Ketamine Infusions: Does the Route of Administration Matter?

Is Ketamine Infusion the best route of administration?

About the Author Dr. Steven P. Levine is a board-certified psychiatrist internationally recognized for his contributions to advancements in mental health care. Though he is a psychiatrist who places great emphasis on the importance of psychotherapy, medication is often a necessary component of treatment, and he was dissatisfied with the relatively ineffective available options with burdensome side effects. Dr. Levine pioneered a protocol for the clinical use of ketamine infusions, has directly supervised many thousands of infusions and has helped establish similar programs across the country and around the world.

Intravenous (IV) Ketamine infusions are very successful in treating patients suffering from major depressive mood disorders.¹  At Actify Neurotherapies, we perform IV (intravenous) Ketamine infusion to treat:

  • depression
  • bipolar depression
  • postpartum depression
  • obsessive-compulsive disorder (OCD)
  • posttraumatic stress disorder (PTSD)
  • generalized anxiety
  • fibromyalgia
  • chronic pain syndromes like complex regional pain syndrome 

Ketamine Infusion: Route of Administration Explained

Route of administration simply describes the particular biological barrier(s) that a given drug or medicine must cross to become absorbed into the bloodstream. Some common routes of administration include oral, transdermal, sublingual, intranasal, rectal, subcutaneous, inhalational, intramuscular, and intravenous (IV). (See table below for various Ketamine routes of administration.) The most common route of administration for most medications, used every day worldwide, is oral or using the gastrointestinal tract after swallowing a pill.

Route of Ketamine Administration Ketamine Bioavailability²Source
Intravenous  100%
Intramuscular~93%Clements et al., 1982
Intranasal~45%Yanagihara et al., 2003
Sublingual 19–50%Chong et al., 2009

Yanagihara et al., 2003

Oral 17–27%Chong et al., 2009

Clements et al., 1982

Rectal ~30%Yanagihara et al., 2003

About Ketamine Dosage 

A very common route of administration in the hospital is IV and there are multiple reasons why. One such reason has to do with the speed of absorption and another has to do with obtaining an accurate dose per a given body weight. IV drugs are frequently given to adult patients in urgent situations where time passed may mean life or death. IV medications are frequently administered to infants when dose accuracy matters to prevent toxicity or accidental overdose. Accuracy is just as important for maintaining efficacy as too little and too much medication can prevent an efficient mechanism of action.

Ketamine Injections: Many Advantages

So how do IV medications achieve increased accuracy and speed as compared to other routes of administration? This primarily has to do with a concept called bioavailability and by definition, IV medications have 100% bioavailability. This simply means 100% of the medication administered will enter into the patient’s bloodstream. Generally speaking, all other routes of administration have less than 100% bioavailability and this has to do with barriers that the medication must cross to enter into the bloodstream. The more barriers a medication must cross, the more variable the absorption. Additionally, certain barriers are more problematic than others and some even modify the chemical composition of drugs in an attempt to eliminate the drug via metabolism.

For example, if we take a swallowed oral pill, it must first travel down the gastrointestinal (GI) tract, transport across the mucosa or lining of the GI tract, then become filtered through the liver before entering the bloodstream. It is the bloodstream which will finally deliver the medication to a targeted organ, such as the brain. The first barrier, being the GI tract, varies from person to person based on the health of the GI tract, gut bacteria, and co-nutrients that may help or preclude absorption. Once the medication makes it across the GI mucosa, it makes its way to the liver. Liver metabolism varies widely from patient to patient and is usually dependent on genetics and liver health. Sometimes the liver can metabolize medications into inactive chemical compositions before they even enter the arterial bloodstream thereby negating any beneficial effects. Furthermore, enzymes in the liver determine how fast any given drug is eliminated if not eliminated directly via the kidney – this is why patients with liver and kidney disease have to take certain drugs at lower doses.

The process described above hopefully makes it more apparent why IV medications have fewer variables that can affect absorption. Understanding this process also allows for appreciation of IV medications in research protocols wherein variables that alter dose can sometimes mean everything. In fact, the most robust studies of Ketamine for treatment of depression use intravenous Ketamine.

Ketamine dose becomes very important as we start to understand how the medication affects a large number of different receptors in the brain (and in different anatomical locations) relative to the dose. We know that too little of any given dose may result in zero efficacy, but along the same lines, too much of a dose could cause toxicity and also lower efficacy! Most research studies have used 0.5 mg/kg of Ketamine over 40-45 minutes for treatment of depression. If we increase Ketamine dose, we know that it starts to affect some parts of the brain relatively more than those parts of the brain that we think may be causing the antidepressant effects (e.g. prefrontal cortex).³ In addition, although Ketamine has a very good safety profile, all drugs have some side effects. We are fortunate that most of Ketamine’s side effects are not troublesome at the lower doses; however, if ketamine infusion causes any negative side effects, an infusion can be disconnected and the side effects will go away within about 15 minutes. If the Ketamine was not given intravenously it may take much longer for any negative side effects to subside.

In conclusion, IV is currently the most common route of administration used for Ketamine in adult patients. This is because the IV route of administration takes away barriers that can impede the mechanism of Ketamine infusion in the brain, and thus creates better standardization. At Actify Neurotherapies, safety is of utmost importance and the intravenous route of administration helps achieve this goal.

Actify Neurotherapies is proudly combatting major depression, bipolar depression, postpartum depression, PTSD, OCD, anxiety, fibromyalgia, CRPS, and chronic pain one patient at a time! If you or your loved one is suffering, give us a call at 888-566-8774 or email us at to learn more about how Ketamine can help.


  1. Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74(4):399-405. doi:10.1001/ jamapsychiatry.2017.0080.
  2. Clements JA, Nimmo WS, Grant IS. Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. J Pharm Sci. 1982;71(5):539-542.
  3. Cusin C, Ionescu DF, Pavone KJ, et al. Ketamine augmentation for outpatients with treatment-resistant depression: preliminary evidence for two-step intravenous dose escalation. Aust N Z J Psychiatry. 2017;51(1):55- 64. doi:10.1177/0004867416631828

Steven Levine, MD, is the CEO and founder of Actify Neurotherapies. He has been treating patients with ketamine therapy since 2011.