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Government-approved cannabis supplied to patients in national programmes in the Netherlands and Canada is gamma-irradiated to sterilize coliform bacteria, but the safety of this technique for a smoked and inhaled product has never been specifically tested. Gamma-radiation significantly reduced linalool titres in fresh cilantro (Fan and Sokorai, 2002), and myrcene and linalool in orange juice (Fan and Gates, 2001).
One important remaining order of business is the elucidation of mono- and sesquiterpenoid biosynthetic pathways in cannabis, as has been achieved previously in other species of plants (Croteau, 1987; Gershenzon and Croteau, 1993; Bohlmann et al ., 1998; Turner et al ., 1999; Trapp and Croteau, 2001).
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.
D-Linalool is a monoterpenoid alcohol ( Table 2 ), common to lavender ( Lavandula angustifolia ), whose psychotropic anxiolytic activity has been reviewed in detail (Russo, 2001). Interestingly, linalyl acetate, the other primary terpenoid in lavender, hydrolyses to linalool in gastric secretions (Bickers et al ., 2003). Linalool proved sedating to mouse activity on inhalation (Buchbauer et al ., 1991; Jirovetz et al ., 1992). In traditional aromatherapy, linalool is the likely suspect in the remarkable therapeutic capabilities of lavender EO to alleviate skin burns without scarring (Gattefosse, 1993). Pertinent to this, the local anaesthetic effects of linalool (Re et al ., 2000) are equal to those of procaine and menthol (Ghelardini et al ., 1999). Another explanation would be its ability to produce hot-plate analgesia in mice ( P < 0.001) that was reduced by administration of an adenosine A 2A antagonist (Peana et al ., 2006). It is also anti-nociceptive at high doses in mice via ionotropic glutamate receptors (Batista et al ., 2008). Linalool demonstrated anticonvulsant and anti-glutamatergic activity (Elisabetsky et al ., 1995), and reduced seizures as part of Ocimum basilicum EO after exposure to pentylenetetrazole, picrotoxin and strychnine (Ismail, 2006). Furthermore, linalool decreased K + -stimulated glutamate release and uptake in mouse synaptosomes (Silva Brum et al ., 2001). These effects were summarized (Nunes et al ., 2010, p. 303): ‘Overall, it seems reasonable to argue that the modulation of glutamate and GABA neurotransmitter systems are likely to be the critical mechanism responsible for the sedative, anxiolytic and anticonvulsant properties of linalool and EOs containing linalool in significant proportions’. Linalool also proved to be a powerful anti-leishmanial agent (do Socorro et al ., 2003), and as a presumed lavender EO component, decreased morphine opioid usage after inhalation versus placebo ( P = 0.04) in gastric banding in morbidly obese surgical patients (Kim et al ., 2007).
β-Caryophyllene ( Table 2 ) is generally the most common sesquiterpenoid encountered in cannabis (Mediavilla and Steinemann, 1997), wherein its evolutionary function may be due to its ability to attract insect predatory green lacewings, while simultaneously inhibiting insect herbivory (Langenheim, 1994). It is frequently the predominant terpenoid overall in cannabis extracts, particularly if they have been processed under heat for decarboxylation (Guy and Stott, 2005). Caryophyllene is common to black pepper ( Piper nigrum ) and Copaiba balsam ( Copaifera officinalis ) (Lawless, 1995). It is anti-inflammatory via PGE-1, comparable in potency to the toxic phenylbutazone (Basile et al ., 1988), and an EO containing it was on par with etodolac and indomethacin (Ozturk and Ozbek, 2005). In contrast to the latter agents, however, caryophyllene was a gastric cytoprotective (Tambe et al ., 1996), much as had been claimed in the past in treating duodenal ulcers in the UK with cannabis extract (Douthwaite, 1947). Caryophyllene may have contributed to antimalarial effects as an EO component (Campbell et al ., 1997). Perhaps the greatest revelation regarding caryophyllene has been its demonstration as a selective full agonist at CB 2 (100 nM), the first proven phytocannabinoid beyond the cannabis genus (Gertsch et al ., 2008). Subsequent work has demonstrated that this dietary component produced anti-inflammatory analgesic activity at the lowest dose of 5 mg·kg −1 in wild-type, but not CB 2 knockout mice (Gertsch, 2008). Given the lack of attributed psychoactivity of CB 2 agonists, caryophyllene offers great promise as a therapeutic compound, whether systemically, or in dermatological applications such as contact dermatitis (Karsak et al ., 2007). Sensitization reactions are quite rare, and probably due to oxidized product (Skold et al ., 2006).
CB 2 is expressed in dopaminergic neurones in the ventral tegmental area and nucleus accumbens, areas mediating addictive phenomena (Xi et al ., 2010). Activation of CB 2 by the synthetic agonist JWH144 administered systemically, intranasally, or by microinjection into the nucleus accumbens in rats inhibited DA release and cocaine self-administration. Caryophyllene, as a high-potency selective CB 2 agonist (Gertsch et al ., 2008), would likely produce similar effects, and have the advantage of being a non-toxic dietary component. All factors considered, CBD, with caryophyllene, and possibly other adjunctive terpenoids in the extract, offers significant promise in future addiction treatment.
An obvious question pertains to the chemical ecology of such syntheses that require obvious metabolic demands on the plant (Gershenzon, 1994), and these will be considered.
Cannabis terpenoids could offer complementary activity. Two citrus EOs primarily composed of limonene inhibited Propionibacterium acnes , the key pathogen in acne (MIC 0.31 µL·mL −1 ), more potently than triclosan (Kim et al ., 2008). Linalool alone demonstrated an MIC of 0.625 µL·mL −1 . Both EOs inhibited P. acnes -induced TNF-α production, suggesting an adjunctive anti-inflammatory effect. In a similar manner, pinene was the most potent component of a tea-tree eucalyptus EO in suppression of P. acnes and Staph spp. in another report (Raman et al ., 1995).
Given that CBG can be produced in selected cannabis chemotypes (de Meijer and Hammond, 2005; de Meijer et al ., 2009a), with no residual THC as a possible drug abuse liability risk, a whole plant extract of a CBG-chemotype also expressing pinene would seem to offer an excellent, safe new antiseptic agent.
Terpenoids are EO components, previously conceived as the quintessential fifth element, ‘life force’ or spirit (Schmidt, 2010), and form the largest group of plant chemicals, with 15–20 000 fully characterized (Langenheim, 1994). Terpenoids, not cannabinoids, are responsible for the aroma of cannabis. Over 200 have been reported in the plant (Hendriks et al ., 1975; 1977; Malingre et al ., 1975; Davalos et al ., 1977; Ross and ElSohly, 1996; Mediavilla and Steinemann, 1997; Rothschild et al ., 2005; Brenneisen, 2007), but only a few studies have concentrated on their pharmacology (McPartland and Pruitt, 1999; McPartland and Mediavilla, 2001a; McPartland and Russo, 2001b). Their yield is less than 1% in most cannabis assays, but they may represent 10% of trichome content (Potter, 2009). Monoterpenes usually predominate (limonene, myrcene, pinene), but these headspace volatiles (Hood et al ., 1973), while only lost at a rate of about 5% before processing (Gershenzon, 1994), do suffer diminished yields with drying and storage (Turner et al ., 1980; Ross and ElSohly, 1996), resulting in a higher relative proportion of sesquiterpenoids (especially caryophyllene), as also often occurs in extracts. A ‘phytochemical polymorphism’ seems operative in the plant (Franz and Novak, 2010), as production favours agents such as limonene and pinene in flowers that are repellent to insects (Nerio et al ., 2010), while lower fan leaves express higher concentrations of bitter sesquiterpenoids that act as anti-feedants for grazing animals (Potter, 2009). Evolutionarily, terpenoids seem to occur in complex and variable mixtures with marked structural diversity to serve various ecological roles. Terpenoid composition is under genetic control (Langenheim, 1994), and some enzymes produce multiple products, again supporting Mechoulam’s ‘Law of Stinginess’. The particular mixture of mono- and sesquiterpenoids will determine viscosity, and in cannabis, this certainly is leveraged to practical advantage as the notable stickiness of cannabis exudations traps insects (McPartland et al ., 2000), and thus, combined with the insecticidal phytocannabinoid acids (Sirikantaramas et al ., 2005), provides a synergistic mechano-chemical defensive strategy versus predators.
Caryophyllene oxide ( Table 2 ) is a sesquiterpenoid oxide common to lemon balm ( Melissa officinalis ), and to the eucalyptus, Melaleuca stypheloides , whose EO contains 43.8% (Farag et al ., 2004). In the plant, it serves as an insecticidal/anti-feedant (Bettarini et al ., 1993) and as broad-spectrum antifungal in plant defence (Langenheim, 1994). Analogously, the latter properties may prove therapeutic, as caryophyllene oxide demonstrated antifungal efficacy in a model of clinical onychomycosis comparable to ciclopiroxalamine and sulconazole, with an 8% concentration affecting eradication in 15 days (Yang et al ., 1999). Caryophyllene oxide is non-toxic and non-sensitizing (Opdyke, 1983). This agent also demonstrates anti-platelet aggregation properties in vitro (Lin et al ., 2003). Caryophyllene oxide has the distinction of being the component responsible for cannabis identification by drug-sniffing dogs (Stahl and Kunde, 1973).
CBD is the most common phytocannabinoid in fibre (hemp) plants, and second most prevalent in some drug chemotypes. It has proven extremely versatile pharmacologically ( Table 1 ) (Pertwee, 2004; Mechoulam et al ., 2007), displaying the unusual ability to antagonize CB 1 at a low nM level in the presence of THC, despite having little binding affinity (Thomas et al ., 2007), and supporting its modulatory effect on THC-associated adverse events such as anxiety, tachycardia, hunger and sedation in rats and humans (Nicholson et al ., 2004; Murillo-Rodriguez et al ., 2006; Russo and Guy, 2006). CBD is an analgesic (Costa et al ., 2007), is a neuroprotective antioxidant more potent than ascorbate or tocopherol (Hampson et al ., 1998), without COX inhibition (Stott et al ., 2005), acts as a TRPV1 agonist analogous to capsaicin but without noxious effect (Bisogno et al ., 2001), while also inhibiting uptake of AEA and weakly inhibiting its hydrolysis. CBD is an antagonist on GPR55, and also on GPR18, possibly supporting a therapeutic role in disorders of cell migration, notably endometriosis (McHugh et al ., 2010). CBD is anticonvulsant (Carlini and Cunha, 1981; Jones et al ., 2010), anti-nausea (Parker et al ., 2002), cytotoxic in breast cancer (Ligresti et al ., 2006) and many other cell lines while being cyto-preservative for normal cells (Parolaro and Massi, 2008), antagonizes tumour necrosis factor-alpha (TNF-α) in a rodent model of rheumatoid arthritis (Malfait et al ., 2000), enhances adenosine receptor A 2A signalling via inhibition of an adenosine transporter (Carrier et al ., 2006), and prevents prion accumulation and neuronal toxicity (Dirikoc et al ., 2007). A CBD extract showed greater anti-hyperalgesia over pure compound in a rat model with decreased allodynia, improved thermal perception and nerve growth factor levels and decreased oxidative damage (Comelli et al ., 2009). CBD also displayed powerful activity against methicillin-resistant Staphylococcus aureus (MRSA), with a minimum inhibitory concentration (MIC) of 0.5–2 µg·mL −1 (Appendino et al ., 2008). In 2005, it was demonstrated that CBD has agonistic activity at 5-hydroxytryptamine (5-HT) 1A at 16 µM (Russo et al ., 2005), and that despite the high concentration, may underlie its anti-anxiety activity (Resstel et al ., 2009; Soares Vde et al ., 2010), reduction of stroke risk (Mishima et al ., 2005), anti-nausea effects (Rock et al ., 2009) and ability to affect improvement in cognition in a mouse model of hepatic encephalopathy (Magen et al ., 2009). A recent study has demonstrated that CBD 30 mg·kg −1 i.p. reduced immobility time in the forced swim test compared to imipramine ( P < 0.01), an effect blocked by pre-treatment with the 5-HT 1A antagonist WAY100635 (Zanelati et al ., 2010), supporting a prospective role for CBD as an antidepressant. CBD also inhibits synthesis of lipids in sebocytes, and produces apoptosis at higher doses in a model of acne ( vide infra ). One example of CBD antagonism to THC would be the recent observation of lymphopenia in rats (CBD 5 mg·kg −1 ) mediated by possible CB 2 inverse agonism (Ignatowska-Jankowska et al ., 2009), an effect not reported in humans even at doses of pure CBD up to 800 mg (Crippa et al ., 2010), possibly due to marked interspecies differences in CB 2 sequences and signal transduction. CBD proved to be a critical factor in the ability of nabiximols oromucosal extract in successfully treating intractable cancer pain patients unresponsive to opioids (30% reduction in pain from baseline), as a high-THC extract devoid of CBD failed to distinguish from placebo (Johnson et al ., 2010). This may represent true synergy if the THC–CBD combination were shown to provide a larger effect than a summation of those from the compounds separately (Berenbaum, 1989).
Various cannabis component combinations or cannabis extracts should be examined via high throughput pharmacological screening where not previously accomplished. Another goal is the investigation of the biochemical targets of the cannabis terpenoids, along with their mechanisms of action, particularly in the central nervous system. Possible techniques for such research include radio-labelling of select agents in animals with subsequent necropsy. On a molecular level, investigation of terpenoid changes to phytocannabinoid signal transduction and trafficking may prove illuminating. While it is known that terpenoids bind to odorant receptors in the nasal mucosa (Friedrich, 2004) and proximal olfactory structures (Barnea et al ., 2004), it would be essential to ascertain if direct effects in limbic or other cerebral structures are operative. Given that farnesyl pyrophosphate is a sesquiterpenoid precursor and the most potent endogenous agonist yet discovered for GPR92 (McHugh et al ., 2010), in silico studies attempting to match minor cannabinoids and terpenoids to orphan GPCRs may prove fruitful. Behavioural assays of agents in animal models may also provide clues. Simple combinations of phytocannabinoids and terpenoids may demonstrate synergy as antibiotics if MICs are appreciable lowered (Wagner and Ulrich-Merzenich, 2009). Ultimately, fMRI and single photon emission computed tomography studies in humans, with simultaneous drug reaction questionnaires and psychometric testing employing individual agents and phytocannabinoid-terpenoid pairings via vaporization or oromucosal application, would likely offer safe and effective methods to investigate possible interactions and synergy.
Phytocannabinoids and terpenoids are synthesized in cannabis, in secretory cells inside glandular trichomes ( Figure 1 ) that are most highly concentrated in unfertilized female flowers prior to senescence (Potter, 2004; Potter, 2009). Geranyl pyrophosphate is formed as a precursor via the deoxyxylulose pathway in cannabis (Fellermeier et al ., 2001), and is a parent compound to both phytocannabinoids and terpenoids ( Figure 2 ). After coupling with either olivetolic acid or divarinic acid, pentyl or propyl cannabinoid acids are produced, respectively, via enzymes that accept either substrate (de Meijer et al ., 2003), a manifestation of Mechoulam’s postulated ‘Nature’s Law of Stinginess’. Although having important biochemical properties in their own right, acid forms of phytocannabinoids are most commonly decarboxylated via heat to produce the more familiar neutral phytocannabinoids ( Table 1 ). Alternatively, geranyl pyrophosphate may form limonene and other monoterpenoids in secretory cell plastids, or couple with isopentenyl pyrophosphate in the cytoplasm to form farnesyl pyrophosphate, parent compound to the sesquiterpenoids, that co-localizes with transient receptor potential vanilloid receptor (TRPV) 1 in human dorsal root ganglion, suggesting a role in sensory processing of noxious stimuli (Bradshaw et al ., 2009), and which is the most potent endogenous ligand to date on the G-protein coupled receptor (GPR) 92 (Oh et al ., 2008).
d -limonene, common to the lemon and other citrus EOs ( Table 2 ), is the second most widely distributed terpenoid in nature (Noma and Asakawa, 2010), and is the precursor to other monoterpenoids ( Figure 2 ) through species-specific synthetic schemes. Unfortunately, these pathways have not yet been investigated in cannabis. The ubiquity of limonene serves, perhaps, as a demonstration of convergent evolution that supports an important ecological role for this monoterpene. Studies with varying methodology and dosing in citrus oils in mice suggest it to be a powerful anxiolytic agent (Carvalho-Freitas and Costa, 2002; Pultrini Ade et al ., 2006), with one EO increasing serotonin in the prefrontal cortex, and dopamine (DA) in hippocampus mediated via 5-HT 1A (Komiya et al ., 2006). Compelling confirmatory evidence in humans was provided in a clinical study (Komori et al ., 1995), in which hospitalized depressed patients were exposed to citrus fragrance in ambient air, with subsequent normalization of Hamilton Depression Scores, successful discontinuation of antidepressant medication in 9/12 patients and serum evidence of immune stimulation (CD4/8 ratio normalization). Limonene also produces apoptosis of breast cancer cells, and was employed at high doses in Phase II RCTs (Vigushin et al ., 1998). Subsequent investigation in cancer treatment has centred on its immediate hepatic metabolite, perillic acid, which demonstrates anti-stress effects in rat brain (Fukumoto et al ., 2008). A patent has been submitted, claiming that limonene effectively treats gastro-oesophageal reflux (Harris, 2010). Citrus EOs containing limonene proved effective against dermatophytes (Sanguinetti et al ., 2007; Singh et al ., 2010), and citrus EOs with terpenoid profiles resembling those in cannabis demonstrated strong radical scavenging properties (Choi et al ., 2000). As noted above, limonene is highly bioavailable (Falk-Filipsson et al ., 1993), and rapidly metabolized, but with indications of accumulation and retention in adipose tissues (e.g. brain). It is highly non-toxic (estimated human lethal dose 0.5–5 g·kg −1 ) and non-sensitizing (Von Burg, 1995)
Phytocannabinoids are exclusively produced in cannabis ( vide infra for exception), but their evolutionary and ecological raisons d’être were obscure until recently. THC production is maximized with increased light energy (Potter, 2009). It has been known for some time that CBG and CBC are mildly antifungal (ElSohly et al ., 1982), as are THC and CBD against a cannabis pathogen (McPartland, 1984). More pertinent, however, is the mechanical stickiness of the trichomes, capable of trapping insects with all six legs (Potter, 2009). Tetrahydrocannabinolic acid (THCA) and cannabichromenic acid (Morimoto et al ., 2007), as well as cannabidiolic acid and cannabigerolic acid (CBGA; Shoyama et al ., 2008) produce necrosis in plant cells. Normally, the cannabinoid acids are sequestered in trichomes away from the flower tissues. Any trichome breakage at senescence may contribute to natural pruning of lower fan leaves that otherwise utilize energy that the plant preferentially diverts to the flower, in continued efforts to affect fertilization, generally in vain when subject to human horticulture for pharmaceutical production. THCA and CBGA have also proven to be insecticidal in their own right (Sirikantaramas et al ., 2005).
Literary icons on both sides of the Atlantic espoused similar support for the citrus cure in the 19th century, notably Bayard Taylor after travels in Syria (Taylor, 1855), and Fitzhugh Ludlow after his voluntary experiments with ever higher cannabis extract doses in the USA (Ludlow, 1857). The sentiment was repeated by Calkins (1871), who noted the suggestion of a friend in Tunis that lemon retained the confidence of cure of overdoses by cannabis users in that region. This is supported by the observation that lemon juice, which normally contains small terpenoid titres, is traditionally enhanced in North Africa by the inclusion in drinks of the limonene-rich rind, as evidenced by the recipe for Agua Limón from modern Morocco (Morse and Mamane, 2001). In his comprehensive review of cannabis in the first half of the 20th century, Walton once more supported its prescription (Walton, 1938).
This claim has gained credence, not only through force of anecdotal accounts that abound on the Internet, but with formal scientific case reports and scientific analysis (McPartland et al ., 2008) documenting clearer thinking and improved memory with the cannabis–calamus combination, and with provision of a scientific rationale: calamus contains beta-asarone, an acetylcholinesterase inhibitor with 10% of the potency of physotigmine (Mukherjee et al ., 2007). Interestingly, the cannabis terpenoid, α-pinene, also has been characterized as a potent inhibitor of that enzyme (Miyazawa and Yamafuji, 2005), bolstering the hypothesis of a second antidote to THC contained in cannabis itself. Historical precedents also support pinene in this pharmacological role.
Considering the known minimal toxicities of CBD and these terpenoids and the above findings, new acne therapies utilizing whole CBD-predominant extracts, via multi-targeting (Wagner and Ulrich-Merzenich, 2009), may present a novel and promising therapeutic approach that poses minimal risks in comparison to isotretinoin.
THCV ( Table 1 ) is a propyl analogue of THC, and can modulate intoxication of the latter, displaying 25% of its potency in early testing (Gill et al ., 1970; Hollister, 1974). A recrudescence of interest accrues to this compound, which is a CB 1 antagonist at lower doses (Thomas et al ., 2005), but is a CB 1 agonist at higher doses (Pertwee, 2008). THCV produces weight loss, decreased body fat and serum leptin concentrations with increased energy expenditure in obese mice (Cawthorne et al ., 2007; Riedel et al ., 2009). THCV also demonstrates prominent anticonvulsant properties in rodent cerebellum and pyriform cortex (Hill et al ., 2010). THCV appears as a fractional component of many southern African cannabis chemotypes, although plants highly predominant in this agent have been produced (de Meijer, 2004). THCV recently demonstrated a CB 2 -based ability to suppress carageenan-induced hyperalgesia and inflammation, and both phases of formalin-induced pain behaviour via CB 1 and CB 2 in mice (Bolognini et al ., 2010).
Phytol ( Table 2 ) is a diterpene (McGinty et al ., 2010), present in cannabis extracts, as a breakdown product of chlorophyll and tocopherol. Phytol prevented vitamin A-induced teratogenesis by inhibiting conversion of retinol to a harmful metabolite, all- trans -retinoic acid (Arnhold et al ., 2002). Phytol increased GABA expression via inhibition of succinic semialdehyde dehydrogenase, one of its degradative enzymes (Bang et al ., 2002). Thus, the presence of phytol could account for the alleged relaxing effect of wild lettuce ( Lactuca sativa ), or green tea ( Camellia sinensis ), despite the latter’s caffeine content.