Psychedelic microdosing has gained increasing popularity for enhancing mood and cognition, yet its effects on psychological outcomes in healthy adults remain unclear. We aim to evaluate the efficacy and safety of psychedelic microdosing on psychological outcomes in healthy/non-clinical adult population. This review was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD420251035294). We searched Embase, MEDLINE, and PsycINFO from inception to February 2026 for original studies in healthy adults using sub-hallucinogenic psychedelic doses on separate days. We included randomized studies, nonrandomized prospective studies, cross-sectional studies, and observational longitudinal designs and stratified meta-analyses by design. Random-effects models were used; safety in randomized controlled trials (RCTs) was pooled as risk differences (RDs). Risk of bias was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools appropriate for each study design. 24 studies (3,681 participants) met inclusion criteria, 6 contributed to meta-analyses. RCTs of psilocybin and LSD microdosing showed subjective and neurophysiological effects but minimal impact on cognition, creativity, or sustained mood. Psilocybin altered EEG and speech with little behavioral change, while LSD caused transient mood and minor physiological effects without lasting cognitive or personality benefits. Observational studies indicated mood and personality improvements, likely influenced by expectancy or lifestyle factors. Meta-analyses included two parallel RCTs (3 comparisons; n = 117) and three non-RCT studies (n = 1,013). Adverse event analyses included two RCTs (4 comparisons; n = 109). RCTs showed no clear evidence of immediate symptom reduction: depressive symptoms (SMD = −0.19; 95
Teriflunomide is widely used as an active comparator in Phase 3 randomised trials for relapsing multiple sclerosis (RMS). Temporal changes in disease activity within teriflunomide-treated cohorts have not been systematically examined. To assess temporal trends in relapse and disability outcomes across teriflunomide arms of Phase 3 multiple sclerosis (MS) trials and identify predictors of between-trial heterogeneity. We performed a systematic review and meta-analysis of Phase 3 randomised controlled trials including a teriflunomide arm. PubMed, Scopus, and ClinicalTrials.gov were searched up to October 2025. Annualised relapse rate (ARR) and 12- and 24-week confirmed disability worsening (CDW) were extracted together with baseline characteristics. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Random-effects meta-analyses, meta-regression, and sensitivity analyses were performed. Twelve teriflunomide cohorts from eight trials involving 4,900 adults with RMS were included. ARR ranged from 0.11 to 0.37 with substantial heterogeneity (I2 = 94
Randomised controlled trials (RCTs) have demonstrated that pharmacotherapy reduces symptoms of attention-deficit/hyperactivity disorder (ADHD) at a group level, but efficacy and tolerability vary across individuals. Clinico-demographic characteristics may act as predictors and/or moderators of treatment efficacy and tolerability, but systematic evidence remains limited. Therefore, we systematically analysed RCTs of ADHD medications to identify potential demographic and clinical predictors/moderators of efficacy and tolerability across the lifespan. Randomised controlled trials were identified from the MED-ADHD database ( https://med-adhd.org/ ), a repository of RCTs of medications for ADHD in children, adolescents and adults. The database is based on systematic searches of multiple electronic sources, including PubMed, BIOSIS Previews, CINAHL, the Cochrane Central Registry of Controlled Trials and EMBASE, and is also complemented by unpublished data obtained from manufacturers and study authors. We used the most recent (2026) version of MED-ADHD. The risk of bias was assessed using the revised Cochrane risk-of-bias tool (RoB 2). Among the 171 RCTs screened, 62 assessed clinico-demographic factors as possible predictors or moderators of treatment efficacy and tolerability. Age was the most examined characteristic (56.4
Alzheimer's disease (AD) remains a major cause of dementia, and currently available therapies provide only modest clinical benefit or are limited by intravenous administration and treatment-related adverse effects. Blarcamesine (ANAVEX 2-73) is an orally administered sigma-1 receptor (S1R) agonist that has demonstrated neuroprotective effects in preclinical studies and has progressed through Phase I, Phase II and Phase IIb/III clinical trials. This systematic review evaluated the current clinical evidence for the efficacy and safety of blarcamesine in early-stage and mild-to-moderate AD. A systematic literature search was conducted in PubMed (including MEDLINE), Scopus, and Google Scholar, together with clinical trial registries, with the final search performed in September 2025. Reference sections of manuscripts were searched, and authors were contacted for additional data. Studies investigating only blarcamesine in participants with mild-to-moderate AD were included. Blarcamesine for other diseases or severe AD were excluded. Data were summarised descriptively in accordance with PRISMA guidelines. The risk of bias was assessed using version 2 of the Cochrane Risk of Bias tool (RoB2) for randomised, placebo-controlled trials, and an adapted version of RoB2 for cross-over trials. One Phase I first-in-human study in healthy volunteers and ten reports describing two randomised clinical trials (NCT02244541, a randomised open-label study, and NCT03790709, a randomized placebo-controlled study) and their associated open-label extension studies (NCT02756858 and NCT04314934) were identified, including two peer-reviewed manuscripts, two preprints, and six conference abstracts. Thirty-two participants were enrolled in the Phase IIa open-label dose-finding study, where outcome measures were compared to baseline (NCT02244541). In the extended open-label study exploring the cognitive effect for another 52 weeks, 21 of 32 remained in the study (NCT02756858). The randomised placebo-controlled trial (NCT03790709) enrolled 509 participants and randomised them into three groups: 167 treated with 30 mg blarcamesine, 168 treated with 50 mg blarcamesine and 168 treated with placebo (for 30 mg blarcamesine, 112 completed the study; for 50 mg blarcamesine, 90 completed the study; and for placebo, 136 completed the study). Subsequently, 300 of 509 participants remained in the open-label extension (NCT04314934). Across these two studies, blarcamesine was generally well tolerated, with adverse events that were predominantly mild, transient, and dose-related. Treatment was associated with slower cognitive and functional decline, improvements in multiple clinical outcome measures, and reduced brain atrophy in genetically defined subgroups. Participants carrying the SIGMAR1 and COL24A1 wild-type genotypes were associated with greater therapeutic benefit, supporting the potential value of pharmacogenomic patient stratification. Current clinical evidence suggests that blarcamesine is a promising orally administered therapeutic candidate for early-stage AD with an acceptable safety profile and encouraging efficacy, particularly in genetically defined populations. However, the available evidence is derived from a limited number of clinical studies, including secondary analyses and conference reports. Additional independent randomised clinical trials are required to confirm these findings and further define the role of blarcamesine in the treatment of AD. CRD420251142826.
Current guidelines recommend initial high-intensity statin monotherapy and “the wait and watch paradigm,” even in patients with acute ischemic stroke (AIS). However, newer lipid-lowering therapies allow aggressive low-density lipoprotein cholesterol (LDL-C) reduction without drug class restriction. The effectiveness of triple therapy (early aggressive strategy) comprising a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, ezetimibe, and a high-intensity statin after endovascular thrombectomy (EVT) for emergent large vessel occlusion (ELVO) remains uncertain. We retrospectively analyzed patients with AIS due to ELVO who underwent successful EVT at four comprehensive stroke centers between January 2021 and December 2024. Patients were classified into triple therapy or high-intensity statin monotherapy (standard therapy) and followed up for 90 days. Multivariable regression and propensity score matching were used. Among 197 patients (mean age, 70.8 ± 12.1; 36.0
Drugs that inhibit phosphodiesterase 10A (PDE10A) activity have shown efficacy in animal models. However, clinical trials of PDE10A inhibitors in patients with schizophrenia have failed to provide clinically significant results up to this point. Our study investigated whether alofropodect (previously referred to as CPL’36 or CPL500036), a PDE10A inhibitor with an improved pharmacological profile compared with other PDE10A inhibitors, including a fast dissociation rate and high activity, could improve symptoms of acute schizophrenia. In this phase 2, randomised, double-blind, placebo-controlled, parallel-group trial (11 centres, three countries), investigators randomly assigned hospitalised patients with acute schizophrenia to treatment or placebo groups. The main inclusion criteria were age 18–65 years, a documented diagnosis of schizophrenia for at least 2 years before screening and a positive and negative syndrome scale (PANSS) total score ≥ 80. Participants were randomly assigned (1:1:1) to receive oral alofropodect (20 mg or 40 mg) or placebo administered once daily in the morning for 4 weeks. The primary endpoint of the study was an improvement in the PANSS positive subscale at week 4. The secondary endpoints included improvements in PANSS total and negative subscale scores, along with other efficacy and safety assessments. Clinical responders were defined as those with a ≥ 30
Glioblastoma remains one of the most aggressive primary brain tumors in adults, with a survival rarely exceeding 15 months despite multimodal therapy. Novel immunotherapeutic strategies, particularly chimeric antigen receptor T-cell therapy, have emerged as promising approaches to overcome the limitations of conventional treatments. This review summarizes recent early-phase clinical trials investigating locoregional chimeric antigen receptor T-cell delivery in recurrent glioblastoma and highlights key considerations for multidisciplinary neuro-oncology teams involved in this evolving therapeutic paradigm. Phase I studies of intratumoral, intracavitary, intraventricular, or combined delivery routes have demonstrated technical feasibility and safety, with most adverse events being manageable. Dual-route delivery may enhance chimeric antigen receptor T-cell distribution and produce early radiographic and clinical responses in selected patients. However, therapeutic durability remains limited by tumor heterogeneity, antigen loss, and the immunosuppressive tumor microenvironment. Multidisciplinary care teams play a critical role in catheter and reservoir placement, infusion planning, and management of neuroinflammatory toxicities. Although current findings are preliminary, ongoing optimization of target selection, dosing strategies, and combination therapies may expand treatment options for recurrent glioblastoma and further integrate immunotherapy into contemporary neuro-oncology care.
Obsessive-compulsive disorder (OCD) remains challenging to treat despite established treatments. Since glutamatergic dysregulation is implicated in OCD, we systematically reviewed and meta-analysed randomized controlled trials (RCTs) comparing adjunctive memantine versus placebo for OCD. We searched CENTRAL, Embase, MEDLINE, PsycINFO, PubMed, Web of Science, Scopus, and trial registries from inception to September 2025 for RCTs of adjunctive memantine in adults with OCD [PROSPERO: CRD420251147106]. The primary outcome was endpoint Yale–Brown Obsessive Compulsive Scale score. Random-effects models used REML estimation with Hartung–Knapp–Sidik–Jonkman confidence intervals. Risk of bias was assessed with RoB 2 and certainty of evidence with GRADE. Six RCTs (n = 288; 8–16 weeks; 5–20 mg/day) met inclusion criteria. Overall, memantine did not produce a statistically significant symptom reduction versus placebo (pooled mean difference −3.74 points, 95
Sublingual (SL) drug delivery represents an important alternative route of analgesic administration, particularly in settings where rapid pain control is desired or oral and parenteral routes are limited. By enabling direct absorption through the oral mucosa, SL administration partially bypasses first-pass hepatic metabolism, potentially improving bioavailability and accelerating the onset of action for select medications. Historically, SL analgesia has been most closely associated with opioid formulations such as fentanyl, buprenorphine, and sufentanil. SL fentanyl has demonstrated efficacy in breakthrough cancer pain among opioid-tolerant patients because of its rapid absorption and potent analgesic properties, whereas buprenorphine remains widely utilized for chronic pain and opioid use disorder owing to its partial µ-opioid receptor agonism and ceiling effect on respiratory depression. More recently, SL sufentanil has gained interest for the supervised management of acute pain in perioperative and emergency settings. Beyond opioids, expanding interest in SL therapeutics has included ketamine, cannabinoids, α2-adrenergic agonists, and investigational nonsteroidal anti-inflammatory drug (NSAID) formulations. Ketamine has shown potential utility in neuropathic and refractory pain syndromes, while cannabinoids are being explored for chronic, inflammatory, neuropathic, and cancer-related pain. Clonidine and dexmedetomidine may also serve as opioid-sparing adjuncts in selected settings. This review summarizes currently available and emerging SL analgesics, emphasizing pharmacologic mechanisms, pharmacokinetics, clinical applications, safety considerations, and therapeutic limitations. Although SL delivery offers advantages, such as noninvasive administration and rapid systemic exposure, limitations including variable bioavailability, formulation challenges, adverse effects, and limited comparative clinical evidence continue to restrict broader adoption.
Plexiform neurofibromas (PN) represent a significant cause of morbidity among patients diagnosed with neurofibromatosis type 1 (NF1). MEK inhibitors continue to be developed as targeted therapies by inhibiting the mitogen-activated protein kinase pathway to treat PN; nonetheless to this day, therapeutic responses have varied across different patient populations and clinical contexts, and the overall efficacy and tolerability of these agents remain incompletely characterized. We aimed to systematically evaluate the efficacy and safety of MEK inhibitor therapy in patients with NF1-associated PN and to evaluate differences among key subgroups based on the most contemporary metadata. A comprehensive search was performed across electronic databases to identify studies that reported outcomes related to MEK inhibitor therapy in NF1-associated PN. Pooled proportions were calculated using a random-effects meta-analysis with logit transformation. Outcomes assessed included objective response rate, disease control rate, disease progression rate, and grade ≥ 3 adverse events. A total of 23 studies comprising 769 patients were included. The pooled objective response rate was estimated at 56
Lumateperone, a simultaneous modulator of serotonin, dopamine, and glutamate neurotransmission, demonstrated efficacy and safety as adjunctive therapy in two phase III, randomized, double-blind, placebo-controlled trials in patients with major depressive disorder with inadequate antidepressant therapy (ADT) response. The objective of this pooled analysis of Studies 501 and 502 was to investigate the safety and tolerability of lumateperone 42 mg + ADT. Data were pooled from two studies that enrolled adults (aged 18–65 years) with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-defined major depressive disorder with inadequate response to one to two ADTs in the current depressive episode (Montgomery–Åsberg Depression Rating Scale Total score ≥ 24; Clinical Global Impression-Severity score ≥ 4). Patients were randomized to 6 weeks of oral lumateperone 42 mg + ADT or placebo + ADT. Safety measures included adverse events, body morphology, cardiometabolic parameters, prolactin levels, extrapyramidal symptoms (EPS), and suicidality. The pooled population comprised 964 patients (lumateperone + ADT, n = 483; placebo + ADT, n = 481). Treatment-emergent adverse events (TEAEs) occurred in 68.1
Angelman syndrome (AS) is a complex neurogenetic disorder characterized by severe global developmental delay, motor dysfunction, and epilepsy, primarily resulting from the lack of functional ubiquitin protein ligase E3A (UBE3A) protein expression in neurons. While current management remains largely symptomatic, the therapeutic landscape for AS is rapidly evolving. Emerging strategies aim to restore UBE3A function through upstream interventions, such as gene replacement therapy or unsilencing of the imprinted paternal allele, which is present but transcriptionally silenced in neurons due to genomic imprinting. This imprinting is mediated by the distal portion of a long non-coding RNA known as the UBE3A-antisense transcript (UBE3A-ATS). This UBE3A-ATS has become a key therapeutic target, with several approaches developed to unsilence the paternal allele, including antisense oligonucleotides (ASOs), CRISPR-based editing, synthetic microRNA, and other modalities. To date, three ASO programs have demonstrated promising signals in early clinical development, with reported improvements in clinical outcomes and electroencephalography (EEG) biomarkers. Given the potential for improved outcomes with early intervention, the inclusion of AS in broader genomic newborn screening programs is currently being explored. An early-intervention approach, or combination of approaches, holds significant promise for transforming the lives of individuals affected by AS with outcomes dependent on their age or genotype.
Psychedelics exert widespread effects on brain activity, but their impact on motor function is unclear. This is clinically relevant given the emerging interest in psychedelic-assisted physical therapy for disorders of motor function. This study examined the feasibility and safety of administering movement tasks following low-to-moderate doses of psilocybin in healthy volunteers. Healthy adult participants were randomly assigned three psilocybin doses consisting of either (1) 5 mg, 10 mg and 15 mg or (2) 10 mg, 15 mg and 20 mg, with at least 1 week between doses. Movement tasks were administered at 1.5 h, 3 h and 4.5 h post-dose. Participants, physiotherapists and statisticians were blinded to the dosing order. Feasibility was assessed by evaluating completion of the de Morton Mobility Index and Functional Movement Exploration (assessing gross motor function). Safety outcomes included vital signs and adverse events. Additional exploratory motor outcomes included the Action Research Arm Test (assessing upper limb functional performance), Box and Block Test (Original and Modified versions) (combining dexterity with motor speed), Digit Symbol Substitution Test (combining motor speed with intellectual functions) and Reaction Time Ruler Drop Test (assessing reaction time). Alterations in conscious states and blinding efficacy were also assessed. Outcomes were summarised descriptively and with post hoc linear mixed-effects modelling performed to explore dose- and time-related effects. A total of 13 participants (62
Friedreich ataxia is a multi-system neurodegenerative disorder with frequent cardiac and metabolic involvement. Omaveloxolone, the first approved therapy for Friedreich ataxia, improves neurological outcomes through nuclear factor erythroid 2-related factor 2 activation and exerts measurable systemic effects. However, its effects on lipid metabolism have not been systematically assessed. The present study aimed to systematically evaluate the longitudinal effects of omaveloxolone on serum lipid parameters in a real-world cohort of patients with Friedreich ataxia over a 12-month observation period. We conducted a retrospective, single-center, real-world observational study in adults with genetically confirmed Friedreich ataxia newly treated with omaveloxolone (150 mg/day). Serum lipid parameters, including total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, very low-density-lipoprotein cholesterol, triglycerides, C-reactive protein, apolipoprotein A-I, and apolipoprotein B (ApoB), were measured at baseline and after 1, 2, 3, 6, and 12 months. Longitudinal changes were analyzed using frequentist and Bayesian linear mixed-effects models. A total of 17 patients were included in the analysis (13 male [76
Trigeminal neuralgia can be a debilitating pain condition that affects women more frequently than men and for which there are only limited therapeutic avenues. Trigeminal neuralgia can either be idiopathic (where there is no clearly identifiable cause), classical (which typically involves neurovascular compression of the trigeminal root entry zone) or secondary which results from nerve damage due to other causes. First-line treatments for trigeminal neuralgia include the sodium channel blockers carbamazepine and oxcarbazepine, whose mechanism of action is to stabilize the inactivated state of sodium channels, thereby reducing the electrical activities of trigeminal neurons. Second-line treatments include gabapentinoids, which act on Cavα2δ subunits of high voltage activated calcium channels to inhibit synaptic transmission in the trigeminal pain pathway. Both of these treatment avenues exhibit a number of adverse effects and many patients are refractory. Hence, new avenues for combatting trigeminal neuralgia are needed. In this review article, we discuss clinical evidence for efficacy and benefits of novel pharmacological treatment approaches for trigeminal neuralgia, including the inhibition of CGRP receptors, activation and desensitization of TRPV1 channels, the development of new generations of sodium channel blockers, and the use of botulinum toxin. We conclude that while there are potential benefits of these approaches, larger well-controlled cohort studies are needed to provide a definitive answer.
Corticosteroids (CSs) are widely prescribed but can induce psychiatric adverse effects (depressive, manic, psychotic, and anxiety symptoms). This systematic review aimed to quantify the association between CS use and psychiatric symptoms and to explore potential moderators across clinical contexts. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review and meta-analysis. MEDLINE and Embase were searched through 10 October, 2025, and 19 hand-searched records were also screened. We included observational studies in medical CS users and excluded sex steroids, neonatal exposure, prescription-only outcomes, purely objective outcomes, sleep/cognition/delirium-focused studies, CS deficiency, withdrawal, and studies confounded by co-medications; randomized controlled trials were excluded by design. Two reviewers screened studies, extracted data, and assessed risk of bias with the Newcastle-Ottawa Scale. Certainty of evidence for each pooled outcome was additionally evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Pairwise meta-analyses pooled standardized mean differences and odds ratios using random-effects models; I2 quantified heterogeneity. The acute phase was operationally defined as ≤ 8 weeks after CS initiation. An exploratory meta-regression across six studies (seven groups) examined dose, duration, cumulative dose, age, and sex. Seventy-three studies (total N = 3,759,659) were included (22 cross-sectional, 31 cohort, 12 pre-post, 2 case-control, 2 registry, and 4 prospective patient-as-own-control investigations comparing outcomes during on-CS vs off-CS periods). Compared with non-users, CS use was associated with higher depressive symptom scores (standardized mean difference = 0.92, 95
Pediatric-acquired demyelinating syndromes, including multiple sclerosis (MS), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) constitute distinct entities arising during critical periods of neurodevelopment. Early and effective treatment is therefore crucial to prevent long-term disability. Converging evidence supports a central role of B-cells in central nervous system autoimmunity, extending beyond antibody production to include antigen presentation, cytokine production, and T-cell modulation. B-cell-depleting anti-CD20 therapies are increasingly used in this setting, but the strength and consistency of evidence differ substantially across diseases and individual drugs. Available data indicate that anti-CD20 treatment provides significant suppression of relapses and MRI activity in pediatric MS. Rituximab, although used off-label, has shown a significant reduction in annualized relapse rates and inflammatory MRI activity across observational cohorts. Ocrelizumab has the most advanced pediatric evidence among approved anti-CD20 agents, including dose-selection data from OPERETTA I and comparative Phase 3 data from OPERETTA II, where it reduced MRI activity compared with fingolimod and showed sustained B-cell depletion. In contrast, evidence for ofatumumab in pediatric MS remains limited to very small case series, although dedicated pediatric trials are ongoing. No pediatric data are currently available for ocrelizumab or ofatumumab in AQP4+NMOSD or MOGAD. In pediatric AQP4+NMOSD, rituximab remains the best-supported anti-CD20 option, with observational studies showing relapse reduction and a close relationship between CD19-positive B-cell repopulation and breakthrough disease activity. In relapsing MOGAD, responses to rituximab are heterogeneous: some cohorts report reduced relapse frequency during sustained B-cell depletion, whereas others describe continued relapses despite treatment, suggesting that pathogenic mechanisms beyond CD20-positive B-cells, including long-lived plasma cells or non-B-cell immune pathways, may contribute to disease activity. Across pediatric cohorts, anti-CD20 therapies are generally well tolerated. Infusion-related reactions are common but usually mild, infections are typically non-severe, and hypogammaglobulinemia, leukopenia, delayed neutropenia, vaccine-response attenuation, and early B-cell repopulation require individualized monitoring. Upcoming trials of ofatumumab, ublituximab, and rituximab-based strategies in MOGAD will be critical to refine pediatric dosing, define biomarkers of treatment durability, and establish age-specific safety surveillance for the developing immune system. This review summarizes knowledge on B-cell maturation in early life and anti-CD20 treatment outcomes in pediatric patients with these conditions. Safety and tolerability considerations, optimal timing of therapy, and remaining gaps in evidence are also explored, highlighting the need for age-specific biomarkers and prospective studies to better define individualized treatment strategies and to clarify long-term consequences of B-cell-depleting therapies in children.
Painful chemotherapy-induced peripheral neuropathy (CIPN) is highly prevalent and functionally disabling yet remains largely refractory to current treatments. Isoform-specific modulation of voltage-gated sodium channels (NaV), particularly NaV1.8, has emerged as a promising strategy to reduce nociceptor hyperexcitability. The recent approval of the NaV1.8-selective inhibitor suzetrigine for acute postoperative pain demonstrates the feasibility of highly selective peripheral sodium-channel inhibition, although its indication is currently restricted to acute pain and its relevance for chronic neuropathic conditions remains uncertain. However, painful CIPN is mechanistically heterogeneous, shaped by oxidative stress, mitochondrial dysfunction, neuroinflammation, activation of transient receptor potential channels, axonal degeneration, and central sensitization. These multidimensional pathways raise important questions about whether NaV selectivity alone can provide meaningful benefit in a condition where neuronal hyperexcitability represents only one component of a broader pathophysiological network. Evidence from sodium-channel–targeted analgesics, including the partial efficacy of NaV1.7 inhibitors and the functional redundancy among NaV1.7, NaV1.8, and NaV1.9, further underscores the limitations of monotherapy approaches. This Current Opinion argues that isoform-specific NaV modulation should be embedded within a broader translational framework. Priorities include mechanistic phenotyping aligned with chemotherapy class, integration of functional and molecular biomarkers, and adoption of patient-centered endpoints. Furthermore, multimodal strategies combining NaV modulators with agents targeting oxidative stress, mitochondrial dysfunction, immune activation, or cytoskeletal injury—alongside mechanism-based rehabilitation and neuromodulation—may offer more realistic therapeutic benefit. By situating NaV modulation within these multidimensional strategies and incorporating pharmacogenetic insights into NaV variants associated with painful neuropathies, the field may move beyond technological promise toward interventions that meaningfully improve outcomes for patients living with painful CIPN.
