Cannabinoids and Endocannabinoids, and Prospective Modulation of EC Signaling in Neurodegenerative, Cardiovascular and Allied Disorders

Dr Vinod Nikhra

ABSTRACT

CANNABIS USE AND AVAILABILITY: The Cannabis derivatives have been used for recreational and medicinal purposes since ancient times. Because of the additive potential of cannabis products, their sale, possession and use are variously regulated in different countries throughout the world. Still as a psychoactive drug, cannabis continues to find extensive favour among recreational and medical users in the USA and other countries having led to decriminalise cannabis use for recreational and medicinal purposes.

ECS: RECEPTORS, LIGANDS AND SIGNALING: The endocannabinoid system comprises of the G-protein coupled CB1 and CB2 receptors, their endogenous lipid ligands or endocannabinoids, and synthetic and degrading enzymes. The CB1 is widely expressed within the CNS. The major endocannabinoids, anandamide and 2- arachidonoylglycerol (2-AG) exert cannabino-mimetic effects through the CB1 and CB2 receptors located on presynaptic membranes in the CNS and in peripheral tissues, respectively.

THE CNS REWARD CIRCUITRY: The cannabinoid receptors and their endogenous ligands are widely expressed in the brain and particularly influence the neuronal circuits such as the meso-cortico-limbic pathways. The CB1R signaling influences the motivation for both natural rewards (such as palatable food, sexual activity and social interaction) and modulates the rewarding effects of food and drugs.

PROSPECTS FOR THERAPEUTIC MODULATION OF ECS: The ECS is involved in various physiological and homeostatic functions, and its derangement has been implicated in a multitude of pathological alterations and diseases. Modulating the ECS activity holds a therapeutic promise for neurodegenerative, cardiovascular and inflammatory disorders; obesity, T2DM, metabolic syndrome and cachexia; chemotherapy-induced nausea and vomiting; tissue inflammation and pain, cardiovascular, gastrointestinal, intractable epilepsy and various psychiatric disorders.

KEYWORDS : Anandamide, 2-arachidonoylglycerol, Cannabis, Cannabinoids, Cannabinoid receptors, Endocannabinoids, Endocannabinoid system, Marijuana, Phytocannabinoids, Synthetic cannabinoids, Tetrahydrocannabinol.

1. CANNABIS USE AND AVAILABILITY

1.1 Cannabis Use through Olden Times
The Cannabis derivatives have been used for recreational and medicinal purposes since ancient times (1). Cannabis extracts known by various names, contain more than 500compounds, of which about 110 are cannabinoids (2). Though each cannabinoid has distinct pharmacological properties, tetra-hydro-cannabinol (THC or Δ9THC), cannabinol (CBN) and cannabidiol (CBD) have been studied in details and have a broad spectrum of actions, including analgesic and anti-inflammatory effects. THC acts selectively in the central nervous system (CNS) by binding to both CB1 and CB2 with high affinity, whereas CBD, a non-psychoactive component, has low affinity for CB1 and CB2 receptors (3). When activated, both these receptors inhibit formation of the second messenger cAMP, and modulate other signal transduction pathways such as extracellular regulated kinases, β- arrestin, and ion channels.

1.2 Regulated Availability
Because of the additive potential of cannabis products, their sale, possession and use are variously regulated in the past and presently, strictly or slackly, in different countries throughout the world where the legality of cannabis for medical and recreational use varies in each country, in terms of its possession, distribution, cultivation and consumption and use for the medical conditions (4). The policies in most countries are regulated by the United Nations Single Convention on Narcotic Drugs ratified in 1961, as well as the 1971 Convention on Psychotropic Substances and the 1988 Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.
The use of cannabis for recreational purposes is prohibited in most countries; however, many have adopted a policy of decriminalization to make the simple possession and use in a low dose a non-criminal act (5). Uruguay and Canada have fully legalized the consumption and sale of recreational cannabis, whereas in the United States of America ten states and the District of Columbia have legalized the recreational use of cannabis although it remains federally illegal, though the laws varying from state to state when it comes to the commercial sale (6). The court rulings in Georgia and South Africa have led to the legalization of cannabis consumption. A policy of limited enforcement has also been adopted in many European countries like Spain and the Netherlands where the sale of cannabis is tolerated at licensed establishments. The countries that have legalized the medical use of cannabis include Australia, Canada, Chile, Colombia, Croatia, Cyprus, Finland, Germany, Greece, Israel, Italy, Luxembourg, North Macedonia, Norway, the Netherlands, New Zealand, Peru, Poland, and Thailand. Other countries have restrictive laws allowing the use of certain cannabis-derived pharmaceutical drugs, such as Sativex, Marinol or Epidiolex. Cannabis in India has been used since ancient times and the common cannabis preparations include charas (resin), ganja (flower) and bhang (seeds and leaves), with a milkshake made from bhang. As per the United Nations Office on Drugs and Crime (UNDOC) South Asia, the prevalence of cannabis abuse in India is ~3.2% (7).

(…)