Rethinking Ketamine in Light of a Newly Approved Depression Treatment

March 19, 2019

On March 5, the US Food and Drug Administration (FDA) approved the prescription treatment Spravato (esketamine), an intranasal spray medicine developed by Janssen Pharmaceuticals, Inc. for treatment-resistant depression.

Significant restrictions will apply. Spravato will be limited to depression patients who have tried and failed at least two conventional antidepressant treatments. Patients must receive the medicine from a doctor in a certified healthcare clinic, and be monitored for at least two hours afterwards. They will be advised not to drive the day of their treatment, and both patient and doctor must sign a Patient Enrollment Form, recognizing the treament’s risks. The drug must be given together with an oral antidepressant, on a recommended course twice a week for four weeks.


A Brief Overview

Generic ketamine is a versatile drug with many applicationsboth medical, most often for anesthesia, and recreational, for its hallucinogenic effects.

It exists as two isomers, (S+) ketamine and (R-) ketamine, which differ in their physiological and psychological effects. Ketamine is usually prepared as a racemic mixtureone containing equal amounts of both molecules. Spravato, however, contains only the isolated (S+) ketamine molecule.

“Unlike most other agents, ketamine offers the important advantage of being able to provide both profound analgesia and adequate sedation without significantly compromising airway reflexes or respiratory function,” wrote Linda Li and Phillip E. Vlisides in a historical review for Frontiers in Human Neuroscience.

Ketamine is ideal then, for patients with significant blood loss or low blood flow, says the World Health Organization (WHO). It does not require external electrical, oxygen, or monitoring systems or highly trained medical staff to administer. “That makes it critical in surgery in low- and middle-income countries and in conflict and disaster zones where such resources are often unavailable.”

Ketamine was first synthesized in 1962 by Calvin Stevens as a structural analog of phencyclidine (PCP), with a fraction of PCP’s potency. Researchers found that ketamine showed promise as a safe anaesthetic that also produced a unique altered state of consciousness—though with a limited duration of effects.

In 1970, the FDA approved the first ketamine treatment for human use, Ketalar, which is usually used to begin and maintain anesthesia.

Ketamine was the most widely-used battlefield anaesthetic during the Vietnam War. It also became the “anaesthetic of choice” in veterinary surgery, and is used on cats, dogs, horses and other mammals. The WHO added ketamine to its Essential Medicines List in 1985.


Recreation, Regulation and Restriction

Recreational or illicit ketamine use has been documented worldwide for decades. Ketamine became a popular drug in party and rave scenes along with “ecstasy” (MDMA), and it has often been mistakenly purchased as ecstasy.

Kellye Greene, president of New York DanceSafe, told Filter about her experience working with people who use ketamine in nightlife, party and music scenes. “People are just using it to enjoy themselves,” she said. “It puts them in a very relaxing state, and it can be very blissful for people when it’s more psychedelic. You enter a state that’s like a ‘mind adventure.’”

“On the outside it may look like something bad is happening because they’re sitting with their mouths open, depending on how deep they are in the ‘K-hole’.”

When taken at a high enough dose, ketamine enables users to enter a sub-anaesthetic state dubbed “the K-hole,” in which they start to de-personalize, de-realize, or dissociate from their body and surroundings. This experience may feel frightening—or peaceful, even spiritual.

“On the outside it may look like something bad is happening because they’re sitting with their mouths open, depending on how deep they are in the ‘K-hole’,” Greene said. “But unless you’re using it with high doses very frequently, it’s relatively safe.”

Problems begin, Greene explained, when ketamine is mixed with other drugs, like alcohol, MDMA, or cocaine—or when users binge by taking rapid doses in a short period of time.

Recreational users usually snort the drug, and may not know the purity or safety of their supply—an issue that applies to all unregulated substances. Problematic ketamine use may result in vomiting, disabled motor skills, blackouts and subsequent harming oneself.

In 1999, the DEA restricted ketamine sales and distribution by placing it in Schedule III of the Controlled Substances Act, in response to reports of illicit use. Drug authorities in the United Kingdom, Canada and elsewhere followed suit.

The United Nations Office on Drugs and Crime (UNODC) reported on illicit ketamine use in 58 countries in 2015, but found that ketamine use was stabilizing or even decreasing around the world. The WHO, for its part, has resisted efforts from the international community to schedule ketamine under global drug controls.

Instead, the WHO recommended nations pursue their own drug policies, “but [they] should ensure ready access to ketamine for surgery and anaesthesia for human and veterinary care.”


From Intravenous to Intranasal

While the FDA-approved Spravato treatment is given as a nasal spray, much medical research on ketamine therapy has focused on intravenous (IV) administrations. Ketamine infusion therapy, given “slowly, intravenously, and at a sub-anesthetic dose” has ballooned in recent years as it has shown potential for treating, for example, depression, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and chronic pain.

The Ketamine Advocacy Alliance, which promotes awareness of ketamine treatments, lists 26 legal ketamine clinics around the country. These ketamine treatments are given “off-label,” meaning for a different medical use than the FDA has approved the drug for, and are not covered by health insurance plans.

“We know that Spravato can be effective because it’s a component of ketamine, the medicine we’ve used successfully for depression for over a decade,” Dr. Steven L. Mandel, founder and president of Ketamine Clinics of Los Angeles, told Filter. “But the nasal route of administration is problematic; it’s about half as effective as IV infusions. Additionally, the dose is fixed and patients will get one of two doses which doesn’t allow for the personalization that we feel is essential for maximum therapeutic benefit.”


Will Spravato Meet the Needs of Millions of Americans?

At first glance, there is good reason to be excited about Spravato as a remedy for treatment-resistant depression. According to the National Institute of Mental Health, 16.2 million adults in the US had at least one major depressive episode in 2016. A separate study showed that between 30-40 percent of patients do not respond to any treatment for depression, and 10-30 percent of this group are “treatment-resistant,” meaning they do not respond to two or more forms of treatment.

Ketamine is a novel treatment because it can act rapidly, within a matter of days or even hours, to reduce depression symptoms. It is particularly effective for reducing thoughts of suicide, even independent of its effects on depression or anxiety symptoms.

Even for patients who can receive the treatment, many of the FDA’s regulations will pose additional obstacles.

But a potential problem with Spravato will be a lack of affordability and access. A one-month course of treatment will cost between $4,700-$6,700. Some of these costs will likely be covered by health insurance plans, but for about 29 million uninsured Americans these costs will either have to be paid out-of-pocket or will prevent access.

Even for patients who can receive the treatment, many of the FDA’s regulations will pose additional obstacles. Patients will be asked to give up two days each week to find a certified doctor, spend several hours at a clinic, and arrange for safe transportation to and from the clinic at their own expense. Requirements that patients also take another antidepressant medication, and that each visit be documented in an FDA registry, will further erode patients’ medical autonomy and privacy rights.

“Esketamine [Spravato] is given as a bolus, all at once, as opposed to a continuous administration over time,” Dr. Mandel said. “Clinical experience has established the benefit of being able to adjust the dose to suit different patients at different times in their treatment. So while this is an important breakthrough, IV ketamine infusions are still superior in every way.”

“With that said, ketamine infusions for depression alone are not a cure,” he continued. “The degree of relief and its duration are tremendously influenced by other interventions, including other medications, talk therapy, improvements in lifestyle choices such as better sleep, nutrition, interpersonal relationships, and more. There are no chemicals known to specifically enhance or retard the benefits of ketamine.”

There is also the matter of the reputation of Janssen Pharmaceuticals, the subsidiary of Johnson & Johnson behind Spravato. In November 2013, the US Department of Justice ordered J&J and its subsidiaries to pay more than $2.2 billion to resolve criminal and civil liabilities related to its marketing of the drugs Risperdal, Invega, and Natrecor, in one of the largest healthcare fraud settlements in US history.

The company was found to have promoted its drugs for unapproved uses, and paid kickbacks to physicians and pharmacy providers. The company’s practices endangered the health of children, the elderly, people suffering dementia, and the developmentally disabled, the ruling said. The unapproved uses of the drugs they promoted resulted in people being put at an increased risk of stroke, diabetes, and developing breasts. I previously profiled one man who was forced to take Risperdal for anxiety symptoms while in federal prison, under threat of solitary confinement.

There are therefore legitimate concerns about how Spravato will be administered and the company profiting from it. It is unlikely the drug will fully meet the needs of a population of millions of Americans in need of a novel treatment for depression.

Nonetheless, if the drug proves effective, it will hopefully encourage further research for other uses of ketamine. A less likely—but more optimistic hope—is that this will reduce stigma around other “drugs of abuse” and encourage us to think more creatively about how we can approach healing.

Photo by Diego PH on Unsplash

Alexander Lekhtman

Alexander is Filter's staff writer. He writes about the movement to end the War on Drugs. He grew up in New Jersey and swears it's actually alright. He's also a musician hoping to change the world through the power of ledger lines and legislation. Alexander was previously Filter's editorial fellow.

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