Neuroscience & Biobehavioral Reviews
May 10, 2021
Laith Alexander, Luke A. Jelen, Mitul A. Mehta et al.
79 citations
The anterior cingulate cortex (ACC), including its subgenual, perigenual, and dorsal zones, plays a key role in major depression and its treatment. Ketamine, a rapidly acting antidepressant, induces acute (over minutes) and post-acute (over hours to days) changes in subgenual and perigenual ACC activity, and these changes can correlate with antidepressant efficacy. The subgenual and dorsal ACC zones are specifically linked to ketamine's anti-anhedonic effects. The review emphasizes combining human neuroimaging with animal brain manipulations to understand causal relationships between brain activity and therapeutic outcomes. Circuit-based perspectives highlight ACC function in a central network mediating affective pain and its role as the anterior node of the default mode network.
Neuroimage
April 4, 2019
Ottavia Dipasquale, Pierluigi Selvaggi, Mattia Veronese et al.
79 citations
A double-blind, placebo-controlled study combined resting-state fMRI with a molecular atlas of serotonin receptors to examine how MDMA alters functional connectivity. Using the REACT method, the researchers found that MDMA-induced connectivity changes were specifically linked to brain regions rich in the serotonin transporter (5-HTT) and the 5-HT1A receptor, the drug's primary targets. Changes in 5-HT1A-enriched maps correlated with MDMA blood levels, while changes in 5-HT2A-enriched maps correlated with spiritual experiences reported by participants. The approach shows that MDMA's effects on brain connectivity can be explained by the distribution of its serotonergic targets, offering a new way to characterize psychoactive compounds.
Psychopharmacology
May 19, 2015
R. Joules, O. Doyle, A. J. Schwarz et al.
77 citations
Ketamine, which blocks N-methyl-D-aspartate receptors (NMDARs), robustly alters functional connectivity in the human brain, shifting patterns from cortex-centered to subcortex-centered connections. This effect was detected with 87.5% accuracy compared to saline. Pre-treatment with risperidone strongly modulated the connectivity changes (81.25% accuracy), whereas lamotrigine did not (43.75% accuracy). The differential modulation suggests the connectivity effects stem primarily from NMDAR blockade rather than downstream glutamate release. No such differential effect was seen in measures of brain response amplitude, underscoring the value of connectivity analysis for understanding how drugs affect the brain.
Cortex; a journal devoted to the study of the nervous system and behavior
April 1, 2014
Quinton Deeley, David A Oakley, Eamonn Walsh et al.
75 citations
Involuntary movements in neuropsychiatric disorders and culturally influenced dissociative states, such as delusions of alien control and spirit possession, involve distinct brain processes. Using fMRI in 15 highly hypnotically susceptible volunteers, suggestions modelled different experiences of loss of self-control: external personal control (like delusions of control), internal personal control (like spirit possession), and impersonal control by a machine (technical delusions). Brain activity and connectivity varied across these conditions.
Psychopharmacology
March 24, 2022
Timothy Lawn, Ottavia Dipasquale, Alexandros Vamvakas et al.
48 citations
LSD alters functional connectivity in the brain in ways that depend on its interactions with multiple serotonin and dopamine receptors, not only the 5-HT2A receptor. By analyzing brain scans from 15 participants, researchers found that LSD-induced changes in connectivity linked to different receptors corresponded to different subjective effects: serotonin-related receptors were predominantly associated with perceptual changes, while dopamine-related receptors were more tied to alterations in selfhood and cognition. These patterns were distinct, with similar relationships appearing within each receptor family but not between them. The findings suggest that LSD's full effects involve a broader set of receptors than previously emphasized.
PLoS One
January 1, 2013
Quinton Deeley, Eamonn Walsh, David A Oakley et al.
48 citations
Voluntary control and awareness of movement are central to selfhood and responsibility, yet can be lost in neuropsychiatric syndromes and dissociative states like spirit possession. Using suggestion and fMRI in 15 highly hypnotically suggestible subjects, loss of perceived control of movements was linked to reduced connectivity between the supplementary motor area (SMA) and motor regions. Reduced awareness of involuntary movements corresponded with less activation in parietal cortices and insula. These results suggest the sense of voluntary control may critically depend on SMA coupling with motor systems, offering a neural basis for narrowed awareness in pathological and culturally influenced dissociative phenomena.
Journal of Neuroscience
November 19, 2018
Anthony S. Gabay, Matthew J. Kempton, James Gilleen et al.
40 citations
MDMA increases cooperative behavior, but only when interacting with trustworthy partners. In a double-blind, placebo-controlled crossover study, 20 male participants received 100 mg MDMA or placebo and played an iterated Prisoner's Dilemma with opponents who varied in cooperation. MDMA enhanced cooperation with trustworthy opponents (odds ratio = 2.01) but not untrustworthy ones. MDMA specifically improved recovery from, not the impact of, breaches in cooperation. Brain activity increased in regions linked to social cognition, including precentral and supramarginal gyri, superior temporal cortex, central operculum/posterior insula, and supplementary motor area. Trust ratings did not change. The effect of MDMA on social decision-making depends on the context of the other person's behavior.
Nature Medicine
July 24, 2025
Luke A. Jelen, David J Lythgoe, James Stone et al.
29 citations
Blocking the opioid system with naltrexone reduced both the brain glutamate response and the antidepressant effect of ketamine in adults with major depressive disorder. In a double-blind crossover study of 26 adults, naltrexone before ketamine infusion attenuated the rise in glutamate+glutamine relative to N-acetylaspartate in the anterior cingulate cortex and lessened the drop in depression scores the next day. The opioid system modulates ketamine's acute brain effects and subsequent mood improvement, suggesting interactions between glutamate and opioid systems may inform new depression treatments.
Translational Psychiatry
December 3, 2023
Laith Alexander, Peter C. T. Hawkins, Jennifer W. Evans et al.
26 citations
Ketamine's antidepressant effects involve changes in brain connectivity that depend on which part of the anterior cingulate cortex (ACC) is examined. In a double-blind, placebo-controlled crossover trial, patients with treatment-resistant depression and healthy volunteers received intravenous ketamine or placebo. Two days later, resting-state functional connectivity between ACC subregions and other brain areas differed between groups. Changes in perigenual ACC connectivity to the insula correlated with improved depression scores. Subgenual ACC connectivity was most altered by ketamine compared to placebo, and changes in its connectivity to other ACC subregions and the ventral striatum correlated with reduced anhedonia. Accurate ACC segmentation is needed to understand ketamine's effects.
Frontiers in Psychiatry
July 3, 2018
Joseph M Barnby, Mitul A. Mehta
18 citations
The therapeutic potential of psilocybin, a psychedelic compound, is increasingly recognized in psychiatry, but its effects depend heavily on the context of use, known as 'set and setting.' This opinion article argues that the psychotherapeutic framework—including the relationship with therapists and the preparation and integration process—is as important as the drug itself for achieving positive outcomes. The authors suggest that neglecting the therapeutic context risks reducing psilocybin to a mere biological intervention, undermining its full potential for psychological healing and personal insight. The piece calls for careful integration of psychotherapeutic principles into psychedelic treatment models.
medRxiv Preprint Server
December 7, 2020
Vasileia Kotoula, Argyris Stringaris, Nuria Mackes et al.
9 citations
preprint
Ketamine, an antidepressant, can alter activity in brain reward areas within two hours of a single infusion, even in people who are not currently depressed. In a study of 37 remitted depression patients, ketamine increased brain responses in the nucleus accumbens and putamen during anticipation and receipt of small rewards, and the level of a ketamine metabolite (2R,6R)-HNK correlated with activation in the ventral tegmental area. These changes occurred without any changes in mood symptoms, suggesting ketamine may improve anhedonia by directly modulating how the brain processes reward feedback.
Wellcome Open Research
January 1, 2024
Matt Butler, Catherine Bird, Carolina Maggio et al.
4 citations
Functional neurological disorder (FND) causes seizures and movement disorders, is debilitating, and often has a poor prognosis. Brain imaging suggests FND involves multiple networks, and mechanisms like dissociation and abnormal motor agency may play a role. Psychedelics disrupt brain networks and are being tested for neuropsychiatric disorders. This open-label neuroimaging study will give 25 mg oral psilocybin with psychological support to 24 people with chronic FND. Resting-state and task-based fMRI, plus measures of interoception, somatisation, and dissociation, will be collected before and after psilocybin, with three-month follow-up. The study aims to probe FND mechanisms and assess safety and feasibility of psychedelic administration in this population.
bioRxiv (Cold Spring Harbor Laboratory)
December 19, 2019
J.M. Barnby, Vaughan Bell, Quinton Deeley et al.
4 citations
preprint
Dopamine transmission influences social attributions related to paranoia, but not the salience of paranormal or other beliefs. In a double-blind, placebo-controlled experiment, 27 healthy men received either L-DOPA (150 mg), haloperidol (3 mg), or placebo across three sessions. Haloperidol reduced attributions of harmful intent in a Dictator Game, while L-DOPA reduced such attributions only in fair conditions. Haloperidol unexpectedly increased attributions of self-interest for opponents' decisions. No changes occurred in belief salience for politics, religion, science, morality, or the paranormal. These results suggest dopamine selectively affects social inferences linked to paranoia, independent of mood or skepticism.
Journal of psychopharmacology (Oxford, England)
June 20, 2025
Mutahira Qureshi, Daniel Silman, Romayne Gadelrab et al.
3 citations
A single dose of immediate-release oral ketamine (40–240 mg) was safe and generally well-tolerated in healthy adults, with no unexpected safety signals or discontinuations due to side effects. Eighty mild or moderate treatment-emergent adverse events occurred after ketamine doses, most commonly dissociation, dizziness, and headache, while only five occurred after placebo. Dissociation events increased with higher doses. Ketamine and its metabolites showed dose-proportional pharmacokinetics. Transient mood and dissociation changes appeared one hour after dosing and resolved within about four hours. These results support further investigation of oral ketamine capsules for treatment-resistant depression.
Wellcome Open Research
April 22, 2025
Matthew Butler, Catherine Bird, Carolina Maggio et al.
3 citations
Functional neurological disorder (FND) is a common, debilitating condition linked to abnormal brain networks, dissociation, interoception, and motor agency. This open-label neuroimaging protocol will administer 25 mg of oral psilocybin with psychological support to 24 people with chronic FND. Resting-state and task-based functional MRI sequences will be compared before and after psilocybin. Additional measures include interoception, somatisation, illness perceptions, suggestibility, and dissociation. Participants will be followed for three months. The study aims to probe mechanisms underlying FND and assess the safety and feasibility of psychedelic administration with psychological support in this population.
Neuroscience and Biobehavioral Reviews
July 1, 2026
Marcus J. Glennon, Catherine Bird, Prateek Yadav et al.
2 citations
Setting up a psychedelic research study involves a long, arduous, and Kafkaesque process with many unstandardised challenges. These complexities challenge existing assumptions about psychiatric prescribing, the placebo effect, and definitions of selfhood. This review brings together major UK psychedelic research teams to formalise these unique considerations, addressing sociocultural, political, legal, pharmacological, safety, study design, and experiential facets. It identifies continuing areas of debate and provides a practical, experience-based guide with recommendations for policymakers and future researchers intending to set up a psychedelic study or clinical trial.
The American journal of psychiatry
June 1, 2026
Luke A. Jelen, Owen O'Daly, Fernando O Zelaya et al.
2 citations
Ketamine increased blood flow in specific brain regions (subgenual, pregenual, and dorsal anterior cingulate cortices) in adults with major depressive disorder, and this effect was not blocked by the opioid blocker naltrexone. However, naltrexone did disrupt the relationships between blood flow changes and both acute subjective effects and antidepressant response. The blood flow changes aligned with patterns of opioid and glutamate receptor distribution, suggesting that ketamine's effects involve interactions among multiple neurotransmitter systems.
Journal of Psychopharmacology
December 26, 2025
Alice Caulfield, Allan H. Young, Mitul A. Mehta
2 citations
Psychedelics may produce lasting behavioral and clinical change by enhancing learning mechanisms. This narrative review synthesizes evidence across behavioral, neural, and computational levels, proposing that viewing psychedelic mechanisms through the lens of learning unifies context-dependent outcomes, increased environmental sensitivity, and neuroplastic change. Persistent changes in top-down and bottom-up information processing at a systems-level may account for both therapeutic and adverse effects, converging with the reopening of critical learning periods. This systems-level framework explains why outcomes vary widely and depend on context: the learning environment—including psychological support and therapeutic insights—shapes lasting effects. Understanding these mechanisms has translational relevance for psychedelic-assisted psychotherapy.
Journal of psychopharmacology (Oxford, England)
June 16, 2026
Alice Caulfield, Matthew Butler, Mitul A. Mehta
Psychedelics show promise for treating neuropsychiatric conditions, but their Schedule 1 status creates regulatory and economic hurdles for research. Rigorous human mechanistic studies are needed to understand how psychedelics produce therapeutic effects. This article offers practical guidance on study design, legislation, and drug sourcing, based on the authors' experience setting up non-clinical studies in the UK. The guidance aims to help researchers navigate the complex process of establishing human psychedelic studies, with some content applicable to investigator-initiated studies more broadly.
bioRxiv : the preprint server for biology
June 12, 2026
Timothy Lawn, Johan Nakuci, Steve Cr Williams et al.
Spatial overlap among brain receptor maps derived from PET imaging can distort analyses that model multiple receptors together. Using test-retest fMRI data, the authors show that as more receptors are included in a multivariate model, the reliability of the resulting functional connectivity networks decreases, and this degradation is driven by collinearity among the receptor maps. A univariate approach, modeling each receptor independently, produces more reliable networks and, in a study comparing LSD to placebo, better captured the known role of the 5HT-2A receptor. Spatial collinearity is a fundamental constraint on multivariate molecular-enriched network estimation, and univariate modeling is recommended as a more robust default.
Translational Psychiatry
May 12, 2026
Linda Bryant, Laith Alexander, Sergio Mena et al.
A machine-learning model using structural brain scans predicted which adults with treatment-resistant depression would respond to a single ketamine infusion. The model, trained on 99 participants, achieved 72% balanced accuracy in the discovery sample and 60% in two independent groups, with performance dropping to chance in a saline-treated control group. Greater gray matter volume in frontal regions predicted response, while greater cerebellar volume predicted non-response. The findings suggest that pre-treatment brain structure may help guide personalized treatment decisions for ketamine therapy.
bioRxiv
July 22, 2025
Alice Caulfield, Lorraine Li, Famia Askari et al.
preprint
Psychedelics show potential for enhancing associative learning in animals, according to a systematic review of 31 studies (29 animal, 2 human). The review found that psychedelic administration improved learning across classical and operant conditioning paradigms, including fear extinction and reversal learning, though effects varied by dose, timing, training intensity, and sex. Possible mechanisms include increased prediction error sensitivity, serotonin receptor agonism, and structural plasticity. Learning enhancements may persist into the post-acute phase and depend on active environmental engagement. These findings have not yet been confirmed in humans, but suggest a window of enhanced learning that could inform psychedelic-assisted psychotherapy.
BJPsych Open
June 1, 2025
Anna Borissova, Allan H. Young, Mitul A. Mehta et al.
In interviews with seven people who had previously received ketamine for treatment-resistant depression, participants were motivated by hope for symptom improvement and a desire to support depression research. They described feeling more open and involved after ketamine and thought it could enhance therapy sessions. They suggested clearer communication that mood changes may not last, providing audiovisual materials to prepare for the infusion experience, and offering check-ins between sessions plus a final session for referrals and support. These insights informed a planned feasibility randomized controlled trial comparing intravenous ketamine plus behavioral activation (n=20) against midazolam plus behavioral activation (n=20) for major depressive disorder with anhedonia.
arXiv Preprint Archive
March 28, 2025
Marcus J. Glennon, Catherine Bird, Prateek Yadav et al.
Setting up a psychedelic study is a long and complex process that presents unique challenges not yet standardized. This review brings together major UK research teams to formalize these considerations, identify ongoing debates, and provide a practical guide for researchers and policymakers. It addresses challenges to existing assumptions about psychiatric prescribing, the placebo effect, and definitions of selfhood. The paper can be read end-to-end or used as a manual with sections for specific needs.