Evidence for enduring cardiac and multiorgan toxicity after repeated exposure to the synthetic cannabinoid JWH-018 in male rats.

The use of synthetic cannabinoid receptor agonists (SCRAs) represents a public health concern. Besides abuse liability and cognitive impairments, SCRAs consumption is associated with serious medical consequences in humans, including cardiotoxicity. The precise mechanisms underlying cardiac or other toxicities induced by SCRAs are not well understood. Here, we used in silico, in vivo, and ex vivo approaches to investigate the toxicological consequences induced by exposure to the SCRA JWH-018. Along with in silico predictive toxicological screening of 36 SCRAs by MC4PC software, adult male Sprague-Dawley rats were repeatedly exposed to JWH-018 (0.25 mg/kg ip) for 14 consecutive days, with body temperature and cardiovascular parameters measured over the course of treatment. At 1 and 7 days after JWH-018 discontinuation, multiorgan tissue pathologies and heart mitochondria bioenergetics were assessed. The in silico findings predicted risk of cardiac adverse effects specifically for JWH-018 and other aminoalkylindole SCRAs (i.e., electrocardiogram abnormality and QT prolongation). The results from rats revealed that repeated, but not single, JWH-018 exposure induced hypothermia and cardiovascular stimulation (e.g., increased blood pressure and heart rate) which persisted throughout treatment. Post-mortem findings demonstrated cardiac lesions (i.e., vacuolization, waving, edema) 1 day after JWH-018 discontinuation, which may contribute to lung, kidney, and liver tissue degeneration observed 7 days later. Importantly, repeated JWH-018 exposure induced mitochondrial dysfunction in cardiomyocytes, i.e., defective lipid OXPHOS, which may represent one mechanism of JWH-018-induced toxicity. Our results demonstrate that repeated administration of even a relatively low dose of JWH-018 is sufficient to affect cardiovascular function and induce enduring toxicological consequences, pointing to risks associated with SCRA consumption.

Immunonutrition, Metabolism, and Programmed Cell Death in Lung Cancer: Translating Bench to Bedside.

Lung cancer presents significant therapeutic challenges, motivating the exploration of novel treatment strategies. Programmed cell death (PCD) mechanisms, encompassing apoptosis, autophagy, and programmed necrosis, are pivotal in lung cancer pathogenesis and the treatment response. Dysregulation of these pathways contributes to tumor progression and therapy resistance. Immunonutrition, employing specific nutrients to modulate immune function, and metabolic reprogramming, a hallmark of cancer cells, offer promising avenues for intervention. Nutritional interventions, such as omega-3 fatty acids, exert modulatory effects on PCD pathways in cancer cells, while targeting metabolic pathways implicated in apoptosis regulation represents a compelling therapeutic approach. Clinical evidence supports the role of immunonutritional interventions, including omega-3 fatty acids, in augmenting PCD and enhancing treatment outcomes in patients with lung cancer. Furthermore, synthetic analogs of natural compounds, such as resveratrol, demonstrate promising anticancer properties by modulating apoptotic signaling pathways. This review underscores the convergence of immunonutrition, metabolism, and PCD pathways in lung cancer biology, emphasizing the potential for therapeutic exploration in this complex disease. Further elucidation of the specific molecular mechanisms governing these interactions is imperative for translating these findings into clinical practice and improving lung cancer management.

Lower levels of plasma syndecan-4 are associated with loss of body weight and fat-free mass after bariatric surgery.

OBJECTIVE: Bariatric surgery induces a significant loss of both fat mass (FM) and fat-free mass (FFM). The proteoglycan receptor syndecan-4 (SDC4) plays a crucial role in adipose tissue and skeletal muscle functions. Thus, this study was performed (i) to assess plasma SDC4 levels after both Sleeve Gastrectomy (SG) and Roux-en-Y Gastric Bypass (RYGB) surgeries, and (ii) to explore potential associations with changes in body composition variables. RESULTS: Twenty-six patients (17 females) with severe obesity underwent SG (n = 13) or RYGB (n = 13) and were followed up to 1 year (1Y). Body weight, FM, FFM, and SCD4 were measured at baseline (BL), and at week 11 (W11) and 1Y after surgery. Independently of procedure, there was a significant body weight loss at W11, with an average FM and FFM reduction of 13.7 ± 0.6 kg and 5.3 ± 0.5 kg, respectively. Participants continued to lose weight afterwards, with a total weigth loss of 38.2 ± 1.5 kg at 1Y. No associations were found at BL between SDC4 levels and any anthropometric variable; however, SDC4 levels were lower than BL at both W11 and 1Y, independently of type of surgery. Additionally, changes in SDC4 between BL and 1Y were positively correlated with weight and FFM loss during the same period. TRIAL REGISTRATION: ClinicalTrials.gov NCT04051190 on 09/08/2019.

Targeting the Gut: A Systematic Review of Specific Drug Nanocarriers.

The intestine is essential for the modulation of nutrient absorption and the removal of waste. Gut pathologies, such as cancer, inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), and celiac disease, which extensively impact gut functions, are thus critical for human health. Targeted drug delivery is essential to tackle these diseases, improve therapy efficacy, and minimize side effects. Recent strategies have taken advantage of both active and passive nanocarriers, which are designed to protect the drug until it reaches the correct delivery site and to modulate drug release via the use of different physical-chemical strategies. In this systematic review, we present a literature overview of the different nanocarriers used for drug delivery in a set of chronic intestinal pathologies, highlighting the rationale behind the controlled release of intestinal therapies. The overall aim is to provide the reader with useful information on the current approaches for gut targeting in novel therapeutic strategies.

Sensitivity and Specificity of Qualitative Visual Field Tests for Screening Visual Hemifield Deficits in Right-Brain-Damaged Stroke Patients.

A timely detection of visual hemifield deficits (VHFDs; hemianopias or quadrantanopias) is critical for both the diagnosis and treatment of stroke patients. The present study determined the sensitivity and specificity of four qualitative visual field tests, including face description, confrontation tests (finger wiggle), and kinetic boundary perimetry, to screen large and dense VHFDs in right-brain-damaged (RBD) stroke patients. Previously, the accuracy of qualitative visual field tests was examined in unselected samples of patients with heterogeneous aetiology, in which stroke patients represented a very small fraction. Building upon existing tests, we introduced some procedural ameliorations (incl. a novel procedure for kinetic boundary perimetry) and provided a scoresheet to facilitate the grading. The qualitative visual field tests' outcome of 67 consecutive RBD stroke patients was compared with the standard automated perimetry (SAP; i.e., reference standard) outcome to calculate sensitivity and specificity, as well as positive and negative predictive values (PPV and NPV), both for each individual test and their combinations. The face description test scored the lowest sensitivity and NPV, while the kinetic boundary perimetry scored the highest. No test returned false positives. Combining the monocular static finger wiggle test (by quadrants) and the kinetic boundary perimetry returned the highest sensitivity and specificity, in line with previous studies, but with higher accuracy (100% sensitivity and specificity). These findings indicate that the combination of these two tests is a valid approach with RBD stroke patients, prompting referral for a formal visual field examination, and representing a quick, easy-to-perform, and inexpensive tool for improving their care and prognosis.

Immune and glial cell alterations in the rat brain after repeated exposure to the synthetic cannabinoid JWH-018.

The use of synthetic cannabinoid receptor agonists (SCRAs) poses major psychiatric risks. We previously showed that repeated exposure to the prototypical SCRA JWH-018 induces alterations in dopamine (DA) transmission, abnormalities in the emotional state, and glial cell activation in the mesocorticolimbic DA circuits of rats. Despite growing evidence suggesting the relationship between substance use disorders (SUD) and neuroinflammation, little is known about the impact of SCRAs on the neuroimmune system. Here, we investigated whether repeated JWH-018 exposure altered neuroimmune signaling, which could be linked with previously reported central effects. Adult male Sprague-Dawley (SD) rats were exposed to JWH-018 (0.25 mg/kg, i.p.) for fourteen consecutive days, and the expression of cytokines, chemokines, and growth factors was measured seven days after treatment discontinuation in the striatum, cortex, and hippocampus. Moreover, microglial (ionized calcium-binding adaptor molecule 1, IBA-1) and astrocyte (glial fibrillary acidic protein, GFAP) activation markers were evaluated in the caudate-putamen (CPu). Repeated JWH-018 exposure induces a perturbation of neuroimmune signaling specifically in the striatum, as shown by increased levels of cytokines [interleukins (IL) -2, -4, -12p70, -13, interferon (IFN) γ], chemokines [macrophage inflammatory protein (MIP) -1α, -3α], and growth factors [macrophage colony-stimulating factor (M-CSF), vascular endothelial growth factor (VEGF)], together with increased IBA-1 and GFAP expression in the CPu. JWH-018 exposure induces persistant brain region-specific immune alterations up to seven days after drug discontinuation, which may contribute to the behavioral and neurochemical dysregulations in striatal areas that play a role in the reward-related processes that are frequently impaired in SUD.

Characterization of the Neurochemical and Behavioral Effects of the Phenethylamine 2-Cl-4,5-MDMA in Adolescent and Adult Male Rats.

BACKGROUND: The proliferation of novel psychoactive substances (NPS) in the drug market raises concerns about uncertainty on their pharmacological profile and the health hazard linked to their use. Within the category of synthetic stimulant NPS, the phenethylamine 2-Cl-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA) has been linked to severe intoxication requiring hospitalization. Thereby, the characterization of its pharmacological profile is urgently warranted. METHODS: By in vivo brain microdialysis in adolescent and adult male rats we investigated the effects of 2-Cl-4,5-MDMA on dopamine (DA) and serotonin (5-HT) neurotransmission in two brain areas critical for the motivational and rewarding properties of drugs, the nucleus accumbens (NAc) shell and the medial prefrontal cortex (mPFC). Moreover, we evaluated the locomotor and stereotyped activity induced by 2-Cl-4,5-MDMA and the emission of 50-kHz ultrasonic vocalizations (USVs) to characterize its affective properties. RESULTS: 2-Cl-4,5-MDMA increased dialysate DA and 5-HT in a dose-, brain area-, and age-dependent manner. Notably, 2-Cl-4,5-MDMA more markedly increased dialysate DA in the NAc shell and mPFC of adult than adolescent rats, while the opposite was observed on dialysate 5-HT in the NAc shell, with adolescent rats being more responsive. Furthermore, 2-Cl-4,5-MDMA stimulated locomotion and stereotyped activity in both adolescent and adult rats, although to a greater extent in adolescents. Finally, 2-Cl-4,5-MDMA did not stimulate the emission of 50-kHz USVs. CONCLUSIONS: This is the first pharmacological characterization of 2-Cl-4,5-MDMA demonstrating that its neurochemical and behavioral effects may differ between adolescence and adulthood. These preclinical data could help understanding the central effects of 2-Cl-4,5-MDMA by increasing awareness on possible health damage in users.

Long-COVID-19 autonomic dysfunction: An integrated view in the framework of inflammaging.

The recently identified syndrome known as Long COVID (LC) is characterized by a constellation of debilitating conditions that impair both physical and cognitive functions, thus reducing the quality of life and increasing the risk of developing the most common age-related diseases. These conditions are linked to the presence of symptoms of autonomic dysfunction, in association with low cortisol levels, suggestive of reduced hypothalamic-pituitary-adrenal (HPA) axis activity, and with increased pro-inflammatory condition. Alterations of dopamine and serotonin neurotransmitter levels were also recently observed in LC. Interestingly, at least some of the proposed mechanisms of LC development overlap with mechanisms of Autonomic Nervous System (ANS) imbalance, previously detailed in the framework of the aging process. ANS imbalance is characterized by a proinflammatory sympathetic overdrive, and a concomitant decreased anti-inflammatory vagal parasympathetic activity, associated with reduced anti-inflammatory effects of the HPA axis and cholinergic anti-inflammatory pathway (CAP). These neuro-immune-endocrine system imbalanced activities fuel the vicious circle of chronic inflammation, i.e. inflammaging. Here, we refine our original hypothesis that ANS dysfunction fuels inflammaging and propose that biomarkers of ANS imbalance could also be considered biomarkers of inflammaging, recognized as the main risk factor for developing age-related diseases and the sequelae of viral infections, i.e. LC.

FunctionaL Assessment Scale of Hemianopia (FLASH): A New Multidisciplinary Tool to Assess Hemianopia in Patients with Severe Acquired Brain Injury.

BACKGROUND: Severe acquired brain injury (sABI) encompasses a range of neurological impairments. Visual dysfunction, particularly homonymous visual field defects (HVFDs) and homonymous hemianopia (HH), commonly afflicts sABI survivors, affecting their cognitive and motor rehabilitation. This study presents the FunctionaL Assessment Scale of Hemianopia (FLASH), developed to analyze the most common postural behaviors exhibited by sABI patients with hemianopia during activities of daily living. A comparison to traditional static automated perimetry for diagnosing visual field deficits (VFDs) to determine the sensitivity and specificity of the FLASH was used. Additionally, this study also aimed to assess its reliability. METHODS: Fifty-six patients (25 F, 31 M, mean age 60.59 ± 14.53) with strokes in the sub-acute phase (<6 months from the onset) were assessed with both FLASH and a Humphrey Field Analyzer. RESULTS: After removing two items found to be less reliable than others, FLASH showed high sensitivity (81%) and specificity (77%) when compared to static automated perimetry. Inter-rater reliability was also high, with an intra-class correlation coefficient of 0.954, as well as the internal consistency computed by Cronbach's alpha, equal to 0.874. CONCLUSION: FLASH could offer a valuable and cost-effective screening tool for VFD in sABI patients during neurorehabilitation, with potential implications for healthcare cost reduction.

Temperature regulation of auxin-related gene expression and its implications for plant growth.

Twenty-five years ago, a seminal paper demonstrated that warm temperatures increase auxin levels to promote hypocotyl growth in Arabidopsis thaliana. Here we highlight recent advances in auxin-mediated thermomorphogenesis and identify unanswered questions. In the warmth, PHYTOCHROME INTERACTING FACTOR 4 (PIF4) and PIF7 bind the YUCCA8 gene promoter and, in concert with histone modifications, enhance its expression to increase auxin synthesis in the cotyledons. Once transported to the hypocotyl, auxin promotes cell elongation. The meta-analysis of expression of auxin-related genes in seedlings exposed to temperatures ranging from cold to hot shows complex patterns of response. Changes in auxin only partially account for these responses. The expression of many SMALL AUXIN UP RNA (SAUR) genes reaches a maximum in the warmth, decreasing towards both temperature extremes in correlation with the rate of hypocotyl growth. Warm temperatures enhance primary root growth, the response requires auxin, and the hormone levels increase in the root tip but the impacts on cell division and cell expansion are not clear. A deeper understanding of auxin-mediated temperature control of plant architecture is necessary to face the challenge of global warming.

Syndecan-4 as a genetic determinant of the metabolic syndrome.

BACKGROUND: Syndecan-4 (SDC4) is a member of the heparan sulfate proteoglycan family of cell-surface receptors. We and others previously reported that variation in the SDC4 gene was associated with several components of the metabolic syndrome, including intra-abdominal fat, fasting glucose and triglyceride levels, and hypertension, in human cohorts. Additionally, we demonstrated that high fat diet (HFD)-induced obese female mice with a Sdc4 genetic deletion had higher visceral adiposity and a worse metabolic profile than control mice. Here, we aimed to first investigate whether the mouse Sdc4 null mutation impacts metabolic phenotypes in a sex- and diet-dependent manner. We then tested whether SDC4 polymorphisms are related to the metabolic syndrome (MetS) in humans. METHODS: For the mouse experiment, Sdc4-deficient (Sdc4-/-) and wild-type (WT) mice were treated with 14-weeks of low-fat diet (LFD). Body composition, energy balance, and selected metabolic phenotypes were assessed. For the human genetic study, we used logistic regression models to test 11 SDC4 SNPs for association with the MetS and its components in a cohort of 274 (113 with MetS) elderly subjects from southern Italy. RESULTS: Following the dietary intervention in mice, we observed that the effects of the Sdc4 null mutation on several phenotypes were different from those previously reported in the mice kept on an HFD. Nonetheless, LFD-fed female Sdc4-/- mice, but not males, displayed higher levels of triglycerides and lower insulin sensitivity at fasting than WT mice, as seen earlier in the HFD conditions. In the parallel human study, we found that carriers of SDC4 rs2228384 allele C and rs2072785 allele T had reduced risk of MetS. The opposite was true for carriers of the SDC4 rs1981429 allele G. Additionally, the SNPs were found related to fasting triglyceride levels and triglyceride glucose (TyG) index, a reliable indicator of insulin resistance, with sex-stratified analysis detecting the association of rs1981429 with these phenotypes only in females. CONCLUSIONS: Altogether, our results suggest that SDC4 is an evolutionary conserved genetic determinant of MetS and that its genetic variation is associated with fasting triglyceride levels in a female-specific manner.

In silico characterization of ligand-receptor interactions for U-47700, N,N-didesmethyl-U-47700, U-50488 at mu- and kappa-opioid receptors.

The increasing misuse of novel synthetic opioids (NSOs) represents a serious public health concern. In this regard, U-47700 (trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide) and related "U-compounds" emerged on recreational drug markets as synthetic substitutes for illicit heroin and constituents of counterfeit pain medications. While the pharmacology of U-compounds has been investigated using in vitro and in vivo methods, there is still a lack of understanding about the details of ligand-receptor interactions at the molecular level. To this end, we have developed a molecular modeling protocol based on docking and molecular dynamics simulations to assess the nature of ligand-receptor interactions for U-47700, N,N-didesmethyl U-47700, and U-50488 at the mu-opioid receptor (MOR) and kappa-opioid receptor (KOR). The evaluation of ligand-receptor and ligand-receptor-membrane interaction energies enabled the identification of subtle conformational shifts in the receptors induced by ligand binding. Interestingly, the removal of two key methyl groups from U-47700, to form N,N-didesmethyl U-47700, caused a loss of hydrogen bond contact with tryptophan (Trp)229, which may underlie the lower interaction energy and reduced MOR affinity for the compound. Taken together, our results are consistent with the reported biological findings for U-compounds and provide a molecular basis for the MOR selectivity of U-47700 and KOR selectivity of U-50488.

Sensitivity and Specificity of the Brentano Illusion Test in the Detection of Visual Hemi-Field Deficits in Patients with Unilateral Spatial Neglect.

Stroke survivors with right-brain damage (RBD) often present with attentional deficits such as left unilateral spatial neglect. Some patients also present with contralesional visual hemi-field deficits. A late detection of visual hemi-field deficits (VHFD) contributes to hampering neurorehabilitation and functional outcome of patients with neglect. The Brentano Illusion Test (BRIT) may be used for an early detection of VHFD during the neuropsychological assessment. In the present study, we determined the sensitivity and specificity of the BRIT for screening VHFD in patients with neglect. Sixty-four consecutive RBD patients were examined. Forty-five presented with neglect. Of these, 23 presented with VHFD (hemianopia or quadrantanopia) as detected by the Humphrey automated static visual field testing (reference standard). Consecutive patients also included 19 participants without neglect, who did not have any VHFD. The sensitivity and specificity of the BRIT for neglect patients were 78.3% (95% CI: 61.4-95.1) and 90.9 (95% CI: 78.9-100.0), respectively. Positive predictive value (PPV) was 89.6% (95% CI: 76.4-100.0); negative predictive value (NPV) 80.7% (95% CI: 65.2-96.2). No false positives in the group without neglect were identified. We conclude that the BRIT is an effective tool for clinical neuropsychologists to screen for possible VHFD in neglect patients during the neuropsychological assessment, allowing the refinement of the clinical picture in the neuropsychological report. An early detection of VHFD also allows referring the patient to standard diagnostics for a formal visual field examination, right from the first neuropsychological assessment.

Ceratonia siliqua L. Pod Extract: From Phytochemical Characterization to Liposomal Formulation and Evaluation of Behaviour in Cells.

The formulation of plant extracts in phospholipid vesicles is a promising strategy to exploit their biological properties while solving problems related to poor solubility in water, high instability, and low skin permeation and retention time. In this study, Ceratonia siliqua ripe pods were used for the preparation of a hydro-ethanolic extract, which showed antioxidant properties owing to the presence of biologically active compounds identified by liquid chromatography-mass spectrometry (e.g., hydroxybenzoic acid and flavonoid derivatives). To improve the applicability of the extract in therapy, a topical formulation based on liposomes was explored. The vesicles were characterized by small size (around 100 nm), negative charge (-13 mV), and high entrapment efficiency (>90%). Furthermore, they displayed both spherical and elongated shapes, with oligolamellar structure. Their biocompatibility was demonstrated in cells, including erythrocytes and representative skin cell lines. The antioxidant activity of the extract was proved by the scavenging of free radicals, the reduction of ferric ions, and the protection of skin cells from oxidative damage.

Dopaminergic signalling and behavioural alterations by Comt-Dtnbp1 genetic interaction and their clinical relevance.

BACKGROUND AND PURPOSE: Cognitive and motor functions are modulated by dopaminergic signalling, which is shaped by several genetic factors. The biological effects of single genetic variants might differ depending on epistatic interactions that can be functionally multi-directional and non-linear. EXPERIMENTAL APPROACH: We performed behavioural and neurochemical assessments in genetically modified mice and behavioural assessments and genetic screening in human patients with 22q11.2 deletion syndrome (22q11.2DS). KEY RESULTS: Here, we confirm a genetic interaction between the Comt (catechol-O-methyltransferase, human orthologue: COMT) and Dtnbp1 (dystrobrevin binding protein 1, alias dysbindin, human orthologue: DTNBP1) genes that modulate cortical and striatal dopaminergic signalling in a manner not predictable by the effects of each single gene. In mice, Comt-by-Dtnbp1 concomitant reduction leads to a hypoactive mesocortical and a hyperactive mesostriatal dopamine pathway, associated with specific cognitive abnormalities. Like mice, in subjects with the 22q11.2DS (characterized by COMT hemideletion and dopamine alterations), COMT-by-DTNBP1 concomitant reduction was associated with analogous cognitive disturbances. We then developed an easy and inexpensive colourimetric kit for the genetic screening of common COMT and DTNBP1 functional genetic variants for clinical application. CONCLUSIONS AND IMPLICATIONS: These findings illustrate an epistatic interaction of two dopamine-related genes and their functional effects, supporting the need to address genetic interaction mechanisms at the base of complex behavioural traits.

Phenolic Fingerprint, Bioactivity and Nanoformulation of Prunus spinosa L. Fruit Extract for Skin Delivery.

The nanoformulation of plant extracts in phospholipid vesicles is a promising strategy to exploit the biological properties of natural bioactive substances and overcome drawbacks such as poor aqueous solubility, chemical instability, low skin permeation and retention time, which strongly limit their topical application. In this study, Prunus spinosa berries were used for the preparation of a hydro-ethanolic extract, which showed antioxidant and antibacterial properties owing to the presence of phenolic compounds. Two types of phospholipid vesicles were developed to improve the applicability as topical formulations. Liposomes and Penetration Enhancer-containing Vesicles were characterized for mean diameter, polydispersity, surface charge, shape, lamellarity, and entrapment efficiency. Additionally, their safety was assayed with different cell models, including erythrocytes and representative skin cell lines.

RNA virus-mediated changes in organismal oxygen consumption rate in young and old Drosophila melanogaster males.

Aging is accompanied by increased susceptibility to infections including with viral pathogens resulting in higher morbidity and mortality among the elderly. Significant changes in host metabolism can take place following virus infection. Efficient immune responses are energetically costly, and viruses divert host molecular resources to promote their own replication. Virus-induced metabolic reprogramming could impact infection outcomes, however, how this is affected by aging and impacts organismal survival remains poorly understood. RNA virus infection of Drosophila melanogaster with Flock House virus (FHV) is an effective model to study antiviral responses with age, where older flies die faster than younger flies due to impaired disease tolerance. Using this aged host-virus model, we conducted longitudinal, single-fly respirometry studies to determine if metabolism impacts infection outcomes. Analysis using linear mixed models on Oxygen Consumption Rate (OCR) following the first 72-hours post-infection showed that FHV modulates respiration, but age has no significant effect on OCR. However, the longitudinal assessment revealed that OCR in young flies progressively and significantly decreases, while OCR in aged flies remains constant throughout the three days of the experiment. Furthermore, we found that the OCR signature at 24-hours varied in response to both experimental treatment and survival status. FHV-injected flies that died prior to 48- or 72-hours measurements had a lower OCR compared to survivors at 48-hours. Our findings suggest the host's metabolic profile could influence the outcome of viral infections.

THC and CBD: Villain versus Hero? Insights into Adolescent Exposure.

Cannabis is the most used drug of abuse worldwide. It is well established that the most abundant phytocannabinoids in this plant are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These two compounds have remarkably similar chemical structures yet vastly different effects in the brain. By binding to the same receptors, THC is psychoactive, while CBD has anxiolytic and antipsychotic properties. Lately, a variety of hemp-based products, including CBD and THC, have become widely available in the food and health industry, and medical and recreational use of cannabis has been legalized in many states/countries. As a result, people, including youths, are consuming CBD because it is considered "safe". An extensive literature exists evaluating the harmful effects of THC in both adults and adolescents, but little is known about the long-term effects of CBD exposure, especially in adolescence. The aim of this review is to collect preclinical and clinical evidence about the effects of cannabidiol.