BACKGROUND: Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD) are two high-prevalent conditions where the Endocannabinoid system (ECS) is believed to play an important role. The ECS regulates how different neurotransmitters interact in both disorders, which is crucial for controlling emotions and responses to stress and reward stimuli. Measuring peripheral endocannabinoids (eCBs) in human serum and plasma can help overcome the limitations of detecting endocannabinoid levels in the brain. This systematic review aims to identify levels of peripheral eCBs in patients with MDD and/or AUD and find eCBs to use as diagnostic, prognostic biomarkers, and potential therapeutic targets.
METHODS: We conducted a systematic literature search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines from the earliest manuscript until October 22, 2023, in three electronic databases. We included studies of human adults who had a current diagnosis of AUD and/or MDD and evaluated plasma or serum endocannabinoids. We carefully considered known variables that may affect endocannabinoid levels.
RESULTS: We included 17 articles in this systematic review, which measured peripheral eCBs in 170 AUD and 359 MDD patients. Stressors increase peripheral 2-arachidonyl-glycerol (2-AG) concentrations, and 2-AG may be a particular feature of depression severity and chronicity. Anxiety symptoms are negatively correlated with anandamide (AEA) concentrations, and AEA significantly increases during early abstinence in AUD. Studies suggest a negative correlation between Oleoylethanolamide (OEA) and length of abstinence in AUD patients. They also show a significant negative correlation between peripheral levels of AEA and OEA and fatty acid amide hydrolase (FAAH) activity. Eicosapentaenoylethanolamide (EPEA) is correlated to clinical remission rates in depression. Included studies show known variables such as gender, chronicity, symptom severity, comorbid psychiatric symptoms, length of abstinence in the case of AUD, and stress-inducibility that can affect peripheral eCBs.
CONCLUSIONS: This systematic review highlights the important role that the ECS plays in MDD and AUD. Peripheral eCBs appear to be useful biomarkers for these disorders, and further research may identify potential therapeutic targets. Using accessible biological samples such as blood in well-designed clinical studies is crucial to develop novel therapies for these disorders.

UNASSIGNED: Of the seventy million people who suffer from epilepsy, 40 percent of them become resistant to more than one antiepileptic medication and have a higher chance of death. While the classical definition of epilepsy was due to the imbalance between excitatory glutamatergic and inhibitory γ-aminobutyric acid (GABA)-ergic signalling, substantial evidence implicates muscarinic receptors in the regulation of neural excitability.
UNASSIGNED: Cannabinoids have shown to reduce seizure activity and neuronal excitability in several epileptic models through the activation of muscarinic receptors with drugs which modulate their activity. Cannabinoids also have been effective in reducing antiepileptic activity in pharmaco-resistant individuals; however, the mechanism of its effects in temporal lobe epilepsy is not clear.
UNASSIGNED: This review seeks to elucidate the relationship between muscarinic and cannabinoid receptors in epilepsy and neural excitability.

Liquid chromatography paired with tandem mass spectrometry (LC-MS/MS) is the gold standard in measurement of endocannabinoid concentrations in biomatrices. We conducted a systematic review of literature to identify advances in targeted LC-MS/MS methods in the period 2017-2024. We found that LC-MS/MS methods for endocannabinoid quantification are relatively consistent both across time and across biomatrices. Recent advances have primarily been in three areas: (1) sample preparation techniques, specific to the chosen biomatrix; (2) the range of biomatrices tested, recently favoring blood matrices; and (3) the breadth of endocannabinoid and endocannabinoid-like analytes incorporated into assays. This review provides a summary of the recent literature and a guide for researchers looking to establish the best methods for quantifying endocannabinoids in a range of biomatrices.

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent mental health disorder with females experiencing higher rates of depression (11.6%), anxiety (15.7%) and physiological distress (14.5%) than males. Recently, the Endocannabinoid system (ECS) has been proposed to be a key contributing factor in the pathogenesis and symptom severity of MDD due to its role in neurotransmitter production, inflammatory response and even regulation of the female reproductive cycle. This review critically evaluates evidence regarding ECS levels in female-sexed individuals with depressive disorders to further understand ECS role.
METHODS: A systematic literature review of available research published prior to April 2022 was identified using PubMed (U.S. National Library of Medicine), CINAHL (EBSCO), Web of Science, AMED and Scopus (Elsevier). Studies were included if they reported ECS analysis of female-sexed individuals with depression and were excluded if they did not differentiate results between sexes, assessed mental health conditions other than depression, tested efficacy of endocannabinoid/n-acylethanolamine/cannabis or marijuana administration and that were unable to be translated. Critical appraisal of each included study was undertaken using the Joanna Briggs Institute Critical Appraisal Tool for Systematic Reviews.
RESULTS: The 894 located citations were screened for duplicates (n = 357) and eligibility by title and abstract (n = 501). The full text of 33 studies were reviewed, and 7 studies were determined eligible for inclusion. These studies indicated that depressed female-sexed individuals have altered levels of ECS however no significant pattern was identified due to variability of study outcomes and measures, limiting overall interpretation.
CONCLUSIONS: This review suggests potential involvement of ECS in underlying mechanisms of MDD in female sexed-individuals, however no pattern was able to be determined. A major contributor to the inability to attain reliable and valid understanding of the ECS levels in female-sexed individuals with depression was the inconsistency of depression screening tools, inclusion criteria\'s and analysis methods used to measure eCBs. Future studies need to implement more standardised methodology to gain a deeper understanding of ECS in female-sexed individuals with depressive disorders. TRIAL REGISTRATION : This review was submitted to PROSPERO for approval in April 2022 (Registration #CRD42022324212).

In recent years, the medical use of cannabinoids has attracted growing attention worldwide. In particular, anti-inflammatory properties of cannabinoids led to their emergence as potential therapeutic options for autoimmune and inflammatory disorders. Recent studies have also shown that cannabinoid receptors are widely expressed and have endogenous ligands in the skin, suggesting that the skin has its own endocannabinoid system. The aim of this review is to discuss the potential therapeutic effects of cannabinoids in autoimmune and inflammatory skin diseases. Following an overview of cannabinoids and the endocannabinoid system, we describe the cellular and molecular mechanisms of cannabinoids in skin health and disease. We then review the clinical studies of cannabinoids in autoimmune and inflammatory skin diseases including systemic sclerosis (SSc), dermatomyositis (DM), psoriasis (Pso) and atopic dermatitis (AD). A primary literature search was conducted in July 2023, using PubMed and Web of Science. A total of 15 articles were included after excluding reviews, non-human studies and in vitro studies from 389 non-duplicated articles. Available evidence suggests that cannabinoids may be beneficial for SSc, DM, Pso and AD. However, further studies, ideally randomized controlled trials, are needed to further evaluate the use of cannabinoids in autoimmune and inflammatory skin diseases.

Aerobic exercise is a widely adopted practice, not solely for enhancing fitness and reducing the risk of various diseases but also for its ability to uplift mood and aid in addressing depression and anxiety disorders. Within the scope of this narrative review, we seek to consolidate current insights into the endocannabinoid-mediated regulation of stress and the brain\'s reward mechanism resulting from engaging in aerobic exercise. A comprehensive search was conducted across Medline, SPORTDiscus, Pubmed, and Scopus, encompassing data available until November 30, 2023. This review indicates that a bout of aerobic exercise, particularly of moderate intensity, markedly augments circulating levels of endocannabinoids - N-arachidonoyl-ethanolamine (AEA) and 2-acylglycerol (2-AG), that significantly contributes to mood elevation and reducing stress in healthy individuals.  The current understanding of how aerobic exercise impacts mental health and mood improvement is still unclear. Moderate and high-intensity aerobic exercise modulates stress through a negative feedback mechanism targeting both the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system, thereby facilitating stress regulation crucial role in endocannabinoid synthesis, ultimately culminating in the orchestration of negative feedback across multiple tiers of the HPA axis, coupled with its influence over cortical and subcortical brain structures. The endocannabinoid has been observed to govern the release of neurotransmitters from diverse neuronal populations, implying a universal mechanism that fine-tunes neuronal activity and consequently modulates both emotional and stress-related responses. Endocannabinoids further assume a pivotal function within brain reward mechanisms, primarily mediated by CB1 receptors distributed across diverse cerebral centers. Notably, these endocannabinoids partake in natural reward processes, as exemplified in aerobic exercise, by synergizing with the dopaminergic reward system. The genesis of this reward pathway can be traced to the ventral tegmental area, with dopamine neurons predominantly projecting to the nucleus accumbens, thereby inciting dopamine release in response to rewarding stimuli.

Cannabis use has increased sharply in the last 20 y among adults, including reproductive-aged women. Its recent widespread legalization is associated with a decrease in risk perception of cannabis use during breastfeeding. However, the effect of cannabis use (if any) on milk production and milk composition is not known. This narrative review summarizes current knowledge related to maternal cannabis use during breastfeeding and provides an overview of possible pathways whereby cannabis might affect milk composition and production. Several studies have demonstrated that cannabinoids and their metabolites are detectable in human milk produced by mothers who use cannabis. Due to their physicochemical properties, cannabinoids are stored in adipose tissue, can easily reach the mammary gland, and can be secreted in milk. Moreover, cannabinoid receptors are present in adipocytes and mammary epithelial cells. The activation of these receptors directly modulates fatty acid metabolism, potentially causing changes in milk fatty acid profiles. Additionally, the endocannabinoid system is intimately connected to the endocrine system. As such, it is probable that interactions of exogenous cannabinoids with the endocannabinoid system might modify release of critical hormones (e.g., prolactin and dopamine) that regulate milk production and secretion. Nonetheless, few studies have investigated effects of cannabis use (including on milk production and composition) in lactating women. Additional research utilizing robust methodologies are needed to elucidate whether and how cannabis use affects human milk production and composition.

UNASSIGNED: Cannabis has been reported to have both anxiogenic and anxiolytic effects. Habitual cannabis use has been associated with anxiety disorders (AD). The causal pathways and mechanisms underlying the association between cannabis use (CU)/cannabis use disorder (CUD) and anxiety remain unclear. We examined the literature via a systematic review to investigate the link between cannabis and anxiety. The hypotheses studied include causality, the common factor theory, and the self-medication hypothesis.
UNASSIGNED: Critical systematic review of published literature examining the relationship of CU/CUD to AD or state-anxiety, including case reports, literature reviews, observational studies, and preclinical and clinical studies. A systematic MEDline search was conducted of terms including: [anxiety], [anxiogenic], [anxiolytic], [PTSD], [OCD], [GAD], [cannabis], [marijuana], [tetrahydrocannabinol], [THC].
UNASSIGNED: While several case-control and cohort studies have reported no correlation between CU/CUD and AD or state anxiety (N = 5), other cross-sectional, and longitudinal studies report significant relationships (N = 20). Meta-analysis supports anxiety correlating with CU (N = 15 studies, OR = 1.24, 95% CI: 1.06-1.45, p = 0.006) or CUD (N = 13 studies, OR = 1.68, 95% CI: 1.23-2.31, p = 0.001). PATH analysis identifies the self-medication hypothesis (N = 8) as the model that best explains the association between CU/CUD and AD or state-anxiety. Despite the support of multiple large cohort studies, causal interpretations (N = 17) are less plausible, while the common factor theory (N = 5), stress-misattribution hypothesis, and reciprocal feedback theory lack substantial evidential support.
UNASSIGNED: The association between cannabis and anxiety is best explained by anxiety predisposing individuals toward CU as a method of self-medication. A causal relationship in which CU causes AD incidence is less likely despite multiple longitudinal studies suggesting so.

As major depressive disorder is becoming a more and more common issue in modern society, it is crucial to discover new possible grip points for its diagnosis and antidepressive therapy. One of them is endocannabinoid system, which has been proposed as a manager of emotional homeostasis, and thus, endocannabinoid alterations have been found in animals undergoing various preclinical models of depression procedures as well as in humans suffering from depressive-like disorders. In this review article, studies regarding those alterations have been summed up and analyzed. Another important issue raised by the researchers is the impact of currently used antidepressive drugs on endocannabinoid system so that it would be possible to predict reversibility of endocannabinoid alterations following stress exposure and, in the future, to be able to design individually personalized therapies. Preclinical studies investigating this topic have been analyzed and described in this article. Unfortunately, too few clinical studies in this field exist, what indicates an urgent need for collecting such data, so that it would be possible to compare them with preclinical outcomes and draw reliable conclusions.

Synthetic cannabinoids (SCs) are chemically classified as psychoactive substances that target the endocannabinoid system in many body organs. SCs can initiate pathophysiological changes in many tissues which can be severe enough to damage the normal functionality of our body systems. The majority of SCs-related side effects are mediated by activating Cannabinoid Receptor 1 (CB1R) and Cannabinoid Receptor 2 (CB2R). The activation of these receptors can enkindle many downstream signalling pathways, including oxidative stress, inflammation, and apoptosis that ultimately can produce deleterious changes in many organs. Besides activating the cannabinoid receptors, SCs can act on non-cannabinoid targets, such as the orphan G protein receptors GPR55 and GPR18, the Peroxisome Proliferator-activated Receptors (PPARs), and the Transient receptor potential vanilloid 1 (TRPV1), which are broadly expressed in the brain and the heart and their activation mediates many pharmacological effects of SCs. In this review, we shed light on the multisystem complications found in SCs abusers, particularly discussing their neurologic, cardiovascular, renal, and hepatic effects, as well as highlighting the mechanisms that intermediate SCs-related pharmacological and toxicological consequences to provide comprehensive understanding of their short and long-term systemic effects.