The HPA–Thyroid–GABA Connection

Allison Sayre, MSN, WHNP

If you’ve ever felt wired but tired, anxious yet foggy, or unable to “switch off” even when your labs look fine, then your hypothalamic-pituitary-adrenal (HPA) axis, thyroid system, and brain’s Gamma-Aminobutyric Acid (GABA) network may be whispering the same story in three languages.

Here we will discuss how these three systems communicate in a dynamic feedback loop that shapes energy, mood, and resilience. This is where physiology meets psychology, and where biochemistry begins to explain why stress, fatigue, and anxiety so often coexist even in the absence of overt disease.

The Neuroendocrine Symphony

Hormones and neurotransmitters don’t play solo—they jam. Thyroid hormones like T4 and T3 don’t just dictate metabolic rate, but they influence how the brain builds and balances its excitatory and inhibitory circuits. Meanwhile, the HPA axis (the brain’s command center for stress) regulates cortisol and other glucocorticoids that directly affect neuronal excitability, mitochondrial function, and mood.

GABA, the brain’s main inhibitory neurotransmitter, acts as the calming conductor in this orchestra. It keeps excitatory glutamate in check and allows for the neural equivalent of “rest and digest”, or a deep exhale. [1] But when stress is chronic or thyroid hormones falter, GABA’s steady rhythm can turn erratic.

Thyroid and GABA: The Reciprocal Relationship

Thyroid hormones and GABA are in constant biochemical conversation. As early as the 1970s, animal studies showed that thyroid dysfunction alters GABA synthesis, release, and receptor function. Modern reviews confirm that this is a bidirectional relationship, meaning that thyroid hormones regulate GABA signaling, and GABA, in turn, influences thyroid output. [1]

In fact, it has been shown that thyroid hormones modulate nearly every aspect of the GABAergic system, from the enzymes that make GABA to how its receptors respond. In developing brains, hypothyroidism decreases GABA levels and enzyme activity, impairing proper neural wiring. In adults, paradoxically, hypothyroidism can increase GABA levels, possibly as a compensatory response to reduced receptor sensitivity. Conversely, hyperthyroidism doesn’t always mirror the opposite, but it can heighten anxiety and alter GABA receptor density in unpredictable ways. [1]

But here’s where it gets even more fascinating. GABA also regulates the thyroid. It inhibits thyroid-stimulating hormone (TSH) release from the pituitary and can dampen thyroid hormone release directly at the gland level. This means that chronic stress, which alters GABA tone, may feed forward into thyroid dysregulation, creating a closed loop between the brain’s inhibitory system and the endocrine axis. [1]

Stress and the HPA Axis: The Missing Link

The HPA axis sits upstream of both systems, translating perceived stress into hormonal reality. When the hypothalamus releases corticotropin-releasing hormone (CRH), it cues the pituitary to secrete ACTH, which stimulates cortisol release from the adrenals. This adaptive mechanism is lifesaving short-term, but chronically, it can suppress thyroid conversion (reducing T4→T3), blunt GABA signaling, and heighten glutamatergic excitability. [2]

This “triple intersection” between the HPA axis, thyroid, and GABA, can explain why so many patients describe a mismatch between lab results and lived experience. A normal TSH might coexist with flattened mood, poor sleep, and low stress resilience because the signal integration across systems is off, not necessarily the numbers themselves.

Modern Imaging Confirms the Connection

A study using high-resolution magnetic resonance spectroscopy (MRS) to measure brain GABA levels in patients with untreated hypothyroidism was performed. The results were striking, showing GABA concentrations in the medial prefrontal cortex (a region critical to mood and decision-making) were significantly lower than in healthy controls. Even more compelling, once optimal thyroid function was restored, GABA levels normalized, alongside improvements in depressive symptoms and memory. [3]

This study gave neurochemical proof to what clinicians have long observed, and that is that restoring thyroid balance can restore calm. The increase in brain GABA following a euthyroid state suggests that hypothyroidism’s emotional weight may stem partly from disrupted inhibitory signaling, meaning that the “tired but wired” feeling, in this light, isn’t just psychological, but neurochemical, as well. [3]

Developmental Insights: Timing Is Everything

From a developmental lens, thyroid hormones act as timing cues for brain maturation. Thyroid hormone availability coordinates the development of key neurotransmitter systems, including glutamate and GABA. Too little thyroid hormone during critical fetal or early postnatal windows can desynchronize brain architecture. This can result in cognitive and behavioral changes that mirror altered GABAergic signaling, such as increased seizure susceptibility, anxiety, or attentional difficulties. [4]

In other words, thyroid hormones don’t just regulate metabolism, but they choreograph brain development. Their absence or excess at the wrong time can leave an enduring imprint on how neurons connect, communicate, and calm themselves.

The Feedback Loop in Practice

Understanding the HPA–thyroid–GABA loop reframes common clinical puzzles:

• Chronic stress → elevated cortisol → reduced T4→T3 conversion → decreased GABA synthesis → anxiety and sleep issues.
• Hypothyroidism → decreased brain T3 → impaired GABAergic tone → mood flattening and cognitive fog.
• GABA deficiency → loss of inhibition on the pituitary and thyroid → dysregulated TSH secretion → metabolic slowdown or fluctuation. [1-4]

It’s a system built on checks and balances. When one node weakens, others compensate—sometimes maladaptively. That’s why an integrative approach matters. We’re not chasing isolated numbers, but rather are looking for resonance across axes.

Shared Decision-Making in a Multisystem Model

For practitioners, this complexity is both daunting and empowering. It reminds us that “normal labs” are only one lens. Functional symptoms often point to subtle biochemical disharmony long before overt lab abnormalities emerge. In shared decision-making, this translates to education over fear. Patients deserve to know that feeling anxious, cold, or cognitively dulled isn’t “in their head”, but it might literally be in their neurotransmitters.

Patients and practitioners can collaborate around measurable goals, tracking both objective markers (TSH, free T3, free T4, cortisol rhythm) and subjective signals (sleep quality, mood regulation, cognitive focus). Addressing lifestyle drivers like sleep deprivation, nutrient insufficiency, and chronic stress supports both thyroid and GABA pathways. Targeted interventions such as mind-body practices, adaptogens, or nutritional support can become tools to restore rhythm, not quick fixes.

Healing the Feedback Loop

Here’s the hopeful part, and that is this loop is plastic. The same circuits that dysregulate can recalibrate. Science has shown that GABA can normalize after thyroid correction, and stress resilience and mood balance often return when these systems are supported in synchrony. Healing begins with pattern recognition. When practitioners and patients work as partners, and they listen to physiology as conversation and not crisis, the body’s feedback loops can find their tempo again.

So, the next time you or your patient feels anxious without cause, tired without reason, or “off” despite normal labs, consider this. The HPA–thyroid–GABA connection isn’t a mystery, but it’s the body’s way of asking for harmony across its instruments. And with the right biochemical, psychological, and relational tuning, that harmony is absolutely achievable.

Disclaimer:

The information provided is for educational purposes only. Consult your physician or healthcare practitioner if you have specific questions before instituting any changes in your daily lifestyle including changes in diet, exercise, and supplement use.

Allison Sayre is a board-certified women’s health nurse practitioner with advanced expertise in hormonal health, integrative gynecology, and patient-centered care across the lifespan. She holds a Master of Science in Nursing and has served as both a clinical provider and educator in functional and conventional women’s health settings.

Allison has led clinical programming, practitioner training, and content development for leading health brands and organizations. Her work bridges the clinical and commercial worlds, helping translate scientific evidence into practical tools for healthcare practitioners. At ARG, Allison contributes to medical education, clinical protocol development, and strategic content that supports the evolving needs of women's healthcare practitioners.