Psychopharmacology
December 1, 2011
Roland R Griffiths, Matthew W Johnson, William A Richards et al.
938 citations
Psilocybin can produce mystical-type experiences that lead to lasting positive changes in attitudes, mood, and behavior. In a double-blind study, 18 adults (17 with no prior hallucinogen use) received 0, 5, 10, 20, or 30 mg/70 kg psilocybin in five sessions under supportive conditions. At the two highest doses, 72% of volunteers reported a mystical-type experience, and 39% experienced extreme anxiety or fear. One month later, participants rated these sessions as having substantial personal and spiritual significance, with the ascending dose sequence showing greater positive effects. At 14 months, these positive ratings remained undiminished and were consistent with observer reports. The effects generally increased with dose.
Journal of Psychopharmacology
September 28, 2011
Katherine A Maclean, Matthew W Johnson, Roland R Griffiths
907 citations
Core personality traits are generally stable after age 30, but a high dose of the hallucinogen psilocybin can increase Openness to experience in healthy adults. In a double-blind controlled study, participants who had a mystical experience during their psilocybin session showed significantly higher Openness than baseline, and this increase persisted for more than a year. The findings suggest that psilocybin and mystical-type experiences can produce lasting personality change in adults.
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.
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.
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.
Journal of Psychopharmacology
May 14, 2019
Albert Garcia-Romeu, Alan K Davis, Fire Erowid et al.
286 citations
In a survey of 343 people who had problematic alcohol use for an average of seven years and then used psychedelics in non-clinical settings, 83% no longer met criteria for alcohol use disorder after the experience. Most respondents were White males in the USA who took moderate or high doses of LSD or psilocybin. They rated the experience as highly meaningful and insightful, and 28% said changes in life priorities or values helped reduce alcohol misuse. Greater dose, insight, mystical-type effects, and personal meaning were linked to larger reductions in drinking. The results suggest naturalistic psychedelic use may reduce problematic alcohol use, supporting further research into psychedelic-assisted treatment.
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.
Journal of psychopharmacology (Oxford, England)
September 1, 2020
Alan K Davis, John M Clifton, Eric G Weaver et al.
144 citations
Inhaling N,N-dimethyltryptamine (DMT) can trigger encounters with seemingly autonomous entities. A survey of 2,561 people (average age 32, 77% male) found that these encounters primarily involve visual and extrasensory perception, such as telepathy. Entities are most often described as beings, guides, spirits, aliens, or helpers. Although 41% of respondents felt fear, the dominant emotions were love, kindness, and joy, both in the respondent and attributed to the entity. Most believed the entity was conscious, intelligent, and benevolent, existing in a real but different dimension. 69% received a message, and 19% a prediction. Over half of those who were atheist before no longer identified as atheist afterward.
The American journal of drug and alcohol abuse
January 1, 2019
Alan K Davis, Sara So, Rafael Lancelotta et al.
141 citations
Among people who used 5-MeO-DMT in a structured group setting with guided dosing and support, 80% of those previously diagnosed with depression and 79% of those previously diagnosed with anxiety reported their condition improved after use. Only 3% with depression and 2% with anxiety said their condition worsened. Greater improvement was linked to more intense mystical experiences and higher ratings of the experience's spiritual significance and personal meaning, but not to the intensity of challenging physical or psychological effects. The findings suggest potential therapeutic benefits, warranting controlled clinical trials.
Psychopharmacology
February 1, 2018
Theresa M Carbonaro, Matthew W Johnson, Ethan Hurwitz et al.
139 citations
Psilocybin and dextromethorphan (DXM) both produce powerful subjective effects, but their experiences differ profoundly. In a double-blind comparison with 20 participants, high doses of both drugs caused similar overall drug effect strength and time-course. Psilocybin uniquely fostered richer, more complex visual experiences—including more movement, brightness, and kaleidoscopic imagery—along with greater mystical-type and psychologically insightful experiences and deeper music absorption. DXM, by contrast, produced stronger feelings of disembodiment, nausea, and light-headedness. Both drugs increased blood pressure, heart rate, and pupil dilation while impairing motor performance and balance.
Psychopharmacology
March 1, 2013
Katherine A Maclean, Matthew W Johnson, Chad J Reissig et al.
134 citations
Inhaled salvinorin A, the active compound in Salvia divinorum, produces intense, dose-related subjective and cognitive effects that peak within 2 minutes and rapidly dissipate. In eight healthy adults with hallucinogen experience, high doses frequently caused maximal drug strength ratings or unresponsiveness. The compound induced dissociative effects and impaired recall and recognition memory, with some overlap with classic hallucinogens but a qualitatively distinct profile. No persisting adverse effects were observed at one-month follow-up. These findings contribute to understanding the kappa opioid system and may inform future therapeutic applications.
Drug and alcohol dependence
May 1, 2011
Matthew W Johnson, Katherine A Maclean, Chad J Reissig et al.
134 citations
Salvinorin A, the psychoactive compound in Salvia divinorum, produces rapid, dose-dependent subjective effects that peak at 2 minutes and subside within 20 minutes after inhalation. In a double-blind, placebo-controlled study with 4 healthy hallucinogen-using adults, doses from 0.375 to 21 μg/kg increased ratings of mystical-type experiences and effects similar to classic hallucinogens. Salvinorin A did not significantly raise heart rate or blood pressure. Participants reported intense experiences involving altered spatial orientation, pressure on the body, childhood memories, cartoon-like imagery, and contact with entities. The findings suggest salvinorin A has a unique profile that includes mystical-type effects.
Drug and alcohol dependence
June 1, 2012
Matthew W Johnson, R Andrew Sewell, Roland R Griffiths
121 citations
Psilocybin frequently causes headache in a dose-dependent manner, with incidence, duration, and severity increasing at higher doses. In a double-blind study with 18 healthy participants given 0, 5, 10, 20, or 30 mg/70 kg of psilocybin, all headaches had delayed onset, were transient, and lasted no more than a day. Headaches were neither severe nor disabling. Possible mechanisms include nitric oxide release. These findings indicate headache is an expected adverse event in both nonmedical use and human research, but should not hinder future psilocybin research.
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
September 1, 2015
Peter S Hendricks, Matthew W Johnson, Roland R Griffiths
107 citations
Adults in the United States who had ever used psilocybin alone showed lower odds of past-month psychological distress (weighted OR = .81) and past-year suicidal thinking, planning, and attempt compared with those who had never used any classic psychedelic. Those who used psilocybin without other psychedelics also had reduced odds of psychological distress relative to users of other classic psychedelics. The findings suggest psilocybin may have therapeutic potential and a favorable safety profile, but do not directly address clinical applications or risk.
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.
Psychopharmacology
September 1, 2012
Chad J Reissig, Lawrence P Carter, Matthew W Johnson et al.
89 citations
High doses of the cough suppressant dextromethorphan (DXM) produce perceptual changes, mystical-type experiences, and physiological effects similar to those of classic hallucinogens like psilocybin. In a double-blind study, 12 healthy volunteers with histories of hallucinogen use received single oral doses of DXM ranging from 100 to 800 mg/70 kg, triazolam, or placebo. DXM dose-dependently increased blood pressure, heart rate, and emesis, and elicited observer-rated hallucinogen-like effects such as visual distortions and joy. After 400 mg/70 kg DXM, 11 of 12 participants thought they had received a classic hallucinogen. At a 1-month follow-up, volunteers reported lasting positive changes in spirituality, attitudes, and mood attributed to the session.
Journal of psychopharmacology (Oxford, England)
January 1, 2023
Sandeep M Nayak, Manvir Singh, David B Yaden et al.
87 citations
A survey of 2374 people who reported a belief-changing psychedelic experience found that a single experience increased non-physicalist beliefs, including dualism, paranormal/spirituality, and consciousness in both mammals and non-mammals, with medium to large effects. Beliefs in superstition changed negligibly. The percentage identifying as a believer in a higher power or ultimate reality rose from 29% before to 59% after the experience. Greater mystical experiences during the psychedelic session were linked to larger belief shifts. These changes persisted an average of 8.4 years later.
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.
Experimental and clinical psychopharmacology
November 1, 2006
Michelle R Lofwall, Roland R Griffiths, Miriam Z Mintzer
57 citations
Ketamine, a drug that blocks NMDA receptors, produces selective, temporary, dose- and time-related effects on memory and cognition. In a double-blind, placebo-controlled crossover study, 18 healthy adults received low or moderate doses of ketamine. Ketamine impaired memory encoding (free recall) and working memory speed, but spared retrieval, recognition, source memory, attention, and accuracy on a symbol substitution task. Subjective effects lasted longer than memory or psychomotor impairments, and there were no hallucinations or mystical experiences. The findings help clarify the role of NMDA receptors in different cognitive processes.