Significance 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 neuroimaging 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.

Abstract 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 level-dependent (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.

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-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 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-HT 2A R 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 level-dependent (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/parahippocampal 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 placebo-controlled neuroimaging design incorporating ASL, BOLD signal measures, and MEG resting state scans. It was predicted that major RSNs (e.g., the DMN) and hippocampal/parahippocampal 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.

Discussion The present findings offer a comprehensive new perspective on the changes in brain activity characterizing the LSD state, enabling us to make confident new inferences about its functional neuroanatomy. Principal findings include increased visual cortex CBF, RSFC, and decreased alpha power, predicting the magnitude of visual hallucinations; and decreased DMN integrity, PH-RSC RSFC, and delta and alpha power (e.g., in the PCC), correlating with profound changes in consciousness, typified by ego-dissolution. More broadly, the results reinforce the view that resting state ASL, BOLD FC, and MEG measures can be used to inform on the neural correlates of the psychedelic state (9, 16). Importantly, strong relationships were found between the different imaging measures, particularly between changes in BOLD RSFC (e.g., network “disintegration” and “desegregation”) and decreases in oscillatory power, enabling us to make firmer inferences about their functional meaning. The present study sheds new light on the relationship between changes in spontaneous brain activity and psychedelic-induced visual hallucinations. Strong relationships were observed between increased V1 RSFC and decreased alpha power, as well as ratings of both simple and complex visual hallucinations. The latter result is consistent with previous findings with psilocybin (29). Importantly, a very strong relationship was also observed between increased V1 RSFC and decreased alpha power in occipital sensors, suggesting that as well as being commonly related to visual hallucinations, these physiological effects are closely interrelated. The increase in V1 RSFC under LSD is a particularly novel and striking finding and suggests that a far greater proportion of the brain contributes to visual processing in the LSD state than under normal conditions. This expansion of V1 RSFC may explain how normally discreet psychological functions (e.g., emotion, cognition, and indeed the other primary senses) can more readily “color” visual experience in the psychedelic state. Biologically informed modeling has suggested that instability within the primary visual cortex may facilitate the emergence of geometric hallucinations via self-organized patterns of neural excitation (30), and eyes-closed fMRI recordings during ayahuasca hallucinations suggest the visual cortex behaves “as if” there is external input when there is none (31) (see also ref. 29). The present findings of increased visual cortex CBF, expanded V1 RSFC, and decreased alpha power may be seen as consistent with the notion of “seeing with eyes-shut” under psychedelics, because they are all properties normally associated with visual stimulation (32, 33). Cortical alpha has been hypothesized to serve a general inhibitory function, filtering out “stimulus-irrelevant” information (34). Thus, reduced alpha power (9, 29, 35) could have disinhibitory consequences, facilitating the release of anarchic patterns of excitation that manifest spontaneously and experientially as visual hallucinations. This hypothesis is leant (indirect) support by two prior studies that found reduced spontaneous visual cortex alpha power under psilocybin alongside reduced evoked visual responses (9, 29). Further work, using higher-resolution brain imaging, machine learning techniques, dynamic measures of functional and effective connectivity, and improved “capture” of visual hallucinations (e.g., via button press or experience sampling), may help to develop this appealing model (e.g., see ref. 36). The present data also inform on another fundamental question; namely, how do psychedelics alter brain function to (so profoundly) alter consciousness? Interestingly, although the effects of LSD on the visual system were pronounced, they did not significantly correlate with its more fundamental effects on consciousness. Instead, a specific relationship was found between DMN disintegration and ego-dissolution, supporting prior findings with psilocybin (17). Also consistent with previous psilocybin research (9), a significant relationship was found between decreased PCC alpha power and ego-dissolution. Moreover, an especially strong relationship was found between PH-RSC decoupling and ego-dissolution (see also ref. 10). Thus, in the same way the neurobiology of psychedelic-induced visual hallucinations can inform on the neurobiology of visual processing, so the neurobiology of psychedelic-induced ego-dissolution can inform on the neurobiology of the “self” or “ego” (37), and the present results extend our understanding in this regard, implying that the preservation of DMN integrity, PH-RSC communication, and regular oscillatory rhythms within the PCC may be important for the maintenance of one’s sense of self or ego. Linking these results to pathology, an especially strong relationship was found between PH-RSC decoupling and the “altered meaning” factor on the ASC. Interestingly, altered activity within the PH-RSC circuit under psilocybin has previously been found to correlate with the spiritual experience and insightfulness dimensions of the 11-factor ASC (10), and altered RSC/PCC activity has been found to correlate with ego-dissolution (9), suggesting modulation of this particular circuit may be an important feature of especially profound psychedelic experiences. The altered meaning factor of the ASC is composed of items such as “some unimportant things acquired a special meaning” and “things in my surroundings had a new or alien meaning” that are phenomenologically resonant with the notion of “aberrant salience” in schizophrenia research (38). Impaired reality testing as a corollary of impaired ego functioning may explain an association between ego-dissolution and altered meaning. Similarities between aspects of psychosis and the psychedelic state have long been debated, and one of the most influential hypotheses on the neurobiology of schizophrenia proposes a functional disconnect between certain brain structures in the disorder (39). In this context, it is intriguing to consider whether the PH-RSC circuit is involved in certain psychosis-related experiences (e.g., refs. 40 and 41). More specifically, it would be interesting to examine the integrity of the PH-RSC connection in cases of endogenous psychoses in which phenomena such as altered meaning, ego-dissolution, and/or impaired reality-testing are observed. To our knowledge, these specific phenomena have never been formally investigated in imaging studies involving patients exhibiting endogenous psychoses, but studies on early psychosis and the at-risk mental state may be informative in this regard (e.g., ref. 40). When the present results are considered in relation to previous human neuroimaging studies with psychedelics, some general principles emerge. It seems increasingly evident that psychedelics reduce the stability and integrity of well-established brain networks (e.g., ref. 16) and simultaneously reduce the degree of separateness or segregation between them (e.g., ref. 42); that is, they induce network disintegration and desegregation. Importantly, these effects are consistent with the more general principle that cortical brain activity becomes more “entropic” under psychedelics (17). Furthermore, with the benefit of the present study’s multimodal imaging design, we can extend on these generic insights to postulate some more specific physiological properties of the psychedelic state and how these relate to some of its key psychological properties; namely, expanded V1 RSFC relates to the magnitude of visual hallucinations and decoupling of the PH-RSC circuit relates to the level of ego-dissolution, and perhaps also the profundity of a psychedelic experience more generally (also see refs. 9 and 10 in this regard). Before concluding, we should highlight some general limitations of the present study and address a discrepant finding in the field. Regarding limitations, a fully randomized, double-blind design is often considered the gold standard; however, experimental blinding is known to be ineffective in studies with conspicuous interventions. Thus, a single-blind, balanced-order design with an inert placebo (offering the simplest and “cleanest” possible control condition) was considered an effective compromise. Also, although the multimodal design of this study was an advantage, the experimental protocol was demanding for participants, and the different scan types (ASL, BOLD, and MEG) occurred separately in time. Simultaneous EEG-fMRI may therefore offer some advantageous in this regard. Another general limitation of imaging studies involving potent psychoactive drugs, is the issue of between-condition differences in head motion and related artifacts. In this study, we opted to use the most rigorous motion-correction strategies available (SI Appendix), despite motion levels being no higher than those seen in previous studies by our group (16). Regarding the discrepant finding, a previous psilocybin ASL study of ours revealed decreased CBF postpsilocybin (i.v.) during eyes-open rest (16), whereas the present i.v. LSD study found increased CBF localized to the visual cortex with eyes-closed rest. One must be cautious of proxy measures of neural activity (that lack temporal resolution), such as CBF or glucose metabolism, lest the relationship between these measures, and the underlying neural activity they are assumed to index, be confounded by extraneous factors, such as a direct vascular action of the drug (43). For this reason, more direct measures of neural activity (e.g., EEG and MEG) and/or more dynamic fMRI measures (e.g., RSFC) should be considered more reliable indices of the functional brain effects of psychedelics, and it is notable in this regard that our previous MEG (9) and RSFC (16, 19, 42) findings with psilocybin are highly consistent with those observed here with LSD. Thus, rather than speculate on the above-mentioned discrepancy, it may be more progressive to highlight the advantages of EEG/MEG and dynamic fMRI and conclude that further work would be required to resolve discrepancies in the literature regarding the effects of psychedelics on metabolically related metrics that lack temporal resolution. Finally, as evidence supporting the therapeutic potential of psychedelics mounts (6, 44⇓–46), so does our need to better understand how these drugs work on the brain. In many psychiatric disorders, the brain may be viewed as having become entrenched in pathology, such that core behaviors become automated and rigid. Consistent with their “entropic” effect on cortical activity (17), psychedelics may work to break down such disorders by dismantling the patterns of activity on which they rest. Future work is required to test this hypothesis and the others that have been presented here as part of a broader initiative to properly utilize these valuable scientific tools.

Methods This study was approved by the National Research Ethics Service committee London-West London and was conducted in accordance with the revised declaration of Helsinki (2000), the International Committee on Harmonization Good Clinical Practice guidelines, and National Health Service Research Governance Framework. Imperial College London sponsored the research, which was conducted under a Home Office license for research with schedule 1 drugs. For more methods see SI Appendix, Methods.

Acknowledgments We thank supporters of the Walacea.com crowdfunding campaign for helping secure the funds required to complete this study. This report presents independent research carried out at the National Institute of Health Research/Wellcome Trust Imperial Clinical Research Facility. This research received financial support from the Safra Foundation (which funds D.J.N. as the Edmond J. Safra Professor of Neuropsychopharmacology) and the Beckley Foundation (the study was conducted as part of the Beckley-Imperial research programme). R.L.C.-H. is supported by an Medical Research Council clinical development scheme grant. S.M. is supported by a Royal Society of New Zealand Rutherford Discovery Fellowship. K.M. is supported by a Wellcome Trust Fellowship (WT090199).

Footnotes Author contributions: R.L.C.-H., S.M., K.M., R.L., J.E., K.D.S., R.G.W., A.F., and D.J.N. designed research; R.L.C.-H., S.M., M.K., W.D., L.T.W., T.M.W., M.B., B.S., and P.H. performed research; C.O., R.L., J.M., M.I.S., D.N., P.J.H., and H.V.C. contributed new reagents/analytic tools; R.L.C.-H., S.M., L.R., M.K., K.M., E.T., E.E.S., T.N., and R.L. analyzed data; and R.L.C.-H., S.M., L.R., and D.J.N. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

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