Last week, I searched for a meeting.

It was tucked away in the far reaches of the hospital in a conference room that wanted to be hidden.

Sometimes, I play a little game with myself called, ‘How much can I get done before I have to walk across the street?’

I had found the room before. I had missed the intended purpose of going to the room before.

I knew I could rely on my second sense for a relative location, but even then, I would be playing with fire.

A few minutes before the start, I found the room. I held my paced breath and sat down with my fellow clinical fellow mates.

I received a folder: _Conscious Sedation Course_.

This training is standard for those of us who were involved or wanted to be involved in studies with Ketamine.

We went through the slides. We answered some questions. We received our certificates.
It’s an incredible way to spend a birthday.

Later that week, I was on everyone’s favorite dopamine manipulator, Instagram.

I saw the headline: Matthew Perry died from acute effects of Ketamine.

My first reaction was, “Oh boy.”

Origins

If you hang out in the Rivertown neighborhood of Detroit, Michigan, you may see an inconspicuous Omni Hotel. This hotel happens to be a National Historic Landmark. If it could talk, it would have quite a story about its past. It used to be a research laboratory. Not just any research laboratory. One that belonged to one of the largest pharmaceutical companies in the world. One you may have never heard of, but one that has specific considerations for this story.

The hotel was once known as Building 55-Detroit Research. It was built in 1902 by the Parke-Davis Pharmaceutical Company. In the 1950s, the company sought to capitalize on the emerging heyday of anesthetic agents with analgesic properties that would be useful during invasive surgery.

One of the company’s first compounds synthesized and tested for these purposes was Cl-395, known as phencyclidine, popularly known as PCP.

If you know anything about PCP, you can probably put together anecdotally that it is not a great anesthetic. First off, recovery was prolonged after its use. There were concerns about increased blood pressure, respiratory rate, nystagmus, or involuntary movement of eyes, and increased salivation. Excitation could persist for hours after a single dose. And in some, there was concern for psychotic symptoms.

To honor the potential promise of PCP, a common route was taken: make derivatives. One of these derivatives produced notable anesthesia and was shorter-acting. It would be called Cl-581, or 2-(O-chloro- phenyl)-2-methyl-amino cyclohexanone (1.2.4), known as Ketamine.

In 1964, Dr. Edward Domino, a neuropharmacologist, and Dr. Guenter Corssen, an anesthesiologist, led the first human trial for Ketamine on volunteer prisoners at Jackson Prison in Michigan. In a bit of an odd, but not surprising, twist, Dr. Corssen happened to be a war hero in Nazi Germany’s Wehrmacht during World War 2 and emigrated to the U.S. post-war.

While describing the state of the prisoners, Dr. Domino struggled to find the words to describe the class of drug ketamine would fall into. Volunteers had reported a disconnection from their environment, like floating beyond themselves with no feeling in their arms or legs. His wife suggested the term that would lead to FDA approval: ‘dissociative anesthesia.’

The Ketamine Tiger

Parke-Davis patented the drug for human and animal use in 1966. Although the initial studies showed some anesthetic potential, global trials of the Ketamine tempered expectations. Medically, adverse effects such as raised intracranial and blood pressures, seizures, and psychotic sequelae such as hallucinations remained issues. Also, there were similar concerns of excitement as in PCP. That being said, Ketamine found usefulness as an anesthetic where needed. The FDA approved the drug for human consumption in 1970, and it was used as a field anesthetic during the Vietnam War.

Alongside the search for use cases in the early 1970s, Ketamine doses that could provide potential analgesic properties with moderate side effects were being worked out. Sadove and colleagues determined sub-dissociative doses ranged from 0.44-1 mg/kg. This will be important later in the piece.

U.S. veterans coming back home from the Vietnam War and those in the shelters of suburban life alike were being exposed to Ketamine at varying degrees of protocol, soon leading to the concern of abuse.

As Dr. Domino once wrote, we must tame the Ketamine Tiger. 

This concern would continue through the 1990s, when Ketamine became a popular street drug, earning names such as Special K. People were putting themselves in K-Holes for recreation. It also has been used as a date rape drug. All this publicity was amplified during a time when Ketamine and other substances tied with the different countercultures were being looked at with disdain.

Ketamine was placed among the class III substances of the U.S. Controlled Substances Act in 1999. However, the World Health Organization (WHO) considers it an essential medicine for pain relief in adults and children. It has been listed on the organization’s Essential Medicines List since 1985 and on the WHO Essential Medicines List for Children.

Although Ketamine continued to be used as an anesthetic, promising anesthetics were being developed left and right and took over the space that Ketamine once occupied.

Among all of the concerns and sensations, the parallel path still progressed slowly: therapeutic for mental health disorders.

Comeback

Amid Ketamine’s shameful moment, a renaissance was brewing. Berman and colleagues at the Connecticut Mental Health Center and Yale University showed it was possible to obtain fast and lasting antidepressant effects within hours up to 3 days with a reduced dose, such as the sub-dissociative doses mentioned earlier. Akira Kudoh and colleagues in Japan found that low-dose Ketamine improves the postoperative state of depressed patients.

Ketamine primarily acts as an N-methyl-D-aspartate (NMDA) receptor antagonist, thus targeting the excitatory amino acid neurotransmitter glutamate. Most approved antidepressant medications primarily target the brain monoamine systems, such as serotonin, dopamine, and norepinephrine. This revelation expanded the targets for depression treatment. Ketamine is also proposed to work on other targets, such as opioid receptors, which are pain modulators and can also inhibit the reuptake of monoamines.

In 2019, intranasal Esketamine became the first approved ketamine-derived therapy by the USA Food and Drug Administration (FDA) for mental health as augmentation therapy for treatment-resistant depression or depression that fails multiple trials of treatment.

Esketamine is an S-enantiomer of Ketamine, which means for those who either avoided organic chemistry like the plague or wiped it out of their memory after undergrad, enantiomers are structures with different orientations that make them mirror images of one another. R is for rectus or right-handed orientation, and S is sinister or for left-handed orientation. My heartfelt apologies to my left-handed friends.

 

So, Esketamine, S-Ketamine, get it?

The orientation matters because different enantiomers may have other functions due to subtle things, such as different binding targets in the body. According to Hirota and Lambert, the affinity of S-ketamine is three times higher than that of R-ketamine. The anesthetic potency of S-ketamine is 2-3-fold higher compared to R-ketamine.

Alright, orgo lesson over.

Intravenous is the most widely used route of administration for Ketamine in clinical settings because of its superior bioavailability and dose control. Treatment doses of the medications remain pretty low and can be done within an hour. They appear to show the most promise for acute exacerbations as the drug is fast-acting. More recent studies typically use 0.4 mg/ kg or 0.5 mg/kg administered intravenously, infused over 40–60 min.

Comparatively, a trial period of 4-6 weeks is needed for SSRIs to assess efficacy at a specific dose, although some mild benefits can occur within the first couple of weeks.

Other modes of Ketamine administration can provide benefits, such as requiring fewer clinical resources, and have clear, practical advantages for repeated dosing and patient comfort, such as oral, intramuscular, sublingual, and intranasal, as noted before.

Ketamine effects in depression generally last from a few days to two weeks, so repeated dosing is usually necessary to extend recovery.

The IV route administration is what brought me to the conscious sedation training. Matthew Perry was also reportedly undergoing Ketamine Infusion Therapy.

Today and the Future

A colleague recently relayed a story about a patient he had followed in the resident clinic. She had delusions of not having breast cancer, which she did have, but instead thought that parasites infected her. The delusions were so potent that she had been buying veterinary albendazole to treat herself with. Unpeeling the layers, he discovered that she had also been paying in cash for appointments with an anesthesiologist in California for as-needed Ketamine for years. She was homeless by the time my colleague saw her.
The current focus on the trials of Ketamine is learning more about its effects, its long-term prospects, and its mechanisms for treatment.

Systematic reviews and meta-analyses provide support for the antidepressant and anti-suicidal effects of Ketamine. Evidence for other indications is less apparent but could be some additional insight.

Doctors can prescribe Ketamine for alternate uses if they think their patients could benefit—hundreds of clinics across the U.S. offer Ketamine infusions and other formulations for various health conditions.

Even within use for depression, there are some concerns with the widespread nature of pop-up shops for Ketamine. This notion was especially noticeable during COVID-19, witnessing the mad dash to meet everyone where they were. Money flooded into digital health delivery companies, and the incentives became out of whack for some.

Ketamine treatments in these cases aren’t covered by insurance and can be costly, ranging from hundreds to thousands of dollars per session, with most patients prescribed multiple sessions.

My colleagues have also been solicited by entrepreneurs of the highest repute who want to borrow their licenses to sprinkle some boutique Ketamine.

The need to try and find something new is a pressing one. It is clear that not only increased knowledge of heterogeneous diseases such as depression is needed, but different approaches in how we treat the various flavors of the disorder are required, too. Also, better ways to triage and meet people with appropriate treatment before they become disorders are necessary. These nuanced treatments are coming.

Sometimes, the road to breakthrough takes a few decades, and it comes along with refined approaches, additional knowledge, and the courage to try things and improve upon prior attempts. However, it is essential to recognize the urge to get things out there for the wrong reasons. Good ideas and breakthroughs should be rewarded, but the line between breakthroughs and false dreams can be thin.

Sometimes, the one with the most access can be the least protected from adverse events. Unfortunately, last week’s events in Los Angeles channel the many that come before it.

The training in the hidden room is a necessary reminder of the risks that can occur with a drug finding its way and the processes needed for some types of administration. It is essential to get as close as we can to the truth so that we can protect others and ourselves.

I hope you gathered from this discussion that any treatment has pros and cons and must be done appropriately, especially if protocols are refined and developed. Often, we don’t know what we don’t know, and more information is better than not having the opportunity to gain more information.

Ketamine, like many emerging treatments, has promise, and its work could open the door to further treatment pathways. We can’t ignore the abuse potential and the need to use substances in appropriate settings with tried and true protocols.

It looks like we are getting closer to taming the tiger. However, taming doesn’t mean de-clawing or de-fanging.

It’s still a tiger, after all.

Resources

1.Bera, K., Kamajaya, A., Shivange, A. V., Muthusamy, A. K., Nichols, A. L., Borden, P. M., … & Lester, H. A. (2019). Biosensors show the pharmacokinetics of S-ketamine in the endoplasmic reticulum. Frontiers in cellular neuroscience, 13, 499.

2. Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000). Antidepressant effects of ketamine in depressed patients. *Biological Psychiatry, 47*(4), 351-354. https://doi.org/10.1016/s0006-3223(99)00230-9

3. Corssen, G., & Domino, E. F. (1966). Dissociative anesthesia: Further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. *Anesthesia & Analgesia, 45*, 29-40.

4. Domino, E. F. (2010). Taming the ketamine tiger. *Anesthesiology, 113*, 678–684.

5. Hirota, K., & Lambert, D. G. (2018). Ketamine and depression. *British Journal of Anaesthesia, 121*, 1198-1202.

6. Kudoh, A., Takahira, Y., Katagai, H., & et al. (2002). Small-dose ketamine improves the postoperative state of depressed patients. *Anesthesia & Analgesia, 95*, 114-118.

7. Mion, G. (2017). History of anaesthesia: The ketamine story – past, present and future. *European Journal of Anaesthesiology| EJA, 34*(9), 571-575.

8. Pereira, V. S., & Hiroaki-Sato, V. A. (2018). A brief history of antidepressant drug development: From tricyclics to beyond ketamine. *Acta Neuropsychiatrica, 30*(6), 307-322.

9. Zarate, C. A., Jr., & Niciu, M. J. (2015). Ketamine for depression: Evidence, challenges and promise. *World Psychiatry, 14*, 348–350.

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