What the research shows

1. Depression is often associated with lower GABA activity

Across many types of studies—brain imaging, spinal fluid measurements, and post-mortem analysis—people with major depressive disorder frequently show:

• Lower levels of GABA, or
• Reduced GABA receptor function, particularly in areas involved in emotion regulation.

This suggests the brain may lose some of its natural inhibitory “calming” ability during depression.

2. GABA interacts with other biological pathways

The authors highlight that GABA is not isolated. GABA changes affect, and are affected by:

• The stress-response system (HPA axis)
• Immune and inflammatory pathways
• Serotonin, norepinephrine, and dopamine systems
• Neuroplasticity (the brain’s ability to adapt and recover)

This reinforces the idea that depression is a multi-system condition, not just a problem with one chemical. It also suggests that GABA has a much more significant role in helping regulate other areas i.e., your happy hormones like serotonin, that can become dysregulated due to mental health challenges.

3. Standard antidepressants may indirectly normalize GABA

There is evidence that SSRIs and other traditional antidepressants can increase GABA levels or improve GABA receptor function over time. This suggests part of their therapeutic effect may involve restoring inhibitory balance in the brain. However, most standard antidepressants indirectly influence the GABA system, but they do so slowly and often inconsistently. They also come with a wide range of potential side effects (such as weight changes, sexual dysfunction, sleep disruption, and emotional blunting) which leads many people to seek gentler, more targeted options.

4. Newer GABA-targeting treatments are especially promising

A major emphasis of the review is on neuroactive steroids that enhance GABA-A receptors. These include:

• Brexanolone (used in postpartum depression)
• Zuranolone (oral neuroactive steroid with promising antidepressant results)

These compounds act quickly and directly on GABA-A receptors, and early studies show rapid improvements in mood, anxiety, and sleep disruptions. The authors view these treatments as strong support for GABA’s role in depression and a potential path for future antidepressant development.

But, What About Topical GABA?

Some studies suggest a possible indirect or limited central effect, while others find no clear penetration at all. What is well-supported is that GABA can act locally on GABA receptors in the skin, muscles, and peripheral nerves, producing calming and tension-reducing effects even without confirmed brain penetration. Topical GABA has been shown in several studies to reduce muscle tightness, calm peripheral nerve activity, and support relaxation through these local pathways. Because the body’s stress and sensory systems are interconnected, calming peripheral GABA receptors may provide a bottom-up calming effect, helping reduce physical tension and promoting a sense of relaxation - effects that align with the broader GABA-related mechanisms discussed in the review.