The Entourage Effect: The Science of Combining Cannabinoids

What is the entourage effect and what does research say about it?
Last Modified: February 22, 2019

The way marijuana affects people has been the subject of much study over the years. It’s known for causing a euphoric high, and it can also make people feel sleepy, energized, and even hungry. These effects are caused by the many different compounds found within the marijuana plant. While those compounds each play an individual role in how marijuana makes people feel, a theory known as “the entourage effect” says that these chemicals behave differently – and potentially even better – when combined together.

Over the years, the existence of the entourage effect has been the subject of much research and debate in the scientific community.

The Compounds Within Cannabis

To fully understand the entourage effect, it’s helpful to learn about the various compounds within the cannabis plant. Cannabinoids and terpenes are found within marijuana as well as within non-psychoactive hemp. They’re responsible for everything about the way the plant works – from the way it affects the human brain and body to the way it tastes and smells.

The main compounds responsible for the cannabis entourage effect are cannabinoids and terpenes.

Cannabinoids

The history of marijuana cannabinoids begins back in the early 1960s with an Israeli scientist named Dr. Raphael Mechoulam. He was curious about the mechanism through which marijuana makes people high. Scientists had been able to figure out that the opium plant causes intoxication because it contains morphine and that cacao leaves cause a high because they contain cocaine, but no one had yet discovered the compound that causes marijuana’s psychotropic effects.

The first compound Mechoulam and his team isolated within marijuana was cannabidiol (CBD). While CBD is a major cannabinoid that’s responsible for some of marijuana’s effects, it doesn’t get people high. About a year later, Mechoulam became the first person to isolate, characterize, and synthesize delta-9-tetrahydrocannabinol, otherwise known as THC. In the years to come, he was also to characterize the human endocannabinoid system – the network of receptors in the brain and body through which cannabinoids like THC work.

In addition to THC and CBD, marijuana also contains many other cannabinoids, albeit in much lower percentages. They include compounds such as tetrahydrocannabivarin (THCV) and cannabinol (CBN) and can cause effects such as sedation, inhibiting pain, and reducing inflammation. All of these cannabinoids are produced in the plant’s trichomes, or resin glands.

Terpenes

Meanwhile, a marijuana plant’s trichomes also secrete oils known as terpenes. At first glance, terpenes simply make cannabis taste or smell a certain way. Linalool, for example, gives some marijuana strains a floral taste and fragrance, while caryophyllene causes a spicy, peppery scent.

Terpenes do more than add a signature taste and aroma to different cannabis strains, however. They’re also responsible for marijuana’s effects. Those who smell linalool will be strongly reminded of lavender – another plant that contains this potent terpene. In marijuana just as in lavender, linalool is responsible for calming anxiety and pain. Citrus oils are famous for their antidepressant properties. Like cannabis, they contain limonene, a terpene that’s known to help lift depression.


What Is the Entourage Effect?

While cannabinoids and terpenes have been studied for their individual effects, proponents of the entourage effect are interested in the way these compounds work when combined with each other. They insist that consuming whole-plant marijuana produces a different effect than consuming individual cannabinoids or terpenes in isolation. The term “entourage effect” was coined by Mechoulam and Shimon Ben-Shabat in a cannabinoid study from 1999. In the study, Mechoulam and Shabat suggested that this phenomenon explains why botanical drugs (containing the entire spectrum of compounds within a plant) can sometimes be more effective than the plant’s isolated components.

Because most cannabinoids and terpenes are present in marijuana in such small concentrations, this makes it difficult to judge the effects that these individual compounds have when the plant is consumed as a whole. The exception to this rule is THC and CBD, the two cannabinoids found in the highest percentages in most marijuana strains. It’s the interaction between these two cannabinoids that provides one of the strongest arguments for the entourage effect.

Individual Effects of THC

Although the effects of THC can vary from one person to another, it’s well-known for causing a euphoric high. It’s useful for a variety of medical purposes, from calming pain and nausea to stimulating appetite. THC may also have negative side effects; it can cause short-term memory loss, an increased heart rate, and anxiety.

While these effects can be uncomfortable for some recreational marijuana consumers, they may be absolutely intolerable for medical marijuana patients. That’s what some people discovered about dronabinol, a synthetic THC medication marketed under the name of Marinol and used to quell nausea and vomiting and stimulate appetite. The THC side effects are too strong for some patients, however, causing them to feel anxious and unable to concentrate and function while taking it.

Individual Effects of CBD

CBD also has a whole host of medical uses. In addition to working as an effective painkiller, it’s also good at calming anxiety and lifting depression. Researchers have also found that CBD is effective at treating seizures in people with rare forms of epilepsy.

Unlike THC, CBD does not cause an intoxicating high and its side effects are generally mild. High doses of CBD can result in lightheadedness and a dry mouth, but it’s usually well-tolerated.

Combining Cannabinoids

Researchers and patients have noticed that in addition to its usefulness as an individual medical treatment, CBD is particularly effective at combating some of the more unpleasant side effects of THC. As mentioned before, this combination is one of the easiest ways to see the cannabis entourage effect at work.

The effects obtained by combining CBD and THC depend on the ratios of each cannabinoid. The most noticeable effect created by consuming CBD with THC is the reduction in THC’s psychoactive high. At a 1:1 CBD-to-THC ratio, the high is greatly reduced. At a 2:1 CBD-to-THC ratio, THC’s psychoactive effects disappear altogether. CBD also counteracts the extreme anxiety THC can cause in those who are sensitive to its effects.

By understanding and utilizing the entourage effect to their advantage, medical marijuana patients are able to choose strains or products with the proper THC-to-CBD ratio to offer relief without creating discomfort. A 1:1 THC-to-CBD ratio was used to create nabiximols (marketed under the name Sativex), a medication used for neuropathic pain and muscle spasticity in multiple sclerosis.

In one study, a 10 milligram dose of THC caused psychotic symptoms in 40 percent of participants. When testing the 1:1 CBD-to-THC ratio for Sativex, researchers found that only 4 out of 250 participants displayed psychotic symptoms, even at THC doses as high as 48 milligrams.


What Science Has to Say

In addition to offering medical patients the ability to fine-tune their treatments, some people feel that the entourage effect also allows recreational marijuana consumers the ability to customize their high by choosing strains with various concentrations of THC, CBD, as well as other cannabinoids and terpenes. Some researchers and other experts in the field have expressed skepticism about the entire entourage effect theory, setting up a sharp disagreement between those who are for it and those who demand more evidence.

Supporting Evidence

Because CBD and THC are the cannabinoids present in marijuana in the highest concentrations, their effects are the most noticeable. This is why the CBD-to-THC ratio of a product or cannabis strain is the most frequently-discussed aspect of the entourage effect. It’s also the factor that researchers explored in a 2011 study into cannabis and psychotic episodes. Since THC is known to exacerbate psychotic symptoms, the scientists wondered if those effects could be lessened by the introduction of CBD. The conclusion of the study showed that marijuana with a higher CBD content did, in fact, result in fewer psychotic outcomes amongst participants.

Other studies that support the entourage effect theory have to do with tumors and terpenes. In 2018, a group of researchers published a report on the anti-tumor activity of pure THC versus a botanical drug preparation. They found that the standardized cannabis drug preparation performed more effectively than the pure cannabinoid. Another study called for further research into the interaction between THC, other cannabinoids, and terpenes. It suggested that a terpene called alpha pinene (responsible for some marijuana strains’ pine scent) might preserve acetylcholine, which prevents the short-term memory loss caused by THC consumption.

Demands for More Research

In recent years, discussion of the entourage effect has increased both amongst marijuana consumers and in cannabis marketing. THCV, a minor cannabinoid that’s found in marijuana, has been studied for its appetite suppressant effects. This has led some companies to market strains with a noticeable percentage of THCV as “marijuana without the munchies” that can cancel out the appetite-stimulating effects of THC. Researchers warn that there is no scientific evidence to support many of these claims (particularly as they relate to cannabinoids that are present in very low concentrations). They demand more research to support the existence of the entourage effect and determine exactly how it may work in various combinations. Due to federal restrictions on possession and testing of marijuana in places such as the U.S., efforts to conduct more thorough studies on the entourage effect have been greatly hampered.

Dr. Margaret Haney of Columbia University is one of the scientists who is concerned that proof of the entourage effect is potentially being based on anecdotal evidence. A study she conducted in 2013 compared the analgesic effects of THC to smoked marijuana flower. While some insist that the entourage effect would cause the whole plant treatment to offer better relief, the conclusion of the study showed the opposite to be true: the THC (administered in the form of dronabinol) offered more long-lasting analgesic relief.


The Entourage Effect: The Sum of Marijuana’s Parts?

Is the cannabis entourage effect a valid event in which each of marijuana’s parts comes together to make a more powerful whole, or are reports of its powers anecdotal and overrated? Some scientists point to studies that have already been conducted as proof of that cannabinoids function more effectively in sync with one another than when isolated and given individually. Meanwhile, other experts demand more research.

Regardless of this debate, the cannabis industry has taken notice and is using the entourage effect to market its products. In many marijuana dispensaries, employees guide customers through the selection process by asking them the type of high or effect they’d like and helping them make a choice based on each strain or product’s combination of cannabinoids and terpenes. A quick search online finds terpenes for sale – products that are meant to enhance or dampen the effects of specific cannabinoids. With this kind of promotion on the rise, it’s safe to say that talk of the entourage effect is here to stay.


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