Low Dose Sublingual Ketamine
A new low-dose, inexpensive, at-home treatment for depression.
Updated February 16, 2026 | Reviewed by Lybi Ma
After practicing psychiatry for 40 years, I started feeling 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 including psychiatric medications and psychotherapy . Some 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, 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 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 doctors from Brazil describing results that seemed too good to be true. Diogo Lara and his colleagues administered a very low dose of ketamine (10 mg) under the tongue every two to seven days to 26 patients who suffered from treatment-refractory depression or bipolar disorder . These were people who had previously failed to respond to at least four medications that were routinely used for their disorder, and had tried these medicines for at least four weeks at therapeutic doses.
Lara and his colleagues reported 20 of these patients (77%) showed "rapid, clear and sustained effects, improving mood level and stability, cognition and sleep." These were patients who did not respond to conventional treatments, yet 77% showed significant improvement with ketamine. Wow!
The History of Ketamine as Medicine
I became familiar with ketamine's use as an antidepressant several years earlier. 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. In 2020, Brazilian researchers discovered ketamine also exists in nature, where it is produced by the fungus Pochonia chlamydosporia .
That same year, some innovative doctors at Yale demonstrated 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. The results were astounding!
IV ketamine treatment produced significantly more improvement in depression than placebo, and these individuals responded within three days of receiving treatment. This was a breakthrough as ketamine was shown to work both faster and better than conventional antidepressants .
The Problems with High-Dose IV Ketamine
Following the publication of this study, IV ketamine clinics popped up all over the country. It's estimated there are now 500-750 of these clinics in the US, and these clinics have provided relief to many people suffering from depression.
However, this treatment has problems. First, the IV administration of ketamine requires specialized medical equipment and trained staff to administer the medicine because it can cause elevations in blood pressure and heart rate. This increases 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 to achieve sustained benefits. 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 include dissociative effects such as feeling as if you're floating outside of your body, disorientation, and hallucinations. 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.
I called a local compounding pharmacist and asked him if he would be willing 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.
"Dr. Rachel Wilkenson," he replied.
I was stunned again. Rachel is a friend and colleague whom I had met several years earlier and for whom I have enormous respect. She is a doctor who is deeply grounded in science, yet is also an outside-the-box thinker. She has helped numerous patients using unconventional treatments when traditional treatments failed. 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 due to my deep respect and admiration for Rachel. I decided to proceed, and I began prescribing LDSL ketamine using a protocol she had developed.
And now, three years later, I have prescribed ketamine for well over 300 patients. The results have been incredible!
The Journey Continues
But the journey with ketamine doesn't stop there. It was only the beginning. As I continued working with patients, I began noticing 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.
In psychiatry, we've 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 produce better outcomes. But ketamine is teaching us something different. Sometimes the most profound healing happens with lower doses.
What I discovered in my clinical practice over the last three years has challenged decades of conventional wisdom about psychiatric treatment. A question arose: 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 post, 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.
Share this post Facebook Bluesky Linkedin Email
There was a problem adding your email address. Please try again.
By submitting your information you agree to the Psychology Today Terms & Conditions and Privacy Policy
Mitchell B. Liester, M.D., is an Assistant Clinical Professor in the Department of Psychiatry at the University of Colorado School of Medicine.
Get the help you need from a therapist near you–a FREE service from Psychology Today.
This article is part of the Bringwise Psychology Journal — daily insights on human behavior, mental health, and personal growth.