Endocannabinoid Modulation Research Articles

The Endocannabinoid System and Cannabidiol: Past, Present, and Prospective for Cardiovascular Diseases.

In the past, cannabis was commonly associated with mysticism and illegality. Fortunately, in recent years perspectives and discourses have changed. More prominence has been given to the rigorous scientific effort that led to the discovery of cannabis’ many physiological actions and endogenous signalling mechanisms. The endocannabinoid system is a complex and heterogeneous pro-homeostatic network comprising different receptors with several endogenous ligands, numerous metabolic enzymes and regulatory proteins. Therefore, it is not surprising that alterations and dysfunctions of the endocannabinoid system are observed in almost every category of disease. Such high degree of pathophysiological involvement suggests the endocannabinoid system is a promising therapeutic target and prompted the translation of resurgent scientific findings into clinical therapies. Shifting attitudes toward cannabis also raised other matters such as increased patient awareness, prescription requests, self-medication, recreational use, recognition of new knowledge gaps, renewed scientific activity, and seemingly exponential growth of the cannabis industry. This review, following a general overview of cannabis and the endocannabinoid system, assiduously describes its role within the context of cardiovascular diseases, paying particular attention to the Janus influence that endocannabinoid system modulators can have on the cardiovascular system.

Increasing Endocannabinoid Tone Alters Anxiety-Like and Stress Coping Behaviour in Female Rats Prenatally Exposed to Valproic Acid.

Given the sex differences evident in the prevalence of autism, there is an increased awareness of the importance of including females in autism research to determine sexual dimorphism and sex-specific treatments. Cannabinoids and endocannabinoid modulators have been proposed as potential novel treatments for autism-related symptoms; however, few studies to date have examined if these pharmacological agents elicit sex-specific effects. The aim of the present study was to use the valproic acid (VPA) model of autism to compare the behavioural responses of male and female rats and examine the effects of increasing endocannabinoid tone on the behavioural responses of VPA-exposed female rats. These data revealed that VPA-exposed male, but not female, rats exhibit reduced social responding in the three-chamber and olfactory habituation/dishabituation (OHD) test during adolescence. In comparison, VPA-exposed female, but not male, adolescent rats exhibited anxiety-like behaviour in the elevated plus maze (EPM) and open field test (OFT). In VPA-exposed female rats, increasing 2-AG levels augmented anxiety-like behaviour in the EPM and OFT, while increasing AEA levels reduced stress coping behaviour in the swim stress test. These data highlight sexual dimorphic behaviours in the VPA model and indicate that enhancing endocannabinoid levels may exacerbate negative affective behaviour in VPA-exposed females. Thus, considerations should be paid to the possible sex-specific effects of cannabinoids for the treatment of symptoms associated with autism.

Modulation of Endocannabinoids by Caloric Restriction Is Conserved in Mice but Is Not Required for Protection from Acute Kidney Injury.

Acute kidney injury (AKI) is a frequent and critical complication in the clinical setting. In rodents, AKI can be effectively prevented through caloric restriction (CR), which has also been shown to increase lifespan in many species. In Caenorhabditis elegans (C. elegans), longevity studies revealed that a marked CR-induced reduction of endocannabinoids may be a key mechanism. Thus, we hypothesized that regulation of endocannabinoids, particularly arachidonoyl ethanolamide (AEA), might also play a role in CR-mediated protection from renal ischemia-reperfusion injury (IRI) in mammals including humans. In male C57Bl6J mice, CR significantly reduced renal IRI and led to a significant decrease of AEA. Supplementation of AEA to near-normal serum concentrations by repetitive intraperitoneal administration in CR mice, however, did not abrogate the protective effect of CR. We also analyzed serum samples taken before and after CR from patients of three different pilot trials of dietary interventions. In contrast to mice and C. elegans, we detected an increase of AEA. We conclude that endocannabinoid levels in mice are modulated by CR, but CR-mediated renal protection does not depend on this effect. Moreover, our results indicate that modulation of endocannabinoids by CR in humans may differ fundamentally from the effects in animal models.

Endocannabinoid Modulation of the Dopamine System: Implications for Motivated Behavior

The endocannabinoid system has widespread influence on other neurotransmitter systems and influences motivation. Given that motivation is influenced by dopamine, and impacted across psychiatric conditions, without CB1 receptors expressed in dopamine cell bodies, the endocannabinoid system likely modulates dopamine release through indirect mechanisms.

Cannabinoids, the endocannabinoid system, and pain: a review of preclinical studies.

This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines for pain management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are (1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; (2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and (3) to identify important directions for future research. In service of these goals, this review (1) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; (2) describes pharmacokinetics of cannabinoids in rodents and humans; and (3) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated.

Systematic review and meta-analysis of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators tested for antinociceptive effects in animal models of injury-related or pathological persistent pain.

We report a systematic review and meta-analysis of studies that assessed the antinociceptive efficacy of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators on pain-associated behavioural outcomes in animal models of pathological or injury-related persistent pain. In April 2019, we systematically searched 3 online databases and used crowd science and machine learning to identify studies for inclusion. We calculated a standardised mean difference effect size for each comparison and performed a random-effects meta-analysis. We assessed the impact of study design characteristics and reporting of mitigations to reduce the risk of bias. We meta-analysed 374 studies in which 171 interventions were assessed for antinociceptive efficacy in rodent models of pathological or injury-related pain. Most experiments were conducted in male animals (86%). Antinociceptive efficacy was most frequently measured by attenuation of hypersensitivity to evoked limb withdrawal. Selective cannabinoid type 1, cannabinoid type 2, nonselective cannabinoid receptor agonists (including delta-9-tetrahydrocannabinol) and peroxisome proliferator-activated receptor-alpha agonists (predominantly palmitoylethanolamide) significantly attenuated pain-associated behaviours in a broad range of inflammatory and neuropathic pain models. Fatty acid amide hydrolase inhibitors, monoacylglycerol lipase inhibitors, and cannabidiol significantly attenuated pain-associated behaviours in neuropathic pain models but yielded mixed results in inflammatory pain models. The reporting of criteria to reduce the risk of bias was low; therefore, the studies have an unclear risk of bias. The value of future studies could be enhanced by improving the reporting of methodological criteria, the clinical relevance of the models, and behavioural assessments. Notwithstanding, the evidence supports the hypothesis of cannabinoid-induced analgesia.

Discovering the Lost Reward: Critical Locations for Endocannabinoid Modulation of the Cortico-Striatal Loop That Are Implicated in Major Depression.

Depression, the most prevalent psychiatric disorder in the Western world, is characterized by increased negative affect (i.e., depressed mood, cost value increase) and reduced positive affect (i.e., anhedonia, reward value decrease), fatigue, loss of appetite, and reduced psychomotor activity except for cases of agitative depression. Some forms, such as post-partum depression, have a high risk for suicidal attempts. Recent studies in humans and in animal models relate major depression occurrence and reoccurrence to alterations in dopaminergic activity, in addition to other neurotransmitter systems. Imaging studies detected decreased activity in the brain reward circuits in major depression. Therefore, the location of dopamine receptors in these circuits is relevant for understanding major depression. Interestingly, in cortico–striatal–dopaminergic pathways within the reward and cost circuits, the expression of dopamine and its contribution to reward are modulated by endocannabinoid receptors. These receptors are enriched in the striosomal compartment of striatum that selectively projects to dopaminergic neurons of substantia nigra compacta and is vulnerable to stress. This review aims to show the crosstalk between endocannabinoid and dopamine receptors and their vulnerability to stress in the reward circuits, especially in corticostriatal regions. The implications for novel treatments of major depression are discussed.

Mechanistic insights into the protective effect of paracetamol against rotenone-induced Parkinson’s disease in rats: Possible role of endocannabinoid system modulation

Parkinson’s disease (PD) is a disabling progressive neurodegenerative disease. So far, PD’s treatment remains symptomatic with no curative effects. Aside from its blatant analgesic and antipyretic efficacy, recent studies highlighted the endowed neuroprotective potentials of paracetamol (PCM). To this end: the present study investigated: (1) Possible protective role of PCM against rotenone-induced PD-like neurotoxicity in rats, and (2) the mechanisms underlying its neuroprotective actions including cannabinoid receptors’ modulation. A dose-response study was conducted using three doses of PCM (25, 50, and 100 mg/kg/day, i.p.) and their effects on body weight changes, spontaneous locomotor activity, rotarod test, tyrosine hydroxylase (TH) and α-synuclein expression, and striatal dopamine (DA) content were evaluated. Results revealed that PCM (100 mg/kg/day, i.p.) halted PD motor impairment, prevented rotenone-induced weight loss, restored normal histological tissue structure, reversed rotenone-induced reduction in TH expression and striatal DA content, and markedly decreased midbrain and striatal α-synuclein expression in rotenone-treated rats. Accordingly, PCM (100 mg/kg/day, i.p.) was selected for further mechanistic investigations, where it ameliorated rotenone-induced oxidative stress, neuro-inflammation, apoptosis, and disturbed cannabinoid receptors’ expression. In conclusion, our findings imply a multi-target neuroprotective effect of PCM in PD which could be attributed to its antioxidant, anti-inflammatory and anti-apoptotic activities, in addition to cannabinoid receptors’ modulation.

Short-Term Plasticity in Cortical GABAergic Synapses on Olfactory Bulb Granule Cells Is Modulated by Endocannabinoids

Olfactory bulb and higher processing areas are synaptically interconnected, providing rapid regulation of olfactory bulb circuit dynamics and sensory processing. Short-term plasticity changes at any of these synapses could modulate sensory processing and potentially short-term sensory memory. A key olfactory bulb circuit for mediating cortical feedback modulation is granule cells, which are targeted by multiple cortical regions including both glutamatergic excitatory inputs and GABAergic inhibitory inputs. There is robust endocannabinoid modulation of excitatory inputs to granule cells and here we explored whether there was also endocannabinoid modulation of the inhibitory cortical inputs to granule cells. We expressed light-gated cation channel channelrhodopsin-2 (ChR2) in GABAergic neurons in the horizontal limb of the diagonal band of Broca (HDB) and their projections to granule cells in olfactory bulb. Selective optical activation of ChR2 positive axons/terminals generated strong, frequency-dependent short-term depression of GABAA-mediated-IPSC in granule cells. As cannabinoid type 1 (CB1) receptor is heavily expressed in olfactory bulb granule cell layer (GCL) and there is endogenous endocannabinoid release in GCL, we investigated whether activation of CB1 receptor modulated the HDB IPSC and short-term depression at the HDB→granule cell synapse. Activation of the CB1 receptor by the exogenous agonist Win 55,212-2 significantly decreased the peak amplitude of individual IPSC and decreased short-term depression, while blockade of the CB1 receptor by AM 251 slightly increased individual IPSCs and increased short-term depression. Thus, we conclude that there is tonic endocannabinoid activation of the GABAergic projections of the HDB to granule cells, similar to the modulation observed with glutamatergic projections to granule cells. Modulation of inhibitory synaptic currents and frequency-dependent short-term depression could regulate the precise balance of cortical feedback excitation and inhibition of granule cells leading to changes in granule cell mediated inhibition of olfactory bulb output to higher processing areas.

What Role Does the Endocannabinoid System Play in the Pathogenesis of Obesity?

The endocannabinoid system (ECS) is an endogenous signaling system formed by specific receptors (cannabinoid type 1 and type 2 (CB1 and CB2)), their endogenous ligands (endocannabinoids), and enzymes involved in their synthesis and degradation. The ECS, centrally and peripherally, is involved in various physiological processes, including regulation of energy balance, promotion of metabolic process, food intake, weight gain, promotion of fat accumulation in adipocytes, and regulation of body homeostasis; thus, its overactivity may be related to obesity. In this review, we try to explain the role of the ECS and the impact of genetic factors on endocannabinoid system modulation in the pathogenesis of obesity, which is a global and civilizational problem affecting the entire world population regardless of age. We also emphasize that the search for potential new targets for health assessment, treatment, and the development of possible therapies in obesity is of great importance.

Sex-dependent effects of endocannabinoid modulation of conditioned fear extinction in rats.

Women are twice as likely as men to develop post-traumatic stress disorder (PTSD) making the search for biological mechanisms underlying these gender disparities especially crucial. One of the hallmark symptoms of PTSD is an alteration in the ability to extinguish fear responses to trauma-associated cues. In male rodents, the endocannabinoid system can modulate fear extinction and has been suggested as a therapeutic target for PTSD. However, whether and how the endocannabinoid system may modulate fear expression and extinction in females remains unknown. To answer this question, we pharmacologically manipulated endocannabinoid signalling in male and female rats prior to extinction of auditory conditioned fear and measured both passive (freezing) and active (darting) conditioned responses. Surprisingly, we found that acute systemic inhibition of the endocannabinoid anandamide (AEA) or 2-arachidonoyl glycerol (2-AG) hydrolysis did not significantly alter fear expression or extinction in males. However, the same manipulations in females produced diverging effects. Increased AEA signalling at vanilloid TRPV1 receptors impaired fear memory extinction. In contrast, inhibition of 2-AG hydrolysis promoted active over passive fear responses acutely via activation of cannabinoid1 (CB1 ) receptors. Measurement of AEA and 2-AG levels after extinction training revealed sex- and brain region-specific changes. We provide the first evidence that AEA and 2-AG signalling affect fear expression and extinction in females in opposite directions. These findings are relevant to future research on sex differences in mechanisms of fear extinction and may help develop sex-specific therapeutics to treat trauma-related disorders.

LC-HRMS/MS-based phytochemical profiling of Piper spices: Global association of piperamides with endocannabinoid system modulation

The plant genus Piper comprises extensively consumed spice taxa like black pepper (P. nigrum L.) or long pepper (P. longum L.). The chronic dietary use of different Piper spices has been associated with different health benefits, though the molecular mechanisms remain poorly understood. The aim of this work was to perform the liquid-chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS) profiling and LC-DAD quantification of piperamides in several Piper species and varieties and study their ability to modulate the endocannabinoid system (ECS). LC-HRMS/MS analysis revealed a number of 42 piperamides grouped into six structural classes, with 22 of them, notably piperine, retrofractamide B, guineensine, piperchabamide C, being also quantified by LC-DAD. The multivariate analysis showed that P. nigrum and P. longum are very similar with respect to their piperamide profile, while the other Piper spices (P. retrofractum, P. guineense, P. cubeba, P. borbonense) might have significantly different metabolite patterns. The results from the biological assays confirmed that guineensine and total piperamides are strongly correlated with anandamide (AEA) cellular uptake inhibition. While none of the Piper spice extracts showed binding activity at cannabinoid CB1 receptors, some P. nigrum varieties exhibited moderate binding interactions with CB2 receptors. Overall, the analytical profiling enabled global annotations of piperamides associated to cannabimimetic effects in Piper spices.

Evidence for the Endocannabinoid System as a Therapeutic Target in the Treatment of Cannabis Use Disorder.

Cannabis use disorder (CUD) is highly prevalent. Psychotherapy alone is not adequately effective, with few individuals achieving abstinence. Pharmacotherapeutic supplementation may improve efficacy, and the endocannabinoid system presents a target specifically dysregulated by heavy cannabis use. This review compiles current literature evaluating endocannabinoid modulation as a treatment strategy for CUD, with implications for future research. Cannabinoid receptor agonists have been found to reduce cannabis withdrawal symptoms without a notable effect on relapse, and antagonists can produce severe psychiatric symptoms. Fatty acid amide hydrolase inhibitors and cannabidiol demonstrate the most promising efficacy in treating CUD thus far, but research with these compounds is still preliminary. Components of the endocannabinoid system may serve as unique treatment targets with differential efficacy for the treatment of cannabis use disorder as a whole. Further research is needed exploring novel methods for targeting endocannabinoid dysfunction in CUD.

Sex differences in endocannabinoid modulation of rat CA1 dendritic neurotransmission

Endocannabinoid sex differences are present in the rat hippocampus. Specifically, at perisomatic GABAergic synapses, tonic anandamide (AEA) and estrogenic-AEA signaling are active in females but not males. Furthermore, in males, hippocampal eCB function varies along the CA1 pyramidal somatodendritic axis. Constitutive CB1 and tonic 2-AG activity are present at perisomatic GABAergic synapses and lacking at dendritic GABAergic synapses. It is unknown if these eCB somatodendritic differences occur at female GABAergic synapses. Moreover, it is unclear whether eCB sex differences occur at hippocampal glutamatergic synapses. In vitro, field potential (fEPSP) recordings were performed to assess eCB sex differences at rat CA3-CA1 dendritic synapses. At female GABAergic synapses, we observed: 1) constitutive CB1 function, 2) tonic AEA, 3) tonic 2-AG and 3) estrogen (ERα)-driven 2-AG activity. In contrast, only constitutive CB1 and tonic 2-AG activity was observed in males. Sex differences in eCB/CB1 signaling at dendritic synapses appear to shift the basal excitatory/inhibitory balance towards excitation in females and towards inhibition in males. Chronic Mild Stress (CMS) exposure (21 days) in female rats reverses CB1constitutive function and impairs both tonic and ERα-driven eCB signaling. Endocannabinoid sex differences under both normal and stress conditions may contribute to sexual disparities in stress-related neurobehavioral disorders.

Hippocampal inputs engage CCK+ interneurons to mediate endocannabinoid-modulated feed-forward inhibition in the prefrontal cortex.

Connections from the ventral hippocampus (vHPC) to the prefrontal cortex (PFC) regulate cognition, emotion, and memory. These functions are also tightly controlled by inhibitory networks in the PFC, whose disruption is thought to contribute to mental health disorders. However, relatively little is known about how the vHPC engages different populations of interneurons in the PFC. Here we use slice physiology and optogenetics to study vHPC-evoked feed-forward inhibition in the mouse PFC. We first show that cholecystokinin (CCK+), parvalbumin (PV+), and somatostatin (SOM+) expressing interneurons are prominent in layer 5 (L5) of infralimbic PFC. We then show that vHPC inputs primarily activate CCK+ and PV+ interneurons, with weaker connections onto SOM+ interneurons. CCK+ interneurons make stronger synapses onto pyramidal tract (PT) cells over nearby intratelencephalic (IT) cells. However, CCK+ inputs undergo depolarization-induced suppression of inhibition (DSI) and CB1 receptor modulation only at IT cells. Moreover, vHPC-evoked feed-forward inhibition undergoes DSI only at IT cells, confirming a central role for CCK+ interneurons. Together, our findings show how vHPC directly engages multiple populations of inhibitory cells in deep layers of the infralimbic PFC, highlighting unexpected roles for both CCK+ interneurons and endocannabinoid modulation in hippocampal-prefrontal communication.

Novel Pharmacological Approaches for Tourette Syndrome

The need to develop novel pharmacological approaches for TS is balanced by the necessity for interventions to be safe and tolerable. This review provides an overview of studies of medications for TS over the last 3 years. Four studies of deutetrabenazine and valbenazine in TS failed in their primary outcomes. Ecopipam was more effective than placebo in reducing tics in children. Preliminary evidence suggests that a new endocannabinoid modulator (ABX-1431) has an acute effect on tics in adults. Intravenous valproic acid was more effective than oral aripiprazole in children with severe tics. Taurine added to tiapride was superior to placebo added to tiapride in decreasing tics in children. The clonidine patch and vitamin D decreased tics in children compared with baseline assessment. Behavioral therapy was as effective as pharmacotherapy in decreasing tics in children. There is emerging evidence for new treatments for tics, but more methodologically rigorous studies are needed to inform practice recommendations.

Targeting Endocannabinoid Metabolism: an Arrow with Multiple Tips Against Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system. At present, there is no definitive cure, and the few available disease-modifying options display either poor efficacy or life-threatening side effects. There is clear evidence that relapsing-remitting clinical attacks in MS are driven by inflammatory demyelination and that the subsequent disease steps, being irresponsive to immunotherapy, result from neurodegeneration. The endocannabinoid system (ECS) stands halfway between three key pathomechanisms underlying MS, namely inflammation, neurodegeneration and oxidative stress, thus representing a kingpin for the identification of novel therapeutic targets in MS. This review summarizes the current state of the art in the field of endocannabinoid metabolism modulators and their in vivo effects on relevant animal models. We also highlight key molecular underpinnings of their therapeutic efficacy as well as the potential to turn them into promising clinical candidates.

Antiarthritic Effects of a Root Extract from Harpagophytum procumbens DC: Novel Insights into the Molecular Mechanisms and Possible Bioactive Phytochemicals

Harpagophytum procumbens (Burch.) DC. ex Meisn. is a traditional remedy for osteoarticular diseases, including osteoarthritis (OA), although the bioactive constituents and mechanisms involved are yet to be clarified. In the present study, an aqueous H. procumbens root extract (HPE; containing 1.2% harpagoside) was characterized for its effects on synoviocytes from OA patients and phytochemical composition in polyphenols, and volatile compounds were detected. HPE powder was dissolved in different solvents, including deionized water (HPEH2O), DMSO (HPEDMSO), 100% v/v ethanol (HPEEtOH100), and 50% v/v ethanol (HPEEtOH50). The highest polyphenol levels were found in HPEDMSO and HPEEtOH50, whereas different volatile compounds, mainly β-caryophyllene and eugenol, were detected in all the extracts except for HPEH2O. HPEH2O and HPEDMSO were able to enhance CB2 receptor expression and to downregulate PI-PLC β2 in synovial membranes; moreover, all the extracts inhibited FAAH activity. The present results highlight for the first time a multitarget modulation of the endocannabinoid system by HPE, likely ascribable to its hydrosoluble compounds, along with the presence of volatile compounds in H. procumbens root. Although hydrosoluble compounds seem to be mainly responsible for endocannabinoid modulation by HPE, a possible contribution of volatile compounds can be suggested, strengthening the hypothesis that the entire phytocomplex can contribute to the H. procumbens healing properties.

Receptor mechanisms mediating the anti-neuroinflammatory effects of endocannabinoid system modulation in a rat model of migraine.

Calcitonin gene-related peptide (CGRP), substance P and dural mast cells are main contributors in neurogenic inflammation underlying migraine pathophysiology. Modulation of endocannabinoid system attenuates migraine pain, but its mechanisms of action remain unclear. We investigated receptor mechanisms mediating anti-neuroinflammatory effects of endocannabinoid system modulation in in vivo migraine model and ex vivo hemiskull preparations in rats. To induce acute model of migraine, a single dose of nitroglycerin was intraperitoneally administered to male rats. Moreover, isolated ex vivo rat hemiskulls were prepared to study CGRP and substance P release from meningeal trigeminal afferents. We used methanandamide (cannabinoid agonist), rimonabant (cannabinoid receptor-1 CB1 antagonist), SR144528 (CB2 antagonist) and capsazepine (transient receptor potential vanilloid-1 TRPV1 antagonist) to explore effects of endocannabinoid system modulation on the neurogenic inflammation, and possible involvement of CB1, CB2 and TRPV1 receptors during endocannabinoid effects. Methanandamide attenuated nitroglycerin-induced CGRP increments in in vivo plasma, trigeminal ganglia and brainstem and also in ex vivo hemiskull preparations. Methanandamide also alleviated enhanced number and degranulation of dural mast cells induced by nitroglycerin. Rimonabant, but not capsazepine or SR144528, reversed the attenuating effects of methanandamide on CGRP release in both in vivo and ex vivo experiments. Additionally, SR144528, but not rimonabant or capsazepine, reversed the attenuating effects of methanandamide on dural mast cells. However, neither nitroglycerin nor methanandamide changed substance P levels in both in vivo and ex vivo experiments. Methanandamide modulates CGRP release in migraine-related structures via CB1 receptors and inhibits the degranulation of dural mast cells through CB2 receptors. Selective ligands targeting CB1 and CB2 receptors may provide novel and effective treatment strategies against migraine.

Effect of flaxseed oil supplementation on the erythrocyte membrane fatty acid composition and endocannabinoid system modulation in patients with coronary artery disease: a double-blind randomized controlled trial

BackgroundThe endocannabinoid system (ECS) overactivation, associated with increased inflammatory process, may act as a risk factor for coronary artery disease (CAD). Dietary fat may influence the ECS tone. The aim of the present study was to investigate the effect of flaxseed oil on the erythrocyte membrane fatty acid profile and ECS activity by the measurement of serum N-arachydonoil ethanolamine (AEA) and cannabinoid receptor type-1 (CB1), cannabinoid receptor type-2 (CB2), and fatty acid amide hydrolase (FAAH) mRNA expression.MethodsThis clinical trial was performed on 44 patients with CAD. The intervention group received 1.5% fat milk supplemented with flaxseed oil (containing 2.5 g α-linolenic acid or ALA), while the placebo group received 1.5% fat milk for 10 weeks. The fatty acid profile of erythrocyte membrane phospholipids was measured by gas chromatography. The AEA level was determined using an ELISA kit, and real-time PCR was performed to measure CB1, CB2, and FAAH mRNA expression pre- and post-intervention.ResultsFlaxseed oil supplementation resulted in a significant increase in the ALA content and a significant reduction in linoleic acid (LA) content of membrane phospholipids, compared to the placebo group (MD = − 0.35 and 2.89, respectively; P < 0.05). The within group analysis showed that flaxseed oil supplementation caused a significant reduction in both LA and arachidonic acid (MD = − 4.84 and − 4.03, respectively; P < 0.05) and an elevation in the ALA (MD = 0.37, P < 0.001) content of membrane phospholipids compared with the baseline. In the intervention group, a marked reduction was observed in the serum AEA level after 10 weeks of intervention, compared with the placebo group (MD = 0.64, P = 0.016). Changes in CB2 mRNA expression in the flaxseed oil group were significant (fold change = 1.30, P = 0.003), compared with the placebo group.ConclusionFlaxseed oil supplementation could attenuate the ECS tone by decreasing the AEA level and increasing CB2 mRNA expression. Therefore, flaxseed oil may be considered a promising agent with cardioprotective properties.