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RainDog

(28,784 posts)
2. Two articles on phytocannabnoids
Wed Mar 12, 2014, 01:21 AM
Mar 2014

Cannabis was used to illustrate 4 features of synergistic plant medical action not obtained by isolating and synthetically reproducing a naturally-occurring multi-molecular interaction. There are over a hundred different cannabinoids in the cannabis plant - which were discovered before we knew we had an endocannabinoid regulatory system in the human body. Some plants other than cannabis do act upon endocannabinoids, however.

At present, the only phytocannabinoid that has been discovered to also exist in plants other than Cannabis is ?-caryophyllene, which is among the most abundant plant essential oil components.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931553/


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165946/

...‘This type of synergism may play a role in the widely held (but not experimentally based) view that in some cases plants are better drugs than the natural products isolated from them’. Support derives from studies in which cannabis extracts demonstrated effects two to four times greater than THC (Carlini et al., 1974); unidentified THC antagonists and synergists were claimed (Fairbairn and Pickens, 1981), anticonvulsant activity was observed beyond the cannabinoid fraction (Wilkinson et al., 2003), and extracts of THC and CBD modulated effects in hippocampal neurones distinctly from pure compounds (Ryan et al., 2006). Older literature also presented refutations: no observed differences were noted by humans ingesting or smoking pure THC versus herbal cannabis (Wachtel et al., 2002); pure THC seemed to account for all tetrad-type effects in mice (Varvel et al., 2005); and smoked cannabis with varying CBD or CBC content failed to yield subjective differences combined with THC (Ilan et al., 2005). Explanations include that the cannabis employed by Wachtel yielded 2.11% THC, but with only 0.3% cannabinol (CBN) and 0.05% CBD (Russo and McPartland, 2003), and Ilan's admission that CBN and CBD content might be too low to modulate THC. 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).

...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).

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, 2004; Mechoulam 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., 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-? 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., 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-HT1A 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 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 (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).
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