Considering Ketamine? Here's how it works

Ketamine's Secondary Mechanism of Action

In addition to ketamine’s effect on the glutamate, ketamine exhibits a variety of activity at other receptor sites. Ketamine has the highest affinity for NMDA receptors, but is also a semi-potent Dopamine (D2) agonist as well as semi-potent kappa-opioid and mu-opioid antagonist. Ketamine is known to have significant affinity for sigma-opioid receptors but it is currently unknown whether it functions as an agonist or antagonist. Ketamine also shows minimal affinity as an antagonist for muscarinic and nicotinic acetylcholine receptors. 

Lastly, Ketamine is a known reuptake inhibitor for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET). It should be noted that the biological metabolites of ketamine may also have psychoactive effects, however the current data is inconclusive. In summary, Ketamine has the most dramatic effect on glutamate, however it has a wide variety of complex chemical interactions in the brain. Ketamine’s downstream effects really “light up” the entire brain and may contribute to the “trip” associated with ketamine treatments.

With IV-drip Ketamine treatments, I have observed a pretty standard progression of effects over the 30-minute infusion, while working as a guide over the last two years. The first symptom of Ketamine is just a mild relaxation (less than 10 mg administered). This usually reduces the pre-treatment anxiety that most patients experience on their first infusion. From there, patients begin to feel numb and tingly; this starts in the fingers, toes, lips, and tongue. The whole body will gradually become numb and patients usually report feeling dizzy and a little disoriented (10-20 mg administered). This sensation is sometimes compared to the physical effects of being very drunk but with a surprisingly clear head. At this point, patients will need to be laying down, as their motor coordination and proprioception are dramatically altered. 

Once the entire body is numb, most patients report feeling like they are floating or weightless; this stage is where things start to get “trippy,” for lack of a better term (20-30 mg administered). For the remainder of the treatment, the patient will feel disconnected from their body, to some extent, which we characterize as “the dissociative state.” This is where hallucinations and out-of-body experiences occur. Dissociative experiences can vary wildly between individuals and are also heavily affected by dosage, physical environment, and mental headspace. It is even difficult to predict how the same dose will affect the same patient a week later. With all this in mind, the dissociative state can result in profound insight, processing of complex emotions, and confronting memories from a detached perspective.

Ketamine and Mental Health

The exact antidepressive effect of Ketamine is still not fully understood but a variety of novel mechanisms have been proposed. Research on mice exposed to chronic stress, which resulted in depressive symptoms, found that chronic stress led to a loss of communication between brain cells in the prefrontal cortex. This was caused by the loss deformation of dendritic spines. Interestingly, after giving these same mice Ketamine, the researchers observed the growth of new, functional dendritic spines in the prefrontal cortex.

In practice, we often refer to this as “neural regrowth.” fMRI studies have also shown that Ketamine reliably increases neuroplasticity for a few days following administration. This allows for the opportunity to create new connections in the brain, and break old ones, with much more ease than usual. We often refer to the combination of these two effects as a “neural reset.” This, in addition to the profound psychological experiences people have during Ketamine treatments are thought to be the primary cause of Ketamine’s effects on mental health.