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The entourage effect is a hypothesis that was first suggested in the early 2000s, based on the notion that consuming a whole plant may be more effective than taking an isolated medication that is based only on one of a plant’s active compounds.
The hypothesis has been developed a lot since it was first posited. Today, some scientists believe different types of cannabis can be more or less effective for specific conditions and symptoms — and also the type of high they can cause — based on their chemical profiles.
What is the entourage effect?
Most prescription drugs are based on a single molecule. There are even two FDA-approved drugs based on the two main molecules in cannabis — the cannabinoids THC and CBD. Cannabis, however, is a plant containing hundreds of compounds.
In 1999, researchers Shimon Ben Shabat and Raphael Mechoulam first mentioned that, as a plant, cannabis may be superior to some pharmaceuticals thanks to the effect of entourage compounds. This hypothesis was based on their observations when researching the endocannabinoid system, however, not the cannabis plant.
They observed that some endocannabinoids naturally produced in the body are more effective when delivered with other, non-active compounds. Or in their words, “Biologically active natural products… are in many instances accompanied by chemically related, though biologically inactive, constituents… Investigations of the effect of the active component in the presence of its ‘entourage’ compounds may lead to results that differ from those observed with the active component only.”
They concluded that “this type of synergism may play a role in the widely held (but not experimentally based) view that in some cases plants are better drugs than the natural products isolated from them.”
A couple of years later, researcher Elizabeth Williamson provided evidence for the concept that “a whole or partially purified extract of a plant offers advantages over a single isolated ingredient.”1
One of the examples used was the ability of CBD to attenuate some of THC’s side effects. She concluded that “this synergistic effect will become very important if cannabis becomes a medicine by reducing the often undesirable psychotropic side effects.”
How does the entourage effect work?
Though a number of researchers have contributed to the entourage effect theory as it relates to cannabis, the name most associated with it is Dr. Ethan Russo. In his 2011 paper, “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects,” Russo thoroughly presented the previous works on cannabinoid synergy, basically coined the term “entourage effect,” and defined its mechanism.2
To explain how the entourage effect works, Dr. Russo cited a 2009 study from Germany that defined the way herbal synergy works in general, not just in cannabis. It described four main mechanisms, three of which are particularly relevant for cannabis:3
Multi-target enhancing effects
Most often, drugs operate on one or two molecular targets in our bodies, creating a specific effect. A multi-target effect means plant compounds can operate on many targets. In cannabis, a popular example would be the interaction of THC with CB1, CB2, GPR18, GPR55, TRPV2, TRPV3, and many other receptors. This multitude of targets can potentiate the effects of THC.
But it’s not just about THC — there are other cannabinoids, terpenes, and maybe even flavonoids that can also potentially activate a multitude of targets, thereby enhancing or modulating the effects of THC.
One of the earliest published examples of the potentiating effects of THC when administered in a synergistic manner, was the comparison of a pure THC medication with a whole plant extraction in the treatment of spasticity. With equal doses of THC, a whole plant extraction was deemed “considerably more effective antispastically than THC alone.”4
Molecular movement enhancing effects
The two main branches of pharmacology are pharmacodynamics (how drugs affect your body) and pharmacokinetics (how your body affects drugs, or the movement of drugs within the body). While the multi-target enhancing effects of cannabis are associated with the former, the movement enhancing effects of cannabis are related to pharmacokinetics.
The result is similar (an enhanced effect of THC or CBD), but the way there is a bit different. The multi-target enhancing effect is caused by the interaction of molecules on a variety of targets. While the movement enhancing effects of whole-plant cannabis is caused by the way a group of molecules (an entourage) travels in the body in a more efficient manner than if one of them travels alone.
One example of molecular movement enhancing effects is exemplified by the terpenes limonene and pinene. These terpenes are biologically active,5,6 and can cause relaxation of the lungs and airway, but when taken may not themselves produce a major bodily response (at least not at safe doses). But when terpenes are inhaled along with cannabinoids, the absorption of cannabinoids through the lungs could be improved by the presence of these bronchodilating terpenes.
Modulation of adverse effects
These effects “can be reached when a constituent contained in a plant extract…’neutralizes’ or destroys a toxicaly acting constituent and, therefore, generates a better effectiveness as compared with the original raw drug.”7
Several adverse effects of cannabis are associated with THC, and though there are a few cannabis compounds that may help counteract these adverse effects, the best and most popular is CBD.
There is a growing amount of research supporting the ability of CBD to attenuate THC adverse effects, particularly impaired memory8, anxiety9, and psychotomimetic effects (such as paranoia and social withdrawal)10.
Terpenes and cannabinoids – the entourage effect in cannabis
In “Taming THC,” Dr. Russo also added a new research direction: Maybe it’s not just the interaction of THC and CBD but also other cannabis compounds — such as minor cannabinoids, terpenes, and flavonoids — that play a role in the entourage effect.
Terpenes are aromatic molecules responsible for the smell and taste in most plants, but they are also pharmacologically active and can influence the body. One of the unique things about cannabis is its terpene content variability (there are almost 200 different terpenes in cannabis).
According to Dr. Russo, the abundant terpenes in a given chemovar are likely to determine its effects. Those terpenes may influence whether it’ll be sedating or stimulating, and whether it will be better for conditions and symptoms such as pain, inflammation, anxiety, epilepsy, or depression.
Some examples of potential cannabinoid-terpenoid synergy suggested in “Taming THC” include:
- THC + pinene = Bronchodilator
- THC + limonene, pinene or linalool = Beneficial in Alzehimer
- THC + linalool and/or myrcene = Muscle relaxant
- CBD + linalool and/or limonene = Anxiolytic
- CBD + linalool = Anticonvulsant
- CBD + limonene = Immunostimulant
- CBD + pinene = Anti-inflammatory
- THC and/or CBD + linalool = Analgesic
Though there’s some evidence for cannabinoid synergy (mainly THC and CBD), the terpenoid-cannabinoid synergy, as logical as it may be, is only supported by little evidence for now. But this may be due to lack of research on the matter.
How to take advantage of the entourage effect
There are a few ways to practically use this information, but before we dive into that, it’s important to note that terpenoid-cannabinoid synergies are mostly based on preliminary research. While it does make a lot of sense, there isn’t a lot of concrete evidence to support whether it can work on humans.
The most important rule when it comes to the entourage effect is to seek out cannabis flowers or whole-plant products over isolates. Then, there are a number of actions you can take to optimize your experience, or when choosing the right strain for you.
- Define an objective. What are you trying to achieve with cannabis? Have a relaxing evening, better focus when working, treat seizures, relieve pain?
- Investigate. Learn about the cannabinoids and terpenes that have been shown to be potentially useful for what you’re trying to achieve.
- Explore. Look for chemovars high in these cannabinoids and terpenes.
- Test. Conduct some trial and error until you find the chemovar that fits you.
Cannabis research still has a long way to go. For now, there’s no way to suggest a specific cannabis product for a given condition or use. But you can use the information we do have to narrow down the possibilities.
What if I don’t have access to the chemical profile?
If you live in a place with no legal cannabis program, or if your neighborhood dispensary doesn’t provide more information than the THC and CBD content of their products, you may still have other ways to sprinkle some entourage in your weed.
Let’s say you’d like to have two main chemovars in your life, one for a good night’s sleep, and another that’s more energizing and focusing for daytime. According to the entourage effect, pinene could help with memory and focus, while beta-caryophyllene (BCP) and linalool may help with insomnia.
All you need to do is infuse your cannabis with some extra pinene for your daytime chemovars, and BCP or linalool for your nighttime chemovar. There are a few ways in which you can do that, and they all involve other plants or their essential oils. However, keep in mind that these methods are based on logic rather than scientific literature.
Also, as described earlier, terpenes aren’t unique to cannabis — they can be found all over nature. In fact, while the variability of different terpenes in cannabis is unique, the total terpene content in cannabis is rather poor compared to other plants, and usually ranges between 1-3.5%.11
In comparison, the essential oil of lavender may consist of more than 85% terpenes12. Here are some ways to get some more terpenes in your weed:
1) Add in botanicals
Get some dry lavender flowers and add them to your nighttime chemovar before you smoke or vape it. The high concentration of linalool from the lavender could synergize with the THC and CBD in your weed. For your daytime chemovar, you can add some dry rosemary leaves, which are often high in pinene that may help with memory and concentration. Be sure to use dried, clean herbs if trying this and be aware that a little goes a long way.
2) Buy it infused
Get some terpene infused rolling papers, these can increase the terpene content of whatever you’re inhaling. Different brands offer infused papers and suggest the potential effects they may create. For instance, uplifting, relaxing and joyful.
3) Set the aroma or mood
Try to guide your cannabis experience with external terpenes by diffusing essential oils while you enjoy your cannabis. Get a diffuser, close the doors and windows, and diffuse a few drops of essential oils (rosemary or sage, for instance, are high in pinene). Once the odors of the essential oil starts kicking in, take a few deep breaths and enjoy the scent, then proceed to smoking or vaping your weed. For night time, you can use the essential oil of clove or cinnamon for some BCP, or an essential oil of lavender or sage for some linalool.
4) Infuse the herbs
Here you can use either dry herbs or essential oils, though the latter may work better as they have higher concentration of terpenes. When putting your cannabis flowers in a container (preferably made of glass), if you add another source of terpenes, the flower within the container will absorb some of the added terpenes from the air in the jar. To infuse your weed with herbs, add some dry rosemary, lavender, or clove to your jar of cannabis or place a few drops of essential oils on some cotton balls and leave them in the jar with the cannabis flowers so they can absorb the terpenes.
If you are using essential oils, make sure to use quality products from reputable brands such as doTERRA or Neal’s Yard, as this is an unregulated market that often offers low quality products with questionable ingredients.
How the entourage may change the industry
Assuming that the entourage effect is true, and cannabinoids and terpenes can synergize and play a role in how different types of cannabis influence the body, there may be some practical implications for cannabis researchers, consumers, health care professionals, growers, and manufacturers.
What the entourage effect means for consumers
One of the main implications of the entourage effect for consumers will be the way they choose cannabis products. If the cannabinoid and terpenoid profiles of cannabis plants determine their effects, we will need a system to categorize and group these products.
In an ideal world, after a lot of research is done on the entourage effect, cannabis products could be grouped for uses and treatments best suited for conditions and symptoms such as pain, sleep, nausea, headaches, and seizures. They could also be distinguished as daytime or nighttime evening products, better suited for a slow evening, partying, or working.
In any case, the current strain names or indica/sativa nomenclature won’t cut it when it comes to chemical profiles. They only refer to morphological differences at best, and often completely ignore the chemical profiles of cannabis products.
What the entourage effect means for research
Two of the main limitations of cannabis research are a lack of funding and conflicting results. Both are related to the entourage effect.
Conventional therapies usually use drugs that are based on one or two molecules that bind to one or a few receptors. The entourage effect intrinsically defies that approach. It suggests an herbal synergy in cannabis, in which multiple compounds target multiple targets.
This encourages a paradigm shift: Should researchers distinguish between cannabis chemotypes or chemovars? Chemotypes are either high in THC or CBD (or they can have a 1:1 ratio). Chemovars, on the other hand, look past the CBD:THC ratio, and are defined by the exact concentrations of cannabinoids, and their most abundant terpenes.
Moving forward with chemovars, while using the preliminary research suggested by the entourage effect may help lead researchers to more accurate results. At the moment there may be different studies that investigate how cannabis can help with a given condition or symptom. But sometimes researchers are using entirely different formulations — sometimes just THC, sometimes a mixture of THC and CBD, or even a whole plant extraction.
According to the entourage effect hypothesis, comparing the results of many of these studies is flawed because they often test different treatments altogether. If the hypothesis is accurate, then future studies should use a more precise chemovar-driven approach to researching cannabis. It could provide health care professionals with valuable insights into therapy, and provide consumers clearer guidance on expected effects of a particular product.
The only problem is that cannabis is a plant, and patenting a plant is no picnic. There is very little incentive to fund expensive clinical trials with specific chemovars — a return on investment comparable to pharmaceutical drugs is unlikely. In addition, the illegality of cannabis has prohibited and effectively banned university-based research that often occurs in emerging fields like cannabinoid science, which is why many of the questions raised by the entourage effect remain unanswered.
What the entourage effect means for cultivation and production
The entourage effect may also affect cannabis cultivation, as it will need to evolve to meet the future demands of the market. Nowadays most chemovars are just high in THC with varying terpenes, but mostly high in myrcene or beta-caryophyllene.
If consumers start seeking out cannabis with more diverse chemical profiles in order to take better advantage of the entourage effect, there will most likely be an increase in demand for varying concentrations of THC and CBD and other minor cannabinoids, but also of a larger variety of terpenes.
On the production side, there will be a need for a more elaborative labeling, one that presents more than just the THC and CBD concentrations, but also other cannabinoids and terpenes. This could happen — and in some places is already happening — either because consumers are demanding to know more, or because of regulations that mandate it.
Criticism
More than 20 years have passed since the first mention of a potential entourage effect in cannabis, but not all scientists agree with the hypothesis. In fact, some openly cast doubt on it.
In a recent article in the journal, “Expert Review of Clinical Pharmacology,” Peter Cogan argued that there is a lack of sufficient scientific evidence to support the entourage effect, that it’s often presented as an established clinical phenomenon as opposed to an hypothesis, and pointed to the vast misuse of that information by marketers in order to promote their cannabis products.13
Indeed, some of this criticism is valid. When the entourage effect was first suggested, it was proposed as an hypothesis — an observed phenomenon that needs to be further investigated. Nevertheless, cannabis companies, particularly CBD ones, use it in their promotional content to promote their whole plant based products as healthier and more efficient.
The lack of evidence, on the other hand, may reflect more on the lack of research rather than on the lack of entourage. In addition, the review ignores some of the more concrete clinical evidence for herbal synergy in cannabis, some of which was presented above.
Other recent studies that looked for evidence of a terpenoid-cannabinoid entourage couldn’t find evidence for such activity. They were preclinical studies that didn’t involve human subjects, however. 14, 15
On the other hand, another recent study does provide early evidence of a cannabis entourage effect. Researchers from the University of Arizona found that terpenes such as alpha humulene, linalool, and beta pinene can boost cannabinoid activity. Furthermore, the researchers wrote, they “are multifunctional cannabimimetic ligands,” or molecules that mimic cannabinoids, “that provide conceptual support for the entourage effect hypothesis and could be used to enhance the therapeutic properties of cannabinoids.”16
There’s a growing number of countries and states that legalize medical use of cannabis, even though they already have access to CBD and THC pharmaceutical drugs. And there is some scientific evidence 17 and a lot of anecdotal reports showing that both THC and CBD pharmaceutical preparations are more likely to cause side effects than whole plant preparation with equivalent amounts of either THC or CBD.
Herbal synergy in cannabis likely does exist, and it could help explain the variable effects of cannabis. However, there’s a lot of hype and marketing around the entourage effect but very limited scientific evidence to support the theory.
Sources
- https://pubmed.ncbi.nlm.nih.gov/11695885/
- Russo E. B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British journal of pharmacology, 163(7), 1344–1364. https://doi.org/10.1111/j.1476-5381.2011.01238.x
- Wagner, H., & Ulrich-Merzenich, G. (2009). Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine : international journal of phytotherapy and phytopharmacology, 16(2-3), 97–110. https://doi.org/10.1016/j.phymed.2008.12.018
- https://pubmed.ncbi.nlm.nih.gov/19211237/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524888/
- https://pubmed.ncbi.nlm.nih.gov/26456328/
- https://pubmed.ncbi.nlm.nih.gov/19211237/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435777/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604171/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719112/
- https://pubmed.ncbi.nlm.nih.gov/29161743/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767019/
- https://pubmed.ncbi.nlm.nih.gov/32116073/
- https://doi.org/10.1089/can.2019.0016
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757239/
- https://www.nature.com/articles/s41598-021-87740-8
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334252/
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