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Learn more: PMC Disclaimer | PMC Copyright Notice Drug Des Devel Ther . 2026 Apr 7;20:580802. doi: 10.2147/DDDT.S580802 Search in PMC Search in PubMed View in NLM Catalog Add to search Lidocaine for Depressive Symptoms and Comorbid Pain: A Narrative Review of Mechanisms, Evidence, and Safety Min Xia Min Xia 1 Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China 2 Department of Anesthesiology, General Hospital of the Yangtze River Shipping, Wuhan Brain Hospital, Wuhan, Hubei, People’s Republic of China Find articles by Min Xia 1, 2, * , Jinnian Duan Jinnian Duan 3 Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, People’s Republic of China Find articles by Jinnian Duan 3, * , Nan Chen Nan Chen 1 Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China Find articles by Nan Chen 1 , Wanru Zhou Wanru Zhou 1 Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China Find articles by Wanru Zhou 1 , Na Zhang Na Zhang 1 Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China Find articles by Na Zhang 1 , Miao Feng Miao Feng 1 Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China Find articles by Miao Feng 1 , Yang Sun Yang Sun 4 Department of Anesthesiology, The General Hospital of Benxi Iron and Steel Group, Benxi, Liaoning, People’s Republic of China Find articles by Yang Sun 4 , Yong Luan Yong Luan 1 Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China Find articles by Yong Luan 1, ✉ Author information Article notes Copyright and License information 1 Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China 2 Department of Anesthesiology, General Hospital of the Yangtze River Shipping, Wuhan Brain Hospital, Wuhan, Hubei, People’s Republic of China 3 Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, People’s Republic of China 4 Department of Anesthesiology, The General Hospital of Benxi Iron and Steel Group, Benxi, Liaoning, People’s Republic of China ✉ Correspondence: Yong Luan, Email [email protected] * These authors contributed equally to this work Received 2025 Nov 11; Accepted 2026 Mar 21; Collection date 2026. © 2026 Xia et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v4.0) License ( http://creativecommons.org/licenses/by-nc/4.0/ ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php ). PMC Copyright notice PMCID: PMC13069958 PMID: 41970207 Abstract Depression, a globally prevalent mental health disorder, poses significant treatment challenges, particularly in treatment-resistant cases. Increasing evidence suggests a strong bidirectional relationship between chronic pain and depression, underpinned by shared neurobiological mechanisms, including dysregulation of glutamatergic signaling and neuroinflammatory processes. In this narrative review, we synthesize preclinical and clinical findings on lidocaine, a local anesthetic that has attracted interest for its potential neuropsychiatric effects. Proposed pharmacological mechanisms of lidocaine, including sodium channel blockade, N-methyl-D-aspartate (NMDA) receptor antagonism, and anti-inflammatory properties, which together may contribute to its putative mood-modulating properties. Clinical evidence to date remains limited and heterogenous, consisting largely of small-sample controlled trials, observational studies, and investigations primarily conducted in pain populations rather than in primary depressive disorders. Despite some studies suggest rapid but transient improvements in depressive symptoms, challenges such as transient effects, dosing optimization, and safety considerations remain. Addressing these gaps through robust clinical trials and exploring biomarkers for personalized treatment could unlock the full potential of lidocaine in bridging pain management and psychiatry, offering a novel avenue for treating complex cases of depression. Keywords: lidocaine, pain management, depression, comorbidity Introduction Depression as a widespread global concern affects more than 300 million people worldwide. 1 It was responsible for a global total of more than 50 million people living with a disability in 2015, ranking it as the single largest contributor to non-fatal impairments. 2 On top of that, depression is one of the leading causes of death by suicide, regardless of major or subthreshold depression. 3 The humanistic and economic burden that depression brings to the patients is not negligible, including lower work productivity and higher healthcare utilization than those without depression. 4–6 The estimated economic burden due to depression is in the hundreds of millions of dollars, accounting for 4–8% of GDP and diverting resources that could be allocated to other critical areas. 5 Despite advancements in pharmacological and psychotherapeutic treatments, depression remains a complex and challenging disorder to treat, especially for individuals with treatment-resistant depression (TRD). A universally accepted definition of TRD is currently lacking. Based on widely accepted research criteria, TRD is generally defined as failure to achieve remission after two or more adequate antidepressant trials of at least 6–8 weeks’ duration. 7 , 8 TRD, characterized by a lack of response to multiple antidepressant treatments, affects a substantial portion of those diagnosed and underscores the need for novel therapeutic strategies. A study from Thailand noted 19.6% of TRD among depressed patients receiving antidepressant treatment. And the aggregated economic costs associated with TRD were nearly twice as high as non-TRD. 9 A significant portion of individuals with depression disorder suffer from chronic pain. Nearly 1 in 20 adults in the U.S. deal with chronic pain while experiencing anxiety or depression and 55.6% of the adults with unremitted anxiety or depression also have chronic pain, according to the new research from Rosa et al. 10 Chronic pain is a heterogeneous condition that can be broadly categorized into nociceptive, neuropathic, and nociplastic phenotypes, each involving distinct underlying mechanisms and potentially differing responses to treatment. 11 Depression often affects and is affected by pain, especially chronic pain. 12–16 A cross-section study enrolling 15,213 populations in China confirmed a partial mediating effect of chronic pain on chronic disease and depression. It found that patients with more chronic diseases had more severe pain (OR = 3.697, P < 0.001, CI = 2.919–4.681) and were more likely to develop depression (OR = 2.777, P < 0.001, CI = 2.497–3.090) 13 and that treatments for pain are just as important to consider when treating depression. 13 , 14 Among adolescents, researchers even more radically stated that pain presence was associated with lifetime depression (OR[95% CI]: 1.76 [1.45, 2.13], p < 0.001). 15 Depression likewise affects patients’ perception and nociceptive threshold thereby altering their perception of pain. 16 This comorbidity complicates diagnosis and treatment, as pain can exacerbate depressive symptoms and vice versa. 13 , 16 Both conditions share common neurobiological pathways, including neurogenesis, 12 excitatory/inhibitory imbalance, 17 , 18 and neuroinflammation, 19 etc, suggesting that targeting these pathways could provide therapeutic benefits for both conditions. Importantly, the expected clinical benefit and underlying mechanisms of analgesic interventions, such as lidocaine, are likely to vary across pain phenotypes, with stronger mechanistic rationale in neuropathic and mixed pain states due to their greater involvement of peripheral and central sensitization processes. Understanding the shared mechanisms between pain and depression is essential for developing more effective treatments that target both conditions simultaneously. Lidocaine was first synthesized in 1942 and approved for use in clinical in 1948. It is well known to the public as a classic local anesthetic for its ability to block nerve conduction by inhibiting sodium channels. Besides perioperative use for pain management, lidocaine is commonly used in clinical settings for anti-ventricular arrhythmias. Expanding on these effects based on the ion channel blocking properties, lidocaine garnered growing attention for its potential role in treating psychiatric disorders, particularly depression with comorbid pain. Current interpretations of its antidepressant potential generally distinguish between a possible direct mood-modulating effect mediated through central neurobiological mechanisms and a secondary improvement in depressive symptoms resulting from interpreting existing clinical evidence. Within current treatment algorithms for depression, lidocaine is not considered a first-line therapy but has been explored primary as a potential adjunctive or investigational option for TRD. Recent studies have suggested the effects of lidocaine on the central nervous system may extend beyond local anesthesia, making it a candidate for treating more conditions such as TRD. 20–23 The researchers also found anti-inflammation, 20 , 21 neuroprotective, 22 and attenuating mitochondrial damage properties 23 of lidocaine. Given the shared neurobiological pathways between chronic pain and depression, lidocaine’s ability to modulate these pathways has sparked interest in its repurposing as an antidepressant, particularly in clinical contexts characterized by comorbid chronic pain, heightened inflammatory activity, or central sensitization. Reversible temporary silencing of basolateral amygdala using lidocaine significantly alleviates depression in mice exposed to chronic stress. 24 Recent research has shown that lidocaine may provide relief from depressive symptoms in patients with comorbid pain conditions. 25 , 26 However, available clinical evidence remains limited and largely derived from small-scale trials and heterogeneous populations, and ongoing investigations are continuing to evaluate its efficacy, durability of response, and safety profile in TRD, positioning lidocaine as a potential but still experimental adjunctive treatment approach. Literature Retrieval A comprehensive literature search was conducted to identify relevant studies on the use of lidocaine in the treatment of depression, particularly in individuals with TRD and comorbid chronic pain. The search covered databases including PubMed, Embase, and Web of Science from January 2000 to September 2025, using search terms such as “lidocaine,” “depression,” “treatment-resistant depression,” “chronic pain,” “neurological mechanisms,” and “antidepressant effects”. Studies were included if they were clinical trials, observational studies, or meta-analyses that assessed the effect of lidocaine on depression or related conditions, particularly those investigating lidocaine administered intravenously or locally for depression with or without comorbid pain in adult populations diagnosed with depression (major depressive disorder or treatment-resistant depression). Articles had to be published in peer-reviewed journals. In addition, selected preclinical studies were included when relevant to elucidate the potential neurobiological mechanisms underlying lidocaine’s antidepressant effects and to provide mechanistic context for the clinical findings. Studies were excluded if they did not provide relevant clinical or mechanistic evidence regarding lidocaine’s effects on depression, lacked a clearly defined methodology or outcome measures, or were published in languages other than English. Case reports, abstracts, and conference proceedings were also excluded. Two dependent reviewers conducted the literature search and screened studies for eligibility. Title and abstract were first screened for relevance, followed by full-text review of potentially eligible articles. Inter-reviewer agreement during the screening process was assessed using Cohen’s kappa coefficient (κ = 0.82), indicating strong agreement. Any discrepancies in study inclusion were resolved through discussion and consensus among the review team. Pharmacological Mechanism of Lidocaine Effects on Ion Channels Lidocaine primarily works by blocking voltage-gated sodium channels (VGSCs, Nav), thereby inhibiting the conduction of nerve impulses. 27 Its blockade of VGSCs constitutes the molecular basis for its local anesthetic effect. Beyond this classical action, growing evidence suggests that lidocaine’s modulation of specific ion channel subtypes may underlie its potential in treating the pain-depression comorbidity. 28 VGSCs can be classified into 9 isoforms (Nav1.1–1.9) enriched in different tissues and organs of the organisms. Among then, Nav1.7, Nav 1.8, and Nav1.9 are strongly linked to the pain perception. 29 , 30 Chronic pain, in turn, is a major driver of depressive symptoms. 10 , 12 , 31 For instance, in a chronic social defeat stress model, mice exhibited depressive-like behavior and displayed hyperalgesia, concomitant with altered Nav1.8 expression. 32 Conversely, dysfunction of Nav1.1 in the prefrontal cortex (PFC) has been directly linked to depressive-like behavior, and reduced expression of SCN1A (encoding Nav1.1) was found in post-mortem PFC samples from depressed individuals. 33 Genetic studies also identified SCN2A (Nav1.2) mutations might contribute to depression susceptibility. 34 Recent research further indicates that lidocaine can modulate Nav1.6, an isoform implicated in mood regulation. 35 , 36 Additionally, some specialized types of sodium channels, such as the Loss of sodium leak channel (NALCN) was found decreased in the dentate gyrus (DG) of the depressed male mice, and NALCN knockdown in DG evokes depression-like behavior in controls. 37 Thus, lidocaine’s simultaneous blockade of pain-associated Nav isoforms (eg, 1.7, 1.8) and mood-regulation-associated isoforms (eg, 1.1, 1.2) provides a plausible dual mechanism for alleviating the pain-depression cycle. Lidocaine also acts on potassium channels, including inward rectifier K + channels (Kir) family 38 and voltage-gated potassium channel (Kv). 39 , 40 Overexpression of Kir channels (eg, Kir1.1, Kir2.1) in the nucleus accumbens is relevant to depressive phenotypes, 41 and Kir3 42 and Kir6.2 43 are implicated in the mechanisms of antidepressants and pain modulation. Kv channels, like Kv1.1 and Kv3.1 are also modulated by lidocaine 39 , 40 and their dysfunction has been linked to depressive-like behaviors. 44 , 45 Furthermore, lidocaine can mediate Transient receptor potential (TRP) ion channels, 46 , 47 which is involved in the regulation of pain and the detection of environmental stimuli. 7 , 48 Genetic polymorphisms in TRPV1 rs222741 [ORadj (95% CI): 1.97 (1.02–3.85), p=0.046], TRPV4 rs3742037 [ORadj (95% CI): 2.03 (1.06–3.96), p=0.035], and TRPM8 rs17862920 [ORadj (95% CI): 0.48 (0.23–0.96), p=0.042] are associated with the comorbidity of migraine and depression, 49 with their roles in depressive-like behavior confirmed in animal models. 50–52 In summary, lidocaine’s multi-target action on ion channels underpins its potential in treating pain-depression comorbidity. By inhibiting pain-transmitting sodium channels (eg, Nav1.7, Nav1.8), it can alleviate a key driver of depression. Concurrently, by modulating potassium and TRP channels involved in mood circuit regulation (eg, in PFC, nucleus accumbens), it may directly correct the neuronal excitability imbalances underlying depressive states. 33 This coordinated action on peripheral and central nervous system (CNS) channels allows lidocaine to target multiple nodes within the shared pathophysiology of chronic pain and depression. Glutamatergic Modulation In addition to its effects on sodium channels, lidocaine has been shown to interact with glutamate receptors, particularly the NMDA receptor. 53–55 Lidocaine concentration-dependently inhibits the NMDA receptor thus reducing the NMDA-induced currents. 53 In oocytes with human NMDA receptor expressed, lidocaine mediates the inhibition of NMDA via the PKC pathway intracellularly. 54 NMDA receptors are involved in synaptic plasticity and the transmission of excitatory signals in the brain. Dysregulation of NMDA receptor function has been implicated in a range of psychiatric disorders, including depression 56–59 besides pain modulation. 54 , 59 , 60 Upregulation of NMDA receptors in the dorsal raphe nucleus significantly improves depressive-like behavior in chronic unpredictable mild stress (CUMS) models. 57 Subsequent research confirmed that blockade of NMDA at rest deactivates CaMKIII and suppresses the translation of neurotrophic factors like brain-derived neurotrophic factor (BDNF), resulting in fast-acting behavioral antidepressant-like effects. 58 Another study demonstrates knockdown of Glutamate Ionotropic Receptor NMDA Type Subunit 2B (GluN2B) subunits of NMDA receptors in mice in γ-aminobutyric acid (GABAergic) interneurons specifically reversed antidepressant-like behaviors. 61 A key role of GluN2B in pain management was also identified in the establishment of a chronic pain model by intraperitoneal injection of cerulein in mice. Glutamatergic neurons in the lateral parabrachial nucleus are activated, leading to excessive glutamate release which binds to the GluN2B subunit of NMDA receptors, ultimately resulting in the development of chronic pain. 60 Independently, Tian et al showed GluN2B-containing-NMDA receptors mediated synaptic plasticity alterations might be a potentially important mechanism for chronic stress-exacerbated neuropathic pain. 59 It has also shown that the process of NMDA receptors involves α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Microinjection of AMPA receptor antagonist in the midbrain ventrolateral periaqueductal gray could abolish the mitigated foot shock stress-induced depression-like behavior in rats. 62 This as well suggests that as targets for glutamate binding, not only the NMDA receptors, but also the AMPA receptors bridge the development of depression and pain. AMAP receptors consist of four subunits (GluA1-GluA4) that are involved in mediating the onset of various pain processes, including neuropathic pain, 63 inflammatory pain, 64 and pain hypersensitivity. 65 As opposed to NMDA receptors, AMPAR receptors are highly mobile, eliciting transport from (to) synapse and migration along the plasma membrane, an underlying mechanism by which it may regulate synaptic plasticity. 66 Enhancement of APMA receptors ameliorated the synaptic plasticity impairments and depressive-like behaviors caused by sleep deprivation, 67 which also occurs similarly in spatial restraint stress mice. 68 Even the APMA receptors are found to modulate the onset of depression and pain through similar molecular mechanisms such as AMPA receptor trafficking. 63 , 69 Injection of lidocaine in vivo triggers synaptic scaling in motoneurons to block spontaneous neural network activity, an effect that may be mediated by reducing GluA2-containing AMPA receptors. 70 It has also been suggested that lidocaine may affect GluA1-containing AMPA receptor trafficking via inhibiting the postoperative inflammatory response. 71 Aside from the direct effects on postsynaptic glutamate receptors, lidocaine accomplishes glutamatergic regulation by affecting the glutamate transport system. Lidocaine enhances Excitatory Amino Acid Transporters 3 (EAAT3) activity at certain concentrations, with this action possibly mediated by PKC and PI3K. 72 Whereas in a model of a genetic rat model of depression, researchers identified upregulation of EAAT3 mRNA and protein expression. 73 Intrathecal injection of siRNA of EAAT3 reduces mechanical pain sensitivity and thermal pain sensitivity, 74 presumably by modulating glutamate-mediated pain transmission. These elucidate the role of lidocaine in glutamatergic regulation, a process that plays an integral role both in the modulation of pain and the development of depression. It might open the possibility of a novel concept for the antidepressant effects or treatment of pain co-morbid depression with lidocaine. Anti-Inflammatory Effects Depression has been increasingly recognized as a disorder with inflammatory components. Pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), are often elevated in individuals with depression and are thought to contribute to the pathophysiology of the disorder. 71 These inflammatory markers can affect brain function and neurotransmitter systems, leading to mood disturbances. Liang et al enrolled 67 depressed patients and 67 healthy controls, and found that inflammation by measuring high-sensitivity C-reactive protein (hsCRP) levels in peripheral blood was markedly higher in the depressed population than in healthy controls. And the level of hsCRP is expressed at different levels in different types of depression. 75 Although hsCRP is not a direct reflection of the true level of inflammation, these results also give relatively reliable evidence in humans. Schmitz et al found that peripheral blood IL-6 concentrations were significantly higher in depressed patients than in healthy controls. 76 This alteration was closely related to abnormal functional connectivity of the default mode network, 76 which is highly correlated with the development of depression. 77 When the depression symptoms improved, peripheral blood levels of IL-1⍺, IL-1β, IL-7, and IL-12p70 were also remarkably reduced in rats. 78 An increase of TNF-⍺ mediates astrocyte activation by binding to its receptor exacerbated depressive-like behavior in CUMS mice. 79 IL-6 improves depressive-like behavior by mediating the SATA/Acp5 pathway in mice with neuropathic pain. 80 Lidocaine has demonstrated anti-inflammatory properties by reducing the levels of these pro-inflammatory cytokines. 20 , 21 , 81 It inhibits inflammation-related pathophysiologic changes, including increased levels of IL-4, IL-5, IL-13, eotaxin-1, and TNF-⍺. 82 , 83 Besides, lidocaine could attenuate local inflammation via blocking peripheral neuronal vesicular exocytosis. 81 Continuous systemic administration of lidocaine significantly reduced accumulation and p38 phosphorylation of microglial cells, thus alleviating the tactile allodynia. 84 These effects are particularly relevant for individuals with depression comorbid pain, as chronic pain is often associated with elevated inflammatory markers. IL-6 and IL-8 mediated inflammation in humans or rats elicits pain as well as depressive symptomatology. 80 , 85 Lopes et al discovered that inflammation, even when well controlled, causes chronic pain and depression in the later stage of the disease Analgesic therapy alone did not alleviate the depressive-like behavior, and intracerebroventricular infusion of anti-TNF antibodies blocked the depressive-like behavior and alleviated the persistent pain. 86 The anti-inflammatory properties, in addition to its analgesic properties, may allow lidocaine to be a better choice for the treatment of chronic pain combined with depression secondary to inflammatory response. It also promises the lidocaine as a potential antidepressant in some way. Neuroplasticity and Synaptic Remodeling Neuroplasticity, the brain’s ability to reorganize itself by forming new neural connections to various stimuli and experiences, is a fundamental mechanism underlying learning, memory, and mood regulation. 87–89 This adaptability is particularly significant in the context of mood disorders such as depression, where alterations in neural circuits and synaptic connections can lead to persistent changes in mood and behavior. The concept of neuroplasticity encompasses a range of processes, including synaptogenesis, dendritic remodeling, and changes in neurotransmitter systems, all of which contribute to the brain’s capacity to maintain emotional homeostasis. 90 Targeting neuroplasticity has therefore become a promising approach in the development of novel antidepressant therapies, including the exploration of lidocaine’s effects on synaptic remodeling. Recent research has highlighted the potential of targeting neuroplasticity as a therapeutic strategy for mood disorders. For instance, modulating the NMDA receptor has been shown to induce rapid synaptogenesis and reverse synaptic deficits caused by chronic stress, offering a promising avenue for the treatment of depression. 56 , 59 , 91 Depression is associated with structural and functional changes in the brain, including reduced synaptic density, diminished dendritic complexity, and decreased levels of BDNF. BDNF is essential for synaptic plasticity and neuronal survival, and its dysregulation is implicated in the pathophysiology of depression. 92 Studies have shown that individuals with depression often exhibit lower levels of BDNF in the hippocampus and prefrontal cortex, regions critical for mood regulation. Moreover, along with the upregulation of BDNF using a drug, the mice exhibited significant improvements in synaptic reversibility and neuronal survival. 93 In the social defeat stress model, overexpression of constitutively active RAS-related C3 botulinum substrate 1 (Rac1) in nucleus accumbens abolished prunes stubby spines to accomplish synaptic remodeling and ameliorate depressive-like behavior in mice. 94 Transitions in synaptic plasticity are also involved in the development of chronic pain. Kiritoshi et al propose a progressive loss of synaptic plasticity during the transition of pain from acute to chronic. 95 Another study identified altered genes related to synaptic plasticity based on transcriptomic profiling as well as neurotransmitter imbalances indicated by altered glutamate and GABA in the Cerebrospinal Fluid in chronic pain model mice. It is believed that changed synaptic plasticity contributes to the persistence of chronic pain and associated emotional disturbances including depression. 96 Synaptic remodeling or modulation is likely to be a breakthrough in the treatment of depression, especially TRD combined with chronic pain. In the functional dyspepsia model, abnormal signals transmitted by the vagus nerve may alter the reduction of BDNF in the central amygdala, affecting synaptic plasticity, leading to gastroparesis hypersensitivity, and inducing depressive-like behavior. Blockade of this signaling by lidocaine ventrolateral periaqueductal gray local injection reversed pain- and depressive-related behaviors in model mice. 97 An in vitro experiment demonstrates that administration of lidocaine blocks embryo spontaneous neuronal network activity triggering synaptic scaling, thus affecting synaptic plasticity. 70 Lidocaine can also suppress glycine transporter 1, 98 which in turn enhances hippocampal theta network connectivity and synaptic plasticity. 99 The rapid onset of lidocaine’s effects suggests that it may induce neuroplastic changes more quickly than traditional antidepressants, making it a potentially valuable option for patients with acute depressive episodes. Moreover, lidocaine’s dual action on pain and depression could be especially beneficial for individuals with comorbid conditions, as chronic pain itself is associated with disruptions in neuroplasticity. Overall, lidocaine’s multifaceted pharmacological profile, including its sodium channel blockade, modulation of glutamatergic neurotransmission, anti-inflammatory effects, and promotion of neuroplasticity ( Figure 1 ), suggests a promising role in the treatment of depression, particularly in cases resistant to conventional therapies. Figure 1. Open in a new tab A schematic overview of potential mechanism and limitation of lidocaine’s antidepressant properties. The left hemisphere summarizes a hypothesis-generating neurobiological mechanisms of lidocaine treatment of TRD comorbid pain. The right hemisphere outlines the key limitations and challenges associated with its clinical application. Clinical Evidence for Lidocaine in Depression Emerging evidence suggests intravenous lidocaine may offer potential rapid antidepressant effects in depression. Recent randomized controlled trials demonstrate that patients receiving lidocaine infusions (a 1.5 mg/kg bolus of intravenous (IV) followed by continuous IV infusion of 1.5 mg/kg/h) often report rapid improvements in mood, with effects emerging within hours and lasting for several days. 100 Although this conclusion is based on a randomized controlled trial (RCT) with a high level of evidence, its interpretation is limited by the small sample size and the reliance on secondary outcomes. It was observed that lidocaine has a fast onset of action, while a single IV injection of 50 or 100 mg has a short duration of 10–20 minutes. 101 In the same period, another study also confirmed a half-life of about 10–20 minutes 1 hour after a bonus intravenous of lidocaine. 102 Whereas without a bonus dose, patients on continuous IV infusion of lidocaine reached acceptable blood levels within 30–60 minutes, and half-life was also 10–20 minutes. 103 Previous studies have established that lidocaine possesses a rapid onset of action and metabolism after IV which sets the pharmacokinetic basis for the rapid onset of action of lidocaine and also brings concerns about the duration of action. Another RCT identified pulsed radiofrequency combined with continuous postoperative intravenous infusion of lidocaine effectively alleviates subacute postherpetic neuralgia and concurrently reduced patient’s anxiety and depression symptoms. However, in contrast to the sustained improvement in pain and anxiety, the antidepressant effect was observed only during the period of lidocaine administration. 104 Local use of lidocaine also had been implicated to regulate mood including alleviating depression scores while treating pain. A randomized, double blinded, placebo-controlled trial found local use of lidocaine relief depression status at 6-month follow-up [(95% CI): 2.2 (1.83–2.56), p=0.001, 4 weeks; (95% CI): 4.4 (4.03–4.76), p=0.001, 6 months]. 105 Another randomized controlled trial also suggested local injection of lidocaine improves depression scores while reducing pain. 106 Therefore, the observed depressive symptom reduction may partly reflect indirect benefits related to pain relief, improved physical functioning, overall recovery rather than a direct antidepressant pharmacological effect of lidocaine. Additionally, nonspecific factors such as anxiolysis associated with procedural care, improved patient–clinical interaction, or expectancy effects cannot be fully excluded. 107 , 108 This pharmacokinetic-independent long-term effect also suggests that lidocaine may accomplish these effects beyond classical sodium channel blockade. It is worth noting that these studies primarily targeted pain outcomes, it remains difficult to distinguish direct antidepressant effects from secondary depressive symptom reduction related to analgesia, functional recovery, or reduced symptom burden. A meta-analysis of 14 RCTs investigating the association between perioperative intravenous lidocaine and subjective quality of recovery demonstrated that the lidocaine group had significantly higher emotional status scores compared with the placebo group. 109 This finding was based on data from 9 of the 14 RCTs, encompassing 769 patients. However, it is important to note that emotional status was assessed as a secondary outcome in these trials, and a substantial proportion of cases were not evaluated using standardized depression scales. The limited clinical and animal experimental evidence supporting lidocaine as a treatment for simple depression may stem from the strong public perception of its local anesthetic effects. Consequently, numerous studies have explored lidocaine for treating depression associated with chronic pain or comorbid pain, a prevalent and significant subtype of TRD. Lidocaine has a well-established molecular mechanism for depression comorbid with pain. Beyond its rapid-acting analgesic properties, whether administered locally or intravenously, also targets the pathogenesis of depression, such as anti-inflammatory, synaptic remodeling, and glutamatergic modulation. 55 , 70 , 81 , 110 Further research on lidocaine as a potential treatment for depression, especially TRD, could expand clinical options and enhance decision-making in depression management. Despite the promising findings outlined above, it is crucial to acknowledge that clinical evidence supporting lidocaine’s antidepressant efficacy remains preliminary. As shown in Table 1 , the existing body of research is characterized by small sample sizes, heterogeneous study designs, and often, the assessment of depressive symptoms as a secondary outcome in trials primarily focused on pain relief. Furthermore, not all studies report positive mood outcomes; some trials have found no significant difference between lidocaine and placebo on depression. A multicenter randomized controlled trial suggested that perioperative lidocaine IV failed to improve postoperative depressive states. 111 Although these findings were derived from secondary outcomes and were not assessed using standardized depression rating scales, they nonetheless suggest that the therapeutic efficacy of lidocaine for pain-associated depression remains questionable. Table 1. Summary of Clinical Studies for Lidocaine in Depression Study Study Design Population Age/Sample Size Dosage Regimen Primary Outcome Depression Measures Depression Improve/Duration Adverse Events Li, et al 100 DB RCT Patients with Thyroidectomy 18–65/117 IV 1.5 mg/kg bolus+1.5 mg/kg/h perioperative QoR-40 SDS Score Yes/2 d a NR Zhang, et al 104 RCT Patients with SHN 50–75/64 IV 3 mg/kg at a rate of 25 mL/ h for 2 h VAS SDS Score Yes/5 d Dizziness and Vomiting b Nambi, et al 105 DB RCT Patients with frozen shoulder 18–60/60 50mg Local Injection VAS HADS Yes/6 m No Karadaş, et al 106 DB RCT Patients with TTH 18–65/48 Multiple localized injections VAS HDS Yes/3 m Injection pain and Dizziness c Hung, et al 109 Meta-analysis Patients undergo surgeries 18–65/769 IV 1.5 or 2 mg/kg bolus+1–3 mg/kg/h perioperative QoR-40 QoR-40 Yes/NR Not Reported Paterson, et al 111 DB RCT d Patients undergo MIC ≥18/495 IV 1.5-mg/kg bolus+1.5 mg/kg/h for 6 or 12 h GI-3 QoR-15 No/NR No Open in a new tab Notes : a The SDS assessments were only conducted up to second day postoperative. b 3 patients experienced injections site and injection pain; 2 experienced dizziness; c 1 patient experienced dizziness, 3 patients experienced vomiting; d This research was a multicentral DB RCT. Abbreviations : DB, Double Blind; RCT, Randomized Controlled Trial; IV, intravenous; QoR-40, Quality of Recovery 40; SDS, Self-Rating Depression Scale; SHN, Subacute Herpe Zoster Neuralgia; NR, Not Reported; VAS, visual analog scale; HADS, Hospital Anxiety and Depression Scale; TTH, Tension-type headache; HDS, Hamilton depression scores; MIC, Minimally Invasive Colectomy; GI-3, The time point at which the patient first tolerates solid food and has their first bowel movement or passes wind. Potential Benefits, Limitations, and Challenges Potential Benefits and Comparative Perspective Lidocaine presents a unique profile of potential benefits that warrants its investigation as an antidepressant, particularly when viewed in the context of existing therapies and the limitations of current evidence. One of the most compelling potential advantages is its capacity for rapid symptom alleviation. Traditional antidepressants, such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, often require weeks to achieve therapeutic effects due to the time needed for synaptic and neuroplastic adaptations. In contrast, intravenous lidocaine administration can lead to significant pain relief within hours, 112 which may indirectly improve mood in patients suffering from chronic pain. 31 This rapid pharmacological action, primarily attributed to its fast blockade of voltage-gated sodium channels, 113 could be particularly advantageous for individuals with severe depression or suicidal ideation who require immediate relief. Moreover, some reported depressive symptom reduction could arise from broader nonspecific therapeutic effects, including reduced anxiety related to pain control, improved sleep following analgesia, or placebo responses associated with interventional treatments. 114 , 115 These possibilities highlight the importance of interpreting current findings cautiously, particularly in studies where depressive symptoms were measured as secondary outcomes rather than primary endpoints. However, it is crucial to note that current evidence remains insufficient to substantiate a direct and independent rapid antidepressant effect of lidocaine, highlighting a key area for further research. Emerging evidence suggests that lidocaine’s effects extend beyond acute symptom relief and may contribute to long-term neuroprotection. 116 Depression is associated with neuroinflammation, oxidative stress, and impaired neuroplasticity, all of which can lead to structural and functional brain changes. Lidocaine has been found to reduce neuroinflammatory markers, 117 decrease excitotoxicity through NMDA receptor modulation, and enhance synaptic plasticity 118 mechanisms that are crucial for sustained mood stabilization. A comparative perspective with ketamine, the established rapid-acting antidepressant, 119 helps define lidocaine’s potential niche. Both agents modulate the NMDA receptor, contributing to rapid onset. However, ketamine is a high-affinity NMDA antagonist with known dissociative side effects and abuse potential, whereas lidocaine offers a broader mechanism (including sodium channel blockade) and lacks these psychiatric side effects, though it carries risks of dose-dependent cardiovascular and CNS toxicity. This profile suggests lidocaine might suit specific subpopulations, such as patient with TRD and significant pain comorbidity or those intolerant to ketamine’s dissociative effects. The dual targeting of pain and depression is another significant benefit. Depression and chronic pain share overlapping neurobiological mechanisms. Lidocaine’s broad pharmacological profile-encompassing sodium channel blockade, NMDA receptor modulation, anti-inflammatory effects, and promotion of neuroplasticity-allows it to address multiple pathways simultaneously. 55 , 70 , 81 , 118 Research indicates that lidocaine’s analgesic properties may confer benefits in mood regulation, 26 as chronic pain itself is a major risk factor for the development and persistence of depression. 120–122 By blocking voltage-gated sodium channels and modulating NMDA receptor activity, lidocaine reduces neuronal hyperexcitability, thereby alleviating both physical pain and emotional distress. 113 , 118 This makes it an attractive option for substantial subpopulation of individuals with comorbid chronic pain and depression, where conventional mono-mechanistic treatments often fall short. From a practical standpoint, lidocaine a well-established safety and accessibility profile in its traditional uses. Its pharmacokinetics, dosing strategies, and potential side effects are well-documented, allowing for controlled administration in medical settings. When used under controlled conditions, it has demonstrated a favorable safety profile, with transient and manageable side effects (eg, dizziness, nausea). 123 Furthermore, it is a relatively affordable and widely available medication, potentially lowering the barrier to treatment for some patients. However, this proposition is tempered by the significant limitations of the current evidence base. The clinical findings supporting lidocaine’s antidepressant efficacy, as discussed in Pharmacological Mechanism of Lidocaine, are preliminary. The existing body of research is characterized by small sizes, heterogeneous study designs, and often, the assessment of depressive symptoms as a secondary outcome in pain trials. This introduces potential bias and limits generalizability. Furthermore, not all studies report positive mood outcomes, underscoring the need to identify predictors of response. Therefore, while the potential benefits are theoretically sound and supported by early data, they must be considered hypothetical until by large-scale, well-controlled trials that directly compare lidocaine to both placebo and established rapid-acting therapies like ketamine. Safety and Limitations Despite lidocaine’s safety profile in anesthesia, the systemic use of lidocaine for psychiatric indications, particularly at higher doses or with repeated administration, necessitates a rigorous evaluation of its potential risks. Lidocaine’s adverse effects are markedly dose dependent. CNS toxicity is the most common concern, presenting initially as dizziness, perioral numbness, and tinnitus, which can progress to tremors, drowsiness, and even seizures at higher plasma concentrations. 124 Animal studies have shown that systemic administration of high-dose lidocaine can induce neurotoxicity in emotion-related brain regions such as the hippocampus and amygdala, 125 raising important safety concerns for its long-term use in depression. Cardiovascular toxicity typically occurs at even higher doses, manifesting as negative inotropy, hypotension, and arrhythmias. Furthermore, lidocaine is primarily metabolized by the liver, posing a risk of prolonged half-life and accumulation in patients with hepatic impairment or the elderly. 126 Studies suggest that the antidepressant effects of lidocaine are short-lived. For example, one study found that lidocaine infusion significantly improved anxiety and depression symptoms, but these effects were observed only two weeks post-infusion, indicating that the duration may be limited. 26 Another study reported that lidocaine was effective in reducing anxiety and depression in patients with chronic tension-type headaches, though it did not specify the duration of these effects. 106 To mitigate these risks and limitations, the implementation of lidocaine for depression treatment must be accompanied by strict clinical protocols. This involves employing standardized, weight-based infusion protocols that initiate with lower doses and are titrated slowly. Continuous monitoring of cardiovascular and neurological status during infusion is commonly recommended in clinical practice because lidocaine can affect cardiac conduction and central nervous system activity, particularly at higher doses or in vulnerable populations. 127–129 Such monitoring requirements may increase the logistical complexity of administering lidocaine in routine psychiatric settings. Administration must be confined to a medical setting equipped with resuscitation facilities and personnel, ensuring continuous monitoring of Electrocardiography, blood pressure, and oxygen saturation throughout the procedure. If feasible, therapeutic drug monitoring is also essential. Healthcare staff should be specifically trained to recognize the early premonitory signs of CNS toxicity. Furthermore, careful patient selection is paramount, avoiding use in individuals with severe cardiac conduction blocks, significant hepatic impairment, or a history of epilepsy. Currently, safety data regarding repeated or long-term intravenous lidocaine infusions for depression are scarce, representing a critical area for focus in future clinical trials. Challenges in Clinical Implementation One of the challenges in clinical implementation is the need to position lidocaine relative to existing treatments. Ketamine has garnered substantial clinical evidence and regulatory acceptance as a rapid-acting antidepressant, particularly for TRD. 130 , 131 Its well-documented efficacy and safety profile set a high standard. While lidocaine shows promise due to its dual action on pain and mood regulation, it must demonstrate clear, distinct benefits over ketamine to justify its adoption, especially in a competitive therapeutic landscape. 26 Clinicians may be more inclined to use treatments with robust data and established protocols. Shifting the paradigm to include lidocaine requires overcoming skepticism and inertia within the medical community. There is currently no consensus on the optimal dosing regimen, infusion duration, or frequency for achieving antidepressant effects. This lack of standardization can lead to variability in outcomes and increased risk of adverse effects. The anesthetic effects of lidocaine are typically transient, necessitating repeated administrations. 132 Lidocaine has a relatively narrow therapeutic window, and systemic toxicity-including neurological symptoms (eg, dizziness, seizures) and cardiovascular complications such as arrhythmias-may occur when plasma concentrations exceed safe thresholds. 129 , 133 For individuals with special constitutions such as obesity or debility, medication administration differs from that for ordinary individuals and requires even greater caution. 111 , 128 , 129 Moreover, unlike oral antidepressants, intravenous administration requires infusion facilities, monitoring equipment, and trained personnel, which may not be routinely available in psychiatric clinics. 134 These logistical constraints could limit widespread clinical adoption unless simplified protocols, clear safety guidelines, and integrated care pathways are developed. Frequent treatments may burden patients, potentially affecting adherence and overall satisfaction with the treatment regimen. The need for continual infusions implies higher cumulative costs, not only in terms of direct treatment expenses but also in terms of time and healthcare personnel. Using lidocaine off-label in psychiatry brings additional risks and uncertainties. Although lidocaine has a well-established safety profile in its traditional uses, its effects and side-effect profile in the context of depression require rigorous monitoring. This includes managing potential cardiovascular effects, central nervous system toxicity, and other adverse reactions. Many psychiatric practitioners lack familiarity with lidocaine administration, as it traditionally falls within the domain of anesthesiology or pain management. Training is particularly important for lidocaine administration involves intravenous delivery and carries a risk of systemic toxicity if dosing or monitoring procedures are not correctly followed. 129 , 135 , 136 Without sufficient clinical training, there may be an increased risk of dosing errors, delayed identification of neurological or cardiovascular adverse effects, or inadequate patient monitoring during infusion. Implementing this treatment would likely necessitate cross-disciplinary collaboration, additional training, and the development of specialized treatment protocols to ensure safe and effective administration. In practice, this may include structured training programs for psychiatric clinicians and nursing staff, the development of standardized clinical guidelines for lidocaine infusion, and collaboration with anesthesiology or pain medicine specialists to provide oversight and technical support during early stages of clinical implementation. Without formal approval for depression, using lidocaine remains off-label, which may deter many clinicians from adopting this treatment due to legal and institutional constraints. 137 Hospitals and clinics may have strict policies regarding off-label use, necessitating additional oversight, documentation, and justification, all of which add to the complexity of integrating lidocaine into psychiatric treatment protocols. The transition of lidocaine from a traditional anesthetic to a potential treatment for depression faces multifaceted challenges. Regulatory hurdles, the need for repeated infusions, comparisons with established rapid-acting antidepressants like ketamine, and the inherent risks of off-label use all contribute to a complex clinical landscape. Mitigating these challenges necessitates rigorous clinical trials, the establishment of standardized treatment protocols, and strengthened interdisciplinary collaboration to facilitate the successful integration of lidocaine into psychiatric practice. Future Research Directions To fully understand lidocaine’s role in depression treatment, several key areas require further exploration. The most important and desirable is clinical trials and long-term efficacy of lidocaine in treating depression. One of the most pressing research needs is the execution of large-scale, randomized controlled trials assessing lidocaine’s effectiveness in depression. Importantly, some reported improvements in depressive symptoms may be secondary to analgesic effects, anxiolytic responses, or nonspecific treatment-related factors, underscoring the need for future trials specifically designed to isolate direct antidepressant effects. Future RCTs should use standardized depression endpoints (eg, Montgomery-Åsberg Depression Rating Scale or Hamilton Depression Rating Scale) as primary outcomes, include placebo-controlled or active comparator arms, and apply clearly defined TRD criteria with stratification by pain phenotype or inflammatory status. Specifically, studies should: (a) compare lidocaine’s effects with placebo and standard antidepressant treatments; (b) define IV dosing protocols (bolus versus continuous infusion), frequency, and treatment duration to determine the optimal regimen for sustained antidepressant effects; (c) investigate lidocaine’s long-term safety profile, particularly in patients requiring repeated infusions; (d) determine whether specific subgroups (eg, those with comorbid pain, inflammation, or neurochemical imbalances) experience greater benefits. Additionally, studies should assess how lidocaine compares to ketamine, another rapidly acting antidepressant that also modulates glutamatergic pathways. Determining whether lidocaine offers similar benefits with fewer side effects could influence its adoption in psychiatric practice. Given that lidocaine’s antidepressant effects appear transient, it may be most effective when used as part of a multimodal treatment strategy. Research might be anchored in the synergistic effects of lidocaine with other anti-depressants or anti-depressive treatments. Investigating whether lidocaine enhances the efficacy of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or tricyclic antidepressants. Exploring whether combining lidocaine with transcranial magnetic stimulation or electroconvulsive therapy yields synergistic benefits. Combination therapies may improve outcomes by addressing both the neurochemical and psychological components of depression, offering a more comprehensive treatment approach. Conclusion Lidocaine, a widely used local anesthetic, has emerged as a candidate adjunctive intervention for depression, particularly in individuals with TRD and comorbid chronic pain. Its pharmacological actions—such as sodium channel blockade, glutamatergic modulation, anti-inflammatory effects, and promotion of neuroplasticity—provide a mechanistic and hypothesis-generating neurobiological rationale for potential antidepressant properties ( Table 2 ), although much of this support remains preclinical or hypothesis-generating. Clinical studies suggest that lidocaine may produce rapid depressive symptom reduction in some patients, especially those with comorbid depression and pain; however, the evidence specifically from trials designed with depressant outcomes as primary endpoints in limited. The evidence remains inconsistent due to small sample sizes, heterogeneous study designs, and methodological differences, including short follow-up durations and differences in dosing and monitoring protocols, which undermine the reliability and generalizability. Many studies lack blinding, use inadequate control groups, or assess depression as a secondary endpoint, complicating the direct evaluation of lidocaine’s antidepressant effects. Additionally, publication and selection biases, along with variability in outcome measures, dosing protocols, and treatment settings, further hinder definitive conclusions about its efficacy and safety. Overall, the current clinical evidence is preliminary and of variable quality. Several critical questions remain unanswered, including the long-term safety with repeated use, optimal dosing for sustained antidepressant effects, and identification of reliable biomarkers or clinical predictors of response. Further studies should prioritize well-powered, double-blind randomized controlled trials with depression severity as a primary endpoint, standardized intravenous protocols, appropriate safety monitoring, and stratification by TRD definition and pain phenotype. Addressing these gaps is essential to determine whether lidocaine can be meaningfully incorporate into depression treatment algorithms. Until such data are available, its role should be considered investigational rather than established. Table 2. Potential Molecular Targets Involved in Lidocaine Treatment for TRD Comorbid Pain Category Targets Effects on Ion Channel Block VGSCs, Kir family, Kv1.1, Kv3.1, and TRP Glutamatergic Modulation NMDA receptors, AMPA receptors, glutamate transport system, EAAT3 activity Anti-Inflammatory Pro-inflammatory cytokines (eg. IL-3, IL-6, TNF-⍺) microglial cell, p38 phosphorylation Neuroplasticity and Synaptic Remodeling Synaptic plasticity, BDNF and synaptic plasticity related signaling Open in a new tab Abbreviations : TRD, Treatment-Resistant Depression; VGSCs, Voltage-Gated Sodium Channels; Kir, Inwardly Rectifying Potassium channel; Kv, Voltage-Gated Potassium channel; TRP, Transient Receptor Potential channel; NMDA, N-methyl-D-aspartate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; EAAT3, Excitatory Amino Acid Transporter 3; IL, Interleukin; TNF, Tumor Necrosis Factor; BDNF, Brain-Derived Neurotrophic Factor. Acknowledgments The technical support provided by the research staff at the First Affiliated Hospital of Dalian Medical University. Financial support from the [Scientific Research Projects from Wuhan Municipal Health Commission (WX23Z26)], the [Key R&D Projects in Liaoning Province (2024JH2/102500060)], the [Natural Science Foundation of Liaoning Province (2024-MS-154)], and the [2025 Chronic Disease Management Research Project (GWJJMB202510042014)], which facilitated the execution of this research. Any other individuals or organizations who contributed but did not meet the criteria for authorship. Co-first authors: Min Xia and Jinnian Duan. Disclosure The authors declare that they have no conflicts of interest related to the publication of this manuscript. No financial relationships with any organizations, government entities, or companies influenced this work. References 1. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. 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