Neuroimaging & Brain MeasuresLSDLSD

Neural correlates of the LSD experience revealed by multimodal neuroimaging

In the first modern multimodal neuroimaging study of LSD, the authors report pronounced changes in cerebral blood flow, electrophysiological activity and large‑scale network communication that strongly correlated with the drug’s hallucinatory and consciousness‑altering effects. These findings clarify neural mechanisms of altered consciousness and point to potential applications of LSD in psychological research.

Authors

  • Suresh Muthukumaraswamy
  • Enzo Tagliazucchi

Published

PNAS
individual Study

Abstract

SignificanceLysergic 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.

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Research Summary of 'Neural correlates of the LSD experience revealed by multimodal neuroimaging'

Introduction

Carhart-Harris and colleagues situate this study within a long hiatus in modern human LSD research: although LSD was central to mid-20th century psychiatry, contemporary neuroimaging of its acute effects had not been undertaken. Earlier work with other psychedelics (for example psilocybin and ayahuasca) and older EEG studies suggested broad reductions in oscillatory power and alterations in resting-state networks, and animal and human data implicated hippocampal/parahippocampal circuitry and high-level cortical hubs such as the posterior cingulate cortex (PCC). However, the neural correlates of LSD in humans using modern multimodal methods remained uncharacterised, and questions persisted about how psychedelic-induced changes in spontaneous brain activity relate to hallmark subjective effects such as visual hallucinations and ego-dissolution. The study therefore set out to characterise the acute brain effects of LSD in healthy volunteers using a comprehensive, placebo-controlled multimodal neuroimaging protocol. Specifically, the investigators tested whether major resting-state networks (including the default-mode network, DMN) and hippocampal/parahippocampal circuitry would be implicated, and whether changes in cerebral blood flow (ASL), BOLD resting-state functional connectivity (RSFC), and MEG-measured oscillatory power would relate to subjective ratings of visual phenomena and alterations in selfhood.

Methods

A within-subjects, balanced-order design was used in which 20 healthy participants attended two dosing days (LSD and placebo) at least two weeks apart. Sessions combined arterial spin labelling (ASL), BOLD-fMRI, and magnetoencephalography (MEG) resting-state recordings acquired under eyes-closed, task-free conditions. LSD (75 μg in 10 mL saline) or placebo (10 mL saline) was administered intravenously over two minutes. Two ASL scans (total 16 min) were completed about 100 minutes after infusion, two BOLD resting-state scans (total 14 min) at 135 minutes, and two MEG resting-state scans (total 14 min) at approximately 225 minutes post-infusion. Analyses applied multiple-comparison correction and two-tailed testing except where strong prior hypotheses justified one-tailed tests. Sample attrition and analytic samples are reported in the extracted text: data from 15 volunteers were suitable for ASL and BOLD analyses and 14 for MEG analyses. Resting-state networks (RSNs) were identified from independent component analysis informed by an external dataset, and four metrics were calculated per RSN: within-RSN CBF, within-RSN RSFC (“integrity”), within-RSN BOLD signal variance, and between-RSN RSFC (“segregation”). MEG data were band-pass filtered into conventional frequency bands (delta through high gamma) and analysed for condition differences in oscillatory power; source modelling and cluster-permutation tests related power changes to subjective measures. Seed-based RSFC analyses used bilateral parahippocampal, primary visual cortex (V1) and ventromedial PFC seeds, with V1 localised via a retinotopic paradigm. The study was approved by the National Research Ethics Service and conducted under institutional and regulatory approvals; further methodological detail is reported in the SI Appendix. The extracted text does not clearly report full inclusion/exclusion criteria or participant demographic breakdown beyond mean ages and sex counts for analysis subsamples.

Results

Subjective effects were robust: all participants reported eyes-closed visual hallucinations and marked changes in consciousness under LSD, with subjective intensity relatively stable during the ASL and BOLD scans and attenuated somewhat by the time of the MEG scans. Fifteen participants contributed to ASL/BOLD analyses (four females; mean age 30.5 ± 8.0 years) and 14 to MEG (three females; mean age 32.1 ± 8.3 years). ASL showed increased cerebral blood flow (CBF) in visual cortex under LSD versus placebo. The magnitude of visual-cortex CBF increases correlated with ASC ratings of complex imagery (r = 0.64; P = 0.01; Bonferroni-corrected P = 0.04). Seed-based RSFC analyses revealed a markedly expanded V1 connectivity profile under LSD, with increased RSFC between V1 and widespread cortical and subcortical regions. Increased V1 RSFC correlated with subjective measures of visual hallucinations: VAS simple hallucinations (r = 0.62; P = 0.012; Bonferroni-corrected P = 0.048) and ASC elementary (r = 0.63; P = 0.012; Bonferroni-corrected P = 0.048) and complex imagery (r = 0.74; P = 0.0016; Bonferroni-corrected P = 0.006). In contrast, decreased RSFC was observed between the parahippocampus (PH) and retrosplenial cortex (RSC) and PCC, while PH showed increased RSFC with dorsal mPFC and right dorsolateral PFC. Decreased PH RSFC correlated strongly with ego-dissolution VAS ratings (r = 0.73; P = 0.0018) and with the ASC "altered meaning" factor (r = 0.82; P = 0.0002; Bonferroni-corrected P = 0.002). DMN integrity (within-RSN RSFC) decreased under LSD, and DMN disintegration correlated with ego-dissolution (r = 0.49; P = 0.03); this relationship was selective in that integrity of the other 11 RSNs did not correlate with ego-dissolution. Across the 12 investigated RSNs, increases in CBF were restricted to visual networks, whereas decreases in BOLD variance and integrity were widespread. Between-RSN segregation was also altered: decreased segregation occurred for eight RSN pairs, with one pair showing increased segregation. Decreased RSN segregation did not correlate with ego-dissolution (r = 0.12; P > 0.05). MEG analyses showed broadband decreases in oscillatory power under LSD, significant across most sensors for frequencies 1–30 Hz; suspected residual muscle artefact affected gamma-band results. Regression analyses linked decreased delta and alpha power to ego-dissolution (mean cluster r = -0.54, P < 0.05 for delta; r = -0.29, P < 0.05 for alpha) and linked decreased alpha power to simple hallucinations (mean cluster r = -0.61; P < 0.05). The alpha peak decreased in amplitude and shifted from about 10 Hz under placebo to about 12 Hz under LSD (t = 4.21; P = 0.0009). Source modelling localised power decreases to distributed regions including the PCC/precuneus (theta, alpha, beta) and other high-level cortical areas. Multimodal correlations connected these outcomes: increases in visual-cortex CBF related inversely to posterior-sensor alpha power (r = -0.59; P = 0.029), and increased V1 RSFC related strongly to decreased posterior alpha power (r = -0.81; P = 0.0015). The relationship between visual-cortex CBF and V1 RSFC trended positive (r = 0.43; P = 0.055). Mean decreases in RSN integrity correlated strongly with decreases in RSN variance (r = 0.89; P = 4 × 10^-6), and integrity/variance changes correlated with mean decreases in oscillatory power [integrity r = 0.79 (P = 0.001); variance r = 0.76 (P = 0.002)]. Mean decreases in RSN segregation correlated with decreases in RSN integrity (r = 0.53; P = 0.02) and with reduced oscillatory power (delta–beta combined, r = 0.67; P = 0.017). The investigators report limiting further exploratory permutations because of multiple-comparison concerns.

Discussion

The investigators interpret their results as providing a comprehensive view of LSD's acute neural effects and their relationship to characteristic subjective phenomena. They emphasise three principal sets of findings: increased visual-cortex CBF, expanded V1 RSFC and decreased occipital alpha power that together predict the magnitude of visual hallucinations; decreased DMN integrity, PH–RSC decoupling and reduced delta/alpha power (including in the PCC) that associate with ego-dissolution; and coherent relationships across imaging modalities that strengthen inferences about functional meaning (for example, links between BOLD-network disintegration and reductions in oscillatory power). Carhart-Harris and colleagues propose that expanded V1 RSFC and reduced alpha—which may reflect diminished cortical inhibition—allow non-visual processes such as emotion and cognition to more readily "colour" visual processing, producing eyes-closed visual imagery that resembles perception. They further suggest that PH–RSC coupling, DMN integrity and regular PCC oscillatory activity may be important for maintaining the sense of self, given the selective correlations between disruptions in these markers and ratings of ego-dissolution and altered meaning. The authors note phenomenological parallels between altered meaning under LSD and notions of "aberrant salience" in psychosis research, and they suggest the PH–RSC circuit may warrant investigation in certain psychotic states. The discussion positions these results alongside prior psychedelic imaging work and advances the broader idea that psychedelics induce network "disintegration" and "desegregation," consistent with an increase in cortical entropy. Methodological caveats acknowledged by the authors include the single-blind, balanced-order design (blinding is challenging with conspicuous psychoactive interventions), the separated timing of ASL, BOLD and MEG scans (simultaneous EEG–fMRI could be advantageous), and potential confounds from head motion despite rigorous correction. They also address a discrepant finding with a prior psilocybin ASL study that reported decreased CBF, noting that proxy metabolic measures can be confounded by vascular effects and advocating for EEG/MEG and dynamic fMRI as more temporally direct indices. Finally, the authors relate their findings to therapeutic hypotheses, suggesting that psychedelic-induced increases in neural entropy could disrupt entrenched pathological brain patterns, and they call for further work to test these ideas and to refine mechanistic understanding.

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RESULTS

The intensity of LSD's subjective effects was relatively stable for the ASL and BOLD scans but attenuated somewhat for the MEG (SI Appendix, Table). Participants carried out VAS-style ratings via button-press and a digital display screen presented after each scan (SI Appendix), and the 11-factor altered states of consciousness (ASC) questionnaire () was completed at the end of each dosing day (SI Appendix, Fig.). All participants reported eyesclosed visual hallucinations and other marked changes in consciousness under LSD. Data from 15 volunteers were suitable for the ASL and BOLD analyses (four females; mean age, 30.5 ± 8.0 y; SI Appendix). Differences in CBF in the two conditions were calculated using a whole-brain analysis (cluster-correction, P < 0.05). Greater CBF under LSD was observed in the visual cortex (Fig.), and the magnitude of these increases correlated positively with ratings of complex imagery on the ASC (r = 0.64; P = 0.01; Bonferroni corrected P = 0.04; SI Appendix, Fig.). The unthresholded difference in CBF can be viewed in Neurovault(neurovault. org/collections/FBVSAVDQ/). Seed-based RSFC analyses were also performed. A bilateral parahippocampal (PH) seed was chosen based on previous findings with psilocybinand a primary visual cortex (V1) seed was chosen based on the characteristic visual perceptual effects of psychedelics. V1 was identified using a retinotopic-localizer paradigm (SI Appendix). Finally, the ventromedial PFC (vmPFC) was chosen because of our previous focus on this region in studies with psilocybin and MDMA. Analyses revealed increased RSFC between V1 and a large number of cortical and subcortical brain regions (Fig.and SI Appendix, Table), decreased RSFC between the PH and the retrosplenial cortex (RSC) and PCC, and increased RSFC between the PH and dorsal mPFC and right dorsolateral PFC (Fig.and SI Appendix, Table). Increased RSFC between the vmPFC and the bilateral caudate and inferior frontal gyrus was also observed, as was decreased vmPFC-PCC RSFC (SI Appendix, Fig.and SI Appendix, Table). All the relevant unthresholded maps can be viewed in Neurovault(neurovault. org/collections/FBVSAVDQ/). Increased V1 RSFC (to the most significant regions shown in Fig.: P < 0.01; 5,000 permutations; SI Appendix, Fig.) correlated with VAS ratings of simple hallucinations (r = 0.62; P = 0.012; Bonferroni corrected P = 0.048; SI Appendix, Fig.), as well as ASC ratings of elementary (r = 0.63; P = 0.012; Bonferroni corrected P = 0.048; SI Appendix, Fig.) and complex (r = 0.74; P = 0.0016; Bonferroni corrected P = 0.006; SI Appendix, Fig.) imagery. Decreased PH RSFC (to the significant regions shown in Fig.) correlated with VAS ratings of ego-dissolution (r = 0.73; P = 0.0018; SI Appendix, Fig.) and "altered meaning" on the ASC (r = 0.82; P = 0.0002; Bonferroni corrected P = 0.002; SI Appendix, Fig.). Importantly, some of these (hypothesized) correlations were phenomenology selective (SI Appendix, Table): increased visual cortex CBF and V1 RSFC correlated more strongly with the visual hallucinatory aspect of the drug experience than the altered meaning/ego-dissolution aspect, whereas the opposite was true for decreased PH RSFC. Changes in vmPFC RSFC did not correlate with any of the ratings. Next, the effect of LSD on brain network properties was investigated. Twelve functionally familiar RSNs were identified in a set of 20 spatially independent components derived from independent data (human connectome project; SI Appendix). These RSNs are as follows: a medial visual network, a lateral visual network (VisL), an occipital pole network (VisO), an auditory network (AUD), a sensorimotor network, the DMN, a parietal cortex network (PAR), the dorsal attention network, the salience network, a posterior opercular network (POP), the left frontoparietal network, and the right frontoparietal network (rFP). Four metrics were calculated for each RSN: within-RSN CBF, within-RSN RSFC or "integrity," within-RSN BOLD signal variance, and between-RSN RSFC or "segregation." Between-condition differences in the first three metrics are shown in Fig., and the between-RSN RSFC results are shown in Fig.. Differences (increases) in CBF were restricted to the visual RSNs, whereas differences in variance and integrity (decreases) were much more pronounced and universal. According to previous research with psilocybin, it was predicted that decreased DMN integrity (or DMN "disintegration") would correlate with ratings of ego-dissolution, and this hypothesis was supported (r = 0.49; P = 0.03; SI Appendix, Fig.). Given the large number of possible permutations, additional correlational analyses were not performed; however, to test the selectivity of the relationship between DMN disintegration and ego-dissolution, correlations were calculated for ego-dissolution and the integrity of the other 11 RSNs, and none were significant (SI Appendix, Table). Disintegration of the visual RSNs did not correlate with ratings of visual hallucinations. See SI Appendix, Fig., for brain images of the RSN integrity results. Between-RSN RSFC or RSN segregation was also markedly modulated by LSD. Decreased segregation (red squares with white asterisks in Fig., right matrix) was observed between eight RSN pairs (VisL-PAR, VisL-dorsal attention network, VisO-POP, AUD-PAR, AUD-rFP, DMN-salience network, PAR-POP, POP-rFP), with only one pair (VisO-rFP) showing increased segregation (blue square with white asterisk in Fig., right matrix). Contrary to a prior hypothesis, decreased RSN segregation (in the eight networks that showed this effect) did not correlate with ratings of ego-dissolution (r = 0.12; P > 0.05). Data from 14 volunteers were suitable for the MEG analyses (three females; mean age, 32.1 ± 8.3 y). Primary analyses focused on between-condition differences in frequency-specific oscillatory power, measured during eyes-closed rest. The relevant data (14 min of rest) were acquired ∼50 min after completion of the MRI protocol and filtered into the following frequency bands: delta (1-4 Hz), theta (4-8 Hz), alpha (8-15 Hz), beta (15-30 Hz), low gamma (31-49 Hz), and high gamma (51-99 Hz). Results revealed decreased oscillatory power under LSD in four frequency bands (Fig.), with some suspected residual muscle artifact confounding the gamma results. For the lower-frequency bands (i.e., 1-30 Hz), the decreases reached significance in most of the sensors. To explore relationships between these outcomes and subjective measures, VAS ratings of ego-dissolution and visual hallucinations (simple and complex) were entered into regression analyses, using cluster permutation testing. Significant relationships were found between ego-dissolution and decreased delta (mean cluster, r = -0.54; P < 0.05) and alpha power (mean cluster, r = -0.29; P < 0.05) and between simple hallucinations and decreased alpha power (mean cluster, r = -0.61; P < 0.05) (Fig.). Plotting the power spectrum independently for each condition for the significant alpha cluster (Fig.), it is evident that the distribution of power is decreased across a broad frequency range under LSD, and the peak alpha rhythm is reduced in amplitude and of higher frequency (i.e., 10 Hz under placebo, 12 Hz under LSD; t = 4.21; P = 0.0009). Source modeling revealed that sources of the power decreases were relatively distributed throughout the brain (SI Appendix, Table), with significant effects in the PCC/precuneus (theta, alpha, and beta) and other high-level cortical regions (delta-beta). This study's multimodal design enabled correlational analyses to be performed between the various (significant) imaging outcomes. This was done in a hypothesis-driven manner, and because the outcomes' directions were already known, one-tailed tests were performed. Relationships were observed between the increases in CBF (localized to the visual cortex) and decreases in alpha power in posterior (occipital cortex) sensors (r = -0.59; P = 0.029; SI Appendix, Fig.) and between increases in V1 RSFC (to the most significant regions: P < 0.01; 5,000 permutations; SI Appendix, Fig.) and decreased posterior-sensor alpha power (r = -0.81; P = 0.0015; SI Appendix, Fig.), but there was only a trend-level relationship between increases in visual cortex CBF and increases in V1 RSFC (r = 0.43; P = 0.055). The mean change (decreases) in the integrity of the 12 RSNs correlated very strongly with the mean change (decreases) in their variance (r = 0.89; P = 4 × 10 -6 ; SI Appendix, Fig.). Neither metric correlated with the mean change in CBF, however [r = 0.1 (P > 0.05) and r = 0.33 (P > 0.05) for integrity and variance, respectively], nor head motion (SI Appendix), but they did correlate with the mean decrease in power (significant sensors) for the four displayed frequency bands [r = 0.79 (P = 0.001; SI Appendix, Fig.) and r = 0.76 (P = 0.002) for integrity and variance, respectively]. Mean decreases in RSN segregation (for the eight pairs that showed this effect) correlated with mean decreases in RSN integrity (mean of all 12 RSNs, r = 0.53; P = 0.02; SI Appendix, Fig.) and reduced oscillatory power (delta-beta combined, r = 0.67; P = 0.017; SI Appendix, Fig.), but not decreased RSN variance (r = 0.33, P > 0.05) nor increased CBF (r = 0.18; P > 0.05). Given the number of possible permutations, we chose not to explore beyond these relationships.

CONCLUSION

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. 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. 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, and eyes-closed fMRI recordings during ayahuasca hallucinations suggest the visual cortex behaves "as if" there is external input when there is none(see also ref.. 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. Cortical alpha has been hypothesized to serve a general inhibitory function, filtering out "stimulus-irrelevant" information. Thus, reduced alpha powercould 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. 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.). 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. 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.). Thus, in the same way the neurobiology of psychedelicinduced visual hallucinations can inform on the neurobiology of visual processing, so the neurobiology of psychedelic-induced egodissolution can inform on the neurobiology of the "self" or "ego", 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, 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. 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. In this context, it is intriguing to consider whether the PH-RSC circuit is involved in certain psychosis-related experiences (e.g., refs.. 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.. 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.) and simultaneously reduce the degree of separateness or segregation between them (e.g., ref.; 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. 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. Regarding the discrepant finding, a previous psilocybin ASL study of ours revealed decreased CBF postpsilocybin (i.v.) during eyes-open rest, 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. 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 MEGand RSFCfindings 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, 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, 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.

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