This fMRI analysis study (n=74 total) looks at how three different drugs -; nitrous oxide, ketamine, and lysergic acid diethylamide (LSD) -; affect the way different parts of the brain communicate with each other. By comparing brain scans taken before and during drug use, the study found that all three drugs reduced connectivity within certain networks in the brain, while enhancing connections between different networks. These effects were seen in areas of the brain that are important for our conscious experiences.
The neurobiology of the psychedelic experience is not fully understood. Identifying common brain network changes induced by both classical (i.e., acting at the 5-HT2 receptor) and non-classical psychedelics would provide mechanistic insight into state-specific characteristics. We analyzed whole-brain functional connectivity based on resting-state fMRI data in humans, acquired before and during the administration of nitrous oxide, ketamine, and lysergic acid diethylamide. We report that, despite distinct molecular mechanisms and modes of delivery, all three psychedelics reduced within-network functional connectivity and enhanced between-network functional connectivity. More specifically, all three drugs increased connectivity between right temporoparietal junction and bilateral intraparietal sulcus as well as between precuneus and left intraparietal sulcus. These regions fall within the posterior cortical hot zone, posited to mediate the qualitative aspects of experience. Thus, both classical and non-classical psychedelics modulate networks within an area of known relevance for consciousness, identifying a biologically plausible candidate for their subjective effects.
Dai and colleagues situate their work in the context of incomplete understanding of the neurobiology of the psychedelic experience. They note that classical psychedelics such as LSD primarily act at the serotonergic 5-HT2 receptor, while non-classical drugs such as ketamine and nitrous oxide act at different molecular targets but can produce overlapping phenomenology, increased neurophysiologic complexity, and changes in oscillatory activity and brain state repertoire. Prior to this study there had been no resting-state fMRI characterisation of nitrous oxide at psychedelic concentrations in humans, and it remained unclear whether diverse psychedelics share drug-invariant network-level signatures. The study therefore set out to identify common brain network changes induced by both classical and non-classical psychedelics. Using a primary, prospective fMRI dataset of nitrous oxide administration and secondary analyses of existing ketamine and LSD fMRI datasets, the investigators compared within- and between-network functional connectivity changes associated with each drug. Propofol sedation was included as a non-psychedelic control to help distinguish general state-dependent connectivity changes from psychedelic-specific effects.
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Hibicke, M., Gobbi, G. · Journal of Neuroscience (2020)
Li, D., Vlisides, P. E., Mashour, G. A. · NeuroImage (2022)
The study combined one prospectively collected dataset of nitrous oxide with three secondary datasets (ketamine, LSD, and propofol) drawn from prior studies or open repositories. Dataset 1 (nitrous oxide) comprised 16 healthy participants (8 female; mean age 24.6 ± 3.7 years) scanned at the University of Michigan. Participants underwent two resting-state scans: baseline (100% oxygen, 20 min) and during inhaled subanesthetic nitrous oxide (35% in oxygen) for 40 min; two subjects were excluded for excessive motion. Altered states of consciousness were assessed with an 11-dimension questionnaire before and after nitrous oxide exposure. Standard clinical monitoring and measures to mitigate adverse effects were used. Dataset 2 (ketamine) included 12 right-handed participants (5 female; mean age 41.4 ± 8.6 years) scanned at Fudan University; the investigators analysed the subanesthetic, pre-loss-of-responsiveness period during intravenous ketamine infusion (stepwise dosing totalling up to 1.0 mg/kg in the analysed window). Dataset 3 (LSD) used open-access preprocessed data from 15 participants (5 female; mean age 38.4 ± 8.6 years) who received 75 μg intravenous LSD with scanning approximately 70 min after dosing. Dataset 4 (propofol) comprised previously published data from 17 participants during light, subanesthetic sedation (target-controlled infusion at an effect-site concentration of 1.3 μg/ml). Scanner platforms and acquisition parameters varied across datasets; each dataset also included high-resolution anatomical scans for co‑registration. Functional MRI preprocessing was performed largely in the CONN toolbox with procedures including slice timing correction, rigid-body motion correction and frame-wise displacement (FD) calculation, co-registration to anatomy, spatial normalisation to MNI space, band-pass filtering, regression of nuisance signals (motion derivatives, white matter, CSF), and spatial smoothing (6 mm FWHM). For the LSD dataset only, preprocessed data from the repository were used; that pipeline included de-spiking, scrubbing with an FD threshold of 0.4 and replacement of scrubbed volumes with local means. The investigators primarily applied an FD threshold of 0.9 mm to preserve at least five minutes of continuous data in the nitrous oxide cohort and then applied the same threshold to ketamine and propofol for consistency; sensitivity analyses using FD = 0.4 produced sparser but broadly similar results. Functional connectivity analyses comprised two complementary approaches. ROI-to-ROI connectivity used a CONN HCP-ICA parcellation derived from the Human Connectome Project (covering seven cortical networks plus a cerebellar network and 32 ROIs) to produce Fisher-transformed pairwise correlation matrices and network-level multivariate tests of intra- and inter-network connectivity. Seed-based voxelwise analyses used the right temporoparietal junction (TPJ) as a seed to map whole-brain connectivity changes. Statistical inference for ROI and voxel analyses employed parametric cluster-based methods with false discovery rate (FDR) control at pFDR < 0.05 for multiple comparisons. Within-group paired comparisons (drug versus each dataset's own baseline) were used because of heterogeneity in scanner parameters; Spearman correlations tested relationships between nitrous-oxide-induced connectivity changes and altered-states questionnaire score changes.
Nitrous oxide produced robust subjective effects on the altered-states questionnaire: all 11 dimensions showed significant increases versus the pre-nitrous-oxide baseline. Reported t-statistics and FDR-corrected p-values included, for example, disembodiment t(12) = 5.302, pFDR = 0.002; blissful state t(12) = 3.692, pFDR = 0.011; and experience of unity t(12) = 3.315, pFDR = 0.013. Among dimensions, disembodiment showed the largest change, consistent with nitrous oxide's dissociative character. At the network level, nitrous oxide increased between-network connectivity and reduced within-network connectivity. Significant between-network increases included visual–salience (pFDR = 0.007), dorsal attention–frontoparietal (pFDR = 0.025), sensorimotor–language (pFDR = 0.025), dorsal attention–language (pFDR = 0.025), salience–default mode (pFDR = 0.025), and dorsal attention–default mode (pFDR = 0.025). Decreases in within-network connectivity were observed in the salience and language networks (both pFDR = 0.025). Ketamine and LSD showed broadly similar network-level patterns. The ketamine analysis enhanced between-network connectivity including frontoparietal–default mode (the extracted text does not clearly report the associated p-value). LSD increased multiple between-network connections with reported pFDR values such as visual–language (pFDR = 0.003), dorsal attention–language (pFDR = 0.020), language–default mode (pFDR = 0.020), visual–default mode (pFDR = 0.025), dorsal attention–default mode (pFDR = 0.025), salience–default mode (pFDR = 0.035), sensorimotor–default mode (pFDR = 0.042), and frontoparietal–default mode (pFDR = 0.042). LSD decreased within-network connectivity in the sensorimotor and dorsal attention networks (both pFDR = 0.030). Direct comparisons among the three psychedelic drugs showed some uncorrected differences (p < 0.05) but none remained significant after FDR correction. ROI-level analyses identified four functional connectivity cluster pairs consistently affected by all three psychedelics: right lateral parietal/TPJ—left intraparietal sulcus (IPS), right lateral parietal—right IPS, precuneus—left IPS, and right lateral parietal—left anterior insula. These changes primarily bridged the default mode and dorsal attention networks, with the right lateral parietal—left anterior insula pair spanning default mode and salience networks. To test whether these patterns were specific to psychedelic states, the investigators analysed propofol sedation: propofol did not show the general decrease in within-network connectivity characteristic of the psychedelics and only one cluster pair overlapped with the psychedelic effects (right lateral parietal—left anterior insula). After excluding connectivity changes shared with propofol, three common psychedelic-altered pairs remained: right TPJ/lateral parietal to bilateral IPS and precuneus to left IPS. Seed-based TPJ maps corroborated the ROI findings: across the three psychedelic drugs, TPJ connectivity increases overlapped in the bilateral IPS. In contrast, the TPJ seed map for propofol was located in occipital cortex and did not overlap the psychedelic pattern. Finally, in the nitrous oxide dataset, changes in TPJ-to-right IPS functional connectivity correlated with subjective intensity on five altered-states subscales: disembodiment (pFDR = 0.018), impaired control and cognition (pFDR = 0.018), anxiety (pFDR = 0.018), changed meaning of percepts (pFDR = 0.019), and experience of unity (pFDR = 0.046). Sensitivity analyses using an FD threshold of 0.4 produced sparser results but were broadly similar to those obtained with FD = 0.9 mm.
The investigators interpret their findings as evidence that both non-classical (nitrous oxide, ketamine) and classical (LSD) psychedelics produce a common large-scale network signature: reduced within-network functional connectivity together with increased between-network connectivity. They highlight the repeated involvement of posterior cortical nodes—particularly the right temporoparietal junction (TPJ), intraparietal sulcus (IPS) and precuneus—which reside in the authors' described ‘‘posterior cortical hot zone’’ and have been proposed to support the contents of conscious experience. TPJ, in particular, was consistently implicated by both ROI-to-ROI and seed-based analyses and is noted for its roles in multisensory integration and body ownership; modulation of TPJ connectivity is proposed as a plausible contributor to psychedelic phenomenology. A key comparative element of the study was the propofol control: propofol produced opposite network changes (enhanced within-network and reduced between-network connectivity) and overlapped with psychedelics only in an anterior insula connection, which the investigators therefore regarded as a nonspecific effect of pharmacological state change. The authors suggest that the shared network reconfiguration across chemically diverse psychedelics implies that the psychedelic experience may be better characterised at the level of network dynamics than by any single molecular target such as the 5-HT2 receptor. They further note potential relevance for therapeutic mechanisms, citing nitrous oxide, ketamine, and classical psychedelics' antidepressant effects and proposing that common network correlates might inform mechanistic understanding of therapeutic benefits. The authors acknowledge several limitations. Heterogeneity in acquisition and protocols across datasets and institutions—plus the use of publicly preprocessed LSD data with a different pipeline—limits comparability. The spatial resolution of 3T fMRI constrains inference about subcortical structures. Only the nitrous oxide dataset included prospective altered-states assessments, so subjective–neural comparisons across drugs are limited. Molecular mechanisms differ across drugs and participants varied in age and dosing protocols, restricting claims about a single common mechanism. The authors also note that while they observed shared TPJ–IPS effects, they did not statistically demonstrate precise identity of network reconfigurations across drugs and recommend further studies, including other psychedelics such as psilocybin and DMT. Despite these caveats, they conclude that this is the first fMRI characterisation of psychedelic-dose nitrous oxide and that the work identifies posterior cortical network alterations that are common to both classical and non-classical psychedelics.
This study was conducted at the University of Michigan Medical School, where Institutional Review Board (IRB, HUM00096321) approval was obtained. The study team carefully discussed risks and benefits with all participants, after which written informed consent was documented. This analysis was part of a clinical study registered with clinicaltrials.gov (NCT03435055); results from the primary study were posted in July 2021. Except for two subjects' data that were completely discarded due to excessive head motion (50% of tagged fMRI volumes), a total of 16 participants (8 females, means ± SD, ages: 24.6 ± 3.7 years) completed two fMRI resting-state scans before and during exposure to subanesthetic concentrations (35%) of nitrous oxide. All participants were classified as American Society of Anesthesiologists physical status I, i.e., healthy. Drug abuse and history of psychosis were exclusion criteria, among other health-related conditions (see published registry for details:). We applied a within-subject design for both fMRI and altered states assessment. Each volunteer participated in two study visits, an initial consent/pre-scan visit and then a scanning visit within three days. During the pre-scan visit, participants were consented and presented with the details of the study protocol and what they would experience during the scanning session. During the scanning visit, each participant first completed a validated altered-states-of-consciousness questionnaire, used for characterizing specific experiences rather than general state profiling. Participants were asked to complete the survey based on experiences during the two weeks that had just passed. Thereafter, fMRI data were collected during placebo (pure oxygen, 20 min) followed by inhaled nitrous oxide at subanesthetic concentrations (35%, in oxygen) over 40 min. It is standard clinical practice to administer 100% oxygen in advance of an inhaled anesthetic because it allows the lungs to denitrogenate and enhances oxygen reserve in the event of sedation-related airway obstruction or compromise. The administration of nitrous oxide was initiated before entering the scanner to achieve at least 5 min of equilibrium prior to the start of the resting state scan so we could monitor and address any adverse physiological or psychological reactions to the state transition. Pressure and visual stimuli, related to a protocol assessing analgesic effects (data not presented here), were not presented until after the resting state scan, to acquire the cleanest data possible. Only resting state fMRI data were analyzed for the purpose of this study. After scanning and 30 min of recovery from nitrous oxide administration, the altered states question-naire was administered again. Participants were asked to complete the survey based on the study period during which nitrous oxide was administered. Among these 16 participants, 13 produced complete data from the altered states questionnaire, whereas three did not complete the questionnaire. To maximize safety, nitrous oxide was delivered using MRIcompatible anesthesia machines, and was first administered outside of the scanner, where airway patency and physiological stability were established prior to imaging. At least two fully trained anesthesiologists directed all anesthetic administration. All participants received ondansetron (4-8 mg IV) with an additional dose of dexamethasone (4 mg IV) if needed to prevent nausea and vomiting. In addition, glycoyrrolate (0.42-0.4 mg IV), labetalol (5-10 mg/kg IV), and midazolam (1-2 mg IV) were available to mitigate any side effects. Standard intraoperative monitors (electrocardiogram, blood pressure, pulse oximetry, capnography) were used throughout the experiment. Participants wore earplugs and headphones during the fMRI scanning. Data were acquired at Michigan Medicine, University of Michigan, using a Philips Achieva 3T scanner (Best, Netherlands). Functional images of the whole brain were acquired by a T2 * weighted echo-planar sequence with parameters: 48 slices, TR/TE = 2000/30 ms, slice thickness = 3 mm, field of view = 200 × 200 mm, flip angle = 90 ˚, scan time = 6 min. High-resolution anatomical images were also acquired for resting state fMRI co-registration.
We demonstrate that non-classical (nitrous oxide, ketamine) and classical (LSD) psychedelic drugs all reduce within-network functional connectivity and increase between-network connectivity. Common neural correlates induced by these psychedelics, controlled for with the use of a non-psychedelic sedative-hypnotic, included increased connectivity between right TPJ and bilateral IPS and between precuneus and left IPS. These network nodes are located in the posterior cortical hot zone, which has been posited to be critical for content of consciousness, i.e., the qualitative aspects of our experience. The consistent results across non-classical and classical psychedelics support the hypothesis that there is a common neurobiology underlying the psychedelic effect at the level of large-scale brain networks. Furthermore, the posterior cortical confluence of sensory and association cortex is a biologi-cally plausible candidate for the altered subjective experiences induced by psychedelic drugs. Finally, these data suggest the possibility that the psychedelic experience might not track with a single molecular mediator (e.g., 5HT 2 receptor) but rather with network-level events that could have a diversity of molecular mechanisms. This is consistent with, for example, the common effects of ketamine and classical psychedelics on alpha oscillations, complexity, repertoire of brain states, neuroplasticity, and clinical effects. Specifically, TPJ was the region most consistently involved in psychedelic-induced connectivity changes from both ROI-to-ROI and seed-based functional connectivity analyses. It is known that TPJ is important for multisensory integration and body ownership, modulation of which might contribute to psychedelic phenomenology. We controlled for the possibility that these changes might reflect a generic brain state transition through a comparison with propofol sedation, which induces functional connectivity changes opposite to those produced by psychedelics, namely, enhanced within-network connectivity and reduced between-network connectivity. Through this control analysis, we were able to eliminate connectivity changes in anterior insula, which was common to all four drugs and thus likely unrelated to the psychedelic state. The findings of our study inform not only psychedelic neuroscience but emerging psychedelic therapy. Nitrous oxide has been found to have anti-depressant effects in patients with treatment-resistant major depressive disorder. More recently, it has been shown that a 25% concentration of nitrous oxide is as effective as a 50% concentration for treatment-resistant major depression. The current study informs the network-level events in the brain that occur during exposure to a comparable concentration of nitrous oxide. Furthermore, ketamine, LSD, and other psychedelics have shown promise as anti-depressants. Identifying the common neural correlates induced by psychedelic drugs may lead to a more comprehensive mechanistic understanding of therapeutic benefits. Our study informs this neurobiology. There are numerous limitations to this investigation. First, fMRI datasets were derived from different study protocols and institutions, leading to heterogeneity (for more details, see Tablesand). LSD data were accessed from an open-resource database, in which only preprocessed data were shared (i.e., raw data were not available); the processing pipeline was distinct from the other datasets. Second, 3T resolution precludes the ability to make meaningful inferences regarding psychedelic effects on subcortical structures, such as those in the brainstem. Third, nitrous oxide was the only drug formally and prospectively studied for psychedelic phenomenology; volunteers participating in the secondary datasets did not have the same assessment. Thus, we must be circumspect in comparing the psychedelic experience across these drug protocols and restrict interpretation to the neural correlates of psychedelic drug administration. Fourth, although both nitrous oxide and ketamine are thought to act at NMDA receptors, there are other distinct targets considered critical for sedative-hypnotic effects, e.g., HCN1 channels for ketamine. Thus, it is not clear what accounts for the changes in subjective experience. Also, nitrous oxide, ketamine, and LSD were administered in different protocols to participants of different ages, without the goal of achieving a consistent target state. This also limits inferences that can be drawn about commonalities across the three drugs. Although we found that nitrous oxide, ketamine, and LSD all reduced within-network functional connectivity and increased between-network connectivity, including shared effects on TPJ and IPS connectivity, we did not statistically demonstrate the precise similarity of these network reconfigurations; further studies need to be performed. Finally, additional psychedelic drugs such as psilocybin, dimethyltryptamine, and methylenedioxymethamphetamine should be investigated for their effects on connectivity in the posterior cortical hot zone. Despite these limitations, this study is the first to characterize functional connectivity changes during the administration of psychedelic doses of nitrous oxide and, to our knowledge, the first study to identify cortical network reconfigurations that appear common to the administration of both classical and non-classical psychedelic drugs. Finally, these network alterations occur consistently in a posterior cortical region argued to be critical for the content of consciousness, presenting a neurobiologically plausible set of network nodes that mediate the psychedelic experience.
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