Psychedelics and the Brain: A Look at Neural Mechanisms

Explore the proposed neural mechanisms behind psychedelic therapy and its therapeutic potential for mental health.

Overview: Recent research has revealed the profound impact of psychedelics on the brain, sparking interest in their therapeutic potential. This blog explores three prominent theories — Cortico-Striato-Thalamo-Cortical (CSTC), Relaxed Beliefs Under Psychedelics (REBUS), and Claustro-Cortical Circuit (CCC) — that shed light on how psychedelics alter brain function:

  • CSTC Theory: Classic psychedelics disrupt feedback loops between the cortex and thalamus, leading to sensory overload. This theory explains how psychedelics intensify sensory processing but has limitations in fully capturing their effects.
  • REBUS Model: Psychedelics loosen rigid beliefs and increase sensitivity to sensory input by disrupting the brain's predictive mechanisms. This model offers insights into altered perception, cognition, and emotion under psychedelics, including synesthesia and ego dissolution.
  • CCC Model: By activating 5-HT2A receptors in the claustrum, psychedelics destabilize brain network states, reducing cognitive control. While this model contributes to our understanding, it faces challenges in explaining the variability of psychedelic effects.

Despite differences in these theories, they all provide valuable insights into the neural mechanisms underlying the effects of psychedelics. Continued research in this field promises to deepen our understanding of these fascinating substances and their therapeutic potential.

Effects of Psychedelics on the Brain: Exploring Neural Mechanisms

In recent years, research has unveiled the profound impact that psychedelics can have on the brain. From altering perception to potentially treating mental health disorders, these substances have captivated scientists and enthusiasts alike.

A 2022 paper outlined proposed possible mechanisms that may underlie the effects and therapeutic potential of psychedelics. Through experimentation and analysis, researchers have begun to unravel how psychedelics influence neural processes, shedding light on their psychedelic effects and therapeutic applications.

In the scientific literature, several neuroscientific explanations have been proposed to account for the effects of psychedelics at a neural-level. These include how psychedelics weaken the brain’s natural filters, disrupt the brain’s normal prediction process and heighten sensitivity to unexpected signals, and activate a specific brain circuit called the claustro-cortical circuit.

This blog provides a brief overview of three of the most prominent explanations: the Thalamo-Cortical Filter Theory, the Relaxed Beliefs Under Psychedelics (REBUS) Model, and the Claustro-Cortical Circuit (CCC) Model. By exploring these theories, this blog aims to shed light on the neural mechanisms underlying the therapeutic potential of psychedelics. 

The Cortico-Striato-Thalamo-Cortical (CSTC) Theory

One of the earliest and most influential theories regarding the effects of psychedelics on the brain is the Cortico-Striato-Thalamo-Cortical (CSTC) theory. This theory helps explain how these substances might alter our perception (how we perceive ourselves and theworld round us), cognition (thinking and mental processes e.g. attention, memory, reasoning), and emotion (feelings and mood) by influencing the brain’s sensory filters.

What is the CSTC Theory?

The CSTC model suggests that psychedelic work by disrupting the normal feedback loops between the cortex (the brain's outer layer responsible for higher-order functions) and the thalamus (a relay station for sensory and motor signals). These loops usually help prevent sensory overload by filtering incoming information.

Key Components:

  • Cortical Regions: These are parts of the brain's cortex involved in processing sensory information, thinking, and decision-making.
  • Thalamic Nuclei: Clusters of neurons in the thalamus that act as relay points for sensory and motor signals.

How Do Psychedelics Disrupt These Loops?

Under normal conditions, the thalamus acts like a gatekeeper, controlling the flow of sensory and internal (interoceptive) signals to the cortex. The prefrontal cortex (PFC) regulates this filtering process, ensuring that we’re not overwhelmed by too much information.

When psychedelics are introduced, this gating mechanism is disrupted. Here's how:

  • Reduced Prefrontal Cortex Control: Psychedelics reduce the inhibitory control of the PFC over the thalamus. This means the thalamus sends more information to the cortex than usual.
  • 5-HT2A Receptor Activation: Classic psychedelics, like LSD, psilocybin, DMT, and mescaline, stimulate the 5-HT2A serotonin receptors, which are like tiny keyholes on the surface of brain cells. Psychedelics act like special keys that fit perfectly into these keyholes. This ‘unlocking’ of the 5-HT2A receptors is a key factor in experiencing the psychedelic effects—like seeing vibrant colors, feeling intense emotions, and having unusual thoughts.
  • NMDA Receptor Blockade: Substances like ketamine block NMDA receptors, leading to altered sensory perceptions and dissociative effects.
  • Dopaminergic and GABAergic Projections: Psychedelics also influence dopamine and GABA systems. Dopamine is a neurotransmitter involved in reward and pleasure, while GABA is an inhibitory neurotransmitter that helps calm neuronal activity.

Evidence Supporting the CSTC Model

Early PET (Positron Emission Tomography) studies and more recent fMRI (Functional Magnetic Resonance Imaging) studies have shown that psychedelics alter the activity and connectivity between the PFC and the thalamus. These changes in brain activity correlate with the subjective experiences reported by participants, such as intensified sensory perception.

For instance, enhanced connectivity between the thalamus and other brain regions has been observed with LSD use. However, increased thalamic activity during acute psychedelic effects is not always consistently observed.

Limitations of the CSTC Model

Despite its insights, the CSTC model has limitations. Behavioral studies that measure reduced thalamic gating show mixed results when participants are under the influence of psychedelics. Thus, while the CSTC model explains some neural and experiential changes caused by psychedelics, it doesn’t capture the full complexity of their effects.

The CSTC theory provides a valuable framework for understanding how psychedelics might intensify sensory processing and alter our perceptions. By disrupting the normal filtering mechanisms in the brain, these substances can lead to a flood of sensory and internal information, contributing to the profound experiences associated with their use. While the model has its limitations, it remains a crucial piece in the puzzle of understanding psychedelics' impact on the brain.

The Relaxed Beliefs Under Psychedelics (REBUS) Model

The REBUS (Relaxed Beliefs Under Psychedelics) model offers an integrative framework for understanding the effects of psychedelics on the brain. This model combines the “entropic brain hypothesis” with the “free-energy principle” to explain how psychedelics might alter our perception, cognition, emotion, and therapeutic potential.

The Brain as a Prediction Machine

Under normal circumstances, our brain functions like a prediction machine. It constantly generates predictions to explain away incoming sensory information, creating a coherent experience of the world. This process involves a hierarchical model where the brain makes predictions and compares them to actual sensory input. When there is a mismatch, a prediction error signal is generated, prompting the brain to update its model to better match reality.

  • Prediction Error Signals: These signals are alerts that something unexpected has occurred, requiring the brain to adjust its understanding or expectations.

Prediction-error signaling is fine-tuned by precision-weighting, where more reliable sensory signals are given higher confidence for belief updating.

How Psychedelics Disrupt This Process

Classic psychedelics, such as LSD and psilocybin, act primarily on 5-HT2A receptors. This action leads to excessive excitability of deep-layer pyramidal neurons, which are crucial for encoding the precision of beliefs. As a result, prediction errors are less suppressed, and the brain becomes more sensitive to new sensory information.

  • 5-HT2A Receptors: As mentioned, these serotonin receptors are crucial for the psychedelic effects of classic psychedelics.
  • Deep-Layer Pyramidal Neurons: Neurons that play a significant role in processing complex information and assigning confidence to predictions.

According to the REBUS model, psychedelics loosen rigid prior predictions and increase sensitivity to bottom-up sensory information. This mechanism can help to explain various psychedelic experiences:

  • Breathing Surfaces: Walls may appear to breathe because the brain's usual constraint that a wall is a solid object is relaxed.
  • Visual Trails: Moving objects, like birds or hands, seem to leave trails because the brain struggles to update the visual representation accurately.

These visual effects are typically strongest with closed eyes, where there is no external input to correct the brain’s internal models.

Higher-Level Effects and the Default Mode Network (DMN)

At higher doses, psychedelics affect more high-level brain regions, altering perceptions of the self and high-level beliefs. The Default Mode Network (DMN), which is involved in mind-wandering and self-referential thinking, is a key area impacted by psychedelics.

  • Default Mode Network (DMN): A network of interconnected brain regions involved in self-referential thoughts and the sense of self.

fMRI studies show that during a psychedelic experience, DMN activity decreases, correlating with experiences of ego-dissolution. This suggests that psychedelics can loosen high-level beliefs and schemas related to the self.

Interestingly, some studies show increased prefrontal activity during psychedelic experiences, highlighting potential methodological differences or the dynamic nature of these experiences.

The Entropic Brain Hypothesis

The REBUS model also draws from the entropic brain hypothesis, which posits that psychedelics increase brain entropy—creating a more disordered and interconnected state compared to normal waking consciousness.

  • Synesthesia: This increased connectivity can lead to experiences like synesthesia, where one sensory modality is experienced through another (e.g., seeing sounds).

The entropic state might explain the unpredictable nature of psychedelic experiences, similar to the analogy of wiping out beaten tracks on a skiing hill, forcing one to explore new paths.

Therapeutic Implications

The REBUS model offers insights into the therapeutic effects of psychedelics. Disorders like depression and OCD are often characterized by rigid, maladaptive beliefs. Psychedelics can temporarily loosen these beliefs, making individuals more open to new perspectives.

  • Maladaptive “Hyperpriors”: Rigid, negative beliefs that strongly influence thoughts and actions, such as an overly negative self-image.
  • Therapeutic Change: By loosening these hyperpriors, psychedelics can help individuals adopt more adaptive beliefs and behaviors, especially when guided in a therapeutic context.

Criticisms and Limitations

While the REBUS model is influential, it faces conceptual and methodological criticisms. For instance, psychedelics could potentially strengthen some beliefs, and small sample sizes in fMRI studies limit generalizability. Additionally, other substances like SSRIs also alter DMN connectivity, suggesting that some effects might not be unique to psychedelics.

Moreover, psychedelics significantly impact other brain networks, such as the task-positive network and the salience network, indicating a broader range of effects.

The REBUS model provides a compelling framework for understanding how psychedelics can disrupt rigid beliefs and promote new perspectives. By increasing brain entropy and altering connectivity, psychedelics can lead to profound changes in perception, cognition, and emotion, offering potential therapeutic benefits for various mental health conditions. While the model has its limitations, it remains a vital piece in the ongoing exploration of psychedelic science.

The Claustro-Cortical Circuit (CCC) Model

The Claustro-Cortical Circuit (CCC) model offers another perspective on how psychedelics affect the brain, particularly focusing on the role of the claustrum—a small, mysterious structure nestled deep within the brain.

Understanding the Claustrum

The claustrum is a small, thin structure located beneath the cerebral cortex. Despite its size, it boasts a high density of 5-HT2A receptors — the same receptors targeted by classic psychedelics. The claustrum is intricately connected to various brain regions, making it a key player in coordinating neural activity.

The CCC Model in Action

According to the CCC model, the claustrum supports cortical network states, acting as a sort of conductor for brain activity. When the claustrum is directly activated, it triggers widespread cortical activation, influencing various cognitive processes.

  • Cortical Network States: Patterns of neural activity across the cortex that underlie different cognitive functions, such as attention, memory, and perception.

Psychedelic Disruption

Psychedelics, by activating 5-HT2A receptors in the claustrum, may destabilize these canonical brain network states. This destabilization can lead to a decoupling between prefrontal areas and the claustrum, disrupting coordination and reducing cognitive control.

  • Cognitive Control: The ability to regulate thoughts, behaviors, and emotions to achieve goals or adapt to changing environments.

Support for the CCC model comes from studies showing that psilocybin decreases claustrum activity, which correlates with the experience of ineffability—the feeling of being unable to fully describe or articulate one’s psychedelic experiences in words.

Limitations and Challenges

While the CCC model offers valuable insights, it also faces limitations. For instance, it's unclear exactly how psychedelics affect specific brain circuits through changes in the claustrum. Additionally, the highly variable effects of psychedelics suggest that generalized brain network instability may not fully explain all subjective experiences.

Variability and Reliability of Certain Effects

While psychedelic experiences can indeed vary widely from person to person and even within the same individual across different sessions, there are certain effects that seem to reliably occur, as evidenced by several reports from study participants displaying orderly dose effects.

  • Orderly Dose Effects: This refers to the consistent effects observed in the effects of psychedelics across different dosage levels. 

Despite this variability, it's unclear how reduced cognitive control alone could account for convergences on some self-reported acute subjective effects. This raises questions about the mechanisms underlying these shared experiences and suggests that additional factors may be at play.

Despite these challenges, the CCC model synthesizes scientific observations and highlights the role of the claustrum in coordinating brain activity. While it may not provide a complete explanation for all effects of psychedelics, it contributes to our understanding of how these substances impact the brain.

The CCC model sheds light on the interplay between psychedelics and the claustrum — a crucial hub for coordinating brain activity. By disrupting canonical brain network states, psychedelics challenge traditional notions of cognitive control and perception.

While the CCC model faces challenges in fully explaining the diverse effects of psychedelics, it represents a significant step forward in unraveling the mysteries of these fascinating substances. Continued research into the role of the claustrum and its interactions with psychedelics promises to deepen our understanding of consciousness and cognition.


In conclusion, the exploration of neural mechanisms underlying the effects of psychedelics offers a fascinating glimpse into the complex interplay between these substances and the brain. While each theory — CSTC, REBUS, and CCC — provides valuable insights, none may fully capture the entirety of psychedelic experiences, yet at least.

Yet, collectively, they contribute to our understanding of how psychedelics alter perception, cognition, emotions, and consciousness. As research in this field continues to evolve, we can anticipate further revelations that may unlock new therapeutic potentials and deepen our appreciation of the profound effects of psychedelics on the human mind.

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