ESKETAMINE HYDROCHLORIDE (Spravato) Side Effects Guide

Table of Contents

Spravato (Esketamine) Side Effects Guide

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Spravato (Esketamine)

The Worst Side Effects

The Most Common Side Effects

Dissociation (Feeling Floaty, Disconnected)

Sedation and Sleepiness

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

Spravato (Esketamine) Side Effects Guide

Side Effects Overview Table

How Other Drugs Compare

Week-by-Week Timeline

Why Doctors Still Prescribe Spravato (Esketamine)

The Worst Side Effects

The Most Common Side Effects

Dissociation (Feeling Floaty, Disconnected)

Sedation and Sleepiness

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 comprehensive, evidence-based look at Spravato (esketamine) side effects, blending clinical trial rates with real-world patient reports and user strategies.

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

Reviewed by the Power Medical Content Team

Spravato (Esketamine) Side Effects Guide

Day 0: Walk into the clinic for the first time, bracing yourself for the unknown. Day 1: Floaty? Sleepy? Maybe a little nauseous by the drive home. By Day 3: A headache sets in, but maybe—just maybe—there’s a flicker of something lifting.

Spravato (esketamine) is the new heavyweight contender in treatment-resistant depression, promising rapid shifts for the 30% of people who never quite click with standard antidepressants. But as one patient put it, "The two main side effects that patients get is sedation (feeling sleepy) and dissociation (feeling loopy)" source. This isn’t your average SSRI. Side effects arrive early and intensely—some pass in hours, others stick around. And for many, those very effects are the price of getting unstuck.

No one takes Spravato for a gentle ride. Most feel something. But does the benefit balance the weirdness? Let’s find out.

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
Feeling floaty or disconnected (dissociation)	69%	🔴 very_frequent (18 posts)	🟢 Mild	Hours to a day	source
Sleepiness/sedation	61%	🟠 frequent (13 posts)	🟢 Mild	Hours to next day	source
Nausea and upset stomach	28%	🟡 occasional (8 posts)	🟡 Moderate	Hours, treatment day	source
Headaches/migraines	20%	🟡 occasional (7 posts)	🟡 Moderate	Days after treatment	source
Dizziness/lightheadedness	29%	🟡 occasional (7 posts)	🟡 Moderate	Hours to days	source
Brain fog/trouble thinking (cognitive impairment)	3%	🟡 occasional (6 posts)	🟡 Moderate	Hours to days/ongoing	source
High blood pressure	10%	🟢 rare (3 posts)	🟢 Mild	During/after treatment	source
Increased anxiety	13%	🟢 rare (3 posts)	🟡 Moderate	Hours to next day	source
Irritability	13% (anxiety group)	🟢 rare (3 posts)	🟢 Mild	Next day	source
Crying/mood swings (emotional lability)	13% (anxiety group)	🟢 rare (3 posts)	🟢 Mild	Hours to next day	source
Vomiting	9%	🟢 rare (2 posts)	🟡 Moderate	Hours	source
Feeling physically impaired/uncoordinated	N/A	🟢 rare (2 posts)	🟢 Mild	Hours	source
Hallucinations	N/A	🟢 rare (2 posts)	🟠 Severe	Up to 3 days	source
Bladder issues/UTI risk	0% (cystitis warning)	🟢 rare (2 posts)	🟡 Moderate	Ongoing	source
Heart issues (long-term, unspecified)	N/A	🟢 rare (2 posts)	🟡 Moderate	Ongoing	source

→ View all 47 side effects from FDA trials → View all 15 user-reported side effects

How Other Drugs Compare

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

Metric	Spravato (Antidepressant)	CYB003 (Deuterated Psilocybin Analogue)	Osavampator (AMPA-PAM)	D-cycloserine (NMDA modulator)
MECHANISM
Drug class	NMDA receptor antagonist	5-HT2A receptor agonist (psychedelic)	AMPA receptor modulator	NMDA partial agonist
How it works	Blocks NMDA (glutamate) receptors (proteins that control brain signaling), rapidly enhancing synaptic activity in mood circuits	Increases serotonin activity via 5-HT2A receptors (causing perception/mood shifts)	Boosts AMPA receptor signaling (rapid neuroplasticity)	Enhances NMDA function (increases learning/brain flexibility)
EFFICACY
Response rate	37-53% (TRD trials) FDA	53.8% (16mg) at 3 weeks source	Not yet reported (ongoing Phase 3) source	Not reported
Remission rate	20-30% (4 weeks)	75% at 4 months	Not yet reported	Not reported
Time to effect	1-2 days (after dosing session)	1-3 weeks	2 weeks (early signs)	2-6 weeks (adjunctive)
KEY SIDE EFFECTS
Dissociation	69%	Mild/none reported	None reported	None reported
Sedation	61%	None reported	None reported	Low rate
Nausea	28%	Mild, transient (occasional)	Mild (rare)	Mild (rare)
Persistent cognitive impairment	Possible	None reported	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	Dissociation, sleepiness, dizziness, nausea	Intense startup effects	Severe anxiety, suicidal thoughts
Week 2-3	Persistent headache, cognitive fog, mood swings	Some side effects linger	Worsening depression, confusion
Week 4-6	Benefits often become noticeable	Gradual stabilization	No benefit or escalating symptoms
Week 6-8	Side effects often plateau, mood clearer	Most resolved or manageable	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 Spravato (Esketamine)

So what’s the draw? Spravato is an NMDA receptor antagonist (blocks a glutamate receptor involved in mood, learning, and pain)—a radical departure from serotonin-centric approaches. By blocking these receptors, it’s thought to trigger a cascade of brain plasticity (the brain’s ability to rewire and adapt), rapidly improving mood circuits gone stale.

But there’s a catch. Those same NMDA receptors are scattered everywhere, which is why the "floaty" dissociation, sudden sleepiness, and even out-of-body experiences are so common. "It feels like an out of body experience when you put an eye mask on and noise canceling headphones" source.

The trade-off? For some, a shot at relief in days rather than weeks—trading predictably intense side effects (but usually short-lived) for the possibility of rapid improvement after years of failed meds. And for all the weirdness, doctors like that Spravato’s side effect pattern is predictable, trackable, and rarely permanent. That’s more than you can say for some SSRIs.

The Worst Side Effects

Dissociation (Feeling floaty, disconnected)

"In general I feel a little floaty/disoriented during treatment." source "It feels like an out of body experience when you put an eye mask on and noise canceling headphones." source

Reported as severe (lasting/interfering) by 1/18, but mild for 10/18
Management tip: Embrace the weird—set up a calm environment, use an eye mask and soothing music; anxiety tends to worsen dissociation, so reframing as a “transient trip” may help. Some find magnesium supplements reduce intensity source.

Sedation (Sleepiness, drowsiness)

"I had my first treatment yesterday and feel very anxious today. Im trying my best to make it at work but its hard feeling anxious and sleepy at the same time." source "It feels like a combination of the lighter ethereal feeling of being at the dentist on nitrous oxide and the sedative effects of alcohol." source

Reported as moderate-to-severe by 2/13; most describe as mild but annoying
Management tip: Do not plan to work, drive, or make major decisions on treatment days. Let a friend drive you home. Next day grogginess usually fades.

Hallucinations

"The side effects just kept getting worse and worse until eventually I started having tactile, auditory, and visual hallucinations for 3 days after that ..." source

Reported as severe by 1/2 users; extremely rare but can be alarming
Management tip: Alert clinic staff if hallucinations persist after treatment. May require skipping doses or stopping entirely.

Brain fog and cognitive issues

"There are many people that are experiencing post spravato issues with cognitive impairment, memory issues and worsening anxiety and depression." source

Reported as moderate or worse by 3/6 users; sometimes lingers between sessions
Management tip: Take notes before sessions, use reminders, and rest after treatment. If persistent, bring up with your doctor—dose adjustments or breaks may help.

How Clinical Trials Compare

Hallucinations: Not reported in CYB003/psilocybin or osavampator studies so far
Dissociation: 69% in Spravato vs rare in other trial drugs (CYB003 Phase 2)
Cognitive impairment: 3% in Spravato vs none reported in trials
Sedation: 61% in Spravato vs none reported with AMPA modulators

→ Find trials with lower rates of these side effects

The Most Common Side Effects

Dissociation (feeling floaty/disconnected)

FDA rate: 69%
Reddit: 18 users (very frequent); mostly mild
What helps: Prepare for the "trip"—lie back, use an eye mask/headphones, remind yourself it's temporary. Peaks within an hour, usually gone after 2-4 hours.
"It feels like an out of body experience when you put an eye mask on and noise canceling headphones." source

Sleepiness/sedation

FDA rate: 61%
Reddit: 13 users (frequent); mostly mild
What helps: Do not drive, work, or operate machinery until after a good night’s sleep. Recovery usually by next morning.
"I had my first treatment yesterday and feel very anxious today. Im trying my best to make it at work but its hard feeling anxious and sleepy at the same time." source

Dizziness/lightheadedness

FDA rate: 29%
Reddit: 7 users (occasional); moderate for most
What helps: Move slowly, hydrate, sit/lie down if dizzy. Usually resolves within several hours.
"It's been 4 days and I'm still feeling light headed, headaches, dizzy, somewhat out of breathe especially when talking. It feels like a hangover that won't go away." source

Nausea/upset stomach

FDA rate: 28%
Reddit: 8 users (occasional); moderate for many
What helps: Take with food or ginger chews, avoid heavy meals before session, consider prescribed anti-nausea meds. Peaks within 1-2 hours, usually gone by evening.
"It's been over a year since I started Spravato. I did a 2-month course and called it quits after, mostly because of how nauseous I always got." source

Headaches/migraines

FDA rate: 20%
Reddit: 7 users (occasional); moderate for most
What helps: Hydration, OTC pain relievers (with doctor approval), ice packs; typically last for hours to a day or two after dosing.
"For me: -Headaches that seem to last for days" source

Dissociation (Feeling Floaty, Disconnected)

Spravato’s dissociation is infamous: 69% in clinical trials FDA, and very frequent (18 user reports) on Reddit. For most, it starts within minutes of dosing and peaks around 40 minutes—a "little floaty/disoriented during treatment" feeling source. A few describe it as an "out of body experience" especially if lying back with headphones source. Severity is usually mild, but some say it’s almost psychedelic: time distortion, altered sense of self, feeling "loopy."

Management tips: Clinic routines are built for this—low lighting, eye masks, minimal stimulation. Many patients find it easier to just "ride the wave" rather than resist. Magnesium supplements or keeping eyes closed may soften the effect source. For nearly all, dissociation fades by the end of the session, with rare lingering effects into the next day. Persistent or distressing dissociation should be flagged to your prescriber, but for most, it’s the cost of rapid change.

Sedation and Sleepiness

Spravato leads to sleepiness or sedation in 61% of users in trials (11% placebo), echoed by 13 Reddit users—most describing it as mild but present. "It feels like a combination of the lighter ethereal feeling of being at the dentist on nitrous oxide and the sedative effects of alcohol," wrote one source. Another noted, "It's hard feeling anxious and sleepy at the same time" source.

FDA mandates two hours of clinic monitoring for this reason. Do not drive or work after a session. Most sedation fades by bedtime; if you’re still groggy the next day, be cautious with anything requiring attention. No persistent sedation is reported after stopping. Patients recommend blocking off the entire day—just to be safe—and arranging a ride home.

Discontinuation & Withdrawal

Discontinuation rates are higher with Spravato than placebo—mostly due to dissociation, dizziness, sedation, anxiety, headache, and nausea. Officially, Spravato’s half-life (how long the drug stays active in your body) is 7-12 hours, but the psychoactive effects are gone much sooner (within hours).

Unlike standard SSRIs/SNRIs, no clear withdrawal syndrome is described. However, many patients report return of baseline symptoms, sometimes with increased anxiety or low mood in the days after stopping. "There are many people that are experiencing post spravato issues with cognitive impairment, memory issues and worsening anxiety and depression" source. Tapering isn’t routinely required, but don’t stop abruptly—always discuss with your doctor.

Management tips: If discontinuing due to side effects, expect most symptoms (except cognitive fog and urinary issues) to resolve within a day or two. If symptoms persist more than a week, or if you experience severe mood swings or suicidality, seek urgent care.

Dosage by Condition

Condition	Starting Dose	Typical Dose	Maximum Dose
Treatment-resistant depression (TRD)	56 mg (twice weekly, weeks 1-4)	56 or 84 mg (weekly or every other week after week 4)	84 mg (per session)
MDD with acute suicidal ideation	56 mg (twice weekly, weeks 1-4)	56 or 84 mg (twice weekly, weeks 1-4; then weekly or every other week)	84 mg (per session)

Dose-dependent side effects: Higher doses (84 mg) increase rates and intensity of dissociation, sedation, and blood pressure spikes. Discuss with your doctor whether starting low and titrating (gradually increasing the dose) makes sense for you.

Find Top Clinical Trials

Choose from over 30,000 active clinical trials.

Alternatives

Tried Spravato and feeling pummeled by the weirdness? Here’s how the options stack up:

Bupropion (Wellbutrin): Dopamine/norepinephrine action, no dissociation or sedation, may worsen anxiety.
SNRIs (e.g., venlafaxine): Work on serotonin/norepinephrine, risk of hypertension, no dissociation, more sexual side effects.
MAOIs: Old-school, powerful, lots of restrictions.
TMS (transcranial magnetic stimulation): Device treatment, minimal systemic side effects, no dissociation.
Ketamine IV: Chemically similar, but often more controlled, potentially different intensity/duration of side effects.
Novel clinical trials (CYB003, osavampator): May avoid dissociation, sedation, and cognitive blunting; see Trials section below.

If dissociation or sedation is the dealbreaker, newer options in clinical trials might fit you.

→ Compare your options on WithPower

Clinical Trials

CYB003 (deuterated psilocybin analogue) — A 5-HT2A receptor agonist (classic psychedelic mechanism). In Phase 2, showed rapid response (53.8% at 3 weeks) and high remission (75% at 4 months) source. Side effects mostly mild—transient headache, anxiety, nausea—but no persistent cognitive effects or dissociation.

Osavampator (AMPA-PAM) — An AMPA receptor positive allosteric modulator, Phase 3 ongoing source. Early studies show benefit within 2 weeks, with headaches and dizziness as main side effects; sedation and dissociation not reported.

D-cycloserine — NMDA modulator, adjunct. Phase 2 trials suggest symptom improvement when added to standard treatment, few side effects source. Not yet widely available.

Psilocybin — Multiple academic/industry trials (NCT06141876). Rapid-acting, no persistent cognitive impairment or sexual dysfunction. Side effects include mild anxiety and headache during dosing. Effect durable for months in some studies.

Trial participation usually means free treatment, close monitoring, and a possibility of placebo (inactive treatment).

Phase 2 and early Phase 3 trials are promising, but not guaranteed—side effect and benefit profiles may change with larger studies.

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 dissociation is the dealbreaker → Try bupropion, TMS, or CYB003/psilocybin trials
If sedation wipes you out → Consider SNRIs or osavampator trials
If persistent brain fog/cognitive impairment is unacceptable → Explore TMS, bupropion, or D-cycloserine/AMPA-PAM trials
If bladder/urinary issues develop → Switch to a non-ketamine-based antidepressant or non-pharmacologic options
If anxiety or irritability increases → Consider MAOIs, buspirone, or psychotherapy-based approaches

No single solution works for all—match your most bothersome side effect to your next option.

Spravato (esketamine) - antidepressant medication Image: NBC News

Monitoring & What to Track

Your doctor should be checking:

PHQ-9 or HAM-D (for depression)
Blood pressure before and after each dose (especially first 2-4 weeks)
Cognitive function (ask about new memory problems)
Bladder and urinary symptoms (over time)
Suicidal ideation, especially for those under 25

What you should track:

Mood/energy/sleep—rate 1-10 each day
Side effects: what, when, how severe, how long
Missed doses and their effects
Any changes in thinking, memory, or urination

If your doctor isn’t tracking these, ask them to (and bring your own notes).

Pregnancy & Breastfeeding

Spravato is contraindicated in pregnancy—there’s evidence from animal studies of embryo-fetal toxicity (harm to the fetus) and insufficient human data. The FDA label warns of this risk, and use is generally avoided unless the potential benefit justifies the possible fetal risk.

Untreated depression also has serious risks in pregnancy, including poor nutrition, sleep loss, and suicide risk. For those who become pregnant on Spravato, do NOT stop suddenly—consult your doctor immediately for a supervised taper. Breastfeeding: It’s not known if esketamine is excreted in breast milk; infants could be exposed, so use is discouraged while nursing.

Bottom line: Risk/benefit is a nuanced discussion; don’t make changes alone.

Emergency Warning Signs

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

Suicidal thoughts or plans
Sudden severe sedation (cannot be roused, breathing slows)
Severe dissociation, agitation, or hallucinations that do not resolve by end of session
Allergic reaction (rash, swelling, difficulty breathing)

📞 Call your doctor urgently if:

High blood pressure headache/chest pain during/after treatment
Worsening depression, anxiety, or confusion
Unusual muscle weakness, impaired coordination that does not resolve
New or worsening bladder/urinary issues

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

Summary & Next Steps

Key takeaways: Spravato’s side effects are nearly universal: 69% experience dissociation, 61% sedation, and real-world reports highlight headaches, cognitive fog, and occasional rare issues like hallucinations. The weirdness is mostly transient, but some symptoms (brain fog, urinary issues) may linger for a few.

If Spravato is working for you: Stick with regular clinic visits, track side effects, and tell your doctor about any changes. Prepare for session days (rest, ride home, downtime) and monitor blood pressure and mood.

If side effects are intolerable: Talk to your prescriber about dose adjustment, slower titration, or a switch. Consider alternatives like bupropion, TMS, or innovative trials targeting the specific symptom that bothers you most. Explore clinical trials with non-dissociative or non-sedating options.

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
dissociation ⚠️	69%	5%	very common	Psychiatric
sedation ⚠️	61%	11%	very common	Nervous System
dizziness	29%	8%	very common	Nervous System
nausea	28%	9%	very common	Gastrointestinal
vertigo	23%	3%	very common	Ear and Labyrinth
headache	20%	17%	very common	Nervous System
dysgeusia	19%	14%	common	Nervous System
hypoesthesia	18%	2%	very common	Nervous System
anxiety	13%	6%	very common	Psychiatric
lethargy	11%	5%	very common	Nervous System
blood pressure increased ⚠️	10%	3%	very common	Cardiovascular
vomiting	9%	2%	very common	Gastrointestinal
insomnia	8%	7%	common	Psychiatric
diarrhea	7%	6%	common	Gastrointestinal
nasal discomfort	7%	5%	common	Respiratory
throat irritation	7%	4%	common	Respiratory
feeling drunk	5%	0.5%	very common	General
dry mouth	5%	3%	common	Gastrointestinal
dysarthria	4%	0%	common	Nervous System
euphoric mood	4%	1%	common	Psychiatric
hyperhidrosis	4%	2%	common	Dermatologic
tachycardia	4%	1%	common	Cardiovascular
constipation	3%	1%	common	Gastrointestinal
tremor	3%	1%	common	Nervous System
mental impairment	3%	1%	common	Nervous System
pollakiuria	3%	0.5%	common	Renal and Urinary
oropharyngeal pain	3%	2%	common	Respiratory
feeling abnormal	3%	0%	common	General
intentional self-injury	3%	1%	common	Psychiatric
feeling of relaxation	2%	1%	common	General

Boxed Warnings (Most Serious)

Sedation: Risk for sedation after administration. Monitor patients for at least two hours after administration.
Dissociation: Risk for dissociative or perceptual changes after administration.
Respiratory depression: Risk for respiratory depression after administration.
Abuse and misuse: Potential for abuse and misuse. Consider risks and benefits before prescribing, especially in patients at higher risk.
SPRAVATO is only available through a restricted program called the SPRAVATO REMS.
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. Not approved for use in pediatric patients.

Drug Interactions

Concomitant use with CNS depressants (e.g., benzodiazepines, opioids, alcohol) may increase sedation. Closely monitor for sedation.
Concomitant use with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) may increase blood pressure. Closely monitor blood pressure.
Concomitant use with monoamine oxidase inhibitors (MAOIs) may increase blood pressure. Closely monitor blood pressure.

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?
Feeling floaty or disconnected from reality	18 posts	🟢 Mild (10/18)	During treatment, sometimes lingering for hours to a day; rarely up to several days	Resolves
Sleepiness and physical sedation	13 posts	🟢 Mild (8/13)	During and immediately after treatment, sometimes lasting into the next day	Resolves
Nausea and upset stomach	8 posts	🟡 Moderate (4/8)	Mostly on treatment days, sometimes lasting a few hours	Resolves
Headaches and migraines	7 posts	🟡 Moderate (4/7)	Can last for days after treatment	Resolves
Dizziness and feeling lightheaded	7 posts	🟡 Moderate (4/7)	Several hours to a few days after treatment	Resolves
Brain fog and trouble thinking clearly	6 posts	🟡 Moderate (3/6)	Several hours to days after treatment; sometimes ongoing	⚠️ Yes
High blood pressure during treatment	3 posts	🟢 Mild (2/3)	During and shortly after treatment	Resolves
Increased anxiety after treatment	3 posts	🟡 Moderate (2/3)	Several hours to a day after treatment	Resolves
Irritability after treatment	3 posts	🟢 Mild (2/3)	Usually the day after treatment	Resolves
Crying and mood swings after treatment	3 posts	🟢 Mild (2/3)	Several hours to a day after treatment	Resolves
Vomiting after treatment	2 posts	🟡 Moderate (1/2)	On treatment day, resolves within hours	Resolves
Feeling physically impaired or uncoordinated	2 posts	🟢 Mild (2/2)	During and immediately after treatment, resolves within hours	Resolves
Hallucinations after treatment	2 posts	🟠 Severe (1/2)	Up to 3 days after treatment	Resolves
Bladder issues and increased risk of urinary tract infections	2 posts	🟡 Moderate (2/2)	Ongoing risk with long-term use	⚠️ Yes
Heart issues with long-term use	2 posts	🟡 Moderate (1/2)	Ongoing concern with long-term use	⚠️ Yes

User Quotes by Side Effect

Feeling floaty or disconnected from reality (Begins within minutes of dosing, peaks around 40 minutes, usually resolves within a few hours after session)

"In general I feel a little floaty/disoriented during treatment." source

"It feels like an out of body experience when you put an eye mask on and noise canceling headphones." source

"The two main side effects that patients get is sedation (feeling sleepy) and dissociation (feeling loopy)." source

Sleepiness and physical sedation (Starts during treatment, peaks within first hour, can last several hours, sometimes into the next day)

"It feels like a combination of the lighter ethereal feeling of being at the dentist on nitrous oxide and the sedative effects of alcohol." source

"I had my first treatment yesterday and feel very anxious today. Im trying my best to make it at work but its hard feeling anxious and sleepy at the same time." source

"The two main side effects that patients get is sedation (feeling sleepy) and dissociation (feeling loopy)." source

Nausea and upset stomach (Usually starts during or shortly after dosing, peaks within first hour, resolves by end of day)

"It's been over a year since I started Spravato. I did a 2-month course and called it quits after, mostly because of how nauseous I always got." source

"early on spravato increased my migraines, light sensitivity, sound sensitivity, and nausea. however, it was worst on the treatment day and not as bad after." source

"You can get nauseous too. It's not worth the effects it has on your body." source

Headaches and migraines (Starts on treatment day, can persist for several days)

"For me: -Headaches that seem to last for days" source

"early on spravato increased my migraines, light sensitivity, sound sensitivity, and nausea. however, it was worst on the treatment day and not as bad after." source

"It's been 4 days and I'm still feeling light headed, headaches, dizzy, somewhat out of breathe especially when talking. It feels like a hangover that won't go away." source

Dizziness and feeling lightheaded (Begins during or after treatment, can last hours to days)

"It's been 4 days and I'm still feeling light headed, headaches, dizzy, somewhat out of breathe especially when talking. It feels like a hangover that won't go away." source

"I had one dose so far at 84mg and I had severe, non-dangerous, side effects (severe dissociation, severe sedation, dizziness, nausea, vomiting) ..." source

"early on spravato increased my migraines, light sensitivity, sound sensitivity, and nausea. however, it was worst on the treatment day and not as bad after." source

Brain fog and trouble thinking clearly (Starts after treatment, can last hours to days, sometimes persists between sessions)

"There are many people that are experiencing post spravato issues with cognitive impairment, memory issues and worsening anxiety and depression." source

"For me: -Headaches that seem to last for days -Visions issues (not all of the time) -High blood pressure -Brain fog *The spravato spray ..." source

"I started eating gummies with Magnesium Complex and L-Threonate daily after 3rd dose and am noticing that the dissociative effects are less sporadic." source

High blood pressure during treatment (Starts during treatment, resolves after session)

"For me: -Headaches that seem to last for days -Visions issues (not all of the time) -High blood pressure -Brain fog *The spravato spray ..." source

"They have ice packs for us, I know they are concerned with people ..." source

"Memory issues, heart issues, and bladder issues are top 3 side effects." source

Increased anxiety after treatment (Usually starts after treatment, peaks within hours, resolves by next day)

"I had my first treatment yesterday and feel very anxious today. Im trying my best to make it at work but its hard feeling anxious and sleepy at the same time." source

"There are many people that are experiencing post spravato issues with cognitive impairment, memory issues and worsening anxiety and depression." source

"I tried it and my second treatment gave me extreme anxiety. I stopped after ..." source

Irritability after treatment (Starts the day after treatment, resolves within a day)

"I usually feel worse the next day after a treatment session. I get irritable and tired and emotionally heightened. But for me it only lasts that day." source

"Irritability is also a sign of depression. Spravato could be making you irritable, but remember that depression can, too." source

"After treatment felt good barely no irritability And next morning feeling good, Noticing sense of clarity less scattered thinking." source

Crying and mood swings after treatment (Starts after treatment, peaks within hours, resolves by next day)

"I usually feel worse the next day after a treatment session. I get irritable and tired and emotionally heightened. But for me it only lasts that day." source

"I've heard people hysterically laughing and others hysterically crying." source

"today ive felt like crying since ..." source

Vomiting after treatment (Starts during or after treatment, resolves within hours)

"I had one dose so far at 84mg and I had severe, non-dangerous, side effects (severe dissociation, severe sedation, dizziness, nausea, vomiting) ..." source

"They have ice packs for us, I know they are concerned with people ..." source

Feeling physically impaired or uncoordinated (Starts within minutes of dosing, peaks during session, resolves within hours)

"About 3-5 minutes after you take it you'll start to feel lighter. You'll feel impaired. Kind of like when you've had too much to drink and don't ..." source

"Not a bad high but communicating is not something I recommend. I would put in your headphones on and jam." source

Hallucinations after treatment (Starts after treatment, can last up to 3 days)

"The side effects just kept getting worse and worse until eventually I started having tactile, auditory, and visual hallucinations for 3 days after that ..." source

"Ketamine/esketamine is a dissociative hallucinogen, and dissociation is a very common side effect; It is unsurprising that you had bad ..." source

Bladder issues and increased risk of urinary tract infections (Develops with ongoing use, persists as long as medication is continued)

"Bravado is excreted through the kidneys and increases risk of urinary tract infections." source

"Memory issues, heart issues, and bladder issues are top 3 side effects." source

Heart issues with long-term use (Develops with long-term use, persists as long as medication is continued)

"Memory issues, heart issues, and bladder issues are top 3 side effects." source

"There certainly hasn't been any indication that long-term use would cause any ..." 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 (Breakthrough Therapy Designation)
NCT: NCT06141876
Mechanism: Deuterated psilocybin analog (psychedelic-derived, 5-HT2A receptor agonist)
Side Effect Comparison: CYB003 showed transient, mostly mild-to-moderate side effects (e.g., headache, nausea, mild anxiety) with no evidence of sexual dysfunction, weight gain, or persistent cognitive impairment, which are common with SSRIs/SNRIs. No serious adverse events reported.
Efficacy Data:
- Response rate: 53.8% (CYB003 16mg) vs 19.2% (placebo) at 3 weeks
- Remission rate: 75% at 4 months (CYB003)
- MADRS change: -14.08 points (CYB003 16mg) vs -8.24 points (placebo) at 3 weeks
- Time to response: 1-3 weeks
- Source
Why it might interest you: Rapid onset (1-3 weeks), durable remission, and a side effect profile lacking sexual dysfunction, weight gain, and persistent cognitive effects make this a compelling alternative for those experiencing side effects from 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 the typical SSRI/SNRI side effects (sexual dysfunction, weight gain, sedation). Reported side effects are mild and include headache and dizziness, with low rates of discontinuation due to adverse events.
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: Early improvement seen in Phase 2 (within 2 weeks)
- Source
Why it might interest you: Novel mechanism (AMPA modulation) with early onset of effect and a side effect profile that avoids sexual dysfunction, weight gain, and sedation, making it attractive for those intolerant to standard antidepressants.
Results: Phase 2 data showed significant improvement in depressive symptoms as adjunctive therapy; Phase 3 underway.
Sources: 1, 2, 3

D-cycloserine (adjunctive)

Sponsor: Not specified (academic/NIH)
Phase: Phase 2
NCT: NCT00408031
Mechanism: NMDA receptor partial agonist (glycine site)
Side Effect Comparison: D-cycloserine is generally well-tolerated, with low rates of sedation, sexual dysfunction, and weight gain compared to SSRIs/SNRIs. Most common side effects are mild (headache, dizziness).
Efficacy Data:
- Response rate: Not reported
- Remission rate: Not reported
- MADRS change: -7.0 points (D-cycloserine) vs -3.0 points (placebo) at 6 weeks (TRD population, adjunctive)
- Time to response: 2-6 weeks
- Source
Why it might interest you: Different mechanism (NMDA modulation), low risk of sexual dysfunction and weight gain, and potential for use as adjunct to current therapy for those not tolerating or responding to standard antidepressants.
Results: Adjunctive D-cycloserine led to greater reduction in depressive symptoms compared to placebo in treatment-resistant depression.
Sources: 1

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

Sponsor: Multiple (COMPASS Pathways, academic centers)
Phase: Phase 2/3
NCT: NCT06141876
Mechanism: Psilocybin (classic psychedelic, 5-HT2A receptor agonist)
Side Effect Comparison: Psilocybin is associated with transient anxiety, headache, and nausea during dosing sessions, but lacks persistent sexual dysfunction, weight gain, or cognitive blunting seen with SSRIs/SNRIs. No evidence of dependence or withdrawal.
Why it might interest you: Single or few-dose treatment with rapid and durable effects, and a side effect profile that avoids the most common and bothersome issues of standard antidepressants.
Results: Multiple studies show rapid and sustained antidepressant effects after 1-2 doses, with high response and remission rates in 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 76 online discussion threads, cross-referencing 47 OpenFDA Drug Label adverse reaction entries. From these sources, 15 key patient-reported side effects were identified, with frequencies and severities rigorously assessed. Patient experiences were quoted directly, ensuring nuanced, real-world context.