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The processes underpinning post-developmental neurogenesis in the mammalian brain continue to be defined. Such processes involve the proliferation of neural stem cells and neural progenitor cells (NPCs), neuronal migration, differentiation and integration into a network of functional synapses within the brain. Both intrinsic (cell signalling cascades) and extrinsic (neurotrophins, neurotransmitters, cytokines, hormones) signalling molecules are intimately associated with adult neurogenesis and largely dictate the proliferative activity and differentiation capacity of neural cells. Cannabinoids are a unique class of chemical compounds incorporating plant-derived cannabinoids (the active components of Cannabis sativa), the endogenous cannabinoids and synthetic cannabinoid ligands, and these compounds are becoming increasingly recognized for their roles in neural developmental processes. Indeed, cannabinoids have clear modulatory roles in adult neurogenesis, probably through activation of both CB1 and CB2 receptors. In recent years, a large body of literature has deciphered the signalling networks involved in cannabinoid-mediated regulation of neurogenesis. This timely review summarizes the evidence that the cannabinoid system is intricately associated with neuronal differentiation and maturation of NPCs and highlights intrinsic/extrinsic signalling mechanisms that are cannabinoid targets. Overall, these findings identify the central role of the cannabinoid system in adult neurogenesis in the hippocampus and the lateral ventricles and hence provide insight into the processes underlying post-developmental neurogenesis in the mammalian brain. Abbreviations2-AG, 2-arachidonoylglycerol; AA, arachidonic acid; ACEA, arachidonyl-2′-chloroethylamide; AEA, anandamide; BDNF, brain-derived neurotrophic factor; BMP, bone morphogenetic protein; BrdU, 5-bromo-2'deoxyuridine; CB, cannabinoid receptor; CBC, cannabichromene; CBD, cannabidiol; CREB, cAMP response element-binding protein; DAGL, DAG lipase; DCX, double cortin; FAAH, fatty acid amide hydrolase; GFAP, glial fibrillary acidic protein; IGF-1, insulin-like growth factor-1; mTORC1, mammalian target of rapamycin complex 1; NGF, nerve-growth factor; NPC, neural progenitor cell; NSC, neural stem cell; Ptc1, patched 1; RMS, rostral migratory stream; SGZ, subgranular zone; Shh, Sonic Hedgehog; Smo, smoothened; SVZ, subventricular zone; THC, Δ IntroductionFor decades, the true plasticity of the mammalian CNS was underestimated and the adult brain was long considered to be a post-mitotic organ incapable of self-regeneration. However, pioneering work in the 1960s by Joseph Altman and colleagues challenged this long-standing dogma (Altman and Das, 1965). In this groundbreaking publication, Altman provided the first evidence that new neurons were generated in the adult rat hippocampus. Subsequent experiments demonstrated that adult neurogenesis was not specific to the hippocampus, with the adult olfactory bulb identified as another brain region where new neurons are added to existin...

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Accumulating clinical evidence shows that psychedelic therapy, by synergistically combining psychopharmacology and psychological support, offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and/or maladaptive habitual patterns of emotion, cognition and behavior, notably, depression (MDD), treatment resistant depression (TRD) and addiction disorders, but perhaps also anxiety disorders, obsessive-compulsive disorder (OCD), Post-Traumatic Stress Disorder (PTSD) and eating disorders. Despite the emergent transdiagnostic evidence, the specific clinical dimensions that psychedelics are efficacious for, and associated underlying neurobiological pathways, remain to be well-characterized. To this end, this review focuses on pre-clinical and clinical evidence of the acute and sustained therapeutic potential of psychedelic therapy in the context of a transdiagnostic dimensional systems framework. Focusing on the Research Domain Criteria (RDoC) as a template, we will describe the multimodal mechanisms underlying the transdiagnostic therapeutic effects of psychedelic therapy, traversing molecular, cellular and network levels. These levels will be mapped to the RDoC constructs of negative and positive valence systems, arousal regulation, social processing, cognitive and sensorimotor systems. In summarizing this literature and framing it transdiagnostically, we hope we can assist the field in moving toward a mechanistic understanding of how psychedelics work for patients and eventually toward a precise-personalized psychedelic therapy paradigm.