Ketamine and serotonergic psychedelics: common mechanisms for rapid antidepressant effects

🔬 Study Title:

"Ketamine and serotonergic psychedelics: common mechanisms for rapid antidepressant effects"
📄 Published in Nature Reviews Drug Discovery, 2022
🔗 Read it on PubMed
👩‍⚕️ Authors: Michael A. Duman, Ronald S. Duman, et al.

🧠 Rewiring the Brain: What Ketamine and Psychedelics Teach Us About Depression

Published: August 1, 2025
(For educational purposes only. This content does not constitute medical advice or imply the availability of any specific treatment at Flowstate Therapy.)

Introduction

In recent years, the field of mental health research has undergone a quiet revolution. A growing number of studies are pointing toward novel compounds like ketamine, psilocybin, and MDMA as potential tools in understanding — and potentially addressing — treatment-resistant depression, PTSD, and other complex conditions.

Among these, ketamine has garnered particular attention due to its rapid onset of action, often showing measurable changes within hours, compared to weeks or months with conventional treatments.

But how does it work? What exactly is happening in the brain?

A 2022 article published in Nature Reviews Drug Discovery, titled "Ketamine and serotonergic psychedelics: common mechanisms for rapid antidepressant effects" explores this question through a rigorous scientific lens. The authors examine how substances like ketamine — along with psilocybin and MDMA — may share overlapping neurological mechanisms that contribute to their profound psychological effects.

This article breaks down the study’s key findings and reflects on what they might mean for the future of mental health research.

The Study at a Glance

Citation: Duman RS, Duman MA, et al. (2022). Nature Reviews Drug Discovery.
Link: PubMed Abstract

This comprehensive review synthesizes findings from neuroscience, pharmacology, and psychiatry to explore how fast-acting antidepressants work at the molecular and systems levels. While the study focuses on ketamine, it also includes serotonergic psychedelics — such as psilocybin and LSD — to highlight shared features in brain mechanisms.

Key Concepts Explored in the Study

1. Glutamate Surge and Synaptic Plasticity

Ketamine triggers a rapid increase in glutamate, the brain’s most abundant excitatory neurotransmitter. This, in turn, activates AMPA receptors, which initiate a cascade of changes that:

• Increase the production of BDNF (Brain-Derived Neurotrophic Factor)

• Enhance synaptogenesis (the formation of new synaptic connections)

• Reverse stress-related damage in the brain's prefrontal cortex and hippocampus

This process is a cornerstone of what researchers describe as "neuroplasticity" — the brain’s ability to adapt, change, and reorganize itself. It is believed that this biological shift plays a key role in ketamine’s rapid mood-elevating effects.

2. mTOR Pathway Activation

Another critical pathway discussed is mTOR (mechanistic Target of Rapamycin), which regulates protein synthesis and cellular growth. When activated, mTOR appears to:

• Support the growth of new dendritic spines (connections between neurons)

• Rebuild damaged neural networks affected by chronic stress or trauma

These mechanisms occur within hours of ketamine administration, marking a stark contrast with traditional antidepressants, which typically rely on serotonin pathways and take weeks to exert effects.

3. Default Mode Network (DMN) Modulation

One of the most compelling sections of the study explores the impact on the Default Mode Network — a brain network linked to self-referential thinking, rumination, and identity. Overactivity in the DMN has been associated with:

• Depression

• Anxiety

• Obsessive thought patterns

Both ketamine and serotonergic psychedelics appear to disrupt or “quiet” the DMN temporarily. This allows for a break in entrenched mental loops, potentially enabling new patterns of thinking or therapeutic insight.

4. Shared Mechanisms with Psychedelics

The authors point out that despite different primary receptors (e.g., NMDA antagonism in ketamine vs. 5-HT2A agonism in psilocybin), both classes of substances lead to:

• Increased cortical entropy (greater brain flexibility)

• Enhanced emotional processing

• Improvements in cognitive flexibility and openness

These overlapping features hint at a broader category of neuroplasticity-promoting interventions that could reshape how we understand — and eventually treat — mental health disorders.

Why This Matters

A New Model for Mental Health

Traditional mental health treatments often focus on correcting neurotransmitter imbalances. This study supports an emerging model: repairing and reactivating the brain’s adaptive capacity.

Instead of merely managing symptoms, these agents may help rebuild functional neural circuits — a potentially transformative shift in psychiatric medicine.

Treatment-Resistant Conditions

One area of particular interest is how these compounds might help individuals who have not responded to standard treatments. While more research is needed, studies like this provide valuable insight into why some people experience rapid relief after a single or limited exposure to neuroplasticity-enhancing agents.

Limitations and Ethical Considerations

It’s important to note that while research is promising, many of these compounds — including ketamine in certain formulations — are still classified as controlled substances in Canada. Access is tightly regulated, and use outside of authorized medical settings is neither legal nor recommended.

Additionally, the long-term effects of these compounds — particularly with repeated use — remain under investigation. Integration, psychotherapy, and ethical safeguards are essential components of any responsible model moving forward.

Final Thoughts

The Nature Reviews article provides a comprehensive, science-backed look at how ketamine and related compounds may catalyze healing in the brain. By promoting rapid neuroplasticity, quieting the default mode network, and reigniting emotional flexibility, these substances could mark a turning point in how we think about healing from depression, trauma, and related conditions.

At Flowstate Therapy, we’re committed to exploring and sharing high-quality research to help foster public understanding, reduce stigma, and support informed conversations about emerging developments in mental health care.