Endocannabinoid system and cardiometabolic risk factors: A comprehensive systematic review insight into the mechanistic effects of omega-3 fatty acids.

Life Sciences“Increased levels of endocannabinoids, 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (AEA) have a pathophysiological role in the setting of cardiometabolic diseases. This systematic review was carried out to appraise the effect of omega-3 on cardiometabolic risk factors by highlighting the mediating effect of endocannabinoids.

Eleven animal studies and two human studies showed a marked reduction in 2-AG and AEA levels following intake of omega-3 which correlated with decreased adiposity, weight gain and improved glucose homeostasis. Moreover, endocannabinoids were elevated in three studies that replaced omega-3 with omega-6.

Omega-3 showed anti-inflammatory properties due to reduced levels of inflammatory cytokines, regulation of T-cells function and increased levels of eicosapentaenoyl ethanolamide, docosahexaenoyl ethanolamide and oxylipins; however, a limited number of studies examined a correlation between inflammatory cytokines and endocannabinoids following omega-3 administration.

In conclusion, omega-3 modulates endocannabinoid tone, which subsequently attenuates inflammation and cardiometabolic risk factors. However, further randomized clinical trials are needed before any recommendations are made to target the ECS using omega-3 as an alternative therapy to drugs for cardiometabolic disease improvement.”

https://www.ncbi.nlm.nih.gov/pubmed/32184122

“Endocannabinoid system (ECS) may mediate favorable effects of omega-3 fatty acids in cardiometabolic disorders. Omega-3 fatty acids showed anti-inflammatory effects due to increased levels of ethanolamide and oxylipins. Plant-derived omega-3 may be as effective as animal-derived omega-3 in ECS modulation. Omega-3 may have a potential to be an alternative to drugs for cardiometabolic disease improvement.”

https://www.sciencedirect.com/science/article/abs/pii/S0024320520303040?via%3Dihub

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Anticancer effects of n-3 EPA and DHA and their endocannabinoid derivatives on breast cancer cell growth and invasion.

Prostaglandins, Leukotrienes and Essential Fatty Acids Home“The anticancer effects of the omega-3 long chain polyunsaturated fatty acids (LCPUFA), EPA and DHA may be due, at least in part, to conversion to their respective endocannabinoid derivatives, eicosapentaenoyl-ethanolamine (EPEA) and docosahexaenoyl-ethanolamine (DHEA).

Here, the effects of EPEA and DHEA and their parent compounds, EPA and DHA, on breast cancer (BC) cell function was examined. EPEA and DHEA exhibited greater anti-cancer effects than EPA and DHA in two BC cells (MCF-7 and MDA-MB-231) whilst displaying no effect in non-malignant breast cells (MCF-10a).

Both BC lines expressed CB1/2 receptors that were responsible, at least partly, for the observed anti-proliferative effects of the omega-3 endocannabinoids as determined by receptor antagonism studies. Additionally, major signalling mechanisms elicited by these CB ligands included altered phosphorylation of p38-MAPK, JNK, and ERK proteins.

Both LCPUFAs and their endocannabinoids attenuated the expression of signal proteins in BC cells, albeit to different extents depending on cell type and lipid effectors. These signal proteins are implicated in apoptosis and attenuation of BC cell migration and invasiveness.

Furthermore, only DHA reduced in vitro MDA-MB-231 migration whereas both LCPUFAs and their endocannabinoids significantly inhibited invasiveness. This finding was consistent with reduced integrin β3 expression observed with all treatments and reduced MMP-1 and VEGF with DHA treatment.

Attenuation of cell viability, migration and invasion of malignant cells indicates a potential adjunct nutritional therapeutic use of these LCPUFAs and/or their endocannabinoids in treatment of breast cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/31679810

https://www.plefa.com/article/S0952-3278(19)30112-7/fulltext

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Ameliorative effects of hempseed (Cannabis sativa) against hypercholesterolemia associated cardiovascular changes.

Nutrition, Metabolism and Cardiovascular Diseases“Hypercholesterolemia (HC) is a major risk factor for cardiovascular (CV) diseases, that are the major cause of mortality worldwide.

Free radicals mediated oxidative stress is a critical player in HC-associated pathophysiological insults including atherosclerosis. Unwanted side effects associated with statins, COX-2 inhibitors, and other synthetic drugs limit their use. Thus, modulation of oxidative stress during HC using green pharmaceuticals seems an appropriate approach against deleterious CV consequences without noticeable side-effect.

In this regard, owing to an abundance of proteins, fiber and optimal ratios of omega 6 PUFA: omega-3 PUFA in Hempseed (HS), we aim to exploit its anti-inflammatory and antioxidant properties to ameliorate HC- associated CV effects.

CONCLUSIONS:

Current study evidently demonstrates that the anti-hypercholesterolemic effects of HS are mediated through redox-sensitive modulation of inflammatory pathways.”

https://www.ncbi.nlm.nih.gov/pubmed/31668458

“Hypercholesterolemia (HC) associated oxidative stress is central to cardiovascular (CV) diseases. Unwanted side effects associated with statins and other synthetic drugs limits their use. Modulation of HC associated oxidative stress by Hempseed (HS) was based on its anti-inflammatory/antioxidant properties. HS exhibited intense anti-inflammatory and anti-atherosclerotic effect via redox modulation of PG biosynthetic pathway. The multipronged approach to characterize HC associated CV effects and its modulation by HS is novel.”

https://www.nmcd-journal.com/article/S0939-4753(19)30345-X/fulltext

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Effects of feeding a source of omega-3 fatty acid during the early postpartum period on the endocannabinoid system in the bovine endometrium.

Theriogenology

“A total of sixteen Holstein dairy cows (35 ± 1.1 kg/d of milk yield) were randomly assigned to consider the effects of feeding omega-3 sources on endometrial endocannabinoids system (ECS) genes expression to understand the effect mechanism of omega-3 on reproductive performances during the early postpartum period to evaluate to what extent can be intervened in reproduction, e.g. via nutrition to improve fertility. Experimental diets were 1) either protected palm oil (control) or 2) extruded linseed (linseed). Cows (n = 16) were fed from calving date to 70 days in milk (DIM). There was no difference between groups (mean ± S.E.M.) in parity (3.0 ± 1.00) or body condition score (BCS) at calving day (3.1 ± 0.25). At 30 DIM, the ovulatory cycles of cows were synchronized using two injections of prostaglandin F2α (PGF2α) with a 14-day interval. On day 15 of synchronized estrous cycle (d0 = ovulation) uterine endometrial biopsies were collected to evaluate the expression of genes related to ECS (endocannabinoid receptor (CNR2), N-acyl phosphatidylethanolamine phospholipase D (NAPEPLD), fatty acid amide hydrolase (FAAH), N-acylethanolamine acid amidase (NAAA), monoglyceride lipase (MGLL)) and PGF2α. Results showed that dry matter intake and milk yield were not affected by diets. Uterine endometrial NAAA (7.69 fold), and MGLL (1.96 fold) genes expression were greater (P < 0.05) in cows fed linseed compared with control ones. The messenger RNA (mRNA) levels of CNR-2 (4.26 fold), and NAPEPLD (20.0 fold) were decreased (P < 0.05) in animals fed linseed compared to control cows. The expression of mRNA for the FAAH was not influenced by the diets. First service conception rate was greater in cows fed linseed compared to control cows (75 vs. 25%). Pregnancy loss within 32-60 day after artificial insemination (AI) was lower in cows fed linseed compared to control cows (0 vs. 100%). In conclusion these data demonstrated that positive effect of omega-3 on reproduction may act through a mechanism involving the ECS. However, more studies to be undertaken to confirm these results.”

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Interplay Between n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair.

 Lipids

“The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFAs) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA), has shown beneficial effects on learning and memory, neuroinflammatory processes, and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids.

The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most widely studied endocannabinoids and are both derived from phospholipid-bound ARA. The endocannabinoid system also has well-established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids.

Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair.”

https://www.ncbi.nlm.nih.gov/pubmed/28875399

https://link.springer.com/article/10.1007%2Fs11745-017-4292-8

“The seed of Cannabis sativa L. has been an important source of nutrition for thousands of years in Old World cultures. Technically a nut, hempseed typically contains over 30% oil and about 25% protein, with considerable amounts of dietary fiber, vitamins and minerals. Hempseed oil is over 80% in polyunsaturated fatty acids (PUFAs), and is an exceptionally rich source of the two essential fatty acids (EFAs) linoleic acid (18:2 omega-6) and alpha-linolenic acid (18:3 omega-3). The omega-6 to omega-3 ratio (n6/n3) in hempseed oil is normally between 2:1 and 3:1, which is considered to be optimal for human health. Hempseed has been used to treat various disorders for thousands of years in traditional oriental medicine.”  http://link.springer.com/article/10.1007%2Fs10681-004-4811-6

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Modulation of Long-Term Potentiation of Cortico-Amygdala Synaptic Responses and Auditory Fear Memory by Dietary Polyunsaturated Fatty Acid.

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“Converging evidence suggests that an imbalance of ω3 to ω6 polyunsaturated fatty acid (PUFA) in the brain is involved in mental illnesses such as anxiety disorders.

We previously reported that the dietary ratio of ω3 to ω6 PUFA alters this ratio in the brain, and influences contextual fear memory.

In addition to behavioral change, enhancement of cannabinoid CB1 receptor-mediated short-term synaptic plasticity and facilitation of the agonist sensitivity of CB1 receptors have been observed in excitatory synaptic responses in the basolateral nucleus of the amygdala (BLA).

These results suggest that the balance of ω3 to ω6 PUFA has an impact on fear memory and cortico-amygdala synaptic plasticity, both in a CB1 receptor-dependent manner.”

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Association between plasma endocannabinoids and appetite in hemodialysis patients: A pilot study.

“Uremia-associated anorexia may be related to altered levels of long chain n-6 and n-3 polyunsaturated fatty acid (PUFA) derived circulating endocannabinoids (EC) and EC-like compounds that are known to mediate appetite. Our study’s hypothesis was that such molecules are associated with appetite in patients with end-stage renal disease. A cross-sectional observational study was performed in 20 chronic hemodialysis patients (9 females, 11 males) and 10 healthy female controls in whom appetite was assessed using the Simplified Nutritional Appetite Questionnaire (SNAQ) and blood drawn in the fasting (and when applicable) pre-dialysis state. Blood levels of PUFA and EC were also measured. Higher blood levels of the long chain n-6 fatty acid 20:4n6 (arachidonic acid) and lower levels of the long chain n-3 fatty acid 20:5n3 (eicosapentaenoic acid) were observed in female hemodialysis patients compared to controls. No differences were observed between male and female patients. In female study participants strong correlations between specific EC-like compounds and total SNAQ scores were noted, including with the n-6 PUFA derived linoleoyl ethanolamide (L-EA; ρ=-0.60, P<.01) and the n-3 PUFA derived docosahexaenoyl ethanolamide (DH-EA; ρ=0.63, P<.01). The L-EA:DH-EA ratio was most strongly associated with the SNAQ score (ρ=-0.74, P≤.001), and its questions associated with appetite (ρ=-0.69, P≤.01) and satiety (ρ=-0.81, P≤.001). These findings support a link between circulating EC and appetite in hemodialysis patients.”

http://www.ncbi.nlm.nih.gov/pubmed/27333956

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An Increase in the Omega-6/Omega-3 Fatty Acid Ratio Increases the Risk for Obesity.

“In the past three decades, total fat and saturated fat intake as a percentage of total calories has continuously decreased in Western diets, while the intake of omega-6 fatty acid increased and the omega-3 fatty acid decreased, resulting in a large increase in the omega-6/omega-3 ratio from 1:1 during evolution to 20:1 today or even higher.

This change in the composition of fatty acids parallels a significant increase in the prevalence of overweight and obesity.

Experimental studies have suggested that omega-6 and omega-3 fatty acids elicit divergent effects on body fat gain through mechanisms of adipogenesis, browning of adipose tissue, lipid homeostasis, brain-gut-adipose tissue axis, and most importantly systemic inflammation.

Prospective studies clearly show an increase in the risk of obesity as the level of omega-6 fatty acids and the omega-6/omega-3 ratio increase in red blood cell (RBC) membrane phospholipids, whereas high omega-3 RBC membrane phospholipids decrease the risk of obesity.

Recent studies in humans show that in addition to absolute amounts of omega-6 and omega-3 fatty acid intake, the omega-6/omega-3 ratio plays an important role in increasing the development of obesity via both AA eicosanoid metabolites and hyperactivity of the cannabinoid system, which can be reversed with increased intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

A balanced omega-6/omega-3 ratio is important for health and in the prevention and management of obesity.”

http://www.ncbi.nlm.nih.gov/pubmed/26950145

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Hempseed as a nutritional resource: An overview

“The seed of Cannabis sativa L. has been an important source of nutrition for thousands of years in Old World cultures. Technically a nut, hempseed typically contains over 30% oil and about 25% protein, with considerable amounts of dietary fiber, vitamins and minerals. Hempseed oil is over 80% in polyunsaturated fatty acids (PUFAs), and is an exceptionally rich source of the two essential fatty acids (EFAs) linoleic acid (18:2 omega-6) and alpha-linolenic acid (18:3 omega-3). The omega-6 to omega-3 ratio (n6/n3) in hempseed oil is normally between 2:1 and 3:1, which is considered to be optimal for human health. Hempseed has been used to treat various disorders for thousands of years in traditional oriental medicine.” http://link.springer.com/article/10.1007%2Fs10681-004-4811-6

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The cardiac and haemostatic effects of dietary hempseed

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“Cannabis sativa L. is an annual plant in the Cannabaceae family. It has been an important source of food, fiber, medicine and psychoactive/religious drug since prehistoric times. Hemp has a botanical relationship to drug/medicinal varieties of Cannabis. However, hempseed no longer contains psychotropic action and instead may provide significant health benefits. Hempseed has an excellent content of omega-3 and omega-6 fatty acids. These compounds have beneficial effects on our cardiovascular health.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2868018/

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