A Primer on the Evolution of Ketamine Therapy: Past, Present, and Future – Part 2 of 2

To stay current with the latest published papers, I frequently browse Google Scholar. Here are a few notable examples of fascinating recent research related to ketamine and ketamine therapy:

• A study called “Ketamine evoked disruption of entorhinal and hippocampal spatial maps.” by Francis Kei Masuda and others used mice to try and locate which parts of the brain are responsible for ketamine’s cognitive changes. In other words, why does ketamine cause unconsciousness at higher doses? Whereas at lower doses, why does ketamine cause dissociation and impaired spatial memory while correlating with clinically-significant improvements in mood disorders? The authors suggest that additional research may find ways to treat depression with ketamine therapy without its psychoactive side effects.
• Theresa R Lii MD and others sought to answer this very question in a creative way in “Randomized Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients.” I posted a response to this thought-provoking preprint in June. While I applauded the researchers’ thoughtfulness, I suggested a few ways to improve future research, starting with more doses.
• In May, Gül Dölen MD PhD, one of the most prominent in psychedelics research, published a paper titled, “Psychedelics reopen the social reward learning critical period.” Dr Dölen and her colleagues found that psychedelics like MDMA, LSD, psilocybin, and ketamine make it possible for adults to learn new thoughts and behaviors during a time known as a critical period for social reward learning. Scientists have been studying critical periods for nearly a hundred years. They are believed to be temporary stages during which our brains are primed to learn things like vision, hearing, balance, imprinting, first languages, and social behaviors. Dr Dölen's paper is significant because it may explain why psychotherapy, a social context, is more effective during a specific timeframe after someone experiences the acute subjective effects of a psychedelic like ketamine. Without a doubt, this should be one of the most active areas of psychedelic research in the coming years.

• Over the summer, many news outlets reported on a well-run study that was published in the New England Journal of Medicine by Amit Anand MD and others. In it, they concluded that subanesthetic IV ketamine is not inferior to electroconvulsive therapy or ECT to relieve treatment resistant major depression without psychosis. ECT is one of the most common ways to help those suffering with TRD but is associated with side effects like memory impairment and muscle pain. This study helps establish that ketamine can be as safe and effective as other ways like ECT to treat persistent depressive symptoms.
• Arguably one of the important research questions is whether psychotherapy improves the safety and effectiveness of ketamine therapy. Aaron E. Philipp-Muller and others in Canada published the results of their research into whether combination therapy is more effective than monotherapy in “Combining Ketamine and Psychotherapy for the Treatment of Posttraumatic Stress Disorder: A Systematic Review and Meta-Analysis” in February. While more research is needed, their findings appear to validate the intuition and practical experience of many ketamine therapy providers: Psychotherapy helps sustain the benefits of ketamine therapy.

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Prediction #6

With hopes to replicate the success of Spravato® and its patentability, drug makers will fund more research comparing the safety and efficacy of racemic (generic) ketamine versus its enantiomers, s-ketamine and r-ketamine. Pharmaceuticals will also team with venture capitalists to fund research into synthetic psychedelics. As part of the burgeoning citizen-science movement, ketamine clinics will join forces with researchers like Conor H. Murray PhD, founder of Psynautics, to populate a research database using anonymous patient data. Scientists from around the world will be able to use the data to study the real-world (as opposed to laboratory settings) safety and effectiveness of ketamine therapy.

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Another Major Reason Why More Research Is Needed

Further research and data on the safety and efficacy of ketamine therapy will help implement standards of care, develop new therapeutic techniques, and ultimately improve patient outcomes. Growing scientific consensus on ketamine therapy will also help increase access. Right now, most health insurance will not cover ketamine therapy other than Spravato®. Rather, patients must self-fund their treatment which can cost hundreds of dollars for a single session.

In limited cases, insurance companies are reimbursing some ketamine therapy costs, but only after recipients prepay. Anecdotal evidence suggests that 30-50% of superbills for ketamine therapy are reimbursed, depending on the insurance carrier and the covered person’s medical history. Unfortunately, payer reimbursements are too unpredictable for many to count on, leaving ketamine therapy accessible to only those who can afford it out-of-pocket.

Worse yet, some have reported that one of the largest payers, the Department of Veterans Affairs or VA, has not made ketamine therapy widely available to those who are burdened with a disproportionate share of depression, PTSD, and suicide. This is despite the VA’s approval of both Spravato and injectable ketamine treatments years ago.

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Prediction #7

After a leading health insurance company abandons its distinction between physical and mental health, it will be the first to cover a full round of ketamine therapy (pharmacotherapy and psychotherapy) for the treatment of depressive symptoms in those who have not had success with traditional antidepressants. Within another year and in response to mounting scientific evidence, others will follow. The VA will continue to invest heavily in mental health care. (From 2006 to 2023, its annual budget for mental health increased 525% to $15 billion.) Because of ketamine’s ability to rapidly treat suicidality, the VA will expand ketamine therapy at its locations and through qualified community providers within its Community Care Network. Eventually, the VA will incorporate ketamine and other psychedelics into its National Strategy for Preventing Veteran Suicide.

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In the Meantime, Some Are Looking for New Ways To Increase Access Today

A quick review of the latest ketamine therapy offerings for both online platforms and in-person clinics, will show couple’s therapy, group sessions, and retreats. By offering a long-held tradition whereby two or more people undergo a psychedelic journey together, in a ceremonial setting, and under the direct supervision of a facilitator or guide, some ketamine therapy providers are finding ways to reduce their costs per patient.

A novel way to increase access to ketamine therapy may come by way of another long-held tradition: employee benefits. Last year, Enthea, a non-profit, third-party, health benefits administrator or TPA, and Dr Bronner’s, a progressive maker of environmentally- and socially-conscious consumer products like soap, partnered to offer Dr Bronner’s employees ketamine therapy as a benefit. In the first year, 7% of the employees completed the employer-paid ketamine therapy treatment which included preparation and integration with a psychotherapist. Early results are promising and hopefully lead to more employers offering ketamine therapy.

Note: Earlier this year, Innerbloom Ketamine Therapy started the application process to join Enthea's provider network. Our hope is to help increase access to ketamine therapy by supporting employees of companies who believe that ketamine therapy may help improve morale and productivity.

Intriguingly, one company is trying to increase access to ketamine therapy by creating a topical cream. This route of administration claims to be not only simpler but to provide therapeutic benefits for the treatment of PTSD without the psychedelic adverse effects like dissociation and nausea. Phase two clinical trials are planned to start in 2024. Many like me will be watching this closely because of what we may learn about the importance of bioavailability and subjective effects of psychedelic therapy.

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Prediction #8

Access to psychedelic therapies, including ketamine therapy, will continue to be a major challenge for those it would benefit and an opportunity for entrepreneurs. The usual players: regulators, drug manufacturers, insurance companies, tech companies, and providers will cooperate on incremental changes which will eventually help millions more gain access to treatments like ketamine therapy each year. However, simultaneously, promising new entrants like Enthea will demonstrate how mental health care can be both feasible and accessible. More and more employers will turn to these non-traditional employee benefits to compete for qualified candidates and retain their best employees.

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It Is a Pivotal Moment for Ketamine Therapy

The apparent tradeoff between profitability and accessibility is just one of several key questions shaping ketamine therapy today. For example:

• Which kind of drug is ketamine? Ketamine plays an essential role in medicine because of its safety, efficacy, and affordability when compared with alternative anesthetics, analgesics, and mental health treatments. As I noted at the beginning of this article, there has been lots of publicity extolling the safety and benefits of ketamine therapy when administered properly. However, its unique subjective experience also makes ketamine a candidate for misuse. For example, in some parts of Asia where many have undesirable reactions to alcohol (which is a common but imperfect way to describe what ketamine feels like), ketamine abuse has been rampant. Closer to home, some have implicated at-home ketamine therapy as well as a general increase in ketamine awareness as growing sources of misuse, unfairly comparing ketamine to opioids. Even those who don’t regularly seek the news have likely heard about illegal trafficking, wrongful deaths, misuse, and abuse relating to ketamine.
• If ketamine is inexpensive, why does treatment cost so much? Generic forms of ketamine are inexpensive. But the costs required to provide ketamine therapy safely by licensed healthcare professionals can make the treatment inaccessible for many.
• Why is this generic medicine in short supply? Many clinics which offer IV and IM ketamine therapy have lowered their doses, turned away patients, and faced existential threats as a worldwide shortage of injectable ketamine continues. While many factors may be to blame including supply chain issues and slow regulatory responses, it emerged that two well-known distributors, McKesson and Henry Schein, may have stock but refuse to supply licensed medical professionals who offer their patients ketamine therapy.
• Why are some skittish to do business? Ask ketamine therapy practitioners about what keeps them awake at night and you’re likely to hear stories of vendors abruptly curtailing or ending services without recourse. For example, insurance companies, online advertisers, payment processors, phone and messaging services, and even farmer’s markets have been known to deny, restrict, or end their relationship with legitimate providers of ketamine therapy. Clearly, ketamine’s negative publicity or the threat of unwanted regulatory scrutiny are making it challenging for some to offer ketamine therapy, despite its fully legal status.
• Are regulators on the same page? Without explanation or criminal charges, the DEA revoked controlled substance prescribing privileges from Scott Smith MD in May. Like online platforms which offer ketamine therapy at-home, Dr Smith was licensed in most states to prescribe ketamine which was shipped from compounding pharmacies to thousands of patients. (It turns out that the DEA may have targeted Dr Smith because of his appearance in a Washington Post article this summer. While facts are still emerging, Dr Smith may not have been registered properly in some jurisdictions to prescribe controlled substances.) Just days later, the DEA and Health and Human Services Department extended a temporary rule which allows doctors to prescribe controlled medications without visiting in person. And in October, the FDA posted a warning about potential risks associated with compounded ketamine which is used to treat psychiatric disorders.

I frequently see the “Wild West” in reference to the current state of ketamine therapy. While it conjures colorful concepts like freedom, discovery, and grit, the analogy is misleading. To the unfamiliar who may see a lawless free-for-all on the frontier of established medicine, it is important to remember that the foundation for ketamine therapy is built upon decades of ketamine administration in medical settings; hundreds of scientific papers studying its mechanisms of action, safety, and efficacy; and a rapidly growing number of positive patient outcomes.

The vast majority of those who provide ketamine therapy chose ketamine because they have seen its healing ability firsthand. And not just anyone can “go west” and provide ketamine therapy. While specific qualifications vary across states, at a minimum, providers must be licensed by their state’s medical or nursing board. They must also register with the DEA to prescribe or handle controlled substances.

This means that for every patient who receives ketamine therapy at home, on a retreat, or in a medical office, there is someone with a license to practice medicine or nursing who is responsible for that patient’s care. Not something to be taken lightly.

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Prediction #9

Ketamine therapy will not advance without some mistakes. That’s how progress works. However, the practice will continue to move forward. Influential professional associations will join the AANA and APNA and voice support for ketamine therapy. With years of experience with ketamine, ketamine clinics will be the first to offer new psychedelic therapies as they become legal. Inspired by the psychedelic renaissance, the ranks of licensed therapists will grow significantly helping to close the projected shortfall. And despite all the profitable clickbait and hot takes involving ketamine and ketamine therapy, public sentiment will shift in favor of ketamine therapy provided by licensed healthcare providers. At first gradually, then suddenly.

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The Future of Ketamine Therapy Is In Our Hands

I feel confident about the future of ketamine therapy for two main reasons. First, I have seen how ketamine can be a safe and effective treatment for many. Second, ketamine therapy practitioners can exchange ideas and coordinate care like never before.

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Prediction #10

When practitioners from different backgrounds are able to safely and openly debate the various tools and techniques, refer patients, and offer timely advice, ketamine therapy will evolve the essential features needed to play a key role in meeting our country’s growing healthcare needs.

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Final Thoughts

In addition to conferences like Psychedelic Science 2023 and ASKP3’s annual meeting, the following are valuable resources which offer ideas and advice, promote standards, and spread best practices with the ultimate goal of achieving better patient outcomes with ketamine therapy. Be well.

• AKSP3 is a non-profit which serves as an advocate for safe clinical use of ketamine for mental health disorders and pain conditions. I find its advice, annual conference, and webinars to be helpful.
• Big Tent Ketamine or BTK is a lively discussion board hosted on Google Groups which was founded by Carl Spitzer MD. Its membership includes over 3,000 licensed medical and mental health professionals (and aspiring interns and students) who exchange advice, ideas, training opportunities, and support in the spirit of advancing ketamine therapy. Thanks to Jayne Gumpel LCSW, BTK members can attend regular video conferences with guest speakers like Dr Krystal, who joined a live Q&A session in September that I wrote about here, as well as Dr Dölen from earlier in December.

• Osmind Practice Community is an active forum provided by Osmind, an electronic health records system which is designed for ketamine therapy workflow and patient outcomes.
• Ketamine StartUp is an invaluable online course which is founded by Sam Ko MD and Kim Ko MD to help medical professionals start their own private practice in a responsible way.

That's a wrap for 2023!