Quality of Life and a Surveillant Endocannabinoid System

Abstract

The endocannabinoid system (ECS) is an important brain modulatory network. ECS regulates brain homeostasis throughout development, from progenitor fate decision to neuro- and gliogenesis, synaptogenesis, brain plasticity and circuit repair, up to learning, memory, fear, protection, and death. It is a major player in the hypothalamic-peripheral system-adipose tissue in the regulation of food intake, energy storage, nutritional status, and adipose tissue mass, consequently affecting obesity. Loss of ECS control might affect mood disorders (anxiety, hyperactivity, psychosis, and depression), lead to drug abuse, and impact neurodegenerative (Alzheimer's, Parkinson, Huntington, Multiple, and Amyotrophic Lateral Sclerosis) and neurodevelopmental (autism spectrum) disorders. Practice of regular physical and/or mind-body mindfulness and meditative activities have been shown to modulate endocannabinoid (eCB) levels, in addition to other players as brain-derived neurotrophic factor (BDNF). ECS is involved in pain, inflammation, metabolic and cardiovascular dysfunctions, general immune responses (asthma, allergy, and arthritis) and tumor expansion, both/either in the brain and/or in the periphery. The reason for such a vast impact is the fact that arachidonic acid, a precursor of eCBs, is present in every membrane cell of the body and on demand eCBs synthesis is regulated by electrical activity and calcium shifts. Novel lipid (lipoxins and resolvins) or peptide (hemopressin) players of the ECS also operate as regulators of physiological allostasis. Indeed, the presence of cannabinoid receptors in intracellular organelles as mitochondria or lysosomes, or in nuclear targets as PPARγ might impact energy consumption, metabolism and cell death. To live a better life implies in a vigilant ECS, through healthy diet selection (based on a balanced omega-3 and -6 polyunsaturated fatty acids), weekly exercises and meditation therapy, all of which regulating eCBs levels, surrounded by a constructive social network. Cannabidiol, a diet supplement has been a major player with anti-inflammatory, anxiolytic, antidepressant, and antioxidant activities. Cognitive challenges and emotional intelligence might strengthen the ECS, which is built on a variety of synapses that modify human behavior. As therapeutically concerned, the ECS is essential for maintaining homeostasis and cannabinoids are promising tools to control innumerous targets.

Keywords: BDNF; THC – tetrahydrocannabinol; anandamide; cannabidiol; diet; exercise; meditation; metabolic programming.

FIGURE 1

The endocannabinoid system (ECS) is composed of lipid endocannabinoids (eCBs), allosteric (lipoxins and resolvins) and peptide (hemopressin derivatives) mediators, their receptors (the cannabinoid type 1 (CB1) and type 2 (CB2), which are activated by phyto- (THC, CBD, and possibly many others) and synthetic cannabinoids (represented by WIN55,212-2, a mixed agonist), metabolic enzymes (FAAH and MAGL, and others) and membrane transporters. Upon activation, CB1 and CB2 signal through fast (Ca²⁺ and K⁺ currents) and/or slow pathways, as cyclic AMP-protein kinase A (cAMP-PKA), ıextracellular signal-regulated (ERK), beta-arrestin, mitogen-activated protein kinase (MAPK) and PI3K; in addition, gene transcription is also turned on by nuclear receptors (PPARγ and others).

FIGURE 2

Dietary patterns, as the Mediterranean (n-3 series enriched) are linked to better physiological parameters decreasing the outcome of several types of diseases, which consists of unsaturated lipids from fish (and olive oil, fruits, vegetables, whole grains and legumes/nuts), impacting on the levels of eCBs; they are influenced by the content of n-3 series derived from alpha-linolenic acid (ALA, 18:3n-3) and n-6 series (enriched in Western diet) derived from linoleic acid (LA, 18:2n-6), essential polyunsaturated fatty acids (PUFA); both AEA and 2-AG are derived from AA of the n-6 family, while N-docosahexaenoyl-ethanolamine (DHEA) and N-eicosapentaenoyl-ethanolamine (EPEA), are derived from the n-3 PUFAs docosahexaenoic acid (DHA) and eicosapentanoic acid (EPA).

FIGURE 3

Cannabimimetic activity of bioactive substances obtained in foods and medicinal plants that if included in the diet could indirectly exert immunomodulatory and beneficial effects to the health. (1) turmeric root; (2) grapes; (3) green tea; (4) Maytenus senegalensis (Lam.) fruit and roots; (5) black peppers; and (6) blueberries. Arrows indicate activation of CB1 and/or CB2 receptors. Dashed arrows indicate inhibition of endocannabinoid transporters (EMT) or enzymatic metabolism via FAAH (Fatty acid amide hydrolase) or MAGL (Monoacylglycerol lipase). DAGL: Diacylglycerol lipase; NAPE-PLD: N-acyl phosphatidylethanolamine phospholipase D; NAT: N-acetyltransferase; 2-AG: 2-Arachidonoylglycerol.

FIGURE 4

Exercise reverts some of the collateral effects of a sedentary lifestyle, and has the potential to improve metabolic, cardiovascular, and immune parameters, providing a better memory, cognition, and sleep cycle regulation, delaying brain aging and chronic and neurodegenerative pathologies. It is a common belief that most of the reward induced by acute or chronic exercises (reward, nociception, mood behavior, anxiety, and performance) are related to the release of endorphins and eCBs, which interact with multiple opioid (mu, kappa, and delta) and cannabinoid receptors; Irrefutable evidence demonstrate that the ECS is a major player in systemic energy metabolism, inflammation, appetite control, and pleasure (acute anxiolysis, analgesia, antidepressant effects, sedation, and euphoria) of the so-called runner’s high.

FIGURE 5

Regular mindfulness practice has consequences on physiological and psychological functioning with performance outcomes in sports, improving sleep quality and work stress. Data on regular yoga users (transcendental meditation) faced modest average reductions in blood pressure. Depression or anxiety have also been alternatively treated with non-conventional interventions, including exercise, yoga, and meditation. In addition, patients with mild-to-moderate Parkinson’s disease, mindfulness yoga has been shown to be effective in improving motor dysfunction and mobility. An experimental study conducted on adults before and after the 4-day Isha Yoga Bhava Spandana Program evaluated AEA, 2-AG, 1-arachidonoylglycerol (1-AG), DEA, oleoylethanolamide (OLA), and BDNF on anxiety and depression through psychological scales. Authors reported changes in major eCBs levels, with increase in AEA, 2-AG, 1-AG, DEA, and BDNF after meditation, suggesting a participation for these biomarkers in the underlying mechanism of meditation (Sadhasivam et al., 2020). Indeed, increased BDNF levels has been linked in meditative practices and brain health in a 3-month yoga and meditation retreat assessed with psychometric measures, circadian salivary cortisol levels, and pro- and anti-inflammatory cytokines (Cahn et al., 2017). In addition, a 3-month meditation retreat has been evaluated on telomerase activity and the experience of stress, with participants controlled in concentrative meditation techniques and collection of peripheral blood mononuclear cell samples for telomerase activity. Authors reported a clear link between meditation and positive psychological change with telomerase activity (Jacobs et al., 2011).

FIGURE 6

Maternal environmental insults such as diet, smoking, and alcohol consumption during critical periods of life, as gestation, may affect the ECS in the hypothalamus-adipose axis of the mother and the progeny. The ECS disruption during early life can program metabolism in a short- and long-term way increasing the risk to develop metabolic syndrome and behavioral changes throughout life.