Endocannabinoid Alterations Research Articles

How depressionand antidepressant drugs affect endocannabinoid system?-review of clinical and preclinical studies.

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.

Peripheral Endogenous Cannabinoid Levels Are Increased in Schizophrenia Patients Evaluated in a Psychiatric Emergency Setting.

BackgroundThe endogenous cannabinoid system mediates the psychoactive effects of cannabis in the brain. It has been argued that this system may play a key role in the pathophysiology of schizophrenia. While some studies have consistently shown that the levels of anandamide, an endogenous cannabinoid ligand, are increased in the cerebrospinal fluid of schizophrenia patients, inconsistent results have been observed in studies measuring anandamide levels in the periphery. Here, we sought to determine if the assessment of peripheral anandamide levels in patients evaluated in a psychiatric emergency setting would show robust increases.MethodsOne hundred seven patients with a schizophrenia-spectrum disorder from the psychiatric emergency settings of the Institut Universitaire en Santé Mentale de Montréal and 36 healthy volunteers were included in the study. A subsample of thirty patients were assessed at two time points: at the emergency and at their discharge from the hospital. Anxious and depressive symptoms, sleep and substance use were assessed using self-report questionnaires. In addition to anandamide, the levels of oleoylethanolamide (OEA), an anorexigenic fatty-acid ethanolamide, were also measured, since the prevalence of the metabolic syndrome is increased in schizophrenia. Plasma levels of anandamide and OEA were measured using liquid chromatography and mass spectrometry.ResultsPlasma anandamide and OEA levels were significantly increased in schizophrenia patients, relative to controls (Cohen’s d=1.0 and 0.5, respectively). Between-group differences remained significant after controlling for metabolic measures. No differences were observed between schizophrenia patients with and without a comorbid substance use disorder at baseline. Importantly, the levels of both endocannabinoids significantly decreased after discharge from the emergency setting.ConclusionThe current results add to the growing body of evidence of endocannabinoid alterations in schizophrenia. The strong elevation of plasma anandamide levels in schizophrenia patients assessed in the psychiatric emergency setting suggests that anandamide and OEA area potential biomarkers of the psychological turmoil associated with this context.

Childhood trauma and being at-risk for psychosis are associated with higher peripheral endocannabinoids.

Evidence has been accumulating regarding alterations in components of the endocannabinoid system in patients with psychosis. Of all the putative risk factors associated with psychosis, being at clinical high-risk for psychosis (CHR) has the strongest association with the onset of psychosis, and exposure to childhood trauma has been linked to an increased risk of development of psychotic disorder. We aimed to investigate whether being at-risk for psychosis and exposure to childhood trauma were associated with altered endocannabinoid levels. We compared 33 CHR participants with 58 healthy controls (HC) and collected information about previous exposure to childhood trauma as well as plasma samples to analyse endocannabinoid levels. Individuals with both CHR and experience of childhood trauma had higher N-palmitoylethanolamine (p < 0.001) and anandamide (p < 0.001) levels in peripheral blood compared to HC and those with no childhood trauma. There was also a significant correlation between N-palmitoylethanolamine levels and symptoms as well as childhood trauma. Our results suggest an association between CHR and/or childhood maltreatment and elevated endocannabinoid levels in peripheral blood, with a greater alteration in those with both CHR status and history of childhood maltreatment compared to those with either of those risks alone. Furthermore, endocannabinoid levels increased linearly with the number of risk factors and elevated endocannabinoid levels correlated with the severity of CHR symptoms and extent of childhood maltreatment. Further studies in larger cohorts, employing longitudinal designs are needed to confirm these findings and delineate the precise role of endocannabinoid alterations in the pathophysiology of psychosis.

The Endocannabinoid System as a Potential Mechanism through which Exercise Influences Episodic Memory Function.

Emerging research demonstrates that exercise, including both acute and chronic exercise, may influence episodic memory function. To date, mechanistic explanations of this effect are often attributed to alterations in long-term potentiation, neurotrophic production, angiogenesis, and neurogenesis. Herein, we discuss a complementary mechanistic model, suggesting that the endocannabinoid system may, in part, influence the effects of exercise on memory function. We discuss the role of the endocannabinoid system on memory function as well as the effects of exercise on endocannabinoid alterations. This is an exciting line of inquiry that should help delineate new insights into the mechanistic role of exercise on memory function.

Endocannabinoid System in Spinocerebellar Ataxia Type-3 and Other Autosomal-Dominant Cerebellar Ataxias: Potential Role in Pathogenesis and Expected Relevance as Neuroprotective Targets.

Spinocerebellar ataxias (SCAs) are a group of hereditary and progressive neurological disorders characterized by a loss of balance and motor coordination typically associated with cerebellar atrophy. The most prevalent SCA types are all polyQ disorders like Huntington’s disease, sharing the most relevant events in pathogenesis with this basal ganglia disorder, but with most of the damage concentrated in cerebellar neurons, and in their afferent and efferent connections (e.g., brainstem nuclei). SCAs have no cure and effective symptom-alleviating and disease-modifying therapies are not currently available. However, based on results obtained in studies conducted in murine models and information derived from analyses in post-mortem tissue samples from patients, which show notably higher levels of CB1 receptors found in different cerebellar neuronal subpopulations, the blockade of these receptors has been proposed for acutely modulating motor incoordination in cerebellar ataxias, whereas their chronic activation has been proposed for preserving specific neuronal losses. Additional studies in post-mortem tissues from SCA patients have also demonstrated elevated levels of CB2 receptors in Purkinje neurons as well as in glial elements in the granular layer and in the cerebellar white matter, with a similar profile found for endocannabinoid hydrolyzing enzymes, then suggesting that activating CB2 receptors and/or inhibiting these enzymes may also serve to develop cannabinoid-based neuroprotective therapies. The present review will address both aspects. On one hand, the endocannabinoid system becomes dysregulated in the cerebellum and also in other CNS structures (e.g., brainstem, basal ganglia) in SCAs, which may contribute to the progression of pathogenic events in these diseases. On the other hand, these endocannabinoid alterations may be pharmacologically corrected or enhanced, and this may have therapeutic consequences, either alleviating specific symptoms or eliciting neuroprotective effects, an objective presently under investigation.

Abnormalities in neuroendocrine stress response in psychosis: the role of endocannabinoids.

The aim of this article is to summarize current evidence regarding alterations in the neuroendocrine stress response system and endocannabinoid system and their relationship in psychotic disorders such as schizophrenia. Exposure to stress is linked to the development of a number of psychiatric disorders including psychosis. However, the precise role of stress in the development of psychosis and the possible mechanisms that might underlie this are not well understood. Recently the cannabinoid hypothesis of schizophrenia has emerged as a potential line of enquiry. Endocannabinoid levels are increased in patients with psychosis compared with healthy volunteers; furthermore, they increase in response to stress, which suggests another potential mechanism for how stress might be a causal factor in the development of psychosis. However, research regarding the links between stress and the endocannabinoid system is in its infancy. Evidence summarized here points to an alteration in the baseline tone and reactivity of the hypothalamic-pituitary-adrenal (HPA) axis as well as in various components of the endocannabinoid system in patients with psychosis. Moreover, the precise nature of the inter-relationship between these two systems is unclear in man, especially their biological relevance in the context of psychosis. Future studies need to simultaneously investigate HPA axis and endocannabinoid alterations both at baseline and following experimental perturbation in healthy individuals and those with psychosis to understand how they interact with each other in health and disease and obtain mechanistic insight as to their relevance to the pathophysiology of schizophrenia.

69. Endocannabinoid alterations in interferon-alpha induced depression

Current treatment for chronic hepatitis C (HCV) viral infection, interferon- α (IFN-α), has been shown to induce depression in more than 30% of patients. We investigated whether genes belonging to the endocannabinoid (eCB) system are involved in mechanisms underlying depression development. We recruited 50 HCV patients receiving IFN-α treatment and assessed them at treatment weeks 0, 4 and 24. We used M.I.N.I. International Neuropsychiatric Interview to follow depression and analysed mRNA levels of selected eCB related genes using Affymetrix® Human Gene 1.1ST Array. NAPE-PLD and DAGL-α – coding for enzymes involved in eCB synthesis – were lower at baseline in those who developed depression vs those who did not (−17%, p = 0.02; −17%, p = 0.003; respectively). After 4 weeks, levels of CNR2 – coding for eCB CB2 receptors – were reduced (−21%, p < 0.001), while levels of FAAH2 – coding for a degrading eCB enzyme – and DAGL-α were increased in the whole sample (+19%, p = 0.01, +19%, p < 0.001, respectively). After controlling for depression development, FAAH2 levels were significantly increased in depressed patients only (+25%, p = 0.005). From baseline to week 24, CNR2 levels decreased in non-depressed patients (−29%, p < 0.001). Interestingly, at week 24 CNR2 levels were higher in depressed compared with non-depressed individuals (+27%, p = 0.001). Our findings suggest that alterations in the eCB system may underlie the increased vulnerability for depression development in HCV infected patients treated with IFN-α.

Plasma Endocannabinoid Alterations in Individuals with Substance Use Disorder are Dependent on the “Mirror Effect” of Schizophrenia

Schizophrenia is a complex psychiatric disorder strongly associated with substance use disorders. Theoretically, schizophrenia and SUD may share endocannabinoid alterations in the brain reward system. The main endocannabinoids, anandamide, and 2-arachidonoylglycerol, are lipids which bind cannabinoid receptors. Oleoylethanolamide (OEA), a fatty-acid ethanolamide, binds peroxisome proliferator-activated receptors. The endocannabinoid system has been shown to be impaired in schizophrenia, and recently, our group has shown that schizophrenia patients with SUD have elevated peripheral levels of anandamide and OEA that do not normalize after 3-month treatment with quetiapine. Objective For comparative purposes, we aimed to measure endocannabinoids in non-psychosis substance abusers and non-abusing schizophrenia patients. Methods Using liquid chromatography and mass spectrometry, we measured plasma levels of anandamide and OEA in non-psychosis SUD patients, non-abusing schizophrenia patients, and healthy controls. In an open-label manner, all patients received 12-week treatment with quetiapine. Results Anandamide and OEA were reduced in substance abusers without schizophrenia, relative to healthy controls (p < 0.05). Both endocannabinoids were unchanged in non-abusing schizophrenia patients. After quetiapine, anandamide, and OEA levels remained significantly reduced the SUD group (p < 0.05). Discussion Taken together with results of our previous study performed in dual-diagnosis patients, our results suggest that peripheral anandamide and OEA levels are impaired in patients with SUD in opposite ways according to the presence or absence of schizophrenia. Endocannabinoid alterations did not change with treatment, suggesting that they are trait markers. Further studies are necessary to understand the role of endocannabinoids in substance abusers with and without schizophrenia and to examine therapeutic implications.