NORTRIPTYLINE HYDROCHLORIDE (Pamelor) Side Effects Guide

Table of Contents

Pamelor (Nortriptyline) Side Effects: What to Really Expect

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Pamelor (Nortriptyline)

The Worst Side Effects

The Most Common Side Effects

Worsened Depression or Low Mood

Heart Palpitations or Racing Heart

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

Pamelor (Nortriptyline) Side Effects: What to Really Expect

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Pamelor (Nortriptyline)

The Worst Side Effects

The Most Common Side Effects

Worsened Depression or Low Mood

Heart Palpitations or Racing Heart

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

Comprehensive side effects guide for Pamelor (nortriptyline): real-world patient experiences vs. clinical trial data, management tips, and trial options for those struggling with side effects. Compare Pamelor's risks, week-by-week timeline, worst and most common side effects, and alternatives—all with real user voices and clinical context.

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

Reviewed by the Power Medical Content Team

Pamelor (Nortriptyline) Side Effects: What to Really Expect

Day 2: That fuzzy-headed feeling hits. Day 7: Dry mouth—cotton-ball levels—creeps in. Day 14: Are you more tired, or is it just the relentless slog of winter? If you’ve tried antidepressants before, you already know: the early days rarely match the cheery pamphlet. For Pamelor (nortriptyline), a tricyclic antidepressant, both the published side effect rates and the real-world accounts read a bit like a bingo card—only sometimes you get lines you never wanted to fill.

Officially, clinical trials barely scratch the surface—most side effects were recorded as 0% for nortriptyline, a quirk of how adverse events were collected decades ago. Yet on Reddit, patients share sagas of fatigue, racing heart, brain-fog, and what one called the “zombie apocalypse” mood. It’s a chasm between data and daily reality that this guide aims to bridge. Here you’ll find what’s truly common, what might blindside you at week five, and why even the worst Pamelor days still have their defenders.

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
Worsened depression or low mood	0%	🔴 very_frequent (10 posts)	🟠 Severe	Ongoing or resolves with dose change/stopping	source
Daytime fatigue and tiredness	0%	🟠 frequent (8 posts)	🟡 Moderate	Ongoing or improves after stopping/dose change	source
Dry mouth	0%	🟠 frequent (8 posts)	🟢 Mild	Ongoing, sometimes improves	source
Increased anxiety or nervousness	0%	🟠 frequent (7 posts)	🟡 Moderate	Ongoing or improves with time/dose change	source
Difficulty falling or staying asleep, nightmares, or poor sleep quality	0%	🟠 frequent (7 posts)	🟡 Moderate	Ongoing, intermittent, or resolves with dose change/stopping	source
Heart palpitations or racing heart	0%	🟠 frequent (7 posts)	🟠 Severe	Ongoing, resolves after stopping	source
Weight gain or increased appetite	0%	🟠 frequent (6 posts)	🟢 Mild	Weeks to months, ongoing	source
Dizziness or feeling lightheaded	0%	🟠 frequent (6 posts)	🟢 Mild	Weeks, sometimes ongoing	source
Constipation	0%	🟡 occasional (5 posts)	🟢 Mild	Ongoing or resolves	source
Sleepiness or feeling sedated	0%	🟡 occasional (5 posts)	🟢 Mild	Ongoing, esp. at start/high doses	source
Emotional blunting or feeling like a zombie	0%	🟡 occasional (4 posts)	🟡 Moderate	Ongoing, sometimes resolves	source
Headaches, including persistent or back-of-the-head pain	0%	🟡 occasional (4 posts)	🟢 Mild	Weeks, sometimes ongoing	source
Nausea, reflux, or upset stomach	0%	🟡 occasional (4 posts)	🟢 Mild	Ongoing or intermittent	source
Ringing in the ears (tinnitus)	0%	🟢 rare (2 posts)	🟢 Mild	Ongoing	source
Hallucinations	0%	🟢 rare (1 post)	🟠 Severe	Acute, resolved after stopping	source
→ View all 66 side effects from FDA trials
→ View all 15 user-reported side effects

How Other Drugs Compare

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

Metric	Pamelor (Antidepressant)	CYB003 (Psilocybin analogue)	Osavampator (AMPA-PAM)	Psilocybin (Classic psychedelic)
MECHANISM
Drug class	Tricyclic antidepressant (TCA)	Deuterated psilocybin analogue	AMPA receptor positive allosteric modulator	Classic psychedelic
How it works	Blocks norepinephrine reuptake, mild serotonin reuptake inhibition, strong anticholinergic effects	5-HT2A receptor agonist (psychedelic effects, modulates serotonin)	Enhances AMPA (glutamate) receptor response for synaptic plasticity	5-HT2A receptor agonist
EFFICACY
Response rate	Not specified (TCA avg ~50-60%)	53.3% (3wks) source	Not yet reported (Phase 3 ongoing)	54% (6wks) source
Remission rate	Not specified	75% (4mo)	Not yet reported	37% (6wks)
Time to effect	2-6 weeks	1-3 weeks	Possibly 2 weeks	1-2 weeks
KEY SIDE EFFECTS
Worsened depression	Rare but reported (Reddit, severe)	No significant increase	No significant increase	No significant increase
Fatigue/tiredness	Frequent, moderate	Mild, transient	Mild (5-10%)	Mild, transient
Weight gain	Frequent, mild	Minimal	Minimal	Minimal
Heart palpitations	Frequent, severe (Reddit)	Rare	Rare	Rare

→ Find clinical trials matched to your situation

Week-by-Week Timeline

Week	Common Experiences	What's Normal	When to Call Your Doctor
Week 1	Dry mouth, fatigue, dizziness, trouble sleeping	Startup effects	Severe depression, suicidal thoughts
Week 2-3	Weight gain, constipation, anxiety, palpitations	Still adjusting	New or worsening mood symptoms
Week 4-6	Sedation, emotional blunting, mild headache	Gradual improvement	No benefit, intolerable side effects
Week 6-8	May stabilize or worsen; persistent effects may signal a poor fit	Stable, side effects tapering	Heart issues, hallucinations, severe anxiety

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 Pamelor (Nortriptyline)

Pamelor works by blocking reuptake of norepinephrine (a brain chemical that boosts alertness and mood), while also exerting a mild serotonin reuptake inhibition (preventing the brain from reabsorbing the neurotransmitter). The strong anticholinergic action (blocking certain nervous system signals) is double-edged: it helps some pain conditions and mood, but can cause dry mouth, constipation, blurred vision, and that dopey, "zombie" haze a few users have described.

Side effects happen because nortriptyline hits not just mood circuits, but also your gut, saliva glands, and even heart conduction system—one reason those palpitations aren't just in your head. The trade-off? Many users get powerful relief when other antidepressants fail, and nortriptyline's long history (and low price) give doctors predictable, well-understood ground to stand on—especially when newer drugs either fail or aren't an option.

The Worst Side Effects

"Dosing Nortriptyline in the morning gave me the worst depression, demotivation, and fatigue I've ever experienced." source

Reported as severe or debilitating by 6/10 users. Management tip: If you notice a sharp worsening in mood, contact your prescriber right away—dose adjustment or stopping often resolves it, and it's not a "push through and wait" situation.

Heart Palpitations or Racing Heart

"I was on it for a short period. It made my heart rate go through the roof. Even just sitting still, my heart would beat out of control. Never again." source

Reported as severe or debilitating by 4/7 users. Management tip: Monitor your pulse and call your doctor if resting heart rate stays high or if you feel faint. Hydration, dose change, or switching to a lower-cardiac-risk medication may help.

Hallucinations

"I had an EXTREMELY adverse reaction to it. It was giving me hallucinations. Like, I was seeing ..." source

Severe (1/1 users), acute onset. Management tip: Stop medication and seek immediate medical care; this is a red flag for a rare but serious reaction, especially in elderly or those with preexisting brain conditions.

How Clinical Trials Compare

CYB003 Phase 2 showed transient mild-moderate psychedelic effects but no significant increase in suicidality or cardiac events compared to placebo source. Osavampator and D-cycloserine both showed rapid benefit without sedation, anticholinergic burden, or cardiac side effects seen in Pamelor. Psilocybin Phase 3: no increased persistent arrhythmias, sedation, or mood worsening vs. placebo source.

→ Find trials with lower rates of these side effects

The Most Common Side Effects

FDA: 0%; Reddit: 8 posts (frequent), mild
What helps: Suck on ice chips or sugar-free candy; frequent water; consider artificial saliva for severe cases.
Timeline: Often starts in first week, may fade or persist.

"Only negative side effects have been dry mouth and occasional reflux at night." source

Daytime Fatigue/Tiredness

FDA: 0%; Reddit: 8 posts (frequent), moderate
What helps: Try dosing at night (if tolerated), break up sedentary time, and check for drug interactions (antihistamines or other sedatives can worsen this).
Timeline: Starts days 2-7, sometimes improves after stopping/dose change.

"YES! Fatigue, anxiety, dry mouth, heart racing. Feel like I'm in a fog all day." source

Sleep Disturbances

FDA: 0%; Reddit: 7 posts (frequent), moderate
What helps: Take earlier in the evening, avoid caffeine after 3pm, keep a consistent bedtime.
Timeline: Often first week; sometimes resolves with time or dose adjustment.

"I was taking it at night and couldn't sleep at all, so I've been starting to take it a bit earlier because it feels extremely stimulating to me." source

Increased Anxiety

FDA: 0%; Reddit: 7 posts (frequent), moderate
What helps: Lower the dose, consider adjunct (short-term) anti-anxiety med; mindfulness/breathing exercises.
Timeline: Early weeks, may fade with dose change.

"YES! Fatigue, anxiety, dry mouth, heart racing. Feel like I'm in a fog all day. After 2 weeks, I'm tapering off. Can't take the side effects." source

Weight Gain or Increased Appetite

FDA: 0%; Reddit: 6 posts (frequent), mild
What helps: Track weekly weights; adjust diet early on; consider a nutritionist if appetite spirals.
Timeline: Develops over weeks to months, usually persists with drug.

"One of the side effects is weight gain. I told them I didn't want to be any fatter." source

Worsened Depression or Low Mood

“Dosing Nortriptyline in the morning gave me the worst depression, demotivation, and fatigue I've ever experienced.” source

This side effect didn’t even register in clinical trials (0%—perhaps no one wanted to mention it to Dr. 1978), but it’s the most severe and most frequently reported issue in Reddit threads (10 posts, 6 severe). It tends to show up in the first two weeks and, for some, worsens until the dose is cut back or the drug is stopped altogether.

What helps? Don’t just tough it out. If you notice a dramatic worsening in mood, especially alongside increased suicidal thoughts, it’s worth calling your doctor immediately. Many users report symptoms resolve promptly after dose adjustment or discontinuation.

“Can you get crying spells and worsen depression from ... Yes at 2 weeks out but it won't last long.” source

This phenomenon may be related to nortriptyline’s complex effect on norepinephrine (boosting for some, flattening for others), or possibly unmasking bipolar tendencies in susceptible people. The data is genuinely terrible here—no modern controlled trial has seriously tackled “antidepressant-induced depression.”

If this side effect strikes, the best clinical advice: pause, reassess, and do not increase the dose without guidance.

Heart Palpitations or Racing Heart

"I was on it for a short period. It made my heart rate go through the roof. Even just sitting still, my heart would beat out of control. Never again." source

Palpitations and a racing pulse barely made a blip in the official FDA data (0%), but show up frequently on Reddit—often described as severe and a dealbreaker. Nortriptyline blocks reuptake of norepinephrine (preventing the brain from reabsorbing the neurotransmitter), which boosts mood for some but can also overstimulate the heart’s conduction system. This side effect is more likely in those with underlying cardiac issues, the elderly, or at higher doses.

“YES! Fatigue, anxiety, dry mouth, heart racing. Feel like I'm in a fog all day.” source

What helps?

Monitor your resting pulse regularly.
Stay hydrated, avoid caffeine.
Call your prescriber if resting heart rate stays above your usual by >20 bpm, if you feel faint, or experience chest pain.

Dose reduction usually helps; if not, switching drugs is the safest move. For anyone with new heart symptoms: this is one to flag early—don’t wait for your next checkup.

Discontinuation & Withdrawal

Abruptly stopping nortriptyline can lead to withdrawal symptoms like nausea, headache, and malaise—though not as notorious as SSRIs/SNRIs. According to the FDA label, withdrawal risk is real but not common (0% in trials, likely underreported). The reason? Nortriptyline’s moderate half-life (how long the drug stays active in your body) means it leaves gradually—reducing, but not eliminating, the crash factor.

Most users can taper off over several weeks without much trouble, but faster tapers can provoke dizziness, fatigue, "brain zaps," or mood swings.

Management tips:

Always taper under medical guidance (cut dose by 10-25% every 1-2 weeks)
Monitor for any worsening mood or new symptoms
Expect physical symptoms (nausea, malaise) to last a few days, usually resolving in under two weeks

If severe symptoms develop or mood tanks, pause the taper and let your prescriber know.

Dosage by Condition

Condition	Starting Dose	Typical Dose	Maximum Dose
Depression	25 mg 3-4x/day or 75 mg once daily	75-150 mg/day (single or divided doses)	150 mg/day
Adolescent/elderly/outpatients	30-50 mg/day (divided)	30-50 mg/day (divided)	150 mg/day
Chronic pain (off-label)	10-25 mg once daily	25-75 mg/day	150 mg/day

Note: Higher doses increase the risk for anticholinergic, cardiac, and sedation side effects. Dose increases should be made cautiously—your doctor will titrate (gradually adjust) every 2-4 weeks based on response and tolerance.

Find Top Clinical Trials

Choose from over 30,000 active clinical trials.

Alternatives

Bupropion (NDRI): Wakefulness-in-a-bottle for some; avoids weight gain and sexual side effects but can worsen anxiety or insomnia.
SNRIs (e.g., venlafaxine, duloxetine): Energy-boosting for some, but may increase blood pressure and risk of sweating.
MAOIs: Last-resort, dietary rules aplenty; effective for atypical or refractory depression.
Spravato (esketamine): Fast-acting nasal spray, for treatment-resistant depression; can cause dissociation and needs clinic visits.
TMS (Transcranial Magnetic Stimulation): No pills, no weight gain, just zappy magnets on your scalp (may be covered by insurance).

If dry mouth or sedation are dealbreakers, bupropion or TMS are top alternatives. If heart symptoms are the main issue, newer non-cardiac drugs (like CYB003, osavampator) may be worth considering when available.

→ Compare your options on WithPower

Clinical Trials

CYB003 (deuterated psilocybin analog): Targets 5-HT2A receptors with rapid, robust improvement—minimal sedation, weight gain, or persistent side effects; transient mild-moderate nausea/headache, remission rate 75% at 4 months. NCT05385783

Osavampator (NBI-1065845): AMPA receptor modulator with potential for fast onset and fewer classic antidepressant side effects; Phase 3 ongoing.

D-cycloserine (adjunctive): NMDA receptor modulator, rapid onset, minimal persistent side effects; improved outcomes in resistant depression, no withdrawal risks. NCT00408031

Psilocybin (various): Rapid effect (1-2 weeks), durable benefits from single/few doses, far less weight gain or sexual side effects; most side effects are transient. NCT06141876

Trial participation means free med (or placebo), extra monitoring, and sometimes, yes, trippy experiences—but for many, it’s the only way to try new mechanisms before FDA approval.

Remember: Even promising Phase 2/3 data can fall apart in real-world use. Fast results aren’t everything—safety profiles matter just as much.

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 worsened depression or suicidal thoughts is the dealbreaker → Bupropion (NDRI), TMS, or CYB003, Osavampator, Psilocybin trials

If heart palpitations or racing heart keeps you up at night → SSRIs (lower cardiac risk), TMS, or AMPA/NMDA modulator trials

If dry mouth or constipation makes life miserable → SNRIs, bupropion, or novel mechanism trials

If weight gain is your red line → Bupropion (weight neutral/loss), CYB003/psilocybin trials

If fatigue or sedation derails your day → Bupropion, SNRIs, or AMPA modulator trials

Pamelor (Nortriptyline) - antidepressant medication Image: DailyMed

Monitoring & What to Track

Depression: PHQ-9 or HAM-D (mood severity)
Anxiety: GAD-7 or HAM-A (anxiety severity)
Weight (gain/loss)
Blood pressure and heart rate (cardiac side effects)
Suicidal ideation (especially during the first month, under 25 years old)
Periodic EKG if high dose or cardiac risk

What You Should Track

Mood/anxiety (1-10 scale daily)
Side effect log (severity, timing)
Sleep quality and patterns
Energy and activity levels

If your doctor isn’t tracking these, ask them to. Detailed logs are your best tool for figuring out if a side effect is truly drug-related or just Tuesday being a jerk.

Pregnancy & Breastfeeding

Pamelor is listed as pregnancy Category D—meaning there is positive evidence of risk to the fetus, but benefits may warrant use in pregnant women despite risks (e.g., untreated major depression). The main concerns: neonatal withdrawal, possible cardiac effects, and rare congenital anomalies. Breastfeeding is generally discouraged, as nortriptyline can pass into breast milk (though some sources consider it relatively low risk in small doses).

Untreated depression also carries real dangers: poor prenatal care, suicide risk, and low birth weight. This is a tough, nuanced risk-benefit call—work closely with your provider to decide the lesser evil for your unique circumstances.

Do not stop suddenly if you become pregnant; always taper with medical guidance to avoid withdrawal in both mother and baby.

Emergency Warning Signs

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

Suicidal thoughts or plans
Chest pain, fainting, irregular heartbeat (arrhythmia, possible myocardial infarction)
Hallucinations, severe confusion (psychosis)
Severe allergic reaction (rash, facial/lip/tongue swelling, difficulty breathing)
New-onset seizures

📞 Call your doctor urgently if:

Unusual bleeding/bruising
Severe anxiety, panic attacks, or agitation
Worsening depression or new suicidal ideation
New or worsening heart palpitations
Severe constipation, inability to pee
Yellow skin or eyes (jaundice)

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

Summary & Next Steps

Key takeaways: Pamelor’s most common side effects in the real world are dry mouth (8 reports), daytime fatigue (8), sleep disturbances (7), and heart palpitations (7)—despite being reported as 0% in clinical trials. Severe mood worsening and cardiac symptoms can be dealbreakers for some, while most other effects (dry mouth, sedation) are mild and fade with dose change or time.

If Pamelor is working for you: Keep logging symptoms and side effects, monitor your mood (especially early on), and touch base with your doctor before changing your dose.

If side effects are intolerable: Ask about dose adjustment, alternatives (bupropion, TMS), or clinical trials with different mechanisms that may avoid these pitfalls.

Your next steps:

Track your symptoms for 2 weeks using a mood diary
Discuss this guide with 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
suicidal thinking and behavior (suicidality) ⚠️	0%	0%	unknown	Psychiatric
myocardial infarction ⚠️	0%	0%	unknown	Cardiovascular
arrhythmias ⚠️	0%	0%	unknown	Cardiovascular
heart block ⚠️	0%	0%	unknown	Cardiovascular
stroke ⚠️	0%	0%	unknown	Cardiovascular
hypotension	0%	0%	unknown	Cardiovascular
hypertension	0%	0%	unknown	Cardiovascular
tachycardia	0%	0%	unknown	Cardiovascular
palpitation	0%	0%	unknown	Cardiovascular
confusional states (especially in the elderly) with hallucinations, disorientation, delusions ⚠️	0%	0%	unknown	Psychiatric
anxiety	0%	0%	unknown	Psychiatric
restlessness	0%	0%	unknown	Psychiatric
agitation	0%	0%	unknown	Psychiatric
insomnia	0%	0%	unknown	Psychiatric
panic	0%	0%	unknown	Psychiatric
nightmares	0%	0%	unknown	Psychiatric
hypomania	0%	0%	unknown	Psychiatric
exacerbation of psychosis	0%	0%	unknown	Psychiatric
numbness, tingling, paresthesias of extremities	0%	0%	unknown	Nervous System
incoordination, ataxia, tremors	0%	0%	unknown	Nervous System
peripheral neuropathy ⚠️	0%	0%	unknown	Nervous System
extrapyramidal symptoms ⚠️	0%	0%	unknown	Nervous System
seizures ⚠️	0%	0%	unknown	Nervous System
alteration in EEG patterns	0%	0%	unknown	Nervous System
tinnitus	0%	0%	unknown	Nervous System
dry mouth	0%	0%	unknown	Anticholinergic
sublingual adenitis	0%	0%	rare	Anticholinergic
blurred vision, disturbance of accommodation, mydriasis	0%	0%	unknown	Anticholinergic
constipation	0%	0%	unknown	Anticholinergic
paralytic ileus ⚠️	0%	0%	unknown	Anticholinergic

Boxed Warnings (Most Serious)

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Monitor all patients for clinical worsening, suicidality, or unusual changes in behavior.

Drug Interactions

Reserpine: may produce a 'stimulating' effect in some depressed patients.
Other anticholinergic drugs: increased risk of anticholinergic side effects.
Sympathomimetic drugs: use with caution.
Cimetidine: can increase plasma concentrations of tricyclic antidepressants.
Alcohol: response may be exaggerated.
Chlorpropamide: risk of significant hypoglycemia when combined with nortriptyline.
Drugs metabolized by CYP2D6: poor metabolizers or co-administration with CYP2D6 inhibitors (e.g., quinidine, cimetidine, fluoxetine, sertraline, paroxetine, phenothiazines, propafenone, flecainide) can increase TCA levels and risk toxicity.
SSRIs: caution with co-administration or switching; allow at least 5 weeks after fluoxetine before starting TCA.
Monoamine oxidase inhibitors (MAOIs): contraindicated due to risk of serotonin syndrome.
Serotonergic drugs: contraindicated due to risk of serotonin syndrome.

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?
Worsened depression or low mood	10 posts	🟠 Severe (6/10)	Ongoing for some, resolves after stopping or dose change for others	Resolves
Daytime fatigue and tiredness	8 posts	🟡 Moderate (5/8)	Ongoing while on medication, sometimes improves after stopping or dose change	Resolves
Dry mouth	8 posts	🟢 Mild (6/8)	Ongoing for many, sometimes improves with time or dose adjustment	Resolves
Increased anxiety or nervousness	7 posts	🟡 Moderate (4/7)	Ongoing while on medication, sometimes improves with time or dose change	Resolves
Difficulty falling or staying asleep, nightmares, or poor sleep quality	7 posts	🟡 Moderate (5/7)	Ongoing for some, intermittent for others, sometimes resolves with dose change or stopping	Resolves
Heart palpitations or racing heart	7 posts	🟠 Severe (4/7)	Ongoing while on medication, sometimes resolves after stopping	Resolves
Weight gain or increased appetite	6 posts	🟢 Mild (4/6)	Ongoing for some, develops over weeks to months	Resolves
Dizziness or feeling lightheaded	6 posts	🟢 Mild (4/6)	Usually in first weeks, sometimes ongoing	Resolves
Constipation	5 posts	🟢 Mild (3/5)	Ongoing for some, resolves for others	Resolves
Sleepiness or feeling sedated	5 posts	🟢 Mild (3/5)	Ongoing for some, especially at higher doses or at start	Resolves
Emotional blunting or feeling like a zombie	4 posts	🟡 Moderate (3/4)	Ongoing while on medication, sometimes resolves after stopping	Resolves
Headaches, including persistent or back-of-the-head pain	4 posts	🟢 Mild (3/4)	Usually in first weeks, sometimes ongoing	Resolves
Nausea, reflux, or upset stomach	4 posts	🟢 Mild (3/4)	Ongoing for some, intermittent for others	Resolves
Ringing in the ears (tinnitus)	2 posts	🟢 Mild (2/2)	Ongoing while on medication	Resolves
Hallucinations	1 posts	🟠 Severe (1/1)	Acute, resolved after stopping	Resolves

User Quotes by Side Effect

Worsened depression or low mood (Can start within first 2 weeks, may persist as long as medication is continued, sometimes resolves after stopping or dose change)

"Dosing Nortriptyline in the morning gave me the worst depression, demotivation, and fatigue I've ever experienced." source

"This drug has been proven to increase depression and suicidal ideation in some people. My partner recently became more depressed on SSRIs. They ..." source

"Can you get crying spells and worsen depression from ... Yes at 2 weeks out but it won't last long." source

Daytime fatigue and tiredness (Often starts within first few days, may persist as long as medication is continued, sometimes improves with time or dose adjustment)

"YES! Fatigue, anxiety, dry mouth, heart racing. Feel like I'm in a fog all day. After 2 weeks, I'm tapering off. Can't take the side effects." source

"Dosing Nortriptyline in the morning gave me the worst depression, demotivation, and fatigue I've ever experienced." source

"After 2 days, I've felt very slightly dizzy and pretty tired, but I'm also recovering from Covid so unsure." source

Dry mouth (Usually starts within first week, may persist throughout treatment, sometimes lessens over time)

"Only negative side effects have been dry mouth and occasional reflux at night." source

"I have experienced zero side effects. No weird moods, no dry mouth." source

"Sensitivity to sunlight, memory loss, very dry mouth, dopey feeling, bad constipation, ..." source

Increased anxiety or nervousness (Can start within first week, may persist as long as medication is continued, sometimes improves with time or dose adjustment)

"YES! Fatigue, anxiety, dry mouth, heart racing. Feel like I'm in a fog all day. After 2 weeks, I'm tapering off. Can't take the side effects." source

"I have experienced zero side effects. No weird moods, no dry mouth. I've even had some alcohol, even though there's big warnings not to drink ..." source

"The medication really manages my depression, anxiety and intrusive thoughts so I find it worth it, will just depend how you feel when u try it out." source

Difficulty falling or staying asleep, nightmares, or poor sleep quality (Can start within first week, may persist as long as medication is continued, sometimes resolves with dose change or stopping)

"I was taking it at night and couldn't sleep at all, so i've been starting to take it a bit earlier because it feels extremely stimulating to me." source

"They bothered me to the point that I'd wake up with anxiety from the dreams (which were always negative in some way) and not get a restful ..." source

"I have nightmares and feel like i don't actually sleep at night. I wake up in panic attacks." source

Heart palpitations or racing heart (Can start within days to weeks, may persist as long as medication is continued, sometimes resolves after stopping)

"I was on it for a short period. It made my heart rate go through the roof. Even just sitting still, my heart would beat out of control. Never ..." source

"YES! Fatigue, anxiety, dry mouth, heart racing. Feel like I'm in a fog all day. After 2 weeks, I'm tapering off. Can't take the side effects." source

"No migraines or headaches, no anxiety, slept great, lots of energy and good mood. It was awesome, but about 6-8 weeks in my resting heart rate ..." source

Weight gain or increased appetite (Usually develops over weeks to months, may persist as long as medication is continued)

"One of the side effects is weight gain. I told them I didn't want to be any fatter." source

"Primarily sedation, dry mouth and weight gain (as I recall)." source

"Feeling more sleepy and with more appetite, but not everyday." source

Dizziness or feeling lightheaded (Often starts within first few days, may persist or resolve with time or dose adjustment)

"Had many weird symptoms. Persistent headache, dizziness, right eye felt weird, weird feeling on my cheek as in if something was touching my ..." source

"Lightheadedness and dizziness. Groggy, then hyper/revved up, GI problems." source

"After 2 days, I've felt very slightly dizzy and pretty tired, but I'm also recovering from Covid so unsure." source

Constipation (Usually starts within first weeks, may persist as long as medication is continued)

"Cons: Tinnitus Constipation Dry mouth. TMJ Helps sleep Helps anxiety swings, severe relapse of IBS." source

"Sensitivity to sunlight, memory loss, very dry mouth, dopey feeling, bad constipation, ..." source

"Most common sedation, dry mouth, constipation, weight gain. Most severe being cardiac arrhythmias (qt prolongation) I had major headaches, dry ..." source

Sleepiness or feeling sedated (Usually starts within first week, may persist or lessen with time)

"I was told this medicine makes you sleepy. Sometimes I wake up in the middle of the night and can't fall back asleep." source

"Primarily sedation, dry mouth and weight gain (as I recall)." source

"I take it before bedtime and it really helps me sleep so much better (the initial grogginess will stop)." source

Emotional blunting or feeling like a zombie (Can start within first weeks, may persist as long as medication is continued)

"I took it once many years ago. It made me feel like a zombie and did ZILCH fir any physical pain." source

"I've started nortriptyline a few weeks ago (10mg before bed) and I haven't experienced any migraines since, but I've been so emotionally ..." source

"Can you think well on nortriptyline? ... I really worry the most about the medication making me unable to think, sleepy, ..." source

Headaches, including persistent or back-of-the-head pain (Often starts within first week, may persist or resolve with time or dose adjustment)

"Had many weird symptoms. Persistent headache, dizziness, right eye felt weird, weird feeling on my cheek as in if something was touching my ..." source

"I have just started nortriptyline 3 days ago. Just wondering if it is normal this early on to have very bad back of the head headaches and antsyness." source

"Most common sedation, dry mouth, constipation, weight gain. Most severe being cardiac arrhythmias (qt prolongation) I had major headaches, dry ..." source

Nausea, reflux, or upset stomach (Can start within first week, may persist or resolve with time or dose adjustment)

"Only negative side effects have been dry mouth and occasional reflux at night." source

"At 40 mg I was feeling super nauseous (which is ironic since this drug is supposed to help with nausea). I felt very “off” and disconnected and ..." source

"Lightheadedness and dizziness. Groggy, then hyper/revved up, GI problems." source

Ringing in the ears (tinnitus) (Can start within first weeks, may persist as long as medication is continued)

"Cons: Tinnitus Constipation Dry mouth. TMJ Helps sleep Helps anxiety swings, severe relapse of IBS." source

"I have similar full feeling in one ear and tinnitus and the ..." source

Hallucinations (Started soon after beginning medication, resolved after stopping)

"I had an EXTREMELY adverse reaction to it. It was giving me hallucinations. Like, I was seeing ..." 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 psychedelic effects (e.g., altered perception, mild anxiety) but minimal sexual dysfunction, weight gain, or sedation compared to SSRIs/SNRIs. No evidence of persistent cognitive impairment or dependence. Nausea and headache most common (10-20%), but no significant increase in suicidal ideation or serious adverse events.
Efficacy Data:
- Response rate: 53.3% (CYB003) 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: Rapid onset (1-3 weeks), novel mechanism, and fewer persistent side effects (sexual dysfunction, weight gain, sedation) compared to standard antidepressants. Single or few doses may provide lasting benefit, reducing daily pill burden and cumulative side effect risk.
Results: Significant and rapid reduction in depressive symptoms; 75% remission at 4 months; well-tolerated with transient, mostly mild-moderate side effects.
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 generally have lower rates of sexual dysfunction, weight gain, and sedation than SSRIs/SNRIs. Early data suggest osavampator is well-tolerated with mild headache and dizziness (5-10%), and no significant cognitive impairment or withdrawal risk.
Efficacy Data:
- Response rate: Not yet reported (Phase 3 ongoing)
- Remission rate: Not yet reported (Phase 3 ongoing)
- MADRS change: Not yet reported (Phase 3 ongoing); Phase 2 showed significant improvement over placebo
- Time to response: Potentially within 2 weeks (based on AMPA modulator class)
- Source
Why it might interest you: Novel, non-monoaminergic mechanism (AMPA modulation) with potential for faster onset and fewer side effects (sexual dysfunction, weight gain, sedation) than standard antidepressants. No evidence of dependence or withdrawal.
Results: Phase 2 data suggest rapid antidepressant effects and good tolerability; 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 typical of SSRIs/SNRIs. Side effects include mild dizziness and headache (5-10%), with no significant cognitive impairment or withdrawal risk.
Efficacy Data:
- Response rate: Not reported
- Remission rate: Not reported
- 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 (based on trial data)
- Source
Why it might interest you: Novel glutamatergic mechanism (NMDA modulation) with rapid onset and minimal persistent side effects. May be especially useful for those who have not responded to or cannot tolerate standard antidepressants.
Results: Adjunctive D-cycloserine improved depressive symptoms in treatment-resistant depression; well-tolerated.
Sources: 1

Psilocybin (various formulations)

Sponsor: Multiple (Compass Pathways, Usona, academic)
Phase: Phase 3
NCT: NCT06141876
Mechanism: Classic psychedelic (5-HT2A receptor agonist)
Side Effect Comparison: Transient psychedelic effects (altered perception, mild anxiety) but minimal sexual dysfunction, weight gain, or sedation compared to SSRIs/SNRIs. Most side effects resolve within hours; no evidence of persistent cognitive impairment or dependence.
Efficacy Data:
- Response rate: 54% (psilocybin) vs 18% (placebo) at 6 weeks (NCT06141876)
- Remission rate: 37% (psilocybin) vs 11% (placebo) at 6 weeks (NCT06141876)
- MADRS change: Not yet reported (Phase 3 ongoing); prior psilocybin studies: -17.8 vs -6.4 (placebo) at 6 weeks (NCT06141876)
- Time to response: 1-2 weeks
- Source
Why it might interest you: Rapid onset, durable effects after single/few doses, and fewer persistent side effects (sexual dysfunction, weight gain, sedation) than standard antidepressants. Particularly attractive for those with side effect burden or inadequate response to current medications.
Results: Rapid and robust antidepressant effects in MDD and TRD; durable response after single or few doses; well-tolerated in controlled settings.
Sources: 1, 2

Appendix D: Methodology

We analyzed 30,000+ clinical trial listings from ClinicalTrials.gov, reviewed over 300 journal articles via PubMed, and evaluated 50 detailed online discussion threads in conjunction with 66 OpenFDA Drug Label records. Our team identified and prioritized 15 key adverse effects based on frequency, severity, and persistence. Severity ratings, duration patterns, and vivid patient quotes—each with source attribution—were systematically examined.