantly delayed advances in medical knowledge on the therapeutic uses of agents such as psilocybin. a 2004 pilot study from the university of california, los angeles, exploring the potential of psilocybin treatment in patients with advanced-stage cancer managed to reignite interest and significantly renewed efforts in psilocybin research, heralding a new age in exploration for psychedelic therapy. since then, significant advances have been made in characterizing the chemical properties of psilocybin as well as its therapeutic uses. this review will explore the potential of psilocybin in the treatment of neuropsychiatry-related conditions, examining recent advances as well as current research. this is not a systematic review.”
Linartevichi, V. F., Froza, M. G., Cury, R. de M., & Nascimento, F. P. do. (2021). POTENCIAL USO DA PSILOCIBINA NO TRATAMENTO DA DEPRESSÃO: UMA REVISÃO / POTENTIAL USE OF PSILOCYBIN IN THE DEPRESSION TREATMENT: A REVIEW. Brazilian Journal of Development
Plain numerical DOI: 10.34117/bjdv7n3-783
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dos Santos, R. G., Osório, F. L., Crippa, J. A. S., Riba, J., Zuardi, A. W., & Hallak, J. E. C.. (2016). Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years. Therapeutic Advances in Psychopharmacology
Plain numerical DOI: 10.1177/2045125316638008
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“To date, pharmacological treatments for mood and anxiety disorders and for drug dependence show limited efficacy, leaving a large number of patients suffering severe and persistent symptoms. preliminary studies in animals and humans suggest that ayahuasca, psilocybin and lysergic acid diethylamide (lsd) may have antidepressive, anxiolytic, and antiaddictive properties. thus, we conducted a systematic review of clinical trials published from 1990 until 2015, assessing these therapeutic properties. electronic searches were performed using the pubmed, lilacs, and scielo databases. only clinical trials published in peer-reviewed journals were included. of these, 151 studies were identified, of which six met the established criteria. reviewed studies suggest beneficial effects for treatment-resistant depression, anxiety and depression associated with life-threatening diseases, and tobacco and alcohol dependence. all drugs were well tolerated. in conclusion, ayahuasca, psilocybin and lsd may be useful pharmacological tools for the treatment of drug dependence, and anxiety and mood disorders, especially in treatment-resistant patients. these drugs may also be useful pharmacological tools to understand psychiatric disorders and to develop new therapeutic agents. however, all studies reviewed had small sample sizes, and half of them were open-label, proof-of-concept studies. randomized, double-blind, placebo-controlled studies with more patients are needed to replicate these preliminary findings.”
Foldi, C. J., Liknaitzky, P., Williams, M., & Oldfield, B. J.. (2020). Rethinking Therapeutic Strategies for Anorexia Nervosa: Insights From Psychedelic Medicine and Animal Models. Frontiers in Neuroscience
Plain numerical DOI: 10.3389/fnins.2020.00043
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“Anorexia nervosa (an) has the highest mortality rate of any psychiatric disease, yet available pharmacological treatments are largely ineffective due, in part, to an inadequate understanding of the neurobiological drivers that underpin the condition. the recent resurgence of research into the clinical applications of psychedelic medicine for a range of mental disorders has highlighted the potential for classical psychedelics, including psilocybin, to alleviate symptoms of an that relate to serotonergic signaling and cognitive inflexibility. clinical trials using psychedelics in treatment-resistant depression have shown promising outcomes, although these studies are unable to circumvent some methodological biases. the first clinical trial to use psilocybin in patients with an commenced in 2019, necessitating a better understanding of the neurobiological mechanisms through which psychedelics act. animal models are beneficial in this respect, allowing for detailed scrutiny of brain function and behavior and the potential to study pharmacology without the confounds of expectancy and bias that are impossible to control for in patient populations. we argue that studies investigating the neurobiological effects of psychedelics in animal models, including the activity-based anorexia (aba) rodent model, are particularly important to inform clinical applications, including the subpopulations of patients that may benefit most from psychedelic medicine.”
A., M., & R, , Gupta. (
2017).
Role of psilocybin in the treatment of depression.
Therapeutic Advances in Psychopharmacology
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“Psilocybin is a naturally occurring alkaloid, pharmacologically similar to the classic hallucinogen lysergic acid diethylamide (lsd). although primarily used as a recreational drug or an entheogen in particular cultural settings, recent population based studies have shown that it does not lead to serious physical or mental health problems or dependent use. in view of recent work demonstrating psilocybin’s potential to increase subjective sense of wellbeing and because of its novel mechanism of 5-ht2a serotonin receptor agonism, it is being explored for possible therapeutic utility in mood and anxiety disorders.copyright © 2016, © the author(s), 2016.”
Russ, S. L., Carhart-Harris, R. L., Maruyama, G., & Elliott, M. S.. (2019). Replication and extension of a model predicting response to psilocybin. Psychopharmacology
Plain numerical DOI: 10.1007/s00213-019-05279-z
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“Background: recent research demonstrated the potential of psychedelic drugs as treatment for depression and death-related anxiety and as an enhancement for well-being. while generally positive, responses to psychedelic drugs can vary according to traits, setting, and mental state (set) before and during ingestion. most earlier models explain minimal response variation, primarily related to dosage and trust, but a recent study found that states of surrender and preoccupation at the time of ingestion explained substantial variance in mystical and adverse psilocybin experiences. objectives: the current study sought to replicate the previous model, extend the model with additional predictors, and examine the role of mystical experience on positive change. method: a hierarchical regression model was created with crowdsourced retrospective data from 183 individuals who had self-administered psilocybin in the past year. scales explored mental states before, during, and after psilocybin ingestion, relying on open-ended memory prompts at each juncture to trigger recollections. controlled drug administration was not employed. results: this study replicated the previous model, finding a state of surrender before ingestion a key predictor of optimal experience and preoccupation a key predictor of adverse experience. additional predictors added to the explanatory power for optimal and adverse experience. the model supported the importance of mystical experiences to long-term change. conclusion: mental states of surrender or preoccupation at the time of ingestion explain variance in mystical or adverse psilocybin experiences, and mystical experiences relate to long-term positive change. the capacity to recognize this optimal preparatory mental state may benefit therapeutic use of psilocybin in clinical settings.”
Berkovitch, L., Roméo, B., Karila, L., Gaillard, R., & Benyamina, A.. (2021). Efficacy of psychedelics in psychiatry, a systematic review of the literature. Encephale
Plain numerical DOI: 10.1016/j.encep.2020.12.002
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“Objectifs: les psychédéliques sont des substances psychoactives puissantes dont les pouvoirs thérapeutiques dans le champ de la psychiatrie et de l’addictologie ont récemment été redécouverts. cet article est une revue systématique de la littérature sur l’efficacité des psychédéliques, tels que la psilocybine, l’ayahuasca ou le diéthylamide de l’acide lysergique (lsd), dans les troubles psychiatriques et addictologiques. méthodes: une recherche systématique utilisant les mots clés « (ayahuasca or psilocybin or lysergic acid diethylamide) and (depression or anxiety or major depressive disorder or bipolar disorder or anxiety disorder or substance use disorder or dependence) » sur les bases de données medline, psycinfo, web of science et scopus entre janvier 1990 et mai 2020 a été réalisée selon les recommandations prisma afin d’identifier les différents articles. résultats: vingt-cinq articles ont été retenus: cinq sur le traitement des symptômes anxio-dépressifs de patients ayant une pathologie grave et incurable, onze dans les épisodes dépressifs caractérisés, huit dans les troubles addictologiques, un dans le trouble obsessionnel compulsif. la plupart de ces études étaient observationnelles ou portaient sur de petits échantillons de patients, en ouvert. elles retrouvaient une efficacité importante des psychédéliques notamment dans des pathologies résistantes ou sans traitement médicamenteux de référence. les bénéfices apparaissaient rapidement après l’administration et pouvaient perdurer plusieurs mois après une prise unique. aucun effet secondaire grave n’a été décrit. conclusions: les psychédéliques constituent des thérapeutiques prometteuses, d’efficacité rapide et durable, dont l’utilisation semble bien tolérée. cependant, leurs effets doivent être confirmés par des études de plus grande ampleur et comparés aux prises en charge habituelles.”
Psilocybin shows potential as treatment for depression. (2021). Pharmaceutical Journal
Plain numerical DOI: 10.1211/pj.2016.20201222
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Carhart-Harris, R. L., & Nutt, D. J.. (
2016).
“Psilocybin: Panacea or placebo?” and “Question-based Drug Development for psilocybin”: Authors’ reply.
The Lancet Psychiatry
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“Reply by the current authors to the comments made by robin l carhart-harris & david j nutt (see record [rid]2016-43093-012[/rid]) on the original article (see record [rid]2016-25160-001[/rid]). they off er two citations to support the claim that placebo can account for 40% remission rates in major depression, equivalent to what we observed 3 months on from only two exposures to psilocybin in treatment-resistant depression. crucially, however, remission rates are not reported in either of the papers cited. finally, it is important to re-emphasise that patients in our trial met criteria for treatment-resistant depression; they had a mean duration of illness of 18 years, did not improve with an average of fi ve diff erent medications and 11 of 12 patients had also tried at least one form of psychotherapy. in such a context, 67% remission rates at 1 week after treatment and 42% at 3 months, should be considered promising in the very least. (psycinfo database record (c) 2016 apa, all rights reserved)”
Vermetten, E., Yehuda, R., Doblin, R., Mithoefer, M., Mithoefer, A., Johnson, M., & Kelmendi, B.. (
2019).
Should MDMA and psilocybin be used for the treatment of PTSD?.
Neuropsychopharmacology
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“Study group summary: results of the early investigations with psychedelics in psychiatry were mixed, with studies often poorly designed. due to class i scheduling in the 70’s, research into the potential therapeutic use of these substances was halted, preventing definitive conclusions about whether or how these compounds might best be utilized. this study group will critically evaluate emergent research that has shed new light on the therapeutic possibilities of two compounds in the treatment of posttraumatic stress disorder (ptsd) and depression: methylenedioxymethamfetamine (mdma) and 4-phosphorloxy-n, n-dimethyltryptamine (psilocybin). although the fda has granted mdma-assisted psychotherapy for ptsd and psilocybin for depression, breakthrough therapy status there are many questions about the efficacy, neurobiology, and exact use of these compounds in these disorders, which this study group will also address. we will present the latest published and unpublished data from phase 2 trials, and supporting neuroscience observation pre and post-treatment for these increasingly hyped, but poorly understood treatments. it is now more important than ever for the acnp community to have the facts and latest knowledge, as there is a growing interest by the public in psychedelic use for trauma related symptoms, including depression and anxiety, as evidenced by michael pollan’s best-selling book ‘how to change your mind.’ additionally, phase 3 trials are now in progress for both mdma and psilocybin, so it is important to separate fact from fiction, and understand, if these compounds do work, how they work, and how this informs us about biological mechanisms of resilience. among the questions addressed: 1. what are the similarities and differences in the way mdma and psilocybin act from a clinical perspective? do these compounds produce similar psychological states? what are the underlying neurobiological correlates, as demonstrated by neuroimaging studies? 2. when in the course of a therapy might these compounds be indicated? are they for treatment resistant conditions? should they be first line treatments? 3. must these therapies be utilized in the context of psychotherapy? 4. what types of psychotherapy are recommended with mdma and psilocybin? 5. what are the dangers regarding the potential for abuse of these medications and in whom are these treatments contra-indicated? 6. how can emerging neurobiological data obtained before and after treatment with mdma and …”
Brown, R. T., Nicholas, C. R., Cozzi, N. V., Gassman, M. C., Cooper, K. M., Muller, D., … Hutson, P. R.. (2017). Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. Clinical Pharmacokinetics
Plain numerical DOI: 10.1007/s40262-017-0540-6
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“Introduction: psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. this open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults. methods: eligible healthy adults received 6–8 h of preparatory counseling in anticipation of the first dose of psilocybin. the escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (lc–ms/ms) assay for psilocybin and psilocin, the active metabolite. the pharmacokinetics of psilocin were determined using both compartmental (nonmem) and noncompartmental (winnonlin) methods. results: no psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. the pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). an extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied. conclusions: the small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild–moderate renal impairment. simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose. clinical trials identifier: nct02163707.”
Brooks, M.. (
2019).
FDA Grants Psilocybin Second Breakthrough Therapy Designation for Resistant Depression
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“The us food and drug administration (fda) has granted the usona institute breakthrough therapy designation for psilocybin for the treatment of major depressive disorder (mdd). this marks the second time the fda has granted breakthrough designation for psilocybin, the psychoactive ingredient in ‘magic mushrooms.’ in october 2018, compass pathways received the designation to test the safety and efficacy of psilocybin-assisted therapy for treatment-resistant depression, as reported by medscape medical news.”
Raval, N. R., Johansen, A., Donovan, L. L., Ros, N. F., Ozenne, B., Hansen, H. D., & Knudsen, G. M.. (2021). A single dose of psilocybin increases synaptic density and decreases 5-HT2A receptor density in the pig brain. International Journal of Molecular Sciences
Plain numerical DOI: 10.3390/ijms22020835
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“A single dose of psilocybin, a psychedelic and serotonin 2a receptor (5-ht2ar) agonist, may be associated with antidepressant effects. the mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5- ht2ar. here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2a (sv2a) and 5-ht2ar density in the pig brain. twenty-four awake pigs received either 0.08 mg/kg psilocybin or saline intravenously. twelve pigs (n = 6/intervention) were euthanized one day post-injection, while the remaining twelve pigs were euthanized seven days post-injection (n = 6/intervention). we performed autoradiography on hippocampus and prefrontal cortex (pfc) sections with [3h]ucb-j (sv2a), [3h]mdl100907 (5-ht2ar antagonist) and [3h]cimbi-36 (5-ht2ar agonist). one day post psilocybin injection, we observed 4.42% higher hippocampal sv2a density and lowered hippocampal and pfc 5-ht2ar density (-15.21% to -50.19%). these differences were statistically significant in the hippocampus for all radioligands and in the pfc for [3h]cimbi-36 only. seven days post-intervention, there was still significantly higher sv2a density in the hippocampus (+9.24%) and the pfc (+6.10%), whereas there were no longer any differences in 5-ht2ar density. our findings suggest that psilocybin causes increased persistent synaptogenesis and an acute decrease in 5-ht2ar density, which may play a role in psilocybin’s antidepressive effects.”
Varker, T., Watson, L., Gibson, K., Forbes, D., & O’Donnell, M. L.. (2021). Efficacy of Psychoactive Drugs for the Treatment of Posttraumatic Stress Disorder: A Systematic Review of MDMA, Ketamine, LSD and Psilocybin. Journal of Psychoactive Drugs
Plain numerical DOI: 10.1080/02791072.2020.1817639
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“The aim of this systematic review was to examine the efficacy of mdma, ketamine, lsd, and psilocybin for the treatment of posttraumatic stress disorder (ptsd). a search of four databases for english language, peer-reviewed literature published from inception to 18th october 2019 yielded 2,959 records, 34 of which were screened on full-text. observational studies and rcts which tested the efficacy of mdma, ketamine, lsd, or psilocybin for reducing ptsd symptoms in adults, and reported changes to ptsd diagnosis or symptomatology, were included. nine trials (five ketamine and four mdma) met inclusion criteria. trials were rated on a quality and bias checklist and grade was used to rank the evidence. the evidence for ketamine as a stand-alone treatment for comorbid ptsd and depression was ranked ‘very low’, and the evidence for ketamine in combination with psychotherapy as a ptsd treatment was ranked ‘low’. the evidence for mdma in combination with psychotherapy as a ptsd treatment was ranked ‘moderate’.”
J.B., S., D.J., N., R.L., C.-H., T.P., F., C., H., W., L., … Carhart-Harris, R. L.. (
2018).
Psilocybin with psychological support improves emotional face recognition in treatment-resistant depression..
Psychopharmacology
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“RATIONALE: depressed patients robustly exhibit affective biases in emotional processing which are altered by ssris and predict clinical outcome.
objectives: the objective of this study is to investigate whether psilocybin, recently shown to rapidly improve mood in treatment-resistant depression (trd), alters patients’ emotional processing biases.
methods: seventeen patients with treatment-resistant depression completed a dynamic emotional face recognition task at baseline and 1 month later after two doses of psilocybin with psychological support. sixteen controls completed the emotional recognition task over the same time frame but did not receive psilocybin.
results: we found evidence for a group × time interaction on speed of emotion recognition (p = .035). at baseline, patients were slower at recognising facial emotions compared with controls (p < .001). after psilocybin, this difference was remediated (p = .208). emotion recognition was faster at follow-up compared with baseline in patients (p = .004, d = .876) but not controls (p = .263, d = .302). in patients, this change was significantly correlated with a reduction in anhedonia over the same time period (r = .640, p = .010).
conclusions: psilocybin with psychological support appears to improve processing of emotional faces in treatment-resistant depression, and this correlates with reduced anhedonia. placebo-controlled studies are warranted to follow up these preliminary findings.”
Blei, F., Baldeweg, F., Fricke, J., & Hoffmeister, D.. (2018). Biocatalytic Production of Psilocybin and Derivatives in Tryptophan Synthase-Enhanced Reactions. Chemistry – A European Journal
Plain numerical DOI: 10.1002/chem.201801047
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“Psilocybin (4-phosphoryloxy-n,n-dimethyltryptamine) is the main alkaloid of the fungal genus psilocybe, the so-called ‘magic mushrooms.’ the pharmaceutical interest in this psychotropic natural product as a future medication to treat depression and anxiety is strongly re-emerging. here, we present an enhanced enzymatic route of psilocybin production by adding trpb, the tryptophan synthase of the mushroom psilocybe cubensis, to the reaction. we capitalized on its substrate flexibility and show psilocybin formation from 4-hydroxyindole and l-serine, which are less cost-intensive substrates, compared to the previous method. furthermore, we show enzymatic production of 7-phosphoryloxytryptamine (isonorbaeocystin), a non-natural congener of the psilocybe alkaloid norbaeocystin (4-phosphoryloxytryptamine), and of serotonin (5-hydroxytryptamine) by means of the same in vitro approach.”
Byock, I.. (2018). Taking Psychedelics Seriously. Journal of Palliative Medicine
Plain numerical DOI: 10.1089/jpm.2017.0684
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“Background: psychiatric research in the 1950s and 1960s showed potential for psychedelic medications to markedly alleviate depression and suffering associated with terminal illness. more recent published studies have demonstrated the safety and efficacy of psilocybin, mdma, and ketamine when administered in a medically supervised and monitored approach. a single or brief series of sessions often results in substantial and sustained improvement among people with treatment-resistant depression and anxiety, including those with serious medical conditions. need and clinical considerations: palliative care clinicians occasionally encounter patients with emotional, existential, or spiritual suffering, which persists despite optimal existing treatments. such suffering may rob people of a sense that life is worth living. data from oregon show that most terminally people who obtain prescriptions to intentionally end their lives are motivated by non-physical suffering. this paper overviews the history of this class of drugs and their therapeutic potential. clinical cautions, adverse reactions, and important steps related to safe administration of psychedelics are presented, emphasizing careful patient screening, preparation, setting and supervision. conclusion: even with an expanding evidence base confirming safety and benefits, political, regulatory, and industry issues impose challenges to the legitimate use of psychedelics. the federal expanded access program and right-to-try laws in multiple states provide precendents for giving terminally ill patients access to medications that have not yet earned fda approval. given the prevalence of persistent suffering and growing acceptance of physician-hastened death as a medical response, it is time to revisit the legitimate therapeutic use of psychedelics.”
Knopf, A.. (2021). Psilocybin: Next to treat depression, OCD and nicotine addiction. Alcoholism & Drug Abuse Weekly
Plain numerical DOI: 10.1002/adaw.33204
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T., L., & R.L., C.-H.. (
2018).
Increased nature relatedness and decreased authoritarian political views after psilocybin for treatment-resistant depression.
Journal of Psychopharmacology
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“Rationale: previous research suggests that classical psychedelic compounds can induce lasting changes in personality traits, attitudes and beliefs in both healthy subjects and patient populations. aim: here we sought to investigate the effects of psilocybin on nature relatedness and libertarian-authoritarian political perspective in patients with treatment-resistant depression (trd). methods: this open-label pilot study with a mixed-model design studied the effects of psilocybin on measures of nature relatedness and libertarian-authoritarian political perspective in patients with moderate to severe trd (n=7) versus age-matched non-treated healthy control subjects (n=7). psilocybin was administered in two oral dosing sessions (10 mg and 25 mg) 1 week apart. main outcome measures were collected 1 week and 7-12 months after the second dosing session. nature relatedness and libertarian-authoritarian political perspective were assessed using the nature relatedness scale (nr-6) and political perspective questionnaire (ppq-5), respectively. results: nature relatedness significantly increased (t(6)=-4.242, p=0.003) and authoritarianism significantly decreased (t(6)=2.120, p=0.039) for the patients 1 week after the dosing sessions. at 7-12 months post-dosing, nature relatedness remained significantly increased (t(5)=-2.707, p=0.021) and authoritarianism remained decreased at trend level (t(5)=-1.811, p=0.065). no differences were found on either measure for the non-treated healthy control subjects. conclusions: this pilot study suggests that psilocybin with psychological support might produce lasting changes in attitudes and beliefs. although it would be premature to infer causality from this small study, the possibility of drug-induced changes in belief systems seems sufficiently intriguing and timely to deserve further investigation.
copyright © the author(s) 2018.”
Rucker, J. J., & Young, A. H.. (2021). Psilocybin: From Serendipity to Credibility?. Frontiers in Psychiatry
Plain numerical DOI: 10.3389/fpsyt.2021.659044
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“Psilocybin has a long history of non-medical use and some seem to infer from this that it has therapeutic utility. early phase clinical trials with psilocybin are encouraging, but suggest only that larger, multicentre trials are required. these are ongoing but will take many years to complete. meanwhile, retreat centers offering paid experiences with psilocybin truffles have opened in some countries, often using early phase clinical trial data as a basis for bold, public facing claims. this seems unwise. early phase trials are not designed for their results to be generalized outside the setting they were undertaken in. to do so risks being misleading. providing what may be seen as an unregulated drug intervention as a paid service is difficult to reconcile with long-held ethical principles underpinning human research and treatment development that were laid down by the 1947 nuremberg code and the 1962 kefauver harris amendments. by using psilocybin before it has been properly tested, retreat centers may be undermining their own credibility and the credibility of the wider field.”
Hamzelou, J.. (2018). Can psychedelic drug help with depression?. New Scientist
Plain numerical DOI: 10.1016/s0262-4079(18)30332-4
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“The way you speak may reveal whether a psychedelic drug could help treat depression or anxiety. robin carhart-harris and his team at imperial college london have been testing psilocybin–a hallucinogen found in magic mushrooms–in people with treatment-resistant depression. their pilot study found that when it was given to 12 volunteers alongside psychological support, five of them no longer met the clinical criteria for a depression diagnosis three months later”
Kraehenmann, R., Schmidt, A., Friston, K., Preller, K. H., Seifritz, E., & Vollenweider, F. X.. (2016). The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity. NeuroImage: Clinical
Plain numerical DOI: 10.1016/j.nicl.2015.08.009
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“Stimulation of serotonergic neurotransmission by psilocybin has been shown to shift emotional biases away from negative towards positive stimuli. we have recently shown that reduced amygdala activity during threat processing might underlie psilocybin’s effect on emotional processing. however, it is still not known whether psilocybin modulates bottom-up or top-down connectivity within the visual-limbic-prefrontal network underlying threat processing. we therefore analyzed our previous fmri data using dynamic causal modeling and used bayesian model selection to infer how psilocybin modulated effective connectivity within the visual-limbic-prefrontal network during threat processing. first, both placebo and psilocybin data were best explained by a model in which threat affect modulated bidirectional connections between the primary visual cortex, amygdala, and lateral prefrontal cortex. second, psilocybin decreased the threat-induced modulation of top-down connectivity from the amygdala to primary visual cortex, speaking to a neural mechanism that might underlie putative shifts towards positive affect states after psilocybin administration. these findings may have important implications for the treatment of mood and anxiety disorders.”
Erritzoe, D., Roseman, L., Nour, M. M., MacLean, K., Kaelen, M., Nutt, D. J., … Erritzoe, D.. (
2018).
Effects of psilocybin therapy on personality structure ACTA PSYCHIATRICA SCANDINAVICA.
Acta Psychiatr Scand
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“DJ, carhart-harris rl. effects of psilocybin therapy on personality structure. 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. significant outcomes • personality trait neuroticism decreased, while traits extraversion, conscientiousness (trend-level), and openness all increased from baseline to the 3-month follow-up after psilocybin-facilitated therapy for treatment-resistant depression. • an exploratory analysis revealed that the degree of insightfulness during the psychedelic experience predicted changes in neuroticism and extraversion. • where changes in neuroticism and conscientiousness are consistent with what has been observed previously among patients responding to antidepressant treatment, the pronounced increases in extraversion and openness might constitute an effect more specific to therapy with a psychedelic. limitations • relatively small sample size of 20 patients suffering treatment-resistant depression. • open-label design and absence of a control condition. • two-thirds of the patients in this study were men, limiting extrapolation to the gen…”
Anderson, B., Danforth, A., Daroff, R., Stauffer, C., Dilley, J., Mitchell, J., & Woolley, J.. (2019). T137. Psilocybin-Assisted Group Therapy for Demoralization in Long-Term AIDS Survivors. Biological Psychiatry
Plain numerical DOI: 10.1016/j.biopsych.2019.03.460
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“Background: long-term aids survivors (ltas) are people with hiv diagnosed prior to the advent of antiretroviral therapy. ltas suffer high rates of multiple psychiatric illnesses; demoralization is a syndrome common in ltas and is characterized by a sense of helplessness, hopelessness, and a loss of meaning and purpose in life. psilocybin is a 5ht2a agonist and classic psychedelic that can improve depression and anxiety in cancer patients when combined with individual psychotherapy, possibly by decreasing demoralization. method(s): we are conducting an open-label trial of psilocybin-assisted group therapy for gay-identified ltas with moderate-to-severe demoralization. participants complete four group-based preparatory sessions, followed by an individual psilocybin administration session (0.3mg/kg po), followed by six group-based integration sessions. primary outcomes include safety and feasibility. secondary outcomes include self-reported demoralization, grief, and symptoms of depression and ptsd. result(s): 18 individuals enrolled in the trial with 100% retention. zero serious adverse events related to psilocybin occurred and no medical interventions were required. changes from baseline to endpoint were found in demoralization scale-ii (mean difference (sd): 6.67 (6.51), p=0.0004, hedge’s g=0.99); center for epidemiologic studies of depression scale-revised (8.94 (14.73), p=0.02, g=0.76); inventory of complicated grief-revised (6.22 (6.74), p=0.001, g=0.52); and ptsd check list-5 (9 (11.47), p=0.004, g=0.74). conclusion(s): this is the first trial to demonstrate the safety, feasibility, and preliminary efficacy of administering psilocybin as an adjunct to group (vs. individual) psychotherapy for any disorder. preliminary results resemble prior findings of rapid improvement in mood and anxiety symptoms in cancer patients. placebo-controlled trials are needed. supported by: gift fund keywords: psilocybin, mood disorders, hiv copyright © 2019”
Carhart-Harris, R. L., & Goodwin, G. M.. (
2017).
The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future THE THERAPEUTIC POTENTIAL OF PSYCHEDELIC DRUGS: TEMPERED OPTIMISM (RLC-H).
Neuropsychopharmacology
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“Plant-based psychedelics, such as psilocybin, have an ancient history of medicinal use. after the first english language report on lsd in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. used most notably as aids to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as lsd showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programs. since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with lsd and three separate clinical trials of psilocybin for depressive symptoms. in this circumspective piece, rlc-h and gmg share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.”
Sloshower, J., Guss, J., Krause, R., Wallace, R. M., Williams, M. T., Reed, S., & Skinta, M. D.. (2020). Psilocybin-assisted therapy of major depressive disorder using Acceptance and Commitment Therapy as a therapeutic frame. Journal of Contextual Behavioral Science
Plain numerical DOI: 10.1016/j.jcbs.2019.11.002
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“Psychedelic-assisted therapy is based on the premise that psychedelic substances can act as catalysts or adjuncts to psychotherapeutic processes. recent clinical trials involving psychedelic-assisted therapy have generally employed a similar three-part structure consisting of preparation, support during the dosing sessions, and subsequent ‘integration.’ however, the content of these sessions and the frame through which the therapists approach participants and understand the clinical process has thus far been inconsistent among studies. in designing a manualized therapy protocol for a small clinical trial of psilocybin-assisted therapy for major depressive disorder, our group sought to delineate an explicit and replicable, evidence-based model that intentionally builds upon both the neurobiological actions of the medication and the phenomenology of the drug experience. having identified considerable concordance in proposed mechanisms of change between acceptance and commitment therapy (act) and psilocybin therapy, we employed act as an overarching psychotherapeutic framework. we hypothesize that the psilocybin experience can provide direct experiential contact with act processes that increase psychological flexibility, and that these deeply felt experiences may in turn be reinforced during act-informed follow-up therapy sessions. in this paper, we describe the rationale for selecting act, areas of potential synergism between act and psilocybin-therapy, the basic structure of our treatment model, and limitations to this approach.”
Earleywine, M., Ueno, L. F., Mian, M. N., & Altman, B. R.. (2021). Cannabis-induced oceanic boundlessness. Journal of Psychopharmacology
Plain numerical DOI: 10.1177/0269881121997099
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“Background: despite tetrahydrocannabinol (thc)’s reputation for creating dramatic effects at high doses, empirical work rarely addresses cannabis’s impact on subjective responses common to the tryptamine psychedelics. we focused on these effects because they have preceded and covaried with the therapeutic impact of psilocybin in previous work. aims: the current study examined if self-reported responses to cannabis products might parallel those found in clinical trials of psilocybin administration. we also investigated if measures of demographics and cannabis use might correlate with these responses. methods: participants reported the subjective effect of their highest thc experience using 27 items that assess oceanic boundlessness, a correlate of mystical experiences. they also answered infrequency items and questions on demographics and cannabis consumption. results: in an effort to address concerns about replication, we divided respondents who passed infrequency items into two random samples. self-reported ‘breakthrough’ experiences were significantly greater than zero but significantly lower than those reported in randomized clinical trials of psilocybin (17–19% vs. 59%). total scores covaried with perceived dosages of thc, but only in one sample. heavier users of cannabis reported lower scores. conclusions: self-report data suggest that high doses of cannabis can create subjective effects comparable to those identified in trials of psilocybin that precede relief from cancer-related distress, treatment-resistant depression, alcohol problems, and cigarette dependence. given the disparate mechanisms of action, comparing thc-induced to psilocybin-induced effects might improve our understanding of the mechanisms underlying subjective experiences. this work might also support the development of a cannabis-assisted psychotherapy comparable to psilocybin-assisted psychotherapy.”
Hutchison, C., & Bressi, S.. (2021). Social Work and Psychedelic-Assisted Therapies: Practice Considerations for Breakthrough Treatments. Clinical Social Work Journal
Plain numerical DOI: 10.1007/s10615-019-00743-x
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“The re-emergence of therapeutic uses for mind-altering, psychedelic drugs has brought the field of mental health to a new frontier in research, practice, and policymaking. in the past two decades dozens of clinical trials investigating therapeutic applications of psychedelics—including mdma, psilocybin, and ketamine—have shown promising results in the treatment of trauma-related disorders, some forms of anxiety, and depression. these substances have also garnered preliminary support from the food and drug administration, which has fast-tracked their development. as the field of psychedelic science continues to grow, a serious consideration of these novel treatments in the context of social work practice and values is imperative. this paper offers a brief overview of mdma-, psilocybin-, and ketamine-assisted treatments, and presents an initial discussion of questions pertinent to social work practice raised by their use, including: safety, efficacy, theory of change, training needs, and social justice considerations.”
TC, M., SE, M., Guss, J., SK, P., LT, O., AP, B., … Ross, S.. (
2018).
Individual Experiences in Four Cancer Patients Following Psilocybin-Assisted Psychotherapy..
Frontiers in Pharmacology
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“A growing body of evidence shows that existential and spiritual well-being in cancer patients is associated with better medical outcomes, improved quality of life, and serves as a buffer against depression, hopelessness, and desire for hastened death. historical and recent research suggests a role for psilocybin-assisted psychotherapy in treating cancer-related anxiety and depression. a double-blind controlled trial was performed, where 29 patients with cancer-related anxiety and depression were randomly assigned to treatment with single-dose psilocybin (0.3 mg/kg) or niacin in conjunction with psychotherapy. previously published results of this trial demonstrated that, in conjunction with psychotherapy, moderate-dose psilocybin produced rapid, robust, and enduring anxiolytic, and anti-depressant effects. here, we illustrate unique clinical courses described by four participants using quantitative measures of acute and persisting effects of psilocybin, anxiety, depression, quality of life, and spiritual well-being, as well as qualitative interviews, written narratives, and clinician notes. although the content of each psilocybin-assisted experience was unique to each participant, several thematic similarities and differences across the various sessions stood out. these four participants’ personal narratives extended beyond the cancer diagnosis itself, frequently revolving around themes of self-compassion and love, acceptance of death, and memories of past trauma, though the specific details or narrative content differ substantially. the results presented here demonstrate the personalized nature of the subjective experiences elicited through treatment with psilocybin, particularly with respect to the spiritual and/or psychological needs of each patient.”
Vollenweider, F. X.. (
2019).
Phenomenology and neuronal correlates of altered self: Teachings from psychedelics.
Neuropsychobiology
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“Recent years have seen a burgeoning scientific interest in psychedelic drug-induced or mindfulness-based alterations in selfexperiences, characterized as the dissolution of the sense of self and the loss of boundaries between self and surroundings. after an initial phase of presenting beneficial effects of psychedelics such as psilocybin or mindfulness practice on mental well-being, research is now seeking to unravel the underlying psychological, neurophysiological, and molecular mechanisms. advances in understanding these processes are require for improving and finetuning psychedelic-assisted or mindfulness-based interventions that target specific conditions such as depression. in this presentation, i will focus on a theoretical framework and recent approaches to identify neuronal correlates and processes that are central for psychedelic-induced alterations in self-experience, emotion regulation, and social interaction. furthermore, based on current available empirical evidence i will discuss as to how such acute psychedelic-induced alterations may be relevant for the recent reported beneficial and sustained effects after application of only one or two doses of psilocybin in patients with depression.”
Young, S. N.. (2013). Single treatments that have lasting effects: Some thoughts on the antidepressant effects of ketamine and botulinum toxin and the anxiolytic effect of psilocybin. Journal of Psychiatry and Neuroscience
Plain numerical DOI: 10.1503/jpn.120128
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“Recent clinical trials suggest that 3 single biological treatments have effects that persist. based on research showing that the muscles involved in facial expressions can feed back to influence mood, a single trial diminishing glabella frown lines with botulinum toxin demonstrated a significant antidepressant effect for 16 weeks. based primarily on research with animal models of depression suggesting that glutamate may be involved in depression, the n-methyl-d-aspartate antagonist ketamine has been tested in several trials. a single dose decreased depression for up to a week. the reported effects of the use of mushrooms containing psilocybin by a number of cultures around the world has stimulated several trials showing beneficial effects of a single dose of psilocybin for over a year in healthy people, and for up to 3 months in patients with anxiety disorders who have advanced cancer. this article discusses these studies, their rationale, their possible mechanisms of action, the future clinical research required to establish these therapies and the basic research required to optimize single treatments that have lasting effects. © 2013 canadian medical association.”
Fradkin, D.. (2021). Psilocybin: A brief overview for psychiatric mental health nurse practitioners. Perspectives in Psychiatric Care
Plain numerical DOI: 10.1111/ppc.12888
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“The use of psychedelics, such as psilocybin, has emerged in recent literature as a novel therapeutic treatment for various psychiatric disorders, including substance use, depression, and anxiety. while international and domestic trials are currently underway, there is data demonstrating both the relative safety and potential efficacy of psilocybin. psychiatric mental health nurse practitioners are essential mental health providers that may be at the forefront of delivering these new treatment modalities. therefore, they must be aware of the psychopharmacological and psychotherapeutic tenets of psilocybin to be prepared to treat patients.”
Gard, D. E., Pleet, M. M., Bradley, E. R., Penn, A. D., Gallenstein, M. L., Riley, L. S., … Woolley, J. D.. (2021). Evaluating the risk of psilocybin for the treatment of bipolar depression: A review of the research literature and published case studies. Journal of Affective Disorders Reports
Plain numerical DOI: 10.1016/j.jadr.2021.100240
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“250 words text: 4998 words number of figures: 1 number of tables: 2. cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april 7, 2021. ;
doi. abstract objective: given the treatment limitations of depression in bipolar disorder, we evaluated the”
Benko, J., & Vranková, S.. (2020). Natural psychoplastogens as antidepressant agents. Molecules
Plain numerical DOI: 10.3390/molecules25051172
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“Increasing prevalence and burden of major depressive disorder presents an unavoidable problem for psychiatry. existing antidepressants exert their effect only after several weeks of continuous treatment. in addition, their serious side effects and ineffectiveness in one-third of patients call for urgent action. recent advances have given rise to the concept of psychoplastogens. these compounds are capable of fast structural and functional rearrangement of neural networks by targeting mechanisms previously implicated in the development of depression. furthermore, evidence shows that they exert a potent acute and long-term positive effects, reaching beyond the treatment of psychiatric diseases. several of them are naturally occurring compounds, such as psilocybin, n,n-dimethyltryptamine, and 7,8-dihydroxyflavone. their pharmacology and effects in animal and human studies were discussed in this article.”
Nkadimeng, S. M., Nabatanzi, A., Steinmann, C. M. L., & Eloff, J. N.. (2020). Phytochemical, cytotoxicity, antioxidant and anti-inflammatory effects of psilocybe natalensis magic mushroom. Plants
Plain numerical DOI: 10.3390/plants9091127
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“Psilocybin-containing mushrooms, commonly known as magic mushrooms, have been used since ancient and recent times for depression and to improve quality of life. however, their anti-inflammatory properties are not known. the study aims at investing cytotoxicity; antioxidant; and, for the first time, anti-inflammatory effects of psilocybe natalensis, a psilocybin-containing mushroom that grows in south africa, on lipopolysaccharide-induced raw 264.7 macrophages. macrophage cells were stimulated with lipopolysaccharide and treated with different concentrations of psilocybe natalensis mushroom extracted with boiling hot water, cold water and ethanol over 24 h. quercetin and n-nitro-l-arginine methyl ester were used as positive controls. effects of extracts on the lipopolysaccharide-induced nitric oxide, prostaglandin e2, and cytokine activities were investigated. phytochemical analysis, and the antioxidant and cytotoxicity of extracts, were determined. results showed that the three extracts inhibited the lipopolysaccharide-induced nitric oxide, prostaglandin e2, and interleukin 1β cytokine production significantly in a dose-dependent manner close to that of the positive controls. a study proposed that ethanol and water extracts of psilocybe natalensis mushroom were safe at concentrations used, and have antioxidant and anti-inflammatory effects. phytochemical analysis confirmed the presence of natural antioxidant and anti-inflammatory compounds in the mushroom extracts.”
Carhart-Harris, R.. (2020). 4 Psychedelics: therapeutic mechanisms. Journal of Neurology, Neurosurgery & Psychiatry
Plain numerical DOI: 10.1136/jnnp-2020-bnpa.4
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“
Robin carhart-harris moved to imperial college london in 2008 after obtaining a phd in psychopharmacology from the university of bristol and an ma in psychoanalysis from brunel university. at imperial, he has designed and/or carried out brain imaging studies involving lsd, psilocybin, mdma and dmt, plus a clinical trial of psilocybin for treatment-resistant depression, and an ongoing study comparing psilocybin with escitalopram for major depressive disorder. in 2019, he set-up the centre for psychedelic research at imperial and he also an honorary position with the university of oxford.
the talk takes a multi-level approach to the question of how psychedelics work in the brain. key themes include: the pharmacology of classic serotonergic psychedelics, what this tells us about the function and evolutionary purpose of the serotonin 2a receptor, the acute brain effects of psychedelics as determined by functional brain imaging, the entropic brain hypothesis, current evidence for psychedelic therapy, the ‘Rebus’ hierarchical predictive processing model of the action of psychedelics, and how this maps on to the phenomenology of the acute psychedelic experience and therapeutic outcomes.
”
Roiser, J. P., & Rees, G.. (2012). Neuroimaging: A scanner, colourfully. Current Biology
Plain numerical DOI: 10.1016/j.cub.2012.02.033
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“Two recent studies report changes in human brain responses after exposure to psilocybin, the active ingredient of hallucinogenic mushrooms. psilocybin increased sensory cortex responses during emotional recollection, but decreased resting-state blood flow in prefrontal cortex, with potential implications for treating depression. © 2012 elsevier ltd.”
Rucker, J. J. H., Jelen, L. A., Flynn, S., Frowde, K. D., & Young, A. H.. (2016). Psychedelics in the treatment of unipolar mood disorders: A systematic review. Journal of Psychopharmacology
Plain numerical DOI: 10.1177/0269881116679368
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“Unipolar mood disorders, including major depressive disorder and persistent depressive disorder (dysthymia), confer high rates of disability and mortality and a very high socioeconomic burden. current treatment is suboptimal in most cases and there is little of note in the pharmaceutical development pipeline. the psychedelic drugs, including lysergic acid diethylamide and psilocybin, were used extensively in the treatment of mood disorders, and other psychiatric conditions, before their prohibition in the late 1960s. they are relatively safe when used in medically controlled environments, with no reported risk of dependence. here, we present a systematic review of published clinical treatment studies using psychedelics in patients with broadly defined umd, and consider their place in psychiatry. whilst all of the included studies have methodological shortcomings, of 423 individuals in 19 studies, 335 (79.2%) showed clinician-judged improvement after treatment with psychedelics. a recently completed pilot study in the uk favours the use of psilocybin with psychological support in treatment resistant depressive disorder. the evidence overall strongly suggests that psychedelics should be re-examined in modern clinical trials for their use in unipolar mood disorders and other non-psychotic mental health conditions.”
Carhart-Harris, R. L., Brugger, S., Nutt, D. J., & Stone, J. M.. (2013). Psychiatry’s next top model: Cause for a re-think on drug models of psychosis and other psychiatric disorders. Journal of Psychopharmacology
Plain numerical DOI: 10.1177/0269881113494107
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“Despite the widespread application of drug modelling in psychiatric research, the relative value of different models has never been formally compared in the same analysis. here we compared the effects of five drugs (cannabis, psilocybin, amphetamine, ketamine and alcohol) in relation to psychiatric symptoms in a two-part subjective analysis. in the first part, mental health professionals associated statements referring to specific experiences, for example ‘i don’t bother to get out of bed’, to one or more psychiatric symptom clusters, for example depression and negative psychotic symptoms. this measured the specificity of an experience for a particular disorder. in the second part, individuals with personal experience with each of the above-listed drugs were asked how reliably each drug produced the experiences listed in part 1, both acutely and sub-acutely. part 1 failed to find any experiences that were specific for negative or cognitive psychotic symptoms over depression. the best model of positive symptoms was psilocybin and the best models overall were the acute alcohol and amphetamine models of mania. these results challenge current assumptions about drug models and motivate further research on this understudied area. © the author(s) 2013.”
Griffiths, R.. (
2015).
A single dose of psilocybin produces substantial and enduring decreases in anxiety and depression in patients with a life-threatening cancer diagnosis: a randomized double-blind trial.
Neuropsychopharmacology
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“Background: patients with cancer often develop chronic, clinically significant symptoms of anxiety and depression that have a significant negative impact on the quality of their life. existing pharmacological and psychological treatments are very limited. several trials in the 1960s and 1970s with the classic hallucinogens lsd and dpt in cancer patients showed clinically significant improvement in ratings of depression and anxiety. these trials involved 236 cancer patients. recently, grob and colleagues (2011) reported a pilot study with a moderate dose of the classic hallucinogen psilocybin (about 14 mg/70 kg) showing decreases in anxiety and depression in 12 cancer patients. methods: the study used a randomized, double-blind, cross-over design to investigate the acute and sustained effects of a very low psilocybin dose (1 or 3 mg/70 kg) vs. a moderate-high dose (22 or 30 mg/70 kg). instructions to participants and staff minimized expectancy effects. 51 patients with a life-threatening cancer diagnosis who had symptoms of anxiety or depression received a low or high dose of psilocybin in counterbalanced order with about 5 weeks between sessions and a final follow up at 6 months. for this preliminary analysis, results between the low (n=25) and high (n=26) dose groups on the first session were compared. enduring effects were assessed at a 6 month follow-up. results: on session days, the high dose group showed substantially greater effects including perceptual changes, mystical-type subjective experiences, and labile mood. at the 5-week follow-up the high dose group showed significantly lower anxiety (stai trait anxiety, ham-a) and depression (bdi, ham-d) compared to the low dose group (effect size mean and range 0.98, 0.60-1.30). the participants attributed significantly greater positive changes in attitudes about life/self, positive social effects, and positive behavior changes to the experience, and a higher percentage reported the experience to be among the 5 most personally meaningful of their lives (54% vs. 16%). total mystical experience scores at the end of the session showed significant negative correlations with the above measures of anxiety and depression at 5 weeks. partial correlation analysis showed this relationship remained significant after controlling for ratings of intensity of drug effect. the decreases in anxiety and depression were sustained at 6 month follow-up. conclusions: a single moderate-high dose of psilocybin, when administe…”
Senthilingam, M.. (
2020).
One dose of “magic mushroom” drug reduces anxiety and depression in cancer patients, study says.
CNN
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“(CNN)a single dose of psilocybin, a compound found in ‘magic mushrooms,’ provides long-term relief of anxiety and depression in cancer patients, a new study finds. cancer patients who were given psilocybin reported reductions in anxiety and depression.”
Mahmoudi, E., Faizi, M., Hajiaghaee, R., & Razmi, A.. (
2018).
Alteration of Depressive-like Behaviors by Psilocybe cubensis Alkaloid Extract in Mice: the Role of Glutamate Pathway.
Research Journal of Pharmacognosy
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“Background and objectives: considering the increasing prevalence of depression, many studies are launched to investigate new antidepressant treatments. the present research has shown how psilocybin as an active compound of psilocybe cubensis (earle) singer extract (pce) can change the parameters related to depression and anxiety in animal models. both serotonin (5-hydroxytryptamine: 5-ht) and glutamate modulate depressive-like behaviors and, therefore, we examined the possible interaction of psilocybin as 5-ht 1 agonist with glutamate receptor n-methyl-d-aspartate (nmda). methods: psilocybe cubensis extract of this mushroom was prepared by ethyl acetate. nmri mice involved in all experiments and were treated with the vehicle, extract, or standard drug intraperitoneally. open field (oft), forced swimming (fst) and tail suspension tests (tst) were applied to measure the intended parameters. oft was performed to verify the applied doses for measuring the following antidepressant activity. results: pce at the doses of 100 mg/kg significantly changed the locomotion, time spent in center and velocity of the animals in oft. while treatment of the animals with pce 10 and 40 mg/kg or ketamine 1 mg/kg did not alter the locomotor activity, co-administration of these subeffective amounts significantly reduced the immobility time in both fst and tst. conclusion: these effects may indicate possible implication of psilocybin with nmda receptor which consequently produces the antidepressant effects.”
Reiche, S., Hermle, L., Gutwinski, S., Jungaberle, H., Gasser, P., & Majić, T.. (2018). Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-threatening disease: A systematic review. Progress in Neuro-Psychopharmacology and Biological Psychiatry
Plain numerical DOI: 10.1016/j.pnpbp.2017.09.012
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“Anxiety and depression are some of the most common psychiatric symptoms of patients suffering with life-threatening diseases, often associated with a low quality of life and a poor overall prognosis. 5-ht2a-receptor agonists (serotonergic hallucinogens, ‘psychedelics’) like lysergic acid diethylamide (lsd) and psilocybin were first investigated as therapeutic agents in the 1960s. recently, after a long hiatus period of regulatory obstacles, interest in the clinical use of these substances has resumed. the current article provides a systematic review of studies investigating psychedelics in the treatment of symptoms of existential distress in life-threatening diseases across different periods of research, highlighting how underlying concepts have developed over time. a systematic search for clinical trials from 1960 to 2017 revealed 11 eligible clinical trials involving a total number of n = 445 participants, of which 7 trials investigated the use of lysergic acid diethylamide (lsd) (n = 323), 3 trials investigated the use of psilocybin (n = 92), and one trial investigated the use of dipropyltryptamine (dpt) (n = 30). the 4 more recent randomized controlled trials (rcts) (n = 104) showed a significantly higher methodological quality than studies carried out in the 1960s and 1970s. evidence supports that patients with life threatening diseases associated with symptoms of depression and anxiety benefit from the anxiolytic and antidepressant properties of serotonergic hallucinogens. some studies anecdotally reported improvements in patients´ quality of life and reduced fear of death. moreover, low rates of side effects were reported in studies that adhered to safety guidelines. further studies are needed to determine how these results can be transferred into clinical practice.”
Psilocybin as a Novel Pharmacotherapy for Treatment-Refractory Anorexia Nervosa. (2021). OBM Neurobiology
Plain numerical DOI: 10.21926/obm.neurobiol.2102102
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“Anorexia nervosa (an) is a major health problem with one of the highest mortalities and treatment costs of any psychiatric condition. cognitive behavioural therapy (cbt) is currently the most widely used treatment for an in adults but provides remission rates ≤ 50%. treatment drop-out is exceedingly high and those that persevere with treatment often relapse, causing increased risk of morbidity and mortality. there is an urgent need to find new interventions, especially as there are no approved pharmacological treatments for an. ideally, new treatments would target treatment-resistance and to decrease the chronicity associated with the disorder. over the past two decades, emerging research into classic psychedelic substances (lysergic diethylamide acid (lsd), 5-methoxy-n,n-dimethyltryptamine (5-meo-dmt), n,n-dimethyltryptamine (dmt) and psilocybin), indicates that marked reductions in anxiety and depression-like symptoms, and lasting improvement in mental health, can follow from one or two exposures to these psychedelic substances. anxiety and depression are the most prevalent co-morbid psychiatric symptoms in an. here we suggest that classic psychedelics, particularly psilocybin, have the potential to normalise dysfunctional neurobiological systems in an and provide a novel treatment intervention that is worthy of consideration, particularly for treatment-resistant patients.”
(2019). Psilocybin for Depression in People With Mild Cognitive Impairment or Early Alzheimer’s Disease. Case Medical Research
Plain numerical DOI: 10.31525/ct1-nct04123314
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De Gregorio, D., Enns, J. P., Nuñez, N. A., Posa, L., & Gobbi, G.. (2018). D-Lysergic acid diethylamide, psilocybin, and other classic hallucinogens: Mechanism of action and potential therapeutic applications in mood disorders. In Progress in Brain Research
Plain numerical DOI: 10.1016/bs.pbr.2018.07.008
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“Depression and anxiety are psychiatric diagnoses commonly associated with low quality of life and low percentage of responsiveness by patients treated with currently available drugs. thus, research into alternative compounds to treat these disorders is essential to guarantee a patient’s remission. the last decade has witnessed a revamped interest for the application of psychedelic medicine for the treatment of mental disorders due to anecdotal reports and clinical studies which show that low doses of d-lysergic acid diethylamide (lsd) and psilocybin may have antidepressant effects. lsd and psilocybin have demonstrated mood-modulating properties likely due to their capacity to modulate serotonergic (5-ht), dopaminergic (da) and glutamatergic systems. lsd, belonging to the category of ‘classic halluginogens,’ interacts with the 5-ht system through 5ht1a, and 5ht2a receptors, with the da system through d2 receptors, and indirectly also the glutamatergic neurotransmission thought the recruitment of n-methyl-d-aspartate (nmda) receptors. randomized clinical studies have confirmed its antidepressant and anxiolytic effects in humans. thus, in this chapter, we will review the pharmacology of psychedelic drugs, report the most striking clinical evidence which substantiate the therapeutic potentials of these fascinating compounds in mood disorders, and look into the horizon of where psychedelic medicine is heading.”
Breeksema, J. J., Koolen, M. H. B., Somers, M., & Schoevers, R. A.. (
2021).
[Treatment with psilocybin: applications for patients with psychiatric disorders]..
Nederlands Tijdschrift Voor Geneeskunde
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“After a cessation of almost 40 years, there is renewed interest into therapeutic applicationsof the serotonergic psychedelic psilocybin for the treatment of patients with various psychiatric disorders. pubmed was searched for clinical trials into ‘psilocybin’ between 2000 and 2020, complemented by handsearching. articles were also screened for explanatory models and working mechanisms. psilocybin has been studied in 9 clinical trials: for the treatment of substance use disorders, depression, end-of-life anxiety, demoralization, and obsessive-compulsive disorder. results show that psilocybin is well tolerated, with only limited side-effects, while even patients with treatment-resistant disorders sometimes show marked, long-term improvements after one or a few sessions. initial results are encouraging, but there are several limitations. more research is needed to determine which patient populations can benefit, what role setting and the placebo response play, and how these novel treatments can be optimized.”
T., P., F., T., M., V., R., A., M., B., P., Z., … J., K.. (
2018).
The effects of psilocybin on brain EEG activity and connectivity in healthy volunteers-focus on the dynamics of the psychedelic state.
European Psychiatry
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“Introduction.- a serotonin 5-ht2a/c agonist, psychedelic drug psilocybin, is gaining attention as a potential therapeutic tool for anxiety and depression. psilocybin induces desynchronization of the eeg during the peak of its effects, continuous data are lacking. objectives.- we focused on the dynamics of changes in neuropsychological parameters, brain activity and connectivity after oral administration of psilocybin. methods.- twenty healthy volunteers (10 m/10f, 28-50yrs) were enrolled in this placebo controlled cross over double blind trial. a standard 19 channel eeg (registered before and 60, 90, 180 and 360 min after psilocybin (0.26 mg/kg) ingestion), brief psychiatric rating scale (bprs), plasma levels of psilocin were collected several times over the session, a subjective scale ‘altered scale of consciousness scale (ascs)’ at the end of measurements. current source density and connectivity were analysed by low resolution brain electromagnetic tomography (loreta). results.- psilocybin induced psychotic-like symptoms, especially changes in perception and thought disturbances, peaking at 90 min after ingestion along with serum psilocin levels. induced global decrease of the alpha current source density in the occipital cortex was negatively correlated with the intensity of effects. the overall connectivity decreased in the alpha band, but increased in all other frequency bands at peak, however, six hours after ingestion, the effects were inverted. conclusions.- the study shows that psilocybin dynamically shifts the brain from one connectivity state at baseline through a peak effect to reach another global connectivity state at the end. this work was supported by grants ed2.1.00/03.0078, lo1611/npu i, micr vi20172020056 and progres q35.”
Veen, B. T. H. De, Schellekens, A. F. A., Verheij, M. M. M., & Judith, R.. (
2017).
Expert Review of Neurotherapeutics Psilocybin for treating substance use disorders ?.
Expert Review of Neurotherapeutics
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“Introduction: evidence based treatment for substance use disorders (sud) includes psychotherapy and pharmacotherapy. however, these are only partially effective. hallucinogens, such as psilocybin, may represent potential new treatment options for sud. this review provides a summary of (human) studies on the putative therapeutic effects of psilocybin, and discusses the receptor systems, brain regions and cognitive and emotional processes mediating psilocybin’s effects. psilocybin’s chemical structure is similar to that of serotonin. dysregulations in the serotonin system are associated with alterations in stress hormones, such as cortisol, and mood disorders. after psilocybin administration cortisol levels spike and activate the executive control network, with subsequent increased control over emotional processes, and relief of negative thinking and persistent negative emotions. preliminary data of ongoing alcohol and smoking addiction studies in humans shows promising effects of psilocybin administration on substance use. importantly, psilo-cybin has a low risk of toxicity and dependence and can be used safely under controlled clinical conditions. areas covered: this paper is a narrative review based on the search terms: psilocybin, substance use disorder, addiction, depression, serotonin. literature on potential efficacy and mechanisms of action of psilocybin in sud is discussed. expert commentary: recent positive findings with psilocybin need confirmation in well-designed placebo controlled randomized trials employing a large sample size.”
Pio, G. P., Vitorino, A. M., Aidar, N. B., Magalhães, A. A., Mombelli, E. C., Ferraz, G. M., & Pio, R. P.. (2021). O papel da Psilocibina no tratamento de depressão resistente / The role of Psilocybin in the treatment of resistant depression. Brazilian Journal of Health Review
Plain numerical DOI: 10.34119/bjhrv4n2-395
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Sherwood, A. M., & Prisinzano, T. E.. (2018). Novel psychotherapeutics–a cautiously optimistic focus on Hallucinogens. Expert Review of Clinical Pharmacology
Plain numerical DOI: 10.1080/17512433.2018.1415755
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Kvam, T.-M., Stewart, L. H., & Andreassen, O. A.. (
2018).
Psychedelic drugs in the treatment of anxiety, depression and addiction.
Tidsskrift for Den Norske Legeforening
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“BACKGROUND there is growing interest in the use of psychedelic drugs for the treatment of mental disorders. the drugs are considered safe when administered within a clinical framework. older studies performed prior to 1970 had methodological shortcomings, but studies in recent years have shown promising results regarding the use of psychedelic drugs in unipolar depression, depression in life-threatening illness, anxiety and addiction. the aim of this literature review is to provide an overview of recent results and the limitations of these studies. method we searched the pubmed database for clinical studies from the period 1990–2017 with the keywords anxiety, depression, addiction and psychedelic drugs. the quality of the studies was then assessed on the basis of their methods and statistical power. results the search yielded 424 articles, of which nine were included (four on anxiety and depression in life-threatening illness, two on depression, two on addiction disorders and one on obsessive-compulsive disorder). two double-blind, randomised, controlled phase ii trials with moderate sample sizes reported immediate, marked and sustained efficacy of a single dose of psilocybin against anxiety and depression in life-threatening illness. the results of the other studies were less clear. there were no serious adverse effects or reports of addiction. interpretation psychedelic drugs have shown promising results in the treatment of several mental disorders, but the studies are small and have methodological shortcomings. there is a need for systematic clinical trials to obtain robust evidence of efficacy and to establish routines for the monitoring of potential adverse effects.”
Mertens, L. J., & Preller, K. H.. (2021). Classical Psychedelics as Therapeutics in Psychiatry – Current Clinical Evidence and Potential Therapeutic Mechanisms in Substance Use and Mood Disorders. Pharmacopsychiatry
Plain numerical DOI: 10.1055/a-1341-1907
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“Classical psychedelics, primarily psilocybin and lysergic acid diethylamide (lsd), have been used and extensively studied in western medicine as part of substance-assisted psychotherapy in the 1950s and 1960s. modern clinical research is currently gaining momentum and provides new evidence for the safety and efficacy of classical psychedelics (primarily psilocybin, but also lsd and ayahuasca) in the treatment of different psychiatric conditions, including substance use and mood disorders. in this review article, we outline common pathological mechanisms of substance use disorders (sud) and unipolar depression. next, the current literature on the effects of psychedelics is summarized in order to generate hypotheses regarding their potential therapeutic mechanisms of action in treating these psychiatric conditions. finally, we review and discuss clinical trials published since 2011 investigating the effects of psychedelics in sud and depression. while results from those modern clinical trials are promising, most of them do not meet the methodological requirements to allow firm conclusions on the clinical efficacy of psychedelics. larger, blinded, randomized controlled trials (rct) with clearly defined patient groups and well-defined primary endpoints are needed. additionally, the therapeutic mechanisms of classical psychedelics are currently unknown. this review presents hypotheses derived from preclinical and human studies that need to be tested in future trials to better understand the clinical potential of psychedelic substances in modern psychiatry.”
Nichols, D. E.. (2016). Psychedelics. Pharmacological Reviews
Plain numerical DOI: 10.1124/pr.115.011478
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“Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. they are generally considered physiologically safe and do not lead to dependence or addiction. their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. after the virtually contemporaneous discovery of (5r,8r)-(+)-lysergic acid-n,n-diethylamide (lsd)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that lsd and other psychedelics had a serotonergic basis for their action. today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2a receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer v. several useful rodent models have been developed over the years to help unravel the neurochemical correlates of serotonin 5-hydroxytryptamine 2a receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics. recent and exciting developments in the field have occurred in clinical research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with cancer-related psychosocial distress have demonstrated unprecedented positive relief of anxiety and depression. two small pilot studies of psilocybinassisted psychotherapy also have shown positive benefit in treating both alcohol and nicotine addiction. recently, blood oxygen level–dependent functional magnetic resonance imaging and magnetoencephalography have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and lsd produce decreases in oscillatory power in areas of the brain’s default mode network.”
Flanagan, T. W., & Nichols, C. D.. (2018). Psychedelics as anti-inflammatory agents. International Review of Psychiatry
Plain numerical DOI: 10.1080/09540261.2018.1481827
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“Serotonin (5-hydroxytryptamine, 5-ht)2a receptor agonists have recently emerged as promising new treatment options for a variety of disorders. the recent success of these agonists, also known as psychedelics, like psilocybin for the treatment of anxiety, depression, obsessive-compulsive disorder (ocd), and addiction, has ushered in a renaissance in the way these compounds are perceived in the medical community and populace at large. one emerging therapeutic area that holds significant promise is their use as anti-inflammatory agents. activation of 5-ht2a receptors produces potent anti-inflammatory effects in animal models of human inflammatory disorders at sub-behavioural levels. this review discusses the role of the 5-ht2a receptor in the inflammatory response, as well as highlight studies using the 5-ht2a agonist (r)-2,5-dimethoxy-4-iodoamphetamine [(r)-doi] to treat inflammation in cellular and animal models. it also examines potential mechanisms by which 5-ht2a agonists produce their therapeutic effects. overall, psychedelics regulate inflammatory pathways via novel mechanisms, and may represent a new and exciting treatment strategy for several inflammatory disorders.”
Hope, S., & Rosa, W.. (
2018).
Holistic Care of the Spirit: The Use of Entheogens in Patients with Advanced Serious Illness.
Beginnings
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“The article discusses about the effectiveness of psilocybin in the reduction o depression and anxiety in patients with cancer. topics include the therapeutic usage of spiritual healing of the patients, the importance of holistic caring practice using hallucinogenic agents and the clinical trials on entheogens.”
Mertens, L. J., Wall, M. B., Roseman, L., Demetriou, L., Nutt, D. J., & Carhart-Harris, R. L.. (2019). P.609 Therapeutic mechanisms of psychedelic drugs: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression. European Neuropsychopharmacology
Plain numerical DOI: 10.1016/j.euroneuro.2019.09.593
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“Background:psilocybin has shown promise as a treatment for depression but its therapeutic mechanisms are not properly understood. in contrast to the presumed actions of antidepressants, we recently…”
Magaraggia, I., Kuiperes, Z., & Schreiber, R.. (2021). Improving cognitive functioning in major depressive disorder with psychedelics: A dimensional approach. Neurobiology of Learning and Memory
Plain numerical DOI: 10.1016/j.nlm.2021.107467
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“The high symptomatic and biological heterogeneity of major depressive disorder (mdd) makes it very difficult to find broadly efficacious treatments that work against all symptoms. concentrating on single core symptoms that are biologically well understood might consist of a more viable approach. the research domain criteria (rdoc) framework is a trans-diagnostic dimensional approach that focuses on symptoms and their underlying neurobiology. evidence is accumulating that psychedelics may possess antidepressant activity, and this can potentially be explained through a multi-level (psychobiological, circuitry, (sub)cellular and molecular) analysis of the cognitive systems rdoc domain. cognitive deficits, such as negative emotional processing and negativity bias, often lead to depressive rumination. psychedelics can increase long-term cognitive flexibility, leading to normalization of negativity bias and reduction in rumination. we propose a theoretical model that explains how psychedelics can reduce the negativity bias in depressed patients. at the psychobiological level, we hypothesize that the negativity bias in mdd is due to impaired pattern separation and that psychedelics such as psilocybin help in depression because they enhance pattern separation and hence reduce negativity bias. pattern separation is a mnemonic process that relies on adult hippocampal neurogenesis, where similar inputs are made more distinct, which is essential for optimal encoding of contextual information. impairment in this process may underlie the negative cognitive bias in mdd by, for example, increased pattern separation of cues with a negative valence that can lead to excessive deliberation on aversive outcomes. on the (sub) cellular level, psychedelics stimulate hippocampal neurogenesis as well as synaptogenesis, spinogenesis and dendritogenesis in the prefrontal cortex. together, these effects help restoring resilience to chronic stress and lead to modulation of the major connectivity hubs of the prefrontal cortex, hippocampus, and amygdala. based on these observations, we propose a new translational framework to guide the development of a novel generation of therapeutics to treat the cognitive symptoms in mdd.”
Leger, R. F., & Unterwald, E. M.. (2021). Assessing the effects of methodological differences on outcomes in the use of psychedelics in the treatment of anxiety and depressive disorders: A systematic review and meta-analysis. Journal of Psychopharmacology
Plain numerical DOI: 10.1177/02698811211044688
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“Background: classical psychedelics are a group of drugs which act as agonists on the serotonin-2a (5-ht2a) receptor. evidence suggests they may have a uniquely rapid and enduring positive effect on mood. however, marked heterogeneity between methodological designs in this emerging field remains a significant concern. aims: to determine how differences in the type of psychedelic agent used and the number of dosing sessions administered affect subjects’ depression and anxiety outcomes and adverse drug reactions (adr). methods: this review collected and screened 1591 records from the medline and web of science databases for clinical trials reporting objective data on mood for subjects with a known anxiety or depression. results: after screening, nine clinical trials met inclusion criteria. meta-analysis of these studies showed significant, large positive effect sizes for measures of anxiety (cohen’s d = 1.26) and depression (cohen’s d = 1.38) overall. these positive effects were also significant at acute (⩽1 week) and extended (>1 week) time points. no significant differences were observed between trials using different psychedelic agents (psilocybin, ayahuasca or lysergic acid diethylamide (lsd)), however, a significant difference was observed in favour of trials with multiple dosing sessions. no serious adr were reported. conclusion: psilocybin, ayahuasca and lsd all appear to be effective and relatively safe agents capable of producing rapid and sustained improvements in anxiety and depression. moreover, the findings of the present analysis suggest that they may show a greater efficacy when given to patients over multiple sessions as compared to the more common single session used in many of the existing trials.”
Anderson, T., Petranker, R., Christopher, A., Rosenbaum, D., Weissman, C., Dinh-Williams, L. A., … Hapke, E.. (2019). Psychedelic microdosing benefits and challenges: An empirical codebook. Harm Reduction Journal
Plain numerical DOI: 10.1186/s12954-019-0308-4
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“Background: microdosing psychedelics is the practice of consuming very low, sub-hallucinogenic doses of a psychedelic substance, such as lysergic acid diethylamide (lsd) or psilocybin-containing mushrooms. according to media reports, microdosing has grown in popularity, yet the scientific literature contains minimal research on this practice. there has been limited reporting on adverse events associated with microdosing, and the experiences of microdosers in community samples have not been categorized. methods: in the present study, we develop a codebook of microdosing benefits and challenges (mdbc) based on the qualitative reports of a real-world sample of 278 microdosers. results: we describe novel findings, both in terms of beneficial outcomes, such as improved mood (26.6%) and focus (14.8%), and in terms of challenging outcomes, such as physiological discomfort (18.0%) and increased anxiety (6.7%). we also show parallels between benefits and drawbacks and discuss the implications of these results. we probe for substance-dependent differences, finding that psilocybin-only users report the benefits of microdosing were more important than other users report. conclusions: these mixed-methods results help summarize and frame the experiences reported by an active microdosing community as high-potential avenues for future scientific research. the mdbc taxonomy reported here informs future research, leveraging participant reports to distil the highest-potential intervention targets so research funding can be efficiently allocated. microdosing research complements the full-dose literature as clinical treatments are developed and neuropharmacological mechanisms are sought. this framework aims to inform researchers and clinicians as experimental microdosing research begins in earnest in the years to come.”
Sakloth, F., Leggett, E., Moerke, M. J., Townsend, E. A., Banks, M. L., & Negus, S. S.. (2019). Effects of acute and repeated treatment with serotonin 5-HT2A receptor agonist hallucinogens on intracranial self-stimulation in rats. Experimental and Clinical Psychopharmacology
Plain numerical DOI: 10.1037/pha0000253
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“The prototype 5-ht2a receptor agonist hallucinogens lsd, mescaline, and psilocybin are classified as schedule 1 drugs of abuse by the u.s. drug enforcement administration. accumulating clinical evidence has also suggested that acute or repeated ‘microdosing’ with these drugs may have utility for treatment of some mental health disorders, including drug abuse and depression. the goal of the present study was to evaluate lsd, mescaline, and psilocybin effects on intracranial self-stimulation (icss), a procedure that has been used to evaluate abuse-related effects of other classes of abused drugs. effects of repeated lsd were also examined to evaluate potential changes in its own effects on icss or changes in effects produced by the abused psychostimulant methamphetamine or the prodepressant kappa opioid receptor (kor) agonist u69,593. male sprague-dawley rats were implanted with microelectrodes targeting the medial forebrain bundle and trained to respond under a ‘frequency-rate’ icss procedure, in which many drugs of abuse increase (or ‘facilitate’) icss. in acute dose-effect and time-course studies, evidence for abuse-related icss facilitation was weak and inconsistent; the predominant effect of all 3 drugs was dose- and time-dependent icss depression. repeated lsd treatment failed to alter either its own icss depressant effects or the abuse-related effects of methamphetamine; however, repeated lsd did attenuate icss depression by u69,593. these results extend those of previous preclinical studies to suggest weak expression of abuse-related effects by 5-ht2a agonist hallucinogens and provide supportive evidence for therapeutic effects of repeated lsd dosing to attenuate kormediated depressant effects but not abuse potential of psychostimulants.”
Zamaria, J. A.. (2016). A phenomenological examination of psilocybin and its positive and persisting aftereffects. NeuroQuantology
Plain numerical DOI: 10.14704/nq.2016.14.2.943
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“This study is an examination of the positive and persisting psychological and behavioral aftereffects in eight individuals who reported consumption of psilocybin-containing mushrooms. mushrooms containing psilocybin have been used for healing and spiritual purposes for thousands of years, and the therapeutic applications of psilocybin were scientifically examined beginning in the mid-20th century. research from this era suggested that psilocybin was indicated as an effective adjunct to psychotherapy for conditions such as depression, anxiety, chemical dependency, and obsessive-compulsive disorder. recent research at the johns hopkins school of medicine demonstrated that participants who consumed psilocybin reported having profoundly meaningful experiences, and that these participants experienced persisting and positive changes to their mood, attitude, and behavior at 1-month and 14-month follow up. however, there has not yet been ample research examining the mechanism of the connection between participants’ experience with psilocybin and the existence of these positive and persisting aftereffects. this study employed a phenomenological approach, using an unstructured interview to gain an understanding of participants’ description of this mechanism. eight adults were interviewed who reported using psilocybin in the past. a within-case analysis and cross-case analysis were conducted on the data, producing 11 themes within three categories: set (which included the themes of preliminary anxiety and substantial preparation); experience of psilocybin effect (which included the themes of profound shift in attention, unity consciousness, increased introspection, positive emotional state, and transcendental experience); and persisting aftereffects (which included the themes of short term reduction in anxiety, persisting insight, assistance with psychological distress, and inspired behavioral change). participants maintained insights gained during their experience of psilocybin far beyond the course of the substance. this research suggests that the positive and persisting aftereffects related to the consumption of psilocybin may be useful for psychological healing and growth, and that these aftereffects should continue to be studied.”
de Gregorio, D., Aguilar-Valles, A., Preller, K. H., Heifets, B. D., Hibicke, M., Mitchell, J., & Gobbi, G.. (2021). Hallucinogens in mental health: Preclinical and clinical studies on LSD, psilocybin, MDMA, and ketamine. In Journal of Neuroscience
Plain numerical DOI: 10.1523/JNEUROSCI.1659-20.2020
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“A revamped interest in the study of hallucinogens has recently emerged, especially with regard to their potential application in the treatment of psychiatric disorders. in the last decade, a plethora of preclinical and clinical studies have confirmed the efficacy of ketamine in the treatment of depression. more recently, emerging evidence has pointed out the potential therapeutic properties of psilocybin and lsd, as well as their ability to modulate functional brain connectivity. moreover, mdma, a compound belonging to the family of entactogens, has been demonstrated to be useful to treat post-traumatic stress disorders. in this review, the pharmacology of hallucinogenic compounds is summarized by underscoring the differences between psychedelic and nonpsychedelic hallucinogens as well as entactogens, and their behavioral effects in both animals and humans are described. together, these data substantiate the potentials of these compounds in treating mental diseases.”
Mathai, D. S., Meyer, M. J., Storch, E. A., & Kosten, T. R.. (2020). The relationship between subjective effects induced by a single dose of ketamine and treatment response in patients with major depressive disorder: A systematic review. Journal of Affective Disorders
Plain numerical DOI: 10.1016/j.jad.2019.12.023
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“Objective: the relationship between ketamine’s hallucinogenic- and dissociative-type effects and antidepressant mechanism of action is poorly understood. this paper reviewed the correlation between subjective effects defined by various psychometric scales and observed clinical outcomes in the treatment of patients with major depressive disorder (mdd). methods: based on prisma guidelines, we reviewed the dissociative and psychotomimetic mental state induced with ketamine during mdd treatment. our selected studies correlated depression rating with validated scales collected at regular intervals throughout the study period such as the clinician-administered dissociative states scale (cadss), brief psychiatric rating scale (bprs), and the 5-dimensional altered states of consciousness rating scale (5d-asc). we excluded studies with bipolar depression or with repeated dosing and no single-dose phase. we included 8 of 556 screened reports. results: two of five cadss studies found significant negative correlations between increases in cadss scores and depression scores. one of six bprs studies demonstrated correlations between bprs scores and depression scores. the 5d-asc’s one study found no correlation with the madrs. conclusions: ketamine’s dissociative and psychotomimetic effects were correlated with depression changes in 37.5% of studies, but most studies did not examine this relationship and future studies should consider this association since it appears important for mdma and psilocybin therapies.”
Bird, C. I. V., Modlin, N. L., & Rucker, J. J. H.. (2021). Psilocybin and MDMA for the treatment of trauma-related psychopathology. International Review of Psychiatry
Plain numerical DOI: 10.1080/09540261.2021.1919062
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“This review examines the role of trauma in psychiatric morbidity and analogous psychoneurobiological changes. trauma is a necessary criterion for post-traumatic stress disorder (ptsd), however, trauma history is highly correlated with a variety of psychiatric conditions. some evidence suggests that major depressive disorder (mdd) is the most common psychiatric condition that arises following trauma. approximately 50% of ptsd cases present with co-morbid mdd. overlapping symptomatology and neurobiology between these conditions underlie the debate over whether these phenomena result from problematic nosology or whether comorbid mdd + ptsd is a distinct phenotype of trauma-related psychopathology. regardless, similar treatment approaches have been employed historically, with varying success. the drug-assisted psychotherapy treatment model, which combines pharmacological and psychotherapeutic approaches, is currently being trialled as a novel treatment approach in psychiatry. both psilocybin- and 3,4-methylenedioxymethamphetamine (mdma)-assisted psychotherapy have received food and drug administration ‘breakthrough therapy’ designation for the treatment of resistant mdd and ptsd, respectively. this paper reviews the therapeutic rationale of both psilocybin and mdma for treating both trauma-related mdd and ptsd.”
Chi, T., & Gold, J. A.. (2020). A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses. Journal of the Neurological Sciences
Plain numerical DOI: 10.1016/j.jns.2020.116715
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“Though there was initial interest in the use of psychedelic drugs for psychiatric treatment, bad outcomes and subsequent passage of the substance act of 1970, which placed psychedelic drugs in the schedule i category, significantly limited potential progress. more recently, however, there has been renewal in interest and promise of psychedelic research. the purpose of this review is to highlight contemporary human studies on the use of select psychedelic drugs, such as psilocybin, lsd, mdma and ayahuasca, in the treatment of various psychiatric illnesses, including but not limited to treatment-resistant depression, post-traumatic stress disorder, end-of-life anxiety, and substance use disorders. the safety and efficacy as reported from human and animal studies will also be discussed. accumulated research to date has suggested the potential for psychedelics to emerge as breakthrough therapies for psychiatric conditions refractory to conventional treatments. however, given the unique history and high potential for misuse with popular distribution, special care and considerations must be undertaken to safeguard their use as viable medical treatments rather than drugs of abuse.”
Voineskos, D., Daskalakis, Z. J., & Blumberger, D. M.. (2020). Management of treatment-resistant depression: Challenges and strategies. Neuropsychiatric Disease and Treatment
Plain numerical DOI: 10.2147/NDT.S198774
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“Treatment-resistant depression (trd) is a subset of major depressive disorder which does not respond to traditional and first-line therapeutic options. there are several definitions and staging models of trd and a consensus for each has not yet been established. however, in common for each model is the inadequate response to at least 2 trials of antidepressant pharmacotherapy. in this review, a comprehensive analysis of existing literature regarding the challenges and management of trd has been compiled. a pubmed search was performed to assemble meta-analyses, trials and reviews on the topic of trd. first, we address the confounds in the definitions and staging models of trd, and subsequently the difficulties inherent in assessing the illness. pharmacological augmentation strategies including lithium, triiodothyronine and second-generation antipsychotics are reviewed, as is switching of antidepressant class. somatic therapies, including several modalities of brain stimulation (electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy and deep brain stimulation) are detailed, psychotherapeutic strategies and subsequently novel therapeutics including ketamine, psilocybin, anti-inflammatories and new directions are reviewed in this manuscript. our review of the evidence suggests that further large-scale work is necessary to understand the appropriate treatment pathways for trd and to prescribe effective therapeutic options for patients suffering from trd.”
Kyzar, E. J., Nichols, C. D., Gainetdinov, R. R., Nichols, D. E., & Kalueff, A. V.. (2017). Psychedelic Drugs in Biomedicine. Trends in Pharmacological Sciences
Plain numerical DOI: 10.1016/j.tips.2017.08.003
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“Psychedelic drugs, such as lysergic acid diethylamide (lsd), mescaline, and psilocybin, exert profound effects on brain and behavior. after decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions. however, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients. psychedelic drugs profoundly alter human behavior, acting primarily via agonism at the 5-ht2a receptor in the brain. research into the mechanisms of psychedelic drugs is experiencing a renaissance after years of stagnation. animal models show that psychedelic drugs alter a number of crucial molecular mechanisms. psychedelic drugs cause widespread changes in cognition and brain connectivity. recent pilot studies show lsd and psilocybin are effective in treating psychiatric disorders and possibly other illnesses. psychedelic biomedicine is rapidly emerging as an important area of translational research.”
NCT03554174. (
2018).
Psilocybin – Induced Neuroplasticity in the Treatment of Major Depressive Disorder.
Clinicaltrials.Gov/Show/NCT03554174
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“In this placebo‐controlled, blinded study, individuals with depression will participate in 2 experimental sessions approximately 4 weeks apart during which they will receive two of the following three interventions: 1) placebo, 2) low dose psilocybin (0.1 mg/kg), and 3) medium dose psilocybin (0.3 mg/kg).”
Dos Santos, R. G., Bouso, J. C., & Hallak, J. E. C.. (2019). Serotonergic hallucinogens/psychedelics could be promising treatments for depressive and anxiety disorders in end-stage cancer. BMC Psychiatry
Plain numerical DOI: 10.1186/s12888-019-2288-z
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“In a recent issue of the bmc psychiatry, the evidence of effectiveness of treatments for psychiatric conditions in end-stage cancer patients was reviewed (johnson, 2018). the review was comprehensive, and included traditional and non-traditional/alternative treatments, including herbal medicines and spirituality. however, evidence showing that classic or serotonergic hallucinogens/psychedelics such as psilocybin and lysergic acid diethylamide (lsd) could be effective treatments for depressive and anxiety disorders in end-stage cancer was not included. in this commentary, we expand the information available on the original article by briefly reviewing data from recent placebo-controlled, double-blind, cross-over clinical trials showing evidence that administration of single (or few) doses of lsd and psilocybin was associated with rapid and sustained reductions in depressive and anxiety symptoms in patients with end-stage cancer and other life-threatening diseases (e.g., bechterew’s disease, parkinson’s disease, celiac disease). since these substances seem to produce rapid and sustained therapeutic effects with single (or few) doses and well tolerated, large-scale, prospective, multi-site studies of end-stage cancer and classical/serotonergic hallucinogens/psychedelics should be performed to improve our understanding of the therapeutic potentials of these drugs and their use on clinical practice.”
Kiilerich, K., Speth, N., Lorenz, J., Casado-Sainz, A., Shalgunov, V., Lange, D., … Palner, M.. (2019). P.228 The polypharmacological profile of psilocybin and potential behavioural effects of very low doses. European Neuropsychopharmacology
Plain numerical DOI: 10.1016/j.euroneuro.2019.09.271
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“Background: acute, hallucinogenic doses of psilocybin show promise in reducing the symptoms of several psychiatric disorders including depression, end-of-life anxiety, and obsessive compulsive disorder [1]. likewise, the use of sub-hallucinogenic doses of psilocybin, so-called ‘microdoses’, have also been reported to increase concentration, problem solving, and decrease anxiety [2]. since most research and toxicology involving psilocybin arise from studies focused on acute, hallucinogenic dosing, establishing the polypharmacological profile of psilocybin at very low doses is important. psilocybin is a pro-drug of psilocin, the psychoactive component currently understood to exert hallucinogenic activity through agonism at the 5-ht2a receptor [3]. however, psilocybin is a non-selective drug and binds with a high affinity towards most 5-ht receptors. given the reported effectiveness of psilocybin at doses below what is considered hallucinogenic, it is highly possible that one or several of these receptors are responsible for the anecdotal evidence of very low doses of psilocybin. method(s): the psilocybin-induced head-twitch response was assessed in long evans rats and correlated to in vivo occupancy at the 5-ht2a receptor pet imaging with [18f]mh.mz, a selective 5-ht2a radioligand. furthermore, binding affinities of psilocybin were determined against a series of serotonergic receptors using in vitro autoradiography in rat brain sections (reported here the 5-ht2a/2c: [3h]cimbi-36)then a treatment regimen was established using 0.05 mg/kg psilocybin every second day for 3 weeks and the effects on behaviours including locomotor activity, grooming, rearing, and pre-pulse inhibition of the acoustic startle reflex were tested. furthermore, induced head-twitches of an acute high dose of psilocybin (1 mg/kg) after ending the treatment regimen were tested and brains were dissected for ex vivo autoradiographic assessment of receptor levels. result(s): head-twitches increased dose-dependently up until 1 mg/kg psilocybin, where locomotor abilities were impeded by sedation. psilocybin (1 mg/kg) induced 25 +/- 6 % occupancy at the 5-ht2a receptors measured in vivo with [18f]mh.mz pet [4], whereas 0.05 mg/kg did not induce head-twitches or occupancy of the 5-ht2a receptor. preliminary data from the in vitro autoradiography confirms a higher binding affinity of psilocin towards the 5-ht2c (ki: 8 +/- 0.1 nm), measured as [3h]cimbi-36 binding in the choride plexus, than the…”
Cotovio, G., Maia, A., Velosa, A., Seybert, C., & Oliveira-Maia, A. J.. (2021). Treating Major Depression Disorder with Psychedelics: A Potential Therapeutic Application for Psilocybin?. Revista Portuguesa de Psiquiatria e Saúde Mental
Plain numerical DOI: 10.51338/rppsm.2021.v7.i3.241
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Lea, T., Amada, N., Jungaberle, H., Schecke, H., & Klein, M.. (2020). Microdosing psychedelics: Motivations, subjective effects and harm reduction. International Journal of Drug Policy
Plain numerical DOI: 10.1016/j.drugpo.2019.11.008
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“Background: in recent years there has been growing media attention on microdosing psychedelics (e.g., lsd, psilocybin). this refers to people routinely taking small doses of psychedelic substances to improve mental health and wellbeing, or to enhance cognitive performance. research evidence is currently limited. this paper examines microdosing motivations, dosing practices, perceived short-term benefits, unwanted effects, and harm reduction practices. methods: an international online survey was conducted in 2018 examining people’s experiences of using psychedelics. eligible participants were aged 16 years or older, had used psychedelics and could comprehend written english. this paper focuses on 525 participants who were microdosing psychedelics at the time of the survey. results: participants were primarily motivated to microdose to improve mental health (40%), for personal development (31%) and cognitive enhancement (18%). most were microdosing with psilocybin (55%) or lsd/1p-lsd (48%). principal components analysis generated three factors examining perceived short-term benefits of microdosing: improved mood and anxiety, enhanced connection to others and environment, and cognitive enhancement; and three factors examining negative and potentially unwanted effects: stronger-than-expected psychedelic effects, anxiety-related effects, and physical adverse effects. most participants (78%) reported at least one harm reduction practice they routinely performed while microdosing. conclusion: our findings suggest that people microdosing are commonly doing so as a self-managed therapy for mental health, either as an alternative or adjunct to conventional treatments. this is despite psychedelics remaining prohibited substances in most jurisdictions. recent findings from clinical trials with standard psychedelic doses for depression and anxiety suggest that a neurobiological effect beyond placebo is not unreasonable. randomised controlled trials are needed, complemented by mixed methods social science research and the development of novel resources on microdosing harm reduction.”
Hibicke, M., Landry, A. N., Talman, Z. K., & Nichols, C.. (2019). Psychedelics Improve the Mental Health of Rats. The FASEB Journal
Plain numerical DOI: 10.1096/fasebj.2019.33.1_supplement.666.1
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“Introduction psilocybin has recently demonstrated profound efficacy to alleviate depression and anxiety in several clinical trials and has received breakthrough status by the fda. symptomatic relief after only one or two therapeutic treatments last for at least several months in the vast majority of individuals. it is unclear whether the persistent antidepressant and anxiolytic effects are a psychological integration of the subject’s personal experience while under the influence of the drug, or are a consequence of neurochemical changes induced by psilocybin that correct abnormalities leading to a healthier brain state. to distinguish between these possibilities, we investigated the antidepressant and anxiolytic effects of psilocybin in a rat model of treatment resistant depression, wistar-kyoto (wky) rats. rats do not, as we currently believe, have a sense of self to reflect upon during a psychedelic experience. therefore, if the effects are purely psychological, psilocybin should not occasion long lasting therapeutic effects as are seen in humans. objective to evaluate the long-term effects of psychedelics on depressive-like and anxiety-like behaviors in a rat model of depression. methods two experiments were performed in which rats were administered a single bolus dose of saline or treatment in saline vehicle: psilocybin (1 mg/kg), lysergic acid diethylamide (lsd, 0.15 mg/kg), or ketamine (5.0 mg/kg) intraperitoneally at a volume of 1 ml/kg. saline (experiment 1, n=8) and repeat measures psilocybin (experiment 1, n=8) groups were evaluated in the forced swim test (fst) weekly for five weeks, and then the evaluated plus maze (epm) on the sixth week. interval psilocybin (experiment 1, n=8), saline (experiment 2, n=6), lsd (experiment 2, n=6), and ketamine (experiment 2, n=6) were evaluated in the fst a single time on the fifth week, and then in the epm on the sixth week. all measures were evaluated with one-way anova using holm-sidak post hoc, or with t-test as appropriate. results remarkably, we have found that a single treatment with psilocybin produces context-dependent, long lasting antidepressant-like (p=0.046, p=0.026, and p<0.0001) and anxiolytic effects (p=0.039) in male wky rats as measured by the fst and epm. we have also found that lsd, a related psychedelic, produces a long lasting antidepressant-like effect in male wky rats (p=0.003), while ketamine does not. conclusions these results indicate that at least a substantial portion of the abi…”
Rucker, J. J. H.. (
2019).
Psilocybin therapy for major depressive disorder. In Advances in psychedelic medicine: State-of-the-art therapeutic applications.
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“Depression is part of the normal spectrum of human experience. at its extreme it exists as a syndrome characterized by pervasive low mood and absence of enjoyment, disproportionately negative thought patterns, disturbed sleep and appetite, difficulty concentrating, and suicidal thoughts and acts. the classic psychedelic drugs were used as catalysts in psychotherapy for depression prior to their prohibition around 1970. most trials before this time were methodologically suboptimal and it remains unclear whether they are safe and effective treatments, although a recent systematic review suggested broadly positive clinical effects without a high risk of serious adverse reactions. this chapter discusses the modern resurgence of interest in psychedelics, particularly psilocybin, in the treatment of depression. it discusses the process of gathering evidence through the clinical trials process in order to make an application for licensing, with commentary on where the field lies within this process as of july 2018. finally, the chapter discusses, through a mixture of evidence and a degree of speculation, how recent basic neuroscience and neuroimaging work may reflect the core subjective psychedelic experience and how this may reflect a therapeutic mechanism that emphasizes the syndrome of depression as a shared emotional and existential predicament. (psycinfo database record (c) 2020 apa, all rights reserved)”
dos Santos, R. G., Bouso, J. C., & Hallak, J. E. C.. (2017). Ayahuasca, dimethyltryptamine, and psychosis: a systematic review of human studies. Therapeutic Advances in Psychopharmacology
Plain numerical DOI: 10.1177/2045125316689030
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“ Ayahuasca is a hallucinogen brew traditionally used for ritual and therapeutic purposes in northwestern amazon. it is rich in the tryptamine hallucinogens dimethyltryptamine (dmt), which acts as a serotonin 5-ht 2a agonist. this mechanism of action is similar to other compounds such as lysergic acid diethylamide (lsd) and psilocybin. the controlled use of lsd and psilocybin in experimental settings is associated with a low incidence of psychotic episodes, and population studies corroborate these findings. both the controlled use of dmt in experimental settings and the use of ayahuasca in experimental and ritual settings are not usually associated with psychotic episodes, but little is known regarding ayahuasca or dmt use outside these controlled contexts. thus, we performed a systematic review of the published case reports describing psychotic episodes associated with ayahuasca and dmt intake. we found three case series and two case reports describing psychotic episodes associated with ayahuasca intake, and three case reports describing psychotic episodes associated with dmt. several reports describe subjects with a personal and possibly a family history of psychosis (including schizophrenia, schizophreniform disorders, psychotic mania, psychotic depression), nonpsychotic mania, or concomitant use of other drugs. however, some cases also described psychotic episodes in subjects without these previous characteristics. overall, the incidence of such episodes appears to be rare in both the ritual and the recreational/noncontrolled settings. performance of a psychiatric screening before administration of these drugs, and other hallucinogens, in controlled settings seems to significantly reduce the possibility of adverse reactions with psychotic symptomatology. individuals with a personal or family history of any psychotic illness or nonpsychotic mania should avoid hallucinogen intake. ”
Schimmel, N., Breeksema, J. J., Veraart, J., Van Den Brink, W., & Schoevers, R. A.. (
2020).
Psychedelics for existential distress in terminally ill patients.
Tijdschrift Voor Psychiatrie
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“BACKGROUND existential distress in patients with a terminal illness is often associated with (symptoms of) anxiety and depression. psychotherapeutic interventions seem effective but effects are short-lived. there are no proven effective pharmacological interventions. aim to present an overview of literature on psychedelic treatment of existential distress in patients with terminal illness. method literature research in pubmed/medline databases, supplemented with cross-references. results 14 clinical studies have been conducted: 6 with classic psychedelics between 1960 and 1980, and 8 with classic psychedelics and ketamine after 2000. results of early pre-post studies are promising but have serious methodological limitations. recent clinical research with lsd, psilocybin and ketamine are also promising although limited in terms of research design and generalizability. overall, studies show a positive effect on existential and spiritual well-being, quality of life, acceptance and (symptoms of) anxiety and depression. mystical experiences are correlated with positive outcomes. few adverse effects are reported. conclusion treatment of existential distress using classical psychedelics or ketamine in patients with terminal illness seems auspicious. larger clinical studies in a more diverse patient population with fewer methodological limitations are needed to draw conclusions about efficacy and generalizability.”
Protocol, S., Griffiths, R. R., Davis, A. K., & Griffiths, R. R.. (
2020).
eMATERIALS : STUDY PROTOCOL.
JAMA Psychiatry
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“Study protocol 52 53 study overview: this study will involve a randomized waitlist control design to investigate the 54 rapid and sustained antidepressant effects following two experimental sessions in which an oral 55 dose of psilocybin is administered to patients with major depressive disorder. the study will 56 include clinician and participant ratings of depression and anxiety pre-and post-drug-session, 57 monitor and participant ratings of subjective drug effects during and after each drug session, 58 tests of executive functioning at baseline and post-drug-session, and magnetic resonance 59 imaging (mri) of the brain at baseline and post-drug-session to assess the effects of psilocybin 60 on cortical glutamate levels, neural response to emotional stimuli, and resting-state functional 61 brain connectivity. 62 63 twenty-four participants will complete two experimental drug sessions. each session will last 64 approximately eight hours, and experimental sessions will be separated by at least one week. 65 acute physiological, subjective, and behavioral effects will be assessed during and at the end of 66 sessions (e.g., ratings completed by session monitors and questionnaire measures of subjective 67 effects completed by participants), consistent with our well-established psilocybin session 68 protocols. during the first experimental drug session, each participant will be administered a 69 moderate dose of psilocybin (20 mg/70 kg), but one that we do not expect to have full 70 therapeutic efficacy. the purpose of the first psilocybin session is to familiarize participants with 71 the subjective effects that may be encountered at a higher dose. the first psilocybin session will 72 also allow for assessment of both the suitability of each participant to the study procedures and 73 drug effects, and the safety of administering a higher dose to each participant. the second 74 session will occur about one week after the first session. if the study team decides that the 75 participant can safely be administered the higher dose, then the participant will be given 30 76 mg/70 kg psilocybin during the second session. if the decision is made that the participant might 77 clinically benefit from another session but not the high dose, the participant will receive 20 78 mg/70 kg psilocybin on the second session, with the dose determined by the clinical judgment of 79 the study team.”
Goldberg, S. B., Shechet, B., Nicholas, C. R., Ng, C. W., Deole, G., Chen, Z., & Raison, C. L.. (2020). Post-acute psychological effects of classical serotonergic psychedelics: A systematic review and meta-analysis. Psychological Medicine
Plain numerical DOI: 10.1017/S003329172000389X
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“Background scientific interest in the therapeutic effects of classical psychedelics has increased in the past two decades. the psychological effects of these substances outside the period of acute intoxication have not been fully characterized. this study aimed to: (1) quantify the effects of psilocybin, ayahuasca, and lysergic acid diethylamide (lsd) on psychological outcomes in the post-acute period; (2) test moderators of these effects; and (3) evaluate adverse effects and risk of bias. methods we conducted a systematic review and meta-analysis of experimental studies (single-group pre-post or randomized controlled trials) that involved administration of psilocybin, ayahuasca, or lsd to clinical or non-clinical samples and assessed psychological outcomes â©3/424 h post-administration. effects were summarized by study design, timepoint, and outcome domain. results a total of 34 studies (24 unique samples, n = 549, mean longest follow-up = 55.34 weeks) were included. classical psychedelics showed significant within-group pre-post and between-group placebo-controlled effects on a range of outcomes including targeted symptoms within psychiatric samples, negative and positive affect-related measures, social outcomes, and existential/spiritual outcomes, with large between-group effect in these domains (hedges’ gs = 0.84 to 1.08). moderator tests suggest some effects may be larger in clinical samples. evidence of effects on big five personality traits and mindfulness was weak. there was no evidence of post-acute adverse effects. conclusions high risk of bias in several domains, heterogeneity across studies, and indications of publication bias for some models highlight the need for careful, large-scale, placebo-controlled randomized trials.”
Tylš, F., Korèák, J., & Horáèek, J.. (
2020).
PSILOCYBIN: ANTIDEPRESSANT and TRANSFORMATIVE POTENTIAL.
Psychiatrie (CZE)
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“The serotonergic psychedelic psilocybin has shown remarkable promise in the treatment of several psychiatric disorders. this article is a summary of the most recent findings about therapeutical and transformative potential of psilocybin, covering the scope of long-term risks and benefits associated with its use. we also provide an overview of ongoing and completed clinical trials of psilocybin-assisted psychotherapy. the antidepressant effect of psilocybin is elaborated in more detail – in terms of pharmacodynamics, neuroplasticity, remodeling of neural circuits, and psychological mechanisms.”
O., J., K., H., B., E., & G., W.. (
2018).
Psilocybin modulated expression of plasticityrelated genes and proteins in rat prefrontal cortex and hippocampus.
Acta Neuropsychiatrica
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“Background: psilocybin has recently shown antidepressant efficacy in human studies (1). however, the underlying molecular mechanisms are still largely unknown. objectives: our studies will examine whether psilocybin-administration induces changes in gene and protein expression related to synaptic plasticity, as this may be related to its antidepressant effect (2). methods: rats will receive a single, intraperitoneal injection of psilocybin. focusing on prefrontal cortex and hippocampus, we will examine changes in immediate early gene expression and protein expression, using qpcr and western blotting, respectively. we will isolate synaptosomal fractions and measure the expression and complex-formation of pre-and postsynaptic proteins using two-color fluorescence immunoblotting and dual immunoprecipitation, to study the acute effects of psilocybin on receptor trafficking and synaptic regulation. results: the studies are ongoing and will be the first to investigate psilocybin-induced changes in gene expression together with proteins expression in rats. conclusion: psilocybin has previously shown a great therapeutic potential for treating depression and has sparked a revival of the field of psychedelic research (3). the results from our studies will likely motivate further investigations into the signaling pathways induced by psilocybin and, in the future, help identify novel pharmacological targets for efficient treatment for depression.”
NCT03715127. (
2018).
Clinical, Neurocognitive, and Emotional Effects of Psilocybin in Depressed Patients – Proof of Concept.
Clinicaltrials
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“Major depressive disorder (mdd) is one of the world’s greatest contributor to the global burden of disease and mdd affects around 17% of the swiss population (tomonaga et al. 2013). it is a chronic condition and can cause the affected person to suffer greatly and function poorly at work, at school and in the family. more than 1’000 suicides were recorded in switzerland in 2014, about 90% of these fatalities were related to depression or other psychiatric problems. suicide is the second leading cause of death in individuals 15-24 years of age (insel & charney 2003). current pharmacotherapies, including monoaminergic-acting antidepressants, require prolonged administration (weeks if not months) for clinical improvement. this lag time, as well as a high non-response rate, emphasizes the need for better and faster-acting antidepressant medications. however, psychopharmacological research has largely failed to produce novel and more efficacious treatment options for mdd since decades. advanced pharmaceutical antidepressants should ideally facilitate the psychotherapeutic process for patients, reduce the time onset of antidepressant efficacy, and prime neuroplastic adaptations relevant to symptom improvement. such novel therapeutics are much needed and would address this detrimental public health problem, particularly in treatment-resistant patients. early clinical studies using the psychotropic compound psilocybin (4-phosphoryloxy-n,n-dimethyltryptamine) as an adjunct in psychotherapy reported a significant improvement of clinical symptoms in depression and anxiety disorder (leuner 1961, 1981). psilocybin is the main psychoactive principle of the group of hallucinogenic fungi (hofmann 1968), commonly known as magic mushrooms, and acts as partial agonist at cortical and sub-cortical serotonin 5-ht2a and 5-ht1a receptors. at moderate doses, psilocybin produces a dream-like state of consciousness (kraehenmann et al. 2016) characterized by perceptual alterations, enhanced mood, facilitated autobiographic memory recollection, and a change of perspective on the self (leuner 1981; studerus et al. 2011). recent clinical studies applying placebo-controlled designs support and extend these early findings by showing that a single dose of psilocybin leads to a fast and sustained reduction in anxiety and depression as well as an improvement of quality of life in advanced cancer patients (griffiths 2015, grob et al. 2011). furthermore, a recent open-label feasibility stud…”
Palenicek, T., Tyls, F., Viktorinova, M., Androvicova, R., Brunovsky, M., Zach, P., … Horacek, J.. (
2018).
The effects of psilocybin on brain EEG activity and connectivity in healthy volunteers-focus on the dynamics of the psychedelic state.
European Psychiatry
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“Introduction.- a serotonin 5-ht2a/c agonist, psychedelic drug psilocybin, is gaining attention as a potential therapeutic tool for anxiety and depression. psilocybin induces desynchronization of the eeg during the peak of its effects, continuous data are lacking. objectives.- we focused on the dynamics of changes in neuropsychological parameters, brain activity and connectivity after oral administration of psilocybin. methods.- twenty healthy volunteers (10 m/10f, 28-50yrs) were enrolled in this placebo controlled cross over double blind trial. a standard 19 channel eeg (registered before and 60, 90, 180 and 360 min after psilocybin (0.26 mg/kg) ingestion), brief psychiatric rating scale (bprs), plasma levels of psilocin were collected several times over the session, a subjective scale ‘altered scale of consciousness scale (ascs)’ at the end of measurements. current source density and connectivity were analysed by low resolution brain electromagnetic tomography (loreta). results.- psilocybin induced psychotic-like symptoms, especially changes in perception and thought disturbances, peaking at 90 min after ingestion along with serum psilocin levels. induced global decrease of the alpha current source density in the occipital cortex was negatively correlated with the intensity of effects. the overall connectivity decreased in the alpha band, but increased in all other frequency bands at peak, however, six hours after ingestion, the effects were inverted. conclusions.- the study shows that psilocybin dynamically shifts the brain from one connectivity state at baseline through a peak effect to reach another global connectivity state at the end. this work was supported by grants ed2.1.00/03.0078, lo1611/npu i, micr vi20172020056 and progres q35.”
Baumeister, D., Barnes, G., Giaroli, G., & Tracy, D.. (2014). Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles. Therapeutic Advances in Psychopharmacology
Plain numerical DOI: 10.1177/2045125314527985
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“Hallucinogens have been part of spiritual practice for millennia, but controversy surrounding their mind-manifesting effects led to their proscription by the mid-20th century, largely without evidence of harm or toxicity and despite nascent data suggesting therapeutic utility in treating depressive illnesses. this review explores their pharmacodynamic actions and the current limited data on their clinic effectiveness. these drugs appear to exert their psychedelic effects through their agonist or partial agonist activity at the serotonergic 5-ht2a receptor, though they also have affinity for other metabotropic serotonin receptors. hallucinogen binding affects a wide range of intracellular signalling pathways, the precise nature of which remains incompletely understood. they alter the serotonergic tone of brainstem raphe nuclei that project through the brain; they interact with receptors in the prefrontal cortex altering connectivity patterns and intracellular functioning; and they disrupt inhibitory control of sensory input via the thalamus to the cortex. the serotonergic system has long been implicated in anxiety and depressive disorders, and is a major target of most existing antidepressants. classical hallucinogens alter the functioning of this system, but not in the same way current medications do: whilst there are identified receptors and neurotransmitter pathways through which hallucinogens could therein produce therapeutic effects, the neurobiology of this remains speculative at this time. there is currently an extremely limited but growing literature on hallucinogen safety and clinical application. the drugs appear well tolerated by healthy controls and clinical populations, and the rapid tolerance to repeated administration might reduce the possibility of dependency. clinical trials reported over the past decade have generally shown positive therapeutic potential, but they are notably few in number. legislative policy has had a freezing effect on evaluation of these compounds, a better understanding of which might improve our knowledge of the processes involved in consciousness, the neuropathology of depression, and potentially open up new pharmacological therapies. © 2014, sage publications. all rights reserved.”
Teixeira, P. J., Johnson, M. W., Timmermann, C., Watts, R., Erritzoe, D., Douglass, H., … Carhart-Harris, R. L.. (2021). Psychedelics and health behaviour change. Journal of Psychopharmacology
Plain numerical DOI: 10.1177/02698811211008554
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“Healthful behaviours such as maintaining a balanced diet, being physically active and refraining from smoking have major impacts on the risk of developing cancer, diabetes, cardiovascular diseases and other serious conditions. the burden of the so-called ‘lifestyle diseases’—in personal suffering, premature mortality and public health costs—is considerable. consequently, interventions designed to promote healthy behaviours are increasingly being studied, e.g., using psychobiological models of behavioural regulation and change. in this article, we explore the notion that psychedelic substances such as psilocybin could be used to assist in promoting positive lifestyle change conducive to good overall health. psilocybin has a low toxicity, is non-addictive and has been shown to predict favourable changes in patients with depression, anxiety and other conditions marked by rigid behavioural patterns, including substance (mis)use. while it is still early days for modern psychedelic science, research is advancing fast and results are promising. here we describe psychedelics’ proposed mechanisms of action and research findings pertinent to health behaviour change science, hoping to generate discussion and new research hypotheses linking the two areas. therapeutic models including psychedelic experiences and common behaviour change methods (e.g., cognitive behaviour therapy, motivational interviewing) are already being tested for addiction and eating disorders. we believe this research may soon be extended to help promote improved diet, exercise, nature exposure and also mindfulness or stress reduction practices, all of which can contribute to physical and psychological health and well-being.”
Kuypers, K. P. C.. (2018). Out of the box: A psychedelic model to study the creative mind. Medical Hypotheses
Plain numerical DOI: 10.1016/j.mehy.2018.03.010
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“Our creativity is challenged daily when facing new situations asking for novel solutions. creativity, a multicomponent construct includes flexible divergent and rigid convergent thinking. psychedelic drugs like psilocybin can enhance creativity and affect state of mind (mood, empathy, openness). of note, flexible thinking is disturbed in psychopathological conditions like anxiety disorders and depression and preliminary findings have shown psychedelics to be efficacious in the treatment of those conditions. the question how psychedelics induce this state of enhanced flexible thinking remains to be answered and investigating the neurobiology underlying this phenomenon will not only help in understanding why psychedelics are of use in the therapeutic setting but also in other settings where flexible thinking is challenged. a model including neuronal networks, neurotransmitters and personal factors playing a role in this process will be proposed which can be put to the test by means of placebo-controlled pharmaco-imaging studies in healthy volunteers.”
Bush, H.. (2020). Psychedelic therapy: Fresh promise for mental health. Mental Health Weekly
Plain numerical DOI: 10.1002/mhw.32207
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“Psychedelic‐assisted psychotherapy is seeing a resurgence as a treatment approach for mental health disorders. it melds pharmacology and psychotherapy, using substances such as lysergic acid diethylamide (lsd) and psilocybin, under medical supervision, to treat conditions such as post‐traumatic stress disorder (ptsd) and extreme depression.”
Anderson, T., Petranker, R., Rosenbaum, D., Weissman, C. R., Dinh-Williams, L. A., Hui, K., … Farb, N. A. S.. (2019). Microdosing psychedelics: personality, mental health, and creativity differences in microdosers. Psychopharmacology
Plain numerical DOI: 10.1007/s00213-018-5106-2
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“Rationale: microdosing psychedelics—the regular consumption of small amounts of psychedelic substances such as lsd or psilocybin—is a growing trend in popular culture. recent studies on full-dose psychedelic psychotherapy reveal promising benefits for mental well-being, especially for depression and end-of-life anxiety. while full-dose therapies include perception-distorting properties, microdosing mayprovide complementary clinical benefits using lower-risk, non-hallucinogenic doses. objectives: this pre-registered study aimed to investigate whether microdosing psychedelics is related to differences in personality, mental health, and creativity. methods: in this observational study, respondents recruited from online forums self-reported their microdosing behaviors and completed questionnaires concerning dysfunctional attitudes, wisdom, negative emotionality, open-mindedness, and mood. respondents also performed the unusual uses task to assess their creativity. results: current and former microdosers scored lower on measures of dysfunctional attitudes (p < 0.001, r = − 0.92) and negative emotionality (p = 0.009, r = − 0.85) and higher on wisdom (p < 0.001, r = 0.88), openmindedness(p = 0.027, r = 0.67), and creativity (p < 0.001, r = 0.15) when compared to non-microdosing controls. conclusions: these findings provide promising initial evidence that warrants controlled experimental research to directly test safety and clinical efficacy. as microdoses are easier to administer than full-doses, this new paradigm has the exciting potential to shape future psychedelic research.”
Luoma, J. B., Chwyl, C., Bathje, G. J., Davis, A. K., & Lancelotta, R.. (2020). A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy. Journal of Psychoactive Drugs
Plain numerical DOI: 10.1080/02791072.2020.1769878
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“After a two-decade hiatus in which research on psychedelics was essentially halted, placebo-controlled clinical trials of psychedelic-assisted therapy for mental health conditions have begun to be published. we identified nine randomized, placebo-controlled clinical trials of psychedelic-assisted therapy published since 1994. studies examined psilocybin, lsd (lysergic acid diethylamide), ayahuasca (which contains a combination of n,n-dimethyltryptamine and harmala monoamine oxidase inhibitor alkaloids), and mdma (3,4-methylenedioxymethamphetamine). we compared the standardized mean difference between the experimental and placebo control group at the primary endpoint. results indicated a significant mean between-groups effect size of 1.21 (hedges g), which is larger than the typical effect size found in trials of psychopharmacological or psychotherapy interventions. for the three studies that maintained a placebo control through a follow-up assessment, effects were generally maintained at follow-up. overall, analyses support the efficacy of psychedelic-assisted therapy across four mental health conditions–post-traumatic stress disorder, anxiety/depression associated with a life-threatening illness, unipolar depression, and social anxiety among autistic adults. while study quality was high, we identify several areas for improvement regarding the conduct and reporting of trials. larger trials with more diverse samples are needed to examine possible moderators and mediators of effects, and to establish whether effects are maintained over time.”
Preller, K.. (2021). Altered Prediction-Error Processing May Underlie Psilocybin-Induced Changes in Self-Processing. Biological Psychiatry
Plain numerical DOI: 10.1016/j.biopsych.2021.02.036
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“Background: psychedelic substances induce subjective alterations in our sense of body and sense of self. despite the importance of altered bodily self-perception in disorders such as anorexia nervosa or depression, the neural mechanisms underlying these changes are poorly understood. we therefore conducted a pharmacological imaging study combining the administration of the classic psychedelic psilocybin with a roving somatosensory oddball task while participants underwent simultaneous eeg/fmri imaging. methods: fifteen healthy humans (n = 10 male and n = 5 female; mean age = 26.86 years) participated in a double-blind, randomized, placebo-controlled, within-subject study. participants received placebo or psilocybin (0.2 mg/kg body weight, orally) on two different occasions at least two weeks apart. the roving somatosensory oddball task was conducted 85 min after psilocybin/placebo administration while participants underwent simultaneous eeg/fmri scanning. stimuli consisted of somatosensory electrical stimulation (50 ms pulse duration) on the median nerve of the left forearm at about twice the individual perceptual threshold. to induce tactile mismatch responses, trains of stimuli switched randomly between high and low intensity after a variable number of 3 to 7 repetitions. the first stimulus of each new train was modeled as the ‘Deviant’ and each third repetition in a train as ‘standard’. fmri images were analyzed using a general linear model implemented in spm12. the contrast deviant > standard was computed for each participant. stimulus-locked eeg segments were created based on the marker position of the deviant and standard stimuli per condition. global field power and event-related potentials were analyzed. the study was registered at clinicaltrials.gov (nct03736980). results: psilocybin reduced the bold signal in the deviant > standard contrast in the ventromedial prefrontal cortex and the dorsomedial prefrontal cortex (p < 0.05, fwe corrected). psilocybin induced a stronger global field potential comparted to placebo across both stimulus types (p < 0.05). in line with the fmri results, a significant interaction between treatment condition and stimulus type was revealed for the frontal electrode af2 (f(1, 14) = 5.129, p < 0.05) at the time interval 216-414 ms after stimulus with a significant difference between standard and deviant in the placebo condition, but not in the psilocybin condition. a significant positive correlation was found between p…”
Preller, K. H., Pokorny, T., Krähenmann, R., Dziobek, I., Stämpfli, P., & Vollenweider, F. X.. (2015). The Effect of 5-HT2A/1a Agonist Treatment On Social Cognition, Empathy, and Social Decision-making. European Psychiatry
Plain numerical DOI: 10.1016/s0924-9338(15)30017-1
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“Social cognition is a crucial factor influencing development, progress, and treatment of psychiatric disorders. however, social cognition skills are insufficiently targeted by current treatment approaches. in particular, patients suffering from depression show an increased negative reaction to social exclusion and deficits in empathy. the 5ht-1a/2a receptor agonist psilocybin has previously been shown to reduce the neural response to negative emotional stimuli. however, it is not known if this extends to negative social interaction and whether 5ht-1a/2a receptor stimulation induces changes in empathy. given the clear need for improved treatment of socio-cognitive functioning in psychiatric disorders, it is important to better understand the neuronal and neuromodulatory substrates of social cognition. in a double-blind, randomized, cross-over design we therefore investigated the neural response to ostracism after the acute administration of psilocybin (0.215mg/kg) and placebo in healthy volunteers using fmri. furthermore, we assessed cognitive and emotional empathy using the multifaceted empathy test. the neural response to social exclusion in the acc – a brain region associated with ‘social pain”- was reduced after psilocybin administration compared to placebo. furthermore, emotional empathy was enhanced after treatment with psilocybin while no significant differences were found in cognitive empathy. these results show that the 5ht-1a/2a receptor subtypes play an important role in the modulation of socio-cognitive functioning and therefore may be relevant for the treatment of social cognition deficits in psychiatric disorders. in particular, they may be important for the normalization of empathy deficits and increased negative reaction to social exclusion in depressed patients.”
Varley, J.. (2019). Psychedelic-assisted therapy for anxiety and depression in the face of death: A critical review with an anthropological lens. Journal of Psychedelic Studies
Plain numerical DOI: 10.1556/2054.2019.005
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“Psychedelics have been investigated for their therapeutic applications in end-of-life care as early as 1960. recently, there have been four main groups conducting clinical trials for either lysergic acid diethylamide or psilocybin for the treatment of anxiety and depression in patients with terminal illnesses. the recent trials have higher methodological quality and demonstrate the profound impact of psychedelics for this particular patient presentation. however, a number of gaps, including understanding the meaning of death and dying in western society; the nature of the psychedelic experience and how this lends itself to assisting those who are facing death; and how suffering and psychological distress are defined and understood in current psychiatric and medical frameworks. this article provides a critical evaluation of the recent publications and suggests how anthropology may contribute knowledge to this emerging field. (psycinfo database record (c) 2020 apa, all rights reserved)”
Barrett, F. S., Bradstreet, M. P., Leoutsakos, J. M. S., Johnson, M. W., & Griffiths, R. R.. (2016). The Challenging Experience Questionnaire: Characterization of challenging experiences with psilocybin mushrooms. Journal of Psychopharmacology
Plain numerical DOI: 10.1177/0269881116678781
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“Acute adverse psychological reactions to classic hallucinogens (‘bad trips’ or ‘challenging experiences’), while usually benign with proper screening, preparation, and support in controlled settings, remain a safety concern in uncontrolled settings (such as illicit use contexts). anecdotal and case reports suggest potential adverse acute symptoms including affective (panic, depressed mood), cognitive (confusion, feelings of losing sanity), and somatic (nausea, heart palpitation) symptoms. responses to items from several hallucinogen-sensitive questionnaires (hallucinogen rating scale, the states of consciousness questionnaire, and the five-dimensional altered states of consciousness questionnaire) in an internet survey of challenging experiences with the classic hallucinogen psilocybin were used to construct and validate a challenging experience questionnaire. the stand-alone challenging experience questionnaire was then validated in a separate sample. seven challenging experience questionnaire factors (grief, fear, death, insanity, isolation, physical distress, and paranoia) provide a phenomenological profile of challenging aspects of experiences with psilocybin. factor scores were associated with difficulty, meaningfulness, spiritual significance, and change in well-being attributed to the challenging experiences. the factor structure did not differ based on gender or prior struggle with anxiety or depression. the challenging experience questionnaire provides a basis for future investigation of predictors and outcomes of challenging experiences with classic hallucinogens.”
Aday, J. S., Mitzkovitz, C. M., Bloesch, E. K., Davoli, C. C., & Davis, A. K.. (2020). Long-term effects of psychedelic drugs: A systematic review. Neuroscience and Biobehavioral Reviews
Plain numerical DOI: 10.1016/j.neubiorev.2020.03.017
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“Research into the basic effects and therapeutic applications of psychedelic drugs has grown considerably in recent years. yet, pressing questions remain regarding the substances’ lasting effects. although individual studies have begun monitoring sustained changes, no study to-date has synthesized this information. therefore, this systematic review aims to fill this important gap in the literature by synthesizing results from 34 contemporary experimental studies which included classic psychedelics, human subjects, and follow-up latencies of at least two weeks. the bulk of this work was published in the last five years, with psilocybin being the most frequently administered drug. enduring changes in personality/attitudes, depression, spirituality, anxiety, wellbeing, substance misuse, meditative practices, and mindfulness were documented. mystical experiences, connectedness, emotional breakthrough, and increased neural entropy were related to these long-term changes in psychological functioning. finally, with proper screening, preparation, supervision, and integration, limited aversive side effects were noted by study participants. future researchers should focus on including larger and more diverse samples, lengthier longitudinal designs, stronger control conditions, and standardized dosages.”
Tullis, P.. (2021). How ecstasy and psilocybin are shaking up psychiatry. Nature
Plain numerical DOI: 10.1038/d41586-021-00187-9
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Nichols, D. E.. (2018). Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD). ACS Chemical Neuroscience
Plain numerical DOI: 10.1021/acschemneuro.8b00043
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“Lysergic acid diethylamide (lsd) is one of the most potent psychoactive agents known, producing dramatic alterations of consciousness after submilligram (≥20 μg) oral doses. following the accidental discovery of its potent psychoactive effects in 1943, it was supplied by sandoz laboratories as an experimental drug that might be useful as an adjunct for psychotherapy, or to give psychiatrists insight into the mental processes in their patients. the finding of serotonin in the mammalian brain in 1953, and its structural resemblance to lsd, quickly led to ideas that serotonin in the brain might be involved in mental disorders, initiating rapid research interest in the neurochemistry of serotonin. lsd proved to be physiologically very safe and nonaddictive, with a very low incidence of adverse events when used in controlled experiments. widely hailed by psychiatry as a breakthrough in the 1950s and early 1960s, clinical research with lsd ended by about 1970, when it was formally placed into schedule 1 of the controlled substances act of 1970 following its growing popularity as a recreational drug. within the past 5 years, clinical research with lsd has begun in europe, but there has been none in the united states. lsd is proving to be a powerful tool to help understand brain dynamics when combined with modern brain imaging methods. it remains to be seen whether therapeutic value for lsd can be confirmed in controlled clinical trials, but promising results have been obtained in small pilot trials of depression, anxiety, and addictions using psilocybin, a related psychedelic molecule.”
Bouso, J. C., Ona, G., Dos Santos, R. G., & Hallak, J. E. C.. (2021). Psychedelic Medicines in Major Depression: Progress and Future Challenges. In Advances in Experimental Medicine and Biology
Plain numerical DOI: 10.1007/978-981-33-6044-0_26
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“The volume of research on the therapeutic use of psychedelic drugs has been increasing during the last decades. partly because of the need of innovative treatments in psychiatry, several studies have assessed the safety and efficacy of drugs like psilocybin or ayahuasca for a wide range of mental disorders, including major depression. the first section of this chapter will offer an introduction to psychedelic research, including a brief historical overview and discussions about appropriate terminology. in the second section, the recently published clinical trials in which psychedelic drugs were administered to patients will be analysed in detail. then, in the third section, the main neurobiological mechanisms of these drugs will be described, noting that while some of these mechanisms could be potentially associated with their therapeutic properties, they are commonly used as adjuvants in psychotherapeutic processes. the last section suggests future challenges for this groundbreaking field of research and therapy.”
Andersen, K. A. A., Carhart-Harris, R., Nutt, D. J., & Erritzoe, D.. (2021). Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern-era clinical studies. Acta Psychiatrica Scandinavica
Plain numerical DOI: 10.1111/acps.13249
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“Objective: to conduct a systematic review of modern-era (post-millennium) clinical studies assessing the therapeutic effects of serotonergic psychedelics drugs for mental health conditions. although the main focus was on efficacy and safety, study characteristics, duration of antidepressants effects across studies, and the role of the subjective drug experiences were also reviewed and presented. method: a systematic literature search (1 jan 2000 to 1 may 2020) was conducted in pubmed and psychinfo for studies of patients undergoing treatment with a serotonergic psychedelic. results: data from 16 papers, representing 10 independent psychedelic-assisted therapy trials (psilocybin = 7, ayahuasca = 2, lsd = 1), were extracted, presented in figures and tables, and narratively synthesized and discussed. across these studies, a total of 188 patients suffering either cancer- or illness-related anxiety and depression disorders (c/i-radd), major depressive disorder (mdd), obsessive-compulsive disorder (ocd) or substance use disorder (sud) were included. the reviewed studies established feasibility and evidence of safety, alongside promising early data of efficacy in the treatment of depression, anxiety, ocd, and tobacco and alcohol use disorders. for a majority of patients, the therapeutic effects appeared to be long-lasting (weeks-months) after only 1 to 3 treatment session(s). all studies were conducted in line with guidelines for the safe conduct of psychedelic therapy, and no severe adverse events were reported. conclusion: the resurrection of clinical psychedelic research provides early evidence for treatment efficacy and safety for a range of psychiatric conditions, and constitutes an exciting new treatment avenue in a health area with major unmet needs.”
B., A., R., G., P., H., A., G.-R., M., B., S.S., F., & A., W.. (
2019).
A new era of treating substance use disorders with psychedelics.
American Journal on Addictions
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“Background and objectives: a growing body of evidence suggests that psychedelics may be highly efficacious in the 162 may 2019 treatment of a range of substance use disorders with effects persisting for years after only two or three treatment sessions. psychedelics are a diverse group of compounds including the tryptamines such as psilocybin, dimethyltryptamine (dmt), lysergic acid diethylamide (lsd), and the phenethylamines such as mescaline, dimethoxy-4-methylamphetamine (dom), and methylenedioxyamphetamine (mda). these compounds bind 5ht2a receptors resulting in perceptual changes, greater emotionality, and dose-dependent mystical experiences. roland griffiths defined the phenomenological dimensions of mystical experience as having a core feature of unity and interconnectedness with all people and things, as well as sacredness, a noetic quality, deeply felt positive mood, transcendence of time and space, and ineffability. a broad spectrum of topics within the field of psychedelic medicine were discussed during a symposium, including: (1) the historical use of psychedelics in the treatment of addiction, (2) the underlying neurobiological mechanisms of action particularly in terms of the 5ht2a receptor, the default mode network, increased neuroplasticity, and anti-inflammatory activity, (3) increases in measures of mystical experience and insight, (4) the persistence of these therapeutic effects, (5) study design in terms of the structure of the therapeutic sessions as well as ensuring participants are carefully screened and psychologically supported, (6) an overview of recent studies administering psychedelics to treat alcohol, opiate, cocaine, and tobacco use disorders, and (7) broader societal implications. this symposium summary aims to provide an overview as well as expand on highlights of the discussion. method(s): psychedelics were first used for addiction treatment in the 1950s by psychiatrists humphry osmond and abram hoffer, who used lsd to treat over 1000 patients addicted to alcohol. a meta-analysis of this older body of literature showed psychedelics to be a promising treatment for alcohol dependence with odds ratio 1.96.1 a 1973 study in a population of 74 inmates previously addicted to heroin showed that a single dose of lsd produced a 25% abstinent rate for at least 1 year compared to 5% in the placebo group.2 by 1970, richard nixon signed the controlled substances act listing psychedelics as schedule i drugs thus establishing new barri…”
Johansen, P. O., & Krebs, T. S.. (2015). Psychedelics not linked to mental health problems or suicidal behavior: A population study. Journal of Psychopharmacology
Plain numerical DOI: 10.1177/0269881114568039
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“A recent large population study of 130,000 adults in the united states failed to find evidence for a link between psychedelic use (lysergic acid diethylamide, psilocybin or mescaline) and mental health problems. using a new data set consisting of 135,095 randomly selected united states adults, including 19,299 psychedelic users, we examine the associations between psychedelic use and mental health. after adjusting for sociodemographics, other drug use and childhood depression, we found no significant associations between lifetime use of psychedelics and increased likelihood of past year serious psychological distress, mental health treatment, suicidal thoughts, suicidal plans and suicide attempt, depression and anxiety. we failed to find evidence that psychedelic use is an independent risk factor for mental health problems. psychedelics are not known to harm the brain or other body organs or to cause addiction or compulsive use; serious adverse events involving psychedelics are extremely rare. overall, it is difficult to see how prohibition of psychedelics can be justified as a public health measure.”
Zeiss, R., Gahr, M., & Graf, H.. (2021). Rediscovering psilocybin as an antidepressive treatment strategy. Pharmaceuticals
Plain numerical DOI: 10.3390/ph14100985
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“There has recently been a renewal of interest in psychedelic research on the use of psilocybin in psychiatric treatment and, in particular, for the treatment of major depressive disorder (mdd). several state-of-the-art studies have provided new insight into the mechanisms of action of psilocybin and its therapeutic potential. nevertheless, many questions remain unanswered. with this review, we provide an overview of the current state of research on the potential mechanisms of psilocybin, its antidepressant potential, and the associated risks and adverse effects, to provide an update on a controversial topic discussed in psychopharmacology. a database search was conducted in medline including articles on psilocybin over the period of the last 20 years. despite the promising progress in understanding the mechanisms of psilocybin, the exact antidepressive mechanism and the role of the psychedelic experience remain elusive. the studies included in this review found high treatment effect sizes for psilocybin as an antidepressant. however, the results must be regarded as preliminary due to several limitations. although the current studies observed no severe adverse events, several questions regarding safety and utility remain and must be subject of future research.”