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The experimental effects of psilocybin on symptoms of anxiety and depression: A meta-analysis
Abstract
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.
... In the contemporary landscape of psychological and therapeutic research, there exists a remarkable resurgence in interest in the therapeutic potential of psychedelic compounds. Termed by some as the psychedelic renaissance, this resurgence yields promising therapeutic benefits for a wide range of mental health problems, from depression and anxiety (Goldberg et al., 2020) to eating disorders (Peck et al., 2023), addictions (Bogenschutz et al., 2022;Johnson et al., 2017), and post-traumatic stress disorder (Averill & Abdallah, 2022;Krediet et al., 2020). However, it is widely accepted that it is not so much the psychedelic compound as it is the insights and mystical experience engendered therein that are responsible for the therapeutic benefits and persisting positive effects (Griffiths et al., 2006;Roseman et al., 2017;Rothberg et al., 2021;Yaden & Griffiths, 2021). ...
This study aimed to determine whether the 30-item Mystical Experience Questionnaire (MEQ30) is suitable for measuring non-psychedelic mystical experiences or whether a subset of questions from the 43-item Mystical Experience Questionnaire (MEQ43) is more appropriate. Participants (N = 136) completed an online survey about their non-psychedelic mystical experience, which included the MEQ43 and its subset of items that make up the MEQ30. Confirmatory Factor Analysis revealed that the MEQ30 was not a good fit for the present study’s non-psychedelic sample. Exploratory Factor Analysis of the MEQ43 suggested that an alternative set of items and corresponding factors may be more appropriate. In the new four-factor instrument (MEQ25), 25 items account for all MEQ43 factors. The new factors are Sacred Unity, Noetic Quality, Time-Space Transcendence, and Ineffable and Paradoxical. The new scale demonstrated excellent internal reliability (α = .93) and strong convergent validity with the M-Scale. The new scale is unique because it has a separate factor for noetic quality, which is considered a salient and therapeutic aspect of mystical experience. Furthermore, the refined time-space subscale better reflects the theory and subjective experience of non-psychedelic mystical experiences.
... In the last decade, a revamped interest in psychedelic research spread in the scientific community as a "psychedelic renaissance" and mounting evidence on the potential applications of psychedelics in several psychiatric disorders was provided by clinical studies [1]. Nowadays, the antidepressant properties of psilocybin are widely reported by randomized clinical trials (RCTs) and confirmed by meta-analyses [2][3][4][5][6]. The evidence of efficacy is not limited to mood disorders, but also extends to the treatment of anxiety disorders, particularly in the context of life-threatening diseases [7,8] and substance use disorders [9,10], and several other trials are currently ongoing on in other clinical populations such as eating disorders, obsessive compulsive disorder, and neurocognitive disorders [11][12][13][14][15]. ...
Psychedelics could have revolutionary potential in psychiatry, although, until recently, the pharmacodynamic properties of such compounds have not seemed to differ much from those of serotonin, whose levels are raised by Serotonin Reuptake Inhibitors (SSRI). The cardinal point is that serotonergic compounds, such as antidepressive drugs, do not have the potential to induce long-lasting neuroplasticity as psychedelics do. Therefore, the biological underpinnings of the peculiar effect of such compounds had not been fully understood until new astonishing molecular findings came out this year to shed new light on them. Specifically, the phenomena of neuroplasticity are triggered by the stimulation of a peculiar type of receptors: the intracellular 5-HT2A receptors. Interestingly, psychedelics can reach this pool of intracellular receptors due to their lipophilic properties, as they can cross the lipophilic neuronal membrane while serotonin cannot. The importance of such a discovery should not be underestimated as the specific mechanisms involved have not yet been elucidated and a better understanding of them could pave the way to the development of new drugs (and/or new tailored therapeutic strategies) able to sustain neuroplasticity while minimizing side effects.
... Psilocybin is a molecule produced by various species of mushrooms, which when consumed leads to psychotropic effects, such as euphoria, changes in consciousness, time distortion, perceptual alterations and spiritual experiences. A meta-analysis has summarised the effectiveness of psilocybin in substantially reducing anxiety and depressive symptoms (Goldberg et al., 2020). Additionally, several narrative reviews have provided theoretical rationales for psychedelics such as psilocybin for the treatment of EDs, including AN (Foldi et al., 2020;Otterman, 2022;Rodan et al., 2021). ...
Objective
Treatment for anorexia nervosa (AN) remains challenging; there are no approved psychopharmacological interventions and psychotherapeutic strategies have variable efficacy. The investigation of evidence‐based treatments has so far been compounded by an underdeveloped understanding into the neurobiological changes associated with the acute stages of AN. There is converging evidence of deficiencies in neuroplasticity in AN.
Method
This paper provides an overview of neuroimaging, neuropsychological, molecular and qualitative findings relating to neuroplasticity in AN, translating these findings to the identification of novel biological and psychotherapeutic strategies.
Results
Novel psychopharmacological approaches that may ameliorate deficiencies in neuroplasticity include medications such as ketamine, psilocybin and human recombinant leptin. Anti‐inflammatory medications and brain‐derived neurotrophic factor mimetics may emerge as potential treatments following further research. Psychotherapeutic strategies that may target neuroplastic deficiencies, as well as having wider effects on identity, include imagery rescripting, memory specificity training, cognitive remediation therapy, exposure therapies, narrative therapies, cultural interventions (e.g. music and arts therapies) and yoga/mindfulness‐based interventions.
Conclusions
Treatments specifically targeted towards mitigating the neurobiological sequalae of AN are warranted, and emerging neurobiological and neuropsychological research utilising longitudinal designs and large sample sizes, as well as initial feasibility studies, are necessitated to bolster translational efforts.
Psilocybin is the main psychoactive compound found in hallucinogenic/magic mushrooms and can bind to both serotonergic and tropomyosin receptor kinase b (TrkB) receptors. Psilocybin has begun to show efficacy for a range of neuropsychiatric conditions, including treatment‐resistant depression and anxiety disorders; however, neurobiological mechanisms are still being elucidated. Clinical research has found that psilocybin can alter functional connectivity patterns in human brains, which is often associated with therapeutic outcomes. However, preclinical research affords the opportunity to assess the potential cellular mechanisms by which psilocybin may exert its therapeutic effects. Preclinical rodent models can also facilitate a more tightly controlled experimental context and minimise placebo effects. Furthermore, where there is a rationale, preclinical researchers can investigate psilocybin administration in neuropsychiatric conditions that have not yet been researched clinically. As a result, we have systematically reviewed the knowledge base, identifying 82 preclinical studies which were screened based on specific criteria. This resulted in the exclusion of 44 articles, with 34 articles being included in the main review and another 2 articles included as Supporting Information materials. We found that psilocybin shows promise as a lead candidate molecule for treating a variety of neuropsychiatric conditions, albeit showing the most efficacy for depression. We discuss the experimental findings, and identify possible mechanisms whereby psilocybin could invoke therapeutic changes. Furthermore, we critically evaluate the between‐study heterogeneity and possible future research avenues. Our review suggests that preclinical rodent models can provide valid and translatable tools for researching novel psilocybin‐induced molecular and cellular mechanisms, and therapeutic outcomes.
Anxiety is one of the most common mental health conditions experienced worldwide. As such, there is significant investment into the treatment of this disorder and to alleviate the effects it has on the individual. While various interventions exist, such as pharmacotherapy, psychotherapy, and lifestyle interventions, more is needed to combat the growing scope of anxiety. This chapter presents empirical evidence for combining two effective treatments: psychotherapy and physical exercise. It also suggests some practical ways in which this can be integrated in healthcare systems. Additional recommendations are provided to facilitate this integration of this combined treatment for both consumers and healthcare professionals.
Das inúmeras plantas utilizadas para tratar a depressão, talvez nenhuma seja mais complexa em terminologia e propriedades botânicas do que a ayahuasca. É uma bebida medicinal alucinógena e psicoativa valorizada pelas tribos indígenas amazônicas que se origina da fervura da casca de uma videira chamada Banisteriopis caapi com as folhas de Psycotria viridis. Vários estudos demonstraram a sua eficácia no tratamento da depressão, pelo que o objetivo deste trabalho foi validar o uso da ayahuasca no tratamento da depressão e da ansiedade. A depressão é uma condição clínica prevalente na população mundial e é uma doença incapacitante na qual os portadores se sentem tristes e perdem o desejo de se envolver em atividades antes prazerosas. Portanto, o uso da ayahuasca em todos os estudos apresenta propriedades benéficas para a melhora da depressão e pode se tornar uma alternativa de tratamento para a depressão no futuro.
Microdosing psychedelics is a growing practice among recreational users, claimed to improve several aspects of mental health, with little supporting empirical research. In this comment, we highlight the potential role of expectations and confirmation bias underlying therapeutic effects of microdosing, and suggest future avenues of research to address this concern.
Mounting evidence suggests safety and tolerability of cannabis-derived and psychedelic drugs as potential novel therapeutics for psychiatric, as well as sleep and pain disorders. Evidence concerning the therapeutic efficacy of these compounds remains controversial, although some promising preliminary results are available for them in specific disorders. For example, CBD is approved as medication for treatment-refractory epilepsy, while MDMA and psilocybin are being tested in phase 3 clinical trials respectively for treatment-refractory PTSD and MDD. Despite encouraging preliminary results, further preclinical and clinical trials are required to validate these findings. Most importantly, more systematic research is required to assess the potential long-term side effects that might arise following the use of cannabinoids and psychedelic compounds in psychiatric settings.
Introduction:
The U.K.'s current National Institute for Health and Care Excellence and the American Psychiatric Association's depression guidelines state that withdrawal reactions from antidepressants are 'self-limiting' (i.e. typically resolving between 1 and 2weeks). This systematic review assesses that claim.
Methods:
A systematic literature review was undertaken to ascertain the incidence, severity and duration of antidepressant withdrawal reactions. We identified 24 relevant studies, with diverse methodologies and sample sizes.
Results:
Withdrawal incidence rates from 14 studies ranged from 27% to 86% with a weighted average of 56%. Four large studies of severity produced a weighted average of 46% of those experiencing antidepressant withdrawal effects endorsing the most extreme severity rating on offer. Seven of the ten very diverse studies providing data on duration contradict the UK and USA withdrawal Guidelines in that they found that a significant proportion of people who experience withdrawal do so for more than two weeks, and that it is not uncommon for people to experience withdrawal for several months. The findings of the only four studies calculating mean duration were, for quite heterogeneous populations, 5days, 10days, 43days and 79weeks.
Conclusions:
We recommend that U.K. and U.S.A. guidelines on antidepressant withdrawal be urgently updated as they are clearly at variance with the evidence on the incidence, severity and duration of antidepressant withdrawal, and are probably leading to the widespread misdiagnosing of withdrawal, the consequent lengthening of antidepressant use, much unnecessary antidepressant prescribing and higher rates of antidepressant prescriptions overall. We also recommend that prescribers fully inform patients about the possibility of withdrawal effects.
Introduction: Mood, anxiety, and substance use disorders are among the most prevalent psychiatric disorders in the population. Although several pharmacological treatments are available, they are not effective for a significant proportion of patients and are associated with several adverse reactions. Therefore, new treatments should be explored. Recent with serotonergic hallucinogens/psychedelics including ayahuasca, psilocybin and lysergic acid diethylamide (LSD) suggest that these drugs have anxiolytic, antidepressive, and antiaddictive effects.
Areas Covered: A systematic review of systematic reviews assessing the efficacy, safety, and tolerability of serotonergic hallucinogens/psychedelic was performed using the PubMed data base until 11 April 2018. Systematic reviews with or without meta-analysis were analyzed, but only reviews that described at least one randomized controlled trial (RCT) were included.
Expert Commentary: Psilocybin and LSD reduced anxiety and depression in cancer patients and symptoms of alcohol and tobacco dependence, and ayahuasca reduced depression symptoms in treatment-resistant depression. Although the results are promising, several studies were open-label and only few were RCTs, and most had small sample sizes and a short duration. Single or few doses of these drugs seem to be well tolerated, but long-term studies are lacking. New RCTs with bigger samples and longer duration are needed to replicate these findings.
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.
Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes.
Trial Registration
ClinicalTrials.gov identifier: NCT00465595
Background:
Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression.
Methods:
In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks.
Results:
Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60-80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression.
Conclusions:
In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress.
Trial registration:
ClinicalTrials.gov Identifier: NCT00957359.
Background:
Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder.
Methods:
We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291.
Findings:
We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89-2·41) for amitriptyline and 1·37 (1·16-1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72-0·97) and fluoxetine (0·88, 0·80-0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01-1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43-0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30-2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.
Interpretation:
All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.
Funding:
National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.
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.