Explore the history, medical applications, and potential therapeutic use of ketamine.
TL;DR: Ketamine is a versatile dissociative anesthetic drug that has found broad applications in medicine. It can serve as a general anesthetic during surgery, a therapeutic aid for depression and other mental health disorders, and an analgesic for managing pain. Ketamine acts on the glutamate system and stimulates the release of glutamate, promoting neuroplasticity and the growth and maintenance of new neurons. It has fast-acting antidepressant effects, and although they are generally transient, clinical trials have shown promising results in treating treatment-resistant depression. However, there are concerns and safety protocols surrounding the use of ketamine for health conditions.
In 1962, chemist Calvin Lee Stevens synthesized ketamine while attempting to create more stable derivatives of a different drug, phencyclidine (PCP). Just two years later, the first human trials using a group of Jackson State Prison inmates were conducted by neuropsychopharmacologist Edward Domino, who observed that high doses of ketamine produced anesthesia, while low doses produced unusual dissociative effects.
At the time, Parke-Davis, now a subsidiary of Pfizer, opposed labeling ketamine a psychedelic due to concerns about it being associated with the counterculture movement. Edward Domino's wife, Antoinette (Toni) Domino, unknowingly coined the term “dissociative anesthetic” during a conversation with her husband about ketamine's effects. This term has since been used to describe a class of psychoactive drugs.
Ketamine is a highly versatile dissociative anesthetic drug that finds broad applications in medicine. It can serve as a general anesthetic during surgery, a therapeutic aid for depression and other mental health disorders, and an analgesic for managing pain.
In 1970, the FDA approved ketamine as an anesthetic sold under the brand name Ketalar, which was used extensively by the U.S. Army during the Vietnam War. Despite the war on drugs outlawing the use and research of classic psychedelics, ketamine remained medically legal, and its medical use and research continued undeterred by the clampdown on mind-altering substances.
However, the drug soon found its way into the nightlife scene as a popular club drug in the '90s, with partygoers snorting low doses to induce pleasurable highs characterized by relaxation, euphoria, and vivid alterations in perception. High doses, on the other hand, produced dissociative effects that often resulted in feelings of derealization and depersonalization, commonly referred to as “the k hole.”
Note: The effects of ketamine can vary depending on the individual's tolerance, the dose, the mode of administration, and the setting in which it is used.
Ketamine's dissociative effects are why it is considered a vital anesthetic in Western medicine and has been included on The World Health Organization's List of Essential Medicines since 1985. It is used in surgery rooms for the induction and maintenance of anesthesia in both animals and humans.
Furthermore, because its anesthetic effects come without the cardiovascular and respiratory depression associated with other anesthetics, all ambulances carry a supply of ketamine, making it one of the safest drugs to administer in pre-hospital emergency care.
However, the recreational use of ketamine caught the attention of the US Food and Drug Administration (FDA), which quickly made it a Schedule III substance per the Controlled Substances Act. While this was happening, Dr. John Krystal and his colleagues at Yale were using ketamine to mimic symptoms of psychosis (psychotomimetic) and inadvertently noticed its antidepressant effects.
Dr. Krystal and his colleagues discovered that ketamine can help treat depression in a completely different way compared to traditional antidepressants. Rather than targeting serotonin, norepinephrine, and dopamine systems, ketamine acts on the glutamate system.
When taken in low doses, it stimulates the release of glutamate, which blocks certain receptors in the brain called N-methyl-D-aspartate receptors (NMDA) allowing for the growth of new connections between neurons. This process is called synaptic plasticity and helps to promote neuroplasticity, the growth and maintenance of new neurons.
Ketamine is a complex compound, and researchers have suggested other mechanisms that may be involved in its antidepressant effects. Some studies have found that ketamine can stimulate the production of brain-derived neurotrophic factor (BDNF), a protein that helps to promote the growth and maintenance of new neurons.
Others have shown that it can stimulate mammalian target of rapamycin (mTOR), an enzyme that regulates neuron growth. Research suggests that when BDNF and mTOR processes are stimulated at the same time, they may help to improve connections in areas of the brain important for emotional regulation and stress reduction.
Recent research from Stanford University has also suggested that ketamine’s antidepressant effects could be tied to the brain’s opioid system. One study reported a significant reduction in depression symptoms in patients given ketamine after a placebo, but not when given after an opioid blocker.
Although further investigation is required, ketamine is a fast-acting antidepressant, alleviating depression symptoms in just a few hours for most people.
However, ketamine's antidepressant effects are generally transient, meaning they are not permanent and tend to last for a limited period of time. Studies have shown that the antidepressant effects of a single dose of ketamine typically last for a few days to 2 weeks, with some patients experiencing longer-lasting benefits.
In 2019, clinical trials were conducted on esketamine, a derivative of ketamine, and showed promising results. Based on these trials, the FDA approved the nasal spray form of esketamine under the brand name Spravato. It is prescribed along with an oral antidepressant to treat adults who suffer from treatment-resistant depression and suicidal thoughts.
In recent years, there has been a surge of interest in ketamine as a potential treatment for a range of health conditions, including depression, anxiety, post-traumatic stress disorder, obsessive-compulsive disorder, substance-use disorders, and chronic pain.
While the FDA has approved esketamine, doctors are still allowed to prescribe ketamine for other mental health conditions off-label. This has led to the rise of stand-alone ketamine clinics offering intravenous infusions or intramuscular injections, which provide access to treatment for many patients who previously had limited options.
However, some medical experts have expressed concerns about the readiness of ketamine therapy for extensive, large-scale use.
There are currently no FDA regulations regarding the control and supervision of ketamine clinics, leaving it up to the clinics themselves to determine how treatment operates. To address these concerns, several associations, including the American Association of Nurse Anesthetists and the American Psychiatric Association (APA), have created guiding principles and recommended safety protocols for the use of ketamine.
The APA advises that every ketamine clinic should have a standard operating procedure based on scientifically sound evidence to ensure that patients receive proper screening and care before, during, and after treatment. The APA advises that these standard operating procedures should ensure:
The Kriya Ketamine Research Institute has also published ethical clinician guidelines that emphasize the importance of specialized psychological care delivered by a mental health professional in preparatory and integration therapy sessions.
It's important to mention that ketamine has a potential for addiction. Furthermore, heavy and repeated use of ketamine can cause severe kidney swelling and bladder inflammation. It may be beneficial for ketamine clinics to consider placing a strong emphasis on conducting routine health assessments as a means of addressing potential issues.
In conclusion, ketamine is a versatile dissociative anesthetic drug that finds broad applications in medicine, serving as a general anesthetic during surgery, a therapeutic aid for depression and other mental health disorders, and an analgesic for managing pain. While further investigation is required, ketamine's unique mechanism of action and fast-acting antidepressant effects make it an exciting area for future research and development. Safety protocols must be in place to ensure the responsible and appropriate use of this powerful drug.
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