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]
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:
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.
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]
General anesthesia induction/maintenence
Dosing and Administration
Route of Administration
As an Antidepressant:
Esketamine nasal spray
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.
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
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.
Andrade C. Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency? J Clin Psychiatry. 2017 Jul;78(7):e852-e857. doi: 10.4088/JCP.17f11738. PMID: 28749092.
Janssen Pharmaceuticals, Inc. SPRAVATO® [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211243lbl.pdf. Revised March 2019. Accessed October 6, 2020.
Kishimoto T, Chawla JM, Hagi K, et al. Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med. 2016;46(7):1459-72.
Molero P, Ramos-quiroga JA, Martin-santos R, Calvo-sánchez E, Gutiérrez-rojas L, Meana JJ. Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review. CNS Drugs. 2018;32(5):411-420.
Price RB, Iosifescu DV, Murrough JW, et al. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depress Anxiety. 2014;31(4):335-43.