BY MARLEIGH SMITH, NEUROSCIENTIST AT DITTO
The Complexity Within the PMDD Brain, and Why it's Not "Just a Low Mood"
PMDD is often described as a ‘hormone sensitivity’. While this rings true in many ways, it is also a massive oversimplification. So what’s actually going on in your brain?
The neurobiology of premenstrual dysphoric disorder (PMDD) has been increasingly researched in recent years.
Findings point to:
• A dysfunction in two different neurotransmitter (brain chemical) systems
• Actual physical changes in your brain’s structure.
With different subtypes of PMDD emerging in recent years, which include differing hormones that someone is sensitive to (estrogen, progesterone, or both) and the symptom timing patterns (full luteal phase, premenstrual week) - the mechanisms behind PMDD are likely to be different between people.
PMDD is not one-size-fits all, which is one reason why it can be so difficult to manage, and a treatment that works for one person might not work for another.
What Brain Chemicals Could be Influencing your PMDD?
As we know, PMDD is not caused by abnormal hormone levels in your body, but rather the sensitivity to hormonal fluctuations.
This could be because of interactions between the hormones and certain brain chemicals (aka neurotransmitters).
- GABA, one of the main neurotransmitters in our brains, is often called the “calming chemical”, as it has inhibitory effects in your neural networks.
- Serotonin, also a main neurotransmitter, important for mood regulation.
Both systems involving GABA and serotonin are thought to be dysregulated in PMDD. Let’s dive in.
The “Calming” (aka GABAergic) System Doesn’t Work So Well
The GABAergic system includes the brain chemical called GABA - your brain's calming system, or brake, that helps stabilise mood.
GABA receptors receive these messages, and they are made up of many different subunits (like puzzle pieces). And the reason they matter when hormones change? These subunits are responsive to a metabolite of progesterone, called ALLO.
In fact, the progesterone metabolite ALLO works similar to anxiety medication, allowing a normal GABAergic, or calming system to be present in the brain.
In the late luteal phase, progesterone, and therefore ALLO, fluctuate. Normally, in this phase, certain GABA receptor subunits (“delta”) are upregulated, to compensate for this hormone change, and ensure that there is enough of a calming effect, so that your mood stability is left unchanged.
However, in PMDD, this is not the case. Studies show that there is different GABA delta subunit expression across the menstrual cycle in women with PMDD, and this upregulation fails to happen (1). As a result, there is reduced GABA activity in the late luteal phase as progesterone falls - and less of a balancing “calming” effect (4). This is thought to underlie the mood changes seen in PMDD.
Indeed, the same study found that this decreased GABA receptor subunit expression was linked to higher amygdala activation in the luteal phase (4). The amygdala is essential for processing emotions - therefore higher activation can lead to volatility and hyperreactivity.
In those who do not have PMDD, the brain is able to adjust so that their mood is not affected severely by this hormone fluctuation.
The Serotonin System and Depressive Symptoms
A recent study provided evidence for serotonin system involvement PMDD. Researchers used PET brain imaging and found that during the premenstrual (symptomatic) phase (2):
- PMDD Patients: They had an 18% increase in midbrain serotonin binding
- Controls: They had a 10% decrease in midbrain serotonin binding
This serotonin binding was on the "presynaptic" receptor, which pulls serotonin out and reduces its availability. This would mean that with this increased binding, there is less serotonin able to create an uplifting mood effect.
The higher binding of serotonin correlated with worse depressive symptoms in those with PMDD.
PMDD as an Inflammatory Condition
While there is less evidence for this, some research is now alluding to PMDD involving inflammation.
PMDD sufferers often have elevated peripheral inflammatory markers, where higher levels of these inflammatory markers are associated with PMDD symptoms (3). This inflammation is not isolated to our body, it reaches the brain, and it can interact with:
• The previously mentioned neurotransmitter systems (GABA and serotonin)
• Our stress response system - the Hypothalamic-Pituitary-Adrenal (HPA) axis.
The HPA axis is influenced by systemic inflammation, and is seen to have lower activation in PMDD patients, which leads to an impaired stress response system in those with PMDD. This inflammation can cause dysregulation in the brain, possibly also contributing to PMDD symptoms.
What Brain Structure Changes are Observed in PMDD?
Recent studies show differences in white and grey matter volume in the brain in those with PMDD (4-5).
1. A Baseline Difference in Brain White Matter in PMDD
In a 2025 study, brain imaging (MRI) was completed in the mid-follicular phase (where PMDD symptoms are unlikely to be present) and the late luteal phase, where symptoms of PMDD are most common. They observed:
• PMDD Differences vs “Healthy Controls”: Increased white matter volumes in women with PMDD during BOTH phases of the menstrual cycle, and there were no significant differences between the two phases.
• Regions impacted: Those involved in cognitive and emotional processing, and emotional regulation (inferior fronto-occipital fasciculus and uncinate fasciculus fornix).
Since the white matter volume changes are not significantly different between the asymptomatic and symptomatic menstrual phases, it appears that there is always a baseline difference between those with PMDD and controls throughout the cycle, rather than a transient change during the late luteal phase.
2. Baseline and Cycle-Specific Differences in Brain Grey Matter in PMDD
In a 2024 study researchers found:
• Persistent Baseline Differences: Those with PMDD had thinner cortices (the outer edges of the brain) and reduced brain folding vs controls, which did not change with menstrual cycle phase. Again, this shows that there are baseline differences between those with PMDD and controls present all month long, rather than transient changes during the late luteal phase.
• Dynamic Cycle-Specific Changes: However, specific brain structure changes were in the late luteal phase only. Cortical thickness decreased compared to the mid-follicular phase. Complex folding changes also occurred throughout the cycle. This shows specific cycle-phase changes in PMDD in grey matter structure.
We have a whole article written on how PMDD can be seen on brain scans here.
Brain Connectivity Changes in PMDD
Potential impact on concentration, overwhelm, motivation, interest, pain sensitivity
It’s not just brain structure changes, but also the activity within these brain structures that could influence PMDD. Women with PMDD were found to have decreased connectivity in the default mode network, which is essential for emotional processing, irrespective of the menstrual cycle phase (6).
Additionally, decreased connectivity in the central executive network, essential for high level cognitive processes was observed in PMDD sufferers.
Interestingly, differences in the salience network were different across all phases in those with PMDD, which is responsible for responses to external information.
These state-like brain changes show that those with PMDD have distinct baseline differences in their neurobiology compared to controls, and also shows how there are specific changes in the luteal phase, when someone suffering with PMDD experiences symptoms, creating a combinatorial effect.
How are these Systems Interacting?
In summary, current research points to the neurobiology of PMDD being defined by:
1. Dysregulation in key brain chemical systems
2. Possibly inflammation within the wider body and brain
3. Actual changes in the structure of your brain and it’s connectivity
With dysregulation in neurotransmitter systems, like maladaptive GABA subunits and serotonergic unavailability, the resulting signals sent from one brain region to another are different in those with PMDD, which can affect functional connectivity. On top of this, differential white and grey matter can also affect how these systems connect, and how your brain regions communicate, creating dysregulation in your brain as a whole, which contributes to the debilitating symptoms of PMDD. Surrounding inflammation may further exacerbate this.
These 3 concepts produce vulnerability in the brains of those with PMDD, and can contribute to the heightened sensitivity to hormonal changes during the menstrual cycle. During the follicular phase, hormones are stable, so these neurobiological changes aren’t noticeable to PMDD sufferers, but when estrogen and progesterone fluctuates around ovulation and/or in the luteal phase, this is when symptoms can appear.
What Does This Mean for the Future of PMDD?
The growing body of research in this area is opening up the underlying biology and revealing just how complex it is - far more than "just low mood" - bringing us closer to targeted solutions for people with PMDD. Defining PMDD subtypes by their underlying neurobiology and biological markers could pave the way for more personalised treatment options, with hope that clinical guidelines will evolve to offer more comprehensive, consistently effective care.
Currently on offer is SSRIs, which are found to work for 60% of those with PMDD, however 40% do not respond (7) - because it involves more than just this one neurotransmitter (as detailed across the article). Hormonal treatments are also available and this is often a journey of trial and error to see what works for you.
For those who want to try it, DITTO Premenstrual Supplement was designed around the above biology. It contains important ingredients that have evidence to help manage PMDD symptoms, and they target the neurotransmitter systems that are shown to be part of the problem in PMDD. For example:
Saffron extract is shown to target the serotonin system and make more available in the brain. It is evidence to improve PMDD depressive symptoms (8).
Chamomile extract contains bioactive compounds that are shown to interact with the GABAergic system and HPA axis that we detailed above. It has been studied in menstrual-related mood disorders, improving mood symptoms all-round (9).
References:
1. Stiernman, L., Comasco, E., Johansson, M. et al. Transcription of GABAA receptor subunits in circulating monocytes and association to emotional brain function in premenstrual dysphoric disorder. Transl Psychiatry. 2025
2. Sacher J, Zsido RG, Barth C, et al. Increase in Serotonin Transporter Binding in Patients With Premenstrual Dysphoric Disorder Across the Menstrual Cycle: A Case-Control Longitudinal Neuroreceptor Ligand Positron Emission Tomography Imaging Study. Biol Psychiatry. 2023
3. Cheng M, Jiang Z, Yang J, et al. The role of the neuroinflammation and stressors in premenstrual syndrome/premenstrual dysphoric disorder: a review. Frontiers in Endocrinology. 2025
4. Stenhammar E, Dubol M, Stiernman L, et al. White Matter Regional Volumes in Relation to Menstrual Cycle Phase and Premenstrual Dysphoric Disorder. Biological Psychiatry Global Open Science. 2025
5. Dubol M, Stiernman L, Sundström-Poromaa I, Bixo M, Comasco E. Cortical morphology variations during the menstrual cycle in individuals with and without premenstrual dysphoric disorder. Journal of Affective Disorders. 2024
6. Reuveni I, Dan R, Canetti L, et al. Aberrant Intrinsic Brain Network Functional Connectivity During a Face-Matching Task in Women Diagnosed With Premenstrual Dysphoric Disorder. Biological Psychiatry. 2023
7. Jespersen C, Lauritsen MP, Frokjaer VG, Schroll JB. Selective serotonin reuptake inhibitors for premenstrual syndrome and premenstrual dysphoric disorder. Cochrane Database Syst Rev. 2024
8. Rajabi F, Rahimi M, Sharbafchizadeh MR, Tarrahi MJ. Saffron for the Management of Premenstrual Dysphoric Disorder: A Randomized Controlled Trial. Adv Biomed Res. 2020
9. Najafi Mollabashi E, Ziaie T, Bostani Khalesi Z. The effect of Matricaria chamomile on menstrual related mood disorders. Eur J Obstet Gynecol Reprod Biol X. 2021
