Ketamine Benefits & Risks for Depression, PTSD, Neuroplasticity

This week we've distilled the key takeaways from Huberman's episode on Ketamine.
He discusses its use as a treatment for Depression and PTSD, its effect on neuroplasticity, mechanisms of action, treatment regimens, dosages, risks, and microdosing.

All takeaways and protocols are databased & searchable on Human3 Wiki.

Ketamine & Depression

Ketamine is a dissociative anesthetic used to induce certain forms of anesthesia for surgery

• At lesser dosages, it can take you into transition points between awake and deeply anesthetized, which is called the dissociative state 

• This state has been employed for the treatment of depression, suicidality, and PTSD

• Ketamine has proven to be a miraculous drug for some people for the treatment of depression, suicidality, and PTSD

• Also has a very high potential for abuse - some people do indeed get addicted to Ketamine

Ketamine provides immediate relief from depressive symptoms, and ongoing relief when treatments are closely stacked

• Likely acts through at least three different mechanisms to provide relief from depression

• These mechanisms produce changes in neurochemistry and neural circuit wiring, providing relief from depression

Ketamine's Role in Neuroplasticity

Neuroplasticity: the brain’s ability to change and adapt in response to experiences

• Involves two major types of neurons: excitatory and inhibitory

• Excitatory neurons activate other neurons, releasing neurotransmitter glutamate

• Inhibitory neurons reduce the probability of the next neuron being electrically active, releasing neurotransmitter GABA

Ketamine’s role

• Binds to NMDA receptors, which are critical for neuroplasticity

• Blocks NMDA receptors on inhibitory neurons, reducing their activity

• This allows excitatory neurons in specific brain circuits to increase their activity, a process called “bursting”

• Bursting patterns of electrical activity induce long-term changes in neural circuits associated with mood and reward

Ketamine increases neuroplasticity in brain circuits involved in mood, reward, and self-reflection

• This is paradoxical as ketamine blocks the NMDA receptor, which would suggest it prevents neuroplasticity

• However, by blocking NMDA receptors on inhibitory neurons, it allows excitatory neurons to increase their activity, leading to neuroplasticity

• The increased neuroplasticity leads to changes in neural circuits that make them more likely to generate positive mood and less likely to generate negative mood

  • This is how ketamine provides relief from symptoms of major depression

Brain-Derived Neutrophic Factor (BDNF)

Brain Derived Neurotrophic Factor (BDNF) is a key molecule in the brain

• BDNF is often referred to as “fertilizer for neurons”

• Burst firing of neurons can invoke the release of BDNF, making circuits very plastic very quickly

• Ketamine itself may be able to cause release of BDNF directly

• BDNF may be required for ketamine to invoke neuroplasticity and improvements in mood

  • Several lines of evidence suggest that ketamine-induced release of BDNF is one of the core mechanisms by which ketamine can relieve depression

Treatment Regiments, Dosages, Types

Regimens

• Some studies have explored giving ketamine twice per week for a duration of three weeks

  • Patients experienced relief from depression throughout the three weeks

  • Effects persisted for months after the end of the three-week regimen 

• Other studies have explored different dosage regimens, such as once per week or three times per week 

  • These studies also found that ketamine provided relief from depression symptoms

  • However, the optimal dosage regimen for ketamine in the treatment of depression is still unclear 

Dosage

• Clinical studies for depression typically administer ketamine intravenously or intramuscularly at a dosage of 0.5mg/kg of body weight

  • This dosage induces dissociative, mild euphoria, and conscious states 

• Anesthetic doses of ketamine are in the range of one to two milligrams per kilogram of body weight

  • This dosage leads to full saturation of all potential receptors that ketamine can bind to

• Recreational use or at-home use often involves oral or sublingual administration

• Oral administration results in only 25% of active ketamine entering the bloodstream

• Sublingual administration results in roughly 35% of active ketamine entering the bloodstream

  • Increase dosage for oral/sublingual: a 100kg person would need 50mg of ketamine by injection, but would need 150mg orally or 200mg sublingually to achieve the same effects

• Intranasal, oral, sublingual, and rectal administration all have different effects on dosage and metabolism

  • Rectal administration bypasses the liver and can be used to avoid potential liver damage from frequent ketamine use

R, S, and RS forms of ketamine have different effects

• S form of ketamine is more potent and binds more robustly to the NMDA receptor, producing less dissociation at a given dosage than the RS form or pure R form

• RS form of ketamine seems to be the most potent for relieving depressive symptoms, followed by the S form, and then the R form

• However, individual responses can vary

Importance of Behavioral Changes w/ Ketamine Treatment

Changes in neural circuits from taking Ketamine need to be reinforced by anti-depressive behaviors

• Engaging in positive behaviors after taking ketamine can lead to relief from depression

  • I.e. viewing morning sunlight, getting regular and sufficient amounts of quality sleep, proper nutrition, and proper social engagement

• Engaging in pro-depressive behaviors after taking ketamine may not lead to relief from depression

  • I.e. viewing blue light in the middle of the night between the hours of 11:00 PM And 04:00 AM invokes a pro-depressive circuit

• “How” and “what” questions cause deep, slow thinking

  • The reaction to these questions can give a clearer picture of who you’re dealing with

  • The answer is secondary to the reaction

Key brain structure: the habenula, a “disappointment circuit” that leads to pro-depressive symptoms

• Ketamine therapy can reduce connections between the habenula and the brain’s reward circuitry

• This makes the reward pathway more available for engagement through daily life activities

The Opioid Pathway

Ketamine can also bind receptors in the opioid pathway

• This may explain why people use ketamine for recreational purposes

• The opioid pathway refers to the system in the body that regulates pain, reward, and addictive behaviors

• Exogenous opioids (opioids taken from outside the body) can lead to addiction and are the cause of the opioid crisis

• Opioid receptors are bound for effects like pain relief, changes in psychic states, dissociation, and euphoric states

Ketamine is metabolized to Hydroxy Nor Ketamine (HNK)

• HNK has an incredible specificity for the mu opioid receptor and maybe the kappa opioid receptor

• When ketamine is taken, it is converted into HNK, which selectively activates the opioid system

Is the Opioid System the cause of Ketamine's Benefits?

• Researchers have questioned whether the relief from depression after taking ketamine is due to neuroplastic changes in NMDA Glutamate BDNF related circuits or due to something happening in the Opioid system

• A study done by Stanford School of Medicine found that when people were given ketamine, they got relief from depression

  • However, if individuals were given naltrexone to block the opioid receptor pathway and they were given ketamine, the antidepressant effects of ketamine were no longer observed

  • This suggests that it is the opioid receptor system that’s responsible for the antidepressant effects of ketamine

The immediate effects of ketamine may not actually be related to the long term clinical benefit of the drug

• The effects of a drug like Ketamine sets off a series of processes in the brain, some of which rely on things like NMDA receptor BDNF, etc. type neuroplasticity, others which rely on the opioid receptor pathway

• These processes have different time courses, some provide immediate relief in the days and hours after treatment, some in the weeks after treatment, and some more durable, long lasting changes that can occur over months or maybe even years

The Frontal Cortex + Theta Brainwaves

Ketamine can improve connectivity between the brain’s reward pathways and the frontal cortex

• The frontal cortex is critical for establishing context-dependent strategy

• Ketamine makes people more sensitive to whether they are getting the results they want from their efforts

Ketamine unveils the theta pattern of brain activity

• Theta is associated with a dreamlike state

• Suppresses Alpha brain activity

• These changes in brain activity contribute to the sense of dissociation experienced when taking ketamine.

Ketamine Risks

A “K-hole” refers to a pseudo-anesthetized state achieved by taking a high dose of ketamine

• This can be dangerous and potentially deadly, especially when combined with other drugs like barbiturates or alcohol  

Ketamine can induce seizures, especially in those who are seizure-prone due to epilepsy, prior head injury, or unknown factors

• This can be dangerous and potentially deadly, especially when combined with other drugs like barbiturates or alcohol

Microdosing Ketamine

There is growing interest in microdosing ketamine, similar to trends with psilocybin and LSD

• Effects and benefits of microdosing ketamine are still being explored and understood

• No published clinical evidence that microdosing ketamine is effective for treating depression

• Editor's Note: Joyous is a company doing delivery of Ketamine microdosing kits.