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INNOSC Theranostics and
Pharmacological Sciences Ketamine for cocaine use disorder

MDD. 77,81,82 Thus, instead of consistently up- or down- this difference. Multiple pre-clinical studies showed that
regulating BDNF, cocaine appears to cause fluctuation in females are more sensitive to ketamine at a lower dose,
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BDNF levels that contribute to the addiction. 74 and its effect is estrogen-dependent but not testosterone-
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Consistent with ketamine’s interaction with the dependent. For instance, in response to ketamine, there
mesolimbic system, ketamine can also modulate BDNF, is a significant increase in BDNF levels in female depressed
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which, along with TrkB, is expressed in the VTA-NAc rats compared to male ones. Specifically, proestrus, but
not diestrus, female C57BL/6 mice exhibited enhanced
circuit. Several studies found that ketamine can increase sensitivity to a very low dose of ketamine (1.5 mg/kg),
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BDNF expression in various brain areas, an effect that can possibly due to estradiol’s effect on synaptic plasticity. 96
last up to 30 days after a single infusion of ketamine. 84,85
In clinical studies, higher plasma BDNF level is associated These studies seem to point to estrogen as the reason
with the anti-depressant effect of ketamine in patients. 86,87 behind females’ heightened sensitivity to ketamine.
Other studies also directly demonstrated BDNF’s However, several other studies that investigated the
effectiveness in reducing cocaine consumption, as pre- pharmacokinetics of ketamine found the male hormones to
clinical research shows that a single injection of BDNF to be responsible for the sex-dependent differences. Highland
the dorsomedial prefrontal cortex and NAc can decrease et al. found that, compared to male rats, female CD-1 rats
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cocaine-seeking behavior. Notably, such effect is specific have a higher plasma level of a ketamine metabolite at
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to cocaine and no other natural awards such as sucrose 10 and 30 min after ketamine injection. This metabolite,
solution. 87,88 Together, this evidence suggests that ketamine hydroxynorketamine, is responsible for the antidepressant
might facilitate CUD treatment by stabilizing the BNDF effect of ketamine. On the other hand, male rats have a
level. Nonetheless, studies that specifically explore this higher plasma level of unmetabolized ketamine. While
relationship should be conducted. ovariectomy did not eliminate the difference between
female and male ketamine metabolism, orchidectomy did,
One limitation of the clinical studies mentioned above
is that most measured plasma BDNF as a proxy for brain suggesting that testosterone may play a role in ketamine
metabolism. This is inconsistent with another study by
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BDNF levels. This is because BDNF crosses the blood– Saland et al.,94 which found that female Sprague-Dawley
brain barrier easily, and there is a high correlation between rats have higher ketamine plasma levels 30 min post-
plasma and cerebral spinal fluid concentration in BDNF.76 injection. Yet, since Saland et al. did not find a difference
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However, BDNF’s effects vary across brain regions. For between proestrus and postestrus rats, both studies
example, increased VTA BDNF expression enhances agreed that female hormones do not play a role in the sex-
cocaine seeking, but injection into the dorsomedial dependent difference in ketamine pharmacokinetics. In
prefrontal cortex attenuates CUD relapse. 89,90 Thus, while addition, studies found that ketamine might exert its effect
plasma or serum BDNF is the best choice for clinical partially through interacting with mu-opioid receptors,
studies, pre-clinical studies can further elucidate the brain and this effect was only significant in male rats. 98,99 This
area where BDNF acts to facilitate ketamine’s therapeutic opioid-dependent effect is reversed by orchiectomy,
effect on CUD. suggesting that testosterone plays a role in the ketamine
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6. Sex differences in response to ketamine effect. This is consistent with a study that showed
concurrently administering naltrexone, a mu-opioid
While plenty of evidence illustrates ketamine’s potential receptor antagonist, with ketamine in a female human
effectiveness in treating CUD, pre-clinical studies also subject did not block ketamine effects. Thus, these
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suggest that there might be a difference in ketamine’s harm- studies suggest that testosterone could either be driving
reduction effect in males versus females. For instance, the observed sex differences in ketamine sensitivity or that
ketamine rescued social isolation-induced decreases in males are more sensitive to ketamine, directly opposing the
mPFC spine density in male but not female rats. In studies mentioned in the previous paragraph.
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addition, continuous administration of a subanesthetic
dose of ketamine resulted in antidepressant effects in male 6.2. Sex- and age-dependent differences in
rats but anxiety- and depressive-like behavior in female ketamine’s abuse potential
rats. 92 In addition to its therapeutic effect, ketamine’s abuse
potential may also be sex-dependent. A study found
6.1. Which hormones are responsible for these sex- that female rats exhibit higher locomotor sensitization
dependent differences?
to repeated antidepressant doses of ketamine, with this
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Although evidence points to a sex-dependent response effect occurring at a lower dose in female rats than in
to ketamine, studies differ on which sex hormone causes male rats. Locomotor sensitization is the increased
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Volume 8 Issue 1 (2025) 37 doi: 10.36922/itps.4458