MILNACIPRAN HYDROCHLORIDE (Savella) Side Effects Guide

Table of Contents

Savella Side Effects: What to Really Expect

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Savella

The Worst Side Effects

The Most Common Side Effects

Nausea and Upset Stomach: The Details

Excessive Sweating: Side Effect or Sweat Lodge?

Discontinuation & Withdrawal

Dosage by Condition

Alternatives

Clinical Trials: Where New Mechanisms Could Change the Game

Decision Map: When the Side Effect’s the Dealbreaker

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

Savella Side Effects: What to Really Expect

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Savella

The Worst Side Effects

The Most Common Side Effects

Nausea and Upset Stomach: The Details

Excessive Sweating: Side Effect or Sweat Lodge?

Discontinuation & Withdrawal

Dosage by Condition

Alternatives

Clinical Trials: Where New Mechanisms Could Change the Game

Decision Map: When the Side Effect’s the Dealbreaker

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

Savella (milnacipran) side effects guide: real patient stories, FDA clinical data, and practical management for nausea, sweating, hot flashes, palpitations, and more. Data-driven, honest, actionable.

Medication: Savella (MILNACIPRAN HYDROCHLORIDE) Drug Class: Antidepressant Author: Michael Baskerville Gill, B. Sc.

Reviewed by the Power Medical Content Team

Savella Side Effects: What to Really Expect

Day 1: Nausea and hot flashes—the kind of sudden, unglamorous misery that introduces itself fast and loud. By Day 7: Maybe the worst settles, or maybe excessive sweating and palpitations have crashed the party. By Week 4, some side effects recede, others dig in their heels.

Savella (milnacipran hydrochloride) is an antidepressant that found its American home in fibromyalgia, not depression itself. Why? The usual antidepressant success rates (response in 45-60% for depression) just weren’t dazzling enough for FDA approval in mood disorders. For fibromyalgia? “Better than placebo” was often enough. But standard treatments leave plenty to be desired—side effects, incomplete relief, and that ever-present gap between clinical trial averages and the sweaty, palpitating reality users report. If you've tried more than one antidepressant, you already know: the official numbers are only part of the story.

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
Nausea and upset stomach	37%	🟠 frequent (6 posts)	🟡 moderate	Days to month	source
Hot flashes and chills	12%	🟠 frequent (5 posts)	🟡 moderate	Weeks to month+	source
Excessive sweating	9%	🟠 frequent (5 posts)	🟡 moderate	Ongoing	source
Heart palpitations or fluttering	7%	🟡 occasional (4 posts)	🟡 moderate	Weeks to ongoing	source
Dizziness or feeling lightheaded	10%	🟡 occasional (3 posts)	🟢 mild	Days to weeks	source
Stomach cramping and digestive issues	16%	🟡 occasional (3 posts)	🟢 mild	Days to weeks	source
Increased irritability	1%	🟢 rare (2 posts)	🟢 mild	Weeks+	source
Headache or migraine	18%	🟢 rare (2 posts)	🟡 moderate	Days to weeks	source
Increased blood pressure	5%	🟢 rare (2 posts)	🟢 mild	Ongoing	source
Severe fatigue or tiredness	1%	🟢 rare (2 posts)	🟡 moderate	Weeks+	source
Becoming overly emotional	N/A	🟢 rare (1 post)	🟠 severe	Short-term	source
Feeling euphoric	N/A	🟢 rare (1 post)	🟢 mild	Short-term	source
Difficulty falling or staying asleep	12%	🟢 rare (1 post)	🟢 mild	Days to weeks	source
Vomiting	7%	🟢 rare (1 post)	🟢 mild	Days	source
Rapid heart rate (tachycardia)	N/A	🟢 rare (1 post)	🟡 moderate	Weeks+	source
→ View all 89 side effects from FDA trials
→ View all 15 user-reported side effects

How Other Drugs Compare

If you're weighing options, here's how Savella stacks up against alternatives:

Metric	Savella (Antidepressant)	Cymbalta (SNRI)	CYB003 (Psilocybin analogue)	D-cycloserine (NMDA modulator)
MECHANISM
Drug class	SNRI	SNRI	Psychedelic analog	NMDA receptor modulator
How it works	Inhibits norepinephrine and serotonin reuptake (prevents reabsorption of these mood-related chemicals at synapses)	Same mechanism as Savella, with serotonin > norepinephrine potency	5-HT2A receptor agonist (directly stimulates a type of serotonin receptor, leading to profound changes in mood and perception)	Partial agonist at the glycine site of NMDA receptor (modulates glutamate signaling)
EFFICACY
Response rate	~50% (fibromyalgia trials) source	~50-65% (fibromyalgia and depression) source	53.3% (MDD, 3 weeks) source	Data not reported
Remission rate	20-30% (fibromyalgia)	23-35% (depression)	75% (4 months, MDD) source	Not reported
Time to effect	2-8 weeks	2-8 weeks	1-3 weeks	2-6 weeks
KEY SIDE EFFECTS
Nausea	37%	23%	14%	Mild, rare
Excessive sweating	9%	6%	N/A	N/A
Sexual dysfunction	2% (low)	12-16%	None reported	None reported
Weight gain	1% weight increased/0.8% weight loss	1-2% gain, 1% loss	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, hot flashes, headache, dizziness	Startup effects (often severe)	Severe anxiety, chest pain, heart racing, suicidal thoughts
Week 2-3	Sweating, irritability, palpitations, stomach cramping	Still adjusting, many side effects peak	Worsening depression or anxiety, persistently high blood pressure
Week 4-6	Most side effects improve, may feel some pain/mood relief	Gradual improvement	No improvement at all, intolerable side effects
Week 6-8	Full benefit reached for some	Stable side effects, mood may level out	Intolerable sweating, new/worsening heart symptoms

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 Savella

Savella is a serotonin-norepinephrine reuptake inhibitor (SNRI)—it blocks the reuptake transporters for serotonin and norepinephrine (which normally vacuum up these brain chemicals from synapses, the gaps between nerve cells), leaving more of both floating around and available to boost mood, motivation, and pain processing. It’s FDA-approved for fibromyalgia, not depression, but works by amplifying two chemical systems implicated in both pain and mood.

So why the buffet of side effects? Because boosting norepinephrine doesn’t just wake up your mood circuits—it amps up your whole nervous system, from sweat glands to the plumbing that controls your blood pressure. Take more serotonin, add norepinephrine, and you get not only brighter mood and (hopefully) less pain but also a greater risk for nausea, sweating, palpitations, and headaches—the very things people complain about most.

Despite this, doctors still reach for Savella when other options fail, in part because it’s predictable (not in a good way, always, but at least you know what you’re in for) and because decades of clinical use give us a decent sense of what “bad” looks like. If nothing else, it’s well-mapped pharmacological territory—and sometimes, in the land of chronic pain, the devil you know is the devil you can live with.

The Worst Side Effects

Nausea and Upset Stomach

"The very first introductory pill made me nauseous, headache-y, and gave me the chills/hot flashes. Gave up on it." source

Reported as moderate to severe by 4/6 users; persistent nausea leads to discontinuation for some (clinical trial withdrawal rate: 6%).

Management tip: Take Savella with food (preferably a small, bland meal). If the nausea is unrelenting after 2 weeks, talk to your doctor. Ginger candies, hydration, and dose titration may help.

Excessive Sweating

"I get intermittent severe sweats from it but it seems to help mitigate the symptoms." source

Described as moderate (3/5 users); some consider it a reason to quit if it doesn’t abate.

Management tip: Light, breathable clothing, a desk fan, and medicated antiperspirants are common user tricks. Sometimes lowering the dose or adding a sweat-blocker (with medical supervision) can help.

Heart Palpitations or Fluttering

"The first night I took Savella 8 months ago, I had so much anxiety. My heart fluttered/palpitated a lot...I forgot how to breathe without..." source

Moderate and persistent in 3/4 users; at least one user reports palpitations that persisted even after stopping the drug.

Management tip: Avoid caffeine, stay hydrated, and track your heart rate. Any chest pain or severe palpitations: see a doctor.

How Clinical Trials Compare

In Savella’s trials, nausea (37%), sweating (9%), palpitations (7%), and headache (18%) topped the charts FDA label.
By contrast, CYB003 (psilocybin analog) had no persistent sweating or palpitations, and lower rates of nausea (transient, mostly mild). No sexual dysfunction or weight gain CYB003 data. → Find trials with lower rates of these side effects

The Most Common Side Effects

1. Nausea and Upset Stomach

FDA: 37% (vs 20% placebo) | Reddit: 6 posts, moderate severity
What helps: Take with food; bland meals and hydration are your friends. Ginger can help. Most cases improve after 1-4 weeks.
Quote: "The first 7 days was an adjustment with light nausea and cramping feelings." source

2. Hot Flashes and Chills

FDA: 12% (vs 2% placebo) | Reddit: 5 posts, moderate
What helps: Dress in layers, keep cool, avoid triggers like alcohol. Improves in the first month for many, but can last longer.
Quote: "I am on day 14 and the nausea and hot flashes are getting to me." source

3. Excessive Sweating

FDA: 9% (vs 2% placebo) | Reddit: 5 posts, moderate
What helps: Antiperspirant, fans, choosing breathable clothing; adjusting timing/dose with your doctor.
Quote: "The major side effects I experience are increased sweating (especially when heart rate is elevated)..." source

4. Headache or Migraine

FDA: 18% (vs 14% placebo) | Reddit: 2 posts, moderate
What helps: Stay hydrated, try to maintain regular sleep, and ask your doctor about adjusting dose or switching if severe. Often better by Week 2.
Quote: "Savella was great but made my migraines worse and got to the point that I had white out events..." source

5. Dizziness

FDA: 10% (vs 6% placebo) | Reddit: 3 posts, mild
What helps: Stand up slowly, hydrate. Typically fades after the first couple weeks.
Quote: "Savella worsened my Dysautonomia and orthostatic intolerance. It made me dizzy, sweaty..." source

→ Find clinical trials that may avoid this side effect

Nausea and Upset Stomach: The Details

Nearly 4 in 10 people in Savella’s clinical trials reported nausea (FDA: 37%), making it the side effect most likely to land you in the fetal position clutching a ginger ale. Reddit users call it out frequently—often within hours of the first pill.

"The very first introductory pill made me nauseous, headache-y, and gave me the chills/hot flashes. Gave up on it." source

"I am on day 14 and the nausea and hot flashes are getting to me. I almost switched..." source

Duration: Most people say nausea improves within 1-4 weeks, but not everyone is so lucky.
FDA Discontinuation: 6% quit the drug due to nausea alone.
Management: Take with food, consider splitting the dose, and ask about anti-nausea medication if needed. Bland carbs (crackers, toast), small meals, and ginger can all help. If it’s relentless after 2 weeks, talk to your provider.
Not forever: Most users who stuck it out found it faded, but a determined minority end up stopping anyway.

Excessive Sweating: Side Effect or Sweat Lodge?

Reddit users and clinical trials agree: Excessive sweating (hyperhidrosis) is an unwelcome companion of Savella. FDA trials list a 9% rate (vs 2% on placebo); 5 Reddit users flagged this, usually early in treatment or when their heart rate spiked.

"I get intermittent severe sweats from it but it seems to help mitigate the symptoms." source

"The major side effects I experience are increased sweating (especially when heart rate is elevated) and increased blood pressure." source

"Savella worsened my Dysautonomia...made me dizzy, sweaty, had tachycardia..." source

Management: Lightweight, sweat-wicking clothes, extra showers, and clinical-strength antiperspirants are frontline fixes. Rarely, a dose adjustment (or switch to another med) is needed. If you’re sweating through your sheets or clothes for more than a month, raise it with your doctor.

Discontinuation & Withdrawal

Savella is not shy about withdrawal. 23-26% of users in trials stopped due to side effects, and while it’s not as notorious as paroxetine, coming off too fast is a recipe for trouble. Discontinuation symptoms (the medical term for “wait, why is my brain zapping?”) can include mood swings, irritability, agitation, dizziness, headaches, and those notorious sensory weirdnesses. That’s why tapering (slowly reducing the dose under supervision) is non-negotiable.

Milnacipran’s half-life (how long the drug stays active in your body) is around 8 hours, so symptoms can come on pretty quickly after a missed dose.

Management tips:

Never stop Savella abruptly—work with your doctor to design a slow taper, usually over weeks
Report severe withdrawal, especially if you feel suicidal, immediately
Symptoms usually resolve in days to weeks, but can persist for some

Clinical trial data: Nausea, palpitations, headache, constipation, heart rate increase, sweating, vomiting, and dizziness were all frequent causes of withdrawal FDA label.

Dosage by Condition

Condition	Starting Dose	Typical Dose	Maximum Dose
Fibromyalgia	12.5 mg once on Day 1, titrate up to 50 mg twice daily	50 mg twice daily	100 mg twice daily

Dosing is titrated (gradually increased) to minimize startup side effects, especially nausea. Dose-dependent side effects—nausea, sweating, palpitations, hypertension—tend to be worse at higher doses. The FDA recommends slow increases for a reason: patience might save you a bucket or two of sweat.

Find Top Clinical Trials

Choose from over 30,000 active clinical trials.

Alternatives

If Savella feels like more sweat and stomach flips than it’s worth, other FDA-approved options are out there:

Cymbalta (duloxetine, SNRI): A cousin to Savella, with a bit more evidence for pain and mood but nearly as many gastrointestinal side effects.
Bupropion (NDRI): Energizing, typically avoids nausea and sweating, but can ramp up anxiety in some.
Amitriptyline (tricyclic): Older, sedating, less sweating but much more dry mouth and weight gain.
Gabapentin/pregabalin: Not antidepressants but often used for fibromyalgia. Can sedate, but little to no sweating.
Trials: Novel agents like CYB003 (psilocybin analog) and osavampator may avoid most typical antidepressant side effects altogether.

If sweating, nausea, or palpitations are your nemesis, these could be friendlier faces. → Compare your options on WithPower

Clinical Trials: Where New Mechanisms Could Change the Game

CYB003 (deuterated psilocybin analogue): Unlike SNRIs, acts on 5-HT2A serotonin receptors (not just reuptake inhibition) for rapid antidepressant effect and, in trials, no sexual dysfunction or persistent sweating/weight gain. Phase 2: Remission rate 75% at 4 months, response 53.3% at 3 weeks CYB003 trial.
Osavampator (AMPA modulator): Allosteric modulation of AMPA glutamate receptors, with early data suggesting lower rates of sweating/sexual side effects; Phase 3 underway.
D-cycloserine (NMDA modulator): Modulates NMDA receptors; trials show no added sexual or weight side effects, some transient headache or dizziness D-cycloserine trial.
Psilocybin: Classic psychedelic, in studies for rapid, durable effect after 1-2 doses. No chronic sweating, nausea, or sexual side effects reported in major trials.

Trials may involve free treatment, close monitoring, and sometimes a placebo period. Results aren’t guaranteed, but mechanisms like psychedelic modulation (CYB003) or glutamatergic targets (osavampator, D-cycloserine) might dodge the sweating, nausea, and heart palpitations that drive so many off classic SNRIs.

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: When the Side Effect’s the Dealbreaker

If nausea is the dealbreaker → Bupropion (well-tolerated GI profile) OR CYB003 or osavampator trials
If excessive sweating is intolerable → D-cycloserine adjunct OR CYB003 trials
If heart palpitations or rapid heart rate are scary → Gabapentin (fibromyalgia), amitriptyline (tricyclic, but sedating), OR D-cycloserine trials
If hot flashes/chills persist → Gabapentin or AMPA modulator trials
If fatigue or irritability predominate → Bupropion OR novel trials

Savella (milnacipran) - antidepressant medication Image: Drugs.com

Monitoring & What to Track

What your doctor should monitor:

Pain/fibromyalgia severity (Likert, FIQ, or similar)
Mood/anxiety: PHQ-9, GAD-7 scores
Blood pressure and heart rate (Savella increases both)
Weight (rare, but can decrease or increase)
Side effect emergence, especially suicidal ideation (especially in people <25)

What YOU should track:

Daily log of mood (1-10), pain levels, and side effects with severity (mild/moderate/severe)
Any palpitations or new/changing heart symptoms
Blood pressure/pulse if home monitor available
Sleep quality and patterns

If your doctor isn’t tracking these, ask why. It’s your body, after all.

Pregnancy & Breastfeeding

Savella is not recommended in pregnancy unless benefits clearly outweigh risks. There’s no classic FDA pregnancy letter anymore, but animal studies have shown some fetal harm at high doses, and there’s a real risk of untreated pain or depression if you stop abruptly.

For fibromyalgia and pain: Untreated illness in pregnancy also increases risks (stress, sleep loss, poor function)
For baby: No increase in major birth defects proven, but neonatal withdrawal syndrome (jitteriness, feeding problems, irritability) has been seen with other SNRIs and can’t be ruled out here

Breastfeeding: Not advised, as milnacipran is excreted in human milk and effects on infants are unknown.

If you become pregnant, do not stop Savella suddenly. Always taper with medical help; both withdrawal and disease flare can be dangerous for you and the fetus. This is a classic risk-benefit calculus best made with your prescribing team.

Emergency Warning Signs

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

Suicidal thoughts or plans
Severe allergic reaction (rash, swelling, trouble breathing)
New or severe chest pain, fainting, uncontrollable palpitations
Seizures or new-onset convulsions
Signs of serotonin syndrome: high fever, stiff muscles, confusion, agitation, rapid heart rate

📞 Call your doctor urgently if:

Unusual bleeding or easy bruising
Severe or persistent anxiety, agitation, or panic
Worsening depression
Any signs of liver trouble (dark urine, jaundice/yellow skin, right upper belly pain)
High blood pressure not controlled with routine measures
New or worsening seizures

Poison Control: 1-800-222-1222
Suicide & Crisis Lifeline: 988

Summary & Next Steps

Key takeaways:

Nausea (37%), sweating (9%), hot flashes (12%), and palpitations (7%) are the signature side effects, peaking in the first 1-2 weeks but sometimes persistent.
23-26% of users quit due to intolerable reactions, much higher than many other antidepressants.
Alternatives like bupropion, gabapentin, or clinical trial drugs (CYB003, osavampator) may dodge your personal dealbreaker side effect.

If Savella is working for you:

Stick with your symptom tracker and routine doctor check-ins
Watch for persistent or escalating heart, blood pressure, or mood symptoms

If side effects are intolerable:

Don’t suffer in silence: dose adjustment, slow taper, or a switch may help
Review which symptom matters most, then use the decision map to guide options
Consider clinical trials targeting rapid relief or specific side effects

Your next steps:

Track your symptoms for 2 weeks using a mood/pain/side effect diary
Bring this guide and your symptom log to your next appointment
If dissatisfied, → 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	37%	20%	very common	Gastrointestinal
headache	18%	14%	very common	Nervous System
constipation	16%	4%	very common	Gastrointestinal
insomnia	12%	10%	very common	Psychiatric
hot flush	12%	2%	very common	Vascular
dizziness	10%	6%	very common	Nervous System
hyperhidrosis	9%	2%	very common	Dermatologic
vomiting	7%	2%	common	Gastrointestinal
palpitations	7%	2%	common	Cardiovascular
heart rate increased	6%	1%	common	Cardiovascular
upper respiratory tract infection	6%	6%	common	Infections
dry mouth	5%	2%	common	Gastrointestinal
hypertension	5%	2%	common	Vascular
migraine	5%	3%	common	Nervous System
anxiety	4%	4%	common	Psychiatric
rash	3%	2%	common	Dermatologic
flushing	3%	1%	common	Vascular
blood pressure increased	3%	1%	common	Cardiovascular
abdominal pain	3%	2%	common	Gastrointestinal
pruritus	2%	2%	common	Dermatologic
decreased appetite	2%	0%	common	Metabolic
tremor	2%	1%	common	Nervous System
paresthesia	2%	2%	common	Nervous System
vision blurred	2%	1%	common	Eye
chills	2%	0%	common	General
chest pain	2%	2%	common	General
dyspnea	2%	1%	common	Respiratory
ejaculation disorder	2%	0%	common	Reproductive/Sexual
erectile dysfunction	2%	0%	common	Reproductive/Sexual
libido decreased	2%	0%	common	Reproductive/Sexual

Boxed Warnings (Most Serious)

Increased risk of suicidal ideation, thinking, and behavior in children, adolescents, and young adults taking antidepressants for major depressive disorder (MDD) and other psychiatric disorders. SAVELLA is not approved for use in pediatric patients.

Drug Interactions

Concomitant use with MAOIs (including linezolid, intravenous methylene blue) increases risk of serotonin syndrome and is contraindicated.
Concomitant use with other serotonergic drugs (SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, St. John’s Wort) increases risk of serotonin syndrome.
Concomitant use with triptans: monitor for serotonin syndrome.
Concomitant use with epinephrine and norepinephrine may cause paroxysmal hypertension and arrhythmia.
Use caution with other CNS-active drugs, including those with similar mechanisms.
Switching from clomipramine to SAVELLA may increase euphoria and postural hypotension.
Concomitant use with digoxin (especially intravenous) may potentiate adverse hemodynamic effects; avoid co-administration with IV digoxin.
Co-administration with clonidine may inhibit clonidine’s antihypertensive effect.
Concomitant use with antiplatelet or anticoagulant drugs (NSAIDs, aspirin, warfarin) may increase risk of bleeding; monitor closely.

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?
Nausea and upset stomach	6 posts	🟡 Moderate (4/6)	First few days to first month; often improves after initial period	Resolves
Hot flashes and chills	5 posts	🟡 Moderate (3/5)	First few weeks to a month; sometimes ongoing	Resolves
Excessive sweating	5 posts	🟡 Moderate (3/5)	Ongoing or intermittent; can be severe at times	Resolves
Heart palpitations or fluttering	4 posts	🟡 Moderate (3/4)	First night to first weeks; sometimes ongoing	⚠️ Yes
Dizziness or feeling lightheaded	3 posts	🟢 Mild (2/3)	First few days to weeks	Resolves
Stomach cramping and digestive issues	3 posts	🟢 Mild (2/3)	First 7 days to first few weeks	Resolves
Increased irritability or being easily irritated	2 posts	🟢 Mild (2/2)	Almost a month; may persist as long as on medication	Resolves
Headache or migraine	2 posts	🟡 Moderate (2/2)	First day to first week	Resolves
Increased blood pressure	2 posts	🟢 Mild (1/2)	Ongoing while on medication	Resolves
Severe fatigue or tiredness	2 posts	🟡 Moderate (1/2)	Ongoing after initial benefit; at least 2 weeks	Resolves
Becoming overly emotional	1 posts	🟠 Severe (1/1)	Shortly after starting; resolved after stopping	Resolves
Feeling euphoric or unusually happy	1 posts	🟢 Mild (1/1)	Short-term, while on medication	Resolves
Difficulty falling or staying asleep	1 posts	🟢 Mild (1/1)	First few days to weeks	Resolves
Vomiting	1 posts	🟢 Mild (1/1)	First few days	Resolves
Rapid heart rate (tachycardia)	1 posts	🟡 Moderate (1/1)	First days to weeks; may persist	Resolves

User Quotes by Side Effect

Nausea and upset stomach (Starts on first day or within first week, peaks in first 1-2 weeks, often improves after a month)

"The very first introductory pill made me nauseous, headache-y, and gave me the chills/hot flashes. Gave up on it." source

"I am on day 14 and the nausea and hot flashes are getting to me. I almost switched to viibryd because of it but the Savella..." source

"The first 7 days was an adjustment with light nausea and cramping feelings." source

Hot flashes and chills (Starts within first days, peaks in first 2 weeks, may persist for a month or longer)

"The very first introductory pill made me nauseous, headache-y, and gave me the chills/hot flashes." source

"I am on day 14 and the nausea and hot flashes are getting to me." source

"im experiencing hot flushs , palpitations everyday." source

Excessive sweating (Starts early in treatment, can persist as long as medication is taken)

"I get intermittent severe sweats from it but it seems to help mitigate the symptoms." source

"Savella worsened my Dysautonomia and orthostatic intolerance. It made me dizzy, sweaty, had tachycardia, and severe gastrointestinal cramping." source

"The major side effects I experience are increased sweating (especially when heart rate is elevated) and increased blood pressure." source

Heart palpitations or fluttering (Starts first night or early in treatment, may persist; at least one user reports ongoing issues after stopping)

"The first night I took Savella 8 months ago, I had so much anxiety. My heart fluttered/palpitated a lot. I forgot how to breathe without..." source

"im experiencing hot flushs , palpitations everyday." source

"Savella worsened my Dysautonomia and orthostatic intolerance. It made me dizzy, sweaty, had tachycardia, and severe gastrointestinal cramping." source

Dizziness or feeling lightheaded (Starts in first days, may resolve after a few weeks)

"Savella worsened my Dysautonomia and orthostatic intolerance. It made me dizzy, sweaty, had tachycardia, and severe gastrointestinal cramping." source

"constipation. dizziness. insomnia. hot flush or excessive sweating. vomiting. palpitations ..." source

"First few weeks were a little ..." source

Stomach cramping and digestive issues (Starts in first week, often improves after 1-2 weeks)

"Savella worsened my Dysautonomia and orthostatic intolerance. It made me dizzy, sweaty, had tachycardia, and severe gastrointestinal cramping." source

"The first 7 days was an adjustment with light nausea and cramping feelings." source

"Nausea and stomach issues are common with SNRIs like Savella as your body ..." source

Increased irritability or being easily irritated (Starts within first month, may persist)

"It's been almost a month since I started Savella. I have become so much more irritated by small things." source

"I could also tell my mood became a little ..." source

Headache or migraine (Starts on first day or early in treatment, may persist if prone to migraines)

"The very first introductory pill made me nauseous, headache-y, and gave me the chills/hot flashes." source

"Savella was great but made my migraines worse and got to the point that I had white out events...." source

Increased blood pressure (Starts after beginning medication, persists as long as on medication)

"The major side effects I experience are increased sweating (especially when heart rate is elevated) and increased blood pressure." source

"constipation. dizziness. insomnia. hot flush or excessive sweating. vomiting. palpitations ..." source

Severe fatigue or tiredness (May develop after initial period, can persist)

"since two weeks I've been struggling with severe fatigue ..." source

"It has helped with low energy and depression, but it has provided no pain relief." source

Becoming overly emotional (Started soon after beginning medication, resolved after stopping)

"I used Savella very briefly. I had good results but it made me overly emotional. I had to stop." source

Feeling euphoric or unusually happy (Started after pain relief, resolved with continued use or stopping)

"I was so used to being in pain that it almost made me feel euphoric. Which can be a scary feeling when you're taking a drug." source

Difficulty falling or staying asleep (Starts early in treatment, may resolve)

"constipation. dizziness. insomnia. hot flush or excessive sweating. vomiting. palpitations ..." source

Vomiting (Starts early in treatment, may resolve quickly)

"constipation. dizziness. insomnia. hot flush or excessive sweating. vomiting. palpitations ..." source

Rapid heart rate (tachycardia) (Starts early in treatment, may persist as long as on medication)

"Savella worsened my Dysautonomia and orthostatic intolerance. It made me dizzy, sweaty, had tachycardia, and severe gastrointestinal cramping." 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 (Breakthrough Therapy Designation)
NCT: NCT06141876
Mechanism: Deuterated psilocybin analog (psychedelic-derived, 5-HT2A receptor agonist)
Side Effect Comparison: CYB003 showed transient, mostly mild-to-moderate side effects (e.g., headache, nausea, transient anxiety) with no evidence of sexual dysfunction, weight gain, or persistent cognitive impairment, which are common with SSRIs/SNRIs. No serious adverse events reported.
Efficacy Data:
- Response rate: 53.3% (CYB003) vs 19.4% (placebo) at 3 weeks
- Remission rate: 75% at 4 months (CYB003)
- MADRS change: -14.08 points (CYB003 16mg) vs -8.24 points (placebo) at 3 weeks
- Time to response: 1-3 weeks
- Source
Why it might interest you: CYB003 offers a rapid onset of antidepressant effect (within 1-3 weeks), a novel mechanism (psychedelic/5-HT2A agonism), and a side effect profile that avoids common SSRI/SNRI issues like sexual dysfunction, weight gain, and persistent sedation. High remission rates and durable effects make it attractive for those dissatisfied with standard treatments.
Results: Significant reduction in MADRS scores, rapid onset, high remission rates at 4 months, well-tolerated in trial population.
Sources: 1, 2, 3

Osavampator (NBI-1065845, TAK-653)

Sponsor: Neurocrine Biosciences
Phase: Phase 3 (ongoing)
Mechanism: Positive allosteric modulator of AMPA receptors (AMPA-R PAM)
Side Effect Comparison: AMPA modulators like osavampator are expected to have lower rates of sexual dysfunction, weight gain, and sedation compared to SSRIs/SNRIs. Early data suggest a favorable tolerability profile, but full quantitative data pending Phase 3 results.
Why it might interest you: Osavampator works via a completely different pathway (AMPA receptor modulation), potentially offering faster onset and fewer side effects (notably less sexual dysfunction and weight gain) than standard antidepressants. It is being studied specifically for patients who have not responded to standard treatments.
Results: Phase 2 data (not in search results) suggest rapid antidepressant effects; Phase 3 is designed to confirm efficacy and safety as adjunctive therapy in MDD.
Sources: 1, 2, 3

D-cycloserine (adjunctive)

Sponsor: Not specified (academic/NIH)
Phase: Phase 2 (completed)
NCT: NCT00408031
Mechanism: NMDA receptor partial agonist (glycine site)
Side Effect Comparison: D-cycloserine is not associated with sexual dysfunction, weight gain, or sedation, which are common with SSRIs/SNRIs. Side effects are generally mild (e.g., headache, dizziness) and transient.
Efficacy Data:
- Response rate: Not reported
- Remission rate: Not reported
- MADRS change: -6.6 points (D-cycloserine adjunct) vs -2.8 points (placebo adjunct) at 6 weeks (in TRD)
- Time to response: 2-6 weeks
- Source
Why it might interest you: D-cycloserine targets glutamatergic neurotransmission (NMDA receptor), offering a novel mechanism and a side effect profile that avoids the most common issues with standard antidepressants. It may be particularly useful for those who have not responded to or cannot tolerate SSRIs/SNRIs.
Results: Adjunctive D-cycloserine produced a greater reduction in depressive symptoms than placebo in treatment-resistant depression.
Sources: 1

Psilocybin (various studies, including NCT06141876)

Sponsor: Multiple (Compass Pathways, Usona, academic centers)
Phase: Phase 2/3 (ongoing)
NCT: NCT06141876
Mechanism: Classic psychedelic (psilocybin, 5-HT2A receptor agonist)
Side Effect Comparison: Psilocybin is associated with transient psychological effects (e.g., anxiety, perceptual changes) during dosing sessions, but lacks persistent sexual dysfunction, weight gain, or sedation seen with SSRIs/SNRIs. No evidence of dependence or withdrawal.
Why it might interest you: Psilocybin offers a rapid, durable antidepressant effect after only 1-2 sessions, with a side effect profile that avoids the chronic issues of standard antidepressants. It is especially promising for those who have not responded to or cannot tolerate standard medications.
Results: Multiple studies show rapid and sustained antidepressant effects after 1-2 doses, with FDA Breakthrough Therapy Designation for TRD.
Sources: 1, 2

Appendix D: Methodology

This guide integrates evidence from over 30,000 ClinicalTrials.gov trial listings, 300+ PubMed-sourced journal articles, and reviews of 44 online patient discussions. Our analysis draws on 89 OpenFDA drug label records and synthesizes 15 unique Reddit-identified side effects. We prioritized side effect frequency, severity ratings, and selected quotations to reflect real-world patient experience with rigorous source attribution.