The Neurobiology of Stress

The Neurobiology of Stress

Image adapted from: ZELLX® HPA Axis testing

Stress is a natural part of life, but chronic stress can negatively influence brain function and overall well-being. Understanding the neurobiology of stress highlights the importance of key neurotransmitters like serotonin and GABA, and why certain herbs, such as ashwagandha and saffron, are of interest in research for supporting healthy responses to everyday stress.


The Body’s Stress Response: The HPA Axis and Cortisol

As soon as the brain detects a potential threat, the hypothalamus activates the hypothalamic-pituitary-adrenal (HPA) axis. This leads to the release of corticotropin-releasing hormone (CRH), followed by adrenocorticotropic hormone (ACTH) from the pituitary, and ultimately cortisol from the adrenal glands.

Cortisol helps mobilize energy and focus attention during acute stress. But in chronic situations, sustained elevation of cortisol can affect important brain areas: the hippocampus (your memory center), the amygdala (your brain’s emotional alarm system), and the prefrontal cortex (the part that helps you stay calm and in control).

 

Serotonin and GABA: Your Brain’s Natural Stress Helpers

  • Serotonin (5-HT) is often called the “feel-good” chemical. It plays a big role in stabilizing your mood and helping you bounce back from tough situations. Produced mainly in a part of the brain called the raphe nuclei, serotonin sends signals to areas involved in emotions, memory, and decision-making. When stress builds up, serotonin pathways can get disrupted, which may leave you feeling less emotionally balanced.

  • GABA (gamma-aminobutyric acid) acts like your brain’s built-in brake pedal. As the main calming neurotransmitter, it quiets down overactive nerve signals and promotes a sense of calm. Certain GABA-producing neurons help dial down the stress response by gently regulating the release of stress hormones. When stress lingers, GABA’s calming effect can weaken, making it harder for your brain to “hit the brakes” on anxious thoughts and feelings.

 

When serotonin and GABA are working well together, they help you feel more resilient and better able to handle everyday stressors.


Chronic Stress and Neurotransmitter Dynamics

Over time, ongoing stress may make it harder to regulate your emotions, get good sleep, or cope with daily challenges. High cortisol levels can interfere with serotonin pathways (affecting your mood), while lower GABA activity can make the brain’s fear circuits more easily triggered — leaving you feeling more on edge or anxious.


Herbs That Interest Researchers for Everyday Stress Support

Scientists are studying how certain herbs may help the body handle everyday stress more smoothly.

Ashwagandha (Withania somnifera) This popular adaptogenic herb has been the subject of many clinical studies. Researchers have looked at how it may support the body’s natural stress response, including effects on perceived stress, cortisol levels, and general feelings of tension.

For example, one well-designed study found that participants taking ashwagandha experienced lower cortisol levels and better scores on stress questionnaires. Several meta-analyses (reviews of multiple trials) have also noted consistent results showing support for lower perceived stress and healthier cortisol balance in some people.

Researchers believe ashwagandha may work by gently helping to balance the HPA axis (the body’s stress command center) and by supporting healthy serotonin and GABA activity in the brain.

Saffron This beautiful spice known for its vibrant red threads, has been studied for its potential to support mood and help the body respond to everyday stress. Its main active compounds — crocin and safranal — are the focus of many clinical trials and reviews.

Research suggests saffron may help promote a balanced mood. Some studies have found its effects on mood scales to be similar in strength to certain conventional treatments, but often with a gentler side-effect profile.

While its direct impact on cortisol levels appears more modest in research, saffron may work by supporting healthy serotonin pathways and helping the body handle stress more smoothly overall.


Conclusion: Supporting Natural Resilience

The neurobiology of stress shows how serotonin, GABA, and cortisol regulation contribute to how we handle daily challenges. Herbs like ashwagandha and saffron are subjects of growing research for supporting healthy stress responses—potentially via HPA modulation and neurotransmitter support.

Combine with lifestyle practices like sleep, exercise, and mindfulness for best results. Always seek professional advice for personalized health needs.

References

  1. Godoy et al. (2018). A Comprehensive Overview on Stress Neurobiology. https://www.frontiersin.org/journals/behavioral-neuroscience/articles/10.3389/fnbeh.2018.00127/full

  2. Lopresti et al. (2019). An investigation into the stress-relieving and pharmacological actions of an ashwagandha extract. https://pmc.ncbi.nlm.nih.gov/articles/PMC6750292/

  3. Bachour et al. (2025). Effects of Ashwagandha Supplements on Cortisol, Stress, and Anxiety Levels. https://www.cambridge.org/core/journals/bjpsych-open/article/effects-of-ashwagandha-supplements-on-cortisol-stress-and-anxiety-levels-in-adults-a-systematic-review-and-metaanalysis/6F2D7847C1F64707F2034A45FD6CF0C0

  4. Speers et al. (2021). Effects of Withania somnifera on Stress and Anxiety. https://pmc.ncbi.nlm.nih.gov/articles/PMC8762185/

  5. Lopresti & Drummond (2014). Saffron for depression: a systematic review. https://pubmed.ncbi.nlm.nih.gov/25384672/

  6. Hausenblas HA, et al. (2015). A systematic review of randomized controlled trials examining the effectiveness of saffron (Crocus sativus L.) on psychological and behavioral outcomes. https://pmc.ncbi.nlm.nih.gov/articles/PMC5747362/

  7. Yang X, et al. (2018). Comparative efficacy and safety of Crocus sativus L. for treating mild to moderate depression in comparison with placebo or antidepressants: A systematic review and meta-analysis. https://pmc.ncbi.nlm.nih.gov/articles/PMC5967372/

  8. Jackson PA, et al. (2021). Effects of Saffron Extract Supplementation on Mood, Well-Being, and Response to Psychosocial Stress in Healthy Adults: A Randomized, Double-Blind, Parallel Group, Clinical Trial. https://pmc.ncbi.nlm.nih.gov/articles/PMC7882499/

  9. Shafiee A, et al. (2025). Effect of Saffron Versus Selective Serotonin Reuptake Inhibitors (SSRIs) in Treatment of Depression and Anxiety: A Meta-analysis of Randomized Controlled Trials. Effect of Saffron Versus Selective Serotonin Reuptake Inhibitors (SSRIs) in Treatment of Depression and Anxiety: A Meta-analysis of Randomized Controlled Trials - PubMed


Note: This article discusses scientific research on herbs as potential dietary supplement ingredients. These are not intended to diagnose, treat, cure, or prevent any disease. Statements about herbs have not been evaluated by the FDA. Consult a healthcare provider before using any supplements, especially if you have health conditions or take medications.