Lancet Psychiatry
May 17, 2016
Robin L Carhart-Harris, Mark Bolstridge, James Rucker et al.
1,546 citations
In an open-label trial, 12 patients with moderate-to-severe treatment-resistant depression received two doses of psilocybin (10 mg and 25 mg, one week apart) in a supportive setting. The psychedelic effects peaked 2-3 hours after dosing and subsided within 6 hours. No serious adverse events occurred; transient anxiety, confusion, nausea, and headache were noted. Depressive symptoms, measured with the Quick Inventory of Depressive Symptoms, were markedly reduced one week after the high dose (mean reduction of 11.8 points) and remained lower at three months (mean reduction of 9.2 points). Improvements in anxiety and anhedonia were also observed. The results provide preliminary support for psilocybin's safety and efficacy in treatment-resistant depression, warranting further controlled trials.
Frontiers in Human Neuroscience
January 1, 2014
Robin Carhart‐Harris, Robert Leech, Peter J. Hellyer et al.
1,289 citations
Entropy, a measure of uncertainty or disorder, is applied to brain function and consciousness, focusing on the psychedelic state induced by psilocybin. The psychedelic state is considered a primary or primitive state of consciousness, characterized by elevated entropy in brain function, including a greater repertoire of functional connectivity motifs that form and fragment over time. This suggests primary states may exhibit criticality, a transition zone between order and disorder. Normal waking consciousness suppresses entropy, operating just below criticality, which constrains cognition and enables metacognitive functions like reality-testing and self-awareness. Entry into primary states involves collapse of default-mode network activity and decoupling from medial temporal lobes. These hypotheses can be tested by comparing brain activity in REM sleep, early psychosis, normal waking consciousness, and anesthesia.
Proceedings of the National Academy of Sciences
January 23, 2012
Alessandro Colasanti, Robin J. Tyacke, Robert Leech et al.
1,191 citations
Psychedelic drugs like psilocybin, found in magic mushrooms, produce profound changes in consciousness by decreasing activity and connectivity in key brain hub regions. Using functional MRI, researchers observed that psilocybin reduced cerebral blood flow and BOLD signal, especially in the thalamus, anterior cingulate cortex (ACC), and posterior cingulate cortex (PCC). Decreased activity in the ACC and medial prefrontal cortex (mPFC) predicted the intensity of subjective psychedelic effects. Psilocybin also reduced positive coupling between the mPFC and PCC. These findings suggest that psychedelics work by dampening the brain's connector hubs, leading to a state of unconstrained cognition.
Proc Natl Acad Sci U S A
April 11, 2016
Robin L. Carhart-Harris, Suresh Muthukumaraswamy, Leor Roseman et al.
887 citations
LSD produces marked changes in brain activity that correlate with its psychological effects. Increased blood flow in the visual cortex, decreased alpha power there, and an expanded functional connectivity profile of the primary visual cortex strongly correlated with visual hallucinations, suggesting that intrinsic brain activity influences visual processing more during the psychedelic state. Decreased connectivity between the parahippocampus and retrosplenial cortex correlated strongly with ego-dissolution and altered meaning, indicating this circuit's role in maintaining the self and processing meaning. Different imaging metrics showed strong relationships, allowing firmer inferences about their functional significance.
Curr Biol
April 13, 2016
Enzo Tagliazucchi, Leor Roseman, Mendel Kaelen et al.
531 citations
LSD, a potent serotonin-receptor agonist, increases global functional connectivity in the human brain, particularly in high-level association cortices and the thalamus, as shown by fMRI. These effects overlap with serotonin 2A receptor densities and correlate with subjective reports of ego dissolution. The drug also enhances communication between normally distinct brain networks, reducing the brain's modular and rich-club organization. This is the first modern human imaging study of LSD's acute effects on brain connectivity, demonstrating that LSD selectively expands global connectivity and blurs perceptual boundaries between self and environment.
Journal of Neuroscience
September 18, 2013
Matthew J. Brookes, David Errtizoe, Ben Sessa et al.
501 citations
Psychedelic drugs like psilocybin produce profound changes in consciousness by desynchronizing ongoing oscillatory rhythms in the cortex. Using magnetoencephalography in healthy participants, psilocybin reduced spontaneous cortical oscillatory power from 1 to 50 Hz in posterior association cortices and from 8 to 100 Hz in frontal association cortices, with large decreases in default-mode network areas. Low-level visually induced and motor-induced gamma-band oscillations were unaffected, suggesting some basic oscillatory activity is preserved. Dynamic causal modeling indicated that posterior cingulate cortex desynchronization results from increased excitability of deep-layer pyramidal neurons rich in 5-HT 2A receptors.
Journal of Psychopharmacology
October 5, 2012
Amir Englund, Paul D. Morrison, Judith Nottage et al.
463 citations
Pre-treatment with 600 mg of cannabidiol (CBD) reduced the likelihood of clinically significant psychotic symptoms and paranoia caused by intravenous delta-9-tetrahydrocannabinol (THC, 1.5 mg) in healthy volunteers. Participants who received CBD before THC had lower scores on the State Social Paranoia Scale and smaller declines in episodic memory compared with those who received placebo before THC. The odds of experiencing a clinically significant increase in positive psychotic symptoms were about 78% lower in the CBD group. These results support the view that cannabis products high in THC and low in CBD pose greater mental health risks.
Human Brain Mapping
May 22, 2015
Alexander V. Lebedev, Martin Lövdén, Gidon Rosenthal et al.
347 citations
Psilocybin, the active compound in magic mushrooms, produces ego-dissolution—a feeling that the self is disintegrating or that the boundary between self and world is dissolving—similar to ego-disturbances seen in schizophrenia. In a placebo-controlled study of 15 healthy volunteers, functional MRI scans showed that psilocybin-induced ego-dissolution was linked to decreased connectivity between the medial temporal lobe and high-level cortical regions, disintegration of the salience network, and reduced communication between brain hemispheres. Individuals with lower diversity of executive network nodes at baseline were more likely to experience ego-dissolution. These findings suggest that maintaining a coherent sense of self depends on normal functioning of these brain systems.
Psychological Medicine
February 5, 2016
Robin Carhart‐Harris, Mendel Kaelen, Mark Bolstridge et al.
301 citations
A single intravenous dose of LSD (75 µg) in 20 healthy volunteers produced robust acute psychological effects, including heightened mood and elevated scores on a measure of psychosis-like symptoms. Two weeks later, participants showed increased optimism and trait openness compared to after placebo, with no changes in delusional thinking. The findings suggest that psychedelics can acutely induce psychosis-like symptoms yet improve psychological wellbeing in the mid to long term. The authors propose that acute mood changes stem from a more fundamental modulation of cognition, and that increased cognitive flexibility from serotonin 2A receptor stimulation promotes emotional lability during intoxication and leaves a lasting loosened cognition conducive to improved wellbeing.
Frontiers in Human Neuroscience
May 27, 2014
Leor Roseman, Robert Leech, Amanda Feilding et al.
293 citations
Psychedelic drugs like psilocybin and MDMA perturb consciousness in distinct ways, offering a tool to study brain mechanisms underlying conscious states. In placebo-controlled studies, psilocybin increased resting-state functional connectivity between brain networks, making them less differentiated, while decreasing connectivity between visual and sensorimotor networks. MDMA produced less marked changes in between-network connectivity, suggesting that the extensive network alterations under psilocybin may be unique to classic psychedelics and relate to their profound effects on consciousness. This analytical approach could help characterize other altered conscious states.
Psychopharmacology
February 1, 2018
Mendel Kaelen, Bruna Giribaldi, Jordan Raine et al.
274 citations
Music plays a central therapeutic role in psychedelic therapy with psilocybin for treatment-resistant depression. In interviews with 19 patients, music had both welcome influences—evoking meaningful emotion, mental imagery, guidance, openness, calm, and safety—and unwelcome influences, such as unpleasant emotion, imagery, and resistance. Patients' experience of the music correlated with mystical experiences and insightfulness. Critically, the nature of the music experience significantly predicted reductions in depression one week after psilocybin, whereas general drug intensity did not.
Schizophrenia Bulletin
October 6, 2012
Robin Carhart‐Harris, Robert Leech, David Erritzøe et al.
267 citations
Psilocybin, a classic psychedelic, increases functional connectivity between the default-mode network (DMN) and task-positive network (TPN), reducing the normal orthogonality between these networks. In 15 healthy volunteers, intravenous psilocybin (vs placebo) during resting-state fMRI scans led to greater DMN-TPN connectivity, a pattern also seen in psychosis and meditative states. Thalamocortical connectivity remained unchanged, suggesting it relates to arousal rather than the separateness of internal versus external focus. The findings support psilocybin as a model for early psychosis, where compromised DMN-TPN orthogonality may explain phenomenological overlaps.
The British Journal of Psychiatry
January 27, 2012
Robin Carhart‐Harris, Robert Leech, Tom A. Williams et al.
241 citations
Psilocybin, a classic psychedelic drug, may enhance the vividness and visual imagery of positive autobiographical memories. In a small study of ten healthy participants, functional magnetic resonance imaging scans showed that under psilocybin, compared to placebo, recollection of positive memories produced additional visual and sensory cortical activations in the late phase of recall. Participants also rated memories as more vivid and visually rich after psilocybin, and higher vividness correlated with greater subjective wellbeing at follow-up. These findings suggest psilocybin could be useful in psychotherapy for facilitating recall of salient memories or reversing negative cognitive biases.
Brain Research Bulletin
March 11, 2016
Elisabet Domínguez‐clavé, Joaquim Soler, Matilde Elices et al.
220 citations
Ayahuasca, a tea made from the vine Banisteriopsis caapi and often combined with Psychotria viridis leaves, induces a transient altered state of consciousness marked by introspection, visions, enhanced emotions, and personal memory recall. Its psychoactive effects come from N,N-dimethyltryptamine (DMT), a 5-HT2A receptor agonist, and β-carboline alkaloids that inhibit monoamine oxidase. A growing body of evidence suggests ayahuasca may help treat substance use disorders, anxiety, and depression. The review discusses how ayahuasca intake increases mindfulness facets related to acceptance and detached observation of thoughts and emotions. The authors conclude ayahuasca shows promise for enhancing self-acceptance and enabling safe exposure to emotional events, potentially useful for impulse-related, personality, and substance use disorders and trauma, though more research is needed.
Psychopharmacology
November 27, 2015
Joaquim Soler, Matilde Elices, Alba Franquesa et al.
212 citations
Ayahuasca, a psychotropic plant tea containing DMT and β-carboline alkaloids, increases mindfulness capacities within 24 hours of a single session. In 25 individuals, ayahuasca significantly reduced judgmental processing of experiences and inner reactivity, as measured by the Five Facets Mindfulness Questionnaire, and increased decentering ability, as measured by the Experiences Questionnaire. These changes match those seen after extensive mindfulness practice and support the tea's therapeutic potential, particularly for addiction and depression.
The International Journal of Neuropsychopharmacology
May 17, 2017
Frederic Sampedro, Mario de la Fuente Revenga, Marta Valle et al.
205 citations
A single dose of ayahuasca reduced glutamate+glutamine, creatine, and N-acetylaspartate+N-acetylaspartylglutamate in the posterior cingulate cortex of 16 healthy volunteers, measured post-acutely with magnetic resonance spectroscopy. Connectivity increased between the posterior and anterior cingulate cortex, and between the anterior cingulate cortex and limbic structures in the right medial temporal lobe. Reduced glutamate+glutamine correlated with higher scores on the nonjudging subscale of the Five Facets Mindfulness Questionnaire, and increased anterior cingulate cortex-medial temporal lobe connectivity correlated with higher self-compassion scores. Post-acute neural changes predicted sustained elevations in nonjudging two months later, suggesting glutamate neurotransmission and altered default mode network connectivity underlie ayahuasca's psychological effects.
Elife
March 2, 2021
Balázs Szigeti, Laura Kärtner, Allan Blemings et al.
192 citations
A self-blinding citizen science trial with 191 participants tested whether microdosing psychedelics produces psychological benefits beyond a placebo. All psychological outcomes improved from baseline to after the four-week dose period in the microdose group, but the placebo group also improved, and no significant between-group differences were observed. Small, significant differences in acute measures (emotional state, drug intensity, mood, energy, creativity) and post-acute anxiety appeared, but these could be explained by participants breaking blind. The findings suggest that anecdotal benefits of microdosing can be explained by the placebo effect.
Biological Psychiatry
January 10, 2014
Robin Carhart‐Harris, Kevin Murphy, Robert Leech et al.
182 citations
The medial temporal lobes (MTLs) are specifically involved in how MDMA works in the brain, though more research is needed to understand how the drug's characteristic subjective effects emerge from its modulation of spontaneous brain activity.
European Neuropsychopharmacology
March 26, 2016
Marta Valle, Ana Maqueda, Mireia Rabella et al.
175 citations
Ayahuasca, a psychoactive Amazonian tea, contains DMT and other compounds. In a double-blind, placebo-controlled study with 12 experienced users, ayahuasca reduced brain oscillations in delta, theta, and alpha frequency bands. The intensity of visual imagery correlated inversely with alpha-band current density in parietal and occipital cortex. Pretreatment with the 5-HT2A antagonist ketanserin blocked these neurophysiological changes, weakened the correlation between alpha activity and visual effects, and reduced subjective intensity. These results indicate that activation of the 5-HT2A receptor is central to ayahuasca's neurophysiological and visual effects in humans, despite the tea's chemical complexity.
Scientific Reports
July 7, 2017
José Á. Morales-García, Mario de la Fuente Revenga, Sandra Alonso‐gil et al.
173 citations
The three main alkaloids of Banisteriopsis caapi—harmine, tetrahydroharmine, and harmaline—along with the harmine metabolite harmol, stimulate adult neurogenesis in vitro. In neurospheres from adult mouse brain progenitor cells, all compounds increased neural stem cell proliferation, migration, and differentiation into adult neurons. This suggests that modulation of brain plasticity may contribute to the antidepressant effects of ayahuasca and expands potential applications of these alkaloids to other brain disorders benefiting from stimulation of endogenous neural precursor niches.
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.
ACS Pharmacology & Translational Science
August 31, 2020
Nadia R. P. W. Hutten, Natasha L. Mason, Patrick C. Dolder et al.
134 citations
Low doses of LSD (5, 10, and 20 μg) increase brain-derived neurotrophic factor (BDNF) levels in blood plasma, a marker of neuroplasticity. In a placebo-controlled within-subject study with healthy volunteers, BDNF levels rose at 4 hours after 5 μg and at 6 hours after both 5 and 20 μg, compared to placebo. This suggests that even low doses of LSD can acutely enhance neuroplasticity, supporting further research in patient populations for psychiatric conditions.
Translational Psychiatry
April 8, 2021
Natasha L. Mason, Kim P. C. Kuypers, Johannes T. Reckweg et al.
132 citations
A double-blind, placebo-controlled experiment with 0.17 mg/kg psilocybin shows that the drug affects creative thinking in time-dependent and task-specific ways. Immediately after consumption, psilocybin increased spontaneous creative insights but decreased deliberate, task-based creativity. Seven days later, participants generated more novel ideas. Brain imaging revealed that both acute and persisting effects were predicted by connectivity within and between networks of the default mode network. These results support historical claims that psychedelics can influence aspects of the creative process and may serve as tools for investigating creativity and its neural basis.
European Neuropsychopharmacology
October 17, 2020
Nadia R. P. W. Hutten, Natasha L. Mason, Patrick C. Dolder et al.
121 citations
Taking very low doses of LSD, known as microdosing, can selectively improve mood and cognition. In a placebo-controlled experiment with 24 healthy adults, doses of 5, 10, and 20 micrograms of LSD were tested. The 20 mcg dose increased positive mood, while 5 mcg and 20 mcg increased friendliness and reduced attentional lapses. Arousal increased at 5 mcg. Negative effects included increased confusion at 20 mcg and increased anxiety at both 5 and 20 mcg. Altered states of waking consciousness occurred at 10 and 20 mcg. The minimal dose producing noticeable effects was 5 mcg, with the clearest effects at 20 mcg.
Journal of Psychopharmacology
January 1, 2016
Jana Speth, Clemens Speth, Mendel Kaelen et al.
119 citations
A single dose of LSD (75 μg) reduced how often people spontaneously thought about the past, while thoughts about the present or future remained unchanged. In a placebo-controlled crossover study with 20 healthy volunteers, fewer references to past mental spaces appeared in reports collected about 2.5 hours after intravenous administration. This reduction correlated with the drug's subjective intensity and with decreased resting-state functional connectivity within the default-mode network, a brain system involved in autobiographical memory and rumination. The findings suggest LSD may reduce past-focused thinking, which could be relevant for treating conditions like depression where excessive reflection on the past is common.