Rewiring the Mind: How Psilocybin, Ketamine, and TMS Reshape Neuroplasticity

By Chris Perez, MSNA, CRNA, CEO and Co-founder of Axis Integrated Mental Health

Mental health treatments have come a long way, moving beyond traditional antidepressants to innovative therapies that reshape the brain’s function. At Axis Integrated Mental Health, we specialize in cutting-edge neuromodulation treatments such as Esketamine (Spravato) and Transcranial Magnetic Stimulation (TMS), and work with organizing bodies who are navigating the world of legal Psilocybins, all of which may offer hope for individuals struggling with treatment-resistant depression, anxiety, PTSD, and other mood disorders.

The State of Mental Health in Colorado are significant.

Out of 51 states (including D.C.), we rank near the bottom of the list.  

• Substance Use Disorder (SUD): Colorado ranks #45 for adolescent SUD and #48 for adult SUD in the U.S.
• Mental health disparities: Only 42% of heterosexual, cisgender adults report good mental health, while the number drops to 29% for LGBTQ+ adults.
• Stigma remains a barrier: Nearly half of Coloradans who needed mental health care avoided treatment due to stigma in 2019.

These statistics highlight the urgent need for effective and innovative interventions beyond standard treatments.

Why Traditional Antidepressants Don’t Work for Everyone

For decades, antidepressants have been the frontline treatment for depression, based on the monoamine hypothesis, which suggests that mood disorders stem from imbalances in serotonin, norepinephrine, and dopamine.

However, new research challenges this idea. The STAR*D clinical trial, one of the largest studies on antidepressant effectiveness, found that only 35% of patients experience relief from these medications. This has led scientists to explore new approaches targeting neuroplasticity—the brain’s ability to form and reorganize neural connections.

Understanding the Brain’s Two Major Networks

The human brain operates through two key networks that regulate mental health:

1. Default Mode Network (DMN)

• Controls self-referential thinking and memory formation
• Active during daydreaming, mind-wandering, and self-reflection
• Can become overactive in conditions like depression and anxiety, leading to excessive rumination and negative thought loops

2. Task Positive Network (TPN)

• Engages in problem-solving, planning, and attention-focused tasks
• Serves as the brain’s mission control center
• When underactive, it leads to poor cognitive flexibility and lack of motivation

The Problem: An Overactive DMN

Many mental health disorders stem from an imbalance between these networks. When the DMN becomes overactive and the TPN underactive, individuals experience persistent negative thinking, cognitive fog, and emotional distress.

This imbalance is often linked to:

• Early childhood trauma and PTSD
• Chronic stress and anxiety
• Genetic factors affecting serotonin pathways

Neuroplasticity: A New Path to Healing

Unlike traditional medications that focus on chemical imbalances, Ketamine, TMS, and Psilocybin work by enhancing neuroplasticity—the brain’s ability to restructure itself and form healthier thought patterns.

The Role of Brain-Derived Neurotrophic Factor (BDNF)

BDNF is a key protein that promotes growth and repair of brain cells. Treatments that increase BDNF can help reverse the damage caused by stress and trauma, leading to lasting improvements in mental health.

How Innovative Treatments Work

1. Ketamine & Esketamine (Spravato)

• Blocks NMDA receptors, increasing glutamate release and BDNF production
• Disrupts negative thought patterns by resetting the DMN
• Provides rapid relief, often within hours, making it effective for suicidal depression

2. Transcranial Magnetic Stimulation (TMS)

• Uses magnetic pulses to stimulate the prefrontal cortex, strengthening TPN-DMN connections
• Increases BDNF production, promoting long-term improvement in mood and cognition
• Ideal for patients wanting a medication-free treatment

3. Psilocybin Therapy

• Activates serotonin 2A receptors, promoting ego dissolution and emotional breakthroughs
• Decouples overactive DMN regions, reducing depressive and anxious thought loops
• Enhances whole-brain connectivity, helping individuals see their struggles from a new perspective

Which Treatment is Right for You?

The right treatment depends on individual needs, diagnosis, and personal circumstances:

A Holistic Approach to Mental Health

While these treatments are revolutionizing mental health care, they work best when combined with:

• Therapy (CBT, EMDR, or psychedelic-assisted therapy)
• Lifestyle changes (exercise, mindfulness, social connection)
• Nutritional psychiatry (diet’s impact on brain function)

At Axis Integrated Mental Health, we believe that neuroplasticity is the key to long-term healing. By combining innovative interventions with holistic care, we see significant success in helping patients achieve lasting mental well-being.

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