Exploring peripheral biomarkers in psychostimulant use: A systematic review on neurotrophins, stress-related hormones, oxidative stress molecules and genetic factors.

BACKGROUND: This systematic review aims to comprehensively explore the impact of psychostimulant substances on neurotrophic and inflammatory pathways, including brain-derived neurotrophic factor (BDNF), pro-BDNF, cortisol, dehydroepiandrosterone sulfate (DHEAS), thiobarbituric acid reactive substances (TBARS), interleukins, and the role of genetic factors. The study seeks to address existing gaps in the literature by providing a thorough evaluation of neurotrophic and inflammatory system alterations associated with different stages of psychostimulant dependence for a more nuanced understanding of substance use disorder (SUD) neurobiology. METHODS: A systematic review was conducted in PubMed, Scopus, and Web of Science databases following the PRISMA guidelines. The research encompasses 50 studies with a participant pool totaling 6792 individuals using psychostimulant substances. RESULTS: Key findings include diverse impacts of cocaine on BDNF levels, mainly consisting of their significant increase during withdrawal. In contrast, NGF showed an opposite behavior, reducing during withdrawal. Cortisol and DHEAS levels exhibited relevant increases after psychostimulant use, while TBARS showed conflicting results. Genetic investigations predominantly focused on the Val66Met polymorphism of the BDNF gene, revealing associations with susceptibility to stimulant addiction. CONCLUSIONS: Neurotrophins and inflammatory molecules play a significant role in the pathophysiological mechanisms following psychostimulant use. A better understanding of their complex interplay could aid clinicians in identifying biomarkers of different disease stages. Moreover, clinical interventions designed to interfere with neurotrophic and inflammatory pathways could possibly lead to craving-modulatory strategies and reduce pathological neuronal and systemic consequences of psychostimulant use.

Enhanced peripheral levels of BDNF and proBDNF: elucidating neurotrophin dynamics in cocaine use disorder.

Brain-derived neurotrophic factor (BDNF) and its precursor, proBDNF, are known to significantly contribute to brain homeostasis, neuroplasticity, and neuronal remodeling. Although these neurotrophins are thought to have opposing roles, both play a critical part in shaping long-lasting behavioral changes following substance use. In this context, our study sought to explore the implications of these neurotrophins in the pathophysiology of cocaine use disorder (CUD). We conducted a case-control study, which included 28 individuals seeking treatment for CUD and 38 matched healthy participants. We measured peripheral neurotrophin concentrations via an enzyme-linked immunosorbent assay. Additionally, all participants were screened for cocaine-associated pathways (e.g., cocaine intake, craving intensity), along with associated psychopathological data. Our findings highlighted an increased concentration of BDNF and proBDNF in CUD individuals when compared to healthy controls (BDNF: 18092.80 ± 6844.62 vs. 11334.42 ± 5061.85 pg/ml, p < 0.001; proBDNF: 87.03 ± 33.23 vs. 55.70 ± 23.26 ng/ml, p < 0.001). We further corroborated the relationship between neurotrophin levels and CUD using a linear regression model. Nevertheless, there was no significant difference in the proBDNF to BDNF ratio between the two groups. Interestingly, our study also demonstrated the influence of factors like usage of psychotropic medications, history of psychiatric hospitalizations, and psychiatric diagnoses on neurotrophin dynamics. In conclusion, our study underscores the significance of neurotrophin fluctuations in CUD. The observed increase in BDNF and proBDNF levels could play a pivotal role in driving craving and relapse risk. Thus, a nuanced understanding of these neurobiological underpinnings in CUD might contribute to the development of more targeted and effective therapeutic strategies.

Investigating the Role of Maintenance TMS Protocols for Major Depression: Systematic Review and Future Perspectives for Personalized Interventions.

Repetitive Transcranial Magnetic Stimulation (rTMS) has been approved by the FDA as an effective intervention for Treatment-Resistant Depression (TRD). However, there is little evidence about maintenance protocol necessity. The aim of this systematic review is to identify, characterize, and evaluate the current maintenance TMS protocols for MDD and TRD patients who have received acute treatment. A literature search was conducted following the PRISMA guidelines of 2015 on PubMed, Scopus, and Web of Science databases for publications up to March 2022. Fourteen articles were included. High protocol heterogeneity was observed. Most studies highlighted significant efficacy of maintenance protocols in decreasing relapse risk, suggesting that administering two or fewer stimulations per month is ineffective in sustaining an antidepressant effect or in reducing the risk of relapse in responder patients. The risk of relapse was most pronounced after five months from the acute treatment. Maintenance TMS appears to be a resourceful strategy to maintain acute antidepressant treatment effects, significantly reducing relapse risk. The ease of administering and the ability to monitor treatment adherence should be considered when evaluating the future use of maintenance TMS protocols. Further studies are needed to clarify the clinical relevance of overlapping acute TMS effects with maintenance protocols and to evaluate their long-term effectiveness.

Rethinking ketamine and esketamine action: Are they antidepressants with mood-stabilizing properties?

Ketamine and esketamine, the S-enantiomer of the racemic mixture, have recently generated considerable interest as potential therapeutic agents for Treatment-Resistant Depression (TRD), a complex disorder that includes various psychopathological dimensions and distinct clinical profiles (e.g., comorbid personality disorder, bipolar spectrum, dysthymic disorder). This perspective article provides a comprehensive overview of the action of ketamine/esketamine from a dimensional point of view, taking into account the high prevalence of bipolarity in TRD and the evidence of the efficacy of these substances on mixed features, anxiety, dysphoric mood, and, generally, bipolar traits. Additionally, the article underscores the complexity of the pharmacodynamic mechanisms of action of ketamine/esketamine, which goes beyond the non-competitive antagonism of NMDA-R. The need for further research and evidence is highlighted, mainly to evaluate the efficacy of esketamine nasal spray in bipolar depression, the presence of bipolar elements as a predictor of response, and the potential role of these substances as mood stabilizers. The article implies that, in the future, ketamine/esketamine could be used with fewer limitations, not only as antidepressants for the most severe form of depression but also as valuable tools to stabilize subjects with mixed symptoms or bipolar spectrum.

Ibogaine/Noribogaine in the Treatment of Substance Use Disorders: A Systematic Review of the Current Literature.

BACKGROUND: Ibogaine and noribogaine are psychedelic substances with dissociative properties naturally occurring in plants of the Apocynaceae family. Research has shown their efficacy in treating substance use disorders (SUD), particularly in opiate detoxification, but their efficacy and toxicity are still unclear. OBJECTIVE: This review aims to assess the anti-addictive role of ibogaine and evaluate its side effects. METHODS: A systematic literature review was conducted on the 29th of November 2021 using PubMed, Scopus and Web of Science databases through the following search strategy: ("Ibogaine" OR "Noribogaine") AND ("SUD" OR "substance use disorder" OR "craving" OR "abstinence" OR "withdrawal" OR "addiction" OR "detoxification") NOT animal NOT review NOT "vitro." The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was followed for data gathering purposes. Research methods were registered on PROSPERO (CRD42021287034). RESULTS: Thirty-one articles were selected for the systematic revision, and two were considered for analysis. The results were organised according to the type of study: case reports/case series, randomised- controlled trials (RCTs), open-label, survey and observational studies. The main outcomes were related to the anti-addictive effect of ibogaine and its cardiac toxicity. A meta-analysis of side effects was conducted using RevMan 5.4 software, showing a significant risk of developing headaches after ibogaine/noribogaine treatment. CONCLUSION: The results show some efficacy of ibogaine in the treatment of SUDs, but its cardiotoxicity and mortality are worrying. Further studies are needed to assess its therapeutic efficacy and actual safety.

Aberrant salience in cannabis-induced psychosis: a comparative study.

Background: Natural Cannabis (NC) and Synthetic Cannabinoids (SCs) use can increase the risk and exacerbate the course of psychotic disorders. These could be influenced by the Aberrant Salience (AS) construct. It refers to an excess of attribution of meaning to stimuli that are otherwise regarded as neutral, thereby transform them into adverse, dangerous, or mysterious entities. This leads the patient to engage in aberrant and consequently incorrect interpretative efforts concerning the normal perception of reality and its relationship with our analytical abilities. AS appears to play a significant role in the onset and perpetuation of psychotic disorders. The internal conflict arising from aberrant attributions of significance leads to delusional thoughts, ultimately culminating in the establishment of a self-sustaining psychosis. Aims: To examine the differences between psychoses course not associated with cannabis use and those associated with NC-use and SCs-use, in terms of psychotic and dissociative symptoms, AS, global functioning and suicidal ideation. Methods: A sample of 62 patients with First Episode Psychosis (FEP) was divided into 3 groups: non cannabis users (non-users, N = 20); NC-users or rather Delta-9-tetrahydrocannabinol (THC) users (THC-users, N = 21); SCs-users, commonly referred to as SPICE-users (SPICE-users, N = 20). Each group underwent assessments at the onset of psychotic symptoms, as well as at the 3 months and 6 months marks, utilizing a range of psychopathological scales. These included the Positive and Negative Syndrome Scale (PANSS) for investigating psychotic symptoms, the Global Assessment of Functioning (GAF) scale for assessing overall functioning, the Dissociative Experiences Scale (DES-II) for measuring dissociative symptoms, the Scale for Suicide Ideation (SSI) for evaluating suicidal ideation and the Aberrant Salience Inventory (ASI) scale for gauging AS. Results: SPICE-users showed more severe and persistent positive symptoms, while negative symptoms were mostly represented among non-users. Non-users showed better recovery than SPICE-users in global functioning. All groups showed a decrease in both ASI scores and subscale scores. SPICE-users exhibited higher global AS scores and less improvement in this aspect compared to other groups. Conclusion: This study may help understanding the role of AS in both non-substance-related and substance-induced psychosis. This knowledge may lead clinician to a better diagnosis and identify patient-tailored psychopharmacological treatment.

Impact of sleep disorders and disease duration on neurotrophins levels in cocaine use disorder.

INTRODUCTION: Brain-derived neurotrophic factor (BDNF) and its precursor proBDNF contribute to brain plasticity and neuronal remodeling. Recently, the ratio between proBDNF and BDNF (RpB) has been proposed as a possible marker in major psychiatric disorders. Convergent lines of evidence suggest neurotrophins alterations could be involved into the pathophysiology of Cocaine Use Disorder (CUD) and insomnia. The aims of the present study are to evaluate the correlations between neurotrophins levels, insomnia and clinical features among CUD patients. MATERIALS AND METHODS: Subjects with a moderate to severe CUD were recruited. ProBDNF, BDNF and consequently RpB values were analyzed using ELISA technique. Insomnia severity index (ISI) scale was used to assess the severity of insomnia. Sociodemographic characteristics and CUD habits (e.g., years of cocaine use) were also collected. RESULTS: Twenty-four subjects (mean age 39.3 ± 6.7 years) were recruited. Correlation analysis showed that lower values of RpB were associated with higher ISI score (r = -0.469; p = 0.021), longer history of cocaine use (r = -0.584, p = 0.022) and higher amount of cocaine used (r = -0.655, p = 0.004). DISCUSSION: These preliminary findings may offer a novel insight on neurobiological alterations sustaining cocaine use. Lower RpB, as observed both in high insomnia levels and in chronic cocaine use, could induce a neuroprotective state as a synaptic homeostatic response to chronic damage. These findings also highlight the important role of neurotrophins balance on neurobiological alterations induced by cocaine misuse and insomnia, suggesting that RpB could be considered as a marker of neurotrophic and metabolic state of neural tissue.

Misuse of Anticholinergic Medications: A Systematic Review.

(1) Background: Over the last decade, misuse and diversion of medications has appeared to be increasingly concerning phenomena, including a range of different molecules. As current knowledge on the abuse of centrally acting anticholinergics is limited, the aim of the present study is to review the relevant published data, focusing on the following molecules: benztropine, biperiden, scopolamine, orphenadrine, and benzhexol/trihexyphenidyl (THP). (2) Methods: A systematic literature review was carried out using Pubmed, Scopus, and Web of Science databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Research methods were registered on PROSPERO (CRD42021257293). (3) Results: A total of 48 articles, including case reports, surveys, and retrospective case series analyses, were included. Most articles focused on benzhexol/THP (n = 25), and benztropine (n = 4). The routes of administration were mostly oral, and macrodoses together concomitant illicit drugs, e.g., cocaine, have been recorded. Toxidromes included both physical (e.g., tachycardia, tachypnoea, dilatated pupils, dry skin, urinary retention, ataxia, etc.) and psychiatric symptoms (e.g., anxiety, agitation, delirium, etc.). Fatal outcomes were very rare but reported. (4) Conclusion: Results from the present study show that anticholinergic misusing issues are both widespread worldwide and popular. Considering the potential adverse effects associated, healthcare professionals should be vigilant and monitor eventual misusing issues.

From a Cycle to a Period: The Potential Role of BDNF as Plasticity and Phase-Specific Biomarker in Cocaine Use Disorder.

Cocaine Use Disorder (CUD) is one of the diseases with the greatest social and health impact, due to the high cost of rehabilitation management and the high risk of dangerous behavior and relapse. This pathology frequently leads to unsuccessful attempts to interrupt the consumption, resulting in relapses and a vicious cycle of binge/intoxication, withdrawal/negative affect, and preoccupation/ anticipation (craving). The alternation of these phases in addiction was well illustrated by Koob and colleagues in the so-called "addictive cycle", which nowadays represents a landmark in the addiction field. Recently, there has been a surge of interest in the worldwide literature for biomarkers that might explain the different stages of addiction, and one of the most studied biomarkers is, without a doubt, Brain-derived Neurotrophic Factor (BDNF). In this perspective article, we discuss the potential role of BDNF as biomarker of the CUD phases described in the "Addictive Cycle", speculating about the close relationship between BDNF fluctuations and the clinical course of CUD. We also discuss BDNF's potential role as "staging" biomarker, predicting the progression of the disease. Finding valuable biomarkers of CUD severity and disease stage could shift clinicians' focus away from behavioral symptomatic treatment and toward a novel brain-based approach, allowing for the development of more effective and targeted therapeutic strategies, thus determining major benefits for CUD patients.