Page 44 - ITPS-8-1

INNOSC Theranostics and
Pharmacological Sciences Ketamine for cocaine use disorder

behavioral response in rodents to repeated exposure in humans. In addition, since most studies of ketamine
to psychostimulant drugs, and it shares features with explore its antidepressant effect, it would be beneficial
addiction in humans. 102,103 Thus, these studies suggest that to specifically study female versus male responses to
females are at a higher risk of ketamine abuse compared ketamine’s therapeutic effect on CUD.
to males.
7. Abstinence or use reduction as primary
However, studies have also shown that, at a higher
dose (20 mg/kg), ketamine administration in juvenile goal of pharmaceutical intervention of CUD
male rats increased the preference for cocaine during While evidence suggests that ketamine may reduce
adulthood. This effect was not observed in female rats at cocaine use, research on whether subanesthetic ketamine
any age, suggesting that males might be at a higher risk for can lead to long-term abstinence generated mixed
ketamine-related drug abuse potential. Another study results. Dakwar et al. measured cocaine use behavior a
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investigating ketamine’s abuse potential at 80 mg/kg found month after ketamine treatment and found that a mere
female Sprague-Dawley rats across all ages produced two of the eight participants achieved urine-confirmed
high locomotor activity, whereas only preweaning male abstinence at follow-up. However, the same group
Sprague-Dawley rats showed a similar response, with adult performed a more extensive study with 55 patients who
and adolescent males displaying less activity. 105 received a single ketamine infusion or midazolam during

One reason for the discrepancy in research results might 5 days of hospitalization. Each participant also attended
be that different strains of rats may respond differently daily sessions of mindfulness-based relapse prevention
111
st
to ketamine. Taken together, these results suggest that (MBRP). After the 1 week, the participants received
106
both age and sex need to be considered when exploring 4 weekly sessions of MBRPs. Six months later, a follow-up
ketamine’s potential side effects. interview is conducted through telephone to assess cocaine
use. This study found that ketamine is associated with
6.3. Implication for developing ketamine as CUD lower levels of cocaine use, craving, and time to relapse.
harm-reduction strategy A significantly greater proportion of people remained
The pre-clinical research results mentioned above highlight abstinent during the 6-month interview. This study shows
the importance of continuing to explore the sex-dependent the potential of using ketamine as a pharmacotherapy
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effect of ketamine. This is especially important since cocaine in conjunction with behavioral therapy to treat CUD.
addiction is also sex-dependent, with females being more However, future studies with larger, more diverse samples
likely to progress through the addiction cycle, and cocaine- and objective evaluations of cocaine use at 6 months
seeking behavior correlates with female sex hormone are needed to assess the effectiveness of subanesthetic
levels. 107,108 However, it is also important to recognize that ketamine better.
the biological differences between humans and rats may Although abstinence is often the primary goal in CUD
render pre-clinical research results less beneficial when interventions, recent research confirms that reducing
developing ketamine as a treatment. cocaine use can be considered a viable treatment outcome
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Clinical research did not seem to find that humans for cocaine-dependent individuals. For instance, Amin-
113
exhibit sex-dependent responses to ketamine. One clinical Esmaeili et al. analyzed data from 13 randomized
study that investigated ketamine’s antidepressant effect controlled clinical trials on pharmacological interventions
found that, although there was no significant difference for cocaine or methamphetamine use disorder. They found
in ketamine’s treatment response in males versus females, that individuals who reduced their use frequency from
females reported more headache and nausea as ketamine’s high to low experienced improvements in drug-related
side effect. However, the difference between the male symptoms, cravings, and comorbid depression scores.
versus female side effects was not significant. In addition, Notably, a significant portion of these individuals tested
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a 2022 systematic review of 27 clinical studies published negative for drugs in urine tests 1 month later, indicating
from 2012 to 2020 found no significant sex difference in that reduced use can improve quality of life and support
response to ketamine treatment. 110 further reductions.
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The discrepancy between the conclusions of the rat Similarly, Roos et al. used data from seven randomized
and human studies might be due to the size limitation controlled trials for CUD to evaluate the clinical utility of
in most clinical trials. While the biological differences reduction in cocaine use frequency as a non-abstinence
between rats and humans should not be overlooked, there endpoint. The investigators separated participants into
is a need for larger trial clinical studies exploring how three levels at baseline and end-of-treatment (EOT):
sex hormones influence response to ketamine therapy Abstinence, low frequency, and high frequency. In general,

Volume 8 Issue 1 (2025) 38 doi: 10.36922/itps.4458