The entourage effect describes how different components of the cannabis plant interact to create the unique effects of various strains and products. This “entourage” of diverse plant chemicals should theoretically provide effects that differ from a single isolated compound like CBD or THC.

Think of it this way: A patient finds pain relief from a certain dose of THC, but cannot tolerate the side effects of this dose, such as anxiety or memory impairment. According to anecdotes, and in some cases scientific studies, other components of the cannabis plant—like CBD—can reduce these side effects and allow this dose to be tolerated.

The interaction between the two main cannabinoids, THC and CBD, is relatively well understood through years of animal and human studies. However, CBD is unlikely to be responsible for the wide array of effects reported for cannabis. So what else could be responsible for the properties that people have attributed to different strains (e.g., uplifting, sedating, creative, or relaxing)?

The primary suspect for a strain’s reported effects is terpenes.

The entourage effect of terpenes

Terpenes are the molecules that give cannabis and other plants their unique aromas. They often have an effect on the brain, at least in animal studies. Their levels in cannabis also vary widely, making them good candidates for explaining why one strain might feel very different from another.

The complex mixtures of terpenes in cannabis make it difficult to pin down a specific effect on a specific component.

You should consider most of what you read about the terpene entourage effects to be untested hypotheses rather than established scientific facts. The reality is that their interactions with THC are practically unstudied in humans. Some studies of terpenes have been performed in animals, but often at incredibly high doses which do not translate to the amount typically consumed from cannabis.

There are thousands of anecdotes about different strains, but we cannot easily use these to determine the effect of a specific terpene. The complex mixtures of terpenes in cannabis make it difficult to pin down a specific effect on a specific component. Hardly anybody knew the terpene profile of the cannabis they were consuming until recently.

Cannabis legalization has increased the popularity of terpene testing, and now many people are able to access the terpene profiles of their cannabis. However, without solid data on the effects of different terpenes in humans, these profiles are difficult to interpret.

Limonene’s role in the entourage effect

One terpene of particular interest is called limonene. This terpene, popularly associated with citrus aromas, has some unique properties. Anecdotally, it’s reported to affect mood; a 2019 study in humans showed that inhalation of limonene odor lowered heart rate.

In fact, limonene can work through a number of mechanisms in our brain. It is capable of interacting with various neurotransmitter systems, including the adenosine system, GABA system and serotonin system. These systems control many things, including alertness, mood, and thinking.

So although there is some solid preliminary evidence that limonene could interact with THC, we can never really know until a clinical study is performed. Clinical studies take money and the main way to obtain this money is through government grants. Until recently, it seemed very unlikely that the government would fund research into cannabinoid-terpene interactions.

Clinical studies on limonene & the entourage effect

Times are changing. Terpene entourage effects are finally about to be put to the test.

Ryan Vandrey, Ph.D., an Associate Professor of Psychiatry and Behavioral Sciences at Johns Hopkins University, has obtained a grant from the National Institutes of Health (NIH) for three clinical trials of cannabinoid-terpene interactions. This seems to show that the NIH is now more disposed to funding studies related to cannabinoids.

The first clinical trial will assess how limonene modulates the effects of THC.

This study will utilize the services of 20 healthy adult participants, who will visit a research unit on several different occasions. On each visit, they will consume (via a vaporizer) either an inactive placebo, limonene alone, THC alone, or the combination of THC and limonene.

Because two different dose levels of THC (15 and 30 mg) and limonene (1 and 5 mg) will be tested in addition to placebos, participants will actually do nine different treks to the laboratory, making this one of the most comprehensive studies of its type to date.

How do this study’s limonene ratios compare to strains?

This study is very well designed, but one thing I had to question was whether the levels of THC and limonene correspond to actual terpene profiles of available strains. For example, is there an existing strain that actually has 5 mg limonene for every 15 mg THC? To answer this, I turned to Leafly’s strain database.

This plot shows the distribution of limonene content in different cannabis flower products. We can see that many products have very little limonene (less than 0.2% by weight). Only a few products have a high level of limonene (above 0.8%). These products deliver about 8 to 10 mg of limonene per gram of cannabis.

We next looked at the ratios of THC to limonene in different strains. The highest ratio of THC to limonene in the clinical study is 30:1 (30 mg THC to 1 mg limonene). A few came close, with Banana OG offering a match:

The other ratios being tested are simply not available in THC-dominant strains. To achieve these ratios, the lowest of which is 3:1 (15 mg THC to 5 mg limonene), you would need to supplement with additional limonene. (This actually wouldn’t be too hard given that limonene is present in so many common foods!)

Whether or not you’re able to replicate these exact ratios in your own cannabis routine, this study will undoubtedly add important findings about how terpenes and cannabinoids interact in our bodies, bringing us that much closer to understanding which strains are best for our individual needs.

Mike Tagen Mike Tagen obtained his B.A. in neuroscience and Ph.D. in pharmacology. He has worked in clinical research and drug development for the past 12 years, and is currently a consultant at Verdient Science. View Mike Tagen's articles