Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental condition, characterised by lifetime difficulties in concentration, hyperactivity, and impulsivity (1). The cross-national prevalence of adult ADHD is 3.4% (2). ADHD often co-occurs with various conditions (3). The sex distribution in adulthood is close to 1:1, but girls and women with ADHD remain underdiagnosed and undertreated (4, 5).

For almost forty years, the literature has called for more insight into ADHD in girls and women (6–10) Even though scientific recognition of the impact of sex on the development of (mental) health conditions is increasing rapidly, therapeutic interventions tailored to women with ADHD remain scarce (11, 12). An expert consensus statement did not identify any differences in pharmacotherapeutic recommendations for ADHD between sexes, but did note that the menstrual phase might affect treatment response (7). Changing hormone levels might decrease effectiveness of stimulant medication (13). Further, the interaction between the menstrual cycle and ADHD might be an important missing link in clarifying ADHD in girls and women (14).

A recent systematic review could only include 4 articles and was unable to identify a clear relationship between hormonal changes and ADHD in the menstrual cycle, during pregnancy, and in the (peri-)menopausal period (15). Another systematic review identified several differences in prescription rates, efficacy and usage of ADHD medication between women and men, but also a lack of information on sex-specific pharmacokinetics and adverse effects of ADHD medication (16). The authors recommended differing dosage patterns to adjust for the menstrual phase, but remain unable to offer any additional specifics due to lack of existing evidence (16). This emphasises the need to investigate the influence of fluctuating reproductive hormones on the psychopharmacology of ADHD.

We, MJ, DW, and JK, are medical practitioners in an outpatient clinic that exclusively treats patients with adult ADHD (and co-occurring conditions). We noticed that many women with ADHD described a stark decrease in wellbeing in the premenstrual week (Box 1), with increased irritability, fatigue and a severe worsening of their mood. Some met the diagnostic criteria of co-occurring premenstrual dysphoric disorder (PMDD), of which the core symptoms include anxiety, irritability and depressed mood (17). Additionally, numerous women reported a worsening of their ADHD symptoms in the premenstrual week. A third, related complaint came from women who had been on stable doses of psychostimulant medication. They reported that their ADHD medication was either less effective or ineffective in the premenstrual week and shortly after commencement of menstruation. Some had independently increased their dosage, initially without adequate follow-up.

Our patients’ reports match the existing evidence. During periods of low oestrogen, increased ADHD symptoms have been described (13, 19–21). Additionally, it has been reported that women respond less strongly to psychostimulant drugs in the luteal phase (16, 22–24). Therefore, we decided to increase the dose of the prescribed psychostimulant in the premenstrual week and evaluate the effect, hoping to improve treatment and establish a foundation for further research.

We report the effect of an increased dose of psychostimulant premenstrually, as part of the treatment at the outpatient specialist clinic for ADHD in adults at PsyQ, The Hague, Netherlands. This project was carried out in accordance with the Declaration of Helsinki; safety and confidentiality were foregrounded. All women gave written consent and were aware of the experimental nature of the pharmacotherapeutic adjustments.

All patients were being treated by MJ or DW, between 09–2021 and 03–2023. All had received a psychiatric assessment at our clinic, where ADHD was diagnosed or confirmed using the DIVA-5 interview (25, 26).

All women received treatment as usual, including pharmacotherapeutic and psychological interventions aimed at minimising complaints of ADHD and co-occurring conditions, in accordance with existing treatment guidelines. Despite the fact that all women had been adhering to their prescribed psychostimulant dosage for several months, they reported that their ADHD and mood symptoms worsened premenstrually. Taking this into account, a clinical decision was made in collaboration with the women to adjust the premenstrual dosage. Other possible interventions (e.g., hormonal contraceptives or antidepressants) were deemed undesirable or insufficient. Initially, the lowest readily available dose was added. If deemed necessary by patient and/or practitioner this dose was further increased monthly, until sufficient (subjective) effect was achieved, taking side effects into account. As with treatment as usual, all dosage adjustments warranted additional check-ups to evaluate the effect and possible side effects, which we describe as reported by the women. From the time the premenstrual dosage was increased, all women had regular follow-ups for six months to two years. As we described more cases, we attempted to delineate more clearly the effect women reported on their ADHD symptoms and mood complaints. We enquired more explicitly about the fluctuation of ADHD symptoms during the menstrual cycle, as well as the presence of mood symptoms in the premenstrual week. Additionally, as we started to describe the cases more systematically, we added a 5-point Likert scale to assess the effects for both ADHD and mood complaints (1: much worse, 2: moderately worse, 3: unchanged, 4: moderately improved, 5: much improved).

We included 9 consecutive women aged 22–48, who were receiving active treatment for their ADHD and co-occurring conditions. Seven patients were referred directly by their General Practitioners for diagnosis or treatment of ADHD symptoms, one by another mental health department and one by a psychiatrist in a neighbouring country. The women had a mean of 3.4 psychiatric co-occurring conditions (varying from 1–6), six had a diagnosis of PMDD and three were being treated with a selective serotonin reuptake inhibitor (SSRI) before the psychostimulant dose adjustment (Table 1).

The exact moment in the cycle when the increased dosage was required (commencement: 3–10 days before; until: 0–5 days after start of menstruation), the duration of using the higher dose (between 3–10 days total) and the amount with which the original dose was increased (range 30–50%), varied between cases. Follow-up ranged from 6–24 months. We summarise the reasons for increasing the premenstrual dosage and the effects thereof per patient (Tables 2, 3).

In this case study, we investigated the impact of increasing premenstrual psychostimulant dosage on nine consecutive adult women with ADHD. These participants reported premenstrual worsening of ADHD and mood symptoms. Our decision to increase psychostimulant dosage during the premenstrual week stemmed from other patients in our ADHD clinic, who independently increased their dosage without proper monitoring. Our approach involved raising the psychostimulant dosage during the premenstrual week and tracking its effects on ADHD, mood, and somatic symptoms over subsequent months, while continuing treatment as usual. To the best of our knowledge, this constitutes the only study of its kind published so far. As is common in adult ADHD (7, 27), these women were diagnosed with ADHD and several co-occurring conditions (Table 1). All had been taking stable psychostimulant treatment for several months, but expressed dissatisfaction with its efficacy during the late luteal phase, with consequential worsening of ADHD and mood symptoms. Methodically elevating the prescribed psychostimulant dosage during the premenstrual phase yielded positive results, with participants noting improvements in ADHD and mood symptoms. Additionally, they could better deal with their somatic symptoms, which improved for some.

Before the premenstrual dosage increase, the women in our study experienced the premenstrual phase as severely invalidating. They reported decreased focus, concentration, productivity, and “brain fog.” They also described compromised self-control, leading to heated arguments, binge-eating, and impulsive behaviours. The aftermath of this phase included feelings of regret, shame, and a perceived lack of control over their actions. This debilitating pattern repeated itself every month and hindered women in finding and maintaining a healthy, balanced life. Unfortunately, the experiences of the patients described here appear to be quite common (13, 28, 29). They align with a growing framework exploring the interplay between hormonal fluctuations and ADHD symptoms (15). This underscores the importance of such investigations for effective treatment for women with ADHD.

Despite variations in symptomatology, age, co-occurring conditions, and type of psychostimulant, all nine women experienced and scored a positive change in premenstrual mood and ADHD symptoms with the increased dosage and wished to continue using it (Table 1). All reported improvement within the first month, except for one participant (Pt 4) who initially struggled with adherence to and timing of the increased dosage. Improvements in ADHD symptoms that were consistently noted were: better concentration, focus, productivity, and a greater ability to regulate or manage emotions. Additional side effects were minimal to absent for all women. Premenstrual mood improved for all patients, with eight reporting reduced irritability (Pts 1,2,3,5,6,7,8,9), seven describing improved energy levels (Pts 1,2,3,4,5,6,9), six experiencing decreased agitation (Pts 1,2,4,6,8,9), and four reporting less anxiety (Pts 3,5,6,7). After dose increase, six women noted fewer mood swings or less impact thereof (Pts 1,3,5,6,8,9) and four women explicitly reported feeling more in control of their emotional reactions (Pts 1,3,6,8). An additional six described being less emotionally volatile or “reactive” (Pts 2,4,6,7,8,9). In general, many described a “normalisation” of premenstrual symptoms, and less pronounced distinctions between premenstrual and non-premenstrual weeks. Notably, some women observed improvement of premenstrual physical symptoms (Pts 1,5,6,7,9) or ability to tolerate these (Pts 3,5,6).

In healthy women, sex hormones are known to influence neurotransmitters, like dopamine (30) and serotonin (31–33). Thus, fluctuations in reproductive hormones during the menstrual cycle are thought to impact emotional states, mood disorders (34–38) and cognition (14, 39). A recent systematic review by Dubol et al. concluded that brain structure and reactivity are affected by hormonal fluctuations, which impact negative affect and cognition (40). Sacher et al. reviewed the existing neuroimaging studies and found that changes across the menstrual cycle influence the reaction to emotional stimuli and rewards. Amongst other effects, cyclical hormone fluctuations appear to interact with dopaminergic transmission (39). In healthy women, the interaction between sex hormones and neurotransmitters is also believed to influence ADHD symptoms (14, 19, 41). Low oestrogen phases correlate with increased ADHD symptoms. Young women without ADHD display heightened ADHD symptoms, particularly high trait impulsivity, during both early follicular and early luteal, or post-ovulatory phases (19). Focussing on menopausal women, Shanmugan et al. linked oestrogen to working memory, sustained attention and executive functions (41) and showed that lisdexamphetamine improved executive functioning in healthy menopausal women with executive difficulties (20). Anticipated work of Wasserstein et al. seems to solidify the relation between ADHD (symptoms) and menopause (21).

Other research findings explicitly link the effect and (ab)use of psychostimulants (particularly amphetamines) to changing levels of progesterone and oestrogens throughout the menstrual cycle (23, 24, 42, 43). In the luteal phase, women appear to respond less strongly to psychostimulant drugs (16, 22–24). In young women, fluctuating oestrogen levels may also influence the effectiveness of stimulant medications. A small study in 16 healthy women by Justice et al. showed that the effects of dextro-amphetamine (15 mg orally) were greater during the follicular phase than the luteal phase (23). During the follicular phase, subjects reported feeling more “high,” “energetic and intellectually efficient” after taking dextro-amphetamine, than during the luteal phase. While oestrogen seems to aid in the effectiveness of stimulants, progesterone likely decreases it (23). These results were replicated by another small study showing that oestrogen and progesterone levels may impact on the subjective euphoric and stimulating effects of dextro-amphetamine in healthy women who are not affected by ADHD (24).

The findings in healthy women regarding hormone interaction with neurotransmitters raise questions about their relevance in women with ADHD. Low oestrogen phases might exacerbate cognitive and mood symptoms in these women. This corresponds with a case study showing worsened ADHD and mood symptoms premenstrually in a young woman with ADHD (13). Our participants’ experiences align with existing evidence of increased ADHD (12–14, 19, 41), coupled with decreased response to psychostimulants during low oestrogen phases (16, 22–24). Notably, six out of nine women exhibited co-occurring PMDD, mirroring our group’s previous findings of increased prevalence and severity of PMDD symptoms in a cohort of women with ADHD (28). Interestingly, the women in this cohort also described an increased prevalence of postpartum depression and peri-menopausal symptoms. These are additional periods in women’s reproductive lives characterised by low oestrogen levels (28). The hypothesis emerges that in the luteal phase, when oestrogen levels fall, dopamine neurotransmission is further compromised in women with ADHD, leading to an exacerbation of their low mood and ADHD symptoms. This may explain the perceived ineffectiveness of the previously established psychostimulant dosage. Therefore, an increased psychostimulant dose may help alleviate worsening ADHD and mood symptoms in the premenstrual phase.

While this study is the first (to our knowledge) to describe the beneficial effect of increased premenstrual psychostimulant dosage for women with ADHD, it does have limitations. Firstly, we present a very small number of patients in a descriptive manner and lack a control group. However, these limitations are inherent to case study design. Secondly, we adjusted our assessment of the effects of our intervention, as we proceeded with describing more cases. However, as we optimised our assessments by adding a Likert-scale, our initial results were confirmed, strengthening their internal validity. Thirdly, the women had several co-occurring conditions, which may have influenced their response to the psychostimulant dose increase, but simultaneously reflects daily practice. Finally, we acknowledge that the intervention offered here requires careful tracking of the menstrual cycle, which may be difficult for women with ADHD, and challenging for those with irregular cycles.

To strengthen our approach, we included consecutive patients, offered detailed descriptions of our nine cases and attempted to provide sufficient demographic, diagnostic and therapeutic background information, conform the JBI critical appraisal tool for case series (44).

This case study demonstrates the potential benefits of increasing premenstrual psychostimulant dosage for managing premenstrual worsening of symptoms in women with ADHD. Improvements in ADHD symptoms, mood stabilisation, emotional control, and productivity were reported, with no worsening of side effects. These findings align with the concept of hormonal fluctuations impacting neurotransmitter function, affecting emotions and cognition. Furthermore, hormonal changes during the menstrual cycle may influence psychostimulant medication effectiveness. While preliminary, these results suggest that elevating premenstrual psychostimulant dosage might offer an efficient option for alleviating ADHD and premenstrual mood symptoms in women with ADHD, contributing to their overall wellbeing. Further research is needed in this important field to validate these findings and establish guidelines for personalised treatment plans based on menstrual cycle phases.

The datasets presented in this article are not readily available because we are describing clinical findings and patient privacy will be protected, further inquiries can be directed to MJ, m.dejong@parnassia.nl.

Ethical approval was not required for the studies involving humans because the intervention described here was offered in the context of regular clinical treatment, after careful discussion with all patients, in accordance with the ethical principles of the Parnassia Group. All patients gave written informed consent for their clinical data to be reported and published. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements because all patients had a therapeutic relationship with either MJ or DW. During the course of the therapeutic intervention and before reporting the data, written informed consent was obtained from all patients to publish clinical findings.

MJ: Conceptualization, Investigation, Writing – original draft. DW: Conceptualization, Investigation, Writing – original draft. EA: Writing – review & editing. AB: Writing – review & editing. JK: Supervision, Writing – review & editing.