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BACKGROUND: Cannabidiol (CBD) is one of the main cannabinoids present in Cannabis sativa female flowers. Previous investigation has already provided insights into the CBD molecular mechanism; however, there is no transcriptome data for CBD effects on hippocampal subfields. Here, we investigate transcriptomic changes in dorsal and ventral CA1 of adult mice hippocampus after 100 mg/kg of CBD administration (i.p.) for one or seven consecutive days. METHODS: C57BL/6JUnib mice were treated with either vehicle or CBD for 1 or 7 days. The collected brains were sectioned, and the hippocampal sub-regions were laser microdissected for RNA-Seq analysis. RESULTS: The transcriptome analysis following 7 days of CBD administration indicates the differential expression of 1559 genes in dCA1 and 2924 genes in vCA1. Furthermore, GO/KEGG analysis identified 88 significantly enriched biological process and 26 significantly enriched pathways for dCBD7, whereas vCBD7 revealed 128 enriched BPs and 24 pathways. CONCLUSION: This dataset indicates a widespread decrease of electron transport chain and ribosome biogenesis transcripts in CA1, while chromatin modifications and synapse organization transcripts were increased following CBD administration for 7 days.

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BACKGROUND AND PURPOSE: Ayahuasca (AYA) is a botanical psychedelic with promising results in observational and small clinical trials for depression, trauma and drug use disorders. Its psychoactive effects primarily stem from N,N-dimethyltryptamine (DMT). However, there is a lack of research on how and where AYA acts in the brain. This study addressed these questions by examining the extinction of aversive memories in AYA-treated rats. EXPERIMENTAL APPROACH: We focused on the 5-HT1A and 5-HT2A receptors, as DMT exhibits a high affinity for both of them, along with the infralimbic cortex in which activity and plasticity play crucial roles in regulating the mnemonic process under analysis. KEY RESULTS: A single oral treatment with AYA containing 0.3 mg·kg-1 of DMT increased the within-session extinction of contextual freezing behaviour without affecting its recall. This protocol, when repeated twice on consecutive days, enhanced extinction recall. These effects were consistent for both 1- and 21-day-old memories in males and females. AYA effects on fear extinction were independent of changes in anxiety and general exploratory activity: AYA- and vehicle-treated animals showed no differences when tested in the elevated plus-maze. The 5-HT2A receptor antagonist MDL-11,939 and the 5-HT1A receptor antagonist WAY-100635 infused into the infralimbic cortex respectively blocked within- and between-session fear extinction effects resulting from repeated oral administration of AYA. CONCLUSION AND IMPLICATIONS: Our findings highlight complementary mechanisms by which AYA facilitates the behavioural suppression of aversive memories in the rat infralimbic cortex. These results suggest potential beneficial effects of AYA or DMT in stress-related disorders.

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OBJECTIVE: The treatment of bipolar depression remains challenging due to the limited effective and safe therapeutic options available; thus, developing newer treatments that are effective and well tolerable is an urgent unmet need. The objective of the present trial was to test 150 to 300 mg/day of cannabidiol as an adjunctive treatment for bipolar depression. METHOD: A randomized, double-blind, placebo-controlled pilot study to assess the efficacy of adjunctive cannabidiol in bipolar depression was used. Efficacy parameters were changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 8. Secondary outcomes included response and remission rates, changes in anxiety and psychotic symptoms, and changes in functioning. Patients continued double-blind treatment until week 12 to monitor for adverse effects, laboratory analysis, and manic symptoms. Study registry: NCT03310593. RESULTS: A total of 35 participants were included. MADRS scores significantly decreased from baseline to the endpoint (placebo, -14.56; cannabidiol, -15.38), but there was no significant difference between the groups. Similarly, there were no other significant effects on the secondary outcomes. However, an exploratory analysis showed a significant effect of cannabidiol 300 mg/day in reducing MADRS scores from week 2 to week 8 (placebo, -6.64; cannabidiol, -13.72). There were no significant differences in the development of manic symptoms or any other adverse effects. CONCLUSION: Cannabidiol did not show significantly higher adverse effects than placebo. Despite the negative finding on the primary outcome, an exploratory analysis suggested that cannabidiol should be further studied in bipolar depression in higher doses of at least 300 mg/day and under research designs that could better control for high placebo response.

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Ibogaine is a psychoactive alkaloid derived from the west-African shrub Tabernanthe iboga. Western cultures are increasing the interest for the substance due to its claimed anti addictive properties, although the evidence supporting this effect is still preliminary. The use of ibogaine often occurs with no medical supervision in uncontrolled settings, and its use has been associated with several reports of severe adverse events. This review aims to evaluate the clinical studies of ibogaine, with a focus on administration settings, to elucidate specific criteria that may promote safer contexts for ibogaine use. A systematic review of the literature was conducted based on PRISMA guidelines. PubMed, Scielo, ClinicalTrials.gov and Core.ac.uk electronic databases were searched, and clinical studies published until November 17, 2022, were retrieved. The final synthesis included 12 sources. Information about general characteristics of the studies, adverse effects, screening of participants and setting characteristics were summarized and discussed. It is concluded that the use of controlled settings, supported by trained professionals and equipment allowing for rigorous medical, psychiatric, and cardiac monitoring, are essential to promote the safety of patients receiving ibogaine.

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BACKGROUND: The FKBP5 and NR3C1 genes play an important role in stress response, thus impacting mental health. Stress factor exposure in early life, such as maternal depression, may contribute to epigenetic modifications in stress response genes, increasing the susceptibility to different psychopathologies. The present study aimed to evaluate the DNA methylation profile in maternal-infant depression in regulatory regions of the FKBP5 gene and the alternative promoter of the NR3C1 gene. METHODS: We evaluated 60 mother-infant pairs. The levels of DNA methylation were analyzed by the MSRED-qPCR technique. RESULTS: We observed an increased DNA methylation profile in the NR3C1 gene promoter in children with depression and children exposed to maternal depression (p < 0.05). In addition, we observed a correlation of DNA methylation between mothers and offspring exposed to maternal depression. This correlation shows a possible intergenerational effect of maternal MDD exposure on the offspring. For FKBP5, we found a decrease in DNA methylation at intron 7 in children exposed to maternal MDD during pregnancy and a correlation of DNA methylation between mothers and children exposed to maternal MDD (p < 0.05). LIMITATIONS: Although the individuals of this study are a rare group, the sample size of the study was small, and we evaluated the DNA methylation of only one CpG site for each region. CONCLUSION: These results indicate changes in DNA methylation levels in regulatory regions of FKBP5 and NR3C1 in the mother-child MDD context and represent a potential target of studies to understand the depression etiology and how it occurs between generations.

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Although results are still preliminary, ketamine and classical hallucinogens have shown promise in recent years as novel, fast-acting antidepressants, especially for the treatment of unipolar treatment-resistant depression (TRD). Depression also seems to be related to abnormal levels of peripheral inflammatory and neurotrophic biomarkers, which may one day help to diagnose of this disorder. In this context, this systematic review of clinical trials evaluated the current evidence that relates the antidepressant effects of ketamine and classical hallucinogens on TRD with changes in inflammatory and neurotrophic biomarkers. Twelve studies were found (n = 587), 2 with oral ayahuasca (1 mL/kg) and 10 with ketamine (mostly intravenous 0.5 mg/kg) administration. Results for all biomarkers assessed were contradictory and thus inconclusive. Randomized controlled trials with bigger samples and higher statistical power are warranted to clarify if peripheral biomarkers can confidently be used to indicate and measure ketamine's and classical hallucinogens' antidepressant effect. The PROSPERO ID for this study is CRD42021249089.

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(1) Background: With the massive demand for the use and commercialization of medicinal cannabidiol (CBD) products, new randomized clinical trials (RCTs) are being published worldwide, with a constant need for safety and efficacy evaluation. (2) Methods: We performed an update on a systematic review published in 2020 that focused on analyzing the serious adverse effects (SAEs) of CBD in RCTs and its possible association with drug interactions. We also updated the report of the most prevalent CBD adverse effects (AEs). We systematically searched EMBASE, MEDLINE/PubMed, and Web of Science without language restriction for RCTs that reported adverse effects after repeated oral CBD administration for at least one week in healthy volunteers or clinical samples published from January 2019 to May 2022. The included studies were assessed for methodological quality by the Quality Assessment of Controlled Intervention Studies tool. The present review is registered on PROSPERO, number CRD42022334399. (3) Results: Twelve studies involving 745 randomized subjects analyzed were included (range 1.1-56.8 y). A total of 454 participants used CBD in the trials. The most common AEs of CBD were mild or moderate and included gastrointestinal symptoms (59.5%), somnolence (16.7%), loss of appetite (16.5%), and hypertransaminasemia (ALT/AST) (12.8%). Serious adverse effects include mainly hypertransaminasemia with serum levels elevations greater than three times the upper limit of the normal (6.4%), seizures (1.3%), and rash (1.1%). All SAEs reported in the studies were observed on CBD as an add-on therapy to anticonvulsant medications, including clobazam and valproate. (4) Conclusion: Recent RCTs involving oral CBD administration for at least a week suggest that CBD has a good safety and tolerability profile, confirming previous data. However, it can potentially interact with other drugs and its use should be monitored, especially at the beginning of treatment.