All the causes of PMS have not yet been conclusively clarified. However, scientific findings suggest that hormonal fluctuations during the female cycle play a role. Women with PMS do not necessarily have altered hormone levels compared to women without PMS, but are particularly sensitive to the release of progesterone. The hormone is mainly produced in the second half of the cycle before the onset of menstruation and, in addition to its actual function during the menstrual cycle and during pregnancy, also has an effect on certain receptor groups in the brain. It has been shown that both progesterone and metabolites of progesterone (e.g. allopregnanolone) influence the formation of extrasynaptic GABAA receptors and modulate the effect of GABA at these receptors. This appears to be a natural process designed to ensure a certain balance of neuronal excitability even during hormonal fluctuations. In women with PMS, these changes in neuronal excitability are particularly noticeable.

Other interactions between progesterone and messenger substances in the brain are also suspected. Tissue hormones, including tryptamines such as serotonin, also play a role here. The influence of the endocannabinoid system (ECS) in the regulation of neuronal excitability and modulation by steroid hormones also plays a central role. Stress and the resulting formation of cortisol also influences progesterone production, which can lead to an increase in symptoms. The exact mechanisms are currently being researched. Both genetic predispositions (familial influences) and environmental factors (epigenetic influences) influence the development of PMS. Furthermore, natural cannabinoids such as cannabidiol (CBD) also have the ability to modulate extrasynaptic GABAA receptors and thus provide a possible therapeutic potential for PMS (Schmiedhofer et al. 2022).