What If Ketamine Therapy Works Better When the Brain Is Active?
The Set and Setting Flip: What a Leading Neuroscientist's Hypothesis Could Mean for Your Ketamine Therapy Patients
Synopsis: A recently published hypothesis from Dr. Roberto Malinow, one of the world's leading NMDA receptor researchers, proposes that ketamine works by weakening hyperactive brain circuits and that those circuits need to be active during treatment for ketamine to have a lasting effect. This post breaks down the science, explores what a landmark Stanford study adds to the picture, and asks what this could mean for how we think about set and setting in clinical practice.
Key Takeaways:
Dr. Roberto Malinow's published hypothesis proposes that ketamine produces lasting antidepressant effects by weakening hyperactive brain circuits, and that those circuits must be active during treatment for ketamine to work.
A 2023 randomized controlled trial found that ketamine delivered under general anesthesia showed no greater antidepressant effect than placebo, lending support to the idea that an active, conscious brain is a necessary condition for ketamine's therapeutic effect.
Professional Education Disclaimer: This content is intended exclusively for licensed healthcare professionals and should not be used by patients for self-treatment or self-education. The information presented reflects current regulatory developments and should not replace clinical judgment, professional training, or comprehensive research. Healthcare providers must conduct their own due diligence, consult current literature, and evaluate treatment approaches within their specific practice context and regulatory environment. This educational content does not constitute medical or legal advice for specific patients or clinical situations.
🎙️ THIS POST IS BASED ON
Ketamine Startup Podcast
Our conversation with Dr. Roberto Malinow, emeritus professor at UC San Diego, member of the National Academy of Sciences and the National Academy of Medicine, and author of How Ketamine Works: An Actionable Hypothesis. Listen to the full episode for the complete conversation.
Listen to the Episode →Introduction
You have thought carefully about your infusion room. The lighting is right. The music is curated. You have worked on helping your patients arrive with a calm and open mindset. You have done your utmost in the set and setting work.
And yet some patients respond beautifully and others do not respond the way you hoped.
If you have ever wondered why, there may be something in the emerging neuroscience worth paying attention to.
Dr. Roberto Malinow is an emeritus professor at UC San Diego, a member of both the National Academy of Sciences and the National Academy of Medicine, and one of the world's most cited researchers in NMDA receptor biology and synaptic plasticity.
His work has been cited more than 30,000 times. In April 2026, he published a perspective piece in the Proceedings of the National Academy of Sciences titled "How Ketamine Works: An Actionable Hypothesis" (Malinow R, PNAS, 2026).
We had the opportunity to speak with him on the Ketamine Startup Podcast, and what he shared challenges some foundational assumptions about how we prepare patients for treatment.
This post is not a protocol recommendation. It is a clinical hypothesis, clearly framed as such by Dr. Malinow himself, that we think deserves a place in the conversation.
Table of Contents
Set and setting shape more than patient comfort during a ketamine session. Originating in the psychedelic therapy space, this framework addresses the mindset and environment a patient brings into treatment, and emerging neuroscience suggests those factors may influence outcomes at the circuit level.
The Standard Model of Set and Setting
The concept of set and setting did not originate in ketamine therapy. It comes from the psychedelic therapy space, where researchers and practitioners have long understood that the therapeutic outcome of a psychedelic experience is shaped by far more than the molecule itself.
Set refers to the patient's mindset coming into the session: their mental state, motives, intentions, beliefs, and their physical, emotional, and cognitive condition before the infusion begins.
Setting refers to the physical and social environment where the ketamine experience will occur, including the room itself, the healthcare team present, and even the person who accompanied the patient to the clinic.
A growing number of ketamine providers have adopted this framework, and for good reason. A patient who arrives activated, anxious, or in emotional distress may have a more difficult session. The dissociative onset can be disorienting, and a nervous system already running hot is more likely to respond with fear rather than openness. Optimizing for calm, safety, and positive orientation makes clinical sense.
But this is not universal. Many ketamine providers operate from a more traditional mainstream healthcare mindset where the primary goal is straightforward: keep the patient medically safe. The infusion room looks more like a procedure suite than a therapeutic environment. Set and setting, if considered at all, is secondary to protocol.
Both approaches exist. And Dr. Malinow's hypothesis introduces a question that is relevant to both camps. What if, at the neurobiological level, the mental and emotional state of the patient during the session matters more than either approach currently accounts for?
A Different Way to Think About What Ketamine Is Doing
Dr. Malinow's hypothesis rests on three connected ideas.
| Dr. Malinow's Hypothesis: How Ketamine Works | ||
| Hypothesis Element | What It Means | Why It Matters Clinically |
|---|---|---|
| 1. Ketamine works through neuroplasticity | For ketamine to produce lasting change in depression, it is likely modifying actual brain circuits rather than producing only a short-lived chemical effect. A temporary receptor block alone is difficult to reconcile with the rapid and sustained antidepressant outcomes ketamine is known for. | This reframes ketamine as a circuit-level intervention, not just a chemical one. It helps explain why some patients experience durable relief after a course of infusions, and invites clinicians to think about what conditions support that circuit-level change. |
| 2. Ketamine preferentially weakens active circuits | Ketamine does not act on all circuits equally. As an open-channel blocker of the NMDA receptor, ketamine can only block channels that are already open and passing current. Circuits that are quiet during treatment are largely unaffected. | Which circuits are active during a session determines which circuits ketamine can modify. This means the patient's mental and emotional state during the infusion is not incidental. It may be a direct factor in treatment outcome. |
| 3. In depression, the target circuits are driven by negative thoughts | A significant contributor to depression may be hyperactive circuits supporting negative thought patterns: rumination, guilt, feelings of worthlessness, and intrusive self-critical loops. If those circuits are active while ketamine is on board, the hypothesis holds that ketamine will selectively weaken them. | If the circuits underlying a patient's depression need to be active for ketamine to weaken them, then what a patient is thinking and feeling during treatment may matter more than we have previously understood. This is the core of the set and setting flip. |
Source: Malinow R. How ketamine works: An actionable hypothesis. Proc Natl Acad Sci U S A. 2026 May 5;123(18):e2533728123. This hypothesis has not yet been validated in prospective clinical trials and does not represent a current standard of care.
The first is that for ketamine to produce a lasting change in depression, it is likely working through neuroplasticity, through actual modification of brain circuits, rather than only through a short-lived chemical effect. A temporary receptor block alone is difficult to fully reconcile with the rapid and sustained antidepressant outcomes that have made ketamine so remarkable in the field.
The second is that ketamine does not act on all circuits equally. In this model, ketamine preferentially affects circuits that are highly active while relatively sparing those that are quiet. This follows directly from how ketamine interacts with the NMDA receptor. Ketamine is an open-channel blocker, meaning it primarily blocks NMDA channels that are already open and passing current. That only happens when those neurons are actively firing.
The third element is where the clinical implication comes in. In depression, a significant contributor to the illness may be hyperactive circuits supporting negative thought patterns: rumination, guilt, feelings of worthlessness, and intrusive self-critical loops. If those circuits are especially active while ketamine is on board, the hypothesis holds that ketamine will selectively weaken those overactive pathways, reducing their influence and in turn reducing depressive symptoms.
Taken together, this hypothesis suggests that what a patient is actively thinking and feeling during a ketamine session could help determine which circuits get modified and which are left relatively unchanged. Which is exactly why set, setting, and therapeutic framing may matter far more than we have previously understood.
📌 WHAT IS SYNAPTIC PLASTICITY?
Synaptic plasticity refers to the ability of the connections between neurons (synapses) to strengthen or weaken over time in response to activity. It is widely considered the cellular basis of learning and memory. When we say ketamine may work through neuroplasticity, we mean it may be driving lasting changes in the strength and structure of specific synaptic connections in the brain, rather than simply producing a short‑lived chemical effect.
The lateral habenula, sometimes called the brain's disappointment center, suppresses dopamine and reward circuits when hyperactive. Understanding its role in depression is central to Dr. Malinow's hypothesis about how ketamine may produce rapid and lasting antidepressant effects.
The Disappointment Center and Its Role in Depression
Part of Dr. Malinow's framework involves a small but significant structure in the brain called the lateral habenula. It is a tiny epithalamic nucleus located near the thalamus and it has been described, quite usefully, as the brain's disappointment center.
The lateral habenula influences mood by inhibiting dopamine and other reward centers. When it is active, it suppresses the brain's reward and motivation systems. Evolutionarily, that makes sense. If you make a choice and the outcome is worse than expected, lateral habenula activity helps encode that disappointment so you are less likely to repeat the same mistake. Disappointment, in this context, is not a flaw in the system. It is a feature. It is how we learn.
The problem arises when the lateral habenula becomes hyperactive, as appears to be the case in some forms of depression. When this structure fires too easily or too often, it keeps the reward circuitry chronically dampened. The result is the low mood, low motivation, and emotional flatness that many depressed patients describe and that clinicians recognize immediately.
Dr. Malinow's lab and others have shown that reducing or blocking this pathological activity in the lateral habenula in animal models of depression can rapidly alleviate depression-like behaviors. This is consistent with the broader hypothesis that depression involves specific overactive circuits working against reward and wellbeing, and that selectively quieting those circuits is part of how ketamine may be producing its therapeutic effects.
📌 WHAT IS THE LATERAL HABENULA?
The lateral habenula is a small brain structure located near the thalamus. It is often described as the brain’s “disappointment center” because it becomes active when outcomes are worse than expected, helping suppress dopamine-related reward signals and contributing to negative feelings. Evidence suggests it may be hyperactive in some forms of depression, making it a potentially important target for understanding how antidepressant treatments work at the circuit level.
Why the Brain Needs to Be Active for Ketamine to Work
Dr. Malinow's hypothesis gains important clinical support from a 2023 randomized controlled trial published in Nature Mental Health (Lii TR, Smith AE, Flohr JR, et al.).
In that study, 40 adult patients with major depressive disorder who were scheduled for routine surgery were randomized to receive either a standard intravenous ketamine infusion at 0.5 mg/kg or a placebo saline infusion. Both were delivered while patients were under general anesthesia. The trial was triple-masked, meaning participants, investigators, and direct care staff were all blinded to which treatment was given.
The result was striking. The group that received ketamine under general anesthesia showed no statistically significant benefit over placebo on depression scores in the days following surgery. Both groups improved to a similar degree.
Let us be clear about what this finding does and does not mean. It does not mean ketamine does not work. The existing body of evidence for ketamine's antidepressant effects in conscious patients is substantial and well established. What this study adds is a critical piece of context. When ketamine is administered while the brain is deeply anesthetized and circuits are largely offline, it does not show its usual advantage over placebo.
That is exactly what Dr. Malinow's hypothesis would predict. If ketamine works by weakening hyperactive circuits, and those circuits are only meaningfully active in a conscious and experiencing brain, then delivering ketamine to an unconscious patient removes the very condition that makes the therapy mechanistically effective. The medicine is on board. The target is not.
📌 WHAT IS THE NMDA RECEPTOR?
The NMDA receptor (N‑methyl‑D‑aspartate receptor) is a type of glutamate receptor found on neurons throughout the brain. It plays a central role in synaptic plasticity, learning, and memory. Ketamine works as an NMDA receptor antagonist, meaning it blocks the receptor’s ion channel. Critically, ketamine is an “open‑channel” blocker: it can only enter and block the channel when it is already open, so NMDA receptors—and the circuits they belong to—need to be active for ketamine to most strongly affect them..
A new hypothesis about how ketamine works at the synaptic level raises a provocative question for ketamine clinicians: what if the mental and emotional state of the patient during an infusion directly influences which brain circuits ketamine can modify?
The Set and Setting Flip
Here is where the hypothesis becomes genuinely thought-provoking, regardless of where you currently land on set and setting.
For providers who have adopted the set and setting framework, the standard approach optimizes for calm, positive mental states during a ketamine session. And that makes clinical sense for patient comfort and safety.
But under Dr. Malinow's hypothesis, the circuits most relevant to a patient's depression are the ones running negative thoughts, rumination, and feelings of guilt or hopelessness. If those circuits need to be active for ketamine to weaken them, then a patient who successfully suppresses all negative thoughts during a session may paradoxically be leaving those circuits less available for ketamine to act on.
For providers operating from a more traditional mainstream healthcare mindset, where the primary goal is patient safety and protocol adherence, this hypothesis introduces a different kind of question. It is not about set and setting as a philosophical framework. It is about what is happening neurobiologically during the infusion and whether the mental and emotional state of the patient is a clinically meaningful variable that deserves more attention.
Either way, the implication is the same. What a patient's brain is doing during a ketamine session may matter more than we have previously accounted for.
Dr. Malinow points to written exposure therapy as an interesting clinical parallel. In the Feder et al. open-label trial on PTSD, patients receiving ketamine were also asked to repeatedly write about their traumatic experiences as part of this structured therapeutic approach. The hypothesis is that this process helps activate trauma-related circuits around the time of treatment, potentially making them more available for ketamine to modify.
For chronic pain, the application is perhaps even more solid. If a patient's pain is driven by sensitized central pathways in the spinal cord or brain rather than ongoing peripheral inflammation, activating that pain stimulus during a ketamine infusion may be what allows ketamine to weaken those sensitized pathways. Preclinical and experimental pain studies with ketamine and related compounds suggest that modulation of pain and descending pain control is most evident when nociceptive stimuli are present while the drug is on board.
We want to be direct about what this is and what it is not. This is a hypothesis published by a highly credentialed researcher with decades of work in NMDA receptor biology. It is supported by a plausible mechanism and by the Lii et al. anesthesia study. It has not yet been validated in prospective clinical trials designed to test it directly. It does not represent a current standard of care and should not be read as a recommendation to change your clinical protocols.
What it is, is a framework that may help explain some of the variability in patient response that clinicians observe and do not yet have a complete answer for.
What This Means for Your Practice Right Now
We are not suggesting you abandon your set and setting approach. The existing rationale for a calm, safe treatment environment remains valid, particularly for patient comfort, safety, and the therapeutic relationship.
What we are suggesting is that this hypothesis is worth holding as a clinician. A few questions worth sitting with:
When a patient does not respond as expected, is there a circuit-level explanation that could inform how you think about their preparation or their session?
Is there a role for structured approaches like written reflection or guided attention to relevant thoughts or sensations in the period surrounding treatment, particularly for patients with treatment-resistant depression or chronic pain?
As research in this area develops, what study designs might your practice be positioned to participate in or observe?
Dr. Malinow himself noted that chronic pain may be the most tractable starting point for testing this hypothesis clinically, because the relevant stimulus can be activated more reliably than complex emotional states. For clinics treating chronic pain with ketamine, that is a particularly relevant signal.
The science of how ketamine works is still being written. What Dr. Malinow's hypothesis offers is not a finished answer but a compelling direction, one that takes seriously what is happening at the synaptic level during a session and invites clinicians to think more carefully about what their patients' brains are doing while the medicine is on board.
Keep Reading: If this topic resonated with you, these posts are worth your time as well.
The Clinician's Guide to Ketamine Therapy: How Ketamine Works and Scientific Studies | Part 2 A deeper look at how ketamine works at the neurological level, the range of patient experiences, and the scientific evidence behind its effectiveness. A solid companion read to the hypothesis discussed in this post.
What A Patient Watches Can Influence Their Ketamine Treatment Experience If what a patient is thinking and feeling during a session may influence which circuits ketamine acts on, what they consume beforehand matters too. This post explores how mindful media consumption before treatment can shape the ketamine experience, with practical guidance for your patients.
Why Your Patient Needs Support Between Ketamine Treatments Circuit-level changes from ketamine do not happen in a vacuum. This post explores why social and emotional support between sessions is an important part of the therapeutic process, not an optional add-on.
Professional Education Disclaimer: This content is intended exclusively for licensed healthcare professionals and should not be used by patients for self-treatment or self-education. The information presented reflects individual provider experiences and should not replace clinical judgment, professional training, or comprehensive research. Healthcare providers must conduct their own due diligence, consult current literature, and evaluate treatment approaches within their specific practice context and regulatory environment. This educational content does not constitute medical advice for specific patients or clinical situations - treatment decisions should always be based on individual patient assessment and adherence to professional medical standards.
Frequently Asked Questions
What is Dr. Malinow's hypothesis about how ketamine works?
Dr. Roberto Malinow, a leading NMDA receptor researcher at UC San Diego, published a 2026 hypothesis arguing that ketamine's rapid, lasting antidepressant effects come from weakening hyperactive brain circuits through synaptic plasticity, not just from a brief chemical effect. A key claim is that these circuits need to be actively firing during the infusion for ketamine to most strongly affect them, because ketamine preferentially blocks NMDA receptors whose channels are already open. In depression, the circuits that matter most are thought to be those driving negative thoughts, rumination, and feelings of guilt or worthlessness. This is a published, mechanistically grounded hypothesis, not yet proven in targeted clinical trials, but one that could fundamentally change how clinicians think about what patients are experiencing during a session.
Why did ketamine show no antidepressant effect in patients under general anesthesia?
A 2023 randomized controlled trial by Lii et al., published in Nature Mental Health, found that a standard antidepressant dose of intravenous ketamine given to adults with major depressive disorder while under general anesthesia for surgery produced no greater improvement in depression scores than placebo. Both groups improved to a similar degree. One interpretation, consistent with Dr. Malinow's hypothesis, is that under deep anesthesia the brain is not consciously processing thoughts or emotions, so the circuits most relevant to depression are not actively firing for ketamine to act on. This supports the idea that an active, conscious brain state may be a necessary condition for ketamine's characteristic antidepressant effects.
What is the lateral habenula and why does it matter for depression?
The lateral habenula is a small brain structure near the thalamus that regulates reward and motivation by suppressing dopamine and other reward centers when active. It has been described as the brain's disappointment center because it becomes engaged when outcomes are worse than expected, discouraging actions that failed to pay off. In animal models of depression, the lateral habenula shows abnormally increased activity, and reducing or blocking that activity has been shown to rapidly relieve depression-like behavior. Dr. Malinow's hypothesis fits this picture by suggesting ketamine may help by weakening hyperactive circuits associated with this structure.
What is synaptic plasticity and why does it matter for ketamine therapy?
Synaptic plasticity refers to the ability of synapses, the connections between neurons, to strengthen or weaken over time in response to activity and experience. Long-lasting forms of synaptic plasticity are widely considered the cellular basis of learning and memory. Dr. Malinow proposes that ketamine's antidepressant effects rely on this same machinery, triggering changes that selectively weaken synaptic connections in hyperactive circuits rather than producing only a short-lived chemical effect. This helps explain how ketamine can produce relatively rapid and sustained improvements in depression instead of only transient symptom relief.
What is the NMDA receptor and how does ketamine affect it?
The NMDA receptor is a subtype of glutamate receptor found throughout the brain that plays a central role in synaptic plasticity, learning, and memory. Ketamine is an NMDA receptor antagonist, meaning it blocks the receptor's ion channel and reduces calcium flow when the receptor is active. Critically, ketamine is an open-channel blocker. It can only enter and block the channel when it is already open, which happens when the receptor is activated and the neuron is firing. This is why the activity state of a circuit may directly influence where and how strongly ketamine has an effect.
Could activating negative thoughts during a ketamine session improve treatment outcomes?
According to Dr. Malinow's hypothesis, ketamine most strongly affects circuits that are actively firing while the drug is on board. For depression, this suggests that engaging with the thoughts or feelings that drive a patient's symptoms, such as rumination, guilt, or trauma-related material, in the period surrounding treatment could in principle make those circuits more available for ketamine to weaken. For chronic pain, a similar idea applies. Activating pain pathways during the infusion, particularly when pain is driven by central sensitization rather than ongoing tissue damage, might allow ketamine to more effectively target those sensitized circuits. This remains a hypothesis. No prospective clinical trials have yet directly tested protocols that deliberately activate negative thoughts or pain during ketamine treatment, and clinicians should not treat this as a current standard of care or a recommendation to change established protocols.
References
The Core Hypothesis
Malinow R. How ketamine works: An actionable hypothesis. Proc Natl Acad Sci U S A. 2026 May 5;123(18):e2533728123. doi: 10.1073/pnas.2533728123. Epub 2026 Apr 30. PMID: 42060723; PMCID: PMC13143036. View on PubMed
Krystal JH, Kavalali ET, Monteggia LM. Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms. Neuropsychopharmacology. 2024 Jan;49(1):41-50. doi: 10.1038/s41386-023-01629-w. Epub 2023 Jul 24. PMID: 37488280; PMCID: PMC10700627. View on PMC
Lullau APM, Haga EMW, Ronold EH, Dwyer GE. Antidepressant mechanisms of ketamine: a review of actions with relevance to treatment-resistance and neuroprogression. Front Neurosci. 2023 Aug 8;17:1223145. doi: 10.3389/fnins.2023.1223145. PMID: 37614344; PMCID: PMC10442706. View on PMC
Zarate CA Jr, Niciu MJ. Ketamine for depression: evidence, challenges and promise. World Psychiatry. 2015 Oct;14(3):348-50. doi: 10.1002/wps.20269. PMID: 26407791; PMCID: PMC4592658. View on PMC
Adam E, Kowalski M, Akeju O, Miller EK, Brown EN, McCarthy MM, Kopell N. Ketamine can produce oscillatory dynamics by engaging mechanisms dependent on the kinetics of NMDA receptors. Proc Natl Acad Sci U S A. 2024 May 28;121(22):e2402732121. doi: 10.1073/pnas.2402732121. Epub 2024 May 20. PMID: 38768339; PMCID: PMC11145256. View on PMC
Klein ME, Chandra J, Sheriff S, Malinow R. Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents. Proc Natl Acad Sci U S A. 2020 Feb 4;117(5):2656-2662. doi: 10.1073/pnas.1916570117. Epub 2020 Jan 15. PMID: 31941713; PMCID: PMC7007545. View on PMC
The Disappointment Center
Yang Y, Cui Y, Sang K, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018;554:317-322. doi: 10.1038/nature25509. View article
Gold PW, Kadriu B. A Major Role for the Lateral Habenula in Depressive Illness: Physiologic and Molecular Mechanisms. Front Psychiatry. 2019 May 22;10:320. doi: 10.3389/fpsyt.2019.00320. PMID: 31231247; PMCID: PMC6558383. View on PMC
Winter C, Vollmayr B, Djodari-Irani A, Klein J, Sartorius A. Pharmacological inhibition of the lateral habenula improves depressive-like behavior in an animal model of treatment resistant depression. Behav Brain Res. 2011 Jan 1;216(1):463-5. doi: 10.1016/j.bbr.2010.07.034. Epub 2010 Aug 3. PMID: 20678526. View article
Why the Brain Must Be Active
Lii TR, Smith AE, Flohr JR, Okada RL, Nyongesa CA, Cianfichi LJ, Hack LM, Schatzberg AF, Heifets BD. Randomized trial of ketamine masked by surgical anesthesia in patients with depression. Nat Ment Health. 2023 Nov;1(11):876-886. doi: 10.1038/s44220-023-00140-x. Epub 2023 Oct 19. PMID: 38188539; PMCID: PMC10769130. View on PMC
The Set and Setting Flip
Feder A, Brown O, Rutter SB, Cahn L, Overbey JR, Seeley SH, Yu A, Bonanno PA, Fremont RA, Delgado AA, Jha MK, Costi S, Yehuda R, Schiller D, Pietrzak RH, Charney DS, Sloan DM, Murrough JW. Combining Ketamine Infusions and Written Exposure Therapy for Chronic PTSD: An Open-Label Trial. J Clin Psychiatry. 2025 Apr 2;86(2):24m15622. doi: 10.4088/JCP.24m15622. PMID: 40215385; PMCID: PMC12645454. View on PMC
Niesters M, Dahan A, Swartjes M, Noppers I, Fillingim RB, Aarts L, Sarton EY. Effect of ketamine on endogenous pain modulation in healthy volunteers. Pain. 2011 Mar;152(3):656-663. doi: 10.1016/j.pain.2010.12.015. Epub 2011 Jan 14. PMID: 21237568. View on PubMed
Faísco A, Dinis R, Seixas T, Lopes L. Ketamine in Chronic Pain: A Review. Cureus. 2024 Feb 1;16(2):e53365. doi: 10.7759/cureus.53365. PMID: 38435232; PMCID: PMC10908414. View on PMC
Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2014 Feb;77(2):357-67. doi: 10.1111/bcp.12094. PMID: 23432384; PMCID: PMC4014022. View on PMC
A new hypothesis from a leading NMDA receptor researcher suggests ketamine may work by weakening active brain circuits. Here is what that could mean for clinical practice.
A new hypothesis from a leading NMDA receptor researcher suggests ketamine may work by weakening active brain circuits. Here is what that could mean for clinical practice.