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Ketamine: Benefits and Risks for Depression, PTSD & Neuroplasticity | Huberman Lab Podcast

Andrew Huberman・2 minutes read

The Huberman Lab podcast explores the clinical benefits and risks of ketamine, highlighting its rapid relief for depression through neuroplasticity and BDNF release. Ketamine's effects on brain circuits and behavior changes are essential for treating depression, alongside the interplay of NMDA receptors, BDNF, and opioid pathways.

Insights

  • Ketamine, a compound used both clinically and recreationally, has shown significant benefits for treating depression, suicidality, and PTSD, with a focus on its mechanisms of action and dissociative effects.
  • The rapid relief from depression offered by ketamine, often within hours of administration, contrasts with traditional antidepressants, making it a promising option for treatment-resistant depression and immediate mental health crises.
  • Ketamine's ability to enhance neuroplasticity, particularly through NMDA receptor antagonism and BDNF release, leads to lasting changes in neural circuits associated with mood, contributing to its therapeutic effects.
  • The interplay of ketamine's effects on excitatory and inhibitory neurons, BDNF release, and opioid receptors plays a critical role in both recreational and therapeutic impacts, emphasizing the complexity of its mechanisms and potential for depression relief.

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Recent questions

  • What is the Huberman Lab podcast about?

    The Huberman Lab podcast delves into science and science-based tools for everyday life, hosted by Andrew Huberman, a professor at Stanford School of Medicine. The podcast discusses various topics related to science and its practical applications in daily life, offering insights and knowledge on a wide range of subjects.

  • How does ketamine impact depression treatment?

    Ketamine has shown rapid relief from depression, often within hours of administration, contrasting with traditional antidepressants that may take weeks or months to show effects. Its ability to change neural circuitry and enhance neuroplasticity in mood-related circuits leads to improvements in mood, making it a promising option for individuals facing immediate mental health crises.

  • What are the clinical benefits of ketamine?

    Ketamine is used clinically for depression, suicidality, and PTSD treatment due to its ability to induce rapid relief from symptoms. It has shown effectiveness in treating major depression, bipolar depression, PTSD, OCD, anxiety, and substance addiction, making it a valuable option for those who do not respond to traditional treatments.

  • How does ketamine induce relief from depression?

    Ketamine blocks the NMDA receptor, crucial for neuroplasticity, by binding to it with high affinity, allowing it to induce changes in neural activity and enhance neuroplasticity in mood-related circuits. By promoting long-term changes in neural circuits associated with mood and reward, ketamine provides relief from depression through a complex interplay of brain processes.

  • What role does BDNF play in ketamine therapy?

    Brain-derived neurotrophic factor (BDNF) is crucial in ketamine therapy for depression, potentially being the central process for mood improvement. BDNF binds to TrkB receptors on neurons, triggering a cascade of events that lead to lasting changes in neural circuits induced by ketamine, supporting the drug's rapid relief effects and durability in treating depression.

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Summary

00:00

"Ketamine: Clinical Benefits and Recreational Risks"

  • The Huberman Lab podcast discusses science and science-based tools for everyday life, hosted by Andrew Huberman, a professor at Stanford School of Medicine.
  • Ketamine is a compound used clinically for depression, suicidality, and PTSD treatment, but also commonly abused recreationally.
  • The podcast delves into the clinical benefits and risks of ketamine, including its mechanisms of action and dissociative effects.
  • Dosages and delivery routes of ketamine are discussed, emphasizing both clinical benefits and potential harms.
  • Ketamine's ability to change neural circuitry for depression, suicidality, and PTSD treatment is highlighted.
  • Neuroplasticity and the role of brain-derived neurotrophic factor (BDNF) in learning and memory are explained.
  • Roca eyeglasses and sunglasses, designed for performance, are recommended for clarity and comfort.
  • Eight Sleep's Smart mattress covers, aiding in temperature regulation for optimal sleep, are endorsed for improved rest.
  • Ketamine's similarity to PCP in mode of action as dissociative anesthetics is explained, with a focus on their clinical and recreational uses.
  • The shift in understanding and use of ketamine for depression treatment, contrasting with its historical association with PCP, is detailed.

13:54

Ketamine: Rapid Relief for Depression

  • Ketamine can induce deep anesthesia at certain doses and transition points between awake and deeply anesthetized at lower doses, leading to a dissociative state.
  • The dissociative state, akin to dreaming, is often sought for treating depression, suicidality, and PTSD, but recreational users may not seek a specific state.
  • Ketamine's effects vary based on dosage and individual response, as well as the delivery route (oral, sublingual, or injection), impacting onset speed and effects on the brain and body.
  • In the early 90s, studies on animal models of depression discovered that ketamine, even at sub-anesthetic doses, prolonged animals' attempts to save themselves in a water-based model of learned helplessness.
  • Ketamine's ability to extend animals' fight for survival contradicted its role as an NMDA receptor antagonist, crucial for neuroplasticity, raising questions about its antidepressant effects.
  • Initial skepticism about ketamine's antidepressant potential shifted as clinicians observed remarkable effects in depressed patients, leading to clinical studies in the early 2000s.
  • A landmark study with seven depressed patients receiving intravenous ketamine at half a milligram per kilogram of body weight showed rapid onset of euphoric effects within minutes, peaking at 45 minutes to an hour, with relief persisting for days.
  • Ketamine's quick relief from depression, often within hours of administration, contrasts with traditional antidepressants that may take weeks or months to show effects, making it a promising option for treatment-resistant depression.
  • Ketamine's rapid antidepressant effects are crucial for individuals facing immediate mental health crises, offering relief on the same day of treatment initiation, potentially preventing suicide in severe cases.
  • While ketamine is not a miracle drug for depression, its rapid relief effects make it a valuable option for those who do not respond to traditional treatments, emphasizing the need for swift interventions in mental health care.

27:48

Ketamine: Rapid Relief, Short-Lived Effects, Mechanisms

  • Ketamine has been found to significantly decrease depression, suicidality, feelings of helplessness, and worthlessness in individuals not responding to other depression treatments like SSRIs.
  • It has shown effectiveness in treating major depression, bipolar depression, PTSD, OCD, anxiety, and substance addiction.
  • While ketamine provides rapid relief from depression, its effects are short-lived, necessitating frequent dosing which may lead to addiction concerns.
  • Studies have explored a dosing regimen of ketamine twice a week for three weeks, showing ongoing relief from depressive symptoms even after treatment cessation.
  • Various dosing regimens have been studied, with some showing relief from depressive symptoms immediately and in the days following treatment, indicating durability of effects.
  • Ketamine likely acts through at least two to three mechanisms to provide relief from depression, inducing short, medium, and long-term changes in neurochemistry and neural circuit wiring.
  • Ketamine blocks the NMDA receptor, crucial for neuroplasticity, by binding to it with high affinity, allowing it to cross the blood-brain barrier and induce changes in neural activity.
  • The NMDA receptor acts as an "and gate," requiring high levels of glutamate and electrical activity to activate, leading to changes in neural circuitry and neuroplasticity.
  • Activation of the NMDA receptor under conditions of unusual or high activity patterns leads to downstream processes that facilitate easier replication of those patterns without the same metabolic demand.
  • The process of NMDA receptor activation and subsequent changes in neural activity and gene expression can be likened to muscle hypertrophy, where overload and rest lead to lasting changes in muscle strength and function.

41:41

Ketamine enhances neuroplasticity for mood improvement.

  • NMDA receptor is a central biological mechanism for neuroplasticity, crucial for detecting unusual activity and prompting cellular changes.
  • Ketamine, an NMDA receptor antagonist, plays a role in transitioning from a depressed state to a non-depressed state by enhancing neuroplasticity.
  • Two major types of neurons in the brain are excitatory neurons, which stimulate other neurons, and inhibitory neurons, which suppress neuronal activity.
  • Inhibitory neurotransmission, involving GABA release, reduces the likelihood of the next neuron being electrically active, maintaining balance in the brain.
  • Seizures, like those in epilepsy, result from runaway excitation in the brain due to an imbalance between inhibitory and excitatory neurons.
  • Ketamine, by blocking NMDA receptors on inhibitory neurons, reduces inhibition, allowing excitatory neurons to increase activity in mood-related circuits.
  • Ketamine induces bursting patterns of electrical activity in excitatory neurons, promoting long-term changes in neural circuits associated with mood and reward.
  • Ketamine's ability to enhance neuroplasticity in mood-related circuits leads to improvements in mood, despite blocking the NMDA receptor.
  • Ketamine's effects on neuroplasticity occur over days to weeks, involving gene expression changes, protein synthesis, and neural circuit rewiring.
  • The durability of ketamine's effects in treating depression is likely due to the lasting changes in neural circuits induced by the drug, supported by the release of brain-derived neurotrophic factor (BDNF) and other growth factors.

56:21

BDNF and Ketamine: Neuronal Growth and Relief

  • BDNF binds to TrkB receptors on neurons, triggering a cascade of events, including the insertion of new glutamate receptors, making neurons more sensitive.
  • BDNF can alter neuron shapes, prompting the growth of new branches to receive inputs from other neurons.
  • BDNF is often referred to as "fertilizer for neurons," but it can also act as a neurotransmitter and stimulate other neurons.
  • Ketamine can induce the release of BDNF, making circuits highly plastic and quickly changing.
  • Ketamine may directly cause the release of BDNF without complex mechanisms.
  • BDNF is crucial in ketamine therapy for depression, potentially being the central process for mood improvement.
  • Studies on mice lacking BDNF show reduced response to ketamine, indicating BDNF's critical role in depression relief.
  • Ketamine can mimic BDNF by binding to TrkB receptors, acting as a growth factor in the brain.
  • Ketamine's effects on excitatory and inhibitory neurons, BDNF, and opioid receptors contribute to its recreational and therapeutic impacts.
  • Blocking the opioid receptor system with Naltrexone during ketamine treatment eliminates antidepressant effects, suggesting the opioid system's role in depression relief.

01:10:41

Ketamine's Role in Depression Relief Explained

  • Ketamine plays a critical role in providing relief from depression by activating the opioid system.
  • Attention must be paid to the effects of ketamine during and after its use, whether for treatment or recreational purposes.
  • Immediate effects of drugs like ketamine may not directly correlate with long-term clinical benefits for conditions like depression or PTSD.
  • The effects of drugs like ketamine involve various brain processes, including NMDA receptor and BDNF neuroplasticity, as well as the opioid receptor pathway.
  • Relief from depression through drugs like ketamine involves a complex interplay of immediate, short-term, and long-lasting effects on neural circuits.
  • Positive behavioral changes, such as returning to work, engaging in relationships, and adopting healthy habits, are integral to the relief from depression experienced with drug treatments.
  • Neural circuits change when individuals take ketamine, affecting structures like the habenula and reward pathways in the brain.
  • Ketamine treatment reduces the output from the habenula to the reward pathway, making the reward pathway more available for engagement through anti-depressive behaviors.
  • Ketamine enhances neuroplasticity in the reward pathway, strengthening connections with the frontal cortex for context-dependent strategy building.
  • Dissociative effects of ketamine, such as feeling separate from one's body, are linked to neuroplastic changes and the uncoupling of brain circuits, contributing to its potential relief from depression and PTSD.

01:24:50

Ketamine: Brain Waves, Delivery, and Effects

  • Ketamine affects brain activity by uncoupling networks, leading to different dominant rhythms like Alpha and Theta patterns.
  • Alpha brain waves signify an alert but calm state, while Theta patterns are dream-like and on the border of wakefulness and sleep.
  • Ketamine abolishes Alpha patterns and induces Theta patterns, creating dissociation.
  • Ketamine is typically administered in clinical studies via injection, but recreationally or at home, it's taken orally or sublingually.
  • Orally, only 25% of ketamine reaches the bloodstream, while sublingually, about 35% is metabolically active.
  • Dosages used in studies involve injections, with lower amounts compared to oral or sublingual consumption.
  • Different modes of ketamine delivery affect the amount needed for desired effects.
  • Ketamine can induce a "k-hole," a state beyond dissociation, potentially leading to anesthesia.
  • Different forms of ketamine (R, S, RS) have varying effects on depression relief, with S ketamine being preferred.
  • Microdosing ketamine has no published clinical evidence for treating depression effectively; macro doses are more studied for positive effects.

01:39:03

Ketamine's Antidepressant Effects and Neuroplasticity

  • Ketamine's antidepressant effects are linked to the activation of the NMDA receptor and the release of BDNF, with additional impact on the opioid receptor system for sustained relief.
  • The drug influences brain circuits and waves associated with dissociative states, providing short-lived depression relief that requires multiple weekly doses over weeks for lasting changes through neuroplasticity.
  • While chemical treatments like ketamine can modify brain circuits, engaging in anti-depressive behaviors is crucial to reinforce positive changes, as emphasized by the need for "Better Living Through Chemistry" to be complemented by "Better Living."
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