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Huberman Lab
Ketamine: Benefits and Risks for Depression, PTSD & Neuroplasticity
Aug 7, 2023
01:39:56
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Quick takeaways
- Ketamine has clinical benefits for treating depression, suicidality, and PTSD, but recreational use poses risks and potential for abuse.
- Ketamine increases neuroplasticity in brain circuits involved in mood and reward, despite being an NMDA receptor blocker.
- Repeated treatments of ketamine provide rapid relief from depression, with effects lasting for several days.
- Ketamine's impacts on neural circuits involved in mood regulation include weakening connections between the habenula and reward pathways, and strengthening connectivity between the reward pathway and frontal cortex.
Deep dives
Ketamine's Clinical Benefits and Risks
Ketamine is a compound used both clinically and recreationally, with clinical benefits including treatment for depression, suicidality, and PTSD. However, there are also risks and potential for abuse associated with its recreational use. The podcast explores the research on the clinical benefits of ketamine, the mechanisms behind its dissociative states, dosage and delivery routes, and emphasizes both the benefits and risks of ketamine use.
Ketamine and Neuroplasticity
Ketamine's unique effects on neuroplasticity are discussed in the podcast. Despite being an NMDA receptor blocker, which is critical for neuroplasticity, ketamine actually increases neuroplasticity in brain circuits involved in mood and reward. It does this by binding to NMDA receptors on inhibitory neurons, reducing inhibition and allowing excitatory neurons to increase their activity in bursting patterns. These bursts of activity induce short-term and long-term changes in neural circuits associated with mood and relieve depressive symptoms.
Ketamine's Short-Term and Long-Term Effects on Depression
Ketamine has been shown in clinical studies to provide rapid relief from depression, often same-day, with effects lasting for several days. However, the anti-depressant effects are usually short-lived, and repeated treatments are necessary. Studies have explored different dosing regimens, such as twice a week for three weeks, which can result in durable relief from depression for months. Ketamine's mechanisms of action, both short-term and long-term, contribute to its effectiveness in treating depression.
The Paradoxical Effects of Ketamine
The podcast highlights the paradoxical effects of ketamine, which acts as an NMDA receptor blocker yet increases neuroplasticity. Ketamine's ability to induce changes in brain circuits involved in mood and reward despite blocking the receptor critical for neuroplasticity is a fascinating conundrum. Understanding how ketamine can induce relief from depression while blocking the NMDA receptor provides crucial insights into the complex mechanisms underlying depression and the potential for alternative treatments.
Ketamine's Impact on Neural Circuits and Neuroplasticity
Ketamine blocks NMDA receptors and reduces inhibitory neuron activity, leading to increased excitatory communication between neurons in mood-related circuits and recruitment of neuroplasticity. This strengthens neural connections associated with positive mood and weakens those associated with negative mood. The process of neuroplasticity takes time, involving gene expression changes over hours or even weeks. Ketamine also suppresses the NMDA receptor, inducing neuroplastic changes through the blockade and release of brain-derived neurotrophic factor (BDNF), which is linked to strengthening neural circuits and providing relief for depression. The effects of ketamine on neural circuits are durable and different from other treatments.
The Role of Opioid Receptors in Ketamine's Effects
Ketamine can bind to opioid receptors in addition to blocking NMDA receptors. The activation of the opioid system is critical for the antidepressant effects of ketamine. Studies have shown that blocking opioid receptors with naltrexone eliminates the antidepressant effects of ketamine. Hydroxynorketamine (HNK), a metabolite of ketamine, specifically activates mu opioid receptors. Ketamine may provide relief from depression by mimicking the effects of growth factors and acting as a brain growth factor itself, making changes in mood-associated neural circuits more durable.
Neural Circuits Affected by Ketamine
Ketamine impacts neural circuits involved in mood regulation. It weakens connections between the habenula, responsible for generating feelings of disappointment, and reward pathways releasing dopamine. This allows the reward pathway to be more available for engagement through adaptive behaviors. Ketamine also strengthens the connectivity between the reward pathway and the frontal cortex, involved in context-dependent strategy building and adjusting behaviors to achieve desired results. Changes in brain wave patterns, such as a shift from alpha rhythms to theta rhythms, occur during ketamine use and contribute to the dissociative experiences associated with the drug.
Dosage, Forms, and Considerations
Different forms of ketamine, such as oral, sublingual, injection, and rectal administration, vary in dosage efficacy and metabolism. The combined S R form of ketamine is generally more effective for treating depression, followed by the S form, while the R form is the least effective. Microdosing ketamine has no published clinical evidence for depression treatment. Ketamine should be used with caution due to its potential for inducing anesthesia, seizures, and dissociative states. The opioid receptor system plays a significant role in ketamine's effects, but caution must be exercised to avoid overdose or combining with other substances.
In this episode, I explain how ketamine causes rewiring of brain circuits and dissociative states to relieve symptoms of depression and post-traumatic stress disorder (PTSD). I explain how ketamine impacts both the brain’s glutamate and its endogenous opioid pathways, which together regulate mood and well-being. I discuss how ketamine therapy is used clinically to treat major depression, bipolar depression, obsessive-compulsive disorder (OCD), suicidality and other psychiatric challenges. I also describe how ketamine causes the subjective effects of dissociation and euphoria and, at higher doses, is an anesthetic. I compare the different routes of ketamine administration, dosages and forms of ketamine, and if micro-dosing ketamine is effective. I also highlight the potential risks of recreational ketamine use (and the colloquial term ‘K-holes’). This episode should interest anyone interested in ketamine, treatments for depression, neuroplasticity mechanisms, psychiatry and mental health.
For show notes, including referenced articles and additional resources, please visit hubermanlab.com.
Use Ask Huberman Lab, our new AI-powered platform, for a summary, clips, and insights from this episode.
Thank you to our sponsors
AG1: https://athleticgreens.com/huberman
LMNT: https://drinklmnt.com/hubermanlab
Waking Up: https://wakingup.com/huberman
Momentous: https://livemomentous.com/huberman
Timestamps
(00:00:00) Ketamine
(00:02:46) Sponsors: LMNT & Waking Up
(00:05:13) Ketamine & PCP; Clinical & Recreational Use
(00:09:00) Depression & Current Treatments
(00:15:17) Preclinical Models of Depression & Ketamine; “Learned Helplessness”
(00:22:11) Ketamine & Clinical Uses; Depression & Suicidality
(00:28:32) Ketamine & Other Psychiatric Challenges; Relief & Durability
(00:33:40) Sponsor: AG1 (Athletic Greens)
(00:34:29) NMDA Receptor & Neuroplasticity
(00:41:36) Excitatory & Inhibitory Communication, Seizure, NMDA Receptors & Ketamine
(00:48:26) How Ketamine Functions in Brain; Acute & Long-Term Effects
(00:55:36) Brain-Derived Neurotrophic Factor (BDNF) & Ketamine Therapy
(01:03:40) Ketamine & Opioid Pathway
(01:10:00) Divergent Mechanisms of Immediate & Long-Term Effects
(01:15:45) Habenula, Pro-Depressive Behaviors & Ketamine Therapy
(01:20:36) Ketamine & Context-Dependent Strategy; Reward Pathway
(01:22:45) Dissociative States
(01:26:04) Doses & Routes of Administration; “K-holes”; Risk & Caution
(01:32:25) Ketamine Forms; R-, S- vs R/S- Ketamine; Micro-Dosing
(01:38:24) Ketamine: Effects & Therapy
(01:40:40) Zero-Cost Support, YouTube Feedback, Spotify & Apple Reviews, Sponsors, Momentous, Social Media, Neural Network Newsletter
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