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  • Writer's pictureAarathi Manchikalapudi

"Special K" as Treatment

Ketamine is an emerging psychedelic treatment for treatment resistant depression (TRD),

due to fundamental differences in how it interacts with the brain compared to other

psychedelics. Coupled into the class of drugs known as psychedelics due to the out of body effects it can cause, ketamine works to relax the brain’s chandelier cells. These cells are responsible for

controlling pyramidal cells, which are heavily involved in neural communication.


Relaxation allows the pyramidal cells to exhibit higher activity, causing a dissociative effect. Other

psychedelics have the opposite effect, wherein the drug works to override the chandelier

cells and overwhelm the pyramidal cells - resulting in strong hallucinations. Although

ketamine can also have hallucinogenic effects, at low doses, it is typically associated with

regrowth and reactivation of synapses that may allow the brain to emerge from its

depressive state.


According to some experts, that difference may make ketamine a more suitable drug for treatment

resistant depression (TRD), and its usage has sometimes been accompanied by incredible outcomes in patients. It primarily targets the glutamatergic system as an N-methyl-D-aspartate (NMDA) antagonist, the pathways of which have been found to be involved in behavioral changes caused by stress. It has become further understood to be involved in cellular mechanisms associated with synaptogenesis and neuroplasticity, in which the inhibition of NMDA has been linked with higher glutamate levels in synapses. This facilitates the activation of other pathways involved in neuroplasticity.


In particular, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor was discovered to be activated by increases in glutamate at synapses, which directly increases

brain-derived neurotrophic factor (BDNF) release. Chronic stress is thought to cause atrophy in

pyramidal cells of the brain's hippocampus, a change that is associated with BDNF inhibition, so the increase of BDNF activity by ketamine facilitates the axonal regeneration of these cells. This is one of the major pathways that ketamine uses (although many of the cellular pathways the

drug utilizes are still under study). However, the multitude of neurotransmitter systems that

it affects, including the opioidergic, monoaminergic, glutamatergic, and muscarinic systems, is

thought to be the reasoning for why it is able to have the most holistic effect in treating TRD.


Thus far, only an intranasal ketamine spray has received FDA approval as a treatment

mechanism for TRD, but many other experimental forms of administration exist. For instance, microdosing ketamine treatments include intravenous-infusion (IV), oral, transmucosal,

subcutaneous injection, and sublingual lozenge, which vary in their bioavailability, method of

delivery, and rate of absorption. Ketamine bioavailability increases from oral to sublingual to

intranasal to intramuscular to intravenous, with rate of absorption increasing in the same order.


The IV infusion allows for the highest concentration of drug absorption at the fastest rate due to

its direct entrance into the bloodstream, allowing for almost immediate effects. In one study, patients with strong suicidal intent who were administered ketamine in emergent situations experienced an antisuicidal effect as early as 40 minutes post-treatment.


The non-intranasal forms of ketamine administration have yet to be approved by the FDA, due to potential side effects of the drugs including dissociation, sedation, psychiatric events, and addiction, but also because of limited testing on the long term effects of the drug. Thus, there is no established safe or effective dosage of ketamine for psychiatric use. Given that ketamine is not FDA approved, it would make sense, in theory, that ketamine would be highly regulated. Yet in reality, the drug is not nearly as regulated as one would think a psychedelic-grade therapy would be.


The oral medications are actually relatively accessible, available for purchase at the online pharmacy Mindwell (following a virtual consultation with one of their clinicians). Surprisingly, the largest barrier to acquisition appears to be factors involving cost, as well as legislation within the patient's state of residence. With regard to cost, most insurance does not cover the cost of ketamine infusion, on account of its lack of FDA approval. Insurance companies classify it as an experimental procedure that is not technically “medically required." Manufacturing one dose of ketamine can cost $2-$5, but the cost of one ketamine infusion treatment can exceed $400-$800. This is largely due to the uncompetitive pricing that ketamine clinics are able to set, owing to specialization of the field and the limited number of clinics offering the treatment.


Furthermore, since no ruling has been handed down on the classification of ketamine at the federal

level, it is left to the states to criminalize or regulate the usage of the drug. In this regard, ketamine has become a de facto legal cousin to marijuana: a matter of the state legislature. This creates a problem of consistent accessibility to potentially required treatments. In the future, perhaps a better understanding of the mechanisms that ketamine utilizes could allow for the creation of a less harmful derivative that would be more accessible to the public.


Other innovations in ketamine treatment involve the creation of ketamine pod devices for

microdosing treatment in pain management. The government heavily sponsors such research in its attempts to address the opioid epidemic, with ketamine being a less addictive substance relative to opioids. The pod works in the same manner as an insulin pump would for a diabetes patient, releasing low doses of ketamine over a period of time via subcutaneous injection.


Administration by injection helps to largely overcome the issue of bioavailability that is seen with oral and intranasal administration. The recipient has no control of how much or when they are taking it, which keeps them from being able to misuse the drug beyond the determined dosage.There is potential for TRD treatment to move in a similar direction, good news for those who seek hope on the horizon.


Aarathi Manchikalapudi is a rising 2nd Year student at the University of Virginia. She hopes to major in neuroscience and global public health, and is currently involved in tissue engineering research.


Sources:


Alagga, A. A. (2023, June 20). Drug absorption. StatPearls [Internet].


Andrade, C., & Sathyanarayana Rao, T. (2017). A possible role for ketamine in suicide

prevention in emergency and mainstream psychiatry. Indian Journal of Psychiatry, 59(3),


At home oral ketamine treatment from Mindwell Health: Breakthrough Therapy for Mood

Disorders. Mindwell Health. (n.d.). https://www.mindwellsc.com/from-home


Bioavailability of ketamine: Maximizing therapeutic efficacy. KureIV Ketamine Therapy. (2023,


Center for Drug Evaluation and Research. (n.d.). FDA warns about compounded ketamine for


Duman, R. S., Deyama, S., & Fogaça, M. V. (2019). Role of BDNF in the pathophysiology and

treatment of depression: Activity‐dependent effects distinguish rapid‐acting

antidepressants. European Journal of Neuroscience, 53(1), 126–139.


Sussex Publishers. (n.d.). How does ketamine work differently from other psychedelics?.


WebMD. (n.d.). What is ketamine? how it works and may help with severe depression. WebMD.


Yavi, M., Lee, H., Henter, I. D., Park, L. T., & Zarate, C. A. (2022). Ketamine treatment for

depression: A Review. Discover Mental Health, 2(1).

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