Neural correlates of the LSD experience revealed by multimodal neuro-imagerie
Robin L. Carhart-Harris, Suresh Muthukumaraswamy, Leor Roseman, Mendel Kaelen, Wouter Droog, Kevin Murphy, Enzo Tagliazucchi, Eduardo E. Schenberg, Timothy Nest, Csaba Orban, Robert Leech, Luke T. Williams, Tim M. Williams, Mark Bolstridge, Ben Sessa, John McGonigle, Martin I. Sereno, David Nichols, Peter J. Hellyer, Peter Hobden, John Evans, Krish D. Singh, Richard G. Wise, H. Valerie Curran, Amanda Feilding, and David J. Nutt
PNAS (Proceedings of The National Academy of Sciences of the USA), 2016, 113, 17, 4853-4858
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.
Keywords : LSD | serotonin | consciousness | brain | psychedelic
Lysergic acid diethylamide (LSD), the prototypical “psychedelic,” may be unique among psychoactive substances. In the decades that followed its discovery, the magnitude of its effect on science, the arts, and society was unprecedented. LSD produces profound, sometimes life-changing experiences in microgram doses, making it a particularly powerful scientific tool. Here we sought to examine its effects on brain activity, using cutting-edge and complementary neuroimaging techniques in the first modern neuro-imaging study of LSD. Results revealed marked changes in brain blood flow, electrical activity, and network communication patterns that correlated strongly with the drug’s hallucinatory and other consciousness-altering properties. These results have implications for the neurobiology of consciousness and for potential applications of LSD in psychological research.
Lysergic acid diethylamide (LSD) 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-HT2AR) 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 in the frequency of alpha rhythms (8). Broadband decreases in cortical oscillatory power have been observed in modern EEG and magnetoencephalography (MEG) studies with psilocybin (9, 10), with EEG and the dimethyltryptamine-containing brew “ayahuasca” (11), and with rodent brain local-field potential recordings and a range of different 5-HT2AR agonists (12–14).
The effects of psychedelics (other than LSD) on human brain activity have also previously been investigated with positron emission tomography (PET) (15) and functional magnetic resonance imaging (fMRI) (16). fMRI studies with psilocybin revealed decreased cerebral blood flow (CBF) and blood oxygen leveldependent (BOLD) signal in connector hubs (16), decreased resting state functional connectivity (RSFC) in major resting state networks (RSNs) such as the default-mode network (DMN) (17), and the emergence of novel patterns of communication (18, 19), whereas increased cortical glucose metabolism was found with PET (15). Notably, the spatial locations of the PET-, fMRI-, EEG-, and MEG-measured effects of psychedelics are relatively consistent; for example, high-level cortical regions, such as the posterior cingulate cortex (PCC), and some of the principal effects of psilocybin revealed by fMRI (e.g., decreased DMN RSFC) were recently replicated by a separate team working with ayahuasca (20).
Consistent with a prior hypothesis (17), these studies suggest that an “entropic” effect on cortical activity is a key characteristic of the psychedelic state. However, a putative excitation of hippocampal/ para-hippocampal gyri activity has also been observed with fMRI and psychedelics in humans (19) and animals (14). Moreover, depth EEG studies in the 1950s reported activations in medial temporal lobe regions during psychosis-like states under LSD and other psychedelics (21, 22). Further, patients with epilepsy with resection of the medial temporal lobes showed attenuated LSD effects postsurgery (23), and electrical stimulation of medial temporal lobe circuitry produces visual hallucinations of somewhat similar nature to those produced by psychedelics [e.g., distorted visual perception (24) and dreamlike “visions” (25)].
The present study sought to investigate the acute brain effects of LSD in healthy volunteers, using a comprehensive placebocontrolled neuroimaging design incorporating ASL, BOLD signal measures, and MEG resting state scans. It was predicted that major RSNs (e.g., the DMN) and hippocampal/ para-hippocampal gyri circuitry would be implicated in the drug’s mechanism of action.
Twenty healthy participants attended two scanning days (LSD and placebo) at least 2 wk apart in a balanced-order, within-subjects design. Sessions included an fMRI followed by a MEG scan, each lasting 75 min. Data were acquired during eye-closed, task-free, “resting state” conditions. Drug/placebo were administered in solution and injected i.v. over the course of 2 min. Two resting state ASL scans totaling 16 min were completed 100 min after i.v. administration of LSD (75 μg in 10 mL saline) or placebo (10 mL saline), corresponding to the initial phase of the peak subjective effects of LSD (peak effects were reached ∼120–150 min postinfusion). Two resting state BOLD scans totaling 14 min were completed 135 min postinfusion, and two resting state MEG scans totaling 14 min were completed 225 min postinfusion. All analyses applied multiple comparison correction (SI Appendix) and two-tailed hypothesis testing unless particularly strong prior hypotheses were held.