Cannabis, components, synthetic analogues and endogenous targets: what is better for the development of new therapies?

Cannabis, components, synthetic analogues, and endogenous targets: what is better for the development of new therapies?

 

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 true 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 industries;
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, there are several varieties of C. Sativa with different chemical compositions that justify their different uses. Consequently, when we talk about the possibility of separating recreational activity (i.e. euphoria and altered moods) of cannabis preparations from their possible therapeutic activity (against many conditions from spasticity, inflammation, pain, seizures, and neurodegenerative diseases, cancer, and metabolic syndrome), in order to safely develop treatments for this plant, 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 ie Δ9tetrahydrocannabinol [THC]) or just the latter (eg 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 that 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 that is intended to be used for therapeutic purposes must take into account that routes of administration such as oral infusions cannot provide sufficient amounts of these compounds to produce the desired effect. of which are produced after desiccation or by heat-induced decarboxylation, even for a certain 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 that is intended to be used for therapeutic purposes must take into account that routes of administration such as oral infusions cannot provide sufficient amounts of these compounds to produce the desired effect. of which are produced after desiccation or by heat-induced decarboxylation, even for a certain 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 that is intended to be used for therapeutic purposes must take into account that routes of administration such as oral infusions cannot provide sufficient amounts of these compounds to produce the desired effect.

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 as well as those of other foods due to their special 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, and 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 types of 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, schizophrenia, metabolic disorders and hepatorenal fibrosis and pulmonary), synthetic compounds antagonists of the action of CB1 receptors were developed and have been shown to be effective in clinical trials against obesity and type 2 diabetes. Unfortunately, however, and unlike CB2, CB1 is very abundant in the neurons of the mammalian brain and, now it is known that it is very important to counteract the consequences of stress.

The presence of CB1 and CB2 receptors in mammals pointed to the existence of endogenous ligands for these receptors. These metabolites, that is, 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 cycle, 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 try to restore homeostasis.

Furthermore, it became clear that, exactly 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 hypothesis 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, therefore, safer, since they would only act “when and where” endocannabinoids are produced to play a protective or counter-protective action.

As a consequence, many efforts have been made in the last 15 years to develop clinically safe inhibitors of 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 act 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 a true “extended endocannabinoid system” or endocannabinoidome. Therefore, the inhibition of endocannabinoid inactivation, for example, will lead to an improvement in the levels of endocannabinoid-type molecules and, subsequently, to modulate the activity of the targets for these molecules.

Recent difficulties in the synthetic development of endocannabinoid-based drugs coincided with a renewed enthusiasm towards 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 the fact that no other type of cannabinoids 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 of the previously known ones. or “new” orphan recipients.

Specifically, CBD 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]), peroxisome proliferator-activated receptors (PPARs and orphan GPCRs) are also receptors for endocannabinoid-like mediators, and therefore belong to the endocannabinoidome.

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. It was also hypothesized that CBD, again thanks to its multi-target nature, 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 two 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 and 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 given mixed results but, nonetheless, always promising and unproblematic security profiles.

In summary, with the discovery of the endocannabinoid system in the first place and the endocannabinoidome later, in addition to the “rediscovery” and clinical development of botanical cannabinoids, the long road to the rational design of new therapies of C. Sativa has finally reached its first major milestone. I believe that 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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