Leandro Jose Bertoglio

Background: Individuals with anxiety and stress-related disorders frequently demonstrate impaired threat extinction. Although psilocybin, lysergic acid diethylamide (LSD), N,N -dimethyltryptamine (DMT), 3,4-methylenedioxymethamphetamine (MDMA), and ketamine can facilitate fear extinction in rodent models, comprehensive integrative analyses remain limited. Methods: Regression-based approaches were employed to estimate cross-study trends to assess whether the dose–effect relationships of these compounds are linear, bell-shaped, or follow alternative patterns. The potential moderating effects of specific biological or procedural factors on extinction learning and recall were also assessed. Effect sizes from 177 experiments in mice and rats were analyzed by compound and pooled across classical psychedelics, with doses normalized using allometric scaling and serotonin 5-HT2A or 5-HT1A receptor-adjusted relative potency. Results: The available data for LSD were insufficient for evaluating the hypothesized relationships. For the other psychedelics, linear models provided the best relative fit for extinction learning and recall. Within the tested ranges, lower doses, except for MDMA, were frequently associated with larger positive effect sizes. Pooled analyses indicated that the interval between treatment administration and extinction recall testing may influence the effects of classical psychedelics on fear extinction. In contrast, sex, age, preconditioning stress/high-intensity conditioning, and the treatment–extinction learning interval did not affect the observed dose–effect relationships. These pooled associations were sensitive to high-leverage observations. Conclusion: Psychedelics appear to enhance fear extinction across a broad range of doses. The timing of administration relative to memory extinction retrieval may contribute to variability in these effects. Evidence supporting nonlinear dose–effect relationships remains limited.

In PTSD, microglia are more engaged in fear-related circuits, where they participate in fear memory processing responses. The reconsolidation-impairing effect of Δ⁹-tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis, is typically linked to cannabinoid type-1 receptor (CB1) signaling. THC also engages peroxisome proliferator-activated receptor gamma (PPARγ), and both CB1 and PPARγ modulate neuroimmune processes, including microglial activity. This dual mechanism suggests that THC’s impact on fear memory reconsolidation may extend beyond classical cannabinoid signaling. We hypothesize that THC disrupts contextual fear memory reconsolidation via microglial recruitment in the dorsal hippocampus (DH) through a sex-specific engagement of CB1 and PPARγ. Adult male and female Wistar rats underwent contextual fear conditioning, followed by THC (0.002 mg/kg, i.p.) or vehicle administration immediately after memory retrieval. Microglial involvement was assessed using immunofluorescence and pharmacological and chemogenetic inhibition in DH. The role of CB1 and PPARγ receptors was assessed via intra-DH selective antagonist infusion. THC impaired reconsolidation in males and females. In males, fear memory retrieval increased microglial engagement in the DH CA1 subfield, which THC further enhanced. Pharmacological and chemogenetic inhibition of microglia, as well as selective CB1 and PPARγ antagonism, blocked THC’s effects in males. In females, THC-induced reconsolidation blockade was cycle-dependent, occurring at estrus and diestrus but not at proestrus, and was mediated exclusively through CB1 activation. These findings identified sex-specific neuroimmune pathways mediating THC’s reconsolidation impairment, offering a mechanistic basis for novel sex-tailored therapeutic opportunities.

The global burden of mental health disorders has intensified over the past few decades, driven by multiple factors, prompting the scientific and biomedical communities to seek novel, more effective...

O canabidiol (CBD) é um fitocanabinoide que apresenta várias propriedades psicotrópicas com potencialterapêutico que têm sido melhor compreendidas através de estudos pré-clínicos que avaliam os alvosmoleculares e regiões encefálicas envolvidas. Esta revisão narrativa compila e discute estudos queinvestigaram os efeitos do CBD sobre a extinção e reconsolidação de memórias aversivas, bem como sobrea expressão de medo e ansiedade em ratos e camundongos. Os resultados obtidos sugerem que aadministração de CBD prejudica a reconsolidação de memórias aversivas, pode acelerar a extinção, alémde reduzir comportamentos relacionados ao medo e à ansiedade. Essas ações envolvem principalmente aativação de receptores canabinoides do tipo 1 (CB1) e de serotonina do tipo 1A (5-HT1A) expressos emdiferentes regiões encefálicas. Entretanto, os efeitos do CBD em protocolos que induzem a formação dememórias com características traumáticas e respostas de medo/ansiedade inadequadas aindapermanecem poucos explorados. Outras três lacunas de conhecimento a serem exploradas incluem asdiferenças sexuais, a suscetibilidade à interferência em memórias aversivas/traumáticas remotas, e osefeitos de regimes de tratamento repetidos. Compreender as bases farmacológicas do CBD é essencialpara estabelecer sua eficácia, segurança e potencial aplicação no tratamento de transtornos de ansiedadee estresse em humanos.

Concerns over the replicability and reproducibility of published research have grown in many research fields, but empirical data to inform policies are still scarce. Biomedical research in Brazil expanded rapidly over the last three decades, with no systematic assessment of the replicability of its findings. With this in mind, we set up the Brazilian Reproducibility Initiative, a multicenter replication of published experiments from Brazilian science using three common experimental methods: the MTT assay, the reverse transcription polymerase chain reaction (RT-PCR) and the elevated plus maze (EPM). A total of 56 laboratories performed 143 replications of 56 experiments; of these, 90 replications of 45 experiments were considered valid by an independent committee. Replication rates for these experiments varied between 20 and 44% according to five predefined criteria. In median terms, ratios between group means were 58% lower in replications than in original experiments, while coefficients of variation were 82% higher. Effect size decrease was smaller for MTT experiments, original results with less variability and those considered more challenging to replicate, while t values for replications were positively correlated with researcher predictions about replicability, and negatively correlated with the rate of publications by the original article’s last author. Deviations from preregistered protocols were very common in replications, most frequently due to reasons inherent to the experimental model or related to infrastructure and logistics. Our results highlight factors that limit the replicability of results published by researchers in Brazil and suggest ways by which this scenario can be improved.

Growing evidence suggests that psychedelic-assisted therapies can alleviate depression, anxiety, posttraumatic stress, and substance use disorder, offering relatively safe profiles, enhanced efficacy, and lasting effects after a few applications. Athletes often experience high levels of stress and pressure, making them susceptible to these psychiatric conditions. However, the effects of psychedelic substances on athletic performance remain largely unknown. Before potential acceptance, evaluating their impact on physical and physiological measures beyond mental health outcomes is crucial. Here, we aim to explore this topic and highlight research directions to advance our understanding. Preclinical studies suggest that psilocybin/psilocin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), and ayahuasca possess anti-inflammatory and anti-nociceptive properties. Studies investigating the effects of classical psychedelics or 3,4-methylenedioxymethamphetamine (MDMA) on factors such as muscle strength, motor coordination, locomotion, endurance, fluid and electrolyte balance, hormonal regulation, and metabolism are still scarce. While adhering to regulatory frameworks, further research in animal models, athletes, and non-athletes is needed to address these gaps, compare psychedelics with commonly used psychoactive drugs, and explore the potential prophylactic and regenerative benefits of specific interventions.

Rationale Therapeutic approaches to mitigating traumatic memories have often faced resistance. Exploring safe reconsolidation blockers, drugs capable of reducing the emotional valence of the memory upon brief retrieval and reactivation, emerges as a promising pharmacological strategy. Towards this objective, preclinical investigations should focus on aversive memories resulting in maladaptive outcomes and consider sex-related differences to enhance their translatability. Objectives After selecting a relatively high training magnitude leading to the formation of a more intense and generalized fear memory in adult female and male rats, we investigated whether two clinically approved drugs disrupting its reconsolidation remain effective. Results We found resistant reconsolidation impairment by the α₂-adrenergic receptor agonist clonidine or cannabidiol, a major non-psychotomimetic Cannabis sativa component. However, pre-retrieval administration of D-cycloserine, a partial agonist at the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex, facilitated their impairing effects on reconsolidation. A similar reconsolidation blockade by clonidine or cannabidiol was achieved following exposure to a non-conditioned but generalized context after D-cycloserine administration. This suggests that sufficient memory destabilization can accompany generalized fear expression. Combining clonidine with cannabidiol without potentiating memory destabilization by D-cycloserine was ineffective. Conclusions These findings highlight the importance of NMDA receptor signaling in memory destabilization and underscore the efficacy of a dual-step pharmacological intervention in attenuating traumatic-like memories, even in a context different from the original learning environment. Graphical Abstract