Once in a while, the “whore for <insert thing>” part of me gets a random flash of inspiration to delve deeply into research because I have an insatiable desire to know “why it do dis?!”

Today’s Inspiration?! Why the hell does my body keep – repeatedly – rejecting medications (specifically after having my period)? For about three years now, I’ve been trying medications for my Treatment Resistant (why, tho?!) Major Depressive Disorder with Anhedonia, anxiety, and recently (finally) diagnosed [c]PTSD. Some of them gave me side effects that weren’t tenable – so those got stopped asap. Some of them worked a little bit, plateaued, got upped, plateaued, got upped to full strength, then may or may not have worked decently for a couple of months and BAM – end of period and they suddenly stopped working. A couple of them have lasted longer than 2 months: one of them worked JUST for my anxiety (though it was for that plus pain/depression) and I was taken off it soon after moving here, so that I could have less medications; the other is what I am currently taking that has recently seemed to have stopped working – shocker, immediately after my last period ended (Sunday Fun Day).

And now, join me for some educational shenanigans (if ya wanna)!

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First Google Search: “why did my medication stop working after my period“

Your medication may stop working after your period because fluctuating hormone levels, particularly the drop in estrogen and dopamine before and during menstruation, can impact the effectiveness of certain medications, especially for conditions like ADHD. This is a well-documented phenomenon for many individuals with ADHD, and adjusting medication dosage around your cycle can often improve efficacy. 

How Hormonal Changes Affect Medication

• Estrogen and Dopamine Fluctuations: Before and during a period, estrogen and progesterone levels are at their lowest. This can lead to a drop in dopamine, a neurotransmitter that is significantly affected by hormonal changes. 
• Impact on Conditions: The decrease in these hormones and neurotransmitters can affect brain functions such as executive functioning, emotional regulation, attention, and motivation, which can make symptoms of ADHD worse. 
• Reduced Medication Effectiveness: This hormonal shift can decrease the effectiveness of medications that target these neurotransmitters, leading to symptoms returning or feeling more pronounced. 

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Thoughts: Ok, so even though I’m not officially diagnosed with ADHD (the Inattentive type)… here’s yet another sign pointing to the suspicions I’ve had for years now. All the same, this isn’t quite what I’m looking for…

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Second Google Search: “why does my body reject medications“

The sensation of your body “rejecting” a medication can be caused by a drug allergy, an intolerance, or genetic factors affecting how you metabolize the drug. The term rejection is most commonly used to describe the immune system’s response to an organ transplant, so it is important to distinguish the specific type of reaction to medication.

(Skipping both Drug Allergy and Drug Intolerance, based on symptoms of these – which I am not encountering)

Genetic variations in metabolism

Genetic differences, a field of study called pharmacogenetics, can affect how your body processes medication. Your body might metabolize a drug too slowly, causing it to build up in your system and lead to toxicity, or too quickly, preventing it from reaching an effective level. 

• Slow metabolizers: An enzyme that breaks down medication may work too slowly, causing the drug to accumulate and increasing the risk of severe side effects, even at a normal dose.
• Rapid metabolizers: If your body metabolizes a drug too quickly, the medication may be cleared from your system before it has a chance to work effectively. In these cases, a standard dose may offer little to no therapeutic benefit. 

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Thoughts: Ugh. Metabolizing. I definitely don’t think that it’s a slow metabolization. As for “rapid” – I suppose this could be a thing, but… I’m not quite sure. Have to do more research on that. Also, I had to Google “metabolization” since WP thought it was spelled wrong or something, but the results of that search looks like I may have to jump down that rabbit hole, too, because:

Metabolism of substances like drugs:

• Detoxification: The liver and other tissues use enzymes to metabolize drugs and other foreign chemicals (xenobiotics) into less toxic forms. 
• Inactivation: The process can inactivate active drugs so that they can be easily removed from the body through urine or feces. 
• Activation: In some cases, metabolism activates a “prodrug” into its active therapeutic form. 
• Excretion: Metabolization makes compounds more water-soluble and polar, which is crucial for the body to efficiently excrete them. 

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Third Google Search: “can menstruation cause medications to stop working“

Yes, fluctuations in hormones during the menstrual cycle, particularly estrogen levels, can affect how some medications work, potentially causing them to be less effective. While research on this topic is still limited and results are often contradictory, it’s recognized that hormonal changes might influence drug absorption, distribution, metabolism, or excretion. A common example is with ADHD medications, where lower estrogen levels before a period might lead to worsening symptoms and a perceived decrease in medication effectiveness. 

How Hormonal Changes Can Impact Medications

• Pharmacodynamics: The menstrual cycle’s hormonal shifts, especially those in estrogen, can influence how a medication interacts with the body’s receptors, potentially altering its effectiveness. 
• Pharmacokinetics: Hormonal changes can also impact how the body handles a drug—how it’s absorbed, distributed, metabolized, or excreted. 
• Disease Severity: Hormone fluctuations can also directly worsen the severity of certain conditions, leading to more pronounced symptoms despite consistent medication use. 

Examples of Medications Affected by the Menstrual Cycle

• ADHD Medications: Studies suggest that stimulant medications may be less effective when combined with lower levels of estrogen, which occur in the days leading up to a period. This can result in increased difficulty concentrating and more pronounced ADHD symptoms. 
• Other Medications: While specific research is lacking, the general scientific understanding is that menstrual cycle hormones could influence other medications by altering the body’s ability to process them. 

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Thoughts: Ok, now we’re getting closer to something tangible, but… feckin damnit to “research on this topic is still limited and results are often contradictory” and “specific research is lacking.” Also, ADHD being mentioned again. HOWEVER! Now we have a our next search!

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Fourth Google Search: “menstrual cycle hormones could influence other medications by altering the body’s ability to process them“

Yes, the hormonal shifts of the menstrual cycle can influence how the body processes certain medications by altering their absorption, distribution, metabolism, and elimination. However, the data on this effect is often limited and sometimes contradictory, so any clinical effects are often inconsistent and not fully understood. 

Mechanisms of interaction

• Changes in metabolism: The primary way hormones affect medication processing is by altering the activity of liver enzymes, particularly the cytochrome P450 (CYP450) enzyme family, which is responsible for breaking down many drugs.
  • Estrogen: High estrogen levels can either inhibit or induce certain CYP450 enzymes, such as CYP1A2. The changes in enzyme activity can cause the metabolism of some drugs to slow down, potentially increasing their concentration in the body and the risk of side effects.
  • Progesterone: During the luteal phase (after ovulation), when both estrogen and progesterone are high, the metabolism of some medications may slow. Progesterone can also inhibit specific drug-metabolizing enzymes.
• Altered absorption: Hormonal fluctuations can impact the speed of gastrointestinal motility and the production of gastric acid. These changes can affect how quickly and how much of an orally administered drug is absorbed into the bloodstream.
• Modified distribution: Sex hormones can influence the ratio of fat to lean mass and the amount of water retention. Since many drugs are either fat-soluble (lipophilic) or water-soluble (hydrophilic), these body composition changes can alter how medications are distributed throughout the body and affect their elimination.
• Competition for proteins: Hormones can compete with medications for binding to plasma proteins, which are important for drug transport. This competition may result in a greater concentration of “free” (unbound) drug in the bloodstream, increasing its effect. 

Medication responses that can be affected

Clinical research on this topic is still evolving, but some studies have indicated potential menstrual cycle influences on the effects of certain medications, such as:

• Psychotropic stimulants: Some studies suggest that the reinforcing and euphoric effects of drugs like cocaine and amphetamines are stronger during the follicular phase, when estrogen levels are higher, compared to the luteal phase.
• Opioid analgesics: Research on opioids and the menstrual cycle is mixed. Some findings suggest greater pain-blocking effects and side effects from morphine during the follicular phase, while other studies have found no difference.
• Medications for chronic conditions: Some health conditions, like epilepsy or schizophrenia, can have symptoms that fluctuate with the menstrual cycle. These hormonal changes may alter a person’s response to medication, potentially requiring adjusted dosing strategies. For example, the symptoms of schizophrenia may change throughout the ovulatory cycle, leading to different medication responses. 

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Thoughts: Oooooh… what’s dis? I have never heard of “cytochrome P450 (CYP450) enzyme family” – my interest is piqued…

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NEXT GOOGLE SEARCH: “cytochrome P450 (CYP450) enzyme family“

The Cytochrome P450 (CYP450) enzyme family is a large group of heme-containing proteins that primarily catalyze the oxidation of a wide variety of endogenous substances (like cholesterol and hormones) and xenobiotics (such as drugs and toxins) through Phase I metabolism. These enzymes, mostly located in the liver’s endoplasmic reticulum, add or unmask polar functional groups to make substances more water-soluble, facilitating their excretion. The term “P450” comes from their characteristic light absorption peak at 450 nm when reduced and bound to carbon monoxide. 

Key Aspects of CYP450 Enzymes

• Phase I Metabolism: CYP450s are crucial for the first phase of drug metabolism, breaking down substances into more polar and water-soluble metabolites. 
• Substrate Diversity: They metabolize not only drugs and chemicals but also vital endogenous compounds, including lipids, steroids, and hormones.
• Drug-Drug Interactions: Many drugs rely on CYP450 enzymes for their breakdown, making the enzymes a common site of drug-drug interactions, where one drug can inhibit or induce the activity of another CYP enzyme.
• Genetic Polymorphism: Genetic variations in CYP enzymes can influence a patient’s response to medications, affecting drug effectiveness and potentially leading to adverse reactions.
• Heme Cofactor: Each CYP enzyme contains a heme group, which is essential for the catalytic process of adding an oxygen atom to the substrate. 
• Location: They are predominantly found in the liver‘s microsomes (pinched-off parts of the smooth endoplasmic reticulum), but also in other cells. 
• Naming Convention: The numerous CYP genes are organized into families and subfamilies based on similarities in their amino acid sequences. 

Role in Human Health

• Drug Metabolism: They are the primary enzymes responsible for the metabolism of a vast number of drugs, which is why understanding their activity is critical in pharmacology. 
• Endogenous Compound Synthesis: CYP enzymes are involved in the synthesis of vital endogenous compounds, such as cholesterol, steroids, and prostaglandins.
• Physiological Homeostasis: By metabolizing endogenous substances, CYP450s help maintain physiological balance within the body.
• Disease: Dysregulation or genetic variations in CYP enzymes can lead to endocrine disorders and influence the development of various diseases. 

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Thoughts: Bruuuuh. This hurts muh poor brains. We are now at the point where I will need to look up a lot of terminology in order to comprehend what this is actually saying, and I’ve hit my limit in brain processing power (it’s time to eat something and take my morning meds – for what good that will do, at this point). However, I will come back to this very soon – because I see my primary doctor this Wednesday and want to have some search results and questions on how we can go about figuring this shit out so I don’t have to keep suffering and losing the efficacy of medications. This Trintellix I’m on has had the most positive results out of all the things I’ve tried (specifically for the Anhedonia!) and I’ll be damned if I have to stop taking it and try something else again.

So yeah… hopefully, with more research and my doctor’s assistance, we can find some answers?!

Stay tuned…