By Josh Kaplan, Ph.D.
Cannabis’ therapeutic potential is enhanced by multiple cannabinoids in combination with terpenes. This results from synergy between a combination of chemicals that impact multiple brain and body targets, affect how cannabinoids are processed by the body, and reduce side effects.
The entourage effect is the theory that multiple cannabinoids in combination with terpenes have stronger therapeutic effects on the brain and body than the individual cannabinoids on their own18,39. It was first termed by Israeli cannabis science pioneers, S. Ben-Shabat and Raphael Machoulam, in 1998 to describe the improved strength of 2-AG’s action in the presence of otherwise inactive molecules39. The entourage effect has since been generalized to the notion that whole-plant extracts (i.e., many cannabinoids, terpenes, and flavonoids) are more therapeutically effective than individual cannabinoids. Fittingly, a survey of medicinal cannabis users found that 98.2% preferred inhaled or infused methods of multiple cannabinoids than just THC40.
A brief survey of cannabinoids beyond THC and CBD
There are over 100 known cannabinoids, but many are present in such low concentrations that they’ve eluded scientific investigation. However, several cannabinoids have received more attention, and like CBD and THC, have therapeutic potential41. A brief summary of these effects are listed in the table below.
|Cannabinoid (common abbreviations)||Observed Effects|
Treatment of metabolic syndrome
Table adapted from 18
Some of these effects occur through action at the cannabinoid receptors, CB1 or CB2, while others are mediated by different brain and body targets. This range of targets enables their spectrum of potential therapeutic applications.
A brief survey of terpenes
Terpenes are not cannabinoids but give cannabis its distinctive odor. Over 200 different terpenes have been reported and often make up only 1% of cannabis extract. The most well-studied individual terpenes are presented in the table below. While terpenes are thought to alter the effects of cannabinoids on brain function, they’re also thought to alter brain function and behavior on their own. Merely inhalation of terpene odor has an effect on mouse behavior42,43. Some of these actions are thought to be mediated directly by terpene action cell membranes, neurotransmitter receptors, and enzymes44.
|Limonene (lemon)||Increases immune system function|
Protects against liver cancer
|Linalool (lavender)||Decrease anxiety
|Beta-Caryophyllene (pepper)||CB2 agonist
Table adapted from 18
As noted above, cannabinoids and terpenes can independently have a range of therapeutic benefits, but these benefits may be enhanced when consumed in combination. The type of enhancement is thought to be synergistic, in which the strength of the beneficial effect is greater than the benefit conveyed by each element, alone.
There are three basic mechanisms* of cannabis synergy that improve therapeutic benefits45:
- Multi-target effects: Cannabis’ therapeutic benefits are elevated when multiple brain and body targets can be activated simultaneously by different cannabinoids and terpenes. This also reduces the risk of developing tolerance, thereby preventing a weakening of therapeutic benefit with long-term use.
- Speed and duration of cannabis’ effects: Certain cannabinoids can block the enzymes that break down other chemicals in the body, including cannabinoids46. This can prolong their duration of effect on brain and body targets.
- Reduction of side effects: Certain cannabinoids and terpenes can reduce drug action on CB1 receptors and other targets. This facilitates cannabis’ therapeutic benefits and enables the consumption of higher doses without many of the adverse side effects.
* There’s also a fourth proposed mechanism, anti-fungal and anti-bacterial effects47, which can aid in the treatment of bacterial infections like MRSA.
The entourage effect doesn’t mean that individual cannabinoids can’t be therapeutically beneficial on their own. Chemically-synthesized THC (Marinol) is FDA-approved and has known therapeutic benefits. But why not improve these effects? Scientific research is shifting from studying the effects of individual cannabinoids towards more whole-plant approaches to harness cannabis’ therapeutic potential. This is the future of medicinal cannabis.
Summary: The entourage effect describes the interactive synergy between multiple cannabinoids and their terpenes. There are numerous cannabinoids beyond CBD and THC that have therapeutic benefits on their own. Similarly, some of the aromatic terpenes in cannabis have demonstrated effects on brain function and behavior. In combination, they can achieve synergistic therapeutic benefits by activating multiple targets, altering the speed and duration that the drug is present in the body, and reduce adverse side effects. This promotes a whole-plant pharmacological approach to achieve therapeutic gains beyond what’s possible with individual elements alone.
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