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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Taming THC: potential cannabis synergy and phytocannabinoid‐terpenoid entourage effects

Differently substituted flavanones were isolated from Leguminosae and their antibacterial activity was comparatively studied against methicillin-resistant Staphylococcus aureus (MRSA). The minimum inhibitory concentrations (MICs) of phytochemical flavanones to clinical isolates of MRSA were determined by a serial agar dilution method. The structure-activity relationship has indicated that 2',4'- or 2',6'-dihydroxylation of the B ring and 5,7-dihydroxylation of the A ring in the flavanone structure are important for significant anti-MRSA activity and that substitution with a certain aliphatic group at the 6- or 8-position also enhances the activity. Among the thirteen flavanones tested, tetrahydroxyflavanones with these structural characteristics isolated from Sophora exigua and Echinosophora koreensis showed intensive activity to inhibit the growth of all MRSA strains at 3.13-6.25 micrograms/ml. The present hydroxyflavanones would be useful in the phytotherapeutic strategy against MRSA infections.

Comparative Study on the Antibacterial Activity of Phytochemical Flavanones against Methicillin-resistant Staphylococcus aureus.

Hybrid materials of the metal–organic framework (MOF), chromium(III) terephthalate (MIL-101), and phosphotungstic acid (PTA) were synthesized in aqueous media in the absence of hydrofluoric acid XRD analysis of the MIL101/PTA composites indicates the presence of ordered PTA assemblies residing in both the large cages and small pores of MIL-101, which suggests the formation of previously undocumented structures The MIL101/PTA structure enables a PTA payload 15–2 times higher than previously achieved The catalytic performance of the MIL101/PTA composites was assessed in the Baeyer condensation of benzaldehyde and 2-naphthol, in the three-component condensation of benzaldehyde, 2-naphthol, and acetamide, and in the epoxidation of caryophyllene by hydrogen peroxide The catalytic efficiency was demonstrated by the high (over 80–90%) conversion of the reactants under microwave-assisted heating In four consecutive reaction cycles, the catalyst recovery was in excess of 75%, whereas the product yields were 

Chromium(III) Terephthalate Metal Organic Framework (MIL-101): HF-Free Synthesis, Structure, Polyoxometalate Composites, and Catalytic Properties

Natural products – antifungal agents derived from plants

Cannabis sativa: A comprehensive ethnopharmacological review of a medicinal plant with a long history.

Caryophyllene oxide, an oxygenated terpenoid, well known as preservative in food, drugs and cosmetics, has been tested in vitro as an antifungal against dermatophytes. Its antifungal activity has been compared to ciclopiroxolamine and sulconazole, commonly used in onychomycosis treatment and chosen because of their very different chemical structures. So, a new model has been tested, utilizing sheep hoof plates in order to simulate human nails, which are almost unobtainable for in vitro tests. Three protocols were utilized: pre-treatment, simultaneous treatment and post-treatment. Among these, the post-treatment method was the best to simulate antifungal therapy, as it permitted testing and comparing the efficiency of different antifungal drugs.

Use of caryophyllene oxide as an antifungal agent in an in vitro experimental model of onychomycosis

Chemical composition and in vitro antifungal and antioxidant activity of the essential oil and methanolic extract of Teucrium sauvagei Le Houerou.

Antimicrobial and antioxidant activities of the methanolic extracts of three Salvia species from Tunisia.

Four essential oil samples of Tunisian Thyme (Coridothymus capitatus (L.) Rchb. f.) were collected from two geographycally different areas, either in vegetative state or flowering, and then analyzed by GC and GC-MS. Antibacterial and antifungal in vitro tests done against pathogenic and saprophytic strains of human and animal skin microflora indicate that samples collected in full flowering period were the most efficient. These strong activities may be linked to high levels of carvacrol.

https://www.tandfonline.com/doi/pdf/10.1080/12538078.2006.10515554

Activités inhibitrices in vitro d'huiles essentielles de Coridothymus capitatus (L.) Rchb. f. vis-à-vis de germes représentatifs de microflores cutanées

The research was carried out with the purpose of ev aluating the effect of the inclusion of increasing levels (0, 10, 20, 30 and 40%) of defatted coconut flo r in the nutritional contribution of cecotropha gy to the nutrient balance of growing rabbits. 35 rabb its of the Chinchilla breed were used, distributed in a completely randomized design, with seven repetiti ons per treatment, the production of cecotrofo was controlled in 24 hours as well as the contents of M S, PB, FB, ashes and MO of the cecotrophs. The diets were supplied at a rate of 150 g.animal.día-1 . Circular wooden necklaces were placed on rabbits to prevent the consumption of cecotrophs. Cecotroph ic collection was performed every two hours uninterrupted for a 24-hour period. The first cecot rophs were collected at 9 am and the last at 7 am t he next day. The composition of the diets influenced t he total production of cecotrophs, with the lowest productions for the inclusions of 30 and 40% of coc onut flour defatted in the same way in the curves of cecotrophic production for 24 hours. The contrib ution of MS and PB were high, with a tendency to decrease in the diet, which included 40% of defatte d coconut flour in the diet.

Laura Michel

Papers

Use of caryophyllene oxide as an antifungal agent in an in vitro experimental model of onychomycosis

Chemical composition and in vitro antifungal and antioxidant activity of the essential oil and methanolic extract of Teucrium sauvagei Le Houerou.

Antimicrobial and antioxidant activities of the methanolic extracts of three Salvia species from Tunisia.

Activités inhibitrices in vitro d'huiles essentielles de Coridothymus capitatus (L.) Rchb. f. vis-à-vis de germes représentatifs de microflores cutanées

Nutritive contribution of growing rabbits caecotrophy, supplied with degrassed coconut flour