Academic Text

THE USE OF KETAMINE AS A TREATMENT

FOR DEPRESSION AND ALCOHOL USE
DISORDERS
By Brendan Kelleher
2020, VOL. 12 NO. 10 | PG. 1/1

ABSTRACT
Ketamine, described by the chemical formula C13H16ClNO, is most commonly associated with adolescent and
adult recreational drug users and ravers who abuse this drug to experience a euphoric and dissociative state.
Although this drug is a federal schedule III controlled substance as a result of this abuse potential, ketamine
has experienced a renaissance in clinical interest in recent years. 1 Although clinical use of ketamine is
controversial, it has become a focal point of pharmacological research due to its considerably diverse
molecular targets and neurophysiological properties. 2 In fact, recent studies have cited ketamine as a potential
therapy for depression, including treatment resistant varieties, as well as alcohol use disorders.

Historical Perspective
Ketamine was first discovered by Parke-Davis laboratories in 1962 as part of an effort to create a powerful,
novel anesthetic agent with analgesic properties. 3 The group initially produced phencyclidine, more commonly
referred to as PCP, and while this substance did induce the desired effects, it produced dangerously severe
excitation and delirium in a significant percentage of the trial population. After the failure of phencyclidine,
the group continued to engineer derivatives and eventually created CI-581, a fused ketone and amine, later
combined as the drug name ketamine, that produced cataleptic, analgesic and anaesthetic action with a much
shorter duration than PCP, without the detrimental excitations. 3 Ketamine proved to be a very powerful
substitute as it produced “potent anesthesia, sedation and analgesia while maintaining cardiopulmonary
stability and airway patency.”2

In the early years after ketamine was developed, significant research and clinical trials were performed. In
1963, ketamine was patented as a veterinary anesthetic. Following this application, ketamine was later
introduced as an FDA-approved prescription medication under the brand name Ketalar in 1970 and was
widely used as an anesthetic throughout the Vietnam war. 2,3 By the end of the war, ketamine was regularly
abused and associated with the psychedelic experiences sought by most recreational users. However,
beginning in the 1990s, researchers began to rediscover ketamine as a potential source of
psychopharmacological treatments.

Pharmacological Profile of Ketamine

Ketamine is a general anesthetic used for short term diagnostic procedures and surgery. 4 However, expanded
use in medical settings has been limited due to its negative psychological effects, including vivid
hallucinations, agitation, and confusion.4 Ketamine’s mechanism of action is different from most hypnotic,
antidepressant and mood disorder treating pharmaceuticals such as benzodiazepines, as ketamine does not
interact with GABA receptors. Its specific and detailed physiological impacts have not been entirely explored,
but at a basic level, ketamine is a noncompetitive (allosteric) antagonist of N-methyl-D-aspartate (NMDA)
receptors.2 There are several theories as to its true mechanism of effect after binding, but none have been
supported by significant empirical data. One theory on the effects of ketamine explores its relationship to
glutamate, a major amino acid neurotransmitter that is often linked with many mood and anxiety
disorders.5 Glutamate is thought to cause changes in mood and psychological state through a network of
signaling involving the binding of glutamate to NMDA receptors. As ketamine is able to allosterically inhibit
the NMDA receptors, it has been proposed that ketamine prevents the binding of glutamate, often producing
antidepressant and other neuromodulation effects. Another more recent theory proposed that ketamine is
involved in rewiring brain circuitry and changing synaptic growth to influence mood and recovery from
depression.6

There are two main types of ketamine that have been used to produce various clinical effects. Racemic
ketamine, often infused directly into the bloodstream, is a blend of “S” and “R” mirror ketamine
molecules.7 Esketamine, often given as a nasal spray, only contains the “S” ketamine molecule and was
approved by the FDA this past March under the name “Spravato.” 7 S-ketamine appears to be a better long term
choice for treating clinical disorders as it appears to be less prone to causing psychomimetic side effects, such
as derealization and hallucinations.8 However, significantly more research must be done to confirm this
finding.

Ketamine’s systematic effects are quite interesting. At low and anesthetic doses, ketamine produces increased
blood pressure and heart rate and does not cause any significant respiratory depression, preserving the upper
airway reflexes.3 However, ketamine can induce several negative side effects in certain populations. These
overall effects have been recorded by various researchers and can be organized into four main categories: (1)
intoxication, similar to other sedatives and anesthesia agents; (2) perceptual changes and disturbances in
auditory, visual, and somatosensory domains as well as feelings of dissociation, depersonalization and
derealization; (3) delusions, including misinterpretation and thought disorders; and (4) other general negative
symptoms such as an inability to speak.3

Another key characteristic of ketamine is its fast absorption time. Ketamine has a maximum plasma absorption
range from three to thirty minutes, depending on the mode of delivery. 3 In addition to fast uptake time,
ketamine binds strongly to receptors, meaning that ketamine exerts its influence very quickly upon
administration.

Solution to Treatment Resistant Depression?

Depression is a sometimes episodic and often chronic mental illness that can feature discrete symptomatic
periods separated by periods of apparent wellness. 8 It is the third leading cause of disability worldwide
affecting close to 350 million individuals. 9,10 Depression in individuals can have varied causation and may be
treated differently for different people. Because of this non-uniformity of causation and manifestation of
depression, it is imperative that these underlying factors be examined to ensure that all relevant issues are
taken into account before treatment.

Major depressive disorder (MDD), a significant diagnostic category of depression, is often associated with
frequent relapses and incomplete recovery and remission. 11 Quite frequently, individuals suffering from MDD
are treated with psychopharmacological agents widely available such selective serotonin reuptake inhibitors
(SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and other antipsychotic
medicals.12 Unfortunately, the majority of these agents take weeks to take effect and in 10-20% of patients,
these antidepressant medications do not result in an improvement in symptoms. This untreatable population
falls under the umbrella of treatment resistance. While traditional treatment has not proven to be effective in
these cases, research on less traditional treatments may provide alternative treatment options in these cases.

In recent years, multiple studies have linked ketamine to antidepressant effects, particularly in cases of
treatment resistant depression. In a study by Murrough et al in 2013, researchers observed an 89%
improvement in depression questionnaires 24 hours post ketamine administration in a population of adults
with treatment resistant depression.5 Furthermore, in a study conducted by Segmiller et al, three of six
participants suffering from treatment resistant depression that were treated using ketamine showed both short
term and long term improvements in his/her outlook and symptoms. 13 In addition to its prospective ability to
alleviate some symptoms of treatment resistant depression, ketamine’s rapid absorption and effect can induce
a response in several hours, providing a rapid, novel treatment compared with most antidepressant regimens,
which take weeks for noticeable effect. While several of these studies examine a very small sample size, early
results suggest promise for future treatment and research.

While the majority of depression-related ketamine research has examined its effects, there has been very little
work done to examine the underlying mechanism behind the effects. In an effort to better understand this
relationship, in April 2019, Conor Liston at Weill Cornell Medicine examined synaptic changes in depressed
mice that resulted from ketamine administration. Liston stressed mice in two distinctly different ways,
observed the results of the stress, and then administered ketamine. He found that the ketamine seemed to
partially reverse the effects of stress, regrowing synapses where stress had destroyed them. Improved behavior
and circuit function were observed in the mice within a three hour span post administration, and synapses
began to regrow between twelve and twenty four hours. 14 While synapses regrow rapidly, they often
deteriorate if not maintained properly. Liston himself admits that while the findings are very promising, there
is still a great deal of additional study needed. Liston states, “Our findings open up new avenues for
research…that could include drugs that stabilize the synapses or behavioral therapies that engage the healed
synapses and circuits, thereby strengthening them.” 14 While Liston’s study is certainly not the first study to
link ketamine to antidepressant actions, it is one of the first to provide solid evidence for the mechanism that
causes the effect. One slight drawback of the study is that Liston’s team only examined the effects of a single
dose of ketamine and did not address how multiple doses would affect an individual. It is unclear whether
multiple doses would result in an increased rejuvenation of synapses or cause some sort of regression. Even
considering its limitations, the study provides empirical supporting evidence and a solid jumping off point for
future clinically directed research.

Treatment of Alcoholism
Substance overuse and abuse disorders such as alcohol use disorder and other substance use disorders are
among the leading causes of avoidable mortality and morbidity worldwide, affecting 19.7 million individuals
in the United states over the age of 12. 15,16 Additionally, 74% of those who suffer from a substance abuse
disorder are simultaneously suffering from an alcohol use disorder. 16 As a result, when treating for alcoholism,
researchers must ensure that they examine the whole clinical formulation, treating all aspects and angles to
ensure nothing is missed. A treatment serving as a suppressor of desire to consume alcohol in an individual
may prove to be an ineffective therapy for the comorbid condition.

A study published in November 2019 suggests that ketamine could serve as a disruptor of negative alcohol
consumption patterns in adults. The study focused on addiction as a memory disorder that relies on
maladaptive reward memories (MRMs) to develop and maintain these addictions. 17 MRMs are learned
associations that are created between drug predictive environmental stimuli such as the look, taste and smell of
a substance, and the specific drug reward that the nervous system experiences. 18 These memories were long
thought to be unalterable and current treatments for substance abuse usually focus solely on learning adaptive
behavior to suppress the desires and cravings. However, recent research has examined memory
reconsolidation, a process involving the reactivation and destabilization of old, long-term memories to update
themselves through the incorporation of new information 19. Their findings suggest that through memory
consolidation it is possible to selectively target and weaken the memory cues, damaging the network of
MRMs and weakening the response to the behavior.20 The research team hypothesized that triggering MRMs in
individuals that drank dangerous amounts of alcohol and immediately administering ketamine would disrupt
the retrieval of associated memories and result in a reduced desire to drink.

To test this hypothesis, the group gathered 90 individuals who admitted that they drank too much alcohol, but
were not formally diagnosed with an alcohol use disorder (Anderson), and split them into three groups: (1)
induced retrieval and administered ketamine (RET+KET group); (2) no retrieval and administered ketamine;
and (3) retrieval and administered placebo (saline). The results were quite intriguing. In the RET+KET, there
was a significant reduction in desire to drink beer placed in front of them post ketamine administration vs. pre
ketamine administration. There was no significant change noted in the control group. 19 The RET+KET group
also showed a significant drop in the number of binges post manipulation while the control group showed no
difference.

Additionally, to ensure that the outcomes examined were not simply short term, the research team continued to
follow subjects up to nine months after the manipulation. Researchers observed reductions in weekly alcohol
drinking in all groups, with no evidence of rebound. 20 This cross-group trend was likely due to some sort of
self-awareness and initiative following their admittance to dangerous alcohol use. Most significantly, the
RET+KET group had cut their average alcohol consumption in half by the nine months check in. This data
suggests a notable, potential relationship between ketamine administration and reduction of alcohol
consumption and the results aligned with a therapeutic mechanism grounded in reconsolidation interference. 20

Future Directions
Ketamine holds a great deal of promise as a potential source of psychological treatments due to its rapid
absorption and effect timing, as well as potential longterm results. Unlike other antidepressants or MRM
reducing treatments that can take weeks to yield results, individuals who received ketamine therapy began to
show results hours after administration for both antidepressant action and reduction in alcohol consumption.
These findings suggest many possible avenues of exploration for future effective and efficient treatments to
psychological disorders. As substance and alcohol use disorders are very often comorbid with depression and
other mood disorders, treatment of both conditions simultaneously could be quite advantageous, and
alleviation of one condition with ketamine treatment may lead to improvements in the other.
While the future does seem bright for clinical use of ketamine, there continue to be impediments to
widespread acceptance due to ketamine’s stigma, as it is an addictive narcotic that continues to be abused as a
recreational drug. Clinical trials and significant research on substances such as ketamine can be expensive,
often requiring the support of grant money. It is often much more difficult to get this limited funding for a
controversial pharmaceutical like ketamine compared to treatments without negative associations. In addition,
there are several aspects of ketamine treatment that require a great deal more research before any real
conclusion can be made about its true efficacy. It is clear that there is still significant work to be done before
ketamine could be a widely accepted psychological treatment.

Based on the evidence provided by recent studies, the use of ketamine as a potential therapy for depression,
including treatment resistant varieties, as well as alcohol use disorders, has the potential to significantly
benefit individuals affected by these conditions as an alternative to traditional treatments. Future clinically
directed research is warranted to determine whether ketamine treatment is the psychological breakthrough that
will best address these conditions.

References
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2.) Li, L., & Vlisides, P. E. (2016). Ketamine: 50 Years of Modulating the Mind. Frontiers in human
neuroscience, 10, 612. https://doi.org/10.3389/fnhum.2016.00612

3.) Mion, G. (2017). History of anaesthesia: The ketamine story – past, present and future. European Journal
of Anesthesiology, 34(9), 571-575. doi:10.1097/EJA.0000000000000638

4.) N. (n.d.). Ketamine. Retrieved February 24, 2020,

from https://pubchem.ncbi.nlm.nih.gov/compound/Ketamine

5.) Murrough, J. W., Perez, A. M., Pillemer, S., Stern, J., Parides, M. K., aan het Rot, M., Collins, K. A.,
Mathew, S. J., Charney, D. S., & Iosifescu, D. V. (2013). Rapid and longer-term antidepressant effects of
repeated ketamine infusions in treatment-resistant major depression. Biological psychiatry, 74(4), 250–
256. https://doi.org/10.1016/j.biopsych.2012.06.022

6.) Moda-Sava, R. N. (2019). Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced

spine formation. Science, 364(6436). doi:10.1126/science.aat8078

7.) Meisner, R. C. (2019, May 22). Ketamine for major depression: New tool, new questions [Web log post].
Retrieved February 24, 2020, from https://www.health.harvard.edu/blog/ketamine-for-major-depression-new-
tool-new-questions-2019052216673

8.) Paul, R., Schaaff, N., F. P., Moller, H., & T. F. (2009). Comparison of racemic ketamine and S-ketamine in
treatment-resistant major depression: Report of two cases. The World Journal of Biological Psychiatry, 10(3),
241-244. doi:https://doi.org/10.1080/15622970701714370

9.) Corriger, A., & Pickering, G. (2019). Ketamine and depression: a narrative review. Drug design,
development and therapy, 13, 3051–3067. https://doi.org/10.2147/DDDT.S221437

10.) Ishak, W. W., Greenberg, J. M., & Cohen, R. M. (2013). Predicting relapse in major depressive disorder
using patient-reported outcomes of depressive symptom severity, functioning, and quality of life in the
Individual Burden of Illness Index for Depression (IBI-D). Journal of affective disorders, 151(1), 59–
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11.) Serafini, G., Howland, R. H., Rovedi, F., Girardi, P., & Amore, M. (2014). The role of ketamine in
treatment-resistant depression: a systematic review. Current neuropharmacology, 12(5), 444–
461. https://doi.org/10.2174/1570159X12666140619204251

12.) M. (2018, February 03). Depression (major depressive disorder). Retrieved February 24, 2020, from
https://www.mayoclinic.org/diseases-conditions/depression/diagnosis-treatment/drc-20356013

13.) Segmiller, F., Rüther, T., Linhardt, A., Padberg, F., Berger, M., Pogarell, O., Möller, H.‐J., Kohler, C. and
Schüle, C. (2013), Repeated S‐ketamine Infusions in Therapy Resistant Depression: A Case Series. The
Journal of Clinical Pharmacology, 53: 996-998. doi:10.1002/jcph.122

14.) Makin, S. (2019, April 12). Behind the Buzz: How Ketamine Changes the Depressed Patient’s
Brain. Scientific American.

15.) Torregrossa, M. M., Corlett, P. R., & Taylor, J. R. (2011). Aberrant learning and memory in
addiction. Neurobiology of learning and memory, 96(4), 609–623. https://doi.org/10.1016/j.nlm.2011.02.014

16.) Thomas, S. (2020, February 3). Addiction statistics: Drug & substance abuse statistics. Retrieved
February 24, 2020, from https://americanaddictioncenters.org/rehab-guide/addiction-statistics

17.) Sanders, L. (2019). Ketamine cultivates new nerve cell connections in mice. Science News.

18.) Hyman, S. E. (2005). Addiction: A Disease of Learning and Memory. The American Journal of
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19.) Lee J. L. (2009). Reconsolidation: maintaining memory relevance. Trends in neurosciences, 32(8), 413–

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Non- Academic Text

Kaguya Hime no Monogatari

One day in the bamboo forest, an old bamboo cutter called Taketori no Okina ( 竹 取 翁 , "old
bamboo harvester") comes across a mysterious, shining stalk of bamboo. When he cuts it open,
he is surprised to find an infant the size of his thumb inside. The old man and his wife, who have
no children of their own, decide to raise the infant as their own daughter, and name her
Nayotake no Kaguya-hime (なよたけのかぐや姫, "Shining Princess of the Young Bamboo").
From that moment on, every time the man cuts a stalk of bamboo, he finds a small nugget
of gold inside. The family soon grows rich, and within just three months, Kaguya-hime grows
from an infant into a woman of ordinary size and extraordinary beauty. At first, the old man tries
to keep news of Kaguya-hime away from outsiders, but as word of her beauty spreads, she
attracts many suitors who seek her hand in marriage.

Among the suitors are five nobles: Prince Ishitsukuri (石作皇子), Prince Kuramochi (車持皇
子 ), the Minister of the Right Abe no Mimuraji ( 右 大 臣 阿 倍 御 主 人 ), the Grand
Counselor Ōtomo no Miyuki ( 大 納 言 大 伴 御 行 ), and the Middle Counselor Isonokami no
Marotari ( 中 納 言 石 上 麻 呂 ). They eventually persuade the old man to have Kaguya-hime
choose from among them. Uninterested, Kaguya-hime devises five impossible tasks, agreeing to
marry the noble who can bring her the item specified for him: the stone begging bowl of
the Buddha, a jeweled branch from the mythical island of Hōrai, a robe of Chinese fire-rat skins,
a colored jewel from a dragon's neck, and a cowry shell born from a swallow.
Realizing the impossibility of his task, the first noble presents a fake stone bowl made from a
blackened pot, but is exposed when Kaguya-hime notices that the bowl does not glow with holy
light. The second noble presents a branch created by the country's finest jewelers, but is revealed
when a messenger of the craftsmen arrives at Kaguya-hime's house to collect payment. The third
noble is deceived by a merchant from China, who sells him a robe that burns when it is tested
with fire. The fourth noble sets out to find a dragon at sea, but abandons his plans after
encountering a storm. The fifth noble falls from a great height while reaching into a swallow's
nest.
After this, the Emperor of Japan comes to visit Kaguya-hime and, after falling in love, asks her
hand in marriage. Although he is not subjected to an impossible trial, Kaguya-hime rejects his
request for marriage as well, telling him that she is not from his country and therefore cannot go
to the palace with him. She remains in contact with the Emperor, but continues to rebuff his
proposals. Three years pass as they continue to communicate by letter.
That summer, whenever Kaguya-hime views the full moon, her eyes fill with tears. Though her
adoptive parents grow very worried and question her, she refuses to tell them what is wrong. Her
behaviour becomes increasingly erratic until she reveals that she is not of the Earth and that she
must return to her people on the Moon. In some versions, it is said that she was sent to the Earth,
where she would inevitably form material attachment, as a punishment for some crime, while in
others, she was sent to Earth for her safety during a celestial war. The gold was a stipend from
the people of the Moon, sent to pay for Kaguya-hime's upkeep.
As the day of her return approaches, the Emperor sends his guards to protect her from the
Moon's people, but when an embassy of heavenly beings descends upon the bamboo cutter's
house, the guards are blinded by a strange light. Kaguya-hime announces that, though she loves
her many friends on Earth, she must return with the beings to her true home on the Moon. She
writes sad notes of apology to her parents and to the Emperor, then gives her parents her own
robe as a memento. She then takes a little of the elixir of immortality, attaches it to her letter to
the Emperor, and gives it to the guard officer. As she hands it to him, a feather robe is placed on
her shoulders, and all of her sadness and compassion for the people of the Earth are apparently
forgotten. The entourage ascends into the sky, taking Kaguya-hime back to Tsuki no Miyako (月
の都, "the Capital of the Moon") and leaving her earthly foster parents in tears.
The old couple become very sad and are soon put to bed sick. The officer returns to the Emperor
with the items Kaguya-hime gave him as her last mortal act, and reports what happened. The
Emperor reads her letter and is overcome with sadness, and asks his servants, "Which mountain
is the closest place to Heaven?"; in response, one suggests the Great Mountain of Suruga
Province. The Emperor then orders his men to take the letter to the summit of the mountain and
burn it, in the hope that his message would reach the distant princess. They are also ordered to
burn the elixir of immortality, as the Emperor does not wish to live without being able to see her.
Legend has it that the word for immortality, 不 死 (fushi), became the name of the
mountain, Mount Fuji. It is also said that the kanji for the mountain, 富士山 (literally "mountain
abounding with warriors"), are derived from the Emperor's army ascending the slopes to carry
out his order. It is said that the smoke from the burning still rises to this day. (In the past, Mount
Fuji was a much more active volcano and therefore produced more smoke.)

COMPONENT ACADEMIC TEXT NON ACADEMIC TEXT

Purpose To inform the Use of Ketamine To tell a legend about Kaguya
as a Treatment for Depression Princess
and Alcohol Use Disorders
Review Received: 2020, Vol. 12 No. 10 unknown
Language Formal and scientific language Use informal and casual
language/words
Author’s Credencial Brendan Kelleher is currently unknown
pursuing a Bachelors degree in
Biology at Tufts University in
Medford, MA.
Referencing Scientific journal article in Unknown, or from a
Inquiries Journal website legend/myth