Sunday, March 6, 2022

The History of Ketamine

In recent years, treating depression with Ketamine has become more known about. People often assume that this use of the medication is a new treatment that has just been developed. The reality is the first study showing ketamines use as an accelerant for the therapy process was published in 1973.

Ketamine is an old medication with a long and winding history.
Let’s start the story all the way back to the lab where ketamine was first created. 

Ketamine was first synthesized in 1962.

To set the stage, in 1962, John F Kennedy was the president, the US established a military presence in Vietnam, the Cuban missile crisis occurred, Marilyn Monroe died, the pull tab beverage can was introduced, and the first Wal-Mart was opened. 

Meanwhile at the Parke-Davis lab in Detroit Michigan, a chemist named Calvin Lee Stevens, Ph.D., was consulted to help synthesize a new phencyclidine (PCP) derivative. 

Phencyclidine was being used as an anesthetic medication at the time under the drug name “Sernyl”. Sernyl had some useful characteristics as an anesthetic agent but also had some troublesome side effects. It was not uncommon for patients to wake up after being administered Sernyl feeling very delirious with jumbled speech, and sometimes even experienced significant hallucinations during the recovery phase, lasting for an uncomfortable amount of time. It was clear that if the anesthetic properties of Sernyl could be maintained while some of the side effects could be decreased, the medication may have greater utility as an anesthetic. Cal Stevens achieved that goal by chemically tinkering with the Phencyclidine molecule, thus creating what is now known today as “Ketamine” (though at the time its first research chemical name was Cl-581). 

Cl-581 was first tested on animals, mostly monkeys, and on August 3, 1964 the first dose was given to a human. The first tests of Cl-581 were done on prison volunteers in Michigan at Jackson Prison by Ed Dommino and Guenter Corssen, M.D. Testing on prisoners is no longer legal today but this element helped to rapidly establish safety of the novel chemical compound. 

The effects of Cl-581 escalated curiosity in Ed Dommino. During a conversation with his wife about the response he had witnessed from the prisoners, he described that the prisoners seemed “disconnected” from their environment. His wife said ‘You mean there’s some kind of dissociation? Why don’t you call it a dissociative anesthetic?’” 

Because Cl-581 had a ketone group, it had been called “Keet-amine” originally. In 1970, the FDA approved Ketamine-HCL under the trade name Ketalar®. 

Ketalar®, the “dissociative anesthetic”, quickly became the most widely-used battlefield anesthetic in the Vietnam War. Ketamine became known as the “buddy drug” on the battlefield due to soldiers carrying it on their person. If a fellow soldier suffered a severe injury, they could have their “buddy” inject them with a dose and get immediate pain relief without any risk of respiratory issues. Prior to having Ketamine as an option, opioids were the main go-to for pain relief. The doses of opiates, like Morphine, that were required to treat severe injuries could sometimes cause respiratory depression, so only so much could be given without causing a soldier to die from the opiate administration itself. 

Meanwhile, as ketamine was being used on the battlefield, its use as an accelerant for psychotherapy was discovered rapidly. The first proof of this work was reported from a psychiatrist named Salvador Roquet practicing out of Mexico City in 1972. 

In 1973, a study of 100 people who received IV ketamine with concurrent psychotherapy showed improvements in their mental health.

Despite these early studies indicating that ketamine paired with psychotherapy might have serious promise for treating mental health disorders, much of the progress in researching this modality didn't take off for many years. 

Given that in 1971 president Nixon had declared the “war on drugs”, researching psychoactive compounds was not easily done during these times. 

As a result, much of the scientific progress on mental health treatment during the 70’s through the early 2000’s was focused on the development of medications that worked to alter the brain's levels of serotonin, norepinephrine, and dopamine. 

It wasn’t until the early 2000’s that research on ketamine took off again and by 2006, the National Institute of Mental Health had given a press release stating their studies were indicating that a single intravenous dose of ketamine had rapid antidepressant effects.

In the early 2010’s, “Ketamine Clinics” began to emerge and proliferate in the US and around the world.

Most early clinics were opened by anesthesiologists who were comfortable using ketamine in the operating room, offering IV ketamine infusions or intramuscular injections. 

To date, more than 300 clinical trials have been held studying ketamine’s utility as an agent to treat mental health disorders.

In 2019, a large review of 235 patients undergoing Ketamine Assisted Psychotherapy demonstrated significant improvements in depression and anxiety. Ketamine Assisted Psychotherapy is currently in the stage of being perfected and continually studied. It is showing promise to treat other mental health conditions such as OCD, PTSD, CPTSD, postpartum depression, and chronic pain disorders. 

It is truly fascinating thinking about how one molecule that has been used in so many different ways, for so many years, continues to find new uses. Ketamine is undeniably one of the most important molecules in medical history.


Ketamine A Review

The Synthesis of Phencyclidine and Other 1-Arylcyclohexlamines

Ketamine: 50 years of Modulating the Mind

Taming the Ketamine Tiger

The Domino Effect: Ed Domino’s early studies of Psychoactive Drugs

The History of Ketamine
March 6, 2022
Will Ratliff
Director of Operations