The Contribution of cocoa additive to cigarette smoking addiction

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Page 188 of 207 RIVM report 650270002 Anandamide brain cannabinoid CB1-receptors, have provided new tools to explore the mechanisms underlying cannabis abuse and dependence. Drug discrimination is the animal model with the most predictive validity and specificity for investigation of the psychoactive effects of cannabinoids related to their abuse potential. However, attempts to train animals to discriminate anandamide (or SR141716A) have so far been unsuccessful (45). The physical dependence on THC [Delta(9)-tetrahydrocannabinol] was demonstrated by using SR 141716A, a cannabinoid antagonist. This demonstration prompted to determine whether anandamide, an endogenous cannabinoid agonist, would also produce physical dependence. A low-dose regimen (10, 20, 40 and 40) or a high-dose regimen (25, 50, 100 and 100) expressed as mg/kg/24 hr was infused i.p. on a continuous basis, from days 1 through 4, respectively. During the infusion, especially at the high-dose regimen, the rats became immobile and developed eyelid ptosis. Abrupt discontinuation of anandamide did not elicit rebound behavioral activity. Neither arachidonic acid, a precursor and metabolite of anandamide (50, 100, 200 and 200 mg/kg/24 hr on days 1 through 4, respectively), nor 2-Me-F-AN [2methylarachidonyl-(2'-fluoroethyl)-amide], a metabolically stable analog of anandamide (5, 10, 20 and 20 mg/kg/24 hr for 4 days, respectively), had remarkable effects. Notably, groups pretreated with anandamide or 2-Rne-F-AN and challenged with SR 141716A did not show significantly elevated behavioral scores when compared with SR 141716A controls. On the other hand, nearly all groups receiving SR 141716A showed significant activation of these behaviors compared with vehicle controls, which suggests that this cannabinoid antagonist itself was activating behavior. It was concluded that anandamide has little if any capacity for physical dependence (46). Effects of smoking cessation No data available. Critical assessment The psychoactive cannabinoids have physical dependence properties, but there is inconclusive evidence that endogenous cannabinoids such as anandamide, have physical dependence properties. The anandamide level in cigarettes (12.5 ng/25 cigarettes) seems to be clearly insufficient to have any dependency properties, compared with the anandamide dose used to investigate the dependency properties of anandamide (10 – 100 mg/kg). Conclusion Anandamide through cigarette smoking does not seem to have physical dependence properties. COMMERCIAL USE No data available. BENEFICIAL EFFECTS Anandamide potently and selectively inhibits the proliferation of human breast cancer cells in vitro. Anandamide dose-dependently inhibited the proliferation of MCF-7 and EFM-19 cells with IC50 (inhibitory concentration) values between 0.5 and 1.5 µM and 83-92% maximal inhibition at 5-10 µM. The proliferation of several other
RIVM report 650270002 Page 189 of 207 Anandamide nonmammary tumoral cell lines was not affected by anandamide. The antiproliferative effect of anandamide was not due to toxicity or to apoptosis of cells but was accompanied by a reduction of cells in the s phase of the cell cycle. Anandamide cytostatic effect was inhibited by the selective CB1 receptor antagonist SR 141716A (47). Critical assessment The beneficial effect of anandamide was investigated in vitro and can not be related to any beneficial effect of anandamide in cigarettes. Conclusion No conclusion can be drawn on beneficial effects of anandamide in cigarettes. SUMMARY AND FINAL CONCLUSION Anandamide does not have a function in cigarette. A source of anandamide in cigarettes is cocoa powder, which is used as flavor enhancer. A typical casing concentration of cocoa powder for cigarette tobacco is 1%. The amount of anandamide found in cocoa powder is around 0.05 µg/g. Assuming one cigarette weights approximately 1 g, the anandamide amount from cocoa powder in one cigarette is estimated to be ± 0.5 ng. On the assumption that anandamide is not degraded during tobacco processing and cigarette combustion, the exposure level of anandamide through cigarette smoking is 12.5 ng/day (at smoking 25 cigarettes per day). The exposure through cigarette smoking can not be compared with environmental anandamide exposure, due to lack of data. However, by comparing the anandamide exposure through cigarette smoking with the endogenous anandamide level in human brain and blood (56 ng/mg protein and 1.4 ng/ml, respectively), it can be concluded that anandamide level in cigarettes is significantly lower than the endogenous pool. No data are available on the pyrolysis/combustion products of anandamide. Two cannabinoid (CB1 and CB2) and the vanilloid receptors are activated by anandamide. It has been suggested that anandamide may control the bronchus tone. Anandamide attenuates bronchospasm induced by capsaicin, but also induces bronchoconstriction (± 5 mg/kg, i.v.) in guinea-pigs. The effective anandamide dose exerting the bronchial effects seems to be significantly higher than the anandamide dose in cigarette smoke (12.5 ng/25 cigarettes). This cigarette anandamide dose is also significantly lower than the dose needed to affect the cardiovascular system (± 2.6 mg/kg bw) and central nervous system (0.001 mg/kg – 10 mg/kg). However, in all the mentioned studies anandamide was administered by other routes than directly to the pulmonary system and therefore, it is not known whether anandamide pulmonary exposure will exert any respiratory effects. The oral data indicate a low bioavailabilty of anandamide and an extensive metabolism in the gastrointestinal tract. Anandamide is widely distributed in the human body. Anandamide is also extensively metabolized as indicated by the half life (t1/2 < 5 min). There are no data on pharmacokinetics in animals and humans from respiratory studies. The TDlo was 140 µg/kg i.p. for rats and 100 mg/kg s.c. for mice. The anandamide
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