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Only 1/3 of depression patients achieve remission with traditional antidepressants.

In a Brazilian study, 77% of treatment-resistant patients improved with just 10mg of sublingual ketamine.

Low-dose sublingual ketamine is affordable, home-based, and is often more effective long-term than IV ketamine

Dr. Rachel Wilkenson pioneered a low-dose protocol used to treat hundreds of patients with remarkable results.

After practicing psychiatry for almost 40 years, I was starting to feel like I had seen and heard it all. Thousands of patients had come to my office seeking relief from depression, anxiety and related disorders, and many of them improved with conventional treatments that include psychiatric medications and psychotherapy. Some even improved to a point where they were no longer depressed, or their anxiety was manageable.

Statistics show that about one-third of people with depression achieve remission—meaning their symptoms are gone—with traditional antidepressant medications. This matched my experience treating people, and I had grown to accept that this was as good as it gets. Although I wasn’t thrilled with the fact that many people continued to struggle with significant symptoms of persistent depression, it seemed this was as good as we could do. The scientific literature demonstrates that about one-third of depressed patients achieve remission, one-third show some improvement, and one-third don't respond at all.

And then, about three and a half years ago, something remarkable happened.

A Study That Seemed Too Good to Be True

While reading through studies describing novel treatments for depression, I stumbled upon an article written by a group of doctors from Brazil describing results that seemed too good to be true. Diogo Lara and his colleagues administered a very low dose of ketamine—just 10 mg under the tongue (sublingual)—to 26 patients who suffered from treatment-refractory depression or bipolar disorder. The patients took this medicine every two to seven days. These were people who had previously failed to respond to at least four medications that were routinely used for their disorder, and they had tried these medicines for at least four weeks at normal therapeutic doses.

Lara and his colleagues reported that 20 of these patients (77%) showed "rapid, clear and sustained effects, improving mood level and stability, cognition and sleep." Wow!

These were patients who did not respond to conventional treatments, and yet 77% showed significant improvement with ketamine!

The History of Ketamine as Medicine

I was familiar with ketamine's use as an antidepressant for several years before this. I had read that ketamine was first synthesized in 1956 by chemists at the Parke-Davis Company who were searching for a new anesthetic. The FDA approved ketamine under the brand name Ketalar in 1970 for human use. Interestingly, in 2020 Brazilian researchers discovered that ketamine also exists in nature, where it is produced by a fungus known as Pochonia chlamydosporia.

That same year, some very bright and innovative doctors at Yale published a study demonstrating that a single sub-anesthetic dose of intravenous (IV) ketamine resulted in rapid antidepressant effects in seven people who met criteria for major depressive episodes. These individuals were administered either a single dose of ketamine or a placebo. Then, at least one week later, they received the other treatment (i.e., individuals who first received a placebo were then given ketamine, and vice versa). The results were astounding!

IV ketamine treatment produced significantly more improvement in depression than placebo, and these individuals responded quickly—within three days of receiving the treatment. This was a major breakthrough as ketamine was shown to work both faster and better than conventional antidepressants.

The Problems with High-Dose IV Ketamine

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Following the publication of this study, IV ketamine clinics began popping up all over the country. It is estimated that there are now between 500 and 750 of these clinics operating in the US, and these clinics have provided significant relief to many people suffering with depression.

However, there are problems associated with this treatment. First, the IV administration of ketamine requires specialized medical equipment and trained medical staff to administer the medicine. This is because, at the doses used, ketamine can cause elevations in blood pressure and heart rate. The medical supervision that is needed to use ketamine IV drives up the cost of the treatment. Ketamine itself is a very inexpensive medicine, but the required medical supervision drives up the cost to $300–$800 per infusion, and most people require three to six infusions in order to achieve sustained benefits. So, we are now talking about a treatment that costs thousands of dollars, and insurance companies don’t pay for it.

But there's more. The side effects of IV ketamine treatment include dissociative effects such as feeling as if you are floating outside of your body, disorientation, and hallucinations. So, IV ketamine treatment is expensive, time consuming, can cause significant unpleasant side effects, and the benefits typically last for only a few weeks.

These problems are what led me to search for a better option, one that is affordable, convenient, safe, and provides lasting benefits. It seemed like low-dose sublingual (LDSL) ketamine might be just what I was looking for.

So, I called a local compounding pharmacist and asked him if he would be willing to learn how to compound this medicine if my patients wanted to try it. His answer shocked me. "Mitch, I've already been compounding ketamine for three years." "Who already figured this out?" I asked him. "Dr. Rachel Wilkenson," he replied.

I was stunned again. Rachel is a friend and colleague who I had met several years earlier and for whom I have enormous respect. She is a doctor who is deeply grounded in science, yet also is an outside-the-box thinker who has helped numerous patients using unconventional treatments when traditional treatments failed. So, I called her.

"Rachel, are you prescribing low-dose sublingual ketamine for your patients?" I asked. "Mitch," she replied, "I am, and you won't believe the results. I have prescribed ketamine for over 300 patients, and I have never seen anything like the results we are getting."

I thought to myself: Why would anyone prescribe ketamine for over 300 patients? But I have a deep respect and admiration for Rachel, so I decided to proceed, and I began prescribing LDSL ketamine using a protocol she had developed for my patients.

And now, three years later, I have prescribed ketamine for well over 300 patients. Why? Because the results are so incredible and people are getting better!

The Journey Continues

But the journey with ketamine doesn't stop there. In fact, it was only just beginning! As I continued working with patients, I began to notice something remarkable: the low doses weren't just safer and more convenient—they were often more effective for long-term healing. This observation would lead me to question everything I thought I knew about psychiatric treatment and dose-response relationships.

In psychiatry, we've often been taught that if our patients don't respond to antidepressant treatment, it's because their medication dose is too low. Higher doses are thought to be associated with better outcomes. But ketamine is teaching us something different. Sometimes the most profound healing happens at lower doses.

What I discovered in my clinical practice over the last three years would challenge decades of conventional wisdom about psychiatric treatment. The question became: Why would lower doses of ketamine work better than higher doses for many patients? The answer lies in understanding how ketamine works in the brain—and that's a story that involves cutting-edge neuroscience.

In my next article, I'll explore the science behind low-dose ketamine, why gentle neuroplastic stimulation may be more powerful than intense dissociative experiences, and who benefits most from this approach.

Ferreira, S. R., Machado, A. R. T., Furtado, L. F., Gomes, J. H. D. S., de Almeida, R. M., de Oliveira Mendes, T., ... & Fujiwara, R. T. (2020). Ketamine can be produced by Pochonia chlamydosporia: an old molecule and a new anthelmintic?. Parasites & Vectors, 13(1), 527.

Lara, D. R., Bisol, L. W., & Munari, L. R. (2013). Antidepressant, mood stabilizing and procognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. International Journal of Neuropsychopharmacology, 16(9), 2111-2117.

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