Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects – By Ethan B Russo

«Another factor is apparent in that terpenoid yields from vaporization of street cannabis were 4.3–8.5 times of those from US National Institute on Drug Abuse cannabis (Bloor et al., 2008). It is undisputed that the black market cannabis in the UK (Potter et al., 2008), Continental Europe (King et al., 2005) and the USA (Mehmedic et al., 2010) has become almost exclusively a high-THC preparation to the almost total exclusion of other phytocannabinoids. If – as many consumers and experts maintain (Clarke, 2010) – there are biochemical, pharmacological and phenomenological distinctions between available cannabis ‘strains’, such phenomena are most likely related to relative terpenoid contents and ratios. This treatise will assess additional evidence for putative synergistic phytocannabinoid-terpenoid effects exclusive of THC, to ascertain whether this botanical may fulfil its promise as, ‘a neglected pharmacological treasure trove’ (Mechoulam, 2005).»

«Over 100 phytocannabinoids have been identified (Brenneisen, 2007Mehmedic et al., 2010), but many are artefacts of analysis or are produced in trace quantities that have not permitted thorough investigation. The pharmacology of the more accessible phytocannabinoids has received excellent recent reviews (Pertwee et al., 2007Izzo et al., 2009De Petrocellis and Di Marzo, 2010De Petrocellis et al., 2011), and will be summarized here, with emphasis on activities with particular synergistic potential.

THC (Table 1) is the most common phytocannabinoid in cannabis drug chemotypes, and is produced in the plant via an allele co-dominant with CBD (de Meijer et al., 2003). THC is a partial agonist at CB1 and cannabinoid receptor 2 (CB2) analogous to AEA, and underlying many of its activities as a psychoactive agent, analgesic, muscle relaxant and antispasmodic (Pacher et al., 2006). Additionally, it is a bronchodilator (Williams et al., 1976), neuroprotective antioxidant (Hampson et al., 1998), antipruritic agent in cholestatic jaundice (Neff et al., 2002) and has 20 times the anti-inflammatory power of aspirin and twice that of hydrocortisone (Evans, 1991). THC is likely to avoid potential pitfalls of either COX-1 or COX-2 inhibition, as such activity is only noted at concentrations far above those attained therapeutically (Stott et al., 2005).

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, 2004Mechoulam et al., 2007), displaying the unusual ability to antagonize CB1 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., 2004Murillo-Rodriguez et al., 2006Russo 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, 1981Jones 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 A2A 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., 2009Soares 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-HT1Aantagonist 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 CB2 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 CB2 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 (Johnsonet 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).