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Low-dose ketamine stimulates neuroplastic changes by increasing brain-derived neurotrophic factor.

Ketamine reduces inflammation and protects neurons from damage by stimulating sigma-1 receptors.

Daily low-dose ketamine may be more effective than intermittent high-doses for sustained improvement.

Low doses of ketamine are inexpensive, safer, and do not cause severe dissociation like higher doses.

In my previous post, I shared my journey discovering that low-dose sublingual (LDSL) ketamine produces remarkable results in patients with treatment-resistant depression. Now, let's explore why lower doses may actually be more effective.

Understanding How Ketamine Works

After 3 years of observing my patients' amazing responses to treatment with low dose sublingual ketamine (LDSK), I wanted to understand more about how this medicine works. The standard explanation is that ketamine blocks NMDA receptors. These receptors bind glutamate, which is a chemical messenger found throughout the brain and body. By blocking NMDA receptors, ketamine increase “brain-derived neurotrophic factor" (BDNF), a protein which I refer to as “Miracle-Grow for the brain.” BDNF promotes neuroplasticity—which is the growth of new connections (synapses) in the brain. This has traditionally been viewed as the primary mechanism responsible for ketamine's therapeutic benefits. But ketamine does so much more!

The Neuroplasticity Advantage

You can think of neuroplasticity as your brain's ability to rewire itself. Depression, anxiety, and trauma are disorders of brain connectivity—neural networks become rigid or break down. Ketamine "repairs" these networks.

These neuroplastic changes don’t require high doses. High-dose intermittent treatment can produce dramatic immediate effects, but may not provide the sustained stimulation needed for lasting change.

The Sigma-1 Receptor Connection

Another important effect of ketamine results from its attachment to sigma-1 receptors. These proteins play an important role in the cellular stress response. When activated, they protect neurons from damage, reduce inflammation, and help repair damaged cells. This may help explain ketamine's benefits in the treatment of chronic pain and neurodegenerative disorders.

Why Frequency and Dose Matter

LDSL ketamine offers several advantages over high-dose IV treatment. High-dose IV ketamine requires medical supervision, time off work, you need someone to drive you home after your treatment, and can cost thousands of dollars. LDSL ketamine can be taken at home, at bedtime, costs $15–$60 per month, and doesn't interfere with your daily life.

While some find high-dose dissociative experiences beneficial, others find them frightening or re-traumatizing. LDSL ketamine eliminates this concern, making the treatment available to patients who don't tolerate higher doses.

LDSL ketamine has a much lower abuse potential. At recreational or high doses, ketamine can be reinforcing and lead to addiction. LDSL doses don't generally produce euphoria or a "high," making them safer for long-term use, especially for patients with substance use histories. Many of my patients report a decreased desire for addictive substances after starting LDSL ketamine. For those patients who do find the effects pleasurable, ongoing monitoring can avoid problems with excessive use.

Chronic high-dose ketamine can cause serious bladder problems in recreational users. LDSL ketamine provides a safer option. High doses of ketamine can cause adverse cognitive effects, whereas LDSL ketamine avoids these concerns, and often enhances cognition. Many of my patients report improvements in memory, learning, and problem-solving skills.

Clinical Evidence and Patient Outcomes

While most published ketamine research focuses on IV infusions, we're seeing incredibly positive results with Dr. Wilkenson’s low-dose protocol. Doses as low as 5 mg per day produce antidepressant effects comparable or superior to IV doses. Repeated low-dose administration has cumulative benefits, with many patients maintaining remission after stopping their convention antidepressants.

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Ketamine works well for depression and bipolar disorder without triggering mania. LDSL ketamine also helps anxiety disorders, post-traumatic stress disorder, ADHD, and borderline personality disorder.

LDSL ketamine requires medical supervision. Even at low doses, it can interact with other medications and rarely can affect blood pressure and heart rate. This treatment isn’t for everyone. Patients with certain cardiac conditions, uncontrolled hypertension, psychotic disorders, or active substance use disorders may not be candidates. Also, ketamine should not be taken during pregnancy or while breastfeeding.

If you work with a clinician who understands both high-dose and low-dose approaches, together you can determine what's the best option for you. Look for practitioners who are willing to find optimal dosing rather than applying a one-size-fits-all approach.

Rethinking Treatment Paradigms

The discovery of LDSL ketamine challenges medicine's bigger-is-better bias. It suggests we may be overshooting therapeutic doses and causing unnecessary side effects. This doesn't mean high-dose ketamine shouldn’t be used—it has a place for severely depressed or suicidal patients. But ketamine's therapeutic properties exist on a continuum, and the lower end may be sufficient—even optimal—for many patients. As we continue learning about this amazing treatment, I suspect LDSL ketamine will one day become the preferred approach for many patients.

Sasi, M., Vignoli, B., Canossa, M., & Blum, R. (2017). Neurobiology of local and intercellular BDNF signaling. Pflügers Archiv-European Journal of Physiology, 469(5), 593-610.

Kalkman, H. O. (2023). Activation of σ1-receptors by R-ketamine may enhance the antidepressant effect of S-ketamine. Biomedicines, 11(10), 2664.

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