What is Ketamine?

Ketamine is a drug/medication that was initially developed in 1962 as a structurally related alternative to phencyclidine (PCP). At that time, phencyclidine (PCP) was being used as a dissociative anesthetic for humans and animals, but its use was discontinued because of concerns about neurotoxicity.

comparing the structures of ketamine and pcp

Interestingly, ketamine and PCP demonstrated similar anesthetic properties, but ketamine was better tolerated and not neurotoxic at anesthetic doses. This resulted in ketamine’s approval as an anesthetic agent by the U.S. Food and Drug Administration (FDA) in 1970.
Ketamine is 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 simply the letter K.

Can it be used for depression?

Yes, ketamine is a fast-acting antidepressant medication and some patients see improvements in mood within hours to days (rather than weeks or months for classic antidepressants). Ketamine appears to rapidly decrease thoughts of suicide as well. However, the effects are often short-lived. Ketamine by mouth, nasal spray, or intravenous infusion are viable options for those suffering with treatment-resistant depression.

Can it be used for anxiety?

Yes, ketamine has been shown to be effective for people with generalized anxiety, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). A study published in the American Journal of Psychiatry found that repeated doses of ketamine can help reduce the symptoms of people who suffer from PTSD. Over a two-week period, patients received six infusions of ketamine.

Can ketamine be used for alcoholism and other substance use disorders?

Yes, studies have looked into ketamine’s effect on depressed people who have a family history of alcoholism. In research that appeared in the American Journal of Psychiatry, people with problem drinking were administered ketamine along with motivational enhancement therapy, compared with a control group, the ketamine plus therapy group drank less and did not relapse as much.

What is ketamine used to treat?

Ketamine has demonstrated efficacy for the following conditions:
  • Depression
  • Anxiety
  • Obsessive Compulsive Disorder (OCD)
  • Post-Traumatic Stress Disorder (PTSD)
  • Alcohol Use Disorder
  • Chronic Pain

How is Ketamine administered?

Ketamine may be administered in oral form (as a troche/lozenge), through the nose (esketamine nasal spray), or by infusions (intravenously) in specialized clinics. A round of ketamine infusions typically comprises six (6) sessions spread over a two to three weeks and may cost several thousand dollars. Patients typically pay out-of-pocket for ketamine therapy except for the nasal spray, which has an FDA indication for treatment resistant depression. Some patients benefit from the oral form of ketamine, which is much less expensive but requires using a compounding pharmacy.

What’s the difference between ketamine and esketamine?

Ketamine itself is a mixture of two compounds, (R)-Ketamine and (S)-Ketamine. These are called stereoisomers. In stereochemistry, stereoisomerism, or spatial isomerism, 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. By definition, molecules that are stereoisomers of each other represent the same structural isomer.

Ketamine itself is not FDA-approved to treat depression, but the stereoisomer S-ketamine, or esketamine, is. The drug is delivered by nasal spray and is designed to be administered alongside a traditional antidepressant. It was approved specifically for treatment-resistant depression, or depression that has failed to respond to other antidepressant medications.

Is ketamine covered by insurance?

Because esketamine, but not ketamine, is FDA-approved, it may be covered by insurance. But the drug must be administered under a doctor’s supervision, which limits its availability/accessibility. 

What are the side effects of ketamine?

Side effects of ketamine can include
  • Dissociation
  • Dizziness
  • Anxiety
  • Nausea
  • Numbness
  • Sedation
  • Vertigo
  • Lethargy
  • Hallucinations
  • Blood pressure elevations
  • Induction of mania/hypomania
Ketamine is toxic to the lining of the bladder and may cause inflammation of the bladder–called ulcerative cystitis.

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. 
  1. Experiential Effects
  2. 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.



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For more information about ketamine, ketamine-assisted therapy, and ketamine infusions, visit the following links:


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