ADHD: Medication Efficacy is Linked to your Menstrual Cycle!

ADHD: Many women can attest to experiencing ‘a volatile efficacy’ of their ADHD medication during various times in their menstrual cycle, without any obvious reasons. Read how to fix it here!

ADHD vs. Estrogen – The Battle Within …

The Reason

This have now been linked to the estrogen levels in the female body during the menstrual cycle. Efficacy increases when estrogen levels are highest,  e.g., at ovulation, and decreases when estrogen levels are lowest, e.g., 2-3 days pre-Period start and 2-3 days post-Period start. This is further complicated by which type of medication you use to treat your ADHD.

The Explanation

Lisdexamfetamine is just a fancy Shake’N’Bake version of Amphetamine

Lisdexamfetamine (LDX) is a so-called prodrug, which means that it only contains the ‘ingredients’ needed to synthesize d-Amphetamine, and the reason for this is, that it is useful for persons with ADHD and current/former addiction problems, as it cannot be abused.

Prodrugs that have a long-lasting formulation, like Lisdexamfetamine (LDX) (e.g., VYVANSE/ADUVANZ) are heavily reliant on estrogen-dependent enzymes in your small intestines, in order for its chemical processes when ‘constructing’ (synthesizing) the active substance – Amphetamine – in your body.

This results in a markedly, and noticeable decrease in effect of Lisdexamfetamine (at the same normal dose, taken at the regular intervals as normal) due to ‘production problems’ across the menstrual cycle.

The Neuroscience of Estrogen

GLOSSARY

• estrogen A steroid hormone (including estradiol) that affects sexual differentiation during development and reproductive function and behavior in mature adults.
• estradiol The principal estrogen, secreted by ovarian follicles.
• progesterone a precursor of both estrogen and testosterone.
• testosterone The principal androgen, synthesized in the testes and, in lesser amounts, in the ovaries and adrenal glands.

[Purves Neuroscience, 6th Edition]

Estrogen influences synaptic transmission.
(A) Electron micrograph showing localization of the estrogen receptor α (ERα; the dark, “electron-dense” label) in postsynaptic processes (presumably spines) in the rat hippocampus.
(B) Estrogen (E2) increases the amplitude of excitatory postsynaptic potentials in individual hippocampal neurons (the same physiological measurement done in artificial cerebrospinal fluid—aCSF—is shown as a control). High-frequency stimulation further enhances the effects of E2, suggesting that estrogen may modulate use-dependent plasticity in hippocampal synapses.
(C) High-frequency stimulation in the presence of E2 in rat hippocampal slices results in enhanced long-term potentiation consistent with a role for estrogen in synaptic and circuit plasticity in the hippocampus. The data shown here plots the frequency of EPSP values (fEPSP) over time. E2 alone results in a clear increase in EPSP values, and this effect is magnified and maintained after high frequency stimulation, denoted by the second arrow. [Purves Neuroscience, 6th Edition]

Differential subjective effects of d-Amphetamine by gender, hormone levels and menstrual cycle phase

The ovarian hormones estrogen and progesterone appear to have direct and opposing actions on brain monoamine (serotonin, dopamine, norepinephrine) systems, which suggests that monoaminergic drugs, such as amphetamine, may produce differential effects in men and women and in women at different phases of the menstrual cycle. [White et al. (2002)]

Estrogen and progesterone interact with monoamines in ways that suggest the potential modulation of responses to psychoactive drugs by endogenous steroids, both between menstrual phases and between the sexes. [White et al. (2002)]

The present study assessed the subjective and physiological effects of a single dose of d-Amphetamine (d-AMPH; 15 mg oral) in healthy, normally cycling women, who received d-AMPH and placebo (PL) during both the follicular and luteal phases of a single menstrual cycle, and in healthy men. [White et al. (2002)]

Key points

The major findings concerning menstrual phase, gender, estradiol and progesterone associations with d-Amphetamine (d-AMPH) responses have several implications for basic and clinical research.

• First, women who initially use a stimulant drug for recreational purposes during the follicular phase may be more likely to repeat use of the drug because of its stronger effects.
• Second, female addicts who are trying to abstain from drug use may be more likely to succeed if the initial abstinence is scheduled to occur during the luteal phase, when the drug effects are less potent.
• Third, the dampened responses to stimulants during the luteal phase may protect women from the risk of use escalation or abuse, because they are expected to be in the luteal phase roughly 46% of the time. In contrast, males may be more at risk for stimulant use than females because they experience the drug maximally on more occasions.
• Fourth, these findings have direct implications for the investigation of individual differences in responses to amphetamine and suggest that women should be tested during the follicular phase when drug effects are maximal.

Conclusion

higher levels of estrogen and lower levels of progesterone are associated with greater subjective stimulation after d-AMPH in women, and these hormonal influences contribute to sex differences in d-AMPH responding.

To sum up, the results of the current study are fourfold:

• First, the current study replicated and extended previous findings such that effects of AMPH appear to be fairly strongly and reliably influenced by menstrual cycle phase.
• Second, gender differences in AMPH responding emergealmost entirely as a function of menstrual cycle phase variation in female responses to amphetamine.
• Third, in normally cycling adult women, the internal hormonal milieu is fairly strongly associated with the magnitude of the maximal psychological effects of AMPH. Progesterone is associated with dampened stimulant responding in the follicular phase, when progesterone levels are relatively minimal and amphetamine responses are relatively maximal.
• Fourth, the current study provided only limited evidence that estradiol might facilitate stimulant responding.

Future studies will be required to investigate the extent to which dopamine and other neurotransmitter systems are involved in the modulation of agonist drug effects by endogenous steroids. [White et al. (2002)]

Menstrual Cyclical Effect on ADHD Symptoms

Although Attention-Deficit/Hyperactivity Disorder shows (ADHD) male predominance, females are significantly impaired and exhibit additional comorbid disorders during adolescence. However, no empirical work has examined the influence of cyclical fluctuating steroids on ADHD symptoms in women. [Roberts et al. (2017)]

The present study examined estradiol (E2), progesterone (P4), and testosterone (T) associations with ADHD symptoms across the menstrual cycle in regularly-cycling young women (N=32), examining trait impulsivity as a moderator. Women completed a baseline measure of trait impulsivity, provided saliva samples each morning, and completed an ADHD symptom checklist every evening for 35 days. [Roberts et al. (2017)]

Results indicated decreased levels of E2 in the context of increased levels of either P4 or T was associated with higher ADHD symptoms on the following day, particularly for those with high trait impulsivity. [Roberts et al. (2017)]

Phase analyses suggested both an early follicular and early luteal, or post-ovulatory, increase in ADHD symptoms. [Roberts et al. (2017)]

Therefore, ADHD symptoms may change across the menstrual cycle in response to endogenous steroid changes.

[Roberts et al. (2017)]

Means plots illustrating the interactive effects of estradiol with testosterone and progesterone in predicting inattentive symptoms across the menstrual cycle among women high (A) and low (B) in sensation seeking. [Roberts et al. (2017)]

Results demonstrating steroid effects across the menstrual cycle on ADHD symptoms for vulnerable women suggests the possibility that ADHD symptoms may be more state-like and variable within women than previously thought. [Roberts et al. (2017)]

If results that ADHD symptoms vary across the menstrual cycle in tandem with steroid changes are replicated, this may suggest the need for clinicians to ask for information about cycle phase, hormonal profiles, use of hormonal birth control, and/or stage of life (i.e., pre- or post-puberty) during ADHD assessment in women. [Roberts et al. (2017)]

These results also suggest the possibility that EF and psychostimulant response might vary across the cycle. These represent critical directions for future work. [Roberts et al. (2017)]

Psychosocial implications of Estrogen levels across the Menstrual Cycle

Although ovarian hormones are thought to have a potential role in the well-known sex difference in mood and anxiety disorders, the mechanisms through which ovarian hormone changes contribute to stress regulation are not well understood. [Albert et al. (2015)]

One mechanism by which ovarian hormones might impact mood regulation is by mediating the effect of psychosocial stress, which often precedes depressive episodes and may have mood consequences that are particularly relevant in women. [Albert et al. (2015)]

Estradiol receptors are located in a number of brain areas, including regions important for the autonomic, hormonal, and cognitive-emotional response to psychosocial stress. [Albert et al. (2015)]

The relation of stress to depression onset and the altered function of the stress system in major depression suggest that modulation of the psychosocial stress response may be a mechanism through which estradiol fluctuation may contribute to MDD and PTSD risk. [Albert et al. (2015)]

The results of this study suggest that estradiol levels may modulate activity in brain areas important for processing emotional information during psychosocial stress. Increased emotional processing and physiological response to psychosocial stress, during low estrogen menstrual phases, may contribute to depressed mood in women with vulnerability to MDD. [Albert et al. (2015)]

Indeed, women with MDD have greater HPA axis dysregulation than men with MDD suggesting that the stress system may be particularly important to depression in women. Estradiol may attenuate sympathetic and HPA axis activity to stress. [Albert et al. (2015)]

This finding indicates that women in the high estradiol phase of the menstrual cycle have a greater left hippocampal activity during psychosocial stress than women in the low estradiol phase. [Albert et al. (2015)]

Women with low estradiol levels had significantly less activity in the left hippocampus than women with high estradiol levels during the stress condition.

[Albert et al. (2015)]

Our findings suggest that greater estradiol levels during the periovulatory phase of the menstrual cycle decrease the brain activity change in response to psychosocial stress, and reduce the acute behavioral and mood consequences of the stress experience. [Albert et al. (2015)]

This interpretation is further supported by the location of estradiol receptors in the central nervous system; the hippocampus is rich in both estradiol and glucocorticoid receptors, making it an important area of interaction between these hormones. [Albert et al. (2015)]

We recognize that menstrual cycle effects are likely not the only, or even the main, determinant of psychosocial stress responding in women; future studies are needed to examine the effects of personality factors, and lifetime trauma or chronic stress. [Albert et al. (2015)]

Effects of sex steroids on neurons.

Estrogen, testosterone, and other steroids are highly lipophilic molecules and are usually transported via carrier proteins circulating in the blood. Thus, the fe- tuses of placental mammals are exposed to estrogens generated by the maternal ovary and placenta de- livered via maternal circulation. [Purves Neuroscience, 6th Edition]

(A) The left panel of this schematic lists the direct effects of steroid hormones on the pre- or post- synaptic membrane, which can alter neurotransmitter release and influence neurotransmitter receptors. On the right are shown some indirect effects of these hormones, which bind to receptors and/ or transcription factors that act in the nucleus to influence gene expression. [Purves Neuroscience, 6th Edition]

(B) Distribution of estradiol-sensitive neurons in a sagittal section of the rat brain. Animals were given radioactively labeled estradiol; dots represent regions where the label accumulated. In the rat, most estradiol-sensitive neurons are located in the basal diencephalon and telencephalon, with a high concentration in the preoptic area, hypothalamus, and more laterally in the amygdala, which is not shown in this mid-sagittal section. [Purves Neuroscience, 6th Edition]

Additional information

Women, ADHD, and Hormones

For more information on ADHD and women, watch Dr. Sandra Kooij, PhD. explain it all in this Webinar from ADHD-Europe.

References

Albert, K., Pruessner, J., & Newhouse, P. (2015). Estradiol levels modulate brain activity and negative responses to psychosocial stress across the menstrual cycle. Psychoneuroendocrinology, 59, 14–24. https://doi.org/10.1016/j.psyneuen.2015.04.022

Dluzen, D. E. (2005). Unconventional effects of estrogen uncovered. In Trends in Pharmacological Sciences (Vol. 26, Issue 10, pp. 485–487). https://doi.org/10.1016/j.tips.2005.08.001

Ermer, J. C., Pennick, M., & Frick, G. (2016). Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy. Clinical Drug Investigation, 36(5), 341. https://doi.org/10.1007/S40261-015-0354-Y

Kim, J. H., Cho, H. T., & Kim, Y. J. (2014). The role of estrogen in adipose tissue metabolism: Insights into glucose homeostasis regulation. In Endocrine Journal (Vol. 61, Issue 11). https://doi.org/10.1507/endocrj.EJ14-0262

McDermott, J. L. (1993). Effects of estrogen upon dopamine release from the corpus striatum of young and aged female rats. In Brain Research (Vol. 606, Issue 1). https://doi.org/10.1016/0006-8993(93)91578-G

Roberts, B., Eisenlohr-Moul, T., & Martel, M. M. (2018). Reproductive steroids and ADHD symptoms across the menstrual cycle. Psychoneuroendocrinology, 88, 105–114. https://doi.org/10.1016/j.psyneuen.2017.11.015

Sahin, N., Altun, H., Kurutaş, E. B., & Fındıklı, E. (2018). Evaluation of estrogen and g protein-coupled estrogen receptor 1 (GPER) levels in drug-naïve patients with attention deficit hyperactivity disorder (ADHD). Bosnian Journal of Basic Medical Sciences, 18(2), 126–131. https://doi.org/10.17305/bjbms.2018.2942

Shoham, Z., & Schachter, M. (1996). Estrogen biosynthesis – Regulation, action, remote effects, and value of monitoring in ovarian stimulation cycles. Fertility and Sterility, 65(4), 687–701. https://doi.org/10.1016/s0015-0282(16)58197-7

Wang, W., Wang, Z., Bai, W., Zhang, H., Ma, X., Yang, M., Wang, K., Zhu, S., Jia, J., & Qin, L. (2014). Effect of low estrogen on neurons in the preoptic area of hypothalamus of ovariectomized rats. Acta Histochemica, 116(8), 1259–1269. https://doi.org/10.1016/j.acthis.2014.07.010

White, T. L., Justice, A. J., & de Wit, H. (2002). Differential subjective effects of D-amphetamine by gender, hormone levels and menstrual cycle phase. Pharmacology, biochemistry, and behavior, 73(4), 729–741. https://doi.org/10.1016/s0091-3057(02)00818-3

Xiao, L., & Becker, J. B. (1998). Effects of estrogen agonists on amphetamine-stimulated striatal dopamine release. In Synapse (Vol. 29, Issue 4). https://doi.org/10.1002/(SICI)1098-2396(199808)29:4<379::AID-SYN10>3.0.CO;2-M