JAMA
August 31, 2023
Charles L. Raison, Gerard Sanacora, Joshua Woolley et al.
493 citations
A single 25-mg dose of synthetic psilocybin, administered with psychological support, produced a clinically significant and sustained reduction in depressive symptoms and functional disability over 43 days in adults with major depressive disorder. In a phase 2 trial of 104 participants, those receiving psilocybin showed a mean 12.3-point greater improvement on the Montgomery-Asberg Depression Rating Scale at day 43 compared with those receiving a niacin placebo. Psilocybin also improved daily functioning and led to more sustained response, though not remission. No serious adverse events occurred, but psilocybin was associated with more overall and severe adverse events.
Frontiers in Human Neuroscience
January 1, 2012
Gaelle Desbordes, Lobsang Negi, Thaddeus W W Pace et al.
445 citations
Eight weeks of mindfulness meditation training reduced right amygdala activation in healthy adults when viewing positive emotional images, even when they were not actively meditating. A compassion-based meditation program showed a trend toward increased right amygdala response to negative images, which correlated with lower depression scores. No changes occurred in a control group. The results suggest meditation training can alter emotional processing in the brain during ordinary, non-meditative states, indicating that such training may produce lasting, process-specific changes in mental function rather than only task-specific effects.
Nature
August 1, 2024
Joshua S. Siegel, Subha Subramanian, Demetrius Perry et al.
241 citations
A single high dose of psilocybin (25 mg) massively disrupts functional connectivity in the human brain, causing more than threefold greater change than methylphenidate (40 mg). These changes are driven by desynchronization across spatial scales, dissolving network distinctions by reducing correlations within and anticorrelations between networks. The strongest effects occur in the default mode network, which is connected to the anterior hippocampus and is thought to create the sense of space, time, and self. Individual differences in connectivity changes are strongly linked to the subjective psychedelic experience. A persistent decrease in connectivity between the anterior hippocampus and default mode network lasts for weeks, suggesting a neuroanatomical correlate of the therapeutic and proplasticity effects of psychedelics.
Psychiatry Research
January 2, 2020
Simon B. Goldberg, Brian T. Pace, Christopher R. Nicholas et al.
234 citations
A meta-analysis of four studies (three randomized, placebo-controlled; one uncontrolled) with 117 participants found that psilocybin combined with behavioral interventions produced large reductions in anxiety and depression among people with elevated symptoms. Within-group effects from before treatment to after treatment and at follow-up were large (Hedges' g = 1.16 to 1.47) and statistically significant. Across the placebo-controlled studies, the pre-post effects compared to placebo were also large (g = 0.82 to 0.83) and statistically significant. No serious adverse events were reported. The results tentatively support further research on psilocybin for anxiety and depression, though the small number of studies and potential bias limit confidence.
Social Cognitive and Affective Neuroscience
September 5, 2012
Jennifer S Mascaro, James K. Rilling, Lobsang Tenzin Negi et al.
225 citations
A randomized controlled trial tested whether an eight-week compassion meditation program (cognitive-based compassion training, CBCT) improves the ability to infer others' mental states from facial expressions. Twenty-one healthy adults completed the Reading the Mind in the Eyes Test during fMRI scans before and after either CBCT or a health discussion control group. Those who completed CBCT showed significantly greater improvement in empathic accuracy scores and increased brain activity in the inferior frontal gyrus and dorsomedial prefrontal cortex compared to controls. Changes in these brain regions correlated with changes in empathic accuracy. The findings suggest CBCT may enhance empathic accuracy and its underlying neural mechanisms.
JAMA Psychiatry
July 1, 2023
Roman Palitsky, Deanna M Kaplan, Caroline Peacock et al.
86 citations
Spiritual, existential, religious, and theological components are important in psychedelic-assisted therapy, but they have not been systematically integrated into clinical practice. Research shows that spiritually integrated psychotherapies are effective and produce additional benefits on spiritually relevant outcomes, which are particularly relevant to psychedelic therapy. Established standards in spiritually integrated psychotherapy can be applied to psychedelic-assisted therapy. Integrating these topics is needed for culturally competent, evidence-based treatment aligned with high clinical standards, and neglecting them may undermine treatment success and increase risks for patients.
Frontiers in Psychiatry
January 1, 2022
Charles L. Raison, Rakesh Jain, Andrew Penn et al.
75 citations
In a large online survey of 2,510 adults who had used psychedelics at least once, psychedelic use was linked to significant improvements in depression, anxiety, and emotional well-being. The benefits grew with more use but showed a ceiling effect; even a single use was associated with improvements. No single psychedelic agent proved clearly superior, but increases in mystical experiences and prosocial perspective-taking were tied to better mental health. However, 13% of participants (330 people) reported at least one harm from psychedelic use, and those individuals experienced less mental health benefit. The findings suggest that naturalistic psychedelic use may offer mental health benefits similar to those in clinical trials, while also posing some risk of harm for a minority.
Psychological Medicine
November 4, 2020
Simon B. Goldberg, Benjamin Shechet, Christopher R. Nicholas et al.
66 citations
Classical psychedelics such as psilocybin, ayahuasca, and LSD produce significant psychological effects lasting at least 24 hours after administration, according to a systematic review and meta-analysis of 34 experimental studies involving 549 participants. Large effects were observed for reducing targeted symptoms in psychiatric samples, improving negative and positive affect, social outcomes, and existential or spiritual well-being, with between-group effect sizes ranging from Hedges' g = 0.84 to 1.08. Effects may be larger in clinical samples. Evidence for changes in personality traits or mindfulness was weak. No post-acute adverse effects were found, but high risk of bias, heterogeneity, and possible publication bias underscore the need for larger, placebo-controlled trials.
Journal of Psychopharmacology
July 31, 2024
Roman Palitsky, Deanna M Kaplan, John Perna et al.
32 citations
A multidisciplinary working group identified 54 potential adverse events that warrant systematic assessment in psychedelic-assisted therapies, finding that existing measurement tools substantially fail to cover these constructs. The group developed recommendations for when and how to assess these adverse events across preparation, dosing, integration, and follow-up phases, and demonstrated a preliminary assessment protocol. The framework addresses the need to capture post-acute dosing adverse events, accounting for both the pharmacotherapy and psychotherapy components of psychedelic-assisted therapy, as well as documented impacts on worldviews and spirituality.
PLoS One
January 2, 2024
Caroline Peacock, Erin Brauer, Ali John Zarrabi et al.
27 citations
Spiritual health practitioners bring unique expertise to psychedelic-assisted therapy based on their training and professional experience. Interviews with 15 such practitioners revealed seven themes in two domains: unique contributions (competency with spiritual material, awareness of power dynamics, familiarity with non-ordinary states, holding space, counterbalancing biomedical perspectives) and general contributions (using general therapeutic skills and supporting interdisciplinary collaboration). Their skills complement other clinical team members, and psychedelic-assisted therapy teams may benefit from including them. Further work is needed to define roles, qualifications, and training for these clinicians.
Frontiers in Psychiatry
November 29, 2022
Ana María Ortiz Bernal, Charles L. Raison, Rafael Lancelotta et al.
26 citations
Reactivations—similar to flashbacks—are common after using the psychedelic 5-MeO-DMT and are often neutral or positive rather than distressing. Analysis of survey data from 513 people who used 5-MeO-DMT outside clinical settings found that women, older age at first dose, higher education, and dosing in a structured group setting were linked to higher odds of reporting a reactivation. Higher mystical experience scores, greater personal wellbeing, and having had a non-substance-induced non-dual awareness experience were associated with neutral or positive emotional valence of the reactivation. The findings suggest reactivations are typically a benign byproduct of the experience, but more research is needed to identify those at risk for negative reactivations.
JAMA Psychiatry
January 1, 2023
Brian D Kiluk, Bethea A Kleykamp, Sandra D Comer et al.
22 citations
A review sponsored by a public-private partnership addresses clinical trial design for new opioid use disorder (OUD) treatments that target systems other than the μ-opioid receptor. The authors present consensus recommendations for evaluating novel therapies such as cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics. Key design elements include specifying the treatment stage (e.g., early abstinence, long-term recovery), defining the treatment's role (adjunctive or independent), selecting patient-informed primary outcomes that assess opioid use patterns, retention, and quality of life, and monitoring adverse events like relapse or overdose, especially when patients are not on maintenance opioid agonist or antagonist medications. Incorporating input from people with lived experience is urged to accelerate development and uptake of effective therapeutics.
JAMA Psychiatry
April 27, 2022
Mazdak M. Bradberry, Natalie Gukasyan, Charles L. Raison
20 citations
No Summary
medRxiv
August 24, 2023
Subha Subramanian, Demetrius Perry, Caterina Gratton et al.
14 citations
preprint
Psilocybin disrupts connectivity across cortical networks and subcortical structures, producing more than three-fold greater acute changes in functional networks than methylphenidate. These changes are driven by desynchronization of brain activity across spatial scales, strongest in the default mode network (DMN), which is connected to the anterior hippocampus and thought to create our sense of self. Performing a perceptual task reduces psilocybin-induced network changes, suggesting a neurobiological basis for grounding during psychedelic therapy. Psilocybin induces a persistent decrease in functional connectivity between the anterior hippocampus and cortex (and DMN in particular), lasting for weeks but normalizing after six months. This persistent suppression of hippocampal-DMN connectivity represents a candidate neuroanatomical and mechanistic correlate for psilocybin's pro-plasticity and anti-depressant effects.
Psychotherapy
January 13, 2025
Roman Palitsky, Jessica L Maples-Keller, Caroline Peacock et al.
13 citations
In an open-label trial of psilocybin-assisted therapy for cancer-related demoralization and chronic pain, patients, facilitators, and caregivers identified key components and improvements for the treatment protocol. Using the Enhanced Critical Incident Technique, interviews revealed critical incidents, wish list items, and contributing factors related to therapy aspects like intention-setting and overall protocol transitions. The findings emphasize tailoring treatment to individual medical history, supporting common therapeutic factors, and ensuring collaborative care. Nine topic areas for protocol improvement emerged from the data.
Translational Psychiatry
September 12, 2024
Christopher R. Nicholas, Matthew I Banks, Richard C Lennertz et al.
10 citations
Psilocybin, a serotonergic psychedelic, can relieve symptoms in several psychiatric disorders and improve well-being, but it was unclear whether these benefits arise during the acute experience or depend on later memory of it. In 8 healthy participants, psilocybin (25 mg) was co-administered with the amnestic benzodiazepine midazolam at a dose that allowed a conscious psychedelic experience while partially impairing memory for it. Higher midazolam doses and greater memory impairment tended to associate with lower salience, insight, and well-being from psilocybin. These results suggest memory plays a role in therapeutically relevant behavioral effects of psilocybin.
Psychedelic medicine (New Rochelle, N.Y.)
September 1, 2023
Zachary Herrmann, Adam W. Levin, Steven P Cole et al.
9 citations
Among 228 healthcare providers who treat psychiatric disorders with medications and reported at least one lifetime psychedelic use, retrospective measures showed improvements in depression, anxiety, and well-being after psychedelic exposure. Suicidality decreased and resilience increased. A factor analysis indicated that a cluster of mystical, interpersonal, and personal experiences predicted these improvements. The preferred psychedelic agent did not affect outcomes, and frequency of use was not associated with outcomes, though effect sizes varied. Harm was reported by 13.2% (n = 30), consistent with general population rates. Pre-exposure alcohol use, aggressive impulses, and desire to die by suicide improved most often, while marijuana use most often worsened or did not change.
International review of psychiatry (Abingdon, England)
December 1, 2024
Roman Palitsky, Nicholas K. Canby, Nicholas T. van Dam et al.
6 citations
Research on adverse effects (AEs) of psychedelics has been limited, leading to underspecified profiles and potential undercounting. This article argues that meditation-related AE research, which shares phenomenological and contextual features with psychedelic AEs, offers valuable insights. An integrative review of both fields is presented, recommending that meditation AEs serve as a comparator condition. The authors propose adopting detailed, comprehensive, user-informed, impact-based, standardized, unbiased, and representative measures of AEs, along with examining factors that influence their impacts and trajectories, to advance psychedelic AE research.
Journal of Psychiatric Practice
September 1, 2023
Amir Garakani, Jeanne L Alexander, Calvin R Sumner et al.
6 citations
Public and clinical interest in psychedelics is growing, with many studies underway for depression, anxiety, PTSD, and substance use disorders. This paper focuses on psilocybin, explaining its mechanism, psychedelic effects, and dosing. It reviews treatment studies, primarily for treatment-resistant depression and cancer-related anxiety, and discusses future directions and potential limitations in studying and regulating psilocybin and other psychedelics.
npj Mental Health Research
February 7, 2025
Ari Brouwer, Joshua K Brown, Earth Erowid et al.
5 citations
Psychedelic therapy may work partly because of an overlooked temporal pattern: the initial 'come-up' phase often feels like an acute stress reaction, while the later 'come-down' phase brings positive feelings similar to recovery from illness or stress. A qualitative analysis of psilocybin experience reports from Erowid.org, using phenomenological, thematic content, and word frequency analysis, shows that negatively valenced states dominate the onset, and positively valenced states dominate the falling phase. This pattern helps explain how initially distressing altered states can ultimately resolve distress, with implications for therapeutic and theoretical understanding of psychedelic treatment.
Psychedelics.
September 13, 2024
Syed F. Rab, Charles L. Raison, Elliot Marseille
5 citations
Between 24% and 62% of U.S. patients with major depressive disorder or treatment-resistant depression may be eligible for psilocybin-assisted therapy, depending on how strictly exclusion criteria are applied. The lower estimate uses stringent criteria from clinical trials; the mid-range (56%) reflects likely real-world scenarios; the upper bound (62%) accounts for patients with multiple comorbidities. The main reason for ineligibility is disqualifying conditions such as alcohol and substance use disorders. Actual demand will also depend on insurance coverage, state regulations, and availability of trained providers, highlighting the need for careful policy planning.
Pharmacology Research & Perspectives
August 1, 2024
Ari Brouwer, Robin Carhart-Harris, Charles L. Raison
5 citations
Psychotomimetic drugs—such as amphetamines, cannabis, psychedelics, and dissociatives—can paradoxically relieve symptoms like attention deficits, pain, and depression, which themselves increase the risk of psychosis or co-occur with it. The authors propose two concepts to explain this paradox. Psychotomimetic compensation describes a short-term, drug-induced relief from stress, mediated by neurotransmitter systems including endocannabinoid, serotonergic, glutamatergic, and dopaminergic pathways. Psychotomimetic sensitization occurs after repeated stress or drug exposure, gradually intensifying psychotic-like experiences over time. The model has theoretical and practical implications.
Research Square (Research Square)
February 23, 2024
Ari Brouwer, Joshua K. Brown, Earth Erowid et al.
5 citations
Psychedelic therapy may work partly because its temporal structure mirrors the narrative arc of the Hero's Journey. A qualitative analysis of self-reported onset (comeup) and offset (comedown) phases of psilocybin experiences found that the comeup is more often characterized by negatively valenced feeling states, while the comedown is more often characterized by positively valenced feeling states resembling recovery from illness or adversity. This trajectory suggests that initially distressing altered states can ultimately resolve distress, offering a framework for understanding the therapeutic benefits of psychedelics.
March 5, 2024
Roman Palitsky, Deanna M Kaplan, John Perna et al.
4 citations
preprint
A multidisciplinary working group identified 53 potential adverse events (AEs) specific to psychedelic-assisted therapies (PATs) that current assessment tools miss. Existing measures cover only a fraction of these constructs. The group recommends new assessment methods—including patient, clinician, and informant reports—and specifies when to measure AEs across preparation, dosing, integration, and follow-up phases. The framework addresses gaps in capturing post-acute dosing effects, including changes in worldview and spirituality, which distinguish PAT from other treatments.
Religion Brain & Behavior
July 11, 2024
Ari Brouwer, Charles L. Raison, F. Leron Shults
3 citations
A theory-building paper compares the trajectory of psilocybin mushroom experiences—aversive comeup, awe-inspiring peak, relief and clarity in the comedown—with spiritual and incipient psychotic experiences. It argues that these shared trajectories inform cognitive scientific perspectives on religion. The authors propose a causal pathway where stress, uncertainty, and arousal increase perception of extra agency (PEA), which may lead either to states that downregulate PEA or to states that perpetuate it. Religions could modulate this pathway to promote social cohesion. The paper emphasizes the need for phenomenological nuance when comparing psychedelic, spiritual, and psychotic experiences.