A Brief History

Ketamine is a safe, fast-acting anesthetic with a variety of applications to treat mental health and chronic pain. It was first synthesized in 1963 as a rapid anesthetic that supported the cardiopulmonary system and had a reduced recovery period, limiting the possibility and severity of adverse side-effects. It was so safe that it became known as a “buddy drug” during the Vietnam War since non-medical personnel could administer it on the battlefield. In 1970, ketamine’s antidepressant properties were discovered, leading to a cascade of positive studies published on its treatment of unipolar depression. Further studies have shown its efficacy for the treatment of PTSD, OCD, Bipolar Depression, Severe Anxiety, Fibromyalgia, Complex Regional Pain Syndrome, and other pain syndromes. Approximately 70% of patients experience a significant reduction in symptoms – many during their first infusion. Now, Ketamine is widely used to heal mood disorders, eliminate suicidal ideations, and alleviate chronic pain.

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How Does It Work?

Ketamine works by increasing synaptogenesis and neuroplasticity, regulating glutamate, and decreasing inflammation.
Increases Synaptogenesis

Increases Synaptogenesis

Synaptogenesis is the formation of new synapses between neurons in the nervous system.
Increases Neuroplasticity

Increases Neuroplasticity

Neuroplasticity is the ability of the brain to form and reorganize synaptic connections, especially in response to new information, new experiences, or following an injury.
Regulates Glutamate

Regulates Glutamate

Glutamate is the primary fuel source for the central nervous system.
Decreases Inflammation

Decreases Inflammation

Inflammation is part of the body’s immune response, but recent studies show a strong link between inflammation and major depression.

Ketamine offers rapid and sustained relief and long-term enhancements in mood by facilitating neuronal plasticity. It builds new neurons and helps neurons communicate effectively.

Ketamine's effects in chronic pain, and as an antidepressant, far outlast the actual drug levels, and are likely related to this increase in synaptic connectivity. 

Ketamine influences the brain's glutamate system.

Glutamate is the primary fuel source of the central nervous system, transmitting signals between neurons.

 Glutamate:

  • Boosts synaptogenesis: The creation of new neuronal connections, fostering new pathways for healing.
  • Increases BDNF (brain-derived neurotrophic factor): A protein crucial for neuronal growth and survival, promoting resilience.
  • Enhances neuroplasticity: Allowing the brain to adapt and form new, healthier pathways. 

Mood disorders, in part, may be the result of our central nervous system (CNS) not having enough glutamate.

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NMDA receptors act like dams for glutamate, regulating its flow. 

The NMDA receptor is an ionotropic glutamate receptor that is suggested to play a central role in cognition and memory.

In mood disorders, the NMDA receptor may be dysfunctional and the dam may remain open, allowing glutamate to flow freely in a very uncontrolled state. This decreases the amount of glutamate (upstream from the NMDA receptor) in the CNS. When glutamate levels decrease to a critical level, the AMPA receptor stops functioning correctly. [Malhotra et al. 1996]; [Newcomer et al. 1999]; [Krystal et al. 2000]

The AMPA receptor is responsible for neurogenesis (the formation of new nerve cells), neuroplasticity (the correct alignment of neurons), and controlling inflammation in the CNS.

Without enough glutamate, the AMPA receptor begins to turn off.  When the AMPA receptor frequently turns off, neurons begin shriveling up and dying off, and inflammatory processes become rampant.

Ketamine's primary target is the NMDA receptor, found on glutamatergic neurons throughout the brain. Ketamine works to slow down or stop the NMDA receptor from allowing the uncontrolled flow of glutamate through. Ketamine selectively blocks the NMDA receptor which allows the CNS to fill back up with glutamate. 

Glutamate activates the postsynaptic AMPA receptors, which are postulated to mediate the rapid antidepressant effects of ketamine.

 

Ketamine increases glutamate release, and promotes synaptic plasticity.

By blocking the NMDA receptor,  Glutamate binds to post-synaptic AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor), allowing for calcium influx and stimulation of downstream pathways including activation of the mammalian target of rapamycin (mTOR).

Calcium influx leads to the calcium-dependent release of BDNF from the post-synaptic membrane. Autocrine signaling of BDNF leads to downstream signaling through pathways that are primarily implicated in synaptic plasticity, while pathways leading to anti-apoptotic signaling and cell survival, and signaling through pathways that are involved in in synaptic plasticity and neuritogenesis.   

Anti-inflammatory effects occur via astrocytes and microglia.

Ketamine reduces glutamate excitotoxicity by inhibiting overactivated microglia and inhibits excessive NMDAR activity in astrocytes.

Ketamine also rapid inhibits pro-inflammatory cytokines which may contribute to the rapid antidepressant effect of ketamine. [Nikkheslat, 2021]. 

Ketamine rapidly reverses the effects of chronic stress.

Chronic stress decreases synaptic connections and produces depressive-like behavior.

Confocal photomicrographs of pyramidal neurons showing the effects of 21 days under stress and reversal by a single dose of ketamine 1 day later.

References

  • Callaway, E., & Miller, R. (1993). Ketamine: History, pharmacology, and clinical applications. Journal of Pain and Symptom Management, 8(6), 349-362.
  • Gould, T. D., Walsh, E., & Krystal, J. H. (2016). Glutamatergic dysfunction in depression and the promise of ketamine. Biological Psychiatry, 79(7), 567-577.
  • Murrough, J. W., Iosifescu, D., Chang, S. L., Perez, J. M., Green, J. P., & Heinz, A. (2013). Antidepressant efficacy of ketamine in treatment-resistant depression: a meta-analysis. Journal of Clinical Psychiatry, 74(1), 50-60.
  • Niesters, M., & Pain, R. (2013). Ketamine for chronic pain: a review of its mechanisms of action and clinical effectiveness. British Journal of Anaesthesia, 111(1), 107-119.
  • Newport, D. J., Krystal, J. H., & Charney, D. S. (2015). Ketamine and glutamate: targeting a core pathophysiology of major depressive disorder. American Journal of Psychiatry, 172(2), 124-134.
  • Sarris, E. A., Sanacra, T., & Preskorn, J. (2011). Ketamine as a novel antidepressant: a review of its efficacy, adverse effects, and mechanism of action. Journal of Clinical Psychopharmacology, 31(4), 281-291.
  • Sanacora G, Schatzberg AF. Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders? Neuropsychopharmacol. 2015;40(2):259-267.