Ketamine and Mental Health Part III

~This blog series is about my approach to mental health and the integration of ketamine therapy with a psychodynamic and affective neuroscientific lens~

This post is written by Caleb Greer, FNP-C

How Does Ketamine Work?

While this list is not exhaustive, it should give a decent overview on the various mechanisms through which ketamine may positively effect mental health. This final blog will be more technical than the previous two simply due to the complexity of the concepts.

NMDA Receptors

There are plenty of working theories on how ketamine works. Most, if not all, are mechanistic and neuroanatomical in nature. Such theories start with the NMDA glutamate receptor subtype, where ketamine acts as a strong inhibitor. Since glutamate is the brain’s primary excitatory neurotransmitter, its inhibition at the NMDA receptor results in a broad span of effects. Consequently, this NMDA inhibition mechanism has to be constrained to a high-resolution brain region where NMDA-positive neuron populations are found. This constraint is because NMDA-positive neurons do not inherently connect downstream to excitatory processes. For example, a glutamate-signaling neuron, A, may be responsible for inhibiting/stopping the transmission it received by its effector neuron by projecting to an inhibitory neuron, B, but neuron B could be excitatory or inhibitory.

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To complicate matters further, there may be hundreds of collateral inputs to neuron B that influence the action of neuron A. So, the NMDA receptor inhibition is an accurate observation and is true, but only applies at a very narrow level of analysis, say when looking at neuronal populations in the nucleus accumbens or lateral habenula where the demographics of inputs and outputs are well-known. Another interesting thing to know in this regard is that other drugs that inhibit the NMDA receptor do not have the same effects on mental health that ketamine does.

AMPA Receptors

The next cell signaling mechanism behind how ketamine works is through another family of glutamate receptors called AMPA receptors. AMPA receptors are a gateway to a brain “venue” that only allows special types of “ VIP guests” to enter. Once enough of them enter, the venue is open to the more “common guests” that can enter through the NMDA gates. AMPA receptors are needed for the development of learning, association, and contextualization that is ultimately maintained by NMDA receptor activity. This is the basis for neuroplasticity*, along with the growth signals that come from molecules like brain-derived neurotrophic factor and post-synaptic density protein-95. Ketamine, through intracellular signaling cascades, increases glutamate signaling and AMPA receptor density across the brain, but particularly in the nucleus accumbens, hippocampus, prefrontal cortex, and other subcortical midline structures. Consequently, with increased AMPA density and reduced NMDA activation, circuits that have been over-plasticized may undergo structural changes that reflect a more un-learned state, especially if other brain functions are being exercised at the same time, such as eye movements, body tapping, talking, using guided imagery, etc. The importance of this ‘un-learning’ will be highlighted in the next section.

*Neuroplasticity is the process by which learning, memory, and changes in both occur and has been shown to be active throughout the lifespan.

Chronic Stress Reversal

As highlighted in the previous blogs, chronic stress, repeated social defeat, and loss of status can lead to mental health fragility. Experience with these negative events coupled with potential already increased susceptibility (from childhood attachment insecurity) begins to be ‘written in stone’, so-to-speak. In this case, neuroplasticity is not in the favor of the ideal persona, but instead encodes lower hierarchical status, increased negative self-reflection, and negative affect. For the resilient folks, such negative affect evokes a rebound sense of potential redemption and hope. They probably screwed up, but at least they realize it’s their fault and they can attempt to fix themselves so the circumstance isn’t likely to happen again. Other less resilient people may fall into the role of the victim, searching outside of themselves for the answer to why they were rejected. Whichever it is, the point here is that if stress happens and it is not sufficiently explored and understood, then it is likely to continue to eat away at the ability to self-regulate emotion. Chronic social stress has been documented to cause negative structural and functional changes in many different brain areas. Some areas include the prefrontal cortices, cingulate cortices, hippocampi, and deeper limbic structures like the nucleus accumbens, lateral habenula, and ventral tegmental area. Such changes are associated with functional deficits in socialization, immune strength, emotional resiliency, motivation, and self-perception. So, what if we could reverse the neurostructural changes that mediate the plastic response to chronic social defeat stress and loss? Well, it appears that through the aforementioned glutamatergic and cell signaling mechanisms, ketamine does act in such a way.

Neuronal Network Shifts

The brain consists of many large-scale networks, but there are three primary ones that interface between the subconscious and conscious levels: the default mode network (DMN), the salience network (SN), and the frontoparietal network (FPN). DMN disruption has been shown to be a mediator of mystical experience and ‘ego-dissolution’ in psychedelic literature. The DMN operates on unconscious memory, which is largely unavailable to conscious consideration. It manifests in behaviors, attitudes, and feelings as well as in much more complex forms such as defenses, self-esteem, and transference. Major depressive disorder (MDD) is hypothesized to be associated with dysfunction in large-scale brain networks, especially hyper-connectivity within the DMN. Abnormally increased resting-state functional connectivity within the DMN has been associated with dysfunctional self-referential processing (how one thinks about themselves in relation to others, the environment, and their desired persona), rumination, and severity of depression. Therefore, abnormal functional connectivity is a trait biomarker of depression and a potential therapeutic target. This observation that dysfunctional connectivity is important in affect regulation because ketamine interrupts the negatively-biased unconscious narrative that arises from the neurotic (meaning increased sensitivity to negative emotion) right orbitomedial/ventromedial prefrontal cortex (om/vmPFC). This interruption allows the hyper-critical superego, developed from cultural and familial expectation, to undergo assimilation of unconscious dreams, desires, complexes, or at least the chance to shed perseverative self-judgments. Such unconscious dreams are the birthplace of thought. Clarifying them may progress to conscious manipulation of thought patterns, which are then more likely to lead to action and behavior change that is more in line with who the individual desires to be. There are also changes in some of the salience network nodes that are responsible for determining what in the environment is worth paying attention to. In major depressive disorder, for example, heightened sensitivity to body signals leads to increased self-referential processing, reduced pain threshold, and reduced processing ability of external stimuli. All of these networks simplify our personal experiences by running the software that has been written in early life. They designate what we should pay attention to, what we should value, explore, avoid, exploit, etc., without which we would be paralyzed with indecision. Ketamine’s disruption of some of these nodes seems to allow new patterns of thought and mental exploration to take place without the intense vulnerability and negative emotion that accompanies a change in very deep-rooted software – especially with the guidance of a therapeutic aim.

Back to Affective Neuroscience

To tie it all together I will return to the affective neuroscience perspective, which I believe to be the fundamental piece of the structure on which all of the other mechanisms laid out above are built. From the primal affective perspective, ketamine seems to result in increased activation of SEEKING as well as PLAY. This idea is supported by literature that shows ketamine-dependent increases in dopamine levels in the brain, dopamine being a neurotransmitter at the core of the SEEKING system. Additionally, co-administration of dopamine receptor antagonists blocks some of ketamine’s anti-depressant effects, further reinforcing the necessity of SEEKING activation in alleviating negative emotion. It is important to distinguish the incentives and rewards that are mediated by dopamine, as the consummatory reward is not associated with ketamine’s action. The activation of the SEEKING system is associated with goal-directed behavior and is the source of pursuit euphoria, a very different experience than consummatory reward. It is the motivational force that designates the importance of such a pursuit. Anhedonia, a condition marked by loss of motivation, is a state where SEEKING is blunted and motivation to pursue previously pleasurable activities is absent. This condition is greatly softened with intravenous ketamine. On the other hand, there are consequences of pathological SEEKING, as has been demonstrated in conditions of mania, delusions of grandeur, and even hyper-religiosity, where administration of dopamine receptor inhibitors (anti-psychotics) rather than activators is the normal therapeutic course. Indeed, administration of ketamine to schizophrenics worsens positive symptoms, but it is important to note that ketamine is still used in psychotic disorders where negative symptoms of anhedonia, depression, and suicidality are primary. It is also plausible that the increase in SEEKING behavior could be a secondary benefit to the reduction in negative emotion, as ketamine seems to reduce FEAR, RAGE, and PANIC through opioid signaling (the opioid antagonist naltrexone blocks some anti-depressant effects), direct glutamatergic inhibition in the PANIC system, and a reduction in dynorphin (an opioid that generally opposes the ‘good’ opioids and is elevated in depression) signaling. Altogether, intravenous ketamine therapy improves the positive affective systems SEEKING and perhaps PLAY, and reduces negative affective systems FEAR, RAGE, and PANIC. It isn’t clear if positive affect enhancement or negative affect softening happens first, or if they happen together. Either way, the result is a reduction in psychic burden along with the return of a glimmer of hope in the form of motivation and clearer understanding.


The goal of this blog series was to invite people into my process of what ketamine-assisted psychotherapy looks like in theory and in practice. There are many moving pieces when viewed through a complex systems approach – I didn’t even touch on other physiological contributors to mental health status, such as nutrition, microbiome composition, inflammation, hormonal dysfunction, medication use, etc. Perhaps I will in a future blog.

Integrating and connecting the working theories and hypotheses of the mechanisms of ketamine will no doubt give rise to a more rigorous approach to its use and study. The clinical effects of ketamine can be described on many different levels of analysis, from the purely neurochemical to psychodynamic reorganization. As a provider of ketamine, it is important to understand, to the extent that one can, the application of ketamine to each of the levels of analysis. If congruity can be established across multiple theories and models, a greater, arch-theory may be developed. Furthermore, not every individual presents on the same level of analysis in regard to neuropsychological health. So, having alternative explanations for the multiple effects of ketamine may help expand the inclusion criteria for its use based on different theoretical approaches, i.e depression vs. anhedonia vs. cognitive decline.

I hope this series has been helpful, and if you feel that you could benefit from this approach please reach out and let us know!

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