The Contribution of cocoa additive to cigarette smoking addiction

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Page 150 of 207 RIVM report 650270002 Phenylethylamine increased the urinary excretion of phenylacetic acid and mandelic acid (27-29). Kinetic parameters Phenylethylamine crosses the blood-brain barrier easily and its concentration in the brain after peripheral injection peaks within 5 minutes and returns to normal level within 30 min. The turnover of endogenous phenylethylamine in the brain is high with a half-life of 0.4 min (11). Critical assessment In-vitro studies have shown that phenylethylamine is rapidly absorbed by the pulmonary endothelial tissue and is also rapidly inactivated by pulmonary MAO. When radioactively labelled 14 C-phenylethylamine was injected intravenously in rat, radioactivity was measured in all tissues, including the brain. Phenylethylamine crosses the blood-brain barrier easily and its concentration in the brain after peripheral injection peaks within 5 minutes and returns to normal level within 30 min. The turnover of endogenous phenylethylamine in the brain is high with a half-life of 0.4 min. Phenylethylamine is metabolized by MAO, primarily by type-B (and to a small extent MAO-A), and aldehyde dehydrogenase to phenylacetic acid, which is the major metabolite of phenylethylamine in the brain. Based on in-vitro kinetic data of phenylethylamine, the pulmonary MAO will reduce the phenylethylamine intake through cigarette smoking. Conclusion There are no in-vivo pharmacokinetic data available on respiratory intake of phenylethylamine. Based on the in-vitro data, probably pulmonary MAO will reduce the bioavailability of phenylethylamine through cigarette smoking. TOXICOLOGY Acute toxicity Human The effect of 5 mg phenylethylamine in apple juice on 27 healthy volunteers was studied using a randomized placebo-controlled double-blind procedure. Phenylethylamine produced symptoms like headache, dizziness and discomfort in some volunteers (30). Animal LD50 oral mouse 400 mg/kg (1) LDLo oral rat 800 mg/kg (1) LD50 subcutaneous mouse 320 mg/kg (1) LD50 intravenous mouse 100 mg/kg (1) LDLo intraperitoneal rat 100 mg/kg (1) In one study, stereotyped sniffing behaviour together with forepaw padding -defined as the phenylethylamine syndrome- was induced by MAO-B inhibitors in rats injected with 30 mg/kg i.p. phenylethylamine. The comparison of the abilities of the MAO-B inhibitors to induce the syndrome and to inhibit MAO-B in rat brain homogenates indicated that at least 75% of MAO-B activity in rat brain had to be inhibited to induce the phenylethylamine syndrome. A good correlation was found between the abilities of MAO-B inhibitors to induce the behavioral syndrome and to
RIVM report 650270002 Page 151 of 207 Phenylethylamine increase levels of phenylethylamine in rat brain (31). In another study, male Swiss mice were treated systemically with phenylethylamine (25-150 mg/kg), and observed in isolation or in groups of five. Phenylethylamine at a dose of 25 mg/kg depressed activity and caused sedation, but at 50 mg/kg produced a brief stimulation of activity. At higher dose levels (75-150 mg/kg bw) the compound induced a biphasic stimulation of activity which was associated with the development of two distinct groups of stereotyped activities. Group testing significantly antagonized early phase stereotypy (forepaw padding, headweaving, compulsive grooming) but had no effect on, or potentiated, late phase stereotypy (rearing, licking). In addition grouped mice were more active and hyperreactive than isolated mice were (32). Local tolerance Human No data are available. Animal No data are available. Repeated dose toxicity Subacute The behavioural consequences of daily phenylethylamine administration for a period of 6 weeks have been examined. Rats showed signs of serotonin behavioral syndrome (forepaw padding, headweaving, splayed hindlimbs) after a single i.p. injection of phenylethylamine 50 mg/kg or 7 daily injections of 25 mg/kg. The syndrome reached peak intensity after 3 weeks treatment. These data provide strong evidence for an effect of phenylethylamine on brain serotonin systems (33). Semichronic No data are available. Chronic No data are available. Carcinogenicity Human No data are available. Animal No data are available. Reproduction toxicology Human No data available. Animal In-vitro studies with mouse embryos showed that phenylethylamine concentrations of 121 and 1210 mg/l were lethal (24 hr) and induced neural tube closure defects in 67% of the embryos at 12 mg/l (34).
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