Selected possibilities for phytocannabinoid-terpenoid synergy
Cannabis and Acne
AEA simulates lipid production in human sebocytes of sebaceous glands at low concentrations, but induces apoptosis at higher levels, suggesting that this system is under ECS control (Dobrosi et al., 2008). CBD 10–20 mMdid not affect basal lipid synthesis in SZ95 sebocytes, but did block such stimulation by AEA and arachidonate (Biro et al., 2009). Higher doses of CBD (30–50 mM) induced sebocyte apoptosis, which was augmented in the presence of AEA. The effect of CBD to increase Ca++ was blocked by ruthenium red, a TRP-inhibitor. RNA mediated silencing of TRPV1 and TRPV3 failed to attenuate CBD effects, but experiments did support the aetiological role of TRPV4, a putative regulator of systemic osmotic pressure (T. Bíró, 2010, pers. comm.). Given the observed ability of CBD to be absorbed transcutaneously, it offers great promise to attenuate the increased sebum production at the pathological root of acne. Cannabis terpenoids could offer complementary activity. Two citrus EOs primarily composed of limonene inhibited Propionibacterium acnes, the key pathogen in acne (MIC 0.31 mL·mL-1), more potently than triclosan (Kim et al., 2008). Linalool alone demonstrated an MIC of 0.625 mL·mL-1. Both EOs inhibited P. acnes-induced TNF-a 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). Considering the known minimal toxicities of CBD and these terpenoids and the above findings, new acne therapies utilizing whole CBD-predominant extracts, via multitargeting (Wagner and Ulrich-Merzenich, 2009), may present a novel and promising therapeutic approach that poses minimal risks in comparison to isotretinoin.
MRSA
MRSA accounted for 10% of cases of septicaemia and 18,650 deaths in the USA in 2005, a number greater than that attributable to human immunodeficiency virus/acquired immunodeficiency syndrome (Bancroft, 2007). Pure CBD and CBG powerfully inhibit MRSA (MIC 0.5–2 mg·mL-1) (Appendino et al., 2008). Amongst terpenoids, pinene was a major component of Sideritis erythrantha EO that was as effective against MRSA and other antibiotic-resistant bacterial strains as vancomycin and other agents (Kose et al., 2010). A Salvia rosifolia EO with 34.8% pinene was also effective against MRSA (MIC 125 mg·mL-1). The ability of monoterpenoids to enhance skin permeability and entry of other drugs may further enhance antibiotic benefits (Wagner and Ulrich-Merzenich, 2009). 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.
Psychopharmacological applications: depression, anxiety, insomnia, dementia and addiction |
Scientific investigation of the therapeutic application of terpenoids in psychiatry has been hampered by methodological concerns, subjective variability of results and a genuine dearth of appropriate randomized controlled studies of high quality (Russo, 2001; Bowles, 2003; Lis-Balchin, 2010). The same is true of phytocannabinoids (Fride and Russo, 2006). Abundant evidence supports the key role of the ECS in mediating depression (Hill and Gorzalka, 2005a,b), as well as anxiety, whether induced by aversive stimuli, such as posttraumatic stress disorder (Marsicano et al., 2002) or pain (Hohmann et al., 2005), and psychosis (Giuffrida et al., 2004). With respect to the latter risk, the presence of CBD in smoked cannabis based on hair analysis seems to be a mitigating factor reducing its observed incidence (Morgan and Curran, 2008). A thorough review of cannabis and psychiatry is beyond the scope of this article, but several suggestions are offered with respect to possible therapeutic synergies operative with phytocannabinoids-terpenoid combinations. While the possible benefits of THC on depression remain controversial (Denson and Earleywine, 2006), much less worrisome would be CBD- or CBG-predominant preparations. Certainly the results obtained in human depression solely with a citrus scent (Komori et al., 1995), strongly suggest the possibility of synergistic benefit of a phytocannabinoid-terpenoid preparation. Enriched odour exposure in adult mice induced olfactory system neurogenesis (Rochefort et al., 2002), an intriguing result that could hypothetically support plasticity mechanisms in depression (Delgado and Moreno, 1999), and similar hypotheses with respect to the ECS in addiction treatment (Gerdeman and Lovinger, 2003). Phytocannabinoidterpenoid synergy might theoretically apply.
The myriad effects of CBD on 5-HT1A activity provide a strong rationale for this and other phytocannabinoids as base compounds for treatment of anxiety. Newer findings, particularly imaging studies of CBD in normal individuals in anxiety models (Fusar-Poli et al., 2009; 2010; Crippa et al., 2010) support this hypothesis. Even more compelling is a recent randomized control trial of pure CBD in patients with social anxiety disorder with highly statistical improvements over placebo in anxiety and cognitive impairment (Crippa et al., 2011). Addition of anxiolytic limonene and linalool could contribute to the clinical efficacy of a CBD extract.
THC was demonstrated effective in a small crossover clinical trial versus placebo in 11 agitated dementia patients with Alzheimer’s disease (Volicer et al., 1997). THC was also observed to be an acetylcholinesterase inhibitor in its own right, as well as preventing amyloid b-peptide aggregation in that disorder (Eubanks et al., 2006). Certainly, the antianxiety and anti-psychotic effects of CBD may be of additional benefit (Zuardi et al., 1991; 2006; Zuardi and Guimaraes, 1997). A recent study supports the concept that CBD, when present in significant proportion to THC, is capable of eliminating induced cognitive and memory deficits in normal subjects smoking cannabis (Morgan et al., 2010b). Furthermore, CBD may also have primary benefits on reduction of b-amyloid in Alzheimer’s disease (Iuvone et al., 2004; Esposito et al., 2006a,b). Psychopharmacological effects of limonene, pinene and linalool could putatively extend benefits in mood in such patients.
The effects of cannabis on sleep have been reviewed (Russo et al., 2007), and highlight the benefits that can accrue in this regard, particularly with respect to symptom reduction permitting better sleep, as opposed to a mere hypnotic effect. Certainly, terpenoids with pain-relieving, anti-anxiety or sedative effects may supplement such activity, notably, caryophyllene, linalool and myrcene.
The issue of cannabis addiction remains controversial.
Some benefit of oral THC has been noted in cannabis withdrawal (Hart et al., 2002; Haney et al., 2004). More intriguing, perhaps, are claims of improvement on other substance dependencies, particularly cocaine (Labigalini et al., 1999; Dreher, 2002). The situation with CBD is yet more promising. CBD and THC at doses of 4 mg·kg-1 i.p. potentiated extinction of cocaine- and amphetamine-induced conditioned place preference in rats, and CBD produced no hedonic effects of its own (Parker et al., 2004). CBD 5 mg·kg-1·d-1 in rats attenuated heroin-seeking behaviour by conditioned stimuli, even after a lapse of 2 weeks (Ren et al., 2009). A suggested mechanism of CBD relates to its ability to reverse changes in a-amino-3-hydroxyl-5-methyl-4- isoxazole-propionate glutamate and CB1 receptor expression in the nucleus accumbens induced by heroin. The authors proposed CBD as a treatment for heroin craving and addiction relapse. A recent study demonstrated the fascinating result that patients with damage to the insula due to cerebrovascular accident were able to quit tobacco smoking without relapse or urges (Naqvi et al., 2007), highlighting this structure as a critical neural centre mediating addiction to nicotine. Further study has confirmed the role of the insula in cocaine, alcohol and heroin addiction (Naqvi and Bechara, 2009; Naqvi and Bechara, 2010). In a provocative parallel, CBD 600 mg p.o. was demonstrated to deactivate functional magnetic resonance imaging (fMRI) activity in human volunteers in the left insula versus placebo (P < 0.01) without accompanying sedation or psychoactive changes (Borgwardt et al., 2008), suggesting the possibility that CBD could act as a pharmaceutical surrogate for insular damage in exerting an anti-addiction therapeutic benefit. Human studies have recently demonstrated that human volunteers smoking cannabis with higher CBD content reduced their liking for drugrelated stimuli, including food (Morgan et al., 2010a). The authors posited that CBD can modulate reinforcing properties of drugs of abuse, and help in training to reduce relapse to alcoholism. A single case report of a successful withdrawa from cannabis dependency utilizing pure CBD treatment was recently published (Crippa et al., 2010).
Perhaps terpenoids can provide adjunctive support. In a clinical trial, 48 cigarette smokers inhaling vapour from an EO of black pepper (Piper nigrum), a mint-menthol mixture or placebo (Rose and Behm, 1994). Black pepper EO reduced nicotine craving significantly (P < 0.01), an effect attributed to irritation of the bronchial tree, simulating the act of cigarette smoking, but without nicotine or actual burning of material. Rather, might not the effect have been pharmacological? The terpenoid profile of black pepper suggests possible candidates: myrcene via sedation, pinene via increased alertness, or especially caryophyllene via CB2 agonism and a newly discovered putative mechanism of action in addiction treatment.
CB2 is expressed in dopaminergic neurones in the ventral tegmental area and nucleus accumbens, areas mediating addictive phenomena (Xi et al., 2010). Activation of CB2 by the synthetic agonist JWH144 administered systemically, intranasally, or by microinjection into the nucleus accumbens in rats inhibited DA release and cocaine selfadministration. Caryophyllene, as a high-potency selective CB2 agonist (Gertsch et al., 2008), would likely produce similar effects, and have the advantage of being a nontoxic dietary component. All factors considered, CBD, with caryophyllene, and possibly other adjunctive terpenoids in the extract, offers significant promise in future addiction treatment.