INTRODUCTION TO THE ENTOURAGE EFFECT

The entourage effect is a phenomenon that describes the effects of cannabis compounds working in synchrony. The theory is that when multiple cannabis compounds are consumed together, they produce a synergistic effect that heightens the body’s response and produces a more pronounced therapeutic benefit than one would receive from consuming a single cannabis compound alone. More specifically, the entourage effect meaning is the synergy that occurs when combining multiple phytocannabinoids and terpenes to enhance the overall pharmacologic effectiveness of the plant.

Phytocannabinoids (cannabinoids derived from plants) and terpenes are compounds synthesized within cannabis.9 Tetrahydrocannabinol (THC) and cannabidiol (CBD) are both examples of cannabinoids.1 Limonene, myrcene, linalool, phytol, and caryophyllene are just a few examples of terpenes. The terpene component of cannabis is what gives cannabis its distinct flavor and unique aroma. Terpenes are potent elements of cannabis and have been studied as a contributing factor to the entourage effect.  It is the combination of cannabinoids and terpenes that creates the entourage effect definition.

This article discusses the physiology of cannabis, the entourage effect meaning, how the entourage effect terpenes and cannabinoids work together, and the uses of cannabis. Furthermore, we will dive into the benefits of pairing CBD with ingredients that are not found in cannabis to examine the potential increased therapeutic effects of such a combination of natural ingredients.

Physiology of Cannabis in the Endocannabinoid System

Cannabis contains over 400 compounds and more than 100 cannabinoids have been isolated from cannabis. Cannabinoids and terpenes are found in flowering tops, buds, leaves, stems, and stalks of cannabis plants. These compounds extracted from cannabis have medicinal and recreational uses. Cannabinoids and terpenes exert their action on the endocannabinoid system in the body, which is a system that is widespread throughout the body and composed of many cannabinoid receptors, endogenous cannabinoids, and enzymes that create and destroy the endogenous cannabinoids.

The most notable cannabinoid receptors in the body are referred to as CB1 and CB2 receptors. Endogenous cannabinoids are cannabinoids that are made in the body, such as anandamide, and exert their action on these CB1 and CB2 receptors. Endogenous cannabinoids regulate the receptor site by causing the neuron to release neurotransmitters (GABA, glutamate, norepinephrine, and dopamine) to exert a physiological effect. Exogenous cannabinoids are cannabinoids that the body does not synthesize and need to be ingested to produce an effect on cannabinoid receptors. THC and CBD are both examples of exogenous cannabinoids. These exogenous cannabinoids interact with CB1 and CB2 receptors to produce a physiological response. CB1 receptors are primarily found within the brain and spinal cord in the central nervous system, while CB2 receptors are mostly located throughout the body in the vascular system.

THC is the most psychoactive agent of cannabis and primarily interacts with the CB1 receptors in the brain to produce a feeling of being “high,” while CBD stimulates both the CB1 and CB2 receptors. Some effects caused by cannabinoids at the CB1 and CB2 receptor sites include slowed reaction time, increased appetite, anxiety stimulation or reduction, and sedation, impaired short term working memory, impaired long-term memory consolidation, impaired coordination and balance, anti-nausea effects, increased seizure threshold, decreased pain sensitivity, heart rate stimulation, stress relief, anti-inflammatory activity, altered menstrual cycle, and more.7

How Synergistic Effects Work

THC and CBD are the most well-known cannabinoids. People consume these cannabinoids in multiple ways, and they can be taken either together or individually. As previously discussed, the combination of entourage effect terpenes and cannabinoids results in a synergistic effect. Studies indicate that the combination of these exogenous cannabinoids can lead to greater benefits than either taken alone. At least three proposed methods have been researched to explain the entourage effect:

Synergistic multi-target effects

The multi-target effect is an explanation of how a singular compound can affect multiple targets throughout the body, as opposed to focusing on a single target. Each target goes on to potentiate a pharmacological effect. This produces an additive response. THC impacts multiple targets throughout the body creating multiple effects such as feeling high, preventing vomiting, decreasing anxiety, inflammation, and pain, and increasing appetite.5

One study that focused on the muscle-antispastic effect of THC demonstrated the synergistic outcome of combining equal amounts of THC and other cannabis derived extracts (such as CBD). The study found that the partnership of cannabinoids working together decreased muscle spasms more than THC alone. This is because there is increased transportation across the membrane of the brain when multiple cannabinoids are used together. The study illustrates that not all therapeutic effects of cannabis are due to THC alone and that combining cannabinoids without THC content may be therapeutically beneficial as well.6

Pharmacokinetic effects

The pharmacokinetic effect describes how multiple components of cannabis work together to improve solubility, the rate of resorption, and the amount of active drug in the body. Research into plant pharmacology has confirmed that extracts from plants that do not deliver a pharmacological effect alone still play a role in augmenting the response of the active extract when both are consumed together. These two independent extracts work together to enhance the effectiveness of the active ingredient.5

Modulation of side effects

Reducing the side effects of a therapeutic agent may occur when a component of a plant extract is combined with another compound of the plant. This happens when the additive agent neutralizes a harmful side effect of the active ingredient and, therefore, produces a complementary reaction and increases the overall effectiveness of the plant.5

In summary, by targeting multiple sites and by using more than one extract at a time to enhance the availability of the active ingredient and to modulate side effects of active ingredients, one can potentially increase the effectiveness of these compounds when used together to provide a synergistic effect.

The Additive Effect of Cannabidiol and Non-Cannabis Ingredients

Cannabidiol is one of the most popular active ingredients derived from the flowers and leaves of cannabis plants. It is widely used throughout the United States by consumers looking to relieve stress, manage pain and maintain a healthy sleep cycle. CBD does not cause the same psychological effects as THC and exerts its actions throughout the body rather than the brain. Some people may enjoy the body effects of CBD and not the psychoactive effects of THC or vice versa. Luckily, it is possible to separate these cannabinoids from each other.

Many cannabis users believe that combining CBD with other extracts will heighten the body’s response to CBD more so than consuming CBD alone. And as we have seen, it is possible to increase the response to a cannabinoid by pairing it with at least one other extract of the cannabis plant. But, is it possible to increase the activity of CBD by coupling it with a non-cannabis ingredient? All signs point to yes. Something as simple as eating a meal or snack with CBD can increase the amount of CBD that enters the body’s circulation. One study demonstrated that consuming CBD with a fatty meal increased the amount of CBD in the blood by fourteen times as much as without taking CBD with a fatty meal. This may be because cannabinoids stick to fat cells and may be absorbed in a greater amount when taken with fatty foods. High-fat meals and snacks that may increase the availability of CBD in the body include meals with olive, coconut, or vegetable oil, mayonnaise, avocado, fish, or nuts.8 It is also possible that combining CBD with terpenes will enhance the effects of CBD.

Terpenes are naturally occurring elements of foods and herbs that can be found in plants besides cannabis as well. Caryophyllene is a terpene found in hops and in rosemary which may complement the effects of CBD. Caryophyllene works on the CB2 receptor in the endocannabinoid system, which gives it a special characteristic that is very similar to CBD; therefore, combining CBD with hops or rosemary may boost the effectiveness of CBD.4 Turmeric and black pepper are spices that may increase the absorption of CBD as well. Turmeric has many health benefits of its own but when paired with CBD may increase the physiological response to cannabidiol.It follows that pairing CBD with one or several of these non-cannabis alternatives produces a synergistic effect that can enhance the effects of CBD as well as the other natural elements being paired with the CBD.

Benefits and Downfalls of Cannabis Use

Components of cannabis have been used for medicinal purposes for many years. But the science and understanding of the structural formations of cannabinoids is relatively new. CBD and THC were only first extracted from cannabis in the 1930’s and 40’s and both cannabinoids would not be successfully isolated for study purposed until the early/mid 1960’s.11 Cannabis research has been ever evolving since then. The use of terpenes and cannabinoids in combination has been studied for the treatment of mood and anxiety disorders, pain, inflammation, migraines, headaches, opioid addiction, and opioid detoxification.10 CBD is often used to quell anxiety and insomnia. Cannabidiol has been praised for its potential to treat many other health issues as well, most notably childhood seizures that are unresponsive to seizure medications. Some research has shown evidence that CBD creams and oils can be effective for the treatment of pain and inflammation caused by arthritis. However, further research is needed to confirm the efficacy of CBD for these uses.9

Although there appear to be many benefits associated with the use of cannabinoids and terpenes, THC (the psychoactive compound found in the marijuana variety of cannabis plants) also contributes negative effects and has been shown in some studies to increase the risk for schizophrenia and potentially cause psychotic side effects in some users.Cannabidiol (CBD), however, is not associated with major side effects and is generally well-tolerated. However, some may experience nausea, irritability, and fatigue with its use.

A critical warning about cannabis use as a whole though is that it has many drug interactions and is likely to interfere with common prescription medications. For example, CBD is known to interact with Coumadin and will increase the levels of this medication in the blood causing an increased risk for bleeding and other serious complications. It also increases the drug levels of many other medications and so it is important to speak with a doctor before consuming CBD. Moreover, CBD products are often marketed as a dietary supplement which can be problematic due to the lack of regulation surrounding dietary supplements. The FDA does not regulate the purity nor safety of dietary supplements, including CBD, so the true ingredients and dosages of products that do not undergo rigorous testing are often unknown.

Conclusion

The bottom line is that the use of cannabinoids like CBD, along with terpenes and other complementary cannabinoids, may have a more beneficial effect when taken together which is explained by the entourage effect definition. Coupling CBD with other agents such as hops, rosemary, turmeric, cinnamon, fatty meals, and black pepper may further reinforce the benefits of CBD compared to using CBD alone.

Cannabinoids are currently being studied for many ailments such as medication symptom management, opioid use disorder, cancer-related side effects, mood, and anxiety disorders, as well as many other diseases.2 There are potential benefits to consuming CBD safely. Cannabis research is rapidly evolving; however, further studies are necessary to enhance our knowledge and validate advocated positions regarding benefits.

It is also important to consider that under current United States law, cannabis of the marijuana variety is highly regulated and illegal in most states as well as illegal at the federal level. And while cannabis of the hemp variety is treated differently and CBD products made from hemp can be sold legally across the country for the most part, it is critical to note that cannabis of any variety will have many drug interactions, so it is important to speak to a doctor about cannabis use in combination with any prescription medications before consuming CBD or any other cannabis derived extracts.

References

Baron EP. Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain: An Update on Current Evidence and Cannabis Science. Headache. 2018;58(7):1139-1186. doi:10.1111/head.13345

Ferber SG, Namdar D, Hen-Shoval D, et al. The “Entourage Effect”: Terpenes Coupled with Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders. Curr Neuropharmacol. 2020;18(2):87-96. doi:10.2174/1570159X17666190903103923

Foods That Enhance CBD: Optimizing Cannabis Effects. Heally. https://getheally.com/patients/news/foods-that-enhance-cbd. Published July 31, 2020. Accessed August 3, 2020.

Gertsch J, Pertwee RG, Di Marzo V. Phytocannabinoids beyond the Cannabis plant – do they exist?. Br J Pharmacol. 2010;160(3):523-529. doi:10.1111/j.1476-5381.2010.00745.x

Wagner, G. Ulrich-Merzenich, Synergy research: Approaching a new generation of phytopharmaceuticals,Phytomedicine, Volume 16, Issues 2–3, 2009, Pages 97-110, ISSN 0944-7113, https://doi.org/10.1016/j.phymed.2008.12.018.

  1. Wilkinson, B.J. Whalley, D. Baker, G. Pryce, G. Gibbons, A. Constanti, E.M. Williamson Medicinal Cannabis: is Δ9 THC responsible for all its effects

Lu HC, Mackie K. An Introduction to the Endogenous Cannabinoid System. Biol Psychiatry. 2016;79(7):516-525. doi:10.1016/j.biopsych.2015.07.028

Omstudio/Depositphotos. CBD absorption significantly affected by high-fat foods. New Atlas. https://newatlas.com/cbd-levels-increase-doasge-high-fat-food/61117/. Published November 1, 2019. Accessed August 3, 2020.

Peter Grinspoon MD. Cannabidiol (CBD) – what we know and what we don’t. Harvard Health Blog. https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-we-dont-2018082414476. Published April 22, 2020. Accessed August 3, 2020.

Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344-1364. doi:10.1111/j.1476-5381.2011.01238.x

Roger G. Pertwee. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol. 2006 Jan; 147(Suppl 1): S163–S171. Published online 2006 Jan 9. doi: 10.1038/sj.bjp.0706406