Ketamine is a drug known both for its potential for abuse and its potential as a therapy.  By the turn of the 21st century, low (sub-anesthetic) doses of ketamine began to show promise as a breakthrough, fast acting therapy for treatment-resistant depression (TRD) (Serafini et al., 2014). Throughout the 2000s ketamine was increasingly used as an off-label therapy for TRD especially among people at risk of suicide.  The potential for therapeutic value has since been reflected in the FDA approval of intranasal esketamine in March 2019. Because of its strong potential as a therapy, but also as a target of abuse, the neural circuit brain mechanisms underlying ketamine’s effects must be fully understood. Developing a better understanding of ketamine’s effects on neural circuits of the brain is critical to optimizing its safety for therapeutic purposes as well as for preventing abuse. 

In this study we use what is called an “acute challenge design”. Acute challenge designs are most suited to understanding the neural circuit mechanisms of ketamine’s effects. In these designs, the goal is to quantify the acute (immediate) neural circuit effects of ketamine. Ketamine (or placebo) is administrated using an infusion procedure, under medical supervision, so that we carefully control the dose and safety. We use functional MRI (fMRI) to assess neural circuit function. fMRI is commenced within about 40 mins of ketamine infusion, so as to assess immediate effects. Studies like ours are undertaken in healthy people because the focus is on understanding the mechanisms. In studies such as ours we use low doses of ketamine, including the dose currently used to treat depression as well as a lower dose, to also determine the minimum dose at which ketamine impacts the brain without generating a feeling of intoxication. Such studies are necessary to develop the knowledge base about how best to use ketamine as a therapy. By understanding the mechanisms, we can understand how it works. We also develop a more precise way to target ketamine as therapy  - for example, if we learn that ketamine primarily impacts one circuit more than another then, in the future, we know that people who have depression characterized by a disruption in that circuit may benefit from the therapeutic effects of ketamine. By establishing the neural effects of different low doses, we also learn what is the minimal dose to use as a future therapy to help stabilize the circuit of interest in disorders such as depression, and thus minimize addiction or risk potential. To ensure the safety of acute challenge studies in healthy subjects we recruit only subjects who have (by their choice) had prior experiences with ketamine but do not currently experience any substance use problems. The study itself follows a clear and established protocol that is approved by the Institutional Review Board at Stanford to meet ethical, safety and regulatory requirements. Thus, we believe, and our Institutional Review Board at Stanford agrees that the benefits of the study outweigh the risks.

We recognize that there may be concern about ketamine’s use for excited delirium given the case of a young Black man who was sedated with ketamine by paramedics and subsequently died as well as two other highly publicized cases where its use was questioned. We first note that we fully support the position statement from The American Society of Anesthesiologists stating that it “firmly opposes the use of ketamine or any other sedative/hypnotic agent to chemically incapacitate someone for a law enforcement purpose and not for a legitimate medical reason.” Second, we note that the circumstances of these cases are quite different than those in our study. We administer much lower doses than used by paramedics or law enforcement, although ketamine is safe even at the doses administered. Additionally, the ketamine in our study is administered in a highly controlled environment by trained medical professionals with appropriate monitoring of vital signs.  ​