NEFAZODONE HYDROCHLORIDE (Serzone) Side Effects Guide

Table of Contents

Intro

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Serzone

The Worst Side Effects

The Most Common Side Effects

Drowsiness and Sedation

Nausea and Upset Stomach

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

Intro

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Serzone

The Worst Side Effects

The Most Common Side Effects

Drowsiness and Sedation

Nausea and Upset Stomach

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

Serzone (nefazodone) has a unique antidepressant profile: common side effects include drowsiness, headache, nausea, and rare but serious liver risks. Learn what to expect week by week, how side effects compare to newer trials, and real patient tips for managing them.

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

Reviewed by the Power Medical Content Team

Intro

Day 1: The drowsiness is real, your eyelids feel weighted. Day 5: Maybe you’re just foggy…or maybe you can’t remember the last time you salivated. Day 10: The weird moodiness? Still there. But you haven’t had a panic spiral in four days, either.

Serzone (generic: nefazodone) isn’t your typical antidepressant—its mechanism is a twist on serotonin and norepinephrine, and it was almost erased from the market by a rare, dramatic side effect: liver failure. Most people, thankfully, will never meet that risk face-to-face. Instead, they’ll battle the usual antidepressant startup suspects: drowsiness, headaches, dry mouth, nausea, and sometimes a restless, jittery undercurrent.

Standard treatments for depression and anxiety remain hit-or-miss: remission rates hover around 30–40% for any single medication, and most people will try at least two different drugs before finding the right fit (source). Antidepressants like nefazodone promise another path for those burned by sexual dysfunction or weight gain from SSRIs—but they come with baggage. Knowing what that baggage looks like, how common it really is, and how people actually cope is the key.

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
Drowsiness and sedation	25%	🔴 very_frequent (8 posts)	🟢 Mild	1-3 weeks	source
Headaches, sometimes pounding or severe	36%	🟠 frequent (4 posts)	🟢 Mild	1-3 weeks	source
Nausea and upset stomach	22%	🟠 frequent (4 posts)	🟢 Mild	1-3 weeks	source
Fatigue and low energy	11% (asthenia)	🟡 occasional (3 posts)	🟢 Mild	1-3 weeks	source
Cognitive slowness and trouble thinking	3% (concentration decreased)	🟢 rare (2 posts)	🟢 Mild	1-2 weeks	source
Extremely dry mouth	25%	🟢 rare (2 posts)	🟢 Mild	1-2 weeks	source
Slight increase in anxiety	N/A	🟢 rare (2 posts)	🟢 Mild	1-2 weeks	source
Dizziness or lightheadedness	17%	🟢 rare (2 posts)	🟢 Mild	1-2 weeks	source
Emotional blunting or moodiness	N/A	🟢 rare (2 posts)	🟢 Mild	Ongoing	source
Impaired motor skills and slower reaction speed	N/A	🟢 rare (1 post)	🟢 Mild	Not specified	source
Loss of appetite	N/A	🟢 rare (1 post)	🟢 Mild	Not specified	source
Restlessness or feeling on edge	N/A	🟢 rare (1 post)	🟢 Mild	Not specified	source
Liver failure (rare but serious risk)	0.0004%	🟢 rare (1 post)	🟠 Severe	Not specified	source
Mood swings and moodiness	N/A	🟢 rare (1 post)	🟢 Mild	Ongoing	source
Self-harm thoughts or urges	1% (suicidal thoughts)	🟢 rare (1 post)	🟠 Severe	Not specified	source

→ View all 193 side effects from FDA trials → View all 15 user-reported side effects

How Other Drugs Compare

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

Metric	Serzone (Antidepressant)	Bupropion (NDRI)	CYB003 (Psilocybin analogue)	Osavampator (AMPA-PAM)
MECHANISM
Drug class	SARI (Serotonin antagonist/reuptake inhibitor)	NDRI (Norepinephrine/dopamine reuptake inhibitor)	Psychedelic analogue (5-HT2A agonist)	AMPA receptor positive allosteric modulator
How it works	Blocks 5-HT2A and 5-HT2C serotonin receptors (proteins on brain cells) and prevents reuptake of serotonin and norepinephrine (leaving more available at synapses)	Boosts norepinephrine/dopamine by reuptake inhibition	Directly stimulates serotonin 5-HT2A receptors (psychedelic effect)	Enhances glutamate signaling via AMPA receptors
EFFICACY
Response rate	48% (varied studies) FDA	~60% source	53.3% at 3 weeks source	Not yet published
Remission rate	~33% FDA	~35%	75% at 4 months source	Not yet published
Time to effect	2-4 weeks	1-2 weeks	1-3 weeks	Possibly days
KEY SIDE EFFECTS
Drowsiness & sedation	25%	6%	10-15% (headache, mild nausea)	5-10% (headache, GI)
Dry mouth	25%	10%	Rare	Rare
Sexual dysfunction	1%	<5%	<5%	Not reported
Liver failure risk	0.0004%	Not reported	None	None
Suicidal thoughts	1%	1%	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	Drowsiness, headache, nausea, dry mouth	Startup effects	Severe anxiety, suicidal thoughts, jaundice
Week 2-3	Fatigue, adjusting sleep, mood swings, GI side effects fade	Still adjusting	No improvement, dark urine, yellow eyes/skin
Week 4-6	Possible benefits begin, energy returns	Gradual improvement	No benefit at all, persistent severe side effects
Week 6-8	Full effect, stable, side effects minimal	Stable	Intolerable or dangerous 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 Serzone

Serzone (nefazodone) does its work by blocking certain serotonin receptors (proteins on brain cells that respond to serotonin), especially 5-HT2A and 5-HT2C, while also performing reuptake inhibition—preventing the brain from reabsorbing serotonin and norepinephrine. This leaves more of these brain chemicals available at synapses (gaps between nerve cells), which should—at least in theory—help regulate mood. One Reddit user summed up the startup effects: "Most common startup side effects: drowsiness, headache, nausea, slight increase in anxiety" source.

Side effects happen because those serotonin and norepinephrine systems aren’t just in the brain—they're in your gut, your blood vessels, even your salivary glands (hello, dry mouth). The trade-off? For some, Serzone brings relief where SSRIs failed, especially with fewer sexual side effects. For others, it's all fog, no fire.

So why do doctors keep reaching for Serzone? For a few, it's about sexual function or weight gain: "I've taken every SSRI, the side effects are terrible ... zero libido, emotional blunting (too much)," one user posted source. And despite the notorious liver warning, the risk is exceedingly low, at about 1 in 250,000 patient-years. Serzone's decades of data, predictability, and the hope of an SSRI workaround keep it on the specialist’s shelf.

The Worst Side Effects

1. Liver failure (rare but serious)

"...I understand the risk of liver failure is pretty low and it is an extremely rare side effect, but as..." source Reported as severe by 1/1 users

Management tip: Get baseline liver tests before starting, repeat frequently (monthly for first 6 months). Report yellow eyes/skin or dark urine immediately. Never combine with other drugs that affect the liver.

2. Self-harm thoughts or urges

"(Serzone had me reaching for sharp things)." source Reported as severe by 1/1 users

Management tip: Suicidal thoughts in the first month? Stop and call your doctor. Don’t try to "tough it out."

3. Nausea and upset stomach

"Feel very tired and a little nauseous. Did anyone else experience this? Hoping it goes away as body adjusts." source Reported as mild by 3/4 users, but was the top reason for stopping in FDA trials.

Management tip: Take with food, split the dose, ginger chews or anti-nausea remedies, hydrate.

How Clinical Trials Compare

CYB003 (psilocybin analogue) Phase 2 had no reports of serious liver injury or suicidality, with 10–15% reporting only transient headaches or nausea source. Osavampator, by comparison, hasn’t shown chronic sedation or GI issues above placebo. Serzone’s unique liver warning stands out among antidepressants—if that’s your dealbreaker, alternatives may be safer.

→ Find trials with lower rates of these side effects

The Most Common Side Effects

Drowsiness and sedation

FDA rate: 25%; Reddit: 8 users, all mild source
What helps: Take at night; avoid driving until you know your reaction
Timeline: Peaks week 1, fades by week 2-4
"Drowsiness, dizziness...extremely dry mouth. My goodness, hopefully with some time my body will adjust."

Headache

FDA rate: 36%; Reddit: 4 users, all mild source
What helps: Hydration, acetaminophen, give it 1-2 weeks
Timeline: Starts day 1, usually resolves by week 2-4
"Most common startup side effects: drowsiness, headache, nausea..."

Nausea and upset stomach

FDA rate: 22%; Reddit: 4 users, mild source
What helps: Take with food, consider ginger, split dosing
Timeline: Peaks in first week, gone by week 3 for most
"Feel very tired and a little nauseous. Did anyone else experience this? Hoping it goes away..."

Dry mouth

FDA rate: 25%; Reddit: 2 users, mild source
What helps: Suck on ice chips or sugar-free candies
Timeline: First week, resolves for most by week 2

Dizziness/lightheadedness

FDA rate: 17%; Reddit: 2 users, mild source
What helps: Stand up slowly, sit or lie down if it hits
Timeline: First few days, usually fades fast

Fatigue/low energy

FDA rate: 11% (asthenia); Reddit: 3 users, mild source
What helps: Dose at night, adjust timing
Timeline: Improves by week 2-3 for most

→ Find clinical trials that may avoid this side effect

Drowsiness and Sedation

"Drowsiness, dizziness, a pounding headache, cognitive slowness and trouble thinking, extremely dry mouth. My goodness, hopefully with some time my body will adjust." source

This is the side effect almost everyone runs into: FDA data shows 25% of trial participants reported drowsiness (and it rises to 28% at higher doses). On Reddit, it's the most discussed side effect—8 separate posts—though nearly all rate it as "mild." "Feel very tired and a little nauseous. Did anyone else experience this? Hoping it goes away as body adjusts," another user wrote source.

For most people, drowsiness peaks in the first week and fades by week 2-4 as your body adapts. One user even found it helpful for sleep: "I did have some fatigue shortly after taking my doses. In the evenings, it was good because it helped me sleep." source

What helps: Take it at night, split the dose if prescribed twice daily, avoid alcohol or other sedating meds, and don’t drive until you’re sure you’re alert enough.

If it doesn’t get better by week 4, talk to your doctor—sometimes a lower dose or slow titration (gradually adjusting the dose) helps. Rarely, persistent sedation is a reason to switch to an alternative.

Nausea and Upset Stomach

"Feel very tired and a little nauseous. Did anyone else expedience this? Hoping it goes away as body adjusts." source

The FDA trial rate for nausea is 22% (vs 12% placebo), and it increases slightly at higher doses. Reddit users repeatedly mention nausea during startup—it's part of that delightful cocktail with drowsiness and headaches.

Most find it fades with time: "Most common startup side effects: drowsiness, headache, nausea, slight increase in anxiety." source

What helps: Always take Serzone with food, split your dose if needed, and consider ginger chews. Hydrate, and don’t force food if your appetite is gone for a few days—it usually returns.

If nausea is severe or persists past week 3-4, this is a common reason people stop the drug, per both clinical trial discontinuation stats (3.5% stopped for nausea) and lived experience. Your doctor may suggest lowering the dose or switching to something else if it doesn’t resolve.

Discontinuation & Withdrawal

Roughly 16% of people in trials discontinued Serzone due to adverse events—nausea, dizziness, insomnia, asthenia (physical weakness), and agitation topping the list. The FDA label doesn't list a classic antidepressant withdrawal syndrome for nefazodone, but abrupt discontinuation is still a bad idea: expect the return of insomnia, mood swings, or "brain zaps" (noted with other drugs).

Serzone’s half-life (how long the drug stays active in your body) is about 2–4 hours for the parent compound but up to 18 hours for its active metabolites. This means it leaves your system relatively fast if you stop suddenly, potentially increasing the chance of withdrawal symptoms—though most users report only mild discomfort.

Management tips:

Always taper (slowly reducing the dose) under medical supervision—over 2–4 weeks
Watch for return of original symptoms or new insomnia, mood swings, or GI upset
If you switched due to side effects, some startup symptoms may temporarily return

Dosage by Condition

Condition	Starting Dose	Typical Dose	Maximum Dose
Depression	100 mg/day in two divided doses	300–400 mg/day in two divided doses	600 mg/day
(elderly/debilitated)	50 mg/day in two divided doses	Use lowest effective dose	300 mg/day
Hepatic impairment	Contraindicated	N/A	N/A

Dose increases should be in 100 mg/day increments every week or more, as tolerated. Side effects like drowsiness, nausea, and headache often increase with higher doses.

See full FDA label for details

Find Top Clinical Trials

Choose from over 30,000 active clinical trials.

Alternatives

If Serzone's side effects aren't working for you, here's how some alternatives stack up, with a bit of personality:

Bupropion (Wellbutrin): NDRI; energetic, famously avoids sexual side effects, but can increase anxiety and insomnia. Minimal weight gain.
SNRIs (venlafaxine, duloxetine): Hit both serotonin and norepinephrine but with higher rates of sexual dysfunction and GI effects than Serzone.
MAOIs: Old-school, strict dietary rules, often last resort for the med-resistant. Unusual side effect risks.
Spravato (esketamine nasal spray): Rapid-acting, but only available in-clinic. May cause dissociation, not chronic drowsiness or liver risk.
TMS (transcranial magnetic stimulation): Device, not a drug. No drowsiness or sexual dysfunction, mild headaches, or scalp discomfort.

If sedation or sexual dysfunction is your dealbreaker, Bupropion or one of the new trial drugs (see below) may be worth a look.

→ Compare your options on WithPower

Clinical Trials

CYB003 (deuterated psilocybin analogue): Acts on 5-HT2A receptors, not a reuptake inhibitor. In trials, lower rates of sedation and sexual dysfunction (both <5%), no liver toxicity, rapid antidepressant effect. Response rate 53% at 3 weeks, remission 75% at 4 months source.
Osavampator (AMPA-PAM): Modulates glutamate transmission, Phase 3 ongoing. Early data: fewer chronic side effects, headache/GI effects in 5-10%, no sedation or liver injury source.
D-cycloserine: NMDA partial agonist, being explored adjunctively; not linked to sexual dysfunction or sedation source.
Psilocybin (classic psychedelic): Trials suggest durable response after 1-2 sessions, transient headache/nausea only.

Participation often means free treatment and close monitoring, but assignment to placebo is possible. Phase 2 results aren't a guarantee—full FDA approval comes only after Phase 3 data confirm safety.

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 drowsiness is the dealbreaker → try Bupropion or new trials with CYB003 (see CYB003 trial)

If liver risk terrifies you → Bupropion or TMS; avoid anything hepatically metabolized; or try CYB003/psilocybin trials

If sexual dysfunction shows up → stick with Serzone (very low risk) or switch to Bupropion, or look at Osavampator or D-cycloserine

If GI side effects (nausea, dry mouth, appetite loss) → split dosing, try Bupropion, or consider the AMPA-PAM or psilocybin trial drugs

→ Find clinical trials and alternatives matched to your needs

Serzone (nefazodone) - antidepressant medication Image: Change.org

Monitoring & What to Track

Mood: Regular PHQ-9 (depression) or GAD-7 (anxiety) scores
Liver function: Baseline and periodic AST/ALT (blood tests for liver injury), especially in first 6 months
Weight: Serzone isn’t known for weight gain, but still worth monitoring
Suicidal ideation: Especially in first month or if under 25

You should log:

Daily mood (1–10), side effect checklist, sleep hours, energy, appetite changes
Any sign of yellow skin/eyes, dark urine, unusual fatigue—report immediately

If your doctor isn't tracking these, ask them to. Don’t be shy: your chart is your lifeline.

Pregnancy & Breastfeeding

Serzone (nefazodone) is Category C: animal studies suggest risk, human data limited. Birth defects in animal models weren’t dramatic, but caution is warranted. Most alarming—untreated depression/anxiety also increases miscarriage, preterm birth, and low infant weight risk.

Serzone is excreted in human milk. Safety in breastfeeding is unknown; most sources advise alternatives, especially for newborns or preemies.

This isn’t a yes/no answer—it's a risk/benefit math problem with your prescriber. If you become pregnant, do NOT stop suddenly; work out a taper (slowly reducing the dose) with your doctor. Never go it alone.

Emergency Warning Signs

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

Suicidal thoughts or plans
New or sudden yellowing of eyes/skin, dark urine (signs of liver failure)
Severe allergic reaction (rash, swelling, difficulty breathing)
Severe confusion, agitation, hallucinations
Seizure

📞 Call your doctor urgently if:

Persistent nausea, vomiting, appetite loss
Unusual bleeding or bruising
Severe anxiety, agitation, or restlessness
Worsening depression or mood swings
Unexplained fatigue
Signs of infection (fever, sore throat)

Poison Control: 1-800-222-1222 National Suicide Prevention Lifeline: 988

Summary & Next Steps

Key takeaways:

Drowsiness (25%), headache (36%), and nausea (22%) are the most common startup side effects, peaking in the first two weeks and usually resolving [Reddit: drowsiness in 8/15 posts; headaches/nausea in 4/15].
Liver failure is extremely rare (1 in 250,000 patient-years), but it’s the headline risk—if you see yellow eyes or skin, get checked immediately.
Most users describe side effects as mild and short-lived; only 16% stop due to side effects in trials.

If Serzone is working for you: Keep tracking side effects, get periodic liver tests, and celebrate avoiding sexual dysfunction and weight gain found with many other antidepressants.

If side effects are intolerable: Don’t wait—ask your doctor about lowering the dose or switching. Consider Bupropion or the new AMPA/psilocybin trial drugs. Safer options are out there.

Your next steps:

Track your symptoms and side effects daily for 2 weeks (simple mood diary).
Bring this guide (or your questions from it) to your doctor at your next appointment.
If considering alternatives, → 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
headache	36%	33%	very common	Nervous System
somnolence	25%	14%	very common	Nervous System
dry mouth	25%	13%	very common	Gastrointestinal
nausea	22%	12%	very common	Gastrointestinal
dizziness	17%	5%	very common	Nervous System
constipation	14%	8%	very common	Gastrointestinal
asthenia	11%	5%	common	Body as a Whole
insomnia	11%	9%	common	Nervous System
lightheadedness	10%	3%	common	Nervous System
blurred vision	9%	3%	common	Special Senses
dyspepsia	9%	7%	common	Gastrointestinal
infection	8%	6%	common	Infection
diarrhea	8%	7%	common	Gastrointestinal
confusion	7%	2%	common	Nervous System
abnormal vision (scotoma, visual trails)	7%	1%	common	Special Senses
pharyngitis	6%	5%	common	Respiratory
increased appetite	5%	3%	common	Metabolic
memory impairment	4%	2%	common	Nervous System
paresthesia	4%	2%	common	Nervous System
vasodilatation (flushing, feeling warm)	4%	2%	common	Cardiovascular
postural hypotension	4%	1%	common	Cardiovascular
abnormal dreams	3%	2%	common	Nervous System
concentration decreased	3%	1%	common	Nervous System
cough increased	3%	1%	common	Respiratory
peripheral edema	3%	2%	common	Metabolic
flu syndrome	3%	2%	common	Infection
chills	2%	1%	common	Body as a Whole
fever	2%	1%	common	Body as a Whole
rash	2%	1%	common	Dermatologic
pruritus	2%	1%	common	Dermatologic

Boxed Warnings (Most Serious)

Suicidality: Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies.
Life-threatening hepatic failure: Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone hydrochloride tablets. The reported rate in the United States is about 1 case of liver failure resulting in death or transplant per 250,000 to 300,000 patient-years of nefazodone hydrochloride treatment.

Drug Interactions

Highly protein-bound drugs: may increase free concentrations of other drugs or nefazodone.
Warfarin: no significant interaction, but monitor as per standard practice.
Monoamine oxidase inhibitors (MAOIs): contraindicated.
Haloperidol: decreased clearance; monitor for increased effects.
Triazolam/Alprazolam: contraindicated.
Alcohol: avoid concomitant use.
Buspirone: marked increases in buspirone levels; use low dose and monitor.
Pimozide: contraindicated.
Fluoxetine: increased mCPP and triazole-dione metabolites; allow washout period before switching.
Phenytoin: monitor if used chronically.

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?
Drowsiness and sedation	8 posts	🟢 Mild (6/8)	First couple of weeks, often resolves as body adjusts	Resolves
Headaches, sometimes pounding or severe	4 posts	🟢 Mild (3/4)	First couple of weeks, resolves for most	Resolves
Nausea and upset stomach	4 posts	🟢 Mild (3/4)	First couple of weeks, resolves for most	Resolves
Fatigue and low energy	3 posts	🟢 Mild (2/3)	Shortly after dose, sometimes ongoing	Resolves
Cognitive slowness and trouble thinking	2 posts	🟢 Mild (2/2)	First week or two, resolves for most	Resolves
Extremely dry mouth	2 posts	🟢 Mild (2/2)	First week or two, resolves for most	Resolves
Slight increase in anxiety	2 posts	🟢 Mild (2/2)	First week or two, resolves for most	Resolves
Dizziness or lightheadedness	2 posts	🟢 Mild (2/2)	First week or two, resolves for most	Resolves
Emotional blunting or moodiness	2 posts	🟢 Mild (2/2)	Ongoing for some, especially at higher doses	Resolves
Impaired motor skills and slower reaction speed	1 posts	🟢 Mild (1/1)	Not specified, based on study reference	Resolves
Loss of appetite	1 posts	🟢 Mild (1/1)	Not specified, likely during treatment	Resolves
Restlessness or feeling on edge	1 posts	🟢 Mild (1/1)	Not specified, likely during startup	Resolves
Liver failure (rare but serious risk)	1 posts	🟠 Severe (1/1)	Not specified, but described as rare and serious	Resolves
Mood swings and moodiness	1 posts	🟢 Mild (1/1)	Ongoing during treatment for some	Resolves
Self-harm thoughts or urges	1 posts	🟠 Severe (1/1)	Not specified, but described as occurring during treatment	Resolves

User Quotes by Side Effect

Drowsiness and sedation (Starts on first day, peaks in first week, often resolves by week 2-4)

"Drowsiness, dizziness, a pounding headache, cognitive slowness and trouble thinking, extremely dry mouth. My goodness, hopefully with some time my body will adjust." source

"Most common startup side effects: drowsiness, headache, nausea, slight increase in anxiety." source

"Feel very tired and a little nauseous. Did anyone else expedience this? Hoping it goes away as body adjusts." source

Headaches, sometimes pounding or severe (Starts on first day, peaks in first week, often resolves by week 2-4)

"Drowsiness, dizziness, a pounding headache, cognitive slowness and trouble thinking, extremely dry mouth." source

"Most common startup side effects: drowsiness, headache, nausea, slight increase in anxiety." source

"Its negative effects such as anxiety, headaches, and appetite loss are likely mediated by its actions on the 5-HT2C receptor." source

Nausea and upset stomach (Starts on first day, peaks in first week, often resolves by week 2-4)

"Feel very tired and a little nauseous. Did anyone else expedience this? Hoping it goes away as body adjusts." source

"Most common startup side effects: drowsiness, headache, nausea, slight increase in anxiety." source

"The worst shakes I've ever had, nausea, felt like someone was squeezing my brain and digging their nails into it." source

Fatigue and low energy (Shortly after dose, starts day 1, often improves after first weeks)

"I had almost none. I did have some fatigue shortly after taking my doses. In the evenings, it was good because it helped me sleep." source

"Feel very tired and a little nauseous. Did anyone else expedience this? Hoping it goes away as body adjusts." source

"The first couple weeks is usually filled with side effects and little benefit." source

Cognitive slowness and trouble thinking (Starts on first day, peaks in first week, often resolves by week 2)

"Drowsiness, dizziness, a pounding headache, cognitive slowness and trouble thinking, extremely dry mouth." source

"I felt better within the first two days but the side effects made me sleepy so I felt meh. Just power through it for a bit and see if sleepiness goes away." source

Extremely dry mouth (Starts on first day, peaks in first week, often resolves by week 2)

"Drowsiness, dizziness, a pounding headache, cognitive slowness and trouble thinking, extremely dry mouth." source

"I had a bit of dry mouth at first but it went away after a week or so." source

Slight increase in anxiety (Starts on first day, peaks in first week, often resolves by week 2)

"Most common startup side effects: drowsiness, headache, nausea, slight increase in anxiety." source

"All of the antidepressants, but particularly the SRI's, cause me to experience a significant increase in my anxiety, insomnia and restlessness ..." source

Dizziness or lightheadedness (Starts on first day, peaks in first week, often resolves by week 2)

"Drowsiness, dizziness, a pounding headache, cognitive slowness and trouble thinking, extremely dry mouth." source

"I felt a bit dizzy the first few days but it went away quickly." source

Emotional blunting or moodiness (Can start within first weeks, may persist if dose is high)

"I am on Day 17 of taking 25 mgs for mainly social anxiety/anxiety. Having an incredibly hard time with it. Lot of up and down, moodiness, some blunting of emotions." source

"I've taken every SSRI, the side effects are terrible ranging from, it didn't help with my anxiety at all, insomnia, zero libido, emotional blunting(too much,) ..." source

Impaired motor skills and slower reaction speed (Not specified; mentioned as a potential effect)

"I also read a study that seems to suggest that the drug can impair motor skills and reaction speed." source

Loss of appetite (Not specified; likely during early treatment)

"Its negative effects such as anxiety, headaches, and appetite loss are likely mediated by its actions on the 5-HT2C receptor." source

Restlessness or feeling on edge (Not specified; likely during early treatment)

"All of the antidepressants, but particularly the SRI's, cause me to experience a significant increase in my anxiety, insomnia and restlessness ..." source

Liver failure (rare but serious risk) (Not specified; risk exists during treatment)

"Anyway, the reason for my post is to ask, I understand the risk of liver failure is pretty low and it is an extremely rare side effect, but as ..." source

Mood swings and moodiness (Can start within first weeks, may persist if dose is high)

"I am on Day 17 of taking 25 mgs for mainly social anxiety/anxiety. Having an incredibly hard time with it. Lot of up and down, moodiness, some blunting of emotions." source

Self-harm thoughts or urges (Not specified; occurred during treatment)

"(Serzone had me reaching for sharp things)." 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: NCT06141876
Mechanism: Deuterated psilocybin analog (psychedelic-derived, 5-HT2A receptor agonist)
Side Effect Comparison: CYB003 showed a favorable side effect profile: no serious adverse events, no evidence of increased suicidality, and lower rates of sexual dysfunction, weight gain, and sedation compared to standard SSRIs/SNRIs. Most common side effects were transient headache and mild nausea (10-15%), much lower than sexual dysfunction (up to 30%) and weight gain (up to 20%) seen with SSRIs/SNRIs.
Efficacy Data:
- Response rate: 53.3% (CYB003 16mg) vs 20% (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 with less sexual dysfunction, weight gain, and sedation than standard antidepressants—ideal for those experiencing these side effects.
Results: Significant and rapid reduction in depressive symptoms; 75% remission at 4 months; well-tolerated in trial population.
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: AMPA modulators like osavampator are not associated with sexual dysfunction, weight gain, or sedation typical of SSRIs/SNRIs. Early data suggest a favorable tolerability profile, with headache and mild GI symptoms as the most common side effects (5-10%).
Efficacy Data:
- Response rate: Not yet published
- Remission rate: Not yet published
- MADRS change: Not yet published (Phase 3 ongoing); Phase 2 showed significant improvement over placebo
- Time to response: Potentially faster than SSRIs (AMPA modulators may act within days)
- Source
Why it might interest you: Osavampator works via a completely different mechanism (AMPA modulation), may have a faster onset than SSRIs, and early data suggest fewer side effects like sexual dysfunction, weight gain, and sedation—making it attractive for those intolerant to standard antidepressants.
Results: Phase 2 data showed significant improvement in depressive symptoms as adjunctive therapy; Phase 3 underway to confirm efficacy and safety.
Sources: 1, 2, 3

D-cycloserine (adjunctive)

Sponsor: Not specified (academic/NIH)
Phase: Phase 2
NCT: NCT00408031
Mechanism: NMDA receptor partial agonist (glycine site)
Side Effect Comparison: D-cycloserine is not associated with sexual dysfunction, weight gain, or sedation seen with SSRIs/SNRIs. Most common side effects are mild (headache, dizziness, GI upset, <10%).
Efficacy Data:
- Response rate: Not specified
- Remission rate: Not specified
- MADRS change: Not specified for D-cycloserine in MDD; in TRD, significant improvement over placebo in phase 2 trial (NCT00408031)
- Time to response: Within 2 weeks (in some studies)
- Source
Why it might interest you: D-cycloserine targets glutamatergic neurotransmission (NMDA), offering a novel mechanism and rapid onset. It is not associated with the common side effects of SSRIs/SNRIs, making it a potential alternative for those with intolerable side effects.
Results: D-cycloserine as adjunctive therapy improved depressive symptoms in treatment-resistant depression and bipolar depression.
Sources: 1

Psilocybin (various trials, e.g., COMPASS Pathways)

Sponsor: COMPASS Pathways, Usona, others
Phase: Phase 2/3
NCT: NCT06141876
Mechanism: Classic psychedelic (psilocybin, 5-HT2A receptor agonist)
Side Effect Comparison: Psilocybin is not associated with sexual dysfunction, weight gain, or chronic sedation. Most side effects are acute and transient (anxiety, headache, nausea during dosing, 10-20%), with no evidence of long-term adverse effects seen with SSRIs/SNRIs.
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 (sexual dysfunction, weight gain, sedation) of standard antidepressants—appealing for those with side effect burden.
Results: Multiple studies show rapid and sustained antidepressant effects after 1-2 doses; FDA Breakthrough Therapy Designation for TRD.
Sources: 1, 2

Appendix D: Methodology

We examined more than 30,000 clinical trial listings from ClinicalTrials.gov, over 300 journal articles via PubMed, and 43 online patient discussions. Our review included 193 OpenFDA Drug Label entries and synthesized both clinical data and 15 distinct user-reported adverse effects. Each effect was ranked for frequency, analyzed for severity and duration, and illustrated with representative patient quotations and links to primary sources.