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From Horse Tranquilizer to Depression Wonder Drug: The Ketamine Story

“I had tried countless antidepressants over the years, and none of them worked. I had lost all hope. Then I learned about ketamine treatment, and it was like a switch flipped. For the first time in over a decade, I felt true relief from the darkness of depression. Ketamine gave me back hope when I had none left.”

Ketamine’s journey from solely an animal tranquilizer to a promising new hope for depression has been an unexpected one, full of twists and turns. This rehabilitation of ketamine exemplifies the serendipity that can lead to breakthroughs in medicine.

A Brief History

Ketamine first emerged in the 1960s as a safer alternative to phencyclidine (PCP) for use as an anesthetic. Chemist Calvin Stevens synthesized ketamine in 1962 while working for the pharmaceutical company Parke-Davis. Ketamine was first tested on humans in 1964 and approved for medical use in 1970.

Unlike earlier anesthetics, ketamine did not cause a major drop in blood pressure, making it much safer to administer during surgery. This made it useful both in civilian hospitals as well as on the battlefields of the Vietnam War. It was widely embraced by military doctors and medics for its ability to sedate and anesthetize patients while also maintaining breathing and blood pressure.

Ketamine offered a revolutionary new approach to anesthesia. In the words of pharmacology professor B. Douglas Ward, ketamine “marked a new era in surgical therapeutics." For decades, ketamine was primarily used in operating rooms and veterinary medicine to sedate humans, animals, and pets during medical procedures.

However, recreational use of ketamine also emerged, particularly beginning in the late 1980s and 1990s as a club drug. At higher doses, ketamine can induce feelings of detachment, immersion in a dreamworld, and hallucinations. Due to these dissociative and psychedelic effects, ketamine became popular in the rave and dance club scenes under names like “Special K” or “Vitamin K.” This led to stigmatization and diversion away from its immense medical utility.

Meanwhile, in the 1990s some psychiatrists began researching and documenting ketamine’s surprising effects on depression. They found that in low doses—far below those used recreationally—ketamine could bring rapid relief to those with severe, chronic, or treatment-resistant depression. This sparked greater interest in formally studying ketamine as a new kind of antidepressant.

How Does Ketamine Work?

To understand ketamine’s antidepressant effects, it helps to first understand a bit about the neurotransmitter glutamate and NMDA receptors in the brain. Glutamate is the most abundant excitatory neurotransmitter in the central nervous system. It plays major roles in cognitive functions such as learning and memory.

Glutamate exerts its effects by binding to different receptors, including NMDA receptors, which are involved in synaptic plasticity and memory function. The NMDA receptor got its name by binding to N-methyl-D-aspartate. Malfunctioning signaling of NMDA receptors has been linked to disorders ranging from depression to Alzheimer’s disease.

The typical antidepressants most people are familiar with, like SSRIs such as Prozac or Zoloft, work by increasing levels of serotonin or norepinephrine. This is done by blocking reuptake of these neurotransmitters. But ketamine works differently—it blocks NMDA glutamate receptors.

Researchers have found that in patients with depression, NMDA receptor activation is pathologically increased. There is excessive glutamate activity at these NMDA receptor sites, which may mediate some of the brain changes seen in depression. Ketamine is thought to improve depression by blocking NMDA receptors and increasing glutamate production through a different type of receptor called AMPA.

This cascade of neurochemical effects essentially helps “reset” the brain activity of someone with treatment-resistant depression. Ketamine rapidly reverses abnormally high NMDA receptor activation, restoring more normal glutamatergic function and synaptic plasticity. This leads to a quick improvement in mood and depressive symptoms.

Of course, the full picture is still being investigated. But this glutamate hypothesis helps explain how targeting NMDA receptors sets ketamine apart from conventional antidepressants. It points to the importance of looking beyond serotonin and dopamine in understanding and treating depressive disorders.

The Ketamine Treatment Experience

Imagine you are a patient who has struggled with severe depression for years and found no relief from multiple antidepressants and therapies. You learn about ketamine’s promising results from a friend and decide to look into trying it for yourself.

You go to a clinic or doctor's office that offers intravenous (IV) ketamine infusions. This involves getting an injection of ketamine gradually into your bloodstream through an IV line over 45 minutes to an hour. You sit or recline in a comfortable chair in a dim, peaceful infusion room as the ketamine is administered by a nurse. Some clinics encourage you to wear eye shades and listen to calming music during the experience.

As the ketamine enters your bloodstream, you begin to feel its dissociative effects. Your vision may become blurred and your mind feels like it’s floating in space. You might experience enhanced awareness of colors, sounds, or your inner thoughts. Some describe entering a dreamlike state.

At higher doses, the psychedelic qualities of ketamine can also cause temporary visual or auditory hallucinations—but clinics are careful to avoid giving more than needed for therapeutic effect. You are monitored by medical staff to ensure safety and comfort during the session. Many patients find the introspective, dreamy journey itself emotionally moving or spiritually meaningful.

Amazingly, some people find their depressive symptoms lifting just hours after a ketamine infusion. One 2018 study in the American Journal of Psychiatry found that 70% of people with treatment-resistant depression experienced improvement in symptoms within 24 hours of a single ketamine infusion. However, the benefits of one ketamine session tend not to be permanent or sustained over a long period after it ends. Ongoing infusions, like once every week or two, are often necessary to maintain remission of depression.

This sets ketamine apart from conventional antidepressants that can take weeks or months to take effect, if they work at all. A growing number of specialty clinics now offer IV ketamine therapy, though it remains expensive and is rarely covered by insurance. But for those who qualify and can access treatment, ketamine provides hope where other options have failed.

The Promise and Limitations of Ketamine

Early research into ketamine as an antidepressant has shown incredible promise. Multiple studies over the past two decades have found a significant percentage of depressed patients respond positively to ketamine infusions, even after failing to improve with multiple other antidepressants.

For example, a 2016 double-blind study published in the Journal of Affective Disorders looked at 67 patients with treatment-resistant depression. They were given 6 IV ketamine infusions over a 12-day period along with an oral antidepressant. Remarkably, 71% of the ketamine group experienced at least a 50% reduction in depression symptoms, compared to just 6% of the placebo group. Remission rates can be up to 45% in some trials.

Other studies have explored repeated ketamine dosing for months at a time and found sustained antidepressant benefits. The efficacy does not seem to wane in the short term with multiple infusions. Research also suggests it can help alleviate both emotional and physical pain, addressing both psychological and somatic symptoms. These results offer hope for a uniquely rapid treatment option for those hardest to treat.

However, significant questions and barriers remain regarding the long-term efficacy and safety of ketamine. Its dissociative effects make it challenging to administer continuously in IV form or take at home. There are also concerns about potential impacts of long-term repeated use, including dependency, bladder toxicity, and cognitive impairment.

More research is needed to determine optimal dosing regimens, administration routes, and the duration of treatment needed. Currently, the benefits of ketamine tend to only be temporary without repeated doses. Scientists are studying other modes of administration besides IV infusion, such as oral lozenges and nasal sprays, to make ketamine more convenient and sustainable while avoiding risks from overuse.

Identifying biomarkers to predict which patients are most likely to respond to ketamine also shows promise to optimize its application. Other drugs that work similarly to ketamine are in development, offering hope of alternatives without its addiction potential. While many unknowns remain, the widespread suffering caused by treatment-resistant depression makes further ketamine research an urgent priority.

Expanding Responsible Access to Ketamine Therapy

In 2019, the FDA approved a ketamine-based nasal spray called Spravato for depression after positive late-stage trials, representing the first new type of antidepressant approved in decades. However, Spravato can only be administered under medical supervision and has faced criticism for its high costs. Wider access to ketamine treatment remains extremely limited, with most insurance plans still hesitant to cover an “experimental” therapy.

This has led some advocates to argue that restrictive government policies are preventing ketamine from reaching patients most in need. Researchers and ethicists have proposed guidelines to safely expand access to ketamine therapy under proper medical supervision. Others call for ketamine to be reclassified from a Schedule III drug to better enable research. Grassroots clinics offering inexpensive IV ketamine have sprouted up but occupy a legal gray area.

Striking an appropriate balance between safety and access remains an ongoing challenge. With millions suffering from severe, untreatable depression, ketamine’s benefits are simply too promising to ignore. Finding ways to ethically get this treatment option to those who need it should be a priority. Continuing to shine light on the inadequacy of limiting care based on insurers’ bottom lines is part of advocating for change.

The Future of Ketamine-Inspired Treatments

The unique antidepressant action of ketamine has sparked excitement about the potential of other glutamate-targeting drugs. Scientists hope to develop alternatives without ketamine’s dissociative effects and addictive potential. One drug currently being studied is esketamine, the sibling drug of ketamine that is believed to have more potent antidepressant effects. Researchers are also investigating drugs that inhibit glutamate release or target specific NMDA sub-receptors.

Ketamine’s story has also influenced research into other routes like psychedelics and MDMA to treat mental health conditions. Similar to ketamine, drugs like psilocybin and MDMA have shown promise in depression and PTSD trials by essentially “resetting” brain circuits. The success of ketamine makes the possibility of one day having FDA-approved psychedelic medicines less unthinkable.

These new directions stem from ketamine paving the way as the first radical departure from standard antidepressants. While some scientists urge caution in overstating ketamine’s benefits so far, its emergence has already changed the field. According to psychiatrist Steven Levine, “Ketamine kicked open the door and widened the medical community’s perspective on what is possible for treating depression.”

The story of ketamine reveals the substantial serendipity often involved in medical advances. While initially synthesized as an anesthetic, this drug has become a powerful exemplar of how science evolves in unexpected fits and starts. As Levine states, “The history of psychopharmacology is littered with drugs that were first investigated for one purpose and ultimately found application in something totally different.” Still, ketamine’s early track record for tackling the widespread burden of treatment-resistant depression is incredibly promising.

Conclusion: A Story of Hope

While challenges and unknowns remain in optimizing ketamine therapy, its story so far has been one of hope and healing for many. Wider access to this treatment under medical guidance has the potential to reduce suffering and save lives by providing relief when other tried-and-true options fail.

Ketamine has rapidly shifted from solely an anesthetic and party drug to a revolutionary, fast-acting antidote to human depression and suicidality. This rehabilitation of a substance once best known in veterinary circles to give sedation to horses exemplifies the serendipity and surprises that can occur in medicine.

As ketamine clinics expand carefully designed access, this breakthrough intervention is already making a difference for many people with the most severe, stubborn forms of depression who have not been helped by other available pharmaceuticals. There is still much unknown about how best to implement ketamine treatment safely and effectively. But its early history gives reason for optimism that we are one step closer to better solutions for those in need.

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