With over 100 apparently unique metabolites in the Cannabis plant, there are a plethora of potential molecular targets. The molecular actions of Δ9-tetrahydrocannabinol are the best-investigated, which have centred mostly on a relatively high-potency, low-efficacy action at the CB1 cannabinoid receptor. By contrast, cannabidiol has a multitude of lower potency molecular targets identified in vitro, but with limited clarity about their relevance for the effects of cannabidiol in humans. This review highlights the incomplete nature of studies of the major phytocannabinoids, particularly the acid phytocannabinoids.
Cannabinoids are increasingly being used to manage pain resulting from a variety of conditions. Both preclinical animal models and human studies have played a crucial role in advancing our knowledge of cannabinoids, their involvement in pain mechanisms, and their potential utility as novel analgesics. This chapter first reviews basic pain neurobiology and the most common experimental pain paradigms, which provide a basis for our discussion of preclinical, human laboratory, and clinical research characterizing the effectiveness of cannabinoids for managing pain. While a substantial body of literature exists describing these effects, findings are complex and largely mixed, dependent on the cannabinoid administered, route of administration, and pain modality/syndrome tested. Herein, we highlight the need for more rigorous, placebo-controlled research defining the therapeutic efficacy of cannabinoids. The chapter concludes by emphasizing the need for further investigation of other cannabis constituents (e.g., minor cannabinoids and terpenes), potential interactions between cannabinoids and other analgesic medications, as well as other emerging issues in the intersection between cannabinoids and pain management.
Cannabis use disorder (CUD) is increasingly prevalent, and there are no FDA-approved medications to facilitate its treatment. Research on the development of CUD pharmacotherapies lags compared to other substance use disorders (SUDs), partly due to the difficulty in establishing robust preclinical models of cannabinoid self-administration. This chapter evaluates the translational pipeline, from preclinical and human laboratory models to randomized controlled clinical trials for CUD, reviewing medication effects observed within these models and discussing the challenges in translating preclinical and human laboratory findings, particularly regarding efficacy endpoints (e.g., prolonged abstinence versus a reduction in use). The chapter concludes by addressing future directions for improving translational validity and optimizing therapeutic development for CUD.
Numerous studies carried out in the last 30-40 years have strongly demonstrated that the endocannabinoid system exerts important modulatory functions in the central nervous system (CNS). These neuromodulatory functions encompass the whole life of animals, with specific activities during neurodevelopment (prenatal, postnatal and adolescent periods), adulthood and possibly senescence too. However, this is the life stage less investigated in relation with the endocannabinoid system to date. In the aged brain, the activity of this system appears to be altered, which contributes to subtle impairments that typically occur during ageing in learning and memory, motor behaviour, social behaviour and other neurobiological functions. Some of the changes in endocannabinoid activity may represent a process to attenuate ageing-related impairment in the brain function, which is consistent with its role as a pro-homeostatic system. An important observation is that these alterations become extreme when normal brain ageing acquires pathological characteristics, as happens in chronic neurodegenerative disorders. This includes the cannabinoid type-1 (CB1) receptor downregulation or impairment in its signalling and the increase in endocannabinoid-inactivating enzymes, both hypothesised to contribute to pathogenic events. By contrast, elevated levels of endocannabinoids due to a reduced Fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) expression and the upregulation of cannabinoid type-2 (CB2) receptors may in turn serve as endogenous pro-homeostatic adaptations against brain impairment. This review synthesises information on: (i) subtle alterations in the endocannabinoid system in the senescent brain in the absence of pathology, with the purpose of demonstrating that these alterations are representative of the extreme changes experienced by this system in the brain pathological ageing; and (ii) the development of neuroprotective therapies based on the pharmacological management of specific endocannabinoid targets to combat neurodegenerative pathologies. Together, research in this area comes at a critical time as global lifespan is increasing, incidence of age-related neurodegenerative disorders is expanding, and the unmet need for efficacious neuroprotective treatments is a public health necessity.
This chapter will review the basic pharmacology of the canonical cannabinoid receptors. The endocannabinoid system is a complex signalling network involved in a wide range of physiological processes, including pain modulation, appetite regulation, and synaptic plasticity. The canonical cannabinoid receptors, CB1 and CB2, are central in orchestrating this system. CB1 is highly enriched in the central nervous system (CNS), where it plays a crucial role in modulating neurotransmitter release and synaptic plasticity. In contrast, CB2 is predominantly expressed in peripheral tissues and immune cells, participating in anti-inflammatory processes. Here, we focus on cannabinoid receptor distribution, intracellular signalling, and receptor regulation. We describe the intracellular signalling pathways activated by CB1, including the modulation of ion channels, second messengers, and protein kinases. Overall, this chapter provides an overview of the canonical cannabinoid receptors and their role in the regulation of neuronal signalling and plasticity, highlighting the molecular and cellular mechanisms underlying their effects in the CNS.
