Cannabinoids are a class of C21 compounds found in resin generated by the glandular hairs of Cannabis sativa L. The phytocannabinoid tetrahydrocannabinol (THC) (Delta9-THC or Delta8-THC), the principal psychoactive ingredient in cannabis, is the most well-known cannabinoid. Cannabidiol (CBD) is another important component of the plant (ref. ScienceDirect).

Cannabinoids are present in all cannabis formulations, with Delta9-tetrahydrocannabinol serving as the primary psychoactive element (Delta9-THC). Delta9-THC-like pharmacological activities are shared by all cannabinoid medicines, whether natural or synthetic. To induce their behavioral effects, all cannabinoids bind as direct agonists to cannabinoid receptors in the brain. Endogenous cannabinoids, which include anandamide and 2-arachidonylglycerol (2-AG), bind as agonists to cannabinoid receptors and are broadly dispersed throughout the brain, with significant concentrations in reward- and pain-related neurocircuits.

Mechanism of Action

Cannabinoids function as retrograde neuromodulators that are generated in neurons' postsynaptic components as needed. This occurs as a result of receptor-stimulated synthesis from membrane lipid precursors in response to depolarization, and they are discharged from cells soon after formation. Cannabinoids' behavioral effects are transmitted by two transmembrane G-protein-coupled opioid receptors – cannabinoid-1 (CB1) and cannabinoid-2 (CB2) – and subsequent modifications in second-messenger gene transcription The CB1 receptor is thought to be substantially responsible for cannabis' intoxication effects, as well as a variety of behavioral and physiological impacts. Cannabinoids' intoxication effects are thought to be mediated through activities on cannabinoid receptors in the mesocorticolimbic dopamine system's origin (ventral tegmental region) and terminal areas (nucleus accumbens) and extended amygdala. It is thought that cannabinoids' addictive potential stems from their powerful within-system neuroadaptations (signal transduction mechanisms) and between-system neuroadaptations (neurocircuitry modifications) in the motivational and stress systems of the brain (ref. Wikipedia).

 

Where Are Cannabinoids Found?

The first cannabinoids found were those originating from the hemp plant, Cannabis sativa. Delta9-tetrahydrocannabinol is the most potent psychoactive chemical generated from cannabis (THC). Cannabinol (CBN) and cannabidiol (CBD) are two more plant-derived cannabinoids (CBD). Cannabidiol (CBD) is another key component, accounting for around 40% of the plant resin extract. Hash oil, a liquid, is the most potent form of hemp plant extract. The dried resins are referred to as 'hashish.' Dried flowering tops and leaves are smoked in the form of a cigarette, and it is usually referred to as a "joint" or "reefer." This plant has been utilized both recreationally and medicinally for thousands of years.

Cannabinoids, a structurally varied family of chemicals with a wide range of biological targets, are divided into three classes based on their origins: phytocannabinoids, endocannabinoids, and synthetic cannabinoids. Phytocannabinoids are found in the plant's stalks, leaves, flowers, and seeds, as well as the resin secreted by the female plant. A 'joint' constructed of skunkweed, netherweed, and other powerful C. Sativa subspecies may contain 150 mg of THC, or 300 mg if laced with hashish oil. Endocannabinoids are naturally created by the body and act as intercellular lipid mediators. These are thought to be synthesized on demand rather than manufactured and stored for later use. Synthetic cannabinoid receptor agonists are a varied set of chemically unrelated substances that work in the same way as Delta9-THC, but are stronger.

Although the term marijuana became widespread in the 1930s, it was initially a slang term for the medical portion of cannabis smoked by Mexican soldiers. Pharmacological studies on this and other phytocannabinoids began in the 1940s and 1950s. Because it was established that phytocannabinoids' pharmacological efficacy is greatly reliant on chemical structure, it became increasingly clear that activity was linked to receptor binding (ref. ResearchGate).

History of cannabinoids

The first individual cannabinoid was discovered in 1940 when British scientist Robert S. Cahn reported the incomplete structure of Cannabinol (CBN), which he later identified as fully formed. Cannabidiol, the first cannabinoid, was discovered two years later, in 1942, by an American chemist named Roger Adams (CBD).

 

Cannabinoid Research in its Early Stages

During the early days of cannabis study, scientists had only a hazy understanding of cannabinoid structure and a hazy comprehension of the biological makeup contained within the plant. As a result, early researchers were unable to establish which molecule was generating which impact.

Dr. Raphael Mechoulam identified the stereochemistry of CBD in 1963, which was the first step toward understanding the effects of individual cannabinoids. A year later, Mecholam identified the stereochemistry of Tetrahydocannabinol (THC), revealing the cannabinoid's direct relationship to the euphoric effects associated with marijuana usage and disassociating CBD as a mind-altering chemical.

CBD was initially thought to be a natural predecessor of THC due to its chemical similarities and ease of synthetic conversion. CBD and THC, on the other hand, are now recognized to be synthesized independently in the cannabis plant from the precursor Cannabigerol CBG. (ref CBDorigin).

As research progressed, a watershed moment occurred when New Mexico passed the Controlled Substances Therapeutic Research Act in 1978, which legally recognized cannabis's therapeutic potential. During the 1980s, Dr. Mechoulam and his colleagues conducted a study on the possible use of CBD as a hypnotic for the treatment of epilepsy.

In the trial, Mechoulam and his colleagues gave daily doses of 300mg of CBD to a group of eight subjects. After only four months of medication, half of the individuals no longer had seizures, while the other half had a reduction in the frequency of their seizures. This was a tremendous discovery with the potential to alter the lives of more than 50 million epilepsy patients worldwide. Unfortunately, because of the stigmas associated with cannabis at the time, the discovery was not as widely recognized as any other form of breakthrough. Dr. Mechoulam's and the other early cannabis pioneers' efforts, however, would not be in vain.

Less than a decade later, interest in cannabis medicinal uses resulted in the discovery of additional cannabinoids, a better knowledge of cannabinoid structure, and the development of new cannabinoids, considering the incredible breakthrough of our body's Endocannabinoid System, a network of receptors that interact with cannabinoid receptors. As studies advanced, there was an explosion of interest across the United States. (ref. CBDorigin).