TRIMIPRAMINE MALEATE (Surmontil) Side Effects Guide

Table of Contents

Surmontil (Trimipramine) Side Effects: The Only Guide You Need

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Surmontil

The Worst Side Effects

The Most Common Side Effects

Burning Sensation in Head/Brain: Deep Dive

Restlessness, Chest Tightness, and Dissociation: Deep Dive

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

Surmontil (Trimipramine) Side Effects: The Only Guide You Need

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Surmontil

The Worst Side Effects

The Most Common Side Effects

Burning Sensation in Head/Brain: Deep Dive

Restlessness, Chest Tightness, and Dissociation: Deep Dive

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

A no-BS guide to Surmontil (trimipramine) side effects: what patients report, real-world frequency, how they feel, and whether clinical trials agree. Includes new trial options for those struggling with drowsiness, sedation, or withdrawal.

Medication: Surmontil (TRIMIPRAMINE MALEATE) Drug Class: Antidepressant Author: Michael Baskerville Gill, B. Sc.

Reviewed by the Power Medical Content Team

Surmontil (Trimipramine) Side Effects: The Only Guide You Need

Day 1: You’re drowsy. Day 2: The sleepiness morphs into a full-body hangover. By Week 2, you may be debating whether being able to nap anywhere is a superpower or a curse. If you’re taking Surmontil (trimipramine)—one of the old-school tricyclic antidepressants—chances are you know the drill: unrelenting sedation, grogginess, and the unpredictable wild card of withdrawal.

Let’s put numbers on it. Antidepressants are the mainstay for millions, but up to 55% of patients stop or switch due to side effects. The standard antidepressant toolkit hasn’t changed much since the ‘80s, and while Surmontil offers a different flavor of sedation, its tolerability profile can be oddly specific: devastating for some, barely a blip for others. And, as one user put it: "The first 2 weeks on this were kinda awful, as I felt sedated all day." source

Clinical trials give us a sanitized picture (0% incidence for nearly every side effect!), but real-world users fill in the messy details. Here’s the hard data—drowsiness, withdrawal, weird brain sensations—and what to actually do if Surmontil sideswipe you. If you’re here, it’s probably not your first rodeo. Let’s dig in.

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
Sedation and drowsiness	0%	🔴 very_frequent (7 posts)	🟡 Moderate	Ongoing, peaks first 2 weeks	source
Worsening anxiety or anxiety (withdrawal-related)	0%	🟠 frequent (4 posts)	🟡 Moderate	First 2 weeks/withdrawal	source
Grogginess or hangover effect next day	0%	🟡 occasional (2 posts)	🟢 Mild	Next day	source
Increased anger or irritability	0%	🟢 rare (1 post)	🟢 Mild	Ongoing while taking	source
Restlessness	0%	🟢 rare (1 post)	🟠 Severe	Minutes after dose	source
Chest tightness	0%	🟢 rare (1 post)	🟠 Severe	Minutes after dose	source
Dissociation	0%	🟢 rare (1 post)	🟠 Severe	Minutes after dose	source
Burning sensation in head/brain	0%	🟢 rare (1 post)	🔴 Debilitating	Several nights, while taking	source
Apathy (withdrawal-related)	0%	🟢 rare (1 post)	🟡 Moderate	During withdrawal	source

→ View all 59 side effects from FDA trials → View all 9 user-reported side effects

How Other Drugs Compare

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

Metric	Surmontil (Antidepressant)	CYB003 (Psilocybin analogue)	Osavampator (AMPA-PAM)	Psilocybin (5-HT2A agonist)
MECHANISM
Drug class	Tricyclic antidepressant	Psychedelic-derived antidepressant	AMPA receptor modulator	Classic psychedelic
How it works	Inhibits serotonin/norepinephrine reuptake (prevents the brain from reabsorbing neurotransmitters); strong antihistamine and anticholinergic effects	5-HT2A receptor agonist (activates serotonin receptors); rapid synaptic plasticity	Positive allosteric modulator of AMPA receptor (boosts excitatory neurotransmission)	5-HT2A receptor agonist; induces neuroplasticity and psychological reset
EFFICACY
Response rate	Not robustly reported in modern trials	79% at 3 weeks source	Phase 3 ongoing, not yet reported	70% at 6 weeks source
Remission rate	Not robustly reported	75% at 4 months (CYB003)	Not yet reported	29% at 6 weeks (vs 8% escitalopram) source
Time to effect	2-4 weeks typical	1-3 weeks	Faster than SSRIs expected	1-2 weeks
KEY SIDE EFFECTS
Sedation/drowsiness	🔴 very frequent (7/14 users)	🟢 rare (no sedation)	🟢 rare (no sedation)	🟢 rare (no sedation)
Anxiety/worsening	🟠 frequent (4/14 users)	🟡 occasional (transient, dose-day)	🟡 occasional (headache)	🟡 occasional (dose-day, transient)
Hangover/grogginess	🟡 occasional (2/14 users)	🟢 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	Sedation, drowsiness, hangover effect	Startup effects	Severe anxiety, suicidal thoughts
Week 2-3	Worsening anxiety, persistent drowsiness, withdrawal effects if stopping	Still adjusting	Worsening depression
Week 4-6	Grogginess may improve, mood benefits start	Gradual improvement	No improvement at all
Week 6-8	Effects stabilize	Stable	Intolerable side effects

Most side effects peak in Week 1-2 and improve by Week 4.

If you're still struggling at Week 8, it may be time to consider alternatives.

→ Explore clinical trials with faster onset

Why Doctors Still Prescribe Surmontil

Surmontil's mechanism is classic: it works by inhibiting reuptake (preventing the brain from reabsorbing the neurotransmitters) of serotonin and norepinephrine (brain chemicals that affect mood and alertness). But unlike its tricyclic cousins, it's also a heavyweight antihistamine (triggers those knockout sedative effects) and has strong anticholinergic activity (leading to dry mouth, constipation, blurred vision, and urinary issues). The very thing that helps you sleep like the dead is what makes mornings feel like molasses.

Doctors still use Surmontil for a simple reason: it predictably knocks patients out, especially those whose depression wears an insomnia disguise. Its decades-long safety record and its lack of stimulant properties make it a low-abuse risk. But they also keep a close eye on side effects—drowsiness, grogginess, withdrawal—because the trade-off is rarely one-sided: "It knocks you out at 25 to 50mg range, so not a good option if you feel tired." source

The Worst Side Effects

"After a short build up of taking the medication every night I develop an unbearabley tight burning sensation within my brain/head that is not like a migraine." source

Reported as debilitating by 1/1 user who mentioned it. This side effect appears rare but extremely distressing.
Management tip: Stop the medication and contact your doctor immediately. Consider switching to an alternative class.

Severe Restlessness, Chest Tightness, Dissociation

"Within ten minutes of taking the medication, he became restless, had chest tightness, and experienced a dissociative state..." source

Each reported as severe by 1/1 user (same episode).
Management tip: Acute onset of these symptoms—especially with chest tightness—warrants immediate medical attention. Discontinue under supervision.

How Clinical Trials Compare

CYB003 (deuterated psilocybin analog) Phase 2 showed no serious adverse events, lower rates of sedation, and no increase in suicidality compared to standard antidepressants. Osavampator, still in late-stage trials, is not linked to sedation or dissociation. CYB003 results

→ Find trials with lower rates of these side effects

The Most Common Side Effects

FDA rate: 0% | Reddit: 7 reports, moderate severity
What helps: Take Surmontil at bedtime. Some split dosing; others find lower doses reduce next-day effects.
Timeline: Starts within hours, peaks in 1-2 weeks, often persists
"Yes it makes you drowsy 1-2 hours after taking it. I take it every night." source

Worsening Anxiety (especially withdrawal)

FDA rate: 0% | Reddit: 4 reports, moderate severity
What helps: Slow tapers, avoid abrupt dose drops, consider adjunct anti-anxiety agents
Timeline: Peaks in withdrawal or early treatment; can last weeks
"Cutting down to 12.5mg has left me with really bad anxiety and apathy (for anything other than anxiety!)." source

Grogginess/Hangover

FDA rate: 0% | Reddit: 2 reports, mild
What helps: Earlier dosing, hydration, caffeine (if tolerated)
Timeline: Morning after dose, resolves by afternoon
"I had a lot of hangover the next day." source

Less Common: Anger/Irritability

FDA rate: 0% | Reddit: 1 report, mild
"It made me angry but it's a good antidepressant because it gives you energy." source

Burning Sensation in Head/Brain: Deep Dive

The FDA label for Surmontil doesn’t mention anything about your brain feeling like it’s smoldering. Yet one user described an "unbearabley tight burning sensation within my brain/head that is not like a migraine." source Not a typo: burning, not just a headache.

It’s impossible to quantify risk, but the mechanism might relate to Surmontil’s impact on histamine and serotonin pathways, possibly producing odd neuroinflammatory sensations in rare individuals. The official data gives this side effect a resounding “N/A.”

Management tips

Stop the drug and tell your doctor immediately. This is not a normal TCA startup side effect.
Rule out other causes—migraines, medication interactions (e.g. serotonin syndrome), underlying neurological conditions.

With only 1 reported case out of dozens, it’s rare but worth knowing about—especially since it can be debilitating and not easily confused with other side effects.

Restlessness, Chest Tightness, and Dissociation: Deep Dive

When a side effect strikes within ten minutes of your first dose, you pay attention. One user’s experience: "Within ten minutes of taking the medication, he became restless, had chest tightness, and experienced a dissociative state..." source

These symptoms overlap with the notorious TCA anticholinergic storm (those "can't pee, can't see, can't spit, can't..." etc.), but in this case, it was more abrupt and severe. The FDA lists all three symptoms (restlessness, chest symptoms, altered mental states), but official clinical trial rates are “0%.”

What helps

If these develop soon after your first dose, this is not normal adjustment—call your doctor right away.
If combined with chest pain or breathing trouble, seek ER evaluation to rule out allergic reaction or cardiac arrhythmia.
Discontinue under supervision. Don’t re-challenge unless directed by a psychiatrist.

Discontinuation & Withdrawal

About 1 in 3 patients on tricyclic antidepressants report some kind of withdrawal symptoms with abrupt cessation. The FDA calls out nausea, headache, malaise—"not indicative of addiction," but that doesn’t make it less annoying.

Surmontil has a moderate half-life (how long the drug stays active in your body), so withdrawal can hit within 24-48 hours after a sudden stop, especially after weeks or months of regular use. User reports point to worsening anxiety and apathy during withdrawal: "Cutting down to 12.5mg has left me with really bad anxiety and apathy." source

Management tips

Always taper slowly—over weeks, not days—under medical supervision
Reduce by 10-25% per week as tolerated
If withdrawal hits: return to prior dose, then taper more slowly
Withdrawal timeline: peaks Day 2-5, resolves by 2 weeks for most
If symptoms persist, ask about alternatives with longer half-lives or different mechanisms

Dosage by Condition

Condition	Starting Dose	Typical Dose	Maximum Dose
Major depressive disorder	75 mg at bedtime	75–200 mg/day (divided or bedtime)	200 mg/day outpatient, 300 mg/day inpatient
Depression with insomnia	25–75 mg at bedtime	75–200 mg/day	200–300 mg/day

Dose increases should be titrated (gradually adjusted) by 25–50 mg increments every few days as tolerated.
For elderly or those sensitive to sedating/anticholinergic effects, start at the lower end (e.g., 25 mg bedtime).
Higher doses may increase risk of sedation, anticholinergic, and cardiovascular side effects. Always adjust under close supervision.

Find Top Clinical Trials

Choose from over 30,000 active clinical trials.

Alternatives

If Surmontil’s drowsiness or withdrawal quirks are a dealbreaker, the antidepressant zoo offers:

Bupropion (NDRI): Activating, little/no sedation, often weight-neutral. Can worsen anxiety for some. Good if sleepiness is intolerable.
SNRIs (venlafaxine, duloxetine): Less sedating than tricyclics; may help if pain or fatigue are big issues.
MAOIs: Ancient, powerful, food restrictions galore—used if everything else fails.
Spravato (esketamine): Rapid acting (hours–days), but logistical headaches and cost.
TMS: Non-drug, brain-zapping, no sexual or weight gain side effects; time-intensive.

If you’re fighting anxiety, buspirone or hydroxyzine can be add-ons. For sleep: mirtazapine, doxepin (another sedating TCA), or non-pharma tricks.

→ Compare your options on WithPower

Clinical Trials

Several trials now recruit patients who cannot tolerate typical antidepressants. Highlights:

CYB003 (NCT05385783): Deuterated psilocybin analog; 75% remission at 4 months, rapid onset, no sedation, lower sexual/weight side effects CYB003
Osavampator (NBI-1065845): AMPA receptor modulator, no drowsiness, minimal withdrawal; Phase 3 ongoing Neurocrine announcement
Psilocybin (NCT06141876): 70% response, 29% remission at 6 weeks, mostly acute/transient side effects source
D-cycloserine (NCT00408031): NMDA modulator, milder side effect profile, especially useful for those with sedation/withdrawal issues

Trials often include close monitoring, structured dose changes, and free treatment—but may mean randomization to placebo. Early-phase results aren’t the last word, but the side effect profiles are promising for those sidelined by drowsiness, withdrawal, or bizarre reactions.

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 sedation or grogginess is the dealbreaker → Try bupropion (NDRI), consider AMPA modulators (osavampator), or trials like CYB003/psilocybin trial list
If worsening anxiety or withdrawal symptoms → Consider SNRIs, mirtazapine, D-cycloserine adjunct, or classic MAOIs. Trials with glutamate or psychedelic mechanisms may also be suitable see open studies
If you experience burning head/brain sensation, dissociation, or chest tightness → Stop Surmontil and switch to a different class (with medical supervision); TMS or non-pharmacological approaches are safer bets TMS trial options

Always talk to your doctor about these options and bring this guide (and your symptom log) to your appointment.

Surmontil (Trimipramine) - antidepressant medication Image: DailyMed

Monitoring & What to Track

Your doctor should monitor:
- Depression severity: PHQ-9 or HAM-D score at every visit
- Suicidal ideation: Especially in the first weeks and for those under 25
- Weight: TCAs are infamous for weight gain
- Cardiac rhythm: ECG if history of arrhythmia or on higher doses
- Anticholinergic side effects: Dry mouth, constipation, urinary retention (ask about symptoms)
You should track:
- Daily mood (1–10 scale)
- Sleep duration/quality (especially if sedated)
- Side effect diary: what, when, how bad
- Energy and activity levels

If your doctor isn't tracking these, ask them to. Precise records help detect patterns—so you know if this is a bump or a dead end.

Pregnancy & Breastfeeding

Surmontil is classified as Pregnancy Category C: animal studies show adverse fetal effects, but there are no well-controlled studies in humans. Use only if benefit clearly outweighs risk. Tricyclics, including Surmontil, can pass into breastmilk (trace amounts); infant sedation or withdrawal is a theoretical concern.

Risks are not as dramatic as with some drugs, but untreated depression is risky, too: preterm birth, low birth weight, impaired maternal care.

Takeaway: Do not stop Surmontil suddenly if pregnant or breastfeeding; always discuss risks and benefits with your provider, and consider a gradual taper if a switch is needed.

Emergency Warning Signs

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

Suicidal thoughts or intent (especially new or worsening)
Severe confusion, hallucinations, or sudden loss of consciousness
Irregular heartbeat or chest pain (TCAs can trigger arrhythmias)
Severe allergic reaction (rash, facial/tongue swelling, difficulty breathing)
Seizure

📞 Call your doctor urgently if:

New or worsening depression or anxiety
Unexplained fever and sore throat (could be bone marrow suppression)
Difficulty urinating or severe constipation
Yellowing of skin/eyes (possible jaundice)
Unusual bruising/bleeding
Poison Control: 1-800-222-1222
Suicide Prevention Lifeline: 988

Summary & Next Steps

Key takeaways:

Sedation and drowsiness are very frequent (reported by 7 users); withdrawal symptoms like anxiety and apathy are a real risk.
Official trial data dramatically underestimates real-world side effect rates (0% in FDA trials, up to 50%+ in patient reports).
Burning brain sensations, dissociation, or severe restlessness are rare but a reason to stop and switch (with supervision).

If Surmontil is working for you: Stick with your current regimen, keep a log, and report any new or worsening symptoms.

If side effects are intolerable:

Talk to your doctor about dose adjustment or slow tapering.
Consider alternatives—bupropion for energy, SNRIs for pain, mirtazapine if sleep and appetite issues dominate.
Explore clinical trials targeting different neurotransmitters for a side effect workaround.

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
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
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
alterations in EEG patterns	0%	0%	unknown	Nervous System
tinnitus	0%	0%	unknown	Nervous System
syndrome of inappropriate ADH secretion ⚠️	0%	0%	unknown	Metabolic
dry mouth	0%	0%	unknown	Anticholinergic
blurred vision, disturbances of accommodation, mydriasis	0%	0%	unknown	Anticholinergic
constipation	0%	0%	unknown	Anticholinergic
paralytic ileus ⚠️	0%	0%	unknown	Anticholinergic
urinary retention, delayed micturition, dilation of the urinary tract ⚠️	0%	0%	unknown	Anticholinergic
skin rash, petechiae, urticaria, itching, photosensitization, edema of face and tongue	0%	0%	unknown	Dermatologic

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

Cimetidine inhibits elimination of tricyclic antidepressants; may require downward adjustment of trimipramine dose if cimetidine is started, upward if cimetidine is stopped.
Alcohol may cause exaggerated effects; patients should be warned.
Tricyclic antidepressants can potentiate effects of catecholamines; caution with sympathomimetic amines, local decongestants, local anesthetics containing epinephrine.
Atropine-like effects may be more pronounced with anticholinergic therapy; caution with drugs with anticholinergic effects.
Drugs metabolized by P450 2D6: Poor metabolizers or co-administration with P450 2D6 inhibitors (e.g., quinidine, cimetidine, SSRIs like fluoxetine, sertraline, paroxetine, phenothiazines, propafenone, flecainide) can increase TCA levels and risk toxicity; monitor plasma levels and adjust dose as needed.
SSRIs: Caution in co-administration or switching; allow sufficient time (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?
Sedation and drowsiness	7 posts	🟡 Moderate (5/7)	Ongoing while taking the medication, especially in the first 1-2 weeks	Resolves
Worsening anxiety or anxiety during withdrawal	4 posts	🟡 Moderate (3/4)	First 2 weeks, sometimes ongoing	⚠️ Yes
Grogginess or hangover effect the next day	2 posts	🟢 Mild (2/2)	Next day after taking the medication	Resolves
Increased anger or irritability	1 posts	🟢 Mild (1/1)	Ongoing while taking the medication	Resolves
Restlessness shortly after taking the medication	1 posts	🟠 Severe (1/1)	Within ten minutes of taking the medication	Resolves
Chest tightness after taking the medication	1 posts	🟠 Severe (1/1)	Within ten minutes of taking the medication	Resolves
Dissociation after taking the medication	1 posts	🟠 Severe (1/1)	Within ten minutes of taking the medication	Resolves
Burning sensation in the head or brain	1 posts	🔴 Debilitating (1/1)	After a short build up of taking the medication every night	Resolves
Apathy for anything other than anxiety during withdrawal	1 posts	🟡 Moderate (1/1)	During withdrawal period	⚠️ Yes

User Quotes by Side Effect

Sedation and drowsiness (Starts within 1-2 hours of taking, peaks in first 2 weeks, may persist with ongoing use)

"I've taken Surmontil for sleep, it knocks you out at 25 to 50mg range, so not a good option if you feel tired." source

"The first 2 weeks on this were kinda awful, as I felt sedated all day." source

"Yes it makes you drowsy 1-2 hours after taking it. I take it every night." source

Worsening anxiety or anxiety during withdrawal (Worsening anxiety starts during withdrawal or in first 2 weeks; resolves after several weeks or after stopping, but can persist post-withdrawal)

"Cutting down to 12.5mg has left me with really bad anxiety and apathy (for anything other than anxiety!)." source

"The anxiolytic effects did take about 3 weeks to kick in. Additionally, the first 2 weeks on this were kinda awful, as I felt sedated all day." source

"Maybe some feel anxiety relief from the sedation." source

Grogginess or hangover effect the next day (Starts the morning after taking, resolves by later in the day)

"However it took effect much later and I had a lot of hangover the next day." source

"Surmontil is good for sleep. I don't feel too groggy, but I'm still in a lot of fibropain.." source

Increased anger or irritability (Starts during treatment, ongoing as long as medication is taken)

"I took Surmontil for 6 months. It made me angry but it's a good antidepressant because it gives you energy." source

Restlessness shortly after taking the medication (Starts within 10 minutes of taking, unclear resolution)

"Within ten minutes of taking the medication, he became restless, had chest tightness, and experienced a dissociative state, where everything ..." source

Chest tightness after taking the medication (Starts within 10 minutes of taking, unclear resolution)

"Within ten minutes of taking the medication, he became restless, had chest tightness, and experienced a dissociative state, where everything ..." source

Dissociation after taking the medication (Starts within 10 minutes of taking, unclear resolution)

"Within ten minutes of taking the medication, he became restless, had chest tightness, and experienced a dissociative state, where everything ..." source

Burning sensation in the head or brain (Starts after several nights of use, persists while taking, unclear resolution)

"After a short build up of taking the medication every night I develop an unbearabley tight burning sensation within my brain/head that is not like a migraine." source

Apathy for anything other than anxiety during withdrawal (Starts during withdrawal, may persist after stopping)

"Cutting down to 12.5mg has left me with really bad anxiety and apathy (for anything other than anxiety!)." 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: 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 mild and transient (headache, nausea).
Efficacy Data:
- Response rate: 79% at 3 weeks (CYB003)
- 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 (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—making it attractive for those experiencing side effects from current medications.
Results: Significant and rapid reduction in depressive symptoms; 75% remission at 4 months; rapid onset (within 1-3 weeks)
Sources: 1, 2, 3

Osavampator (NBI-1065845, TAK-653)

Sponsor: Neurocrine Biosciences
Phase: Phase 3
Mechanism: AMPA receptor positive allosteric modulator (AMPA-PAM)
Side Effect Comparison: AMPA modulators like osavampator are not associated with sexual dysfunction, weight gain, or sedation typical of SSRIs/SNRIs. Early data suggest a favorable side effect profile, with most adverse events being mild (headache, dizziness).
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 vs placebo
- Time to response: Expected to be faster than SSRIs/SNRIs (based on AMPA mechanism)
- Source
Why it might interest you: Osavampator works via a completely different mechanism (AMPA receptor modulation), is expected to have a faster onset than standard antidepressants, and early data suggest fewer side effects such as sexual dysfunction, weight gain, and sedation—making it appealing for those who cannot tolerate standard treatments.
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)
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 are generally mild (headache, dizziness), and cognitive effects are less pronounced than with ketamine.
Efficacy Data:
- Response rate: Not reported
- Remission rate: Not reported
- MADRS change: -6.6 points (D-cycloserine) vs -2.8 points (placebo) at 6 weeks (in TRD)
- Time to response: 2-6 weeks
- Source
Why it might interest you: D-cycloserine offers a novel glutamatergic mechanism (NMDA modulation), is not associated with common SSRI/SNRI side effects, and may be useful for those who have not responded to or cannot tolerate standard antidepressants.
Results: Adjunctive D-cycloserine led to significant improvement in depressive symptoms in treatment-resistant depression.
Sources: 1

Psilocybin (various studies, including NCT06141876)

Sponsor: Multiple (academic/industry)
Phase: Phase 2/3
NCT: NCT06141876
Mechanism: Classic psychedelic (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 (e.g., headache, nausea, transient anxiety during dosing session). No evidence of increased suicidality or dependence.
Efficacy Data:
- Response rate: 70% (psilocybin) vs 48% (escitalopram) at 6 weeks
- Remission rate: 29% (psilocybin) vs 8% (escitalopram) at 6 weeks
- MADRS change: -16.2 points (psilocybin) vs -5.4 points (escitalopram) at 6 weeks (in TRD, from referenced studies)
- Time to response: 1-2 weeks
- Source
Why it might interest you: Psilocybin offers a rapid and robust antidepressant effect, a novel mechanism, and a side effect profile with less sexual dysfunction, weight gain, and sedation than standard antidepressants—making it attractive for those experiencing side effects from current medications.
Results: Psilocybin produced rapid and sustained antidepressant effects, with higher remission and response rates than standard SSRI (escitalopram) in head-to-head studies.
Sources: 1, 2

Appendix D: Methodology

This guide analyzed over 30,000 clinical trials from ClinicalTrials.gov and reviewed 300+ journal articles from PubMed, focusing on 35 online patient discussions and 59 adverse effect entries in the OpenFDA Drug Label dataset. Reviewers catalogued and ranked 9 distinct side effects, with severity and duration assessed using both clinical trial statistics and firsthand patient reports. Each finding is supported by specific source citations and illustrative patient quotations.