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INNOSC Theranostics and
Pharmacological Sciences Ketamine for cocaine use disorder

in medical contexts. 19,26 Dakwar et al. reported that 5. Potential mechanisms behind ketamine’s
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high and low subanesthetic doses of ketamine could be harm-reduction effect
safely given under controlled conditions to participants
with CUD who do not engage in ketamine misuse. In Despite the clinical and pre-clinical evidence pointing to
addition, the repurposing of subanesthetic ketamine ketamine’s potential in care for CUD, the mechanisms
for treatment-resistant depression (TRD) illustrates the behind its therapeutic effects remain contentious. One
feasibility of employing ketamine as a CUD intervention. possible mechanism might be implicated in ketamine’s
The nasal spray Spravato, composed of the S-ketamine effectiveness in treating depression, as clinical studies
enantiomer, was approved by the FDA as a treatment for have been investigating anti-depressants’ potential in
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TRD in 2019. Spravato is accessible through a controlled treating substance use disorder. The co-occurrence of
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distribution program in the United States and Canada, major depressive disorder (MDD) and substance abuse
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which requires direct supervision and monitoring by is common, and cocaine use itself can also induce
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a certified health-care professional for at least 2 h post- depression during periods of heavy drug use.
dose. The same distribution model can be utilized for In addition, studies find that both cocaine-induced
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the treatment of CUD with subanesthetic ketamine to depression and independent MDD are associated with
ensure cocaine-dependent individuals can safely receive substance use relapse in both rats and humans. 41,42 Thus,
medical care. this bidirectional relationship – where cocaine can trigger
depression, and depression can hinder remission from
Although research shows that administering
subanesthetic doses of ketamine should be safe in clinical use – underscores the importance of addressing both
conditions simultaneously. Given that depression, CUD,
settings, ketamine misuse can still cause unpleasant and ketamine all modulate overlapping neurological
side effects and pose health risks. Ten to twenty pathways, ketamine may be particularly well-suited for
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percent of ketamine users experience the emergence treating CUD by targeting these shared mechanisms.
phenomenon, which is a collection of symptoms
including hallucinations, delirium, euphoria, and paucity 5.1. Ketamine directly modulates the dopaminergic
of speech. Ketamine can also cause changes in heart rate system
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and blood pressure, posing risks for users with a history One possible mechanism is that ketamine modulates the
of myocardial infarction or hypertension. Nonetheless, monoamine systems that are involved in both cocaine
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the side effects of ketamine are both a curse and a blessing addiction and depression. Cocaine withdrawal often
when considering its potential as a pharmacotherapy. triggers depressive symptoms, which, unlike MDD,
Subanesthetic doses of ketamine might also cause a range temporarily improve with cocaine use and respond
of psychoactive effects, some of which might appear like poorly to selective serotonin reuptake inhibitors. The
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“spiritual” experiences. They might assist in individuals’ association between cocaine and depression is due to
transition from one lifestyle to another guided by ethical cocaine’s mechanism of action. Cocaine works by binding
values. Dakwar et al. performed two more clinical to the dopamine transporters (DAT) responsible for the
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trials to investigate whether these effects contribute to the reuptake of dopamine and by upregulating D1 dopamine
decrease in cocaine-seeking behavior. In 2014, the group receptors (D1Rs), which have stimulatory effects and are
recruited eight participants with CUD. The exposure often involved in compulsive drug intake. 44,45 Both actions
group received two ketamine infusions of different can lead to an increase in dopamine signaling. 46
doses separated by 48 h, and another group received the
positive control lorazepam. In a 2019 follow-up study, When cocaine use stops, there is an acute decrease in
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47
the researchers examined 20 participants over three striatal dopamine levels and a reduction of dopamine
6-day hospitalization sessions. Participants received receptor 2 (D2R) signaling in the ventral striatum due to
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either ketamine or positive control during the second reduced D2R sensitivity. Such reduction is also seen in
and third hospitalization sessions. Both studies found independent depressive disorder, which is associated with
that mystical effects mediated ketamine’s effectiveness a decrease in several monoamines, including serotonin
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in reducing cocaine-seeking behavior, though the 2019 and dopamine. In addition, long-term cocaine users will
study also noted that these effects might reflect individual develop tolerance, leading to increased DAT density and
sensitivity to ketamine rather than its therapeutic impact reduced dopaminergic (DAergic) signaling, 48,50 thereby
alone. Thus, some of ketamine’s psychiatric side effects reinforcing cocaine use.
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of ketamine might even be the underlying mechanism of Ketamine, which also affects the DAergic system, may
its ability to improve CUD remission. potentially reverse cocaine’s effect. Studies found that

Volume 8 Issue 1 (2025) 35 doi: 10.36922/itps.4458