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Oral Ketamine vs. Depression! What Took So Long?

There is growing evidence that ORAL ketamine can be helpful against hard-to-treat depression. It could be safer and less expensive than IV!

Drug discovery can sometimes seem interminably slow. A small study published in Biological Psychiatry (Feb. 15, 2000) was one of the first placebo-controlled trials to demonstrate that low-dose ketamine infusions could quickly decrease depressive symptoms. In 2002 a study of depressed people undergoing orthopedic surgery found that those who received ketamine as their intravenous anesthetic had improvement in their depressive symptoms and suicidal tendencies (Anesthesia and Analgesia, July, 2002). But intravenous infusions are time consuming and expensive. What about oral ketamine to treat depression?

The FDA has not approved oral ketamine for depression even though there is growing evidence that such a convenient form of ketamine can also ease symptoms of depression (Nature Medicine, June 24, 2024). What makes oral ketamine intriguing is that it seems to help patients who have not benefitted from conventional antidepressant treatments. Another benefit: side effects are less common. Will the FDA ever approve oral ketamine to treat depression? Do not hold your breath.

A VERY Quick History of Ketamine:

The first study of ketamine as an injectable anesthetic was published in 1965. It was a unique medication that offered both fast acting sedation and impressive pain relief. It did these two things without the worrisome respiratory depression sometimes seen with other anesthetic agents.

I have had a personal interest in ketamine for decades. That’s because my dear friend, advisor and professor of neuropharmacology at the University of Michigan was Edward Domino, MD. I began my study there in 1969. A few years earlier, though, Dr. Domino and his co-authors published a study about a new medication labeled CI-581 (Clinical Pharmacology and Therapeutics, May-June, 1965). They described it as a “Dissociative Anesthetic.”

Dr. Domino was enthusiastic about ketamine because it had dual properties. It put people to sleep quickly, and it produced a “profound analgesia.” In other words, it was amazingly effective against severe pain. That meant that burn patients, who were often in extreme distress, could be put to sleep and treated successfully with ketamine as their anesthetic and analgesic.

The FDA approved ketamine as an injectable anesthetic in 1970 under the name Ketalar. You can read more about the pros and cons of ketamine at this link.

Ketamine Infusions for Depression:

Ketamine is no longer under patent protection. That means it is a relatively inexpensive generic anesthetic. It is also being prescribed off label to treat depression at ketamine clinics around the country.

The FDA does not regulate the practice of medicine. Once a drug is approved for one purpose, it can be used for just about anything a physician deems appropriate. That has allowed hundreds of ketamine clinics to proliferate. Some estimates put the number of such treatment centers at over 500.

Because the FDA has not approved intravenous ketamine for depression, insurance rarely, if ever, pays for such treatment. It’s a billion-dollar industry. A single infusion might cost as much as $500 to $800 and a full course of treatment might run over $4,000. That means patients are paying a lot of money out of pocket for an unapproved use.

It also takes time. The patient has to travel to the clinic. The infusion can last up to an hour or longer, depending upon the protocol. And there can be side effects. Patients often have to remain at the clinic for some time because of “dissociation.”

Remember, my mentor, Dr. Domino, described ketamine as a “dissociative” anesthetic. Even in the lower doses used during treatment for depression some patients describe an “out-of-body” sensation. Others may feel dizzy or drowsy and cannot drive. Additional adverse reactions might include elevated blood pressure, nausea, headache, confusion or even hallucinations.

The Nasal Spray Esketamine (Spravato):

There is substantial evidence that ketamine infusions do help some people who have been suffering from life-long depression. Here is a link that describes this effect. But as described above, the treatment is pricey and comes with a fair number of adverse reactions.

The FDA approved a chemical cousin of ketamine called esketamine (Spravato) in 2019. It is a nasal spray. It is not a do-it-yourself project, however.

The FDA requires this oversight:

“SPRAVATO must be administered under the direct supervision of a healthcare provider. A treatment session consists of nasal administration of SPRAVATO and post-administration observation under supervision.

“Respiratory Status Assessment During Treatment

  • Monitor patients for changes in respiratory status for at least 2 hours (including pulse oximetry) at each treatment session.”

Spravato is administered twice per week from weeks 1 to 4 and then once weekly from weeks 5 to 8. After week 9 the patient receives a nasal spritz every week or every two weeks. It is often sold and administered at a doctor’s office.

According to Drugs.Com:

“The cost for Spravato nasal spray (28 mg/device (56 mg dose)) is around $823 for a supply of 2 spray, depending on the pharmacy you visit. Quoted prices are for cash-paying customers and are not valid with insurance plans. This price guide is based on using the Drugs.com discount card which is accepted at most U.S. pharmacies.”

The Growing Case for Oral Ketamine Against Depression:

There has been growing recognition that oral ketamine represents another option for treating depression. A systematic review published in the World Journal of Biological Psychiatry (Sept-Oct, 2023) reviewed the use of oral ketamine for depression.

The authors describe the nature of their analysis:

“Twenty-two studies, including four randomized clinical trials (RCTs), one case series, six case reports, five open-label trials and six retrospective chart review studies involving 2336 patients with depression were included. All included studies reported significant improvement following ketamine administration. Ketamine was well tolerated without serious adverse events.”

Their conclusions regarding oral ketamine for depression:

“Taken together, preliminary evidence suggests the potential for antidepressant effect of oral ketamine. However, further research with large sample size and long follow-up period is needed to better determine the antisuicidal effect and efficacy in treatment-resistant depression.”

A New Study of Oral Ketamine for Depression:

A new and larger study was published on June 24, 2024 (Nature Medicine, June 24, 2024). It evaluated an extended-release oral formulation of ketamine. People who received the ketamine pills were significantly less likely to experience a return of their depression compared to those on placebo.

These were patients who had “treatment-resistant depression.” In other words, these people had not responded well to conventional treatment for depression.

The summary:

“In conclusion, extended-release R-107 [oral ketamine] tablets were effective, safe and well tolerated in an enriched patient population with TRD [treatment-resistant depression]. Use of an extended-release oral dosage ketamine formulation may be advantageous compared with intranasal or intravenous dosing, in terms of reduced intensity of dissociation, lower risk of abuse, reduced frequency and intensity of sedative and cardiovascular side effects, and improved convenience for administration in the community.”

The Problem for Patients in the United States:

The most recent research was carried out by a team of international investigators. They were from New Zealand, Australia, Singapore, Taiwan and London. The extended-release oral ketamine pills were developed by Douglas Pharmaceuticals in New Zealand. The oral formulation was designed to gradually release ketamine over a 10-hour period of time.

There were no US researchers involved in this study. Although liquid ketamine (for IV use) is approved and widely available in the US, there are no oral formulations permitted by the FDA.

Of course, that has not stopped the illicit use of oral ketamine. It has been used as a “club drug” for many years. Some of its codenames include Special K, Kit Kat, Purple, Bump, K-land and Vitamin K (not to be confused with the actual vitamin). But the FDA is not likely to approve oral ketamine use for depression unless a drug company were to spend hundreds of millions of dollars on randomized controlled trials and submit a new drug application (NDA).

Since ketamine is “off patent,” it is unlikely that a pharmaceutical manufacturer will take on this project. As a result, it is unlikely that an official extended-release formulation of oral ketamine will become available in the US any time soon, if ever.

Could compounding pharmacies create such a product? Would it be legal? Those are questions for the FDA or the courts. All we can do is report on the latest research. You can see the recent study for yourself at this link.

Final Words:

There is an enormous flaw in our medical system when it comes to developing new uses for old drugs. Ketamine has been available for more than 50 years. That means it is no longer protected by a patent and can be manufactured inexpensively.

A story on NPR from January 30, 2024 was titled “The Ketamine economy: New mental health clinics are a ‘Wild West’ with few rules.”

Here is a key quote:

“A typical dose of ketamine to treat depression, which is one-tenth the dosage used in anesthesia, costs clinics about $1, but clinics charge $600 to $1,000 per treatment.”

We interpret that to mean that an oral ketamine extended-release formulation to treat depression could be amazingly affordable. But few, if any, drug companies in the US are likely to undertake the research necessary to get the FDA to approve this generic medication. And foreign drug companies, like Douglas Pharmaceuticals in New Zealand, are not likely to seek FDA approval in the US because of the expense such an undertaking would entail. Remember, the drug has been off patent for decades.

There are hundreds of old, inexpensive medications that could likely be repurposed for new uses. And yet there is no system that encourages the development of such drugs. It could likely save Americans billions of dollars and lead to amazing improvements in care. Sadly, our current medical system does not make such research and development easy.

We have written about “Teaching Old Drugs New Tricks” at this link. And we have interviewed an amazing researcher, Dr. David Fajgenbaum, on our nationally syndicated radio show heard on many NPR stations. You will want to listen to his incredible story at this link.

W have just interviewed Dr. Fajgenbaum again about his organization, “EVERY CURE: Unlocking the hidden potential of existing drugs to save lives.” We will let you know when that interview airs on The People’s Pharmacy in coming weeks.

Please share your thoughts about oral ketamine in the comment section below.

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About the Author
Joe Graedon is a pharmacologist who has dedicated his career to making drug information understandable to consumers. His best-selling book, The People’s Pharmacy, was published in 1976 and led to a syndicated newspaper column, syndicated public radio show and web site. In 2006, Long Island University awarded him an honorary doctorate as “one of the country's leading drug experts for the consumer.”.
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  • Rosenblat, J.D., et al, "Oral Ketamine for Depression: A Systematic Review," Journal of Clinical Psychiatry, April 16, 2019, doi: 10.4088/JCP.18r12475
  • Meshkat, S., et al, "Oral ketamine for depression: An updated systematic review," World Journal of Biological Psychiatry, Sep-Oct, 2023, doi: 10.1080/15622975.2023.2169349
  • Glue, P., et al, "Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial," Nature Medicine, June 24, 2024, doi: 10.1038/s41591-024-03063-x
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