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.
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.
Scientific Reports
April 19, 2017
Michael Schartner, Robin Carhart‐Harris, Adam B. Barrett et al.
450 citations
Measures of neural signal diversity, such as entropy and Lempel-Ziv complexity, are higher during wakeful rest than during anesthesia. In this study, these measures were computed for spontaneous magnetoencephalographic signals from humans under psilocybin, ketamine, and LSD. All three psychedelics produced reliably higher signal diversity, even after controlling for spectral changes, with the most pronounced increase in temporal (single-channel LZ complexity) rather than spatial diversity. Selective correlations emerged between changes in signal diversity and the intensity of psychedelic experience. This is the first time these measures have been applied to the psychedelic state and have yielded values exceeding normal waking consciousness, suggesting that psychedelic phenomenology constitutes an elevated level of consciousness.
Sci Rep
November 19, 2019
Christopher Timmermann, Leor Roseman, Michael Schartner et al.
325 citations
Intravenous DMT, a fast-acting psychedelic, markedly reduces alpha and beta brain wave power and increases spontaneous signal diversity in the human brain, as measured by EEG. The emergence of delta and theta oscillatory activity correlates with the peak of the subjective experience, especially its eyes-closed visual component. Relationships between changes in subjective experience and brain activity were observed across time, linking specific brain changes to specific aspects of the experience.
Expert Review of Clinical Pharmacology
May 26, 2021
Suresh Muthukumaraswamy, Anna Forsyth, Thomas Lumley
312 citations
Psychedelic drugs like psilocybin, LSD, and ketamine show promise for treating mental health disorders, but their effectiveness in randomized controlled trials may be overstated. Previous research indicates that participants in psychedelic trials often become unblinded—they can tell whether they received the drug or a placebo—and may have strong expectations of improvement. A systematic review of trials from 1990 to 2020 found that most did not measure pre-trial expectancy or check whether blinding was successful. The authors argue that reported treatment effect sizes are likely overestimated due to these confounds. They recommend routine measurement of de-blinding and expectancy, careful trial design, and caution when interpreting existing effect size estimates.
Journal of Neuroscience
August 19, 2015
Suresh Muthukumaraswamy, Alexander D. Shaw, Laura E. Jackson et al.
244 citations
Subanesthetic doses of ketamine, similar to those used in antidepressant studies, increase anterior theta and gamma power but decrease posterior theta, delta, and alpha power, as shown by magnetoencephalographic recordings. Dynamic causal modeling revealed a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity, with AMPA-mediated changes persisting up to 50 minutes after infusion ceased, even after perceptual distortions had ended. A decrease in gain of parietal pyramidal cells correlated with participants' self-reports of blissful state. These alterations in frontoparietal connectivity patterns may be important in generating the antidepressant response to ketamine.
Proc Natl Acad Sci U S A
February 1, 2022
Daniel Toker, Ioannis Pappas, Janna D. Lendner et al.
148 citations
During conscious states, the cortex operates near a mathematically specific critical point called the edge-of-chaos, the boundary between stability and chaos. Applying a modified 0-1 chaos test to ECoG and MEG recordings from humans and macaques, evidence suggests that unconscious states—such as generalized seizure and anesthesia—involve a shift of low-frequency cortical oscillations away from this critical point, disrupting information processing. Psychedelic states tune these oscillations closer to the critical point, potentially increasing information richness. Analysis of clinical EEG from patients with disorders of consciousness indicates that measuring proximity to this critical point may serve as a clinical index of consciousness.
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.
PLoS ONE
September 30, 2015
Eduardo Ekman Schenberg, João Felipe Morel Alexandre, Renato Filev et al.
115 citations
Ayahuasca, an Amazonian plant-based brew used ritually in Brazil and increasingly worldwide, produces a two-phase brain effect. Electroencephalogram recordings and blood measurements of the brew's compounds (DMT, harmine, harmaline, tetrahydroharmine, and their metabolites) showed that 50 minutes after ingestion, alpha brainwave power (8–13 Hz) decreased, mostly in the left parieto-occipital cortex. Between 75 and 125 minutes, slow- and fast-gamma power (30–50 and 50–100 Hz, respectively) increased across multiple cortical regions, including left centro-parieto-occipital, left fronto-temporal, and right frontal areas. These brain changes were significantly linked to circulating levels of ayahuasca's active chemicals. The authors interpret these effects within cognitive and emotional frameworks relevant to ritual use and potential therapeutic applications.
Molecular Psychiatry
September 7, 2022
Rebecca B Price, Nicholas Kissel, Andrew Baumeister et al.
80 citations
Ketamine given intravenously rapidly reduces depressive symptoms, with effects lasting at least a week. In an analysis of 17 randomized controlled trials with 809 participants, the benefit over placebo was larger for patients who had already failed two or more prior antidepressant trials. However, no patient-level clinical or demographic characteristics—such as age, sex, or diagnosis—could predict who would respond best, limiting the ability to personalize ketamine prescriptions. The findings confirm ketamine's broad effectiveness for depression but show that precision medicine approaches cannot yet guide treatment decisions.
Biological psychiatry
September 15, 2023
Robin J Murphy, Rachael Sumner, William Evans et al.
69 citations
Microdosing LSD (10 μg every three days for six weeks) in healthy adult men produced transient improvements in creativity, connectedness, energy, happiness, irritability, and wellness on dose days compared with nondose days, even after controlling for preintervention expectancy. However, no enduring changes in overall mood or cognition were observed between baseline and six-week assessments. The most notable adverse event was treatment-related anxiety, which led four participants in the LSD group to withdraw. Microdosing appears relatively safe in this population but does not support claims of lasting mood or cognitive benefits.
Neuroimage
June 24, 2019
Carla Pallavicini, Martina G. Vilas, Mirta Villarreal et al.
66 citations
Classic serotonergic psychedelics and dissociative drugs like ketamine produce overlapping subjective effects despite different pharmacological mechanisms. Using source-localized magnetoencephalography, researchers found that LSD, psilocybin, and ketamine all caused widespread broadband reductions in spectral power. Machine learning classifiers trained on one pair of drugs could identify the third, confirming similarity. Functional connectivity analysis revealed decreases in low alpha and theta bands specific to LSD and psilocybin, linked to 5-HT2A agonism, while low beta band decreases were common to all three drugs. These findings quantify shared large-scale brain activity patterns across drug classes and suggest that beta band decoupling is an effect shared between NMDA antagonists and 5-HT2A agonists.
ACS chemical neuroscience
February 7, 2024
Pedro A M Mediano, Fernando E Rosas, Christopher Timmermann et al.
60 citations
LSD increases brain entropy (neural signal diversity) across all conditions, but the effect is strongest when eyes are closed. Brain entropy changes correlate with subjective psychedelic experience ratings, except when viewing a video, possibly because external stimuli compete with LSD-induced imagery. This shows context modulates neural dynamics during psychedelic experiences, highlighting the importance of environment in psychedelic psychotherapy.
Australian & New Zealand Journal of Psychiatry
March 4, 2022
Suresh Muthukumaraswamy, Anna Forsyth, Rachael L Sumner
59 citations
The psychedelic renaissance has generated excitement about potential medical uses, but the field faces significant challenges that must be addressed. This viewpoint identifies three categories of challenges: research study design issues including blinding, expectancy, therapy use, and bias; broader research environment problems such as evidence standards, funding, and scheduling that contradicts risk profiles; and implementation hurdles related to social and economic contexts. The authors offer suggestions for improving research protocols to mitigate these challenges.
Reviews in the Neurosciences
May 5, 2020
Rebecca McMillan, Suresh Muthukumaraswamy
53 citations
Ketamine has multiple uses—as an anesthetic, a model of psychosis, and an antidepressant—but its physiology is complex because it acts on several sites at clinically relevant doses. This review examines ketamine's acute effects on the resting brain, moving from its pharmacology through in vitro and in vivo electrophysiology to EEG/MEG and neuroimaging studies (MRI and PET). The picture of ketamine's effects is complicated and sometimes confusing, likely due to differences in species, doses, and analytical methods. The authors suggest strategies for future research to address these issues.
Psychological Medicine
July 19, 2023
Tehseen Noorani, Gillinder Bedi, Suresh Muthukumaraswamy
49 citations
When a medical research program overlaps with a social movement, new forms of sociality—termed 'chemosociality'—emerge from shared chemical exposure. In psychedelic-assisted therapy (PAT) clinical trials, this chemosociality creates 'dark loops': unrecorded social interactions that breach assumptions underlying causal inference used to establish treatment efficacy. These loops affect participant experiences but are not incorporated into trial data interpretation. Three researcher responses are proposed: chemosocial minimization (designing trials to reduce dark loops), chemosocial description (openly documenting them), and chemosocial valorization (actively leveraging them for positive outcomes). The hype surrounding psychedelic research continues to shape the phenomena under study, even as trials grow larger and more rigorous.
PLoS ONE
June 23, 2014
Christopher Allen, Benjamin T. Dunkley, Suresh Muthukumaraswamy et al.
45 citations
Continuous theta burst stimulation (cTBS) over the occipital cortex, expected to impair conscious vision, instead enhanced it relative to a sham control. The stimulation decreased cortical excitability and increased regional GABA concentration, suggesting that suppression of neural noise can improve the signal-to-noise ratio for conscious vision. No significant effects on magnetoencephalography measures were observed, though weak evidence for potentiation of beta-band event-related desynchronisation appeared. The authors propose that gating-by-inhibition in the visual cortex may be a foundation of consciousness.
bioRxiv (Cold Spring Harbor Laboratory)
November 2, 2020
Pedro A. M. Mediano, Fernando E. Rosas, Christopher Timmermann et al.
39 citations
preprint
Psychedelics reliably increase brain entropy (neural signal diversity), an effect linked to psychological changes and opposite to the decrease seen during loss of consciousness. This study investigated how context—specifically stimulus manipulation—modulates that entropy increase. Participants under LSD or placebo experienced eyes-closed versus eyes-open conditions, or no stimulus, music, or video. Brain entropy rose with LSD across all conditions but was largest with eyes closed. Entropy changes consistently matched subjective ratings of the psychedelic experience, except during video viewing, suggesting competition between external stimuli and internal LSD-induced imagery. The findings provide quantitative evidence that context shapes neural dynamics during psychedelic experiences, supporting the practice of eyes-closed psychedelic psychotherapy, and challenge simplistic views of brain entropy as a direct measure of conscious level.
International Journal of Environmental Research and Public Health
August 2, 2021
Lisa Reynolds, Amelia Akroyd, Frederick Sundram et al.
33 citations
Cancer healthcare professionals—doctors, nurses, psychologists, and social workers—show openness to psychedelic-assisted therapy for advanced cancer patients, driven by a desire to alleviate suffering and a lack of effective current treatments. However, this openness is tempered by concerns about patient safety and the need for rigorous, well-designed trials. The study identified four themes: beneficence (alleviating suffering), non-maleficence (keeping vulnerable patients safe), viewing psychedelic-assisted therapy as a transformative approach with real potential, and recognizing that new frontiers carry risks. These findings offer a foundation for engaging healthcare professionals in future research and clinical applications.
Biological psychiatry. Cognitive neuroscience and neuroimaging
May 1, 2024
Robin J Murphy, Suresh Muthukumaraswamy, Harriet de Wit
31 citations
Taking regular low doses of psychedelic drugs (microdosing) has drawn attention for potential psychotherapeutic effects, but controlled studies have lagged. A review of 14 rigorous double-blind placebo-controlled studies using investigator-supplied lysergic acid diethylamide (LSD) at 5-20 micrograms found that acute microdoses dose-dependently altered blood pressure, sleep, neural connectivity, social cognition, mood, and perception of pain and time. Perceptible drug effects occurred at 10-20 micrograms but not 5 micrograms. No serious adverse effects were reported. Repeated doses did not alter mood or cognition on any measures. Low doses of LSD appear safe and produce acute behavioral and neural effects in healthy adults, warranting further study in patient samples and with other psychedelics.
Human Brain Mapping
October 21, 2019
Bhim M. Adhikari, Juergen Dukart, Joerg F. Hipp et al.
24 citations
Ketamine, given at subanesthetic doses to healthy volunteers, produces psychosis-like symptoms and reduces functional connectivity in the salience network, auditory network, and default mode network (DMN). Midazolam, a sedative, only reduces DMN connectivity. The pattern of connectivity deficits caused by ketamine positively correlates with the pattern seen in schizophrenia, whereas midazolam's effects do not. After subtracting midazolam's effects, the remaining ketamine-specific disconnectivity pattern still correlates with schizophrenia deficits. This suggests that ketamine's psychosis-like effects have a brain functional basis that overlaps with schizophrenia-related connectivity disruptions.
Pilot and feasibility studies
October 5, 2023
Carina Joy Donegan, Dimitri Daldegan-Bueno, Rachael Sumner et al.
23 citations
An estimated 260 million people worldwide have depression, and many self-treat with microdoses of psychedelics like LSD and psilocybin despite limited clinical evidence. A prior phase 1 study in healthy volunteers found LSD microdosing safe, well tolerated, and feasible with good adherence. This open-label pilot trial (LSDDEP1) will test tolerability and feasibility of an 8-week LSD microdosing regimen in 20 patients with major depressive disorder. Participants receive a sublingual LSD formulation (MB-22001) twice weekly at 5–15 µg. Tolerability is measured by withdrawal due to adverse events; feasibility by clinic visit attendance. Antidepressant response will be assessed with MADRS scores over 8 weeks. Results will inform a future randomized controlled trial.
NeuroImage
November 1, 2022
Hardik Rajpal, Pedro A M Mediano, Fernando E Rosas et al.
23 citations
Schizophrenia and drug-induced states from LSD and ketamine both increase neural signal diversity, but they differ in brain connectivity: schizophrenia shows increased information flow from front to back of the brain, while the drugs reduce it. These differences can be modeled by altering Bayesian inference in a predictive processing framework: drug effects correspond to reduced precision of prior beliefs, whereas schizophrenia involves increased precision of sensory information. The findings clarify similarities and differences between these altered states, with implications for understanding consciousness and developing mental health treatments.
Trials
April 23, 2021
Robin J. Murphy, Rachael L. Sumner, William J. Evans et al.
23 citations
A proposed study will test whether regular low doses of LSD, known as microdosing, produce the cognitive and emotional benefits reported anecdotally. Eighty healthy men will receive either a placebo or 10 micrograms of LSD every third day for six weeks. The study will measure personality, creativity, mood, cognition, brain plasticity, and brain imaging at baseline and after the protocol, with additional acute measures after the first dose. Daily functioning will be tracked via questionnaires and a wearable device. The goal is to rigorously evaluate microdosing claims using objective measures, with potential future applications for treating depression, addiction, and other conditions.
Journal of Psychopharmacology
January 21, 2019
Rebecca McMillan, Anna Forsyth, Doug Campbell et al.
23 citations
Ketamine infusion in healthy men increases blood-oxygen-level dependent signals across the cortex and decreases them in the subgenual anterior cingulate cortex, but the decrease is largely due to physiological noise, especially cardiac pulsatility, rather than neural activity. Modeling the pharmacological MRI response with a single time course misses the full range of neural dynamics; using simultaneously recorded electroencephalography power time series reveals distinct temporal responses to ketamine, though no EEG band correlated with the subgenual anterior cingulate cortex decrease.