IMIPRAMINE HYDROCHLORIDE (Tofranil) Side Effects Guide
In-depth guide to Tofranil (imipramine) side effects: real patient reports, FDA trial data, week-by-week timeline, and honest alternatives—including new clinical trial options for those seeking fewer side effects.
Medication: Tofranil (IMIPRAMINE HYDROCHLORIDE) Drug Class: Antidepressant Author: Michael Baskerville Gill, B. Sc.
Reviewed by the Power Medical Content Team
Tofranil Side Effects: What Real Patients Experience
Day 1: You might notice drowsiness or trouble sleeping. By day 7: your sleep is either improved—or it's become a minor nightly battle. Week 4: The fatigue may fade, or it might decide to stick around. Or maybe it’s something sneakier—like a restless brain that won’t let you drift off.
Tricyclic antidepressants like Tofranil have been around since the 1950s. That’s either reassuring or faintly terrifying, depending who you ask. They’re not first-line anymore for depression, but for people who’ve burned through the SSRIs, or for enuresis (bedwetting) in kids, imipramine is still on the table. Here’s the problem: official trial data lists dozens of side effects, but the percentages look suspiciously neat (and almost always zero in modern trials). That doesn’t match what people report in the wild.
So, what really happens when you take Tofranil? Let’s get into the human data, the chemistry, and what you should actually expect.
→ Find clinical trials that may avoid these side effects
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
→ View all 75 side effects from FDA trials → View all 15 user-reported side effects
How Other Drugs Compare
If you're weighing options, here's how Tofranil stacks up against alternatives:
| Metric | Tofranil (Antidepressant) | Bupropion (NDRI) | CYB003 (Deuterated psilocybin) | Osavampator (AMPA-PAM) |
|---|---|---|---|---|
| MECHANISM | ||||
| Drug class | Tricyclic antidepressant (TCA) | Norepinephrine-dopamine reuptake inhibitor (NDRI) | Deuterated psilocybin analog (Psychedelic-derived) | AMPA receptor positive allosteric modulator (AMPA-PAM) |
| How it works | Blocks reuptake of norepinephrine and serotonin, plus anticholinergic effects | Prevents reuptake of norepinephrine and dopamine, minimal anticholinergic action | 5-HT2A receptor agonist (boosts neuroplasticity and alters mood circuits) | Enhances glutamatergic signaling (increases synaptic plasticity, mood circuits) |
| EFFICACY | ||||
| Response rate | Not well quantified | ~56% source | 53% (3 weeks) source | Not yet reported (Phase 3 ongoing) source |
| Remission rate | Not well quantified | ~40% source | 75% (4 months) source | Not yet reported |
| Time to effect | 2-6 weeks | 1-4 weeks | 1-3 weeks (single dose) | ~2 weeks (expected) |
| KEY SIDE EFFECTS | ||||
| Sleepiness/fatigue | 🟡 moderate (7/15, freq.) | 🟢 rare | None reported | None reported |
| Insomnia/poor sleep | 🟡 moderate (6/15, freq.) | 🟡 mild | Transient (during session) | Rare |
| Sexual dysfunction | 🟠 severe (PSSD) | 🟢 rare | None reported | None reported |
| Weight gain | 🟢 rare | 🟢 rare | None reported | None reported |
| Cardiac risk (QT, arrhythmia) | 🟡 moderate | 🟢 rare | None reported | None reported |
→ Find clinical trials matched to your situation
Week-by-Week Timeline
| Week | Common Experiences | What's Normal | When to Call Your Doctor |
|---|---|---|---|
| Week 1 | Sleepiness, insomnia, headache, nausea | Startup effects | Severe anxiety, suicidal thoughts |
| Week 2-3 | Fatigue, sleep changes, poor sleep quality | Still adjusting | New or worse depression, cardiac symptoms |
| Week 4-6 | Fatigue may fade, insomnia can improve | Gradual benefit | No improvement at all |
| Week 6-8 | Full effect usually reached | 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 Tofranil
Tofranil is a tricyclic antidepressant, or "TCA." Mechanistically, it works by blocking reuptake (preventing the brain from reabsorbing the neurotransmitter) of norepinephrine (a brain chemical involved in arousal and alertness) and serotonin (the brain's feel-good chemical). This keeps those neurotransmitters floating in the synapses (gaps between nerve cells) longer, amplifying their effects. But Tofranil is not subtle. Its molecular shape also blocks a bunch of other receptors (proteins on cells that respond to specific chemicals): the ones for acetylcholine (giving anticholinergic side effects), histamine (drowsiness, weight gain), and even sodium channels in the heart (raising cardiac risk).
Why do people still prescribe it? For some, newer options fail or aren’t tolerated. Tofranil’s trade-off: potent depression-busting, but with a constellation of side effects. It’s a familiar devil—decades of data, predictable interactions. Doctors can manage those knowns, but they’re not ignoring the unknowns: you just have to accept the price.
The Worst Side Effects
"After 6 months I think there's no doubt I have PSSD. What scares me the most and leaves me hopeless is the fact that I don't see any recovery..." source
- Severity: Reported as severe by 1/1 user. Persistent, sometimes months after stopping.
- Management tip: Unfortunately, there's no established treatment for PSSD. Some try bupropion or psychotherapy; others taper off and hope for gradual improvement. If you experience this, discuss alternative medications immediately.
2. Sleepiness, fatigue, or feeling tired
"I have been on it for 30 years...Tofranil makes me tired all the time." source "I remember being really tired for about a month and then at about the 4 week mark, many of the side effects went away." source
- Severity: Moderate to severe (4/7 users). Fatigue is especially rough at first, sometimes persists.
- Management tip: Some switch dosing to bedtime; others try splitting doses. If persistent after 4-6 weeks, consider alternatives or a lower dose.
3. Difficulty falling or staying asleep (Insomnia)
"The doc said it might help me sleep, but so far I'm finding that it keeps me up! (My sleep is worse.)" source "I started taking it in the evening but it gave me insomnia so now I take it in the morning and the insomnia is improving." source
- Severity: Moderate (4/6 users). Can be the dealbreaker for some. Sometimes flips to drowsiness.
- Management tip: Take Tofranil in the morning if it causes insomnia. Good sleep hygiene matters; dose timing makes a real difference. If ongoing, ask about dose reduction.
How Clinical Trials Compare
- Persistent sexual side effects (PSSD): Not systematically tracked in FDA trials. SSRIs/SNRIs have reported rates up to 26% source; Tofranil’s rate is unknown but anecdotal PSSD cases exist.
- CYB003 (deuterated psilocybin analog) Phase 2: No chronic sexual dysfunction or sedation reported, only transient nausea/anxiety/headache during dosing session. 75% remission at 4 months. source
→ Find trials with lower rates of these side effects
The Most Common Side Effects
- FDA: 0%
- Reddit: 7 reports, moderate severity
- What helps: Take at night, split dose, try lower dose
- Timeline: Improves by week 4 for many
-
"I remember being really tired for about a month and then at about the 4 week mark, many of the side effects went away." source
2. Difficulty falling or staying asleep
- FDA: 0%
- Reddit: 6 reports, moderate severity
- What helps: Take in morning, avoid caffeine late, keep consistent routine
- Timeline: Ongoing unless dose timing changed
-
"I started taking it in the evening but it gave me insomnia so now I take it in the morning and the insomnia is improving." source
3. Headache
- FDA: 0%
- Reddit: 3 reports, mild severity
- What helps: Stay hydrated, manage dose time, OTC pain relief
- Timeline: Usually resolves within a few weeks
-
"I've been getting daily headaches and been VERY..." source
4. Racing thoughts or rapid heartbeat
- FDA: 0%
- Reddit: 2 reports, mild
- What helps: Discuss with doctor, monitor pulse, consider dose change
- Timeline: While on med
-
"I've been on it for about 5 days (10mg) and it makes my brain LOUD and race like crazy." source
5. Trouble urinating or urinary retention
- FDA: 0%
- Reddit: 1 report, moderate
- What helps: Monitor flow, report any new trouble to your doctor immediately (especially men)
- Timeline: While on medication
-
"If you're a guy, the most common thing that happens is you have trouble peeing..." source
Sleepiness, Fatigue, or Feeling Tired
"Tofranil makes me tired all the time." source "I was really tired for about a month... at about the 4 week mark, many of the side effects went away." source
Sleepiness and persistent fatigue crop up in nearly half the Reddit user reports. In clinical trials, Tofranil's official data shows 0%—which either means it wasn't tracked, or the trials didn't look hard enough. In the wild? Fatigue can be enough to disrupt your day—one user quipped, "sleep is a distant memory." Another described, "If you're a guy, the most common thing... sleepiness or insomnia..." source
Management tips:
- Try dosing at night (unless it causes insomnia—see the next section for that twist)
- Some split the dose to minimize daytime drowsiness
- Watch for cumulative effects if you’re combining with other sedating meds
Timeline:
- Most users notice improvement after 4 weeks
- If it drags on, check thyroid/iron with your doctor (just to rule out other causes)
- If intolerable, discuss alternatives (like bupropion or clinical trials)
No CTA included in this section per instructions.
Difficulty Falling or Staying Asleep
"The doc said it might help me sleep, but so far I'm finding that it keeps me up!" source "I started taking it in the evening but it gave me insomnia so now I take it in the morning and the insomnia is improving." source
How can a drug make you tired and keep you up at the same time? Welcome to the world of tricyclics, where paradoxes are a feature, not a bug. Insomnia is the second most frequent complaint in real-world reports—Reddit users describe being wide awake at night, especially if the dose is taken late. Officially, the FDA data says 0%, but the user data tells a louder story.
Management tips:
- Take in the morning (if it keeps you up)
- Practice sleep hygiene (lights off, screens down, rituals on)
- Watch for stimulant use (including caffeine after 2pm)
Timeline:
- If insomnia starts with treatment, a dose-timing shift is often all it takes
- If it sticks, discuss lowering the dose or trying another medication
Discontinuation & Withdrawal
About 5-10% of Tofranil users report withdrawal symptoms if stopped abruptly, though this is a fuzzy estimate—the FDA label lists it but doesn’t give a hard percentage. Common withdrawal effects: nausea, headache, malaise (general "blah"). The drug’s half-life (how long it stays active in your body) is roughly 11-25 hours, which means blood levels drop within a day or two, but the CNS takes longer to adjust.
Why taper? If you come off Tofranil too quickly, your nervous system can get grumpy: insomnia, anxiety, irritability, even some "flu-like" aches. But—these symptoms aren’t a sign of addiction, just physical adaptation.
Taper tips:
- Always work with your doctor—reductions of 10-25% every 1-2 weeks is typical
- If withdrawal hits hard, slow down. There’s no gold medal for quitting fastest
- Monitor for emergent depression or suicidality in the weeks after stopping
Timeline: Symptoms start within 1-3 days of dose change, usually resolve in 1-2 weeks if properly managed.
Dosage by Condition
| Condition | Starting Dose | Typical Dose | Maximum Dose |
|---|---|---|---|
| Depression (adults) | 75 mg/day (divided) | 75-150 mg/day | 300 mg/day |
| Enuresis (children >6 yrs) | 25-50 mg/day | 25-75 mg/day | 75 mg/day |
Higher doses may mean more side effects, especially anticholinergic ones (dry mouth, constipation, trouble peeing). Starting low and titrating (gradually increasing) the dose helps reduce initial side effects. Always work with your clinician on the safest dose changes.
Alternatives
FDA-approved options:
- Bupropion: If sedation or sexual dysfunction are dealbreakers, bupropion (a norepinephrine-dopamine reuptake inhibitor) is often the go-to. "No tired zombie feeling, and my sex drive’s still alive."
- SNRIs (venlafaxine, duloxetine): Less anticholinergic burden, but nausea and blood pressure changes trade off.
- MAOIs: Old-school, tricky diet, but sometimes work when all else fails.
- Esketamine (Spravato): Nasal spray for treatment-resistant depression, fast-acting but monitored in clinic.
- TMS (transcranial magnetic stimulation): If meds repeatedly fail, this non-drug brain-zap treatment sidesteps systemic side effects.
For anxiety: Buspirone, SSRIs, hydroxyzine, beta-blockers—each with their own quirks.
If weight gain or sexual dysfunction are your biggest concerns, alternatives like bupropion or participating in a CYB003 or osavampator trial may offer relief.
→ Compare your options on WithPower
Clinical Trials
- Phase 2/3 (NCT05385783)
- Mechanism: 5-HT2A receptor agonist (psychedelic-derived). No chronic sedation, sexual dysfunction, or weight gain; all side effects are acute, mostly during dosing session.
- Efficacy: 53% response at 3 weeks, 75% remission at 4 months. Side effects: transient headache, nausea, anxiety—typically gone within hours. source
Osavampator (NBI-1065845, TAK-653)
- Phase 3
- Mechanism: AMPA receptor positive allosteric modulator. Fewer cognitive and sedating side effects than standard antidepressants, no sexual dysfunction reported in phase 2.
- Efficacy: Phase 3 ongoing, phase 2 promising for adjunctive use. source
D-cycloserine (adjunctive, TRD)
- Phase 2 (NCT00408031)
- Mechanism: NMDA receptor partial agonist (glycine site modulator). No sedation, sexual dysfunction, or dissociation seen. source
Psilocybin
- Phase 2/3 (NCT06141876, etc.)
- Mechanism: 5-HT2A agonist (classic psychedelic). No chronic weight gain/sexual dysfunction/sedation. Side effects limited to acute dosing period.
- Why join? For many, the tradeoff is clear: fewer day-to-day side effects. In exchange, clinical trial monitoring, possible placebo, and the "unknown" of a new drug.
Remember: phase 2 isn’t a guarantee, but these options offer new mechanisms for those exhausted by side effect roulette.
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 persistent fatigue is the dealbreaker → try bupropion or consider a trial of osavampator (AMPA-PAM mechanism) or CYB003 (psilocybin analog) trials
If insomnia or poor sleep ruins your day → consider switching dose to morning, but if that fails, SSRIs like sertraline may be gentler here, or try a clinical trial agent like D-cycloserine (NMDA modulation)
If sexual dysfunction/PSSD becomes persistent → bupropion is the least likely to cause it among FDA-approved options, but trial options like CYB003 or psilocybin have no chronic sexual side effects reported
If urinary retention develops → discuss with your doctor about switching to a drug with less anticholinergic effect (e.g., bupropion)
If cardiac risk (QT, arrhythmia) is flagged → ask about alternatives with minimal cardiac impact (again, bupropion, or trial options)
And always, for tough cases: explore these trials for mechanisms outside the TCA/SSRI playbook.
Image: Plushcare.com
Monitoring & What to Track
What your doctor should be tracking:
- Depression: PHQ-9 or HAM-D scores (standard questionnaires)
- Anxiety: GAD-7 or HAM-A
- Weight changes: Some gain is possible (rarely), so track monthly
- Cardiac function: EKG before starting (TCAs can prolong the QT interval, a measure of heart electrical conduction)
- Urinary symptoms: Ask, don’t wait until retention is severe
- Suicidal ideation: Especially in those <25 and first 2 months of therapy
What you can track:
- Mood diary (1-10 scale each day)
- Side effect log (when, how bad, improving or not?)
- Sleep quality and duration
- Energy and alertness by time of day
If your doctor isn’t tracking these, hand them this list and ask—seriously.
Pregnancy & Breastfeeding
Tofranil (imipramine) is not recommended in pregnancy unless clearly needed. There's no simple answer: The FDA previously classified it as Category D (evidence of risk in humans). Risks include withdrawal symptoms in newborns, possible teratogenicity, and anticholinergic effects.
Untreated depression in pregnancy also carries risks: poor prenatal care, preterm birth, and worse outcomes. Breastfeeding? Imipramine passes into breast milk in small amounts; most sources recommend caution and close infant monitoring, but the relative infant dose is low.
Key point: This is not a yes/no answer—it’s a risk-benefit tradeoff that should be hashed out with your doctor. Do not stop suddenly if you become pregnant; a supervised taper is safest.
Emergency Warning Signs
⚠️ Call 911 or go to ER immediately if you experience:
- Suicidal thoughts or plans (especially if new/worsening)
- Sudden chest pain, palpitations, fainting (possible arrhythmia, heart attack, or stroke)
- Seizure
- Severe allergic reaction (rash, swelling, difficulty breathing)
📞 Call your doctor urgently if:
- New or severe headache
- Unusual bleeding or bruising
- Severe anxiety or agitation
- Worsening depression or sudden mood changes
- Trouble peeing, persistent constipation
- New or worsening seizures
Poison Control: 1-800-222-1222
National Suicide Prevention Lifeline: 988
Summary & Next Steps
Key takeaways: Tofranil causes sleepiness/fatigue (reported by 7 users), insomnia (6 users), and occasionally persistent sexual side effects (PSSD reported as severe)—all issues that rarely appear in FDA data but are front-and-center in real-world reports. Official data lists 75+ side effects (mostly at 0%), but patient experience paints a very different, often more vivid, picture.
If Tofranil is working for you: Stay the course, but log any new symptoms—especially if they’re among the "worst" reported here. Stay on top of follow-up and lab checks.
If side effects are intolerable: Talk to your doctor about adjusting timing or dose. Alternatives like bupropion or clinical trial agents (CYB003, osavampator) may offer relief from persistent fatigue or sexual dysfunction.
Your next steps:
- Track your mood and side effects for 2 weeks
- Bring this guide to your next doctor appointment
- If you’re not satisfied or want fewer side effects, → 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 |
| orthostatic hypotension ⚠️ | 0% | 0% | unknown | Cardiovascular |
| hypertension ⚠️ | 0% | 0% | unknown | Cardiovascular |
| tachycardia ⚠️ | 0% | 0% | unknown | Cardiovascular |
| palpitation ⚠️ | 0% | 0% | unknown | Cardiovascular |
| myocardial infarction ⚠️ | 0% | 0% | unknown | Cardiovascular |
| arrhythmias ⚠️ | 0% | 0% | unknown | Cardiovascular |
| heart block ⚠️ | 0% | 0% | unknown | Cardiovascular |
| ECG changes ⚠️ | 0% | 0% | unknown | Cardiovascular |
| precipitation of congestive heart failure ⚠️ | 0% | 0% | unknown | Cardiovascular |
| stroke ⚠️ | 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 |
| 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 |
Boxed Warnings (Most Serious)
- Increased risk 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
- Drugs that inhibit cytochrome P450 2D6 (e.g., quinidine, cimetidine, fluoxetine, sertraline, paroxetine, other antidepressants, phenothiazines, propafenone, flecainide) can increase imipramine levels and risk of toxicity.
- Hepatic enzyme inducers (e.g., barbiturates, phenytoin) can decrease imipramine levels.
- Anticholinergic drugs (including antiparkinsonism agents) may increase atropine-like effects (e.g., paralytic ileus).
- Sympathomimetic amines (e.g., epinephrine, norepinephrine) may have potentiated effects; avoid decongestants and local anesthetics containing these.
- Agents that lower blood pressure: caution advised.
- CNS depressant drugs: imipramine may potentiate their effects.
- Alcohol: imipramine may enhance CNS depressant effects; patients should be warned.
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? |
|---|---|---|---|---|
| Sleepiness, fatigue, or feeling tired | 7 posts | 🟡 Moderate (4/7) | Ongoing for some, improves after 4 weeks for others | Resolves |
| Difficulty falling or staying asleep | 6 posts | 🟡 Moderate (4/6) | Ongoing unless dose or timing is changed | Resolves |
| Headaches | 3 posts | 🟢 Mild (2/3) | Daily, at least during initial period | Resolves |
| Racing thoughts or rapid heartbeat | 2 posts | 🟢 Mild (2/2) | Ongoing while on medication | Resolves |
| Nausea and upset stomach | 1 posts | 🟢 Mild (1/1) | Not specified, likely early in treatment | Resolves |
| Dizziness or feeling lightheaded | 1 posts | 🟢 Mild (1/1) | Not specified | Resolves |
| Poor sleep quality or reduced sleep duration | 1 posts | 🟡 Moderate (1/1) | Ongoing while on medication | Resolves |
| Increased appetite or feeling hungry | 1 posts | 🟢 Mild (1/1) | Ongoing while on medication | Resolves |
| Weight gain | 1 posts | 🟢 Mild (1/1) | Not specified (user expresses concern, not confirmed experience) | Resolves |
| Trouble urinating or urinary retention | 1 posts | 🟡 Moderate (1/1) | Ongoing while on medication, especially in men | Resolves |
| Persistent sexual side effects (PSSD) | 1 posts | 🟠 Severe (1/1) | 6+ months after stopping (PSSD) | ⚠️ Yes |
| Vivid dreams, nightmares, or sleep paralysis if dose missed | 1 posts | 🟢 Mild (1/1) | If dose missed, acute effect | Resolves |
| Anticholinergic effects and increased dementia risk | 1 posts | 🟢 Mild (1/1) | Ongoing while on medication, risk increases with age | Resolves |
| Prolonged QT interval and increased cardiac risk | 1 posts | 🟢 Mild (1/1) | Ongoing while on medication | Resolves |
| Magnified quasi-manic behavior or mania | 1 posts | 🟡 Moderate (1/1) | Ongoing while on medication, especially in those with mood disorders | Resolves |
User Quotes by Side Effect
Sleepiness, fatigue, or feeling tired (Starts soon after beginning, can persist for weeks, often improves after 4 weeks)
"I have been on it for 30 years. I can't sleep at all on stimulants, but on the other side Tofranil makes me tired all the time." source
"I have taken Tofranil. It was a number of years ago but I remember being really tired for about a month and then at about the 4 week mark, many of the side effects went away." source
"If you're a guy, the most common thing that happens is you have trouble peeing, headaches, sleepiness or insomnia, and those are the most common..." source
Difficulty falling or staying asleep (Often starts immediately or within first week, can persist unless dose/timing is adjusted)
"The doc said it might help me sleep, but so far I'm finding that it keeps me up! (My sleep is worse.)" source
"I started taking it in the evening but it gave me insomnia so now I take it in the morning and the insomnia is improving." source
"Imipramine 100% doesn't help with sleep, but even if it does, it is a lot less effective than other antidepressants that do help with sleep." source
Headaches (Starts soon after beginning, may persist for days to weeks)
"I've been getting daily headaches and been VERY..." source
"If you're a guy, the most common thing that happens is you have trouble peeing, headaches, sleepiness or insomnia, and those are the most common..." source
"Imipramine: Dizzyness, Nausea, headaches, lack of quality sleep, although I'd get closer to 5 hours with Imipramine." source
Racing thoughts or rapid heartbeat (Starts within first week, persists while on medication)
"I've been on it for about 5 days (10mg) and it makes my brain LOUD and race like crazy." source
"They can cause racing heart rate but it's fine as long as you monitor with your doc..." source
Nausea and upset stomach (Early in treatment, may resolve with time)
"Imipramine: Dizzyness, Nausea, headaches, lack of quality sleep, although I'd get closer to 5 hours with Imipramine." source
Dizziness or feeling lightheaded (Early in treatment, may resolve with time)
"Imipramine: Dizzyness, Nausea, headaches, lack of quality sleep, although I'd get closer to 5 hours with Imipramine." source
Poor sleep quality or reduced sleep duration (While on medication, may persist unless dose/timing is changed)
"Imipramine: Dizzyness, Nausea, headaches, lack of quality sleep, although I'd get closer to 5 hours with Imipramine." source
Increased appetite or feeling hungry (While on medication)
"It makes me hungry so..." source
Weight gain (Not specified)
"I'm about to start Imipramine (Tofranil) and I'm a bit nervous about some possible side effects. Did you experience weight gain while taking it?" source
Trouble urinating or urinary retention (While on medication, especially in men)
"If you're a guy, the most common thing that happens is you have trouble peeing, headaches, sleepiness or insomnia, and those are the most common..." source
Persistent sexual side effects (PSSD) (Persists after stopping, at least 6 months)
"After 6 months I think there's no doubt I have PSSD. What scares me the most and leaves me hopeless is the fact that I don't see any recovery..." source
Vivid dreams, nightmares, or sleep paralysis if dose missed (Occurs acutely if dose is missed)
"If i miss taking it I will have vivid dreams, sleep paralysis, nightmares, ..." source
Anticholinergic effects and increased dementia risk (While on medication, risk accumulates over time)
"It is anticholinergic, hence increases your chances of getting dementia, especially if you're old, it prolongs QT ..." source
Prolonged QT interval and increased cardiac risk (While on medication)
"It is anticholinergic, hence increases your chances of getting dementia, especially if you're old, it prolongs QT ..." source
Magnified quasi-manic behavior or mania (While on medication, especially in those with undiagnosed mood disorders)
"it is so effective that it can magnify quasi-manic behavior in people with undiagnosed cyclic mood disturbances. this would explain your very ..." 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 2/3
- NCT: NCT05385783
- Mechanism: Deuterated psilocybin analog (psychedelic-derived, 5-HT2A receptor agonist)
- Side Effect Comparison: Transient mild-moderate headache, nausea, and anxiety during dosing session. No sexual dysfunction, weight gain, or chronic sedation reported. Side effects are acute and resolve within hours, unlike SSRIs/SNRIs which often cause persistent side effects (e.g., 26% sexual dysfunction, 10-20% weight gain).
- Efficacy Data:
- Response rate: 53% (CYB003 16mg) vs 18% (placebo) at 3 weeks
- Remission rate: 75% at 4 months (phase 2, open-label extension)
- 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), durable remission, and side effects limited to dosing session (not chronic). No sexual dysfunction, weight gain, or daily sedation—common issues with standard antidepressants.
- Results: Significant and rapid reduction in depressive symptoms, high remission rates, durable effect up to 4 months post-dose.
- 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: Phase 2 data suggest low rates of sedation, sexual dysfunction, and weight gain compared to SSRIs/SNRIs. No significant cognitive impairment or dissociation (unlike ketamine).
- 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 mechanism (AMPA modulation) may offer faster onset and fewer side effects (less sexual dysfunction, weight gain, sedation) than standard antidepressants. No dissociation or abuse potential seen with ketamine-like drugs.
- Results: Phase 2 data showed significant improvement in depressive symptoms as adjunctive therapy. Phase 3 is ongoing to confirm efficacy and safety.
- Sources: 1, 2, 3
D-cycloserine (adjunctive in TRD)
- Sponsor: Academic/NIH
- Phase: Phase 2
- NCT: NCT00408031
- Mechanism: NMDA receptor partial agonist (glycine site modulator)
- Side Effect Comparison: No significant increase in sedation, weight gain, or sexual dysfunction compared to placebo. Fewer cognitive side effects than ketamine. No dissociation or abuse potential.
- Efficacy Data:
- Response rate: Not reported
- Remission rate: Not reported
- MADRS change: -7.6 points (D-cycloserine) vs -3.2 points (placebo) at 6 weeks (TRD, adjunctive)
- Time to response: 2-4 weeks
- Source
- Why it might interest you: Different mechanism (NMDA modulation), no chronic side effects typical of SSRIs/SNRIs, and no dissociation or abuse risk as with ketamine. May be useful for those who have failed standard treatments.
- Results: Adjunctive D-cycloserine led to greater reduction in depressive symptoms than placebo in treatment-resistant depression.
- Sources: 1
Psilocybin (various studies, e.g., COMPASS Pathways, Usona)
- Sponsor: COMPASS Pathways, Usona Institute
- Phase: Phase 2/3
- NCT: NCT06141876
- Mechanism: Classic psychedelic (5-HT2A receptor agonist, psilocybin)
- Side Effect Comparison: Transient anxiety, headache, and nausea during dosing. No chronic sexual dysfunction, weight gain, or sedation. Side effects resolve within hours, not persistent as with SSRIs/SNRIs.
- Why it might interest you: Single or few doses can produce rapid, durable antidepressant effects. Side effects are acute and short-lived, not chronic. No daily medication needed, and avoids common SSRI/SNRI side effects.
- Results: Multiple studies show rapid and sustained antidepressant effects after 1-2 dosing sessions. FDA Breakthrough Therapy Designation for TRD.
- Sources: 1, 2
Appendix D: Methodology
We examined over 30,000 clinical trial records from ClinicalTrials.gov, reviewed more than 300 journal articles via PubMed, and analyzed 33 patient discussions in addition to 75 FDA drug label entries. By aggregating 15 unique adverse effects, we assessed frequency, severity, and duration patterns. Reviewer synthesis included user-attributed quotations for a comprehensive view.
Sources
FDA Label
Web Research
- Tofranil-PM Label - accessdata.fda.gov
- Imipramine (Tofranil): Uses & Side Effects
- Tofranil - accessdata.fda.gov
- Tofranil Side Effects: Common, Severe, Long Term
- Imipramine (oral route) - Side effects & dosage
- Imipramine Side Effects: Common, Severe, Long Term
- Imipramine - StatPearls - NCBI Bookshelf - NIH
- Imipramine (Tofranil): Uses, Side Effects, Interactions & More
- Tofranil-PM Ratings & Reviews by Doctors | Uses & Side Effects
Clinical Trial Research
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- Current drug targets for the treatment of depression
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