The Contribution of cocoa additive to cigarette smoking addiction

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Page 182 of 207 RIVM report 650270002 Anandamide 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 systems than the pulmonary system. Conclusion Anandamide level in cigarette smoke seems to be insufficient to exert any systemic pharmacological effects. However, no data on pulmonary exposure of anandamide are available and therefore, the local anandamide effects are unknown. PHARMACOKINETICS Absorption No data are available on absorption through the pulmonary system. An in vitro study with celllines (neuroblastoma, glioma and laryngeal carcinoma cells) showed that cellular uptake of anandamide is governed by a concentration gradient of unbound anandamide e.g. facilitated diffusion-mediated transport (32). Bioavailability No data are available on the anandamide bioavailability through the pulmonary system. Di Marzo et al (6) suggested that 1.6 – 5% of orally administered anandamide enter the bloodstream, probably due to extensive metabolism in the gastrointestinal tract by enzyme fatty acid amide hydrolyse. Distribution Anandamide was found in human hippocampus and parahippocampal cortex, striatum, and cerebellum, which are the brain areas known to express high levels of CB1-receptors. Significant levels of anandamide were also found in the thalamus which expresses low levels of CB1-receptors and in the spleen which expresses high levels of the CB2-receptor. Small amounts of anandamide were detected in the heart. Only trace quantities were detected in pooled serum, plasma and cerebrospinal fluid (CSF). The distribution of anandamide in brain and spleen supports its potential role as an endogenous agonist in central and peripheral tissues, The low levels found in serum, plasma, and CSF suggest that it is metabolized in tissues where it is synthesized and that its action is probably not hormonal in nature (33). Male mice were administered 50 mg/kg 3 H-anandamide (i.v.). At 1, 5, 15 and 30 min after administration, the animals were sacrificed and the distribution of radio activity in various tissues was determined. The radio activity was detectable in brain by 1 min after injection. At 1 min after injection, the rank order of radioactivity per milligram or microliter of tissue was adrenal > lung > kidney > plasma > heart > liver > diaphragm > brain > fat (34). Metabolism Anandamide is hydrolysed by fatty-acid amide hydrolase (FAAH) to free arachidonic acid and ethanolamine. FAAH is an endoplasmic reticular integral membrane-bound enzyme. FAAH is widely distributed in the brain. Outside the brain, high FAAH levels are found in pancreas, kidney and in smaller extent in the liver (11, 35). Excretion No data available.
RIVM report 650270002 Page 183 of 207 Anandamide Kinetic parameters Male mice were administered 50 mg/kg 3 H-anandamide (i.v.). At 1, 5, 15 and 30 min after administration, the animals were sacrificed and various tissues were removed, solubilized and counted to determine the distribution of the radioactivity. Also, the anadamide were determined in the samples from brain, adrenal gland and in plasma.The radio activity was detectable in brain 1 min after injection. Although the 1 and 5 min metabolic profiles of brain radio activity showed that anandamide was clearly present, most anandamide had already been transformed to arachidonic acid and other polar metabolites, and there were almost no detectable brain levels of anandamide at 15 and 30 min in plasma and adrenal gland. It is suggested tha anandamide quickly reaches the brain and that the rapid metabolism of anandamide plays a key role in the time course of the pharmacological activity of this naturally occurring cannabinoid receptor ligand (34). Critical assessment The oral data indicate a low bioavailabilty of anandamide. The in vivo studies seems to indicate that anandamide is endogenously distributed widely in the human body. Anandamide is also extensively metabolized as indicated by the half life (t1/2 < 5 min). There are no data available on pharmacokinetics in animals and humans from respiratory studies. Conclusion There are no in-vivo pharmacokinetic data available on respiratory exposure of anandamide. The rapid elimination of anandamide indicates that pulmonary anandamide exposure will not exert any systemic effects. TOXICOLOGY Acute toxicity Human No data available. Animal TDLo i.p. rat:140 µg/kg (1) TDLo s.c. mouse: 100 mg/kg (1) High doses of injected anandamide (10 – 100 mg/kg of body weight) cause typical in vivo cannabimimetic inhibitory effects (decreased motor activity, rearing activity, ring catalepsy, hypothermia, analgesia and agonistic behaviour) and inhibition of leukocyte phagocytosis. In contrast, low doses of injected anandamide (0.01 mg/kg) stimulated activities in open field and ring, increase aggresive behaviour and stimulated phagocytosis (36). The acute anandamide effects were studied in unanaesthetized freely behaving rats. Intravenous anandamide caused dose-related decreases in locomotor behaviour, a pronounced hyper-reflexia, and a moderate antinociceptive state. At doses between 3 and 30 mg/kg, a dose-dependent hypothermia and profound, time-dependent cardiovascular changes were also observed.The exerted behavioural and physiological effects were similar to those seen following natural cannabinoids (22). Local tolerance Human
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The Contribution of cocoa additive to cigarette smoking addiction

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