


The Stanford Regulating Circuits of the Brain (RBRAIN) - Ketamine study is the first of its kind to detail how brain circuits and experiences change in real time during ketamine administration. The study is aimed at developing a characterization of the acute effects of ketamine on the brain, cognition, and subjective experiences in healthy volunteers.
Little is known about the mode of action of ketamine. In this study, we are characterizing in detail how the acute administration of ketamine impacts brain circuits and experiences for each individual person. As a mechanistic trial, we focus first on healthy people.
This information is an essential foundation for then making progress in using ketamine as a personalized and safe therapeutic. Faculty members involved in this study are Drs. Leanne Williams, Brian Knutson, Karl Deisseroth, Robert Malenka, Laura Hack, Carolyn Rodriguez, Trisha Suppes, Boris Heifets, Peter van Roessel and Christina Khan.
Overview
Ketamine is a dissociative anesthetic that can produce hallucinogenic effects. It is known as a street drug of abuse, “Special K”, as well as an anesthetic sometimes used during surgical procedures. Despite its recent popularity, little is known about its mode of action, subjective effects, and how its effects promote continued use. By integrating four Research Projects led by Drs. Karl Deisseroth, Lisa Giocomo, Robert Malenka, Leanne Williams, and Brian Knutson, we aim to develop a theoretically-informed characterization of the effects of these drugs on the neurobehavior of specific circuits for processing risk and reward, the connectivity of these circuits, and how these circuits and their connectivity predict acute drug experience and drug use outcomes in healthy subjects. To do this we will administer 3 randomized doses of ketamine (.05 mg/kg, .5 mg/kg, and placebo) while undergoing an MRI scan, cognitive assessments, and surveys assessing mood and dissociative effects.
Goals
We seek to better understand the acute effects of ketamine on the brain, cognition, and subjective experiences in healthy individuals to better understand addictive and therapeutic mechanisms.
RBRAIN - KETAMINE
Meet the Team

Leanne Williams, PhD
Principal Investigator

Xue Zhang, PhD
Postdoctoral Fellow

Laura Hack, MD, PhD
Lead Psychiatrist

Rachel Hilton, MSN, PMHNP-BC
Research Nurse Practitioner

Jessica Laudie
Clinical Research Coordinator
Collaborators

Karl Deisseroth, MD, PhD

Brian Knutson, PhD

Lisa Giocomo, PhD

Patricia Suppes, MD, PhD

Robert Malenka, MD, PhD

Carolyn Rodriguez

Boris Heifets, MD, PhD

Peter van Roessel, MD, PhD

Christina Khan, MD, PhD
Funding
RBRAIN is funded through a National Institute of Drug Abuse (NIDA) Specialized Center (P50) grant.
Grant: P50DA042012
FAQ
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. ​