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  • Writer's pictureMegan Begley, LCSW

How Ketamine Works for Mental Health: A Deep Dive FAQ

Updated: May 6




How does ketamine work for depression? 


The exact reason ketamine can reduce depression and other symptoms hasn't been proven. Historically, research behind these applications emphasized ketamine’s effect on a neurotransmitter called glutamate, which has downstream effects on other neurotransmitters like serotonin, dopamine, and endorphins. This is the likely explanation for ketamine’s rapid and dramatic mood-boosting effect.  


In more recent years, ketamine research has suggested that glutamate also plays a role in synaptic neuroplasticity, or the brain’s capacity for rewiring. Research also indicates that ketamine affects a neurotransmitter modulator called brain-derived neurotrophic factor (BDNF), also linked to neuroplasticity.  Neuroplasticity creates higher capacity for mental change, but as psychedelic researcher and neuroscientist Robin Carhart-Harris has noted, ‘’Plasticity in itself is not an intrinsically healing force.’ For lasting benefit, it must be harnessed in a purposeful way, and this is a primary goal of Ketamine-Assisted Psychotherapy (KAP).


The dissociative effect of ketamine, which ranges from a mildly altered state of consciousness (e.g., dizziness, mild sense of floating) to a much deeper ''hallucinogenic'' one depending on the dosage, may be the most important reason ketamine facilitates mental change:  it creates a broad impact to the brain shared by psychedelic drugs.


Historically, however, the medical ketamine approach for Treatment-Resistant Depression has viewed the dissociation as a side effect to block or lower, and sometimes IV infusions include another drug to minimize it.


While the term ''KAP'' refers to different things locally and nationally, a goal of this particular KAP approach is to limit psychological risk associated with the psychedelic property of the dissociative effect, while also maximizing it through development of strategic intention. Read more about this below.

Is ketamine a psychedelic? 

Although ketamine affects neurotransmitters differently than the ''classic'' psychedelics (e.g., psilocybin, LSD) and has different subjective effects, they share a key mechanism of action. Ketamine's dissociative effect creates temporary entropy across the brain as psychedelics do, disorganizing its normal communication patterns. This includes disconnection of midbrain structures collectively known as the Default Mode Network (DMN), or the brain's ''idle'' setting--the seat of habitual rumination and reflection when we aren't otherwise focused or distracted.  As the site of our repetitive thought patterns, the DMN is also understood as the source of our identity, or ego. Some people have a ''bigger ego'' or more ego stability than others, but we all have this sense of self created by developmental and cultural factors. 

The DMN's capacity for reflection and ''me''-ness are necessary and useful. Along with the rest of the prefrontal cortex, it's the product of human evolution beyond the instinctual animal brain, or limbic system, which connects learning with pleasure or distress. The DMN enables us to create personal narratives (ego stories about ourselves and the world) that make sense of what we experience. Often, our ego stories hold cognitive distortions that contribute to depression and anxiety, and the entropy caused by ketamine's dissociative effect loosens their grip much faster than cognitive therapy (talk therapy). However, even positive narratives--such as those identifying with strength, resilience, and control--benefit from temporary entropy. Often, they block unconscious feelings and nervous system reactions fueling physical symptoms of depression, anxiety, and even chronic pain. Psychedelic researcher David Nutt has stated that in the DMN, ''we've found the neural correlate for repression.'' Read more about this below.

What are the psychological risks of ketamine therapy? 

Thanks to advances in trauma neuroscience and now psychedelic neuroimaging, repression is no longer the abstract concept that it was in the days of Sigmund Freud. Increasingly, it's recognized that the evolutionary trade-off for our analytical, creative, and meaning-making minds has been repression of a key biological process that discharges tension created by danger, emotional threat, or chronic stress. Sometimes referred to as the autonomic nervous system defense cascade, it creates the anger (fight), fear (flight), or immobilization (freeze) instinct needed to survive. In humans, depression sets in when the body can no longer maintain this energetically expensive level of activation. Dissociative numbness can set in when depression is coupled with no hope of escape, a state facilitated by endogenous opioid release that creates distance from pain.


Alleviating depression can actually take the nervous system backward into anxiety, anger, or emotional pain related to the original perceived threat. The actual level of danger that was present is irrelevant, as the pattern was typically established in childhood when sensitivity and vulnerability is exponentially higher.  In other words, when the habitual cognitive patterns anchoring our perspective get loosened, so can repressed nervous system reactions and associated feelings, which are almost always rooted in key childhood experiences and relationships. This is an under-recognized risk of standard ketamine treatment, and psychedelic use in general. This is not as much a reference to what occurs while under the influence of the drug itself, but to what occurs afterward. However, it does also illuminate some of the reasons people can have challenging experiences with psychedelics or ketamine. On the other hand, if dissociation is too active in the system, it can block the entire response.

The REBUS model (RElaxed Beliefs Under pSychedelics and the Anarchic Brain), published by Carhart-Harris and colleagues, describes how brain entropy disruption of the Default Mode Network creates ''liberation of bottom-up signaling.'' This scientific jargon fails to indicate any risk, and in fact, liberation sounds like a purely positive thing. It is a primary benefit of ketamine and psychedelics, but you have understand how to navigate it.


For example, as a trauma therapist using ''bottom-up'' therapies which access the nervous system (e.g. EMDR, somatic therapy), I recognize that it must done with caution to avoid overwhelming someone's window of affective tolerance--the amount of sympathetic nervous system activation they can handle at a given time. Ketamine and psychedelics amplify the effect of bottom-up therapies from a screwdriver to a power drill, creating even greater risk in most cases. However, when ketamine treatment is done with the harm reduction concepts, psychological preparation, and integration essential to responsible psychedelic therapy, the potential for risk is translated into equal capacity for healing. It exceeds what even the best bottom-up, non-drug assisted therapies can do.




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