Jorge Manzanares

Benzodiazepines (BZDs) are globally prevalent psychotropic substances valued for their anxiolytic, hypnotic, anticonvulsant, and myorelaxant properties. Pharmacologically, they act as positive allosteric modulators of the ionotropic GABA_A receptor, enhancing inhibitory synaptic transmission. However, prolonged use poses a significant public health concern, risking adverse effects such as cognitive impairment, motor incoordination, tolerance, and physical dependence. The development of tolerance is mediated by complex neurobiological changes, notably the downregulation of GABA_A receptor subunits and a compensatory sensitization of excitatory glutamatergic systems. Effective management of established dependence requires comprehensive psychological intervention coupled with pharmacological substitution (switching to a long-acting BZD) and gradual dose tapering. Preventive measures are complex, emphasizing short-term prescriptions, minimum effective dosing, and selecting non-pharmacological or alternative pharmacological agents, such as SSRIs/SNRIs, to mitigate the risk of developing tolerance and dependence. This expert review aims to compile the most relevant, representative, and recent literature summarizing the pharmacology, clinical indications, adverse effects, misuse, and abuse of BZDs that ultimately lead to BZD use disorder (BUD). It also details the involved neurobiological mechanisms and discusses critical preventive and therapeutic strategies, providing readers with the main aspects to consider for addressing this global public health problem.

The glucagon-like peptide-1 receptor (GLP-1R) has emerged as a promising therapeutic option for alcohol use disorder (AUD), yet the underlying mechanisms and neurocircuitry involved remain unclear. This study aimed to analyze GLP-1R gene expression changes in brain regions associated with alcohol’s effects, including the prefrontal cortex (PFC), nucleus accumbens (NAc), and hippocampus (HIP), in mice following 42 days of voluntary ethanol consumption (VEC; 10% v/v) and postmortem samples from 18 patients with AUD. Additionally, we examined the expression of OPRM1 (mu-opioid receptor) and BDNF (brain-derived neurotrophic factor), key targets related to alcohol intake and reward, in the NAc and HIP, respectively. GLP-1R gene expression was significantly reduced in all brain regions of ethanol-exposed mice and AUD patients. These reductions paralleled decreased OPRM1 and BDNF expression in the NAc and HIP, respectively. Pearson and Spearman correlation analyses revealed no significant associations between gene expression and age, RIN, pH, postmortem interval (PMI), body mass index (BMI), smoking status, age of onset of alcohol use, or years of drinking. In summary, chronic alcohol consumption in humans or mice was associated with decreased GLP-1R gene expression in brain regions involved in the reinforcing effects of ethanol. These findings open new avenues for further research into how this emerging receptor could serve as a potential biomarker and therapeutic target in AUD.

Aims: To describe differences in the expression of genes encoding cannabinoid receptors ( CNR1 , CNR2 ), the associated receptor GRP55 and the enzymes fatty acid amide hydrolase ( FAAH ) and monoacylglycerol lipase ( MGLL ) between individuals with alcohol use disorder (AUD) and controls in key mesocorticolimbic brain regions. Design: Case‐control, observational postmortem study comparing gene expression in brain tissue from individuals diagnosed with AUD and matched controls. The study was not pre‐registered and should therefore be considered exploratory. Setting: Brain collection from the New South Wales Tissue Resource Centre (NSWTRC) at the University of Sydney, Australia. Participants/cases: Brain samples were obtained from 18 patients with AUD (mean alcohol use = 35.5 ± 8.7 drinking years) and 18 controls (C). Groups were matched for age (AUD: 55.8 ± 9; C: 56.3 ± 9.4) and postmortem interval (AUD: 39.7 ± 16.9 h; C: 31.8 ± 13.2 h). Measurements: Relative gene expression of CNR1 , CNR2 , GPR55 , FAAH and MGLL was quantified using real‐time polymerase chain reaction (qPCR) in the prefrontal cortex (PFC) and nucleus accumbens (NAc). Findings: Compared with controls, individuals with AUD showed higher CNR1 in the PFC (+125%) and NAc (+78%) and lower CNR 2 expression in both regions (PFC: −50%; NAc: −49%). GPR55 was higher in the PFC (+19%) and lower in the NAc (−51%). FAAH expression was lower in the PFC (−15%) and higher in the NAc (+24%), whereas MGLL expression did not differ in the PFC and was lower in the NAc (−15%). Conclusions: This descriptive postmortem study identifying region‐specific differences in endocannabinoid system gene expression between individuals with alcohol use disorder (AUD) and controls supports an involvement of the endocannabinoid system in the neuropathological features associated with AUD, although causal relationships cannot be inferred.

Neuropathic pain is a clinically challenging syndrome that is largely refractory to conventional therapies. It arises from lesions or diseases affecting somatosensory pathways, which trigger extensive neuroplastic and neuroimmune remodeling. Unlike nociceptive pain, which establishes a protective response to tissue injury, neuropathic pain arises from maladaptive signaling within the nervous system. In this context, the spinal endocannabinoid system (ECS) has emerged as a pivotal modulator of nociceptive processing. However, its precise role in neuropathic pain remains debated due to its dual effects. Numerous studies report antinociceptive and neuroprotective effects; however, emerging data indicate that under specific pathological conditions, ECS activation may paradoxically facilitate pain transmission. This review examines spinal ECS context dependence, uncovering its bidirectional antinociceptive and pronociceptive effects in neuropathic pain. By integrating current evidence on cellular, molecular, and pathophysiological mechanisms, we delineate the factors that determine whether ECS modulation inhibits or promotes pain. A comprehensive understanding of these mechanisms is essential for optimizing cannabinoid-based strategies to maximize therapeutic benefits while minimizing adverse outcomes. Finally, we highlight the spinal cord’s centrality as the principal site for the initiation and maintenance of neuropathic pain and advocate for rigorous translational research to clarify the therapeutic potential of spinal ECS-targeted interventions.

Alcohol consumption during pregnancy and lactation remains a significant global issue. Preventive policies have proven insufficient, and consumption rates remain high, mainly due to a lack of awareness, the misconception that only high alcohol intake harms the fetus, inconsistent medical advice, and pre-existing alcohol use disorders. Alcohol consumption is linked to child harm during critical stages of development. Using a recently published model of fetal alcohol spectrum disorder (FASD) developed by our group, we analyzed brain changes in mothers who consumed alcohol during pregnancy and lactation and the behavioral consequences at the emotional-cognitive level and in caring for their offspring. We also considered the previous drinking history, using the paradigm of voluntary pre-gestational alcohol consumption. In addition, from gestational day 7 (GD7) until the day of sacrifice, mothers received a 3 g/kg dose of alcohol every 12 h via gavage. Our findings revealed deficiencies in maternal care, anxiety and depressive-like behavior, and aversive stimulus learning disturbances. These were associated with changes in gene targets linked to stress-axis regulation, reward circuits, and neuroplasticity. Additionally, we observed increased microgliosis and astrogliosis, indicating neuroinflammation in brain regions involved in cognition and emotional states’ regulation.