"Ketalar", "ketamine"

Street names: "K", "Special K", "Keets", "Green", "Jet", "Super Acid", "Super C"

Ketamine is a racemic mixture of its two enantiomers: (R)-ketamine (“arketamine”) and (L)-ketamine (“esketamine”).

Starting in 2014, proof-of-concept single-dose and repeat-dose studies with IV ketamine showed significant antidepressant and probably anti-suicidal effects in patients in the short-term. Response rates were over 60% as early as 4.5 hours after a single dose, and over 40% after 7 days. Sustained effects were achieved after 24 hours. Repeat doses of 2 - 3 doses a week could sustain the response over several weeks. [Kishimoto et al.]

Esketamine has higher affinity for NMDARs than arketamine, and so was selected for development as an antidepressant. Esketamine nasal spray was approved by the FDA on 3/5/2019. Later preclinical data on arketamine, however, showed greater potency and longer-lasting antidepressant effects in animal models, and with less adverse effects when compared to both ketamine and esketamine. [Hashimoto]

Main Concepts:

  • Sedative hypnotic used to provide anesthesia for short diagnostic and surgical procedures as an inducing agent, as an adjunct to supplement low-potency anesthetics like nitrous oxide, and as a supplement to local and regional anesthesia.

  • It causes sedation, immobility, amnesia, and marked analgesia.

  • Increasing doses result in anesthesia, specifically dissociative anesthesia. It produces an anesthetic state characterized by:

    • Profound analgesia

    • Normal pharyngeal-laryngeal reflexes

    • Normal or slightly enhanced skeletal muscle tone

    • Cardiovascular and respiratory stimulation

    • Occasional transient, minimal respiratory depression

  • Similar in structure, mechanism, and activity to phencyclidine (PCP), but is less potent and has a shorter duration of action

  • Has been associated with substance abuse and illicit use, with some abusers reporting superior effects compared to PCP or LSD

  • Has been reportedly use to facilitate rape through administration in beverages to unknowning victims

Mechanism of Action

As an Anesthetic

Ketamine appears to selectively interrupt association pathways of the brain before producing somatesthetic sensory blockade. It may selectively depress the thalamoneocortical system before more significantly obtunding more ancient cerebral centers and pathways.

Unlike barbiturates, which act on the RAS in the brainstem, ketamine acts on cortical and limbic system receptors, specifically non-competitively blocking NMDA receptors. Antagonizing this receptor may be responsible for the analgesic as well as psychotic effects of ketamine.

As an Antidepressant

There are several hypotheses of how ketamine exerts its antidepressant effects. Potential mechanisms include:

  • Continuous NMDAR inhibition

    • Synaptic or GluN2B-selective extra-synaptic NMDAR inhibition

    • Inhibition of NMDARs localized on GABAergic interneurons

    • Inhibition of NMDAR-dependent burst firing of lateral habenula neurons

  • Role of AMPAR activation

  • Increased downstream expression and inhibition of certain enzymes and transcription factors, which modulate synaptic plasticity

    • Increased expression of BDNF (brain-derived neurotrophic factor) and TrKB (tropomysin receptor kinase B)

    • Inhibition of phosphorylation of eEF2 kinase (eukaryotic elongation factor 2)

These proposed mechanisms may not be mutually exclusive, and may work in a complementary manner to exert acute changes in synaptic plasticity, leading to strengthened excitatory synapses necessary for ketamine’s antidepressant effects.


  • Depression

    • Ketamine has rapid antidepressant effects in patients with treatment-resistant depression (TRD). 1/3 cases of depression are treatment-resistant.

    • Most antidepressants have a signficant therapeutic time lag of weeks to months.

    • Depression in bipolar disorder is poorly responsive to antidepressants. [Hashimoto]

  • Moderate-to-severe pain

  • Status asthmaticus

  • General anesthesia induction/maintenence

  • Rapid-sequence intubation

  • Sedation induction

Dosing and Administration

Route of Administration

  • As an Antidepressant:

  • Esketamine nasal spray

Side Effects

Antidepressant Dosing

With dosing for antidepressant effects, side effects include:

  • Transient elevation in BP

  • Transient, mild dissociative and psychotomimetic effects

Tolerability seems acceptable in the short-term. Side effects include a transient elevation in BP and mild, transient dissociative and psychotomimetic effects.

Drug Interactions

  • Concomitant CNS depressants use (eg. Benzodiazepines, opioids, alcohol) can increase sedation

  • Concomitant use with psychostimulants (eg. amphetamines, methylphenidate, modafinil, armodafinil) may increase BP

  • Concomitant use with MAOIs may increase BP

Other Considerations

Esketamine is classified as a Schedule III controlled substance and patients, especially those with an active or past substance use disorder, should be closely monitored for dependence, abuse, or drug-seeking behavior. The nasal spray can only be obtained through the Risk Evaluation and Mitigation Strategy (REMS) program, because of risks of sedation, dissociation, and abuse/misuse.