Entourage effect in cannabis: Enhancing the benefits of cannabinoids

Cannabis is a plant with a long history of use in various cultures, both as food, textile fiber and medicine. Although it has been used for millennia, some of its properties are not 100% known and are still under investigation.

One of the fields that generates more interest is the entourage effect of cannabis, which refers to the synergistic interaction between cannabinoids, terpenes and flavonoids present in the plant. Like a team of superheroes working together to enhance their powers, this interaction is credited with some effects that could be interesting in explaining the effects the plant has on the body. In this installment, we will explain exactly what the entourage effect of cannabis is and how it works.

What is the entourage effect?

The entourage effect (also known as entourage effect is the phenomenon that occurs when two or more compounds in the cannabis plant work synergistically to modulate or generate a greater effect than they would on their own.

Synergy refers to the cooperative benefit of cannabinoids, terpenes and flavonoids resulting in an amplified effect. These types of cooperative interactions can occur either cannabinoid-cannabinoid, cannabinoid-terpene, terpene-terpene, plus their respective combinations with flavonoids.

Importance of the Entourage Effect: Therapeutic Uses

The entourage effect in cannabis is an interesting phenomenon due to its ability to enhance the therapeutic efficacy of cannabis by combining cannabinoids, terpenes and flavonoids.

This is quite useful for medical purposes, as undesirable effects could be minimized by optimizing the therapeutic dose used. Implicit in this theory of the entourage effect is the fact that using isolated cannabinoids is not the same as using cannabis extracts. For example, as already mentioned several times in the blog, for particular cases it has been shown that the use of full-spectrum CBD better results than pure CBD.

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Differences between entourage effect and synergistic effect: Are they the same?

The entourage effect is a synergistic effect, but not vice versa. The entourage effect only refers to the synergy that occurs with the compounds of the cannabis plant.

The concepts of entourage effect and synergy would seem to be the same thing, but in reality they are only related concepts. The difference between the entourage effect and the synergistic effect is that the former refers to the interaction between cannabis compounds. either to modulate or enhance their effects, and synergy itself refers to the working together of these compounds.

Advantages of the entourage effect

The entourage effect can offer therapeutic benefits by allowing various compounds in the cannabis plant to work together. Here is a summary of the advantages of the entourage effect:

  • Amplified therapeutic effect: Greater effectiveness with lower doses.
  • Minimization of side effects: Lower required dose of THC reducing unwanted psychoactive effects.
  • Balanced effects: The complex combinations that can occur with all cannabis compounds can give rise to a holistic or multidimensional effect.
  • Tolerance reduction: Terpenes can promote a consistent effect of phytocannabinoids.

Cannabis components that contribute to the entourage effect

The entourage effect involves the interaction of all the constituent substances of Cannabis. The Cannabis sativa plant has more than 500 components reported to date (1). Of these, only 125 are cannabinoids and the rest are non-cannabinoids, including terpenes and flavonoids, among other compounds.

Within the study of the entourage effect, tetrahydrocannabinol tetrahydrocannabinol (THC) and tetrahydrocannabinol (THC) and cannabidiol (CBD) have been the most explored cannabinoids in the laboratory, and among those that have been described to a lesser extent are cannabigerol (CBG) and CBN (cannabinol).

On the other hand, the non-cannabinoid compounds of the cannabis plant are classified into phenols, flavonoids, terpenes and alkaloids (1), which are not only found in cannabis; they are also essential components of different plant foods providing organoleptic characteristics, i.e., they provide odor, color and flavor.

Among all these non-cannabinoid compounds, only the relationship of terpenes in the entourage effect has been studied. Of the terpenes of the cannabis plant, the best known are limonene, myrcene, pinene and linalool (2).

How does the entourage effect work?

The mechanisms of the entourage effect are very varied. Each substance that makes up cannabis has its own mechanisms of action, and when acting together can give rise to additive effects. The possibility of interactions is as wide as the possibility of combinations of cannabinoids, terpenes and flavonoids.

Different research groups have focused on the study of cannabinoids and terpenes and their dynamics within the entourage effect. Flavonoids, on the other hand, since they are found in such low quantities, have not been analyzed under experimental conditions; however, their addition to the entourage effect has not been ruled out.

Benefits of the entourage effect

Cannabinoid interactions

Although the entourage effect involves various compounds in the cannabis plant, most studies have looked at the interaction between THC and CBD.

Analgesia

Preparations of THC and CBD have been compared with the administration of pure THC to observe their effectiveness in the treatment of cancer pain. As a result, the combination of THC and CBD was found to provide greater relief compared to the administration of THC alone (3).

On the other hand, a study on neuropathic pain that evaluated different doses of the combination of THC with CBD showed that, although together they can potentiate the analgesic effect in the organism, this effect is also dose-dependent. Cannabinoids can present a bell effect, where higher doses do not translate into better results, but quite the opposite. Thus, in this study it was found that low doses of THC with CBD are more effective for the treatment of neuropathic pain than high doses of THC with CBD (4).

Reduction of the harmful effects of THC

CBD helps mitigate the side effects of chronic and acute THC marijuana use (5). In a study where the residual THC and CBD content in the hair of 140 cannabis users with schizoid symptoms was analyzed, it was found that patients with more hallucinations and delusions were those who contained traces of THC only, while patients who had also consumed CBD (and therefore traces were found in the hair) had lower levels of these psychotic symptoms (6).

Addiction treatment

An experimental model of the conditioning paradigm in laboratory animals, used to evaluate cocaine and amphetamine preference and addiction, found that treatment with the combination of THC and CBD helped reduce substance preference, whereas administration of CBD alone did not. (7).

This leads to think that the cannabinoid-cannabinoid interaction of THC and CBD can result in positive effects for the treatment of addictions. This supports clinical studies conducted in Jamaica and Brazil (8, 9) where cannabis has been used to assist in the treatment of cocaine addiction.

Interactions between cannabinoids and terpenes

Cancer treatment

In a study on breast cancer tumor cells, the effect of isolated THC and a marijuana-based preparation was compared to evaluate its effectiveness as an antitumor treatment. The results yielded a large difference pointing to the entourage effect between THC and terpenes, as the marijuana preparation containing terpenes was more potent in terms of its antitumor action than when THC alone was used. Among the terpenes of the preparation, the following was found beta-caryophyllene linalool, linalool, nerolidol and beta-pinene, which helped to potentiate the antitumor effect of THC (10).

Many other in vitro studies (studies conducted in cells) have proven the anti-cancer effect of cannabis preparations containing terpenes and cannabinoids. One of these studies demonstrated the entourage effect of the marijuana buds The study showed that marijuana buds, predominantly high in THC and CBG, for the elimination of colon cancer tumor cells (11).

Analgesic effect

It has been shown that the analgesic effect of some CBD-rich cannabis extracts is due to the entourage effect of CBD with terpenes. A study in laboratory animals compared the analgesic effect of a CBD-rich cannabis extract with a preparation of pure CBD and THC, showing that the cannabis product containing all the plant components was more effective than the synthetic preparation, despite the fact that both the natural and synthetic products contained similar proportions of CBD and THC. This study confirms that the terpenes contained in the plant amplify the effect of CBD to obtain an analgesic effect (12).

On the other hand, within the entourage effect of THC and its interaction with terpenes, it has been observed that it can also induce an analgesic effect in animal models (13).

Antiepileptic

The septic effect of CBD for the treatment of epilepsy has been postulated as a theory resulting from a meta-analysis conducted by a research group (14). The study analyzed several observationally based clinical studies where CBD products were used for the treatment of refractory epilepsy. This research group proposes that CBD-rich cannabis extracts have better therapeutic results than those cases where CBD alone or isolated CBD was used. This infers that the entourage effect between CBD and terpenes is responsible for the most favorable results in the treatment of refractory epilepsy.

Interestingly, molecular mechanisms indicate that the cannabinoid-terpene interaction is not mediated by the endocannabinoid receptors CB1 and CB2 (15), indicating that they help induce the entourage effect through intricate signaling pathways that potentiate the effect of phytocannabinoids.

Interactions between terpenes

The terpenes alone are considered anxiolytic (16), anti-inflammatory (17) and anticarcinogenic (18). In the cannabis plant, terpenes are involved in the entourage effect as enhancers or promoters of the action of cannabinoids in the cannabis plant (19).

The study of terpenes from the cannabis plant is difficult, as these aromatic compounds are found in very low concentrations. Likewise, the great variation in terpene profiles of each cannabis strain makes their specific study even more complicated.

Some examples of terpene-terpene interactions that have been described in experimental settings and generally from essential oils are:

  • Limonene and alpha-pinene: have a synergistic antibacterial effect (20, 21).
  • Myrcene and limonene: increase the sedative effects of THC (22).
  • Alpha-pinene and beta-pinene: may act synergistically to reduce inflammation (23).

Potential drawbacks of the entourage effect

It might seem that the entourage effect only implies benefits. However, there are some aspects that should be taken into consideration:

  • Lack of standardization of cannabis products: Because the concentration of cannabinoids and terpenes can vary even between two plants of the same strain, obtaining consistent results between batches and strains is almost impossible. While estimates of the profiles are available, pharmaceutical grade accuracy cannot be achieved from natural cannabis products, making them difficult to study in the laboratory.
  • Unknown side effects: Due to the complexity and variety of the terpene profiles of the cannabis plant, it is very difficult to know absolutely all of the possible adverse events that a person might experience from a particular combination of terpenes contained in the cannabis plant.
  • Potentiation of the psychoactive effect of THC: The use of medical marijuana leads to the manifestation of undesirable side effects. Some cannabis strains may contain terpenes that amplify the psychoactive effect of THC.

Clinical applications of the entourage effect

The entourage effect could encompass various clinical applications, favoring the use of more efficient doses of cannabinoids. Although the entourage effect is difficult to characterize because cannabis strains have such different cannabinoid and terpene profiles, the synergistic effect could contribute to the treatment of some medical conditions.

Clinical applications of the entourage effect of THC would be more focused on minimizing the necessary dose of medical marijuana, thus reducing side effects and increasing its safety profile.

The CBD entourage effect, that is, the synergistic phenomenon that occurs with the use of CBD-rich cannabis strains, can have useful therapeutic implications for very particular cases. Refractory epilepsy resulting from encephalopathies such as Lennox-Gastaut syndrome and Dravet syndrome appear to have favorable results with pharmaceutical CBD (Epidolex) and the use of extracts of CBD extracts (24).

Looking to the future

The entourage effect offers a more balanced and effective effect than the administration of cannabinoids or terpenes in isolation. This opens the door to endless possibilities if isolated combinations of some cannabis compounds are used.

Scientific research is helping to understand the mechanisms of the entourage effect with the intention of finding particularities that would lead to more specific and effective treatments.

Another topic that is rarely discussed in scientific publications is the impressive complexity of the plant world. The cannabis plant is so complex that no laboratory could accurately recreate it synthetically, and therein lies the potential of the cannabis entourage effect. The synergy of cannabis plant components is an example of how plants can be better drugs than products isolated from them. Despite this, different cannabinoid-cannabinoid, cannabinoid-terpene and terpene-terpene combinations and interactions can be explored, however, laboratories interested in studying natural products are limited.

We hope that in the coming years there will be more information on the entourage effect and its potential applications, which will support a more effective and safer use of cannabis.

References
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Masha Burelo
Investigadora en cannabinoides | Doctoranda en Neurociencia

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