Set of molecules that interact with the receptors of the Endocannabinoid System

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Cannabinoids are a group of molecules that interact with the receptors of the endocannabinoid system. They are referred to as endocannabinoids if they occur in our body as part of physiological processes. They are called phytocannabinoides when they are of plant origin and synthetic cannabinoids when they have been created artificially in a laboratory.

In the beginning, the term cannabinoid was linked to the compounds of cannabis itself. Now, the cannabinoid concept is given to all the chemicals that interact with cannabinoid receptors.

Usually, the study of cannabinoids has focused on the human endocannabinoid system but, taking into account its mechanisms of action and the therapeutic possibilities that they offer, researchers have also begun to study the animal endocannabinoid system.

Infographics on how cannabinoids work


Endocannabinoids are molecules produced by our bodies that act as messengers through cannabinoid receptors. The most important are anandamide (SAA) and 2-Araquidonil-glycerol (2-AG), as both are synthesized on demand (endocannabinoids are not stored in the body, but are synthesized on demand where and when the body requires them to function). Moreover, they act on their respective receptors and are degraded through the FAAH enzyme, all in the same place of action. They do not act in a systemic way, ie, they only act in the exact location of our body where a specific and selective effect is needed, depending on the type of cell in which the endocannabinoid receptors are activated.

In recent years, knowledge about the implications of cannabinoids on different physiological systems has increased significantly. It is also known that the endocannabinoid system can influence the three basic systems of physiological regulation: the neurotransmitter system, the immune system, and the endocrine system.

Endocannabinoids that have been studied

  • Anandamida (AEA)
  • 2-Araquidonil-glicerol (2-AG),
  • Noladina
  • Virodamida
  • N-araquidonil dopamina

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Cannabis Phytocannabinoids

The varieties of the Cannabis plant contain about 500 different chemical compounds, of which one hundred, approximately, are part of the phytocannabinoids family (Waseem, 2014). The most studied cannabinoids, from a therapeutic point of view, are delta-9-tetrahydrocannabinol (THC) and Cannabidiol (CBD)although researchers are beginning to investigate into cannabinoids such as Cannabinol (CBN), Tetrahydrocannabivarin (THCV) and Cannabigerol (CBG), as they are showing characteristics of potential medical interest in different pre-clinical studies.

When cannabinoids are in the plant they are in their acidic form. In this state, THC, for example, has no psychoactive effect. With the application of heat it undergoes the process of decarboxylation and it passes into its active form, which has psychoactive properties.

Apart from the cannabinoids contained in the plant, there are other chemical compounds with therapeutic potential. Particularly noteworthy are the terpenoids, which are an attributed part of the organoleptic properties of Cannabis (McPartland et al., 2014). There are also other families of compounds that have not been studied yet such as flavonoids, alkaloids, phytosterols, etc.

The cannabinoid entourage effect

The presence of such a high quantity of different compounds in the cannabis plant can lead to pharmacological interactions, either synergistically or antagonistically.

Studying these interactions has shown that, both in terms of efficacy and tolerability, treatments with whole plant preparations have been more promising than the use of isolated cannabinoids.

This effect, called the “entourage” effect, was first described by Raphael Mechoulam in 1998 (Ben-Shabat, 1998; Russo and Taming, 2011). The best example described so far is the THC-CBD couple whose combination makes THC better distributed, increases bioavailability (our body uses the available amount in the most efficient way) and reduces possible side effects (McPartland et al, 2014).

Although there are few studies on the subject, it is believed that the entourage effect is not only due to interactions between different phytocannabinoids, but also to the functional interaction between cannabinoids and noncannabinoid plant components such as terpenes and flavonoids.

The entourage effect is the interaction between phytocannabinoids such as THC and the other elements present in the plant. In the case of Cannabis Sativa L, interactions between terpenes, flavonoids and at the time of ingestion, with endocannabinoids such as anandamide, are being studied.

There is limited information about the entourage effect, however, Dr. Ethan Russo from the University of Massachusetts published a study on the synergy of phytocannabinoids and terpenes back in 2011.

Sometimes there are pathologies that cannot be treated with just one cannabinoid. The synergy between different cannabinoids also produce the entourage effect, which is very useful for treating diseases in which a single component is not enough. Several research studies explain the main medicinal benefits of cannabis, such as its analgesic effects.

However, there are other studies that support CBD and other components of cannabis combined, which can, increase its benefits, reduce adverse effects, and produce less toxicity than with THC alone. 

The range of effects of phytocannabinoids is very wide which is why it is necessary to continue investigating their therapeutic potentials

Similarly, these two terpenes and pinene may help to increase the effect of THC on dementia in Alzheimer’s patients. Linalool, together with caryophyllene and myrcene, can increase the effects of several cannabinoids on sleep problems. Finally, caryophyllene, myrcene and pinene may be useful in providing adjuvant support in treating addictions

Four basic synergy mechanisms have recently been proposed (Wagner and Ulrich-Merzenich, 2009):

  1. Multi-target effects
  2. Pharmacokinetic effects such as improved solubility or bioavailability
  3. Interactions of agents affecting bacterial resistance
  4. Modulation of the adverse effects that can be achieved by the entourage

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Synthetic Cannabinoids

Synthetic cannabinoids are generated, as the name suggests, artificially, taking in to account the qualities of the endocannabinoids and phytocannabinoids.

hey are extracts made in laboratories and are copies of the most relevant characteristics of endocannabinoids, so they work and are metabolized in receptors CB1 and CB2 but they do not have the same effects as phytocannabinoides or endocannabinoids and do not have pharmacological effects as potent as those of THC (Mechoulam, 2016).

The first synthetic cannabinoids were discovered in the 1970’s in order to explore and understand the pathways of the endogenous cannabinoid system.

Some synthetic cannabinoids, such as Dronabinol and Nabilone, are used at a medical level to treat nausea and vomiting caused by treatment with chemotherapy or in cases of anorexia caused by immunodeficiency’s due to their orexigenic properties.

THC is approved by the FDA to treat nausea and vomiting caused by chemotherapy in people who do not respond to other treatments. It is also used to stimulate appetite in HIV-positive people

Dronabinol (Marinol) is the synthetic form of THC that is found as capsules, oral solution or inhaled.

On the other hand, in Spain there is only one precedent for a medicine composed of Tetrahydrocannabinol called Sativex. This is a pharmacological solution developed by GW Pharma, composed of CBD and THC (1:1 ratio), indicated for the treatment of pain and spasticity in people with multiple sclerosis. [3]

Nabilone (Cesament) is another of the approved synthetic THC drugs used to palliate vomiting caused by chemotherapy

Molecular Structure of Tetrahydrocannabinol and Tetrahydrocannabinolic Acid

Bibliography on cannabinoids

El Sohly M, Waseeem G. Constituents of Cannabis Sativa. In: Pertwee RG, editor. Handbook of Cannabis. Oxford, United Kingdom: Oxford University Press; 2014. p. 3-22.

Ben-Shabat S, Fride E, Sheskin T, Tamiri T, y cols. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2- arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol. 1998;353(1):23-31.

Russo EB. Taming THC: potential cannabis synergy and phytocanna- binoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344-64.

McPartland JM, Russo EB. Non-Phytocannabinoid Constituents of Cannabis and Herbal Synergy. In: Pertwee RG, editor. Hand- book of Cannabis. Oxford, United Kingdom: Oxford University Press; 2014. p. 280-95.

Mechoulam R. Cannabis – the Israeli perspective. J Basic Clin Physiol Pharmacol. 2016, 27(3):181-187

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