Verified by 
This is part 1 in a multi-part series on ketamine.
Over the past 10 years, ketamine has generated considerable excitement because of its ability to help people with depression feel better quickly. As someone who has conducted research and treatment in this area for the last 10 years, here is what I want my prospective patients to know.
A Brief History of Ketamine
Ketamine has been around for a long time. It was developed as a drug for anesthesia in the 1960s and approved by the Food and Drug Administration (FDA) in 1970. It was quickly adopted for use in “battlefield medicine” (the Vietnam war was raging at this time) because, unlike many drugs for anesthesia, it causes patients to fall asleep without causing them to stop breathing.
In the late 1990s, researchers at Yale University observed that, when it was given at low doses, ketamine unexpectedly caused patients with severe depression to feel better quickly. Since that time, many studies have confirmed this finding.
In the earliest studies of depression, ketamine was given intravenously (or directly into the bloodstream). A plastic catheter was inserted into a vein in the arm, and the medicine was infused over a period of about 40 minutes. The “traditional” dose in these studies was based on a patient’s weight and was calculated as 0.5mg of drug per 1 kg of body weight. So a person who weighs 70kg (~154 lbs.) would receive a dose of 35mg.
Despite many studies since this time, the best available evidence still suggests that the traditional dose of 0.5mg/kg is the optimal one, at least to start with. Some clinics that provide ketamine for depression will administer much higher doses to patients. While it’s certainly reasonable to increase a dose if a patient isn’t showing much improvement after several treatments, the practice of using a starting dose much higher than 0.5mg/kg is not based in established clinical evidence.
What About Esketamine?
A form of ketamine called esketamine (brand name Spravato) was developed and tested with financial support from Janssen (a subsidiary of Johnson and Johnson). Esketamine received FDA approval for treatment-resistant depression in 2019 and approval for depression with suicidal ideation in 2020. In contrast to ketamine (which is most commonly administered intravenously), esketamine is administered as a nasal spray.
What’s the difference between ketamine and esketamine? As their names imply, they are quite similar. In fact, ketamine is comprised of a 50/50 mix of two molecules: esketamine and arketamine. The decision was made early on to develop esketamine (as opposed to arketamine or ketamine) in part because the prevailing belief was that esketamine more efficiently interacted with the brain to produce the antidepressant response (through a type of glutamate receptor).
Today, patients can receive both treatments for depression. As to whether one of these options is a better treatment for depression, this is still an open question. There are a lot of strong opinions on this matter from providers, but not very much evidence. So far, there has only been one study that compared these two treatments head-to-head in a randomized trial (this trial showed no difference between the two treatments, but it was a relatively small study, and study participants only received one dose of either treatment). Other studies on this question have key weaknesses (most notably that they were not randomized) that make it problematic to interpret them. A new study which I will help lead will hopefully answer this question definitively, though the conclusions of the study won’t be clear for several years.
Given how similar the treatments are biochemically, if there is a difference between them, I suspect it is a small one. Both treatments have been shown to significantly improve depression.
What’s the Practical Difference Between Ketamine and Esketamine (Spravato)?
Even if we don’t know definitively about a meaningful clinical difference between these two treatment options (which one is a better treatment for depression), there are some important practical differences. Even though it is more expensive overall, esketamine (Spravato) is more likely to be covered by insurance companies; hence the cost to patients is likely to be less. Generally, ketamine is paid for by patients in cash, and costs are usually in the neighborhood of $300 to $1,000 per treatment. (Keep in mind that a usual "course" of ketamine typically starts with 6-8 treatments in the first month, so things get very expensive very quickly.)
Esketamine is more tightly regulated than ketamine, meaning that doctors have to stick with a very specific treatment protocol for esketamine. So when a friend, family member, or patient asks me if I know of a prescriber in another area that I feel comfortable referring someone to, I have more confidence that esketamine is going to be administered in line with clinical evidence. In other words, it’s hard for a doctor to botch the treatment approach with esketamine because of the tight legal restrictions in place. This is not the case with ketamine. If I’m referring someone to a clinic that only provides ketamine, I will want to do more research to understand what doses the clinic offers, if they offer ketamine at home (see below), if they have practicing psychiatrists as part of their clinic, or if they offer any other psychiatric treatment besides ketamine. Dr. Brian Johns has a great Psychology Today post to help people decide whether a ketamine clinic offers a reasonable level of quality care.
At Home Ketamine?
Some clinics will give patients ketamine to take at home. This is illegal for esketamine. Unless this is done as part of a clinical trial or other research study, the practice of at-home ketamine administration is something I strongly recommend against. The reason this is problematic is because at some doses, patients can have very frightening experiences. Without proper supervision, patients might unintentionally injure themselves or others while in these transient but altered mental states. At-home ketamine also increases the risk that patients might misuse the drug or become addicted, a problem experts are increasingly concerned about.
Ketamine and esketamine can both profoundly help patients struggling with debilitating forms of depression. But like any treatment that has both risk and reward, it's important for prospective patients to understand some of the potential downsides of treatment so they can be managed.
References
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000 Feb 15;47(4):351-4.
Correia-Melo FS, Leal GC, Vieira F, Jesus-Nunes AP, Mello RP, Magnavita G, Caliman-Fontes AT, Echegaray MVF, Bandeira ID, Silva SS, Cavalcanti DE, Araújo-de-Freitas L, Sarin LM, Tuena MA, Nakahira C, Sampaio AS, Del-Porto JA, Turecki G, Loo C, Lacerda ALT, Quarantini LC. Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-inferiority study. J Affect Disord. 2020 Mar 1;264:527-534.
Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C, Ionescu DF, Mathew SJ, Chang LC, Iosifescu DV, Murrough J, Debattista C, Schatzberg AF, Trivedi MH, Jha MK, Sanacora G, Wilkinson ST, Papakostas GI. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry. 2020 Jul;25(7):1592-1603.
McIntyre RS, Rosenblat JD, Nemeroff CB, Sanacora G, Murrough JW, Berk M, Brietzke E, Dodd S, Gorwood P, Ho R, Iosifescu DV, Lopez Jaramillo C, Kasper S, Kratiuk K, Lee JG, Lee Y, Lui LMW, Mansur RB, Papakostas GI, Subramaniapillai M, Thase M, Vieta E, Young AH, Zarate CA Jr, Stahl S. Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation. Am J Psychiatry. 2021 May 1;178(5):383-399.
Wilkinson ST, Sanacora G. At-home ketamine; still a lot to learn. J Affect Disord. 2022 Dec 1;318:150-151
