Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen leveldependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD's marked effects on the visual cortex did not significantly correlate with the drug's other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of "ego-dissolution" and "altered meaning," implying the importance of this particular circuit for the maintenance of "self" or "ego" and its processing of "meaning." Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.is a potent serotonergic hallucinogen or "psychedelic" that alters consciousness in a profound and characteristic way. First synthesized in 1938, its extraordinary psychological properties were not discovered until 1943 (1). LSD would go on to have a major effect on psychology and psychiatry in the 1950s and 1960s; however, increasing recreational use and its influence on youth culture provoked the drug's being made illegal in the late 1960s. As a consequence, human research with LSD has been on pause for half a century. However, inspired by a revival of research with other psychedelics, such as psilocybin and ayahuasca, a small number of new reports on the psychological effects of LSD have recently been published (2-6).LSD has a high affinity for a range of different neurotransmitter receptors, but its characteristic psychological effects are thought to be mediated by serotonin 2A receptor (5-HT 2A R) agonism (7). Previous neurophysiological research with LSD is limited to electroencephalography (EEG) studies in the 1950s and 1960s. These reported reductions in oscillatory power, predominantly in the lower-frequency bands, and an increase i...

Psychedelic drugs have a long history of use in healing ceremonies, but despite renewed interest in their therapeutic potential, we continue to know very little about how they work in the brain. Here we used psilocybin, a classic psychedelic found in magic mushrooms, and a task-free functional MRI (fMRI) protocol designed to capture the transition from normal waking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen leveldependent (BOLD) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin. Fifteen healthy volunteers were scanned with arterial spin labeling and a separate 15 with BOLD. As predicted, profound changes in consciousness were observed after psilocybin, but surprisingly, only decreases in cerebral blood flow and BOLD signal were seen, and these were maximal in hub regions, such as the thalamus and anterior and posterior cingulate cortex (ACC and PCC). Decreased activity in the ACC/medial prefrontal cortex (mPFC) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects. Based on these results, a seed-based pharmaco-physiological interaction/ functional connectivity analysis was performed using a medial prefrontal seed. Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC. These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.receptor P silocybin is the prodrug of psilocin (4-hydroxy-dimethyltryptamine), the primary hallucinogenic component of magic mushrooms, and a classic psychedelic ("mind-manifesting") drug. Psilocybin has been used for centuries in healing ceremonies (1) and more recently in psychotherapy (2); it is capable of stimulating profound existential experiences (3), which can leave a lasting psychological impression (4). However, despite a wealth of literature on its phenomenology, we currently know very little about how its effects are produced in the brain. The present study sought to address this question using complementary functional MRI (fMRI) techniques and a protocol designed to image the transition from normal waking consciousness to the psychedelic state. Two groups of healthy subjects were scanned using arterial spin labeling (ASL) perfusion and blood-oxygen level-dependent (BOLD) fMRI during intravenous infusion of psilocybin. Infused over 60 s (2 mg in 10-mL saline), psilocybin's subjective effects begin within seconds (5), allowing the capture of the corresponding change in brain state.Results ASL Perfusion fMRI. Fifteen healthy, hallucinogen-experienced subjects (five females), mean age 34.1 (SD 8.2) were scanned with ASL. Subjects underwent an anatomical scan followed by two taskfree functional scans, each lasting 18 min. Subjects were instructed to relax and a fixation cross was displayed. Solutions were inf...

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