Big changes are coming to mental health care. We now recognize that disorders like depression and post-traumatic stress disorder (PTSD) take just as big a toll on health and well being as cardiovascular disease and cancer. Challenges like these require innovative and disruptive solutions. Well-controlled clinical studies increasingly support the use of powerful, rapid-acting pscyhoactive drugs for the treatment of severe psychiatric disease. These treatments include ketamine and psilocybin for depression, and MDMA-assisted psychotherapy for PTSD. Though the details of each treatment differ in important ways, they share a remarkable property: single doses can help patients with severe psychiatric disability achieve remission of their symptoms. These effects can last from weeks to years. Understanding how these drugs trigger lasting transformations is the first step toward designing precision therapies.
Isolating MDMA’s prosocial effect
MDMA, the once-demonized party drug still known as “ecstasy”, shows promise as a powerful adjunct to psychotherapy for the treatment of PTSD. In patients, the therapeutic effect of MDMA appears to stem from its ability to foster strong feelings of social connection, empathy and trust in the context of psychotherapy. However, MDMA has abuse potential, and long-term use is associated with a host of neurological, psychiatric and cardiovascular complications. Improving on MDMA to develop a safe, scalable treatment for millions of patients requires an understanding of the neural circuit mechanism underlying MDMA’s therapeutic effects. Our group has recently demonstrated that supraphysiological serotonin release in a major brain reward center, the nucleus accumbens, fully accounts for MDMA’s prosocial effect. However, it is still unknown how this local pharmacological mechanism alters brain-wide activity when a mouse is in a social versus nonsocial environment. By identifying and characterizing new brain circuits engaged by MDMA, we hope to develop safer, effective therapy for patients.
Mapping ketamine’s antidepressant properties in the brain
Ketamine, one of our oldest anesthetics, has found new life as a rapid-acting antidepressant, and has been heralded as the first antidepressant in a generation with a novel-mechanism. Ketamine’s primary mechanism, as an anesthetic, analgesic, and now antidepressant, has been pinned to its high affinity NMDA receptor (NMDAR) antagonism. Yet, mounting evidence suggests more to the story: no other NMDAR antagonist has shown efficacy as an antidepressant in clinical trials, and key preclinical predictions of mechanism have failed to replicate in humans. We recently found that ketamine’s antidepressant and anti-suicidality effects are completely blocked by pretreating severely depressed patients with naltrexone, an opioid receptor antagonist. While surprising in the context of antidepressant activity, ketamine’s interaction with opioid receptor signaling has long been known in the realm of analgesia and opioid tolerance. Using this key insight gained from human work, we have begun to map opioid-receptor dependent ketamine effects across the entire rodent brain.
Psilocybin & Chronic Pain
Chronic pain is a public health crisis deeply intertwined with epidemic levels of depression, suicidality and opioid abuse in the United States. The mainstay of chronic pain therapy typically consists of medication, often opioids, and medical interventions, like epidural steroid injections, neither of which are reliably effective at restoring a person to full function. Similarly, while psychological factors have a well-known role in the maintenance of chronic pain and development of functional coping strategies, traditional psychotherapeutic approaches have shown limited efficacy for changing the deeply ingrained behaviors, expectations, and beliefs that patients maintain in relation to their pain. Growing clinical evidence suggests that psilocybin, unlike any currently available therapy, can accelerate a therapeutic psychological transformation, showing promise in treating major depressive disorder, nicotine addiction and alcohol use disorder. Psilocybin-assisted therapy may similarly enable patients to cope with chronic pain more effectively. In collaboration with the laboratories of Dr. Joshua Woolley MD, PhD, UCSF, and Dr. Michael Silver PhD, UC Berkeley, we are planning a clinical trial to test this idea.
Depression & Surgery
Millions of Americans have major surgery each year, and many of these patients have major illnesses, including depression. In depressed patients, surgery is associated with potentially preventable outcomes such as opioid use disorder, chronic pain, and longer hospital stays. We know when and in whom to intervene to reduce cardiovascular complications, but there are few if any efforts to identify and treat psychiatric risk factors, like depression, before the highly predictable stress of surgery. Mood optimization prior to surgery has not been seriously considered as a risk reduction strategy until now, in part because conventional antidepressants aren’t compatible with the fast pace of a typical surgical timetable. Fortunately, high quality clinical trials now support ketamine’s use as a rapid-acting antidepressant, paving the way to investigate its use for psychiatric optimization in surgical patients. Our group has instituted a comprehensive preoperative screening program for depression, and clinical trials testing ketamine in surgical patients are underway.
I am a board certified anesthesiologist practicing at Stanford Hospital, and fellowship trained in neuroanesthesia, which is anesthesia specifically for neurological surgery. Our division takes care of patients from all over the country and world, from all walks of life, undergoing highly complex neurosurgical procedures including bypass surgery for moyamoya disease, awake craniotomies, and MRI-guided laser ablation for epilepsy.
We get patients safely through one of the most stressful events in their lives, and our top notch anesthesiology residency program is training the next generation of outstanding anesthesiologists.
Interested in combining a career in science and anesthesiology? See this guide I wrote for prospective applicants.