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Treating addiction with an addictive drug: the ketamine paradox revisited

BackgroundSubstance use disorders (SUDs) and treatment-resistant depression (TRD) remain a major global health challenge, marked by high relapse rates and limited long-term effectiveness of existing treatments. Ketamine, a glutamatergic modulator with rapid neuroplastic effects, has emerged as a novel intervention for TRD and is increasingly investigated as an adjunctive treatment for addiction, yet concerns about its abuse liability persist.ObjectiveThis review critically evaluates ketamine’s therapeutic potential for SUDs while examining its neurobiological mechanisms, clinical efficacy, and risk of misuse within a unified risk–benefit framework.MethodsA structured narrative review conducted in accordance with the SANRA framework using the PubMed, Scopus, PsycINFO, and Web of Science databases, covering literature published until March 2026. Eligible studies included clinical trials, experimental studies, and mechanistic investigations relevant to ketamine use in addiction and depression. Evidence was synthesized thematically across the domains of efficacy, mechanisms, and safety.ResultsAcross alcohol and cocaine use disorders, ketamine combined with psychotherapy has demonstrated promising reductions in craving and increases in abstinent days in small-to moderate-sized Phase 2 trials. However, findings remain difficult to generalize due to considerable variability in dosing strategies, comparator conditions, and follow-up periods. Effects on relapse prevention have been more inconsistent and less reliably positive. Mechanistically, ketamine promotes synaptic plasticity via NMDA receptor antagonism and downstream glutamatergic signaling, potentially disrupting maladaptive reward-related memories and reversing maladaptive neurocircuitry involved in both depression and addiction. While acute adverse effects are generally transient under clinical supervision, ketamine carries a well-established risk of misuse, particularly in unsupervised or high-dose settings.ConclusionsKetamine represents a promising but still experimental intervention for both refractory depression and selected SUDs. Its clinical use depends on careful patient selection, structured delivery, and integration with psychotherapy. Although ketamine may redefine treatment paradigms for TRD and addiction, larger-scale trials and long-term safety data are essential to define its role within psychiatric and addiction treatment frameworks.
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Loneliness, rumination, and adolescent psychological crisis in China: a pilot moderated mediation study

BackgroundAdolescent psychological crisis—encompassing depressive disorder, anxiety disorder, and suicidal ideation—is a major public health challenge. One in five adolescents experiences a clinically significant mental health condition globally. Loneliness is a well-documented, modifiable risk factor for these outcomes. However, the exact cognitive-emotional pathways linking loneliness to acute psychological crisis remain unclear. This is particularly true in China, where rapid social change and intense academic pressure increasingly strain adolescent mental health. We do not yet fully understand how protective resources might buffer these specific pathways.Objectives and methodsThis pilot study tests a moderated mediation model based on the Evolutionary Theory of Loneliness and the stress-vulnerability framework. We investigate ruminative thinking as a cognitive-emotional mediator between loneliness and psychological crisis. We also test whether perceived social support and psychological resilience moderate distinct stages of this pathway. Based on a pilot sample of N = 312 Chinese adolescents (ages 12–18), we use structural equation modelling (SEM), confirmatory factor analysis (CFA), and Hayes’ PROCESS Macro (Model 14) with 5, 000 bootstrap replications. Two-wave longitudinal data (n = 187, 8-week interval) were available for the depression outcome only; the anxiety and suicidal-ideation pathways were examined cross-sectionally.ResultsLoneliness is significantly associated with depressive symptoms (β = 0.43, p < 0.001), anxiety (β = 0.38, p < 0.001), and suicidal ideation (β = 0.27, p < 0.001). Ruminative thinking accounts for 40–46% of the total indirect association across all three outcomes. Social support buffers the transmission from loneliness to rumination (b = −0.16, p = 0.002, ΔR2 = 0.023), while resilience buffers the transmission from rumination to crisis (b = −0.19, p < 0.001, ΔR2 = 0.031).ConclusionsThese preliminary, exploratory findings are consistent with the possibility that ruminative thinking partially accounts for the cross-sectional association between loneliness and adolescent psychological crisis in China, and with social support and resilience attenuating this association at potentially distinct stages. Because the pilot is underpowered for the moderated mediation model and the available longitudinal evidence covers depression only, the moderation and stage-specificity results should be read as hypothesis-generating rather than confirmatory. A planned full-scale study (N ≥ 1, 200) will test these mechanisms further. We also outline initial practical implications for school-based interventions.
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Real-world outcomes of intranasal esketamine and intravenous ketamine induction therapy for treatment-resistant depression in a community clinic: a retrospective cohort study

IntroductionIntravenous (IV) ketamine and intranasal esketamine are NMDA receptor antagonists used for treatment-resistant depression (TRD). Both have demonstrated efficacy in controlled trials, but observational evidence from real-world community settings is limited.MethodsWe conducted a single-center retrospective cohort study of adults aged 18 to 65 receiving induction therapy for TRD with intranasal esketamine or IV ketamine at a community psychiatric clinic from January 1 through December 31, 2025. Patients with prior exposure to either medication or to oral ketamine derivatives were excluded. The primary outcome was change in Patient Health Questionnaire-9 (PHQ-9) score from baseline to end of induction. Secondary outcomes included response (≥50% PHQ-9 reduction), remission (final PHQ-9 ≤4), clinically meaningful improvement (≥5 PHQ-9 reduction), induction completion, and adverse events. Within-group and per-protocol analyses were exploratory.ResultsSixty-three patients met inclusion criteria (esketamine n=37; IV ketamine n=26). Baseline PHQ-9 scores were similar (18.22±4.49 vs. 18.27±5.41; P = 0.967), as was mean change from baseline (-10.31±5.59 vs. -9.50±5.69; mean difference 0.81, 95% CI -2.12 to 3.75; P = 0.589). Response rates were 64.9% vs. 69.2% (RR 0.94, 95% CI 0.66 to 1.33; P = 0.790), remission 32.4% vs. 23.1% (RR 1.41, 95% CI 0.61 to 3.26; P = 0.573), and clinically meaningful improvement 83.8% vs 73.1% (RR 1.15, 95% CI 0.87 to 1.51; P = 0.353). Induction completion exceeded 90% in both groups; one patient per cohort discontinued from intolerable side effects, and no serious adverse events occurred. Within-group PHQ-9 reduction was large: 10.31±5.59 points (paired t[34]=10.91; P<0.001; Cohen’s d=1.84) for esketamine and 9.50±5.69 points (paired t[23]=8.18; P<0.001; Cohen’s d=1.67) for ketamine. Findings remained statistically significant and clinically large under a pre-specified baseline observation carried forward (BOCF) sensitivity analysis (Cohen’s d=1.65 and 1.45).ConclusionsInduction therapy with intranasal esketamine and intravenous ketamine was associated with robust antidepressant effects in a community outpatient setting, consistent with prior trial data. The modest sample size limits power to detect between-group differences and increases the risk of type II error; the absence of statistically significant between-group differences should therefore not be interpreted as evidence of equivalence. Protocol asymmetry between arms (esketamine: 12 sessions over 8 weeks; IV ketamine: 6 sessions over 3 weeks) further limits direct comparison of endpoint values between groups. Practical considerations including insurance coverage, cost, and administration logistics may help guide treatment selection. Longitudinal follow-up is planned to characterize treatment durability.
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Autism service barriers for Latine children and their families: a participatory approach to adapting autism diagnostic care

IntroductionLatine children from families with limited English proficiency (LEP) experience barriers to timely autism diagnosis resulting in persistent health inequities. This participatory mixed-methods study examined these barriers and identified multi-level strategies to adapt diagnostic care models for Spanish-speaking Latine families.MethodsParticipants included twelve caregivers of thirteen autistic children with parent reported diagnosis of autism, twelve clinicians, and six care coordinators. All participants completed surveys and participated in qualitative interviews or focus groups.ResultsQuantitative findings revealed significant lag between caregiver’s first developmental concern and diagnosis, limited autism knowledge, and difficulty navigating care. Qualitative results highlighted systemic barriers, including clinician-patient language discordance, interpreter inaccuracies and quality variability, cultural stigma, and long waitlists. Clinicians reported challenges with communicating about autism with Spanish-speaking families and emphasized language and cultural differences as primary barriers. Caregivers described social isolation, mistrust of health systems, and emotional distress compounded by immigration-related stressors.DiscussionFindings underscore the need for structural adaptation of care approaches beyond translation services.