No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Trial of Psilocybin versus Escitalopram for Depression
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-blind, randomized, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6.
Results
A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were −8.0±1.0 points in the psilocybin group and −6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], −5.0 to 0.9) (P=0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, −3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups.
Conclusions
On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants. (Funded by the Alexander Mosley Charitable Trust and Imperial College London’s Centre for Psychedelic Research; ClinicalTrials.gov number, NCT03429075.)
VISUAL ABSTRACT
Psilocybin versus Escitalopram for Depression
... In addition, SSRIs often fall short in addressing the symptom of anhedonia, which is a particularly difficult symptom to treat [10,11]. Conversely, psilocybin therapy (PT) is a promising intervention for the treatment of MDD [12,13], which has been shown to reduce symptoms of anhedonia post-acutely [14] and mediate persisting changes in brain activation and connectivity in response to emotional stimuli [15,16]. Moreover, a significant treatment difference was found between escitalopram and PT on experiential avoidance, indicating the putative dissociable treatment effects on processing emotional and rewarding stimuli [12]. ...
... Conversely, psilocybin therapy (PT) is a promising intervention for the treatment of MDD [12,13], which has been shown to reduce symptoms of anhedonia post-acutely [14] and mediate persisting changes in brain activation and connectivity in response to emotional stimuli [15,16]. Moreover, a significant treatment difference was found between escitalopram and PT on experiential avoidance, indicating the putative dissociable treatment effects on processing emotional and rewarding stimuli [12]. ...
... This was a specific fMRI analysis carried out on data from a phase II, double-blind, randomised, controlled trial involving the allocation of participants with MDD to either PT or escitalopram treatment groups; the main study report has been previously published [12]. A total of 59 patients were enrolled but 50 were included in this present analysis, with nine lost due to an incomplete dataset owing to COVID-19 lockdowns. ...
Psilocybin therapy (PT) is emerging as an effective intervention for Major Depressive Disorder (MDD), offering comparable efficacy to conventional treatments like selective serotonin reuptake inhibitors (SSRIs). Music, an emotionally evocative stimulus, provides a valuable tool to explore changes in hedonic and predictive processing mechanisms via expectancy violations, or ‘surprises’. This study sought to compare behavioural and functional magnetic resonance imaging (fMRI) responses to musical surprises in MDD patients treated with either PT or the SSRI, escitalopram. In this secondary analysis of a trial, 41 MDD patients (with usable fMRI data) were randomly assigned to either PT (n = 22) or escitalopram (n = 19) treatment groups. Participants listened to music during fMRI and tracked their emotional experience, both before and after a 6-week intervention. Surprise-related valence and arousal indices were calculated. Musical surprises were entered as regressors for whole-brain and region of interest fMRI analyses. PT caused a greater decrease in anhedonia scores compared with escitalopram. While escitalopram led to reductions in surprise-related affective responses, PT showed no significant change. Escitalopram was associated with increased activation in memory and emotional processing areas during musical surprises (versus control events) when compared with PT. Following PT, there was greater activation in the ventromedial prefrontal cortex and sensory regions, and reduced activation in the angular gyrus. PT may allow for the subjective response to musical surprises to be maintained through a lasting reduction in the salience of prediction errors, or, alternatively, by increasing hedonic priors. Contrastingly, escitalopram may diminish hedonic priors, highlighting fundamental differences in treatment mechanisms.
... In addition, the use of psilocybin as a hallucinogen in the treatment of depression has been widely reported [47][48][49][50][51][52][53]. Preliminary research on psilocybin-assisted therapy suggests that this approach may represent a novel and innovative treatment for depression, with efficacy potentially exceeding that of conventional antidepressant medications, such as MAOIs [51,52]. ...
... These compounds were studied in both low-dose psychotherapy and psychedelic-assisted psychotherapy at varying doses, involving approximately 40 000 subjects [107]. Over time, the antidepressant properties of psilocybin have gained increasing recognition [48,49,[108][109][110][111]. ...
... These effects typically last 3 to 6 h but may be accompanied by adverse side effects such as nausea [111]. Carhart-Harris et al. compared psilocybin with escitalopram in the treatment of chronic depression, observing no significant differences in primary outcomes but identifying secondary benefits favoring psilocybin, which warrants larger-scale trials [48]. In a related study, psilocybin-assisted psychotherapy demonstrated significant reductions in depression scores and improved clinical outcomes. ...
This systematic review examines the antidepressant potential of edible medicinal fungi (EMFs), focusing on their bioactive compounds and mechanisms of action. EMFs modulate neurotransmitter systems, including serotonin (5-HT) and dopamine (DA), alleviating depressive symptoms. Extracts from EMFs, such as Ganoderma lucidum, Hericium erinaceus, Poria cocos, and Cordyceps militaris, demonstrate significant antidepressant-like effects in preclinical studies. Their bioactive compounds influence the tryptophan-kynurenine (KYN) pathway, regulate the hypothalamus-pituitary-adrenal (HPA) axis, and reduce neuroinflammation, all of which are linked to stress response and mood regulation. The review also explores the gut-brain axis, highlighting how EMF-derived polysaccharides improve gut health by modulating microbiota, potentially mitigating depressive symptoms. Additionally, it discusses the use of EMFs in functional foods and dietary supplements, innovations like 3D food printing for depression-related issues, and synthetic biology for enhancing compound production. Artificial intelligence is used to model complex mechanisms. However, challenges remain, such as standardization and lack ofclinical validation. Future research should address these gaps, emphasizing personalized interventions and advanced technologies for next-generation antidepressant foods.
... Of those, Daws et al. (2022) stands out as an example of how researchers are trying to answer MoA questions. They compared brain states using fMRI in participants from Carhart-Harris et al. (2021). Their results provided evidence that participant response to psilocybin was correlated with increased brain "network flexibility" relative to an absence of commensurate brain state changes in participants in the escitalopram condition. ...
... However, almost all the studies used non-psychotropic agents as controls. Carhart-Harris et al. (2021) was the only exception, demonstrating a non-significant incremental effect. Observation of studyby-study effects suggests the strongest effects come from studies like Davis et al. (2021;incremental g = 3.08) and Rosenblat et al. (2024;incremental g = 1.33), which utilized waitlist controls and had extremely small samples (i.e., unstable metrics/effect size inflation). ...
... ,Carhart-Harris et al. (2021),Goodwin et al. (2022),Rosenblat et al. (2024), andRaison et al. (2023) administering 25 mgs of psilocybin. Control conditions were more variable in content and dosage. ...
Rationale
Psilocybin is a potentially paradigm-shifting depression intervention. We conducted a systematic review and meta-analysis of psilocybin-for-depression randomized controlled trials (RCTs).
Objectives
Systematically assess harm reporting, risk of bias, action mechanism specification, and incremental therapeutic effect sizes in the psilocybin-for-depression RCT literature.
Methods
Assessed databases included PsycINFO, CINAHL, Embase, Medline, Web of Science, and Scopus. Search terms “Psilocybin” or “Psychedelic” were paired with “Depression”, and "Randomized Controlled Trial" or “RCT”.
Results
We identified k = 9 RCTs (k = 10 subgroups) involving n = 602 participants (56% psilocybin). Five studies had low/very low harm quality reporting, opposed to two with high. Most studies demonstrated a high risk of bias. Therapeutic mechanisms of action (MoAs) were discussed in varying detail but rarely assessed in original publications. Psilocybin was moderately superior to controls at reducing depression (g = 0.62; 95% CI = 0.27, 0.98). Effects were heterogenous (τ = .47). Smaller studies evidenced stronger effects that favored psilocybin (Egger’s b0 = 3.63, p = .014). Almost all studies documented financial conflicts of interests.
Conclusion
Psilocybin demonstrates significant depression reduction relative to controls. However, researchers, clinicians, and stakeholders should consider several contextual factors. Effects were moderate and attenuated in larger and better-controlled studies. Harms reporting and risk of bias was high, though partly driven by unique challenges of psilocybin research. MoAs were variably specified but rarely assessed; suggesting it is unclear how depression is reduced. We advise researchers conduct RCTs with active control conditions, larger samples, and include MoA assessments. Independent RCTs from researchers without financial conflicts of interest are needed.
... The primary outcomes of the clinical trial have been discussed in (16). For the interest of this secondary analysis, the primary outcomes were post-treatment changes in cognitive biases (i.e., pessimism versus optimism bias and dysfunctional attitudes) at six weeks compared with baseline, as measured using three validated psychological scales. ...
... Depression severity was quantified using the Beck Depression Inventory 1A (BDI-1A)-a twenty one item questionnaire designed to assess characteristic attitudes and symptoms of depression (3). In this analysis, we chose to correlate measures of cognitive bias with BDI-1A, as the clinical trial analysis found a discrepancy between the Quick Inventory of Depression Symptomatology (QIDS) and other major efficacy outcome measures (16) (19). Well-being was measured using the Flourishing Scale (FS) (20) -an eight item questionnaire assessing domains of self-perceived success such as relationships, self-esteem and purpose. ...
... The number of the participants recruited and included in this analysis and the adverse events of the clinical trial have been discussed in (16). ...
Background: Patients with Major Depressive Disorder (MDD) have more dysfunctional attitudes and pessimism than healthy individuals and these biases are correlated with depression severity. Psilocybin has demonstrated sustained remission in MDD.
Methods: Secondary analysis of a two-arm, randomized controlled trial (ClinicalTrials.gov Identifier: NCT03429075) assessing the effect of psilocybin therapy versus escitalopram on maladaptive cognitive biases relevant to the construct of depression. Psilocybin group participants received two 25mg doses and escitalopram group received three weeks of daily 10mg, increased to 20mg for a following three weeks. Primary outcomes in this analysis were post-treatment changes in biases at six weeks compared with baseline, as measured using three validated psychological scales.
Findings: Fifty-nine MDD patients were randomly allocated to the psilocybin (n=30) or escitalopram (n=29) groups. Self-reported optimism showed a large and significant increase six-weeks after psilocybin treatment (Mdiff=6.63, p<0.0001; 95% CI [4.06, 9.20], d=1.1), whereas there was no change following escitalopram (Mdiff=1.52, p=0.205; 95% CI [-0.59, 3.62], d=0.4). Behavioral results found that patients were more optimistic about desirable life events after psilocybin treatment (Mdiff=0.16, p=0.0002; 95% CI [0.08, 0.23], d=1.1), but they were also less pessimistic about negative life events after escitalopram treatment (Mdiff=0.07, p=0.018; 95% CI [0.01, 0.13], d=0.5). We found improvements in all three domains of dysfunctional attitudes following psilocybin treatment: achievement (Mdiff=10.37, p<0.0001; 95% CI [6.38, 14.53], d=1.0); dependency (Mdiff=7.97, p<0.0001; 95% CI [4.00, 11.93], d=0.9) and self-control (Mdiff=6.40, p=0.0006; 95% CI [2.60, 10.20], d=0.8)), whereas only the achievement domain improved after escitalopram (Mdiff=4.10, p=0.005; 95% CI [1.35, 6.86], d=0.6).
Interpretation: These results suggest that two high-dose sessions with psilocybin therapy are superior to a six-week daily course of a selective serotonin-reuptake inhibitor antidepressant, in remediating negative cognitive biases in depression.
... Compounds such as psilocybin, LSD, and mescaline, classified as classical psychedelics due to their potent 5-HT2A receptor agonism, have demonstrated the ability to rapidly alleviate depressive symptoms, often within hours after a single administration [15][16][17][18]. Psilocybin, for example, has shown robust and prolonged antidepressant efficacy in clinical trials, with symptom improvements persisting for up to 12 months in some patients, and a favourable safety profile, lacking addictive potential and eliciting no serious adverse effects [19][20][21][22][23]. Notably, these compounds have been shown to enhance neuroplasticity and promote various aspects of neurogenesis, including the proliferation, migration, and differentiation of neurons [24]. ...
Major depressive disorder (MDD) remains a leading cause of disability worldwide, with current treatments limited by delayed onset and low efficacy. The serotonergic psychedelic N,N-dimethyltryptamine (DMT) has shown rapid antidepressant effects in early clinical studies, yet its mechanisms and efficacy remain poorly characterized in established models of depression. Here, we evaluated the effects of a single dose of DMT in the Chronic Unpredictable Mild Stress (UCMS) paradigm, a robust mouse model recapitulating key features of MDD, including anhedonia and cognitive impairment. DMT administered after UCMS reversed depressive-like behavior and restored cognitive performance, outperforming chronic fluoxetine across most domains. When administered during the stress period, DMT prevented the development of anhedonia but did not rescue cognitive deficits, suggesting partial protection. Notably, DMT remained effective under isoflurane anesthesia, indicating that its therapeutic action can occur independently of the psychedelic experience. Histological analyses revealed that all DMT regimes significantly increased adult-born granule cell (abGC) integration and reduced the number of ectopically abnormally integrated abGCs,. Together, our findings highlight the robust and multifaceted effects of DMT on behavior and neurogenesis, positioning it as a promising candidate for rapid-acting antidepressant strategies that target structural circuit repair.
... 14 Recent studies in depressed patients report comparable efficacy following the administration of one or two doses. [15][16][17][18][19] However, while important for increasing accessibility, the efficacy of a single dose of psilocybin has not been tested in AUD. Therefore, in this RCT we test the efficacy of a single oral dose of psilocybin in combination with a brief psychotherapeutic intervention for preventing relapse in participants with AUD who have undergone withdrawal treatment. ...
... The Research Domain Criteria (RDoC, Insel et al., 2010) that created a conceptual basis for Volume 1 thus seems to be delivering on its promise to integrate science and practice using, in this case, the construct of reward processing spanning laboratory work and clinical practice. Furthermore, innovative findings in well-controlled and randomized clinical trials have provided a new avenue for pharmacological management of depression with new rapid-acting therapeutics, both ketamine/esketamine (Anand et al., 2023) and psychedelics (Carhart-Harris et al., 2021). ...
... PcncAAAD displays a broad substrate selectivity towards both proteinogenic and non-proteinogenic aromatic amino acids including L-phenylalanine, L-tyrosine, L-tryptophan and L-kynurenine, and is capable of catalyzing both decarboxylation and latent decarboxylation-dependent oxidative deamination activities towards L-kynurenine and 3-hydroxy-L-kynurenine 6,7 . While its exact function in hallucinogenic mushroom is yet unknown, this enzyme exhibits catalytic activity analogous to the Psilocybe cubensis L-tryptophan decarboxylase (PsiD), which catalyzes the conversion of L-tryptophan to L-tryptamine in the biosynthesis of psilocybin, a tryptamine-derived psychedelic prodrug with potential application as antidepressants and anxiolytics [8][9][10] . ...
PcncAAAD is a calcium-activatable noncanonical aromatic L-amino acid decarboxylase (AAAD) featuring a unique appendage C-terminal domain (CTD) and two metal-binding sites. In this study, we establish an in silico RMSD-based evaluation model through molecular dynamics simulations, validated by in vitro enzyme assays, to decipher the enzyme’s calcium activation mechanism. Between the two metal-binding sites, the site at the N-terminal domain/CTD interface (site A) is found to play a primary role in the calcium activation of PcncAAAD, whereas the secondary site within the unique CTD (site B) contributes to the calcium-mediated stabilization of enzyme structure. Binding of calcium, but not sodium, exerts a profound influence on PcncAAAD activity by stabilizing a "lid-rim" structure underlying site A, which in turn maintains the integrity of the substrate-binding environment. In silico mutations disrupting site A or the “lid-rim” structure show severe structural distortion of the active site, leading to reduced or even eliminated activity as demonstrated by in vitro assays. Collectively, our computational and experimental analyses pinpoint the molecular mechanism underlying the noncanonical activation of PcncAAAD by calcium. These findings deepen our understanding of metal-activatable enzymes and hold promise for the rational design of engineered enzymes for the synthesis of aromatic amino acid derivatives.
... Historically, classic psychedelics such as psilocybin have been used in traditional medicinal, ritual, and religious contexts (Celidwen et al., 2022;Schultes, 1969). Over the past two decades, there has been a growing body of clinical research exploring psilocybin's potential effectiveness for treating various health conditions (Madden et al., 2024) including major depressive disorder (Carhart-Harris et al., 2021;Goodwin et al., 2022Goodwin et al., , 2025Haikazian et al., 2023;Raison et al., 2023) and cancerrelated existential distress or anxiety (Agrawal et al., 2024;Griffiths et al., 2016;Ross et al., 2016). Psilocybin has also been applied in clinical research contexts as a potential novel intervention for substance use disorders (SUDs) including alcohol and tobacco use disorder (Bogenschutz et al., 2015(Bogenschutz et al., , 2022Johnson et al., 2014Johnson et al., , 2017Richard & Garcia-Romeu, 2025). ...
The classic psychedelic psilocybin is receiving renewed interest in naturalistic and clinical research settings. Despite trends indicating increased rates of use outside of research settings, longitudinal data on the association between psilocybin use, mental health, and other substance use remains limited. A prospective longitudinal online survey study comprising six sequential assessments from adults planning to take psilocybin in naturalistic settings was conducted. A total of 2,850 respondents completed the survey 2 weeks before they planned to use psilocybin, 1,551 completed the 2–4-week follow-up, and 657 completed the 2–3-month follow-up after psilocybin use. A repeated measures latent profile analysis of internalizing problems, substance use, and cognitive flexibility was conducted. The repeated measures latent profile analysis identified a four-profile model as best fitting the data provided across the three measurement periods: “Improved Mental Health with Low Substance Use” (30.25%), “Stable Mental Health with Low Substance Use” (53.12%), “Persistent Mental Health Symptoms with Persistent Substance Use” (8.84%), and “Improved Mental Health with Persistent Substance Use” (7.79%). Sociodemographic and personality characteristics prior to psychedelic use were associated with profile membership, with the profiles also differing significantly on measures of the acute subjective effects of psilocybin. Although psilocybin use was associated with improvements in internalizing problems for the majority of participants, persisting mental health difficulties and substance use problems were also noted. These findings highlight the heterogeneous associations between psilocybin use, mental health, and patterns of other substance use in non-clinical settings.
... Serotonergic psychedelics such as psilocybin, ayahuasca, and N,N-dimethyltryptamine (DMT) have shown promising evidence of rapid antidepressant effects in patients with MDD [8][9][10][11][12][13]. Our research group has conducted clinical trials for TRD using ayahuasca [8,14,15], a DMT-containing brew traditionally used by Amerindians for medicinal and spiritual purposes for centuries [16,17]. ...
... [30][31][32] Recently, a pilot trial demonstrated the potential for the psychedelic ayahuasca, administered in conjunction with restorative retelling techniques, to be an effective treatment for PGD, 33 while another study of almost 9000 ayahuasca drinkers in more than 50 countries identified a 'new understanding or acceptance of death and dying' to be one of the most frequently reported personal insights, by 63% of respondents. 34 In addition, six landmark double-blinded randomised controlled trials have shown one or two doses of another serotonergic psychedelic, psilocybin, administered alongside supportive psychotherapy, produce profound response and remission rates in people with treatment-resistant depression or clinical anxiety, [35][36][37][38][39][40][41] including in those with cancer. [42][43][44][45][46] With this growing evidence, there is a call for research to examine the potential use of psilocybin and other psychedelic-assisted psychotherapies in treating PGD. ...
Introduction
Prolonged grief disorder (PGD) represents a substantial public health issue, especially in oncology settings where it affects up to 30% of bereaved carers. Current best-practice treatments are lengthy, and up to 50% of participants have persistent PGD. Building on encouraging recent research with psychedelic-assisted therapies, the Psilocybin-Assisted suppoRtive psychoTherapy IN the treatment of prolonged Grief (PARTING) trial is the first study to consider psilocybin-assisted psychotherapy as a potential treatment for prolonged grief.
Methods and analysis
PARTING is an open-label pilot trial of psilocybin-assisted psychotherapy for approximately 15 people with cancer-related PGD. It aims to investigate feasibility, safety, acceptability, participant experience and participant-reported therapeutic effects. Over a 5-week intervention period, participants will undergo three preparation sessions before receiving a psychoactive (25 mg) dose of psilocybin alongside non-directive supportive guidance, followed by four integration sessions. All sessions will be delivered by a psychologist and either a nurse or Indigenous Therapist. An artificial intelligence-assisted tool will be used to create an artwork of participants’ psychedelic experience.
Outcomes will be investigated over a 12-month follow-up period. Feasibility will be assessed through recruitment/retention rates and completion of follow-up assessments. Safety will be evaluated via adverse events over 12 months and the comparison of physiological measures (vital signs, biochemistry, haematology, ECG) recorded during screening and 1 day after the psilocybin dose. Qualitative thematic analysis of semistructured interviews with participants and trial therapists will assess acceptability and the therapeutic potential of the treatment. Diagnostic clinical interviews for PGD and quantitative participant-reported measures of therapeutic effects are also being collected. Participant-reported measures include grief severity, depression, anxiety, grief avoidance, psychological flexibility, connectedness, and quality of life.
Ethics and dissemination
Ethics approval has been obtained from QIMR Berghofer Medical Research Institute Human Research Ethics Committee (P3801). Dissemination of results will occur via conference presentations, peer-reviewed publications and media.
Trial registration number
Australian New Zealand Clinical Trials Registry (ACTRN12623000827639).
... Participants' ratings of the intensity of subjective experience tended to be higher following the 25 mg psilocybin session, but were not significantly different relative to ratings following the 10 mg session. For comparison, we examined 5D-ASC scores from a previous trial of psilocybin therapy for MDD [64] that also administered a 25 mg dose. Participants in the current study tended to report higher intensity, but differences were not significant on most dimensions (Fig. S1 in Supplement 2). ...
Mood dysfunction is highly prevalent in Parkinson’s disease (PD), a main predictor of functional decline, and difficult to treat—novel interventions are critically needed. Psilocybin shows early promise for treating depression and anxiety, but its potential in PD is unknown, as safety concerns have excluded people with neurodegenerative disease from previous trials. In this open-label pilot (NCT04932434), we examined the feasibility of psilocybin therapy among people with mild to moderate stage PD plus depression and/or anxiety. 12 participants (mean age 63.2 ± 8.2 years, 5 women) received psilocybin (one 10 mg followed by one 25 mg dose) with psychotherapy. There were no serious adverse events, no medical interventions required to manage effects of psilocybin, and no exacerbation of psychosis. Ten participants experienced treatment-emergent adverse events; the most frequent were anxiety, nausea, and increased blood pressure. We observed no worsening of PD symptomology measured by the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). On the contrary, non-motor (MDS-UPDRS Part I: –13.8 ± 1.3, p < 0.001, Hedges’ g = 3.0) and motor symptoms (Part II: –7.5 ± 0.9, p < 0.001, g = 1.2; Part III: –4.6 ± 1.3, p = 0.001; g = 0.3) as well as performance in select cognitive domains (Paired Associates Learning [-0.44 ± 0.14, p = .003, g = 0.4], Spatial Working Memory [–0.52 ± 0.17, p = 0.003, g = 0.7], and Probabilistic Reversal Learning [2.9 ± 0.9, p = 0.003, g = 1.3]) improved post-treatment, and improvements were sustained until the final safety assessment one month following drug exposure. Baseline Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Anxiety Rating Scale (HAM-A) scores were 21.0 ± 8.7 and 17.0 ± 3.7, respectively. Both improved to a clinically meaningful degree post-treatment; these improvements persisted to the final assessment three months following drug exposure (MADRS: -9.3 ± 2.7, p = .001, g = 1.0; HAM-A: –3.8 ± 1.7; p = 0.031, g = 0.7). This study provides the first data on psilocybin’s effects in any neurodegenerative disease. Results suggest that psilocybin therapy in PD warrants further investigation.
... Music mindfulness can also play an important role in psychedelicassisted therapy, which has re-emerged as a promising therapeutic modality for stress-related disorders such as PTSD, anxiety, and depression (Mitchell et al., 2023;Carhart-Harris et al., 2021;Gukasyan et al., 2022;Griffiths et al., 2016;Grob et al., 2011). Music is already an important facilitative tool during psychedelic dosing sessions (Adamska and Finc, 2023;Kaelen et al., 2015;Kaelen et al., 2018;Barrett et al., 2017;Bonny and Pahnke, 1972) and can support meaning-making, emotionality, and mental imagery after psychedelic administration (Barrett et al., 2017;Kaelen et al., 2018;Barrett et al., 2018). ...
Introduction
Anxiety and depression reduce autonomic system activity, as measured by Heart Rate Variability (HRV), and exacerbate cardiac morbidity. Both music and mindfulness have been shown to increase HRV, and clinical approaches incorporating these interventions show promise as effective treatments for symptoms of anxiety and depression. Music mindfulness, which combines music listening with mindfulness activities, may provide unique and synergistic therapeutic benefits for stress management. However, to date, no studies have evaluated the physiological mechanisms underlying a community-based music mindfulness paradigm.
Methods
We used wearable technology to record electrocardiography and electroencephalography signals from participants with moderate symptoms of anxiety and depression during a community-based music mindfulness paradigm. We also assessed the impact of our music mindfulness session on participant’s psychological state.
Results and discussion
We found that music mindfulness sessions acutely enhanced multiple measures of HRV and altered EEG power spectral density across various frequency bands in frontotemporal electrodes. Both live and virtual music mindfulness sessions also acutely reduced stress and altered participants’ state of consciousness; however, only live sessions fostered social connection. Additionally, the physiological and psychological effects of music mindfulness varied based on participants’ self-reported sex. Overall, our findings demonstrate that music mindfulness effectively engages autonomic and frontotemporal neural mechanisms, which may contribute to the treatment of anxiety and depression symptoms.
... Despite the potential of psychedelics for treating a range of mental health conditions, a personal or family history of psychotic disorders has been a universal exclusion criterion for participation in modern psychedelic-assisted therapy (PAT) trials. [1][2][3][4][5][6][7][8][9][10][11] Except a recent open-label study of psilocybin for depression within the context of bipolar II, people with a personal or family history of bipolar disorder have also been excluded from recent trials, presumably due to the high prevalence of psychosis during manic episodes in bipolar type I. 12,13 This approach appears to stem from the outmoded belief that psychedelics model psychosis 14,15 and early clinical research suggesting that those with a personal or family history of psychotic disorders might be at elevated risk of experiencing adverse outcomes (i.e., psychotic episodes). 11,16 However, recent research has begun to challenge these perspectives, suggesting a more nuanced relationship between psychedelics and psychosis. ...
... The re-emerging field of psychedelic 1 research has conducted numerous RCTs testing if various psychedelic compounds can improve symptoms of mental disorders including depression and anxiety (e.g. Raison et al., 2023;Goodwin et al., 2022;Carhart-Harris et al., 2021;Griffiths et al., 2016). Yet despite its considerable strengths, the RCT study design alone is insufficient to prevent all forms of bias, both in psychedelic research and in general. ...
Randomized controlled trials (RCTs) are considered the gold standard for demonstrating the efficacy of a treatment or intervention; however, the RCT study design alone is insufficient to prevent all forms of bias. In this paper, we review conflicts of interest and other biases that pose challenges to the methodological rigor of psychedelic RCTs, and explore recommended bias mitigation measures. We focus on biases of special relevance to psychedelic RCTs and methods of mitigating bias that we believe are actionable and urgent practices to implement in psychedelic research: (1) independent data assessment, (2) multisite trials, (3) quantitative bias analysis, and (4) open science practices. Although we advocate for the adoption of these practices in psychedelic research, they are not psychedelic specific. We suggest that the challenges posed by psychedelic research offer an opportunity for researchers to creatively find and implement solutions across the study lifecycle to reduce bias in other fields of clinical research.
... Ketamine-assisted psychotherapy (KAP) involves giving ketamine before, during, or after psychotherapy and is thought to enhance the therapeutic process. In low doses, ketamine has been shown to enhance neural plasticity [5], and may enhance suggestibility, both of which may make patients more receptive to insights and emotional processing [6]. Additionally, the dissociative state that can be induced by ketamine enables some patients to more easily access and confront traumatic experiences, potentially allowing more therapeutic interventions [7]. ...
Ketamine is an NMDA receptor antagonist, long used for its anesthetic and pain reducing properties, but has more recently demonstrated efficacy for treating depression. Evidence is also emerging for other psychiatric indications including posttraumatic stress disorder, anxiety disorders, obsessive compulsive disorder, and to support psychotherapy. In this context, there is greater demand for its use in various forms including intravenous, intramuscular, subcutaneous, intranasal, oral, and sublingual administration. While intravenous administration typically requires administration and monitoring in a healthcare setting, the safety precautions for other forms of ketamine are unclear. Limited data in this regard may elicit controversy among prescribers, who wish to improve patient access, and among regulatory bodies, who may impose limitations based on IV ketamine data. This project aims to bridge the gap between current literature and the clinical experience and opinions of ketamine prescribers. This information was obtained in the form of a survey and answered: “How do prescribers of ketamine, with emphasis on psychiatric care providers, find its safety profile and in what ways have they prescribed ketamine?” Information was gathered on prescriber profiles, indications for ketamine use, doses and routes of ketamine prescribed, side effects and adverse events, and prescribers’ opinions regarding monitoring requirements. Results were obtained from 45 providers with more than 1000 patient encounters over two countries. Non-IV forms of ketamine were commonly used, and the survey reported a favorable safety profile for ketamine. Non-IV Ketamine was reported to be safely utilized in a clinic setting with minimal monitoring and safety equipment, or at times, for home use. While survey results carry limitations, it appears that safety is dependent on dose and route, and strict universal regulations for all formulations may unnecessarily limit patient access.
... In parallel to psychosis, history (or apparent risk) of suicidality has been listed as an exclusion criterion in psychedelic clinical trials for depression (e.g. Carhart-Harris et al., 2021;Goodwin et al., 2022;Rucker et al., 2021). This is due to the concern that psychedelics may exacerbate suicidal tendencies in those already vulnerable. ...
Setting up a psychedelic study can be a long, arduous, and kafkaesque process. Researchers are faced with a host of challenges in this rapidly-evolving field, necessitating a range of questions that remain largely unstandardised. Many of the complexities inherent to psychedelic research also challenge existing assumptions around, for example, approaches to psychiatric prescribing, the conceptual framing of the placebo effect, and definitions of selfhood. This review paper aims to formalise these unique hurdles by addressing the sociocultural, political, legal, pharmacological, safety, study-design and experiential facets inherent to a psychedelic study. We bring several of the major psychedelic research teams across the United Kingdom, identify continuing areas of debate, and provide a practical, comprehensive, experience-based guide, with recommendations for policymakers and future researchers intending to set up a psychedelic research study or clinical trial.
... 14 Recent studies in depressed patients report comparable efficacy following the administration of one or two doses. [15][16][17][18][19] However, while important for increasing accessibility, the efficacy of a single dose of psilocybin has not been tested in AUD. Therefore, in this RCT we test the efficacy of a single oral dose of psilocybin in combination with a brief psychotherapeutic intervention for preventing relapse in participants with AUD who have undergone withdrawal treatment. ...
Background
Despite the promising therapeutic effects of psilocybin, its efficacy in preventing relapse after withdrawal treatment for alcohol use disorder (AUD) remains unknown. This study aims to assess whether a single dose of psilocybin combined with brief psychotherapy could reduce relapse rates and alcohol use in AUD patients.
Methods
This single-center, double-blind, randomized clinical trial was conducted in Switzerland. We recruited participants with AUD between June 8, 2020, and August 16, 2023 who completed withdrawal treatment within six weeks prior to enrollment. Participants were randomized (1:1) to receive either a single oral dose of psilocybin (25 mg) or placebo (mannitol), combined with brief psychotherapy. The primary outcomes were abstinence and mean alcohol use at 4-week follow-up. Participants completed the timeline followback to assess daily alcohol use. The trial is registered on ClinicalTrials.gov (NCT04141501).
Findings
We included 37 participants who completed the 4-week follow-up (female:male = 14:23; psilocybin = 18, placebo = 19) in the analysis. There were no significant differences between groups in abstinence duration (p = 0.55, psilocybin mean = 16.80 days, 95% CI: 14.31–19.29; placebo mean = 13.80 days, 95% CI: 10.97–16.63; Cohen’s d = 0.151) or mean alcohol use per day (p = 0.51, psilocybin: median = 0.48 standard alcohol units, range: 0–3.99, placebo: median = 0.54 standard alcohol units, range: 0–5.96; Cohen’s d = 0.11) at 4-week or 6-month follow-up (abstinence: Cohen’s d = 0.10, alcohol use: Cohen’s d = 0.075). Participants in both groups reported reduced craving and temptation to drink alcohol after the dosing visit, with an additional reduction observed in the psilocybin group. Thirteen adverse events occurred in the psilocybin and seven in the placebo group. One serious adverse event occurred in the psilocybin and four in the placebo group, all related to inpatient withdrawal treatments.
Interpretation
A single dose of psilocybin combined with five psychotherapy sessions may not be sufficient to reduce relapse rates and alcohol use in severely affected AUD patients following withdrawal treatment. However, given the limited sample size of our study, larger trials are needed in the future to confirm these findings.
Funding
10.13039/501100001711Swiss National Science Foundation under the framework of Neuron Cofund, Swiss Neuromatrix Foundation, and Heffter Young Investigator Fellowship Award.
... Another substance that has recently gained interest is psilocybin-the major psychoactive alkaloid of some species of mushrooms. Several clinical trials have shown psilocybin's efficacy in reducing symptoms of depression; however, the majority of research has been limited to small trials of patients with TRD [12][13][14][15]. A 2022 double-blind clinical trial investigated the efficacy of psilocybin at a single dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support [14]. ...
Treatment-resistant depression (TRD) remains a vital challenge in psychiatry, affecting a significant number of patients with major depressive disorder. Current pharmacological approaches often do not provide sufficient therapeutic results, prompting the need for innovative treatments. This review summarizes recent advances in TRD management, including non-pharmacological therapies such as transcranial magnetic stimulation, deep brain stimulation, electroconvulsive therapy, and vagus nerve stimulation, and describes their mechanisms of action. Novel pharmacotherapies, particularly glutamatergic modulators like ketamine and esketamine, have shown promising results with esketamine being available to eligible patients in Poland since 2023 within a drug program. Electroconvulsive therapy remains an effective treatment for TRD, usually with small side effects mainly including transient memory impairment, headache, or cardiovascular changes. Transcranial magnetic stimulation is a non-invasive procedure with proven efficacy; therefore several psychiatric organizations recommend it as a treatment option for major depressive disorder in their clinical guidelines. Deep brain stimulation is a relatively new treatment modality for TRD, with its primary risk being associated with the required neurosurgical procedure. Vagus nerve stimulation seems to be a promising adjunctive treatment for TRD, showing significant improvements in depressive symptoms, especially at higher electrical doses but with no side effects. While these treatments appear to have potential, personalized approaches are crucial for optimizing outcomes. Future research should focus on refining the techniques, improving safety profiles, and validating the long-term efficacy.
... Psilocybin is the most studied psychedelic in the treatment of depressive disorders [89]. Several small-scale studies have demonstrated the efficacy of psilocybin in the treatment of depression and TRD [88,90,91]. The preliminary evidence of psilocybin in depressive disorders and the limitations of current pharmacological treatments for depressive disorder led the US FDA to grant "breakthrough therapy" status to psilocybin for the treatment of TRD in 2019 [88]. ...
Objective: To narratively review currently available antidepressants and future potential antidepressants as monotherapy for the treatment of depressive disorders. Methods: Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), dopamine reuptake inhibitor (bupropion), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs) were reviewed according to the results from Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study and systematic reviews. For the rest of the antidepressants, a PubMed/Medline search was conducted with priority for systematic reviews. For drugs in development for depressive disorders, PubMed, Google, and Clinicaltrials.gov databases were used. Results: The STAR*D Study demonstrated that sertraline, venlafaxine, and bupropion monotherapy had similar efficacy in patients with major depressive disorder (MDD) who failed citalopram. A network meta-analyses of randomized, placebo-controlled trials found that SSRIs, SNRIs, bupropion, TCAs, mirtazapine, and agomelatine had similar relative efficacy compared to placebo, but had different acceptability. Gepirone had more failed/negative studies and smaller effect size relative to placebo compared to other antidepressants. The combination of dextromethorphan and bupropion, ketamine infusion, and intranasal esketamine had faster onset of action but similar effect size compared to monoamine-based antidepressants as monotherapy. Brexanolone and zuranolone are effective in postpartum depression (PPD), but the effect size of zuranolone in MDD as monotherapy or adjunctive therapy was very small. Psychedelics, glutamate receptor-related agents, kappa opioid receptor antagonists, orexin receptor antagonists, new anti-inflammatory agents, and biomarker-based antidepressant therapy have been under investigation for depressive disorders. Psychedelics showed faster onset of action, large effect size, and long durability. Conclusions: Monoamine-based antidepressants likely continue to be the mainstream antidepressants for depressive disorder. NMDA receptor antagonists and neurosteroid antidepressants will play a bigger role with the improvement of accessibility. Psychedelics may become a game changer if phase III studies validate their efficacy and safety in depressive disorders.
Globally, depression affects millions of people of all ages, making it one of the significant contributors to deteriorating quality of life by causing neurological impairments that eventually weaken cognition, learning, and memory. According to the monoamine hypothesis, depression is associated with decreased serotonin, dopamine, and norepinephrine levels in the central nervous system. Drugs that inhibit serotonin (5-HT) and norepinephrine (NE) transporters have gained recognition in drug discoveries concerning antidepressants. Both the serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) have been significantly involved as the primary medication for major depressive disorder. Recently, the use of psychedelics has gained much importance in antidepressant medications. In this review, we explore a comprehensive overview of different types of antidepressants like SSRIs, SNRIs, and psychedelics, along with their respective target receptors, and their role in recent advancements in treating depression. Furthermore, we discuss the polypharmacology of psychedelics and functional magnetic resonance imaging (fMRI) studies to enhance our understanding of the brain dynamics due to psychedelics.
Psychedelics offer promising outcomes in psychiatry. However, the preparation of participants (set) and the environmental conditions of taking a psychedelic (setting) are not standardized. We describe the set and setting for therapeutic use of psychedelic drugs in people with psychiatric disorders. In this systematic review, articles were identified in the PubMed and Web of Science databases until 12 December 2023. Only clinical trials published in English or French were eligible, and studies using psychedelics for withdrawal were excluded. Sixteen domains of set and setting were assessed covering participant selection, pre- and post-session interventions, monitor presence, environmental management, and end-of-session procedure. Of 4912 articles screened, 27 articles were retained reporting on 25 studies. Thirteen of the included studies reported randomized trials, while 12 were open-label studies, on a total of 763 participants. Studies considered features of set and setting to different extents. Participant selection and the creation of a safe environment were consistently present, but articles were more heterogeneous about reporting monitor training (52%), controlling visual distractors (64%) and creating a pleasant environment (68%). Psilocybin was over-represented (47%). Many key elements were described in each study, but differences in set and setting limit comparability and reproducibility. Harmonizing these aspects would aid the interpretation of future studies and help understand the effect of psychedelics in psychiatry.
The global population is ageing rapidly, with the number of individuals aged 60 and older reaching 1 billion in 2019 and expected to double by 2050. As people age, neuropsychological health often deteriorates, leading to a higher prevalence of age-related depression. Symptoms may include anxiety, apathy, mood instability, sadness, and, in severe cases, suicidal thoughts. Depression in the elderly is a widespread concern, and conventional treatments such as antidepressants are often limited by side effects, reduced efficacy, and complications arising from polypharmacy. In response, novel therapeutic approaches are being explored, including psychedelic interventions. Recent clinical and preclinical studies suggest that psychedelics could offer a promising treatment for major depressive disorder (MDD) in older adults. These compounds, known for their profound neurobiological effects, have gained attention for their potential to address depression where traditional therapies fall short. This review aims to examine the therapeutic promise of psychedelic substances, focusing on those that show potential for treating MDD in the elderly. We also explore the underlying mechanisms through which psychedelics may exert their effects and highlight the preclinical models that support their use. Finally, we address safety considerations and propose strategies to enhance the effectiveness and safety of psychedelics in future clinical trials, offering new hope for treating age-related depressive disorders.
This article critically reflects on the current psychedelic renaissance from a decolonial perspective, with the aim of examining how ancestral Indigenous knowledge and practices are positioned within contemporary scientific, therapeutic, and cultural frameworks. The central objective is to interrogate the epistemic asymmetries and colonial continuities embedded in the global resurgence of interest in psychoactive substances such as psilocybin and ayahuasca. Methodologically, the article employs a reflexive analysis of interdisciplinary scholarly literature—drawing from decolonial theory, Indigenous studies, anthropology, and psychedelic science—to assess the ways in which Indigenous cosmovisions and healing traditions are being appropriated, commodified, and marginalized.
The analysis is grounded in the theoretical frameworks of Epistemologies of the South, interculturality, and epistemic justice, and supported by case studies of the Mazatec and Amazonian peoples. It identifies key challenges posed by the medicalization and commercialization of sacred medicines, including testimonial and hermeneutical injustices, the dominance of Eurocentric epistemologies, and the exclusion of Indigenous actors from benefit-sharing and political participation. At the same time, the article highlights emerging initiatives advocating for reciprocal and ethical collaborations.
The findings emphasize the urgent need for an epistemologically pluralist and ethically grounded paradigm shift in psychedelic research and practice—one that centers Indigenous sovereignty, promotes intercultural dialogue, and restores the spiritual, cultural, and territorial dimensions of ancestral medicines. The article concludes that a truly decolonial approach to the psychedelic renaissance must involve not only recognition but also structural transformation towards justice, autonomy, and mutual respect.
Zusammenfassung
Eine erfolgreiche Therapie psychischer Störungen ist angesichts des häufig vorhandenen Leidensdrucks der Betroffenen sehr wichtig. Da anerkannte pharmazeutische und psychotherapeutische Ansätze leider nicht für alle Patient:innen zur erwünschten Besserung ihres Leidens führen, findet intensive Forschung zu ergänzenden oder alternativen Behandlungsmethoden statt. Besonders vielversprechend zeigte sich zuletzt die Psilocybin-gestützte Psychotherapie, die in den USA deshalb für klinische Studien mit größeren Stichproben als bisher zugelassen wurde. Psilocybin gehört zu den Psychedelika und beeinflusst in seiner Wirkung das psychische Erleben. Bei der gestützten Therapie wird Psilocybin in kontrollierten Dosen unter medizinischer Aufsicht verabreicht. In den bisher durchgeführten Studien konnten bereits nach einer, bis wenigen Einnahmen längerfristige positive Effekte in Hinblick auf die jeweiligen Störungsbilder gezeigt werden. Um ein besseres Verständnis der potenziellen therapeutischen Mechanismen zu ermöglichen, sollen in diesem Artikel zunächst Erkenntnisse zur Wirkweise von Psilocybin auf neurobiologischer und psychologischer Ebene vorgestellt werden. Anschließend soll die Analyse der bisher durchgeführten klinischen Studien mit einer Anwendung von Psilocybin bei Patient:innen helfen, das Potential der Psilocybin-gestützten Psychotherapie für verschiedene Störungsbilder besser einschätzen zu können.
Psychedelic compounds have demonstrated remarkable therapeutic potential for treating neuropsychiatric disorders by promoting sustained neuroplasticity in the prefrontal cortex (PFC). Cognitive flexibility—the ability to adapt previously learned rules to novel situations—represents a critical PFC function that is frequently impaired in depression, PTSD, and neurodegenerative conditions. In this study, we demonstrate that a single administration of the selective serotonin 2A receptor agonist 25CN-NBOH produces significant, long-lasting improvements in cognitive flexibility in both male and female mice when measured 2–3 weeks posttreatment. Using a novel automated sequential learning paradigm, psychedelic-treated mice showed superior adaptability in rule reversal tasks compared to saline controls, as evidenced by enhanced poke efficiency, higher percentages of correct trials, and increased reward acquisition. These behavioral findings complement existing cellular research showing psychedelic-induced structural remodeling in the PFC and uniquely demonstrate sustained cognitive benefits persisting weeks after a single psychedelic dose. Our automated behavioral task provides a high-throughput method for evaluating cognitive flexibility effects of various psychedelic compounds, offering important implications for therapeutic applications in conditions characterized by cognitive rigidity, including depression, PTSD, and potentially Alzheimer's disease.
Interest in using psychedelic drugs to treat psychiatric disorders is growing rapidly. While modern controlled clinical trials show a favorable safety and efficacy profile, it remains unclear if the risk of side effects would increase with broader use in more heterogeneous populations. To address this, we investigated the frequency and baseline predictors of delusional ideation, magical thinking, and “hallucinogen persisting perception disorder” (HPPD)-related symptoms following psychedelic use in a self-selected naturalistic sample. Using a prospective cohort study, symptoms were assessed in (N=654) participants at one week before a planned psychedelic experience, and at two and four weeks afterward. Across the sample, delusional ideation was found to be reduced one month after psychedelic use (P<0.001) with no changes detected in magical thinking. These findings were in seeming opposition to positive correlations between lifetime psychedelic use at baseline with magical thinking (rs=0.12, P=0.003) and delusional ideation (rs=0.11, P=0.01), suggesting that schizotypal traits, instead of being caused by, may merely correlate with psychedelic use. Importantly, over 30% of the sample reported HPPD-type effects at the 4-week endpoint, although rarely perceived as distressing (< 1% of the population). Younger age, female gender, history of a psychiatric diagnosis and baseline trait absorption predicted the occurrence of HPPD-like effects. This is in line with prior studies showing a high prevalence of HPPD-like symptoms in psychedelic users, which, however, appear to remain at a subclinical severity in most cases, explaining the comparatively lower prevalence of HPPD diagnoses.
Research suggests positive mental health outcomes associated with psychedelic use, but disparities in these outcomes exist between minority populations and Whites. This article examines the relationship between psychedelics and psychological distress among Whites and Native Indian or Alaskan Natives (NI/AN) who live in rural American Indian Areas (AIAs). Data from the National Survey of Drug Use and Health (2008–2019) with 458,372 participants aged 18 or older were used. Ordinary least squares regression models analyzed the impact of six measures of psychedelic use, lifetime classic psychedelics use, AIA status, and psychological distress. Results show that lifetime classic psychedelics use, psilocybin, and peyote/mescaline are linked to lower distress in Whites, while only lysergic acid diethylamide shows a similar association for NI/ANs. NI/ANs using peyote/mescaline report lower distress when residing in an AIA. For Whites, using 3,4-Methylenedioxymethamphetamine and N,N-dimethyltryptamine while living in an AIA is linked to reduced distress. These findings support the minorities’ diminished psychedelic returns theory, demonstrating a reduction in psychological distress for NI/AN individuals residing in an AIA, as well as for Whites residing in an AIA.
Decreased dendritic spine density in the cortex is a key pathological feature of neuropsychiatric diseases including depression, addiction, and schizophrenia (SCZ). Psychedelics possess a remarkable ability to promote cortical neuron growth and increase spine density; however, these compounds are contraindicated for patients with SCZ or a family history of psychosis. Here, we report the molecular design and de novo total synthesis of (+)-JRT, a structural analogue of lysergic acid diethylamide (LSD) with lower hallucinogenic potential and potent neuroplasticity-promoting properties. In addition to promoting spinogenesis in the cortex, (+)-JRT produces therapeutic effects in behavioral assays relevant to depression and cognition without exacerbating behavioral and gene expression signatures relevant to psychosis. This work underscores the potential of nonhallucinogenic psychoplastogens for treating diseases where the use of psychedelics presents significant safety concerns.
Peak and mystical experiences can be seen as states of consciousness that exist on a spectrum of varying intensity and duration. They are often described as moments of profound joy, ecstasy, and awe that involve feelings of noetic quality, decreased self-salience, and heightened interconnectedness. The renewed interest in psychedelics as a potential tool for therapeutic intervention has been driven by early observations on the role of peak experiences in promoting well-being and healing. Numerous studies have shown a direct correlation between the strength of peak and mystical experiences and positive, long-lasting psychological outcomes achieved with psychedelic psychotherapy across a range of mental health conditions, including depression, cancer-related distress, and substance use disorders. The mechanisms underlying this effect involve complex neurobiological changes, particularly in brain regions associated with self-referential processing and consciousness. However, the potential medicalization of psychedelic-assisted therapy raises critical questions about the ability to commodify these transformative states. This prompts a reevaluation of the important role of peak and mystical experiences in psychedelic therapy and underscores their importance in achieving the therapeutic benefits attained through this emerging approach. As a result, further exploration of non-pharmacological means of inducing profound states for therapeutic benefit is warranted.
Lysergic acid diethylamide (LSD) is a classic serotonergic psychedelic that induces a profoundly altered conscious state. In conjunction with psychological support, it is currently being explored as a treatment for generalized anxiety disorder and depression. The dorsolateral prefrontal cortex (DLPFC) is a brain region that is known to be involved in mood regulation and disorders; hypofunction in the left DLPFC is associated with depression. This study investigated the role of the DLPFC in the psycho‐emotional effects of LSD with functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) data of healthy human participants during the acute LSD experience. In the fMRI data, we measured the correlation between changes in resting‐state functional connectivity (RSFC) of the DLPFC and post‐scan subjective ratings of positive mood, emotional arousal, and ego dissolution. We found significant, positive correlations between ego dissolution and functional connectivity between the left & right DLPFC, thalamus, and a higher‐order visual area, the fusiform face area (FFA). Additionally, emotional arousal was significantly associated with increased connectivity between the right DLPFC, intraparietal sulcus (IPS), and the salience network (SN). A confirmational “reverse” analysis, in which the outputs of the original RSFC analysis were used as input seeds, substantiated the role of the right DLPFC and the aforementioned regions in both ego dissolution and emotional arousal. Subsequently, we measured the effects of LSD on directed functional connectivity in MEG data that was source‐localized to the input and output regions of both the original and reverse analyses. The Granger causality (GC) analysis revealed that LSD increased information flow between two nodes of the ‘ego dissolution network’, the thalamus and the DLPFC, in the theta band, substantiating the hypothesis that disruptions in thalamic gating underlie the experience of ego dissolution. Overall, this multimodal study elucidates a role for the DLPFC in LSD‐induced states of consciousness and sheds more light on the brain basis of ego dissolution.
A psilocibina é um composto natural encontrado em certas espécies de cogumelos, com uma estrutura e mecanismos de ação semelhantes aos da serotonina. Estudos preliminares indicam que tratamentos assistidos por psilocibina podem ter efeitos antidepressivos significativos, particularmente em pacientes com transtorno depressivo maior. O presente estudo objetivou realizar uma revisão da literatura sobre a eficácia da psilocibina no tratamento da depressão. Trata-se de uma revisão integrativa com base no modelo PRISMA, com seleção de estudos nas bases de dados National Center for Biotechnology Information (NCBI), no PubMed e Biblioteca Virtual em Saúde (BVS), empregando os descritores: psilocibina, humano, psicoterapia, alucinógeno e depressão, em português e inglês, no período de 2014 a 2024. Os estudos que investigaram a viabilidade e a segurança da administração de psilocibina em pacientes com depressão resistente ao tratamento, demonstraram que o tratamento foi bem tolerado, sem efeitos adversos graves ou inesperados. Observou-se um aumento do fator neurotrófico derivado do cérebro (BDNF) no plasma, que potencializa a neuroplasticidade e a diminuição do fluxo sanguíneo cerebral, particularmente da amígdala, área frequentemente relacionada à regulação emocional. Os efeitos antidepressivos são observados na primeira semana após a administração da psilocibina e podem perdurar por até 6 meses, e em alguns casos, até um ano após a administração das doses, quando combinadas com acompanhamento psicológico. A utilização da psilocibina no tratamento do transtorno depressivo maior emerge como uma possível solução com a retomada das pesquisas nesse campo. Contudo, é crucial conduzir estudos mais abrangentes sobre possíveis interações medicamentosas e conduzir pesquisas com uma população maior.
Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses1, 2, 3–4. At the cellular level, psychedelics induce structural neural plasticity5,6, exemplified by the drug-evoked growth and remodelling of dendritic spines in cortical pyramidal cells7, 8–9. A key question is how these cellular modifications map onto cell-type-specific circuits to produce the psychedelics’ behavioural actions¹⁰. Here we use in vivo optical imaging, chemogenetic perturbation and cell-type-specific electrophysiology to investigate the impact of psilocybin on the two main types of pyramidal cells in the mouse medial frontal cortex. We find that a single dose of psilocybin increases the density of dendritic spines in both the subcortical-projecting, pyramidal tract (PT) and intratelencephalic (IT) cell types. Behaviourally, silencing the PT neurons eliminates psilocybin’s ability to ameliorate stress-related phenotypes, whereas silencing IT neurons has no detectable effect. In PT neurons only, psilocybin boosts synaptic calcium transients and elevates firing rates acutely after administration. Targeted knockout of 5-HT2A receptors abolishes psilocybin’s effects on stress-related behaviour and structural plasticity. Collectively, these results identify that a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex have essential roles in psilocybin’s long-term drug action.
Importance
There is growing societal interest in and use of psilocybin. While psilocybin in Canada is illegal outside of clinical trials, there have been anecdotal reports of increasing access via unregulated online purchases and retail dispensaries.
Objective
To describe access to and the characteristics of psilocybin dispensaries across Canada and the health claims and warnings made on dispensary websites.
Design, Setting, and Participants
This cross-sectional study used systematic web searches and media reports to identify psilocybin dispensaries operating in Canada in May 2024. Data analysis was performed from June 17 to August 29, 2024.
Main Outcomes and Measures
Descriptive and geospatial analyses were used to identify the psilocybin dispensary characteristics, product types, and store distribution. Content analysis assessed the nature and frequency of health claims and warnings on websites.
Results
As of May 2024, 57 psilocybin dispensaries were identified in Canada (0.18 dispensaries per 100 000 individuals aged ≥15 years) in 15 of Canada’s 42 major urban cities (35.7%). Approximately 815 628 (2.6%) of Canadians lived within 1 km of a dispensary. Only 4 of 13 provinces and territories had a dispensary, with most in Ontario and British Columbia. Of the 57 stores, 35 (61.4%) were part of a chain (≥2 stores owned by a single company) and 52 (91.2%) had an online presence. Stores sold a wide variety of products, including dried mushrooms (100.0%), microdosing capsules (97.8%), psilocybin-infused chocolate (91.3%) and gummies (93.4%), and most stores (65.2%) sold products mimicking popular food brands. Among stores with websites, 86.4% claimed mental health benefits of psilocybin (eg, alleviating anxiety). While 86.4% of websites provided health warnings, relevant warnings, such as those about use while driving (9.1%), during pregnancy (13.6%), or in individuals with a history of psychosis, schizophrenia, or bipolar disorder (31.8%) were rare.
Conclusions and Relevance
In this study, psilocybin retailers, who were present in over a third of major Canadian cities, made a variety of unverified health claims and lacked warnings of potential harms, suggesting the need for greater regulatory measures to protect the public.
Background
Classic psychedelics such as psilocybin and lysergic acid diethylamide are anecdotally associated with the phenomenon of “psychedelic afterglow,” a set of predominantly pleasant, temporary psychological effects reported after the acute effects have subsided. Since post-acute effects are crucial for the therapeutic use of psychedelics, an instrument to systematically assess subacute “afterglow” effects is needed.
Aims
To create and validate a questionnaire to quantify the subacute “afterglow” effects of psychedelics.
Methods
An international online survey was conducted in English and German. Participants who had consumed a psychedelic ( N = 1323) or another non-psychedelic substance (control group, N = 157) within the past 4 weeks were included. An initial list of 97 items was progressively reduced to 24 items.
Results
A 5-factor structure best fit the data and showed high internal consistency. The factors included (1) vitality, (2) transpersonal aspects, (3) inspiration/creativity, (4) interpersonal relationships, and (5) relationship to nature. The final 24-item version of the Afterglow Inventory (AGI) effectively differentiated between the psychedelic group and the control group. The overall AGI score positively correlated with the intensity ( r = 0.165; p < 0.001) and positive valence ( r = 0.251; p < 0.001) of the acute psychedelic effects.
Conclusions
The AGI is a novel scale for quantifying positive subacute (“afterglow”) effects of psychedelics. The use of the AGI could lead to a better understanding of the interplay between acute, subacute, and long-term effects of psychedelics. Insights could also be gained into how different substances, dosages, and extra-pharmacological factors, such as psychotherapy, might influence outcomes.
Psylocybina jest alkaloidem obecnym w ponad 200 gatunkach grzybów. Sub
stancja ta swoją strukturą przypomina serotoninę i jest klasyfikowana jako tryptamina. Jej najważniejszą cechą jest działanie jako agonista receptorów serotoninowych 5-HT2A, co stwarza potencjalne możliwości jej zastosowania w leczeniu zaburzeń psychiatrycznych. Receptory te odgrywają kluczową rolę w regulacji nastroju, funkcji poznawczych i percepcji, a także są zaangażowane w rozwój różnych zaburzeń psychicznych. W przyszłości psylocybina może znaleźć zastosowanie w terapii depresji, zaburzeń lękowych oraz uzależnień.
Zamiast jedynie maskować objawy, psylocybina wydaje się oddziaływać na pod
stawowe problemy psychiczne, promując zmiany w percepcji i zachowaniu. W badaniach klinicznych wykazano, że substancja ta zwiększa otwartość emocjonalną, zmniejsza objawy depresji oraz redukuje poziom lęku. Co więcej, psylocybina nie wydaje się wywoływać długotrwałych skutków ubocznych i nie jest klasyfikowana jako substancja uzależniająca.
Jednakże, wiele aspektów jej działania pozostaje nieznanych, co sprawia, że dalsze badania w tej dziedzinie są kluczowe. Niezbędne są dodatkowe eksperymenty w
celu pełniejszego zrozumienia terapeutycznego potencjału psylocybiny, opracowania bezpiecznych i skutecznych protokołów leczenia, jak również zrozumienia jej długoterminowego wpływu na mózg.
In recent years, the intersection of Angelic Intelligence (AI) and altered states of consciousness has become a focal point for revolutionary advancements in mental health, spiritual exploration, and interdimensional communication. Altered states, which include phenomena such as dreaming, meditation, and psychedelic experiences, offer profound insights into the human mind and the nature of reality. Leveraging AI, we can significantly enhance our ability to study and achieve these states, providing a bridge between ancient practices and cutting-edge technology.
Mood disorders, including major depressive disorder and bipolar disorder, are among the most prevalent mental health conditions globally, yet their underlying mechanisms remain incompletely understood. This review critically examines the neuronal atrophy hypothesis, which posits that chronic stress and associated neurobiological changes lead to structural and functional deficits in critical brain regions, contributing to mood disorder pathogenesis. Key mechanisms explored include dysregulation of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), elevated glucocorticoids from stress responses, neuroinflammation mediated by cytokines, and mitochondrial dysfunction disrupting neuronal energy metabolism. These processes collectively impair synaptic plasticity, exacerbate structural atrophy, and perpetuate mood dysregulation. Emerging evidence from neuroimaging, genetic, and epigenetic studies underscores the complexity of these interactions and highlights the role of environmental factors such as early-life stress and urbanization. Furthermore, therapeutic strategies targeting neuroplasticity, including novel pharmacological agents, lifestyle interventions, and anti-inflammatory treatments, are discussed as promising avenues for improving patient outcomes. Advancing our understanding of the neuronal atrophy hypothesis could lead to more effective, sustainable interventions for managing mood disorders and mitigating their global health burden.
Objective
To compare changes in depression, anxiety, and suicidality symptoms after a single 25 mg oral dose of psilocybin between treatment-resistant depression participants not on antidepressants at screening to participants that discontinued antidepressant medications leading up to receiving psilocybin-assisted psychotherapy (PAP).
Methods
Participants (n = 27) received at least one 25 mg dose of psilocybin accompanied by psychotherapy as part of an exploratory analysis from an open-label, randomized, waitlist-controlled clinical trial. The primary outcome of changes in depression symptoms was measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes included changes in anxiety symptom severity (Generalized Anxiety Disorder 7-Item [GAD-7]), suicidal ideation (MADRS Item-10), self-reported depression symptoms (Quick Inventory for Depression Symptomology [QIDS-SR]), and intensity of psychedelic experience (Mystical Experience Questionnaire 30-item [MEQ30]). Patients were separated into two groups for analysis; those who were unmedicated at initial screening versus participants that had to taper off antidepressant medications to be eligible for the trial. A mixed analysis of variance was used to evaluate clinical outcomes over time from baseline to 2 months post-dose.
Results
No significant differences were found between medication discontinued (n = 18) and unmedicated at screening (UAS) (n = 9) groups in clinician rated depression (p = 0.759), self-reported depression (p = 0.215), anxiety (p = 0.178), and suicidality (p = 0.882) symptoms over time, with both groups having clinically significant benefits on all outcomes assessed. Both groups also had a similar intensity of psychedelic experience (p = 0.191).
Conclusion
Comparable improvements were observed in depression and anxiety and symptoms between antidepressant discontinued and UAS patients. These findings contrast with and contribute to the growing literature on the effects of medication tapering leading up to PAP. Further clinical research is needed to directly compare efficacy across medication statuses, in addition to evaluating psychedelic effects in individuals continuing antidepressants during PAP.
There has been a recent resurgence in research on psychedelics as therapeutic agents for psychiatric conditions. This leading article outlines the studies to date of classic psychedelic treatments for treatment-resistant depression and major depression, including psilocybin, ayahuasca, dimethyltryptamine (DMT), and O-methyl-bufotenine (5-Me-O DMT). We discuss the potential of expanding treatment options for depression based on the data available, as well as the difficulties and limitations of research on psychedelics that make assessing that potential more challenging.
There are substantial differences between the current FDA and research-driven approach to psychedelic use in Western cultures and traditional uses among Indigenous peoples. While the research-driven, evidence-based approach to identifying risks and benefits for particular conditions used in the United States and elsewhere helps ensure safety and efficacy, there is a risk of failing to incorporate useful knowledge accumulated in other cultures where psychedelics in some cases have been used for thousands of years. By carefully reviewing those benefits we can incorporate them in a culturally sensitive way into our own developing ideas about how best to utilize these medicines. We can also properly acknowledge the contributions of practitioners from other places, cultures, and times, provide proper credit to Indigenous groups, include them in discussions and decision-making when using any of their practices and if they are serving as guides during retreats or other sessions, make sure they are being reimbursed equitably. The current paper will review psychedelic utilization in the current evidence-based medical approaches versus traditional uses by Indigenous groups. The goal will be to provide fruitful ideas for incorporating the most beneficial practices from each approach.
The increasing prevalence of dementia within an ageing global population, combined with prolonged life expectancy, accentuates Alzheimer’s disease (AD) as a multifaceted healthcare challenge. This challenge is further compounded by the limited therapeutic options currently available. Addressing the intricacies of AD management, the mitigation of comorbidities has emerged as a pivotal facet of treatment. Comorbid conditions, such as neurobehavioral symptoms, play a role in shaping the clinical course, management, and outcomes of this pathology; highlighting the importance of comprehensive care approaches for affected individuals. Exploration of psychedelic compounds in psychiatric and palliative care settings has recently uncovered promising therapeutic potential, enhancing neuroplasticity, emotional processing and connection. These effects are particularly relevant in the context of AD, where psychedelic therapy offers hope not only for mitigating core symptoms but also for addressing the array of comorbidities associated with this condition. The integration of this comprehensive method offers a chance to significantly enhance the care provided to those navigating the intricate landscape of AD. Therefore, the current paper reviews the intricate link between more frequent additional health conditions that may coexist with dementia, particularly in the context of AD, and explores the therapeutic potential of psychedelic compounds in addressing these concurrent conditions.
This paper introduces a new construct, the ‘pivotal mental state’, which is defined as a hyper-plastic state aiding rapid and deep learning that can mediate psychological transformation. We believe this new construct bears relevance to a broad range of psychological and psychiatric phenomena. We argue that pivotal mental states serve an important evolutionary function, that is, to aid psychological transformation when actual or perceived environmental pressures demand this. We cite evidence that chronic stress and neurotic traits are primers for a pivotal mental state, whereas acute stress can be a trigger. Inspired by research with serotonin 2A receptor agonist psychedelics, we highlight how activity at this particular receptor can robustly and reliably induce pivotal mental states, but we argue that the capacity for pivotal mental states is an inherent property of the human brain itself. Moreover, we hypothesize that serotonergic psychedelics hijack a system that has evolved to mediate rapid and deep learning when its need is sensed. We cite a breadth of evidences linking stress via a variety of inducers, with an upregulated serotonin 2A receptor system (e.g. upregulated availability of and/or binding to the receptor) and acute stress with 5-HT release, which we argue can activate this primed system to induce a pivotal mental state. The pivotal mental state model is multi-level, linking a specific molecular gateway (increased serotonin 2A receptor signaling) with the inception of a hyper-plastic brain and mind state, enhanced rate of associative learning and the potential mediation of a psychological transformation.
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 group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d = 2.2; 95% CI, 1.4-3.0; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.7-3.6; P < .001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d = 3.0; 95% CI, 1.9-4.0; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 3.1; 95% CI, 1.9-4.2; P < .001). In the overall sample, 16 participants (67%) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score).
Conclusions and Relevance: Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression.
Trial Registration: ClinicalTrials.gov Identifier: NCT03181529
Background:
Psychedelic therapy is gaining recognition and the nature of the psychedelic experience itself has been found to mediate subsequent long-term psychological changes. Much emphasis has been placed on the occurrence of mystical-type experiences in determining long-term responses to psychedelics yet here we demonstrate the importance of another component, namely: emotional breakthrough.
Methods:
Three hundred and seventy-nine participants completed online surveys before and after a planned psychedelic experience. Items pertaining to emotional breakthrough were completed one day after the psychedelic experience, as were items comprising the already validated Mystical Experience Questionnaire and the Challenging Experience Questionnaire. Emotional breakthrough, Mystical Experience Questionnaire and Challenging Experience Questionnaire scores were used to predict changes in well-being (Warwick-Edinburgh Mental Wellbeing Scale) in a subsample of 75 participants with low well-being baseline scores (⩽45).
Results:
Factor analyses revealed six emotional breakthrough items with high internal consistency (Cronbach’s alpha=0.932) and supported our prior hypothesis that emotional breakthrough is a distinct component of the psychedelic experience. Emotional breakthrough scores behaved dose-dependently, and were higher if the psychedelic was taken with therapeutic planning and intent. Emotional breakthrough, Mystical Experience Questionnaire and Challenging Experience Questionnaire scores combined, significantly predicted subsequent changes in well-being (r=0.45, p=0.0005, n=75), with each scale contributing significant predictive value. Emotional breakthrough and Mystical Experience Questionnaire scores predicted increases in well-being and Challenging Experience Questionnaire scores predicted less increases.
Conclusions:
Here we validate a six-item ‘Emotional Breakthrough Inventory’. Emotional breakthrough is an important and distinct component of the acute psychedelic experience that appears to be a key mediator of subsequent longer-term psychological changes. Implications for psychedelic therapy are discussed.
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.
Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.
Psychedelic drugs are making waves as modern trials support their therapeutic potential and various media continue to pique public interest. In this opinion piece, we draw attention to a long-recognised component of the psychedelic treatment model, namely ‘set’ and ‘setting’ – subsumed here under the umbrella term ‘context’. We highlight: (a) the pharmacological mechanisms of classic psychedelics (5-HT2A receptor agonism and associated plasticity) that we believe render their effects exceptionally sensitive to context, (b) a study design for testing assumptions regarding positive interactions between psychedelics and context, and (c) new findings from our group regarding contextual determinants of the quality of a psychedelic experience and how acute experience predicts subsequent long-term mental health outcomes. We hope that this article can: (a) inform on good practice in psychedelic research, (b) provide a roadmap for optimising treatment models, and (c) help tackle unhelpful stigma still surrounding these compounds, while developing an evidence base for long-held assumptions about the critical importance of context in relation to psychedelic use that can help minimise harms and maximise potential benefits.
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.
Trial Registration: ISRCTN, number ISRCTN14426797, http://www.isrctn.com/ISRCTN14426797
The classical psychedelic drugs, including psilocybin, lysergic acid diethylamide and mescaline, were used extensively in psychiatry before they were placed in Schedule I of the UN Convention on Drugs in 1967. Experimentation and clinical trials undertaken prior to legal sanction suggest that they are not helpful for those with established psychotic disorders and should be avoided in those liable to develop them. However, those with so-called 'psychoneurotic' disorders sometimes benefited considerably from their tendency to 'loosen' otherwise fixed, maladaptive patterns of cognition and behaviour, particularly when given in a supportive, therapeutic setting. Pre-prohibition studies in this area were sub-optimal, although a recent systematic review in unipolar mood disorder and a meta-analysis in alcoholism have both suggested efficacy. The incidence of serious adverse events appears to be low. Since 2006, there have been several pilot trials and randomised controlled trials using psychedelics (mostly psilocybin) in various non-psychotic psychiatric disorders. These have provided encouraging results that provide initial evidence of safety and efficacy, however the regulatory and legal hurdles to licensing psychedelics as medicines are formidable. This paper summarises clinical trials using psychedelics pre and post prohibition, discusses the methodological challenges of performing good quality trials in this area and considers a strategic approach to the legal and regulatory barriers to licensing psychedelics as a treatment in mainstream psychiatry.
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.
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 aides 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 programmes. 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 3 separate clinical trials of psilocybin for depressive symptoms. In this Circumspective piece, Robin Carhart-Harris and Guy Goodwin 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.Neuropsychopharmacology accepted article preview online, 26 April 2017. doi:10.1038/npp.2017.84.
Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes.
Trial Registration
ClinicalTrials.gov identifier: NCT00465595
Background:
Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression.
Methods:
In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks.
Results:
Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60-80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression.
Conclusions:
In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress.
Trial registration:
ClinicalTrials.gov Identifier: NCT00957359.
Background:
Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression.
Methods:
In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin's effects. Patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797.
Findings:
Psilocybin's acute psychedelic effects typically became detectable 30-60 min after dosing, peaked 2-3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0-1 scale) was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week (mean QIDS difference -11·8, 95% CI -9·15 to -14·35, p=0·002, Hedges' g=3·1) and 3 months (-9·2, 95% CI -5·69 to -12·71, p=0·003, Hedges' g=2) after high-dose treatment. Marked and sustained improvements in anxiety and anhedonia were also noted.
Interpretation:
This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach.
Funding:
Medical Research Council.
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. © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
Rationale:
Lysergic acid diethylamide (LSD) has a history of use as a psychotherapeutic aid in the treatment of mood disorders and addiction, and it was also explored as an enhancer of mind control.
Objectives:
The present study sought to test the effect of LSD on suggestibility in a modern research study.
Methods:
Ten healthy volunteers were administered with intravenous (i.v.) LSD (40-80 μg) in a within-subject placebo-controlled design. Suggestibility and cued mental imagery were assessed using the Creative Imagination Scale (CIS) and a mental imagery test (MIT). CIS and MIT items were split into two versions (A and B), balanced for 'efficacy' (i.e. A ≈ B) and counterbalanced across conditions (i.e. 50 % completed version 'A' under LSD). The MIT and CIS were issued 110 and 140 min, respectively, post-infusion, corresponding with the peak drug effects.
Results:
Volunteers gave significantly higher ratings for the CIS (p = 0.018), but not the MIT (p = 0.11), after LSD than placebo. The magnitude of suggestibility enhancement under LSD was positively correlated with trait conscientiousness measured at baseline (p = 0.0005).
Conclusions:
These results imply that the influence of suggestion is enhanced by LSD. Enhanced suggestibility under LSD may have implications for its use as an adjunct to psychotherapy, where suggestibility plays a major role. That cued imagery was unaffected by LSD implies that suggestions must be of a sufficient duration and level of detail to be enhanced by the drug. The results also imply that individuals with high trait conscientiousness are especially sensitive to the suggestibility-enhancing effects of LSD.
Anecdotal and published case reports suggest that some patients taking selective serotonin reuptake inhibitors (SSRI) experience diminution in emotional responsiveness. This study aims to define the individual components of emotion disturbed in these patients. Fifteen patients reporting SSRI-induced sexual dysfunction completed the Laukes Emotional Intensity Scale (LEIS), a questionnaire about various emotions. Compared to controls, patients reported significantly (p<0.05) less ability to cry, irritation, care about others' feelings, sadness, erotic dreaming, creativity, surprise, anger, expression of their feelings, worry over things or situations, sexual pleasure, and interest in sex. Total score on the LEIS did not correlate with total score on the Hamilton Depression Rating Scale. In our sample, 80% of patients with SSRI-induced sexual dysfunction also describe clinically significant blunting of several emotions. Emotional blunting may be an under-appreciated side-effect of SSRIs that may contribute to treatment non-compliance and/or reduced quality of life.
Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression, but the rates, timing, and baseline predictors of remission in "real world" patients are not established. The authors' primary objectives in this study were to evaluate the effectiveness of citalopram, an SSRI, using measurement-based care in actual practice, and to identify predictors of symptom remission in outpatients with major depressive disorder.
This clinical study included outpatients with major depressive disorder who were treated in 23 psychiatric and 18 primary care "real world" settings. The patients received flexible doses of citalopram prescribed by clinicians for up to 14 weeks. The clinicians were assisted by a clinical research coordinator in the application of measurement-based care, which included the routine measurement of symptoms and side effects at each treatment visit and the use of a treatment manual that described when and how to modify medication doses based on these measures. Remission was defined as an exit score of <or=7 on the 17-item Hamilton Depression Rating Scale (HAM-D) (primary outcome) or a score of <or=5 on the 16-item Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR) (secondary outcome). Response was defined as a reduction of >or=50% in baseline QIDS-SR score.
Nearly 80% of the 2,876 outpatients in the analyzed sample had chronic or recurrent major depression; most also had a number of comorbid general medical and psychiatric conditions. The mean exit citalopram dose was 41.8 mg/day. Remission rates were 28% (HAM-D) and 33% (QIDS-SR). The response rate was 47% (QIDS-SR). Patients in primary and psychiatric care settings did not differ in remission or response rates. A substantial portion of participants who achieved either response or remission at study exit did so at or after 8 weeks of treatment. Participants who were Caucasian, female, employed, or had higher levels of education or income had higher HAM-D remission rates; longer index episodes, more concurrent psychiatric disorders (especially anxiety disorders or drug abuse), more general medical disorders, and lower baseline function and quality of life were associated with lower HAM-D remission rates.
The response and remission rates in this highly generalizable sample with substantial axis I and axis III comorbidity closely resemble those seen in 8-week efficacy trials. The systematic use of easily implemented measurement-based care procedures may have assisted in achieving these results.
There has recently been a renewal of human research with classical hallucinogens (psychedelics). This paper first briefly discusses the unique history of human hallucinogen research, and then reviews the risks of hallucinogen administration and safeguards for minimizing these risks. Although hallucinogens are relatively safe physiologically and are not considered drugs of dependence, their administration involves unique psychological risks. The most likely risk is overwhelming distress during drug action ('bad trip'), which could lead to potentially dangerous behaviour such as leaving the study site. Less common are prolonged psychoses triggered by hallucinogens. Safeguards against these risks include the exclusion of volunteers with personal or family history of psychotic disorders or other severe psychiatric disorders, establishing trust and rapport between session monitors and volunteer before the session, careful volunteer preparation, a safe physical session environment and interpersonal support from at least two study monitors during the session. Investigators should probe for the relatively rare hallucinogen persisting perception disorder in follow-up contact. Persisting adverse reactions are rare when research is conducted along these guidelines. Incautious research may jeopardize participant safety and future research. However, carefully conducted research may inform the treatment of psychiatric disorders, and may lead to advances in basic science.
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.
Major depression is a common illness that severely limits psychosocial functioning and diminishes quality of life. In 2008, WHO ranked major depression as the third cause of burden of disease worldwide and projected that the disease will rank first by 2030. 1 WHO
The global burden of disease: 2004 update. World Health Organization, Geneva 2008
• Google Scholar
In practice, its detection, diagnosis, and management often pose challenges for clinicians because of its various presentations, unpredictable course and prognosis, and variable response to treatment.
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.
Background and Aims
Escitalopram has widely been recognized as one of the most frequently used antidepressants, with superior tolerability and great efficacy in preventing major depressive disorder (MDD) relapse and recurrence. However, anhedonia, which is a core symptom of MDD, remains difficult to treat. This study investigates the hedonic levels of MDD patients treated with Escitalopram.
Materials and Methods
A total of 108 participants, 26 of whom with MDD on Escitalopram, were recruited in this cross sectional study. They were evaluated using the Snaith-Hamilton Pleasure Scale (SHAPS) and Beck Depression Inventory (BDI) questionnaires to assess their hedonic state, general mental health condition and level of depression.
Results
Our study shows that most items in the SHAPS scores are significantly different between MDD patients on Escitalopram and the controls.
Conclusions
The hedonic capacity remains different between the two groups despite patients with MDD are put on Escitalopram treatment. Escitalopram fails to alleviate the hedonic state of MDD patients. Antidepressants that improve both depressive symptoms and hedonic states should be considered when treating MDD patients in clinical settings
Background and Aims
Escitalopram has widely been recognized as one of the most frequently used antidepressants, with superior tolerability and great efficacy in preventing major depressive disorder (MDD) relapse and recurrence. However, anhedonia, which is a core symptom of MDD, remains difficult to treat. This study investigates the hedonic levels of MDD patients treated with Escitalopram.
Materials and Methods
A total of 108 participants, 26 of whom with MDD on Escitalopram, were recruited in this cross sectional study. They were evaluated using the Snaith-Hamilton Pleasure Scale (SHAPS) and Beck Depression Inventory (BDI) questionnaires to assess their hedonic state, general mental health condition and level of depression.
Results
Our study shows that most items in the SHAPS scores are significantly different between MDD patients on Escitalopram and the controls.
Conclusions
The hedonic capacity remains different between the two groups despite patients with MDD are put on Escitalopram treatment. Escitalopram fails to alleviate the hedonic state of MDD patients. Antidepressants that improve both depressive symptoms and hedonic states should be considered when treating MDD patients in clinical settings
Psilocybin is a well-characterized classic hallucinogen (psychedelic) with a long history of religious use by indigenous cultures, and nonmedical use in modern societies. Although psilocybin is structurally related to migraine medications, and case studies suggest that psilocybin may be efficacious in treatment of cluster headache, little is known about the relationship between psilocybin and headache.
This double-blind study examined a broad range of psilocybin doses (0, 5, 10, 20, and 30 mg/70 kg) on headache in 18 healthy participants.
Psilocybin frequently caused headache, the incidence, duration, and severity of which increased in a dose-dependent manner. All headaches had delayed onset, were transient, and lasted no more than a day after psilocybin administration.
Possible mechanisms for these observations are discussed, and include induction of delayed headache through nitric oxide release. These data suggest that headache is an adverse event to be expected with the nonmedical use of psilocybin-containing mushrooms as well as the administration of psilocybin in human research. Headaches were neither severe nor disabling, and should not present a barrier to future psilocybin research.
Background:
Although pharmacological and psychological interventions are both effective for major depression, antidepressant drugs remain the mainstay of treatment in primary and secondary care settings. During the last 20 years, antidepressant prescribing has risen dramatically in western countries, mainly because of the increasing consumption of selective serotonin reuptake inhibitors (SSRIs) and newer antidepressants, which have progressively become the most commonly prescribed antidepressants. Escitalopram is the pure S-enantiomer of the racemic citalopram.
Objectives:
To assess the evidence for the efficacy, acceptability and tolerability of escitalopram in comparison with tricyclics, other SSRIs, heterocyclics and newer agents in the acute-phase treatment of major depression.
Search strategy:
Electronic databases were searched up to July 2008. Trial databases of drug-approving agencies were hand-searched for published, unpublished and ongoing controlled trials.
Selection criteria:
All randomised controlled trials comparing escitalopram against any other antidepressant (including non-conventional agents such as hypericum) for patients with major depressive disorder (regardless of the diagnostic criteria used).
Data collection and analysis:
Data were entered by two review authors (double data entry). Responders and remitters to treatment were calculated on an intention-to-treat basis. For dichotomous data, odds ratios (ORs) were calculated with 95% confidence intervals (CI). Continuous data were analysed using standardised mean differences (with 95% CI) using the random effects model.
Main results:
Fourteen trials compared escitalopram with another SSRI and eight compared escitalopram with a newer antidepressive agent (venlafaxine, bupropion and duloxetine). Escitalopram was shown to be significantly more effective than citalopram in achieving acute response (OR 0.67, 95% CI 0.50 to 0.87). Escitalopram was also more effective than citalopram in terms of remission (OR 0.53, 95% CI 0.30 to 0.93). Significantly fewer patients allocated to escitalopram withdrew from trials compared with patients allocated to duloxetine, for discontinuation due to any cause (OR 0.62, 95% CI 0.38 to 0.99).
Authors' conclusions:
Some statistically significant differences favouring escitalopram over other antidepressive agents for the acute phase treatment of major depression were found, in terms of efficacy (citalopram and fluoxetine) and acceptability (duloxetine). There is insufficient evidence to detect a difference between escitalopram and other antidepressants in early response to treatment (after two weeks of treatment). Cost-effectiveness information is also needed in the field of antidepressant trials. Furthermore, as with most standard systematic reviews, the findings rely on evidence from direct comparisons. The potential for overestimation of treatment effect due to sponsorship bias should also be borne in mind.
The construct of experiential avoidance has become more frequently used by clinical researchers. Experiential avoidance involves the unwillingness to remain in contact with private experiences such as painful thoughts and emotions and is often proposed to be critical to the development and maintenance of psychopathology. This review summarizes the empirical studies on experiential avoidance as a factor in the etiology of maladaptive behavior and its relationship to specific diagnostic categories. Although some of the current literature suggests that experiential avoidance may be implicated in various forms of psychopathology, a fundamental limitation of this research is the lack of theoretical integration and refinement with regard to operationalizing and assessing experiential avoidance. Future studies should attempt to understand the core processes involved in experiential avoidance better, and then clearly operationalize the construct and determine its incremental validity relative to other constructs.
- G S Malhi
- J J Mann
Malhi GS, Mann JJ. Depression. Lancet 2018; 392: 2299-312.
- D E Nichols
- Psychedelics
Nichols DE. Psychedelics. Pharmacol
Rev 2016; 68: 264-355.