On Ketamine

The Hippies Were On To Something

If the world were to shatter and fall on him, its ruins would strike him, but fear would not. - Horace

Ketamine is a drug that's been available in the United States for a long time, more than 50 years. Since its synthesis in a Detroit laboratory nearly six decades ago, ketamine has proven to be a complex medication with unusual properties, heterogeneous, interconnected mechanisms, and diverse, sometimes contested, clinical uses.

Ketamine’s story begins in 1956 when scientists identified a new class of anesthetic medications called cyclohexaylamines. The first of this class of medications was called phencyclidine (PCP, yes that PCP you Hippie). In 1962, a new compound was discovered (CI-581) that possessed all of the positive qualities of PCP without major negative side effects such as severe excitation and profound psychosis. This new medication would eventually be called ketamine. In its initial study, several subjects who received ketamine described feeling as though they had “no arms or legs.” Others felt “like they were dead” and experienced vivid hallucinations. These descriptions led researchers to coin the term, “dissociative anesthesia”

Ketamine is also known as blind, Kit Kat, vitamin K, special K, cat tranquilizers. Two out of four sound like a good time, the other three sound like they are for an old spinster.

It was approved as an anesthetic used mainly on battlefields and in operating rooms, so it's used in anesthesia often in combination with other drugs for surgical procedures. It's also analgesic, which means it reduces pain. It's actually unusual even as an anesthetic just in the way it works, in its pharmacology, it's considered the only medicine of that type that affects the way people think and feel. It works by stopping the brain from getting nerve messages about pain. It also alters how you experience sight and sound.

One day, in retrospect, the years of struggle will strike you as the most beautiful.
― Sigmund Freud

Short-term effects of ketamine

Ketamine is fast acting. It affects you in minutes if taken by:

• nose (nasally)

• injection in a vein (intravenously)

• injection into a muscle (intramuscularly)

Effects are much slower if you take ketamine by mouth. Ketamine use leads to short-term mental and physical effects.

Mental effects

Some of the short-term mental effects can include:

• being unable to speak

• a drunken, dizzy feeling

• sleepiness, confusion and loss of coordination

• sensations of weightlessness or inability to move

• vivid dreams or hallucinations, which may be intense and terrifying

• feeling like the mind is separated from the body (dissociation sometimes referred to as the "K-hole")

Physical effects

A person who uses ketamine may also experience physical symptoms, such as:

• numbness

• blurred vision

• difficulty breathing

• loss of consciousness

• unpleasant taste in the mouth

• increased blood pressure and heart rate, which can lead to:

  • stroke

  • accidents

  • heart attack

• decreased response to pain, which puts the person at risk for injuries

When the effects of ketamine wear off you may feel anxious and depressed. You may also be unable to remember what happened while you were on the drug.

Ketamine can also cause nausea and vomiting. People who eat or drink before taking the drug increase their risk of choking on vomit.

Long-term effects of ketamine

With long-term use the effects of ketamine can become more severe. Common side effects for people who use ketamine regularly may include urinary and bladder problems, such as:

• bladder inflammation

• difficult or painful urination

• frequent or urgent urination

• inability to hold in urine (incontinence)

Long-term mental side effects may include:

• flashbacks

• impaired memory

• decreased sociability

• attention deficit or dysfunction

Ketamine as an Antidepressant

Now that the scary side effects are out of the way. Sounds like you can disassociate and shit your pants, but not care. Win Win, right? Ketamine is produced as a racemic mixture of esketamine and arketamine. In March 2019, scientific and public interest in ketamine erupted with the FDA’s approval of esketamine, racemic ketamine’s positive enantiomer, as a first-in-class antidepressant medication for the management of treatment-resistant depression.

Ketamine demonstrates robust anti-suicidal and antidepressant properties. But as an antidepressant, it may exert categorically different effects at different serum concentrations, and its effects may not follow standard dose-response curves. At doses well above full induction anesthetic doses, ketamine’s antidepressant effect does not appear to be greater than at sub-anesthetic doses. In this regard, it resembles other psychiatric medications such as trazodone, a common multi mechanism medication that functions as a sedative at doses below 150 mg but as an antidepressant at doses above 150 mg.

Ketamine’s antisuicidal and antidepressant mechanism of action may be due to serum glutamate concentrations following AMPA activation. In general, clinicians at academic centers who administer intravenous ketamine to patients as a treatment for depression have, until somewhat recently, gravitated toward a dosing regimen of 0.5 mg/kg over 40 minutes. This tendency reflects the preponderance of research at this dose, which corresponds to a serum concentration of approximately 2000–3000 ng/mL. Treatments are typically administered 1 to 3 times per week. However, ketamine protocols are not widely shared, and a variety of different dosing regimens exist in various centers, with both research and experience in practice suggesting the utility of cautiously up-titrating doses.

Similar to anesthesia society guidelines, the American Psychiatric Association recommends that providers administering ketamine in outpatient settings should be ACLS certified. Ketamine’s low likelihood of producing respiratory suppression when used at low doses has contributed to its perception as a relatively “safe” medication at low doses. While the sympathomimetic effects (elevated heart rate and blood pressure) are often seen with anesthesia induction doses, these changes are uncommon when sub-anesthetic doses are administered.

Monitoring during sedation, at a minimum, should include continuous pulse oximetry and blood pressure checks every ten minutes. Likewise, when used in the context of active suicidal ideation or severe depression, the psychiatric effects, both short and long-term, must be followed and managed to ensure patient safety. Prior to treatment, patients are interviewed to assess their baseline symptoms and response to treatment. After the infusion is complete, patients typically recover for 30 minutes to 2 hours before they are discharged with an escort. It should be noted that these guidelines are specific to our practice and other institutions are likely to have different monitoring and treatment pathways. Further evidence-based recommendations are needed before widespread adoption of one set of guidelines.

What else should you know about ketamine?

• A much lower dose of ketamine is given for depression compared with the dose necessary for anesthesia.

• Like opioids, ketamine has addictive properties. It’s important to understand this when weighing risks and benefits. If you have a history of substance abuse –– such as alcohol or drugs –– it’s especially important for you and your doctor to consider whether ketamine is a good option for you.

• When IV (racemic) ketamine works, people usually respond to it within one to three infusions. If a person has no response at all, further infusions are unlikely to help. Instead, it’s probably best to try other treatments for depression.

• People who experience some relief from depression within one to three ketamine treatments are probably likely to extend these positive effects if the treatment is repeated several more times. The subsequent sessions may help prolong the effects of ketamine, rather than achieving further dramatic relief of symptoms. There are no standard guidelines for this. Many studies offer eight treatments initially (acute phase). After this, patient and doctor decide whether to taper or stop ketamine treatments or continue treatments at longer intervals.

In Sum

Ketamine is an old drug that is experiencing a new emergence of interest among clinicians in preoperative medicine and depression management. With progressively more patients suffering from chronic pain who require pain management without opioids, and with evolving utility at minute doses in the treatment of depression and potentially other psychiatric disorders, this old drug now has further applications for patient care. However, further investigation is forthcoming as to the appropriate monitoring for administration of this drug in postoperative and outpatient settings. Ketamine is just not a club/partying drug as its affects can serve great utility to many people.