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INNOSC Theranostics and
Pharmacological Sciences Ketamine for cocaine use disorder

craving and drug-seeking behaviors in cocaine users specialists, to identify ketamine as the best candidate
while acknowledging its potential for misuse. In addition, for reducing the harm of CUD. They then assessed
we review ketamine’s potential mechanisms and sex- ketamine’s therapeutic effects retrospectively using data
dependent differences in ketamine’s therapeutic effect. from a de-identified patient database. Compared to
Finally, we identify a barrier to developing interventions cohorts who received other antidepressants or anesthesia
for cocaine abuse as the expectation of abstinence. medications, cohorts that received ketamine had a
Grounding the approval standards for pharmacological higher CUD remission rate. Prospective clinical studies
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interventions on more realistic patient-centered also support subanesthetic ketamine’s effectiveness in
outcomes would allow for the repurposing of ketamine decreasing craving and drug-seeking behaviors. In a
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as an efficacious harm-reduction medication for CUD. 2013 clinical trial, Dakwar et al. evaluated the effect
of subanesthetic ketamine in eight non-treatment-
2. Pre-clinical studies on ketamine’s seeking cocaine-dependent participants. A single
effectiveness in reducing cocaine use ketamine infusion significantly increased motivation to
quit and reduced cue-induced craving, demonstrating
In pre-clinical settings, subanesthetic ketamine can ketamine’s potential to motivate behavioral change.
decrease cue-induced drug-seeking behaviors and lead to The same investigators later explored whether a single
changes in brain connectivity associated with increased subanesthetic dose of ketamine could disrupt cocaine
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executive control. Fitzpatrick and Morrow conducted self-administration in a cohort of 20 cocaine-dependent
a study using a Pavlovian-conditioned approach to individuals disinterested in abstinence. After infusions
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investigate the effect of subanesthetic ketamine in rats, of subanesthetic doses of ketamine, participants chose
focusing on two behaviors: sign-tracking and goal-tracking. between immediate cocaine self-administration and
Sign tracker rats, who attribute motivation incentives to delayed monetary rewards. Remarkably, a single
reward cues, display increased drug-seeking behavior, ketamine dose also significantly decreased cocaine
whereas goal tracker rats do not model addictive behavior. self-administration. A hallmark feature of substance
Subanesthetic ketamine at 32 mg/kg dose decreased sign- use disorders is a persistent desire to use the drug such
tracking behavior in sign-trackers without affecting goal- that it becomes the only goal of the affected individual’s
tracking behavior in goal-trackers, with effects lasting life. The fact that a single subanesthetic dose of
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up to 48 h post-administration. This indicates that a ketamine enabled non-treatment-seeking subjects to
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subanesthetic dose of ketamine reduced reward-seeking choose money over cocaine is a testament to ketamine’s
behaviors in the rats that were most vulnerable to impaired potential as a CUD harm-reduction therapy.
executive function related to addiction. Similarly, a study
on cocaine-exposed rhesus monkeys evaluated the effects 4. Abuse potential of ketamine
of subanesthetic ketamine on functional brain connectivity
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and cocaine self-administration. Ketamine treatment Due to its history of recreational misuse, ketamine
as a treatment for CUD may raise concerns about
at 48 h before cocaine self-administration reduced the abuse potential and adverse effects. Ketamine use for
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cocaine-induced decrease of functional brain connectivity
between brain regions involved in decision-making and recreational purposes has increased in recent years,
reward processing. A separate cohort of cocaine-exposed as reflected by a significant rise in ketamine-related
seizures from 2012 to 2019. However, ketamine differs
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rhesus monkeys exhibited reduced drug- and cue-induced from substances such as cocaine in that ketamine does
reinstatement following subanesthetic ketamine. These not modulate synaptic plasticity in the same way. Both
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findings demonstrate ketamine’s ability to decrease drug clinical and pre-clinical studies suggest low abuse potential
intake by modulating the interaction between different at subanesthetic doses of ketamine. For instance, a study
brain areas.
found that daily ketamine doses of 2.5 and 5 mg/kg over
3. Clinical studies on ketamine’s 6 days failed to evoke a conditioned place preference in
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effectiveness in reducing cocaine use rats. In addition, although the S enantiomer of ketamine
has a more substantial behavioral effect and is responsible
Although clinical studies provide relevant models of for ketamine’s abuse potential, 30,31 most clinical trials
substance abuse behaviors, their findings may not use a racemic mixture of ketamine to improve CUD
always translate directly to human subjects. Nonetheless, outcomes. Because substance abuse is greatly context-
many clinical research results were consistent with that dependent, when subanesthetic ketamine is administered
of the pre-clinical studies. In an observational study, in professionally controlled settings, ketamine’s abuse risk
Gao et al. used artificial intelligence, validated by is minimized by effective monitoring and administration
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Volume 8 Issue 1 (2025) 34 doi: 10.36922/itps.4458