The Neuroscience of Psychedelics

Overview

The scientific study of psychedelic compounds has undergone a remarkable renaissance since the early 2010s, producing some of the most significant advances in our understanding of consciousness, neural connectivity, and brain plasticity in modern neuroscience. Classic psychedelics — psilocybin, LSD, DMT, and mescaline — share a common primary mechanism: agonism at the serotonin 5-HT2A receptor. Yet the downstream effects of this seemingly simple pharmacological action cascade into profound alterations in neural network dynamics, information processing, and structural brain plasticity that challenge foundational assumptions about how the brain generates conscious experience.

The field has moved far beyond cataloguing subjective effects. Researchers now possess detailed mechanistic models — from Robin Carhart-Harris’s entropic brain hypothesis and the REBUS (Relaxed Beliefs Under Psychedelics) framework to Karl Friston’s free energy formulations — that position psychedelics as powerful tools for understanding the hierarchical predictive processing architecture of the human brain. These compounds do not merely alter perception; they temporarily reorganize the fundamental computational principles by which the brain constructs its model of reality.

This article examines the neuroscience of psychedelic action across multiple scales: from receptor-level pharmacology through network-level dynamics to the emergent properties of consciousness itself, integrating findings from neuroimaging, electrophysiology, molecular biology, and computational neuroscience.

Serotonin 5-HT2A Receptor Agonism

Receptor Pharmacology

The 5-HT2A receptor is a G-protein coupled receptor (GPCR) densely expressed in cortical pyramidal neurons, particularly in layer V of the prefrontal cortex, posterior cingulate cortex, and temporal-parietal regions. Classic psychedelics act as agonists or partial agonists at this receptor, and the correlation between 5-HT2A binding affinity and subjective potency is remarkably tight — established by Glennon et al. in the 1980s and confirmed repeatedly since.

However, the pharmacology is more nuanced than simple agonism. Psychedelics exhibit “biased agonism” at the 5-HT2A receptor, preferentially activating certain intracellular signaling cascades over others. While serotonin itself activates both Gq-protein and beta-arrestin pathways, psychedelics like psilocin and LSD show preferential activation of the Gq/phospholipase C (PLC) pathway and downstream protein kinase C (PKC) signaling. Research by Bryan Roth’s laboratory at UNC Chapel Hill has demonstrated that this biased signaling profile is critical: compounds that activate the same receptor but with different bias profiles produce markedly different behavioral and neurological effects.

Additionally, LSD displays an unusually long duration of action (8-12 hours) explained by crystallographic studies from Roth’s group showing that LSD becomes physically “trapped” within the 5-HT2A receptor binding pocket by a lid formed from extracellular loop 2 (EL2). This structural finding, published in Cell in 2017, elegantly explains why LSD’s subjective effects persist far longer than its plasma half-life would predict.

Cortical Pyramidal Neuron Activation

When psychedelics bind 5-HT2A receptors on cortical pyramidal neurons, they increase the excitability of these cells and enhance glutamatergic transmission. Specifically, 5-HT2A activation in prefrontal cortex increases the frequency of excitatory postsynaptic potentials (EPSPs) in layer V pyramidal neurons, primarily through enhanced release of glutamate from thalamocortical afferents. This was elegantly demonstrated in rodent electrophysiology studies by George Bhatt Aghajanian at Yale in the late 1990s and early 2000s.

The result is a complex shift in the excitation-inhibition balance of cortical circuits: increased glutamatergic excitation coupled with altered GABAergic inhibition produces a state of heightened cortical activity that is simultaneously more excitable and less organized — a neural correlate of the “entropic” brain state described below.

Beyond 5-HT2A: Polypharmacology

While 5-HT2A agonism is the necessary trigger for psychedelic effects (proven by the ability of 5-HT2A antagonists like ketanserin to completely block the experience), most psychedelics also interact with other receptors. Psilocin has meaningful affinity for 5-HT1A, 5-HT2B, and 5-HT2C receptors. DMT activates sigma-1 receptors and trace amine-associated receptors (TAARs). LSD is a promiscuous ligand active at D2 dopamine receptors and multiple serotonin receptor subtypes. These secondary targets modulate the qualitative character of each compound’s subjective effects and may contribute to their therapeutic potential.

Default Mode Network Disruption

The Default Mode Network

The default mode network (DMN) — comprising the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), precuneus, angular gyrus, and medial temporal lobe structures — was first characterized by Marcus Raichle’s group at Washington University as a set of brain regions more active during rest than during task performance. The DMN is now understood to be the neural substrate of self-referential processing, autobiographical memory, mental time travel, and the narrative self — the continuous inner monologue that constitutes our sense of being a persisting, bounded individual.

Psychedelic-Induced DMN Disintegration

The landmark 2012 fMRI study by Robin Carhart-Harris and David Nutt at Imperial College London demonstrated that psilocybin produces marked decreases in cerebral blood flow and BOLD signal in key DMN hubs, particularly the medial prefrontal cortex and posterior cingulate cortex. This finding was initially counterintuitive — the richness of the psychedelic experience was associated with decreased, not increased, activity in these regions.

Subsequent analyses revealed that the critical change was not merely reduced activity but reduced functional connectivity within the DMN. The normally tightly coupled oscillations between DMN nodes became desynchronized, and the sharp boundaries between the DMN and other large-scale networks (task-positive network, salience network, visual cortex) dissolved. This “network dissolution” creates a state where brain regions that normally do not communicate begin exchanging information — a phenomenon visible in functional connectivity matrices as a dramatic increase in between-network connectivity paired with decreased within-network connectivity.

Ego Dissolution and Neural Correlates

The subjective experience of ego dissolution — the temporary loss of the sense of being a separate self — correlates specifically with the degree of DMN disintegration. Lebedev et al. (2015) showed that ratings on the Ego Dissolution Inventory correlated with decreased alpha-power integrity in the PCC and decreased DMN functional connectivity. This provides one of the strongest empirical links between a specific neural network and a specific dimension of conscious experience in the entire neuroscience literature.

The Entropic Brain Hypothesis

Theoretical Framework

Carhart-Harris’s entropic brain hypothesis, first formalized in 2014 in Frontiers in Human Neuroscience, proposes that the quality of conscious experience can be mapped along a spectrum of neural entropy — the mathematical measure of disorder, randomness, and information content in brain dynamics. Normal waking consciousness occupies a “critical” zone that balances order and disorder. Below this zone lie states of reduced entropy: unconsciousness, deep sleep, and certain rigid psychiatric conditions (depression, addiction, OCD). Above it lies the psychedelic state, characterized by increased entropy.

The hypothesis draws on complexity science and the concept of self-organized criticality. The healthy brain operates near a phase transition — the edge of chaos — where information processing capacity is maximized. Psychedelics push the brain temporarily beyond this critical point into a state of supercriticality, where entropy increases, more neural configurations become accessible, and the repertoire of possible brain states expands dramatically.

Empirical Support

Lempel-Ziv complexity analysis of MEG data during the psilocybin state confirmed increased neural signal diversity compared to placebo — the first empirical demonstration that a pharmacological intervention could reliably increase a measure of neural complexity beyond normal waking baseline (Schartner et al., 2017). Similar findings have been replicated with LSD and DMT using multiple entropy measures including sample entropy, permutation entropy, and Lempel-Ziv-Welch complexity.

Importantly, the degree of entropy increase correlates with the intensity of subjective effects, providing a quantitative bridge between neural dynamics and phenomenology. This entropy increase is not random noise — it reflects a structured expansion of the brain’s dynamical repertoire.

The REBUS Model

Relaxed Beliefs Under Psychedelics

The REBUS (Relaxed Beliefs Under Psychedelics) model, published by Carhart-Harris and Friston in Pharmacological Reviews in 2019, represents the most comprehensive theoretical framework for psychedelic action to date. It integrates the entropic brain hypothesis with Karl Friston’s free energy principle and hierarchical predictive processing.

In predictive processing theory, the brain is fundamentally a prediction machine. High-level cortical areas (particularly the DMN and association cortices) encode “priors” — beliefs, expectations, and models of the world — that generate top-down predictions about sensory input. These priors constrain and shape perception, cognition, and behavior. In psychiatric conditions like depression, addiction, and PTSD, pathological priors become deeply entrenched: rigid, self-reinforcing belief patterns that resist updating by new evidence (“I am worthless,” “I need this substance,” “The world is dangerous”).

REBUS proposes that psychedelics work therapeutically by relaxing the precision weighting of these high-level priors. By disrupting the hierarchical organization of cortical processing — particularly through DMN disintegration — psychedelics reduce the constraining influence of top-down predictions, allowing bottom-up sensory information and suppressed emotional content to emerge into consciousness with greater force. The brain enters a state of heightened plasticity where entrenched beliefs become temporarily malleable and available for revision.

The Therapeutic Window

The REBUS model explains why psychedelics require a therapeutic context to produce lasting benefit. The relaxation of priors creates a window of opportunity — a critical period of enhanced neural and psychological plasticity — during which new, healthier beliefs and perspectives can be installed through the therapeutic relationship, the content of the experience itself, and subsequent integration work. Without this supportive scaffolding, the brain may simply re-establish its previous pathological priors once the acute effects subside.

Neuroplasticity: BDNF, Dendritic Growth, and Structural Remodeling

Psychoplastogens

David Olson’s laboratory at UC Davis introduced the term “psychoplastogens” to describe compounds that rapidly promote structural and functional neural plasticity. In a landmark 2018 study published in Cell Reports, Olson’s group demonstrated that psychedelics including DMT, LSD, and DOI promote neuritogenesis, spinogenesis, and synaptogenesis in cortical neurons — both in vitro and in vivo. The magnitude of these plasticity-promoting effects was comparable to BDNF (brain-derived neurotrophic factor) itself, the brain’s primary endogenous neuroplasticity signal.

Specifically, psychedelics increase dendritic arbor complexity (the branching of neuronal projections), dendritic spine density (the small protrusions where synapses form), and the number of functional synaptic connections. These structural changes occur rapidly — within 24 hours of a single administration — and persist for at least days to weeks after the compound has been cleared from the body. This time course aligns with the clinical observation that a single psychedelic session can produce therapeutic benefits lasting weeks to months.

BDNF and TrkB Signaling

The molecular pathway involves psychedelic-induced 5-HT2A activation stimulating intracellular signaling cascades that converge on BDNF release and TrkB (tropomyosin receptor kinase B) activation. Downstream effectors include mTOR (mechanistic target of rapamycin), which promotes protein synthesis necessary for new synaptic connections, and AMPA receptor trafficking, which strengthens existing synapses. The mTOR pathway is shared with ketamine’s rapid antidepressant mechanism, suggesting a convergent plasticity pathway between these pharmacologically distinct compound classes.

Ly et al. (2018) demonstrated that blocking TrkB signaling attenuated psychedelic-induced dendritic growth, confirming the centrality of this pathway. More recently, Hesselgrave et al. (2021) showed that psilocybin restores prefrontal cortical plasticity markers in a rodent model of chronic stress, with effects persisting for at least one month after a single dose.

Connectome-Level Reorganization

At the macroscopic level, psychedelics produce lasting changes in functional connectivity patterns detectable by resting-state fMRI. Carhart-Harris et al. (2017) showed that two psilocybin sessions for treatment-resistant depression produced changes in amygdala functional connectivity that correlated with clinical improvement and persisted at five-week follow-up. Barrett et al. (2020) at Johns Hopkins found that psilocybin increased global functional connectivity and specifically strengthened connections between the DMN and frontoparietal control network, changes associated with increased psychological flexibility.

Connectome Harmonics and Neural Field Theory

Harmonic Decomposition of Brain Activity

An elegant mathematical framework developed by Selen Atasoy and colleagues models brain activity as a combination of connectome harmonics — spatial patterns of neural oscillation determined by the brain’s structural connectivity (the white matter wiring diagram). Just as a vibrating string produces a fundamental frequency plus overtones determined by its physical structure, the brain’s structural connectome supports a set of natural resonant patterns.

Atasoy et al. (2017) demonstrated that the LSD state is characterized by a shift in the energy distribution across connectome harmonics: specifically, higher-frequency harmonics (more complex, spatially distributed patterns) gain energy at the expense of lower-frequency harmonics (simpler, more localized patterns). This mathematical description captures the psychedelic state’s characteristic quality of increased complexity and information richness.

Implications for Consciousness Research

This framework provides a principled way to quantify the relationship between brain structure, brain dynamics, and conscious experience. The psychedelic state, by shifting the harmonic energy distribution, accesses brain states that are structurally supported but rarely visited during normal waking consciousness — analogous to exciting higher harmonics on an instrument to produce notes that the physical structure supports but that are not typically heard.

Clinical and Practical Applications

The neuroscience reviewed above has direct implications for psychedelic-assisted therapy protocols. The REBUS model suggests that therapeutic benefit depends on achieving sufficient DMN disruption to relax pathological priors, which requires adequate dosing — sub-threshold doses that do not disrupt the DMN may not access the therapeutic mechanism. The neuroplasticity data suggests a “critical period” following psychedelic administration during which the brain is maximally receptive to new learning and belief revision, supporting the importance of integration sessions in the days and weeks following a psychedelic experience.

Understanding 5-HT2A biased agonism opens pathways for designing next-generation psychedelic therapeutics that preserve plasticity-promoting effects while minimizing challenging perceptual distortions — an active area of research at companies like Delix Therapeutics and Usona Institute. The connectome harmonics framework may eventually enable personalized prediction of response based on individual structural connectivity patterns.

For clinicians, the key insight is that psychedelics do not “fix” the brain directly. They temporarily open a window of heightened plasticity and cognitive flexibility. The therapeutic work — building new neural and psychological patterns — must occur within this window through skillful therapeutic support.

Four Directions Integration

• Serpent (Physical/Body): At the molecular level, psychedelics catalyze physical restructuring of neurons — new dendrites, new spines, new synapses. The body is literally rebuilt in the wake of the experience. The glutamate surge, the BDNF cascade, the mTOR-mediated protein synthesis are all deeply embodied processes. Somatic experiences during psychedelic states (body sensations, energy movements, trembling, temperature changes) may reflect this underlying neural remodeling in real time.

• Jaguar (Emotional/Heart): The dissolution of the DMN and relaxation of rigid priors allows suppressed emotional material to surface with extraordinary vividness and immediacy. The psychedelic state strips away the cognitive defenses that normally keep difficult emotions at bay, creating space for the emotional processing that underlies therapeutic transformation. This is not intellectual insight alone — it is felt, embodied emotional reckoning.

• Hummingbird (Soul/Mind): The entropic brain hypothesis and REBUS model describe a state where the mind’s habitual patterns of meaning-making are temporarily suspended, allowing entirely new perspectives and narrative frames to emerge. The “mystical experience” — the encounter with unity, sacredness, and deep meaning reported in 60-80% of high-dose psilocybin sessions — represents a profound reorganization of the soul-level architecture of identity and purpose.

• Eagle (Spirit): The connectome harmonics framework reveals that the psychedelic state accesses brain configurations that exist as latent possibilities within our neural structure but are rarely visited. This suggests that transcendent experiences are not fabrications but rather expressions of our brain’s inherent capacity for expanded modes of consciousness — an empirical resonance with contemplative traditions that describe enlightenment as the uncovering of what was always already present.

Cross-Disciplinary Connections

The neuroscience of psychedelics intersects profoundly with contemplative neuroscience — advanced meditators show DMN changes that parallel, in attenuated form, those produced by psychedelics. Judson Brewer’s work on the “experiential” self-referential network and its relationship to meditation and psychedelic states bridges these domains. Somatic therapy modalities (Somatic Experiencing, sensorimotor psychotherapy) work with the same body-based emotional processing that psychedelics catalyze. Functional medicine perspectives on neuroinflammation and gut-brain axis signaling are relevant given emerging data on psychedelics’ anti-inflammatory properties (including TNF-alpha suppression and 5-HT2A-mediated immunomodulation). Traditional Chinese Medicine concepts of shen (spirit) disturbance and its relationship to the heart organ system offer a framework that resonates with the psychedelic therapy emphasis on heart-opening emotional processing.

Key Takeaways

• Classic psychedelics produce their effects primarily through 5-HT2A receptor agonism, but the downstream consequences cascade across multiple scales of brain organization from synapses to global network dynamics.
• DMN disruption is the network-level signature of psychedelic action, correlating with ego dissolution and the temporary relaxation of entrenched self-referential patterns.
• The REBUS model provides the most comprehensive framework: psychedelics relax the precision of high-level beliefs (priors), creating a window of plasticity where rigid pathological patterns become available for revision.
• Psychedelics are potent psychoplastogens, promoting dendritic growth, spinogenesis, and synaptogenesis through BDNF/TrkB/mTOR signaling cascades that persist weeks beyond acute effects.
• The therapeutic potential depends not on the drug alone but on the interaction between pharmacological plasticity and the therapeutic context in which new patterns are established.
• Connectome harmonics offer a mathematical framework showing that psychedelic states access latent brain configurations supported by existing neural architecture.

References and Further Reading

• Carhart-Harris, R. L., & Friston, K. J. (2019). REBUS and the anarchic brain: Toward a unified model of the brain action of psychedelics. Pharmacological Reviews, 71(3), 316-344.
• Carhart-Harris, R. L. et al. (2014). The entropic brain: A theory of conscious states informed by neuroimaging research with psychedelic drugs. Frontiers in Human Neuroscience, 8, 20.
• Carhart-Harris, R. L. et al. (2012). Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of the National Academy of Sciences, 109(6), 2138-2143.
• Ly, C. et al. (2018). Psychedelics promote structural and functional neural plasticity. Cell Reports, 23(11), 3170-3182.
• Atasoy, S. et al. (2017). Connectome-harmonic decomposition of human brain activity reveals dynamical repertoire re-organization under LSD. Scientific Reports, 7, 17661.
• Wacker, D. et al. (2017). Crystal structure of an LSD-bound human serotonin receptor. Cell, 168(3), 377-389.
• Schartner, M. M. et al. (2017). Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin. Scientific Reports, 7, 46421.
• Barrett, F. S. et al. (2020). Psilocybin acutely alters the functional connectivity of the claustrum with brain networks that support perception, memory, and attention. NeuroImage, 218, 116980.
• Aghajanian, G. K., & Marek, G. J. (1999). Serotonin and hallucinogens. Neuropsychopharmacology, 21(2), 16S-23S.
• Hesselgrave, N. et al. (2021). Harnessing psilocybin: Antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R/β-arrestin2 signaling. Proceedings of the National Academy of Sciences, 118(17).