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.
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.
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.
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.
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.
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.
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.
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.
The lancet. Psychiatry
October 1, 2023
Gustavo C Medeiros, Malcolm Matheson, Isabella Demo et al.
38 citations
A systematic review of 69 neuroimaging studies (1751 participants) found no well-replicated biomarker for ketamine's antidepressant response, but identified several promising candidates. Response to ketamine was associated with post-treatment increases in gamma power in frontoparietal regions, increased functional connectivity within the prefrontal cortex, and increased functional activation of the striatum. The review highlights substantial methodological heterogeneity across studies and calls for further investigation of these biomarkers.
NeuroImage
October 15, 2022
Andrew Gaddis, Daniel E Lidstone, Mary Beth Nebel et al.
38 citations
Psilocybin alters the functional organization of distinct thalamic subregions and their connections to cortical networks, particularly the mediodorsal and pulvinar nuclei. Using a novel ICA-based approach in 18 healthy meditators, psilocybin-induced changes in intrathalamic spatial organization correlated with subjective drug effects. Thalamocortical connectivity predominantly decreased with visual and default mode networks. In contrast, treating the thalamus as a single unit showed a non-significant numerical increase in connectivity, suggesting that whole-thalamus analyses may mask focal decreases in specific nuclei that express serotonin 2A receptors.
Psychological review
March 1, 2024
Manoj K Doss, Jason Samaha, Frederick S Barrett et al.
24 citations
Psychoactive drugs produce unique subjective states, but their effects on episodic memory often overlap. This reanalysis of 10 data sets (28 drug conditions) used signal detection models to separate three memory processes: recollection (retrieving specific details), familiarity (recognizing without details), and metamemory (introspecting about memory accuracy). Sedatives impaired both recollection and familiarity during encoding but enhanced recollection during consolidation. Dissociatives and cannabinoids impaired recollection during encoding, and cannabinoids increased false recollections during retrieval. Psychedelics impaired recollection during encoding but tended to enhance familiarity. Stimulants enhanced metamemory during encoding and retrieval but impaired metamemory during consolidation. These distinct patterns help explain drug-specific phenomena like sedative-induced blackouts and psychedelic presque vu, and suggest that memory quantity and stability influence metamemory.
Journal of psychopharmacology (Oxford, England)
May 1, 2025
Sean P Goldy, Benjamin A Du, Julia S Rohde et al.
15 citations
Classic psychedelics carry both greater acute challenging effects and persisting negative effects compared to cannabis, but also produce greater positive acute and persisting effects. In two studies using quota-based sampling to approximate US Census demographics, participants reported on their first or most memorable experiences with either substance. Predictors of psychedelic outcomes—such as dose level, presence of others, religiosity, and personality—explained only a small degree of the variation. The findings offer a more nuanced characterization of the risks and benefits of psychedelic experiences relative to cannabis.
International journal of methods in psychiatric research
June 1, 2026
Kurt Stocker, Matthias Hartmann, Frederick S Barrett et al.
The eight-factor structure of the Psychedelic Experience Scale (PES48), which includes the Mystical Experience Questionnaire (MEQ30) and additional factors for paradoxicality, connectedness, visual experience, and distressing experience, is valid for use in English. Analysis of 280 measurements from 145 healthy participants in four placebo-controlled psilocybin studies found that six subscales have high internal consistency, one good, and one acceptable. Both the MEQ30 and MEQ40 models show acceptable to good model fits, with better fits in English than in German. All six MEQ40 scale means were higher in English data, suggesting that the PES48 provides a broader conceptualization of mystical and non-mystical psychedelic experiences, and that setting may influence mystical experience.
Psychopharmacology
May 28, 2026
Mazen A Atiq, Eli Weisman, Rodrigo B Guerra et al.
A healthy 35-year-old man experienced a rare hypotensive adverse event—neurocardiogenic syncope (fainting)—about 60 minutes after taking 25 mg of oral psilocybin in a clinical trial. His blood pressure dropped to 93/51 mmHg, with rapid heart rate and sweating, but he stabilized quickly with leg elevation and oral hydration. The episode may have been triggered by upright seated posture, restrictive EEG equipment, and anxiety about upcoming transcranial magnetic stimulation. Fewer than one-quarter of contemporary psychedelic trials report systematic adverse event assessment, highlighting the need for transparent documentation of both hypertensive and hypotensive events as psilocybin moves toward potential FDA approval.
Journal of psychopharmacology (Oxford, England)
February 5, 2026
Benjamin R Lewis, Matthew J Reid, Andrew M Novick et al.
Clinical trials of classical psychedelics like psilocybin for mental health conditions face unique challenges that may persist if these treatments enter clinical practice. Four categories of challenges with trial participants are identified: treatment nonresponse, expectancy effects and functional unblinding, post-session psychological difficulties, and contagion effects. Management strategies for study teams to mitigate these risks are described. The National Network of Depression Centers and similar organizations can guide best practices to responsibly advance this promising field.
Journal of psychopharmacology (Oxford, England)
January 1, 2026
Jack E Henningfield, Frederick S Barrett, Suzette M Evans et al.
Roland R. Griffiths was a highly influential scientist in behavioral and neuropsychopharmacology, known for his rigorous research on abuse liability of substances including alcohol, benzodiazepines, caffeine, tobacco, and psychedelics. This review, authored by his former mentees and collaborators, describes his methodical approach to research, his inclusive and collegial mentoring style, and his role in advancing scientific methods for abuse liability assessment, policy, and regulation. His work culminated in the establishment of the Johns Hopkins Center for Psychedelic and Consciousness Research, reflecting his curiosity-driven, humanity-serving science that continues to inspire innovation.