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.

Structures of Ketamine and PCP

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.

WHY IS KETAMINE USED?

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.

HOW DOES KETAMINE WORK?

Ketamine’s antidepressant effects are changing our understanding of the neurobiology of depression. While it remains unclear EXACTLY how ketamine relieves depression, there are two ways of thinking about 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 uncomfortable and even anxiety-inducing. Over the course of multiple treatments, people learn to “let go” of control and become detached observers of their experiences. The idea is to learn how to become detached observers of our thoughts in our everyday lives.

Some people will report losing their sense of “self” during their ketamine treatments. Once the treatment experience ends, people often describe a “reintegration” and a stronger connection with themselves, which fosters a renewed sense of hope and optimism.

It is very common for people to have negative experiences initially, but most people notice a shift after a few sessions and eventually find peace and comfort during their sessions.

The rapid antidepressant effects of ketamine do not appear to 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 a fast-acting “perspective shifter” and/or “behavioral activator.”

BIOCHEMICAL/PHARMACOLOGICAL EFFECTS

Ketamine affects multiple neurotransmitter systems—including the opioid system, monoaminergic systems (e.g., norepinephrine, serotonin, dopamine), glutamatergic system (glutamate), and muscarinic (cholinergic) system to name a few.

Skolnick and colleagues (1996) first postulated a role for the glutamate system in depression when they noted that drugs that blocked a type of glutamate receptor, called the NMDA receptor, mimicked the effects of clinically effective antidepressants.

NMDA receptors work together with another type of glutamate receptor called AMPA receptors to initiate changes within neurons–such as promoting growth, viability, and stronger connections. The formation of new and “stronger” neuronal connections is termed neuroplasticity. Neuroplasticity is the underlying neurobiological process for learning and memory.

Glutamate, a brain chemical, stimulates both NMDA and AMPA receptors to produce a response such as growth and stronger connections. Normally, both NMDA and AMPA receptors are activated together so a response occurs (see figure above).

If only NMDA receptors are activated and AMPA receptors are blocked, the signals for cell growth and survival don’t occur (see figure below).

But, if NMDA receptors are blocked and AMPA receptors are activated, then a response does occur (see figure below).

This means that AMPA receptors are more important in producing a response!

By blocking NMDA receptors with ketamine, there is more glutamate available to activate more AMPA receptors. Increased activation of AMPA receptors quickens AMPA-mediated production of important growth factors and other 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), which are involved in promoting neuronal growth, survival, and stronger connections (see figure below).

This NMDA (glutamate) hypothesis is widely accepted as the primary biochemical mechanism for how ketamine works as an antidepressant. While this is a simplified explanation (it is much more complicated than this) it provides a basic understanding of how we think Ketamine may help induce neuroplastic changes in the brain that lead to an antidepressant response.

It is important to mention that the precise mechanisms implicated in the antidepressant response to ketamine remains unknown but is likely multifactorial.

Interestingly, NMDA receptors are the primary targets for phencyclidine (PCP) as well as for medications such as Memantine (Namenda, for dementia) and Dextromethorphan (active ingredient in Robitussin). It isn’t surprising that both Memantine (Namenda) and Dextromethorphan are now being studied as antidepressants.

WHAT ARE THE 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.