Summary of Huberman Lab Podcast Episode: Ketamines Impact on Depression, PTSD, and Neuroplasticity | Huberman Lab
Podcast: Huberman Lab
7 min. read
— Description —
Discover how ketamine affects the brains neural circuits, improving mood and providing relief from depression Learn about its impact on NMDA receptors, excitatory activity, and the release of BDNF Explore the connection between ketamine, the glutamate system, and the opioid receptor system
Understand why medication and therapies work best when combined with behavioral changes Find out why the dose of ketamine is more important than the route of administration.
Ketamines Impact on Depression, PTSD, and Neuroplasticity | Huberman Lab
Table of contents
Key Takeaways
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Ketamine makes its way into the bloodstream then the brain and binds to NMDA receptors and blocks the activity of inhibitory neurons
- NMDA function is to detect abnormal levels of activity and recruit changes to cells for improved response in the future (neuroplasticity)
- When ketamine binds to the NMDA receptor, inhibitory activity is reduced and excitatory activity increases which strengthens neuroplasticity
- The firing of excitatory neurons following ketamine invokes the release of BDNF which makes neurons very plastic, very quickly
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Ketamine changes neural circuits which improves mood
- Ketamine provides relief from depression through 3 mechanisms: (1) induces relief from depression quickly via a euphoric, dream-like state; (2) provides relief from depression in days and weeks following ketamine; (3) long-lasting changes in nervous system and neural circuit wiring
- Ketamine acts on the glutamate system and opioid receptor system
- “It is impossible to separate the positive behavioral consequences of a drug treatment for depression from the drug itself.” – Dr. Andrew Huberman
- Medication and therapies don’t act alone – circuits in the brain are designed to respond to behavior and activities, not just medication alone
- The effectiveness of modes of delivery is more related to dose than the actual route
Introduction
- Dr. Andrew Huberman, Ph.D. is a Professor of Neurobiology and Ophthalmology at Stanford University School of Medicine. His lab focuses on neural regeneration, neuroplasticity, and brain states such as stress, focus, fear, and optimal performance.
- In this episode of Huberman Lab, Andrew Huberman dives into the benefits and risks of ketamine including the mechanism of ketamine, therapeutic use for depression, PTSD, and mood regulation, differences in ketamine routes of administration, and much more.
- Host: Andrew Huberman (@hubermanlab)
Understanding Ketamine As A Drug
- Ketamine is similar to PCP in the mode of action on the brain – both are dissociative anesthetics, but ketamine has evolved from a drug of abuse to clinically beneficial
- You can get addicted to ketamine
- Ketamine does have established uses in PTSD, depression, bipolar and suicidality
- Delivery routes of ketamine produce different effects
History Of Depression & Treatment
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Monoamine hypothesis: deficiencies in monoamines give rise to depression
- There is little evidence this is true but we do know that drugs that increase monoamine activity can provide relief in symptoms of depression for about 40% of people
- Monoamines like dopamine and serotonin are neurotransmitters – they can ramp up or reduce activity in parts of the brain and body
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The use of ketamine arose in the 90s out of a desire to find a more widespread treatment of depression and treatment with fewer side effects
- A dissociative state which has dream-like qualities is the zone of therapy for depression
- Studied via a model of learned helplessness where rats and mice are put in situations where they have to save their own life (e.g., put in water and see how long it takes them to give up trying to fight for life)
- Animals injected with ketamine would swim for life longer
- Ketamine is an NMDA blocker that is critical for changing neuroplasticity and changes in the brain
Use Of Ketamine For Treatment-Resistant Depression
- Ketamine: level of dissociation appears correlated with antidepressant effect – but dissociation (separateness from the body) is necessary but not sufficient
- People get relief from depression almost immediately after ketamine use (versus pharmaceuticals which take weeks or months)
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Antidepressant effects of ketamine last 1-2 weeks; dosing and cycling matter in longevity of therapeutic effect
- Ketamine provides relief from depression through 3 mechanisms: (1) induces relief from depression quickly via a euphoric, dream-like state; (2) provides relief from depression in days and weeks following ketamine; (3) long-lasting changes in nervous system and neural circuit wiring
- In studies with naltrexone and ketamine, there was a dramatic blocking of antidepressant effect when naltrexone was present even when the dissociation level was the same – the opioid receptor may have a role in mood regulation
- Ketamine also has therapeutic benefits for bipolar depression, PTSD, OCD, and anxiety
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Antidepressant effects of ketamine wear off after 1-2 weeks but addictive properties and dissociative state of ketamine make it risky for ongoing use
- Potential dosing: twice per week for two weeks, take some time off, cycle again – or – once per week for five weeks then take time off and cycle again
Mechanisms Of Ketamine In The Brain
- There are excitatory (stimulate activity of other neurons) and inhibitory (inhibit activity of other neurons) neurons in the brain
- Ketamine gets into the bloodstream and readily passes the blood-brain barrier
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Ketamine blocks the NMDA receptor, responsible for many mechanisms of neuroplasticity
- In the presence of glutamate, the NMDA receptor responds to unusually high levels of electrical activity
- The nervous system is capable of changing but it’s an energetically demanding process – NMDA facilitates learning so activity can be performed in the future with less energy
- Paradox: you need neuroplasticity to get relief from depression and ketamine blocks the NMDA receptor involved in neuroplasticity
- Mechanism: ketamine binds to NMDA receptors present on inhibitory neurons which reduces inhibition onto excitatory neurons which can then increase activity and bursting pattern
- At clinical doses, ketamine does not overly excite and lead to seizures (which would be a concern with too much excitation)
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Brain-Derived Neurotrophic Factor (BDNF) is a growth factor in the brain with its own set of receptors
- Burst firing of excitatory neurons following ketamine invokes the release of BDNF which makes neurons very plastic, very quickly
- BDNF is one of the critical functions that allow ketamine to reduce depression
- Ketamine can also bind receptors in the opioid pathway which induces pain relief, changes in psychic state, and euphoric states
- Dissociative effects are the uncoupling of certain brain circuits which creates different rhythms in the brain while under the influence of ketamine at sub-anesthetic doses
Ketamine Dosing & Routes Of Administration
- Ketamine is dose-dependent based on the route of administration
- Clinical dosing: injection of 1/2mg per kg of bodyweight
- Recreational (legal) ketamine is taken orally or sublingual at higher doses (less is absorbed through these routes)
- K-hole: taking enough ketamine to put the brain and body beyond the boundary of sub-anesthetic dose and into an anesthetic state
- The effectiveness of modes of delivery is more related to dose than the actual route
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Forms of ketamine (R vs S): controversial research with no clear answer but it does seem that the S form is more potent with less dissociation than the R form (Podcast Notes Note – R is less potent, and there is some data to imply it’s actually less dissociative at clinical levels, but clinical data on efficacy is still to be shown)
- Combined RS form is best at providing relief from depressive symptoms; S form is second best and most commonly prescribed; R form is least potent and effective at treating depression
- Microdosing of ketamine doesn’t seem effective for the treatment of depression
Articles
- Antidepressant effects of ketamine in depressed patients (Biological Psychiatry)
- Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism (Molecular Psychiatry)
- atai Life Sciences Announces Results from Phase 2a Trial of PCN-101 (R-ketamine) for Treatment-Resistant Depression
- Comparative effects of (S)-ketamine and racemic (R/S)-ketamine on psychopathology, state of consciousness and neurocognitive performance in healthy volunteers (European Neuropsychopharmacology)
- Ketamine Metabolite (2R,6R)-Hydroxynorketamine Interacts with μ and κ Opioid Receptors (ACS Chemical Neuroscience)
Relevant Previous Episode
- The Science & Treatment of Bipolar Disorder