Ketamine

Sponsors: ROKA & Eight Sleep

Ketamine & PCP; Clinical & Recreational Use

Depression & Current Treatments

Preclinical Models of Depression & Ketamine; “Learned Helplessness”

Ketamine & Clinical Uses; Depression & Suicidality

Ketamine & Other Psychiatric Challenges; Relief & Durability

Sponsor: AG1

NMDA Receptor & Neuroplasticity

Excitatory & Inhibitory Communication, Seizure, NMDA Receptors & Ketamine

How Ketamine Functions in Brain; Acute & Long-Term Effects

Brain-Derived Neurotrophic Factor (BDNF) & Ketamine Therapy

Sponsor: LMNT

Ketamine & Opioid Pathway

Divergent Mechanisms of Immediate & Long-Term Effects

Habenula, Pro-Depressive Behaviors & Ketamine Therapy

Ketamine & Context-Dependent Strategy; Reward Pathway

Dissociative States

Doses & Routes of Administration; “K-holes”; Risk & Caution

Ketamine Forms; R-, S- vs R/S- Ketamine; Micro-Dosing

Ketamine: Effects & Therapy

Zero-Cost Support, YouTube Feedback, Spotify & Apple Reviews, Sponsors, Momentous, Social Media, Neural Network Newsletter

- The Huberman Lab Podcast discusses science and science-based tools for everyday life.
- Ketamine is a compound used clinically for depression, suicidality, and PTSD, but it is also commonly abused.
- The podcast will discuss the research on the clinical benefits and risks of ketamine, including mechanisms of action, dosages, and delivery routes.
- The podcast will explore the long-term changes in the brain caused by ketamine and the role of neuroplasticity and BDNF in learning.
- The podcast aims to provide free information about science and science-related tools to the general public.
- The first sponsor is Roka, a company that makes high-quality eyeglasses and sunglasses designed for optimal performance in various conditions.
- The second sponsor is Eight Sleep, which makes smart mattress covers that can customize the temperature of the sleeping environment for better sleep.
- Listeners can save 20% on Roka eyeglasses and sunglasses by using the code "Huberman" and save $150 on Eight Sleep mattress covers by visiting eightsleep.com/huberman.

- Ketamine is a compound used clinically for depression, suicidality, and PTSD, but is also commonly abused.
- The podcast will discuss the research on the clinical benefits and risks of ketamine, as well as its mechanisms of action and dosages.
- The episode will also cover the long-term changes in the brain caused by ketamine, as well as the role of neuroplasticity and brain-derived nootrophic factor (BDNF) in learning and memory.

- The podcast is separate from the speaker's teaching and research roles at Stanford.
- The podcast aims to provide free information about science and science-related tools to the general public.
- The sponsors of the podcast are Roka, which makes high-quality eyeglasses and sunglasses, and Eight Sleep, which makes smart mattress covers with cooling, heating, and sleep tracking capabilities.

- Ketamine binds to the NMDA receptor in the brain, which normally detects abnormal neural activity. This binding reduces the activity of inhibitory neurons and increases excitatory communication between neurons in mood-related circuits.
- Ketamine induces neuroplasticity in these circuits, strengthening connections and making them more likely to generate positive mood and less likely to generate negative mood.
- The process of ketamine-induced neuroplasticity takes many days and involves changes in gene expression and the production of new proteins and receptors. This explains the longer-term changes in mood associated with ketamine therapy for depression.

- Neuroplasticity in response to ketamine treatment for depression involves the release of BDNF (brain-derived neurotrophic factor).
- BDNF can induce the insertion of new glutamate receptors and alter the shape of neurons, allowing for increased sensitivity and new inputs.
- BDNF is a central process in ketamine therapy for depression, and its release is one of the core mechanisms by which ketamine relieves depression.

- Element is an electrolyte drink that contains salt, sodium, magnesium, and potassium, which are important for cell function and performance.
- It has a science-backed electrolyte ratio of 1,000mg sodium, 200mg potassium, and 60mg magnesium.
- The speaker drinks Element in the morning, during physical training, and after sweating, and recommends it for hydration and electrolyte replenishment.

- Ketamine induces neuroplasticity, leading to improvements in mood and affect for depression.
- Ketamine can bind to opioid receptors, which can result in pain relief, changes in mood, and even euphoria.
- A study showed that blocking the opioid receptor pathway with naltrexone eliminated the antidepressant effects of ketamine, suggesting that the opioid system is responsible for its antidepressant effects.

- Ketamine provides immediate effects such as mild euphoria and dissociation, but the longer-term relief from depression may not be directly related to these immediate effects.
- Ketamine activates the opioid system, which plays a critical role in providing relief from depression.
- The effects of drugs like ketamine are influenced by both immediate and long-term changes in neural circuits, as well as the behaviors and activities that individuals engage in.

- Ketamine treatment can reduce the output from the habenula to the reward pathway, making the reward pathway more available for anti-depressive thoughts and behaviors.
- Ketamine can strengthen the connections between areas of the brain associated with context-dependent strategy building and reward pathways.
- NMDA receptor blockade is not the mechanism by which ketamine provides relief from depression, as another NMDA receptor blocker called memantine has no antidepressant effects.

- Ketamine is a dissociative anesthetic that creates a feeling of dissociation, where people feel separate from their body and observe themselves.
- Dissociation is a symptom of PTSD and trauma, but ketamine can provide relief from depression by inducing neuroplastic changes and affecting the mu opioid receptor system.
- Ketamine uncouples brain circuits, particularly neocortical circuits, and abolishes the alpha pattern of brain activity, replacing it with the theta pattern associated with a dreamlike state.

- Ketamine can be taken through different routes of delivery, including injection, oral ingestion, and sublingual administration.
- When taken orally, only 25% of the active form of ketamine enters the bloodstream, while sublingual administration converts about 35% of the total amount into metabolically active ketamine.
- Different individuals respond differently to ketamine, and the dosage and mode of delivery can greatly affect the effects and risks associated with its use.

- Different forms of ketamine (intranasal, oral, sublingual, rectal) are primarily related to dosage and liver metabolism.
- The S form of ketamine is more potent and produces less dissociation, making it the preferred form for depression relief.
- The combined SR form of ketamine is the most potent for relieving depressive symptoms, followed by the S form, while the R form is the least effective. Microdosing ketamine has no published clinical evidence for treating depression.

- Ketamine and PCP are similar compounds that block the NMDA receptor, producing dissociation and mild euphoria at low dosages, and anesthesia and potential for seizure and death at higher dosages.
- The activation of the NMDA receptor and the opioid receptor system are both involved in the antidepressant effects of ketamine.
- Ketamine provides short-lived depression relief, but durable changes require multiple treatments over weeks and engagement in antidepressive behaviors.

- Ketamine is similar to PCP and has the same mode of action in the brain as a dissociative anesthetic.
- Ketamine has proven to be effective in treating depression, suicidality, and PTSD in the appropriate clinical context.
- However, ketamine also has a high potential for abuse and is used recreationally, leading to addiction and negative impacts on overall life performance.

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- The monoamine hypothesis of depression suggests that deficiencies in certain neurotransmitters like serotonin and dopamine contribute to depression, but there is little evidence to support this.
- Drugs that increase these neurotransmitters, such as Prozac and Zoloft, can provide relief for some people with depression, but they only work for about 40% of patients and have side effects.
- Ketamine, originally studied for its anesthetic properties, is being explored as a potential treatment for depression, suicidality, and PTSD due to its ability to induce a dissociative state.

- Researchers discovered a preclinical model of depression called learned helplessness, where rats or mice are placed in water and observed to see when they give up swimming.
- Ketamine, an NMDA receptor antagonist, was found to prolong the duration of swimming in these animals, despite blocking neuroplasticity.
- Scientists who embraced the contradiction between ketamine's effects and its mechanism of action discovered its potential as an antidepressant, leading to its use in treating depressed patients with remarkable results.

- In the year 2000, ketamine started being explored as a treatment for depression due to the limited effectiveness and side effects of existing drugs.
- A small study with seven subjects found that ketamine injections provided immediate relief from depression, with effects lasting for several days.
- Ketamine is not considered a miracle drug, but it has shown significant decreases in depression, suicidality, and feelings of helplessness and worthlessness in patients who do not respond to other treatments.

- Ketamine has been shown to provide relief for treatment-resistant depression, bipolar depression, PTSD, OCD, anxiety, and substance addiction.
- The antidepressant effects of ketamine wear off after a few days or a week, requiring frequent dosing, but this is not feasible due to its dissociative effects and potential for abuse.
- Studies have found that a twice-weekly dosing regimen for three weeks provides ongoing relief from depressive symptoms, with some durability extending for months or more.

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- The speaker has been taking AG1 daily since 2012 and feels better with increased focus, energy, and improved sleep.
- AG1 is offering a special offer of 10 free travel packs and a year supply of vitamin D3K2 if you go to drinkag1.com/huberman.

- Ketamine blocks the NMDA receptor, which is critical for neuroplasticity.
- The NMDA receptor binds glutamate and requires high levels of electrical activity to activate.
- Activation of the NMDA receptor can lead to changes in gene expression and the introduction of new receptors, allowing for the recreation of patterns of activity without high metabolic demand.

- NMDA receptors are a key mechanism in neuroplasticity and play a role in detecting unusual activity and making changes to cells.
- Ketamine is an NMDA receptor blocker, but paradoxically increases neuroplasticity in brain circuits involved in mood, reward, and self-reflection.
- Ketamine binds to inhibitory neurons, reducing inhibition and allowing excitatory neurons to increase their activity, leading to bursting patterns of electrical activity that induce long-term changes in neural circuits associated with mood.

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