Podcast Host: Dr. Andrew Huberman (Stanford Associate Professor - brain development, brain plasticity, and neural regeneration and repair fields).

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Key takeaways

Ketamine's clinical potential and misuse hazards have rekindled interest in it (Segment 02)
Ketamine and other monoamine-based drugs may help with depression (Segment 03).
Ketamine's quick success in treating refractory depression gives it clinical potential (Segment 05).
Ketamine's versatility and durability make it a promising psychiatric treatment (Segment 06).
Ketamine's NMDA receptor effects reveal neuroplasticity and antidepressant pathways (Segment 07).
Ketamine's effects on brain circuitry and behavior suggest a long-term depression alleviation (Segment 13).

Summary

This episode explains the mechanisms by which ketamine stimulates neuroplasticity in brain circuits and promotes dissociative states as a therapeutic approach for alleviating symptoms related to depression and post-traumatic stress disorder (PTSD). Furthermore, he also clarifies the impact of ketamine on the glutamate and endogenous opioid pathways inside the brain, which collectively regulate mood and overall well-being. The purpose of this discourse is to provide a comprehensive analysis of the therapeutic use of ketamine therapy in the management of major depression, bipolar depression, obsessive-compulsive disorder (OCD), suicidality, and other diverse mental disorders. In addition, Huberman provides a comprehensive explanation of the processes via which ketamine triggers the subjective experiences of dissociation and pleasure. The potential of ketamine as an anesthetic when administered in higher doses is interesting. He aims to undertake a comparative analysis of different approaches to administering ketamine, examine the range of dosages and formulations available for ketamine, and analyze the possible effectiveness of micro-dosing ketamine. The speaker also clarifies the potential risks linked to the recreational use of ketamine, including the widely employed informal term "K-holes." This specific occurrence is expected to attract the interest of those with a curiosity in several fields, such as ketamine, depression therapies, neuroplasticity mechanisms, psychiatry, and mental well-being.

1. 00:00:00 Ketamine

The chemical known as ketamine is of significant interest and warrants more investigation. Presently, in the field of medicine, it is utilized to treat a range of conditions including depression, suicidal ideation, and PTSD. However, it is crucial to recognize that this chemical is commonly misused for recreational use, hence giving rise to concerns over its addictive qualities. To develop a thorough comprehension of the processes by which ketamine generates dissociative experiences and mitigates depression, it is crucial to investigate its impact on both the brain and the body. Ketamine possesses the ability to produce modifications in the neural circuits located within the brain. The argument's significance becomes particularly evident when considering its applicability in the context of treating depression, suicidality, and PTSD. When an individual is exposed to the effects of ketamine, they experience its immediate consequences. However, it is important to note that this description only provides a limited understanding of the broader context. Furthermore, it is crucial to understand the enduring changes that take place in the brain [1].

The current discussion will focus significantly on the subject of neuroplasticity. Neuroplasticity pertains to the intrinsic capacity of the nervous system to undergo adaptations and alterations in its structure and functionality as a result of various experiences. The following discussion will explore the concept of neuroplasticity, not only within the framework of ketamine but as a broader concept that emerges with the acquisition of new knowledge or abilities. The present conversation will also address a molecule known as BDNF, which stands for Brain-Derived Neurotrophic Factor. The molecule under consideration possesses substantial significance in the realms of cognition, memory formation, and neural adaptability within the central nervous system. This educational opportunity will not only facilitate the acquisition of knowledge pertaining to the clinical applications and potential risks associated with ketamine, but it will also offer valuable insights into the phenomenon of neuroplasticity and the significance of BDNF in cognitive processes related to the acquisition of new information [2].

Figure 1. Ketamine effects on serotonin1B receptor [3].

References

1. Tian, F., et al., Characterizing brain dynamics during ketamine-induced dissociation and subsequent interactions with propofol using human intracranial neurophysiology. Nat Commun, 2023. 14(1): p. 1748.

2. Lu, B., G. Nagappan, and Y. Lu, BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol, 2014. 220: p. 223-50.

3. Tiger, M., et al., A randomized placebo-controlled PET study of ketamine´s effect on serotonin1B receptor binding in patients with SSRI-resistant depression. Translational Psychiatry, 2020. 10(1): p. 159.

2. 00:05:13 Ketamine & PCP; Clinical & Recreational Use

Ketamine, a chemical molecule that possesses some recognizable characteristics, displays notable similarities to another substance generally known as PCP, colloquially referred to as angel dust or Sherm in illicit contexts. Phencyclidine (PCP), a chemical compound, has been extensively discussed within academic circles, primarily in relation to its correlation with stimulant substances such as cocaine and methamphetamine. The existing discourse occasionally overlooks the comparative impact of ketamine on the brain, particularly in relation to PCP. Both ketamine and PCP have been observed to elicit comparable effects on the brain that bear resemblance to those induced by dissociative anesthetics. The efficacy of ketamine in the treatment of depression, reduction of suicidal ideation, and management of PTSD is widely acknowledged. However, it is crucial to acknowledge that the attainment of these outcomes is contingent upon specific clinical conditions, appropriate dosage, and regulated administration schedules. Ketamine has demonstrated notable efficacy in individuals afflicted with several diseases. Nevertheless, it is imperative to emphasize that ketamine demonstrates a significant propensity for misuse [4].

Ketamine has garnered significant attention in contemporary times because of its therapeutic effectiveness and its utilization for recreational purposes. Instances of incorrect application of ketamine may be observed in social settings, resulting in occurrences sometimes referred to as "k-holes," where the dosage of ketamine administered exceeds the recommended levels. There exist distinct dangers linked with this subject matter, which will be further examined in the subsequent investigation. Ketamine and PCP have notable resemblances, leading to a convergence in their applications within clinical and recreational contexts. Certain individuals obtain authorized prescriptions for ketamine in order to cure depression. Nevertheless, it is important to acknowledge the potential for misuse in non-clinical environments, as safety protocols may vary significantly from those implemented in research studies. The association between the increased availability of a substance with the potential for abuse and the following increase in its recreational usage often raises concerns about the potential for addiction [5].

Undoubtedly, ketamine has the potential to induce addiction in specific individuals. There is a subgroup of individuals who have a pronounced preoccupation with the consequences of ketamine, prompting them to persist in its consumption despite the detrimental consequences it imposes on various domains of their lives, such as professional pursuits, educational endeavors, social connections, and financial well-being. Nevertheless, the effectiveness of ketamine in clinical environments has been extensively proven. In the preceding decade, a noticeable shift in the perception of ketamine has been documented. Historically, a notable correlation existed between it and PCP, resulting in its predominantly unfavorable reputation as a substance susceptible to misuse. The utilization of ketamine for the treatment of PTSD has been well-documented in prior studies, notably among individuals who served in the Vietnam War. In recent years, there has been an increasing emphasis on the clinical utilization of this approach for addressing conditions such as depression, suicidal thoughts, and PTSD. The continuously changing characteristics of this dynamic setting have sparked a revived curiosity in comprehending and utilizing the capabilities of ketamine, both within the field of healthcare and beyond [6].

Figure 2. Ketamine Treatment and Global Brain Connectivity in Major Depression [7].

References

4. Lodge, D. and M.S. Mercier, Ketamine and phencyclidine: the good, the bad and the unexpected. Br J Pharmacol, 2015. 172(17): p. 4254-76.

5. Muetzelfeldt, L., et al., Journey through the K-hole: phenomenological aspects of ketamine use. Drug Alcohol Depend, 2008. 95(3): p. 219-29.

6. Liriano, F., C. Hatten, and T.L. Schwartz, Ketamine as a treatment for post-traumatic stress disorder: a review. Drugs Context, 2019. 8: p. 212305.

7. Abdallah, C.G., et al., Ketamine Treatment and Global Brain Connectivity in Major Depression. Neuropsychopharmacology, 2017. 42(6): p. 1210-1219.

3. 00:09:00 Depression & Current Treatments

The "monoamine hypothesis of depression" gained prominence as a significant notion throughout the mid-20th century, namely in the 1980s and 90s. Monoamines are a class of neurotransmitters that include serotonin, dopamine, and norepinephrine. These neurotransmitters are produced from amino acids. Neurological circuits are susceptible to external influences, and they can have effects on various physiological processes, including digestion. Based on the theoretical framework under consideration, it is proposed that depression may stem from an insufficiency in monoamine neurotransmitters, specifically serotonin or dopamine. However, it is important to note that current studies have not produced definitive findings that unequivocally support the hypothesis that a deficiency in monoamines is a direct etiological factor in the development of depression. Pharmaceutical compounds, such as Prozac, which acts as a serotonin reuptake inhibitor, and Wellbutrin, which modulates dopamine and norepinephrine levels, have exhibited effectiveness in mitigating depressive symptoms. Nevertheless, it is crucial to acknowledge that the efficacy of these medications is limited to around 40% of the population, and they are concomitant with specific undesirable consequences. A significant number of individuals encounter discomfort due to unpleasant effects, including changes in appetite, reduced libido, or disturbances in sleep habits. There is a subgroup of persons who fail to demonstrate any response to these medicinal medicines [8].

Ketamine, a substance that has undergone prior examination for its anesthetic properties and susceptibility to misuse, is presently being contemplated as a feasible replacement. Ketamine is a frequently utilized dissociative anesthetic in the context of surgical interventions. At designated dosage thresholds, it elicits a state characterized by an intermediary condition between wakefulness and deep sedation, generally denoted as the dissociative state. This specific state has attracted considerable attention due to its endeavors in addressing depression, suicidality, and PTSD. However, within recreational settings, individuals consciously opt for different levels of disengagement, leading to a spectrum of both favorable and unfavorable consequences. The variability in an individual's response to ketamine is dependent on factors such as the precise dosage and route of administration, which may include oral intake, sublingual absorption, or injection. The impact of ketamine is diverse, as it affects both the neurologic and physiological reactions of the brain and body [9].

Figure 3. Ketamine normalizes brain activity in depression [10].

References

8. Delgado, P.L., Depression: the case for a monoamine deficiency. J Clin Psychiatry, 2000. 61 Suppl 6: p. 7-11.

9. Acevedo-Diaz, E.E., et al., Can 'floating' predict treatment response to ketamine? Data from three randomized trials of individuals with treatment-resistant depression. J Psychiatr Res, 2020. 130: p. 280-285.

10. Reed, J.L., et al., Ketamine normalizes brain activity during emotionally valenced attentional processing in depression. NeuroImage: Clinical, 2018. 20: p. 92-101.

4. 00:15:17 Preclinical Models of Depression & Ketamine; “Learned Helplessness”

In the early 1990s, researchers serendipitously found a significant discovery while studying animal models of depression. The investigators utilized a "learned helplessness" paradigm in which rodents, specifically rats or mice, were exposed to a water-based job and eventually discontinued their efforts to swim, resulting in submersion. The observed behavior demonstrated resemblances to traits commonly associated with human depression, such as a reduced ability to anticipate positive outcomes in the future. Significantly, the injection of ketamine, a dissociative anesthetic, at doses below the anesthetic threshold led to a prolonged duration of swimming in mice. The observed occurrence is perplexing due to the fact that ketamine has been shown to efficiently inhibit NMDA receptors, which are crucial for enabling neuroplasticity inside the brain. The findings of this study have challenged the previously established notion that suppressing plasticity would intensify the manifestations of depression. There are two discernible groups of scientists that have emerged: one group is characterized by their perplexity towards the seeming inconsistency, while the other group is fascinated by the cryptic aspect of the topic. The latter conducted preclinical research and formed collaborations with experts in the field of depression treatment. The examination conducted by the researchers resulted in a noteworthy discovery that ketamine, despite its impact on neuroplasticity, had strong antidepressant effects when provided to persons afflicted with depression [11].

References

11. Matveychuk, D., et al., Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers. Ther Adv Psychopharmacol, 2020. 10: p. 2045125320916657.

5. 00:22:11 Ketamine & Clinical Uses; Depression & Suicidality

In the early 2000s, a number of research studies emerged that focused on the clinical application of ketamine for the treatment of depression. During that particular era, medicines such as Prozac garnered significant attention and recognition owing to their varying degrees of efficacy and concomitant negative consequences. The first dissociative effects of ketamine raised skepticism over its potential. However, pioneering practitioners took the initiative to explore its effectiveness in treating depression that does not respond to traditional therapy. A prominent research study conducted an experiment involving the administration of a modest dose of ketamine to persons who had been diagnosed with depression. This intervention led to the quick emergence of a state characterized by dream-like and euphoric experiences. Significantly, this led to an immediate reduction in depression symptoms, which persisted for a duration of several days. The rapid onset of ketamine's effects has positioned it as a possible solution for patients in need of instant relief, as opposed to traditional antidepressants which often have delayed efficacy spanning many weeks. Although ketamine may not contain miraculous characteristics, multiple studies consistently highlight its effectiveness in reducing symptoms of depression, suicidality, helplessness, and worthlessness. This is particularly evident in cases where conventional therapies, such as SSRIs, have been unsuccessful. The domain of biology is distinguished by its sophisticated complexity, and the science of pharmacology is intricately interconnected with the investigation of behavior. Within this particular context, the remarkable and noteworthy characteristic of ketamine is its unique capacity to generate rapid therapeutic outcomes [12].

Figure 4. Ketamine: A Drug That Could Revolutionize Depression Treatment.

References

12. Berman, R.M., et al., Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 2000. 47(4): p. 351-354.

6. 00:28:32 Ketamine & Other Psychiatric Challenges; Relief & Durability

Ketamine has demonstrated effectiveness in various clinical trials for a wide range of depressive conditions, including major depression, bipolar depression (commonly known as bipolar disorder), PTSD, OCD, anxiety disorders, and substance use disorders. While not regarded as a cure-all, this therapeutic intervention demonstrates promise in effectively addressing substantial psychological challenges. However, the prompt start of its mitigating effects is temporally restricted, often last for a short span ranging from several days to one week. This poses challenges as the regular and frequent utilization of ketamine is impractical due to its dissociative characteristics and vulnerability to abuse [13].

Numerous studies have examined a range of dosing regimens. A notable approach involves the regular delivery of ketamine every two weeks for a duration of three weeks. It is important to highlight that this therapeutic regimen provides both rapid comfort throughout the course of treatment and long-lasting effects that might endure for several months after the regimen is discontinued. Prior studies have investigated various drug administration regimes, including weekly, thrice weekly, or intermittent treatment with subsequent periods of non-treatment. Collectively, the results derived from these trials suggest that ketamine is probable to manifest its antidepressant properties through two or even three distinct mechanisms. The primary mechanism rapidly induces relief, often associated with the dream-like state induced by ketamine. The second mechanism offers relief in the days and weeks following the treatment. Additionally, it is important to acknowledge the presence of a third mechanism that appears to be accountable for producing long-lasting alterations in brain circuits, therefore playing a substantial role in offering prolonged relief from symptoms associated with depression. The understanding of these neural pathways not only provides insights into the mechanisms of ketamine but also offers vital insights into the underlying brain circuitry involved in depression and the connection between relief and neuroplasticity [14].

Figure 5. Structural Plasticity Induced by Ketamine in Human Dopaminergic Neurons [15].

References

13. Mandal, S., V.K. Sinha, and N. Goyal, Efficacy of ketamine therapy in the treatment of depression. Indian J Psychiatry, 2019. 61(5): p. 480-485.

14. Andrade, C., Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency? J Clin Psychiatry, 2017. 78(7): p. e852-e857.

15. Collo, G., L. Cavalleri, and E. Merlo Pich, Structural Plasticity Induced by Ketamine in Human Dopaminergic Neurons as Mechanism Relevant for Treatment-Resistant Depression. 2019. 3: p. 2470547019842545.

7. 00:34:29 NMDA Receptor & Neuroplasticity

The mechanism of action of ketamine involves the inhibition of the NMDA receptor, a crucial component implicated in numerous neuroplasticity mechanisms that underpin the brain's capacity for adaptation. Neuroplasticity is contingent upon the intricate interaction between receptors and ligands, which are chemical compounds that exhibit an inclination to connect with receptors located on neuronal surfaces. The N-Methyl-D-aspartate (NMDA) receptors are stimulated by the neurotransmitter glutamate, known for its excitatory properties, during conditions marked by abnormally elevated electrical activity. Ketamine exhibits a notable affinity for the aforementioned receptors, hence augmenting its binding following administration into the bloodstream. The NMDA receptor functions as a computational component that exhibits characteristics similar to those of a logical "AND gate." The activation mechanism necessitates a simultaneous elevation in glutamate levels and heightened electrical activity. Under typical circumstances, the activity of glutamate and other receptors is stable, whereas NMDA receptors necessitate a substantial influx of glutamate within a restricted timeframe. The activation of this receptor exerts a substantial influence on neuroplasticity, as it augments the formation of novel synaptic connections and pathways among neurons in response to distinct patterns of neuronal activity [16].

This phenomenon demonstrates resemblances to the process of acquiring a novel skill or language. When an individual engages in a novel activity multiple times, different patterns of neuronal firing can be detected, leading to the activation of NMDA receptors as a result of elevated levels of glutamate. The aforementioned event elicits intracellular mechanisms that facilitate the process of adapting to the behavior, hence enhancing its ease of execution through repetitive repetition. The aforementioned process demonstrates resemblances to muscular hypertrophy, as it entails adaptation and enhanced efficiency in neural networks, enabling the brain to replicate the action with reduced metabolic requirements. The modulation of NMDA receptors by ketamine hinders the conventional mechanism of neuroplasticity, perhaps resulting in expedited antidepressant outcomes. Gaining a comprehensive understanding of the implications of NMDA receptors on brain circuitry yields valuable insights into the mechanisms underlying ketamine's effects and the broader idea of neuroplasticity [17].

Figure 6. NMDA receptor trafficking in synaptic plasticity [18].

References

16. Das, V., Chapter One - An Introduction to Pain Pathways and Pain “Targets”, in Progress in Molecular Biology and Translational Science, T.J. Price and G. Dussor, Editors. 2015, Academic Press. p. 1-30.

17. Rajani, V., A.S. Sengar, and M.W. Salter, Tripartite signaling by NMDA receptors. Molecular Brain, 2020. 13(1): p. 23.

18. Lau, C.G. and R.S. Zukin, NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nature Reviews Neuroscience, 2007. 8(6): p. 413-426.

8. 00:41:36 Excitatory & Inhibitory Communication, Seizure, NMDA Receptors & Ketamine

The NMDA receptor plays a pivotal role in multiple crucial forms of neuroplasticity. The device serves as a tool for detecting abnormal brain activity, enabling cellular adjustments to anticipate future patterns. The primary mode of action of ketamine is centered on its ability to block the NMDA receptor, which is known to have a significant role in aiding the shift from depression to non-depressive states through means of neuroplasticity. There exist two principal classifications of neurons that exert a pivotal influence on the modulation of brain functionality. Excitatory neurons play a crucial role in the facilitation of neural activity by stimulating other neurons, whilst inhibitory neurons function to modulate and govern their activity. The occurrence of seizures in illnesses such as epilepsy can be traced to an imbalance between two separate neuronal populations, leading to dysregulated excitatory activity. The NMDA receptor plays a crucial role in the regulation of brain activity that surpasses the norm, hence enabling the establishment of enduring changes in neural circuits [19].

Ketamine, acting as an antagonist of the NMDA receptor, seems to question the assumed necessity of neuroplasticity in the context of mitigating depression. Notably, it enhances neuroplasticity within neural circuits linked to emotion and reward. The chemical interacts with the NMDA receptors of inhibitory neurons, resulting in a decrease in their inhibitory influence on excitable neurons. Excitatory neurons possess the ability to exhibit bursting, a phenomenon characterized by a repetitive pattern of electrical activity that promotes the establishment of long-lasting modifications within neural circuits. The adoption of these alterations, which are initiated as a result of the impacts of ketamine-induced surges, is of utmost importance for the alleviation of depressive symptoms [20].

Figure 7. Uncovering the Underlying Mechanisms of Ketamine as a Novel Antidepressant [21].

References

19. Kalia, L.V., S.K. Kalia, and M.W. Salter, NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol, 2008. 7(8): p. 742-55.

20. Zhang, Y., et al., Structural basis of ketamine action on human NMDA receptors. Nature, 2021. 596(7871): p. 301-305.

21. Xu, S., et al., Uncovering the Underlying Mechanisms of Ketamine as a Novel Antidepressant. 2022. 12.

9. 00:48:26 How Ketamine Functions in Brain; Acute & Long-Term Effects

When ketamine is consumed orally, injected, or absorbed sublingually by an individual, it undergoes systemic circulation and subsequently binds to NMDA receptors located inside the central nervous system. In general, these receptors are accountable for the detection of unconventional neural activity, leading to subsequent cellular alterations that facilitate neuronal adaptation and response to comparable activity in subsequent occurrences, so encouraging neuroplasticity. Ketamine, a substance that blocks the NMDA receptors, has been reported to induce neuroplasticity in brain circuits associated with mood, resulting in improved mood [22].

The paradoxical behavior under consideration is heavily influenced by the interaction between ketamine and inhibitory neurons. The mechanism of action of ketamine involves specific binding to NMDA receptors situated on inhibitory neurons, resulting in a reduction of their inhibitory impact on adjacent neurons. This technique enables the augmentation of activity in excitatory neurons, hence promoting the occurrence of bursts of electrical signals that drive the process of neuroplasticity. Ketamine does not provoke seizures or excessive excitation; instead, it produces alterations in circuits linked to the regulation of mood, leading to an increase in positive mood and a decrease in negative mood tendencies. To fully grasp the functioning of the brain, it is important to comprehend the complex interplay between inhibitory and excitatory transmission across neurons. The impact of ketamine on circuits associated with mood is emphasized by its ability to enhance neuroplasticity, even while it blocks NMDA receptors. This specific biological phenomenon involves modifications in the expression of genes and the consequent synthesis of proteins, taking place over a period of many days to weeks. The persistent improvements in mood observed after ketamine therapy aligns with the phenomenon of brain circuit remodeling, shedding light on the prolonged advantages that surpass the treatment period [23].

Figure 8. How Ketamine Functions in Brain [24].

References

22. Rogers, J., Ketamine–NMDA receptor binding structure. Nature Reviews Neuroscience, 2021. 22(10): p. 591-591.

23. Sleigh, J., et al., Ketamine – More mechanisms of action than just NMDA blockade. Trends in Anaesthesia and Critical Care, 2014. 4(2): p. 76-81.

24. Abram, S.V., et al., Validation of ketamine as a pharmacological model of thalamic dysconnectivity across the illness course of schizophrenia. Molecular Psychiatry, 2022. 27(5): p. 2448-2456.

10. 00:55:36 Brain-Derived Neurotrophic Factor (BDNF) & Ketamine Therapy

The examination of the significance of neuroplasticity in relation to the utilization of ketamine as a therapeutic intervention for depression holds great significance. The administration of ketamine induces the occurrence of burst firing in neurons, hence promoting the mechanism of neural plasticity. The procedure involves the incorporation of more glutamate receptors, specifically AMPA receptors. The involvement of BDNF and its associated receptor, TrkB, is a critical component in this specific process. BDNF is a molecular entity that induces various alterations when interacting with TrkB. BDNF plays a role in receptor integration, produces changes in neuronal morphology, and demonstrates qualities similar to neurotransmitters. The significance of BDNF in the context of ketamine therapy is substantial. The infusion of ketamine elicits burst firing of neurons, resulting in the subsequent release of BDNF, hence facilitating the prompt augmentation of neural circuit plasticity. Empirical evidence suggests that ketamine may possess the capacity to directly elicit the release of BDNF, potentially bypassing distinct physiological mechanisms. The role of BDNF in the efficacy of ketamine for depression treatment is supported by evidence gathered from studies conducted on animals as well as clinical trials involving individuals with depression who had genetic mutations in BDNF. The theoretical underpinning of ketamine's ability to mimic the effects of BDNF via interacting with the TrkB receptor is highly persuasive [25].

The concept of ketamine's potential as a growth factor is progressively attracting the attention of scholars and medical professionals. The argument suggests that ketamine demonstrates unique mechanisms in the management of depression, distinguishing it from other therapies like psilocybin, which predominantly affects serotonin-related changes. Ketamine offers rapid and sustained relief, attributed to its inhibition of NMDA receptors, activation of neural circuitry disruption, the release of BDNF, and its capacity to mimic the actions of BDNF. This perspective emphasizes the mechanism via which ketamine acts as a neurotrophic drug, facilitating neuronal plasticity and sustaining long-term enhancements in mood [25].

Figure 9. The Role of BDNF on Neural Plasticity in Depression [26].

References

25. Woelfer, M., et al., Ketamine-induced changes in plasma brain-derived neurotrophic factor (BDNF) levels are associated with the resting-state functional connectivity of the prefrontal cortex. World J Biol Psychiatry, 2020. 21(9): p. 696-710.

26. Yang, T., et al., The Role of BDNF on Neural Plasticity in Depression. 2020. 14.

11. 01:03:40 Ketamine & Opioid Pathway

The effects of ketamine on neuroplasticity in the context of alleviating depression encompass two concurrent pathways, as elucidated by Dr. Andrew Huberman. The phenomenon elicits burst firing inside neuronal cells, hence initiating neuroplasticity, while concurrently exhibiting affinity for opioid receptors. The opioid pathway, which is involved in pain modulation and mood regulation, holds significance in both clinical and recreational domains. Ketamine exerts an impact on both excitatory and inhibitory neurons, while furthermore exhibiting affinity for the opioid receptors located in the brain. The opioid epidemic pertains to the misuse of exogenous opioids that have an affinity for these receptors. In contrast, ketamine exhibits binding affinity for both opioid and NMDA receptors. Additionally, it undergoes a transformation into hydroxy nor ketamine (HNK), which exhibits specific activation of the MU opioid receptor. In order to ascertain the extent to which ketamine's impact on depression is influenced by its interaction with the opioid system, a series of investigations were undertaken by researchers. Ketamine was delivered to persons diagnosed with depression, with concurrent administration of Naltrexone to selectively block the opioid pathway. The findings of the study demonstrated that the administration of Naltrexone effectively counteracted the antidepressant properties of ketamine. This finding implies that the opioid receptor system, maybe through the action of HNK, exerts a substantial influence on ketamine's efficacy in relieving symptoms of depression [27]

Figure 10. Naltrexone's Interference with Ketamine's Antidepressant Effect [28].

References

27. Williams, N.R., et al., Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism. Molecular Psychiatry, 2019. 24(12): p. 1779-1786.

28. Michael Wang, B.Sc. and Adam Kaplin, M.D., Ph.D., Explaining Naltrexone’s Interference With Ketamine’s Antidepressant Effect. 2019. 176(5): p. 410-411.

12. 01:10:00 Divergent Mechanisms of Immediate & Long-Term Effects

The current discussion focuses on a significant study that explores the effects of ketamine on depression and its interaction with the opioid system. The study findings indicate that the administration of both ketamine and Naltrexone, an opioid receptor antagonist, contributed to the prompt onset of ketamine-induced pleasure. Nevertheless, the long-term improvement of depression symptoms, typically accompanied by an uplift in mood, was not observed. The findings of this study pose a substantial obstacle to current understandings of the mechanisms via which ketamine produces its antidepressant benefits, thereby underscoring the significance of considering both immediate and long-lasting outcomes. The present study suggests that the opioid system, in concert with other mechanisms such as neuroplasticity, may exert a substantial influence. The mitigation of depression entails a complex interplay of the impacts of pharmacological interventions, alterations in behavioral patterns, and improvements in one's way of life. The improvement of mental health illnesses through pharmacological interventions, namely the utilization of substances like ketamine, psilocybin, or MDMA, involves intricate neurobiological processes that occur over different time frames. The convergence of immediate sensory experiences and brain mechanisms, namely involving the opioid pathway, plays a crucial role in the mitigation of discomfort. It is imperative to acknowledge the holistic approach to addressing depression since beneficial behaviors such as exposure to sunlight, sufficient sleep, regular physical activity, and fostering social ties are closely interconnected with the medication advantages. The amelioration of depression entails a complex interplay of the pharmacological impacts of medication, neural mechanisms within the brain, and the implementation of positive behavioral practices. this discussion highlights the idea that the effects of ketamine on depression are influenced by multiple factors, emphasizing the need for a comprehensive understanding [29].

References

29. Williams, N.R., et al., Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. Am J Psychiatry, 2018. 175(12): p. 1205-1215.

13. 00:15:45 Habenula, Pro-Depressive Behaviors & Ketamine Therapy

This discourse aims to demonstrate a correlation between the mitigation of depression at an elevated degree and the fundamental biological mechanisms that facilitate this phenomenon. The subjects that have been examined encompass alterations in cognition and conduct, with intricate molecular processes. The correlation between these perspectives can be discerned in the neural circuits within the brain that undergo alterations as a result of ketamine. Key neural networks, such as the habenula, have a central function in various physiological processes. The habenula, commonly known as the "disappointment circuit," forms a neural connection with the reward system, namely the mood-enhancing release of dopamine. Ketamine demonstrates inhibitory actions on the habenula, hence augmenting activation within this specific pathway and potentially playing a role in the mitigation of depressive symptoms. Additional reinforcement through behavioral processes is necessary to support further the brain modifications induced by the treatment of ketamine. The effects of ketamine are consistent with actions that have been identified as possessing anti-depressive qualities, including the active pursuit of stimulation, the cultivation of social connections, and the prioritization of personal well-being. This underscores the significance of aligning behavior with brain modifications in order to attain long-lasting mental health benefits. This dialogue highlights the fundamental relationship between the mitigation of depression, the alterations of brain circuits through the administration of ketamine, and the synchronization of conduct to attain long-lasting mental well-being [30].

Figure 11. Ketamine Treatment for Mood Disorders [31].

References

30. Yang, Y., et al., Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature, 2018. 554(7692): p. 317-322.

31. Gagne, C., A. Piot, and W.G. Brake, Depression, Estrogens, and Neuroinflammation: A Preclinical Review of Ketamine Treatment for Mood Disorders in Women. 2022. 12.

14. 01:20:36 Ketamine & Context-Dependent Strategy; Reward Pathway

Understanding the effects of medications on clinical challenges frequently necessitates the adoption of a multifaceted perspective. The mental processes, specifically those pertaining to depression, demonstrate a multifaceted nature. Within the confines of this theoretical framework, there exists a concurrent engagement of both pro-depressive and anti-depressive behaviors and brain circuits. Empirical evidence indicates that the administration of ketamine possesses the capacity to mitigate the influence of the habenula on the reward pathway. This alteration diminishes the link between disappointment and reward, hence enhancing the vulnerability of the reward pathway to be impacted by anti-depressive thoughts and actions. Furthermore, it has been noted that ketamine possesses the capacity to enhance neuroplasticity in the reward system, particularly through its interaction with the frontal brain. The role of the frontal brain in the development of context-dependent strategies has great significance. It enables the ability to adjust and respond well to a diverse range of situations, so improving interpersonal interactions, the achievement of goals, and general well-being. The empirical evidence indicates that the utilization of ketamine has the capacity to enhance the neural connectivity between distinct brain regions implicated in the formation of context-dependent strategic cognition and the stimulation of reward pathways. This enhancement facilitates an increased level of consciousness among individuals regarding the repercussions of their actions and their capacity to modify their behaviors in order to get desired results. Contrary to initial hypotheses, it is evident that the amelioration of depression with the use of ketamine is not solely attributed to the inhibition of NMDA receptors. The lack of antidepressant efficacy in memantine, an NMDA receptor antagonist utilized in the management of Alzheimer's disease, is evident [32].

Figure 12. Suicide prevention and ketamine [33].

References

32. Blackman, R.K., A.W. Macdonald, 3rd, and M.V. Chafee, Effects of ketamine on context-processing performance in monkeys: a new animal model of cognitive deficits in schizophrenia. Neuropsychopharmacology, 2013. 38(11): p. 2090-100.

33. Charlton, C.E., et al., Suicide prevention and ketamine: insights from computational modeling. 2023. 14.

15. 01:22:45 Dissociative States

Ketamine, classified as a dissociative anesthetic, elicits a dissociative state marked by individuals experiencing a sense of detachment from their physical body and frequently adopting a third-person perspective. This phenomenon exhibits resemblances to the dissociation encountered by those diagnosed with PTSD or trauma. This phenomenon prompts investigations into the possibility of using trauma-induced states as a means to treat depression, maybe through leveraging neuroplasticity and changes in the MU opioid receptor system. The investigation into the underlying processes responsible for the dissociative effects of ketamine holds significant significance due to its prominent manifestation. In order to comprehend the phenomena of dissociation induced by ketamine, it is imperative to conduct a comprehensive analysis of the alterations that transpire in cerebral circuits, namely those located within the neocortex. The neocortex is of paramount importance in the process of action planning and exhibits interconnections with subcortical areas. The administration of ketamine induces disruption in these neural networks, resulting in subsequent alterations in the dominant patterns of brain oscillations. The alpha rhythms commonly observed during states of relaxed awareness undergo a transition into the theta pattern, which is associated with dream-like experiences that occur during the transitional stage between awake and sleep. The alterations in neural activity provide valuable insights into the distinct dissociative phenomena that have been documented following the application of ketamine. To have a comprehensive understanding of the dissociative effects of ketamine, it is crucial to go into the examination of brain network recalibration and the concept of rhythm dominance. The analysis of the perturbation of cerebral networks and the manifestation of theta oscillations provides vital insights into the specific dissociation caused by ketamine [34].

References

34. Liu, G.L., et al., Ketamine a dissociative anesthetic: Neurobiology and biomolecular exploration in depression. Chem Biol Interact, 2020. 319: p. 109006.

16. 01:26:04 Doses & Routes of Administration; “K-holes”; Risk & Caution

Ketamine, a pharmaceutical substance categorized as a dissociative anesthetic, elicits dissociation and alters cerebral function when given in doses that do not reach the level required for inducing anesthesia. The effects of the chemical vary based on the method of administration. The administration of clinical injections at a dosage of 0.5 mg/kg produces distinct results when compared to recreational oral or sublingual consumption, as the latter methods exhibit lower bioavailability. The existence of variability in dosage presents possible risks, including the manifestation of the "k-hole" phenomenon, characterized by the individual experiencing anesthesia-like experiences. A thorough understanding of dosages is crucial in clinical settings, as healthcare professionals closely monitor the possibility of dissociation and the accompanying hazards of anesthesia. The implementation of telehealth for lawful in-home applications raises noteworthy safety considerations. Participating in leisure activities carries inherent hazards, especially when accompanied by the usage of alcohol or drugs. The diverse range of dosages and resulting effects linked to ketamine underscores the importance of exercising prudence. The prospective use of this medication may induce a condition of unconsciousness and seizures by decreasing the function of NMDA receptors, hence presenting a notable risk, particularly for individuals who are prone to seizures. It is of utmost importance to refrain from participating in activities such as operating a vehicle and to thoroughly assess the risk of experiencing seizures, considering their significant consequences [14].

Figure 13. Administration of ketamine via injection [35].

References

35. Ketamine Administration Routes at a Glance: A Quick Comparison for Clinicians on the Go. Available from: https://www.ketamineacademy.com/post/ketamine-administration-routes-at-a-glance-a-quick-comparison-for-clinicians-on-the-go.

17. 01:32:25 Ketamine Forms; R-, S- vs R/S- Ketamine; Micro-Dosing

The delivery methods of ketamine are tightly linked to the dosage that undergoes metabolic processes. The rectal injection of ketamine bypasses hepatic metabolism, hence mitigating the likelihood of increased liver enzyme levels commonly observed with ketamine utilization. Divergent findings have arisen from clinical investigations and academic discussions about the R, S, and RS configurations of ketamine. In the realm of clinical examinations, it has been shown that the amalgamated strontium (Sr) formulation of ketamine demonstrates the highest level of efficacy in mitigating symptoms associated with depression. Following this, it has been shown that the S form of ketamine exhibits a lower level of efficiency, whereas the R form is determined to be the least efficacious. The diverse response to different forms of ketamine indicates that there may be variations in individual experiences, potentially influenced by factors such as the route of administration and an individual's metabolic pathways. The current body of published clinical evidence does not provide support for the effectiveness of micro-dosing ketamine in the treatment of depression. This stands in contrast to the documented positive outcomes associated with higher dosages of ketamine. Presently, a dearth of scientific or clinical research exists that substantiates the efficacy of ketamine micro-dosing as a therapeutic intervention for depression [36].

Figure 14. Ketamine Forms; R-, S- [37].

References

36. Passie, T., et al., Comparative effects of (S)-ketamine and racemic (R/S)-ketamine on psychopathology, state of consciousness and neurocognitive performance in healthy volunteers. European Neuropsychopharmacology, 2021. 44: p. 92-104.

37. The Nuances of Ketamine’s Neurochemistry. Available from: https://psychedelicreview.com/the-nuances-of-ketamines-neurochemistry/.

18. 01:38:24 Ketamine: Effects & Therapy

Ketamine and PCP are structurally analogous substances that exhibit antagonistic properties towards NMDA receptors, resulting in a wide range of effects spanning from dissociation to anesthesia. The involvement of the NMDA receptor and brain-derived neurotrophic factor (BDNF) has been shown in the mechanisms underlying the antidepressant effects of ketamine. Ketamine exhibits an influence on the opioid receptor system, a pivotal component in aiding its antidepressant characteristics. The relief brought about by ketamine is associated with the reorganization of brain circuits, however, the maintenance of long-lasting rehabilitation necessitates the adoption of constructive behaviors. Ketamine possesses distinct characteristics, such as its temporary efficacy that mandates frequent administration, as well as the imperative need to supplement its therapeutic application with proactive measures to address depression [38].

References

38. Sepulveda Ramos, C., et al., The Therapeutic Effects of Ketamine in Mental Health Disorders: A Narrative Review. Cureus, 2022. 14(3): p. e23647

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