Michal Beneš
Tomáš Páleníček
Jiří Horáček- 1Department of Psychiatry and Medical Psychology, Third Faculty of Medicine, Charles University, Prague, Czechia
- 2Center for Advanced Studies of Brain and Consciousness, National Institute of Mental Health, Klecany, Czechia
- 3Psychedelic Research Center, National Institute of Mental Health, Klecany, Czechia
Research on psychedelic drugs, such as psilocybin, LSD or DMT, is a burgeoning field, with an increasing number of studies showing their promise in treatment of mental disorders as well as examining their mechanism of action. Determining their effect on the brain is crucial from clinical standpoint, but also offers highly promising avenues of advancement in basic neuroscience—functional magnetic resonance imaging (fMRI) is one of the most useful techniques to do so, with a number of newly published studies increasing every year. Here we present a scoping review of existing fMRI studies of serotonergic psychedelics to date, with a focus on finding unifying themes among them, in order to comprehensively grasp current directions within this field. We cluster the existing studies by fMRI modality and find several lines of developing concepts complementing the established models of psychedelic actions on the brain: namely, we describe a general picture of de-differentiation with the default mode network at its core captured by a diverse array of different techniques, complex changes to the thalamus, amygdala and medial temporal lobe structures, and the importance of the phenomenon of ego dissolution. Finally, contrasts to phenomenologically similar states and the successful process of anchoring fMRI findings to other markers are discussed.
1 Introduction
The research into psychedelics is undergoing a resurgence. Accumulating clinical data point to a great potential of these substances in treatment of a range of psychiatric disorders. If proven effective, psychedelic drugs would provide a sorely needed addition to the armamentarium of psychiatric therapies, which currently still remain inadequate for an unacceptably large portion of patients—as an example, in a respected study for treatment of depression, a full third of patients did not achieve remission (Gaynes et al., 2009). Psychedelics with their radically different mechanism of action thus present an opportunity to narrow or even fill this gap. Not just in treatment-resistant depression—research shows promise in addictions, OCD, existential distress in terminal conditions (Nichols, 2016), anorexia nervosa (Peck et al., 2023), depressive episodes in type II bipolar disorder (Aaronson et al., 2024), and even beyond psychiatry as in migraine (Schindler et al., 2021), cluster headache (Madsen et al., 2024) and more.
With such promising empirical data, research into elucidating mechanisms of action becomes indispensable. It has long been known that the key receptor target for classical serotonergic psychedelics is the 5HT2A receptor (Nichols, 2016), but that still tells us very little about the complex effect these compounds clearly have on the human brain on all levels, from deeper molecular mechanisms within cells to neuron-to-neuron interaction, regional activity changes, whole-brain function changes all the way to subjective effects and observable behavior. Fortunately, substantial progress is being made on all of these levels. Especially when looking at their whole-brain and regional effects, it can be appreciated how psychedelics can also serve as a tool for informing work in more theoretical areas of neuroscience such as consciousness research (Rankaduwa and Owen, 2023), painting a rich picture of the human brain function all the way from health to disease and how that function can be externally perturbed and further studied that way.
Functional magnetic resonance imaging (fMRI) allows for investigating multiple aspects of brain function on this large-scale level, depending on the modality used. Task-based fMRI studies visualize activations of brain areas in response to a defined stimulus (e.g., presentation of a picture). On the other hand, resting-state fMRI studies investigate functional connectivity of brain regions without any outside stimulus, thus reflecting (as the name suggests) communication between brain areas at rest. This way, organization of the brain into so called canonical resting state networks emerges. Functional connectivity can be further expanded upon in studies of effective connectivity—this method employs further statistical methods to determine the direction and valence (excitatory or inhibitory) of the signal (Chen and Glover, 2015). A different approach is presented by a heterogenous group of methods we collectively call here global measures, which instead of subdividing the brain into areas study its functional integration as a whole.
There have been groundbreaking psychedelic fMRI studies made in the previous decades, making findings that form the basis of current research and helping formulate the general contemporary theories of psychedelic action on the brain—the most frequently discussed being the Cortico-Striatal-Thalamo-Cortical (CSTC) model and the Relaxed Beliefs Under Psychedelics (REBUS) model, as well as the more recent Cortico-Claustro-Cortical (CCC) model and a number of others. More specifically, the CSTC model posits psychedelics to disinhibit the thalamus via direct 5HT2A receptor action, causing more excitatory action on the cortex, and thus weakening its function as a filter and allowing more information to pass through—e.g. as visual hallucinations (Vollenweider and Geyer, 2001). The REBUS model builds on the predictive coding principle and proposes that psychedelic drugs cause decrease in confidence in prior beliefs though increase in brain entropy (see section 3.1 for definition and discussion of the term), and thus allow for their revision (Carhart-Harris and Friston, 2019). Other models have been proposed as well, such as the CCC model, which attributes the observed desynchronization of canonical resting state networks (such as the DMN) to their functional decoupling from the claustrum, which is rich in the 5HT2A receptors (Doss et al., 2022). For a review of these models of psychedelic action see Doss et al. (2022).
As of now, as the field is further maturing, a sufficient number of papers exists to allow for formulation of broader conceptual “flows” within the current discourse independently of the theoretical models, offering a broad snapshot of the current state of knowledge. There has already been a number of review and systematic review articles conducted in this field, bringing into focus various aspects of the developing field: a review (McCulloch et al., 2022b) and a systematic review (Linguiti et al., 2023) of psychedelic neuroimaging mainly focused on methodology, a systematic review specifically on the DMN modulation (Gattuso et al., 2022), a meta-analysis of functional imaging (Castelhano et al., 2021), a review of neuroimaging in psilocybin-based psychotherapy (Gill et al., 2022), and more (Müller and Borgwardt, 2019; Soares et al., 2023). Also see Vollenweider and Preller (2020) and Kwan et al. (2022) for broader reviews of psychedelic mechanisms of action. However, to the best of our knowledge, a work solely focused at summarizing all of the current themes within the findings in psychedelic fMRI has been missing. To remediate this gap, we have conducted the present scoping review, which we believe would be valuable especially for new researchers seeking to enter the field. We would also like to bring attention to a very recent review published that brings valuable perspective on differences between fMRI (and PET) findings between individual psychedelic substances (Frautschi et al., 2024), whereas we choose to treat the serotonergic psychedelics as a whole.
For the sake of intelligibility, we cluster the results to several categories. There are multiple possible ways to do this: by specific substances, by acute vs. longitudinal effects, by population and more. We chose a rough clustering by different fMRI techniques as outlined above—each of them examines different aspects of brain function not available to the others, thus reflecting distinct processes (the line between these clusters naturally becoming blurry in multiple instances). In addition, we add a specific section dedicated to ego dissolution, which seems to be emerging as a key subjective phenomenon within the psychedelic experience, and which on its own carries enough fMRI correlates to be discussed here separately. The findings we discuss in the narrative text are those that have been detected by multiple studies, or are otherwise in line with other research.
2 Methods
To conduct this scoping review, we carried out search of the existing literature on fMRI imaging of the effect of serotonergic psychedelics, published as of time of search. Inclusion criteria were: articles in English language, use of fMRI, direct analysis of fMRI data from human subjects who received psilocybin, LSD, DMT, ayahuasca or mescaline. The literature available on Pubmed was searched in September 2024. The following search string was applied: (psychedelic OR psilocybin OR lsd OR mescaline OR ayahuasca OR dimethyltryptamine) AND (fmri OR “functional magnetic” OR BOLD OR “arterial spin labeling”) In total, 566 references were obtained. See Figure 1 for PRISMA flow diagram of study selection and for exclusion criteria (Page et al., 2021). Articles selected for analysis were extracted and organized using a reference manager, read in full text and reviewed by M. B. and J. H. with disagreements resolved by discussion, and with all authors then contributing to the information synthesis.
Figure 1. PRISMA flow diagram for study selection and exclusion process.
3 Results
A total of 71 original studies were reviewed in full text. Thirty five of these studies examined psilocybin, 30 LSD, 8 ayahuasca and 5 DMT. There was no fMRI study concerning mescaline. As for clustering by fMRI techniques we use in this review, 27 studies examined functional connectivity, 22 global measures, 15 were task-based, and 7 examined effective connectivity. Multiple studies examined more than one substance, and some studies belong into more than one fMRI modality. Overview of findings from all studies reviewed is presented in Table 1. As mentioned above, not all of these studies are discussed in the narrative text, as our main focus was to capture broader concepts. Vast majority of studies examined the acute effect of the substances, i.e., fMRI scans being acquired during intoxication; for studies where this is not the case (e.g., scans made before and after intoxication), this fact is highlighted in Table 1. Methodological parameters of all studies reviewed are presented in Table 2.
Table 1. Summary of findings of and techniques utilized in the reviewed studies.
Table 2. Summary of methodologies of reviewed studies.
While the studies within the field remain very heterogenous, owing in part to the breadth of problems possible to study through psychedelics, we have indeed been able to identify several main themes which repeat in variations across studies and sometimes different substances. Some of these have already been so widely replicated that they have their firm place in the current discourse (e.g., decrease in modularity, increase in global connectivity), some correspond to the respective models of psychedelic action described above, while others could be described as more outlying.
3.1 Global measures
We begin with description of the effects psychedelics exert on the brain as a whole. Among these, the clearest finding is a general increase in global functional connectivity, found across multiple psychedelic substances (Timmermann et al., 2023; Tagliazucchi et al., 2016); in some cases, the findings become more nuanced, observing a simultaneous increase in sensory global connectivity and decrease in associative global connectivity (Preller et al., 2018b, 2020). Global brain hyperconnection was also linked to heightened subjective effects (Mortaheb et al., 2024).
Another widely discussed finding is an increase in entropy, with one study even finding a correlation with an increase in openness after 2 weeks (Lebedev et al., 2016). Entropy is a quantity originally derived from thermodynamics, broadly defined as a measure of uncertainty of a system, or the degree of its disorder—in neurobiological sense, this degree of disorder has been posited to reflect the measure of subjective uncertainty and ultimately level of consciousness (Carhart-Harris et al., 2014). It can also be viewed as a measure of complexity (Mikoláš et al., 2012). However, entropy remains an elusive metric, with a number of different techniques employed to determine it (see McCulloch et al., 2024) for their discussion and evaluation. These include Shannon entropy (Viol et al., 2017), sample entropy (Lebedev et al., 2016), entropy of possible states (Tagliazucchi et al., 2014) or examining complexity more generally through brain activity fractal dimension analysis (Varley et al., 2020). In addition, entropy is explored in EEG and MEG studies (Schartner et al., 2017)—these however are beyond the scope of this paper.
Apart from these findings, there is a number of other experimental approaches to examining global brain function, such as studies on brain dynamics, which investigate temporal changes within the fMRI time series. Consistent with the findings of increased entropy, a series of studies with psilocybin, LSD (Singleton et al., 2022) and DMT (Singleton et al., 2023) utilizing network control theory has found a reduction of energy needed for transitioning from one brain state (here defined as commonly recurring patterns of co-activation) to another, thus allowing for more facile switching between them. Leading Eigenvector Dynamics Analysis (LEiDA), a method examining time-varying functional connectivity patterns, has revealed a suppression of a pattern corresponding to the fronto-parietal network and at the same time a state of increased global coherence, suggestive of weakening of the normally present network structure and instead transition into globally highly integrated state (Lord et al., 2019); a more recent study then replicated these findings and found their correlation with psilocin plasma levels and subjective drug effects (Olsen et al., 2022). General de-differentiation (we define de-differentiation here as a reduction in normally present difference in function of distinct brain regions or networks) of brain function was shown by a finding of a compression of a gradient of cortical hierarchy across different psychedelic substances (Girn et al., 2022; Timmermann et al., 2023). Multiple studies have also explored connectome harmonics in different substances, decomposing brain activity into harmonic states to explore the functional connectome, and finding a move toward higher frequencies representing a divergence from structural connectome—those findings can be interpreted as a move toward criticality (Atasoy et al., 2017; Atasoy et al., 2018). The most recent study in this area conducted with DMT also found correlation of these effects with subjective intensity of the experience (Vohryzek et al., 2024).
In sum, these heterogenous studies show functional de-differentiation of the brain with increased entropy and more fluid dynamics. These results can be interpreted as consistent with the REBUS hypothesis, which posits a highly malleable state of the brain during the psychedelic experience. Further work is now needed in reducing this heterogeneity (e.g., through replication) to bring about a more coherent and rigorous basis for the REBUS model (McCulloch et al., 2024).
3.2 Resting-state functional connectivity
As described above, the brain is ordered into a number of resting-state networks under normal circumstances. Among major of these, the central executive network (CEN) is associated with focused attention, in contrast to the default mode network being associated with introspection; the activity of these two networks is thus anticorrelated, with the salience network posited to switch between them (Nekovarova et al., 2014). Possibly the most consistent finding within the fMRI of the psychedelic state is a general dissolving of this brain modularity—a decrease in connectivity within the resting-state networks, and increase in connectivity between them. This has been widely replicated across different studies and different substances (Müller et al., 2018; Madsen et al., 2021; Timmermann et al., 2023; Roseman et al., 2014). In line with these findings, network integrity has been observed to negatively correlate with psilocin plasma levels and its subjective effects (Madsen et al., 2021). Significantly, in a set of patients with treatment-resistant depression where psilocybin was effective in treating their symptoms, this alleviation correlated with the decrease in network modularity after dosing (Daws et al., 2022).
This modularity decrease seems to be the most pronounced in the DMN: its disintegration correlates with subjective measures of ego-dissolution and with an improvement in psychosocial functioning (Smigielski et al., 2019). In a study with ayahuasca, the decrease of connectivity within the DMN lingered even 24 h after dosing (Pasquini et al., 2020). In line with the general breakdown of standard DMN functioning, there is a decrease of its anticorrelation with the task-positive networks, normally a defining feature of the DMN (Carhart-Harris et al., 2013); a reduction of functional connectivity between its components was one of the very first findings within the psilocybin fMRI studies (Carhart-Harris et al., 2012a). Underscoring the importance of the DMN, a recent longitudinal study found a decrease of its connectivity with anterior hippocampus, another key structure implicated in the psychedelic state discussed below, lasting for 3 weeks after dosing (Siegel et al., 2024).
A second major finding that has been widely replicated and discussed is an increase in connectivity between the thalamus and the cortex (Müller et al., 2018; Tagliazucchi et al., 2016; Preller et al., 2018b) (see also the general CSTC model Vollenweider and Geyer, 2001; Avram et al., 2021), with individual studies finding associations with subjective sensory effects (Avram et al., 2022; Müller et al., 2017). However, this connectivity pattern seems to be more complicated with a closer look: more detailed analyses of thalamic connectivity bring conflicting and more nuanced results. While one study with LSD found increased connectivity of the pulvinar and ventral nuclei of thalamus with the cortex (Pizzi et al., 2023b), a 7 tesla MRI study pinpointing the effect of psilocybin on the thalamus to the pulvinar and the mediodorsal nucleus surprisingly found a decrease in connectivity of these structures with cortical areas—consistent with these nuclei maximally expressing the 5HT2A receptor within the thalamus (Gaddis et al., 2022).
Among other specific brain structures, there are numerous changes in the medial temporal lobe structures, with a reduction of connectivity of the parahippocampal cortex correlating with ego dissolution (Carhart-Harris et al., 2016), an already mentioned longitudinal decrease in connectivity of the hippocampi with the DMN (Siegel et al., 2024) and an increase of signal variability and entropy within them (Tagliazucchi et al., 2014); all of these studies being done with psilocybin, while an infusion of DMT produced a deactivation of the hippocampi, which correlated with subjective meaningfulness of the experience (Pasquini et al., 2024). Apart from the hippocampus, the claustrum has been implicated in psychedelic drug action, with alterations of its connectivity to the DMN, frontoparietal and auditory networks (Barrett et al., 2020b), forming the basis of the CCC model (Doss et al., 2022); these findings have recently been corroborated by a nonhuman primate study which found psilocybin-induced increase in connectivity of the claustrum with the anterior cingulate cortex, the precuneus and areas of the prefrontal cortex (Bagdasarian et al., 2024).
Taken together, studies on functional connectivity broadly show dissolving of resting-state networks most prominent in the DMN, increase of thalamocortical connectivity with a need for further clarification, decreases in connectivity of medial temporal lobe structures and alterations of connectivity of the claustrum. The CCC model, while intriguing, is currently still based on only one human study, making replication indispensable to prove its validity—the increasing use of higher-resolution MRI scanners (see Table 2) has the potential to make studying this difficult-to-measure structure more accessible.
3.3 Task-based fMRI—activation studies
A large number of activation studies have been conducted as well, with intriguing but highly heterogenous paradigms and results, making any attempt at generalization difficult. A closely examined brain region is the amygdala, a key structure of emotional processing that in depression has been demonstrated to be hyperactive in response to negative stimuli and hypoactive in response to positive stimuli (Stuhrmann et al., 2011), with this finding being attenuated by SSRI treatment (Ma, 2015). With psychedelics, multiple studies with psilocybin, LSD and ayahuasca observe a decrease of its activity in response to negative stimuli (Barrett et al., 2020a; Kraehenmann et al., 2015b; Arruda Sanchez et al., 2024); in one study, this correlated with the intensity of the subjective effects (Mueller et al., 2017). A study of patients with treatment-resistant depression found an increase of amygdala reactivity to both fearful and happy faces (in contrast to neutral faces), with this phenomenon predictive of alleviation of depression in the first week after dosing (Roseman et al., 2018). Thus, these findings seem to validate the potential of psychedelics to treat depression, with an interesting difference of the finding of increased reactivity to happy and fearful faces in the population of patients with depression. Additionally, changes to effective connectivity of the amygdala have been identified by two studies discussed in the following section.
3.4 Effective connectivity
Findings of functional connectivity changes described above can be further expanded by exploring effective connectivity (EC). Building on the CSTC model, LSD has been found to increase EC from the thalamus to posterior cingulate cortex (a part of the DMN) while also decreasing EC from striatum ventrale to the thalamus (Preller et al., 2019); it was also shown to increase EC from the thalamus to both unimodal and transmodal cortex, contrasted to MDMA and amphetamine which increased EC only to the unimodal cortex, highlighting a possible breach in cortical hierarchy (see the section on global measures) as a feature unique to psychedelics (Avram et al., 2023). Expanding on the picture of complex interplay between the main resting-state networks with the central role of the DMN, LSD was shown to flip the valence of connectivity (inhibitory to excitatory) from the salience network to the DMN, and decrease the inhibitory connectivity from the DMN to the dorsal attention network (Stoliker et al., 2023). Lastly, the knowledge on changes to amygdala was expanded by two studies: (a) psilocybin was shown to weaken modulatory effect of visual threat on the connection from the amygdala to primary visual cortex (Kraehenmann et al., 2015a) and (b) psilocybin decreased EC from cortical regions to the amygdala, with the notable exception of the DMN (as well as to alter EC within the DMN, CEN, and SN), suggesting changes to hierarchical organization of brain function (Stoliker et al., 2024). See Figure 2 for schematic summary of effective connectivity changes.
Figure 2. Schematic summary of major findings of effective connectivity changes. Blue neurons represent decreases in EC, red neurons represent increases in EC, pink neurons represent change from inhibitory EC to excitatory. The direction of effective connectivity is represented by the arrow. Study with music not shown. A, amygdala; C, cortex; DMN, default mode network; PCC, posterior cingular cortex; PVC, primary visual cortex; SN, salience network; SV, striatum ventrale; T, thalamus; TMC, transmodal cortex; UMC, unimodal cortex.
Together with functional connectivity investigations, effective connectivity studies put the CSTC model on a solid footing, showing the actual flow of information in the expected direction and highlighting its breadth compared to non-psychedelic drugs. Regarding the model in general, clarifications are needed as to precisely which cortical regions are affected; an attempt at replicating the Gaddis et al. (2022) study is warranted, as its findings challenge the model in its current form.
3.5 fMRI correlates of ego dissolution
Lastly, outsize importance of ego dissolution, a specific phenomenon within the psychedelic experience characterized by a breakdown of the sense of self (Stoliker et al., 2022), is becoming clear through fMRI studies. In itself, ego dissolution is not an fMRI concept, but a subjective phenomenon—in psychedelic research these are generally ascertained by psychometric scales, such as the Five Dimensional Altered States of Consciousness (5D-ASC). This scale groups the subjective elements of the psychedelic experience into 3 main themes (Visionary Restructuralization, Oceanic Boundlessness and Anxious-Ego Dissolution) with 11 subthemes among these. We choose to include ego dissolution as a section here as there are multiple fMRI findings associated specifically with it, and it has connections beyond them, with its extent shown to predict positive changes in psycho-social functioning 4 months after dosing of psilocybin (Smigielski et al., 2019). In relation to fMRI, its occurrence is specifically associated with a decrease in connectivity between the parahippocampal cortex and retrosplenial cortex (Carhart-Harris et al., 2016), decrease in connectivity between the medial temporal lobe and the cortex, disintegration of the salience network and a decrease in interhemispheric communication (Lebedev et al., 2015). The changes observed by Stoliker et al. (2023) described in the section on effective connectivity also correlated with measures of ego dissolution. In addition, an increase in global connectivity (Tagliazucchi et al., 2016) and disintegration of the DMN (Smigielski et al., 2019) have been observed specifically during ego dissolution, both in line with more general findings during the psychedelic experience, suggesting their deepening during this phenomenon. However, as stated above, fMRI correlates are just one of many aspects of ego dissolution—for a comprehensive review of its mechanisms see Stoliker et al. (2022).
4 Discussion
Taken together, a look at the entirety of the studies reviewed offers a rich and diverse landscape of findings, where lines of consistency are starting to take shape. These lines are present both “horizontally” in the form of converging results we have highlighted here, but also “vertically,” in the form of associations with findings outside of the fMRI sphere: namely with the subjectively reported effects, drug plasma levels, and also different neuroimaging modalities [e.g., employment of simultaneously recorded EEG-fMRI (Timmermann et al., 2023)]. Overall, this consistency is putting the fMRI findings on firmer footing. Another instance of this could be seen in tracking of longitudinal changes, with well-known studies that show persisting effects through subjective measures (Griffiths et al., 2018) and through disease symptom remission (Carhart-Harris et al., 2021) recently being shored up by findings of fMRI changes persisting as well (Siegel et al., 2024; Pasquini et al., 2020; McCulloch et al., 2022a; Barrett et al., 2020a). Given the time course of mental disorders potentially treatable by psychedelics, possibility of their relapse and discussions of deeper personality change through psychedelic treatment, further ascertaining the specifics of these long-term effects will be a crucial direction moving forward.
Further research into subdivision of the psychedelic state itself also appears crucial—this is exemplified by studies on ego dissolution, which generally show specific changes unique to this phenomenon and not present in the psychedelic state as a whole, and which have been shown to translate into long-term effects (Smigielski et al., 2019), demonstrating their significance. An example of advancing this line of thinking can be seen in recent studies on DMT (Timmermann et al., 2023), which take advantage of its short half-life allowing to capture the whole or most of the psychedelic state within the session.
With progress in the MR technology itself, findings suggestive a new level of complexity are emerging and showing the necessity of further clarification to established findings, such as the discovery of decreased thalamocortical connectivity when looking at individual thalamic nuclei by Gaddis et al. (2022). Further, as new approaches are also being developed in the area of global measures, the overarching picture of general de-differentiation of brain function keeps emerging through a wide variety of different techniques—this would seem to be broadly consistent with the REBUS hypothesis, and speculatively with the potential of psychedelics being able to act transdiagnostically (Kočárová et al., 2021; Carhart-Harris et al., 2023). Further work on integrating the models of action together is warranted.
Lastly, a meaningful route of filtering out noise and exploring neurobiological undercurrents appears to be one of drawing contrasts between psychedelics and phenomenologically similar yet neurobiologically different states: (a) those elicited by psychoactive substances other than classical psychedelics, such as the finding that MDMA (and amphetamine) increase effective connectivity to unimodal cortex contrasted with LSD increasing EC also to transmodal cortex (Avram et al., 2023), of methylphenidate (which was used in the study as an active control) showing changes corresponding to general arousal contrasted with more specific changes of psilocybin (Siegel et al., 2024), or of ketamine (and NO) producing similar changes (decrease in within-network connectivity and increase in between-network connectivity) to LSD (Dai et al., 2023); and (b) altered states of consciousness such as meditation, hypnosis or schizophrenia. Specifically, the parallels with schizophrenia form an avenue of research as old as the psychedelic substances themselves (Nichols, 2016), which is promising inways into two states that both warrant more complete understanding, as well as into more fundamental concepts of neuroscience and psychology such as the self, of which there are clear alterations in both conditions (Kozáková et al., 2020; Stoliker et al., 2022). There has been a constant stream of studies drawing these parallels with schizophrenia, many of which are consistent with the themes explored in this review: altered thalamocortical connectivity (Avram et al., 2021), disruption to the DMN-task positive network anticorrelation (Carhart-Harris et al., 2013) and principal cortical gradient compression (Girn et al., 2022; Timmermann et al., 2023). Another compelling parallel could be represented by the deep disruptions within the triad of DMN, central executive and salience network, which have also been described in schizophrenia (Nekovarova et al., 2014). For further discussions on this topic (see also Leptourgos et al., 2020; Sapienza et al., 2023). As for meditation, previous studies have intriguingly shown changes in similar areas compared to psychedelics, such as more robust DMN activation compared to rest (Xu et al., 2014) and subacute increase in connectivity of the DMN with the dorsal attention network and visual cortex (Zhang et al., 2021); see Boccia et al. (2015) for a meta-analysis. For a direct comparison of fMRI correlates of the psychedelic state, hypnosis and meditation see Moujaes et al. (2024).
From a methodological standpoint and as highlighted by McCulloch et al. (2022b), there is a great need for more independent replication of the available findings, as the studies available come from a limited number of relatively small datasets. To this end, focus on data standardization will be crucial moving forward, as currently there is a great degree of heterogeneity in multiple aspects. Scan timepoints vary, and while each of them may be justified (or simply necessary, e.g., with the need to fit multiple tasks into one administration session), the resulting data originate from different sections of the psychedelic experience—this can be a complication for instance in studying ego dissolution, as it is a phenomenon that occurs only during a fraction of the whole experience. Further complicating matters, drug administration methods vary, with both per os and i.v. being utilized, resulting in different plasma level dynamics for same substances and thus making it difficult to pinpoint equivalent scan timepoints. Another potential source of heterogeneity lies in fMRI data processing, for instance in using in-house pre-processing pipelines, which by definition vary between institutions, and can for example influence whether a given result reaches the level of statistical significance or not. Finally, subject characteristics can be a source of heterogeneity—in a large part of the ayahuasca studies, participants were experienced users, while long term use of ayahuasca has been shown to elicit structural changes (specifically, thinning of the posterior cingulate cortex) in the brain (Bouso et al., 2015), potentially leading to different fMRI findings compared to first-time users; other example would be potential differences between clinical populations and healthy volunteers. In sum, this heterogeneity will need to be taken into account in studies aiming to replicate these results.
5 Limitations
There are limitations to this study to be mentioned here. While our aim was to offer a conceptual overview of the field, this led to a large number of existing studies not being mentioned in the narrative text for the sake of clarity. Furthermore, with the decision to mostly treat the serotonergic psychedelics as a whole also necessary to formulate a somewhat digestible picture of the field, it is naturally an oversimplification, with significant differences among the substances in themselves. Perhaps the most obvious of these would be different pharmacokinetics, for instance half-life (approximately 4 h for LSD, compared to only 5–15 min for DMT), but also speed of onset and offset, adding to the heterogeneity discussed above (Holze et al., 2024). Differences also lie in subjective effects, in the simplest form in perceived intensity of the experience, but also in more nuanced phenomenological aspects—for instance in the form of perceived entity encounters, which is a phenomenon characteristic for DMT. There are also nuances in receptor profiles of the substances. Generally, these differences could be explored by further research combining fMRI with other modalities: namely, studies with PET (both FDG and specific receptor ligands) and EEG. Also refer to Frautschi et al. (2024) for a discussion of this heterogeneity.
As for methodological limitations, only one database (PubMed) was used to search for articles—however, given that it is a database most relevant in the research field (neuroscience with overlap into psychiatry) and we did not aim to review entries such as conference abstracts or case reports, we do not consider this a major limitation. Risk of bias assessment and review protocol pre-registration were not performed for this scoping review.
6 Conclusion
In conclusion, we show that numerous changes to brain function induced by serotonergic psychedelics have been observed using fMRI. The converging findings with the strongest evidence are: a general increase in connectivity throughout the brain, increase in entropy, dissolution of resting-state brain networks which is most pronounced in the DMN, increased thalamocortical connectivity, decreased amygdala reactivity to negative stimuli, changes to medial temporal lobe structures, and the significance of ego dissolution. In addition, a diverse array of other individual results show possible directions of further research. Independent replication of these findings and their further validation through associations with drug plasma levels, subjective and longitudinal effects, as well as with findings from other imaging modalities, will be necessary moving forward.
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Author contributions
MB: Investigation, Formal analysis, Methodology, Visualization, Conceptualization, Writing – original draft. TP: Investigation, Funding acquisition, Writing – review & editing. JH: Investigation, Formal analysis, Methodology, Funding acquisition, Supervision, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by grants from Czech Health Research Council (projects NU21-04-00307 and NW24-04-00413), Horizon Europe (grant no. 101137378, HORIZON-HLTH-2023-DISEASE-03-01), Long-term conceptual development of research organization (RVO 00023752), and Specific University Research, Czech Ministry of Education, Youth and Sports (project 260648/SVV/2024), ERDF-Project Brain dynamics, No. CZ.02.01.01/00/22_008/0004643, project VVI CZECRIN (LM2023049), and Charles University research program Cooperatio-Neurosciences and private funds obtained via PSYRES, Psychedelic Research Foundation (https://psyresfoundation.eu).
Conflict of interest
TP and JH founded the PSYRES-Psychedelic Research Foundation and have shares in Psyon s.r.o. and Spolecnost pro podporu neurovedniho vyzkumu s.r.o. TP reports consulting fees from GH Research and CB21-Pharma outside the submitted work and is involved in Compass Pathways and/or MAPS clinical trial with psilocybin/MDMA trials outside the submitted work.
The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The authors declare that no Gen AI was used in the creation of this manuscript.
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Keywords: psychedelics, psilocybin, LSD, ayahuasca, DMT, fMRI, functional connectivity, entropy
Citation: Beneš M, Páleníček T and Horáček J (2025) What fMRI studies say about the nature of the psychedelic effect: a scoping review. Front. Neurosci. 19:1606798. doi: 10.3389/fnins.2025.1606798
Edited by:
Alexandre Henriques, Neuro-Sys, FranceReviewed by:
Jahan Marcu, Northeastern University, United StatesAmir Lotfi, Beckley Psytech Ltd., United Kingdom
Samuel Slocum, Transneural Therapeutics, United States
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*Correspondence: Michal Beneš, bWljaGFsLmJlbmVzQG51ZHouY3o=