Ketamine Drug Interactions

Organized by mechanism and clinical effect.

CNS depressants

MechanismSynergistic CNS and respiratory suppression

Clinical effectIncreased sedation, hypoventilation, coma, death risk

  • Opioids (morphine, fentanyl, oxycodone)
  • Benzodiazepines (midazolam, lorazepam, diazepam)
  • Alcohol
  • Barbiturates
  • Z-hypnotics (zolpidem)
  • Gabapentinoids (gabapentin, pregabalin)
  • Other sedatives / anesthetics (propofol)
High-risk combination: monitor airway and respiration.

Sympathomimetic agents

MechanismKetamine increases catecholamines and causes excessive cardiovascular stimulation

Clinical effectSevere hypertension, tachycardia, arrhythmias

  • Amphetamines
  • Cocaine
  • Methylphenidate
  • Ephedrine
  • Pseudoephedrine
Caution: particularly dangerous with CAD, aneurysm, or stroke risk.

MAO inhibitors (MAOIs)

MechanismExcess catecholamine accumulation and causes hypertensive crisis.

Clinical effectHypertensive crisis, arrhythmias, hyperthermia

  • Phenelzine
  • Tranylcypromine
  • Isocarboxazid
  • Linezolid (functional MAOI)
Generally contraindicated.

Antidepressants (SSRIs, SNRIs, TCAs)

SSRIs / SNRIs

  • Fluoxetine, sertraline, venlafaxine, duloxetine

Effect Usually safe; possible increased BP/HR; rare serotonin toxicity (especially with high doses or polypharmacy).

TCAs

  • Amitriptyline, imipramine

Effect Increased arrhythmia risk; additive anticholinergic and CNS effects.

Antipsychotics

MechanismDopamine antagonism vs ketamine psychotomimetic effects

Clinical effectVariable sedation; QT risk

  • Haloperidol → decreases emergence reactions
  • Atypicals (quetiapine, risperidone)
Watch: QT prolongation and hypotension.

CYP450 interactions (metabolism effects)

MetabolismKetamine is metabolized mainly by CYP3A4, CYP2B6, and CYP2C9.

CYP inhibitors cause increased ketamine levels

  • Clarithromycin
  • Erythromycin
  • Azoles (ketoconazole)
  • Protease inhibitors
  • Grapefruit juice

EffectProlonged dissociation, sedation, psychosis.

CYP inducers cause decreased ketamine levels

  • Rifampin
  • Carbamazepine
  • Phenytoin
  • Phenobarbital
  • St. John’s wort

EffectReduced anesthetic/antidepressant efficacy.

Antihypertensives

MechanismOpposing hemodynamic effects

Clinical effectHypotension or unpredictable BP swings

  • Beta-blockers
  • ACE inhibitors
  • ARBs
  • Calcium channel blockers
Caution: especially during anesthesia.

Theophylline

MechanismLowers seizure threshold

Clinical effectSeizures

  • Theophylline
  • Aminophylline
Avoid combination.

Anticholinergic agents

MechanismAdditive antimuscarinic effects

Clinical effectDelirium, agitation, tachycardia

  • Atropine
  • Scopolamine
  • TCAs
  • First-generation antihistamines

Other notable interactions

  • Lithium → increased neurotoxicity, confusion
  • Levodopa → exaggerated BP/HR response
  • Neuromuscular blockers causes prolonged weakness
  • Valproate causes increased sedation