Ketamine is easier to prescribe than ever, and the FDA is not happy about it

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A year or so ago, I talked with a man who said ketamine saved his life. He had been depressed, contemplating suicide, and then found a psychiatrist who prescribed him ketamine lozenges. Ketamine is used as an anesthetic, but some studies suggest it also holds promise as a treatment for depression and other psychiatric disorders. So many doctors prescribe the medication to people with those conditions, even though it’s not approved to treat them.

Ketamine is actually pretty easy to find. I’ve gotten social media ads for online ketamine clinics, and you probably have too. According to the FDA, it might be a little too available. Last week, the agency issued a warning against the use of compounded versions of ketamine to treat psychiatric disorders, especially oral dissolving versions that make it possible to use the medication at home. “The lack of monitoring for adverse events, such as sedation and dissociation, by an onsite health care provider may put patients at risk,” the letter states.

So how did we get here? Let’s take a step back.

Ketamine is FDA approved for general anesthesia. It is not approved for the treatment of any psychiatric disorder, a point that the warning letter makes abundantly clear. (The nasal spray, Spravato, which is FDA approved to treat depression, contains esketamine, which is only one of the two molecular forms found in ketamine.) 

But just because ketamine isn’t FDA approved for psychiatric problems  doesn’t mean doctors can’t prescribe it for such uses. They can and often do. It’s called off-label use. When used for anesthesia, ketamine is delivered intravenously or as an injection, both of which require a health-care professional. And many clinics offer ketamine this way for depression too.

But compounding pharmacies can create custom-made formulations of ketamine that can be taken at home, including nasal sprays and oral versions. These formulations are not FDA approved, meaning the agency has not verified their safety or effectiveness—hence the warning letter. 

Ketamine has become especially readily available in the past several years. When the government relaxed the rules around telehealth access to controlled substances during the pandemic, a new opportunity arose. Suddenly doctors could prescribe ketamine without ever seeing the patient in person, and then pharmacies could ship out an oral formulation to take at home. “Startup companies cropped up almost overnight,” according to one Medscape article. 

Ketamine, like all drugs, does come with some risks. At high doses, the medication can induce a trance-like state, where users feel numb and dissociated from their body. It can spark hallucinations. Ketamine can also cause sedation, slow breathing, and elevated blood pressure.

But Boris Heifets, an anesthesiologist and neuroscientist at Stanford, doesn’t see the warning letter as primarily as an expression of concern over the safety of compounded ketamine. “If you read closely, it’s actually pretty flimsy,” he says of the case made for the dangers. He views the letter more as an attempt to curtail the rampant spread of telehealth ketamine clinics, which rely on compounding pharmacies to prepare the drug in ways that make it convenient to take at home. “The public health issue is that people are being indiscriminately prescribed the drug that has abuse liability, and with minimal supervision,” he says.

So is at-home ketamine safe? William Dudney, a psychiatrist in Tampa, Florida, has been offering patients ketamine for five years in the form of “troches,” waxy lozenges about the size of a Chiclet. The troche gets tucked between the lip and gum until it melts. His patients do take ketamine at home, but he prescribes troches that contain very low doses—between 35 and 70 milligrams.

Some doctors prescribe much higher doses. On various Reddit threads, patients who make use of online ketamine clinics say they’ve started their treatment with 450 mg doses and ramped up to 900 or even 1,200 mg per session. 

“It is way too much, way too fast,” Dudney says. “This 400-to-600-milligram craziness—this is for people who are seeking a hallucinatory experience. Hallucinations and dissociations are considered side effects, and that’s not the purpose. That’s recreational abuse.”

The latest warning from the FDA is actually the second risk alert the agency has issued addressing compounded ketamine. The first came last year and targeted nasal sprays. Heifets says these letters are intended to put pressure on the supply side. “They’re basically raising an alarm,” he says. “If you are supplying ketamine for these off-label practices, be sure you know exactly what you’re doing, because there may be some regulatory action here.” Will it be enough to chill the rampant off-label use of ketamine? Probably not. But there are signs the industry’s meteoric rise may be slowing anyway. 

In a previous version of The Checkup, we predicted that the ketamine bubble might be about to burst. The shuttering of some high-profile clinics this year, coupled with increased regulatory attention, suggests maybe it already has. 

Another thing

Whether a ketamine “trip” is necessary to experience the antidepressant benefits of the drug is a matter of some debate. And it’s a question Heiferts and his colleagues tried to answer in a unique study that just came out on Thursday.

One of the difficulties in trying to assess the efficacy of ketamine is that blinding is nearly impossible. Patients know whether they got the real thing or a placebo. But this study was designed to offer a clever workaround. The researchers enrolled 40 participants with moderate to severe depression who also happened to be undergoing surgery. They gave half of them ketamine as part of their anesthetic protocol. Because the participants were under anesthesia, they had no way of knowing whether they received ketamine or not.

The study design also gave the scientists a chance to examine whether the experience of ketamine—the trip—is required for the drug to work. Because the patients were under anesthesia, “they’re not having any particular conscious experience,” Heiferts says.

The results weren’t quite what the researchers expected. The participants who received ketamine during anesthesia did experience a large improvement in their depression symptoms. But so did participants in the placebo group. I asked Heiferts what he makes of these results. “I think expectancy is incredibly powerful,” he says. “This study does not show that ketamine is ineffective.” What it shows, he says, is that it was possible to match ketamine’s effect size by providing the placebo group with that same expectation of benefit coupled with a landmark event: surgery. “You have expectations that something is going to change afterwards, and you step through a door. That’s basically what we’ve re-created with surgery,” he says.

Read more from Tech Review’s archive

Psychedelics are undeniably having a moment, and the therapy might prove particularly beneficial to women, wrote Taylor Majewski in this feature from 2022.

But will the moment last? In a previous issue of The Checkup, Jessica Hamzelou argued that the psychedelic hype bubble might be about to burst.

How do psychedelics change our mental state? Scientists are using natural-language processing to analyze people’s trips.

Emery Brown has been studying anesthesia for more than a decade to understand how different anesthetics affect the brain. Now he and his colleagues plan to harness these compounds as tools to study the brain’s inner workings, writes Adam Piore in this profile of Brown from earlier this year.

From around the web

A fascinating new study sheds light on what might be causing neurological problems in people with long covid: lower serotonin levels caused by lingering virus in the gut. (New York Times)

Scientists found that a dietary supplement reverses declining fertility in older mice. This “undeniably groundbreaking” work provides a potential path to new fertility treatments for humans. (Nature)

A City University neuroscientist whose research propped up an experimental Alzheimer’s drug has been accused of scientific misconduct, and now some scientists are calling for the clinical trials to be suspended. (Science)

Wearable devices outperform human observers when it comes to tracking changes in the movement of people with Parkinson’s disease, a finding that could help scientists better assess the effectiveness of experimental therapies. (New York Times)

The FDA has greenlighted a pivotal in vivo trial of a gene-editing therapy. This one, from Intellia Therapeutics, is a CRISPR-based therapy for a rare type of amyloidosis that stops the heart from functioning properly. (Fierce Biotech)

Scientists just drafted an incredibly detailed map of the human brain

This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.

When scientists first looked at brain tissue under a microscope, they saw an impenetrable and jumbled mess. Santiago Ramon y Cajal, the father of modern neuroscience, likened the experience to walking into a forest with a hundred billion trees, “looking each day at blurry pieces of a few of those trees entangled with one another, and, after a few years of this, trying to write an illustrated field guide to the forest,” according to the authors of The Beautiful Brain, a book about Cajal’s work.

Today, scientists have a first draft of that guide. In a set of 21 new papers published across three journals, the teams report that they’ve developed large-scale whole-brain cell atlases for humans and non-human primates. This work, part of the National Institutes of Health  BRAIN Initiative, is the culmination of five years of research. “It’s not just an atlas,” says Ed Lein, a neuroscientist at the  Allen Institute for Brain Science and one of the lead authors. “It’s really opening up a whole new field, where you can now look with extremely high cellular resolution in brains of species where this typically hasn’t been possible in the past.”

Welcome back to The Checkup. Let’s talk brains.

What is a brain atlas, and what makes this one different?

A brain atlas is a 3-D map of the brain. Some brain atlases already exist, but this new suite of papers provides unprecedented resolution of the whole brain for humans and non-human primates. The human brain atlas includes the location and function of more than 3,000 cell types in adult and developing individuals. “This is far and away the most complete description of the human brain at this kind of level, and the first description in many brain regions,”  Lein says. But it’s still a first draft. 

The work is part of the BRAIN Initiative Cell Census Network, which kicked off in 2017 with the aim of generating a comprehensive 3-D reference brain cell atlas for mice (that project is still in the works). The results reported on October 12 were part of a set of pilot studies to validate whether the methods used in mice would work for bigger brains. Spoiler: those methods did work. Really well, in fact.

What did these initial studies find?

The human brain is really, really complex. I know, shocker! Thus far, the teams have identified more than 3,300 cell types. And as the resolution gets even higher (that’s what they’re working on now), they’re likely to uncover many more. Efforts to develop an atlas of the mouse brain, which are further along, have identified 5,000 cell types. (For more, check out these preprints: 1 and 2)

But underneath that complexity are some commonalities. Many regions, for example, share cell types, but they have them in different proportions. 

And the location of that complexity is surprising. Neuroscience has focused much of its research on the outer shell of the brain, which is responsible for memory, learning, language, and more. But the majority of cellular diversity is actually in older evolutionary structures deep inside the brain,  Lein says. 

How did they make these atlases?

The classic neuroscience approach to classifying cell types relies on either cell shape–think of star-shaped astrocytes–or the cells’ type of activity–such as fast-spiking interneurons. “These cell atlases capitalize on a new suite of technologies that come from genomics,”  Lein says, primarily a technique known as single-cell sequencing.

First, the researchers start with a small piece of frozen brain tissue from a biobank. “You take a tissue, you grind it up, you profile lots of cells to try to make sense of it,”  Lein says. They make sense of it by sequencing the cells’ nuclei to look at the genes that are being expressed. “Each cell type has a coherent set of genes that they typically use. And you can measure all these genes and then cluster all the types of cells on the basis of their overall gene expression pattern,” Lein says. Then, using imaging data from the donor brain, they can put this functional information where it belongs spatially.

How can scientists use these brain cell atlases?

So many ways. But one crucial use is to help understand the basis of brain diseases.  A reference human brain atlas that describes a normal or neurotypical brain could help researchers understand depression or schizophrenia or many other kinds of diseases, Lein says. Take Alzheimer’s as an example. You could apply these same methods to characterize the brains of people with differing levels of severity of Alzheimer’s, and then compare those brain maps with the reference atlas. “And now you can start to ask questions like, ‘Are certain kinds of cells vulnerable in disease, or are certain kinds of cells causal,” Lein says. (He’s part of a team that’s already working on this.) Rather than investigating plaques and tangles, researchers can ask questions about “very specific kinds of neurons that are the real circuit elements that are likely to be perturbed and have functional consequences,” he says. 

What’s the next step?

Better resolution. “The next phase is really moving into very comprehensive coverage of the human and non-human primate brain in adults and development.” In fact, that work has already begun with the BRAIN Initiative Cell Atlas Network, a five-year, $500 million project.  The aim is to generate a complete reference atlas of cell types in the human brain across the lifespan, and also to map cell interactions that underlie a wide range of brain disorders.

It’s a level of detail that Ramon y Cajal couldn’t have imagined. 

Another thing

Gene editing helped chickens resist bird flu. “It could take decades to work through the necessary technical and regulatory steps, but researchers say CRISPR gene editing could eventually save countless chickens’ lives—and transform animal farming,” writes Abdullahi Tsanni.  

Read more from Tech Review’s archive

Brain atlases have been around for a minute. In 2013, Courtney Humphries reported on the development of BigBrain, a human brain atlas based on MRI images of more than 7,000 brain slices. 

And in 2017, we flagged the Human Cell Atlas project, which aims to categorize all the cells of the human body, as a breakthrough technology. That project is still underway. 

Cell atlases could help provide the data needed for AI to build a virtual cell, argue Priscilla Chan and Mark Zuckerberg in an op-ed published last month. 

From around the web

An experimental RSV vaccine launched in the 1960s worsened symptoms of the illness rather than providing protection. A months-long investigation into the history of RSV research reveals that the families who participated in these trials knew little about the risks. This is a long one, but worth it. (Undark)

A fascinating commentary on the new class of weight-loss drugs and the problems it can’t solve. Ozempic mania is “an example of how the American penchant for solving structural issues by fixing individual bodies is excellent at creating demand without solving social problems,” writes Tressie McMillan Cottom. (New York Times)

The FDA is launching an advisory committee on digital health technologies. (FDA)

One of the terrifying things we always hear about the 1918 flu is how hard it hit the young and healthy. But genetic research suggests that people with chronic diseases or nutritional deficiencies were twice as likely to die than healthy people. (New York Times)