Cannabis, Components, Synthetic Analogues and Endogenous Targets

Cannabis, Components, Synthetic Analogues, and Endogenous Targets


The recent debate on the possible legalization of the consumption of Cannabis sativa, not only for therapeutic purposes, has reactivated interest in several countries in this ancient plant and its industrial, medicinal, and recreational exploitation. However, when talking about cannabis, very few remember that its actual or alleged properties are due to its chemical components:

its fibers (which are composed of complex carbohydrates and proteins) for use in the textile industry and other technological sectors;

the proteins and fatty acids (and also fibers) from its seeds for use in food and, possibly, in the nutraceutical industry; and

for the recreational and therapeutic use of the cannabis flower, a typical class of compounds of mixed biosynthetic origin, cannabinoids.

In fact, several varieties of C. Sativa with different chemical compositions justify their various uses. Consequently, when we talk about the possibility of separating the recreational activity (i.e., euphoria and altered moods) of cannabis preparations from their possible therapeutic action (against many conditions from spasticity, inflammation, pain, seizures, and neurodegenerative diseases, cancer, and metabolic syndrome), to safely develop treatments for this plant, 

Is Cannabinoids THC

We need to understand how these types of how these preparations differ in their compositions of cannabinoids that exert psychotropic and therapeutic effects (that is, i.e., Δ9tetrahydrocannabinol [THC]) or just the latter (e.g., cannabidiol [CBD]). Also, cannabinoids from all plants are present in cannabis flowers as precursors of carboxylic acid, which is produced after drying or by heat-induced decarboxylation. Even for a certain Marijuana Dispensary, the type of cannabinoids it contains depends on the storage and treatment of the flower.

Finally, cannabinoids are lipophilic compounds (which do not dissolve easily in water) and, therefore, any cannabis flower preparation intended to be used for therapeutic purposes. 

It must consider that routes of administration, such as oral infusions, cannot provide sufficient amounts of these compounds to produce the desired effect. These are made after desiccation or heat-induced decarboxylation, even for a particular cannabis strain. The type of cannabinoids it contains depends on the storage and treatment of the flower.

Finally, cannabinoids are lipophilic compounds (which do not dissolve easily in water) and, therefore, any cannabis flower preparation intended to be used for therapeutic purposes. 

This lengthy preamble is intended to state that the first thing to remember about cannabis is that there is no “one type of cannabis,” and therefore, when someone asks, “What do you think of the therapeutic use of cannabis? “Unfortunately, the right answer may be a completely different set of questions:” What kind? Saved and managed how? In fact, I think it is much better to talk about the potential for the therapeutic effects of cannabinoids, just as the layperson is now familiar with the nutritional properties of cannabis seeds and those of other foods due to their particular proteins, fibers, and fatty acids.

What do we know about cannabinoids? 

We know a lot about THC, whose pharmacological effects on mammals and humans are almost exclusively due to their ability to activate two G-protein-coupled receptors (GPCR) on the outer membrane of the cell, that of cannabinoid receptors type 1 (CB1) and type 2 (CB2). The euphoria caused by the properties of THC is due to the first of these two receptors. Therefore, when the CB2 receptor was discovered, it was immediately believed that it could be selectively targeted by synthetic ligands that would produce a series of therapeutic effects (against, among others, various inflammatory. 

and autoimmune disorders, pain, fibrosis, and osteoporosis) without the unwanted psychotropic effects of THC. In fact, tremendous activity is taking place in developing these compounds for clinical evaluation and as possible substitutes for THC (Marinol, 

dronabinol) and its derivatives (for example, nabilone).

It was already clear that not only the defective activity of the CB1 receptors but also the hyperactivity of this receptor could be the basis of the disease in animal models (for example, obesity, hyperphagia, and recovery of addictions,

Cannabinoids in Weed 

Schizophrenia, metabolic disorders, hepatorenal fibrosis, and pulmonary) synthetic compounds antagonists of the action of CB1 receptors were developed and are effective in clinical trials against obesity and type 2 diabetes. Unfortunately, unlike CB2, CB1 is abundant in the neurons of the mammalian brain, and now it is known that it is imperative to counteract the consequences of stress.

The presence of CB1 and CB2 receptors in mammals pointed to endogenous ligands for these receptors. These metabolites, anandamide, and 2-arachidonoylglycerol (2-AG) were discovered in the 1990s and were soon called endocannabinoids. The enzymes responsible for its biosynthesis and inactivation were identified and characterized between the end of the last century and the beginning of the present. 

These discoveries and the finding that tissue concentrations of endocannabinoids are altered in animal models of most disorders during physiological changes (night and day cycles, short-term food deprivation and re-feeding, 

Estrous revolution, short-term stressful stimuli at the cellular and organic level, etc. ) or pathological alterations in cell homeostasis led to the suggestion that the endocannabinoid system, that is, the set of endocannabinoids, 

their metabolic enzymes and the CB1 and CB2 receptors are activated “on-demand” in a cell-specific way and time to restore homeostasis.

Furthermore, it became clear that, precisely as in the other endogenous pro-homeostatic signaling systems (i.e., the immune system), the endocannabinoid system can become unhinged for a long time by disturbances of cells and organs in steady-state, 

and therefore, sometimes contributes to the symptoms of the disease or its development. These hypotheses have been increasingly confirmed during the last two decades, which leads to the belief that inhibitors of endocannabinoid biosynthesis or inactivation could substitute for CB1 receptor agonists (for example, 

THC and its synthetic analogs) or antagonists, respectively, as more specific pharmacotherapy and, therefore, safer, 

Since they would only act “when and where,” endocannabinoids are produced to play a protective or counter-protective action.

Consequently, many efforts have been made in the last 15 years to develop clinically safe inhibitors for the production or degradation of anandamide and 2-AG. This strategy, however, has been complicated by the fact that the biosynthetic and catabolic pathways of endocannabinoids are redundant and shared with other bioactive lipid mediators that do not act on cannabinoid receptors but have molecular targets that often operate in the opposite way to CB1 receptors and CB2. 

In fact, we now know that there are probably hundreds of such endocannabinoid-type mediators and that they constitute an actual “extended endocannabinoid system” or endocannabinoidome. 

Therefore, the inhibition of endocannabinoid inactivation, for example, will improve the levels of endocannabinoid-type molecules and, 

subsequently, modulate the activity of the targets for these molecules.

Recent difficulties in the cannabis dispensary development of endocannabinoid-based drugs coincided with a renewed enthusiasm toward exploiting the potential therapeutic effects of non-psychotropic plant cannabinoids. In fact, and curiously, of the around 100 such compounds that have been found to date in the various varieties of C. Sativa, only THC is capable of activating CB1 (and CB2) receptors which, by the way, in my opinion, should be called “THC receptors” instead of “cannabinoid receptors.” We must also consider that no other type of cannabinoid has been found so far that only acts on a specific type of receptor that seems to be modulating, not necessarily with great power, 

The activity of any previously known ones. or “new” orphan recipients.

Specifically, the Cannabis plant has been the subject of an enormous number of pharmacological investigations that led to the identification of this compound in a dozen molecular targets, some of which (such as some receptor channels with thermosensitive transient potential [PRT]), 

Furthermore, studies carried out in experimental models, among others, (neuro) inflammatory, neurological diseases, skeletal muscle, oncological and metabolic disorders, suggest that CBD, acting simultaneously on some of these targets, maybe a valuable therapeutic tool. Thanks to its multi-target nature, it was also hypothesized that CBD could “lessen” some of the unwanted core effects of THC, thereby widening its narrow therapeutic window (i.e., the difference between the most effective and highest safe dose).

This led to the development of Sativex, a combination of two botanical extracts from different varieties of C. Sativa, one rich in THC and the other in CBD, that delivers roughly equal doses of the two cannabinoids through an oromucosal spray. This first-of-its-kind drug is currently marketed in more than 30 countries against spasticity and (only in Canada) against neuropathic pain in patients with multiple sclerosis.

More recently, the therapeutic potential of botanical CBD per se against seizures in rare and incurable forms of pediatric epilepsy was also recognized in several clinical trials. The compound was subsequently approved by the FDA for this use as Epidiolex. The results of other clinical trials with Sativex (in chronic cancer pain, glioblastoma, and Huntington’s disease), CBD (for example, in type 2 diabetic dyslipidemia and schizophrenia), 

and Δ9-tetrahydrocannabivarin (THCV) (in type 2 diabetes) have mixed results but always have excellent and unproblematic security profiles.

In summary, with the discovery of the endocannabinoid system in the first place and later, in addition to the “rediscovery” and clinical development of botanical cannabinoids, 

the long road to the rational design of new therapies for C. Sativa has finally reached its first significant milestone. Considering their possible clinical implications, the successes achieved so far (rather than the disappointments despite the many complications and challenges posed by the complex world of endocannabinoid biochemistry and physiology. 

and the pharmacology of non-psychoactive plant cannabinoids) are what really should count when deciding whether or not we should make additional efforts to expand and improve the therapeutic arsenal generated from the study of cannabis and its components.

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