Ketamine Guide: Pharmacology, Indications, Dosing Guidelines and Adverse Effects

In a nutshell

Ketamine is a dissociative anesthetic with rapid-acting antidepressant properties that has gained significant attention in psychiatric practice over the past decade. Like esketamine, it delivers a very rapid antidepressant effect (within 40 min-24 h). Still, evidence for sustained benefit beyond a few weeks is limited, and all psychiatric uses remain off-label in the United States.

• Consider esketamine vs ketamine when:
  • Insurance coverage is available 
  • Standardized protocols are preferred – REMS program provides structured safety monitoring and dosing guidelines.
  • Legal protection is prioritized 
  • Patient prefers non-invasive administration
  • Maintenance treatment is planned – Superior evidence base for relapse prevention during maintenance phase
• Consider ketamine vs esketamine when:
  • Rapid, robust response is needed – IV ketamine achieves remission faster than esketamine (hazard ratio = 5.0) ^[1]
  • Cost is a primary concern and insurance coverage is unavailable
  • Flexible dosing is required – Ability to adjust doses (0.5-1.0 mg/kg) based on individual response
  • Clinical expertise exists – Established IV ketamine protocols and experienced clinical staff

Pharmacodynamics and mechanism of action

• Primary mechanism: Non-competitive, nonselective NMDA receptor antagonist ^[2–4]
  • Racemic mixture containing equal parts of S-ketamine (esketamine) and R-ketamine enantiomers ^[5]
  • Binds to phencyclidine (PCP) site within NMDA receptor channel pore, blocking glutamate-induced calcium influx ^[3]
  • Preferentially inhibits NMDA receptors on GABAergic interneurons, causing disinhibition of pyramidal neurons and increased glutamate release ^[4]
  • Enantiomer differences
    • S-ketamine (esketamine) has 2-3 fold higher NMDA receptor affinity than R-ketamine ^[3,6,7]
    • R-ketamine may have distinct properties, including potentially greater BDNF effects and fewer psychotomimetic effects in preclinical studies, though clinical significance remains under investigation ^[8]
• AMPA receptor modulation

  • Indirectly enhances AMPA receptor signaling through increased glutamate release ^[3]

  • Ketamine metabolite (2R,6R)-hydroxynorketamine directly activates AMPA receptors, contributing to antidepressant effects without NMDA antagonism ^[9]

  • This shift from NMDA to AMPA signaling appears critical for rapid antidepressant effects ^[4]

• Downstream effects on brain plasticity
  • Increases BDNF release, potentially explaining rapid synaptogenic and antidepressant effects ^[3,4]
  • Activates mTOR signaling pathway, leading to increased protein synthesis and dendritic spine formation in prefrontal cortex ^[10]
• Opioid receptors
  • Clinical evidence suggests opioid system involvement: naltrexone pretreatment significantly attenuated ketamine’s antidepressant effects in humans ^[11]
  • Binds to μ-, κ-, and δ-opioid receptors with Ki values of 42.1, 28.1, and 272 μM respectively ^[3,4,11]
  • Contribution to therapeutic effects remains debated, with conflicting evidence from naltrexone studies and genetic analyses ^[4,11,12]
  • May explain why other NMDA antagonists (e.g., memantine) lack antidepressant efficacy ^[13,14]
• Additional pharmacological targets
  • Sigma receptors: R-ketamine shows higher σ1 receptor affinity than S-ketamine; racemic ketamine preferentially binds σ2 receptors, potentially modulating neuroplasticity pathways ^[3]
  • Other targets: Weak inhibition of monoamine transporters (SERT, NET, DAT), antagonism at 5-HT3 and nicotinic receptors, and weak D2 receptor agonism at subanesthetic doses ^[3,4]

Pharmacokinetics and Interactions

Metabolism and pharmacokinetic interactions

• Ketamine is primarily metabolized through N-dealkylation via CYP2B6 and CYP3A4 to form the active metabolite Norketamine ^[2,3]
• Minor pathways involve CYP2C9 and other CYP enzymes ^[3]
• Norketamine has approximately one-third the anesthetic potency of ketamine ^[2]
• Ketamine levels potentially increased by:
  • Strong CYP3A4 inhibitors:
    • Ketoconazole, clarithromycin ^[15]
    • Grapefruit juice ^[16,17]
  • CYP2B6 inhibitors:
    • Fluvoxamine, ticlopidine, orphenadrine ^[15,18]
  • Monitor for evidence of increased ketamine effects and consider dose reduction
• Ketamine levels potentially decreased by:
  • Strong CYP3A4 inducers:
    • Rifampin, carbamazepine, phenytoin, St. John’s Wort ^[15]
    • Monitor for reduced efficacy; dose increase may be necessary
  • CYP2B6 inducers:
    • Rifampin, efavirenz, nevirapine, phenobarbital
    • Monitor for signs of reduced ketamine efficacy
• CYP2B6 polymorphisms:
  • The CYP2B6*6 allele (15-60% frequency, highest in African and Asian populations) reduces enzyme activity
  • May require lower ketamine doses in homozygous carriers ^[15]
  • Clinical significance unclear due to conflicting study results ^[15,19]
• Oral route is less reliable than parenteral administration
  • Bioavailability only 20-30% due to extensive first-pass metabolism ^[20]
  • Results in higher norketamine:ketamine ratios and less predictable dosing

Pharmacodynamic interactions

• Drug interactions
  • CNS depressants(benzodiazepines, opioids, alcohol)
    • May result in profound sedation, respiratory depression, coma, and death ^[2]
    • Closely monitor respiratory parameters and consider dose reductions
    • Opioid analgesics may prolong recovery time ^[2]
  • Benzodiazepines and antidepressant efficacy
    • May diminish antidepressant benefits of ketamine ^[21,22]
    • Clinical reports suggest delayed response, earlier relapse with concurrent benzodiazepine use ^[23]
    • Possible mechanisms: GABA-mediated CNS depression or suppression of ketamine-induced glutamatergic signaling ^[15]
  • Theophylline/Aminophylline
    • Concomitant use may lower seizure threshold ^[2]
    • Consider alternative to ketamine in patients receiving these medications
  • Sympathomimetics and vasopressin:
    • May enhance ketamine’s sympathomimetic effects ^[2]
    • Monitor vital signs closely and consider individualized dose adjustments
  • Glutamatergic modulators:
    • Lamotrigine: May reduce some of ketamine’s effects, but unknown impact on antidepressant efficacy ^[15]
    • Memantine: theoretical antagonism of ketamine effects through NMDA receptor competition ^[15,24]
    • Clozapine: may theoretically influence glutamatergic neurotransmission through action on glycine transporters, blunting effects of ketamine ^[15,25,26]
    • Use caution until formal studies clarify impact on therapeutic benefits
  • MAOIs:
    • Recent systematic review suggests combination may be safer than previously thought ^[27]
    • No cases of hypertensive crisis or serotonin syndrome reported
    • Blood pressure and heart rate increases were clinically insignificant in all but one patient
    • Traditional concerns about hypertensive reactions remain; further research needed
    • Monitor cardiovascular parameters closely if combination is considered necessary

Half-life

• Ketamine has a biphasic elimination pattern:
  • Alpha phase (anesthetic effect): 10-15 minutes – rapid onset and offset of anesthetic effects ^[2]
  • Beta phase (redistribution): 2.5 hours – reflects redistribution from CNS to peripheral tissues ^[2]
  • Effects typically last 1-2 hours for IV administration and 3-4 hours for IM administration

Dosage forms

Dosage forms

• Immediate-release:
  • Injectable solution (IV/IM, multiple-dose vials)
    • 10 mg/mL (200 mg/20 mL), 50 mg/mL (500 mg/10 mL), 100 mg/mL (500 mg/5 mL)
    • Ketalar, Generic
  • Intranasal solution (compounded, off-label)
    • Variable concentrations (typically prepared from 50 mg/mL or 100 mg/mL injectable solutions)
    • Compounded preparations
  • Oral solution (compounded, off-label)
    • Variable concentrations (prepared from injectable solutions for weight-based dosing)
    • Compounded preparations
• Formulation considerations:
  • Injectable solutions
    • IM administration requires deep injection into large muscle mass
    • IV bolus doses should be administered over 1 minute (0.5 mg/kg/minute); depression treatment requires a 40-minute infusion ^[28]
  • Off-label preparations:
    • Intranasal: Volume limitations restrict adequate adult dosing.
    • Oral: Injectable solution may be administered undiluted or mixed with flavoring agents; administer immediately after preparation.
    • Other routes (subcutaneous, rectal) exist but are not used in psychiatric practice
  • Investigational formulations:
    • Preservative-free formulations (NRX-100) aim to eliminate benzethonium chloride found in current preparations
    • pH-neutral formulations (HTX-100) designed for both IV and subcutaneous administration
    • Extended-release oral tablets (R-107) being studied to minimize dissociative effects and enable potential at-home use

Indications

Psychiatric off-label uses

Treatment-resistant depression (TRD)

• Ketamine may be considered for patients with treatment-resistant depression (TRD) who have not responded to other antidepressant therapies.
  • Note: Esketamine (intranasal) is an FDA-approved formulation for TRD and MDD with acute suicidal ideation or behavior (MDSI) ^[29]
• Ketamine provides rapid antidepressant effects within hours (vs. weeks for traditional antidepressants) ^[30–32]
• IV ketamine appears as a viable option for patients with acute suicidality or who need ultra-rapid antidepressant response ^[33]
• Efficacy evidence:
  • Single IV infusion produces a rapid response beginning at 40 min and peaking at 24 hours ^[34,35]
  • Response typically diminishes by day 10-14 without maintenance treatment ^[13].
  • Relapse rates up to 90% at four weeks following a single treatment ^[34]
  • May be as effective as ECT for treatment-resistant cases according to recent trials ^[36]
  • Repeated infusions (2-3 times weekly) may sustain antidepressant effects ^[31]
    • Onset of antidepressant effect may perhaps be faster with repeated infusions of ketamine, compared with repeated treatments with ECT ^[37]
    • Ketamine showed the largest improvement at two weeks compared to other treatments such as medications, ECT, and rTMS in treatment-resistant depression ^[38]
  • Treatment duration up to 6 weeks has been studied, though optimal length of therapy and maintenance dosing protocols remain to be established ^[39]
  • Long-term ketamine efficacy and safety remain largely unknown due to limited high-quality studies with short treatment durations and inadequate follow-up ^[40,41]
    • Sparse observational data show variable responses and high relapse rates, raising concerns about tolerance, tachyphylaxis, and potential dependence with repeated use ^[28,42–44]
• Ketamine as augmentation
  • Ketamine can be safely combined with most standard antidepressants. Randomized trials support its use both as monotherapy and as add-on therapy to antidepressants and antipsychotics ^[30]
  • May accelerate antidepressant response when combined with conventional therapy
    • One trial found higher response rates and faster improvement when ketamine was added to escitalopram ^[45]
• Dosing:
  • Intravenous (IV) route (most studied)
    • Initial: 0.5 mg/kg (less than the dose used for inducing general anesthesia) administered over 40 minutes ^[46,47]
    • May increase to 0.75-1 mg/kg based on response and tolerability ^[48]
    • Obesity adjustment: Use ideal body weight for BMI ≥30 kg/m² to reduce cardiovascular risks ^[49]
    • Infusion rate: Standard 40 minutes, though rates have varied from 2-100 minutes across studies; slower rates may reduce adverse effects ^[48]
    • Frequency: Initially 2-3 times weekly, then once weekly or biweekly for maintenance ^[39]
  • Intramuscular (IM) route
    • Initial: 0.25-0.5 mg/kg/dose ^[50]
    • Comparable efficacy to IV route in small head-to-head studies ^[50]
    • May be preferred when IV access is difficult or for outpatient settings ^[51]
    • Additional doses described, but frequency and dosing poorly defined ^[51]
  • Intranasal route (limited evidence):
    • Can be prescribed in an intranasal formulation from compounding pharmacies.
    • 50 mg demonstrated efficacy in one small randomized crossover trial ^[52]
  • Oral route (limited evidence):
    • 1 mg/kg thrice weekly showed benefit over placebo in small RCT ^[53]
    • Bioavailability only 20-30% due to extensive first-pass metabolism ^[54]
    • Currently available formulations taste poorly and have limited duration ^[30]
    • Investigational extended-release formulation: Phase 2 study showed promise with twice weekly dosing, designed to mitigate abuse concerns ^[55]

Acute suicidal ideation

• Rapid antisuicidal effects reported in multiple randomized controlled trials ^[33]
• Meta-analysis shows a significant reduction in suicidal ideation compared to placebo within 24 hours, lasting up to 7 days ^[56]
• Can provide a crucial therapeutic window during acute crisis while conventional antidepressants take effect ^[33]
• Effective in both unipolar and bipolar depression with suicidal ideation ^[57]
• Dosing:
  • Similar to TRD dosing:
    • IV: 0.5 mg/kg over 40 minutes ^[57]
    • May consider more frequent initial dosing (e.g., 2-3 times in first week) for high-risk patients ^[39]

Bipolar depression

• Has been studied and used as an adjunct to mood stabilizers rather than monotherapy [ ^[58];Bahji2022a; ^[59]; ^[60]; ^[13]]
• Initial reduction in depressive symptoms up to 3-6 days, but no sustained superiority over controls from 7-13 days onward according to recent meta-analyses ^[29]
  • Evidence quality is generally poor with low certainty, and insufficient data to differentiate racemic ketamine from esketamine effects ^[29]
• No clear benefit for remission/response rates in bipolar-only analyses beyond the acute phase, further research needed [ ^[29]; Bahji2022a]
• Dosing:
  • Similar to TRD dosing with careful monitoring:
    • IV: 0.5 mg/kg over 40 minutes ^[59]
    • Consider concurrent mood stabilizer therapy to prevent mood switching ^[13]

Post-traumatic stress disorder (PTSD)

• VA/DoD Clinical Practice Guideline suggests against the use of ketamine for the treatment of PTSD ^[61]
• Significant improvement in PTSD symptoms at 24 hours and 1-4 week endpoints with small to moderate effect size (standardized effect = 0.25) ^[62]
  • However, high heterogeneity across studies and methodological quality concerns limit the certainty of findings ^[62,63]
• Anxiolytic effects across acute (<12h), subacute (24h), and sustained (7-14 days) timepoints ^[63]
• Evidence suggests potential for both rapid symptom relief and sustained neuroplastic changes ^[64]
• May be helpful for comorbid PTSD and depression ^[65]
• Dosing:
  • Limited data, generally follows TRD dosing:
    • IV: 0.5 mg/kg over 40 minutes ^[66]

FDA-approved Indications

General anesthesia (induction ± maintenance)

• Intravenous or intramuscular dissociative anesthetic used as a sole agent, for induction before other agents, or as a supplement when hemodynamic stability is desirable ^[2]
• Used as an adjunct to decrease the need for other anesthetic medications. Particularly valuable in opioid-tolerant patients to minimize opioid requirements.
• Dosing
  • Anesthetic doses (2-4.5 mg/kg IV) are approximately 4-10x higher than doses used for depression ^[2]

Side Effects

Most common side effects

Neurological/Psychiatric

• Dissociation and psychotomimetic effects (>70% of patients) ^[67]
  • It may occur more often with ketamine than with esketamine. However, no head-to-head trials comparing the two drugs have been published ^[68]
  • Most common adverse effect and primary reason for treatment discontinuation ^[2,67]
  • Includes transient perceptual changes, depersonalization, derealization, hallucinations, and emergence reactions
  • Typically begins during infusion and resolves within 2-4 hours ^[2,13]
  • May manifest as pleasant dream-like states to frank delirium and irrational behavior ^[2]
  • Intensity tends to diminish with repeated administrations ^[31]
• Emergence reactions (12% incidence)
  • Postoperative confusional states, agitation, and vivid imagery during recovery period ^[2]
  • Duration generally a few hours, with no known residual psychological effects from anesthetic use
  • Higher incidence with intravenous administration and higher doses
  • Can be reduced by minimizing verbal, tactile, and visual stimulation during recovery ^[2]
• Anxiety, blurred vision, poor coordination
• Headache
• Nausea or vomiting

Cardiovascular

• Blood pressure elevation (frequently observed) (30-40% incidence) ^[67]
  • Typically occur 30-40 minutes post-infusion and resolve within 70-90 minutes ^[2]
  • Systolic BP (20 mmHg average peak) ^{[13,49,57,69]}
  • Diastolic BP (13 mmHg average peak) ^[49,57,69]
  • Dose-dependent response with higher elevations at increased doses ^[70]
• Heart rate increase
  • Mean increases of 9 beats/minute within 2 hours of infusion ^[69]
  • Changes typically normalize within hours of administration
• Increased cardiac output and cardiac index ^[2]
  • Results from ketamine’s sympathomimetic effects and catecholamine reuptake inhibition
  • May increase myocardial oxygen demand
• Other effects: Chest pain, palpitations, and pressure may occur but typically resolve within 90 minutes ^[67]

Gastrointestinal

• Nausea and vomiting
  • Common transient adverse effects in randomized trials ^[31,57]
  • Generally resolve within hours of administration

Other common side effects

• Dizziness and coordination difficulties
• Increased salivation ^[2]
  • Antisialagogue may be administered prior to induction to manage hypersalivation
• Diplopia and nystagmus ^[2]
• Elevation in intraocular pressure ^[2]

Severe side effects

• Respiratory depression and apnea
  • May occur with overdosage or rapid rate of administration ^[2]
  • Emergency airway equipment must be immediately available ^[2]
• Abuse and dependence potential
  • Schedule III controlled substance due to abuse potential ^[2]
  • The addictive potential of ketamine could be attributed to its chemical structure being similar to phencyclidine, as well as its agonistic effects on opioid receptors ^[67,71]
  • Street Names: Special K, K, Kit Kat, Cat Valium, Super Acid, Special La Coke, Purple, Jet, and Vitamin K ^[67,72]
  • Physical and psychological dependence may occur with prolonged use; tolerance may develop with repeated use.
• Renal and urinary disorders (with chronic use)
  • Lower urinary tract symptoms, including dysuria, frequency, urgency, and hematuria ^[2]
  • Cystitis and reduced bladder capacity have been reported with long-term off-label use
  • Regular monitoring recommended for patients with a history of chronic ketamine use ^[2]
• Neurotoxicity (with long-term use)
  • Studies in abusers show adverse effects on brain structure and cognitive function ^[67]
• Hepatotoxicity (with recurrent use)
  • Drug-induced liver injury with cholestatic pattern ^[2]
  • Baseline liver function tests recommended for patients receiving recurrent ketamine ^[2]

Contraindications

• Patients for whom significant elevation of blood pressure would constitute a serious hazard ^[2]
• Known hypersensitivity to ketamine or any component of the formulation ^[2]
• Known or suspected schizophrenia (absolute contraindication) ^[73]

Use in special populations

Pregnancy

• Not recommended: Animal studies show dose-dependent histopathologic changes in fetal organs and neurodevelopmental concerns ^[74,75]
• Fetal brain development may be affected through NMDA receptor antagonism.

Breastfeeding

• Ketamine and metabolites present in breast milk with relative infant dose 0.34-0.77% of maternal dose ^[76,77]
• Single-dose use (e.g., surgical procedures) generally considered acceptable with no reported adverse effects in breastfed infants ^[78,79]
• Repeated/chronic use for depression:
  • Limited safety data available; case series of 4 patients showed no adverse effects ^[76]
  • The manufacturer of Esketamine does not recommend breastfeeding during treatment since NMDA receptor antagonism affects rapid brain development in infants ^[80]
• Monitor breastfed infants for sedation, poor feeding, and adequate weight gain

Hepatic impairment

• No dosage adjustments are provided in the manufacturer’s labeling.
• Ketamine undergoes extensive metabolism in the liver.
  • Hepatic impairment is expected to reduce the clearance of ketamine, leading to increased plasma concentrations and a prolonged elimination half-life.
• Hepatobiliary dysfunction has been reported with recurrent or prolonged use of ketamine (e.g., scenarios of misuse/abuse, or medically supervised but unapproved off-label indications such as certain chronic pain regimens) ^[2,81]

Renal impairment

• Mild to moderate impairment:
  • No dose adjustment necessary for single doses ^[20]
• Severe impairment/End-stage renal disease:
  • No dosage adjustment necessary ^[82]
  • Use with caution. Avoid prolonged use or monitor for signs of toxicity
  • Parenteral: Ketamine levels may be 20% higher; active metabolites may accumulate with unknown clinical significance ^[82,83]
  • Oral administration (off-label): Limited pharmacokinetic data; extensive first-pass metabolism results in higher norketamine and dehydronorketamine concentrations compared to parenteral routes ^[54,84]

Obesity

• Limited data. Inconsistent dosing strategies prevent universal weight-based recommendations ^[85,86]
• Class 1 and 2 obesity (BMI 30-39 kg/m²):
  • Use actual body weight for initial dosing
  • Titrate to clinical effect as needed
• Class 3 obesity (BMI ≥40 kg/m²):
  • Use adjusted body weight or ideal body weight for initial dosing ^[87]
  • Maintain consistent dosing weight throughout therapy (do not switch between weight calculations). Monitor for metabolite accumulation with prolonged use.

Elderly

• No specific dose adjustments needed
• Older adults metabolize ketamine slowly and need lower dosing.

Brand names

• US: Ketalar
• Canada: Ketalar
• Other countries/regions: Calypsol, Inducmina, Kain, Keiran, Ketalar, Ketanest, Ketamin, Ketamin curamed, Ketamin Inresa, Ketamin sintetica, Ketamine, Ketamine HCL, Ketamine interpharma, Ketlar, Ketomin, Micro ketamine, Narkamon, Tekam

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