Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.
Open accessAbstract
Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α‐pinene, linalool, β‐caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL −1 . They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis‐based medicinal extracts. Particular focus will be placed on phytocannabinoid‐terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin‐resistant Staphylococcus aureus ). Scientific evidence is presented for non‐cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid‐terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue‐7
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Non-THC Cannabis active components may act synergistically and contribute to the pharmacological power and entourage effects of medicinal-based Cannabis extract.
“Further attentions is now drawn toward non-THC Cannabis active components, which may act synergistically and contribute to the pharmacological power and entourage effects of medicinal-based Cannabis extract (Russo, 2011).”
From Cannabis sativa: The Plant of the Thousand and One Molecules (2016) · cites this paper as Russo, 2011
THC has been also associated with a number of side effects, including anxiety, cholinergic deficits, and immunosuppression.
“However, THC has been also associated with a number of side effects, including anxiety, cholinergic deficits, and immunosuppression (Russo, 2011).”
From Cannabis sativa: The Plant of the Thousand and One Molecules (2016) · cites this paper as Russo, 2011
Terpenes present a wide-array of pharmacological properties.
“They present a wide-array of pharmacological properties, which have recently been described in several reviews (Russo, 2011; Singh and Sharma, 2015).”
From Cannabis sativa: The Plant of the Thousand and One Molecules (2016) · cites this paper as Russo, 2011
Linalool possesses similar properties to the ones described for its monoterpene counterparts, i.e., analgesic, anti-anxiety, anti-inflammatory, and anticonvulsant.
“Linalool, commonly found in Lavandula angustifolia, possesses similar properties to the ones described for its monoterpene counterparts, i.e., analgesic, anti-anxiety, anti-inflammatory, and anticonvulsant (Russo, 2011).”
From Cannabis sativa: The Plant of the Thousand and One Molecules (2016) · cites this paper as Russo, 2011
Flavonoids may modulate the pharmacokinetic of THC via inhibition of hepatic P450 enzymes (3A11 and 3A4).
“Flavonoids may also modulate the pharmacokinetic of THC, via inhibition of the hepatic P450 enzymes (3A11 and 3A4) (McPartland and Russo, 2001; Russo, 2011).”
From Cannabis sativa: The Plant of the Thousand and One Molecules (2016) · cites this paper as Russo, 2011
Cannabis trichomes produce terpenes responsible for the typical plant aroma.
“Besides cannabinoids, Cannabis trichomes produce other secondary metabolites, namely terpenes (see previous paragraph on Cannabis phytochemicals), which are responsible for the typical plant aroma (Russo, 2011).”
From Cannabis sativa: The Plant of the Thousand and One Molecules (2016) · cites this paper as Russo, 2011
Terpenes may modulate the affinity of THC for the CB1 receptor and interact with neurotransmitter receptors, which may support contributions of terpenes on cannabinoid-mediated analgesic and psychotic effects.
“Terpenes may also modulate the affinity of THC for the CB1 receptor and interact with neurotransmitter receptors, which may support contributions of terpenes on cannabinoid-mediated analgesic and psychotic effects (McPartland and Russo, 2001; Russo, 2011).”
From Cannabis sativa: The Plant of the Thousand and One Molecules (2016) · cites this paper as Russo, 2011
Nerolidol has anti-malarial and anti-leishmanial effects.
“which, interestingly, has anti-malarial and anti-leishmanial effects (reviewed by Russo, 2011).”
From Cannabis sativa: The Plant of the Thousand and One Molecules (2016) · cites this paper as Russo, 2011
Phytocannabinoid acid acts as potent insecticidal molecules.
“and on the other one, the phytocannabinoid acid acts as potent insecticidal molecules (Sirikantaramas et al., 2005; Russo, 2011).”
From Cannabis sativa: The Plant of the Thousand and One Molecules (2016) · cites this paper as Russo, 2011
In the Cannabis plant, the specific mixture of monoterpenes and sesquiterpenes determines viscosity and thereby the stickiness of Cannabis exudations necessary to trap insects.
“on one side, the specific mixture of monoterpenes and sesquiterpenes determines viscosity and thereby the stickiness of Cannabis exudations necessary to trap the insects”
From Cannabis sativa: The Plant of the Thousand and One Molecules (2016) · cites this paper as Russo, 2011
Ingestion of terpenes such as α-pinene, myrcene, limonene, and β-caryophyllene together with cannabinoids can modulate cannabis medicinal effects, called the entourage effect.
“Despite the phytocannabinoids being described as mainly responsible for the therapeutic properties of cannabis, studies have demonstrated that the ingestion of terpenes like α-pinene, myrcene, limonene, and β-caryophyllene together with the cannabinoids can modulate its medicinal effects, which is called the entourage effect [6].”
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- Authors
- Russo, E. B.
- Affiliations
- GW Pharmaceuticals (United Kingdom) (GB)
- Corresponding author
- Russo, Ethan B
- ORCID
- Russo, Ethan B
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2011-07-12
- Volume
- 163
- Issue
- 7
- Pages
- 1344-1364
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC3165946
- OpenAlex
- W2148841660
- Cited by
- 1,535
- References
- 21
- Citations by year
- 2026: 80 · 2025: 128 · 2024: 132 · 2023: 154 · 2022: 167 · 2021: 199 · 2020: 192 · 2019: 144 · 2018: 100 · 2017: 70 · 2016: 61 · 2015: 37 · 2014: 31 · 2013: 19 · 2012: 15
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- GW Pharmaceuticals
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plant Extracts Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
- Keywords
- tetrahydrocannabinol, entourage effect, phytocannabinoids, terpenoids, cannabis, cannabidiol, tetrahydrocannabivarin, cannabigerol, cannabichromene, limonene, myrcene, β-caryophyllene, caryophyllene oxide, nerolidol, phytol, pain, inflammation, depression, anxiety, epilepsy, antimicrobial activity, methicillin-resistant Staphylococcus aureus, medical cannabis
- MeSH terms
- Animals, Cannabis, Drug Synergism, Humans, Phytotherapy, Terpenes, Dronabinol
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