Novel neurotherapeutic targets for substance use disorders: Neuroplasticity, neuroinflammation, gasotransmitters and non-canonical organ systems

Abstract

Substance use disorders (SUDs) are chronic disorders marked by intense and compulsive drug-seeking behavior, coupled with a high risk of relapse. Different theories have emerged over time regarding mechanisms that induce and exacerbate SUDs. This review explores new and evolving evidence on the role of reward systems and processes and aligns those conceptual frameworks with neuroplastic and neuroinflammatory mechanisms and potential therapeutic targets. As the addiction cycle progresses, substance use shifts to long-term chronic use, marked by reduced hedonic effects and intensified compulsion. Thus, a “euphoria reward” model fails to completely capture the progression and complexity of SUDs. Substantive research suggests that the brain circuits that subserve pleasure and craving are distinct, which may explain why individuals with SUDs continue to seek out substances in the absence of pleasure. Additionally, the alleviation of negative affect, anhedonia, post-acute withdrawal symptoms, or other symptoms, may play a key part in preventing relapse. Recent studies emphasize the critical roles of neuroinflammation and oxidative stress in shaping SUDs by altering neural circuitry involved in reward, motivation, negative affect, and decision-making, thereby heightening relapse risk. Molecular adaptations, neuroplasticity and neuroinflammation appear to be important mediators of these changes. This review examines toxicity across the brain, heart and liver, focusing on mechanisms of neuroinflammation, neuroplasticity and gasotransmitter systems. It is proposed that an emphasis on developing pharmacotherapies targeting these mechanisms, while also addressing interactions between the brain and peripheral systems, both as consequences of SUDs and as drivers of the progression of SUDs, may provide new success in SUD therapeutic development.

Overview of addiction – including epidemiology and theoretical framework

Substance use disorders (SUDs), alternatively referred to as addiction or addictive disorders, affect a substantial portion of the global population, representing a major public health challenge. Tens of millions of individuals throughout the world suffer from the devastating consequences of SUDs. SUDs are chronic disorders marked by intense and compulsive drug-seeking behavior coupled with a high risk of relapse. Research to understand the motivational, social, contextual, biological, evolutionary, and other multidimensional elements of SUDs has revealed much about the mechanisms and acute effects of addictive drugs, as well as provided new targets for treating the disease of addiction. A prevailing notion guiding a significant portion of SUD research and therapeutic development posits that addiction can be conceptualized by consistently seeking the euphoric psychoactive effects of misused substances, with drug-seeking behavior reinforced by the dopamine rewarding system of the brain [1]. Another common framework has focused on the idea that drug-taking behavior is driven by dysphoric or aversive effects that arise from acute or post-acute withdrawal symptoms. In this regard, neuroscience research indicates that the chronic intense and compulsive drug-seeking behavior coupled with high risks of relapse may be mediated by brain alterations caused by repeated drug exposure, particularly in genetically or socially vulnerable individuals. This leads to reduced responsiveness in the brain's reward system and loss of the ability to feel pleasure, enhanced emotional sensitivity to stress, and impaired self-regulation including inhibiting unwanted responses [2]. Both these frameworks have been highly influential in guiding thinking on how to develop effective treatments for SUDs and have achieved notable success. In the current review, we will provide the reader with background and relate changes in the development of compulsive substance use and its treatment to new and emerging systems that may afford new neurotherapeutic targets for SUDs, with a focus on neuroplasticity, neuroinflammation, gasotransmitters, and non-canonical organ systems. We do not focus on alcohol use disorder (AUD) in this review, however some pertinent literature is described as it relates to other SUDs. For example, prolonged alcohol use induces oxidative stress and neuroinflammation, and alcohol use is associated with complications in non-canonical organ systems such as the liver. Increasing evidence supports investigating shared molecular targets across AUD and SUDs to inform the development of cross-substance therapeutic interventions.

Extensive research has been conducted to understand SUDs and their impact on the brain, particularly focusing on the rewarding properties of addictive substances [1]. Misused substances have been shown to be rewarding because they activate the brain's mesolimbic dopaminergic pathway, which encompasses the ventral tegmental area (VTA) and nucleus accumbens (NA), with an extended and associated set of connections to the amygdala, basal forebrain, dorsal striatum, and prefrontal cortex (PFC) [[3], [4], [5], [6]]. Brain reward systems can be divided into hedonic and craving components, with each aspect involved in distinct region-specific pathways [Fig. 1] [[3], [4], [5], [6]]. The hedonic pleasure of receiving a reward, or “liking”, has been associated with pathways beginning in the VTA and projecting to the ventral striatum. Behavioral pursuit of a reward, or “wanting” (incentive salience/craving) involves pathways projecting from the VTA to NA during acute substance exposure and shifts to pathways from the VTA to the dorsal striatum with chronic use over time. [[7], [8], [9]]. These regions are modulated by dopamine projections that integrate the reward functions of these areas [5,10].

Fig. 1.

A representative framework of ventral and dorsal dopamine pathways that are believed to be involved in substance use disorders. The dopamine pathways are located in the brain as indicated by the arrows. A generalized theoretical framework for each is described in the text. This schematic was created with ​BioRender. VTA: ventral tegmental area; NA: nucleus accumbens.

Addiction is commonly conceptualized as a three-stage cycle: bingeing or intoxication, withdrawal or negative effect, and preoccupation-anticipation or craving. In alignment with each stage there are phasic disruptions in three major neurocircuits: the basal ganglia for bingeing; the extended amygdala in withdrawal; and the PFC for cravings. [11,12]. Likewise, there are distinct neurotransmitter-specific circuits with fluctuating release patterns in line with each stage. Understanding divergent neurotransmitter-specific neuroplasticity in each circuit may help guide the development of targeted neurotherapeutics. [12,13]. For example, the bingeing phase is characterized by increases in neuroactive substances such as dopamine, opioid peptides, serotonin, γ-aminobutyric acid (GABA), and acetylcholine in either the VTA or NA [12,13]. Consequently, during withdrawal, there are decreases in these and other neuroactive agents, as well as increases in levels of norepinephrine and stress-related peptides such as corticotropin-releasing factor (CRF) and dynorphin [12]. In turn, the anticipation stage is marked by increases in dopamine, serotonin, glutamate, and GABA among other neurotransmitter systems [12]. It is the withdrawal and anticipation stages that have been associated with the dysphoric or aversive effects experienced in addiction, both in the acute and post-acute phases, that also drive drug-taking behavior. As the neurobiological and neurophysiological systems involved in these phases appear to diverge, that has and continues to present non-overlapping targets for neurotherapeutic development. In this review, we intend to address the reward system, dopamine theory in addiction, anhedonia, and putative neurobiological and neurophysiological mechanisms involved in these processes including neuroplasticity, neuroinflammation, gasotransmitters, and non-canonical organ systems.

Canonical neurobiological frameworks for the development of neurotherapeutics

Dopamine Hypothesis of Reward

Different theoretical frameworks have emerged related to SUDs, each shedding light on different aspects of the disease, and each touching differently on hyper- and hypo-dopaminergic states modulated by chronic drug misuse. Some of the major theories include the Dopamine Hypothesis of Reward, Incentive-Sensitization, the Allostatic Model of Addiction, Opponent Process Drivers of Motivation, Pathology of Motivation and Choice, Cognitive-Behavioral Models, Stress-Reward Dysregulation, and Biopsychosocial Models. To maintain focus for the purposes of this review, and to relate clear neurobiological physiology to the novel neurotherapeutic targets that will be discussed later, we will limit discussion in this review primarily to hyper- and hypo-dopaminergic states and how they may be affected or modulated by neuroplasticity, neuroinflammation, gasotransmitters, and non-canonical organ systems.

The dopamine hypothesis is a key theory in addiction research, proposing that dopamine plays a central role in the brain reward system [14,15] and this system contributes to the development of addiction. It is well established that all addictive substances and non-drug addictive stimuli significantly elevate dopamine levels in brain regions like the NA upon acute exposure [2]. The elevation of dopamine levels is associated with reinforcing these behaviors and increasing the probability that drug-associated behaviors will recur [2,16]. Indeed, outside of supporting locomotion, one of the key functions of dopamine is the maintenance of motivated behaviors [17,18]. Additionally, the release of dopamine within the brain's reward system is believed to contribute to the experience of pleasure and satisfaction [15]. The dopamine hypothesis posits that addictive substances hijack the brain's reward system by intensely increasing dopamine levels [[19], [20], [21], [22]]. As noted above, these effects have been closely linked to “liking” the drug, and over time lead to the compulsive seeking of the drug (“wanting”), often to the exclusion of all other rewarding stimuli including adaptive natural rewards such as food or reproduction.

Hypodopaminergic states in SUD

In contrast to the hyperdopaminergic effects of acute exposure to substances, hypodopaminergic states have been extensively documented with persistent use. Over time, the brain adapts by downregulating dopamine receptors and decreasing dopamine production [23,24], resulting in tolerance and escalating use [21]. When substance use is reduced or stopped, this results in withdrawal symptoms such as dysphoria, depression, intense cravings, fatigue, irritability, and anhedonia [25]. These symptoms drive the individual to use the substance again to avoid discomfort associated with withdrawal, and perhaps more perniciously, they can lead to a long-term post-withdrawal phase that is associated with persistent behavioral, cognitive, and emotional changes that increase the vulnerability to relapse. This hypodopaminergic state shares symptoms that overlap with mood and anxiety disorders, which are common and debilitating conditions characterized in part by profound deficits in reward-related behavioral domains, that are transdiagnostic to addiction [26]. As such, mood and anxiety disorders are highly comorbid with addiction and likely contribute to its development as well as treatment resistance. It is important to note that symptoms such as anhedonia can likely be induced by the neurobiological and neurophysiological changes that occur with chronic drug exposure. As such, it is a complex interaction between organic and drug-induced factors that drives the cycle of addiction.

Anhedonia, a reduced ability to experience pleasure, is a common and persistent symptom in addiction, thought to arise from hypodopaminergic states following chronic drug use. Anhedonia in addiction is proposed to arise through several mechanisms, including downregulation of dopamine receptors, reduced dopamine synthesis and release, and impaired signaling within the mesocorticolimbic reward pathway [[27], [28], [29]]. As far as receptor regulation, several drugs of misuse lead to a marked reduction in striatal dopamine D2/D3 receptors, which imaging studies have shown are particularly diminished during withdrawal [28,[30], [31], [32], [33], [34], [35], [36], [37], [38]]) As well, the availability of remaining D2/D3 receptors is reduced as confirmed by binding potential studies [38,39]. Symptoms of anhedonia also arise in response to excessive brain reward system activation, which contributes to the recruitment of anti-reward systems, including heightened activation of stress-related systems via release of stress-related neurotransmitters [30,40]. Another proposed mechanism is reduced dopamine transporter (DAT) availability [35]. For example, positron emission tomography (PET) imaging studies have shown a stark decrease in DAT expression in the striatum of chronic methamphetamine users [28]. Likewise, reduced DAT binding has also been implicated. A molecular imaging study utilizing single photon emission computed tomography (SPECT) with the radiotracer DATSCAN found that depressed patients with anhedonia had significantly reduced DAT binding ratios compared to healthy controls [31]. Summarizing these individual studies, a systematic review of 31 studies comparing stimulant misusers to healthy controls found consistent evidence for differences in dopamine release, D2/D3 receptor availability, and DAT availability [39]. PET imaging studies also demonstrate blunted dopamine release across patients with inclusive of stimulant and opioid use disorders [41]. Taken together, these findings suggest that dopamine-mediated anhedonia in addiction may be attributed to several converging mechanisms, providing multiple possible treatment targets. Aside from molecular level changes, there are key structural and functional alterations within the brain's reward circuitry particularly in the VTA-NA pathway that are associated with symptoms such as anhedonia and reward processing. Recent advances also highlight the important role of the medial habenula (MHb)–interpeduncular nucleus (IPN) system in the regulation of reward, anti-reward, and withdrawal neurocircuitry in addiction [42,43]. The MHb-IPN pathway is anatomically and functionally distinct from the canonical midbrain dopamine circuits but serves as a critical node linking limbic forebrain regions with midbrain and hindbrain structures [44,45]. Dysfunction within this axis has been shown to modulate aversive states, negative affect, and withdrawal symptoms across multiple substances, including nicotine, opiates, and psychostimulants [42,[46], [47], [48]]. Activity within the MHb-IPN circuit interacts with classical reward and anti-reward systems during abstinence and withdrawal, contributing to anxiety, anhedonia, increased stress responsivity, and elevated relapse risk [[49], [50], [51]]. Studies reveal direct influences of MHb-IPN signaling on dopaminergic transmission and motivational states relevant to both dependence and withdrawal, supporting its emergence as a novel therapeutic target in SUDs Furthermore, there is a literature and mechanistic rationale to suggest that processes such as neuroplasticity, neuroinflammation, gasotransmitters, and non-canonical organ systems may contribute to the chronic alterations that lead to this hypodopaminergic state, and that these systems may present novel neurotherapeutic targets to address both hyper and hypo dopaminergic activity in individuals with SUDs.

Presentation and current treatment strategies for addiction

SUDs are often present as a pattern of compulsive substance use that persists despite mounting negative consequences. Individuals frequently report diminished pleasure in everyday activities (i.e., anhedonia) alongside heightened craving and drug-seeking behaviors. This reflects a core disruption in reward processing, wherein the salience of drug-related cues is pathologically enhanced, while natural rewards lose motivational value. Concurrently, negative affective states such as anxiety, irritability, and dysphoria become more pronounced during withdrawal and between episodes of use, reinforcing a cycle of use to alleviate these aversive states. These symptoms map into well-characterized neuropathological changes within the mesocorticolimbic dopamine system. Chronic exposure to opioids, stimulants, or other substances leads to dysregulated dopamine transmission in the NA, VTA, and PFC, including reduced dopamine receptor availability and impaired phasic dopamine signaling. These alterations are associated with weakened response inhibition and loss of flexible decision-making executive deficits that reflect diminished top-down control from the PFC. Together, these circuit-level disruptions promote habit-based, inflexible behaviors and contribute to the persistence and severity of SUDs.

Current treatment options for SUDs include a range of pharmacotherapies and device-based interventions, broadly categorized into two mechanistic classes: antagonist therapies and substitute agonist therapies. Antagonist therapies function by blocking the euphoric and reinforcing effects of substances; notable examples include naltrexone for opioid and alcohol use disorders, which inhibits μ-opioid receptors and reduces reward-related signaling, and varenicline for nicotine dependence, a partial agonist-antagonist at nicotinic acetylcholine receptors that blunts nicotine-induced dopaminergic activation [52]. In contrast, substitute agonist therapies aim to stabilize neurobiological dysregulation by mitigating acute and post-acute withdrawal symptoms such as dysphoria, negative affect, cognitive impairment, and craving. Methadone and buprenorphine, both opioid receptor agonists, are first-line treatments for opioid use disorder that restore functional dopamine signaling and support executive control [53]. Although no FDA-approved pharmacotherapy exists for stimulant use disorder, off-label use of agonist-type treatments such as bupropion or modafinil have shown modest benefit. For withdrawal management, benzodiazepines remain standard for severe alcohol withdrawal, while alpha-2 agonists like clonidine or lofexidine are used to reduce adrenergic symptoms in opioid withdrawal [54]. Device-based interventions, such as transcranial-magnetic stimulation (TMS) and deep-brain stimulation (DBS), are emerging tools aimed at modulating dysfunctional reward and executive neurocircuitry to reduce craving and improve cognitive control, with preliminary efficacy demonstrated in nicotine, alcohol, and stimulant use disorders [[55], [56], [57]].

There are several caveats to these frameworks that should be noted. First, epidemiological data indicates that while many individuals experiment with psychoactive substances, only a minority transition to compulsive use that qualifies as a disorder, typically during adolescence or early adulthood. As such, risk is influenced not just by the effects of substances on reward pathways, but also by a confluence of genetic predispositions, developmental stage, and socio-environmental factors such as adverse childhood experiences, family and peer dynamics, and socioeconomic stressors. Second, some preclinical studies suggest that dopamine also functions as a signal detection mechanism for unexpected events, regardless of the stimulus's valence, including both rewarding and aversive experiences, such as exposure to electric shocks [32,58]. As such, there may be significant nuance to the outcomes associated with neurotherapeutic modulation of hyper dopaminergic states. Third, complementing neurobiological models are integrative frameworks such as behavioral economics perspectives that primarily focus on behavioral antecedents to substance use. These emphasize the imbalance between an impulsive, reward-driven system and a dysregulated executive control system, producing what is sometimes called “reinforcer pathology,” where substance use becomes overvalued relative to other rewards [59]. Despite these caveats and alternative frameworks, for the purposes of this review, we have focused on hyper- and hypo-dopaminergic states and their neurobiological framework, providing a discussion of interactions with new targets for medications development that may be of primary interest to the readership of Neurotherapeutics.

The application of neuroscientific technologies in humans as well as laboratory animals has led to some remarkable advances in SUD research as well. The diagnostic tools in neuroscience such as electrophysiology (EEG), PET imaging, and functional magnetic resonance imaging (fMRI) have helped us understand where and when reward circuitry is altered [1]. Out of all other techniques, EEG has relatively high temporal resolution and is much less expensive and much more portable and user-friendly, and can thus be used extensively by scientific groups around the world due to lower cost and greater accessibility [60]. The next section will focus on electrophysiological alterations in reward networks in SUDs.

Transitions from non-medical use to an SUD

Electrophysiological alterations in reward networks related to SUDs

• a.Alteration at the neuronal level:

As previously discussed, acute exposure to addictive substances significantly elevates extracellular dopamine levels, particularly in the mesolimbic pathway. This increase in dopamine can contribute to several functional changes including increased or decreased neuronal excitability and changes in neuronal firing. However, the resulting changes in neuronal firing markedly vary based on the drug's mechanism of action, dopamine receptor subtype expression, the affected brain regions within the reward pathway, and, importantly, the stage of addiction. In drug naïve subjects, dopamine neurons often increase their firing rates in response to opiates [61], while cocaine [62] can suppress dopaminergic firing due to D2 dopamine receptor autoinhibitory effects [62,63]. Non-dopaminergic neurons, such as cortical pyramidal neurons and striatal medium spiny neurons, also may exhibit differential responses to elevated dopamine levels, either increasing or decreasing excitability and firing depending on the prevalence of D1-or D2-receptors, respectively [64]. Dopamine is released via two distinct modes that are driven by dopamine neuron firing rates. In the first mode, dopamine neurons have consistent, low frequency firing patterns. This pacemaker-like firing pattern determines basal or tonic dopamine levels in downstream regions and occurs on the minutes to hours time scales. This tonic dopamine supports overall motivation and arousal [65]. The second mode of dopamine release results from rapid increases in dopamine neuron firing rates, typically in response to an excitatory afferent stimulus or a local disinhibition. These firing rate increases are transient and typically last on the order of seconds. This ‘bursting’ activity typically results in phasic elevations in dopamine release and typically occurs in response to detection of unexpected rewards or events [66]. Consequently, it is believed that these phasic dopamine fluctuations may encode learning signals (i.e. reward prediction errors) [17].

Chronic drug experience alters the synaptic and intrinsic properties of dopamine neurons. For example, after repeated drug use, the valence of drug associated stimuli becomes strengthened, leading to greater phasic dopamine neuron firing/dopamine release in response to drug related stimuli [67]. This pronounced shift from tonic to burst-dominant firing may provide insight into drug-induced compulsive craving tendencies. The two firing patterns interact and influence each other, with baseline tonic activity regulating the intensity of the phasic response [65]. This dynamic interplay, along with changes in firing rates and patterns at different stages of addiction, transiently modulates neuronal oscillations and other spectral behavior across multiple local territories. However, as previously discussed in this review, this persistent increase in dopamine ultimately results in neuroadaptations to limit dopamine release or responses to dopamine that may ultimately result in a hypodopaminergic state. These can include changes in dopamine receptor expression, upregulation of dopamine transporters, and/or changes in dopamine synthesis or release. In addition, chronic drug use can result in changes in glutamatergic pathways that drive dopamine neuron firing rate [68].

• b.Alterations in higher level neural activity:

The acute and chronic effects of SUDs can affect a broad spectrum of oscillatory frequencies throughout the entire reward circuitry. Studies have reported alterations in all frequency bands –delta (1–4 ​Hz), theta (4–8 ​Hz), alpha (8–13 ​Hz), beta (14–30 ​Hz), and gamma (>30 ​Hz) – indicating heightened neural activity and cognitive engagement, particularly following acute drug administration.

Gamma oscillations reflect synaptic integration [69] and synchronized neural oscillations during many higher-order cognitive processes and are significantly impacted by both acute and chronic drug use [70]. Thus, gamma bands may serve as an electrophysiological metric to evaluate their effects. Most stimulant drugs, including cocaine [71] and methamphetamine [72], can increase dopamine, norepinephrine, and glutamate release, producing enhanced gamma oscillations in multiple brain regions. This results in heightened alertness and cognitive excitability. In contrast, opioids increase GABA receptor activity, leading to reductions in gamma power leading to sedation and relaxation [73].

Long-term substance misuse leads to brain adaptations such as dopamine depletion, alterations in synaptic strengths, decrease or hypofunction in NMDA receptors, and reduced cortical excitability [74]. As mentioned earlier, these widespread network changes lead to an increase in pathological burst patterns. Following chronic misuse, with stimulant drugs, these burst patterns lead to excessive erratic gamma bursts linked to psychosis [71], whereas depressants produce persistent gamma suppression. The gradual changes for chronic substance use can also be explained with changes in theta oscillations, which are associated with long-term potentiation [75] and memory formation. Theta oscillations are reported to be primarily enhanced during the emergence of compulsive drug-seeking behavior [76] caused by reward memory during use of cocaine [77] and opioids [78]. The long-term alterations are also observed in other frequency bands. The low frequency delta rhythms that are also associated with reward circuits [79,80] and drug craving [81] are reduced during cocaine sensitization [82]. NA neurons exhibit a long-lasting increase in alpha and beta bands post-conditioning, along with a sustained rise in baseline theta and high gamma band oscillations [83].

The gradual neuroplastic anatomical and synaptic changes at different stages of SUD are also evident in the corresponding changes in the inter-frequency coupling and network coordination. These changes are assessed using a modulation index, which calculates the coupling between the phase of a low frequency oscillation and the amplitude of the higher frequency oscillations [84]. In the reward and memory circuits, enhanced phase amplitude coupling between theta and gamma frequency bands is observed in the basolateral amygdala under methamphetamine use [85] and in the medial prefrontal cortex (mPFC) prelimbic area when heroin is present [86]. The anatomical changes in the reward network are also reflected by alterations in network coordination. Cocaine use strengthens location-specific hippocampal coupling to NA, highlighting the role of these neural adaptations in reinforcing drug-seeking behaviors and conditioned place preference [87].

These findings underscore the profound impact of substance use on information transmission and coordination within the reward network, providing insights into the mechanisms of addiction and potential biomarkers for SUDs. However, more electrophysiology and electrochemical research is needed to fully understand these dynamics and their implications for treatment.

Molecular alterations in reward networks related to SUDs and neuroplasticity

Understanding the molecular underpinnings of altered reward processing is paramount in deciphering the neurobiology of SUDs and informing the development of effective treatment strategies. Substantial evidence suggests that chronic drug exposure leads to neuroplastic changes in dopamine reward pathways, which contribute to the long-lasting nature of addiction. These changes are not only functional but also structural, affecting synaptic plasticity and neural circuitry in areas such as the NA and PFC. Core processes include neuroplastic changes in reward pathways (e.g. mesocorticolimbic dopamine projections); synaptic adaptations mediated by transcriptional modulators like ΔFosB and cyclic AMP response element-binding protein (CREB); drug-induced neuroadaptations of enzymes key to dopamine-mediated reward signaling like phosphdiesterases (PDEs) and adenylyl cyclases (ACs); and altered incentive salience learning that transforms recreational use into compulsive drug seeking. As previously mentioned, the widely-accepted neurocircuitry model emphasizes dysfunction across three interacting domains: binge/intoxication, exacerbated withdrawal and negative effect, and preoccupation/anticipation (craving), which correspond to key structures, including basal ganglia, extended amygdala, and PFC, and together contribute to compulsive use despite adverse consequences. Neuroadaptation and allostasis in addiction involve molecular and cellular changes influenced by genetic and environmental factors. Dopamine D1 receptor activation in the mesocorticolimbic system also increases the activity of AC, the biosynthetic enzyme responsible for cyclic AMP (cAMP) formation. Several other receptor systems important in the action of drugs of misuse also indirectly increase the activity of AC via this mechanism, including opioid, cannabinoid, acetylcholine, and adenosine receptors [88]. Chronic drug use, particularly during binges, increases cAMP and protein kinase A in the NA. With cocaine, its effects are mediated by dopamine receptors that control cAMP production, and repeated use raises cAMP levels, enhancing compulsive drug-seeking behavior [89]. Chronic cocaine exposure can lead to tolerance through persistent cAMP system upregulation, while acute inhibition might trigger cravings and relapse [89]. Long-term substance use can lead to an expression switch from c-fos to FosB, which has a longer half-life and results in more stable changes in gene transcription which is critical for the development of addiction [90]. Likewise, the critical proteins involved in the biosynthesis (i.e., AC) and catabolism (i.e., cyclic nucleotide phosphodiesterases) of cAMP are related to the development of SUDs as well. Several lines of preclinical evidence demonstrate that inhibition of phosphodiesterase activity (particularly PDE4) in the central nervous system (CNS) can decrease addiction-related behaviors including alcohol and heroin self-administration and cocaine- or morphine-induced conditioned place preference [91]. Upstream of transcriptional regulators like ACs and PDEs mediates cAMP synthesis and degradation, influencing neuronal signaling and plasticity underlying addiction. Notably, PDE4 inhibitors can restore this balance and attenuate cocaine's rewarding and reinforcing effects, highlighting AC5 and PDE4 as promising molecular targets for therapeutic intervention in SUDs [92].

Early onset of substance misuse during adolescence increases the risk of developing an SUD through brain neuroadaptations. Additionally, changes in inflammatory cells like microglia and astrocytes affect addiction and neuroinflammation ([89]. Stress impacts mesolimbic reward processing in both humans and animals, leading to anhedonic behavior. It causes dendritic remodeling in the mPFC and affects the mPFC-mesolimbic circuit, contributing to anhedonia. CRF activity in this pathway may alter reward processing by regulating brain-derived neurotrophic factor (BDNF) release. Glucagon-like peptide receptor (GLP-1) neurons (a group of neurons in the brain that produce and release the hormone GLP-1) and other energy regulation systems can reduce reward-seeking behavior after stress [93]. Pro-inflammatory cytokines from prolonged stress may cross the blood-brain barrier (BBB), interact with mesolimbic circuitry, and increase susceptibility to anhedonia, potentially disrupting dopamine synthesis. Conflicting research results highlight the need for a unified model that integrates findings across molecular, neural, and behavioral levels, and addresses discrepancies such as the dual effects of stress on dopamine neuron firing rates [93]. Neuroplasticity plays a critical role in both the development and potentially, the treatment of SUDs. BDNF is first synthesized as a precursor protein known as pre-pro-BDNF, then cleaved into pro-BDNF and finally mature BDNF. Cleavage occurs intracellularly via enzymes like furin or extracellularly through matrix metalloproteinases or the tissue plasminogen activator/plasmin system. These forms activate different pathways: pro-BDNF binds low-affinity neurotrophin receptor p75, triggering JNK, RhoA, and NF-κB signaling linked to growth cone retraction and apoptosis, while mature BDNF binds TrkB, causing receptor dimerization, autophosphorylation, and activation of signaling cascades that enhance NMDA receptor activity. BDNF–TrkB signaling activates three main pathways: phospholipase Cγ (PLCγ)– protein kinase C (PKC), the phosphatidylinositol 3-kinase (PI3K–AKT), and mitogen-activated protein kinase (MAPK), each regulating distinct downstream targets [94].

An imbalance in proBDNF–mBDNF conversion impairs synaptic plasticity and contributes to neurodegeneration. Neuronal loss in regions like the substantia nigra, striatum, and hippocampus can reduce this conversion, elevating proBDNF, which correlates with disease severity and promotes neuroinflammation and glial activation. In patients with severe depression, proBDNF and neurotrophin receptor-p75 were upregulated in CD4⁺ and CD8⁺ T cells and normalized after treatment, and depression can present with anhedonic symptoms that are transdiagnostic to SUDs. Elevated IL-1β, reduced tight junction proteins, and lower anti-apoptotic protein expression indicate pro-BDNF's role in neuroinflammation, synapse loss, and neuronal apoptosis, contributing to cognitive decline. The proBDNF/neurotrophin receptor-p75/sortilin pathway is a promising therapeutic target for cognitive impairment in depression, which is a key symptom that also presents in SUDs [95], warranting further translational research [96,97]. Neuroplasticity is the brain's ability to grow, reorganize, and rewire neural networks in response to life experiences and challenges. This phenomenon plays a critical role in both the development and potentially the treatment of SUDs. These neuroplastic changes can also strengthen maladaptive learned behaviors that underpin the transition from voluntary to compulsive drug-taking behavior. [98,99]. The acquisition of these behaviors is preceded by unusually high levels of dopamine release, induced by drugs of misuse, within the mesocorticolimbic pathway. These elevations in dopamine will activate its cognate receptors in target areas leading to changes in biochemical signaling and neuronal physiology both acutely and chronically. Dopamine is therefore a central neurotransmitter mediating neuroplastic changes that underlie reward-related learning and is especially important in the context of substance-induced plasticity and the progression of the addiction cycle in stimulant and opioid use disorders [100].

Novel Neurotherapeutic Targets for SUDs

Reversing neuroplastic changes

A promising frontier in the restoration of dopamine function post-SUD is gene therapy aimed at reversing or mitigating chronic drug use induced aberrant neuroplasticity and enhancing dopaminergic neuron function or survival. One key target is BDNF, a protein involved in neuronal growth, synaptic plasticity, and the regulation of dopaminergic pathways. Chronic drug exposure has been shown to downregulate BDNF expression, particularly in the mesocorticolimbic system, contributing to dopamine system dysfunction and impaired reward [101].

Targeting genes that enhance neuroplasticity may help resolve the hypodopaminergic state observed in addiction by restoring dopamine signaling, given dopamine's role as a critical modulator of synaptic plasticity [98]. BDNF is a well-characterized target of therapeutic agents that enhance neuroplasticity a central mechanism of action for traditional small molecule antidepressants, ketamine and classical psychedelics in the treatment of neuropsychiatric disorders [100]. The Tyrosine Kinase B (TrkB) receptor, which mediates BDNF signaling, may also serve as a target itself, as psychoplastogens are thought to work by activating this receptor and thereby elevating BDNF mRNA levels to promote plasticity [102]. Notably, BDNF transcripts are upregulated in response to TrkB activation, forming a positive feedback loop within the BDNF-TrkB signaling pathway that may serve as a focal point for adaptive neuroplasticity [103]. Additional targets downstream of this pathway include Protein Kinase B (Akt), which plays a critical role in synaptic plasticity [104]. Importantly, evidence suggests both chronic cocaine [105] and morphine use [106] are associated with reduced Akt activity, further implicating this pathway in addiction treatment. Collectively, there is considerable evidence that targeting neuroplasticity-related genes may help to restore dopamine signaling balance in individuals with stimulant or opioid use disorders.

In addition, methods that directly target synaptic neuroplasticity (e.g. DBS or TMS) have been considered as potential therapeutic options. [107]. For example, in preclinical models, the reversal of chronic drug induced synaptic plasticity in the nucleus accumbens (with optogenetic stimulation or DBS) has been shown to reverse drug associated behaviors. [108]. DBS has also been used in the treatment of addiction to psychoactive substances in human patients with modest success [109].

Although enhancing neuroplasticity is a promising therapeutic approach, the relationship between plasticity and clinical outcomes in addiction is complex. Neuroplastic changes could be either adaptive or maladaptive in relation to reward-related behavior, and neuroplasticity-related genes may exhibit dynamic regulation. While an in-depth examination of maladaptive plasticity in addiction is beyond the scope of this paper, certain key aspects warrant brief discussion. For example, neuroplasticity contributes to the acquisition, consolidation, and recall of memories associated with drug use [110]. BDNF levels also fluctuate across different stages of the addiction cycle, particularly in cocaine use disorder [111]. Preclinical studies have suggested that behavioral sensitization to cocaine is associated with increased levels of BDNF, TrkB, and phosphorylated Akt in the mPFC and NAc, highlighting the importance of region-specific changes in plasticity-related genes when identifying therapeutic targets [112]. In opioid addiction, disrupted epigenetic and transcriptional regulation of key non-coding microRNAs which also regulate neuroplasticity contribute to drug-induced maladaptive neuroplasticity [113]. Therefore, therapeutic approaches designed to enhance neuroplasticity must account for the context-dependent nature of plasticity and selectively target adaptive mechanisms to achieve meaningful clinical benefits. Furthermore, as noted earlier in this review, there are multiple systems that contribute to both hyper and hypo functional dopamine states in SUDs. There may be a diverse and complex pattern of neuroplastic changes that occurs across these systems along the stages of the addiction cycle. This warrants deep study to provide effective treatment options.

Neuroinflammation

Addiction can be understood not only as a disorder of neuronal reward processing but also as a disorder of brain plasticity, belying both functional and structural modifications. Neuroinflammation appears to be an important mediator of these changes, influencing the brain's response to repeated drug exposure and potentially contributing to the difficulties in breaking the cycle of addiction. Initially thought to be a secondary effect of addiction, neuroinflammation is beginning to be recognized as one of the key factors in the development and persistence of addictive disorders. While mechanisms of addiction have been traditionally studied through reward pathways and dopamine dysregulation, recent research has expanded the understanding to include the role of neuroplastic changes and neuroinflammation [114] in altering brain function. Persistent neuroinflammation associated with addiction can result in widespread neural dysfunction, neurotoxicity, and neurodegeneration, intensifying drug cravings and increasing the risk of relapse [89,115]. Chronic drug use activates inflammatory pathways in the brain, which in turn influence both the development of addiction and the neuroplasticity of the brain's reward system. Overall, the three phases of the addiction cycle (binge/intoxication, withdrawal/negative effect, and preoccupation/anticipation) and progression of SUDs involve neuroplastic changes in multiple circuits, alongside neuroinflammation, causing alterations in the processes of reward, stress, and executive function [11,13,116].

General Mechanism of Neuroinflammation

Neuroinflammation is defined as pathological inflammation in the CNS, mediated by the production of cytokines, chemokines, secondary messengers (nitric oxide and prostaglandins), as well as reactive oxygen species (ROS). Neuroinflammation involves the brain's defense immune cells (microglia and astrocytes), endothelial cells, and peripheral immune cells. Microglia are specialized macrophages localized to the brain parenchyma, which produce cytokines and chemokines and clear pathological debris. Astrocytes support homeostasis of neurotransmitters and maintain integrity of the BBB [117]. Astrocytes play an important role in controlling synaptic homeostasis with an additional role in energy metabolite supply and glutamate metabolism. Additionally, astrocytes also control extracellular levels and diffusion of neuroactive substances and take part in signaling with neurons and synapses [118]. Apart from neurotransmitter activity, dopamine also acts as immunomodulatory molecules that are synthesized by different immune effector cells (in CNS as well as in peripheral tissue) [119].

Building on this, recent research has significantly advanced understanding of astrocytes as dynamic, dopamine-sensitive participants in reward circuitry and addiction. Astrocytes in key regions such as the NA and striatum express dopamine receptors including D1 and D2 subtypes, enabling functional responses to dopaminergic transmission, particularly during drug exposure and withdrawal. Dopamine signaling in astrocytes triggers intracellular calcium increases, which modulate gliotransmitter release and impact neural network activity and behavior [120,121]. Experimental studies demonstrate that psychostimulants such as amphetamine and cocaine enhance extracellular dopamine, producing marked calcium elevations in astrocytes that promote ATP and adenosine release, thereby regulating local excitatory transmission and influencing reward-seeking behavior. Disruption of astrocytic dopamine signaling, for example, via receptor knockout or chemogenetic inhibition, reduces drug-induced locomotion and cue-driven reinstatement, highlighting a role for astrocytes in relapse vulnerability [120]. Mechanistically, astrocytic dopamine receptors participate in multi-receptor complexes (e.g., A2A-D2 heteromers) that allow astrocytes to act as precision modulators of glutamate uptake, neuroinflammatory tone, and excitotoxicity risk during addictive states. These findings underscore astrocytes not just as passive supporters but as dopamine-responsive sensors and integrators within addiction-relevant circuits [122,123]. Collectively, these advances position astrocytes as central players in dopaminergic adaption and plasticity associated with SUDs, suggesting new glial targets for therapeutic intervention [121,123].

There are numerous factors that can trigger neuroinflammation: microbial infections, traumatic brain or cord injury, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, multiple sclerosis), chronic stress, aging, and exposure to environmental toxins or illicit substances. Short-term neuroinflammation serves as a protective mechanism to resolve the consequences of acute insults on the brain or spinal cord and to promote neuroimmune adaptation. However, chronic neuroinflammation may lead to neuronal damage, disruption of the BBB, and exacerbation of other neurologic pathologies due to gliosis, microglia activation, pro-inflammatory cytokine and chemokine production, increased permeability in the BBB, infiltration of peripheral immune cells, and edema [114]. Neurotoxicity can cause reversible (alternatively referred to as neuroadaptations) or irreversible adverse effects on neuron structure and function as well as dopaminergic/serotonergic terminals. Such adverse effects include activation of microglia and subsequent glial mediated synaptic plasticity that may contribute to behavioral abnormalities [[124], [125], [126]].

Substance-induced Neuroinflammation

Neuroinflammation is a dynamic process crucial to the neurobiology of addiction involving pro-inflammatory aspects of the innate immune response of the CNS [127,128]. The most common forms of neurotoxicity are the death of neurons (neuronopathy), the degeneration of axons (axonopathy), damage to glial cells (e.g., myelinopathy), and interference with the axonal membrane or neurotransmission [129]. Multiple studies document a correlation between the development of neuronal degeneration and chronic drug misuse. Shrinking areas of gray matter and degeneration of white matter have been reported in patients with SUDs. Reduction of white matter has been demonstrated in patients with alcohol and other drugs of misuse [130]. Chronic use of methamphetamine [131,132], alcohol [133] or cocaine was associated with degeneration of myelinated fibers and axons [134]. Long term use of cocaine and polydrug misuse alters cellular components including inhibition of neurite extension, reduction in dilation of endoplasmic reticulum and abnormal lysosomal proteolysis that may contribute to maladaptive neuroplastic changes. These changes further induce neurotoxicity that may develop into brain dysfunction and may predispose the brain to neurodegeneration [135].

The BBB is a crucial, dynamic interface between the CNS and the rest of the body. It is composed of endothelial cells and various proteins, such as tight junction proteins (occludin, claudin), and cells like pericytes, which work together to protect the brain. Exposure to addictive substances can disrupt this protective barrier by affecting tight junction proteins, transport systems, and intracellular signaling, leading to increased vessel permeability. Chronic use of substances like methamphetamine, cocaine, alcohol [136] and opioids impair BBB function; triggering neuroinflammatory pathways, ultimately making the brain more susceptible to external toxins, bacteria, and viruses [134,137]. This disruption facilitates the entry of immune cells and toxins into the brain, worsening neuroinflammation and oxidative stress [138], exacerbates neuroinflammation and increases the risk of neurotoxic effects [128].

The combined effects of neuroinflammation, oxidative stress, and excitotoxicity can trigger apoptotic pathways, leading to programmed cell death. This loss of neurons and synaptic connections is associated with cognitive deficits, mood disturbances, and other neurological impairments observed in chronic methamphetamine users [139]. Several pre-clinical studies demonstrated a correlation between neuroinflammation and drug exposure. In cell culture, the neurotoxicity of MDMA is concentration- and time-dependent and follows an apoptotic pattern partly due to activation of the 5-HT2A receptor [125]. Studies have highlighted the roles of neuroinflammation and oxidative stress throughout the progression of addiction. Oxidative stress not only results from increased ROS production but also from the depletion of antioxidants like glutathione. This imbalance between ROS and antioxidants leads to the oxidation of lipids, proteins, and DNA, causing significant cellular damage. The enzyme monoamine oxidase oxidizes dopamine to form ROS and reactive nitrogen species (RNS) and subsequently leads to mitochondrial dysfunction and ER stress (Fig. 2). Abnormal mitochondrial respiration is one of the main causes of neuronal death and neurodegenerative diseases. Mitochondria are the major organelle of substance-induced ROS production in neuronal cells. Methamphetamine-induced dopaminergic neurotoxicity is through inhibition of electron transport chain (ETC); specifically, inhibition of enzyme complexes I, II, III and IV. Blocking the ETC leads to the buildup and leakage of protons, causing cell dysfunction, neurotoxicity and cell death. [125,139]. Toxic aldehyde 4-hydroxynonenal (4HNE) and malondialdehyde produced as a result of lipid peroxidation followed by oxidative stress found in the post mortem brains of adults and dose of methamphetamine was directly related to level of 4HNE and malondialdehyde in the brain (striatum and cortex) in the dopamine-rich caudate nucleus, which supports the involvement of ROS in the action of methamphetamine in both dopamine rich and poor areas of human brain [140].

Fig. 2.

Diagrammatic representation of substance-induced neurotoxicity. This schematic was created with BioRender.com.; NMDA: ​N-methyl-D-aspartate; DA: Dopamine; DAT: Dopamine transporter; TH: Tyrosine hydroxylase; VMAT: Vesicular monoamine transporter; nNOS: Neuronal nitric oxide synthase; NO: Nitric oxide; ER: Endoplasmic reticulum; ROS: Reactive oxygen species; H₂O₂: Hydrogen peroxide; •OH: Hydroxyl radical; O₂•⁻: Superoxide.

CNS stimulants. Methamphetamine, amphetamine and cocaine are widely used addictive CNS stimulants that could cause a widespread neuroinflammation and toxicity in the brain, and other organ systems [141],152, 108, 153). The effects of chronic exposure to addictive substances are different from those to acute exposure. Chronic exposure to stimulants has been shown to decrease expression of tyrosine hydroxylase, DAT, and dopamine receptors, as well as decrease levels of the dopamine neurotransmitter itself and potentially induce neuronal degeneration [142] both in human postmortem studies as well as in vivo PET scans of stimulant users [139,143]. These changes seem to be concentrated in areas relevant for motivated behavior, including the PFC, NAc, and the striatum.

Previous human studies using PET scans and magnetic resonance imaging (MRI) to measure neuroinflammation involves the quantification of the translocator protein TSPO. TSPO is widely expressed across cell types within the CNS in the outer mitochondrial membrane. Based on pattern of expression of TSPO one can identify/diagnose normal and injured CNS [144]. Methamphetamine users had high TSPO levels whereas TSPO levels were variable in cocaine users. The neuroimaging study also confirmed methamphetamine-mediated neuroinflammation. It is assumed that neuroinflammation in methamphetamine users may cause altered activity of mesocorticolimbic dopamine system and cognitive deficits. There is low dopamine D2 receptor availability in methamphetamine users which negatively impacts mesolimbic functional connectivity [39]. Chronic methamphetamine user brains show a significant reduction in grey matter volume and brain function [114,125]. The human postmortem results from methamphetamine users revealed gliosis and marked increase in microglial markers [145], which is also true for cocaine users as well in the mid brain [146]. Another study on human postmortem data suggests that methamphetamine can increase oxidative stress in both dopamine-rich (caudate) and -poor (cerebral cortex) areas of the human brain, which is true for animal preclinical data as well [140].

Opioids. A neurodegenerative effect of opioids on the CNS has been reported in multiple studies. In human studies, it was found that axonal demyelination leads to lesions in white matter in those subjects who were addicted to heroin [[147], [148], [149]] and also for methadone over-dosed patients [150] as well as individuals after morphine or oxycodone overdose [151]. Axonal structures affected by chronic opioid use were located in brain areas responsible for impulse control, reward and motivation [152].

There are several factors contributing to opioid-induced toxicity, such as hypoxia, increased intracellular Ca²⁺ levels [153], induction of nitric oxide [154], and increased extracellular glutamate transmission [155] (LaLumiere and Kalivas 2008). Opioid-treated rats demonstrated increased levels of pro-apoptotic Bax and activated caspase 3 [156] and apoptosis in neuronal cells [157]. The exact molecular mechanisms driving substance induced neurodegeneration are still not well understood, posing a significant challenge to developing effective treatments. Consequently, it is crucial to enhance our comprehension of these molecular processes and to identify potential therapeutic targets for both treatment and prevention.

Alcohol. Excessive alcohol consumption has been associated with severe effects on human health and the CNS [158]. Neuronal degeneration has been documented as a reason for the alcohol-induced Wernicke–Korsakoff syndrome, including Wernike's encephalopathy during acute alcohol episode and Korsakoff's psychosis during chronic consumption, premature cortical aging, dementia, and fetal alcohol spectrum disorders [159]. Alcohol alters white matter structures due to ethanol-induced inflammation and myelin disruption, as well as generalized atrophy of the cerebral cortex [160,161]. These long-term toxic effects may underly the alcohol-induced cognitive deficits including learning and memory loss associated with hippocampal neuronal degeneration. Alcohol-induced brain atrophy can occur in the thalamus, hypothalamus, and other areas of the ventral forebrain, impacting various functions. In cerebellum, alcohol toxicity can impact motor control and coordination [162]. High levels of lipids and low levels of antioxidant signaling make brain more vulnerable to alcohol toxic effects compared to other organs. Activation of inflammatory signaling in brain due to accumulation of ROS and RNS, cytotoxic reactive lipid aldehydes, and ER and mitochondrial stress, lead to neuronal damage [158,163]. Toll-like receptor 4 (TLR4) signaling has been identified as one of the major mechanisms underlying pro-inflammatory toxic effects of alcohol via microglia activation and cytokine expression [161,[164], [165], [166]]. Interestingly, in the hippocampus, the increase in TLR4 mRNA level was observed in both male and female rats, but in prefrontal cortex, males but not females had an increase in TLR4 mRNA [167] that might explain more robust effect of alcohol on demyelination in males compared to females [167,168]. Moreover, albeit the fact that heavy alcohol exposure induced increase in IL-1 receptor mRNA level in mPFC areas of both male and female animals, it triggered proinflammatory signaling in males and neuroprotective signaling in female mice [163] depending on the isoform of the accessory protein bound to the IL-1 receptor [169]. Currently, there are three medications that are approved by FDA to treat AUD: acamprosate, naltrexone, and disulfiram. Acamprosate targets glutamatergic neurocircuits; naltrexone blocks the mu opioid receptor; and disulfiram prevents the breakdown of the toxic acetaldehyde. While these treatments have been huge advances, many patient remain refractory to these agents. A new focus on neuroplasticity, neuroinflammation, gasotransmitters, and non-canonical organ systems may provide new neurotherapeutic targets for alcoholism and its consequences.

In summary, substance-induced neuroinflammation and toxicity result from a complex interplay of neurotransmitter imbalance, immune response activation, oxidative stress, excitotoxicity, and BBB disruption (Fig. 2). Therefore, neuroinflammation induced by methamphetamine, cocaine, opioids, and alcohol share similar pathways, primarily involving BBB dysfunction, microglial activation, oxidative stress, and neurotransmitter dysregulation. These mechanisms contribute to the long-term cognitive, emotional, and structural damage seen in animal models and individuals with SUDs [95,170,171].

Substance-Induced Neuroinflammation and Addiction

The molecular mechanisms underlying neuroinflammation in addiction are complex. Toll-like receptors (TLRs), traditionally linked to the immune system, have become significant in this context. For example, TLR4 (target MD-2) can be upregulated by exposure to cocaine, methamphetamine [172] and opioids [173] like morphine, and that upregulation further activates NF-κB signaling in microglia [174] leading to the activation of inflammatory pathways in the brain. This activation can cause synaptic remodeling, disrupt neurotransmission, and heighten susceptibility to addiction [89,175]. While the mechanisms differ in specifics, all three drug classes methamphetamine, cocaine, and opioids share common features in their ability to trigger neuroinflammation by microglial activation, oxidative stress, BBB dysfunction and neurotransmitter imbalance.

Many stimulants increase the release or inhibit the reuptake of dopamine, leading to an excess of this neurotransmitter in the synaptic cleft. Methamphetamine enhances extracellular dopamine in reward-related pathways by inhibiting vesicular monoamine transporter-2 (VMAT2), which stimulates dopamine release from synaptic vesicles. This results in higher levels of cytosolic dopamine, which can then be reverse transported into the synaptic cleft by the DAT [176] (Fig. 2). The elevated dopamine further oxidizes to form toxic quinones that will cause oxidative stress, mitochondrial stress and damage to presynaptic membrane (due to ROS and hydrogen peroxide) and neuronal damage [177,178]. The increased release of glutamate further activates glutamate receptors, which causes the release of nuclear transcription factor NF-κB through AKT/P13 ​cell signaling pathway [177,178]. Activated microglia releases toxic factors and cytokines, causing neuroinflammation and neurotoxicity [175]. Substances of misuse damage neurons and trigger microglial activation, which increases inflammatory markers and ROS (Fig. 2). This exacerbates neuroinflammation and neuronal injury. Damaged neurons further activate microglia through inflammatory signaling induced by damage-associated molecular patterns, intensifying the inflammation. The active microglia and astrocytes cause release of pro-inflammatory cytokines (Fig. 2), such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α). This inflammatory response contributes to neuroinflammation, exacerbating neural damage and promoting further neuronal loss [178]. Methamphetamine, cocaine, alcohol [179], and opioids activate TLR4 signaling acting as TLR4 agonists which induces IL6 signaling that mediates neuroinflammation in both human and animal models [174]. Stimulants may induce excitotoxicity. This process is often linked to the overactivation of glutamate receptors, particularly the NMDA receptors. Methamphetamine-induced neurotoxicity not only affects dopamine of the striatum but is also associated with activated microglia and neuroimmune response through increased expression of pro-inflammatory cytokines which will promote neuroinflammation and oxidative stress (reactive oxygen and nitrogen species) [180]. Chronic cocaine use also increases dopaminergic and glutamatergic signaling similar to methamphetamine, causing inflammatory response including high levels of inflammatory cytokine IL-6. However, the mechanism of microglial activation is different in cocaine and methamphetamine addiction due to differences in dopamine kinetics. Slower clearance of methamphetamine contributes to longer behavioral effects, oxidative stress and dopaminergic signaling [181].

The illustration outlines the key mechanisms of substance-induced neurotoxicity, including dopamine oxidation, excessive glutamate release, and generation of ROS and RNS, which trigger mitochondrial dysfunction and ER stress. Microglia-driven neuroinflammation further exacerbates neuronal injury through inflammatory cytokines, ultimately leading to apoptosis or degeneration. Methamphetamine misuse reduces dopaminergic markers such as dopamine itself, tyrosine hydroxylase (TH), and DATs. Additionally, activates TLR4 signaling, that stimulates NF-κB, releasing pro-inflammatory cytokines.

Treatments of the Substance-induced Neuroinflammation

Methamphetamine, alcohol [179] and cocaine trigger a neuroinflammatory response. Therefore, treatments that target inflammation could be a beneficial complement to behavioral therapies for SUDs. For example several compounds are known to suppress the production of nitric oxide (NO), reactive oxygen species, IL-1β, IL-6, and TNF-α and enhance the production of anti-inflammatory markers, including nerve growth factor, glia-derived neurotrophic factor, and neurotrophin-4 in activated microglia [128,182]. These findings collectively suggest that psychostimulants such as methamphetamine and cocaine may alter dopamine transmission and reward processing through similar immunomodulatory mechanisms such as TLR4 signaling. TLR4 antagonists may be efficacious pharmacotherapies to treat SUDs. Studies from cellular, preclinical and clinical data reveal new mechanisms by which substances trigger central immune activation via TLR4-IL-6 signaling, suggesting TLR4 as a potential target for addiction treatments. The involvement of glial cells, TLR4, and proinflammatory mediators in dopamine system function and toxicity has broader implications for developing therapies for diseases affecting dopamine systems. Drugs that enhance glutamatergic neurotransmission might increase excitotoxicity and neuroinflammation, while neuroprotective drugs may reduce neuroinflammation by up-regulating receptors and inhibiting microglia activation. Inhibiting neuroimmune responses through IL-6 and TNF-α is linked to the activation of nicotinic acetylcholine or GABA receptors. Acknowledging the role of neuroinflammation in addiction paves the way for new treatment options. By targeting specific immune signaling pathways or leveraging the brain's natural anti-inflammatory processes, innovative therapeutic strategies may emerge. Focusing on the inflammatory aspects of addiction presents a promising opportunity to break the cycle of drug dependence and enhance treatment effectiveness. A deeper understanding of the mechanisms linking addiction and the negative impact of addiction on neuroplasticity, neuroinflammation, and oxidative stress is essential for advancing treatment options and supporting recovery efforts. Further research in this area of immunopharmacology is necessary to unravel the complexities of these processes and to find targeted interventions that can mitigate the impact of addiction on the brain and overall health.

Gasotransmitters as a novel neurotherapeutic target for addiction

Gasotransmitters are signaling molecules that play a crucial role in various physiological and pathological processes [[183], [184], [185], [186]]. The gasotransmitters NO and hydrogen sulfide (H₂S) are generated endogenously via enzymatic and non-enzymatic pathways [183,184]. These molecules are beneficial in lower concentrations and can mediate signal transduction pathways that regulate various cellular functions, including induction of vasodilation, reduced inflammatory and oxidative stress signaling [187], and modulation of nervous system changes that dysregulated in aging and brain disease [186]. Gasotransmitters play critical roles as a reliable biomarker for various disease conditions, including potentially neurological and psychiatric diseases [188,189]. Over the years, gasotransmitters have gained significant attention leading to extensive clinical trials to test their effectiveness in treating a range of diseases, including SUDs [190]. On the contrary, some studies suggest that they may produce neurotoxic effects, including with higher concentrations [184,191,192]. However, increasing research focused on better understanding of the synthesis, functions and controlled exogenous delivery of gasotransmitters, toward effective therapeutics is constantly growing. In this section, we will focus on H₂S and NO signaling.

NO was the first identified gasotransmitter and is a reactive gaseous messenger like H₂S. Rather than diffusing randomly, NO typically reaches its targets via NOS enzymes bound near target proteins, avoiding rapid inactivation by abundant cellular antioxidants like glutathione. Its vasodilatory effects were linked to cyclic guanosine monophosphate (cGMP) signaling before NO was recognized as EDRF (endothelium-derived relaxing factor). Once NO binds, this triggers a conformational change that stimulates cGMP synthesis. The activation of soluble guanylyl cyclase (at nanomolar levels), leads to increased cGMP concentration and transmitting the NO signal to downstream proteins in the signaling cascade, including cGMP-dependent protein kinase, cGMP-gated cation channels, and cGMP-regulated phosphodiesterase. NO also binds to the transmembrane receptor guanylyl cyclase; this converts GTP to cGMP, which acts as a second messenger to activate protein kinase G. Beyond this, NO also modulates mitochondrial heme proteins, such as cytochrome c oxidase, where it can compete with oxygen and influence cellular energy metabolism [193,194].

NO signaling in the brain: NO is among the earlier identified and a well-studied gasotransmitter that is a vital neurotransmitter in both the central and peripheral nervous systems [195]. There are three isoforms of the synthase (NOS) that produces NO: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Interestingly, every isoform of NOS has been implicated in a variety of neurological and psychiatric disorders. However, previous research has pointed to nNOS as being the the most closely tied to physiology and pathology in the brain [196]. NO is heavily implicated in neurophysiology, with key roles in neuromodulation and neurotransmission [197]. NO activates NMDA receptors, supports synapse formation and nerve growth, regulates astrocyte migration, and contributes to glutamate-induced neuronal death [198], all of which may be involved in key aspects of SUDs as described earlier in this review. Increased NO production is associated with neuroinflammation and accompanied by elevated nitrosative/oxidative stress [199]. Brain tissue injury, pro-inflammatory neurotoxic cytokines, such as TNF-α can initiate a response in astrocytes and microglial cells subsequent to the neural cells being harmed by NO free radicals [200]. Inhibiting iNOS with S-methylisothiourea showed opposite effects, underscoring NO's role in controlling neuron and glial cell survival after neurotrauma [185,201] BDNF can affect inflammatory-related processes and reduce pro-inflammatory progress mediated by increased ROS via inducible NO synthase (iNOS), and COX-2 signaling [202]. Overexpression of BDNF can reduce p38-MAPK mediated inflammation by suppressing TNF-α, IL-1β, IL-6, IL-18, iNOS, and COX-2 in a spinal cord injury model [202]. Additionally, patients with multiple system atrophy had nitration of α-synucleins in the glial cells of the autopsied cerebellar white matter, while patients with neurodegeneration and brain iron accumulation type 1 had nitration of Lewy body-like inclusions and neuroaxonal spheroids in the autopsied globus pallidus [203].

Numerous studies have shown that nNOS negatively regulates neurogenesis, a critical process in neuroplasticity as discussed elsewhere in this review [[204], [205], [206]]. Several toxic effects of nNOS were reported in different models of PD, including rotenone, MPTP, and 6-hydroxy dopamine (6-OHDA) [207], tissue plasminogen activator mediated excitotoxicity via kainic acid in hippocampal regions of the brain [208,209]. This highlights that modulation of nNOS may be crucial in the development of therapeutic interventions for substances use disorders. Inhibition of iNOS-mediated NO generation can be crucial for treating neuroinflammation [210]. High NO levels, produced by iNOS expression in glia, cause induce neuronal death through inhibition of neuronal mitochondrial cytochrome oxidase [211,212].

Contrarily, studies have demonstrated neuroprotective roles of NO [[213], [214], [215]]. Maintaining optimum concentration of NO can be crucial for maintaining normal homeostasis. Exogenous NO corrects nerve relaxation in the stomach, which is negated by NOS inhibitors [216]. The restriction of neuronal respiration by NO results in depolarization of neurons, glutamate release, and subsequent excitotoxicity after activation of the N-methyl ​d-aspartate ​ (NMDA) receptor [[217], [218], [219]]. NO/nNOS can mediate neuroprotection against nigrostriatal dopaminergic insults, such as exposure to toxic stimulants [220].

Innovative strategies for controlled NO delivery, via hybrid molecules, peptide conjugates, and nanoparticles and provide a targeted and sustained release of NO at therapeutic concentrations to maintain NO homeostasis. While there could be a significant impact of NO on the development of new neurotherapeutics for SUDs, a better understanding of its molecular signaling will be crucial. However, more investigation is required from pre-clinical studies extending it to clinical studies for effective therapeutic strategies targeting NO signaling for addiction and its associated consequences.

Hydrogen sulfide, reactive sulfur species and neuro-regulation: More recent among the gasotransmitters receiving increasing attention is H₂S, which has a particularly prominent role in modulating neuronal health and survival under both normal and pathological conditions. It is now widely appreciated that several sulfide metabolites are produced via the transsulfuration enzymes CBS (cystathionine beta-synthase) and CSE (cystathionine gamma-lyase) besides H₂S [183,184]. It was shown in a study that H₂S significantly attenuates the development of opioid dependence via suppression of AC/cAMP/CREB pathway in both pre-clinical and cellular models, which provides a potential molecular target for pharmacological intervention to relieve withdrawal-induced symptoms and prevent the development of opioid dependence [221]. H₂S also activates the TrKB or mTOR signaling pathways to exert antidepressant effects that are indirectly associated with synaptic protein synthesis or restoration of synaptic plasticity. By influencing mitochondrial function and NMDA receptor expression, gasotransmitters like H₂S help maintain synaptic plasticity in the nervous system [185,198].

Unlike traditional neurotransmitters, H₂S as a gas can exert its physiological effects by crossing the membrane, can target proteins on reactive cysteine residues via persulfidation/sulfhydration. These metabolites called reactive sulfur species (RSS) that include persulfides (RSSH), polysulfides (RSS(n)H), that are signaling agents themselves mediating many biological activities via persulfidation/sulfhydration regulating a range of pathophysiological responses from inflammation to neuroprotection [184,222,223].

Disrupted cysteine and H₂S homeostasis have been associated with brain disease [192,222,224], which is characterized by elevated oxidative stress and impaired cysteine metabolism that stems from dysregulation of sulfide homeostasis or the synthesizing enzymes [188,192,222,224,225]. Mitigating oxidative stress via antioxidant therapy, a cysteine precursor, N-acetyl cysteine (NAC) could reverse symptoms of neuroinflammation. H₂S induces the release of GABA and the activation of GABA_A receptors induces the release of d-serine, which enhances the activity of NMDA receptors, by which glutamatergic and GABAergic neurons maintain balance their activity [226]. Cystine deprivation induced cell death is suppressed by the transport of cystathionine, a product of CBS and a substrate of CSE, by this transporter [227]. However, H₂S/polysulfide rectifies GSH levels and oxidative stress defects by enhancing cystine/glutamate antiporter activity [228]. This reveals the therapeutic potential of H₂S/polysulfide rectifying disturbances.

H₂S can induce the activation and release of GABA_A receptors and d-serine thereby enhancing the activity of NMDA receptors [226]. H₂S can induce hippocampal long-term potentiation (LTP) via activation of NMDA receptors via reduction of cysteine disulfide bond at the hinge of the ligand binding domain localized to the extracellular side of NMDA receptors [226,229]. Neuroprotective effects of H₂S can be mediated via PI3K/Akt and NF-κB pathways to prevent the production of amyloid β protein in AD. It also suppresses the hyperphosphorylation of tau by inhibiting GSK3β [230,231]. Additionally, persulfidation inhibits glycogen synthase kinase 3β (GSK3β), which suppresses tau hyperphosphorylation [232]. Levels of H₂S, cysteine, GSH, and CSE are significantly low in AD, thereby elevating the levels of amyloid β protein. Study on AD mice model (FAD) shows a significantly lower brain polysulfides levels [233]. H₂S stops excessive phosphorylation of Tau by persulfidating GSK3β, and the application of H₂S donor GYY4137 to the AD model mice ameliorates motor and cognitive deficits [232]. Decreased CSE expression in neurons causes decreased cysteine and H₂S bioavailability that contributes to redox imbalance and altered stress responses [234].

Additionally, excess polysulfide production is involved in the pathogenesis of brain diseases. Persulfidation or sulfhydration, is a regulation mechanism of target proteins mediated by sulfide. Persulfidation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) increases its catalytic activity by seven-fold, while S-nitrosylation of the same cysteine residue abolishes its catalytic activity [235]. Understanding of the H2S/polysulfide signaling is complex but once unraveled can lead to developing as a futuristic therapeutic approach, which is currently still a challenge.

Dysregulation of gasotransmitters is another facet that contributes to neuroinflammatory diseases. Reduced H₂S levels may play a role in neuronal disorders, warranting further investigation using preclinical as well as clinical studies. Adjusting the regulation of these molecules could offer therapeutic benefits, especially for SUD-related neuroinflammation and degeneration. Treatment with H₂S donors increased synaptic plasticity and cognitive function [236]. A deeper understanding of these pathways could lead to new treatment strategies for SUDs, including associated neurodegeneration [185,237]. Over the years, extensive studies and clinical trials have been conducted to test the effectiveness of gasotransmitters in treating a range of diseases. Although gasotransmitters have shown promise in the treatment of neurological disorders in various preclinical studies, there are no gasotransmitter-releasing approved drugs for treating neurological disorders. In addition, gasotransmitter signaling interactions and regulatory feedback loops remain largely unexplored. Future strategies using clinically relevant models focused on identifying gasotransmitter regulation, and how these abnormalities could lead to neurological dysfunctions could lead to innovative and effective gasotransmitter-based neurotherapies.

Beyond the Brain: New Neurotherapeutic Targets for Addiction

Addiction has long been viewed primarily as a disorder of the brain, rooted in the dysfunction of reward circuits, neurotransmitter systems, and neural plasticity. Conventional treatments have thus focused largely on pharmacological approaches aimed at altering brain activity such as dopamine-targeting medications. However, recent research has increasingly recognized that addiction is a multifaceted disorder that involves not only the brain but also peripheral systems. This growing body of evidence suggests that addiction is influenced by a complex interplay between the CNS and various peripheral systems, including the immune system, endocrine pathways, the autonomic nervous system, and even the gut microbiome.

The next section will explore emerging neurotherapeutic targets outside of the brain, including cardiovascular (CV) system regulation as well as the liver-brain axis peripheral immune and metabolic systems. We will discuss the potential for targeting these systems to address the underlying biological mechanisms of addiction, reduce relapse rates, and improve long-term recovery outcomes. There have also been cases of heroin-induced pulmonary edema, acute cardiac injury and acute rhabdomyolysis. The intravenous form of buprenorphine has been linked to acute liver injury [238].

Non-canonical organ systems

Cardiovascular drivers of addiction

Although the CV consequences of drug use are well established, far less attention has been given to how CV processes themselves may actively shape the maintenance and progression of addiction. Traditionally, the CV system has been viewed primarily as a target of damage, but growing evidence indicates it also plays an active role in the addiction cycle profoundly interacting with brain reward circuits, particularly those governed by dopamine signaling [24,239,240].

Mechanistically, signals from the heart travel to the brainstem and then to higher-order regions involved in autonomic, emotional, and reward regulation, including the PFC, amygdala, and VTA. These regions overlap with the central autonomic network (CAN) and the mesolimbic dopamine system, which integrates bodily states and influences addictive-behaviors [239]. Cardiac interoceptive signals shape how drug-related cues are processed in the brain by modulating attention, emotional responses, decision-making, and reward anticipation through dopamine pathways. For instance, during opioid withdrawal, the extended amygdala triggers autonomic symptoms such as rapid heartbeat and sweating, while CV signals feed into the neurocircuitry involved in stress and craving. In parallel, opioids exert direct CV effects, lowering blood pressure, promoting vasodilation, and reducing cardiac workload. The baroreflex, which stabilizes blood pressure, relays signals to emotion- and cognition-related areas, further linking CV regulation with behavioral control and reward processing [12,239].

These brain–heart interactions form the basis of interoception of the brain's representation of internal bodily states, which is increasingly implicated in SUDs [239,241,242]. Shifts in heart rate and blood pressure create bodily sensations that can become tightly coupled to drug use behaviors and motivational states regulated by dopamine. Importantly, these processes are predictive: the body attempts to anticipate demands, and errors in these predictions may intensify craving or stress responses that fuel relapse. The insula, a key hub for interoceptive processing, helps translate autonomic arousal into drug urges, reward anticipation, and drug-seeking decisions by interacting with dopamine-driven motivational systems [239,243]. Converging evidence shows that people with SUDs often exhibit lower resting heart rate variability (HRV), reflecting reduced emotional flexibility and dysfunction in the CAN patterns also observed in other psychiatric disorders and linked to altered dopamine signaling [244].

Physiological markers of CV function provide further evidence of this connection. Patients with SUDs often show heightened sympathetic arousal, manifesting as elevated baseline autonomic activity [244]. Reduced HRV, increased blood pressure reactivity, and heightened stress responses suggest that CV dysregulation may sustain vulnerability to relapse potentially by interacting with dopamine-dependent reward and stress circuitry. Importantly, these markers are easily measurable, making them attractive candidates for both mechanistic studies and clinical monitoring [242,244].

Because the CV system is highly accessible, it also represents a promising treatment target. HRV biofeedback, for example, trains individuals to regulate autonomic responses to drug cues and reward anticipation. HRV biofeedback training can reduce stress and cravings [244,245], while also supporting treatment for depression, anger, and physical health. The scalability of this approach has increased with the availability of consumer wearables and mobile apps capable of monitoring HRV, enabling low-cost integration into behavioral interventions for SUDs.

Methamphetamine provides a striking case of how CV and addictive processes become intertwined. This stimulant is both highly addictive and is a profound cardiometabolic toxin [246], [247], [248], [249], [250]. Its CV consequences including vascular dysfunction, hypertension, and metabolic disruption and are well described [251]. Yet whether baseline CV health predicts treatment retention or sustained abstinence remains unresolved. CV dysfunction may also exacerbate psychiatric symptoms—such as depression, anxiety, and stress—that are themselves strongly linked to ongoing drug use [[252], [253], [254]]. Chronic stress, a hallmark of both CV disease [[255], [256], [257]] and addiction vulnerability [256,258], reinforces this overlap. Yet despite these associations, relatively few studies have directly tested how CV dysfunction may causally sustain methamphetamine addiction [252,259].

Importantly, addiction follows a relapsing–remitting trajectory rather than a linear course. Individuals cycle through phases of use, abstinence, and relapses, with relapse rates exceeding 95 ​%. Each cycle compounds the next: prior drug use and CV burden increase vulnerability for continued use, while each new episode further damages CV integrity. Even without pre-existing CV disease, repeated methamphetamine exposure drives CV pathology that amplifies craving and relapse susceptibility. Methamphetamine thus exemplifies how CV dysfunction and addiction co-evolve in a self-reinforcing loop: each episode worsens physiological and psychiatric vulnerability, which in turn perpetuates drug seeking and relapse.

Hepatic drivers of addiction

Neurotoxicity is traditionally believed to arise primarily from the brain. However, because the brain relies on the function of peripheral organs and is highly sensitive to changes in overall bodily physiology, damage to peripheral organs may play a significant role in the neurological damage caused by methamphetamine [260]. Ammonia has been shown to be a key mediator of the neurotoxicity induced by methamphetamine [261], and altered bioenergetics and oxidative stress appear to be critical factors in the pathogenesis of methamphetamine addiction [262]. It was reported that substance induced liver damage was associated with an increase in brain and peripheral ammonia and long-term decrease in brain dopamine and serotonin content, but the mechanism by which methamphetamine causes hepatocellular changes were unknown [261]. Acute methamphetamine exposure both in-vivo and in-vitro induces hepatotoxicity revealed by high levels of liver enzymes in serum and histopathology of hepatocytes. This acute methamphetamine-induced hepatotoxicity is via cell cycle arrest and activation of apoptosis [263,264]. Further characterization and understanding of the hepatotoxicity produced by methamphetamine is very important/significant because hepatotoxicity appears to contribute to its well-established neurotoxicity [265]. Despite this, there are few effective treatments for methamphetamine-induced hepatotoxicity, which may further exacerbate the degree of neurotoxicity and poor treatment outcomes.

Substance-induced acute liver failure presents sudden liver damage and encephalopathy in those without chronic liver disease. Opioid-related liver or multi-organ failure is rare. It was found that transient liver damage is often due to high doses of heroin and cocaine, with a high percentage of users showing elevated ALT, especially during relapse. Similarly, chronic use of heroin causes liver fibrosis [238].

Cocaine overdose can cause ischemic liver damage, especially in the centrilobular and midzonal areas, or lead to mild, unnoticed transaminase elevation. Liver injury mechanisms include direct toxicity, oxidative stress, and inflammation. In acute cases, transaminases, LDH, and coagulopathy rise sharply, with hyperbilirubinemia appearing after 2–3 days. Chronic use may cause asymptomatic transaminase elevation. One mechanism of liver injury involves the P450 enzyme system converting cocaine into a toxic metabolite known as norcocaine (NC). Another pathway involves cocaine-induced vasoconstriction of central liver veins, resulting in significant inflammation and tissue death [266]. N-acetyl cysteine is found to be beneficial in cocaine-induced hepatotoxicity. Opioid-related sedation and constipation can trigger hepatic encephalopathy in patients with advanced liver disease. While some studies report elevated transaminase levels with heroin and methadone use, clear evidence of a direct causal link is lacking. SUDs significantly impact liver health, contributing to conditions from fatty liver to cirrhosis and liver cancer [267].

Despite its direct hepatotoxic effects, alcohol is primarily metabolized in the liver by alcohol dehydrogenase. Alternatively, ethanol can be metabolized by CYP2E1 [268]. Both pathways result in acetaldehyde, which can increase ROS and lead to toxicity if allowed to build up. Chronic alcohol use has particularly pernicious effects on liver and can result in alcohol associated liver disease (ALD) following several years of heavy alcohol use. ALD encompasses several progressive liver damage related disorders including alcoholic fatty liver, steatosis, fibrosis, cirrhosis, and alcoholic hepatitis [269]. The underlying mechanisms of alcohol induced liver damage is complex and have been reviewed elsewhere [270]. Suffice it to say that the increases in ROS and their induced downstream signaling molecules (e.g. interleukins, interferons) disrupt normal hepatic function and increase fatty liver, ultimately resulting in ALD.

Beyond the brain for neurotherapeutic targets for addiction

Pharmacotherapies targeting the CV system have shown promise for treating SUDs. Adrenergic-targeting medications may support recovery in part by mediating blood pressure and lowering baseline sympathetic arousal [241]. Propranolol, a beta-blocker, has demonstrated promise in preclinical studies by reducing memory consolidation related to heroin use and drug seeking [271]. It has also been shown to attenuate craving and CV reactivity in cocaine-dependent humans [272]. Propranolol has shown an additional promise in blocking methamphetamine-induced hyperactivity in rats, suggesting a role for the beta-adrenergic system in mediating the psychostimulant effects of methamphetamine [273]. Doxazosin, an alpha-blocker, has also shown potential in clinical studies for treating cocaine use disorder by attenuating subjective drug effects [274] and decreasing cocaine use when rapidly titrated [275]. Addressing the CV consequences of substance misuse, including through medications to stabilize heart rhythm and manage hypertension, may indirectly improve treatment outcomes for addiction itself.

Likewise, integrated care combining hepatology and addiction treatment has shown promise in improving liver health and potentially reducing relapse rates. This suggests that addressing the physical health of patients with SUDs can support their recovery process. N-acetylcysteine, used for cocaine-induced hepatotoxicity due to its similarity to acetaminophen toxicity, helped reduce liver enzymes in this case, suggesting hepatotoxicity from combined heroin and cocaine use [238]. GLP-1 receptor agonists such as semaglutide, liraglutide, and exenatide have been shown to decrease neuroinflammation. An expanding base of preclinical studies supports their use in SUD, pointing to their promising therapeutic potential. [276]. Beyond neuroinflammation, emerging clinical evidence has also shown the therapeutic potential in opioid use and alcohol use. In one study, patients prescribed GIP/GLP-1 agonists exhibited a lower rate of opioid overdose compared to those without prescriptions. Similarly, the rate of alcohol intoxication was lower in patients with prescriptions compared to those without. These findings, which were from a large-scale electronic health record study, suggest that GLP-1 agonists are associated with a significant reduction in the incidence of overdoses and recurring use [266].

GLP-1 receptor agonists, including semaglutide, liraglutide, and exenatide, have demonstrated promising neurotherapeutic effects for addiction in both preclinical and clinical research settings. Animal studies have shown that GLP-1 analogues can attenuate drug-seeking behaviors, decrease reward sensitivity to substances of misuse, and reduce neuroinflammation, highlighting potential mechanisms for these agents in modulating addiction-relevant pathways [277,278]. Mechanistically, GLP-1 receptor activation influences neuroinflammatory cascades, modulates dopaminergic transmission in the mesolimbic reward system, and impacts cognitive and emotional processing implicated in relapse and drug reinforcement.

Beyond preclinical work, a rapidly expanding body of empirical evidence from large electronic health record (EHR) datasets reveals that GLP-1 agonist use is robustly associated with reduced incidence and recurrence of SUDs as well as markedly lower rates of overdose events in diverse clinical populations [279,280]. Retrospective cohort analyses involving over a million patients across multiple healthcare systems have demonstrated that individuals with opioid use disorder or AUD who were prescribed GLP-1 agonists experienced a lower risk of opioid overdose and fewer alcohol intoxication events, compared to matched controls not receiving these medications. These findings have been replicated in independent health systems, including Veterans Affairs, further bolstering confidence in the observed associations [[281], [282], [283]].

Semaglutide and liraglutide, in particular, have been linked with a large reduction in risk of alcohol-related hospitalizations when compared to patients treated with standard medications for AUD, alongside persistent reductions in recurrent AUD diagnoses over multi-year follow-up. Furthermore, population-based EHR analyses consistently report that GLP-1 agonist exposure yields adjusted hazard ratios ranging from 0.64 to 0.78 for both initial and repeat hospitalizations related to SUDs, including opioid, alcohol, stimulant, and cannabis use disorders, compared with individuals using other anti-obesity therapies or diabetes medications [284].

Importantly, these protective clinical associations persist even after statistical adjustments for potential confounders such as baseline diabetes and obesity, medication adherence, and socioeconomic differences, suggesting the effects are not explained solely by underlying metabolic health. Several studies utilizing target trial emulation and multi-institutional replication provide further support for the reliability and validity of these findings, and ongoing analyses are extending these relationships to stimulant and polysubstance use with similarly encouraging results. Overall, the convergence of preclinical mechanistic insight and large-scale, real-world EHR evidence positions GLP-1 receptor agonists as compelling, evidence-based adjunctive therapies warranting further clinical investigation for addiction treatment and prevention [285].

The ketogenic diet (KD) has recently shown promise in treating various neurological disorders and may offer benefits for SUD as well. SUD is often linked to increased sugar intake, compulsive food intake is believed to engage neural pathways and neuroplastic changes like those seen in SUDs, potentially leading to cross-sensitization. By lowering carbohydrate intake, KD may help counteract these effects. Additionally, since SUD is associated with mitochondrial dysfunction, oxidative stress, inflammation, glial abnormalities, and gut microbiota imbalance, KD's ability to address these issues suggests it could play a therapeutic role in addiction management [286].

A final novel approach for SUD treatment is developing vaccine therapies that would prevent misused drugs from entering the brain at all. Due to their small molecular size and low immunogenic nature of the addictive drugs, the immune system does not produce antibodies directed against them endogenously. This problem has been addressed by a group from Weill Cornell Medical College via two approaches: either active or passive immunization strategies. Active vaccination strategies combine the addictive drug to adenovirus capsid proteins to trigger an immune response. One example, the dAd5GNE vaccine, uses a cocaine analog GNE to produce strong anticocaine antibody levels, block cocaine entry into the brain, and reduce drug self-administration in both rodent and primate models. Passive immunization delivers a gene encoding an anticocaine antibody to the liver using an adeno-associated viral (AAV) vector. A single dose of this vaccine (e.g., AAVrh.10) produces long-lasting antibody levels, reducing brain cocaine levels and drug-induced hyperactivity in mice for months [287]. Other vaccine developments include work by Kim Janda and Cessation Therapeutics, who have developed an anti-opioid monoclonal antibody vaccine (CSX-1004) soon to begin clinical trials. Such efforts may eventually lead to development of anti-fentanyl vaccines which could curb rising overdose rates. Moreover, advancements in vaccine design and delivery have been essential in improving upon previous attempts at vaccine immunotherapies for SUDs, which have yet to be adopted due to shortcomings in clinical trials. For instance, TA-CD, a cocaine cholera toxin B conjugate vaccine developed by a group led by Thomas Kosten (Baylor College of Medicine), failed to produce a sufficient titer response in habitual cocaine users [288], but nonetheless was well-tolerated and showed promise in decreasing cocaine use [289,290].

Conclusion

In summary, SUDs are driven by a combination of neurobiological, psychological, and social factors. The limitations of the dopamine hypothesis, particularly with non-stimulant substances, highlight the need for a more integrative approach. Key to understanding SUDs are the roles of mood alterations and anhedonia, which perpetuate negative emotional states during withdrawal and drive the cycle of drug use through negative reinforcement.

The landscape of pharmacological interventions in SUD treatment is rapidly evolving. Innovative approaches include gasotransmitter-based neurotherapies, repurposing medications with anti-inflammatory or neuroprotective properties, investigating psychedelics (e.g., psilocybin) and ketamine for their potential to reset maladaptive neural circuits, and exploring personalized medicine approaches based on genetic and neurobiological profiles [53,[291], [292], [293]]. As our understanding of addiction neurobiology deepens, pharmacological treatments are becoming more targeted, with the goal of improving outcomes across a broader spectrum of SUDs.

To fully implement a multi-system, multi-level approach to characterizing the psychopathology of SUDs, greater interdisciplinary collaboration is essential, involving fields such as psychology, neuroscience, immunology, endocrinology, and economics. As SUDs often co-occur with anhedonia (diminished ability to feel pleasure) and hyperkatifeia (dejection or heightened negative emotional states), future research may aim to delineate the distinct neuroadaptations underlying these states. Elucidating how anhedonia and hyperkatifeia contribute to stress and neuroinflammation may expand treatment options beyond behavioral interventions and inform the development of both novel pharmaceutical and nonpharmaceutical interventions. Understanding complex psychiatric phenotypes necessitates research that spans various levels, from genetics and molecular signaling to functional circuits, cognition, behavior, and cultural factors. Recognizing and targeting the connections between the brain and peripheral systems like the CV, liver, and gasotransmitter systems is crucial for advancing more comprehensive and effective treatments for SUDs, ultimately enhancing recovery and long-term health outcomes. This approach has the potential to provide crucial answers for individuals suffering from debilitating psychiatric disorders. Future efforts should focus on developing comprehensive strategies that consider both the neuropharmacological and neuroinflammatory perspectives to develop more effective treatments for SUDs.

Author contributions

Papori Sharma – Conceptualization, Methodology, Investigation, Writing – Original Draft, Writing – Review & Editing.

M. Farris Sawaya –Writing – Original Draft, Writing – Review & Editing.

Alexandru M. Dumitrescu –Writing – review & editing, Supervision, Project Administration.

Gopi K. Kolluru – Conceptualization, Writing – Original Draft, Writing – Review & Editing.

Christopher D. Schmoutz – Conceptualization, Writing – Review & Editing.

Armando Salinas – Writing – Review & Editing.

Christopher E. Cannon –Writing – Review & Editing.

Deepak Kumbhare – Writing – Original Draft.

Nadejda Korneeva – Writing – Original Draft, Writing – Review & Editing.

M. Frances Vest – Writing – Review & Editing.

Bo J. Wood – Writing – Review & Editing.

Bracey Paul – Writing – Review & Editing.

Shawn McNeil – Writing – Review & Editing.

Alan D. Kaye –Writing – Review & Editing.

Sarah E. Murnane –Writing – Review & Editing.

Jason Jordan – Writing – Review & Editing.

Kelsea Keys – Writing – Original Draft, Writing – Review & Editing.

Ethan Brackett- Review & Editing.

Kaushik Avadhanula- Writing – Original Draft, Review & Editing.

Kevin S. Murnane – Conceptualization, Resources, Writing – Original Draft, Writing – review & editing, Supervision, Project Administration, Funding Acquisition.

Funding

These studies were supported by the Louisiana Addiction Research Center, a grant from the Louisiana State University Ag Center, grants from the National Institute on Drug Abuse (UG3DA061709; R41DA059296 and R01DA061433), a grant from the National Institutes of General Medical Sciences (P20GM121307) to GKK, a grant from the Caddo Commission for pain and opioid addiction research and abatement, the Department of Pharmacology, Toxicology & Neuroscience, and LSU Health Shreveport.

Declaration of competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.