The legal psychedelic: Ketamine is a fast-acting treatment for depression (if you have the money)

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For the past two weeks, we’ve traversed the burgeoning frontier of psychedelic-assisted therapies, from the thought-pattern shifting potential of psilocybin to the self-compassion-provoking effects of MDMA.

Although the U.S. Food and Drug Administration hasn’t approved those drugs for medical use, they are well on their way. Ketamine, the final stop on our psychedelic sojourn, has a notable advantage over the others — it’s legal. The number of ketamine clinics in the U.S. has risen from a few dozen to several hundred in the past few years, thanks to the soaring interest in psychedelic-assisted therapy.

Emily Witt of the New Yorker describes the ways the ketamine landscape has burst forth over the past decade: “Today, a self-referring depressive with several hundred dollars on hand who is not in the throes of active mania or psychosis can seek out a wide array of clinical treatments with the drug: a titrated dose given intravenously by an anesthesiologist at a retail clinic, a shot in the arm from a psychiatrist in private practice, an oral lozenge sent in the mail by a startup taking advantage of pandemic-era changes to the regulation of remote prescriptions. If you can get to the right city, and have sufficient funds, you can easily secure a legal, therapist-guided, mind-expanding trip at a clinic that advertises on Facebook and is funded by venture capital.”

In today’s newsletter, we’ll take a closer look at how ketamine is being used to treat depression, the path the drug took from general anesthetic to taboo rave drug to an off-label psychiatric medication, and the potential pitfalls of this largely unregulated industry for those who are seeking relief.

The history of ketamine

Ketamine was first synthesized in 1962 by American scientist Calvin Stevens, who was searching for an anesthetic alternative to phencyclidine, also called PCP or angel dust. The inaugural human trial of ketamine was given two years later to men incarcerated at Jackson State Prison in Michigan. (The ability of those men to consent is at best debatable, an ethical oversight explored in this article.) Researchers found that at higher doses, ketamine effectively knocked people out; but, as people emerged from their anesthesia, they felt a sort of sensory dissociation, “like floating on clouds,” as if they had no arms or legs.

The FDA approved ketamine as an anesthetic in 1970, and the compound made its debut in the battlefields of Vietnam (and was used routinely by the U.S. military during that war to treat wounded soldiers). Ketamine is used as a sedative in emergency rooms worldwide.

Yet research on ketamine’s antidepressant powers has taken off only in the last couple of decades. Like MDMA, ketamine became a popular club drug in the ’90s. The first time I heard of it, I was a fifth-grader in DARE class, terrified by the foreboding description of a “K-hole” (an intense, out-of-body experience that can happen when taking very large doses of ketamine).

The U.S. Drug Enforcement Administration classified ketamine as a Schedule III drug in 1999, which means the government views it as having a moderate to low potential for physical and psychological dependence. Around the same time, a team at Yale School of Medicine published the first randomized controlled trial that showed ketamine’s ability to improve the mood of people living with depression. By 2006, the National Institute of Mental Health concluded that an intravenous dose of ketamine had rapid antidepressant effects. About 300 clinical trials have been held, and they have broadly found that ketamine is extremely fast-acting compared with traditional antidepressants and can relieve depression for a period that can last days or weeks.

Many doctors have prescribed ketamine off-label to patients with severe depression since 2010 (using an approved drug for unapproved purposes is legal with a patient’s informed consent). Ketamine clinics started cropping up across the U.S. around that time, and a prescription version of ketamine called Spravato, given through a nasal spray, was approved in 2019 by the FDA for treatment-resistant depression. Spravato can be used only if you’re in a clinic or doctor’s office and being supervised by a medical professional.

The science of ketamine

These past two weeks we learned that scientists suspect psilocybin, or “magic mushrooms,” helps depressed patients generate new connections between neurons, rebuilding critical pathways lost to depression.

And MDMA seems to help patients with PTSD feel safer to talk about their traumatic memories, possibly in part because it elevates levels of feel-good brain chemicals that help the patient feel more trusting and at peace.

So, how does ketamine work?

Similar to these other psychedelics, scientists aren’t quite sure why ketamine appears to quickly relieve depression in its users.

Its workings remains a mystery, in part, because depression has historically been what scientists call a “black box” disease, meaning relatively little is known about its cause. Conventional antidepressants work by increasing levels of the brain chemicals serotonin, dopamine and norepinephrine to improve mood, while ketamine seems to mostly generate the neurotransmitter glutamate, which helps stimulate communication among brain cells.

“Ketamine administration rapidly … increases the number, complexity, and strength of connections between neurons, and this effect appears to be directly correlated with its antidepressant benefit,” said Dr. Kelley O’Donnell, a psychiatrist who studies and provides psychedelic-assisted psychotherapy at New York University’s Langone Center for Psychedelic Medicine. In other words, similarly to psilocybin, ketamine may help regenerate synaptic connections between brain cells that have been damaged by stress and depression.

Taking ketamine

But what does it feel like? That depends on the dosage. Generally speaking, users describe a sort of bodily weightlessness and a felt sense of distance between themselves and their environment — “like you’re watching your own life happen instead of living it,” writes Anna Silman for the Cut.

“From personal experience, I can say ketamine generates a uniquely dissociative state that allows you to view your life in cold abstraction — without the subjective distortions of trauma, incessant chatter of self-criticism, or maybe even just feelings,” writes Michelle Lhooq for DoubleBlind Mag. “ The numbing sense of calm that ketamine envelops you in perhaps makes it an easier aid for plumbing the subconscious than more mischievous medicines like magic mushrooms … where trips can take more unpredictable turns.”

There are many different models for using ketamine, which O’Donnell described for me.

🔬 The biomedical model: Ketamine is treated as a pharmaceutical agent. Little attention paid to “set and setting,” the dissociative effects are minimized, and psychotherapy is not generally part of the intervention.

🌌The psychedelic model: Moderate to high doses of ketamine are given in an effort to occasion a non-ordinary state of consciousness that is meant to promote deeper psychological, or psycho-spiritual, transformation.

🗣 The “relational” or “psycholytic” model: a type of ketamine-assisted therapy where lower doses of ketamine are administered in the context of an ongoing therapy. Clinicians reported that at lower doses, “ketamine appears to decrease the fear and anxiety associated with emotionally charged topics, softening the defenses and increasing a sense of connection and empathy, acting as a lubricant for psychotherapy,” O’Donnell said.

With the drug alone, therapeutic benefits are usually short-lived, O’Donnell told me, and often require ongoing doses. Psychotherapy can deepen the benefits of ketamine. “When ketamine is used as a catalyst for psychotherapy, we’re taking advantage of that increased neuroplasticity by integrating any psychedelic insights in an ongoing way, while learning and practicing new ways of being in the world, and cultivating new, more adaptive habits of thought and behavior.”

Clinical ketamine is given through an IV over the course of about an hour, if therapy isn’t involved. A typical treatment plan using the biomedical model is four to six sessions over two to three weeks. “Then some folks will monitor symptoms over time, and see if and when the symptoms start to creep back in. At that time they might get a booster dose — once a month, once every three months, depending on the patient,” O’Donnell said.

The business of ketamine & risks

The surge in demand for ketamine therapy has paved the way for a cottage industry of ketamine clinics. Some companies make sweeping claims in their advertisements of being able to treat dozens of conditions, including chronic pain, PTSD, bipolar disorder and migraines (which may well be true, but more research is needed to back those claims, experts told me). Because the industry is unregulated, what you get at these clinics can be highly variable. “Many clinics are run by anesthesiologists, not psychiatrists, and are pain management clinics that have been repurposed to treat depression,” said Dr. John Mann, a Columbia University psychiatrist and ketamine researcher.

And it’s expensive: usually between $400 to $1,000 per session and thousands for the full course of treatment.

In the early days of the pandemic, the DEA loosened remote prescribing restrictions so clinicians could prescribe medications virtually. That change brought a proliferation of startups that provide at-home ketamine therapy for much less than what you’d pay at a brick-and-mortar clinic.

These startups, which send customers ketamine in lozenge-form, have been scrutinized for not providing enough clinical oversight. Lhooq, who wrote the DoubleBlind piece referenced above, signed up for ketamine therapy with two competing companies in this marketplace, and wrote that “qualifying for these treatments required jumping through several requisite hoops: first taking an online survey about my mental health, then video chatting with a nurse about my medical history, and finally, meeting with a psychiatrist over Zoom, who diagnosed me with anxiety and wrote my script.” But neither company asked to review her medical or psychiatric records.

California

Three years after clinical trial, ketamine provides hope for severely depressed

Ketamine or more specifically, its cousin — esketamine — has started to change the landscape of depression, especially where it borders on suicide.

Oct. 2, 2022

O’Donnell said many patients pursuing this treatment route aren’t getting thorough diagnostic workshops. Ketamine could be dangerous for people with certain heart conditions or a history of substance use disorders (though conversely, ketamine might also be helpful in the treatment of substance use disorders). The risk for dependence on psychedelics is very low at clinical doses, but may be higher for ketamine, which in some cases can be psychologically addictive.

“We don’t have good data to support how safe ketamine is in this less controlled way,” O’Donnell said. “I’ve heard of these companies sending doses that are much higher than I would even use in my office when I’m directly monitoring patients.”

Yet, in a world where in-clinic ketamine treatments cost far more than most people can afford (especially lower-income patients), services like this are expanding access. For now, many insurance companies won’t cover the cost of off-label treatments like ketamine therapy, and because the drug is widely available, there’s no incentive for a pharmaceutical company to finance a large, high-quality trial, Mann said. There’s a movement to get new billing codes for psychedelic-assisted psychotherapies, but that process could take years.

O’Donnell described a potential middle-ground, where patients might take ketamine lozenges at home between in-office sessions, reducing the overall cost; ketamine itself is an inexpensive drug, and what people are paying for is the clinical oversight (and, in some cases, the profit sought by private equity companies financing the operation). To be most effective, “there would need to be very clear agreements about how ketamine is used and how often in order to mitigate risks as much as possible,” O’Donnell said.

Lastly, the Biden administration last week proposed new rules that could majorly affect clinics virtually prescribing ketamine. Under the proposal, which the public has 30 days to review and comment on, doctors could write patients 30-day ketamine prescriptions after telehealth visits, but for refills, would need to schedule in-person consultations.

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I hope you all walked away from this series feeling fortified (and less confused) by the exciting potential of psychedelics in mental health treatment. Personally, I learned through this reporting process the distinct psychological and emotional effects of each drug, and why they each represent so much promise for those for whom no other treatment has worked. I also learned how far we have to go until these treatments are proved safe and are accessible.

If you have any experience with these treatments (psilocybin, MDMA or ketamine) please consider sending us a note. We’d love to answer more of your follow-up questions and share your perspectives in a future newsletter. Reader questions are what inspired this trip (it’s the last time we make the joke, we swear) through the fascinating word of psychedelics, and it’s the readers we’re here to serve.

Until next week,

Laura

If what you learned today from these experts spoke to you or you’d like to tell us about your own experiences, please email us and let us know if it is OK to share your thoughts with the larger Group Therapy community. The email [email protected] gets right to our team. As always, find us on Instagram at @latimesforyourmind, where we’ll continue this conversation.

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More perspectives on today’s topic & other resources

The increasing popularity of ketamine as both a party drug and a clinical treatment should not blind us to its addictive potential at high doses, writes Jose Guzman of DoubleBlind mag. “For a subset of people, it is the most interesting thing they have ever experienced and something they feel like they have to keep doing,” one physician said. “That can be a very powerful draw that can lead to daily use and hiding the use, and can eventually lead to paranoia and the loss of important things in their life like people, work.”

Ketamine therapy is going mainstream. Are we ready? This piece by the New Yorker offers a deeper dive into the question of how the drug helps, who it will serve, and who will profit.

Ketamine’s cousin — fast-acting, easily administered and insurance-billable esketamine — has started to change the landscape of depression since it was approved by the Food and Drug Administration in 2019. “It doesn’t work for everyone,” one psychiatrist told Times writer Tom Curwen. “But when it does, it is truly astonishing.”

Legalizing psychedelics for medical purposes would have been highly unlikely 20 years ago. The sudden change of heart has a lot to do with who is pushing for it. This podcast episode of the New York Times’ “The Daily” tells the story of the military veterans who are pushing for legalization.

Other interesting stuff

Faced with high levels of worker stress, anxiety and burnout fueled by the COVID-19 pandemic, many companies pledged that employee mental health would become a top priority, write my colleagues Denise Guerra and Samantha Masunaga. Despite the increased attention, however, the stigma of mental health struggles persists, preventing many with bipolar disorder, clinical depression and other conditions from feeling safe enough to be open with employers about their diagnoses, and seek out workplace supports to which they’re legally entitled.

Racism has negatively impacted generations of people, from lost economic opportunities, racist policing and incarceration, and in many cases, death. Perhaps unsurprisingly, the pernicious effects of racial discrimination and structural racism also take a grave toll on the brain and mental health, emerging research shows.

For the first Black man to wear hiking’s ‘triple crown,’ the trails are a place for healing. Akuna Robinson completed the three most challenging U.S. trails: the Pacific Crest Trail, the Appalachian Trail and the Continental Divide Trail. But his advocacy and kindness loom even larger than his accomplishments: He’s someone who’s lived with depression and anxiety, and is an ardent advocate for the mental and emotional well-being that nature can offer, writes my colleague Dakota Kim.