Why Women Get More Side Effects from Psychiatric Medications

If meds feel too strong or unpredictable, you’re not imagining it.

A Story You May Recognize

Julia, 32, started Lexapro (escitalopram), a selective serotonin reuptake inhibitor or SSRI (serotonin-boosting antidepressant), after months of worsening anxiety. Her prescriber told her that the initial dose was “the usual starting dose.”

Within hours, she felt nauseated, jittery, and mentally wired. She spent the night wide awake, fighting the urge to cry.

Her prescriber told her, “That means the medication is kicking in. Try to ride it out.”

But the truth was that the standard starting dose was too high for her physiology. Months later, she retried the medication at half the dose, aligned with her menstrual cycle, and increased the dose slowly over time. It felt like an entirely different drug.

Five Key Factors

Women’s responses to medication can be understood through five interconnected factors:

• Absorption – how your digestive system moves medicine into your bloodstream

• Metabolism – how your liver enzymes break medicine down

• Distribution – how medicine spreads through fat, water, and blood

• Brain response – how your brain reacts to the medication

• Hormones – how estrogen and progesterone alter sensitivity

The Five-Factor Table

Factor	What Changes In Women	How This Alters Medication Effects	Examples You Might Notice
Absorption	Slower gastric emptying (slower stomach emptying)	Higher early peaks for the same dose	Nausea, dizziness, jitteriness, “wired but tired” insomnia in week 1
Metabolism	Cytochrome P450 or CYP450 enzymes (liver drug-breaking proteins) shift with the cycle	Alters blood levels and impact on brain	Liver toxicity, GI side effects and skin rashes
Distribution	Higher body fat and lower total body water	More medicine stored in fat, higher blood levels at the same dose	Prolonged sedation, harsher tapers, “drug hangover” the next morning
Brain Response	Different serotonin dopamine, and GABA (brain-calming chemical) sensitivity	Brain circuits may react more strongly to the same dose	More activation, weight gain, agitation, or inner restlessness
Hormones	Estrogen and progesterone (key female hormones) rise and fall across the cycle	Brain sensitivity and liver metabolism shift week to week	Dose feels fine one week and too strong or too weak the next

It isn’t about women being “sensitive” in a negative way. It’s about how each person processes medicine differently.

Women Absorb Medications Differently

Women tend to have slower gastric emptying – the stomach sends food and medicine forward more slowly. That means a pill can sit longer in the stomach before moving into the intestine, where it is absorbed.

Slower gastric emptying means the drug can linger longer and peak higher for the same dose.

Typical early side effects, especially in week 1:

• Nausea

• Dizziness

• Jitteriness

• “Wired but tired” insomnia

Practical tip: starting at half the usual dose is often a rational, not “overly cautious,” approach.

Women Metabolize Medications at Different Speeds

Drug metabolism is largely driven by CYP450 enzymes, the liver proteins that break medications down. Some of these enzymes, such as CYP3A4 and CYP2D6, are influenced by estrogen and progesterone levels.

That means:

• In some phases of the cycle, your liver clears a drug faster.

• In others, it clears the same drug slower.

  
  

Examples:

Clear faster in many women (may “wear off” sooner):

• BuSpar (buspirone)

• Xanax (alprazolam)

Clear slower in many women (may cause more side effects):

• Paxil (paroxetine)

• Prozac (fluoxetine)

• Seroquel (quetiapine)

• Cymbalta (duloxetine)

Hormone shifts can nudge these enzymes up or down. The same dose can act like two very different doses depending on the month.

Women Distribute Medication Differently

On average, women have:

• Higher body fat percentage – more storage space for fat-soluble drugs

• Lower total body water and smaller blood volume – less fluid to dilute the dose

Consequences:

• Some medicines linger longer in the body.

• The same milligram dose can lead to higher effective blood levels.

• You may experience prolonged sedation, harsher withdrawal during a taper (slow dose reduction), or a “drug hangover” the next morning.

This is not psychological. It is individual biology.

Women’s Brains Respond Differently

Brain chemistry differs between the sexes. Women often have:

• Higher serotonin transporter density (proteins moving serotonin between cells)

• Different dopamine and GABA sensitivity (dopamine helps drive motivation, GABA is a major calming chemical)

  
  

For many women, that means:

• SSRIs and SNRIs – more early activation, nausea, and insomnia

• Stimulants – sharper “crash,” more anxiety or irritability

• Benzodiazepines – stronger sedation and cognitive fog

• Antipsychotics – more akathisia (inner restlessness with urge to move) and weight gain, plus more prolactin changes (hormone that can affect breast tissue and periods)

  
  

The same dose that is fine in a 90-kilogram man can be too intense in a smaller woman with different brain sensitivity and distribution.

Hormones Shape Sensitivity – Dramatically

Women experience fluctuating hormone patterns. Estrogen and progesterone levels rise and fall throughout the menstrual cycle and different life stages. These changes influence both brain circuits and liver enzymes.

• High estrogen mid-cycle (around ovulation) can heighten serotonin sensitivity. SSRIs may feel more activating and cause more insomnia that week.

• High progesterone in the late luteal phase (the week before your period) can increase sedation and cognitive slowing. Sedatives and benzodiazepines may feel heavier or more intoxicating.

• Low estrogen states – during your period, postpartum, and in perimenopause – can make you feel withdrawal-like sensations even at a stable dose: irritability, flu-like feelings, electric-shock sensations, or new dose intolerance.

Visual Guide: Hormone Cycle and Medication Sensitivity

This diagram makes one point clear: if you only look at the prescription and ignore the cycle, you can easily miss why you feel different from week to week.

Tracking your cycle against symptoms often reveals patterns that are invisible if you only track the calendar date.

Life Stages Magnify Differences

Hormones do not just change across one month. They also shift across decades. Each major life stage changes how medication feels.

Life Stage	Biological Shifts	Medication Impact
Pregnancy	Increased blood volume, slower gastric emptying, metabolism shifts	Some medicines need a higher dose, others cause new or stronger effects
Postpartum	Sharp estrogen drop, fragmented sleep, highly reactive anxiety circuits	Doses that felt fine in pregnancy may now feel too strong
Perimenopause	Unstable month-to-month hormone levels, including estrogen swings and irregular ovulation	New insomnia, irritability, and loss of a stable “dose window”

A dose that works in one life stage can become too strong or too weak in the next, even when the milligrams do not change.

A Second Vignette

Danielle, 29, quit three SSRIs because of grogginess and nausea. She concluded: “My body just hates meds.”

But she always started late luteal, the week before her period, when progesterone is high and sedation is stronger, and she always started at a full standard dose.

When she retried escitalopram at one-quarter dose, on day 6 of her cycle, and increased slowly, she tolerated it easily.

Same woman. Same medication. Different plan.

Non-Hormonal Factors That Stack On

Biology is a big part of the story, but not the whole story. Other factors add layers:

• Drug–drug interactions with birth control pills, antibiotics, migraine medicines, and pain medicines

• Alcohol, cannabis, and grapefruit – all of which can change liver metabolism

• Gut issues such as irritable bowel or celiac disease

• Thyroid disorders – underactive or overactive thyroid changes mood and sensitivity

• Iron deficiency and inflammation – both can alter fatigue, mood, and drug response

Most stories of ‘not being able to tolerate meds’ rarely come down to a single factor—they’re usually the result of several factors.

How Women Can Reduce Side Effects

You cannot change your biology, but you can change your medication strategy. Discuss with your prescriber practical, evidence-aligned moves which include:

• Start lower than the standard dose. Half or even one-quarter of the usual starting dose is often a smart and safer way to begin.

• Increase more slowly. Instead of weekly increases, many women do better with changes every 2 to 4 weeks.

• Align dose changes with your cycle. Many women tolerate increases best on days 5 to 10, when estrogen is rising and progesterone is still low.

• Prioritize your sleep. Poor sleep amplifies every side effect.

• Revisit doses during life stage changes. Pregnancy, postpartum, and perimenopause often require fresh planning.

• Review interactions. Bring a full list of medications and supplements to your prescriber, every time.

• 
  

The goal is not to avoid medication. It is to use medication in a way that respects how your body actually works.

FAQs

1. Why do my side effects spike around day 3 to 5 on a new medicine?

That is often when blood levels are reaching steady state (a stable level after repeated doses).

2. Could my genes affect how I metabolize medication?

Yes. Variants in genes like CYP2D6 and CYP2C19 (liver enzyme genes that affect drug breakdown) can make you a rapid or slow metabolizer. Rapid metabolizers may feel the drug “wear off” or be ineffective. Slow metabolizers may feel overstimulated or sedated at doses that seem average on paper.

3. Why do I get withdrawal symptoms even when I taper slowly?

Low-estrogen phases such as during your period, postpartum, or parts of perimenopause can heighten brain sensitivity to serotonin changes. Even a careful taper can feel harsher if the lowest doses overlap with these hormone windows.

4. Is there a “best” antidepressant for women?

There is no single best antidepressant. What matters most is matching the medicine to your symptom pattern, medical history, and life stage, then starting low, adjusting slowly, and aligning with your cycle. Many women do well with medications that have more predictable pharmacokinetics, such as sertraline, escitalopram, or duloxetine, when used in this tailored way.

Further Reading

1. ACOG: Treatment and Management of Mental Health Conditions

   https://www.acog.org/clinical/clinical-guidance

   Excellent overview of pregnancy and postpartum medication considerations.

2. NIMH: Sex Differences in Mental Health Research

   https://www.nimh.nih.gov/health/topics

   Clear discussions of biological differences relevant to mental health.

3. Harvard Women’s Health: Hormones and Medication Response

   https://www.health.harvard.edu

   Readable summaries of how hormonal shifts affect mood and medication effects.

   
   

   Full bibliography available on request

Authorship

Frederic Kass, MD — Professor Emeritus of Psychiatry, Columbia University Medical Center; former Clinical Vice Chair, Department of Psychiatry Profile: Medical News Today

Erica Gettenberg, MD — Board-Certified in Adult, Child, and Adolescent Psychiatry; expertise in mood and anxiety disorders and ADHD. LinkedIn: Erica Gettenberg, MD

All vignettes are fictional and for educational purposes only. This is not a substitute for professional medical advice.