Paroxetine Side Effects Guide

Table of Contents

Paroxetine (Paxil) Side Effects: The Honest Guide

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Paroxetine

The Worst Side Effects

The Most Common Side Effects

Emotional Blunting & Flat Affect

Withdrawal & Discontinuation

Discontinuation & Withdrawal

Dosage by Condition

Alternatives

Clinical Trials

Decision Map

Monitoring & What to Track

Pregnancy & Breastfeeding

Emergency Warning Signs

Summary & Next Steps

Appendix A: FDA Label Data Summary

Appendix B: Reddit User-Reported Side Effects

Appendix C: Clinical Trials with Different Mechanisms

Appendix D: Methodology

Sources

Paroxetine (Paxil) Side Effects: The Honest Guide

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Paroxetine

The Worst Side Effects

The Most Common Side Effects

Emotional Blunting & Flat Affect

Withdrawal & Discontinuation

Discontinuation & Withdrawal

Dosage by Condition

Alternatives

Clinical Trials

Decision Map

Monitoring & What to Track

Pregnancy & Breastfeeding

Emergency Warning Signs

Summary & Next Steps

Appendix A: FDA Label Data Summary

Appendix B: Reddit User-Reported Side Effects

Appendix C: Clinical Trials with Different Mechanisms

Appendix D: Methodology

Sources

Paroxetine (Paxil) side effects guide: real patient experiences, clinical trial stats, and what to expect week by week. Tips for managing withdrawal, weight gain, and alternatives.

Medication: Paroxetine (PAROXETINE HYDROCHLORIDE HEMIHYDRATE) Drug Class: Antidepressant Author: Michael Baskerville Gill, B. Sc.

Reviewed by the Power Medical Content Team

Paroxetine (Paxil) Side Effects: The Honest Guide

Day 1: You swallow the tiny pink pill. Day 2: You feel...not much, maybe a little jittery, maybe a little tired. Day 7: Your stomach is queasy, your appetite has nosedived (or, paradoxically, you're suddenly eyeing your fridge like a competitive eater). By Day 14, some people say they're "emotionally blunted"—not exactly depressed, but not themselves either. For many, the real rollercoaster begins not when you start paroxetine (Paxil), but when you try to stop.

Let's put it in perspective: Antidepressants help millions, but the side effect rates are no joke—26% for nausea, 23% for sleepiness, and up to 28% for sexual problems in men in FDA trials. And Reddit is brimming with "Paxil ruined my libido" and "nightmarish withdrawals" tales. Yet, for every horror story, there's someone quietly managing their symptoms, weighing trade-offs, and just trying to function. This guide won't tell you to "hang in there"—it'll give you the real odds, the worst-case scenarios, and honest takes on what works (and what doesn't) for side effects like weight gain, fatigue, emotional flattening, and the dreaded withdrawal.

Interested in clinical trials? Many trials for depression now target different mechanisms than Antidepressant—potentially offering different side effect profiles. Browse clinical trials →

Side Effects Overview Table

Side Effect	FDA Rate	Reddit Reports	Severity	Duration	Example
Weight gain and increased appetite	1%	🟠 frequent (5 posts)	🟡 Moderate	Weeks to ongoing	"It has been causing me weight gain and makes feel like I'm always constantly hungry."
Sleepiness, fatigue, and tiredness	23% (somnolence)	🟠 frequent (5 posts)	🟡 Moderate	First weeks to months, sometimes ongoing	"I was extremely fatigued and tired the first couple of months, but..."
Emotional blunting and flat affect	0% (not in FDA)	🟠 frequent (5 posts)	🟡 Moderate	Ongoing while on medication	"I became unable to cry, and for a long time I became emotionally empty."
Withdrawal symptoms and discontinuation syndrome	0% (discontinuation syndrome: rare, serious)	🟠 frequent (4 posts)	🟠 Severe	Weeks to months after stopping	"This stuff is VERY hard to stop taking. I get some really weird side-effects."
Nausea and upset stomach	26%	🟡 occasional (3 posts)	🟢 Mild	First 1-2 weeks, sometimes longer	"At first I didn't notice any side effects apart from nausea."
Excessive sweating	11%	🟡 occasional (3 posts)	🟢 Mild	Ongoing	"Sweating constantly, headaches, nausea, stomach aches..."
Digestive system issues (constipation, stomach aches, IBS)	14% (constipation)	🟡 occasional (3 posts)	🟡 Moderate	First 2 weeks to ongoing	"I stopped it as I had severe constipation in the first 2 weeks."
Loss of appetite	6% (decreased appetite)	🟢 rare (2 posts)	🟢 Mild	First weeks, sometimes ongoing	"I've lost my appetite."
Headaches in the first two weeks	18%	🟢 rare (1 post)	🟢 Mild	First two weeks	"Headaches, nausea, stomach aches..."
Difficulty falling or staying asleep	13% (insomnia)	🟢 rare (1 post)	🟡 Moderate	After a few weeks	"Now 3 weeks in I can't sleep, feel really on ..."
Increased anxiety when starting	5%	🟢 rare (1 post)	🟢 Mild	First weeks	"Raise my anxiety."
Memory issues and cognitive impairment	0% (not in FDA)	🟢 rare (1 post)	🟡 Moderate	Long-term, ongoing	"Long term effects I do not experience besides memory issues..."
Demotivation and laziness	0% (not in FDA)	🟢 rare (1 post)	🟡 Moderate	Ongoing	"It was making me feel demotivated and lazy."
Lethargy compared to other SSRIs	0% (not in FDA)	🟢 rare (1 post)	🟢 Mild	First weeks after switch	"Paxil definitely reduced the lethargy side effect..."
Sexual dysfunction and loss of sexual feelings	13% (abnormal ejaculation; up to 28% males), 10% (other male genital disorders), 2% (female)	🟢 rare (1 post)	🟠 Severe	Long-term, ongoing	"SSRIs destroyed my health, my sexual life, my emotions..."

→ View all 149 side effects from FDA trials → View all 15 user-reported side effects

How Other Drugs Compare

If you're weighing options, here's how Paroxetine (Antidepressant) stacks up against alternatives:

Metric	Paroxetine (Antidepressant)	Bupropion (NDRI)	CYB003 (Psilocybin analogue)	Esmethadone (NMDA antagonist)
MECHANISM
Drug class	SSRI	NDRI	Psychedelic analogue	NMDA antagonist
How it works	Inhibits reuptake of serotonin (prevents the brain from reabsorbing the neurotransmitter, increasing its levels in synapses)	Inhibits reuptake of norepinephrine and dopamine	Agonist at 5-HT2A receptor (mimics serotonin at this site, causing downstream effects)	NMDA receptor antagonist (blocks NMDA receptors to modulate glutamate neurotransmission)
EFFICACY
Response rate	54% (depression, typical) source	50-55% (major depression) source	79% at 6 weeks (16mg) source	Not reported
Remission rate	35% (depression, typical) source	33% (major depression) source	75% at 4 months (16mg) source	Not reported
Time to effect	4-6 weeks	2-4 weeks	1-2 weeks	1 week
KEY SIDE EFFECTS
Weight gain	1% (FDA), frequent in user reports	Rare	None reported	None reported
Fatigue	23% (FDA), frequent in user reports	Uncommon	None reported	None reported
Sexual dysfunction	13-28% (FDA), rare in user reports	Rare	None reported	None reported

→ Find clinical trials matched to your situation

Week-by-Week Timeline

Week	Common Experiences	What's Normal	When to Call Your Doctor
Week 1	Nausea, headache, sleepiness, anxiety spike	Startup effects	Severe anxiety, suicidal thoughts
Week 2-3	Fatigue, digestive changes, appetite shifts, sleep disturbance	Still adjusting	Worsening depression
Week 4-6	May start feeling benefits, emotional blunting emerges	Gradual improvement	No improvement at all
Week 6-8	Full effect usually reached, possible weight gain, sweating	Stable	Intolerable side effects

Most side effects peak in Week 1-2 and improve by Week 4. If you're still struggling at Week 8, it may be time to consider alternatives.

→ Explore clinical trials with faster onset

Why Doctors Still Prescribe Paroxetine

Paroxetine works by inhibiting the reuptake of serotonin (a brain chemical that affects mood, sleep, and appetite), keeping more of it available in the synapses (the gaps between nerve cells where signals pass). This excess serotonin boosts mood for many—but, as anyone who's read the fine print knows, the "spray effect" on other serotonin circuits means you also get a greatest-hits medley of side effects, from upset stomach to sexual dysfunction. Why? Because serotonin is everywhere: in your gut, your sweat glands, your libido.

Why do doctors keep writing prescriptions, knowing all this? Three words: safety, predictability, longevity. Paroxetine has decades of data, and for all its side effects, it's familiar. Doctors know how to start, how to titrate (gradually adjust the dose), how to get you off (with pain, but not with medical mysteries). It's not a gentle ride, but it's one with the seatbelts well-tested.

The Worst Side Effects

"I became unable to cry, and for a long time I became emotionally empty. I didn't feel sadness, I didn't feel anger..." source Reported as moderate to severe by 3/5 users. Management tip: Sometimes dose reduction helps, but often the only fix is switching medications. Some users report "feeling themselves" again within a week or two after stopping—though withdrawal is another beast entirely.

Withdrawal Symptoms and Discontinuation Syndrome

"I had all kinds of horrible side effects when I was on paroxetine -- fatigue, brain fog, etc. -- followed by nightmarish withdrawals after I went off it." source Reported as severe or debilitating by 3/4 users. Management tip: Slow, ultra-gradual tapering—over months, not weeks—is crucial. Some users advocate cutting pills into quarters or even eighths. Beware "brain zaps" (electric shock sensations) and severe mood swings.

Sexual Dysfunction and Loss of Sexual Feelings

"SSRIs destroyed my health, my sexual life, my emotions, my feelings, gave me permanent tinnitus, destroyed my cognition, made me stupid, destroyed my eyesight." source Reported as severe by 1/1 user who mentioned it. Management tip: If this emerges, it rarely gets better while on the drug. Strategies include switching to bupropion or trying medication holidays—though the evidence for either is spotty, and never do this without a doctor's guidance.

How Clinical Trials Compare

Trial drugs like CYB003 (psilocybin analogue) show no sexual dysfunction or emotional blunting and only transient nausea/headache (CYB003 results). In contrast, 13–28% of men on paroxetine have sexual dysfunction and up to 23% experience sedation or fatigue. Esmethadone and AMPA modulators report lower rates of sedation, cognitive dulling, and sexual side effects.→ Find trials with lower rates of these side effects

The Most Common Side Effects

FDA: 1% (but Reddit says frequent)
Reddit: 🟡 Moderate, 5 posts
What helps: Some switch to bupropion or focus on meal timing; tracking calories can help.
Timeline: Starts in weeks, often persists.

"It has been causing me weight gain and makes feel like I'm always constantly hungry." source

2. Sleepiness, Fatigue, and Tiredness

FDA: 23% (somnolence)
Reddit: 🟡 Moderate, 5 posts
What helps: Taking at night, splitting dose, caffeine (with caution).
Timeline: Peaks in the first month, sometimes fades.

"I was extremely fatigued and tired the first couple of months." source

3. Emotional Blunting and Flat Affect

FDA: Not measured
Reddit: 🟡 Moderate, 5 posts
What helps: Dose reduction, switching to bupropion, or discontinuing.
Timeline: Persists while on medication.

"I became unable to cry... I became emotionally empty." source

4. Withdrawal Symptoms/Discontinuation Syndrome

FDA: Warns of severe withdrawal with abrupt stop
Reddit: 🟠 Severe, 4 posts
What helps: Slow taper only, doctor supervision
Timeline: Begins in days, can last months

"Nightmarish withdrawals after I went off it." source

5. Nausea and Upset Stomach

FDA: 26% (nausea)
Reddit: 🟢 Mild, 3 posts
What helps: Take with food, ginger, smaller doses
Timeline: Peaks in week 1, resolves by week 2-3 for most

"At first I didn't notice any side effects apart from nausea." source

6. Excessive Sweating

FDA: 11%
Reddit: 🟢 Mild, 3 posts
What helps: Light, breathable clothes, fans, antiperspirants
Timeline: Persists as long as medication is taken for some

"Sweating constantly, headaches, nausea, stomach aches..." source

Emotional Blunting & Flat Affect

"I became unable to cry, and for a long time I became emotionally empty. I didn't feel sadness, I didn't feel anger..." This isn't a rare poetic exaggeration—it's a surprisingly common story in paroxetine Reddit land, with 5 users mentioning emotional blunting as a core issue source. In FDA trials, this symptom is rarely measured directly (the data is essentially 'not assessed'), but patient accounts suggest it runs at least as high as other top side effects.

Mechanistically, it's not mysterious: paroxetine floods the synapses (gaps between nerve cells) with serotonin, which can blunt highs as effectively as lows. One user summed up: "My lows are less low, but my highs are less high also." source

Practical fix? Sometimes a dose reduction helps, but many users only recover after discontinuation—a process that, as you'll read next, is anything but pleasant. There are no reliable add-on treatments for this numbness.

Tips:

Log your emotional state for 2-3 weeks after starting or changing your dose
If you lose the ability to feel joy (or even to cry), discuss other antidepressant classes (e.g., bupropion)
Remember: this effect almost always fades after stopping, but only after weathering withdrawal

Withdrawal & Discontinuation

If there's one thing Paxil is famous for (infamous, really), it's withdrawal. Three out of four users reporting withdrawal described it as severe or even "nightmarish". Official label calls it "discontinuation syndrome" (and gives the classic list: mood swings, dizziness, "brain zaps"). Reddit is blunter: "This stuff is VERY hard to stop taking. I get some really weird side-effects." source

In FDA trials, withdrawal was serious enough to merit black box warnings for abrupt stops, especially compared to other SSRIs. Why is it so bad? Paroxetine's short half-life (how long the drug stays active in your body) means your brain feels the absence quickly. No slow ramp-down—just a serotonin drop-off cliff.

What works?

Taper extremely slowly—think months, not weeks
Cut pills into quarters or smaller, with liquid formulations if possible
Never skip days as a "taper"; keep daily dosing
Always taper under your doctor's supervision

Symptoms timeline:

Start within days of stopping; peak at 1 week; can drag on for months (yes, really)
"Brain zaps," insomnia, irritability, dizziness, and mood swings are classic
For some, the withdrawal is worse than the original symptoms

"Paroxetine has a bad reputation only because of its really hard withdrawal symptoms. It is the most toughest anti-depressant to withdraw from." source

Discontinuation & Withdrawal

Percentage with withdrawal: Exact numbers vary, but studies suggest up to 40-60% of patients experience symptoms when stopping abruptly; higher for paroxetine due to its short half-life (active in your body for only 24 hours or less).
Common withdrawal effects: Mood swings, irritability, agitation, dizziness, sensory shocks ("brain zaps"), anxiety, confusion, insomnia, lethargy, emotional lability, tinnitus. Seizures are rare but possible.
Why it happens: Paroxetine's short half-life leads to rapid drop in serotonin in synapses.
Management tips:
- Taper extremely slowly (months, not weeks), decreasing by 5-10% per step
- Use a pill splitter or ask about liquid formulations for micro-tapering
- Never skip days as a strategy
- Always taper under medical supervision
Timeline: Symptoms typically begin within 1-3 days of dose reduction or stopping, peak by day 7, and can last weeks to months (especially with long-term, high-dose use)

Remember: withdrawal can look like relapse. If in doubt, talk to your doctor—never stop suddenly.

Dosage by Condition

Condition	Starting Dose	Typical Dose	Maximum Dose
Major Depressive Disorder	20 mg/day	20–50 mg/day	50 mg/day
Panic Disorder	10 mg/day	40 mg/day	60 mg/day
Social Anxiety Disorder	20 mg/day	20–50 mg/day	50 mg/day
Generalized Anxiety Disorder	20 mg/day	20–50 mg/day	50 mg/day
Obsessive-Compulsive Disorder	20 mg/day	40 mg/day	60 mg/day
Posttraumatic Stress Disorder	20 mg/day	20–50 mg/day	50 mg/day

Dose-related side effects: Higher doses raise the risk of nausea, somnolence, sexual dysfunction, and discontinuation syndrome.
Titration (gradually adjusting the dose) is recommended; never start high. Dose changes should be slow and with medical oversight.

Find Top Clinical Trials

Choose from over 30,000 active clinical trials.

Alternatives

If the side effects of paroxetine are too much, here are the usual suspects (and what makes them different):

Bupropion: More activating, almost no sexual dysfunction, may cause anxiety, can lead to weight loss—popular for those who want energy back.
SNRIs (venlafaxine, duloxetine): Similar efficacy to SSRIs, slightly higher blood pressure risks, can cause sweating and sometimes nausea.
MAOIs: Old-school, powerful, but tons of food/drug interactions and rarely a first choice.
Mirtazapine: Great for sleep, can cause weight gain, often chosen for insomniac/anxious types who can't tolerate SSRIs.
Spravato (esketamine): Nasal spray, for treatment-resistant depression, rapid acting but access is tightly controlled.
TMS (Transcranial Magnetic Stimulation): Device, not drug; for depression unresponsive to medication.

If weight gain or sexual dysfunction are a dealbreaker, bupropion is often the first consideration. For rapid onset, clinical trials of psilocybin derivatives (CYB003), AMPA modulators, or esmethadone may offer options.

→ Compare your options on WithPower

Clinical Trials

CYB003 (deuterated psilocybin analogue): Acts as a 5-HT2A receptor agonist (activating serotonin receptors that affect mood and perception). In Phase 2, 79% responded and 75% reached remission by 4 months, with no sexual dysfunction, sedation, or weight gain seen in the trial source.
Osavampator (AMPA positive allosteric modulator): Aims for rapid effect (within 2 weeks), minimal sedation or weight/sexual side effects, no dissociation as with ketamine source.
Esmethadone (NMDA antagonist): No dissociation or abuse risk, rapid antidepressant effect (1 week), and low rates of weight, sexual, or cognitive side effects source.
COMP360 (psilocybin): 37% response at 3 weeks, 29% remission—rapid action, no chronic sedation, weight gain, or sexual dysfunction source.

Why join a trial? You might get free treatment, close medical monitoring, and a shot at something that works when nothing else does (but, yes, you could be on placebo, and phase 2 isn't phase 3). These studies target people who haven't done well on or can't tolerate standard antidepressants.

Interested in clinical trials? Many trials for depression now target different mechanisms than Antidepressant—potentially offering different side effect profiles. Browse clinical trials →

Decision Map

If weight gain and increased appetite is the dealbreaker → Bupropion (NDRI) OR CYB003/psilocybin trials

If sleepiness/fatigue is the dealbreaker → Bupropion, SNRIs (venlafaxine) OR osavampator trials

If emotional blunting/flat affect is the dealbreaker → Bupropion OR CYB003 trials

If severe withdrawal is the dealbreaker → Fluoxetine (longer half-life, milder withdrawal) OR COMP360/esmethadone trials

If sexual dysfunction is the dealbreaker → Bupropion, vortioxetine OR psilocybin/esmethadone trials

Paroxetine (Paroxetine) - antidepressant medication Image: Plushcare.com

Monitoring & What to Track

What your doctor should track:

Mood with PHQ-9 or HAM-D (for depression), GAD-7 (for anxiety)
Weight and BMI (especially if weight gain or loss is a concern)
Sexual functioning (ask specifically)
Liver function in long-term/high-dose use
Suicidal ideation, especially in the first month or if under age 25

What you should track:

Mood/anxiety: 1–10 daily score
Side effects: list, severity (0–10), and timing
Sleep quality (hours slept, how rested)
Energy and motivation

If your doctor isn't tracking these, ask them to. Detailed logs help spot side effect patterns early—and can make your next appointment far less awkward.

Pregnancy & Breastfeeding

FDA category: Paroxetine is a pregnancy Category D drug (evidence of human fetal risk), especially associated with cardiac malformations when used in the first trimester.
Risks: First trimester exposure is linked to an increased risk of congenital heart defects; late third trimester exposure can cause withdrawal in the newborn (irritability, feeding difficulties, respiratory distress). SSRIs in general are also associated with low birth weight and, rarely, persistent pulmonary hypertension of the newborn.
Benefits: Untreated depression/anxiety can be dangerous in pregnancy—there is no zero-risk option.
Breastfeeding: Paroxetine is considered one of the safer SSRIs if an antidepressant is needed during breastfeeding (low infant plasma levels, few reported adverse effects), but data is still limited.
Key message: All decisions about use in pregnancy or while breastfeeding should be made with your doctor. Do not stop suddenly if you become pregnant—always taper with medical guidance.

Emergency Warning Signs

⚠️ Call 911 or go to ER immediately if you experience:

Suicidal thoughts or plans
Signs of serotonin syndrome: agitation, hallucinations, rapid heartbeat, fever, muscle stiffness, coordination problems
Severe allergic reaction: rash, swelling, difficulty breathing

📞 Call your doctor urgently if:

Unusual bleeding or bruising (possible low platelet count)
Severe anxiety, restlessness, or agitation
Worsening depression
New or worsening seizures
Poison Control: 1-800-222-1222
Suicide Prevention Lifeline: 988

These aren't exhaustive lists—if something feels wrong or dangerous, trust your gut and seek help.

Summary & Next Steps

Key takeaways: Paroxetine helps many, but weight gain (frequent), sleepiness/fatigue (23%), emotional blunting, and severe withdrawal are common challenges. If the drug works and side effects are tolerable, keep tracking symptoms and consider a gradual taper only with your doctor's help.

If Paroxetine is working for you: Monitor weight, mood, and sexual side effects. Watch for emotional numbness. Stay in touch with your doctor, especially if you plan any dose change.

If side effects are intolerable: Consider switching to alternatives like bupropion, SNRIs, or mirtazapine—or join a clinical trial targeting the symptoms you hate most. Slow taper is a must for coming off paroxetine.

Your next steps:

Track your symptoms for 2 weeks using a mood and side effect diary
Discuss this guide and your log with your doctor at your next appointment
If considering alternatives or new trials, → explore clinical trials

→ Find clinical trials matched to your situation

Appendix A: FDA Label Data Summary

Adverse Reactions by Prevalence (Clinical Trial Data)

Side Effect	Drug Rate	Placebo Rate	Category	System
nausea	26%	9%	very common	Gastrointestinal
somnolence	23%	9%	very common	Nervous System
dry mouth	18%	12%	very common	Gastrointestinal
headache	18%	17%	common	Nervous System
asthenia	15%	6%	very common	Metabolic
constipation	14%	9%	very common	Gastrointestinal
insomnia	13%	6%	very common	Nervous System
dizziness	13%	6%	very common	Nervous System
abnormal ejaculation	13%	0%	very common	Reproductive/Sexual
diarrhea	12%	9%	common	Gastrointestinal
sweating	11%	2%	very common	Dermatologic
other male genital disorders	10%	0%	very common	Reproductive/Sexual
tremor	8%	2%	very common	Nervous System
respiratory disorder	7%	5%	common	Respiratory
decreased appetite	6%	2%	very common	Metabolic
infection	6%	4%	common	Infection
nervousness	5%	3%	very common	Nervous System
anxiety	5%	3%	common	Psychiatric
dysmenorrhea	5%	4%	common	Reproductive/Sexual
libido decreased	4%	2%	very common	Reproductive/Sexual
yawn	4%	0%	very common	Respiratory
flatulence	4%	2%	common	Gastrointestinal
paresthesia	4%	2%	common	Nervous System
blurred vision	4%	1%	common	Special Senses
abnormal dreams	4%	1%	common	Nervous System
abnormal vision	4%	2%	common	Special Senses
sinusitis	4%	3%	common	Respiratory
palpitation	3%	1%	common	Cardiovascular
vasodilation	3%	1%	common	Cardiovascular
urinary frequency	3%	1%	common	Urogenital

Boxed Warnings (Most Serious)

Suicidal thoughts and behaviors: Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. Paroxetine tablets are not approved for use in pediatric patients.

Drug Interactions

Monoamine oxidase inhibitors (MAOIs): Risk of serotonin syndrome. Contraindicated.
Pimozide and thioridazine: Increased risk of QT prolongation and ventricular arrhythmias. Contraindicated.
Other serotonergic drugs (SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, St. John’s Wort): Increased risk of serotonin syndrome.
Antiplatelet agents and anticoagulants (aspirin, clopidogrel, heparin, warfarin): Increased risk of bleeding.
Drugs highly bound to plasma protein (e.g., warfarin): May increase free concentrations of paroxetine or other drugs.
Drugs metabolized by CYP2D6 (propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine, risperidone): Paroxetine is a CYP2D6 inhibitor; may increase exposure of these drugs.
Tamoxifen: Paroxetine may reduce efficacy of tamoxifen by reducing active metabolite (endoxifen) levels.
Fosamprenavir/ritonavir: May decrease plasma levels of paroxetine.

Appendix B: Reddit User-Reported Side Effects

Data extracted from Reddit discussions. Counts show how many posts/comments mentioned each side effect.

Side Effect	Mentions	Severity	Duration	Persists?
Weight gain and increased appetite	5 posts	🟡 Moderate (3/5)	Ongoing for many; some report it starts within weeks and persists as long as medication is taken	Resolves
Sleepiness, fatigue, and tiredness	5 posts	🟡 Moderate (3/5)	First weeks to months, sometimes ongoing	Resolves
Emotional blunting and flat affect	5 posts	🟡 Moderate (3/5)	Ongoing while on medication; some report it lasting months	Resolves
Withdrawal symptoms and discontinuation syndrome	4 posts	🟠 Severe (3/4)	Withdrawal symptoms can last weeks to months after stopping	⚠️ Yes
Nausea and upset stomach	3 posts	🟢 Mild (2/3)	First 1-2 weeks, sometimes longer	Resolves
Excessive sweating	3 posts	🟢 Mild (2/3)	Ongoing while on medication	Resolves
Digestive system issues (constipation, stomach aches, IBS)	3 posts	🟡 Moderate (2/3)	First 1-2 weeks, sometimes ongoing	Resolves
Loss of appetite	2 posts	🟢 Mild (1/2)	First weeks, sometimes ongoing	Resolves
Headaches in the first two weeks	1 posts	🟢 Mild (1/1)	First two weeks	Resolves
Difficulty falling or staying asleep	1 posts	🟡 Moderate (1/1)	After a few weeks	Resolves
Increased anxiety when starting	1 posts	🟢 Mild (1/1)	First weeks	Resolves
Memory issues and cognitive impairment	1 posts	🟡 Moderate (1/1)	Long-term, ongoing	Resolves
Demotivation and laziness	1 posts	🟡 Moderate (1/1)	Ongoing while on medication	Resolves
Lethargy compared to other SSRIs	1 posts	🟢 Mild (1/1)	First weeks after switching from another SSRI	Resolves
Sexual dysfunction and loss of sexual feelings	1 posts	🟠 Severe (1/1)	Long-term, ongoing	Resolves

User Quotes by Side Effect

Weight gain and increased appetite (Often starts within first few weeks, persists as long as medication is taken, no clear resolution unless stopped)

"It seems to help my anxiety but I'm trying to ween off of it cause it has been causing me weight gain and makes feel like I'm always constantly hungry." source

"Side effects- sleepiness and some weight gain (as with any ssri)." source

"Does anyone take Paxil and like it? Is weight gain guaranteed to happen? Please share your Paxil experience whether good or bad." source

Sleepiness, fatigue, and tiredness (Starts within first days to week, peaks in first month, may improve after several weeks but can persist)

"It will make sedated first month. I took paroxetine 30 mg." source

"It took more than 12 weeks for me to feel the full effect of paroxetine. I was extremely fatigued and tired the first couple of months, but..." source

"I had all kinds of horrible side effects when I was on paroxetine -- fatigue, brain fog, etc." source

Emotional blunting and flat affect (Can start within first week, persists as long as medication is taken, no clear resolution unless stopped)

"Now, as for the side effects, I became unable to cry, and for a long time I became emotionally empty. I didn't feel sadness, I didn't feel anger..." source

"BF started Paroxetine 1 week ago, says he has zero ... Now he says “I don't feel anything for you anymore” - completely flat, no emotion." source

"My lows are less low, but my highs are less high also." source

Withdrawal symptoms and discontinuation syndrome (Begins within days of stopping, peaks in first week, can persist for weeks to months)

"This stuff is VERY hard to stop taking. I get some really weird side-effects." source

"I had all kinds of horrible side effects when I was on paroxetine -- fatigue, brain fog, etc. -- followed by nightmarish withdrawals after I went off it." source

"Paroxetine has a bad reputation only because of its really hard withdrawal symptoms. It is the most toughest anti-depressant to withdraw from." source

Nausea and upset stomach (Starts within first days, peaks in first week, often resolves by week 2-3)

"Ive been on 3 and a half weeks now of Paroxetine 10mg. At first I didn't notice any side effects apart from nausea." source

"The first two weeks on Paroxetine 30mg were like hell: horrible sleep, sweating constantly, headaches, nausea, stomach aches, ..." source

Excessive sweating (Can start within first week, may persist as long as medication is taken)

"The first two weeks on Paroxetine 30mg were like hell: horrible sleep, sweating constantly, headaches, nausea, stomach aches, ..." source

"Seriously concerned about: weight gain, addition, being so "happy" that I lose the brain/mouth filter, sweating (I already sweat a ton in the ..." source

Digestive system issues (constipation, stomach aches, IBS) (Starts within first days, peaks in first 2 weeks, may resolve or persist)

"I stopped it as I had severe constipation in the first 2 weeks." source

"The first two weeks on Paroxetine 30mg were like hell: horrible sleep, sweating constantly, headaches, nausea, stomach aches, ..." source

"I've been on Paxil for a couple months now and when I first started taking it, it did mess up my digestive system and raise my anxiety." source

Loss of appetite (Starts within first week, may resolve or persist)

"I'm only on 10mg, I've lost my appetite." source

Headaches in the first two weeks (Starts within first days, peaks in first week, resolves by week 2)

"The first two weeks on Paroxetine 30mg were like hell: horrible sleep, sweating constantly, headaches, nausea, stomach aches, ..." source

Difficulty falling or staying asleep (Starts after a few weeks, may persist)

"Now 3 weeks in I cant sleep, feel really on ..." source

Increased anxiety when starting (Starts in first week, may resolve after a few weeks)

"I've been on Paxil for a couple months now and when I first started taking it, it did mess up my digestive system and raise my anxiety." source

Memory issues and cognitive impairment (Develops over long-term use, persists as long as medication is taken)

"Long term effects I do not experience besides memory issues, depression, and instrusive thoughts." source

Demotivation and laziness (Starts after beginning medication, persists as long as medication is taken)

"I was on Paroxetine (Paxil) for a month for mild anxiety but decided to come off it because the it was making feel demotivated and lazy." source

Lethargy compared to other SSRIs (Noted after switching from another SSRI, may resolve after a few weeks)

"The Paxil definitely reduced the lethargy side effect our dog had on Prozac though. She started playing ball again a few weeks after the switch ..." source

Sexual dysfunction and loss of sexual feelings (Develops over long-term use, persists as long as medication is taken)

"SSRIs destroyed my health, my sexual life, my emotions, my feelings, gave me permanent tinnitus, destroyed my cognition, made me stupid, destroyed my eyesight." source

Appendix C: Clinical Trials with Different Mechanisms

These trials target mechanisms different from Antidepressant. Phase 2 results do not guarantee Phase 3 success.

CYB003 (deuterated psilocybin analog)

Sponsor: Cybin Inc.
Phase: Phase 2
NCT: NCT05385783
Mechanism: Deuterated psilocybin analog (psychedelic-derived, 5-HT2A receptor agonist)
Side Effect Comparison: Transient mild-to-moderate headache and nausea most common; no sexual dysfunction, weight gain, or sedation reported (unlike SSRIs/SNRIs); no serious adverse events reported in trial.
Efficacy Data:
- Response rate: 79% (CYB003 16mg) at 6 weeks
- Remission rate: 75% (CYB003 16mg) at 4 months
- MADRS change: -14.08 points (CYB003 16mg) vs -8.24 (placebo) at 6 weeks
- Time to response: 1-2 weeks
- Source
Why it might interest you: Rapid onset of action, high remission rates, and a side effect profile lacking common SSRI/SNRI issues (sexual dysfunction, weight gain, sedation). Novel mechanism may help those not responding to or intolerant of standard antidepressants.
Results: Significant and rapid reduction in depressive symptoms; 75% remission at 4 months; rapid onset (within 1-2 weeks)
Sources: 1, 2, 3

Osavampator (NBI-1065845, TAK-653)

Sponsor: Neurocrine Biosciences
Phase: Phase 3
Mechanism: AMPA receptor positive allosteric modulator (AMPA-PAM)
Side Effect Comparison: No significant increase in weight gain, sexual dysfunction, or sedation compared to placebo; side effect profile appears favorable vs SSRIs/SNRIs.
Efficacy Data:
- Response rate: Not reported
- Remission rate: Not reported
- MADRS change: -14.3 (osavampator) vs -10.1 (placebo) at 6 weeks (Phase 2)
- Time to response: 2 weeks (significant separation from placebo)
- Source
Why it might interest you: AMPA modulation is a novel, non-monoaminergic mechanism with rapid onset and a side effect profile that may avoid sexual dysfunction, weight gain, and sedation common with standard antidepressants.
Results: Statistically significant improvement in depressive symptoms vs placebo; rapid onset (2 weeks)
Sources: 1, 2, 3

Esmethadone (REL-1017)

Sponsor: Relmada Therapeutics
Phase: Phase 3
NCT: NCT04855747
Mechanism: NMDA receptor antagonist (non-ketamine, esmethadone)
Side Effect Comparison: No dissociation, psychotomimetic effects, or abuse potential seen with ketamine/esketamine; no significant weight gain, sexual dysfunction, or sedation (unlike SSRIs/SNRIs).
Efficacy Data:
- Response rate: Not reported
- Remission rate: Not reported
- MADRS change: -15.2 (esmethadone) vs -9.5 (placebo) at 4 weeks (Phase 2)
- Time to response: 1 week (significant separation from placebo)
- Source
Why it might interest you: NMDA antagonism offers rapid antidepressant effects without the dissociation or abuse risk of ketamine, and with fewer side effects than standard antidepressants.
Results: Rapid and significant reduction in depressive symptoms; well-tolerated in trials
Sources: 1, 2

Psilocybin (COMP360)

Sponsor: COMPASS Pathways
Phase: Phase 3
NCT: NCT06141876
Mechanism: Classic psychedelic (5-HT2A receptor agonist, psilocybin)
Side Effect Comparison: Transient headache, nausea, and anxiety during dosing session; no sexual dysfunction, weight gain, or chronic sedation (unlike SSRIs/SNRIs). No evidence of dependence or withdrawal.
Efficacy Data:
- Response rate: 37% (psilocybin 25mg) vs 18% (placebo) at 3 weeks
- Remission rate: 29% (psilocybin 25mg) vs 8% (placebo) at 3 weeks
- MADRS change: -16.2 (psilocybin 25mg) vs -5.4 (placebo) at 3 weeks (COMPASS Pathways Phase 2b)
- Time to response: 1-2 days (peak effect), sustained for weeks
- Source
Why it might interest you: Single or few doses can produce rapid and sustained antidepressant effects, with a side effect profile that avoids the chronic issues of standard antidepressants.
Results: Rapid, robust reduction in depressive symptoms; significant remission and response rates
Sources: 1, 2

Appendix D: Methodology

Our review involved analyzing 30,000+ clinical trial listings from ClinicalTrials.gov, 300+ PubMed-indexed articles, and evaluating 50 online patient discussions, together with 149 side effect entries from OpenFDA Drug Label data. We identified 15 distinct adverse effects and ranked them by frequency in both trials and user reports. Severity, duration, and key user quotations were then assessed to provide an accurate, patient-centered profile of paroxetine's side effects.