Int Rev Neurobiol
· 2024 · PMID 39523061
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Decades of research have implicated the gamma-aminobutyric acid (GABA)ergic system as one of the main mediators of the behavioral effects of alcohol. Of importance, the addiction-related effects of alcohol also have been...Decades of research have implicated the gamma-aminobutyric acid (GABA)ergic system as one of the main mediators of the behavioral effects of alcohol. Of importance, the addiction-related effects of alcohol also have been shown to be mediated in part by GABAergic systems, raising the possibility that pharmacotherapies targeting GABAergic receptors may be promising candidates for the treatment of alcohol use disorder (AUD). Alcohol modulates the activity of GAB and GAA receptors, and studies show that compounds targeting some of those receptors may decrease the addiction-related behavioral effects of alcohol. Specifically, drugs that share similar pharmacological properties with alcohol, such as positive allosteric modulators (PAMs) of GAB and GAA receptors, have been proposed as substitution therapies for AUD. Available evidence also suggests that negative allosteric modulators (NAMs) of GABAergic receptors may be potential therapeutics for AUD, although this effect is selective for specific receptor subtypes. Therefore, this Chapter reviews the available evidence on the use of GABAergic compounds for the treatment of AUD. Several GAB and GAA ligands show promising results, with a particularly positive therapeutic profile demonstrated for α5GAB receptor NAMs, α4/6δGAB receptor modulators (both positive and negative, including neurosteroids), and GAA receptor PAMs. As newer and better GABAergic compounds become available, future research should focus on understanding how these ligands can modulate different clinical symptoms of AUD, with potential new areas of research encompassing alcohol withdrawal syndrome and AUD-related insomnia.
Over the decades, preclinical models have been developed and refined to investigate the rewarding effects of addictive substances and the neurobiological underpinnings of alcohol and other drug use disorders. This chapte...Over the decades, preclinical models have been developed and refined to investigate the rewarding effects of addictive substances and the neurobiological underpinnings of alcohol and other drug use disorders. This chapter delves into the methodological foundations, advantages, and limitations of leading animal models used to study alcohol use disorders (AUDs). Some models focus on the early stages of alcohol use and abuse. For instance, conditioned place preference assesses associative learning between a specific context and the effects of the drug, while locomotor sensitization measures increased locomotor activity following repeated drug exposure. In contrast, contingent models such as operant and non-operant alcohol self-administration protocols gauge voluntary intake, preference, motivation, and seeking behavior for alcohol solutions among experimental subjects. Additionally, we discuss the chronic intermittent alcohol vapor model, extensively utilized to induce a phenotype resembling dependence through non-contingent inhalation of alcohol vapor, resulting in elevated blood alcohol concentrations. Given the focus on pharmacological treatments for AUDs, we explore how different animal models can be employed to evaluate potential therapies and extrapolate findings to alcohol-related behaviors in humans. This chapter aims to provide readers with a comprehensive understanding of various animal models for AUDs, aiding in the interpretation of preclinical studies and the selection of suitable models for future research endeavors.
Alcohol use disorder (AUD) is a multifactorial disorder arising from a complex interplay of various genetic, environmental, psychological, and social factors. Environmental factors influence alcohol misuse and can lead t...Alcohol use disorder (AUD) is a multifactorial disorder arising from a complex interplay of various genetic, environmental, psychological, and social factors. Environmental factors influence alcohol misuse and can lead to AUD. While stress plays a crucial role in the onset and progression of this disorder, environmental enrichment (EE) also influences ethanol-induced behavioral and neurobiological responses. These alterations include reduced ethanol consumption, diminished operant self-administration, attenuated behavioral sensitization, and enhanced conditioned place preference. EE exerts modulatory effects on multiple neurobiological processes, such as the brain-derived neurotrophic factor/TrkB signaling pathway, the oxytocinergic system, and the hypothalamic-pituitary-adrenal axis. EE, which includes stimulating activities to counteract ethanol effects in animal studies, has parallels in human intervention that have shown potential benefits. Physical activity, cognitive behavioral therapy, and meditation, alongside techniques involving cognitive stimulation, social interaction, and recreational activities, may lead to more effective therapeutic outcomes in treatments of AUD.
Several pieces of evidence have implicated the endocannabinoid system on dopaminergic mesolimbic brain reward, as well as the potential role of cannabinoid receptors CB1 and CB2 on modulation of reinforced properties of...Several pieces of evidence have implicated the endocannabinoid system on dopaminergic mesolimbic brain reward, as well as the potential role of cannabinoid receptors CB1 and CB2 on modulation of reinforced properties of drug abuse and consequently to the treatment of substance use disorder, including alcoholism. Moreover, growing evidence has been proposed that cannabis or cannabinoid compounds may be helpful to treat alcohol use disorder (AUD). Cannabis is prevalent among individuals who also consume alcohol. While some authors reported that cannabis may be a promising candidate as a substitute medication for AUD, some studies have demonstrated that concomitant use of alcohol and cannabis may increase the risk of adverse outcomes. Considering that advances in the legalization and decriminalization movements regarding cannabis have led to increased availability worldwide, the current chapter aims to provide evidence on the benefits and risks of combining alcohol and cannabis, as well as the potential therapeutic use of cannabinoid compounds in treating AUD.
For decades, psychedelics have been investigated for the treatment of psychiatric disorders. Specifically, evidence suggests that psychedelics may have therapeutic potential for the treatment of alcohol use disorder. Sev...For decades, psychedelics have been investigated for the treatment of psychiatric disorders. Specifically, evidence suggests that psychedelics may have therapeutic potential for the treatment of alcohol use disorder. Several studies with classic psychedelics, including LSD and psilocybin, show promising results, with psychedelics decreasing alcohol drinking and promoting abstinence in individuals with alcohol use disorder. In the last two decades, ayahuasca has emerged as another psychedelic with therapeutic potential for alcohol use disorder. Although its use by indigenous people from South America has been reported for thousands of years, ayahuasca, an Amazonian brewed beverage used in rituals, has gained attention in recent decades due to its reported effects in the central nervous system. Ayahuasca is a hallucinogenic beverage produced from the decoction of Banisteriopsis caapi and Psychotria viridis, plants that contain β-carbolines and N,N-dimethyltryptamine (DMT), respectively. The majority of clinical studies investigating ayahuasca for the treatment of alcohol use disorder are retrospective, and all show a significant decrease in alcohol use among ayahuasca users. Corroborating the clinical evidence, pre-clinical studies also have demonstrated that ayahuasca can block several of the abuse-related effects of alcohol. This chapter reviews the accumulating evidence from clinical and pre-clinical studies suggesting that ayahuasca may be a promising new pharmacotherapy for the treatment of alcohol use disorders, and discusses the potential mechanisms involved in these and other effects of ayahuasca.
Published works highlight the role of neuropeptides in both the development and treatment of AUD. Closely related hypothalamic neuropeptides, oxytocin (OT) and vasopressin (VP), initially recognized for their physiologic...Published works highlight the role of neuropeptides in both the development and treatment of AUD. Closely related hypothalamic neuropeptides, oxytocin (OT) and vasopressin (VP), initially recognized for their physiological hormone effects, are increasingly acknowledged for their behavioral influences. Studies consistently demonstrate that OT and VP impact alcohol consumption and related behaviors, implicating them in the neurobiology of addiction. Moreover, stress is a pivotal risk factor for alcohol use and relapse, with OT and VP playing an integral role in the body's stress response system. While previous work has explored the interaction of OT and VP with other substances of abuse, this review focuses on their roles in alcohol-associated behaviors specifically to better understand the role of OT and VP in AUD. Here we synthesize recent preclinical and clinical literature examining changes in OT and VP protein and receptor expression in response to alcohol, as well as research investigating the effects of modulating these systems on alcohol-related behaviors. This review aims to deepen the understanding of OT and VP in the context of AUD with the goal of facilitating future research and enhancing treatment outcomes.
Alcohol dependence (AD) significantly impacts public health, affecting 3.4% of people aged 18-64 and contributing to around 12% of overall mortality. Individuals with AD have a markedly reduced life expectancy, dying up...Alcohol dependence (AD) significantly impacts public health, affecting 3.4% of people aged 18-64 and contributing to around 12% of overall mortality. Individuals with AD have a markedly reduced life expectancy, dying up to 28 years earlier than the general population. Current treatments for AD show limited efficacy, with many patients not responding to these interventions, highlighting the need for new therapeutic options with novel mechanisms of action. Sodium oxybate (SMO), the sodium salt of GHB, is one such candidate, pharmacologically similar to alcohol; it acts on several neurotransmitters including GABA, potentially mitigating withdrawal symptoms and craving for alcohol. SMO has been clinically used in Italy and Austria since the 1990s, approved for treating alcohol withdrawal syndrome (AWS) and for maintaining abstinence in AD patients. Several randomized clinical trials (RCTs) and meta-analyses showed evidence of SMO to be effective and safe in these indications. For AWS, SMO was more effective than placebo and as effective as benzodiazepines in reducing withdrawal symptoms. For maintaining abstinence, SMO significantly improved continuous abstinence duration and abstinence rate compared to placebo. Comprehensive clinical data indicate that SMO is well-tolerated, with main adverse effects being mild, such as dizziness and vertigo, and serious adverse events being rare. The effectiveness and safety of SMO, coupled with its approval in two EU countries affirm its potential as a treatment option for AD, particularly in severe cases. Further RCTs, especially with stratification by severity of dependence, are suggested to refine our understanding of its efficacy across different patient subgroups.
Alcohol Use Disorder (AUD) is a highly prevalent medical condition characterized by impaired control over alcohol consumption, despite negative consequences on the individual's daily life and health. There is increasing...Alcohol Use Disorder (AUD) is a highly prevalent medical condition characterized by impaired control over alcohol consumption, despite negative consequences on the individual's daily life and health. There is increasing evidence suggesting that chronic alcohol intake, like other addictive drugs, induces neuroinflammation and oxidative stress, disrupting glutamate homeostasis in the main brain areas related to drug addiction. This review explores the potential application of mesenchymal stem cells (MSCs)-based therapy for the treatment of AUD. MSCs secrete a broad array of anti-inflammatory and antioxidant molecules, thus, the administration of MSCs, or their secretome, could reduce neuroinflammation and oxidative stress in the brain. These effects correlate with an increase in the expression of the main glutamate transporter, GLT1, which, through the normalization of the extracellular glutamate levels, could mediate the inhibitory effect of MSCs' secretome on chronic alcohol consumption, thus highlighting GLT1 as a central target to reduce chronic alcohol consumption.
In mammals, ethanol is metabolized to acetaldehyde mainly by the liver alcohol dehydrogenase (ADH), and acetaldehyde is subsequently oxidized to acetate by mitochondrial aldehyde dehydrogenase (ALDH2). The presence of an...In mammals, ethanol is metabolized to acetaldehyde mainly by the liver alcohol dehydrogenase (ADH), and acetaldehyde is subsequently oxidized to acetate by mitochondrial aldehyde dehydrogenase (ALDH2). The presence of an inactive variant of ALDH2 or the use of inhibitors of this enzyme leads to an accumulation of acetaldehyde after ethanol consumption, generating an aversive reaction that inhibits subsequent alcohol intake. However, experimental evidence shows that acetaldehyde has potent rewarding effects at the central level, suggesting that acetaldehyde would be responsible for the addictive effect of alcohol. Alda-1 is an organic molecule that acts as a pharmacological activator of ALDH2. Studies in animal models of alcohol use disorders (AUD; i.e. alcoholism) have shown that Alda-1 can inhibit the acquisition, the chronic intake, and the relapse of alcohol consumption. These effects are reversible without any effects on water consumption or other natural reinforcer such as saccharin. It has also been reported that Alda-1 can act as a protective agent from the toxic effects on various tissues and organs mediated by ethanol-derived acetaldehyde, including liver damage, cancer, and central nervous system (CNS) alterations. Using in silico tools such as molecular docking the identification of important molecular interactions between Alda-1 and ALDH2 has been demonstrated, identifying new molecules with higher pharmacological features. Thus, there is now preclinical evidence supporting the use of activators of ALDH2 as a pharmacological strategy for the treatment of AUD.
Alcohol, the most widely consumed substance globally, can lead to severe adverse effects for both users and those around them. Chronic ethanol consumption may lead to alcohol use disorder (AUD), a chronic relapsing condi...Alcohol, the most widely consumed substance globally, can lead to severe adverse effects for both users and those around them. Chronic ethanol consumption may lead to alcohol use disorder (AUD), a chronic relapsing condition characterized by compulsive drinking despite negative consequences. AUD is marked by a high relapse rate among individuals attempting abstinence. Currently, only a few medications, such as disulfiram, naltrexone, nalmefene, and acamprosate, are approved to treat AUD. Moreover, genetic factors and comorbid conditions can significantly influence both the development of AUD and the efficacy of its treatment. This chapter explores the genetic underpinnings of AUD and reviews the main pharmacological treatments available for managing this disorder.
The absence of blood flow in cerebral ischemic conditions triggers a multitude of intricate pathophysiological mechanisms, including excitotoxicity, oxidative stress, neuroinflammation, disruption of the blood-brain barr...The absence of blood flow in cerebral ischemic conditions triggers a multitude of intricate pathophysiological mechanisms, including excitotoxicity, oxidative stress, neuroinflammation, disruption of the blood-brain barrier and white matter disarrangement. Despite numerous experimental studies conducted in preclinical settings, existing treatments for cerebral ischemia (CI), such as mechanical and pharmacological therapies, remain constrained and often entail significant side effects. Therefore, there is an imperative to explore innovative strategies for addressing CI outcomes. Cannabidiol (CBD), the most abundant non-psychotomimetic compound derived from Cannabis sativa, is a pleiotropic substance that interacts with diverse molecular targets and has the potential to influence various pathophysiological processes, thereby contributing to enhanced outcomes in CI. This chapter provides a comprehensive overview of the primary effects of CBD in in vitro and diverse animal models of CI and delves into some of its plausible mechanisms of neuroprotection.
Del-Bel E, Barros-Pereira N, Moraes RP
… +10 more, Mattos BA, Alves-Fernandes TA, Abreu LB, Nascimento GC, Escobar-Espinal D, Pedrazzi JFC, Jacob G, Milan BA, Bálico GG, Antonieto LR
Parkinson's disease is a chronic neurodegenerative disorder with no known cure characterized by motor symptoms such as tremors, rigidity, bradykinesia (slowness of movement), and postural instability. Non-motor symptoms...Parkinson's disease is a chronic neurodegenerative disorder with no known cure characterized by motor symptoms such as tremors, rigidity, bradykinesia (slowness of movement), and postural instability. Non-motor symptoms like cognitive impairment, mood disturbances, and sleep disorders often accompany the disease. Pharmacological treatments for these symptoms are limited and frequently induce significant adverse reactions, underscoring the necessity for appropriate treatment options. Cannabidiol is a phytocannabinoid devoid of the euphoric and cognitive effects of tetrahydrocannabinol. The study of cannabidiol's pharmacological effects has increased exponentially in recent years. Preclinical and preliminary clinical studies suggest that cannabidiol holds therapeutic potential for alleviating symptoms of Parkinson's disease, offering neuroprotective, anti-inflammatory, and antioxidant properties. However, knowledge of cannabidiol neuromolecular mechanisms is limited, and its pharmacology, which appears complex, has not yet been fully elucidated. By examining the evidence, this review aims to provide and synthesize scientifically proven evidence for the potential use of cannabidiol as a novel treatment option for Parkinson's disease. We focus on studies that administrated cannabidiol alone. The results of preclinical trials using cannabidiol in models of Parkinson's disease are encouraging. Nevertheless, drawing firm conclusions on the therapeutic efficacy of cannabidiol for patients is challenging. Cannabidiol doses, formulations, outcome measures, and methodologies vary considerably across studies. Though, cannabidiol holds promise as a novel therapeutic option for managing both motor and non-motor symptoms of Parkinson's disease, offering hope for improved quality of life for affected individuals.
Cannabidiol (CBD) has been investigated for several therapeutic applications, having reached the clinics for the treatment of certain types of epilepsies. This chapter reviews the potential of CBD for the treatment of su...Cannabidiol (CBD) has been investigated for several therapeutic applications, having reached the clinics for the treatment of certain types of epilepsies. This chapter reviews the potential of CBD for the treatment of substance use disorders (SUD). We will present a brief introduction on SUD and current treatments. In the second part, preclinical and clinical studies with CBD are discussed, focusing on its potential therapeutic application for SUD. Next, we will consider the potential molecular mechanism of action of CBD in SUD. Finally, we will summarize the main findings and perspectives in this field. There is a lack of studies on CBD and SUD in comparison to the extensive literature investigating the use of this phytocannabinoid for other neurological and psychiatric disorders, such as epilepsy. However, the few studies available do suggest a promising role of CBD in the pharmacotherapy of SUD, particularly related to cocaine and other psychostimulant drugs.
Cannabidiol (CBD) is a major phytocannabinoid in the Cannabis sativa plant. In contrast to Δ-tetrahydrocannabinol (THC), CBD does not produce the typical psychotomimetic effects of the plant. In addition, CBD has attract...Cannabidiol (CBD) is a major phytocannabinoid in the Cannabis sativa plant. In contrast to Δ-tetrahydrocannabinol (THC), CBD does not produce the typical psychotomimetic effects of the plant. In addition, CBD has attracted increased interest due to its potential therapeutic effects in various psychiatric disorders, including schizophrenia. Several studies have proposed that CBD has pharmacological properties similar to atypical antipsychotics. Despite accumulating evidence supporting the antipsychotic potential of CBD, the mechanisms of action in which this phytocannabinoid produces antipsychotic effects are still not fully elucidated. Here, we focused on the antipsychotic properties of CBD indicated by a series of preclinical and clinical studies and the evidence currently available about its possible mechanisms. Findings from preclinical studies suggest that CBD effects may depend on the animal model (pharmacological, neurodevelopmental, or genetic models for schizophrenia), dose, treatment schedule (acute vs. repeated) and route of administration (intraperitoneal vs local injection into specific brain regions). Clinical studies suggest a potential role for CBD in the treatment of psychotic disorders. However, future studies with more robust sample sizes are needed to confirm these positive findings. Overall, although more studies are needed, current evidence indicates that CBD may be a promising therapeutic option for the treatment of schizophrenia.
Chronic pain presents significant personal, psychological, and socioeconomic hurdles, impacting over 30% of adults worldwide and substantially contributing to disability. Unfortunately, current pharmacotherapy often prov...Chronic pain presents significant personal, psychological, and socioeconomic hurdles, impacting over 30% of adults worldwide and substantially contributing to disability. Unfortunately, current pharmacotherapy often proves inadequate, leaving fewer than 70% of patients with relief. This shortfall has sparked a drive to seek alternative treatments offering superior safety and efficacy profiles. Cannabinoid-based pharmaceuticals, notably cannabidiol (CBD), hold promise in pain management, driven by their natural origins, versatility, and reduced risk of addiction. As we navigate the opioid crisis, ongoing research plunges into CBD's therapeutic potential, buoyed by animal studies revealing its pain-relieving prowess through various system tweaks. However, the efficacy of cannabis in chronic pain management remains a contentious and stigmatized issue. The International Association for the Study of Pain (IASP) presently refrains from endorsing cannabinoid use for pain relief. Nevertheless, evidence indicates their potential in alleviating cancer-related, neuropathic, arthritis, and musculoskeletal pain, necessitating further investigation. Crucially, our comprehension of CBD's role in pain management is a journey still unfolding, with animal studies illustrating its analgesic effects through interactions with the endocannabinoid, inflammatory, and nociceptive systems. As the plot thickens, it's clear: the saga of chronic pain and CBD's potential offers a compelling narrative ripe for further exploration and understanding.
Major depressive disorder (MDD) is a widespread and debilitating condition affecting a significant portion of the global population. Traditional treatment for MDD has primarily involved drugs that increase brain monoamin...Major depressive disorder (MDD) is a widespread and debilitating condition affecting a significant portion of the global population. Traditional treatment for MDD has primarily involved drugs that increase brain monoamines by inhibiting their uptake or metabolism, which is the basis for the monoaminergic hypothesis of depression. However, these treatments are only partially effective, with many patients experiencing delayed responses, residual symptoms, or complete non-response, rendering the current view of the hypothesis as reductionist. Cannabidiol (CBD) has shown promising results in preclinical models and human studies. Its mechanism is not well-understood, but may involve monoamine and endocannabinoid signaling, control of neuroinflammation and enhanced neuroplasticity. This chapter will explore CBD's effects in preclinical and clinical studies, its molecular mechanisms, and its potential as a treatment for MDD.
Cannabidiol (CBD) modulates aversive memory and its extinction, with potential implications for treating anxiety- and stress-related disorders. Here, we summarize and discuss scientific evidence showing that CBD administ...Cannabidiol (CBD) modulates aversive memory and its extinction, with potential implications for treating anxiety- and stress-related disorders. Here, we summarize and discuss scientific evidence showing that CBD administered after the acquisition (consolidation) and retrieval (reconsolidation) of fear memory attenuates it persistently in rats and mice. CBD also reduces fear expression and enhances fear extinction. These effects involve the activation of cannabinoid type-1 (CB1) receptors in the dorsal hippocampus, bed nucleus of stria terminalis, and medial prefrontal cortex, comprising the anterior cingulate, prelimbic, and infralimbic subregions. Serotonin type-1A (5-HT1A) receptors also mediate some CBD effects on fear memory. CBD effects on fear memory acquisition vary, depending on the aversiveness of the conditioning procedure. While rodent findings are relatively consistent and encouraging, human studies investigating CBD's efficacy in modulating aversive/traumatic memories are still limited. More studies are needed to investigate CBD's effects on maladaptive, traumatic memories, particularly in post-traumatic stress disorder patients.
Anxiety disorders are highly prevalent psychiatric disorders, characterized by a chronic course and often accompanied by comorbid symptoms that impair functionality and decrease quality of life. Despite advances in basic...Anxiety disorders are highly prevalent psychiatric disorders, characterized by a chronic course and often accompanied by comorbid symptoms that impair functionality and decrease quality of life. Despite advances in basic and clinical research in our understanding of these disorders, currently available pharmacological options are associated with limited clinical benefits and side effects that frequently lead to treatment discontinuation. Importantly, a significant number of patients do not achieve remission and live with lifelong residual symptoms that limit daily functioning. Since the 1970s, basic and clinical research on cannabidiol (CBD), a non-psychotomimetic compound found in the Cannabis sativa plant, has indicated relevant anxiolytic effects, garnering attention for its therapeutic potential as an option in anxiety disorder treatment. This chapter aims to review the history of these studies on the anxiolytic effects of CBD within the current understanding of anxiety disorders. It highlights the most compelling current evidence supporting its anxiolytic effects and explores future perspectives for its clinical use in anxiety disorders.
Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and interaction, as well as restricted and repetitive patterns of behavior. Despite extensive...Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and interaction, as well as restricted and repetitive patterns of behavior. Despite extensive research, effective pharmacological interventions for ASD remain limited. Cannabidiol (CBD), a non-psychotomimetic compound of the Cannabis sativa plant, has potential therapeutic effects on several neurological and psychiatric disorders. CBD interacts with the endocannabinoid system, a complex cell-signaling system that plays a crucial role in regulating various physiological processes, maintaining homeostasis, participating in social and behavioral processing, and neuronal development and maturation with great relevance to ASD. Furthermore, preliminary findings from clinical trials indicate that CBD may have a modulatory effect on specific ASD symptoms and comorbidities in humans. Interestingly, emerging evidence suggests that CBD may influence the gut microbiota, with implications for the bidirectional communication between the gut and the central nervous system. CBD is a safe drug with low induction of side effects. As it has a multi-target pharmacological profile, it becomes a candidate compound for treating the central symptoms and comorbidities of ASD.
Cannabidiol (CBD) has been investigated as a pharmacological approach for treating a myriad of neurological and psychiatric disorders, the most successful of them being its use as an antiseizure drug (ASD). Indeed, CBD h...Cannabidiol (CBD) has been investigated as a pharmacological approach for treating a myriad of neurological and psychiatric disorders, the most successful of them being its use as an antiseizure drug (ASD). Indeed, CBD has reached the clinics for the treatment of certain epileptic syndromes. This chapter aims to overview the pharmacology of CBD and its potential mechanisms of action as an ASD. First, we give an outline of the concepts, mechanisms and pharmacology pertaining to the field of study of epilepsy and epileptic seizures. In the second section, we will summarize the effects of CBD as an ASD. Next, we will discuss its potential mechanisms of action to alleviate epileptic seizures, which seem to entail multiple neurotransmitters, receptors and intracellular pathways. Finally, we will conclude and present some limitations and perspectives for future studies.