The entourage effect is a hypothesis that

cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae. The number of species within the genus is disputed. Three species may be recognized: ''Cannabis sativa'', '' C. indica'', and '' C. ruderalis''. Alternatively ...

compounds other than

tetrahydrocannabinol Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC'' ...

(THC) act synergistically with it to modulate the overall psychoactive effects of the plant.

Compounds

Cannabinoids

CBD

Vaped or smoked

Cannabidiol Cannabidiol (CBD) is a phytocannabinoid discovered in 1940. It is one of 113 identified cannabinoids in cannabis plants, along with tetrahydrocannabinol (THC), and accounts for up to 40% of the plant's extract. , clinical research on CBD incl ...

(CBD), primarily between to , may be converted into THC. However, CBD oil can be delivered via other

routes of administration A route of administration in pharmacology and toxicology is the way by which a medication, drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance i ...

if this effect is not desired. For example, CBD is under preliminary research for its potential to modify the effects of THC, possibly mitigating some of the negative, *

psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...

-like effects of

THC Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC' ...

. ''Cannabis'' strains with relatively high CBD:THC ratios have been proposed to be less likely to induce

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

than vice versa, though this assertion has been challenged on account of contradictory findings in the literature. As an example, a 2022 cross-over study based on 47 participants exposed to pure THC as well as 1:1, 2:1, and 3:1 ratios of CBD:THC concluded that CBD did not mitigate any of the studied effects of THC at any ratio tested. This may be due to CBD's antagonistic effects at the

cannabinoid receptor Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid recepto ...

s, compared to THC's

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonistic e ...

effect. CBD is also a 5-HT_1A receptor (

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...

) agonist, which may also contribute to an anxiolytic-content effect.

Terpenes

There are numerous

terpene Terpenes () are a class of natural products consisting of compounds with the formula (C5H8)n for n > 1. Comprising more than 30,000 compounds, these unsaturated hydrocarbons are produced predominantly by plants, particularly conifers. Terpenes ar ...

s present in the cannabis plant and variation between strains. Some of the different terpenes have known pharmacological effects and have been studied. One hypothesis is that

myrcene Myrcene, or β-myrcene, is a monoterpene. A colorless oil, it occurs widely in essential oils. It is produced mainly semi-synthetically from '' Myrcia'', from which it gets its name. It is an intermediate in the production of several fragrances. � ...

is a prominent sedative terpenoid in cannabis, and combined with THC, may produce the 'couch-lock' phenomenon.

Hypothetical differences between ''C. indica'' and ''C. sativa''

The effects of ''sativa'' are well known for its cerebral high, while ''indica'' is well known for its sedative effects, which some prefer for nighttime use. Both types are used as

medical cannabis Medical cannabis, or medical marijuana (MMJ), is cannabis and cannabinoids that are prescribed by physicians for their patients. The use of cannabis as medicine has not been rigorously tested due to production and governmental restrictions ...

. * Cannabinoid ratios: On average, ''Cannabis indica'' has higher levels of

compared to CBD, whereas ''Cannabis sativa'' has lower levels of THC to CBD. However, huge variability exists within either species. A 2015 study shows the average THC content of the most popular herbal cannabis products in the Netherlands has decreased slightly since 2005. * Terpene ratios: Sativa ancestry is associated with

farnesene The term farnesene refers to a set of six closely related chemical compounds which all are sesquiterpenes. α-Farnesene and β-farnesene are isomers, differing by the location of one double bond. α-Farnesene is 3,7,11-trimethyl-1,3,6,10-dodec ...

and

bergamotene Bergamotenes are a group of isomeric chemical compounds with the molecular formula C15H24. The bergamotenes are found in a variety of plants, particularly in their essential oils. There are two structural isomers, α-bergamotene and β-berga ...

, while Indica ancestry is associated with

elemene Elemenes are a group of closely related natural chemical compounds found in a variety of plants. The elemenes, which include α-, β-, γ-, and δ-elemene, are structural isomers of each other and are classified as sesquiterpenes. The elemenes c ...

, and

sesquiterpene Sesquiterpenes are a class of terpenes that consist of three isoprene units and often have the molecular formula C15H24. Like monoterpenes, sesquiterpenes may be cyclic or contain rings, including many unique combinations. Biochemical modificatio ...

alcohols.

Criticism

In 2022, studies found that plants identified as “indica” or “sativa” based on common methods of differentiation (e.g. plant height or leaf shape) are not, in fact, chemically distinguishable, with many identified as “sativa” having cannabinoid ratios predicted of “indica” plants and vice versa. The authors have concluded that the chemical makeup of cannabis plants cannot be reliably determined by simple inspection of the plants' physical characteristics and that the “indica” and “sativa” labels are not informative as to the cannabinoids (or other chemical components) delivered.

Background

The phrase ''entourage effect'' was introduced in 1999. While originally identified as a novel method of endocannabinoid regulation by which multiple endogenous chemical species display a cooperative effect in eliciting a cellular response, the term has evolved to describe the polypharmacy effects of combined cannabis phytochemicals or whole plant extracts. The phrase now commonly refers to the compounds present in cannabis supposedly working in concert to create "the sum of all the parts that leads to the magic or power of cannabis". Other cannabinoids, terpenoids, and flavonoids may be part of an entourage effect.

Criticism

A 2020 review of research found no entourage effect in most studies, while other reports claimed mixed results, including the possibility of increased

adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complica ...

s. The review concluded that the term, "entourage effect", is unfounded and used mainly for marketing. The author also notes that there is no reason to expect that entourage synergism should result in a net benefit. That is to say, one might just as well expect cannabinoid/cannabinoid or cannabinoid/terpene interactions to amplify/augment the adverse effects or mitigate/diminish any beneficial effects of both cannabinoids and terpenes.

References

{{Cannabinoidergics Cannabinoids Cannabis and health Hypotheses