Evidence based

What is the Entourage Effect?

There are over 113 known cannabinoids and hundreds of other phytochemicals in the cannabis plant, all working together to produce the entourage effect.

Article By
Justin Cooke , posted 4 months ago

  • Table of Contents

Many people are familiar with the cannabinoids CBD and THC — but they’re just two of over 113 different cannabinoids found in the cannabis plant.

Although CBD and THC have clear physiological effects on the body — highlighted by five decades of scientific research — there’s more to the effects of cannabis than these two compounds alone.

Researchers became puzzled as they noticed that whole plant extracts had different — often stronger — effects than isolated pure compounds.

It was later discovered that the reason for this was a complex interaction between all of the cannabinoids, terpenes, and other phytochemicals in the cannabis plant — called the entourage effect.

Findings like this give us useful insight into how we can best use the plant as medicine.

Here, we get personal with the hemp/marijuana plant and discuss several key cannabinoids, terpenes, and other phytochemicals to highlight how they work together to produce stronger, longer-lasting benefits than any cannabinoid on their own.

What is the Entourage Effect?

The Entourage Effect is a term used to describe the complex interaction between all the different chemical compounds or “entourage” of the cannabis plant.

This includes all 113 cannabinoids, hundreds of different terpenes, lignans, flavonoids, polyphenols, and numerous other trace chemicals found within the cannabis plant.

In the early days of cannabis research, in the 1960s, researchers identified the primary psychoactive effects produced by the plant were the result of tetrahydrocannabinol (THC). The studies discovered other cannabinoids, but most efforts were dedicated to unlocking the secrets of THC.

It was later discovered that THC produces psychoactive effects in its isolated form but whole plant extracts caused fewer side-effects and had much stronger overall benefits.

Purified, synthetic THC compounds were shown to produce unpredictable, often dangerous side-effects.

The synergy in the cannabis plant began to develop when researchers investigated the role CBD played in cannabis’ medicinal benefits.

In 2006, research showed that by adding CBD to a dose of THC significantly reduced the negative side-effects of THC [1]. Although there are several theories as to why this happens, the prominent theory is that CBD has a protective effect on THC, slowing its breakdown and offering opposing effects on things like anxiety and mental stimulation. This offsets some negative side-effects of THC and improves many of its benefits.

Other cannabinoids have demonstrated similar effects as well — including CBC, CBG, and CBN to name a few (more on these later).

Most people refer to these positive interactions of various cannabis compounds as the entourage effect. However, this concept is familiar in the world of herbal medicine.

The more common term for the entourage effect is plant synergy.

Defining Plant Synergy

Synergy is the idea that certain compounds, when taken together, will produce effects greater in combination than the sum of their parts [4].

Here’s another way to think of synergy:

Another Example of Synergy

The entourage effect specifically refers to cannabinoids and how they interact. But there are other examples of how the original contents of plants work best when taken alongside each other.

St. John’s Wort is a herb best known for its antidepressant effects because of a compound called hypericin. However, when isolated, hypericin offers no benefits and actually makes symptoms worse.

Scientists tested the entire plant extract containing everything except hypericin as a control to see if this works the other way — the results showed no antidepressant benefit.

Researchers concluded that hypericin is the active ingredient for the antidepressant activity of St John’s Wort, but relies on all the other constituents to do its job effectively. The plant essentially needs all of its compounds to produce any measurable benefits.

Cannabis works similarly, and we’re starting to find discrepancies between the uses of CBD in full-spectrum extracts compared to CBD isolates (extracts made without the rest of the entourage).

St. John’s Wort

Synergy is Like an Orchestra

Synergy is like an orchestra — each of the compounds in the plant acts as an instrument in the orchestra. When teamed up, they produce a complex and harmonious sound pleasing to the ears. However, it’s difficult to pinpoint any single instrument. Instead, we hear the orchestra as a whole.

Listening to only one of these instruments — like isolating a single cannabinoid for research — is far less pleasing to the ears, and lacks the complexity of an orchestra as a whole.

Try listening to just the tuba in an orchestra, it won’t sound like much. Even the more central players—the trumpets violin, flute— will lack the depth the orchestra provides.

How Synergy Works

There are many ways compounds can work together to produce their effects.

Some relevant examples include:
  1. Increasing bioavailability (absorption of the compounds through the gastrointestinal tract)
  2. Interfering with cellular transport processes (such as improving passage through the blood-brain barrier)
  3. Activation of pro-drugs (non-active compounds that convert to active ones in the liver)
  4. Slowing the deactivation of active compounds to inactive metabolites
  5. Providing similar benefits through separate mechanisms
  6. Inhibiting the binding of compounds to cell receptors (blocking the effects of other compounds)
  7. Enhancing the binding of compounds to cell receptors (increasing the effects of compounds)

Introducing the Cannabis Entourage

There are hundreds of different compounds in the plant — each offering its own contribution to the overall effects of the plant.

This makes it difficult to study the plant quantitatively — with so many compounds to study, it’s nearly impossible to determine which one is responsible for what effect. It’s even harder to determine which compounds are interacting synergistically to produce these effects.

What makes things even more confusing is that the concentrations of each compound can vary significantly from one cannabis strain to the next.

Although there’s no way to definitively highlight each cannabinoid and its role in the entourage effect, we can highlight our current understanding of some of the most prominent compounds.

Let’s dive into some of the primary members of the cannabis entourage.

1. The Cannabinoids

Cannabinoids are the primary active constituents of the cannabis plant.

Powerhouses like THC and CBD carry much of the weight of the plants’ therapeutic effects.

Other cannabinoids like CBC, CBG, or CBN offer their own set of benefits and interact with these powerhouses to either improve absorption, reduce negative side-effects, or otherwise improve effects on the body.

A) THC (Delta-9 Tetrahydrocannabinol)

THC is the primary psychoactive ingredient in the cannabis plant. It works by activating the CB1 and CB2 receptors of the endocannabinoid system. Triggering the CB1 receptors in the central nervous system causes a change in serotonin levels, which gives this compound its psychoactive side-effects.

Most hemp oils only contain THC only in small amounts (less than 0.3%). Marijuana strains, however, can contain up to 30% THC by weight.

The Effects of THC:

  • Appetite stimulant
  • Sedative (low doses)
  • Stimulant (high doses)
  • Psychoactive

B) THCV (Tetrahydrocannabivarin)

The effects of this compound are similar to THC, and it may produce mild psychoactive effects. However, THCV is significantly weaker in its effects when compared to THC. Some research suggests that THCV is only 20-25% as strong in its psychoactive effects compared to THC [2].

Effects of THCV

  • Appetite-suppressant
  • Euphoric
  • Antispasmodic
  • Paranoic (induces paranoia)

C) CBD (Cannabidiol)

CBD is the primary medicinal compound of the cannabis plant. It works much differently to THC.

While THC stimulates the endocannabinoid receptors, CBD has minor interactions with them. Instead, CBD activates different receptors such as the opioid pain receptors, vanilloid receptors, and competitively inhibits the breakdown of our endocannabinoids like anandamide and 2-AG.

CBD is much better at improving our ability to maintain homeostasis (balance) compared to THC or most other cannabinoids. This ability to regulate homeostasis gives it a long list of benefits on the human body — ranging from inflammation and pain inhibition to hormone regulation and stress reduction.

Effects of CBD

  • Anti Inflammatory
  • Mild appetite suppressant
  • Lowers stress
  • Mild sedative
  • Antiemetic (prevents vomiting)
  • Reduces the side-effects of THC

D) CBC (cannabichromene)

In most cases, CBC is the third most abundant cannabinoid, though there are exceptions to this. This compound is non-psychoactive and offers excellent anti-anxiety and antidepressant activity, especially in combination with CBD. Unfortunately, there are few studies to quantify the effects of this cannabinoid, though we can expect to see a lot more information released on this cannabinoid in the near future.

Effects of CBC

  • Antidepressant
  • Mild sedative
  • Anti-anxiety

E) CBG (Cannabigerol)

CBG is one of the precursors for other cannabinoids like THC. It inhibits many effects of THC by producing an opposite effect — blocking the activation of serotonin to reduce the psychoactive side-effects. CBG is one of the strongest anti-anxiety cannabinoids found in the cannabis plant.

Effects of CBG

  • Anti-anxiety
  • Adaptogenic (stress reduction)
  • Mild sedative
  • Inhibits some of the effects of THC

F) CBN (Cannabinol)

CBN is a byproduct of THC. As THC breaks down, some of it is converted to CBN. This cannabinoid is mostly non-psychoactive but will produce some mild psychoactive side-effects in some individuals.

CBN is more sedative than most other cannabinoids and therefore is excellent for people using cannabis for conditions like insomnia, anxiety, or high stress.

Effects of CBN

  • Sedative
  • Anti-anxiety
  • Appetite stimulant

2. The Terpenes

Terpenes are small aromatic compounds (they evaporate in low temperatures and have an aroma).

If you’ve ever used marijuana or a high-quality hemp extract, you’ve most likely experienced the aroma of the cannabis plant. The fragrance can vary significantly from one strain of cannabis to the next — mostly due to the different terpenes in cannabis.

Some of the terpenes in cannabis are shared in other, unrelated species — such as limonene from citrus fruits, myrcene from nutmeg, or pinene from the pine tree. The shared terpenes is what gives hemp and marijuana plants a complex set of aromas.

These terpenes contribute heavily to the entourage effect of the plant despite making up only 1% of the cannabis plant by weight [3].

Some terpenes improve the absorption of the cannabinoids from the digestive tract and lungs — producing stronger effects. Others slow the metabolism of cannabinoids in the liver, and others will provide therapeutic effects on depression, anxiety, pain, or muscle tension — further adding to the overall effect of the plant.

List of Common Cannabis Terpenes

  • A-humulene — a powerful antibacterial
  • Alpha Bisabolol —anti-inflammatory
  • Alpha-Terpineol — sedative, antioxidant, and memory enhancer
  • Beta-Pinene — memory enhancer, neuroprotective, and anti-inflammatory
  • Beta-Caryophyllene —anti-anxiety, antidepressant, sedative
  • Bisabolol — anti-inflammatory
  • Borneol — sedative, muscle relaxant, neuroprotective
  • D-Linalool — muscle relaxant, pain-reliever, anti-anxiety
  • Geraniol — powerful antioxidant
  • Limonene — anti-anxiety, antidepressant, enhances cannabinoid receptor binding
  • Myrcene — analgesic, sedative, improves cannabinoid absorption

3. Other Phytochemicals

There are hundreds of compounds in the cannabis plant, many of which have powerful therapeutic effects. There are far too many to list here, and most remain poorly understood by science.

Many phytochemicals in cannabis are active constituents of other medicinal plants, but some are unique to the cannabis genus.

It’s debatable what role each of these phytochemicals plays in the overall effects of hemp and marijuana plants. However, it’s well-understood that they’re an important contributing factor to the overall entourage effect of the plant.

The Top Five Non-Cannabinoid and Non-Terpene Compounds of Cannabis:

  • Benzoic acid — antibacterial
  • Hydroxycinnamic acid — anti-inflammatory
  • Apigenin — a potent anti-anxiety and estrogenic compound
  • Lignanamides — anti-inflammatory and anti-cancer
  • Stilbenes — potent antioxidants

Full-Spectrum Hemp Oils vs. Isolates

When discussing the entourage effect, we need to consider two forms of hemp extracts — full-spectrum hemp oils and CBD isolates.

The distinction is essential because full-spectrum oils are the only products that leverage the entourage effect. The collection of multiple cannabinoids, terpenes, and other phytochemicals in the final product offer broader and more powerful benefits on the body.

Isolates, on the other hand, are purely CBD — there’s no entourage effect from these products.

Some companies try to add these compounds in after the purification, which does bring some benefits but won’t provide the same level of intricacy as full-spectrum oil in terms of synergy.

Choosing the Right CBD Extracts

Generally speaking, full-spectrum extracts are a better option for most applications of cannabis. The additional phytochemicals make the overall effect of the extract broader (covers a more extensive range of conditions) and tend to produce fewer side-effects compared to isolated or synthetic versions.

With that said, not all full-spectrum extracts are created equal. For certain conditions, it’s beneficial to find an extract high in other phytochemicals that have been proven to offer benefit to those conditions.

Anxiety, for example, will do much better on a hemp extract that contains CBN, CBG, CBD, and terpenes like myrcene or limonene.

Depression will do better with the more stimulating cannabinoids THC, and THCV, as well as more stimulating terpenes like beta-caryophyllene.

For this reason, we recommend following the guidance of third-party review websites, like Daily CBD that has knowledgeable staff who understand the complexities of the entourage effect and can recommend specific products depending on the cannabinoid, terpenoid, and other phytochemical makeup.

Summing it All Up

The Entourage Effect shows how amazing mother nature is — when cannabinoids are isolated, they tend to have a less pronounced effect — but when they work together, they can amplify the impact of the plant.

When shopping for CBD, you should consider your needs. Full-spectrum CBD includes as many cannabinoids as possible in its extract to use this effect to its full advantage.

Consider the many benefits of the entire spectrum of cannabinoids. Each cannabinoid has unique properties that provide medicinal benefits to the human body and work best together.


References

  1. Russo, E., & Guy, G. W. (2006). A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Medical Hypotheses66(2), 234-246.
  2. Hollister, L. E. (1974). Structure-activity relationships in man of cannabis constituents, and homologs and metabolites of Δ9-tetrahydrocannabinol. Pharmacology, 11(1), 3-11.
  3. Potter, D. (2009). The propagation, characterization and optimisation of cannabis sativa L as a phytopharmaceutical (Doctoral dissertation, King’s College London).
  4. Andre, C. M., Hausman, J. F., & Guerriero, G. (2016). Cannabis sativa: the plant of the thousand and one molecules. Frontiers in plant science, 7, 19.

Further Reading

Further Reading