How Does Ketamine Work?

The wide range of chemical processes that occur in the human brain are very complex and fully understanding them is something that neurobiologists spend their entire lives doing.

That being said, here is a very simplified explanation of how Ketamine interacts with receptors and chemicals in the brain to cause (often immediate) anti-depressant effects, even in patients with severe Treatment Resistant Depression (TRD). It’s important to note this interaction is exclusive to IV Ketamine Infusion Therapy where ketamine is given slowly, intravenously, and at a sub-anesthetic dose. One of the brain’s key neurotransmitters is glutamate, an amino acid found in 80% of neurons. Glutamate influences the formation and number of brain synapses – the vital connections between neurons. Glutamate acts with another important neurotransmitter, GABA, to maintain a healthy, well-functioning nervous system. An imbalance between GABA and glutamate can cause problems, including anxiety, difficulties with sleep, overstimulation, and issues with focus. Imbalance in the glutamatergic system is also associated with major depressive disorder (MDD). Growing evidence suggests that ketamine helps rebalance the glutamate system by acting as a receptor “antagonist.” Ketamine works by blocking the NMDA (N-methyl-D-aspartate) receptor, one of three major glutamate receptors. This receptor is involved in synaptic plasticity and memory function, among other functions. A ketamine-induced blockade of the NMDA receptor results in an increase in glutamate. This initiates a cascade of neurobiological events that researchers believe is a key reason behind ketamine’s rapid antidepressant effects. With Complex Regional Pain Syndrome (CRPS/RSD) and other chronic pain, a process known as central sensitization is thought to intensify pain by increasing the number of NMDA receptors thus amplifying the pain signal. Ketamine’s interference with the NMDA receptor is thought to block and “reset” pain signaling, providing relief where other treatments have failed. By blocking the NMDA receptors of peripheral nerves, peripheral nerve pain transmission is intercepted before reaching the spinal cord and brain. This allows for “rebooting” of central pain centers and desensitization to peripheral pain signals.

Benefits of Ketamine Infusion Therapy

In the last 20 years, Ketamine has gradually been used more in non-traditional ways, including treating depression and other mood disorders, Complex Regional Pain Syndrome (CRPS/RSD), and other pain conditions. In the last decade, a great deal of clinical research has been conducted by leading institutions all over the world proving IV (intravenous) ketamine’s efficacy in the treatment of these conditions; regularly reporting a 70% success rate or higher. Much of the research that has been conducted has been based around a single infusion, which proposes two problems. The first one is that many of our patients don’t respond to treatment until after their 2nd infusion. The second problem is that results are generally reported to last an average of 10 days. Because of this, we provide a series of 6 infusions, producing a more pronounced and much longer lasting benefit.

Pharmacology of Ketamine

Ketamine (ketamine hydrocholoride), a Schedule III class drug, is a dissociative anesthetic and analgesic used in both children and adults. Ketamine is highly soluble in lipids and easily crosses the blood-brain barrier. Following intravenous administration, ketamine concentration has an initial phase, corresponding to its anesthetic effect, lasting about 45 minutes (with a serum half-life of 10 to 15 minutes). The anesthetic action ends through redistribution from the central nervous system to peripheral tissues and metabolic transformation to norketamine, which has about one-third the activity of ketamine. The elimination half-life of ketamine is about 2.5 hours.

Treating Depression With Ketamine

Growing evidence shows that ketamine produces remarkable antidepressant effects. In 2000, Berman and colleagues were the first to demonstrate the rapid onset of antidepressant effects with an NMDA receptor antagonist. In their placebo-controlled, proof-of-concept, crossover study of 7 patients, a subanesthetic dose (0.5 mg/kg) of ketamine administered through a 40-minute infusion yielded significant antidepressant effects within hours and lasted several days. In a placebo-controlled, randomized crossover study by Zarate and colleagues in 2006, 12 out of 17 participants (71%) showed a more than 50% reduction in depressive symptoms within 24 hours of receiving ketamine. These same participants showed almost no change in symptoms following a placebo saline injection. A 1-week follow-up confirmed a sustained response in approximately one-third of participants. An additional three placebo-controlled, crossover studies examining ketamine’s effects on major depressive episodes associated with both major depressive disorder (MDD) and bipolar disorder showed very similar results: rapid, robust antidepressant effects persisting for at least several days to weeks following a single subanesthetic ketamine dose. More recently, research has indicated that a series of infusions produces more pronounced and longer lasting benefits. There have been over 100 independent clinical trials on ketamine treatment for depression. Their results consistently prove the efficacy of IV Ketamine Infusion Therapy with a 70% success rate or higher.

Treating Chronic Pain With Ketamine

At Mackay Base Hospital in Australia, 33 patients suffering from complex regional pain syndrome (CRPS), also known as reflex sympathetic dystrophy (RSD), were administered continuous subanesthetic intravenous infusions of ketamine. Twelve of the 33 patients received a second course of therapy; two received a third. Twenty-five (76%) experienced complete pain relief, six (18%) felt partial relief, and two (6%) had no relief. Repeat treatment was correlated with improved response. The 12 patients receiving second treatment courses experienced complete relief of CRPS pain. After their first course of ketamine therapy, 18 patients (54%) were found to be free of pain for three months or longer and another 10 (31%), for six months or longer. Of the 12 patients who were administered a second course of treatment, 7 (58%) experienced relief for a year or longer. Many other studies have confirmed the efficacy and safety of ketamine for pain relief in a variety of conditions.

Interesting Facts about Ketamine

• Ketamine is an anesthetic that has been used on both humans and animals for over 50 years. Its ability to anesthetize patients quickly and safely, with few side effects, was quickly realized by the medical community; it was approved by the Food and Drug Administration (FDA) in 1970.


• It is commonly used as a pain killer, especially for severe injuries and in crisis situations, since slowing respiration and circulation is a major problem with alternatives, such as opiates and barbiturate analgesics.


• It’s also very fast-acting. Ketamine is one of only two anesthetics listed by the World Health Organization (WHO) as an “essential drug”. The WHO is a specialized agency of the United Nations concerned with international public health.


• Their essential drugs are “those drugs that satisfy the health care needs of the majority of the population; they should therefore be available at all times in adequate amounts and in appropriate dosage forms, at a price the community can afford”. WHO’s essential drugs are the basis for many countries’ national drugs policy.