Routine Surgery Gone Wrong

The year is 1958 and a patient is undergoing a routine surgical procedure. There’s only one catch: the patient has agreed to participate in the experimental use of a new anesthetic that’s been proven to be safe in animals. Everything goes smoothly; the surgery is a success. Seeing that the patient’s vitals are normal by the end of the operation, the surgeon takes a sigh of relief. But as the patient wakes up, something is clearly wrong.

The patient returns to consciousness kicking and flailing. He is extremely agitated and confused but cannot be consoled despite the doctor’s desperate attempts of reassurance. The patient complains of disturbing symptoms: extreme anxiety, vision difficulties, dysphoria, frightening hallucinations, and detachment from reality. The patient reports total numbness and can’t feel any of his limbs.

The doctors quickly link these symptoms to the new anesthetic they had been using.

The experimental sedative used during this surgery was phencyclidine — or PCP. After numerous reports of similarly concerning cases along with a sharp rise in the abuse of PCP recreationally, clinical research on the pervasive substance was discontinued, and PCP was classified as a Schedule II drug.

Fast forward to March 2019 and a variation of PCP, known as ketamine, is approved by the FDA for the treatment of depression. So what happened?

K is for Ketamine

Ketamine, an analog of PCP, is a powerful, sedating painkiller, pain-reliever, and tranquilizer, producing mild euphoria and enhanced sensory perception. Ketamine is also a dissociative hallucinogen, meaning that it can cause a sense of detachment from reality.

Being a hallucinogen, ketamine carries a certain stigma. This stigma largely originated when a multitude of mind-altering drugs became scheduled substances under the Controlled Substances Act of 1970, which labeled them as having a high potential for abuse. Basically, when the “War on Drugs” started in the US in the 1970s, ketamine and PCP were targeted.

It’s definitely true that ketamine has a potential for abuse — all drugs have side effects, some of which are worse than others. Dosage can also be a big problem with drugs like ketamine. It’s the dose that makes the poison, but some also have a much narrower margin between their healing dosages and their deleterious dosages. Furthermore, high doses and prolonged exposure to any psychotropic substance can lead to complications. All in all, ketamine can be a dangerous drug. But that’s not to say that all applications of psychedelics are harmful, and it certainly shouldn’t discredit their potential therapeutic benefits.

Ketamine has a fascinating history that begins with PCP. Ketamine is a less concentrated form of PCP, which is entirely man-made. PCP was first synthesized in 1926, and following preclinical trials in monkeys, it was subsequently developed as an anesthetic for humans in the 1950s. Higher doses were needed to properly sedate humans as opposed to monkeys, and while PCP worked relatively well as an anesthetic, problems arose when people began experiencing troubling side effects upon regaining consciousness after surgery.

In no time, PCP was being abused by increasingly large numbers of people. Chronic, high doses of PCP were causing schizophrenia-like impairments: paranoia, disordered thinking, memory issues, erratic speech and behavior, and so on. PCP was clearly a dangerous drug and was therefore prohibited for human use shortly thereafter.

In an attempt to minimize these unpleasant side effects, ketamine was derived and was thought to be safer because it is roughly ten times less potent than PCP. In its very first clinical study, ketamine was also used as a general sedative for surgery. Unlike PCP, ketamine exhibited few side effects. It additionally acted profoundly as a painkiller without high risk of impacting breathing function. Ketamine was so successful that it is still used in operating rooms today.

However, ketamine also has a high risk for abuse, so it too became a controlled substance in 1970 along with several other substances, and almost all research on these psychedelics was halted. That is, until the past couple of decades, when scientists have reopened new avenues of research on numerous mind-altering drugs.

Antidepressant Effects

The 21st century has brought major breakthroughs in our understanding of ketamine. Some of ketamine’s most exciting applications have involved the treatment of treatment-resistant depression. Treatment-resistant depression refers to patients with major depressive disorder who do not respond to several standard interventions, including antidepressants and talk therapy.

Multiple ground-breaking studies have found that as little as a single dose of ketamine can have rapid antidepressant properties with effects lasting up to two weeks or longer, taking mere hours to alleviate depressive symptoms as opposed to the days and weeks it takes typical antidepressant medications to stabilize mood if they ever do; only about one-third of people achieve remission in response to typical antidepressants. Especially in patients at risk of taking their lives, this can truly be a lifesaving intervention.

These results aren’t based solely on subjective reports of mood. There are actual, measurable alterations in brain chemistry to further support these findings. Ketamine significantly increases the expression of brain-derived neurotrophic factor (BDNF), a protein that essentially supports brain cells and is typically reduced in patients with major depression.

In terms of efficacy, that’s pretty incredible. So incredible, in fact, that ketamine is one of the first treatments in decades to show such a pronounced, rapid relief of depressive symptoms. Before ketamine, electroconvulsive therapy, or ECT, was the touchstone treatment for medication-resistant depression – and that technique was introduced nearly a century ago.

After years of research, a ketamine-derived nasal spray was approved by the FDA in 2019 as a novel treatment for depression. The spray is administered in very low doses, thus avoiding complications experienced during the first round of clinical trials in the 1960s.

It’s important to note that ketamine should only be used in strictly monitored clinical settings because it does have a potential for abuse, and there is still so much that we don’t know.

The Future of Psychedelics in Medicine

Interestingly, ketamine isn’t the only hallucinogen with therapeutic implications. All sorts of hallucinogens have made their way back to the forefront of research. For instance, psilocybin, or “magic mushrooms,” also exhibit antidepressant properties. In June 2021, a study published in JAMA Psychiatry found similarly powerful, rapid antidepressant effects in a large clinical trial using psilocybin to treat major depressive disorders. Institutions like Johns Hopkins have even opened laboratories specifically centered around such research. These insightful findings challenge everything we thought we knew about this class of drugs.

Patients battling major depression, post-traumatic stress disorder, and other mood disorders are in desperate need of new, effective treatments, and ketamine seems to be just one of many massive steps in the right direction. Even more exciting is the fact that the therapeutic benefits of ketamine and other hallucinogens don’t stop there. The success of these drugs has also been implicated in myriad other conditions including cancer, fibromyalgia, migraine, obsessive-compulsive disorder, social anxiety disorder, anorexia, and more.

Throughout the years, ketamine transformed from being an anesthetic to a party drug to an antidepressant, and yet the molecular makeup itself didn’t change at all — just our perception and understanding of it. There is vast terrain yet to be covered before fully appreciating the complex mechanisms of psychedelics, but recent studies have provided unprecedented leaps in knowledge. Though hallucinogens still hold rightfully frightening connotations, when it comes to finding relief for patients suffering from debilitating conditions, we mustn’t allow fear and ignorance to impede further investigation that might just lead to revolutionary treatment for millions of people.

As 19th century physicist and chemist Marie Curie so eloquently put it, “Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less.”