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)
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
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
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
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)
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
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
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
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)
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 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
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
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)
The Science & Treatment of Bipolar Disorder