Sex differences in sub-anesthetic ketamine’s antidepressant effects and abuse liability

This paper is a narrative synthesis of clinical and preclinical literature rather than a systematic review with a formal, reproducible search strategy. The extracted text does not report databases searched, date ranges, explicit inclusion/exclusion criteria, or a risk‑of‑bias assessment, so the methods for study selection and synthesis are not clearly specified in the provided material. Within that narrative framework, the authors consider randomized clinical ketamine trials and meta‑analyses where sex was reported or explored, human observational work on recreational ketamine use, and a range of rodent experiments assessing antidepressant‑ and addiction‑like behaviours and molecular endpoints. Preclinical studies discussed include acute and repeated dosing regimens across behavioural assays (forced‑swim test, novelty‑suppressed feeding, sucrose preference, locomotor sensitisation, conditioned place preference, intravenous self‑administration) and molecular measures (spine density, synaptic protein expression, BDNF, Akt/mTOR signalling, metabolite levels). Where dosing and experimental details are available in the extraction, these are noted (for example, clinical acute infusion 0.5 mg/kg over 40 minutes; preclinical doses ranging from 2.5 to 14 mg/kg and a chronic regimen of 10 mg/kg daily for 21 days).

Clinical evidence examining sex as a moderator of ketamine's antidepressant efficacy is limited and mixed. A small meta‑regression of six studies (n = 103) reported no contribution of sex, age or drug history to efficacy. A larger meta‑analysis of 21 studies (n = 437) found no sex effect at 4‑hour and 24‑hour time points after a single 0.5 mg/kg/40 min infusion, but a higher proportion of male subjects predicted greater efficacy at the 7‑day time point. The extracted text notes that dose‑ and repeated‑infusion effects by sex have not been reported clinically. Preclinical findings more consistently indicate sex differences. Stress‑naïve female rodents often respond behaviourally to lower ketamine doses than males on assays relevant to antidepressant efficacy (forced‑swim test, novelty‑suppressed feeding). Results for anhedonia measured by sucrose preference are conflicting, complicated by baseline sex differences in sucrose intake and methodological factors such as access duration. In some chronic stress paradigms males show decreases in sucrose preference and synaptic markers that are reversed by acute ketamine, whereas females do not always show the same behavioural or synaptic rescue. Notably, chronic ketamine (10 mg/kg daily for 21 days) produced antidepressant‑like effects in males but pro‑depressive and anxiogenic effects in females in one study. At the molecular level, ketamine's putative mechanism in males involves NMDA receptor blockade on inhibitory interneurons in the medial prefrontal cortex (mPFC), leading to increased excitatory drive, activation of Akt and mTOR signalling, rapid protein synthesis, synaptogenesis and increased spine density. Several studies in males report reversal of stress‑induced reductions in mPFC spine density and synaptic proteins (PSD‑95, synapsin, GluA1) after acute ketamine. By contrast, females sometimes show different neurochemical responses: ketamine did not rescue mPFC spine density in certain female models despite behavioural effects, hippocampal glutamate increases seen in males were absent in females, females showed increased aspartate in the mPFC and increased hippocampal serotonin turnover. Gonadal hormones influence responsivity: ovariectomy abolished responsiveness to a low ketamine dose that is effective in intact females, and replacement of estradiol and progesterone restored the effect; pharmacological activation of estrogen receptors enhanced ketamine's behavioural response in intact females. Preclinical pharmacokinetic differences were reported, with female rodents showing higher brain levels of norketamine and hydroxynorketamine (HNK) metabolites; in humans females showed higher plasma (2S,6S;2R,6R)‑HNK levels, though correlations with clinical response were inconsistent across metabolites. Regarding abuse liability, observational human data and preclinical models suggest sex‑specific patterns. Female recreational users report greater cognitive impairment and stronger withdrawal than males, and women using ketamine with amphetamine‑type drugs have higher rates of mood disorders compared with males. Neuroimaging in a predominantly male chronic user sample showed decreased thalamocortical connectivity; in mixed samples female users had higher depression scores and different prefrontal connectivity correlates with depression severity. In rodents, females display greater locomotor sensitisation to intermittent ketamine at depression‑relevant doses (2.5–10 mg/kg), an effect linked to plasticity in reward circuits that might predispose to addiction. Conditioned place preference (CPP) findings are mixed: some studies report aversion in females at 5 mg/kg, whereas other studies using higher doses (6–14 mg/kg daily) found greater CPP in females than males. Hormonal state modulates reinforcing effects: females maintain self‑administration during proestrus (high estradiol and progesterone) but not during diestrus 1 (low hormones), and adolescent females show stronger locomotor responses than males, suggesting developmental and activational hormone influences. Molecularly, single ketamine increases hippocampal BDNF while chronic self‑administration decreases it; Akt signalling and mTOR phosphorylation can be regulated in opposite directions after acute versus repeated exposure, with region‑ and sex‑specific patterns. The nucleus accumbens shows opposite GluA1 phosphorylation after single versus chronic exposure. Many of these addiction‑related molecular studies have been conducted only in males, limiting conclusions about females.

Wright and colleagues interpret the assembled literature as indicating that sex is an important, yet under‑studied, factor in ketamine's antidepressant efficacy and abuse liability. They emphasise that while ketamine produces rapid, clinically meaningful antidepressant effects in treatment‑resistant depression, critical gaps remain concerning long‑term safety and the point at which therapeutic benefit may be offset by risk of addiction. The authors highlight preclinical evidence that females can be more sensitive to ketamine's behavioural effects at lower doses, and that ovarian hormones and sex‑specific pharmacokinetics (for example, higher levels of certain HNK metabolites in females) may underlie these differences. The review positions these findings relative to earlier work by noting that mechanistic models developed largely in male animals—such as mPFC disinhibition, Akt/mTOR activation and synaptogenesis—may not fully explain female responses. Several studies cited show divergent molecular outcomes in females, including a failure to rescue mPFC spine density at doses effective in males, and distinct patterns of glutamate, aspartate and serotonin turnover. The authors therefore argue that translational interpretation of male‑centric mechanistic data is limited and that sex‑specific pathways merit direct investigation. Key limitations acknowledged in the extracted text include the scarcity of clinical analyses testing sex as a moderator (no dose‑dependent or repeated‑infusion sex analyses reported), the predominance of male subjects in many preclinical molecular studies, inconsistent behavioural assays and methodological factors that complicate interpretation (for example in sucrose preference testing), and incomplete characterisation of ketamine metabolites across sexes. The authors call for more systematic research that includes females, examines hormonal status and developmental stage, characterises pharmacokinetics and metabolites by sex, and compares acute versus repeated exposure paradigms to delineate therapeutic versus addiction‑related mechanisms.

The authors conclude that ketamine's rapid antidepressant properties are promising but that important uncertainties about long‑term effects and addiction risk remain, particularly for women who have higher depression prevalence and may progress more rapidly through addiction stages. Preclinical evidence suggests sex differences in sensitivity, mechanism and vulnerability, yet clinical and molecular studies frequently omit sex‑specific analyses. Wright and colleagues recommend prioritising sex‑inclusive experimental designs, systematic study of dose and repeated regimens by sex, investigation of gonadal hormone modulation and metabolite pharmacology, and focused efforts to determine the threshold at which therapeutic use could carry unacceptable addiction risk.