Molecular pathways of ketamine: A systematic review of immediate and sustained effects on PTSD

Summary & key facts

Researchers reviewed about 300 studies and closely read 29 that tested how ketamine changes the brain at the molecular level in post-traumatic stress disorder (PTSD). They looked at short-term changes that happen while the drug is active and longer-term changes that can last after the drug is gone. Short-term changes include shifts in key brain chemicals that quickly boost a growth protein called BDNF and make connections between nerve cells more flexible. Longer-term changes involve lasting shifts in gene activity and in markers that turn genes up or down, which could help keep those brain connections stable. Most evidence comes from animal studies, so we still need more human research to know how these molecular changes map onto lasting recovery and safety for people with PTSD.

Key facts:

• This was a systematic review that started with about 300 articles and included 29 studies that matched the authors’ rules.
• In the short term (roughly the first day), ketamine changes levels of GABA, glutamate, and glutamine, and these changes help increase BDNF, a protein that supports nerve-cell growth and flexibility.
• Immediate molecular signals linked to ketamine include activation of TrkB and PSD-95, and changes in markers such as c-Fos, GSK-3, HDAC, and HCN1.
• Ketamine also affects stress hormones (like corticotropin-releasing hormone and ACTH) and immune signals that are often higher in PTSD, such as IL-6, IL-1β, and TNF-α.
• Sustained effects (seen after the drug is gone) include prolonged changes in gene expression driven by pathways like mTOR that keep BDNF levels up, and changes in proteins such as GSK-3β, FKBP5, GFAP, and ERK phosphorylation.
• The review reports epigenetic changes after ketamine. Epigenetic changes are chemical tags that can turn genes on or off without changing the DNA sequence. Examples here include DNMT3, MeCP2, H3K27me3, and microRNAs like mir-132 and mir-206.
• Much of the detailed molecular evidence comes from rodent experiments. That means these findings help form hypotheses but need more human studies to be sure how they affect symptoms, how long benefits last, and what risks might appear with longer treatment.
• Ketamine exists as two mirror forms: S-ketamine acts faster and is linked to stronger dissociative effects, while R-ketamine may last longer and could have fewer side effects. Both forms and their metabolites (norketamine and hydroxynorketamine) show different actions in the brain.
• Individual differences in liver enzymes (for example, common variants in CYP2B6) can change how fast a person breaks down ketamine, which could affect how strong and how long its effects last.

Abstract

These molecular changes promote long-term synaptic stability and re-regulation in key brain regions, contributing to prolonged therapeutic benefits. Understanding the sustained molecular and epigenetic mechanisms behind ketamine's effects is critical for developing safe and effective personalised treatments, potentially leading to more effective recovery.

Topics

Anesthesia and Neurotoxicity Research Treatment of Major Depression Tryptophan and brain disorders

Categories

Health Sciences Medicine Pharmacology

Tags

Bioinformatics Biology Epigenetics Gene Genetics Internal medicine Medicine Neurochemical Neuroplasticity Neuroscience Pharmacology Psychology Receptor Synaptic plasticity

Substances

Ketamine

Conditions & symptoms

PTSD