INTRODUCTION

Psychedelics are a class of hallucinogenic agents that have cultural, spiritual, and scientific implications (McKenna, 1998; Nichols, 2016). The etymology of the term psychedelic is from the Greek words ψυχή (psyche, “soul, mind”) and δηλοῦν (deloun, “to manifest”). Therefore, psychedelics are “mind/soul manifesting” and are suggested to illuminate hidden terrains of the human psyche (Weil and Winifred, 2004). “Classical psychedelics” is a broad term describing a variety of substances whose primary mechanism of action resides in serotonin (5-HT_2A) receptors in the brain and, in turn, produce profound alterations of consciousness, including modulations in the sense of self, sensory perception, and emotions (Table 1) (Morris, 2008; Nichols, 2016; Speth et al., 2016).

Neuroimaging studies have shown that when an individual is at rest, multiple interconnected brain regions are activated above baseline, and, conversely, there is decreased activity in these regions during task-dependent attention (Raichle, 2015) (Figure 1). These regions amalgamate to create 4 functional hubs: the medial prefrontal cortex (mPFC), the posterior cingulate cortex (PCC), precuneus, and the angular gyrus, together referred to as the Default Mode Network (DMN) (Andrews-Hanna et al., 2014). The DMN is one of many resting-state networks (RSNs). RSNs are derived from the cognitive origin hypothesis of resting-state connectivity, where resting-state connectivity is defined as the synchronous fluctuation of low-frequency signals between functionally related brain areas (Biswal et al., 1997).

Functional connectivity (FC) is defined as the temporal coactivation patterns of neural activity between anatomically distinct brain regions, it is an important and well-established variable of interest when understanding DMN connectivity (van den Heuvel and Pol, 2010). RSNs, such as the DMN, are imaged prior to the experimental stimulus (i.e., engaging in a memory task), and DMN FC has been found to be anti-correlated and orthogonal to task-dependent brain networks such as the salience network (SLN) (Raichle, 2015; Smallwood et al., 2021). Furthermore, altered FC within the DMN has been correlated with a variety of psychometric components in clinical questionnaires, which may have downstream therapeutic effects. For instance, reduced FC with brain regions that comprise the DMN has been associated with positive states of ego dissolution such as Oceanic Self-Boundlessness (measured by the 5-Dimensional Altered States of Consciousness Rating scale; see Table 2), which may facilitate the cognitive reappraisal that can occur during the psychedelic experience (Smigielski et al., 2019; Yaden and Griffiths, 2020).

Alterations in the FC signatures of the DMN, consisting of intra-connectivity changes (FC alterations within the DMN brain regions) and inter-connectivity changes (changes in FC parameters between brain regions within the DMN and brain regions within other cognitive networks), have been implicated in a variety of complex cognitive functions such as theory of mind, self-referencing, memory, and rumination (Andrews-Hanna, 2012; Raichle, 2015). However, the underlying mechanisms are not fully understood (Smallwood et al., 2021). Additionally, altered DMN function has been implicated in a range of neuropsychiatric and neurodegenerative conditions such as depression, attention deficit hyperactivity disorder, schizophrenia, anxiety, and post-traumatic stress disorder, Alzheimer’s disease, and aging in general (Mohan et al., 2016; Zhang and Volkow, 2019). As such, altered DMN connectivity in specific clinical populations or groups consuming therapies that impact functional brain activity (e.g., psychedelics) appears to offer a window into the variability of complex human functioning that can also be modulated by psychedelic treatment.

The “mind-manifesting” properties of psychedelics illuminated by figures like Aldous Huxley, Timothy Leary, and Albert Hofmann created a surge of trials during the 1960s, which highlighted psychedelics as potential therapeutic agents for a range of mental health and substance use disorders (Carhart-Harris, 2019). In particular, lysergic acid diethylamide (LSD) was on the market as Delysid/Sandoz in the 1950s and 1960s, prescribed for the treatment of “psychoneuroses, psychoses” as well as other neuropsychiatric disorders, always to be administered in a controlled setting (psychiatric clinic or hospital) by properly trained health professionals. The use of LSD and all other psychedelics in clinical or preclinical research was severely constrained for political reasons in the 1970s, although LSD continued to be prescribed by psychiatrists outside the United States well into the 1990s. Based on the promising yet preliminary findings with LSD and other drugs such as psilocybin, N,N-dimethyltryptamine (DMT), ayahuasca, or mescaline, but also 3,4-methylenedioxymethamphetamine (MDMA) and ketamine, psychedelics are regaining scientific attention, especially in the field of clinical neuroscience. As a result, a number of more recent studies have begun to elucidate how psychedelics modulate the DMN (Carhart-Harris et al., 2012, 2016; Bouso et al., 2015; Palhano-Fontes et al., 2015; Thomas et al., 2017; Millière et al., 2018; Müller et al., 2018; Kelly et al., 2019; Smigielski et al., 2019; Mason et al., 2020; Mertens et al., 2020; Daws et al., 2022; de Gregorio et al., 2021; Grandjean et al., 2021).

Psychedelics often induce meaningful and mystical experiences that have been associated with increased measures of brain entropy (Carhart-Harris, 2018). Entropy is a measure of the uncertainty of the system, and regarding the brain, it is associated with functional disorder, unpredictability, and flexibility, which may lead to an enhanced array of dynamic brain states (Tagliazucchi et al., 2014; Atasoy et al., 2017; Carhart-Harris, 2018). Yaden and Griffiths (2020) argue that a considerable variance in the therapeutic outcome associated with psychedelics can be explained by the altered state of consciousness that psychedelics produce. Furthermore, one of the most ubiquitous and transformative components of the psychedelic experience is the feeling of ego dissolution, a relaxation of subject-object distinctions during which the borders and constraints of the self seem to dissolve (Letheby and Gerrans, 2017; Mason et al., 2020). Feelings of ego dissolution also appear to be a central component of the unitive experience (a sub-component of the mystical states), which is an experience of perceived union with nature or a higher power or an all-pervading sense of oneness (Nour et al., 2016). It has been hypothesized that ego dissolution can be therapeutic because an individual’s cognitive attributions and affect are viewed with a greater distance and objectivity (Letheby and Gerrans, 2017; Mason et al., 2020). Psychedelic-induced ego dissolution may be precipitated via Bayesian belief updating wherein reduced precision of previously held beliefs lends to revision of the self and world, as hypothesized by Stolicker and colleagues (2022). This has parallels with the practice of meditation, which is also associated with decreased activity of the DMN and alterations to precision-weighting of beliefs and attention (Brewer et al., 2011; Palhano-Fontes et al., 2015; Letheby and Gerrans, 2017; Millière et al., 2018). Functional magnetic resonance imaging (fMRI) studies involving psychedelics show that the modulation of the DMN acutely decreases connectivity and blood flow within nodes of this network (Table 2). These changes are paralleled by magneto/electroencephalography studies showing neuronal desynchronization of alpha power (itself previously shown to be highly correlated with DMN connectivity), at times specifically located in the PCC (one of the main hubs of the DMN), which has been tentatively hypothesized to result in a mind that is less constrained, more flexible, and less self-referential and egoic (Muthukumaraswamy et al., 2013; Letheby and Gerrans, 2017; Nour and Carhart-Harris, 2017; Carhart-Harris, 2018; Mason et al., 2020).

Although the DMN is a RSN that is featured in a vast array of psychedelic trials, there is still some ambiguity as to what changes/modulation to this network mean and what motifs and differences are seen across the literature regarding this network. Therefore, this systematic review seeks to explore the following aims: (1) to critically evaluate the impact of classic psychedelics on the DMN; (2) to evaluate the evidence regarding DMN modulation and resultant psychotherapeutic effects; (3) to identify challenges and limitations associated with the current literature surrounding DMN modulation by psychedelics; and (4) to provide a discussion surrounding future research and the potential future utility of DMN modulation–focused psychedelic therapies. This review focuses on the classical psychedelics: LSD, psilocybin, DMT, mescaline, and ayahuasca (which contains DMT and harmala alkaloids), complementing previous reviews of these agents (Carhart-Harris and Friston, 2019; Aday et al., 2020; Inserra et al., 2021). To this end we conducted a literature review via Scopus and PubMed databases on August 28, 2021, up to November 14, 2021.

METHODS

This systematic review followed the PRISMA statement (Moher et al., 2015) for transparent and comprehensive reporting. The review was not registered, and a review protocol was not prepared.

Search Strategy

We conducted an electronic database search of PubMed and Scopus from inception to April 2022. We structured our search according to the PICO framework (Schardt et al., 2007) using search terms related to the DMN, along with the names of the classical psychedelics, to return all potentially eligible studies. The search string was: default mode network OR DMN OR neuro circuitry AND ayahuasca OR DMT OR dimethyltryptamine OR psilocybin OR psilocin OR LSD OR Lysergic acid diethylamide OR mescaline OR peyote OR psychedelic. A search of Google Scholar was conducted to identify any additional relevant articles.

Eligibility Criteria

Articles were screened by 2 reviewers (J.G., S.R.). Disagreements were resolved through discussion until consensus was reached (with J.S. arbitrating if required). We included only human clinical trials (rodent studies were excluded) assessing DMN modulation by the classical psychedelics. Papers that performed novel analyses on previously published datasets were also included [i.e., Carhart-Harris et al., (2013) and Varley et al., (2020)]. Only English language papers were eligible, and there was no psychedelic dose requirement and no requirement on the length of treatment or on the statistical methods used. All clinical diagnoses and healthy controls were included. The full article screening and selection process is detailed in Figure 2.

RESULTS

Results Overview

The initial database search was performed on 28th of August 2021 and a second database search was performed on the 20th of April 2022. The search returned 163 results which were reduced to 119 after the duplicates were removed. A further 95 articles were removed due to ineligibility. This left 28 articles that were included in the study (Figure 2).

A total of 17 psilocybin studies were assessed, twelve using fMRI (2 of 12 using 7 Tesla fMRI, remaining using 3 Tesla) and two using Electroencephalogram (EEG) or Magnetoencephalogram (MEG). The average age of subjects across these studies was 34.6 years with a standard deviation (SD) of 8.8 years. The average number of participants across the studies was 26 with a SD of 19. Out of the 17 studies, 13 had a placebo control group. Four Ayahuasca studies were assessed, with all four using fMRI (two using 1.5 Tesla and two, 3 Tesla). The average age of subjects across these studies was 35 years with a SD of 17.8 years, and the average number of participants was 28 with a SD of 5.9 years. Only one of these studies had a placebo control group. Eight LSD studies were assessed, with seven using (3 Tesla) fMRI, one using EEG and one using MEG. The average age across these studies was 29.6 years with a SD of 2.8, and the average number of participants was 20, and the SD was 6.4 participants. All studies had a placebo control group. No published research papers assessing how mescaline and DMT modulates the DMN in humans were found. Table 2 is a summary of the findings and study characteristics for the research articles included in this systematic review. Figure 3 shows the specific DMN brain regions detected via fMRI that are modulated by psychedelics.

DISCUSSION

Synthesis of Data

Based on the evidence (see Table 2), there are clear associations between a psychedelic’s ability to reduce the functional connectivity within the DMN (and increase its connectivity to other networks), altered states of consciousness, and therapeutic outcomes (Letheby and Gerrans, 2017; Müller et al., 2018; Smigielski et al., 2019; dos Santos and Hallak, 2021; Mason et al., 2021; Daws et al., 2022). At this stage, however, it is difficult to ascertain the direction of causality.

A recent review from Aleksandrova and Phillips (Aleksandrova and Phillips, 2021) also revealed that the classical psychedelics can induce marked neuronal structural and functional changes via neurotrophic signaling and neuroplasticity. These psychoplastic changes are most likely mediated by brain-derived neurotrophic factor and mammalian target of rapamycin (Inserra et al., 2021). Furthermore, Martin and Nichols (2017) showed that psychedelics have the potential to alter gene expression and immunomodulatory mechanisms. These effects are proposed to rewire pathological cortical networks (possibly by reducing neuronal inflammation, a burgeoning hypothesis of addiction, depression and neurodegeneration), thereby explaining how psychedelics may neurobiologically induce positive long-term health outcomes. Thus, it is challenging to delineate how much of the benefit in psychedelic therapy is derived from neuroplastic changes on the cellular level or on the network level (DMN modulation) and the degree to which the two are linked. This is further confounded by the fact that studies use varying dosages of psychedelics are not all placebo controlled and often investigate participants who are not drug naïve.

Depression is often characterized by excessive activity in the mPFC, and there appears to be an inverse correlation between depressive symptomatology and the degree of 5-HT_2Areceptor stimulation in this region (Morris, 2008; Nichols, 2016; Carhart-Harris, 2019). Psilocybin can acutely increase anxiety, which may be mediated by glutamate hyperfrontality; however, long-term reductions in anxiety could occur due to 5-HT_2Areceptor downregulation in this area (Mason et al., 2020). Another hypothesis is that psilocybin, and the classical psychedelics more broadly, have a significant affinity for and agonize the 5-HT_1A receptors. These are the primary inhibitory serotonergic receptors and may be responsible for the decreased blood oxygen level–dependent (BOLD) coactivation often seen in the DMN and other brain regions on the administration of psychedelics. On the macro-scale, connectivity between the parahippocampal cortex and prefrontal regions was a reliable predictor of depressive symptoms 5 weeks after psilocybin treatment (Carhart-Harris et al., 2018).

A review by Thomas et al. (2017) concluded that based on the totality of evidence at that time (7 clinical trials), psilocybin, by disrupting the hyperconnectivity in the DMN of psychiatric conditions, may be a novel treatment for a range of neuropsychiatric conditions. A recent analysis by Daws et al. (2022) found that psilocybin therapy reduced depressive symptoms for up to 6 weeks post intervention and that this effect was likely dependent on increased brain network integration. Interestingly, this group also found that increased within-DMN connectivity and reduced between-network DMN connectivity (specifically with the executive and salience network) were correlated with baseline depressive severity, which aligns with the previous findings of other researchers (Hamilton et al., 2011; Lydon-Staley et al., 2019; Feurer et al., 2021).

The literature reviewed clearly indicates that classical psychedelics acutely decrease functional connectivity within the DMN and increase between-network connectivity (see Table 2) (Roseman et al., 2014; Lebedev et al., 2015; Palhano-Fontes et al., 2015; Carhart-Harris et al., 2016; Nichols, 2016; Tagliazucchi et al., 2016; Atasoy et al., 2017; Müller et al., 2018; Mason et al., 2020; Mertens et al., 2020; de Gregorio et al., 2021; Grandjean et al., 2021; Daws et al., 2022; Madsen et al., 2021). Thus, during the psychedelic experience, there seems to be a unique shift in neural connectivity, reflecting a shift from a more modular, segregated brain to a more interconnected global network (Palhano-Fontes et al., 2015; Smigielski et al., 2019). This decrease in between-network segregation seems to be somewhat specific to the classical psychedelics, although this decreased segregation is also seen in ketamine (Bonhomme et al., 2016) and salvinorin A (Doss et al., 2020). It is not seen with selective serotonin reuptake inhibitor antidepressants (Klaassens et al., 2015; Daws et al., 2022), stimulants (Konova et al., 2015), sedatives (Stamatakis et al., 2010), or MDMA (Roseman et al., 2014). This increase in inter-network FC can be interpreted via a dynamical systems theory approach [see Roseman et al., (2014) for more details]. For instance, RSNs are canonical networks of brain activity and when reflected graphically, the valleys in this 2D plane are indications of the metastable “sub-states” of these RSNs. Thus, deeper valleys imply a prolonged sub-state with greater rigidity, whereas shallower valleys indicate less stable and more flexible sub-states. The increase in FC between the DMN and other RSNs seems to align with the latter graphical representation (i.e., shallow troughs), which may indicate that the brain/mind can access a greater dynamic repertoire of metastable sub-states. This more flexible brain state seems to persist in the recovered state of patients with major depressive disorder (MDD) treated with psilocybin (Daws et al., 2022).

Psychedelics may in part disrupt the DMN because they promote a cognitively intensive experience where one is dealing with the “task” of one’s subconscious and grappling with the deep metaphysical and personal questions that generally arise during the experience (Shanon, 2002). This aligns with the definition of the DMN, which is anticorrelated with task-based activities. Although mind-wandering is associated with increased DMN activity, awareness of mind-wandering—as seen in meditation—decreases the resting FC of the DMN (Brewer et al., 2011; Palhano-Fontes et al., 2015). This is a plausible mechanism by which ayahuasca, as well as psilocybin and LSD, also decrease activity within the DMN because the experience is characterized by a hyper-awareness of one’s internal dispositions and attributions (Brewer et al., 2011; Preller and Vollenweider, 2016; Millière et al., 2018). Furthermore, it could be argued that hyper-awareness of one’s mind and internal cognition is a feature of a brain that has increasing entropy and is approaching criticality (Carhart-Harris et al., 2012, 2016; Carhart-Harris, 2018; Millière et al., 2018), although this needs to be further examined. It is also clear that various individuals will respond differently to distinct treatments because their baseline levels of awareness will differ. Another plausible mechanism of reduced coactivation within the DMN is that psychedelics produce less mentation to the past, as seen with LSD, but whether this effect is unique to psychedelics is unclear (Speth et al., 2016).

Models of Psychedelic Action

It is important to note that the “relaxed beliefs under psychedelics” (REBUS) model is 1 of 3 prominent models of the biological mechanisms underpinning psychedelics’ mode of action, and each model exhibits unique strengths and weaknesses. The REBUS model has been the primary focus of this article (refer to Table 2, where 24 of the 28 papers were most closely aligned with the REBUS model) because it included DMN activity and modulation as a central axiom (REBUS is based on the brain’s hierarchical organization with DMN at the top of this hierarchy). The two other models suggest mechanisms that are relatively independent of DMN modulation (Doss et al., 2022).

Relaxed Beliefs Under Psychedelics and Brain Entropy

It has been hypothesized that the underlying neurobiology of DMN perturbation and its downstream effects is caused by entropy (Carhart-Harris, 2018). Psychedelics exert their hallucinogenic effects primarily by activating the 5-HT_2A receptor, resulting in increased 5-HT release, enhancing the excitability of layer V pyramidal cells in the cortex and hence leading to increased glutamate in the neocortex (Nichols, 2016; Carhart-Harris, 2019; Mason et al., 2020). In the cortex 5-HT2A receptor activation can lead to asynchronous glutamate release resulting in desynchronized ensembles of neurons (Nichols, 2016; Riba et al., 2002; Tagliazucchi et al., 2014). Subsequently, the brain becomes more desynchronized resulting in a loss of oscillatory power, aligning with the brain entropy hypothesis (Aghajanian and Marek, 1999; Tagliazucchi et al., 2014; Carhart-Harris, 2018).

Brain entropy is characterized by increased randomness, unpredictability, and disorderliness (with respect to neuronal firing), which in turn disrupts top-down, goal-oriented cognitive processing (Carhart-Harris, 2018, 2019; Kelly et al., 2019; Varley et al., 2020). It is proposed that this disruption in top-down processing may facilitate increased neural and cognitive flexibility (Doss et al., 2021), which is a viable explanation for the mechanistic underpinnings of the therapeutic effect of psychedelics (Gallimore, 2015; Mason et al., 2021; Daws et al., 2022). The REBUS model postulates that psychedelics serve to relax the precision-weighting of previous beliefs while freeing up and increasing the information flow from bottom-up information processing (Carhart-Harris and Friston, 2019). This process can enable the revision of pathologically overweighted priors, which affects the functional systems of the brain such as those related to the self (Ho et al., 2020).

Evidence from Barrett et al. (2020a) and Daws et al. (2022) may support this model and the notion of a “resetting mechanism” because the acute disruption in top-down cognitive control showed enduring benefits (up to 1 month) in top-down control of emotion, leading to less negative affect and increased positive affect after psilocybin administration. Anatomical connectivity can be conceived as a Bayesian prior on FC, and under anesthetic, external information is minimally processed and integrated, which means that there is a strong association between the FC and structurally encoded priors. However, under classical psychedelics, the brain is less constrained by pre-existing structural priors and therefore these pre-existing priors have less of an effect on cognition, aligning with the REBUS model.

Interestingly, the decreased weight of structural priors frees up the ability for the brain to create a greater array of FC patterns and networks, supposedly enabling the bizarre and ineffable experiences associated with psychedelics (Luppi et al., 2021) [see Table 1 and Preller and Vollenweider, (2016) for the phenomenology of psychedelics]. Specifically, a reduction in FC of the mPFC (a key DMN hub) has been observed following the administration of LSD, and this area is known to be implicated in reality monitoring (Taylor et al., 2007; Subramaniam et al., 2020). Thus, a disruption in this brain region’s function may underpin and support the attenuated top-down processing, impairing an individual to accurately differentiate endogenously or exogenously generated percepts. Further evidence for the REBUS model is seen by the findings that entropy and mystical experiences involving ego dissolution (MacLean et al., 2011) have been correlated with increases in trait openness (Lebedev et al., 2016), which itself is associated with creativity, intelligence, and even increased grey matter in the inferior parietal lobule (Schretlen et al., 2010; Taki et al., 2013). Long-term meditators have decreased DMN FC (Brewer et al., 2011; Brewer and Garrison, 2014; Millière et al., 2018), with psychedelic and meditative states sharing some key characteristics such as heightened levels of perceptual sensitivity, ego dissolution, and decreased negative rumination (Brewer et al., 2011; Millière et al., 2018). Increased awareness of thoughts and feelings also seems to be a key characteristic of the ayahuasca experience and may explain the long-term thinning of the PCC in experienced users (Bouso et al., 2015). Furthermore, thinning of the PCC and thickening of the ACC, supporting DMN-TPN orthogonality, has been associated with greater levels of attention, emotional regulation, and feelings of self-transcendence, which is positively correlated with well-being and negatively associated with depression and end-of-life anxiety (Reed, 2008; Bouso et al., 2015).

Cortico-Striatal-Thalamo-Cortical Model (CSTC)

The CSTC postulates that 5-HT_2A receptor activation leads to alterations in the CSTC circuitry, resulting in disinhibition of the thalamus and reduced sensory gating, thereby increasing the amount of sensory information reaching the cortex (Vollenweider et al., 1997). Evidence for this model comes from Preller et al. (2019), who found that LSD increased excitatory connections from the thalamus to the PCC and reduced effective connectivity from the ventral striatum to the thalamus. These connectivity patterns suggest that LSD increases bottom-up informational flow by reducing thalamic-sensory gating, lending credence to the CSTC model.

Cortico-Claustro-Cortical (CCC) Model

The third model is known as the cortico-claustro-cortical model. The claustrum is situated between the insula and putamen and is a thin, curved sheet of neurons embedded in white mater. It contains a large density of 5-HT_2A receptors and bidirectional glutamatergic connections to most of the cortex. The CCC model proposes psychedelic effects are a function of activating receptors in the claustrum [the claustrum also contains k-opioid receptors, the primary target of Salvia A (Stiefel et al., 2014)], which leads to a disruption in higher cortical networks through CCC circuits that may underpin the neural and subjective effects that have been associated with the psychedelic experience. Evidence for this model is supported by the findings from Barrett et al. (2020b) (Table 2). Barret and colleagues observed that psilocybin reduced the BOLD signal of the claustrum, which was also predictive of the participant’s subjective experience.

Limitations of REBUS, CTSC, and CCC Models

The REBUS model needs to be clearer as to what constitutes higher and lower brain regions and would benefit from dividing key brain regions (for example the hippocampus) into its constituent nuclei. Furthermore, functional outcomes of increased entropy (and region-specific entropy) are not entirely clear. For example, a recent study showed that individuals with Major Depressive Disorder (MDD) had increased entropy in bilateral hippocampi (Xue et al., 2019) and it does not seem that MDD patients have a ‘richer subjective experience’ and tend to have a more rigid rather than dynamic cognition (Carhart-Harris et al., 2017). Finally, the majority of studies supporting the REBUS model employ a seed-based approach, which assumes dysconnectivity across homogeneous brain structures, regions and networks. Thus, this presupposition has an a priori connectivity bias which limits the measurement of pharmacologically induced connectivity alterations in unaccounted brain regions and networks (Preller et al., 2018). However, it is promising that Preller et al., (2018)who used the data-driven Global Brain Connectivity (GBC) approach, recapitulated connectivity patterns from previous seed-based analyses.

The CSTC model is also incomplete because it does not account for the “efference copies” that also interact with sensory and predictive cortices (Pynn and DeSouza, 2013). Additionally, like the REBUS model, the CSTC model would be strengthened by a revision that includes more specificity regarding the models’ neuroanatomical constituents (e.g., difference in efferent and afferent output of various thalamic nuclei). Finally, the CCC model is the most recent and thereby has the least amount of support, and as newer technologies emerge this will facilitate research investigation into claustrum connectivity (because the claustrum is naturally hard to measure) in response to psychedelic drugs, which will enable this model’s validity and reliability to be further evaluated.

It is important to discuss that these models are not necessarily distinct from one another and that they are all likely involved in mediating psychedelic therapeutic effects. For instance, the feedforward thalamocortical loop that occurs due to increased serotonergic activity (5-HT_2A receptor agonism in the CSTC circuit), which leads to “sensory overload” and ego-dissolution, is compatible with the increased bottom-up information flow, relaxed priors, and entropy findings that support the REBUS model. Additionally, it is also possible that 5-HT_2A receptor activation within the claustrum leads to CSTC alteration and DMN modulation, increasing entropy and brain plasticity (Barrett et al., 2020b). Hence, it may be appropriate for psychedelics researchers to strive for a unifying psychedelic theory where various theoretical and empirical models are simultaneously tested and juxtaposed with one another. This will enable a more integrated mechanistic understanding of psychedelics’ mode of action; we can potentially understand the similarities and differences of these models and how they relate to the complex phenomenology and clinical outcomes associated with psychedelics.

Current Challenges and Limitations of the DMN

This article rests on the fundamental premise that the DMN is an inherently valuable and meaningful network; however, this presupposition is not without challenge (Fair et al., 2008). It has been argued that the DMN is plagued by the methodological confounder that certain brain regions show intrinsic structural connectivity through vascular coupling rather than functional connectivity (Andrews-Hanna, 2012). However, the assessment of the DMN is not limited to measurements of BOLD fMRI; it has also been assessed through positron emission tomography, which measures glucose metabolism via radioactive tracers (Raichle, 2015). In addition, the neuronal activity of the DMN can be estimated by the electrical activity and magnetic fields associated with this electrophysiological activity via EEG (Foster and Parvizi, 2012) and MEG (Brookes et al., 2011), respectively.

Additionally, Morcom and Fletcher (2007) question the assumption that the DMN reveals substantial information about cognition; however, these early criticisms were based on the simple subtraction design utilized by Raichle et al. (2001) and the scarcity of literature at the time. Furthermore, Morcom and Fletcher concede that controlled experimental manipulations are necessary to further explore the DMN, and the unique experimental conditions that meditation and psychedelics offer have addressed exactly this. Over a decade later, there is a surge in publications suggesting the DMN can offer insight into the variability of human cognition (Brewer et al., 2011; Palhano-Fontes et al., 2015; Raichle, 2015; Mohan et al., 2016; Speth et al., 2016; Smigielski et al., 2019; Zhang and Volkow, 2019; Marstrand-Joergensen et al., 2021; Smallwood et al., 2021; Yeshurun et al., 2021). Furthermore, the DMN has continuously been correlated with the sense of self, ego dissolution, top-down cognitive processes (executive function), cognitive flexibility, awareness, and a number of neuropsychiatric conditions (Andrews-Hanna et al., 2014; Lebedev et al., 2015; Palhano-Fontes et al., 2015; Mohan et al., 2016; Carhart-Harris et al., 2018; Smigielski et al., 2019). For instance, a review by Barrett and Griffiths (2017)hypothesized that decreased activity and FC within DMN hubs such as the PCC and mPFC on administration of classical psychedelics are key facets that mediate the mystical experience via decreased self-referencing and disintegration in the feeling of self. These authors further posit that decreased activity and FC in the inferior parietal lobule (a lateral node of the DMN) is responsible for the feeling of timelessness and spacelessness that often governs the psychedelic experience. Therefore, although Morcom and Fletcher provided valid critiques at the time (2007), current evidence suggests the DMN is a revealing and insightful network that should remain in the purview of cognitive neuroscience and psychedelic research.

Psychedelics are not the only class of drug to alter the DMN. Alcohol also reduces FC within the DMN (Fang et al., 2021). Indeed, this decrease in resting state FC can explain 33% of the variance in alcohol craving in individuals with alcohol use disorder, thereby showing that DMN connectivity profiles/signatures may act as a possible biomarker for this condition (Fede et al., 2019). Fang et al. (2021) found that moderate alcohol consumption acutely and significantly decreased FC within the right hippocampus and right medial temporal gyrus. Unlike psychedelics, alcohol did not significantly affect the inter-network connectivity of the DMN with other cortical networks. Therefore, the acute disruption in intra-network connectivity of the DMN induced by both alcohol and psychedelics may in part explain the euphoric experience characteristic of intoxication with both drugs. The ability of psychedelics to increase global integration and connectivity (via increased internetwork connectivity) juxtaposed with its neuroplastic properties may explain its unique capacity to produce positive therapeutic health outcomes. Interestingly, it does seem that ketamine has the capacity to decrease FC within the DMN (at doses that alter consciousness) and alter the FC between the DMN and other networks (Bonhomme et al., 2016), and it has been argued that neuroplasticity is a convergent mode of action between psychedelics and ketamine (via mechanisms described above) (Aleksandrova and Phillips, 2021). Additionally, findings from Doss et al. (2020) showed that the k-opioid receptor agonist and atypical dissociative Salvinorin A decreased within network FC and increased between network FC. Static and entropic functional connectivity were best predicted by the DMN, questioning the specificity of the entropic brain hypothesis to the classical psychedelics. It is unclear if Salvinorin A elicits the same neuroplastic properties as ketamine and the classical psychedelics and whether this relates to their intra- and internetwork modulation capacity.

Table 2 outlines and summarizes the limitations of each study included in the systematic review, so a brief overview of the common limitations will be discussed. The majority of included studies were, for ethical reasons, conducted on people with prior psychedelic experience and were of small sample sizes. Therefore, it is encouraged that future researchers report effect sizes, as a power analysis by McCulloch et al., (2022) found that sample sizes greater than 60 are needed for adequately powered studies. Strikingly, only 2 of 28 papers had 60 or more participants (Mason et al., 2020, 2021). Furthermore, a number of studies included new analysis on two previously small sample datasets (Carhart-Harris et al., 2012, 2016), which is problematic for a number of reasons. The primary limitation from this sort of analysis is that one would expect that in the absence of any serious fundamental methodological flaw in the dataset that different analytical methods should support the same hypothesis. Thus, we emphasize that these findings are not necessarily independent evidence, though the fact that different analytical methodologies generated similar conclusions is reassuring. Future research should aim to carry out similar analysis on novel datasets, which would provide more robust and reliable evidence for the REBUS and entropic brain hypothesis.

The problem of inferring psychological processes or cognition from patterns of activation via neuroimaging technologies is known as reverse inference. It is not entirely clear as to whether alterations in DMN activity and connectivity are merely a by-product or epiphenomenon of psychedelics or if they play a mediating role in psychedelics’ specific psychological effects and therapeutic benefit. Thus, researchers should be tentative in drawing causal conclusions from correlative evidence.

With any field of research there is a risk of publication bias. In the context of the papers reviewed in this article, when initial articles linking the DMN to various cognitive outcomes were established in prestigious journals (refer Figure 3, Carhart-Harris et al., 2012, 2016, and Palhano-Fontes et al., 2015), it directs the field of psychedelic research and expected findings and hypotheses generated by researchers. Thus, we urge the scientific community to remain wary of overly enthusiastic claims and consider theories as parsimonious models rather than established facts. Pre-print journals such as bioRxiv and PsyArXiv can also be useful in sharing studies that may have difficulty getting published elsewhere due to negative results but can still contribute to the corpus of scientific knowledge. However, it is important to consider that due to the renewed interest in psychedelic medicine, publications with negative findings are still likely to be published and the currently published data have all been attached to registered trials.

Potential Future of DMN Modulation–Focused Psychedelic Therapies

Studies have highlighted the potential application of the intrinsic FC of the DMN as a biomarker. The DMN has been utilized as a biomarker for attention deficit hyperactivity disorder, early antidepressant response, chemotherapy-related brain injury, depression, epilepsy, Parkinson’s disease (Yanbing et al., 2020), bipolar affective disorder, and schizophrenia (Meda et al., 2014). Using resting and task-influenced DMN activity as a cognitive biomarker is aligned with the research domain criteria of the National Institute of Mental Health. Research domain criteria is a research framework for investigating mental disorders and places an emphasis on using different biological and cognitive markers as transdiagnostic tools. Therefore, using the DMN as a biomarker of neuropsychiatric conditions can help overcome many of the limitations often associated with diagnosing these pathologies via symptomatology. These include heterogeneity of symptoms for the same condition and less reliance on the subjective judgment of a clinician.

The REBUS and predictive-coding models may offer explanatory power in terms of psychedelics transdiagnostic potential. Neuropsychiatric conditions are characterized by distinct DMN signature abnormalities, which psychedelics may therapeutically normalize. Little is known regarding how psychedelics influence top-down and bottom-up information-processing streams and whether these pathways converge upon the DMN. Future research might take Bayesian approaches to determine if psychedelics alter hierarchical sensory processing and if this may contribute to updating models of the self and world as proposed in the REBUS model. Moreover, belief system updating may alter top-down processing, with greater cognitive flexibility modulating distinctions of exogenous and interoceptive information. These hypotheses can be directly assessed in future research by examining how nodes of the DMN may modulate thalamic activity via effective connectivity analyses, and vice versa, to gain a deeper understanding about information transfer as demonstrated by Preller et al. (2019).

Micro-dosing of psychedelics (particularly LSD and psilocybin), which generally involves taking sub-hallucinogenic doses, has been reported to lead to decreased mind-wandering (Polito and Stevenson, 2019), which at the neural level is reflected by reduced DMN activity. For instance, a double-blinded placebo-controlled study by Murray et al., (2022)administered low doses of LSD (13 or 26 μg sublingual). Using EEG, scalp electrodes were placed on the midline of the brain to infer source localization for key DMN regions and showed a reduction in broadband oscillatory power, consistent with findings using larger doses. Across all EEG frequencies (delta, theta, alpha, beta, and gamma), the 26-μg dose saw greater reductions in oscillatory power compared with the 13-μg dose. There is, however, currently no direct evidence or clinical trials that show how micro-dosing modulates the DMN, and this should be explored in subsequent research. This can illuminate how much DMN modulation (and its potential downstream benefits) is dependent on the rich subjective experience associated with larger doses of psychedelics. Furthermore, studies could aim at determining a “minimum effective dose,” which would likely cause fewer challenging experiences that may result from administration of high-dose psychedelics. The same rationale also applies to non-hallucinogenic psychedelic analogues, which are currently being explored and have shown anti-depressant effects, at least in rodent models (Cao et al., 2022). However, it is important to note that challenging experiences may also be conducive of positive therapeutic outcomes (Yaden and Griffiths, 2020).

A worthwhile future direction would be the comparison of DMN modulation for experienced psychedelic users and psychedelic naïve individuals because it would help decipher the interaction between the acute and enduring effects of these substances on this network. Alternatively, well-designed longitudinal research involving several scanning sessions could clarify how modulations of DMN FC may reflect the dynamics of lasting effects of psychedelics in brain activity as demonstrated by McCulloch et al. (2022). Interestingly, in this recent study within and between DMN FC differences were not significantly (with low effect size, d = 0.2) modulated at 1-week and 3-months post injection. This study design could be replicated with a greater sample size and additional acute time points to further delineate the acute and enduring connectivity patterns of psychedelic drugs.

Clinically, psychedelics could be used in conjunction with psychotherapeutic techniques such as mindfulness meditation. Mindfulness and psilocybin retreats have shown promising outcomes for people with depression (Carhart-Harris et al., 2017). It seems that mindfulness and psilocybin therapy modulate the DMN in similar ways (a reduction in FC and activity within the DMN) and may act synergistically. This may be because mindfulness, which acts to increase and cultivate non-judgmental awareness of one’s thoughts and feelings, may help facilitate a positive psychedelic experience and vice versa.

Additionally, a legitimate research question in the context of depression is whether infrequent psilocybin treatment (i.e., quarterly) juxtaposed with standard frontline treatments such as cognitive behavioral therapy and selective serotonin reuptake inhibitors such as escitalopram may yield a superior continued reduction in depressive symptomatology. This type of study design could be within the purview of future research scientists and, if effective, could be translated to a variety of other neuropsychiatric conditions. Furthermore, it is important that clinical (and pre-clinical) research promotes a “bench-to-bedside” approach; with scheduled drugs such as psychedelics, there will be a need for government lobbying and policy reform [see Marks and Cohen, (2021) for a roadmap for psychedelic therapy].

CONCLUSIONS

This systematic review provides evidence to support the notion that classical psychedelics are capable of modulating the DMN, which is correlated with ego dissolution, increased brain entropy, and improved mental health and well-being. Our review of the data shows psychedelics are a valuable tool for investigating this network and considers the potential therapeutic implications of this effect. Psychedelics are showing promise as tools to aid our understanding of the brain and mind in greater detail. Finally, this understanding can be harnessed to treat a variety of neuropsychiatric conditions and potentially increase healthy individuals’ psychological well-being.

Default Mode Network Modulation by Psychedelics: A Systematic Review

Introduction

Psychedelics are a group of substances known for their hallucinogenic effects, with significance in cultural, spiritual, and scientific contexts. The term "psychedelic" originates from Greek words meaning "mind-manifesting," suggesting an ability to reveal aspects of the human mind. Classical psychedelics, which include substances like LSD and psilocybin, primarily act on serotonin (5-HT2A) receptors in the brain, leading to significant changes in consciousness, including alterations in self-perception, sensory experience, and emotions.

Neuroimaging research indicates that when a person is at rest, specific brain regions show increased activity. This activity decreases when an individual focuses on a task. These interconnected regions form four main functional areas: the medial prefrontal cortex (mPFC), the posterior cingulate cortex (PCC), the precuneus, and the angular gyrus. Collectively, these areas are known as the Default Mode Network (DMN). The DMN is one of several resting-state networks (RSNs), which are identified by the synchronized fluctuations of low-frequency signals between functionally related brain areas during periods of rest.

Functional connectivity (FC), which describes how neural activity in different brain regions coordinates over time, is crucial for understanding the DMN. The DMN's FC is often observed to be inversely related to the activity of brain networks involved in tasks, such as the salience network. Changes in DMN functional connectivity have been linked to various psychological measures and may have therapeutic implications. For example, reduced connectivity within DMN regions has been associated with states of ego dissolution, which can aid in cognitive reframing during a psychedelic experience.

The "mind-manifesting" qualities of psychedelics led to a surge of research in the 1960s, identifying their potential as treatments for various mental health conditions. Substances like lysergic acid diethylamide (LSD) were even prescribed clinically during that era. Political factors in the 1970s severely restricted psychedelic research; however, due to promising preliminary findings, scientific interest in psychedelics, including psilocybin, DMT, and ayahuasca, has re-emerged in clinical neuroscience. Recent studies are now investigating how these compounds affect the DMN. Psychedelics often induce profound experiences, including mystical states, which have been linked to increased brain entropy. This systematic review aims to assess how classical psychedelics affect the DMN, evaluate the evidence linking DMN modulation to psychotherapeutic outcomes, identify current challenges in the literature, and discuss future research and clinical applications.

Methods

This systematic review adhered to the PRISMA statement for reporting. Electronic database searches were conducted in PubMed and Scopus, from their inception up to April 2022. The search strategy used the PICO framework, combining terms related to the Default Mode Network (e.g., "default mode network," "DMN," "neuro circuitry") with names of classical psychedelics (e.g., "ayahuasca," "DMT," "psilocybin," "LSD," "mescaline"). Google Scholar was also searched for additional relevant articles.

Inclusion criteria specified human clinical trials that evaluated DMN modulation by classical psychedelics. This also included new analyses of previously published datasets. Only English-language papers were eligible, without specific requirements for psychedelic dose, treatment duration, or statistical methods. Studies involving all clinical diagnoses and healthy controls were considered. Two reviewers independently screened articles, resolving disagreements through discussion.

Results

The initial database searches, conducted in August 2021 and April 2022, yielded 163 results. After removing duplicates and ineligible articles, 28 studies were included in the review.

The included studies comprised 17 on psilocybin, primarily using fMRI (12 studies, mostly 3 Tesla), with some using EEG or MEG. These studies involved an average of 26 participants (SD 19) with an average age of 34.6 years (SD 8.8); 13 of these studies included a placebo control. Four ayahuasca studies, all using fMRI, had an average of 28 participants (SD 5.9) with an average age of 35 years (SD 17.8), and only one was placebo-controlled. Eight LSD studies, mostly fMRI-based, included an average of 20 participants (SD 6.4) with an average age of 29.6 years (SD 2.8), and all had placebo controls. No published human studies examining mescaline or DMT modulation of the DMN were found.

Discussion

Synthesis of Data

Evidence suggests a clear link between the ability of psychedelics to reduce functional connectivity within the Default Mode Network (DMN) while increasing its connectivity to other networks, the occurrence of altered states of consciousness, and positive therapeutic outcomes. However, the exact causal relationship remains to be fully determined. Recent reviews highlight that classical psychedelics can induce significant neuronal structural and functional changes through mechanisms like neurotrophic signaling and neuroplasticity. These effects, possibly involving the reduction of neuronal inflammation, may explain the long-term health benefits observed. It is challenging to distinguish how much of the therapeutic effect stems from these cellular neuroplastic changes versus DMN modulation, and how these levels of action are interconnected.

Depression is often characterized by excessive activity in the medial prefrontal cortex (mPFC). Studies have shown an inverse relationship between depressive symptoms and the degree of 5-HT2A receptor stimulation in this region. While psilocybin may acutely increase anxiety, long-term reductions could relate to 5-HT2A receptor downregulation. Another hypothesis suggests that psychedelics' affinity for and agonism of inhibitory 5-HT1A receptors may contribute to the observed decrease in DMN coactivation. Connectivity patterns within the DMN, specifically between the parahippocampal cortex and prefrontal regions, have been predictive of depressive symptoms after psilocybin treatment. Overall, the literature indicates that classical psychedelics acutely decrease intra-DMN functional connectivity and increase inter-network connectivity, shifting the brain from a more segregated to a more globally interconnected state. This increased flexibility, also seen with ketamine and salvinorin A but not other classes of drugs, appears to persist in patients with major depressive disorder treated with psilocybin. The DMN disruption by psychedelics may stem from the cognitively intensive experience they induce, aligning with the DMN's anti-correlation with task-based activities. Awareness of mind-wandering, as in meditation, similarly decreases DMN resting functional connectivity, suggesting a mechanism for psychedelics' effects.

Models of Psychedelic Action and Their Limitations

Three prominent models describe the biological mechanisms of psychedelic action. The "Relaxed Beliefs Under Psychedelics" (REBUS) model, central to many studies, proposes that psychedelics activate 5-HT2A receptors, leading to increased glutamate and neuronal desynchronization, which in turn increases brain entropy. This increased randomness and flexibility are thought to disrupt rigid, top-down cognitive processes, allowing for increased bottom-up information flow and the revision of unhelpful beliefs. This disruption of top-down control has been linked to sustained positive emotional changes and a "resetting" mechanism in the brain. The REBUS model suggests a reduced influence of existing structural brain patterns on cognition, enabling new patterns and subjective experiences.

The Cortico-Striatal-Thalamo-Cortical (CSTC) model posits that 5-HT2A receptor activation alters CSTC circuitry, leading to reduced sensory gating in the thalamus and increased sensory information reaching the cortex. Research supporting this model has shown that LSD increases excitatory connections from the thalamus. The third model, the Cortico-Claustro-Cortical (CCC) model, proposes that psychedelic effects stem from activating receptors in the claustrum, a brain region with extensive connections to the cortex. This activation could disrupt higher cortical networks, leading to the observed neural and subjective effects.

Each model has limitations. The REBUS model requires clearer definitions of brain regions and functional outcomes of entropy, particularly since increased entropy is also observed in conditions like Major Depressive Disorder, where rigid cognition is common. Most REBUS studies rely on seed-based analyses, which may introduce a bias in connectivity measurements. The CSTC model lacks comprehensive accounting for "efference copies" and needs greater neuroanatomical specificity. The CCC model, being newer, currently has the least empirical support, with ongoing research needed to validate its role due to the claustrum's difficulty in measurement. Nevertheless, these models are not mutually exclusive and likely contribute in concert to the therapeutic effects of psychedelics. A unifying theory that integrates these various models is desirable for a more comprehensive understanding of psychedelic action and their clinical outcomes.

Current Challenges and Future Directions

The fundamental premise of the DMN's significance is not without debate. Some argue that DMN activity might reflect vascular coupling rather than true functional connectivity. However, DMN assessment extends beyond fMRI to techniques like positron emission tomography (PET), EEG, and MEG, which measure metabolic activity and electrical/magnetic fields, respectively, thus addressing some of these concerns. While early criticisms questioned the DMN's cognitive relevance, subsequent controlled studies, particularly those involving meditation and psychedelics, have demonstrated its insight into human cognition. The DMN has consistently been linked to self-perception, ego dissolution, cognitive flexibility, and various neuropsychiatric conditions. For instance, reduced activity and functional connectivity within DMN hubs following psychedelic administration are hypothesized to mediate mystical experiences through decreased self-referencing.

It is important to note that psychedelics are not unique in altering the DMN. Alcohol, ketamine, and salvinorin A also reduce DMN functional connectivity, though psychedelics are distinct in their ability to increase global brain integration and connectivity between networks, which may contribute to their unique therapeutic potential and neuroplastic properties. A common limitation across many included studies is the reliance on small sample sizes and participants with prior psychedelic experience, due to ethical considerations. This suggests a need for future research with larger, adequately powered studies, and novel datasets to provide more robust evidence.

The challenge of "reverse inference"—inferring psychological processes from neuroimaging patterns—means that DMN alterations may be a byproduct rather than a direct mediator of psychedelic effects. Therefore, caution is warranted when drawing causal conclusions from correlative data. Publication bias is also a concern, as early influential studies linking the DMN to cognitive outcomes may have shaped subsequent research expectations. The scientific community is encouraged to approach claims cautiously, viewing theories as models rather than established facts. Future research could explore the DMN as a transdiagnostic biomarker for neuropsychiatric conditions, leveraging its unique connectivity profiles. Investigating how psychedelics influence top-down and bottom-up information processing streams relative to the DMN, possibly using Bayesian approaches, could further refine understanding of belief system updating. Research into micro-dosing and non-hallucinogenic analogues could clarify the extent to which DMN modulation depends on subjective psychedelic experiences. Comparisons between experienced and naive psychedelic users, as well as longitudinal studies, are also crucial for understanding the enduring effects on the DMN. Furthermore, integrating psychedelic treatment with psychotherapeutic techniques like mindfulness meditation, which similarly modulate the DMN, or juxtaposing it with standard frontline treatments, represents a promising direction for future clinical research.

Conclusions

This systematic review supports the idea that classical psychedelics can modulate the Default Mode Network (DMN), a process linked to ego dissolution, increased brain entropy, and improvements in mental health and well-being. The findings indicate that psychedelics are a valuable tool for studying this brain network and offer potential therapeutic applications. These substances show promise in advancing the understanding of the brain and mind, an understanding that could be applied to treat various neuropsychiatric conditions and enhance psychological well-being in healthy individuals.

Introduction

Psychedelics are a group of substances that cause strong changes in perception and thought, and they have cultural, spiritual, and scientific importance. The word "psychedelic" means "mind-manifesting," suggesting these substances can reveal hidden aspects of the human mind. "Classical psychedelics" are a group of substances that work primarily by affecting serotonin receptors (5-HT2A) in the brain. This action leads to significant changes in consciousness, including how a person feels about themselves, their senses, and their emotions.

Brain imaging studies show that when a person is at rest, certain brain regions become more active. When the person focuses on a task, activity in these regions decreases. These areas form four main connection points: the medial prefrontal cortex, the posterior cingulate cortex, the precuneus, and the angular gyrus. Together, these are called the Default Mode Network (DMN). The DMN is one of several resting-state networks, which are groups of brain areas that show synchronized activity when the brain is not focused on a specific task.

Functional connectivity describes how different brain regions show coordinated activity over time. This is an important factor in understanding the DMN. Resting-state networks like the DMN are measured before a person starts a task. The DMN's functional connectivity often shows an opposite pattern of activity compared to brain networks active during tasks, such as the salience network. Changes in DMN connectivity have also been linked to various psychological factors measured by questionnaires, which may relate to the healing effects of psychedelics. For example, reduced connectivity within the DMN has been connected to feelings of "ego dissolution," where the sense of self seems to fade. This experience might help people re-evaluate their thoughts during a psychedelic session.

Changes in DMN functional connectivity, both within its own regions and between the DMN and other brain networks, have been linked to complex brain functions like understanding others' perspectives, self-reflection, memory, and repetitive thoughts. However, how these changes happen is not fully understood. Also, altered DMN function has been observed in various mental health conditions and brain diseases, such as depression, attention deficit hyperactivity disorder, schizophrenia, anxiety, post-traumatic stress disorder, Alzheimer’s disease, and normal aging. Therefore, changes in DMN connectivity in people with certain conditions or those using treatments like psychedelics can offer insights into how the brain functions.

The mind-altering effects of psychedelics led to many studies in the 1960s, which suggested these substances could be used to treat mental health and substance use disorders. For instance, LSD was prescribed in the 1950s and 1960s for mental health conditions, always in a controlled medical setting. However, the use of LSD and other psychedelics in research was severely limited in the 1970s for political reasons. Despite this, based on promising early findings, psychedelics like psilocybin, DMT, ayahuasca, and mescaline, as well as MDMA and ketamine, are now regaining scientific interest, especially in clinical neuroscience. Many recent studies have begun to explore how psychedelics affect the DMN.

Psychedelics often create profound and meaningful experiences that are linked to increased brain entropy. Brain entropy measures the randomness or unpredictability of a system, and in the brain, it relates to functional flexibility, which can lead to a wider range of brain states. Researchers propose that much of the therapeutic benefit of psychedelics comes from the altered state of consciousness they produce. One of the most common and transformative parts of the psychedelic experience is the feeling of ego dissolution, where the boundaries of the self seem to dissolve. This feeling also appears to be a key part of "unitive experiences," where a person feels a sense of oneness with nature or a higher power. It is thought that ego dissolution can be therapeutic because it allows a person to view their thoughts and emotions with more distance and objectivity. This might happen because psychedelics reduce the certainty of old beliefs, allowing for new ways of thinking about the self and the world. This is similar to meditation, which also leads to decreased DMN activity and changes in how beliefs and attention are processed. Brain imaging studies of psychedelics show that DMN activity and blood flow within its regions decrease. These changes are also seen in brain wave studies, where there is a desynchronization of alpha waves, particularly in the posterior cingulate cortex (a main DMN hub). This is thought to result in a mind that is less restricted, more flexible, and less focused on the self.

Even though the DMN is often studied in psychedelic research, there is still some uncertainty about what changes to this network mean. This review aims to (1) evaluate how classical psychedelics affect the DMN; (2) assess the evidence linking DMN changes to positive mental health outcomes; (3) identify challenges and limitations in current research on DMN modulation by psychedelics; and (4) discuss future research and potential uses of DMN-focused psychedelic therapies. This review concentrates on classical psychedelics: LSD, psilocybin, DMT, mescaline, and ayahuasca.

Methods

This review followed standard guidelines for clear and complete reporting.

Search Strategy

A search was conducted using electronic databases for studies related to the DMN and classical psychedelics. The search terms included "default mode network" or "DMN" or "neuro circuitry" combined with names of psychedelics like "ayahuasca," "DMT," "psilocybin," "LSD," or "mescaline." Additional articles were also sought through other academic search engines.

Eligibility Criteria

Two researchers reviewed articles to determine if they met the criteria. Any disagreements were resolved through discussion. Only human studies that examined DMN changes caused by classical psychedelics were included. Papers that re-analyzed data from previously published studies were also considered. Only articles written in English were eligible. There were no specific requirements for psychedelic dose, treatment length, or statistical methods. Studies involving participants with various clinical diagnoses and healthy individuals were included.

Results

Results Overview

The initial search yielded 163 results, which were narrowed down to 119 after removing duplicates. An additional 95 articles were excluded because they did not meet the eligibility criteria. This left 28 articles for inclusion in the review.

Among the included studies, 17 focused on psilocybin, primarily using brain imaging techniques. Participants in these studies had an average age of about 34.6 years, and the average number of participants per study was 26. Most of these studies (13 out of 17) included a placebo control group. Four studies examined Ayahuasca, all using brain imaging. Participants averaged 35 years old, with an average of 28 participants per study. Only one of these studies had a placebo control group. Eight studies investigated LSD, mostly using brain imaging, with participants averaging 29.6 years old and 20 participants per study. All LSD studies included a placebo control group. No published research papers were found that assessed how mescaline and DMT specifically modulate the DMN in humans.

Discussion

Synthesis of Data

Evidence suggests a clear connection between psychedelics' ability to reduce functional connectivity within the DMN (and increase its connectivity to other networks), the experience of altered states of consciousness, and positive therapeutic outcomes. However, it is currently difficult to determine if these DMN changes directly cause the therapeutic effects or if they are simply associated with them.

Recent research indicates that classical psychedelics can cause notable structural and functional changes in neurons, likely through processes related to brain growth and repair. These changes might be driven by specific proteins and pathways in the brain. Furthermore, psychedelics have been shown to potentially alter gene expression and immune system responses. These effects are thought to reorganize problematic brain networks, possibly by reducing brain inflammation (a growing idea in addiction, depression, and neurodegeneration research). This may explain how psychedelics can lead to long-term health improvements at a biological level. Therefore, it is challenging to separate how much of the benefit from psychedelic therapy comes from these cellular-level changes or from DMN modulation, and how closely these two levels are linked. This challenge is further complicated by studies using different psychedelic doses, some lacking placebo controls, and often including participants who have used drugs before.

Depression is often linked to excessive activity in the medial prefrontal cortex. There seems to be an inverse relationship between depressive symptoms and how much serotonin 5-HT2A receptors are stimulated in this area. While psilocybin can temporarily increase anxiety (possibly due to increased glutamate in the frontal brain), long-term reductions in anxiety might occur as serotonin receptors in this area become less responsive over time. Another idea is that psychedelics largely affect the 5-HT1A receptors, which are primary inhibitory serotonin receptors. These might be responsible for the reduced brain activity often seen in the DMN and other brain regions when psychedelics are administered. On a larger scale, connectivity between certain brain regions was a reliable predictor of depressive symptoms five weeks after psilocybin treatment.

One review concluded that psilocybin, by disrupting the overly connected DMN in people with mental health conditions, could be a new treatment for various neuropsychiatric conditions. A recent analysis found that psilocybin therapy reduced depressive symptoms for up to six weeks after treatment, and this effect was likely due to increased integration across brain networks. Interestingly, this research also found that greater connectivity within the DMN and reduced connectivity between the DMN and other networks (like the executive and salience networks) were linked to how severe depression was at the start of the study, which supports earlier findings.

The reviewed literature clearly shows that classical psychedelics acutely decrease functional connectivity within the DMN and increase connectivity between different brain networks. This suggests that during a psychedelic experience, there is a unique shift in brain connections, moving from a more separate and modular brain to a more interconnected global network. This reduced separation between networks seems somewhat specific to classical psychedelics, though it is also seen with ketamine and salvinorin A. This effect is not observed with common antidepressants, stimulants, sedatives, or MDMA. The increased connectivity between networks can be understood as the brain being able to access a wider range of flexible states. This more flexible brain state appears to remain even after psilocybin treatment for major depressive disorder.

Psychedelics might disrupt the DMN because they promote an experience that is very mentally engaging, where a person deals with their subconscious and explores profound personal and metaphysical questions that often arise. This fits with the DMN's known characteristic of being less active during focused, task-oriented activities. Although mind-wandering is associated with increased DMN activity, awareness of mind-wandering—as practiced in meditation—decreases the DMN's resting connectivity. This is a plausible way in which ayahuasca, psilocybin, and LSD also decrease DMN activity, as the experience often involves a heightened awareness of one's internal thoughts and feelings. It could also be argued that this hyper-awareness is a sign of a brain with increasing entropy, though this needs further study. It is also clear that individuals will respond differently to treatments based on their baseline awareness levels. Another possible reason for reduced DMN activity is that psychedelics may lead to less dwelling on the past, as seen with LSD, but whether this effect is unique to psychedelics is unclear.

Models of Psychedelic Action

It is important to note that the "Relaxed Beliefs Under Psychedelics" (REBUS) model is one of three main models explaining how psychedelics work biologically. Each model has strengths and weaknesses. The REBUS model has been a primary focus of this review because it considers DMN activity and its changes as central. The other two models suggest mechanisms that are relatively independent of DMN modulation.

Relaxed Beliefs Under Psychedelics and Brain Entropy

It has been suggested that the underlying brain biology of DMN disruption and its effects are caused by entropy. Psychedelics mainly cause their hallucinogenic effects by activating the 5-HT2A receptor, which leads to increased serotonin release. This makes certain brain cells in the cortex more excitable, leading to increased glutamate in the neocortex. In the cortex, 5-HT2A receptor activation can cause glutamate to be released in an uncoordinated way, leading to desynchronized groups of neurons. Consequently, the brain becomes more desynchronized, resulting in a loss of rhythmic brain activity, which aligns with the brain entropy idea.

Brain entropy is characterized by increased randomness and unpredictability in how neurons fire. This disrupts "top-down" cognitive processing, which is usually goal-oriented. It is thought that this disruption in top-down control can lead to increased brain and cognitive flexibility, providing a plausible explanation for the therapeutic effects of psychedelics. The REBUS model proposes that psychedelics reduce the "weight" or certainty of previous beliefs, while increasing the flow of "bottom-up" information processing. This process can allow people to revise deeply ingrained, often problematic, beliefs that affect how their brain systems function, particularly those related to the self.

Evidence from recent studies may support this model and the idea of a "resetting mechanism." The temporary disruption in top-down cognitive control showed lasting benefits (up to one month), leading to less negative emotion and more positive emotion after psilocybin use. Brain connectivity can be thought of as existing beliefs. Under anesthesia, outside information is minimally processed, meaning brain connectivity strongly reflects pre-existing structural beliefs. However, with classical psychedelics, the brain is less restricted by these pre-existing structural beliefs, so they have less influence on thinking, which aligns with the REBUS model.

Interestingly, the reduced influence of structural beliefs allows the brain to create a wider range of connectivity patterns and networks, which supposedly explains the unusual and hard-to-describe experiences associated with psychedelics. Specifically, a reduction in connectivity of the medial prefrontal cortex (a key DMN hub) has been observed after LSD administration. This area is known to be involved in distinguishing between internal and external reality. Thus, a disruption in this brain region's function might explain the reduced top-down processing, making it harder for a person to accurately tell the difference between thoughts generated internally or those from external perception. Further evidence for the REBUS model comes from findings that entropy and mystical experiences involving ego dissolution have been linked to increases in openness as a personality trait. Openness is itself associated with creativity, intelligence, and even increased gray matter in certain brain areas. Long-term meditators also show decreased DMN functional connectivity, and psychedelic and meditative states share some key features like heightened sensory perception, ego dissolution, and reduced negative rumination. Increased awareness of thoughts and feelings also seems to be a key characteristic of the ayahuasca experience and may explain the long-term thinning of a specific DMN region in experienced users. Furthermore, changes in brain thickness in certain areas, supporting the DMN's opposite relationship with task networks, have been linked to greater attention, emotional regulation, and feelings of self-transcendence, which are positively related to well-being and negatively associated with depression and end-of-life anxiety.

Cortico-Striatal-Thalamo-Cortical Model (CSTC)

The CSTC model suggests that activating the 5-HT2A receptor changes the circuitry involving the cortex, striatum, and thalamus. This leads to the thalamus becoming less inhibited and sensory filtering being reduced, which then increases the amount of sensory information reaching the cortex. Evidence for this model includes findings that LSD increased excitatory connections from the thalamus to the posterior cingulate cortex and reduced connections from the ventral striatum to the thalamus. These patterns suggest that LSD increases the flow of "bottom-up" information by reducing the thalamus's ability to filter sensory input, supporting the CSTC model.

Cortico-Claustro-Cortical (CCC) Model

The third model is the cortico-claustro-cortical (CCC) model. The claustrum is a thin sheet of neurons located between other brain structures. It has a high density of 5-HT2A receptors and strong connections to most of the cortex. The CCC model proposes that psychedelic effects come from activating receptors in the claustrum, which then disrupts higher cortical networks through these connections. This disruption may explain the brain activity and subjective experiences linked to psychedelics. Evidence for this model includes observations that psilocybin reduced activity in the claustrum, and this reduction was also linked to the participant's subjective experience.

Limitations of REBUS, CTSC, and CCC Models

The REBUS model needs to be more precise about what constitutes "higher" and "lower" brain regions and would benefit from breaking down key brain regions into smaller parts. Also, the specific functional outcomes of increased entropy (and entropy in specific brain regions) are not fully clear. For example, a recent study showed that individuals with major depressive disorder had increased entropy in certain brain areas, but it does not seem that these patients have a "richer subjective experience"; instead, they tend to have more rigid thinking. Finally, most studies supporting the REBUS model use an approach that assumes connectivity problems occur across large, uniform brain structures, which can limit the measurement of drug-induced changes in other brain regions or networks. However, it is promising that some studies using different, data-driven approaches have found similar connectivity patterns.

The CSTC model is also incomplete because it does not account for certain feedback loops that interact with sensory and predictive parts of the brain. Like the REBUS model, the CSTC model would be stronger with more specific details about its neuroanatomical components. Lastly, the CCC model is the newest and therefore has the least support. As new technologies emerge, more research will be possible to investigate claustrum connectivity in response to psychedelics, which will help evaluate this model's accuracy.

It is important to understand that these models are not necessarily separate from each other; they are likely all involved in how psychedelics produce therapeutic effects. For example, the feedback loop between the thalamus and cortex that occurs due to increased serotonin activity, leading to "sensory overload" and ego-dissolution, is consistent with the increased bottom-up information flow, relaxed beliefs, and entropy findings that support the REBUS model. Additionally, it is possible that serotonin receptor activation within the claustrum leads to changes in the CSTC circuit and DMN modulation, increasing entropy and brain plasticity. Therefore, it may be beneficial for psychedelic researchers to aim for a unified theory that tests and compares various theoretical and empirical models simultaneously. This approach would allow for a more integrated understanding of how psychedelics work, helping to clarify the similarities and differences among these models and how they relate to the complex experiences and clinical outcomes associated with psychedelics.

Current Challenges and Limitations of the DMN

This discussion is based on the idea that the DMN is an important and meaningful network, but this idea does have its critics. Some argue that DMN measurements are affected by the fact that certain brain regions are structurally connected through blood vessels rather than purely by their functional activity. However, DMN activity can be measured using different methods beyond specific brain imaging techniques, such as those that measure glucose metabolism or electrical and magnetic brain activity.

Furthermore, some researchers have questioned whether the DMN provides significant information about cognition. However, these early criticisms were based on simple study designs and limited research at the time. These critics also conceded that controlled experiments were needed to further explore the DMN, and the unique conditions offered by meditation and psychedelics have addressed this need. Over a decade later, many publications suggest the DMN offers insight into the variety of human cognition. Moreover, the DMN has consistently been linked to the sense of self, ego dissolution, top-down cognitive processes (like executive function), cognitive flexibility, awareness, and several mental health conditions. For example, a review hypothesized that decreased activity and connectivity within DMN hubs, such as the posterior cingulate cortex and medial prefrontal cortex, after taking classical psychedelics are key factors that contribute to mystical experiences by reducing self-referencing and dissolving the sense of self. These authors also suggested that decreased activity and connectivity in another DMN region (the inferior parietal lobule) explains the feelings of timelessness and spacelessness often reported during psychedelic experiences. Therefore, while early criticisms were valid at the time, current evidence suggests the DMN is a revealing network that should continue to be studied in cognitive neuroscience and psychedelic research.

Psychedelics are not the only type of drug that alters the DMN. Alcohol also reduces functional connectivity within the DMN. This decrease in resting-state connectivity can explain a significant portion of alcohol craving in individuals with alcohol use disorder, suggesting that DMN connectivity patterns might serve as a possible marker for this condition. One study found that moderate alcohol consumption acutely and significantly decreased connectivity within the right hippocampus and right medial temporal gyrus. Unlike psychedelics, alcohol did not significantly affect the connectivity between the DMN and other brain networks. Therefore, the immediate disruption in DMN connectivity caused by both alcohol and psychedelics may partly explain the euphoric experience linked to both drugs. Psychedelics' ability to increase overall brain integration and connectivity, combined with their ability to promote brain plasticity, may explain their unique potential to produce lasting positive health outcomes. Interestingly, ketamine also seems to decrease DMN connectivity (at doses that alter consciousness) and alter connectivity between the DMN and other networks. It has been argued that brain plasticity is a common way in which psychedelics and ketamine work. Additionally, findings from another study showed that salvinorin A, an opioid receptor agonist, also decreased connectivity within brain networks and increased connectivity between networks. Static and entropic functional connectivity were best predicted by the DMN, which raises questions about whether the "entropic brain" idea is specific only to classical psychedelics. It is unclear if salvinorin A causes the same brain plasticity as ketamine and classical psychedelics, and if this relates to how they affect brain networks.

The limitations of each study included in this review are outlined in a table, but a brief overview of common limitations is important. Most included studies, for ethical reasons, involved people who had used psychedelics before and had small sample sizes. Therefore, future researchers should report effect sizes, as larger sample sizes (greater than 60 participants) are generally needed for studies to have enough statistical power. Strikingly, only two of the 28 reviewed papers had 60 or more participants. Furthermore, several studies presented new analyses of previously small datasets. A primary limitation of this type of analysis is that if there are no fundamental flaws in the original data, different analysis methods should support the same hypothesis. Therefore, these findings are not necessarily independent evidence, although the fact that different analytical methods produced similar conclusions is reassuring. Future research should aim to conduct similar analyses on new datasets, which would provide more robust and reliable evidence for the REBUS model and the entropic brain hypothesis.

The challenge of inferring psychological processes or cognition from brain imaging patterns is known as reverse inference. It is not entirely clear whether changes in DMN activity and connectivity are simply a side effect of psychedelics or if they play a direct role in the specific psychological effects and therapeutic benefits of these substances. Therefore, researchers should be cautious about drawing conclusions about cause and effect from evidence that only shows correlation.

As with any research field, there is a risk of publication bias. In the context of the papers reviewed here, when initial articles linking the DMN to various cognitive outcomes were published in prominent journals, it influenced the direction of psychedelic research and the expected findings and hypotheses generated by researchers. Therefore, the scientific community is urged to remain cautious of overly enthusiastic claims and to view theories as simple models rather than established facts. Pre-print journals can also be useful for sharing studies that might have difficulty getting published elsewhere due to negative results, but which can still contribute to scientific knowledge. However, due to the renewed interest in psychedelic medicine, publications with negative findings are still likely to be published, and the currently published data have all been linked to registered trials.

Potential Future of DMN Modulation–Focused Psychedelic Therapies

Studies have highlighted the potential use of DMN functional connectivity as a biomarker. The DMN has been used as a biomarker for various conditions such as attention deficit hyperactivity disorder, early antidepressant response, chemotherapy-related brain injury, depression, epilepsy, Parkinson's disease, bipolar affective disorder, and schizophrenia. Using DMN activity (both at rest and during tasks) as a cognitive biomarker aligns with a research framework from the National Institute of Mental Health. This framework emphasizes using different biological and cognitive markers as tools that can apply across various diagnoses. Therefore, using the DMN as a biomarker for mental health conditions can help overcome limitations often associated with diagnosing these conditions based solely on symptoms, such as the wide range of symptoms for the same condition and reliance on a clinician's subjective judgment.

The REBUS and predictive-coding models may help explain the potential of psychedelics to treat multiple conditions. Mental health conditions are characterized by specific DMN abnormalities, which psychedelics may help to normalize. Little is known about how psychedelics influence "top-down" (from higher brain functions) and "bottom-up" (from sensory input) information processing streams, and whether these pathways converge on the DMN. Future research could use approaches to determine if psychedelics alter how sensory information is processed in a hierarchical manner and if this contributes to updating a person's understanding of themselves and the world, as proposed by the REBUS model. Moreover, changes in belief systems might alter top-down processing, with greater cognitive flexibility changing how external and internal information is distinguished. These ideas can be directly tested in future research by examining how DMN regions might influence thalamic activity, and vice versa, to gain a deeper understanding of information transfer.

Microdosing psychedelics (especially LSD and psilocybin), which involves taking very small, non-hallucinogenic doses, has been reported to reduce mind-wandering. At the brain level, this is reflected by reduced DMN activity. For example, one study administered low doses of LSD and found a reduction in brain wave activity, consistent with findings using larger doses. Across all brain wave frequencies, the higher microdose showed greater reductions in activity compared to the lower dose. However, there is currently no direct evidence or clinical trials showing how microdosing specifically modulates the DMN, and this should be explored in future research. This can reveal how much DMN modulation (and its potential benefits) depends on the intense subjective experience associated with larger psychedelic doses. Furthermore, studies could aim to determine a "minimum effective dose" that would likely cause fewer challenging experiences sometimes resulting from high-dose psychedelics. The same reasoning applies to non-hallucinogenic psychedelic-like compounds, which are currently being studied and have shown antidepressant effects, at least in animal models. However, it is important to note that challenging experiences may also contribute to positive therapeutic outcomes.

A valuable future research direction would be to compare DMN modulation in experienced psychedelic users versus those who have never used them. This would help to understand the interaction between the immediate and lasting effects of these substances on the DMN. Alternatively, well-designed long-term studies with multiple brain scanning sessions could clarify how DMN functional connectivity changes reflect the ongoing effects of psychedelics on brain activity. Interestingly, a recent study found that differences in DMN connectivity were not significantly modulated at one week and three months after administration, though the effect size was small. This study design could be repeated with a larger number of participants and additional immediate time points to further understand the acute and lasting connectivity patterns of psychedelic drugs.

Clinically, psychedelics could be used alongside psychotherapeutic techniques such as mindfulness meditation. Mindfulness and psilocybin retreats have shown promising results for people with depression. It appears that mindfulness and psilocybin therapy affect the DMN in similar ways (reducing connectivity and activity within the DMN) and may work together synergistically. This might be because mindfulness, which helps to increase non-judgmental awareness of one's thoughts and feelings, could facilitate a positive psychedelic experience, and vice versa.

Additionally, a valid research question in the context of depression is whether infrequent psilocybin treatment (e.g., quarterly), combined with standard treatments like cognitive behavioral therapy and selective serotonin reuptake inhibitors, might lead to a greater and more sustained reduction in depressive symptoms. This type of study design could be pursued by future researchers and, if effective, could be applied to various other mental health conditions. Furthermore, it is important that clinical (and preclinical) research promotes a "bench-to-bedside" approach, meaning translating lab findings to patient care. For controlled substances like psychedelics, this will require government advocacy and policy reform.

Conclusions

This systematic review provides evidence that classical psychedelics can modulate the Default Mode Network. This modulation is linked to ego dissolution, increased brain entropy, and improved mental health and well-being. The review of the data shows that psychedelics are a valuable tool for investigating this network and explores the potential therapeutic implications of these effects. Psychedelics are showing promise as tools to help understand the brain and mind in greater detail. Finally, this understanding can be used to treat various mental health conditions and potentially improve the psychological well-being of healthy individuals.

Default Mode Network Modulation by Psychedelics: A Systematic Review

Introduction

Psychedelics are a group of substances that can cause powerful changes in consciousness. The word "psychedelic" comes from Greek words meaning "mind" or "soul manifesting," suggesting these substances can reveal hidden parts of the human mind. "Classical psychedelics" refer to various drugs that primarily affect serotonin receptors in the brain. They lead to significant changes in a person's sense of self, how they perceive things, and their emotions.

Brain imaging studies show that when a person is at rest, certain connected brain regions become highly active. This network of regions is called the Default Mode Network (DMN). The DMN includes key areas such as the medial prefrontal cortex and the posterior cingulate cortex. When a person focuses on a specific task, activity in these DMN regions tends to decrease.

Functional connectivity (FC) measures how different brain regions work together over time. Changes in FC within the DMN are important for understanding its activity. Altered DMN connectivity has been linked to positive experiences like a feeling of "ego dissolution," where the boundaries of the self seem to dissolve. This feeling may help a person re-evaluate their thoughts and feelings during a psychedelic experience.

Changes in how the DMN connects, both internally and with other brain networks, are involved in complex mental functions like understanding others' thoughts, self-reflection, memory, and worrying. Altered DMN function is also connected to various mental health and brain conditions, including depression, anxiety, attention deficit hyperactivity disorder, and Alzheimer’s disease. This suggests that how the DMN works can reflect a person's overall mental functioning and may be impacted by treatments like psychedelics.

In the 1960s, there was a surge of interest in psychedelics as potential treatments for mental health and substance use disorders. However, their use in research was severely restricted for political reasons in the 1970s. Recently, based on promising early findings, psychedelics like LSD, psilocybin, and ayahuasca are gaining new scientific attention, especially in brain research. Many recent studies have begun to explore how these substances change the DMN. This review aims to evaluate how classical psychedelics affect the DMN, assess their potential therapeutic effects, identify current challenges in this research, and discuss future directions for DMN-focused psychedelic therapies.

Methods

This systematic review followed standard guidelines for reporting scientific studies. The research involved searching electronic databases, including PubMed and Scopus, from their start dates through April 2022. The search used specific keywords related to the Default Mode Network (DMN) along with the names of classical psychedelics, such as ayahuasca, DMT, psilocybin, LSD, and mescaline. An additional search of Google Scholar was also conducted to find any other relevant articles.

Studies were selected by two reviewers, and any disagreements were resolved through discussion. Only human clinical trials that assessed how classical psychedelics changed the DMN were included; studies on animals were excluded. Papers that re-analyzed data from previously published studies were also considered. Only articles published in English were eligible, and there were no specific requirements for the dose of the psychedelic, the length of treatment, or the statistical methods used. The review included participants with various clinical diagnoses as well as healthy individuals.

Results Overview

The initial search on August 28, 2021, and a second search on April 20, 2022, together found 163 articles. After removing duplicate entries, 119 articles remained, and 95 of these were removed because they did not meet the eligibility criteria. This left 28 articles that were included in the review.

Of the included studies, 17 focused on psilocybin, with most using fMRI brain imaging. The participants in these studies had an average age of about 34.6 years, and the average number of participants per study was 26. Most psilocybin studies included a placebo control group. Four studies assessed ayahuasca, all using fMRI. The average age in these studies was 35 years, with about 28 participants per study. Only one ayahuasca study used a placebo control. Eight studies investigated LSD, primarily using fMRI. Participants averaged 29.6 years old, and studies had about 20 participants. All LSD studies included a placebo control group. No published research papers were found that assessed how mescaline and DMT specifically change the DMN in humans. Overall, the findings suggest that psychedelics modulate specific DMN brain regions.

Discussion

Classical psychedelics clearly reduce the connections within the Default Mode Network (DMN) and increase connections between the DMN and other brain networks. These changes are linked to altered states of consciousness and positive therapeutic outcomes, though researchers are still working to understand the exact cause-and-effect. Additionally, recent reviews suggest that psychedelics can also lead to significant brain changes at the cellular level, which may contribute to long-term health benefits. It is challenging to determine how much of the therapeutic effect comes from these cellular changes versus DMN changes, and how the two are related.

Several models attempt to explain how psychedelics affect the DMN. The "Relaxed Beliefs Under Psychedelics" (REBUS) model suggests that psychedelics cause the brain to become more flexible and unpredictable, disrupting normal thought patterns and allowing the revision of strongly held beliefs. This can lead to increased brain flexibility and new ways of thinking, which may explain their therapeutic effects. Other models include the Cortico-Striatal-Thalamo-Cortical (CSTC) model, which proposes that psychedelics alter brain circuits, leading to increased sensory information reaching the brain, and the Cortico-Claustro-Cortical (CCC) model, which focuses on the claustrum brain region and its role in disrupting higher brain networks. It is likely that these models are not separate but rather work together to explain the complex effects of psychedelics.

Despite promising findings, these models and DMN research in general have limitations. For instance, the REBUS model needs more specific details about how different brain regions are involved and how increased brain unpredictability translates to specific outcomes. The CSTC and CCC models also require further refinement and more research to fully understand their mechanisms. It is important to note that the DMN is not without its critics, with some questioning its direct link to specific cognitive processes, though current evidence increasingly supports its importance. Moreover, psychedelics are not the only substances that alter the DMN; alcohol, ketamine, and salvinorin A also show some similar effects, which raises questions about the unique aspects of psychedelics.

Common limitations in the reviewed studies include small sample sizes and the fact that many participants had prior experience with psychedelics, which might affect the results. Drawing conclusions about cause and effect from observed brain changes can also be difficult. There is also a risk of publication bias, where studies with positive or expected findings are more likely to be published. To improve the reliability of findings, future research should aim for larger, more diverse study populations and use new datasets rather than re-analyzing old ones.

The DMN shows potential as a "biomarker" for various mental health conditions. Future research could explore how psychedelics affect brain processing and whether this helps update a person's understanding of themselves and the world. Studies could also investigate the effects of micro-dosing psychedelics, which involve taking very low, non-hallucinogenic doses, to see if DMN modulation still occurs without intense subjective experiences. Comparing DMN changes in people with prior psychedelic use versus those who are new to them, and conducting long-term studies, would also be valuable. Combining psychedelic treatment with psychological therapies like mindfulness meditation, which also modulates the DMN, could also be a promising direction, potentially leading to improved mental health outcomes compared to standard treatments alone.

Conclusions

This systematic review supports the idea that classical psychedelics can change the activity within the Default Mode Network (DMN). These changes are linked to experiences like ego dissolution, increased brain flexibility, and improved mental health and well-being. This review shows that psychedelics are valuable tools for understanding the brain and mind in more detail. This enhanced understanding could be used to treat various mental health conditions and potentially improve the psychological well-being of healthy individuals.

Introduction

Psychedelics make people see, hear, and feel things in new ways. The word "psychedelic" means "mind-manifesting." This means these drugs can show new things about how the mind works. Common psychedelics like LSD and psilocybin work by affecting certain parts of the brain. They can cause big changes in how a person thinks, feels, and sees the world.

Brain studies show that when a person is resting, a certain group of brain parts works together a lot. This group is called the Default Mode Network, or DMN. When a person is focused on a task, these brain parts become less active. The DMN is like the brain's "resting state" network.

The way these brain parts connect and work together is called "functional connectivity." Changes in how the DMN connects have been linked to different ways of thinking and feeling. For example, when DMN connections are lower, some people feel less like a separate "self," a feeling sometimes called "ego dissolution." This change might help people see their problems in a new way. Issues with DMN connections have also been linked to mind problems like depression and anxiety, and even diseases like Alzheimer's.

For a long time, starting in the 1960s, scientists studied psychedelics to help with mental health. Then, for political reasons, this research largely stopped. But now, there is new interest. Many recent studies are looking at how psychedelics change the DMN.

This paper looks closely at how common psychedelics like LSD, psilocybin, DMT, mescaline, and ayahuasca affect the DMN. It also explores if these changes are helpful for people's mental health, what problems there are in the research, and what future studies should explore.

Methods

To find studies for this paper, researchers looked through databases like PubMed and Scopus. They used search terms related to the Default Mode Network and common psychedelics. They also checked Google Scholar for more studies.

Only studies involving humans were included. Studies that looked at how classic psychedelics changed the DMN were chosen. Papers written in English were used. The studies did not need to use a certain amount of the drug or treat people for a certain time. Studies with healthy people or people with different health conditions were all included.

Results

The search found many studies at first. After removing duplicates and studies that did not fit the rules, 28 studies were left. Most of these studies looked at psilocybin (17 studies). Four studies looked at Ayahuasca, and eight looked at LSD. No studies were found that showed how mescaline or DMT change the DMN in humans.

Many of the studies used special brain scans to see how the DMN changed. Most studies included a control group, where some people received a placebo (a fake drug) instead of a psychedelic. The studies usually involved small groups of people, with an average of 26 participants. The average age of people in the studies was around 30 to 35 years old.

Discussion

Studies show that psychedelics can make the connections within the DMN weaker. At the same time, they can make connections between the DMN and other parts of the brain stronger. These changes are linked to new ways of thinking and feeling, as well as good results for mental health. However, it is not yet clear if the DMN changes cause these good results, or if they just happen at the same time.

Psychedelics also cause changes at the level of brain cells and even how genes work. It is hard to know if the helpful effects come from these cell-level changes, the DMN changes, or both working together.

One main idea for how psychedelics work is called the "Relaxed Beliefs Under Psychedelics" (REBUS) model. This idea suggests that psychedelics make old ways of thinking and old beliefs less strong. This allows the brain to be more flexible and open to new information, which can help people change how they see themselves and the world. Brain studies have shown that psychedelics make brain activity more "flexible" or "random," which supports this idea. This "flexibility" can help the brain learn new ways of thinking. Other ideas also suggest that psychedelics change how the brain handles information or how certain brain parts connect. It is likely that all these ways of working happen together.

There are still challenges in this area of research. While the DMN is now seen as very important for understanding the mind, early studies questioned its role. Most studies on psychedelics and the DMN have been small, and many participants had used psychedelics before. This means larger studies with more people who have not used psychedelics are needed. Also, it's hard to be sure if changes in the DMN are the main cause of the helpful effects, or just something that happens alongside them.

Looking to the future, the DMN could be used as a biomarker, which is a sign of certain brain conditions. This could help doctors understand and treat these problems better. Researchers are also looking at how very small doses of psychedelics might affect the DMN. Studies could also compare how psychedelics affect the DMN in people who have used them before versus those who haven't. Combining psychedelics with other treatments, like mindfulness therapy, might also be a powerful way to help people, as both seem to affect the DMN in similar ways.

Conclusions

This paper shows that common psychedelics can change the Default Mode Network (DMN). These changes are linked to feelings like "ego dissolution" (feeling less like a separate self), increased brain flexibility, and better mental well-being. Psychedelics are a valuable tool for learning more about the brain and mind. This new knowledge could help treat many brain and mind problems and potentially improve the well-being of healthy people too.