Neuroscience of Psychedelics: How They Reshape the Mind
Part 2 of Understanding Psychedelics as Allies in Healing Series
by Katie Simons, PharmD, BCPS
Back to Psychedelics…
So what do psychedelics have to do with healing? Well, simply stated, they assist in several parts of the above healing practice. I will explain how below, but here is where I prefer to make some admissions. First, the previously published working definition of healing is through my own lens of myself and working with clients - I do not claim it to be ultimate truth. Second, as someone with an intimate relationship with many psychedelic plants and substances, I do insert my perspectives in the below material. Much of what I discuss is from my own experience and that of clients, friends, and colleagues, and everyone’s journey into the psychedelic realm is individual. The substance, dose, set and setting, facilitator/guide/container, medications you are on, where you are at in your journey, and intentions all make a difference in the experience you have. Third, as a healthcare professional, nothing in this document is medical advice or a condoning of illegal activity ;) So, as always, take what works for you, and leave what does not behind. Shall we?
The Psychedelic Receptor Pathway
From a scientific perspective, the ability of psychedelics to assist in healing lies in the fascinating interplay between these substances and the brain, particularly how they shift typical brain function in ways that can be profoundly therapeutic. This interaction begins at the molecular level, specifically with their interaction with serotonin receptors in the brain. Most psychedelics stimulate the 5-HT2A receptors (with ketamine being a notable exception), which are densely packed in areas of the brain involved in mood regulation, imagination, and self-reflection. This receptor activation explains why psychedelics can have such powerful effects on emotional processing and awareness.
Fascinatingly, when psychedelics stimulate the 5-HT2A receptors, they activate not only the typical serotonin signaling pathway—associated with mood and cognition when triggered by our own endogenous serotonin—but also a separate pathway unique to psychedelics, sometimes referred to as the “hallucinogenic pathway.” This phenomenon, called biased agonism, allows psychedelics to amplify imagination, emotional awareness, and altered perceptions far beyond what endogenous serotonin alone can achieve. When both signaling pathways are engaged, they don’t just boost mood—they open the mind to new thoughts, feelings, and ways of experiencing reality, creating a fertile ground for deep insight and emotional release. It’s like a one-two punch—psychedelics for the win!
Creating New Patterns: The Default Mode Network (DMN)
These receptor interactions set the stage for the broader, arguably more intriguing, neural effects of psychedelics - their disruption of the brain’s default mode network (DMN). The DMN is a network of neural pathways located primarily in the medial prefrontal cortex, posterior cingulate cortex, and precuneus. It’s responsible for storing information from the past and using it to predict the future. This function creates stability within the nervous system since our brains “know what to expect” based on prior experiences. For this reason, we often think of the DMN as the brain’s “autopilot mode,” governing habitual thoughts and behaviors. It’s the part of the brain that’s active when we’re driving to work but are contemplating today’s to-do list — we’re still able to stop at a red light or swerve to avoid a squirrel, without conscious effort.
The DMN is also the part of the brain that is responsible for self-referential thinking and sense of separation from the world around us. This network is central to our sense of identity, acting as the neural substrate for what we often think of as the ego. It governs our self-referential thoughts, personal narratives, and the mental loops that shape how we perceive ourselves and the world. Lastly, the DMN is the part of the brain that exercises our deep-rooted subconscious belief systems. The DMN runs “information” that is based on past experience through neural pathways like a computer program, over and over, until those pathways are so entrenched in our mind that we are not conscious they are running. In this way, this area of the brain reinforces mental loops of self-doubt, rumination, and rigid thought patterns.
As you can see, the DMN is, arguably, the system of brain structures and neural pathways that are responsible for mind chatter, subconscious belief systems, and therefore, maladaptive nervous system responses, otherwise known as triggers. Enter psychedelics stage right: These substances disrupt the entrenched activity of the DMN, breaking up repetitive thought loops and habitual mental patterns. This may not seem like a big deal, but its the reason some folks in the psychedelic community say therapy without psychedelics is like working with a MS-DOS (floppy disk computer operating system, for young folks) - it’s old technology.
With the DMN quieted, the mind is free to explore new ways of perceiving and understanding self and the world. Other brain networks begin to communicate more freely, leading to a highly flexible and interconnected brain state. This freedom can bring up fresh perspectives, new insights, and a sense of unity and interconnectedness that are often hallmarks of the psychedelic experience (more on this later). Some describe this as a sort of “defragging” of the mind, where old thought patterns are released, making room for fresh neural connections—a state neuroscientists refer to as enhanced neuroplasticity. In simple terms, neuroplasticity is the brain’s ability to reorganize and form new connections, which is crucial for learning, emotional flexibility, and behavioral change. This means that after a psychedelic experience or while microdosing, the brain is more adaptable, ready to rewire itself in alignment with healthier perspectives and more supportive beliefs.
How Disrupting the DMN Can Help Address Trauma
One of the most profound impacts of psychedelics lies in their ability to address trauma. In individuals with PTSD, the brain often becomes locked in trauma loops—repeating patterns of fear, hypervigilance, and intrusive memories. These loops are maintained by overactive neural circuits and an inability to access broader cognitive resources to reprocess the experience. Psychedelics interrupt this cycle by enhancing connectivity across the brain, allowing for a kind of “mental reset.” This expanded neural communication enables individuals to revisit traumatic memories in a way that feels less overwhelming and more manageable, often accompanied by a greater sense of safety and perspective.
This reprocessing is not just about confronting past pain; it’s about reshaping the emotional associations tied to those memories. Psychedelics facilitate what many describe as a “decompression” of the emotional charge surrounding traumatic events. By reducing the grip of fear and activating more compassionate, integrative brain states, individuals can move from a place of survival to one of understanding and healing. The result is often a profound sense of relief and an increased ability to engage with life without the shadow of past trauma dictating their every move.
Go With the Flow: Activating the Task-Positive Network (TPN)
Interestingly, as psychedelics quiet the DMN, they simultaneously allow the brain’s task-positive network (TPN) to take center stage. The TPN, which includes the dorsolateral prefrontal cortex (DLPFC), inferior parietal lobule, and premotor areas, is the brain’s anticorrelate to the DMN and supports present-moment awareness, goal-directed behavior, and sensory engagement. These regions work together to help us focus, solve problems, and take purposeful action. By quieting the DMN’s inward chatter, psychedelics enable the TPN to take the reins, shifting us from self-referential rumination to one of flow state, characterized by heightened focus, mindful presence, and optimal task performance.
The TPN is the yang to the DMN yin - their dynamic balance is essential for well-being. Psychedelics foster harmony between these networks, creating space for individuals to move beyond paralyzing self-reflection and engage more fully with life. By strengthening the TPN’s activity, psychedelics not only enhance present-moment awareness but also improve cognitive flexibility, allowing for creative problem-solving and adaptability in the face of life’s challenges. This balance of "being" and "doing" encourages a deeper sense of agency and the ability to implement meaningful change. The TPN becomes a neural ally in building new habits, fostering resilience, and creating a sense of agency.
Soothing the Effects of Inflammation
Beyond their effects on neural pathways, psychedelics also appear to influence inflammatory processes in the body—a connection that highlights the intricate relationship between mental and physical health. Chronic stress and trauma are known to drive systemic inflammation by overactivating the hypothalamic-pituitary-adrenal (HPA) axis and increasing the production of pro-inflammatory cytokines such as TNF-alpha and IL-6. This persistent inflammation not only contributes to mental health conditions like depression, anxiety, and PTSD but also plays a central role in pain disorders and chronic illnesses. Emerging research suggests that psychedelics may reduce inflammation by modulating immune system activity, including suppressing the release of these cytokines. For instance, studies on ayahuasca have shown that its active compounds, such as harmine, possess potent anti-inflammatory and neuroprotective properties.
One fascinating area of exploration is the impact of psychedelics on neuroinflammation, which is increasingly recognized as a factor in chronic pain syndromes, migraines, and even fibromyalgia. By reducing microglial activation—key drivers of inflammation in the central nervous system—psychedelics may help create a healthier brain environment that supports emotional resilience and physical well-being. By lowering inflammation, psychedelics may help reduce the “background noise” of stress in the body, allowing individuals to focus more fully on their emotional and cognitive processes. This interplay between the body and mind reinforces the holistic nature of healing facilitated by psychedelics, where physical well-being supports emotional breakthroughs and vice versa.
Do the Effects of Psychedelics Last?
What’s striking is that these brain changes are not just transient states; the neuroplasticity and access to emotions lasts during the duration of a microdose course or for days to weeks after a macrodose experience (duration is dependent on the substance). Enhanced neuroplasticity allows the brain to “rewrite” its pathways, facilitating new habits, emotional responses, and thought patterns. Whether it’s breaking free from addiction, processing trauma, or adopting healthier behaviors, psychedelics provide the groundwork for these changes to take root.
In essence, psychedelics help us open the prison doors to our own minds. While these pathways of healing are possible without psychedelics, why settle for the clunky limitations of an old DOS when you could work with cutting-edge neural technology?
This is part 2 to a series of blog entries. A full downloadable copy of the series document is available here. Please be respectful of intellectual property when using and sharing.
If you are looking for assistance with coaching or building a personalized taper plan, please reach out to set up a strategy call with me at TheHolisticApothec.com.
Please remember, this document is not intended as medical advice, a substitute for medical care, or promotion for illegal activity.
