JAMA Psychiatry
November 4, 2020
Mary P Cosimano, Alan K. Davis, Frederick S. Barrett et al.
1,269 citations
Two doses of psilocybin (20 and 30 mg per 70 kg) combined with supportive psychotherapy produced large, rapid antidepressant effects in adults with major depressive disorder who were not taking other antidepressants. In a randomized waiting list-controlled trial with 24 completers, depression scores on the GRID-Hamilton scale dropped from a mean of 22.8 at baseline to 8.0 one week after the second session, compared with 23.8 at the same time point in the delayed-treatment group. Seventy-one percent of participants showed a clinically significant response at week 1, and 58% met remission criteria. Effects persisted through the four-week follow-up.
Journal of Psychopharmacology
October 6, 2015
Frederick S. Barrett, Matthew W Johnson, Roland R. Griffiths
634 citations
The 30-item revised Mystical Experience Questionnaire (MEQ30) is validated using data from five controlled laboratory experiments with psilocybin. Participants (n=184) received a moderate to high oral dose of psilocybin (at least 20 mg/70 kg). Confirmatory factor analysis shows the MEQ30 is reliable and internally valid. Structural equation models demonstrate external and convergent validity: latent variable scores on the MEQ30 positively predict persisting changes in attitudes, behavior, and well-being attributed to psilocybin experiences, beyond the participant-rated intensity of drug effects. The findings support the MEQ30 as an efficient measure of individual mystical experiences. A method to score a "complete mystical experience" from previous versions is validated, and a stand-alone MEQ30 is provided.
Journal of Psychopharmacology
August 31, 2016
Theresa M. Carbonaro, Matthew P. Bradstreet, Frederick S. Barrett et al.
541 citations
In a survey of 1,993 people who recalled their worst 'bad trip' after taking psilocybin mushrooms, 39% ranked it among the top five most challenging experiences of their lives. Eleven percent put themselves or others at risk of physical harm, with factors such as higher dose, longer duration, and lack of physical comfort or social support increasing that risk. About 2.6% acted aggressively and 2.7% needed medical help. Among those whose experience was more than a year prior, 7.6% sought treatment for lasting psychological symptoms, with three cases linked to enduring psychotic symptoms and three to attempted suicide. Despite difficulties, 84% reported benefiting from the experience. The incidence of risky behavior or lasting distress is very low when psilocybin is given in controlled laboratory settings.
Journal of Psychopharmacology
October 11, 2017
Roland R. Griffiths, Matthew W. Johnson, William A. Richards et al.
528 citations
A double-blind trial compared a high dose of psilocybin (20 and 30 mg/70 kg) with a very low dose (1 mg/70 kg) in healthy adults who also undertook a program of meditation and spiritual practices. At six months, the high-dose groups, compared with the low-dose group, showed large, significant positive changes in interpersonal closeness, gratitude, life meaning, forgiveness, death transcendence, daily spiritual experiences, religious faith and coping, and community observer ratings. The enduring trait-level increases in prosocial attitudes and healthy psychological functioning were linked to the mystical-type experience occasioned by psilocybin and the rate of meditation or spiritual practices.
Pharmacology & Therapeutics
May 1, 2019
Matthew W Johnson, Peter S. Hendricks, Frederick S. Barrett et al.
520 citations
Classic psychedelics like LSD, mescaline, and psilocybin are serotonin 2A receptor agonists with a long history of sacramental use and a resurgence in research. Epidemiological studies suggest naturalistic nonmedical use may be linked to positive mental health and prosocial outcomes, though some individuals are harmed in unsupervised settings. Recent therapeutic studies indicate efficacy in treating psychological distress from life-threatening diseases, depression, and nicotine and alcohol addictions. These compounds fairly reliably occasion mystical experiences, which are associated with improved psychological outcomes in healthy volunteers and patients. Neuroimaging studies reveal neurobiological mechanisms, broadening understanding of the brain, serotonin system, and consciousness. Overall, classic psychedelics show strong therapeutic potential and as tools for investigating mystical experiences and brain function.
Journal of Psychopharmacology
February 1, 2022
Natalie Gukasyan, Alan K. Davis, Frederick S. Barrett et al.
419 citations
In patients with moderate to severe major depressive disorder, psilocybin-assisted therapy produced large and sustained decreases in depression severity through 12 months. Scores on the GRID-Hamilton Depression Rating Scale dropped substantially from baseline at 1, 3, 6, and 12 months (effect sizes of 2.3, 2.0, 2.6, and 2.4, respectively). At 12 months, 75% of participants showed a 50% or greater reduction in symptoms and 58% achieved remission. No serious adverse events linked to psilocybin occurred during long-term follow-up, and no participants used psilocybin outside the study. Ratings of personal meaning, spiritual experience, and mystical experience after sessions predicted greater well-being at 12 months but did not predict depression improvement.
Scientific Reports
February 10, 2020
Frederick S. Barrett, Manoj K. Doss, Nathan D. Sepeda et al.
375 citations
A single 25 mg/70 kg dose of psilocybin temporarily reduced negative affect and amygdala response to negative facial expressions one week later in twelve healthy volunteers, while positive affect and prefrontal cortex responses to emotional conflict increased. One month later, negative affect and amygdala reactivity returned to baseline, but positive affect remained elevated and trait anxiety was lower. The number of resting-state functional connections across the brain increased from baseline to both one week and one month after dosing. These preliminary findings suggest psilocybin may enhance emotional and brain plasticity, with negative affect as a potential therapeutic target.
Journal of Contextual Behavioral Science
January 1, 2020
Alan K. Davis, Frederick S. Barrett, Roland R. Griffiths
369 citations
Acute subjective effects of psychedelics, particularly mystical and insightful experiences, are linked to reductions in depression and anxiety. In a cross-sectional survey of 985 people who had used a psychedelic, increases in psychological flexibility fully mediated the relationship between these acute effects and decreases in depression and anxiety. This suggests that psychological flexibility may be a key mechanism through which psychedelics produce therapeutic benefits. Future prospective studies are needed to test this directly.
Journal of Psychopharmacology
November 18, 2016
Frederick S. Barrett, Matthew P. Bradstreet, Jeannie‐marie Leoutsakos et al.
364 citations
A questionnaire was developed and validated to measure challenging psychological reactions to the hallucinogen psilocybin, often called 'bad trips.' Seven factors emerged: grief, fear, death, insanity, isolation, physical distress, and paranoia. These factors were linked to how difficult, meaningful, spiritually significant, and impactful on well-being participants rated their experiences. The factor structure was consistent regardless of gender or prior struggles with anxiety or depression. The questionnaire offers a tool for studying predictors and outcomes of such challenging experiences.
Translational Psychiatry
November 8, 2021
Manoj K. Doss, Michal Považan, Monica D Rosenberg et al.
343 citations
Psilocybin therapy increased cognitive flexibility for at least four weeks in 24 patients with major depressive disorder, though these improvements were not linked to antidepressant effects. One week after treatment, glutamate and N-acetylaspartate concentrations decreased in the anterior cingulate cortex (ACC), and functional connectivity dynamics increased between the ACC and posterior cingulate cortex. Surprisingly, larger increases in this neural flexibility were associated with smaller gains in cognitive flexibility. Baseline brain connectivity from the ACC predicted cognitive flexibility improvements, with greater baseline connectivity linked to better baseline flexibility but less improvement. The findings suggest that while some increase in neural dynamics may help shift from rigid states, larger persisting increases may be less beneficial.
Curr Top Behav Neurosci
January 1, 2018
Frederick S. Barrett, Roland R. Griffiths
268 citations
Mystical-type experiences, historically linked to classic hallucinogens, can be reliably measured with a validated questionnaire. Under double-blind conditions controlling for expectancy, psilocybin produces complete mystical experiences in most people, with effects that are dose-dependent and specific compared to placebo or an active control. These experiences have lasting positive impacts on mood, attitudes, and behavior, as reported by participants and community observers. In healthy volunteers, they generate enduring personal meaning; in patients, they are associated with reduced substance abuse and decreased anxiety and depression, including in those with life-threatening cancer. Parallels in brain activity between hallucinogens and meditative practices suggest a neural model based on changes in the default mode network.
Brain
October 22, 2021
Manoj K. Doss, Maxwell B. Madden, Andrew Gaddis et al.
196 citations
Classic psychedelic drugs like psilocybin and LSD may help treat psychiatric disorders by altering brain circuits. Two existing models—the cortico-striatal thalamo-cortical (CSTC) model and the relaxed beliefs under psychedelics (REBUS) model—highlight different subcortical structures in mediating these effects. This paper introduces a third circuit-level model, the cortico-claustro-cortical (CCC) model, focusing on the claustrum, a thin strip of grey matter that densely expresses serotonin 2A receptors. The CCC model proposes that the claustrum entrains canonical cortical network states, and psychedelic drugs disrupt 5-HT2A-mediated coupling between claustrum and cortex, attenuating these networks. Together, the three models may explain many phenomena of the psychedelic experience.
Neuroimage
September 1, 2020
Frederick S. Barrett, Samuel R Krimmel, Roland R. Griffiths et al.
191 citations
Psilocybin, a serotonin 2A receptor partial agonist, alters claustrum function in humans. In 15 healthy participants, psilocybin decreased the amplitude of low-frequency fluctuations and variance of BOLD signal in the left and right claustrum. It also changed functional connectivity: right claustrum connectivity with auditory and default mode networks decreased, while connectivity with the fronto-parietal task control network increased; left claustrum connectivity with the fronto-parietal task control network decreased. Subjective effects predicted these neural changes. The findings provide the first empirical evidence that 5-HT2A receptor signaling significantly modulates claustrum activity, suggesting a role for the claustrum in psilocybin's subjective and therapeutic effects.
Journal of Psychopharmacology
January 9, 2021
Alan K. Davis, Frederick S. Barrett, Sara So et al.
166 citations
A new questionnaire, the Psychological Insight Questionnaire, was developed to measure psychologically insightful experiences during psychedelic use. Among 1,661 psilocybin and LSD users, the 23-item measure showed two subscales: Avoidance and Maladaptive Patterns Insights and Goals and Adaptive Patterns Insights. Scores correlated strongly with an existing insight measure and moderately with mystical and challenging experience questionnaires. They also correlated with retrospectively reported increases in psychological flexibility, well-being, and life satisfaction attributed to a memorable psychedelic experience. The questionnaire predicted unique variance in these outcomes beyond mystical and challenging effects, suggesting it may help understand how psychological insight contributes to psychedelics' enduring effects.
Eur Neuropsychopharmacol
April 12, 2016
Mendel Kaelen, Leor Roseman, Joshua Kahan et al.
143 citations
Psychedelic drugs like LSD are being re-examined for therapeutic use, often combined with music during psychotherapy. In a placebo-controlled fMRI study with 12 healthy volunteers, researchers investigated how LSD and music together affect mental imagery. They found that the combination of LSD and music increased functional connectivity and information flow from the parahippocampal cortex to the visual cortex. This enhanced connectivity correlated with stronger eyes-closed visual imagery, including autobiographical imagery. The findings suggest a neural mechanism by which music and LSD synergistically enhance subjective experiences that may be valuable in therapeutic settings.
Psychopharmacology
October 1, 2018
Frederick S. Barrett, Theresa M. Carbonaro, Ethan Hurwitz et al.
109 citations
Classic psychedelics and dissociative hallucinogens may share some neuropsychological effects despite different pharmacology. In a double-blind, placebo-controlled study, 20 hallucinogen users received 10, 20, and 30 mg/70 kg psilocybin, 400 mg/70 kg dextromethorphan (DXM), and placebo across five sessions. Neither drug caused global cognitive impairment. Psilocybin produced dose-dependent effects on psychomotor performance, working memory, episodic memory, associative learning, and visual perception. DXM affected psychomotor performance, visual perception, and associative learning similarly to moderate-to-high psilocybin doses. Psilocybin affected working memory more than DXM, while DXM had greater effects on balance, episodic memory, response inhibition, and executive control.
Journal of Psychopharmacology
February 20, 2021
Albert Garcia‐romeu, Frederick S. Barrett, Theresa M. Carbonaro et al.
101 citations
Psilocybin, a naturally occurring psychedelic, shows promise for treating mood and substance use disorders when given in structured settings. Most trials have adjusted the dose by body weight, but fixed dosing is simpler and cheaper. Analyzing data from ten previous studies (total 288 participants) that used weight-adjusted doses of 20 or 30 mg per 70 kg, or a fixed dose approximating 25 mg, no significant associations emerged between body weight or sex and the subjective effects (mystical, challenging, or intensity). Across body weights from 49 to 113 kg, body weight did not affect psilocybin's subjective effects, suggesting fixed dosing is as effective and more practical than weight-adjusted dosing.
Personality and Individual Differences
October 15, 2017
Frederick S. Barrett, Matthew W Johnson, Roland R. Griffiths
98 citations
People who score higher on neuroticism (or lower on emotional stability) tend to report more intense challenging experiences, such as fear, grief, and paranoia, during psilocybin sessions. Data from two online surveys with 1,993 and 981 participants showed that scores on the Challenging Experience Questionnaire were negatively associated with emotional stability in the first study and positively associated with neuroticism in the second. The findings suggest that personality traits, particularly neuroticism, may help explain why some individuals have more difficult “bad trips” with classic hallucinogens like psilocybin.
Current Topics in Behavioral Neurosciences
January 1, 2022
Tasha L. Golden, Susan Magsamen, Clara C. Sandu et al.
89 citations
A rapid scoping review of 43 studies on the role of setting and aesthetics in psychedelic experiences and therapies found broad consensus that setting matters, but rigorous, prospective tests of specific setting elements are lacking. The field agrees on the importance of setting yet remains without clear understanding of which elements affect outcomes, how they work, for whom, or under what conditions. Further research could improve psychedelic therapies and also inform non-psychedelic interventions.
Frontiers in Psychiatry
September 19, 2023
Hillary Jackson, Sara So, Abigail Yaffe et al.
87 citations
A large prospective survey of adults planning to take psilocybin outside clinical settings found that, on average, participants reported lasting reductions in anxiety, depression, and alcohol misuse, along with improvements in cognitive flexibility, emotion regulation, spiritual wellbeing, and extraversion, and decreases in neuroticism and burnout after use. However, a minority reported persisting negative effects: 11% at 2–4 weeks and 7% at 2–3 months after use, including mood fluctuations and depressive symptoms. The study included 2,833 respondents at baseline, 1,182 at 2–4 weeks, and 657 at 2–3 months post-use. Participants were primarily college-educated White men in the United States, mean age 40, who used dried psilocybin mushrooms (mean dose 3.1 grams) for self-exploration.
International Review of Psychiatry
July 4, 2018
Frederick S. Barrett, Katrin H. Preller, Mendel Kaelen
85 citations
Music listening has been used consistently from the beginning of therapeutic psychedelic research to guide experiences during the acute effects of psychedelic drugs. Recent findings indicate that music can support meaning-making, emotionality, and mental imagery after psychedelic administration, and suggest it plays an important role in facilitating positive clinical outcomes. This review examines the history, current research, and future directions of music in psychedelic therapy, arguing for more detailed and rigorous investigation into music's contribution to treating psychiatric disorders within this novel framework.
Pharmacopsychiatry
August 4, 2021
Sandeep M. Nayak, Natalie Gukasyan, Frederick S. Barrett et al.
67 citations
Combining classic psychedelics like LSD or psilocybin with the mood stabilizer lithium carries a high risk of seizures. In an analysis of 62 online reports of such combinations, 47% involved seizures and 18% resulted in bad trips; 39% required medical attention. In contrast, none of 34 reports combining psychedelics with the mood stabilizer lamotrigine involved seizures, and most lamotrigine reports (65%) indicated no effect on the psychedelic experience. The findings suggest that lithium, but not lamotrigine, may pose a significant seizure danger when taken with psychedelics, though further research is needed.
PLoS One
March 14, 2024
Adam W. Levin, Rafaelle Lancelotta, Nathan D. Sepeda et al.
65 citations
In a small randomized trial of psilocybin-assisted therapy for adults with major depressive disorder, the therapeutic alliance between participants and facilitators strengthened from the final preparation session to one week after the intervention. A stronger alliance before the psilocybin sessions predicted lower depression scores at 4 weeks, 6 months, and 12 months afterward. Stronger alliance also correlated with more intense mystical experiences and psychological insight during the drug sessions, which in turn predicted better depression outcomes. The findings suggest the therapeutic relationship is important for treatment success.
Frontiers in Psychology
July 25, 2017
Hollis Robbins, David Smooke, Frederick S. Barrett et al.
62 citations
Music chosen to support psilocybin sessions tends to be regular, predictable, and slowly building, with lower perceptual brightness during peak mystical experiences compared to the pre-peak period. An expert survey of therapists and researchers yielded 24 musical recommendations for peak effects and 24 for the pre-peak period. Qualitative and quantitative analyses of 22 stimuli revealed that peak-period music features formulaic phrase structure, continuous forward motion, and less brightness. These findings provide a basis for standardizing music selection in psychedelic research and therapy.
The International Journal of Neuropsychopharmacology
May 10, 2021
Natalie Gukasyan, David B. Yaden, Matthew W. Johnson et al.
56 citations
Psychedelic substances produce unusual changes in conscious experience, leading some to propose they offer unique insights into consciousness. However, psychedelics are unlikely to provide information relevant to the "hard problem of consciousness," which involves explaining how first-person experience emerges. Instead, they bear on multiple "easy problems of consciousness," involving relations between subjectivity, brain function, and behavior. This review discusses common meanings of "consciousness" regarding psychedelics and considers models of their effects on the brain linked to explanatory claims about consciousness. It calls for epistemic humility about psychedelic research's potential to explain the hard problem while noting ways psychedelics may advance study of specific aspects of consciousness.