What is Ketamine? How does it work?
What is Ketamine?
Ketamine is a chemical compound developed in 1962 as an alternative to phencyclidine (PCP), a dissociative anesthetic that was used at that time to sedate humans and other animals. Interestingly, ketamine and PCP demonstrated similar anesthetic properties, but ketamine was better tolerated and was not neurotoxic at anesthetic doses. This resulted in ketamine’s approval as a general anesthetic agent by the U.S. Food and Drug Administration (FDA) in 1970.
Today, Ketamine is widely used to treat a variety of medical and mental health conditions. Unfortunately, Ketamine is also abused as a recreational drug and goes by many street names including Barry Farrell, Blind Squid, Cat Food, Cat Valium, Donkey; Green, Honey Oil, Jet, Keller, Kelly’s Day, Ket, Kit Kat, Kitty Flip, Purple, Special La Coke, Super Acid, Super C, Vitamin K, Wobble, Wonk, or “K”.
How is Ketamine Administered?
Ketamine may be administered in oral form (as a sublingual troche/lozenge), through the nose (intranasal spray), or through the vein (intravenous) in specialized clinics.
What is ketamine used for?
Intravenous (IV) Ketamine was approved by the Food and Drug Administration (FDA) for induction and maintenance of general anesthesia. Intranasal esketamine (SPRAVATO) was recently approved by the FDA for treatment resistant depression (in conjunction with an antidepressant).
Intravenous (IV) ketamine, oral ketamine, and intranasal esketamine are also used “off-label” and have demonstrated efficacy for the following conditions:
- Depression
- Anxiety
- Obsessive Compulsive Disorder (OCD)
- Post-Traumatic Stress Disorder (PTSD)
- Alcohol Use Disorder
- Chronic Pain
For IV ketamine therapy, a round of ketamine intravenous infusions typically comprises six (6) sessions spread over two to three weeks and may cost several thousand dollars. Patients typically pay out-of-pocket for intravenous ketamine therapy. Many patients also benefit from the oral/sublingual form of ketamine, which is much less expensive but requires using a compounding pharmacy.
What is the difference between ketamine and esketamine?
Ketamine itself is a racemic mixture of two compounds, (R)-Ketamine and (S)-Ketamine. These are called stereoisomers.
In stereochemistry, stereoisomerism is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms but differ in the three-dimensional orientations of their atoms in space.
Although intravenous ketamine (Ketalar) is FDA approved for the induction and maintenance of general anesthesia, ketamine itself has no other FDA approved indications.
However, as mentioned previously, the stereoisomer (S)-ketamine, or esketamine (SPRAVATO), is FDA approved for treatment resistant depression. SPRAVATO is delivered by nasal spray and is designed to be administered alongside a traditional antidepressant.
It is important to know that ketamine sublingual troches (“tro-kees”) are not approved by the Food and Drug Administration (FDA) for depression, obsessive compulsive disorder (OCD), anxiety, post-traumatic stress disorder (PTSD), or alcohol use disorder.
What are potential side effects of ketamine?
Ketamine is considered a dissociative anesthetic and is known to induce a dissociative state. That is, people feel as though their minds have detached from their bodies. Initially, this can be terrifying and can make you feel like you’ve lost control. Over the course of multiple sessions, many people learn to “let go” of the control and become detached observers of their experiences. Therefore, it is very common and normal to feel uncomfortable during and after the first few sessions. For most people, a shift occurs after the 3rd or 4th session (especially infusions), and the experience becomes more pleasant and peaceful.
Common side effects of ketamine include:
- Elevated blood pressure
- Elevated heart rate
- Nausea
- Fatigue
- Dissociation/out-of-body sensations
- Hallucinations
- Dizziness
- Dry mouth
- Blurred vision
- Confusion
- Lack of motor coordination
- Restlessness
- Anxiety
- Tooth enamel damage (chronic use)
- Headache
- Vivid dreams/nightmares
- Insomnia
- Sedation
- Induction of mania/hypomania
- Feeling vulnerable, sensitive, and/or emotional
If these symptoms occur, they are often short-lived and transient. In general, ketamine is well-tolerated.
Chronic ketamine exposure is toxic to the lining of the bladder and may cause inflammation of the bladder–called ulcerative cystitis. This is exceedingly rare in people who occasionally use ketamine for therapeutic purposes.
Long-term side effects of ketamine lozenges prescribed for mood disorders, OCD, trauma, alcohol addiction, or pain are not currently known.
In the excessive street abuse population, cystitis (bladder irritability) and cognitive impairment (learning/memory problems) have been reported. There is no data to support a connection between the long-term side effects in the street abuse population and those who receive ketamine clinically.
Is ketamine covered by insurance?
Only esketamine (SPRAVATO) may be covered by insurance. But the drug must be administered under a doctor’s supervision, which limits its availability/accessibility.
How does ketamine work? What is the mechanism of action underlying ketamine’s antidepressant effects?
Ketamine’s antidepressant effects are changing our understanding of the neurobiology of depression. While it remains unclear exactly how ketamine relieves depression, there are different ways to look at ketamine’s therapeutic effects.
- Experiential Effects
- Biochemical/Pharmacological Effects
Experiential Effects
Ketamine induces a dissociative state. That is, people feel as though their minds have detached from their bodies. Initially, this can be terrifying because of the loss of control. Over the course of multiple infusions, people learn to “let go” of that control and become detached observers of their experiences. As a result, many will report discomfort during the first few infusions. Invariably, a shift occurs, and the experience becomes more pleasant and peaceful.
I recall multiple patients reporting back to me how they felt a renewed sense of optimism and hope after their ketamine experiences.
For most people, the rapid antidepressant effects of ketamine do not last longer than a few weeks to months. However, if used appropriately in conjunction with psychotherapy and lifestyle changes, ketamine can be an effective way to overcome the initial “hump” that keeps people stuck in repetitive patterns of thoughts and behaviors. In a way, ketamine is like the fast-acting “behavioral activator.”
Biochemical/Pharmacological Effects
Ketamine affects multiple neurotransmitter systems—including the opioid system, monoaminergic (i.e., norepinephrine, serotonin, dopamine) systems, glutamatergic system, and the muscarinic (cholinergic) system to name a few—but the leading theories for how ketamine works as an antidepressant implicate the glutamatergic (glutamate) system.
Below is a video explaining the proposed pharmacological mechanism of action of ketamine.
Watch the video below before continuing.
As illustrated in the video, Ketamine’s primary mechanism of action is antagonism, or blockade, of N-methyl-d-aspartate (NMDA) receptors.
N-methyl-d-aspartate (NMDA) receptors are glutamate receptors (glutamate binds and activates NMDA receptors on neurons). NMDA receptors work together with AMPA receptors, another type of glutamate receptor, to initiate changes within neurons. These changes include increased survival, viability, and stronger connections with other neurons.
NMDA receptors are the primary targets for both ketamine and PCP. Interestingly, NMDA receptors are also targets for medications such as Memantine (Namenda), a medication for Alzheimer’s Dementia, and Dextromethorphan, the active ingredient in Robitussin. It isn’t surprising that both of these medications are now being investigated for depression.
Skolnick and colleagues (1996) first postulated a role for the glutamate system in depression when they noted that drugs that block NMDA receptors mimicked the effects of clinically effective antidepressants.
The leading hypothesis is that the initial effects at NMDA and AMPA receptors modulate cellular and molecular processes that are known to be important mediators in the formation of new and “stronger” neuronal connections–a concept termed neuroplasticity. This is the primary molecular mechanism for learning and memory.
Normally, glutamate stimulates both NMDA and AMPA receptors. Activation of BOTH these receptors “tells” the neuron to produce important proteins involved in cell growth and survival. Although both NMDA and AMPA receptors must be activated together for this to occur, it appears that AMPA receptors are most important. That is, when only NMDA receptors are activated and AMPA receptors are blocked, these changes don’t occur (see figure below).
Selectively blocking NMDA receptors with ketamine means there is more glutamate available to activate AMPA receptors. Increased activation of AMPA receptors hastens AMPA-mediated changes in the cell such as production of more AMPA receptors and production of growth factors to name a few. These changes ultimately strengthen the connection between neurons and produce more connections (see figure below). While this is a simplified explanation (it is much more complicated than this) it provides a basic understanding of how we think Ketamine works as an antidepressant.
In summary, ketamine’s downstream effects include upregulation of important growth factor proteins such as mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (EEF-2), glycogen synthase kinase 3 (GSK-3), and brain-derived neurotrophic factor (BDNF) that increase neuronal cell growth, survival, and formation of new connections. It is important to mention that the precise mechanisms implicated in the antidepressant response to ketamine remains unknown and is likely multifactorial.
References
- Ebenezer, Ivor. Neuropsychopharmacology and Therapeutics. John Wiley & Sons, Ltd. 2015.
- Cooper, J. R., Bloom, F. E., & Roth, R. H. (2003). The biochemical basis of neuropharmacology (8th ed.). New York, NY, US: Oxford University Press.
- Iversen, L. L., Iversen, S. D., Bloom, F. E., & Roth, R. H. (2009). Introduction to neuropsychopharmacology. Oxford: Oxford University Press.
- Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
- Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
- Purves, D., et al. (2018) Neuroscience. 6th Edition, Sinauer Associates, New York.
- Stahl, S. M. (2021). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (5th ed.). New York, NY, US: Cambridge University Press.
- Meyer, Jerrold, and Quenzer, Linda. Psychopharmacology: Drugs, the Brain, and Behavior. Sinauer Associates. 2018.
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