1. Introduction

Substance use disorder (SUD) is defined as a chronic state of the uncontrolled exploration and use of drugs that exert detrimental effects on the family, society, and professional aspects of a patient’s life. The high prevalence of psychotic symptoms such as hallucinations and delusions has been reported in patients with substance use [1]. For instance, cannabis and amphetamine users exhibit a higher prevalence of psychotic disorders and cognitive symptoms like schizophrenia [2,3,4]. Moreover, a greater frequency of both opioid and cocaine use has been reported in individuals with psychotic symptoms compared to individuals with nonpsychotic symptoms [5]. Similar to other neuropsychiatric diseases, the etiology of SUDs is complex and multifactorial, in which a variety of responsible genes interplay among each other and with the environment. This interplay alerts neuronal function and structure in different brain areas and gives rise to continuous changes at the cellular, molecular, and behavioral levels [6]. For example, it appears that amphetamine affects brain function via interplay with nerve terminals that utilize indoleamines, like serotonin and catecholamines, including norepinephrine and dopamine as multifunctional neurotransmitters [7]. The prevalence of psychotic symptoms in substance users may be due to the burst release of dopamine in the striatum and subsequently excessive secretion of glutamate into the brain cortex, which further leads to the injury of cortical interneurons and the disruption of thalamocortical signals [8]. It has been found that there is also a potent relationship between any type of SUD and the polygenic risk score for schizophrenia [9]. Genetic factors with a heritability of almost 50% (h² = ~50%) are associated with SUDs and their adverse consequences. For example, alcohol-related tendencies can be affected by loci in alcohol-metabolizing genes (e.g., ADH1B and ALDH2), and nicotine-related tendencies can be influenced by loci within the CHRNA5–CHRNA3–CHRNB4 gene cluster [10]. More information about the genetics of SUDs is provided in a review written by Gelernter and Polimanti [11].

The tight relationship among genes and environmental factors in the development of psychotic symptoms in substance users can be mediated by epigenetic mechanisms as well [12]. During this process, transcription factors and some specific enzymatic protein complexes play a critical role in modulating gene expression and creating long-lasting alterations through modification of chromatin structure [13,14]. These chromatin-modifying mechanisms or other epigenetic alterations have the capacity to alter gene expression without changing DNA sequences. Moreover, drug use or the toxic effects of alcohol may create disturbances in the absorption of micronutrients (omega–3, choline, vitamins, and folic acid) and hence imbalances in the levels of methyl donors, which further give rise to the development of neuropsychiatric diseases via brain epigenetic changes, especially DNA methylation [15]. Therefore, diet modifications and using supplementations with adequate levels of methyl donors is a promising strategy in alleviating the development of psychotic symptoms and neurological impairments in substance users (Figure 1).

_{Figure 1. Therapeutic approaches using diet or epigenetic drugs (methyl donor micronutrients, antipsychotic drugs, and gut microbiome-derived metabolites) for improving substance-induced neurological impairments via normalizing epigenetic aberrations. Methyl donor nutrients, such as methionine, choline, folate, and some B vitamins, participate in one-carbon metabolism and hence could serve as potential epigenetic diets to reduce substance-induced neurological impairments. Likewise, antipsychotic drugs and gut microbiome–derived metabolites like butyrate and acetate can target a gene for epigenetic regulation and thus could serve as potential epigenetic modifiers to improve psychotic symptoms, learning and memory impairments, and depressive-like behaviors in substance users.}

This narrative review aims to elaborate links between substance use-induced neuropsychiatric impairments and epigenetic alterations in brain tissue and the role of diet modifications in alleviating such deficits via normalizing epigenetic aberrations. To this end, we briefly present associations between substance use and the development of psychotic symptoms and neuropsychiatric diseases via epigenetic aberrations. We will discuss studies that support the link between substance use and epigenetic alterations, including DNA methylation, histone modifications, and microRNAs (miRNAs), in particular, in the brain tissue. Note that in DNA methylation, a methyl group is added to a cytosine residue, or less frequently, to an adenine residue that is followed by guanine. This process, mediated by different enzymes, results in methylated cytosines acting as targets for DNA-binding proteins (e.g., MeCP2, MBD1, MBD3, and MBD4), which mediate chromatin condensation and gene silencing. Histone modifications are another type of epigenetic regulation, during which different amino acids of histone tail proteins can become acetylated or methylated (mediated by various enzymes). These modifications affect the positive electric charge of histone proteins and thus the intensity of their binding to DNA, which has a negative electric charge. Histone acetylation generally decreases chromatin condensation and stimulates gene expression, whereas histone methylation can either increase or decrease gene expression depending on the identity or location of the methylated amino acids of histone tail proteins. Additionally, in RNA interference, another type of epigenetic regulation, miRNAs—small non-coding RNAs approximately 20 bases in length—bind to their cognate RNAs and inhibit gene transcription or promote RNA degradation [16].

In this work, we will summarize those studies that show the impact of paternal and maternal exposure to substances on epigenetic alterations in the brains of offspring and the role of maternal diet on the prevention of substance induced neurological impairments notably psychosis, possibly via epigenetic mechanisms. In addition, we provide an overview on the use of different types of diet, especially the methyl-rich diet, for alleviating psychotic symptoms and depressive-like behaviors in patients with SUDs. The next step involves determining how substance use–gut microbiome interactions contribute to the development of psychotic symptoms and depressive-like behaviors through epigenetic alterations and how gut microbiome-derived metabolites help researchers in the design of new therapies based on normalizing epigenetic aberrations. The last section discusses potential challenges and presents future perspectives relevant to alleviating psychotic symptoms and depressive-like behaviors in patients with SUDs using diet modifications and modulation of the gut microbiome.

2. Association between Substance Use and the Development of Psychotic Symptoms and Depressive-Like Behaviors

There is increasing evidence that drug use is associated with the development of psychotic symptoms in various contexts encompassing substance withdrawal, acute or chronic intoxication, in the form of substance-induced psychosis, and delirium [17]. Substance-induced psychosis is described as a condition in which the onset of psychosis appears to be due to substance use, but it remains for days, weeks, or even months in the absence of substance use [18]. Long-term neuropsychiatric deficits induced by substance use are mainly attributed to the activation of different signaling pathways relevant to triggering and the progression of oxidative stress and inflammation [19,20]. For example, methamphetamine-induced psychosis is related to changes in the balance of the immune system, the activation of a variety of chemokines and cytokines (e.g., IL-1α, CCL11, and CCL27), elevated lipid peroxidation, and decreased antioxidant defenses [21,22]. Persistent psychotic symptoms can be induced by amphetamines, cannabis, and alcohol [23]. It is estimated that almost 40% of methamphetamine users suffer from psychotic symptoms like hallucinations and delusions in addition to violence, impulsivity, and cognitive disturbance [24,25].

Mechanistically, the emergence of psychotic symptoms in patients with SUDs could be linked to epigenetic alterations leading to gene expression dysregulation. For example, it was found that decreased DNA methylation at a particular dopamine receptor type 4 (DRD4) CpG2.3 unit was associated with paranoid symptoms in patients with methamphetamine use disorder, and higher methylation levels at the catechol-O-methyltransferase (COMT) CpG 51.52 unit was linked to reduced motor-impulsivity scores in the same set of patients [26]. In another study, Veerasakul et al. found a significant elevation in parvalbumin (PVALB) DNA methylation in methamphetamine-induced psychosis, indicating that methamphetamine dependence confers the GABAergic deficits by epigenetic changes [27]. Kalayasiri et al. reported a strong link between methamphetamine-induced paranoia and alterations in long interspersed element-1 methylation patterns, which modulate the immune and neuro-oxidative pathways [28]. In addition to DNA methylation and histone modifications, substance-induced psychosis is connected to alterations in miRNAs. In this line, an interesting study demonstrated that patients with methamphetamine-induced psychosis exhibited significant differences in the levels of miR-let-7d, miR-let-7e, miR-15b, and miR-181a compared to control subjects [29]. In a more recent study, Chen et al. reported that psychological comorbidities in substance users are linked to the dysregulation of some crucial exosomal miRNAs connected to changes in the levels of certain neurotransmitters, such as serotonin, in these patients [30]. In another study by the same group, they found a negative correlation between the expression levels of exosomal miR-92a-3p, miR-16-5p, miR-129-5p, and miR-363-3p and Hamilton Anxiety/Depression scores in methamphetamine-dependent patients as well as heroin-dependent patients.

In the following sections, we address more details pertaining to the link between substance use and substance-induced psychiatric diseases. Overall, current findings demonstrate that substance use is associated with the development of psychotic symptoms and depressive-like behaviors, and such malfunctions are mediated by epigenetic shifts causing gene expression dysregulation.

3. The Effects of Substance Use on Changing Brain Functions via Epigenetic Alterations

Epigenetic regulatory mechanisms such as DNA methylation, histone modifications, and miRNAs play powerful roles in adaptive alterations in neuroplasticity following prolonged drug use [31,32]. Previous studies have shown that neuronal functions relevant to learning, memory, and synaptic plasticity can be dynamically regulated by DNA methylation and histone modifications in individuals with SUDs [33,34]. For example, heroin-induced remodeling of the actin cytoskeleton via alterations in DNA methylation levels might participate in behavioral plasticity [35]. In this process, the proteasomal degradation of DNA methyltransferase DNMT3a by the E2 ubiquitin-conjugating enzyme contributes to the initiation of CaMKK1 gene transcription and the elevation of CaMKK1 protein expression via decreasing DNA methylation of its promoter region and thereby facilitates actin polymerization through the activation of the CaMKIα/βPIX/Rac1 pathway in the dorsal hippocampus [35]. Likewise, there is an interesting association between DNA hypermethylation of the dopamine transporter gene (DAT1) and dopamine release in individuals addicted to psychoactive substances [36]. Furthermore, reduced levels of brain-derived neurotrophic factor (BDNF) methylation in CpG 5–11 have been found in subjects with tobacco use and depression compared to those who did not consume tobacco with or without depression [37]. In addition to DNA methylation, histone modifications may play important roles in altering neuronal functions in subjects with SUDs [38]. For example, human primary astrocytes treated with opioid and psychostimulants exhibited elevated levels of global acetylation of H3 histone lysine residues, except for the acetylation of the 14th lysine residue [39]. It is hypothesized that illicit drugs like ∆9-tetrahydrocannabinol have the capacity for the activation of histone deacetylases, causing heterochromatic sequences of genes involved in cognitive functions, and higher risks of schizophrenia development and aggravation [40]. Similarly, the retrieval of heroin-related memories is associated with changes in histone acetylation during reconsolidation, and hence interventions to modulate histone acetylation can serve as valid approaches to cure SUD and hamper relapses [41]. Another study showed that adolescent-intermittent ethanol exposure diminishes the level of H3 acetylation in the hippocampus, reduces the expression of BDNF, and, subsequently, suppresses neurogenesis in this brain region [42]. Figure 2 illustrates how drug use and alcohol consumption increase the risk of psychosis, anxiety, depressive-like behaviors, and learning and memory deficits in users via epigenetic alterations.

_{Figure 2. An illustration of association among substance use, epigenetic aberrations, and the development of neurological impairments in users. Substance use causes aberrant alterations in DNA methylation, post-translational histone modifications, and microRNA (miRNA) expression in different brain areas of substance users and subsequently gives rise to the development of psychosis, depressive-like behaviors, and learning or memory deficits. Ethanol intake and illicit drugs (for example, cannabis, methamphetamine, and cocaine) lead to changes in gene expression by combinatorial epigenetic events and, hence, increase the risk of developing psychosis and other neurological impairments.}

Other lines of evidence linking substance use to epigenetic alterations, including DNA methylation and histone modifications in the different brain areas, are summarized in Table 1 and Table 2, respectively. In addition to DNA methylation and histone modifications, substance use epigenetically alters gene expression by changing the levels of endogenous non-coding RNAs, like miRNA and circular RNA (circRNA), in the brain tissue [43,44,45]. circRNAs are capable of influencing substance behavioral effects through interplay with miRNAs [44]. For instance, striatal miRNAs play powerful roles in neuroplasticity, learning and memory, and reward circuit function and regulation [46,47]. As another example, a study by Chavoshi et al. indicated that astrocyte over-activation and striatal atrophy following treatment with methamphetamine is connected to 167 differentially expressed miRNAs in the striatum region [48]. Gu et al. reported that heroin users could exhibit elevated serum levels of miR-486-5p, miR-206, and let-7b-5p, whereas methamphetamine users had increased serum levels of miR-9-3p [49]. Another study found that elevated levels of let-7b-3p in the nucleus accumbens and the ventral tegmental area of methamphetamine users may be considered a potential biomarker for the diagnosis of addiction in these patients [50]. Furthermore, miRNA–mRNA network analysis of postmortem brains and blood samples of subjects with opioid use disorder revealed a potent overlap between their differentially expressed target genes, despite the distinct profiles of the altered brain and blood miRNAs [51].

_{Table 1. Substance-induced DNA methylation alterations in brain tissue.}

_{Table 2. Substance-induced histone modifications in brain tissue.}

_{Table 3. Association between substance use and alterations in miRNAs in various brain regions.}

Generally, aberrant changes in DNA methylation, post-translational histone modifications, and miRNA expression in various brain regions of substance users heavily affect neuronal functions relevant to synaptic plasticity, learning, and memory, which may accelerate the development of psychiatric disorders. However, it is crucial to recognize that while these epigenetic alterations are associated with substance use, the exact causal mechanisms and their implications for psychiatric disorders require further investigation. Understanding these complex interactions will necessitate extensive research to differentiate between correlation and causation and develop targeted therapeutic interventions.

4. Paternal and Maternal Substance Use and Epigenetic Alterations in the Brains of the Offspring

It has been reported that illicit drugs and other substances are capable of passing via the placenta, activation of the immune system, and disrupting the development of offspring by changing gene expression and/or causing epigenetic aberrations in various body organs, especially the brain tissue, and subsequently increasing the risk of mental disorders (Figure 3) [110,111].

_{Figure 3. An illustration of association among maternal substance use, epigenetic alterations, and risk of mental disorders in offspring. Prenatal exposure to substances like alcohol affects the immune system, epigenetic mechanisms, and, hence, the development of mental disorders in offspring.}

For example, methamphetamine has been found to be the most common illicit drug taken by pregnant mothers, which gives rise to changes in the expression of neurodevelopment-related genes and thereby cognitive deficits and neuropsychiatric diseases in offspring [112,113]. Other lines of evidence linking paternal and maternal substance use during pregnancy to epigenetic changes with respect to DNA methylation and histone modifications in various brain regions are summarized in Table 4. It has been found that maternal substance use during pregnancy is connected to an elevated risk of psychotic symptoms in offspring as well [114]. For example, both paternal and maternal cannabis use is linked to the higher number of psychotic-like experiences in the offspring in childhood (at age ten years) [115]. The development of psychotic symptoms and other neurological impairments in offspring owing to substance use can be mediated by epigenetic changes. For instance, a recent study by Wendt Viola et al. indicated that prenatal cocaine exposure in humans can increase the risk for psychosis in offspring, which is connected to epigenetic alterations [116]. In another study by Hollins et al., it was shown that a combination of prenatal treatment with poly I:C and cannabinoid exposure caused strong differences (98%) in the miRNA expression of the brain hemispheric region within the Dlk1-Dio3-imprinted domain on 6q32 that is related to the syntenic human locus in schizophrenia [117]. A more recent genome-wide human study showed that subjects with cannabis use disorder had differential DNA methylation at four CpG sites, remarkably at the AHRR cg0557592 site, found to be an important mediator linking cannabis use to mental disorders, particularly mood disorders [118]. Moreover, maternal exposure to e-cigarette aerosols with nicotine could impair short-term memory, which was connected to the elevated levels of global DNA methylation in the brains of offspring [119].

There is evidence showing that such epigenetic changes in offspring can occur due to malabsorption of nutrients in pregnant women with SUDs. In this line, it has been shown that drug use and alcohol consumption result in derangements in the absorption of micronutrients such as folic acid, choline, and omega 3 during pregnancy, and hence supplementation with such diets in pregnant women with SUD may prevent neurological deficits in the offspring through normalizing epigenetic aberrations [120,121,122,123]. As another interesting example, it was shown that prenatal alcohol exposure caused perturbances in hippocampal miRNA expression, and choline supplementation could reverse an ethanol-dependent increase in hippocampal miR-200c expression [124]. Another animal study demonstrated that alcohol consumption increases DNA methylation in the PFC and hippocampus of rat pups during the neonatal period, and supplementation with choline could reduce DNA hypermethylation in both of these brain regions [125]. Collectively, these findings show that drugs and other substances like alcohol can pass through the placenta, activate the immune system, impair the development of offspring, and elevate the risk of mental illnesses by altering gene expression and/or causing epigenetic aberrations in brain tissue. However, while these studies provide significant insights, further research is needed to fully understand the mechanisms involved and determine the short- and long-term effects of these substances on human development and mental health.

Table 4 shows more examples of the associations between paternal and maternal substance use and epigenetic alterations in various brain regions in offspring.

_{Table 4. Paternal and maternal substance use and epigenetic changes in various brain regions of offspring.}

5. Therapeutic Approaches Using Diet Modification or Epigenetic Drugs to Improve Psychotic Symptoms, Learning Deficits, and Memory Impairments in Animal Models and Patients with SUDs

Several lines of evidence have indicated that psychotic symptoms in patients with SUDs are associated with changes in the nutrients that influence methylation machinery for post-transcriptional gene regulation. For example, lower levels of folate, a cofactor for methylation reactions involved in gene transcription regulation levels [139], have been reported in psychotic methamphetamine users versus non-psychotic methamphetamine users. In fact, every 1-unit decrease in serum folate level may increase the risk of psychosis by 27% [140]. Therefore, the use of a methyl-rich diet is considered a promising strategy for alleviating psychotic symptoms in patients with methamphetamine use. As another remarkable example, one study showed DNA hypomethylation of the promoter regions of the DRD3, DRD4, MB-COMT, and AKT1 genes in patients with methamphetamine psychosis [141]. It was concluded that the use of a methyl-rich diet may help improve psychotic symptoms in these patients [141]. Tian et al. also reported that repeated treatment with methionine (the main methyl donor amino acid in mammals) for 25 days before and during conditioned place preference training could suppress the establishment of cocaine rewarding effects by reversing global DNA hypomethylation in the PFCs of mice [142].

In another study, Wright et al. found that global hypomethylation and decreased methylation at CpG dinucleotides in the c-Fos gene promoter are connected to cocaine-induced c-Fos expression in the nucleus accumbens cores of rats [143]. Their results revealed that prolonged methyl supplementation by L-methionine could alleviate drug-seeking attitudes and behavioral sensitization to the locomotor-activating effects of cocaine by enhancing DNA methylation of the c-Fos promoter region [143]. Likewise, treatment with choline (the main source of methyl groups in mammals) is capable of reversing detrimental effects of alcohol on brain function [121]. As other examples, in the adult offspring of rats who consumed alcohol during pregnancy, elevated levels of MeCP2 (methyl-CpG-binding protein), the Dnmt1 enzyme (DNA-methylating enzyme 1), and several repressive histone marks (Setdb1, H3K9me2, and G9a), along with reduced levels of histone activation marks (H3K9ac, H3K4me3, and H3S10 phosphorylation), were reported in the thalamic β-EP-producing proopiomelanocortin neurons, which were normalized by gestational choline supplementation [144]. Gitik et al. also identified 462 genes with altered promoter DNA methylation in adult mice dorsal hippocampus after nicotine exposure associated with learning deficits. They found that dietary choline supplementation was capable of reducing learning deficits in mice exposed to nicotine by normalizing DNA methylation of the hippocampus [145]. In addition to methyl-rich diets, a ketogenic diet is a promising candidate for reducing neurotoxicity in substance users. During alcohol detoxification, a paradoxical energy-deficit state occurs in the human brain owing to reduced plasma levels of acetate and beta-hydroxybutyrate as epigenetic modifiers, which further contributes to withdrawal symptoms and neurotoxicity in patients with alcohol use disorder [146]. Wiers et al. found that a shift in energy substrates during withdrawal in patients with alcohol use disorder may be a major reason for withdrawal severity and neurotoxicity, and a ketogenic diet could contribute to reducing withdrawal symptoms by elevating ketone bodies (beta-hydroxybutyrate, acetoacetate, and acetone) and decreasing levels of neuroinflammatory markers [147]. In another study, the same group reported that three weeks of treatment with a ketogenic diet is capable of reducing a neurobiological craving signature in patients with alcohol use disorder [148].

Likewise, some drugs are capable of maintaining neuronal function in substance users by reversing epigenetic aberrations. For instance, Wang et al. reported that acute treatment of mice with phencyclidine resulted in a drastic decrease in miRNA-143 expression in astrocytes of the PFC region and hence the development of psychotic symptoms resembling schizophrenia. Their results revealed that while a D2 receptor-specific agonist (quinpirole) also decreased miRNA-143 expression, antipsychotic drugs like clozapine or haloperidol could prevent phencyclidine-induced hyperactivity by restoring miR-143 expression and suppress D2 receptors induced expression of Neuregulin-1, a target of miRNA-143 [149]. In another study, it was found that cocaine could impair DNMT activity in astrocytes, which, in turn, accelerates neurodegeneration [150]. However, Piracetam, a drug for the treatment of cognitive disorders, could hamper cocaine induced-impairments of DNMT activity and reduce cell death [150]. In sum, psychotic symptoms, learning deficits, and memory impairments in patients with SUDs are linked to altering the nutrients capable of modulating methylation machinery for post-transcriptional gene regulation, and, hence, methyl donor micronutrients or epigenetic drugs may be considered as potential candidates to prevent or treat such abnormalities in patients with SUDs. However, it is important to note that the results from animal studies presented in this work cannot be directly translated to humans; clinical trials are necessary to validate the efficacy of these approaches and their potential side effects in human subjects.

6. Substance Use-Induced Gut Microbiome Alterations May Intensify Psychopathology via Epigenetic Aberrations

Accumulating evidence has demonstrated that substance use contributes to the disturbance of gut barrier integrity, elevation of intestinal permeability, and changing the gut microbiota composition, which further result in derangements in brain function and the patient’s mental status. Alterations in the gut microbiota and their metabolites by substance use heavily affect brain function by causing unfavorable shifts in the immune and inflammatory pathways and the release of specific neurotransmitters [151,152]. Numerous bacteria have demonstrated their ability to produce different types of neurotransmitters, like serotonin, dopamine, and GABA [153]. While the link between gut dysbiosis and the pathogenesis of various psychiatric diseases are reviewed elsewhere [154], the impacts of substance use on the gut microbiome and corresponding neurochemical changes in the brain tissue may also contribute to the development of psychiatric disorders [155]. For instance, as patients with psychiatric disorders exhibit reduced abundance of the butyrate-producing Faecalibacterium and increased abundance of pathogenic and pro-inflammatory bacteria such as Eggerthella and Streptococcus, methamphetamine use can lead to similar bacterial dysbiosis as well [154,156,157].

A growing body of evidence has demonstrated a close relationship between SUDs and gut microbiome dysbiosis [158,159,160]. Opioid-induced bowel dysfunction is one of the adverse effects of chronic opioid use [161]. A clinical study showed that methadone-treated individuals exhibited lower fecal bacterial α-diversity and composition compared to non-opioid users [162]. In addition, patients with heroin use disorder exhibited drastic changes in gut microbiome diversity, composition, and functions, and the abundance levels of Turicibacter, Actinomyces, and Weissella bacteria could be considered biomarkers for predicting heroin-induced depression symptoms [163]. In methamphetamine users, it has been shown that an altered gut microbiome is associated with cognitive decline, psychotic syndrome, and the pathogenesis of methamphetamine-induced psychosis [164]. Furthermore, elevated abundance levels of Lachnospiraceae, Xanthomonadale, Romboutsia, and Sphingomonadales, as well as decreased abundance levels of Bacteroidaceae and Deltaproteobacteria, were connected to the development of psychotic symptoms in methamphetamine users [164]. Interestingly, fecal microbiota transplantation from methamphetamine-administered mice was also capable of creating methamphetamine-induced anxiety- and depressive-like behaviors and elevating neuroinflammation in the hippocampus region of recipient mice [165].

In another study, Panee et al. found that the lower Prevotella–Bacteroides ratio of the fecal microbiome in marijuana users was associated with cognitive deficits [166].

Remarkably, alerted gut microbiome composition in subjects with SUDs can heavily influence the production of gut microbiome-derived metabolites as well, which further affect mental health. For example, a reduction in the abundance of Akkermansia muciniphila, a species responsible for the production of some metabolites involved in modulating the expression of tight junction proteins and maintenance of intestinal barrier integrity, was seen in methadone-treated individuals in comparison with non-opioid users [162]. It has been reported that substances like cannabis, nicotine, and methamphetamine have a great impact on the regulation of bacterially derived products like neuroactive metabolites, epigenetic modifiers, neurotransmitters, and anti-inflammatory metabolites, which play critical roles in the cross-talk between the gut and the central nervous system (CNS) [167,168,169,170]. For instance, a reduced concentration of butyric acid, an epigenetic modifier and anti-inflammatory metabolite involved in preventing the development and progression of neuropsychiatric diseases, has been reported as the result of oral and fecal bacteria alterations in patients with cocaine use disorder [171]. Overall, it appears that systemic inflammation in methamphetamine use disorder is due to the decreased abundance levels of butyrate-producing bacteria like Faecalibacterium, Dorea, and Blautia as well as increased abundance of pro-inflammatory bacteria [157,172,173].

Therefore, dietary sodium butyrate supplementation and the microbiome-derived short-chain fatty acids (SCFAs) may act as potent epigenetic modifiers and anti-inflammatory agents to treat drug-induced toxicity and substance-induced psychosis [174,175,176,177]. Some supporting evidence comes from the recent Zhang et al. studies showing that gut microbiome-derived SCFAs could exhibit great potential for reducing methamphetamine-induced anxiety- and depressive-like behaviors by suppressing colonic inflammation and improving gut homeostasis [178]. In another study, it has been shown that sodium butyrate supplementation is capable of alleviating detrimental effects of alcohol use disorder on the CNS by inhibiting neuroinflammation [179]. Some therapeutic agents are also capable of improving mental disorders induced by methamphetamine use through increasing the abundance of butyrate-producing and hydrogen-producing bacteria. For example, Wang et al. reported altered gut microbial composition (decreased abundance of butyrate-producing bacteria like Bacteroides and Roseburia), reduced alpha diversity, and elevated self-rating scales of depression (SDS) and anxiety (SAS) in methamphetamine users compared to their age-matched healthy subjects [180]. They found that inhaling hydrogen could improve neuropsychiatric impairments induced by methamphetamine use through changing gut microbiota profiles and increasing the abundance of Bacteroides and Roseburia [180]. Considering current data indicating that SCFAs are affected in SUDs and microbial or other therapeutic interventions improve substance-induced psychiatric symptoms by increasing butyrate or other SCFAs levels, it is conceivable to suggest that epigenetic alterations mediate mental health impacts of substance-induced gut dysbiosis in SUDs. Taken together, these findings indicate that substance use is capable of disturbing the gut barrier’s integrity, increasing intestinal permeability, and alterations in the gut microbiota composition, which further lead to disturbances in brain function and the patient’s mental status. As an example, since gut microbiome dysbiosis in patients with SUDs is related to a reduced abundance of butyrate-producing bacteria and increased abundance of pathogenic and pro-inflammatory bacteria, dietary sodium butyrate supplementation and/or SCFA-producing probiotics may serve as epigenetic remedies to reduce the risk of mental illnesses in substance users pending confirmation in human clinical studies.

7. Challenges and Potentials for Clinical Translation

In order to accelerate translational relevance, consistency in substance exposure paradigms and the establishment of human-relevant dosage regimens or change to volitional models of substance exposure are essential. In addition, epigenetic alterations in the brain tissue should be assessed in both short-term and long-term use/exposure or withdrawal to precisely estimate the stability of substance-induced epigenetic aberrations [181]. Moreover, in order to obtain greater insights on shared substance-induced neuroplasticity changes and neurological impairments and promote clinical translation based on these findings, systematic comparisons of different substances and their epigenetic consequences are required. Some studies have shown that there are sex-dependent differences in substance-induced epigenetic modifications in the brain; hence, future studies should have more of a focus on unresolved issues to explore how sex differences affect substance-induced epigenetic alterations [182].

In order to achieve more effective diagnostic and therapeutic strategies for substance-induced neurological impairments, single-cell next-generation sequencing technologies and approaches should be utilized more extensively in future research relevant to substance-induced epigenetic alterations in the brain tissue. Single-cell RNA sequencing can also be applied for the detection of new gene targets regulated by opioids and other substances. Investigation of the genome for areas of opened or closed chromatin after short or long-term exposures to substance can be conducted by ATAC-seq. ChIP-seq is capable of connecting this type of epigenetic alteration with the affected gene loci. Moreover, locus-specific epigenetic editing tools provide an opportunity for researchers to detect the functional consequences of substance-induced epigenetic alterations via manipulating such targets in a cell type-specific manner [183,184].

Owing to the complexity of experimental variables like the host’s genotype and diet and the difficulty of controlling them, investigating substance use disorder–gut microbiome interactions in humans and their roles in the development and progression of mental disorders is still a great challenge [185]. Similarly, it might be difficult to reproduce microbiome research data using animal models since many factors, such as co-housing with other animals, vendors, facility conditions, and other environmental conditions, give rise to differences in the composition and structure of the gut microbiome [186].

8. Conclusions

This literature review supports the idea that drug use is capable of influencing neuroplasticity, learning and memory, and reward circuit functions by targeting DNA methylation, post-translational histone modifications, and miRNA in different regions of the brain tissue. Moreover, these findings show that substance-induced psychosis can be associated with epigenetic alterations, and, hence, epigenetic-based therapies can be considered interesting approaches for alleviating psychotic symptoms in patients with SUDs. Dietary nutrients such as methyl donors (folic acid, vitamins B6 and B12, methionine, betaine, and choline) can serve as therapeutic agents for alleviating psychotic symptoms and depressive-like behaviors in patients with SUDs by reversing the epigenetic aberrations caused by substance use or modulation of the gut microbiome. Therefore, it is strongly reasonable to investigate new connections between them, since alterations in the human diet may be considered the easiest and first stage of treatment of substance-induced psychosis or may actualize a neuroprotective role in neuropsychiatric diseases.

Introduction

Substance use disorder (SUD) is a chronic condition involving uncontrolled drug use that negatively affects an individual's family life, social interactions, and professional aspects. Many individuals with substance use experience psychotic symptoms like hallucinations and delusions. For instance, those who use cannabis and amphetamine often show a higher likelihood of developing psychotic disorders and cognitive symptoms similar to schizophrenia. Additionally, a greater frequency of opioid and cocaine use has been observed in individuals with psychotic symptoms compared to those without. The causes of SUDs are complex and involve many factors, including how various genes interact with each other and with the environment. This interaction can alter the function and structure of neurons in different brain areas, leading to ongoing changes at cellular, molecular, and behavioral levels. For example, amphetamine appears to affect brain function by interacting with nerve terminals that use neurotransmitters like serotonin, norepinephrine, and dopamine. The presence of psychotic symptoms in substance users may be due to a sudden release of dopamine in the striatum, followed by excessive release of glutamate into the brain cortex, which can damage cortical interneurons and disrupt signals within the brain. Research indicates a strong relationship between any type of SUD and the genetic risk for schizophrenia. Genetic factors account for almost 50% of the heritability of SUDs and their negative consequences. For instance, alcohol-related tendencies can be influenced by genes involved in alcohol metabolism, and nicotine-related tendencies can be affected by specific gene clusters.

The strong connection between genes and environmental factors in the development of psychotic symptoms in substance users can also be influenced by epigenetic mechanisms. During this process, specific proteins play a crucial role in controlling gene activity and creating lasting changes by altering the structure of chromatin, which is the material that makes up chromosomes. These mechanisms can change how genes are expressed without altering the underlying DNA sequence. Furthermore, drug use or the harmful effects of alcohol may interfere with the absorption of essential nutrients, leading to imbalances in molecules that donate methyl groups. These imbalances can then contribute to the development of brain-related disorders through epigenetic changes, particularly DNA methylation. Therefore, dietary changes and the use of supplements that provide sufficient methyl donors are promising strategies for reducing the development of psychotic symptoms and brain damage in substance users.

This narrative review aims to explore the connections between brain impairments caused by substance use and epigenetic changes in brain tissue, as well as the role of diet in improving these deficits by normalizing epigenetic abnormalities. To achieve this, the review briefly presents associations between substance use and the development of psychotic symptoms and other brain disorders through epigenetic changes. It discusses studies that support the link between substance use and epigenetic alterations, including DNA methylation, histone modifications, and microRNAs (miRNAs), especially in brain tissue. In DNA methylation, a methyl group is added to a DNA base, often cytosine, which can lead to gene silencing. Histone modifications involve changes to histone proteins, which can affect how tightly DNA is packed, thereby influencing gene expression. For example, histone acetylation generally increases gene activity, while histone methylation can either increase or decrease it depending on the specific modification. Additionally, miRNAs are small non-coding RNAs that regulate gene expression by binding to target RNAs, inhibiting protein production or promoting RNA degradation.

The review summarizes studies showing the impact of substance exposure by a parent on epigenetic changes in the brains of offspring. It also highlights the role of a mother's diet in preventing substance-induced neurological impairments, especially psychosis, possibly through epigenetic mechanisms. Additionally, it provides an overview of using different diets, particularly those rich in methyl groups, to alleviate psychotic symptoms and depressive behaviors in individuals with SUDs.

The review further explores how interactions between substance use and the gut microbiome contribute to psychotic symptoms and depressive behaviors through epigenetic changes. It also discusses how metabolites from the gut microbiome could help in designing new therapies by normalizing epigenetic abnormalities. The final section addresses potential challenges and future outlooks for reducing psychotic symptoms and depressive behaviors in individuals with SUDs using diet modifications and gut microbiome modulation.

Association between Substance Use and the Development of Psychotic Symptoms and Depressive-Like Behaviors

There is growing evidence that drug use can lead to psychotic symptoms, which may occur during substance withdrawal, acute or chronic intoxication, or as a distinct substance-induced psychosis or delirium. Substance-induced psychosis is a condition where the onset of psychosis appears to be due to substance use, but it can persist for days, weeks, or even months after substance use has stopped. Long-term brain deficits caused by substance use are primarily linked to the activation of signaling pathways that trigger and advance oxidative stress and inflammation. For example, methamphetamine-induced psychosis is related to imbalances in the immune system, the activation of various immune signaling molecules, increased cellular damage, and reduced antioxidant defenses. Persistent psychotic symptoms can be caused by amphetamines, cannabis, and alcohol. It is estimated that nearly 40% of methamphetamine users experience psychotic symptoms like hallucinations and delusions, in addition to violence, impulsivity, and cognitive impairment.

From a mechanistic perspective, the appearance of psychotic symptoms in individuals with SUDs could be linked to epigenetic alterations that lead to improper gene regulation. For example, decreased DNA methylation at a specific part of the dopamine receptor type 4 (DRD4) gene was associated with paranoid symptoms in individuals with methamphetamine use disorder. Higher methylation levels at the catechol-O-methyltransferase (COMT) gene were linked to reduced motor impulsivity in the same group of individuals. In another study, a significant increase in parvalbumin (PVALB) DNA methylation was found in methamphetamine-induced psychosis, suggesting that methamphetamine dependence can cause GABAergic deficits through epigenetic changes. Alterations in global DNA methylation patterns, which influence immune and oxidative pathways, have also been strongly linked to methamphetamine-induced paranoia. In addition to DNA methylation and histone modifications, substance-induced psychosis is connected to changes in microRNAs (miRNAs). One study showed that individuals with methamphetamine-induced psychosis had significant differences in levels of specific miRNAs compared to control subjects. More recent research indicates that psychological comorbidities in substance users are linked to the dysregulation of crucial exosomal miRNAs, which are connected to changes in neurotransmitter levels, such as serotonin. Another study found a negative correlation between the expression levels of certain exosomal miRNAs and anxiety/depression scores in patients dependent on methamphetamine and heroin.

The following sections provide more details on the link between substance use and substance-induced psychiatric conditions. Overall, current findings demonstrate that substance use is associated with the development of psychotic symptoms and depressive-like behaviors, and these dysfunctions are mediated by epigenetic shifts that cause gene expression dysregulation.

The Effects of Substance Use on Changing Brain Functions via Epigenetic Alterations

Epigenetic regulatory mechanisms, such as DNA methylation, histone modifications, and microRNAs (miRNAs), play significant roles in changes in brain adaptability following prolonged drug use. Previous studies have shown that brain functions related to learning, memory, and synaptic plasticity can be dynamically regulated by DNA methylation and histone modifications in individuals with SUDs. For example, heroin-induced reshaping of the cell's internal structure through changes in DNA methylation levels might contribute to behavioral plasticity. Similarly, there is an interesting association between increased DNA methylation of the dopamine transporter gene (DAT1) and dopamine release in individuals addicted to psychoactive substances. Furthermore, reduced levels of brain-derived neurotrophic factor (BDNF) methylation have been observed in individuals with tobacco use and depression compared to those who do not use tobacco.

In addition to DNA methylation, histone modifications may play important roles in altering brain functions in individuals with SUDs. For instance, human primary astrocytes treated with opioids and psychostimulants showed increased levels of global acetylation of H3 histone lysine residues, except for a specific lysine residue. It is thought that illicit drugs like ∆9-tetrahydrocannabinol can activate enzymes that remove histone acetyl groups, leading to condensed DNA sequences in genes involved in cognitive functions, and increasing the risk and severity of schizophrenia. Similarly, the recall of heroin-related memories is associated with changes in histone acetylation during memory reconsolidation. Therefore, interventions that modulate histone acetylation could be effective approaches to treat SUD and prevent relapse. Another study indicated that intermittent ethanol exposure during adolescence reduces H3 acetylation in the hippocampus, lowers BDNF expression, and subsequently suppresses new neuron growth in this brain region. Substance use and alcohol consumption appear to increase the risk of psychosis, anxiety, depressive behaviors, and learning and memory deficits in users through epigenetic alterations.

Other evidence linking substance use to epigenetic alterations, including DNA methylation and histone modifications in different brain areas, has been summarized in detailed research. Beyond DNA methylation and histone modifications, substance use epigenetically alters gene expression by changing the levels of endogenous non-coding RNAs, such as microRNA (miRNA) and circular RNA (circRNA), in brain tissue. CircRNAs can influence substance-related behaviors by interacting with miRNAs. For instance, striatal miRNAs play powerful roles in brain adaptability, learning and memory, and the function and regulation of the reward system. As another example, one study indicated that over-activation of astrocytes and shrinkage of the striatum following methamphetamine treatment were connected to many differentially expressed miRNAs in the striatum. Researchers also reported that heroin users could exhibit elevated serum levels of specific miRNAs, while methamphetamine users had increased serum levels of another miRNA. Another study found that elevated levels of a particular miRNA in certain brain regions of methamphetamine users might serve as a potential biomarker for diagnosing addiction in these individuals. Furthermore, an analysis of postmortem brains and blood samples from individuals with opioid use disorder revealed a significant overlap in their altered target genes, despite different profiles of altered brain and blood miRNAs.

Generally, abnormal changes in DNA methylation, histone modifications, and miRNA expression in various brain regions of substance users significantly affect neuronal functions related to synaptic plasticity, learning, and memory, which may accelerate the development of psychiatric disorders. However, while these epigenetic alterations are associated with substance use, the exact causal mechanisms and their implications for psychiatric disorders require further investigation. Understanding these complex interactions will necessitate extensive research to differentiate between correlation and causation and develop targeted therapeutic interventions.

Paternal and Maternal Substance Use and Epigenetic Alterations in the Brains of the Offspring

Illicit drugs and other substances can pass through the placenta, activating the immune system and disrupting offspring development by altering gene expression or causing epigenetic changes in various body organs, especially brain tissue, thereby increasing the risk of mental disorders. For example, methamphetamine has been identified as a common illicit drug used by pregnant mothers, which leads to changes in the expression of genes involved in brain development, resulting in cognitive deficits and brain-related diseases in offspring.

Other evidence links paternal and maternal substance use during pregnancy to epigenetic changes in various brain regions, including DNA methylation and histone modifications. It has been found that a mother's substance use during pregnancy is connected to an elevated risk of psychotic symptoms in her offspring. For example, both paternal and maternal cannabis use are linked to a higher number of psychotic-like experiences in children at age ten. The development of psychotic symptoms and other brain impairments in offspring due to substance use can be mediated by epigenetic changes. For instance, a recent study indicated that prenatal cocaine exposure in humans can increase the risk for psychosis in offspring, which is connected to epigenetic alterations. In another study, a combination of prenatal immune activation and cannabinoid exposure resulted in significant differences in miRNA expression in specific brain regions, linked to human genetic areas associated with schizophrenia. More recent genome-wide human studies showed that individuals with cannabis use disorder had different DNA methylation at specific sites, notably one site that appears to be an important link between cannabis use and mental disorders, particularly mood disorders. Moreover, a mother's exposure to e-cigarette aerosols containing nicotine could impair short-term memory, which was linked to increased overall DNA methylation in the brains of offspring.

Evidence suggests that such epigenetic changes in offspring can occur due to poor absorption of nutrients in pregnant women with SUDs. Drug use and alcohol consumption can disrupt the absorption of micronutrients such as folic acid, choline, and omega-3 during pregnancy. Therefore, supplementing pregnant women with SUD with these nutrients may prevent neurological deficits in offspring by normalizing epigenetic abnormalities. As another interesting example, it was shown that prenatal alcohol exposure caused disturbances in hippocampal miRNA expression, and choline supplementation could reverse an alcohol-dependent increase in a specific hippocampal miRNA. An animal study also demonstrated that alcohol consumption increases DNA methylation in the PFC and hippocampus of rat pups during the neonatal period, and choline supplementation could reduce this increased DNA methylation in both brain regions. Collectively, these findings show that drugs and other substances like alcohol can pass through the placenta, activate the immune system, impair the development of offspring, and elevate the risk of mental illnesses by altering gene expression and/or causing epigenetic changes in brain tissue. However, while these studies provide significant insights, further research is needed to fully understand the mechanisms involved and determine the short- and long-term effects of these substances on human development and mental health.

Therapeutic Approaches Using Diet Modification or Epigenetic Drugs to Improve Psychotic Symptoms, Learning Deficits, and Memory Impairments in Animal Models and Patients with SUDs

Several lines of evidence indicate that psychotic symptoms in individuals with SUDs are associated with changes in nutrients that influence the methylation processes critical for gene regulation. For example, lower levels of folate, a cofactor for methylation reactions involved in gene transcription regulation, have been reported in psychotic methamphetamine users compared to non-psychotic methamphetamine users. A reduction in serum folate levels has been associated with an increased risk of psychosis. Therefore, the use of a diet rich in methyl groups is considered a promising strategy for alleviating psychotic symptoms in individuals who use methamphetamine. Another example showed decreased DNA methylation in the promoter regions of several genes (DRD3, DRD4, MB-COMT, and AKT1) in patients with methamphetamine psychosis. It was concluded that a methyl-rich diet might help improve psychotic symptoms in these individuals. Researchers also reported that repeated treatment with methionine (a key methyl-donating amino acid in mammals) before and during a conditioning experiment could suppress the rewarding effects of cocaine by reversing overall DNA hypomethylation in the prefrontal cortex of mice.

In another study, researchers found that global hypomethylation and decreased methylation at specific DNA sites in the c-Fos gene promoter were connected to cocaine-induced c-Fos expression in rat brain regions. Their results revealed that prolonged methyl supplementation with L-methionine could reduce drug-seeking behaviors and behavioral sensitization to cocaine's activating effects by increasing DNA methylation of the c-Fos promoter region. Similarly, treatment with choline (a main source of methyl groups in mammals) is capable of reversing the harmful effects of alcohol on brain function. As other examples, in adult offspring of rats that consumed alcohol during pregnancy, increased levels of specific proteins and repressive histone marks were observed in certain brain neurons. These were normalized by choline supplementation during pregnancy. Another study identified many genes with altered DNA methylation in the dorsal hippocampus of adult mice after nicotine exposure, which was associated with learning deficits. They found that dietary choline supplementation could reduce learning deficits in mice exposed to nicotine by normalizing DNA methylation in the hippocampus.

In addition to methyl-rich diets, a ketogenic diet is a promising candidate for reducing neurotoxicity in substance users. During alcohol detoxification, a state of energy deficit occurs in the human brain due to low levels of certain energy-related molecules like acetate and beta-hydroxybutyrate, which also act as epigenetic modifiers. This deficit further contributes to withdrawal symptoms and brain damage in individuals with alcohol use disorder. Researchers found that a shift in energy sources during withdrawal in patients with alcohol use disorder may be a major reason for withdrawal severity and neurotoxicity, and a ketogenic diet could help reduce withdrawal symptoms by increasing ketone bodies and decreasing levels of brain inflammation markers. In another study, the same group reported that three weeks of treatment with a ketogenic diet could reduce a neurobiological craving signature in patients with alcohol use disorder.

Similarly, some drugs can help maintain brain function in substance users by reversing epigenetic abnormalities. For instance, researchers reported that acute treatment of mice with phencyclidine led to a sharp decrease in miRNA-143 expression in astrocytes of the prefrontal cortex, leading to psychotic symptoms similar to schizophrenia. Their results revealed that while a dopamine receptor agonist also decreased miRNA-143 expression, antipsychotic drugs like clozapine or haloperidol could prevent phencyclidine-induced hyperactivity by restoring miR-143 expression and suppressing the expression of Neuregulin-1, a target of miRNA-143, induced by dopamine receptors. In another study, it was found that cocaine could impair the activity of an enzyme called DNMT in astrocytes, which in turn accelerates brain cell degeneration. However, Piracetam, a drug for treating cognitive disorders, could prevent cocaine-induced impairments of DNMT activity and reduce cell death. In summary, psychotic symptoms, learning deficits, and memory impairments in individuals with SUDs are linked to changes in nutrients capable of modulating methylation processes for gene regulation. Therefore, methyl-donating micronutrients or epigenetic drugs may be considered as potential candidates to prevent or treat such abnormalities in individuals with SUDs. However, it is important to note that results from animal studies cannot be directly translated to humans; clinical trials are necessary to confirm the effectiveness and potential side effects of these approaches in human subjects.

Substance Use-Induced Gut Microbiome Alterations May Intensify Psychopathology via Epigenetic Aberrations

Growing evidence shows that substance use contributes to disruptions in gut barrier health, increased intestinal permeability, and changes in the gut microbiota composition. These changes further lead to disturbances in brain function and an individual's mental state. Alterations in the gut microbiota and their metabolites due to substance use significantly affect brain function by causing unfavorable shifts in immune and inflammatory pathways and the release of specific neurotransmitters. Many gut bacteria can produce neurotransmitters such as serotonin, dopamine, and GABA. While the link between gut imbalance and the development of various brain disorders is reviewed elsewhere, the impacts of substance use on the gut microbiome and corresponding brain chemical changes may also contribute to the development of psychiatric disorders. For instance, just as individuals with psychiatric disorders show a decrease in beneficial bacteria that produce butyrate and an increase in harmful, inflammation-causing bacteria, methamphetamine use can lead to similar bacterial imbalances.

A growing body of evidence has demonstrated a close relationship between SUDs and gut microbiome dysbiosis. Opioid-induced bowel dysfunction is one of the negative effects of chronic opioid use. A clinical study showed that individuals treated with methadone exhibited lower diversity and different composition of fecal bacteria compared to non-opioid users. Additionally, individuals with heroin use disorder showed drastic changes in gut microbiome diversity, composition, and functions. The abundance levels of certain bacteria (Turicibacter, Actinomyces, and Weissella) could be considered biomarkers for predicting heroin-induced depression symptoms. In methamphetamine users, it has been shown that an altered gut microbiome is associated with cognitive decline, psychotic syndrome, and the development of methamphetamine-induced psychosis. Furthermore, increased abundance levels of certain bacteria (Lachnospiraceae, Xanthomonadale, Romboutsia, and Sphingomonadales), as well as decreased abundance levels of others (Bacteroidaceae and Deltaproteobacteria), were connected to the development of psychotic symptoms in methamphetamine users. Interestingly, transferring fecal microbiota from methamphetamine-treated mice was also capable of inducing methamphetamine-related anxiety and depressive-like behaviors and increasing brain inflammation in recipient mice. In another study, researchers found that a lower ratio of certain gut bacteria (Prevotella to Bacteroides) in marijuana users was associated with cognitive deficits.

Notably, an altered gut microbiome composition in individuals with SUDs can also significantly influence the production of metabolites derived from the gut microbiome, which further affect mental health. For example, a reduction in the abundance of Akkermansia muciniphila, a species responsible for producing metabolites involved in maintaining intestinal barrier health, was observed in methadone-treated individuals compared to non-opioid users. Substances like cannabis, nicotine, and methamphetamine have a great impact on the regulation of bacterially derived products, including neuroactive metabolites, epigenetic modifiers, neurotransmitters, and anti-inflammatory metabolites, all of which play critical roles in the communication between the gut and the central nervous system. For instance, a reduced concentration of butyric acid, an epigenetic modifier and anti-inflammatory metabolite involved in preventing the development and progression of brain-related diseases, has been reported as a result of oral and fecal bacteria alterations in individuals with cocaine use disorder. Overall, it appears that systemic inflammation in methamphetamine use disorder is due to a decreased abundance of butyrate-producing bacteria and an increased abundance of inflammation-causing bacteria.

Therefore, dietary sodium butyrate supplementation and short-chain fatty acids (SCFAs) derived from the microbiome may act as powerful epigenetic modifiers and anti-inflammatory agents to treat drug-induced toxicity and substance-induced psychosis. Some supporting evidence comes from recent studies showing that gut microbiome-derived SCFAs could significantly reduce methamphetamine-induced anxiety and depressive-like behaviors by suppressing colon inflammation and improving gut health. In another study, it was shown that sodium butyrate supplementation is capable of alleviating the harmful effects of alcohol use disorder on the central nervous system by inhibiting neuroinflammation. Some therapeutic agents are also capable of improving mental disorders induced by methamphetamine use by increasing the abundance of butyrate-producing and hydrogen-producing bacteria. For example, researchers reported altered gut microbial composition (decreased abundance of butyrate-producing bacteria like Bacteroides and Roseburia), reduced diversity, and elevated self-reported depression and anxiety scores in methamphetamine users compared to healthy individuals of the same age. They found that inhaling hydrogen could improve brain impairments induced by methamphetamine use by changing gut microbiota profiles and increasing the abundance of Bacteroides and Roseburia. Considering current data indicating that SCFAs are affected in SUDs and that microbial or other therapeutic interventions improve substance-induced psychiatric symptoms by increasing butyrate or other SCFAs levels, it is reasonable to suggest that epigenetic alterations mediate the mental health impacts of substance-induced gut imbalances in SUDs. Taken together, these findings indicate that substance use is capable of disturbing the gut barrier's integrity, increasing intestinal permeability, and altering gut microbiota composition, which further leads to disturbances in brain function and an individual's mental status. As an example, since gut microbiome imbalance in individuals with SUDs is related to a reduced abundance of butyrate-producing bacteria and an increased abundance of harmful, inflammation-causing bacteria, dietary sodium butyrate supplementation and/or SCFA-producing probiotics may serve as epigenetic remedies to reduce the risk of mental illnesses in substance users, pending confirmation in human clinical studies.

Challenges and Potentials for Clinical Translation

To move research findings into clinical practice more quickly, consistency in substance exposure methods and the establishment of human-relevant dosage regimens, or changes to models where substance use is self-initiated, are essential. Additionally, epigenetic alterations in brain tissue should be assessed in both short-term and long-term use/exposure or withdrawal to precisely estimate the stability of substance-induced epigenetic changes. Moreover, to gain greater insights into shared brain adaptability changes and neurological impairments caused by substances and to promote clinical translation based on these findings, systematic comparisons of different substances and their epigenetic consequences are required. Some studies have shown that there are sex-dependent differences in substance-induced epigenetic modifications in the brain; therefore, future studies should focus more on unresolved issues to explore how sex differences affect substance-induced epigenetic alterations.

To achieve more effective diagnostic and therapeutic strategies for substance-induced neurological impairments, single-cell next-generation sequencing technologies and approaches should be utilized more extensively in future research relevant to substance-induced epigenetic alterations in brain tissue. Single-cell RNA sequencing can also be applied for detecting new gene targets regulated by opioids and other substances. Investigation of the genome for areas of opened or closed chromatin after short or long-term exposures to substances can be conducted by ATAC-seq. ChIP-seq is capable of connecting this type of epigenetic alteration with the affected gene locations. Moreover, precise epigenetic editing tools offer an opportunity for researchers to detect the functional consequences of substance-induced epigenetic alterations by manipulating such targets in a cell type-specific manner.

Due to the complexity of experimental variables like an individual's genetic makeup and diet, and the difficulty of controlling them, investigating substance use disorder–gut microbiome interactions in humans and their roles in the development and progression of mental disorders remains a great challenge. Similarly, it might be difficult to reproduce microbiome research data using animal models since many factors, such as housing with other animals, suppliers, facility conditions, and other environmental influences, lead to differences in the composition and structure of the gut microbiome.

Conclusions

This literature review supports the idea that drug use can influence brain adaptability, learning and memory, and reward circuit functions by targeting DNA methylation, histone modifications, and microRNAs in different regions of brain tissue. Moreover, these findings show that substance-induced psychosis can be associated with epigenetic alterations, and therefore, epigenetic-based therapies can be considered interesting approaches for alleviating psychotic symptoms in individuals with SUDs. Dietary nutrients such as methyl donors (folic acid, vitamins B6 and B12, methionine, betaine, and choline) can serve as therapeutic agents for alleviating psychotic symptoms and depressive-like behaviors in individuals with SUDs by reversing the epigenetic abnormalities caused by substance use or by modulating the gut microbiome. Therefore, it is reasonable to explore further connections between these areas, as changes in diet could serve as a foundational, accessible treatment for substance-induced psychosis or offer protection against other neurological conditions.

Introduction

Substance Use Disorder (SUD) is a long-term condition where drug use becomes uncontrollable and harms a person's life, family, and work. There is a high occurrence of psychotic symptoms, such as hallucinations and delusions, in individuals with substance use. For example, cannabis and amphetamine users show higher rates of psychotic disorders and cognitive symptoms similar to schizophrenia. Also, more frequent opioid and cocaine use has been reported in individuals experiencing psychotic symptoms compared to those without. Like other brain-related diseases, the origins of SUDs are complex, involving many genes interacting with each other and with the environment. This interaction alters neuronal function and structure in different brain areas, leading to continuous changes at the cellular, molecular, and behavioral levels. For instance, amphetamine appears to affect brain function by interacting with nerve terminals that use indoleamines, such as serotonin, and catecholamines, including norepinephrine and dopamine, as important neurotransmitters. The presence of psychotic symptoms in substance users may be due to a sudden release of dopamine in the striatum, followed by excessive release of glutamate into the brain cortex. This can further damage cortical interneurons and disrupt signals within the brain. Research also shows a strong link between any type of SUD and the overall genetic risk for schizophrenia. Genetic factors, with an estimated heritability of about 50%, are associated with SUDs and their negative consequences. For example, tendencies related to alcohol can be affected by specific genetic locations in alcohol-metabolizing genes, while nicotine-related tendencies can be influenced by locations within a particular gene cluster.

The close relationship between genes and environmental factors in the development of psychotic symptoms in substance users can also be mediated by epigenetic mechanisms. During this process, specific proteins, such as transcription factors and enzymatic complexes, play a critical role in controlling gene expression and creating long-lasting changes by modifying the structure of chromatin, which is how DNA is packaged. These chromatin-modifying mechanisms, or other epigenetic alterations, can change gene expression without altering the underlying DNA sequences. Additionally, drug use or the toxic effects of alcohol can disrupt the absorption of micronutrients (like omega-3s, choline, vitamins, and folic acid), leading to imbalances in the levels of "methyl donors." This further contributes to the development of neuropsychiatric diseases through brain epigenetic changes, especially DNA methylation. Therefore, adjusting one's diet and using supplements with adequate levels of methyl donors is a promising strategy to lessen the development of psychotic symptoms and neurological impairments in substance users.

This review aims to explain the links between substance use-induced brain impairments and epigenetic alterations in brain tissue, as well as the role of diet modifications in alleviating such deficits by correcting epigenetic abnormalities. To achieve this, the review briefly presents associations between substance use and the development of psychotic symptoms and neuropsychiatric diseases through epigenetic changes. It will discuss studies that support the link between substance use and epigenetic alterations, including DNA methylation, histone modifications, and microRNAs (miRNAs), particularly in brain tissue. In DNA methylation, a methyl group is added to a cytosine residue, or less often, to an adenine residue that is followed by guanine. This process, carried out by various enzymes, causes methylated cytosines to act as targets for DNA-binding proteins, which then lead to chromatin condensation and gene silencing. Histone modifications are another type of epigenetic regulation, where different amino acids of histone tail proteins can be acetylated or methylated by various enzymes. These modifications affect the positive electrical charge of histone proteins and, consequently, how strongly they bind to DNA, which has a negative charge. Histone acetylation generally reduces chromatin condensation and promotes gene expression, whereas histone methylation can either increase or decrease gene expression depending on the specific amino acids modified or their location on the histone tail proteins. Additionally, in RNA interference, another type of epigenetic regulation, miRNAs—small non-coding RNAs about 20 bases long—bind to their target RNAs and either inhibit gene transcription or promote RNA degradation.

The review will summarize studies that demonstrate the impact of paternal and maternal exposure to substances on epigenetic alterations in the brains of offspring and the role of maternal diet in preventing substance-induced neurological impairments, particularly psychosis, possibly through epigenetic mechanisms. In addition, it provides an overview of the use of different types of diet, especially methyl-rich diets, for alleviating psychotic symptoms and depressive-like behaviors in patients with SUDs. The next step involves determining how interactions between substance use and the gut microbiome contribute to the development of psychotic symptoms and depressive-like behaviors through epigenetic alterations, and how metabolites derived from the gut microbiome can help researchers design new therapies based on correcting epigenetic abnormalities. The final section discusses potential challenges and presents future perspectives relevant to alleviating psychotic symptoms and depressive-like behaviors in patients with SUDs using diet modifications and modulation of the gut microbiome.

Association between Substance Use and the Development of Psychotic Symptoms and Depressive-Like Behaviors

Growing evidence suggests that drug use is associated with the development of psychotic symptoms, which can appear during substance withdrawal, acute intoxication, chronic use, or as a distinct substance-induced psychosis or delirium. Substance-induced psychosis is a condition where psychosis begins due to substance use but can persist for days, weeks, or even months after the substance is no longer used. Long-term brain deficits caused by substance use are mainly linked to the activation of pathways involved in oxidative stress and inflammation. For example, methamphetamine-induced psychosis is connected to changes in the immune system, the activation of various inflammatory molecules, increased cell damage, and reduced antioxidant defenses. Persistent psychotic symptoms can be triggered by amphetamines, cannabis, and alcohol. It is estimated that nearly 40% of methamphetamine users experience psychotic symptoms such as hallucinations and delusions, along with aggression, impulsivity, and cognitive issues.

Mechanistically, the appearance of psychotic symptoms in individuals with Substance Use Disorders (SUDs) may be connected to epigenetic changes that lead to problems with gene regulation. For instance, reduced DNA methylation at a specific site on the dopamine receptor type 4 (DRD4) gene has been linked to paranoid symptoms in patients with methamphetamine use disorder. Conversely, higher methylation levels at a site on the catechol-O-methyltransferase (COMT) gene have been associated with lower motor impulsivity in the same patient group. Research has also shown increased parvalbumin (PVALB) DNA methylation in methamphetamine-induced psychosis, suggesting that methamphetamine dependence causes deficits in GABAergic signaling through epigenetic changes. Furthermore, alterations in patterns of long interspersed element-1 methylation, which affect immune and neuro-oxidative pathways, have been strongly linked to methamphetamine-induced paranoia. In addition to DNA methylation and histone modifications, substance-induced psychosis is related to changes in microRNAs (miRNAs). Studies have shown differences in the levels of certain miRNAs (like miR-let-7d, miR-let-7e, miR-15b, and miR-181a) in patients with methamphetamine-induced psychosis compared to control groups. More recent work has also connected psychological issues in substance users to the dysregulation of specific exosomal miRNAs, which are tied to changes in neurotransmitter levels, such as serotonin. Negative correlations have been found between the expression of certain exosomal miRNAs (miR-92a-3p, miR-16-5p, miR-129-5p, and miR-363-3p) and anxiety/depression scores in patients dependent on methamphetamine and heroin.

These findings collectively demonstrate that substance use is linked to the development of psychotic symptoms and depressive-like behaviors, and these issues appear to be influenced by epigenetic shifts that disrupt normal gene expression.

The Effects of Substance Use on Changing Brain Functions via Epigenetic Alterations

Epigenetic regulatory mechanisms, including DNA methylation, histone modifications, and microRNAs (miRNAs), play significant roles in the brain's adaptive changes (neuroplasticity) that occur after prolonged drug use. Previous research indicates that brain functions related to learning, memory, and how neurons connect (synaptic plasticity) are dynamically regulated by DNA methylation and histone modifications in individuals with Substance Use Disorders (SUDs). For example, heroin use can alter the actin cytoskeleton, a cell's internal framework, through changes in DNA methylation, which may affect behavior. This process involves the degradation of a specific enzyme (DNMT3a), leading to increased expression of the CaMKK1 gene and affecting actin assembly in a brain region called the dorsal hippocampus. Similarly, there is a connection between increased DNA methylation of the dopamine transporter gene (DAT1) and dopamine release in people with psychoactive substance addiction. Reduced methylation levels of the brain-derived neurotrophic factor (BDNF) have also been observed in individuals who use tobacco and have depression. Beyond DNA methylation, histone modifications appear crucial in altering neuronal functions in individuals with SUDs. For instance, human primary astrocytes (a type of brain cell) treated with opioids and psychostimulants showed increased overall acetylation of H3 histone lysine residues, a modification that can affect gene expression. Some illicit drugs, like ∆9-tetrahydrocannabinol (THC), are hypothesized to activate histone deacetylases, leading to tighter packaging of genes involved in cognitive functions, which could increase the risk of schizophrenia. The recall of heroin-related memories is also linked to changes in histone acetylation, suggesting that targeting histone acetylation could help in SUD treatment and prevent relapse. Another study showed that intermittent alcohol exposure during adolescence reduces H3 acetylation in the hippocampus, decreases BDNF expression, and suppresses the growth of new neurons in this brain area.

Further research has documented additional instances where substance use leads to epigenetic alterations, including changes in DNA methylation and histone modifications across various brain regions.

In addition to DNA methylation and histone modifications, substance use epigenetically alters gene expression by changing the levels of endogenous non-coding RNAs, such as microRNAs (miRNAs) and circular RNAs (circRNAs), within brain tissue. CircRNAs have the ability to influence the behavioral effects of substances by interacting with miRNAs. For example, miRNAs found in the striatum, a brain region, are crucial for neuroplasticity, learning, memory, and the regulation of the brain's reward system. One study found that excessive activation of astrocytes and a reduction in striatal size after methamphetamine treatment were linked to 167 distinctively expressed miRNAs in the striatum. Another study reported elevated serum levels of certain miRNAs (miR-486-5p, miR-206, and let-7b-5p) in heroin users, while methamphetamine users showed increased serum levels of miR-9-3p. Elevated levels of let-7b-3p in the nucleus accumbens and ventral tegmental area of methamphetamine users may serve as a potential biomarker for addiction diagnosis in these individuals. Furthermore, an analysis of miRNA–mRNA networks in postmortem brain and blood samples from individuals with opioid use disorder revealed significant overlap in their altered target genes, even though the miRNA profiles in the brain and blood were different.

In summary, abnormal changes in DNA methylation, histone modifications after protein synthesis, and miRNA expression across different brain regions of substance users significantly affect neuronal functions related to synaptic plasticity, learning, and memory, potentially accelerating the development of psychiatric disorders. However, it is crucial to recognize that while these epigenetic alterations are associated with substance use, the precise causal mechanisms and their implications for psychiatric disorders require further investigation. Understanding these complex interactions will necessitate extensive research to differentiate between correlation and causation and to develop targeted therapeutic interventions.

Paternal and Maternal Substance Use and Epigenetic Alterations in the Brains of the Offspring

Research indicates that illicit drugs and other substances can cross the placenta, activate the immune system, and disrupt the development of offspring by altering gene expression or causing epigenetic changes in various organs, especially the brain. These alterations can increase the risk of mental disorders in the offspring. For instance, methamphetamine is a common illicit drug used by pregnant mothers, and its use is linked to changes in the expression of genes important for neurodevelopment, leading to cognitive deficits and neuropsychiatric conditions in their children. Further details on how parental substance use during pregnancy relates to epigenetic changes in various brain regions are also available in relevant research summaries.

Maternal substance use during pregnancy has been connected to an increased risk of psychotic symptoms in offspring. For example, both paternal and maternal cannabis use are linked to a higher number of psychotic-like experiences in children by age ten. The development of psychotic symptoms and other neurological impairments in offspring due to substance use can be influenced by epigenetic changes. A recent study indicated that prenatal cocaine exposure in humans might raise the risk for psychosis in offspring, and this risk is associated with epigenetic alterations. Another study showed that a combination of prenatal exposure to poly I:C (a substance used to simulate viral infection) and cannabinoids caused significant differences in miRNA expression in a brain region linked to schizophrenia. A more recent human genome-wide study found that individuals with cannabis use disorder had different DNA methylation patterns at specific sites, notably at the AHRR cg0557592 site, which appears to mediate the link between cannabis use and mental disorders, particularly mood disorders. Furthermore, maternal exposure to e-cigarette aerosols containing nicotine could impair short-term memory in offspring, which was connected to increased overall DNA methylation in their brains.

Evidence suggests that such epigenetic changes in offspring can arise from poor nutrient absorption in pregnant women with Substance Use Disorders (SUDs). Drug use and alcohol consumption can disrupt the absorption of micronutrients like folic acid, choline, and omega-3s during pregnancy. Therefore, supplementing the diets of pregnant women with SUDs with these nutrients may prevent neurological deficits in their offspring by correcting epigenetic abnormalities. For instance, prenatal alcohol exposure has been shown to disturb miRNA expression in the hippocampus, and choline supplementation was able to reverse an alcohol-dependent increase in miR-200c expression in this area. An animal study also demonstrated that alcohol consumption increases DNA methylation in the prefrontal cortex (PFC) and hippocampus of rat pups during the neonatal period, and choline supplementation could reduce this excess DNA methylation in both brain regions. Collectively, these findings indicate that drugs and other substances like alcohol can cross the placenta, activate the immune system, impair offspring development, and increase the risk of mental illnesses by altering gene expression or causing epigenetic changes in brain tissue. However, while these studies provide significant insights, further research is needed to fully understand the mechanisms involved and determine the short- and long-term effects of these substances on human development and mental health.

Therapeutic Approaches Using Diet Modification or Epigenetic Drugs to Improve Psychotic Symptoms, Learning Deficits, and Memory Impairments in Animal Models and Patients with SUDs

Several lines of evidence suggest that psychotic symptoms in individuals with Substance Use Disorders (SUDs) are linked to alterations in nutrients that affect the methylation processes vital for gene regulation. For instance, lower folate levels, which is a cofactor for methylation reactions, have been reported in psychotic methamphetamine users compared to those without psychosis. In fact, a one-unit decrease in serum folate level may increase the risk of psychosis by 27%. This suggests that a diet rich in methyl groups could be a promising strategy for alleviating psychotic symptoms in patients with methamphetamine use. Another notable example showed that DNA hypomethylation (reduced methylation) in the promoter regions of genes like DRD3, DRD4, MB-COMT, and AKT1 was present in patients with methamphetamine psychosis, and a methyl-rich diet was believed to help improve these psychotic symptoms. Research has also shown that repeated treatment with methionine, a key methyl donor amino acid, before and during cocaine reward training could suppress the development of cocaine's rewarding effects by reversing overall DNA hypomethylation in the prefrontal cortex of mice.

In another study, researchers found that widespread reduced DNA methylation, along with decreased methylation at specific sites in the c-Fos gene promoter, was linked to cocaine-induced c-Fos gene expression in a brain region called the nucleus accumbens in rats. Their results indicated that prolonged supplementation with L-methionine could lessen drug-seeking behaviors and behavioral sensitization to cocaine's activating effects by increasing DNA methylation of the c-Fos promoter region. Similarly, treatment with choline, a major source of methyl groups, is capable of reversing the harmful effects of alcohol on brain function. For example, in adult offspring of rats that consumed alcohol during pregnancy, elevated levels of certain proteins (MeCP2, Dnmt1) and several repressive histone marks were observed in specific neurons of the thalamus. These changes, along with reduced levels of histone activation marks, were normalized by providing choline supplementation during gestation. Another study identified 462 genes with altered DNA methylation in the dorsal hippocampus of adult mice after nicotine exposure, which was associated with learning deficits. Dietary choline supplementation was found to reduce these learning deficits by normalizing DNA methylation in the hippocampus.

In addition to methyl-rich diets, a ketogenic diet is a promising candidate for reducing neurotoxicity in substance users. During alcohol detoxification, the human brain can experience a paradoxical energy deficit due to reduced plasma levels of acetate and beta-hydroxybutyrate, which act as epigenetic modifiers. This deficit contributes to withdrawal symptoms and neurotoxicity in patients with alcohol use disorder. Researchers found that a shift in energy sources during withdrawal in patients with alcohol use disorder might be a major reason for the severity of withdrawal and neurotoxicity. A ketogenic diet could help reduce withdrawal symptoms by increasing ketone bodies (beta-hydroxybutyrate, acetoacetate, and acetone) and lowering levels of markers associated with brain inflammation. In a separate study, the same group reported that three weeks of a ketogenic diet was capable of reducing a neurobiological craving signature in patients with alcohol use disorder.

Furthermore, some medications can help maintain neuronal function in substance users by reversing epigenetic abnormalities. For example, a study reported that acute treatment of mice with phencyclidine led to a significant decrease in miRNA-143 expression in astrocytes of the prefrontal cortex, resulting in psychotic symptoms similar to schizophrenia. While a D2 receptor-specific agonist (quinpirole) also reduced miRNA-143 expression, antipsychotic drugs like clozapine or haloperidol were able to prevent phencyclidine-induced hyperactivity by restoring miR-143 expression and suppressing the D2 receptor-induced expression of Neuregulin-1, a target of miRNA-143. In another study, it was found that cocaine could impair the activity of an enzyme called DNMT (DNA methyltransferase) in astrocytes, which in turn speeds up neurodegeneration. However, Piracetam, a drug used for cognitive disorders, was able to prevent cocaine-induced DNMT impairment and reduce cell death.

In summary, psychotic symptoms, learning deficits, and memory impairments in individuals with Substance Use Disorders (SUDs) are linked to changes in nutrients that modulate the methylation processes for gene regulation. Therefore, methyl donor micronutrients or certain epigenetic drugs may be considered potential candidates to prevent or treat these abnormalities in patients with SUDs. However, it is important to note that the results from animal studies presented cannot be directly translated to humans; clinical trials are necessary to validate the efficacy of these approaches and their potential side effects in human subjects.

Substance Use-Induced Gut Microbiome Alterations May Intensify Psychopathology via Epigenetic Aberrations

Mounting evidence shows that substance use contributes to disruptions in the gut barrier, increasing its permeability and changing the composition of gut microbiota. These alterations can then lead to issues with brain function and a person's mental state. Changes in the gut microbiota and the metabolites they produce significantly affect brain function by causing unfavorable shifts in immune and inflammatory pathways and altering the release of specific neurotransmitters. Many types of bacteria are known to produce various neurotransmitters, such as serotonin, dopamine, and GABA. While the connection between an imbalance in gut bacteria (gut dysbiosis) and the development of various psychiatric diseases has been reviewed elsewhere, the effects of substance use on the gut microbiome and subsequent neurochemical changes in the brain may also contribute to the development of psychiatric disorders. For example, individuals with psychiatric disorders often show a reduced amount of butyrate-producing Faecalibacterium and an increased presence of harmful and pro-inflammatory bacteria like Eggerthella and Streptococcus, and methamphetamine use can lead to similar imbalances in gut bacteria.

A growing body of evidence indicates a close relationship between Substance Use Disorders (SUDs) and an imbalance in the gut microbiome. Opioid use, for instance, is often linked to opioid-induced bowel dysfunction. A clinical study showed that individuals treated with methadone had lower diversity and different compositions of fecal bacteria compared to non-opioid users. Additionally, patients with heroin use disorder exhibited significant changes in gut microbiome diversity, composition, and function, with the abundance levels of Turicibacter, Actinomyces, and Weissella bacteria potentially serving as indicators for predicting heroin-induced depression symptoms. In methamphetamine users, an altered gut microbiome has been associated with cognitive decline, psychotic syndrome, and the development of methamphetamine-induced psychosis. Specifically, elevated levels of certain bacteria (Lachnospiraceae, Xanthomonadale, Romboutsia, and Sphingomonadales) and decreased levels of others (Bacteroidaceae and Deltaproteobacteria) were connected to the onset of psychotic symptoms in methamphetamine users. Interestingly, transferring fecal microbiota from methamphetamine-treated mice to other mice was also able to induce methamphetamine-like anxiety and depressive behaviors and increase brain inflammation in the recipient mice's hippocampus.

One study found that marijuana users with a lower Prevotella–Bacteroides ratio in their fecal microbiome experienced cognitive deficits. Significantly, changes in the gut microbiome composition in individuals with Substance Use Disorders (SUDs) can also strongly influence the production of metabolites derived from the gut microbiome, which in turn affect mental health. For example, a reduction in the beneficial bacterium Akkermansia muciniphila, which produces metabolites important for maintaining the integrity of the intestinal barrier, was observed in individuals undergoing methadone treatment compared to non-opioid users. Substances like cannabis, nicotine, and methamphetamine have a considerable impact on regulating bacterially derived products, including neuroactive metabolites, epigenetic modifiers, neurotransmitters, and anti-inflammatory metabolites. These products play crucial roles in the communication between the gut and the central nervous system. A reduced concentration of butyric acid, an epigenetic modifier and anti-inflammatory metabolite known to help prevent brain-related diseases, has been reported in patients with cocaine use disorder due to alterations in their oral and fecal bacteria.

Overall, it appears that systemic inflammation in methamphetamine use disorder stems from a decrease in butyrate-producing bacteria, such as Faecalibacterium, Dorea, and Blautia, alongside an increase in pro-inflammatory bacteria. Therefore, supplementing the diet with sodium butyrate and/or short-chain fatty acids (SCFAs) derived from the gut microbiome might act as powerful epigenetic modifiers and anti-inflammatory agents to treat drug-induced toxicity and substance-induced psychosis. Supporting this, recent studies have shown that gut microbiome-derived SCFAs could significantly reduce methamphetamine-induced anxiety and depressive behaviors by suppressing inflammation in the colon and improving overall gut health. In another study, sodium butyrate supplementation was shown to alleviate the harmful effects of alcohol use disorder on the central nervous system by reducing neuroinflammation.

Some therapeutic agents are also capable of improving mental disorders induced by methamphetamine use by increasing the abundance of butyrate-producing and hydrogen-producing bacteria. For instance, researchers reported an altered gut microbial composition, specifically decreased levels of butyrate-producing bacteria like Bacteroides and Roseburia, along with reduced bacterial diversity and elevated self-reported depression and anxiety scores, in methamphetamine users compared to healthy controls. They found that inhaling hydrogen could improve these methamphetamine-induced neuropsychiatric impairments by altering gut microbiota profiles and increasing the presence of Bacteroides and Roseburia. Considering current data indicating that short-chain fatty acids (SCFAs) are affected in Substance Use Disorders (SUDs) and that microbial or other therapeutic interventions improve substance-induced psychiatric symptoms by increasing butyrate or other SCFAs, it is plausible to suggest that epigenetic alterations mediate the mental health impacts of substance-induced gut dysbiosis in SUDs. In summary, these findings indicate that substance use can disrupt the integrity of the gut barrier, increase intestinal permeability, and alter the composition of the gut microbiota, which in turn leads to disturbances in brain function and a person's mental state. For example, since gut microbiome imbalance in individuals with SUDs is related to reduced numbers of butyrate-producing bacteria and increased numbers of harmful and pro-inflammatory bacteria, dietary sodium butyrate supplementation and/or SCFA-producing probiotics may serve as epigenetic remedies to reduce the risk of mental illnesses in substance users, pending confirmation in human clinical studies.

Challenges and Potentials for Clinical Translation

To enhance the relevance of research findings for clinical application, it is crucial to standardize how substances are administered in studies and to establish dosage regimens that reflect human use. Moving towards models where substance exposure is self-initiated by subjects could also be beneficial. It is essential to assess epigenetic alterations in brain tissue during both short-term and long-term substance use or exposure, as well as during withdrawal, to accurately determine the stability of these substance-induced epigenetic changes. Furthermore, to gain deeper insights into common substance-induced changes in brain plasticity and neurological impairments, and to advance clinical translation based on these findings, systematic comparisons of different substances and their epigenetic effects are necessary. Some studies have indicated sex-dependent differences in substance-induced epigenetic modifications in the brain; therefore, future research should focus more on exploring how sex differences influence these alterations.

To develop more effective diagnostic and therapeutic strategies for neurological impairments caused by substance use, advanced technologies such as single-cell next-generation sequencing should be more widely utilized in future research on substance-induced epigenetic changes in brain tissue. Single-cell RNA sequencing can be applied to identify new genes regulated by opioids and other substances. Techniques like ATAC-seq can investigate the genome for areas of opened or closed chromatin after short or long-term substance exposures, while ChIP-seq can connect these types of epigenetic alterations with specific gene locations. Moreover, precise epigenetic editing tools, which target specific locations, offer researchers the opportunity to determine the functional consequences of substance-induced epigenetic alterations by manipulating these targets in a cell type-specific manner.

Investigating the interactions between substance use disorder and the gut microbiome in humans, and their roles in the development and progression of mental disorders, remains a significant challenge due to the complexity of experimental variables like a host's genetic makeup and diet, which are difficult to control. Similarly, reproducing microbiome research data using animal models can be difficult because numerous factors, such as co-housing with other animals, different suppliers, facility conditions, and other environmental factors, contribute to variations in the composition and structure of the gut microbiome.

Conclusions

This literature review supports the idea that drug use can influence neuroplasticity, learning and memory, and the function of the brain's reward circuits by affecting DNA methylation, histone modifications, and microRNAs in different brain regions. Furthermore, these findings indicate that substance-induced psychosis may be linked to epigenetic alterations, suggesting that therapies based on epigenetics could be promising approaches for alleviating psychotic symptoms in individuals with Substance Use Disorders. Dietary nutrients such as methyl donors (e.g., folic acid, vitamins B6 and B12, methionine, betaine, and choline) may serve as therapeutic agents for reducing psychotic symptoms and depressive-like behaviors in patients with SUDs, either by reversing the epigenetic abnormalities caused by substance use or by modulating the gut microbiome. Therefore, it is highly reasonable to explore new connections between these factors, as changes in diet could be considered the simplest and initial step in treating substance-induced psychosis or might play a protective role in neuropsychiatric diseases.

Introduction

Substance use disorder (SUD) describes a long-term pattern of uncontrolled drug use that harms a person's family life, social interactions, and work. Many individuals with substance use also experience symptoms like hallucinations and delusions, which are common in psychosis. For example, people who use cannabis and amphetamines often show higher rates of psychotic disorders and thinking problems similar to those seen in schizophrenia. Individuals with psychotic symptoms also report more frequent use of opioids and cocaine compared to those without such symptoms. Like other brain-related diseases, the causes of SUDs are complex, involving many genes interacting with each each other and with a person's surroundings. This interaction changes how brain cells work and are structured, leading to ongoing changes at the cellular, molecular, and behavioral levels. For instance, amphetamines appear to affect brain function by interacting with nerve cells that use serotonin, norepinephrine, and dopamine as chemical messengers. The presence of psychotic symptoms in substance users might be due to a sudden release of dopamine in one brain area, leading to too much glutamate in another, which can then damage certain brain cells and disrupt brain signals. Research indicates a strong connection between any type of SUD and the genetic risk for schizophrenia. Genetic factors account for almost 50% of the risk for SUDs and their negative effects. For example, alcohol-related tendencies can be influenced by genes involved in alcohol processing, and nicotine habits by specific gene clusters.

The close relationship between genes and environmental factors in developing psychotic symptoms in substance users can also involve epigenetic changes. During this process, certain proteins play a key role in controlling how genes are expressed, leading to long-lasting changes without altering the original DNA sequence. Drug use or the harmful effects of alcohol can disrupt the body's absorption of important nutrients like omega-3s, choline, vitamins, and folic acid. This imbalance in key substances can then lead to brain epigenetic changes, especially in DNA methylation, contributing to the development of brain disorders. Therefore, adjusting one's diet and using supplements that provide these essential nutrients is a promising way to lessen the development of psychotic symptoms and brain damage in substance users.

This review aims to explain the links between brain impairments caused by substance use and epigenetic changes in brain tissue, as well as how diet modifications can help by correcting these epigenetic problems. The discussion will cover how substance use is connected to psychotic symptoms and brain diseases through epigenetic changes. It will also examine studies that show the link between substance use and epigenetic alterations, including DNA methylation, histone modifications, and microRNAs (miRNAs), particularly in the brain. DNA methylation involves adding a chemical group to DNA, which can silence genes. Histone modifications involve changes to proteins that DNA wraps around, affecting how tightly DNA is packed and whether genes are turned on or off. MicroRNAs are small non-coding RNAs that can prevent genes from being expressed or cause RNA to break down.

This work will also summarize studies showing how a parent's exposure to substances can lead to epigenetic changes in their children's brains and how a mother's diet might prevent substance-induced brain problems, especially psychosis, likely through epigenetic mechanisms. Additionally, it will provide an overview of using different diets, particularly those rich in certain nutrients, to reduce psychotic symptoms and depressive-like behaviors in patients with SUDs. The discussion will also explore how interactions between substance use and the gut microbiome contribute to psychotic symptoms and depressive-like behaviors through epigenetic changes, and how substances produced by the gut microbiome can help in designing new treatments based on correcting these epigenetic problems. Finally, the review will address potential challenges and future outlooks for reducing psychotic symptoms and depressive-like behaviors in SUD patients using diet changes and modifications to the gut microbiome.

Association between Substance Use and the Development of Psychotic Symptoms and Depressive-Like Behaviors

There is growing evidence that drug use is linked to the development of psychotic symptoms in various situations, including during substance withdrawal, acute or chronic intoxication, as substance-induced psychosis, and in delirium. Substance-induced psychosis is a condition where psychosis appears to start because of substance use, but it can continue for days, weeks, or even months after the substance is no longer being used. Long-term brain and mental health problems caused by substance use are mainly due to processes that trigger and advance oxidative stress and inflammation. For example, psychosis caused by methamphetamine is linked to changes in the immune system's balance, the activation of various chemical messengers, increased fat breakdown, and reduced antioxidant defenses. Persistent psychotic symptoms can be caused by amphetamines, cannabis, and alcohol. It is estimated that nearly 40% of methamphetamine users experience psychotic symptoms like hallucinations and delusions, in addition to violence, impulsivity, and problems with thinking.

The appearance of psychotic symptoms in people with SUDs may be connected to epigenetic changes that lead to abnormal gene expression. For example, less DNA methylation in a specific part of the dopamine receptor type 4 (DRD4) gene was linked to paranoid symptoms in patients with methamphetamine use disorder. Higher methylation levels in another gene (COMT) were associated with reduced impulsive actions in the same patients. Another study found a significant increase in DNA methylation of the parvalbumin (PVALB) gene in methamphetamine-induced psychosis, suggesting that methamphetamine dependence causes deficits in certain brain cells through epigenetic changes. Other research reported a strong link between methamphetamine-induced paranoia and changes in specific DNA methylation patterns that affect immune and nerve-related oxidative pathways. Besides DNA methylation and histone modifications, substance-induced psychosis is connected to changes in microRNAs (miRNAs). One study showed that patients with methamphetamine-induced psychosis had noticeable differences in the levels of certain miRNAs compared to control subjects. More recently, another study found that mental health issues in substance users are linked to problems with crucial exosomal miRNAs, which are connected to changes in neurotransmitter levels, such as serotonin. The same group also observed a negative relationship between the levels of certain exosomal miRNAs and scores for anxiety and depression in patients dependent on methamphetamine and heroin.

In summary, current findings show that substance use is associated with the development of psychotic symptoms and depressive-like behaviors. These problems are believed to be caused by epigenetic shifts that lead to abnormal gene expression.

The Effects of Substance Use on Changing Brain Functions via Epigenetic Alterations

Epigenetic control mechanisms, such as DNA methylation, histone modifications, and microRNAs (miRNAs), play significant roles in the brain's ability to adapt after prolonged drug use. Previous studies have shown that brain functions related to learning, memory, and how brain cells communicate can be actively regulated by DNA methylation and histone modifications in individuals with SUDs. For example, heroin use may change the structure of certain cell components through altered DNA methylation levels, contributing to changes in behavior. Similarly, there is an interesting link between increased DNA methylation of the dopamine transporter gene (DAT1) and dopamine release in people addicted to psychoactive substances. Furthermore, reduced levels of brain-derived neurotrophic factor (BDNF) methylation have been found in individuals who use tobacco and also have depression, compared to those who do not use tobacco or have depression. In addition to DNA methylation, histone modifications may be important in changing brain functions in people with SUDs. For instance, human brain support cells (astrocytes) treated with opioids and psychostimulants showed increased overall acetylation of certain histone proteins, except for one specific site. It is thought that illegal drugs like ∆9-tetrahydrocannabinol can activate enzymes that remove acetyl groups from histones, causing genes involved in thinking abilities to become more tightly packed and increasing the risk of schizophrenia. Similarly, recalling memories related to heroin use is linked to changes in histone acetylation during memory reconsolidation. Therefore, treatments that alter histone acetylation could be effective ways to treat SUDs and prevent relapses. Another study showed that occasional alcohol exposure in adolescents reduces histone acetylation in the hippocampus, a brain region important for memory, which then lowers levels of BDNF and suppresses the growth of new brain cells in that area.

Substance use can also epigenetically alter gene expression by changing the levels of natural non-coding RNAs, like miRNAs and circular RNAs (circRNAs), in brain tissue. CircRNAs can influence substance-related behaviors by interacting with miRNAs. For instance, miRNAs in the striatum, a brain region, play important roles in brain plasticity, learning and memory, and the function of the brain's reward system. Another study indicated that excessive activation of astrocytes and shrinkage in the striatum after methamphetamine treatment were connected to 167 differently expressed miRNAs in the striatum. Researchers also reported that heroin users showed higher levels of certain miRNAs in their blood, while methamphetamine users had increased levels of another miRNA. Another study found that elevated levels of a specific miRNA in the nucleus accumbens and ventral tegmental area of methamphetamine users might be a potential biomarker for addiction in these patients. Furthermore, an analysis of brain and blood samples from individuals with opioid use disorder revealed a strong overlap between their differently expressed target genes, even though the miRNA profiles in the brain and blood were distinct.

In general, abnormal changes in DNA methylation, histone modifications, and miRNA expression in various brain regions of substance users heavily impact brain functions related to how brain cells communicate, learning, and memory, which can speed up the development of psychiatric disorders. However, it is important to recognize that while these epigenetic changes are associated with substance use, the exact ways they cause problems and their implications for psychiatric disorders still need more research. Understanding these complex interactions will require extensive study to tell the difference between a connection and a direct cause, and to develop specific treatments.

Paternal and Maternal Substance Use and Epigenetic Alterations in the Brains of the Offspring

It has been reported that illegal drugs and other substances can cross the placenta, activate the immune system, and disrupt a child's development by changing gene expression or causing epigenetic problems in various body organs, especially the brain. This, in turn, increases the risk of mental disorders.

For example, methamphetamine has been found to be the most common illegal drug taken by pregnant mothers, which leads to changes in the expression of genes important for brain development, resulting in thinking problems and brain disorders in their children. It has been observed that a mother's substance use during pregnancy is linked to a higher risk of psychotic symptoms in her children. For instance, both paternal and maternal cannabis use are connected to a higher number of psychotic-like experiences in children at age ten. The development of psychotic symptoms and other brain problems in children due to substance use can be mediated by epigenetic changes. For example, a recent study indicated that prenatal cocaine exposure in humans can increase the risk for psychosis in children, which is linked to epigenetic changes. In another study, a combination of prenatal exposure to a certain chemical and cannabinoids caused significant differences in miRNA expression in a brain region related to a human gene site connected to schizophrenia. A more recent human study across the genome showed that individuals with cannabis use disorder had different DNA methylation at specific gene locations, notably one site that appears to be an important link between cannabis use and mental disorders, particularly mood disorders. Moreover, a mother's exposure to e-cigarette aerosols containing nicotine could impair her child's short-term memory, which was linked to increased overall DNA methylation in the children's brains.

There is evidence that such epigenetic changes in children can happen because pregnant women with SUDs may not absorb enough nutrients. In this regard, it has been shown that drug and alcohol consumption during pregnancy can disrupt the absorption of micronutrients such as folic acid, choline, and omega-3s. Therefore, providing supplements with these nutrients to pregnant women with SUD may prevent brain deficits in their children by correcting epigenetic problems. As another interesting example, prenatal alcohol exposure was shown to disturb miRNA expression in the hippocampus, and choline supplementation could reverse an alcohol-dependent increase in a specific hippocampal miRNA. Another animal study showed that alcohol consumption increases DNA methylation in certain brain regions of rat pups during the neonatal period, and choline supplementation could reduce this increased DNA methylation in both of these brain regions. Together, these findings show that drugs and other substances like alcohol can cross the placenta, activate the immune system, harm the development of offspring, and increase the risk of mental illnesses by altering gene expression or causing epigenetic problems in brain tissue. However, while these studies offer important insights, further research is needed to fully understand the exact mechanisms involved and to determine the short-term and long-term effects of these substances on human development and mental health.

Therapeutic Approaches Using Diet Modification or Epigenetic Drugs to Improve Psychotic Symptoms, Learning Deficits, and Memory Impairments in Animal Models and Patients with SUDs

Several lines of evidence suggest that psychotic symptoms in patients with SUDs are linked to changes in nutrients that affect the processes involved in controlling gene expression. For instance, lower levels of folate, a substance important for methylation reactions in gene regulation, have been reported in psychotic methamphetamine users compared to non-psychotic users. In fact, every slight decrease in blood folate level may increase the risk of psychosis by 27%. Therefore, consuming a diet rich in methyl groups is considered a promising approach for reducing psychotic symptoms in patients who use methamphetamine. Another notable example showed that certain genes (DRD3, DRD4, MB-COMT, and AKT1) had reduced DNA methylation in patients with methamphetamine psychosis. It was concluded that a methyl-rich diet might help improve psychotic symptoms in these patients. Other research also reported that repeated treatment with methionine (a key amino acid for methyl groups in mammals) before and during training could prevent the development of cocaine's rewarding effects by reversing reduced DNA methylation in the frontal brain regions of mice.

In another study, researchers found that reduced overall methylation and decreased methylation at specific DNA sites in the c-Fos gene were linked to cocaine-induced c-Fos expression in parts of the brain related to reward. Their results showed that long-term methyl supplementation with L-methionine could lessen drug-seeking behaviors and sensitivity to cocaine's movement-activating effects by increasing DNA methylation of the c-Fos gene. Similarly, treatment with choline (a major source of methyl groups) can reverse the harmful effects of alcohol on brain function. As other examples, in adult offspring of rats that consumed alcohol during pregnancy, increased levels of certain proteins and gene markers, along with reduced levels of gene activation markers, were observed in specific brain cells, which were normalized by choline supplementation during pregnancy. Other researchers identified 462 genes with altered DNA methylation in the hippocampus of adult mice after nicotine exposure, which was linked to learning problems. They found that dietary choline supplementation could reduce learning deficits in mice exposed to nicotine by correcting DNA methylation in the hippocampus. In addition to diets rich in methyl groups, a ketogenic diet is a promising option for reducing brain damage in substance users. During alcohol detoxification, the human brain experiences an energy deficit due to reduced levels of certain chemical compounds, which contributes to withdrawal symptoms and brain damage in patients with alcohol use disorder. Researchers found that a shift in energy sources during withdrawal in patients with alcohol use disorder might be a major reason for the severity of withdrawal and brain damage. A ketogenic diet could help reduce withdrawal symptoms by increasing beneficial substances and decreasing inflammatory markers. In another study, the same group reported that three weeks of a ketogenic diet could reduce brain signals related to craving in patients with alcohol use disorder.

Similarly, some drugs are able to maintain brain function in substance users by reversing epigenetic problems. For example, acute treatment of mice with phencyclidine led to a sharp decrease in a specific microRNA (miRNA-143) in brain support cells (astrocytes) in the frontal brain region, leading to psychotic symptoms similar to schizophrenia. Their results showed that while another drug (quinpirole) also decreased miRNA-143 expression, antipsychotic drugs like clozapine or haloperidol could prevent phencyclidine-induced hyperactivity by restoring miR-143 expression and suppressing the expression of a target gene of miRNA-143. In another study, it was found that cocaine could impair the activity of an enzyme (DNMT) in astrocytes, which then speeds up nerve cell degeneration. However, Piracetam, a drug used to treat cognitive disorders, could prevent cocaine-induced impairment of DNMT activity and reduce cell death. In summary, psychotic symptoms, learning deficits, and memory problems in patients with SUDs are linked to changes in nutrients that affect how genes are regulated. Therefore, nutrients that donate methyl groups or epigenetic drugs might be considered potential treatments to prevent or alleviate such problems in patients with SUDs. However, it is important to note that results from animal studies presented here cannot be directly applied to humans; clinical trials are necessary to confirm the effectiveness of these approaches and their potential side effects in human subjects.

Substance Use-Induced Gut Microbiome Alterations May Intensify Psychopathology via Epigenetic Aberrations

Growing evidence shows that substance use contributes to damage of the gut lining, increased gut permeability, and changes in the composition of gut bacteria. These changes then lead to problems in brain function and a person's mental state. Alterations in gut bacteria and the substances they produce due to substance use strongly affect brain function by causing negative changes in immune and inflammatory pathways and the release of specific chemical messengers in the brain. Many types of bacteria have shown the ability to produce different chemical messengers like serotonin, dopamine, and GABA. While the link between imbalances in gut bacteria and the development of various psychiatric diseases has been reviewed elsewhere, the effects of substance use on the gut microbiome and related chemical changes in the brain may also contribute to the development of psychiatric disorders. For example, just as patients with psychiatric disorders show fewer beneficial bacteria (like Faecalibacterium, which produces butyrate) and more harmful, inflammation-causing bacteria (like Eggerthella and Streptococcus), methamphetamine use can lead to similar imbalances in gut bacteria.

An increasing amount of evidence demonstrates a close relationship between SUDs and imbalances in gut bacteria. Opioid-induced bowel dysfunction is one of the negative effects of chronic opioid use. A clinical study showed that individuals treated with methadone had less diverse and different compositions of gut bacteria compared to people who did not use opioids. In addition, patients with heroin use disorder showed drastic changes in the diversity, composition, and functions of their gut microbiome. The levels of certain bacteria (Turicibacter, Actinomyces, and Weissella) could be used as indicators for predicting heroin-induced depression symptoms. In methamphetamine users, it has been shown that an altered gut microbiome is linked to declining cognitive abilities, psychotic syndrome, and the development of methamphetamine-induced psychosis. Furthermore, increased levels of certain bacteria (like Lachnospiraceae, Xanthomonadale, Romboutsia, and Sphingomonadales) and decreased levels of others (Bacteroidaceae and Deltaproteobacteria) were connected to the development of psychotic symptoms in methamphetamine users. Interestingly, transplanting gut bacteria from mice given methamphetamine also caused methamphetamine-induced anxiety- and depressive-like behaviors and increased brain inflammation in the recipient mice. In another study, researchers found that a lower ratio of certain gut bacteria in marijuana users was linked to thinking problems.

Notably, changes in the gut bacteria composition in individuals with SUDs can also significantly affect the production of substances derived from gut bacteria, which further influence mental health. For instance, a reduction in the amount of Akkermansia muciniphila, a bacterium that produces substances involved in maintaining the gut barrier, was observed in individuals treated with methadone compared to non-opioid users. It has been reported that substances like cannabis, nicotine, and methamphetamine greatly influence the regulation of bacteria-derived products such as neuroactive metabolites, epigenetic modifiers, neurotransmitters, and anti-inflammatory metabolites, all of which play critical roles in the communication between the gut and the central nervous system. For example, a reduced concentration of butyric acid, an epigenetic modifier and anti-inflammatory substance that helps prevent brain disorders, has been reported as a result of changes in oral and fecal bacteria in patients with cocaine use disorder. Overall, it appears that widespread inflammation in methamphetamine use disorder is due to decreased amounts of butyrate-producing bacteria (like Faecalibacterium, Dorea, and Blautia) and increased amounts of bacteria that promote inflammation.

Therefore, supplementing with dietary sodium butyrate and other short-chain fatty acids (SCFAs) produced by gut bacteria may act as powerful epigenetic modifiers and anti-inflammatory agents to treat drug-induced toxicity and psychosis caused by substances. Some supporting evidence comes from recent studies showing that SCFAs derived from gut bacteria could significantly reduce methamphetamine-induced anxiety- and depressive-like behaviors by suppressing inflammation in the colon and improving gut health. In another study, sodium butyrate supplementation was shown to lessen the harmful effects of alcohol use disorder on the central nervous system by reducing brain inflammation. Some therapeutic agents are also able to improve mental disorders caused by methamphetamine use by increasing the amount of butyrate-producing and hydrogen-producing bacteria. For example, researchers reported altered gut bacteria composition (decreased amounts of butyrate-producing bacteria like Bacteroides and Roseburia), reduced diversity, and elevated self-reported scores for depression and anxiety in methamphetamine users compared to healthy individuals of the same age. They found that inhaling hydrogen could improve brain and mental health problems caused by methamphetamine use by changing gut bacteria profiles and increasing the abundance of Bacteroides and Roseburia. Considering current data indicating that SCFAs are affected in SUDs and that microbial or other treatments improve substance-induced psychiatric symptoms by increasing butyrate or other SCFAs, it is reasonable to suggest that epigenetic changes mediate the mental health impacts of substance-induced gut imbalances in SUDs. Taken together, these findings indicate that substance use can disrupt the gut barrier's integrity, increase gut permeability, and alter the composition of gut bacteria, which further leads to disturbances in brain function and a person's mental state. For example, since gut microbiome imbalances in patients with SUDs are related to fewer butyrate-producing bacteria and more harmful, inflammation-promoting bacteria, dietary sodium butyrate supplementation and/or probiotics that produce SCFAs may serve as epigenetic treatments to reduce the risk of mental illnesses in substance users, pending confirmation in human clinical studies.

Challenges and Potentials for Clinical Translation

To make research more relevant to clinical practice, it is crucial to standardize how substances are used in studies and to establish doses that reflect human use, or to use models where substance exposure is voluntary. Additionally, epigenetic changes in brain tissue should be evaluated during both short-term and long-term substance use or withdrawal to accurately determine how stable these substance-induced epigenetic problems are. Moreover, to gain deeper insights into shared brain plasticity changes and neurological impairments caused by substances and to advance clinical translation based on these findings, systematic comparisons of different substances and their epigenetic effects are needed. Some studies have shown that there are sex-dependent differences in substance-induced epigenetic changes in the brain; therefore, future studies should focus more on unresolved issues to explore how sex differences affect these changes.

To develop more effective diagnostic and therapeutic strategies for brain impairments caused by substances, advanced single-cell sequencing technologies should be used more widely in future research on substance-induced epigenetic changes in brain tissue. Single-cell RNA sequencing can also be applied to discover new genes regulated by opioids and other substances. Researching the genome for areas where DNA is more open or closed after short or long-term substance exposures can be done using a technique called ATAC-seq. Another technique, ChIP-seq, can connect these types of epigenetic changes with the affected gene locations. Furthermore, tools that allow specific epigenetic editing provide an opportunity for researchers to discover the functional consequences of substance-induced epigenetic changes by manipulating these targets in specific cell types.

Due to the complexity of experimental factors like a person's genetic makeup and diet, and the difficulty in controlling them, investigating how substance use disorders and gut microbiome interactions play a role in the development and progression of mental disorders in humans remains a significant challenge. Similarly, it can be difficult to reproduce gut microbiome research data using animal models because many factors, such as housing conditions with other animals, suppliers, facility conditions, and other environmental factors, lead to differences in the composition and structure of the gut microbiome.

Conclusions

This review of scientific literature supports the idea that drug use can influence how the brain adapts, as well as learning, memory, and reward system functions by affecting DNA methylation, histone modifications, and microRNAs in different brain regions. Moreover, these findings show that psychosis caused by substance use can be linked to epigenetic changes. Therefore, therapies based on epigenetics could be interesting approaches for reducing psychotic symptoms in patients with SUDs. Dietary nutrients such as methyl donors (like folic acid, vitamins B6 and B12, methionine, betaine, and choline) can serve as therapeutic agents to alleviate psychotic symptoms and depressive-like behaviors in patients with SUDs by reversing the epigenetic problems caused by substance use or by changing the gut microbiome. For these reasons, it is highly sensible to investigate new connections among these factors, as changes in a person's diet may be considered the simplest and first step in treating substance-induced psychosis or may play a protective role in brain and mental health disorders.

Introduction

Addiction to drugs or alcohol is a long-term problem where a person keeps using substances even when it causes harm to their family, community, and work. People who use drugs often have mental health problems like seeing or hearing things that are not there, or having strong false beliefs. For example, people who use cannabis or amphetamines often show more mental health issues, similar to those seen in schizophrenia. Also, people with mental health issues are more likely to use opioids and cocaine.

Addiction is complex and has many causes. It involves both a person's genes and their life experiences working together. This can change how brain cells work and are built, leading to ongoing changes in the body, brain, and behavior. For instance, amphetamines can affect brain function by changing brain chemicals like dopamine. Drug use can also lead to a sudden release of dopamine, causing problems in certain brain areas. Genes play a big role in addiction, with about half the risk coming from inherited traits. People with addiction may also have genes that increase their risk for mental illnesses like schizophrenia.

The strong link between genes, the environment, and mental health issues in people who use drugs can also be explained by something called epigenetics. Epigenetics describes ways that genes can be turned on or off without changing the basic DNA code itself. This happens when certain proteins help turn genes on or off by changing how DNA is packed. Drug or alcohol use can also make it harder for the body to absorb important nutrients like omega-3, choline, and certain vitamins. These nutrients are needed to help with epigenetic changes in the brain. Because of this, eating certain foods or taking supplements might help lessen mental health problems and brain damage in people who use drugs.

This paper explains the connections between drug use, brain damage, and epigenetic changes. It also looks at how changes in diet might help improve these problems. The discussion will cover how drug use is linked to mental health issues through epigenetics, including changes to DNA tags, how DNA is packaged, and tiny bits of RNA. The paper also looks at how parents' drug use can affect their children's brains through epigenetics and how a mother's diet might help prevent these problems. Finally, it explores how drug use affects gut bacteria, which can worsen mental health, and how certain gut-related treatments might help.

Association between Substance Use and the Development of Psychotic Symptoms and Depressive-Like Behaviors

Drug use is strongly linked to mental health problems, including those that appear during withdrawal or from heavy, long-term use. These issues are often called "substance-induced psychosis," where mental health problems seem to be caused by drug use but can last for weeks or months even after the person stops using. Long-term brain problems from drug use are often due to an increase in harmful stress and swelling in the body. For example, mental health issues from methamphetamine use are tied to changes in the body's defense system and an increase in harmful chemicals. Amphetamines, cannabis, and alcohol can cause lasting mental health problems. It is thought that almost 40% of people who use methamphetamine have mental health issues like seeing or hearing things that are not there, strong false beliefs, anger, poor impulse control, and thinking problems.

Mental health issues in people with addiction may be linked to epigenetic changes that cause genes to work incorrectly. For example, lower levels of DNA tagging on a certain gene related to dopamine were found in people with methamphetamine use disorder who also had mental health problems. Other studies showed that methamphetamine use could cause higher DNA tagging on other genes, which was linked to certain brain problems. Besides DNA tagging, changes in tiny bits of RNA are also linked to mental health problems caused by methamphetamine.

In short, current findings show that drug use is tied to mental health issues and feelings of sadness. These problems often happen because of epigenetic changes that make genes work differently than they should.

The Effects of Substance Use on Changing Brain Functions via Epigenetic Alterations

Epigenetic changes, like DNA tagging and changes to how DNA is packaged, play a big role in how the brain adapts after long-term drug use. Studies have shown that brain functions important for learning, memory, and how brain cells connect can be changed by DNA tagging and packaging in people with addiction. For instance, heroin can change DNA tagging, which affects how brain cells are built and how people behave. Similarly, addiction to drugs can affect a gene that controls dopamine in the brain. People who use tobacco and also feel sad have been found to have less DNA tagging on a gene important for brain health.

Beyond DNA tagging, changes in how DNA is packaged can also affect brain functions in people with addiction. For example, studies found more overall packaging changes in brain cells treated with opioids and stimulants. It is believed that some illegal drugs, like cannabis, can make certain genes involved in thinking work incorrectly, possibly increasing the risk of schizophrenia. Also, memories related to heroin use are linked to changes in DNA packaging, suggesting that targeting these changes could help treat addiction. Alcohol use in young people can also reduce positive changes in DNA packaging, lower levels of a brain health protein, and harm new brain cell growth.

Drug use can also change how genes work by changing tiny bits of RNA in the brain. These tiny RNAs are important for how brain cells connect, for learning, memory, and for the brain's reward system. For instance, methamphetamine use was linked to many different changes in these tiny RNAs in a part of the brain called the striatum. Also, people who use heroin or methamphetamine can show changes in the levels of certain tiny RNAs in their blood.

Overall, big changes in DNA tagging, how DNA is packaged, and tiny RNAs in different brain areas of people who use drugs greatly affect how brain cells work. This impacts how the brain connects, how a person learns, and how they remember things, which can speed up the start of mental health problems. However, it is important to know that while these epigenetic changes are linked to drug use, more study is needed to fully understand if they cause mental health problems and how they do so.

Paternal and Maternal Substance Use and Epigenetic Alterations in the Brains of the Offspring

It has been shown that illegal drugs and other substances can pass from a pregnant mother to her unborn child, harm the child's body defense system, and disturb their development. This happens by changing how genes work or by causing epigenetic changes in the child's body, especially in the brain, which increases the risk of mental health problems later in life. For example, methamphetamine is a common illegal drug used by pregnant mothers. It can change how genes important for brain development work, leading to thinking problems and mental health issues in their children.

Studies also show that a parent's use of cannabis or cocaine is linked to a higher number of mental health problems in their children. Mental health issues and other brain problems in children due to parental drug use may happen because of epigenetic changes. For example, one study found that cocaine use by pregnant mothers could increase the risk of mental health problems in their children, which was linked to epigenetic changes. Another study showed that if a mother was exposed to both infection and cannabis during pregnancy, it led to big changes in tiny RNAs in her child's brain, in an area linked to schizophrenia. Also, a recent study found that people with cannabis use disorder had changes in DNA tagging at certain spots, which seems to link cannabis use to mental health issues, especially mood problems. And when mothers were exposed to e-cigarette vapor with nicotine, their children had worse short-term memory, which was connected to more overall DNA tagging in their brains.

There is also proof that these epigenetic changes in children can happen because pregnant women with addiction may not absorb enough nutrients. Drug and alcohol use can disrupt the absorption of important nutrients like folic acid, choline, and omega-3 during pregnancy. So, giving these supplements to pregnant women with addiction might help prevent brain problems in their children by correcting epigenetic changes. For example, it was shown that alcohol exposure before birth caused problems with tiny RNAs in a brain area called the hippocampus. But giving choline supplements could reverse some of these changes. Another study in animals showed that alcohol use increased DNA tagging in certain brain areas of rat pups, and giving choline could reduce this extra DNA tagging. All these findings show that drugs and alcohol can pass to unborn children, affect their body defense system, harm their development, and raise the risk of mental illnesses by changing how genes work or by causing epigenetic changes in the brain. However, more research is needed to fully understand these effects and how they impact human development and mental health in the long term.

Therapeutic Approaches Using Diet Modification or Epigenetic Drugs to Improve Psychotic Symptoms, Learning Deficits, and Memory Impairments in Animal Models and Patients with SUDs

There is evidence that mental health problems in people with addiction are linked to changes in nutrients that affect the process of gene tagging. For example, lower levels of folate, a nutrient important for gene tagging, have been found in people with methamphetamine-related mental health issues. In fact, a small drop in folate levels can greatly increase the risk of mental health problems. This means that a diet rich in certain nutrients might help lessen mental health problems in people who use methamphetamine. Another study found that using a diet rich in certain nutrients might help improve mental health issues in these patients. It was also found that giving methionine, an important nutrient for gene tagging, could stop cocaine from being rewarding in mice by reversing unwanted DNA tagging in their brains.

Other research showed that prolonged nutrient supplements could reduce drug-seeking behavior and the body's response to cocaine by increasing DNA tagging on a certain gene. Also, giving choline, another key nutrient, can reverse the harmful effects of alcohol on brain function. For example, choline supplements helped fix epigenetic changes caused by alcohol use during pregnancy in animal studies. And in mice exposed to nicotine, choline supplements reduced learning problems by correcting DNA tagging in the brain. Beyond these specific nutrients, a "ketogenic diet" might also help reduce brain damage in people who use drugs. This diet could help lessen withdrawal symptoms in people with alcohol addiction by changing how the brain gets energy and by reducing swelling.

Some medicines can also help brain function in people who use drugs by reversing epigenetic changes. For instance, one study found that an antipsychotic drug could prevent certain mental health problems in mice by restoring the levels of a tiny RNA in brain cells. Another study showed that cocaine could harm an enzyme involved in DNA tagging, which leads to brain cell damage. However, a drug used to treat thinking problems could stop this harm and reduce cell death. In summary, mental health problems, learning difficulties, and memory issues in people with addiction are linked to changes in nutrients that affect gene tagging. Therefore, certain nutrient supplements or medicines that target epigenetics might be good options to prevent or treat these problems in people with addiction. It is important to remember that results from animal studies need to be confirmed in human trials.

Substance Use-Induced Gut Microbiome Alterations May Intensify Psychopathology via Epigenetic Aberrations

More and more evidence shows that drug use can harm the lining of the gut, make it more permeable, and change the types of bacteria living there. This can then lead to problems with brain function and a person's mental state. Changes in gut bacteria and their products from drug use greatly affect brain function by causing harmful changes in the body's defense and swelling systems, and by changing how certain brain chemicals are released. Many bacteria can produce brain chemicals like serotonin, dopamine, and GABA. While the link between unhealthy gut bacteria and many mental health problems is known, drug use's impact on gut bacteria and the resulting brain chemical changes can also lead to mental disorders. For example, methamphetamine use can cause similar changes in gut bacteria as seen in people with mental health disorders.

There is strong evidence linking addiction to changes in gut bacteria. Opioid use, for instance, often causes bowel problems. Studies have shown that people treated with methadone had less variety in their gut bacteria compared to those who did not use opioids. Also, people with heroin use disorder showed big changes in their gut bacteria, and certain types of bacteria could even predict symptoms of depression. In people who use methamphetamine, altered gut bacteria are linked to thinking problems and the start of mental health issues.

Importantly, changes in gut bacteria in people with addiction can also affect the production of chemicals made by these bacteria, which then influence mental health. For example, a decrease in a specific helpful gut bacteria that produces chemicals vital for gut health was seen in people treated with methadone. Substances like cannabis, nicotine, and methamphetamine greatly affect the levels of products made by bacteria, such as brain-active chemicals, substances that change genes, brain chemicals, and chemicals that reduce swelling. For instance, a reduced level of butyric acid, a chemical that affects genes and reduces swelling, was found in people with cocaine use disorder. It seems that widespread swelling in methamphetamine use disorder happens because of fewer bacteria that produce butyrate (a helpful chemical) and more bacteria that cause swelling.

Because of this, adding sodium butyrate to the diet or using certain helpful gut bacteria might be strong ways to treat drug-related harm and mental health problems caused by drugs. Some studies show that chemicals produced by gut bacteria can reduce anxiety and depression in mice caused by methamphetamine by reducing swelling in the gut and improving gut health. Another study showed that sodium butyrate could lessen the harmful effects of alcohol on the brain by stopping swelling. Also, some treatments can improve mental disorders caused by methamphetamine use by increasing helpful bacteria. Since gut bacteria chemicals are affected in addiction, and certain treatments improve drug-related mental health problems by increasing helpful chemicals like butyrate, it suggests that epigenetic changes play a role in how gut bacteria problems affect mental health in addiction.

Challenges and Potentials for Clinical Translation

To make research results useful for people, it is important to have consistent ways of exposing people to substances in studies and to figure out the right amounts that relate to real-world human use. Also, epigenetic changes in the brain should be checked for both short and long-term drug use or withdrawal to understand how stable these changes are. To better understand shared brain changes and problems caused by drugs, and to help bring these findings to patient care, researchers need to compare how different substances affect epigenetics in the body. Some studies have shown that there are differences between males and females in drug-related epigenetic changes in the brain, so future studies should focus on this as well.

To find better ways to diagnose and treat brain problems caused by drugs, newer technologies that look at single cells in the brain should be used more in research on epigenetic changes. These technologies can help find new genes affected by drugs and identify specific areas of DNA that are opened or closed after drug exposure. Also, special tools that can edit epigenetics at specific gene locations allow researchers to see what happens when they change these targets in a specific type of cell.

However, studying how drug use affects gut bacteria in humans and its role in mental disorders is still hard. This is because many things like a person's genes, diet, and even where they live are hard to control. It can also be difficult to repeat gut bacteria research using animal models because many factors, such as sharing living spaces with other animals or different lab conditions, can change the types of gut bacteria found.

Conclusions

This review supports the idea that drug use can affect how the brain adapts, learns, remembers, and responds to rewards. It does this by changing DNA tagging, how DNA is packaged, and tiny bits of RNA in different parts of the brain. Also, mental health problems caused by drugs can be linked to epigenetic changes. This means that treatments based on epigenetics could be helpful for people with addiction who experience mental health issues.

Nutrients like folic acid, vitamins B6 and B12, methionine, betaine, and choline can act as treatments to help lessen mental health problems and feelings of sadness in people with addiction. They do this by reversing the epigenetic changes caused by drug use or by changing the gut bacteria. Therefore, it is very important to explore new connections between diet and addiction. Changes in a person's diet could be the easiest first step in treating mental health problems caused by drugs, or they might even help protect the brain from such illnesses.