Science of the ECS

 ECS Overview

The Endocannabinoid System (ECS) is relatively new and recognized as a modulator in endocrine, brain and immune tissue. The system is comprised of endogenous lipid-based ligands known as Endocannabinoids, the receptors they bind (CB1 and CB2) and the biochemical regulators which synthesize or degrade them. Endocannabinoids are synthesized from specific types of Omega 3 and Omega 6 fatty acids. The ECS is a homeostatic regulator controlling energy homeostasis and influencing the food intake centers of the gastrointestinal (GI) tract and central nervous system (CNS).

To better understand the ECSs’ function in the body, lets look at homeostasis. Homeostasis is the balance and steady state equilibrium of internal, physical and chemical conditions maintained by the body. Homeostasis is important for many organs and organisms to survive. Disruption in physiological equilibrium can lead to serious health complications if left untreated. Symptoms can range from headaches, blurry vision, or can be as life threatening as a chest pains and Myocardial Ischemia or cancer.

The ECS regulates homeostasis through lipid synthesis and turnover in adipose tissue and the liver, while also regulating glucose metabolism in skeletal muscle. The ECS is also important for its role in cognition, memory, appetite, immune system response, inflammation, cancer, epilepsy, female reproduction, pregnancy (pre and postnatal development), analgesia, thermoregulation and even physical exercise. Through these endogenous lipids and receptors, the ECS is triggered for its beneficial effects.

ECS History

The Godfather of cannabis research, Dr. Raphael Mechoulam, first identified and isolated tetrahydrocannabinol (THC) in 1964. Historically THC is known for is psychoactive properties. Dr. Mechoulam also isolated cannabidiol (CBD), a non-psychotropic cannabinoid with antioxidant and neuroprotective characteristics. Cannabinoids made in the body (from within) and endocannabinoids. Cannabinoids naturally occurring in plants are Phytocannabinoids.

In 1990, Lisa Matsuda, a molecular biologist at the National Institute of Mental Health, and her colleagues, identified THC-sensitive receptor in lab rat brains. This was the first time the Endocannabinoid system was defined. The endogenous cannabinoid system was named after the plant that led to its discovery. Soon after, Dr. Mechoulam discovered two endocannabinoids: anandamide and 2-arachidonoylglycerol (2-AG). Endocannabinoids are cannabinoids made within the body by the brain. When endocannabinoids bind to cannabinoid receptors, they trigger a cellular response which is diminished or amplified. These cellular responses range from euphoria to anti-inflammatory.

Endocannabinoids

Endocannabinoids are bioactive lipids that have the potential to signal through cannabinoid receptors to modulate the functional activities of a variety of cells. Through proper diet and exercise the body synthesizes these endocannabinoids which have analogous Phyto-cannabinoids like those in Cannabis.

• Endocannabinoids are endogenous lipid-based signaling molecules that are synthesized or made from dietary fatty acids and bind to specific G protein-coupled cannabinoid receptors CB1 and CB2.
• The two best illustrated endogenous ligands are anandamide (AEA) and 2-arachindonoylglycerol (2-AG).
  • The others include: noladin ether, dihomo-γ-linolenoylethanolamide, virodhamine, oleamide, docosahexaenoylethanolamide, eicosapentaenoylethanolamide, sphingosine, docosatetraenoylethanolamide, N-arachidonoyldopamine, N-oleoyldopamine and haemopressin.
• Anandamide AEA is also refered to as Arachidonoylethanolamine.
  • AEA is an endogenous cannabinoid that has a stronger affinity and binds tightly to the cannabinoids CB1 and CB2 receptors.
  • AEA is analogous to the phytocannabinoid THC. THC helps stimulate AEA production.
  • Regulation of sleep pattern and pain maybe partially influenced by Anandamide. In different pain research studies, Anandamide was shown to promote analgesic actions by binding strictly to peripheral CB1 receptors.
  • AEA also plays a role in regulation of metabolism, pleasure and reward.
• 2-AG is an endogenous agonist of the CB1 receptor. 

Endocannabinoid’s and their chemical structure

Phyto-cannabinoids

• THC from the cannabis plant imitates AEA and 2AG much the same way that opioids from the poppy plant imitate endorphins produced by the body. This  causes the psychoactive “high” from Cannabis Sativa vs Hemp.
  • THC has been shown to be a  bronchodilator, neuroprotective antioxidant, psychoactive agent, analgesic, muscle relaxant and antispasmodic, antipruritic agent in cholestatic jaundice, and has 20 times the anti-inflammatory power of aspirin and twice that of hydrocortisone .
• CBD has the ability to help a wide range of conditions including diabetes, epilepsy, chronic pain, schizophrenia, alcoholism, rheumatoid arthritis, antibiotic-resistant infections, PTSD and various neurological disorders.
  • CBD is an analgesic, anticonvulsant, anti-nausea, and cytotoxic in breast cancer.
  • CBD has also displayed powerful activity against methicillin-resistant Staphylococcus aureus (MRSA).
• CBG has been shown to stimulate bone and brain cell growth.
  • CBG studies suggests GABA uptake inhibition greater than THC or CBD, which could suggest muscle relaxant properties.
  • CBG is shown to be an effective cytotoxin in high dosage on human epithelioid carcinoma.
  • CBG has demonstrated some  antifungal effects as well.
  • CBG has analgesic and anti-erythemic effects.
  • CBG  and CBD are the most effective phytocannabinoid against breast cancer.
  • CBG inhibits keratinocyte proliferation which would suggest treatments for psoriasis.
• CBN acts as a mild sedative and sleep aid.
  • CBN was judged inactive when tested alone in human volunteers, but produced greater sedation combined with THC.
  • CBN demonstrates anticonvulsant, anti-inflammatory and potent effects against MRSA.
  • CBN stimulates the recruitment of quiescent mesenchymal stem cells in marrow, suggesting promotion of bone formation.
  • CBN at high concentrations inhibits breast cancer resistance protein.
• THC-A is anti-inflammatory and can suppress muscle spasms.
  • THC-A turns into THC when the plant is vaporized, smoked, or cooked into edibles.
• CBC Acid is anti-bacterial and antifungal.
  • CBCa has demonstrated analgesic activity, been shown to reduce THC intoxification in mice, demonstrated antibiotic and antifungal effects, and shown cytotoxicity in cancer cell lines.
  • CBC has recently been shown to increase the viability of adult neural stem progenitor cells essential for brain plasticity and suggestive of neurogenesis.
• CBC is analgesic, anti-inflammatory, anti-proliferative in cancer, can reduce anxiety, and has been shown to stimulate bone growth.
• THCV can promote bone growth, anti- epileptic and can suppress appetite. It also helps regulate blood sugar, and can help with type 2 diabetes.
  • THCV shows anticonvulsant properties in rodent pyriform cortex and cerebellum
  • THCV reveals a CB2-based ability to suppress hyperalgesia and inflammation in mice.
• CBDV has also been shown to be an anticonvulsant

Terpenes 

• Terpenoids account for the aroma of cannabis and are essential oil components of the plant.
• Pinene is the most widely encountered terpenoid in nature.
  • At low exposure levels, pinene is anti-inflammatory and a bronchodilator.
• Myrcene is very common terpenoid in cannabis.
  • Myrcene reduces inflammation via prostaglandin E-2.
  • Myrcene blocks hepatic carcinogenesis by aflatoxin.
• Limonene is the second most abundant terpenoid in nature.
  • Limonene stimulates apoptosis of breast cancer cells.
  • Strong radical scavenging properties can be found in citrus essential oils with terpenoid profiles resembling those in cannabis.
• Linalool is a terpenoid that has shown to have psychotropic anxiolytic activity.
  • Linalool has shown to be sedating upon inhalation to mice.
  • Linalool has confirmed its anticonvulsant and anti-glutamatergic activity.
• Nerolidol is a terpenoid alcohol with sedative properties.Nerolidol has potent antimalarial agent.
• Phytol is a terpenoid present in cannabis extracts.
  • Phytol was confirmed to prevent vitamin A-induced teratogenesis by inhibiting conversion of retinol.
  • Phytol has shown to increase GABA expression.

Cannabinoid Receptors

• Phytocannabinoids such as CBD and THC, and the body’s own natural endocannabinoids, anandamide (AEA) and 2-AG, generate effects by binding to and activating the G protein coupled CB1 receptor and the CB2 receptor.
• CB1 receptors are expressed more widely throughout the body than CB2.
  • The Central Nervous System is abundant with CB1, particularly in the brain where it mediates the infamous effects of the typical Cannabis high (memory blocking, pain control and increased appetite).
  • CB1 receptors are located on either of the two nerve terminals: excitatory, which excite or increase the activity of target neurons, and inhibitory, which inhibit or reduce activity.
  • The ability for CB1 to excite or inhibit the synaptic signal, demonstrates its homeostatic ability, by increasing or decreasing message flow between cells.
  • Stimulating central CB1 receptors induces increase food intake and thereby weight gain. However, this is only seen in acute cases
• CB2 receptors are more commonly seen in the immune system and are implicated to be involved in pain as well as inflammatory responses.
  • CB2 receptors are also located in the central nervous system and have been shown functioning during certain kinds of inflammatory responses.
  • CB2 expression is most abundant in immune cells, where it is implicated to have innumerable immunosuppressive effects, including inhibition of proinflammatory cytokine production and signaling apoptosis and autophagia in breast cancer.
  • Evidence shows that the CB1/CB2 receptors increase in density during diseased states.
  • The body’s mechanism is to increase the receptor sites during disease states. This allows for more cannabinoids to bind the receptor.
  • The increase in cannabinoids bind to receptors. We then begin to see a decrease in disease symptoms and or inhibition of the progression of disease.

Cannabinoid Degraders

• Cannabinoids are fatty acids and are therefore broken down broken down by enzymes in the body such as hydrolase or lipase. Once degraded they no longer function.
• FAAH is Fatty Acid Amide Hydrolase.FAAH degrades AEA near the synapses it activates.
  • Blocking the enzyme FAAH has similar results as increasing the amount of AEA.
• 2-AG is degraded by MonoAcylGlycerol Lipase (MAGL); it is the main enzyme responsible for inactivating 2-AG.
• Current studies are working on inhibiting the above enzymes to increase the levels of AEA and 2-AG.

Source: Drug Discovery Today, Vol 22, Issue 1, January 2017