SELEGILINE (Emsam) Side Effects Guide

Table of Contents

Emsam (Selegiline) Side Effects: Real Data & Real Stories

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Emsam

The Worst Side Effects

The Most Common Side Effects

Difficulty Falling or Staying Asleep (Insomnia)

Increased Anxiety and Agitation

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

Emsam (Selegiline) Side Effects: Real Data & Real Stories

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Emsam

The Worst Side Effects

The Most Common Side Effects

Difficulty Falling or Staying Asleep (Insomnia)

Increased Anxiety and Agitation

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 guide to Emsam (selegiline) side effects: FDA trial rates, real patient experiences, worst and most common effects, management tips, alternatives, and clinical trial options for depression. Honest, data-driven, and patient-focused.

Medication: Emsam (SELEGILINE) Drug Class: Monoamine Oxidase Inhibitor [EPC] Author: Michael Baskerville Gill, B. Sc.

Reviewed by the Power Medical Content Team

Emsam (Selegiline) Side Effects: Real Data & Real Stories

Day 2: Mild headache and a tingling feeling under the patch. Day 7: Sleep's getting weird—"the insomnia was relentless," as one user bluntly put it source. Week 3: Mood shifting, anxiety prickling at the edges. Week 6: Some glimpse of improvement, but still feeling "more agitated/anxious/irritable than usual" source.

Emsam (selegiline transdermal patch) is the oddball of antidepressants: a Monoamine Oxidase Inhibitor (MAOI) you stick on your skin. This patch sidesteps many dietary headaches at lower doses but brings its own batch of quirks—especially insomnia, blood pressure changes, and skin reactions. Officially, most side effects are called "mild" or "rare" in trials. In reality? Some stick around, some get weirdly worse before better, and some (think relentless insomnia or "robotic" emotional numbness) can blindside even seasoned med veterans. Standard antidepressants often fizzle for treatment-resistant depression; that's why people (and prescribers) keep circling back to Emsam, despite its reputation for side effects and dietary drama. The reality: results are inconsistent, the trade-offs are real, and honest data is overdue.

Interested in clinical trials? Many trials for depression now target different mechanisms than Monoamine Oxidase Inhibitor [EPC]—potentially offering different side effect profiles. Browse clinical trials →

Side Effects Overview Table

Side Effect	FDA Rate	Reddit Reports	Severity	Duration	Example
Increased anxiety and agitation	N/A	🟠 Frequent (7 posts)	🟡 Moderate	Ongoing, weeks	source
Difficulty falling or staying asleep	12%	🟡 Occasional (4 posts)	🟠 Severe	Persistent, months–years	source
Increased irritability or short temper	N/A	🟡 Occasional (4 posts)	🟢 Mild	Ongoing, variable	source
Emotional numbness or feeling robotic	N/A	🟢 Rare (3 posts)	🟡 Moderate	Ongoing	source
Dizziness and low blood pressure when standing up	9.8% (orthostatic BP)	🟢 Rare (2 posts)	🟠 Severe	Acute/ongoing	source
Persistent tiredness or lack of energy	N/A	🟢 Rare (2 posts)	🟡 Moderate	Ongoing	source
Nausea and upset stomach during withdrawal	9% (diarrhea)	🟢 Rare (1 post)	🟢 Mild	Withdrawal	source
Skin flushing during withdrawal	N/A	🟢 Rare (1 post)	🟢 Mild	Withdrawal	source
Rapid and irregular heartbeat	N/A	🟢 Rare (1 post)	🟡 Moderate	Acute	source
Increased gas and flatulence	N/A	🟢 Rare (1 post)	🟢 Mild	Ongoing	source
Heavy inflammation after prolonged use	N/A	🟢 Rare (1 post)	🟡 Moderate	Months	source
Serotonin syndrome	0%	🟢 Rare (1 post)	🔴 Debilitating	Acute	source
Feeling more agitated than usual	N/A	🟢 Rare (1 post)	🟢 Mild	Ongoing	source
Lingering brain fog and cognitive dulling	N/A	🟢 Rare (1 post)	🟡 Moderate	Ongoing	source
Anxiety and overstimulation in dogs	N/A	🟢 Rare (1 post)	🟡 Moderate	Acute	source

→ View all 34 side effects from FDA trials → View all 15 user-reported side effects

How Other Drugs Compare

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

Metric	Emsam (Monoamine Oxidase Inhibitor [EPC])	CYB003 (Deuterated Psilocybin Analogue)	Osavampator (AMPA-PAM)	D-cycloserine (NMDA partial agonist)
MECHANISM
Drug class	MAOI (patch)	Psychedelic analogue	AMPA receptor modulator	NMDA receptor partial agonist
How it works	Blocks MAO-B enzyme to raise brain dopamine, norepinephrine, serotonin levels	Activates 5-HT2A receptor (psychedelic effect)	Boosts AMPA receptor response (increases synaptic activity)	Enhances glycine binding to NMDA receptor
EFFICACY
Response rate	Not specified	53% @ 3wks source	Not yet reported (Ph3)	Not reported
Remission rate	Not specified	75% @ 4mo source	Not yet reported	Not reported
Time to effect	2–6 weeks	1–3 weeks	1–2 weeks	2–4 weeks
KEY SIDE EFFECTS
Anxiety/agitation	~5–15%	10% transient	<5%	<5%
Insomnia	12%	N/A	N/A	N/A
Weight gain	2.1%	0%	0%	0%
Sexual dysfunction	~1% (likely underreported)	0%	0%	0%

→ Find clinical trials matched to your situation

Week-by-Week Timeline

Week	Common Experiences	What's Normal	When to Call Your Doctor
Week 1	Patch-site redness, headache, anxiety, irritability	Startup effects	Suicidal thoughts, severe insomnia
Week 2-3	Insomnia, more agitation, appetite changes	Body adjusting	Worsening depression, intense agitation
Week 4-6	Possible early mood lift, persistent insomnia/irritability	Subtle improvement	No benefit, intolerable side effects
Week 6-8	Plateau—what you get may be what you keep	Stabilization	Orthostatic fainting, blood pressure issues

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 Emsam

Emsam works by blocking monoamine oxidase B (MAO-B), an enzyme that breaks down dopamine, norepinephrine, and (at higher doses) serotonin in the brain. This means your naturally produced mood-lifting neurotransmitters (brain chemicals that affect mood, motivation, and alertness) get to stick around longer at the synapses (the gaps between nerve cells where signals pass).

So why all the side effects? It’s partly because monoamine oxidase hangs out in more places than just your brain. Block it there, and you get more dopamine; block it everywhere else and blood pressure and sleep cycles get involved, sometimes with disastrous effect. The trade-off is stark: more robust antidepressant power for some, but a much higher rate of things like insomnia, blood pressure drops, and (in rare cases) life-threatening serotonin syndrome.

Despite these risks, prescribers still reach for Emsam when other treatments flop: its decades-long track record means side effect patterns are well-mapped, and it sidesteps many food interactions at low doses.

The Worst Side Effects

1. Difficulty falling or staying asleep (Insomnia)

"The insomnia was relentless." source Reported as severe by 3/4 users. Management tip: Apply the patch in the morning, avoid caffeine after noon, and talk to your doctor about adjunct sleep medications (gabapentin, Dayvigo, or short-term benzodiazepines—all under supervision).

2. Dizziness and low blood pressure when standing up (Orthostatic Hypotension)

"It tanked my blood pressure to about 80/60 and I would see stars walking up the stairs in my house." source Reported as severe by 2/2 users. Management tip: Rise slowly from sitting or lying positions, increase salt and fluid intake if appropriate, and monitor blood pressure regularly. If fainting, call your doctor—dose adjustment may be needed.

3. Serotonin syndrome (Dangerous drug reaction)

"After 3-4 months of being on EMSAM I have to quit for a while, maybe indefinitely, because of serotonin syndrome." source Reported as debilitating by 1/1 user. Management tip: Recognize early warning signs: confusion, fever, muscle rigidity, rapid heart rate. Stop all serotonergic meds and seek ER care. Never combine Emsam with SSRIs/SNRIs, meperidine, tramadol, or cough medicines like dextromethorphan.

How Clinical Trials Compare

CYB003 and other modern trial drugs show much lower rates of insomnia, blood pressure effects, and dangerous drug reactions. For example, CYB003 trials report only 10-20% mild headache or nausea and no serotonin syndrome or severe blood pressure effects source. That’s a big reason why people burned by MAOI side effects are watching these trials so closely.

→ Find trials with lower rates of these side effects

The Most Common Side Effects

1. Increased anxiety and agitation

FDA: N/A; Reddit: 7 posts (moderate)
"My libido and emotions are coming back, but so is my anxiety and my mind and body cannot rest." source
What helps: Dose adjustment, short-term adjuncts (gabapentin, low-dose benzodiazepines), and time. Usually starts early; may fade after a few weeks.

2. Difficulty falling or staying asleep (insomnia)

FDA: 12% (7% placebo); Reddit: 4 posts (severe)
"Stayed on it for most of a decade despite brutal insomnia..." source
What helps: Apply patch in AM, try sleep hygiene, ask about non-addictive sleep meds. Insomnia may not resolve spontaneously.

3. Increased irritability

FDA: N/A; Reddit: 4 posts (mild)
"I have noticed a little more irritability lately." source
What helps: Mindfulness, time, sometimes adjunct mood stabilizer. Often peaks in early weeks, then subsides.

4. Emotional numbness or feeling robotic

FDA: N/A; Reddit: 3 posts (moderate)
"Told my therapist I feel like a robot (dulled emotions...)." source
What helps: Dose reduction, reassessment. Often persists if not addressed.

5. Dizziness/low blood pressure when standing

FDA: 9.8% orthostatic change; Reddit: 2 posts (severe)
"It **tanked my blood pressure... I would see stars..." source
What helps: Stand up slowly, increase salt/fluid if ok, track blood pressure. May persist.

6. Persistent tiredness/fatigue

FDA: N/A; Reddit: 2 posts (moderate)
"The main issues I have been having are the fatigue and brain fog..." source
What helps: Manage sleep, screen for other causes. Sometimes ongoing.

7. Nausea and GI issues during withdrawal

FDA: 9% diarrhea, 4% dyspepsia; Reddit: 1 post (mild, withdrawal)
"I've had some nausea and skin flushing." source
What helps: Go slow on taper, hydrate, treat symptomatically. Resolves after stopping.

→ Find clinical trials that may avoid this side effect

Difficulty Falling or Staying Asleep (Insomnia)

If your brain starts feeling wired but your body is leaden, welcome to the club: "The insomnia was relentless," said one user, echoing three others who called it "brutal" or "persistent" source.

FDA label: 12% of patients reported insomnia (vs 7% placebo), but Reddit paints a harsher picture: severe for 3 out of 4 users who posted, sometimes lasting years. "Stayed on it for most of a decade despite brutal insomnia and..." source.

What helps:

Apply patch in the morning only (not before bed).
Avoid caffeine after noon (you may be more sensitive on MAOIs).
Maintain a dark, cool, screen-free sleep space.
If behavioral tweaks flop, clinicians may try short-term gabapentin, low-dose sedatives, or Dayvigo—never mix with contraindicated meds (especially other psychotropics) without your prescriber’s OK.
If insomnia becomes unlivable, a dose reduction or med switch is usually the next step.

Most users found this problem didn't resolve on its own. If you're one of them, don't tough it out alone: persistent sleep loss can torpedo your recovery.

Increased Anxiety and Agitation

"My libido and emotions are coming back, but so is my anxiety and my mind and body cannot rest," said one Emsam user after three weeks source. It's the classic paradox: an antidepressant that sometimes jacks up your jitters. Seven different users called out heightened anxiety or physical agitation, rating it as moderate and—more annoyingly—often persistent. It's not unique to Emsam: "Any depression medication can cause heightened anxiety at the beginning, the only meds that immediately blunt anxiety are benzodiazepines," another commented source.

FDA label: No line for "anxiety" per se, but agitation, irritability, and tension show up in premarketing and postmarketing reports. Given the moderate frequency on Reddit (frequent: 7 posts), this is under-reported in trials.

What helps:

Don't expect this effect to fade within days: some users needed several weeks, dose changes, or (ironically) an adjunct medication to take the edge off.
Gabapentin (100mg), Dayvigo, and—short term—benzodiazepines are occasionally used, but always under prescriber supervision.
Avoid caffeine and watch for triggers that spike anxiety (social events, sleep disruption, dietary tyramine, etc.).

If your anxiety ramps up to panic or gets worse over time, loop in your prescriber fast: that's not just "startup effects."

Discontinuation & Withdrawal

There’s no classic "Emsam withdrawal"—no official syndrome described in the FDA label. Still, users report GI issues: "I've had some nausea and skin flushing" during withdrawal source. For most, symptoms like stomach upset, fatigue, or irritability fade over days to weeks.

Why does half-life matter? Emsam’s half-life (how long the drug stays active in your body) is long—so its levels drop gradually, reducing acute withdrawal. Still, you MUST space at least two weeks between stopping Emsam and starting a contraindicated drug (like SSRIs, SNRIs, or bupropion), and up to five weeks after fluoxetine (Prozac), or you risk serotonin syndrome.

Management tips:

Always taper under medical supervision—even if you "feel fine".
Expect symptoms (nausea, irritability, sleep disruption) for up to 2 weeks; rare cases persist longer.
Hydrate, eat small frequent meals if GI symptoms hit, and use symptom logs to track your trajectory.

Most users felt withdrawal symptoms resolved after stopping. But if new psychiatric or physical symptoms emerge, or you’re starting another med, get medical guidance immediately.

Dosage by Condition

Condition	Starting Dose	Typical Dose	Maximum Dose
Major depressive disorder	6 mg/24 hours patch	6 mg/24 hours patch	12 mg/24 hours patch

Most start at 6 mg/24h; doses above 6 mg require dietary restrictions due to risk of hypertensive crisis. Higher doses (9 mg, 12 mg) may increase both efficacy and side effect burden (skin reaction rates rise to 40% at high dose, orthostatic BP changes more common). Dose-response for efficacy and side effects is well-documented in FDA trials.

Find Top Clinical Trials

Choose from over 30,000 active clinical trials.

Alternatives

Bupropion: The "activator"—great for low energy, low libido, and generally lower risk of sexual side effects or weight gain. Anxiety may worsen for some.
SNRIs (venlafaxine, duloxetine): The "workhorses"—can help pain and anxiety, but sometimes cause sexual dysfunction and insomnia.
Other MAOIs (phenelzine, tranylcypromine): The "nuclear option"—strong efficacy but higher risk for dangerous food and drug interactions. Sedation more common.
Spravato (esketamine): The "dissociative"—works quickly, nasal spray, can be sedating and cause dissociation.
TMS (Transcranial Magnetic Stimulation): The "hardware fix"—not a drug, no systemic side effects, time-intensive.

If insomnia, orthostatic hypotension, or anxiety are the dealbreakers, bupropion or TMS may be best bets; if emotional numbness is your nemesis, some find bupropion or clinical trials (like CYB003) better for emotional recovery.

→ Compare your options on WithPower

Clinical Trials

CYB003 (deuterated psilocybin analogue) (NCT05385783)
- Mechanism: 5-HT2A receptor agonist (psychedelic class)
- Efficacy: Rapid onset (1-3 weeks), remission rate 75% at 4 months, response rate 53% at 3 weeks source
- Side effects: Headache, nausea (10-20%), no reported weight gain or sexual dysfunction
Osavampator (NBI-1065845, AMPA-PAM):
- Mechanism: Positive allosteric modulator of AMPA receptor
- Phase 3
- Side effects: Early reports suggest less insomnia, sexual side effects, and weight gain than standard antidepressants source
D-cycloserine:
- Mechanism: NMDA partial agonist
- Phase 2 (NCT00408031)
- Side effects: Headache, dizziness (5-10%), not associated with sexual dysfunction or weight gain
Psilocybin (COMP360):
- Mechanism: Classic psychedelic (5-HT2A)
- Phase 3 (NCT06141876)
- Side effects: Transient anxiety, headache, but not sedation or sexual dysfunction

Why are people excited? Faster onset, different side effect profile (especially less insomnia, emotional blunting, weight gain), and possibly higher response/remission rates. Downsides: Uncertainty, insurance, possible placebo, and regulatory hurdles. Trial participation generally means close monitoring and free treatment, but you may be in the placebo arm.

Interested in clinical trials? Many trials for depression now target different mechanisms than Monoamine Oxidase Inhibitor [EPC]—potentially offering different side effect profiles. Browse clinical trials →

Decision Map

If insomnia is the dealbreaker → bupropion OR CYB003 trial
If orthostatic hypotension or blood pressure drops are unbearable → bupropion OR osavampator trial
If increased anxiety is intolerable → buspirone (for some), TMS, or psilocybin trials
If emotional numbness or brain fog hits hard → bupropion, D-cycloserine trial, or TMS
If serotonin syndrome risk is a top concern → Avoid all serotonergic drugs and discuss novel mechanism trials with your doctor

Always discuss these pivots with your prescriber, especially for trial enrollment: different mechanisms mean different risks.

Emsam (selegiline) - antidepressant medication Image: Rood & Riddle Veterinary Pharmacy

Monitoring & What to Track

What your doctor should monitor:

PHQ-9 or HAM-D score (depression severity)
Blood pressure (standing and lying, especially first few weeks)
Weight
Suicidal ideation (especially if under 25)

What you should track:

Mood (daily 1–10 scale)
Side effect diary (time of day, severity)
Sleep quality
Blood pressure (if available)

If your doctor isn't tracking these, ask them to—especially with meds like Emsam, where side effects and efficacy can shift dramatically over the first month.

Pregnancy & Breastfeeding

FDA pregnancy category: Not assigned (old system); animal data: adverse embryo-fetal effects at high doses. No adequate human studies exist. Risk/benefit must be weighed.

Risks specific to MAOIs/Emsam: Not recommended during pregnancy or breastfeeding. Animal studies show embryo toxicity, but no definitive human data. MAOIs (like Emsam) can trigger hypertensive crises in pregnant women (dangerous blood pressure spikes). Lactation: Not recommended; it is not known if selegiline passes into human milk.

Untreated depression/anxiety risks: Preterm birth, low birth weight, maternal complications.

Key: This is a risk-benefit discussion with your doctor, not a yes/no answer. Do NOT stop suddenly if you become pregnant—always taper with medical guidance.

Emergency Warning Signs

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

Suicidal thoughts or plans
Sudden, severe headache
Chest pain
Signs of hypertensive crisis: neck stiffness, vomiting, confusion, sweating, fever
Severe allergic reaction: rash, swelling, difficulty breathing
Seizures, sudden loss of consciousness

📞 Call your doctor urgently if:

Unusual bleeding or bruising
Severe anxiety or agitation
New or worsening confusion or hallucinations
Worsening depression
Fainting or very low blood pressure

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

Summary & Next Steps

Key takeaways:

Insomnia (12% FDA, severe for 3/4 Reddit users), increased anxiety (7 posts, moderate), and blood pressure drops (9.8% FDA, severe for some) are the main hurdles on Emsam. Real-world experience is often harsher than clinical trial stats suggest. Side effects may persist, not fade, and switching may be the answer if these are dealbreakers.

If Emsam is working for you:

Track mood and side effects. Watch for blood pressure changes and insomnia—these often respond to tweaks, not just "pushing through."

If side effects are intolerable:

Talk to your doctor about dose reduction or switching.
Consider alternatives like bupropion, TMS, or one of the clinical trials targeting your toughest symptoms (less insomnia, blood pressure issues, or emotional blunting).

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
Application site reaction	24%	12%	very common	Dermatologic
Headache	18%	17%	very common	Nervous System
Insomnia	12%	7%	common	Nervous System
Orthostatic change in blood pressure	9.8%	6.7%	common	Cardiovascular
Diarrhea	9%	7%	common	Gastrointestinal
Dry mouth	8%	6%	common	Gastrointestinal
Weight loss (≥5%)	5%	2.8%	common	Metabolic
Dyspepsia	4%	3%	common	Gastrointestinal
Rash	4%	2%	common	Dermatologic
Pharyngitis	3%	2%	common	Respiratory
Sinusitis	3%	1%	common	Respiratory
Low systolic blood pressure	3%	1.5%	common	Cardiovascular
Weight gain (≥5%)	2.1%	2.4%	uncommon	Metabolic
Abnormal ejaculation (males)	1%	0%	uncommon	Reproductive/Sexual
Decreased libido (males)	0.7%	0%	uncommon	Reproductive/Sexual
Impotence (males)	0.7%	0.4%	uncommon	Reproductive/Sexual
Anorgasmia (males)	0.2%	0%	rare	Reproductive/Sexual
Decreased libido (females)	0%	0.2%	rare	Reproductive/Sexual
Tachycardia	0%	0%	unknown	Cardiovascular
Anorexia	0%	0%	unknown	Gastrointestinal
Agitation	0%	0%	unknown	Psychiatric
Amnesia	0%	0%	unknown	Nervous System
Tremor	0%	0%	unknown	Nervous System
Twitching	0%	0%	unknown	Nervous System
Pruritus	0%	0%	unknown	Dermatologic
Convulsion ⚠️	0%	0%	unknown	Nervous System
Hypoesthesia	0%	0%	unknown	Nervous System
Disorientation	0%	0%	unknown	Psychiatric
Hallucination (visual)	0%	0%	unknown	Psychiatric
Tension	0%	0%	unknown	Psychiatric

Boxed Warnings (Most Serious)

Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors.
EMSAM is contraindicated in patients less than 12 years of age because of an increased risk of hypertensive crisis.

Drug Interactions

Serotonergic drugs (SSRIs, SNRIs, clomipramine, imipramine, meperidine, tramadol, methadone, pentazocine, propoxyphene, dextromethorphan): risk of serotonin syndrome; contraindicated.
Carbamazepine: contraindicated due to risk of hypertensive crisis.
Tyramine-rich foods and beverages (especially at 9 mg/24h and 12 mg/24h): risk of hypertensive crisis; dietary restrictions required at higher doses.
Sympathomimetic amines (e.g., pseudoephedrine, phenylephrine, phenylpropanolamine, ephedrine): risk of blood pressure elevation; monitor BP.
Buspirone: risk of blood pressure elevation; monitor BP.
Alcohol: use not recommended, though no significant pharmacokinetic interaction observed.
No dose adjustment needed for alprazolam, ibuprofen, olanzapine, risperidone, levothyroxine, warfarin, or strong CYP3A4 inhibitors (e.g., ketoconazole) when used with EMSAM.

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?
Increased anxiety and agitation	7 posts	🟡 Moderate (5/7)	Ongoing for several weeks; sometimes persists as long as medication is continued	Resolves
Increased irritability or short temper	4 posts	🟢 Mild (3/4)	Ongoing while on medication; sometimes improves with time or dose adjustment	Resolves
Difficulty falling or staying asleep	4 posts	🟠 Severe (3/4)	Ongoing for many; some report it as relentless and persistent	Resolves
Emotional numbness or feeling robotic	3 posts	🟡 Moderate (2/3)	Ongoing while on medication; sometimes leads to discontinuation	Resolves
Dizziness and low blood pressure when standing up	2 posts	🟠 Severe (2/2)	Acute episodes; occurs while on medication	Resolves
Persistent tiredness or lack of energy	2 posts	🟡 Moderate (2/2)	Ongoing; sometimes returns after initial improvement	Resolves
Nausea and upset stomach during withdrawal	1 posts	🟢 Mild (1/1)	During withdrawal period	Resolves
Skin flushing during withdrawal	1 posts	🟢 Mild (1/1)	During withdrawal period	Resolves
Rapid and irregular heartbeat	1 posts	🟡 Moderate (1/1)	Acute episode after starting medication	Resolves
Increased gas and flatulence	1 posts	🟢 Mild (1/1)	Ongoing while on medication	Resolves
Heavy inflammation after prolonged use	1 posts	🟡 Moderate (1/1)	After two months on medication	Resolves
Serotonin syndrome (dangerous drug reaction)	1 posts	🔴 Debilitating (1/1)	Acute, led to discontinuation	Resolves
Feeling more agitated than usual	1 posts	🟢 Mild (1/1)	Ongoing while on medication	Resolves
Anxiety and overstimulation in dogs	1 posts	🟡 Moderate (1/1)	Acute, after each dose (in dogs)	Resolves
Lingering brain fog and cognitive dulling	1 posts	🟡 Moderate (1/1)	Ongoing while on medication	Resolves

User Quotes by Side Effect

Increased anxiety and agitation (Often starts within the first week, can persist for several weeks, sometimes requires adjunct medication to manage, may improve over time or with dose adjustment)

"I have been on emsam 6mg for about 3 weeks now, and I haven't seen much in terms of progress. My libido and emotions are coming back, but so is my anxiety and my mind and body cannot rest." source

"Any depression medication can cause heightened anxiety at the beginning, the only meds that immediately blunt anxiety are benzodiazepines." source

"You may have to combine the EMSAM with sleep medication to lower this anxiety - people usually take gabapentin 100mg/Dayvigo/Benzodiazepine." source

Increased irritability or short temper (Begins within first week, may persist or fluctuate, sometimes improves with continued use)

"I was on Emsam briefly and definitely felt more agitated/anxious/irritable than usual." source

"I have noticed a little more irritability lately." source

"I am on day 4 of the emsam patch and having quite a bit of irritability, but I think it has helped numb the despair I had been feeling when I was on no meds." source

Difficulty falling or staying asleep (Often starts within first few days, can persist for months or years, rarely resolves spontaneously)

"The insomnia was relentless." source

"Stayed on it for most of a decade despite brutal insomnia and..." source

"The other side effects can be quite severe: insomnia, restlessness, orthostatic hypotension. Those symptoms can make it hard to function..." source

Emotional numbness or feeling robotic (Develops after initial weeks, can persist as long as medication is continued, sometimes resolves after stopping)

"Told my therapist I feel like a robot (dulled emotions - which is a welcome break... I'll take it over depression)." source

"At first it was amazing but over time it started to make me robotic and numb. I don't feel creative anymore." source

Dizziness and low blood pressure when standing up (Can start within days of beginning medication, may persist or fluctuate, sometimes improves with dose adjustment)

"It tanked my blood pressure to about 80/60 and I would see stars walking up the stairs in my house." source

"The other side effects can be quite severe: insomnia, restlessness, orthostatic hypotension. Those symptoms can make it hard to function..." source

Persistent tiredness or lack of energy (Can develop after initial weeks or months, may persist as long as medication is continued)

"The main issues I have been having are the fatigue and brain fog that linger despite and/or because of my medications." source

"The first couple months are great but once I get pasted that my depression and fatigue returns ten fold and im struck with heavy inflammation." source

Nausea and upset stomach during withdrawal (Occurs during withdrawal, resolves after stopping)

"I've had some nausea and skin flushing. I think I may have some improvement in vision but it's still not normal. I feel more tired and..." source

Skin flushing during withdrawal (Occurs during withdrawal, resolves after stopping)

"I've had some nausea and skin flushing. I think I may have some improvement in vision but it's still not normal. I feel more tired and..." source

Rapid and irregular heartbeat (Started after beginning medication, unclear if it resolves)

"Since then I have experienced side effects such as gas, and more recently rapid and irregular heartbeat as..." source

Increased gas and flatulence (Started after beginning medication, unclear if it resolves)

"Since then I have experienced side effects such as gas, and more recently rapid and irregular heartbeat as..." source

Heavy inflammation after prolonged use (Develops after two months, persists as long as medication is continued)

"The first couple months are great but once I get pasted that my depression and fatigue returns ten fold and im struck with heavy inflammation." source

Serotonin syndrome (dangerous drug reaction) (Develops after 3-4 months, resolves after stopping)

"In short, after 3-4 months of being on EMSAM I have to quit for a while, maybe indefinitely, because of serotonin syndrome." source

Feeling more agitated than usual (Started soon after beginning medication, unclear if it resolves)

"I was on Emsam briefly and definitely felt more agitated/anxious/irritable than usual." source

Anxiety and overstimulation in dogs (Occurs about an hour after each dose, resolves between doses)

"Has anyone else experienced anipryl/selegiline making their dogs anxious and over stimulated? About an hour after he takes the medicine he is super anxious, ..." source

Lingering brain fog and cognitive dulling (Ongoing while on medication, unclear if it resolves after stopping)

"The main issues I have been having are the fatigue and brain fog that linger despite and/or because of my medications." source

Appendix C: Clinical Trials with Different Mechanisms

These trials target mechanisms different from Monoamine Oxidase Inhibitor [EPC]. 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 transient mild-moderate headache and nausea (10-20%), with no sexual dysfunction, weight gain, or persistent cognitive impairment reported. Standard SSRIs/SNRIs have 20-40% rates of sexual dysfunction and 10-20% weight gain. No evidence of withdrawal or dependence.
Efficacy Data:
- Response rate: 53% at 3 weeks (CYB003) vs 18% (placebo)
- 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), durable remission, and a side effect profile lacking sexual dysfunction, weight gain, or persistent cognitive effects make this attractive for those intolerant to standard antidepressants.
Results: Significant and rapid reduction in depressive symptoms, high remission rates, durable effect at 4 months.
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 have not shown increased rates of sexual dysfunction, weight gain, or sedation compared to SSRIs/SNRIs. Early data suggest a favorable side effect profile, with headache and mild GI symptoms most common (5-10%).
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: 1-2 weeks (based on AMPA modulator class)
- Source
Why it might interest you: Novel mechanism (AMPA modulation), rapid onset, and early evidence of fewer sexual and metabolic side effects than standard antidepressants.
Results: Phase 2 data showed rapid and significant improvement in depressive symptoms as adjunctive therapy.
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. Most common side effects were mild headache and dizziness (5-10%). Standard antidepressants have higher rates of sexual dysfunction (20-40%) and weight gain (10-20%).
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 population)
- Time to response: 2-4 weeks
- Source
Why it might interest you: Different mechanism (NMDA modulation), low risk of sexual/metabolic side effects, and potential benefit for those not responding to standard antidepressants.
Results: Adjunctive D-cycloserine led to significant improvement in depressive symptoms in treatment-resistant depression.
Sources: 1

Psilocybin (COMP360 and others)

Sponsor: Multiple (COMPASS Pathways, academic)
Phase: Phase 3
NCT: NCT06141876
Mechanism: Classic psilocybin (5-HT2A receptor agonist, psychedelic)
Side Effect Comparison: Psilocybin is associated with transient anxiety, headache, and nausea (10-20%), but not with sexual dysfunction, weight gain, or persistent cognitive impairment. No withdrawal or dependence risk. SSRIs/SNRIs have higher rates of sexual dysfunction and weight gain.
Why it might interest you: Rapid and durable antidepressant effects, with a side effect profile that avoids the most common and bothersome issues of standard antidepressants.
Results: Multiple studies show rapid and robust antidepressant effects, with FDA Breakthrough Therapy Designation for TRD.
Sources: 1, 2

Appendix D: Methodology

We reviewed over 30,000 clinical trial listings on ClinicalTrials.gov, screened more than 300 PubMed-indexed journal articles, and analyzed 41 patient discussions along with 34 OpenFDA Drug Label entries. Through this process, 15 unique adverse effects were categorized by frequency, with severity, persistence, and representative patient narratives independently assessed by reviewers. This synthesized guide integrates quantified rates from FDA trials and real-world patient experiences, providing a comprehensive reference for Emsam (selegiline).