A decades-old anesthetic that, at lower doses, lifts severe low mood faster than any other treatment. The strongest evidence covers depression resistant to other treatments, short-term relief of suicidal thinking, and pain control around surgery. Nothing speaks to lifespan or to healthy people. Harms scale with dose and frequency; benefit fades once dosing stops. (Full Review)

Protocol

Standard intravenous induction protocol

0.5 mg/kg over 40 minutes

Racemic ketamine in saline, twice weekly for three weeks (six sessions), then reassessed.

Intranasal esketamine protocol

56 mg, then 56 or 84 mg

Twice weekly, then weekly, then every one or two weeks, alongside a continuing oral antidepressant.

Sublingual and oral protocols

50–300 mg lozenge

Under the tongue for 10–15 minutes, two to three times weekly, or 0.5–3 mg/kg orally.

Time to effect

Mood improvement

40 minutes to 4 hours

Peaks at 24 hours; maximum benefit by the fourth to sixth session.

Suicidal thinking

Within 24 hours

With intravenous racemic ketamine. Conflicted: the 2025 esketamine synthesis found no effect on suicidality.

Pain relief

During the infusion

In chronic pain, relief outlasts the infusion by weeks rather than months; repeat courses required.

Benefits

High: Rapid reduction of treatment-resistant depressive symptoms; rapid reduction in suicidal thinking (conflicted); perioperative pain relief and opioid sparing

Medium: Chronic and neuropathic pain; anxiety symptoms; postpartum depressive symptoms; post-traumatic stress symptoms (conflicted); heavy drinking in alcohol use disorder

Low: Anhedonia; obsessive-compulsive symptoms; postoperative depressive symptoms and delirium in older surgical patients (conflicted)

Speculative: Synaptic density in the aging brain; anti-inflammatory and immune modulation

Contraindications

Aneurysmal disease (thoracic, aortic, intracranial)

Arteriovenous malformation

Any history of intracerebral haemorrhage

Known hypersensitivity

Uncontrolled hypertension (above 180/110 mmHg)

Myocardial infarction/unstable angina within 6 weeks

Heart failure (New York Heart Association III/IV)

Severe liver impairment (Child-Pugh Class C)

Active schizophrenia-spectrum psychosis

Moderate-to-severe substance use disorder (ketamine, alcohol, opioids)

Interstitial cystitis or contracted bladder

Pregnancy and breastfeeding

Untreated obstructive sleep apnoea (sedating routes)

Key Interactions

CYP3A4 and CYP2B6 inhibitors (ketoconazole, ritonavir, grapefruit juice)

CYP3A4 and CYP2B6 inducers (rifampicin, carbamazepine, phenytoin, St. John's wort)

Benzodiazepines (diazepam, lorazepam, alprazolam)

Lamotrigine and other glutamate-release inhibitors

Opioid receptor antagonists (naltrexone including low-dose, naloxone)

Central nervous system depressants (opioids, alcohol, gabapentinoids, sodium oxybate)

Monoamine oxidase inhibitors, stimulants, thyroid hormone, sympathomimetics (pseudoephedrine)

Theophylline and aminophylline

Over-the-counter dextromethorphan, sedating antihistamines, nonsteroidal anti-inflammatory drugs

Supplements (magnesium, agmatine, zinc, kava, valerian, 5-HTP, caffeine, cannabidiol)

Electroconvulsive therapy, other psychedelics, sauna, cold exposure, intense exercise

Risk & Side Effects

High: Acute dissociation and perceptual distortion; blood pressure and heart rate elevation; nausea and vomiting; sedation, dizziness, headache, impaired coordination; urinary tract damage with frequent high-dose use

Medium: Misuse, craving, dependence; cognitive impairment (conflicted); liver enzyme elevation and bile duct injury; loss of response with repeated dosing

Low: Worsening psychotic symptoms in susceptible individuals; emergent suicidal thinking; raised intraocular and intracranial pressure (conflicted)

Speculative: Accelerated brain aging from long-term exposure; gut microbiome alteration

Monitoring

Marker	Target	Why
Blood pressure	110–125 / 70–80 mmHg resting	Defines eligibility; predicts the acute pressor response
Alanine aminotransferase (ALT)	10–26 U/L (women), 10–33 U/L (men)	Detects liver enzyme elevation with repeated dosing
Gamma-glutamyl transferase (GGT)	Below 20 U/L	Earliest marker of biliary stress and alcohol use
Estimated glomerular filtration rate (eGFR)	Above 90 mL/min/1.73 m²	Kidney reserve; obstruction from bladder disease
Urinalysis with microscopy	No blood, white cells, or protein	Earliest objective signal of bladder lining injury
C-reactive protein, high-sensitivity	Below 1.0 mg/L	Predicts antidepressant response; tracks inflammation
Depression symptom score (validated scale)	Below 10 on a 27-point scale	Primary efficacy endpoint for continuation
Dissociation score (validated scale)	Peak below 20, returning to baseline by 2 hours	Confirms the acute effect; defines safe discharge

Cadence: Vital signs and symptom scales every session; liver panel, kidney function, and urinalysis at 1 month, then every 3 months; cognitive and urinary review every 6 months.

Qualitative Assessment

Anhedonia: whether previously enjoyable activities regain their pull
Rumination: whether negative thought loops become interruptible
Sleep quality and continuity: particularly early-morning waking
Cognitive clarity: subjective processing speed and word-finding
Energy and initiation: the capacity to begin tasks
Urinary comfort: frequency, urgency, and suprapubic discomfort
Craving and clock-watching: anticipating the next session for its own sake

Ketamine for Health & Longevity

Protocol

Benefits

Risk & Side Effects

Monitoring

Qualitative Assessment