Introduction

Addiction is a chronic, relapsing systemic disorder characterized by persistent drug craving and compulsive use, despite the emergence of serious adverse consequences. Its high prevalence poses significant social burdens, severely affecting physical and mental health, with rising trends in drug abuse1,2,3,4. Many individuals use addictive substances over extended periods for recreational or medical purposes, with some developing compulsive behaviors. This group is considered susceptible to addiction1,4,5,6. Key brain regions implicated in drug addiction include the ventral tegmental area (VTA), nucleus accumbens (NAc), medial prefrontal cortex (mPFC), hippocampus, among others7. Importantly, prolonged or excessive substance exposure increases vulnerability to negative affective states, including depression, yet the pathophysiological mechanisms bridging addiction and depression remain incompletely understood. This gap highlights the need for mechanistic frameworks that explain how chronic drug exposure interacts with stress and mood-related circuits.

Depression is a complex mental disorder characterized by low mood, anhedonia, worthlessness, suicidal thoughts, psychomotor delay or agitation, and disturbed sleep patterns8,9,10. The World Health Organization predicts that depression will become the leading global health burden by 2030, incurring substantial social and economic costs11. The prevalence of depression is increasing year by year, and it is increasing faster in adolescents than in adults. There is a worrying rise in depression among teenagers, who are 30 times more likely to commit suicide12. The pathogenesis of depression involves environmental, genetic and epigenetic factors, and the etiology is complex and disabling5,13. Both acute and chronic use of addictive substances—such as cocaine, alcohol, and heroin-can result in drug-induced depression5,9,12,14. However, most existing studies tend to address addiction and depression related mechanisms separately, resulting in an insufficiently integrated understanding of the biological basis underlying their comorbidity (Fig. 1).

Fig. 1: The mechanism of physiological changes in depression.
Fig. 1: The mechanism of physiological changes in depression.
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a By affecting the function of the hypothalamic-pituitary-adrenal axis, it leads to its hypofunction, thereby causing the occurrence of depression. b In the body of patients with depression, the release of neurotransmitters and energy from synapses is reduced, thereby affecting the neural plasticity of synapses. c The elevated levels of pro-inflammatory cytokines in the blood of patients with depression animal models, along with the decreased permeability of the blood-brain barrier, may facilitate monocyte infiltration into the brain, thereby leading to increased inflammation and microglial activation. Stimulate the peripheral immune system and a series of immune cells to generate immune responses, thereby altering the growth and development of neurons. Dopamine(DA), 5-hydroxy tryptamine(5-HT), brain-derived neurotrophic factor(BDNF), adenosine triphosphate(ATP), interleukin-1beta(IL-1β), interleukin-6(IL-6), interleukin-1(IL-10), tumor necrosis factor-α(TNF-α). (Figure was created by Adobe Illustrator 2023).

Epigenetics involves the reversible regulation of gene expression without changes to the DNA sequence. These mechanisms are vital for proper cell development and differentiation15. Epigenetic mechanisms—such as DNA methylation, histone modifications, noncoding RNAs, and RNA editing-contribute to key neural processes, including learning, memory, and emotional regulation, and are increasingly recognized as central to both depression and drug addiction16,17,18. Because epigenetic pathways translate environmental exposures into enduring neural alterations, they offer a unifying framework for understanding the shared biology of addiction and depression.

Recent findings indicate that addictive drugs can induce persistent epigenetic remodeling in reward and stress-related pathways, changes that may contribute to the emotional dysregulation frequently observed during and after substance use9,19. Understanding these shared mechanisms may help clarify inconsistencies across studies and reveal new therapeutic opportunities. In this article, we review current evidence on the relationship between depression and drug abuse from an epigenetic perspective, aiming to provide a more integrated understanding of their comorbidity and potential directions for clinical intervention (Fig. 2).

Fig. 2: Addiction and depression comorbidity: epigenetic mechanisms.
Fig. 2: Addiction and depression comorbidity: epigenetic mechanisms.
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Summarize the common changes in the body caused by addictive drug abuse and depression the mechanism mainly involves the pathophysiological changes resulting from epigenetic modifications. Addictive drugs, such as cannabis, nicotine, and cocaine, as well as depression, affect brain pathways and physiological regulatory processes through various epigenetic mechanisms, including histone modification, DNA modification and noncoding RNA. (Figure was created by Adobe Illustrator 2023).

Addictive drug abuse and depression

The abuse of addictive drugs can lead to serious neurotoxicity, then lead to serious brain damage and mental disorders20. Studies indicate that individuals abusing addictive drugs exhibit elevated depression scale scores, correlating with both frequency of use and injection frequency. Notably, injecting users report more suicide attempts and suicidal ideation20,21,22,23. Treating depression resulting from substance abuse requires a thorough understanding of the underlying mechanisms and interactions, along with the implementation of varied treatment approaches. Although a wide range of neurobiological effects have been described, these mechanisms are often presented independently in the literature, making it difficult to understand how drug exposure produces persistent depressive vulnerability. Integrating these findings into a coherent framework is therefore essential for clarifying the shared pathways linking addiction and depression. This article summarizes amphetamines, opioids, cannabis, and other drugs to elucidate these mechanisms and offer insights for clinical drug use and development.

Amphetamines and their analogs and depression

Amphetamine-type substances (ATS), such as amphetamine, methamphetamine (METH), and methylene dioxy methamphetamine (MDMA), are synthetic central nervous system (CNS) stimulants widely abused worldwide and commonly prescribed for attention deficit hyperactivity disorder20,24. Studies indicate that illegal amphetamine users have a 5.28 times higher risk of developing psychosis compared to nonusers22. Amphetamine-induced depression may be associated with changes in the monoaminergic and glutamatergic systems, the hypothalamic-pituitary-adrenal (HPA) axis, chronic stress, increased inflammation, decreased levels of brain-derived neurotrophic factor (BDNF), and impacts on synaptic function, neuroplasticity, autophagy, and neurogenesis. Research indicates that the dopamine (DA) surge from amphetamine abuse can cause oxidative stress, neuronal death, and morphological changes in the hippocampus, particularly reducing neuron density in the CA1 region and Zn²⁺ concentration25,26,27. Prolonged or repeated exposure to MDMA can lead to long-term abnormalities in the serotonergic system, including decreased levels of serotonin (5-HT) and its major metabolites in the thalamus, striatum, and cortex. 5-hydroxyindoleacetic acid, 5-HT transporter density, and tryptophan hydroxylase (TPH) activity are also decreased21,28,29. DA, 5-HT, BDNF, and Tyrosine Kinase receptor B in the striatum and hippocampus were all reduced over the next 75 days after METH injection in rats30. Amphetamines induced the activation of the endoplasmic reticulum (ER) stress signaling pathway in hippocampal neurons, accompanied by the destruction of ER function and the change of calcium homeostasis31,32. Overactive neuronal autophagy depletes BDNF, impairs adult hippocampal neurogenesis and induces depressive behavior in experimental animals33,34. Both protein kinase B (AKT) and DNA damage-inducing transcript 4 (DDIT4) are mammalian target of rapamycin (mTOR) regulators, which play an important role in the regulation of autophagy35,36. Studies have shown that exposure to METH can increase the expression of DDIT4, and also up-regulate the expression of Beclin-1 and LC3-II35,36,37,38. These changes suggest that the autophagy process in the brain is altered during the administration of METH. These findings suggest that METH may influence cell function and neuronal health by regulating autophagy processes. Amphetamines can also increase the release of excess glutamate from nerve endings of the CNS into the cortex, resulting in an imbalance of cortical signaling. The HPA axis is involved in many psychopathological processes, such as depression, and long-term amphetamine abuse can damage the HPA axis, leading to impaired negative feedback, adrenal enlargement, and hypercortisolemia39,40. Taken together, ATS-induced depressive symptoms arise from the convergence of monoaminergic depletion, ER-stress-related autophagy, glutamatergic imbalance, and HPA-axis disruption. These interacting pathways impair synaptic plasticity and stress resilience, helping explain the persistent emotional vulnerability seen in chronic ATS users. Because key elements of these processes-such as BDNF–TrkB signaling and mTOR-dependent autophagy-are epigenetically regulated41,42, they may represent promising targets for treating ATS-related depression.

Synthetic cathinone (SC), the second most common new psychoactive substance, is a β-ketone analog resembling amphetamine and is often called “natural amphetamine” due to its similar chemical structure and effects43,44. There are many SCs, such as 3, 4-methylenedioxypyrrolidone (MDPV), n-ethylpentanone (NEP) and mephedrone. New SC continue to increase, acting primarily by increasing synaptic levels of DA, 5-HT, and norepinephrine (NA) in the brain45. High doses of methcathinone can lead to severe psychiatric symptoms, such as depression. After exposure to NEP, mice may exhibit symptoms of anorexia and depression, with decreased levels of 5-HT and NA in the striatum and mPFC. The tail suspension test indicates that withdrawal from NEP increases the immobility time in mice, suggesting that drug withdrawal can trigger depression-like symptoms46,47. Reduced expression of tyrosine hydroxylase and TPH, biochemical markers of neuronal integrity, was observed after mephedrone administration, along with downregulation of dopamine D2 receptors in the striatum, indicating the presence of damaged nerve endings48,49. Exposure to mephedrone, methylone, and MDPV caused oxidative stress in neuronal cell lines, including dopaminergic neuroblastoma and mouse hippocampal neurons. This included increased reactive oxygen and nitrogen species, reduced glutathione, and elevated oxidized glutathione. Additionally, these substances depleted ATP levels, impaired mitochondrial function, reduced cell proliferation, and induced autophagy, necrosis, and apoptosis50. The mechanism of the toxic action of cathinone is still unclear, and the mechanism of drug-induced depression caused by cathinone abuse needs further study. Overall, SCs appear to induce depression-like effects through overlapping mechanisms—including monoamine imbalance, oxidative stress, and mitochondrial dysfunction—that may converge on persistent epigenetic alterations.

Cannabis and depression

Approximately 3.8% of the global population has used cannabis, primarily due to cannabinoids, which are classified as endocannabinoids, phytocannabinoids, and synthetic cannabinoids. The main active component of cannabis is Δ−9 tetrahydrocannabinol (THC), which causes most psychoactive effects and addiction. Data show that adolescent marijuana use is associated with an increased risk of major depression and suicide in early adulthood51,52. Adolescent cannabis use can lead to anhedonia and anxiety symptoms in adulthood, along with decreased 5-HT levels and increased NA levels53. In addition, adolescents exposed to cannabis over a long period of time have a diminished response of their DA neurons to cannabis, while developing persistent cross-resistance to other substances, such as morphine, cocaine, and amphetamines54. This may be one of the mechanisms by which cannabis abuse triggers depression. The study found that regular marijuana use was associated with decreased frontal white matter integrity and was regulated by the fatty acid amide hydrolase genotype. This decline in white matter integrity is associated with negative emotions and greater symptoms of apathy among cannabis users55. Because cannabinoid receptor 1 (CB1) activation results in inhibition of selective adenylate cyclase activity, THC binding to CB1 receptors may affect perception, memory, and movement, and may trigger depression. Simultaneously, the hippocampus is rich in CB1 receptors. THC and CB1 agonists can reduce the release of presynaptic neurotransmitters and disrupt the long-term plasticity of hippocampal synapses52,56. Some studies suggest that cannabis may have antidepressant effects, but this remains controversial57. Further research is needed to clarify the line between its pharmacological and toxicological effects. As some countries move towards legalizing marijuana, additional studies will help establish a foundation for responsible and informed cannabis use.

Opioids and depression

Prescription opioids are frequently abused, with nearly 30% of chronic pain patients misusing them and about 12% developing opioid use disorder58. While effective for pain relief, long-term opioid use can lead to adverse effects, including immunosuppression and neurohormonal deficiencies59,60. Opioid use is often comorbid with depression and anxiety, affecting around 7.8 million adults with mental disorders61. Mendelian randomization analysis suggests a potential genetic link between increased opioid use and the risk of major depressive disorder (MDD) and anxiety-related disorders62. MTT assay found that fentanyl and remifentanil had cytotoxic effects on neuronal cell lines, which were also found in oxycodone, morphine, tapentadol, and tramadol63,64. Studies have found that fentanyl causes inflammation and increases the levels of total mercaptan, acetylcholine, butyrylcholine, and paraoxonase-1, leading to neuronal cell death, and the level of TNF-α in neuronal cells increased by 2.3 times after fentanyl administration65. After tramadol exposure, the expression of BDNF decreased, and the expression of apoptosis and autophagy genes increased in the striatum and hippocampus66. Overall, opioid-related depressive symptoms appear to result from neuroinflammation, mitochondrial dysfunction, and impaired neurotrophic signaling. These pathways may also interact with stress-related epigenetic regulators, providing a mechanistic basis for the persistent emotional dysregulation seen in opioid misuse.

Cocaine and depression

Cocaine is a natural stimulant derived from the coca plant, used both recreationally and as a local anesthetic67. Its abuse poses significant public health issues globally, with approximately 0.4% of individuals aged 15–64 reporting use. Cocaine affects the CNS, leading to various physical and psychological issues, including neurodegeneration and seizures. Additionally, repeated use and withdrawal can result in persistent overactivation of the HPA axis, causing elevated cortisol levels and disrupted negative feedback mechanisms68,69,70,71. Long-term withdrawal from cocaine can cause emotional symptoms similar to mental and stress-related illnesses72. The study found an increase in anxiety and depression-like behavior in male rats 24 h after withdrawal. Cocaine reduces motor activity in the rodents’ brains, reduces DA levels and increases γ-aminobutyric acid levels. Acute exposure to cocaine can cause abnormal behavior and damage of the dopaminergic system in zebrafish73. FK506 binding protein 5 (FKBP5) is an auxiliary companion of the glucocorticoid receptor (GR) complex that regulates the sensitivity of GR to cortisol and has been implicated in the pathology of human psychiatric disorders, such as anxiety, depression, and post-traumatic stress disorder. It was found that the mRNA expression of FKBP5 increased significantly in the early stage of chronic cocaine withdrawal74. Current evidence indicates that cocaine withdrawal alters stress-glucocorticoid signaling and FKBP5-related transcriptional pathways, which may partially underlie its depressive consequences. Although causal relationships remain to be fully established, these mechanisms provide a preliminary basis for exploring HPA-axis modulation as a therapeutic approach (Fig. 3).

Fig. 3: Schematic illustration of brain circuits implicated in depression and addictive drug abuse.
Fig. 3: Schematic illustration of brain circuits implicated in depression and addictive drug abuse.
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Addictive drug exposure induces widespread neuroadaptations across multiple brain regions, altering glutamatergic, dopaminergic, and GABAergic signaling and contributing to vulnerability to depressive symptoms. a Depictive summary of the classical neural circuits involved in major depression and stress-related depressive phenotypes, including dysregulation within monoaminergic pathways, neuroinflammatory signaling, and reduced neurotrophic support (e.g., BDNF–TrkB pathways); b schematic representation of the core reward- and motivation-related neurocircuitry underlying addiction. This panel is not intended to represent depression-specific circuits, but rather the canonical pathways involved in reinforcement learning and drug seeking. These addiction circuits partially overlap with depressive circuits (e.g., PFC–NAc), providing a mechanistic basis for comorbidity, while also containing addiction-specific nodes (e.g., LH, VP). Norepinephrine (NA), interleukin-8 (IL-8), tropomyosin receptor kinase B (TrkB), nuclear factor kappa-B (NF-κB), hypothalamus (Hyp), amygdala (Amy), lateral hypothalamic area (LHA), ventral tegmental area (VTA), lateral habenula (LHb), ventral pallidum (VP), basolateral amygdala (BLA), lateral hypothalamus (LH), mediodorsal thalamus (MDT). (Figure created with Adobe Illustrator 2023).

Addictive drug abuse and epigenetics

Beyond these neurobiological outcomes, addictive drugs also exert regulatory effects at the epigenetic level. Repeated exposure can induce epigenetic adaptations within reward-related circuits, contributing to persistent functional changes that support long-term drug-seeking behaviors75. Epigenetic mechanisms provide a regulatory framework that promotes the plasticity required for addiction and persists in the long term after the cessation of drug use76. Studies indicate that repeated drug use can cause histone modification and DNA methylation changes in various brain regions77. Such findings highlight epigenetic regulation as a promising avenue for identifying new therapeutic targets for addiction.

Addictive drug abuse and DNA methylation

DNA methylation was first discovered in CpG regions, known as CpG islands, which are roughly 1000 base-pair long stretches of DNA with high CpG density. Most gene promoters are located within the CpG island78. DNA methylation is a dynamic and reversible process catalyzed by enzymes, such as DNA methyltransferase (DNMT), which covalently adds methyl groups to site 5 of the cytosine nucleotide to produce 5-methylcytosine76,79. This methylation of cytosine regulates transcriptional plasticity of the mammalian genome and is the most stable and well-studied epigenetic modification known to date15. Intermediates of methylation and demethylation may play important roles in disease-related transcriptional plasticity76,80,81.

Genome-wide DNA methylation tests reveal altered DNA methylation status in the blood of drug-addicted patients82. Genome-wide analysis found that changes in different hydroxymethylation regions in the brain and increased expression of specific potassium channels may inhibit METH smoking behavior83. METH injection induced differential changes of DNMT1 expression in the NAc region and dorsal striatum of two strains of rats. The expression of DNMT1 in the striatum and NAc was increased in Fisher 344 rats after acute and repeated METH injections, while the corresponding expression was decreased in Lewis rats84. Long-term use of METH inhibits CpG demethylation in the synuclein alpha promoter region and leads to increased expression of alpha-synuclein in striate neurons. Notably, this demethylation persists even during withdrawal from meth use85. Repeated injection of cocaine dramatically reduces levels of the methyltransferase DNMT3a, which continues to increase after cocaine withdrawal, i.e., the increase in DNMT3a may be an epigenetic mechanism that is particularly important for the withdrawal phase of addiction86. DNA hydroxymethylation markers have also been studied after taking cocaine and METH. Overall levels of 5-hydroxymethylcytosine increased after repeated administration of cocaine77,87. Restricting access to cocaine was found to reduce DNA hydroxymethylation levels in the Homer2 promoter region of rats87. Together, the evidence indicates that addictive drugs alter DNA methylation across stress- and reward-related circuits, leading to lasting changes in gene regulation and behavior. Although these methylation shifts are reversible and may hold therapeutic value, their direction and specificity differ across brain regions and cell types, underscoring substantial mechanistic heterogeneity (Table 1).

Table 1 Addictive drug abuse and DNA methylation
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Addictive drug abuse and histone modification

Histone modification is a key mechanism in epigenetics, particularly the acetylation of lysine residues in histone tails. Gene expression depends on DNA accessibility, as DNA is tightly packaged in chromatin, wrapping around histone octamers composed of H2A, H2B, H3, and H4. The N-terminal “tails” of these histones undergo various modifications-acetylation, phosphorylation, methylation, and ubiquitination—that affect their interaction with DNA, thereby altering chromatin structure and regulating gene expression15,88.

Addictive drug abuse and histone acetylation

Histone acetylation is a dynamic and reversible process occurring on all core histones, catalyzed by histone acetyltransferases and reversed by histone deacetylases (HDACs). It is often associated with an “open” higher-order chromatin structure, increasing nucleosome spacing and allowing easier access for transcription factors and transcription machinery, thereby promoting transcriptional activation76,89,90.

Acute or chronic exposure to psychostimulants, alcohol, or nicotine can elevate total cellular acetylation levels of histones H3 and H4 in the NAc, while reducing HDAC enzymatic activity and disrupting its cellular localization. Chronic cocaine exposure enhances the expression of acetylases in the NAc but decreases the genomic accessibility of class III HDACs, particularly at gene promoters. This limits acetylases’ ability to lower histone acetylation at crucial gene loci91,92,93,94,95. Repeated opioid use increases H3 acetylation in the mesolimbic DA system, notably at H3K9, H3K14, H3K18, and H3K27. Elevated H3K27ac levels were observed in the striatum of humans and rats using heroin, highlighting its importance in opioid dependence. Additionally, the overall high acetylation of H3 in heroin users correlates with the duration of use, resulting from altered functional balance of HAT and HDAC due to the drug75,96,97,98,99,100,101,102. Long-term METH use increases H3 acetylation in the brain, decreasing H3K9ac and H3K18ac while increasing H4K5 and H4K8 acetylation over time. METH use also lowers mRNA levels of HDAC3, HDAC8, and HDAC11, and reduces HDAC1 protein expression in the NAc, while increasing HDAC2 protein levels3,80,103,104,105. Chronic METH exposure reduced acetylated histone H4 levels at the GluA1, GluA2, and GluN1 promoters, while increasing HDAC2 and SIN3A binding at GluA1 and GluA2, suggesting suppressed glutamate receptor expression through epigenetic mechanisms80. In conclusion, addictive drugs remodel histone acetylation in a region- and residue-specific manner, promoting chromatin accessibility and transcription of plasticity-related genes. However, the direction and magnitude of these acetylation changes vary across drugs and experimental paradigms, highlighting the need for more standardized and mechanistically focused investigations.

Addictive drug abuse and histone dopaminination

Histone H3-glutamine 5-dopaminization (H3Q5dop) plays a key role in cocaine induction of midbrain transcriptional plasticity. Researchers collected VTA tissues at different time points after the self-administration of cocaine intravenously in rats. In the VTAs of animals exposed to cocaine for a long time, the level of H3Q5dop was significantly downregulated106. The level of H3Q5dop in NAc significantly increased during the acute withdrawal period and the long-term withdrawal period, while no similar changes were observed in mPFC. This accumulation relies on voluntary drug intake, and natural rewards cannot induce it. By injecting the dominant negative mutant H3.3Q5A, which inhibits the formation of H3Q5dopinto NAc, the cocaine seeking behavior after withdrawal can be significantly reduced. On the contrary, the inhibition of H3Q5dop in mPFC has no effect on behavior, indicating that its effect is region-specific. RNA sequencing revealed that the inhibition of H3Q5dop in NAc led to the differential expression of 112 genes, involving DA metabolism, calcium homeostasis and endogenous opioid pathways. The general downregulation of these genes suggests that H3Q5dop functions by maintaining the cocaine-induced pro-relapse transcriptional program107. Only 9 genes in the mPFC were affected, with no overlap in the NAc. The weakening of H3Q5dop during withdrawal impairs gene expression related to neuronal signaling and dopaminergic function. Expressing the dominant negative mutant H3.3Q5A in the VTA significantly reduced seeking behavior after heroin withdrawal, with behavioral tests showing over a 50% reduction in active responses, highlighting its role in reuptake susceptibility. RNA sequencing revealed that about 50% of gene expression changes from heroin withdrawal (including opioid pathways and DA signaling) could be reversed by inhibiting H3Q5dop. Notably, gene expression changes induced by heroin and cocaine in the VTA overlap significantly, indicating that different drugs regulate similar pathways through H3Q5dop in opposing directions108. Together, current evidence indicates that addictive drugs induce stimulus- and region-specific dopaminylation of histone H3, shaping transcriptional programs involved in reward processing and drug-seeking behavior. However, H3Q5 dopaminylation findings remain heterogeneous across drugs and experimental paradigms, and, notably, no studies to date have established a direct role for this modification in depressive pathology (Table 2).

Table 2 Histone modification induced by addictive drugs
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Addictive drug abuse and noncoding RNA

In recent years, ncRNAs have gained attention for their role in various biological processes and post-transcriptional regulation. NcRNAs include microRNA (miRNA), circular RNA (circRNA), long noncoding RNAs (lncRNA), and other undiscovered small regulatory RNAs. Both miRNA and siRNA inhibit translation and promote mRNA degradation by binding to transcripts76.

MiRNA is a small noncoding RNA molecule, 21–22 nucleotides long, that promotes mRNA degradation by inhibiting translation or binding semi-complementarily to the 3’ untranslated region (UTR), thereby regulating post-transcriptional gene expression109,110. Studies indicate that miRNA regulates gene networks involved in synaptic plasticity. Chronic drug exposure can cause adverse changes in neural networks, particularly affecting synaptic plasticity in the mesocortical limbic DA system, which may contribute to compulsive drug behavior. Research on the plasma miRNA of METH use disorder (MUD) patients revealed that miR-181a, miR-15b, miR-let-7e, and miR-let-7d could serve as potential biomarkers for MUD. Additionally, miR-181a was found to directly negatively regulate the expression of the human glutamate receptor gene GRIA2 in MUD111,112. The study found 78 significantly different miRNAs in the VTA of rats with long-term METH use, of which 71 miRNAs were down-regulated. MiR-26a, miR-29a/b/c, miR-222 and miR-383 are expected to bind to the 3’UTR of Dnmt3B, affecting the expression of Dnmt3B and the vulnerability to addiction113. Cocaine exposure boosts miR-212 expression in the dorsal striatum, which is linked to reduced cocaine intake. This suggests that increased miR-212 acts as a compensatory mechanism to diminish cocaine’s motivational effects114. MiR-495 was rapidly down-regulated after acute cocaine injection. MiR-495 was found in the cocaine model to directly target the 30 UTR of multiple genes known to be increased in substance use disorder, such as BDNF and calmodulin-dependent protein kinase II alpha115. METH and cocaine reduce novel-m009C expression in the NAc via D1R activation. Blocking D1R prevents both novel-m009C suppression and METH-induced sensitization. Conversely, NAc overexpression of novel-m009C diminishes METH reward and lowers Grin1 expression, an effect reversed by NMDA receptor activation. These findings indicate that D1R-dependent repression of novel-m009C relieves inhibition of Grin1, enhancing NMDAR signaling to promote METH reward109. In conclusion, miRNAs play a key role in drug addiction by modulating synaptic plasticity and gene-regulatory programs across reward and stress circuits.

LncRNA is an endogenous noncoding RNA longer than 200 nucleotides, involved in various biological functions by interacting with protein partners. They can also engage with chromatin modification complexes to target specific genomic regions110,116,117,118,119. In the study, high throughput chain-specific complementary DNA sequencing was used to detect the changes of lncRNA expression profile in METH-sensitized mice NAc. In METH sensitized mice, a few lncRNAs were up-regulated, but most lncRNAs were down-regulated. These lncRNAs that react to METH have been identified, but more experiments are needed to study the unique function and precise regulatory mechanism of each candidate lncRNA120.

CircRNA is a ncRNA formed by reverse splicing and covalent fusion, resistant to RNA exonucleases. It inhibits miRNAs and regulates gene expression by absorbing miRNA, thus creating a functional circRNA-miRNA-mRNA regulatory network121,122. The study aimed to screen circRNA expression and analyze its potential functions by culturing primary cortical neurons and using high-throughput RNA filtration. It identified circRNA Homer1 and circRNA Tlk1 as highly correlated with addiction. Homer1 is upregulated in the NAc, VTA, and hippocampus, while Tlk1 is downregulated only in the VTA. Additionally, low circHIPK2 expression significantly inhibited METH-induced astrocyte activation by targeting miR124 and SIGMAR1. CircTmeff-1 promotes morphine craving by sponging miR-541/miR-6934 in the NAc123,124. CircRNA Homer1 may inhibit miR-101-3p and play an important role in the mechanism of meth addiction125. The study found that high concentrations of circ-0015891 blocked miR-129-1-3p during METH treatment, negatively affecting dopaminergic cells. A total of 195 differentially expressed circRNAs were identified in METH-treated mice compared to saline-treated mice, with 88 upregulated and 107 downregulated122. The research of circRNA in the field of addictive drug abuse urgently needs to be strengthened and further elucidated by more studies (Table 3).

Table 3 Addictive drug abuse and noncoding RNA
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Together, current evidence shows that addictive drugs dysregulate multiple classes of ncRNAs—including miRNAs, lncRNAs, and circRNAs—in pathways that control synaptic plasticity, neuroinflammation, and reward-related transcription. However, ncRNA alterations remain highly inconsistent across drugs, brain regions, and experimental paradigms, highlighting the need for more causal, cell-type-specific, and temporally resolved studies (Fig. 4).

Fig. 4: Addictive drug abuse and epigenetic modifications.
Fig. 4: Addictive drug abuse and epigenetic modifications.
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DNA methylation and histone modifications both participate in the pathogenesis of addictive drug abuse and depression. Drug abuse and depression-related histone modifications include several types, most prominently acetylation and methylation. Histone acetylation is catalyzed by HATs and reversed by HDACs. Histone methylation is catalyzed by HMTs/KMTs. a DNA methylation. In MDD, aberrant DNA methylation of NR3C1 and FKBP5 was found. Cocaine administration significantly elevated FKBP5 during the early withdrawal phase. Early postpartum alcohol exposure led to persistent hypermethylation of the hippocampal FKBP5 promoter, disrupting HPA axis feedback and thus enhancing susceptibility to depression-like behaviors. In the prefrontal cortex of patients with alcohol use disorder, elevated NR3C1 promoter methylation levels have also been observed; b histone methylation. In addiction research, cocaine enhanced the expression of G9a (an H3K9-specific methyltransferase), leading to increased H3K9me2 in the NAc and enhanced drug reward. Similarly, the antidepressant fluoxetine alleviates depressive behaviors by promoting G9a-mediated restoration of H3K9me2. Both depression and drug addiction are associated with increased H3K4me3. METH reduced the expression of the methyltransferase Mll1 KMT2A and the demethylase Kdm5c in the NAc, leading to elevated H3K4me3 at the Oxtr and Fos promoters and strengthening drug-seeking behavior. In patients with depression—particularly in the prefrontal cortex-elevated H3K4me3 contributes to astrocytic dysfunction, exacerbating depressive symptoms and increasing suicide risk; c histone acetylation. Both addiction and depression exhibit dysregulated histone acetylation. METH exposure and stress-susceptible depressive phenotypes are characterized by reduced H3K9ac. METH and most depressive models show increased HDAC2 activity. The specific mechanisms underlying these changes require further investigation. Histone acetyltransferases (HATs), histone deacetylases (HDACs), histone methyltransferases (HMTs/KMTs), major depressive disorder (MDD), FK506 binding protein 5 (FKBP5), nuclear receptor subfamily 3 group C member 1 (NR3C1), nucleus accumbens (NAc), methamphetamine (METH), mixed lineage leukemia 1 (Mll1), lysine-specific methyltransferase 2A (KMT2A), lysine-specific demethylase 5C (Kdm5c), oxytocin receptor (Oxtr). (Figure was created by Adobe Illustrator 2023).

Depression and epigenetics

Building upon the epigenetic alterations described in drug-exposure models, the following section discusses how similar regulatory layers contribute to depression. The symptoms of depression are usually diagnosed by SIGECAPS mnemonic symbols and the DSM-5 criteria, and are classified into MDD, dysthymia and premenstrual irritability disorder, etc126,127. Rodent depression models mainly include olfactory bulb resection models, mother-child separation and early life stress models, learned helplessness models, repeated restraint stress models, chronic unpredictable mild stress (CUMS), social isolation models, chronic social failure stress (CSDS), witnessed failure models, etc.128.

Epigenetic mechanisms increase the risk of depression following adverse life events, integrating genetic and environmental factors. Research highlights the impact of epigenetic changes on the pathophysiology of MDD, particularly in abnormal stress responses, monoamine dysfunction, and neuroinflammation. These mechanisms alter chromatin structure, modulating gene expression related to neuronal plasticity and responses to stress, depression, and antidepressants9,129. This review summarizes the role of epigenetics in depression, focusing on DNA methylation, RNA modification, and histone modification (Fig. 5).

Fig. 5: Epigenetics in depression.
Fig. 5: Epigenetics in depression.
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RNA modification, chromatin modification and noncoding RNA: the generation and mechanism of lncRNA, miRNA, and circRNA. m6A methylation is a common internal mRNA modification in patients with depression; chromatin remodeling disorder is a key mechanism in the pathophysiology of depression; LncRNAs transcribed by RNA polymerase II are involved in the pathophysiological processes of depression through multiple mechanisms: chromatin modification, inhibition of transcriptional activation, sponges and scaffolders; mature miRNAs are produced by a series of cleavage processes of nucleases from longer primary transcripts. miRNAs affect NMDAR and D1R and regulate the expression of regulatory factors by targeting the 3’UTR of regulatory factors; there are various types of circRNAs. They can mediate the expression of regulatory factors by adsorbing miRNAs through sponges, mediate depression, and inhibit cell death through the CEBPB/ZC3H4 axis. Fat mass and obesity-associated protein (FTO), the β2 adrenergic receptor (ADRB2), myelocytomatosis viral oncogene homolog (c-MYC), Silent mating type information regulation 2 homolog-1 (SIRT1), Drosha ribonuclease III (DROSHA), digeorge syndrome critical region 8 (DGCR8), transactivation response element RNA-binding protein (TRBP), argonaute (AGO), CCAAT enhancer binding protein beta (CEBPB), zinc finger CCCH-type containing 4 (ZC3H4), N-methyl-D-aspartic acid receptor (NMDAR). (Figure was created by Adobe Illustrator 2023).

DNA methylation and depression

Studies have found that stress-related MDD is associated with DNA methylation changes in multiple human genes. These include glucocorticoid receptor genes, FK506 binding protein 5 and spindle, centromere-associated complex 2, oxytocin receptor, oligodendrocyte genes and BDNF, among ohters130,131. Acute inhibition of stress-induced DNA methylation with DNMT inhibitors (DNMTi) promotes rapid and sustained antidepressant effects associated with enhanced BDNF-TrkB-mTOR signaling in PFC132. It was found that the BICD2 gene in the peripheral blood of MDD patients and depressed mice showed DNA hypermethylation and mRNA downregulation, while the BICD2 gene in the hippocampus of depressed mice showed DNA hypomethylation and mRNA and protein up-regulation, and the BICD2 protein was also up-regulated in the hippocampus of MDD patients after death. Hippocampal BICD2 knockout in CUMS mouse models of depression shows an antidepressant effect, which may be mediated by increased BDNF expression133. A study found that by examining the postmortem brain tissue of suicidal patients with depression, the astrocyte-specific methylation map in the genome showed that glutamate receptor ionotropic kainate 2 and brain-rich guanosine kinase-related protein, which are associated with depressive psychopathology, were less methylated134. DNMT1 levels were low in the frontopolar cortex, while DNMT3B levels were high. The expression of DNMT1 and DNMT3B in the amygdala decreased, while that of DNMT3B in the paraventricular nucleus increased. In other words, DNMT mRNA expression changes occurred in specific cells in the brain tissue of depressed suicide patients135. CUMS enhanced DNA methylation at specific CpG sites on the glial cell line-derived neurotrophic factor (GDNF) promoter of BALB mice. The use of DNMTi within NAc reversed CUMS-induced depression-like behavior and decreased GDNF expression, and DNA methylation and methyl CpG binding protein 2 binding were also increased in stress-resilient C57BL/6J mice136. Collectively, current evidence shows that depression involves locus-specific and cell type-specific alterations in DNA methylation across the HPA-axis, neurotrophic and glutamatergic pathways. Clarifying the causal relevance of these signatures will require longitudinal human studies and targeted epigenetic manipulation in defined neural circuits.

Histone modifications and depression

Histone crotonylation and depression

Histone crotonylation (Kcr) is the introduction of crotonyl groups to the amino acid residues of histone proteins. Crotonylation modification has been confirmed to promote gene expression. After the introduction of negatively charged crotonyl group, the positive charge of histone decreases, and binds to negatively charged DNA more loosely, which is conducive to the binding of transcription factors137.

Chromosome domain Y-like protein (CDYL) (a transcriptional co-suppressor and histone H3K9/27 methyllysine) acts as crotonyl-CoA hydrase and negatively regulates histone Kcr. In the CSDS model, histone Kcr in the anterior limbic cortex region of stress-sensitive mice was significantly decreased, while the expression of CDYL protein continued to increase. CDYL converts crotonyl-CoA to β-hydroxybutyryl-CoA through C-terminal hydrase, reduces crotonylation donors, and thereby inhibits Kcr. The N-terminal chromodomain of CDYL recruits H3K27 trimethyl transferase EZH2, which cooperates to inhibit the transcription of the target gene nerve growth factor inducible (VGF). The downregulation of VGF reduces the formation of dendritic spines, damages synaptic plasticity, and ultimately leads to depressive-like behavior138. Together, these findings highlight histone crotonylation as a stress-sensitive epigenetic mechanism that regulates synaptic plasticity and depressive-like behaviors, primarily via CDYL–EZH2–VGF signaling. Nonetheless, crotonylation studies remain limited, and its region specificity, behavioral causality, and interaction with other histone marks require further clarification.

Histone acetylation and depression

The first evidence of histone acetylation’s role in depression came from studies showing that HDAC inhibitors (HDACi), used alone or with antidepressants, enhanced antidepressant responses in animal models139,140,141. The study found that histone acetylation (H3K14ac) in NAc was temporarily reduced after chronic social defeat stress and then continued to increase with a decrease in HDAC2 levels, as was also observed in postmortem brain tissue NAC of depressed patients. The injection of MS275 (a specific class I HDACi) into NAc was found to have a powerful antidepressant effect, suggesting that histone acetylation plays an adaptive role in the stress response140. HDAC5, a class II HDAC, may play a similar elastic role in NAc. Mice affected by chronic social failure stress showed decreased HDAC5 expression, while imipramine treatment increased HDAC5 expression. Mice lacking HDAC5 exhibit more depression-like behavior after prolonged social failure stress92. Neuronal plasticity and cognitive function are associated with transcriptional changes mediated by HDAC-mediated epigenetic modifications129,142,143. Overexpression of HDAC2 in neurons induces a decrease in dendritic spine density, synaptic number, synaptic plasticity, and memory formation in mice. Long-term use of HDAC inhibitors can improve the number of synapses and learning disabilities. Virus-mediated knockdown of HDAC2 can also restore structural and synaptic plasticity, ultimately improving memory loss associated with neurodegenerative diseases144,145. Together, these data position histone acetylation as a dynamic regulator of stress adaptation and antidepressant responsiveness across multiple brain circuits. However, acetylation patterns vary by cell type, histone residue, and stress paradigm, and the therapeutic specificity of HDAC inhibitors remains an important challenge for clinical translation.

RNA modifications and depression

RNA molecules can create a dynamic and reversible regulatory network through covalent modifications, influencing gene expression by affecting RNA stability, translation efficiency, and post-transcriptional regulation. Over 100 types of RNA modifications have been identified, including N6-methyladenine (m6A) and N1-methyladenine, primarily in rRNA and tRNA146. Recent studies highlight the significant role of RNA modifications, particularly m6A, in the onset and progression of nervous system diseases, with m6A homeostasis being crucial for maintaining brain functional balance147,148,149. Its methylation levels are carefully controlled by a ternary “writing-erasing-reading” regulatory system: writers, also known as methyltransferases, include Wilms tumor 1 associated protein (WTAP), methyltransferase-like 3 (METTL3), and methyltransferase-like 14 (METTL14), which are responsible for installing the m6A modification. The eraser includes several demethylases, such as AlkB homologate 5 (ALKBH5) and fat mass and obesity associated protein (FTO)150. It is noteworthy that this regulatory system has a cross-dialogue with epigenetic mechanisms—m6A modification can target the regulation of mRNA metabolism of genes associated with histone modification, suggesting that there is a collaborative regulatory network between the epigenome and the epigenome151,152.

In patients with MDD and in depressive models, the mRNA levels of FTO and m6A methyltransferases (METTL3, METTL14, and WTAP) are significantly down-regulated. Experiments showed that knocking down FTO in adult hippocampal neurons induced depression-like behavior, while overexpressing FTO reversed such behavior in response to unpredictable chronic mild stress. MeRIP-Seq analysis revealed that FTO knockout increased hippocampal m6A methylation, whereas overexpression decreased it. FTO enhances the stability of ADRB2 mRNA by demethylating its 3’ UTR. Moreover, knocking down YTHDF2, an m6A reading protein, elevated ADRB2 expression. Activation of ADRB2 counteracted the behavioral and synaptic deficits in FTO-deficient mice, with the ADRB2 agonist formoterol alleviating depression-like behavior and restoring dendritic spine density, while an antagonist blocked these effects. ADRB2 activation also promoted SIRT1 expression via up-regulation of c-MYC, influencing hippocampal synaptic plasticity and depression-like symptoms149. mRNA levels of ALKBH5 were elevated in the blood and PFC of MDD patients as well as in mouse models of depression, and selective knocking out ALKBH5 in astrocytes produced antidepressant like behavior. ALKBH5 reduces glutamate uptake by astrocytes by reducing m6A modification of glutamate transporter GLT-1, inhibiting its translation and protein expression. Glutamate homeostasis and synaptic dysfunction ultimately lead to depression-like behavior153. The study found that the plasma circHECW2 level in MDD patients was significantly increased and was positively correlated with depression severity and anxiety symptoms. CircHECW2 regulates Gng4 mRNA stability through WTAP-mediated m⁶A methylation, and GNG4 deletion leads to astrocyte dysfunction, which further affects astrocyte function and depressive phenotype152. CircSTAG1 expression was significantly down-regulated in plasma and whole blood of MDD patients and in hippocampus and peripheral blood of mice with chronic unpredictable stress. And its expression was negatively correlated with the depression scale score of MDD patients. Fatty acid amide hydrolase (FAAH) is an endocannabinoid-degrading enzyme, and its overexpression is related to depression. CircSTAG1 inhibits its nuclear translocation by binding to the m6A demethylase ALKBH5, thereby reducing the m6A demethylation of the target gene FAAH mRNA, and the increase of m6A methylation of FAAH mRNA leads to the decrease of its stability. Ultimately, reduced expression of FAAH protein induces astrocyte damage, leading to depression-like behavior150. In summary, the close relationship between RNA modification and depression not only provides a new perspective on our understanding of the complexity of depression but also opens new paths for future treatment strategies. However, the directionality, cell specificity, and functional hierarchy among different RNA modifications remain incompletely defined, and future studies are needed to determine which modifications are causal drivers versus secondary stress responses.

Noncoding RNAs and depression

Studies have shown that after death, the expression level of miR-1202 in the brain tissues and blood samples of MDD patients decreased significantly154. The expression levels of miR-15, miR-182 and miR-206 were higher than those in healthy people and regulated the BDNF gene155. However, miR-204-5p is downregulated in the ventral prefrontal cortex, activating the JAK2/STAT3 signaling pathway, causing neuronal damage and leading to depressive and anxiety-like behaviors156. In addition, the expression of miR-16-2 in the brains of MDD patients was also significantly decreased157. A study analyzed the correlation between miR-30e ss178077483 and MDD patients and control subjects, and found that miR-30e ss178077483 was significantly positively correlated with MDD158. miRNAs, such as miR-34a, -34b, -34c, -137, and -140-3p, -21-3p, -30d-5p, -330-5p, -378a-5p, -134, -19b-3p have potential roles in the diagnosis of patients with depression159. All the above indicate that multiple types of miRNAs are involved in the pathological process of depression and affect the occurrence and development of the disease.

LncRNA can be involved in the pathogenesis of MDD by regulating neurotrophic factors, affecting the development and function of the CNS, as well as synaptic function160. LncRNA BDNF-AS is associated with supporting neuronal survival and synaptic plasticity161. Magnetic resonance imaging was used to measure the hippocampal volume. The differences in ncRNA BASP-AS1 between MDD patients and healthy controls were analyzed, and it was found that the expression of BASP1-AS1 was higher in MDD patients162. LncRNA XR_351665 can up-regulate the expression of DNMT1 by sponging miR-152-3p, thereby promoting the development of depression induced by chronic pain163. LncRNA NONHSAG045500 activates the cAMP-PKA-CREB pathway, improves the level of 5-HT, reduces the expression of 5-HT transporter, and exerts an inhibitory effect on depression-like behaviors164. The studies indicate that lncRNA is linked to synaptic plasticity and may trigger depressive symptoms by regulating miRNA, making it a potential biomarker for depression.

CircRNAs are ideal biomarkers for the diagnosis of depression165,166. Compared with patients with type 2 diabetes mellitus (T2DM) and depressive T2DM, the study found that 183 his-circRNAs were significantly upregulated and 64 were downregulated in patients with T2DM. Differentially expressed circRNA can serve as an important clue for studying the pathogenesis of depression in patients167. CircRNA is linked to microglial apoptosis. In LPS-induced mouse models, circDYM was found to inhibit microglial apoptosis via the CEBPB/ZC3H4 axis, improving depressive-like behaviors168. Studies have shown that extracellular vesicle-mediated delivery of circDYM can treat depression by inhibiting microglial activation and binding transcription factor TATA-box binding protein-related factor 1 to suppress neuroinflammation169. CircRNAs, as endogenous miR-9 sponges, can target miR-9 to participate in the ubiquitination of HSP90, thereby regulating microglial polarization and reducing depressive-like behaviors170. In conclusion, circRNAs can affect the occurrence of depressive symptoms by influencing the molecular activities of body cells and miRNAs, etc.

Yet ncRNA signatures remain heterogeneous across brain regions, patient populations, and experimental models, and only a minority have been validated functionally, highlighting the need for more mechanistic and clinically oriented studies (Table 4).

Table 4 Noncoding RNAs and depression
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Shared epigenetic mechanisms in depression-drug addiction comorbidity

To better integrate these findings, we introduce a unifying three-axis framework, stress-response regulation, reward-circuit remodeling, and synaptic plasticity, which provides a coherent structure for understanding how epigenetic alterations converge across depression, drug addiction, and drug addiction-induced depression. This framework positions the mechanisms reviewed above not as isolated pathways, but as interconnected processes that jointly shape vulnerability and behavioral outcomes (Fig. 6).

Fig. 6: Convergent and condition-specific alterations of ncRNAs in drug addiction and depression.
Fig. 6: Convergent and condition-specific alterations of ncRNAs in drug addiction and depression.
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a miRNAs. a1 Cocaine-induced upregulation of miR-212/132 in the striatum modulates MeCP2 and BDNF signaling, constituting a shared regulatory node implicated in both drug reinforcement and depressive vulnerability. a2 Cocaine also alters miR-16, increasing SERT expression and 5-HT reuptake, a pathway linked to serotonergic dysfunction in addiction and depression; b LncRNAs. b1 Malat1 is involved in both drug exposure and stress-related phenotypes and regulates transcriptional programs affecting neuronal excitability and synaptic plasticity. b2 NEAT1 is downregulated by METH but upregulated by heroin; through competitive interaction with miR-320-3p, it increases CRHR1 expression and contributes to hippocampal impairment and depressive-like outcomes; c circRNAs. c1 circHIPK2 is elevated following METH exposure and CUS. Acting as a sponge for miR-124-2HG, circHIPK2 influence astrocyte activation and behavioral sensitivity, whereas knockdown of circHIPK2 or microbiome-mediated suppression alleviates both addiction-related and depressive phenotypes. c2 Across both addictive drug exposure and depression, dysregulated circRNAs converge on m⁶A-dependent pathways, suggesting a shared circRNA–m⁶A regulatory axis that may represent a unifying mechanism and a promising future therapeutic target. Metastasis-associated lung adenocarcinoma transcript 1 (Malat1), nuclear paraspeckle assembly transcript 1 (NEAT1), circular RNA homeodomain-interacting protein kinase 2 (circHIPK2), methyl-CpG-binding protein 2 (MeCP2), brain-derived neurotrophic factor (BDNF), serotonin transporter(SERT), 5-Hydroxytryptamine (5-HT),corticotropin-releasing hormone receptor 1 (CRHR1), chronic unpredictable stress (CUS), N6-methyladenosine(m⁶A). (Figure was created by Adobe Illustrator 2023).

Multiple lines of evidence indicate that chronic stress and drug addiction converge on common epigenetic targets, particularly stress-axis regulators and neuroplasticity genes. Additionally, in MDD, aberrant DNA methylation at stress-related loci, including the glucocorticoid receptor gene NR3C1 and FKBP5 and neurotrophic genes (such as BDNF) are well documented9. Remarkably, addictive drugs similarly remodel these same loci171. For example, early postnatal alcohol exposure leads to persistent hypermethylation of the FKBP5 promoter in the hippocampus, likely disrupting HPA axis feedback regulation and enhancing susceptibility to depression-like phenotypes through epigenetically mediated stress-response dysregulation172. Similarly, experimental studies have shown that cocaine administration markedly increased FKBP5 expression in stress-related brain regions, such as the paraventricular nucleus and bed nucleus of the stria terminalis during early withdrawal, implicating a convergent role for FKBP5 dysregulation across substances in stress-related mood vulnerability74. Moreover, increased NR3C1 promoter methylation-particularly at the exon 1H region, has been observed in the PFC of individuals with alcohol use disorder, accompanied by reduced NR3C1 mRNA and protein expression171. Given NR3C1’s central role in HPA axis regulation and its known involvement in depression, such epigenetic dysregulation may represent a shared vulnerability mechanism across addiction and mood disorders. It is important to note that, despite these convergent findings, direct mechanistic evidence demonstrating that addictive substances induce depressive phenotypes via specific epigenetic pathways remains extremely limited, with only a few studies providing clear causal links.

Neurotrophic and synaptic plasticity pathways likewise show overlapping epigenetic regulation. BDNF, a key mediator of neuronal survival and plasticity, is epigenetically modulated in both disorders. Depressed subjects and stress models reduced BDNF levels, and chronic drug exposure reprogramed its expression173,174. For instance, repeated cocaine in rodents enhanced histone H3 acetylation at the BDNF promoter in PFC, boosting BDNF transcription175. By contrast, alcohol exposure tended to impose repressive marks on BDNF. Early-onset alcohol use increased H3K27 trimethylation at amygdalar BDNF and Arc loci, correlating with decreased gene expression42. Noncoding RNAs also contribute: the antisense lncRNA BDNF-AS was upregulated in individuals with alcohol use disorder and suppressed BDNF expression. Increasing prefrontal BDNF experimentally reduced cocaine-seeking behavior, underscoring BDNF as a shared epigenetic target linking mood regulation and drug reward42,176.

Critically, these shared targets are embedded in complex epigenetic networks and feedback loops. DNA methylation, histone modifications and ncRNAs often act in concert at the same loci. Chronic stress or drug use can simultaneously alter promoter methylation and histone marks to stably repress or activate synaptic genes177,178,179. Moreover, several miRNAs form homeostatic loops that span both stress and reward pathways. For instance, cocaine upregulates miR-212/132 in the striatum, which feeds back via CREB, MeCP2 and BDNF to limit cocaine reinforcement180. Conversely, acute stimulant exposure downregulates miR-495, relieving its suppression of BDNF and calcium/calmodulin-dependent protein kinase II alpha in NAc115. Such interactions create crosstalk between epigenetic layers: MeCP2, a methyl-DNA binding protein, can recruit histone modifiers, while histone acetylation status influences DNA methyltransferase access to chromatin181,182. Together, this multi-layer remodeling across the PFC, NAc, amygdala, and hippocampus provides a mechanistic bridge linking depressive and addictive pathology (Fig. 7).

Fig. 7: Convergent epigenetic regulation of BDNF in addiction and depression.
Fig. 7: Convergent epigenetic regulation of BDNF in addiction and depression.
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The figure depicts how shared and substance-specific epigenetic mechanisms converge on BDNF in the context of drug addiction and depression. a Alcohol use disorder is associated with increased levels of the lncRNA BDNF-AS. Alcohol exposure imposes repressive H3K27me3 marks on BDNF and Arc loci in the amygdala, thereby suppressing BDNF transcription; b cocaine enhances miR-212/132 expression in the striatum, reducing MeCP2 levels and consequently decreasing BDNF. MeCP2, a methyl-DNA–binding protein, can recruit histone-modifying enzymes, and histone acetylation states further influence DNA methyltransferase access to chromatin; c prenatal cocaine exposure induces persistent histone deacetylation at the BDNF and NR3C1 promoters, increasing long-term vulnerability to depression-like phenotypes; d in contrast, repeated cocaine administration increases H3 acetylation at the BDNF promoter in the prefrontal cortex, leading to elevated BDNF expression. Acute stimulant exposure downregulates miR-495 in the nucleus accumbens, which increases BDNF and Camk2a expression. Together, these shared and substance-specific epigenetic pathways highlight BDNF as a central molecular node linking addiction-related neuroadaptations with stress-related depressive phenotypes. Brain-derived neurotrophic factor (BDNF), BDNF antisense RNA (BDNF-AS), activity-regulated (Arc), methyl-CpG binding protein 2 (MeCP2), nuclear receptor subfamily 3 group C member 1 (NR3C1), calcium/calmodulin-dependent protein kinase II alpha (Camk2a). (Figure was created by Adobe Illustrator 2023).

Collectively, these findings show that stress-axis genes, neurotrophic pathways and multi-layer epigenetic networks converge across depression and addiction, providing a unified mechanistic basis for their frequent comorbidity (Table 5).

Table 5 Epigenetic modifications in addiction and depression: a comparative summary
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Concluding remarks and future directions

Researches on the epigenetic mechanisms underlying depression and addiction have uncovered diverse alterations in DNA methylation, histone modifications and noncoding RNA pathways across stress- and reward-related circuits77,179. These findings outline a molecular framework, which link mood dysregulation, addictive behaviors and highlight how depression and drug exposure lead to enduring changes in gene regulation and neural function. However, many important questions remain unresolved.

Although many studies have reported changes in DNA methylation or histone states alongside depressive or addiction-related phenotypes, it is still unclear whether these changes exert causal influence or simply arise as consequences of the disease process. This uncertainty is due in part to the historical lack of tools capable of manipulating specific epigenetic marks and evaluating their behavioral effects. Only with the recent development of locus-targeted tools, such as clustered regularly interspaced short palindromic repeats (CRISPR-Cas9) or transcription activator-like effector nucleases-based epigenetic editors, has it become feasible to directly test how defined chromatin or methylation changes influence neural and behavioral outcomes9,183,184.

In addition, most of what we know about epigenetic regulation in depression and addiction comes from rodent models. Paradigms, such as CUMS or CSDS, are useful for probing mechanisms, but they capture only fragments of the human condition and cannot fully reproduce the complexity of real depressive or addictive states185. As a result, it is still uncertain to what extent epigenetic findings from mouse models can be applied to humans. A related limitation is that many experiments rely on whole-brain or large tissue samples, which mix together signals from neurons, glia and other cell types. These cells carry distinct chromatin and DNA methylation patterns, so important cell-specific changes can easily be obscured186,187. Newer methods, such as Fluorescence-Activated Cell Sorting-based nuclear isolation and single-cell or single-nucleus epigenomic profiling, are only now allowing researchers to look past these averaged signals and observe epigenetic changes at true cellular resolution. However, such high-resolution datasets are still limited, leaving important gaps in our understanding188. Together, these challenges highlight how far the field still is from fully connecting epigenetic findings in animal models and bulk tissues to the complex biology of human depression and addiction.

Moreover, most studies examine patients and controls at only one time point, so it is still difficult to tell how epigenetic marks change during the illness or whether they reflect causes or consequences189. Common factors, such as smoking, medications, and metabolic conditions can also leave strong background signals190,191, and differences in how studies define behavioral or clinical phenotypes further reduce comparability. In addition, future research must pay closer attention to biological moderators, such as sex, age, genetic background, and early-life stress. Evidence has indicated that males and females exhibited markedly different epigenetic responses to stress, and early adversity can leaft persistent marks on the epigenome thereby influencing later vulnerability to depression or addiction192,193. Together, these issues make it challenging to determine which epigenetic alterations have real biological significance in depression or addiction.

Future progress in this field will require advances on several fronts. First, methodological improvements remain essential. As single-cell and multi-omics technologies continue to mature, researchers will increasingly be able to profile DNA methylation, histone modifications, chromatin accessibility, and gene expression within the same cell, thereby generating a more accurate picture of epigenetic changes associated with depression and addiction186,187. Recent developments in CRISPR-cas9-based epigenome editing tools, DNA methylation probes, and programmable systems for modifying histone marks at specific loci have opened new possibilities for testing whether particular epigenetic signatures exert causal effects194,195. However, the application of these tools in the nervous system is still in its early stages, especially with respect to behavioral validation.

Second, future therapeutic exploration will require greater precision. Conventional epigenetic drugs, such as HDAC inhibitors or DNMTi, broadly alter chromatin states and often exhibit substantial off-target effects, limiting their suitability for treating depression or addiction in a targeted manner196. Emerging approaches that modulate noncoding RNAs, including miRNA mimics or inhibitors and antisense oligonucleotides targeting lncRNAs, have shown some promise in animal models, but further validation is still needed197,198,199. Clarifying how addiction and depression intersect at the level of epigenetic regulation will lay essential groundwork for translating these mechanistic insights into more precise and effective therapeutic strategies.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.