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Trick Or Treat from Food Endocannabinoids?

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Trick Or Treat from Food Endocannabinoids? scientific correspondence 3. Casselman, J. M. in Proc. 1980 North Am. Eel Conf. (ed. Loftus, NAEs (0.01–5.8 mg per g) and oleamide of magnitude below those required, if K. H.) 74–82 (Ontario Ministry of Natural Resources, Ontario, (0.17–6.0 g per g), but no or very little administered by mouth, to reach the blood 1982). m 4. Radtke, R. L. Comp. Biochem. Physiol. A 92, 189–193 (1989). anandamide and no 2-AG. NAE levels are and cause observable ‘central’ effects. The 5. Kalish, J. M. J. Exp. Mar. Biol. Ecol. 132, 151–178 (1989). much lower in unfermented cocoa beans assays used here provide a gross evaluation of 6. Secor, D. H. Fish. Bull. US 90, 798–806 (1992). than in cocoa powder (which contained less cannabimimetic activity, and tests 7. Tzeng, W. N., Severin, K. P. & Wickström, H. Mar. Ecol. Prog. Ser. 149, 73–81 (1997). than 0.003 mg per g anandamide). Tiny monitoring more subtle behavioural changes 8. Angino, E. E., Billings, G. K. & Anderson, N. Chem. Geol. 1, amounts of anandamide in cocoa could that might be induced by low oral doses of 145–153 (1966). therefore be explained as artefacts of pro- NAEs/oleamide are needed before the rele- 9. Nakai, I., Iwata, R. & Tsukamoto, K. Spectrochim. Acta B (in the 2 cessing . Like all higher plants, cocoa plants vance of these compounds to the purported press). 8 10. Otake, T., Ishii, T., Nakahara, M. & Nakamura, R. Mar. Ecol. cannot synthesize arachidonic acid or its mild rewarding and craving-inducing effects 7 Prog. Ser. 112, 189–193 (1994). derivatives . Notably, in their NAE and of cocoa can be dismissed. The presence in oleamide content, cocoa and dark chocolate milk of 2-AG (which may be released from are similar to other plant-derived foods triglycerides during digestion) and oleamide (including soybean, hazelnuts, oatmeal and also needs to be investigated. Trick or treat from food millet), in which we detected up to 2.3, 1.1 Vincenzo Di Marzo*, Nunzio Sepe*, and 2.8 mg per g oleamide, N-oleoyl- Luciano De Petrocellis†, Alvin Berger‡, endocannabinoids? ethanolamine and N-linoleoyl-ethanol- Gayle Crozier‡, Ester Fride§, amine, respectively. Raphael Mechoulam§ The discovery of the endogenous cannabi- To establish whether endocannabinoids *Istituto per la Chimica di Molecole di Interesse noid N-arachidonoylethanolamine (anan- survive their passage through the digestive Biologico and †Istituto di Cibernetica, damide)1 and other N-acylethanolamines system, we assayed anandamide and 2-AG Consiglio Nazionale delle Ricerche, (NAEs) in chocolate2 has led to speculation after oral administration in a series of in Via Toiano 6, 80072 Arco Felice, Naples, Italy that the purported rewarding properties of vivo tests that are used widely to assess e-mail: [email protected] cocoa are due to the presence of cannabimimetic activity8 (Table 1). The two ‡Nestlé Research Centre, compounds “that could act as cannabinoid compounds were active in four of the five Nestec Ltd, Vers-Chez-Les Blanc, mimics”2. This observation raises some behavioural tests, but only at very high con- 1000 Lausanne 26, Switzerland important questions. First, are NAEs and centrations relative to those in foods. In §Department of Natural Products, anandamide, or the ‘endocannabinoid’ contrast, a smaller dose of the psychoactive David Bloom Centre for Pharmacy, 2-arachidonoylglycerol (2-AG)3, present in component of marijuana, (1)-D9-tetra- Faculty of Medicine, Hebrew University, widely consumed foods (such as milk) that hydrocannabinol (D9-THC), was sufficient Jerusalem 91120, Israel are less ‘rewarding’ than chocolate? And to give a strong effect in all tests. 1. Devane, W. A. et al. Science 258, 1946–1949 (1992). second, to what extent do these compounds Because intraperitoneal anandamide 2. di Tomaso, E., Beltramo, M. & Piomelli, D. Nature 382, reach the bloodstream and exert pharmaco- and 2-AG are active in the same tests at 677–678 (1996). logical effects when consumed orally? We doses 20- to 60-fold lower3,9, these results 3. Mechoulam, R. et al. Biochem. Pharmacol. 50, 83–90 (1995). 4. Cravatt, B.F. et al. Science 268, 1506–1509 (1995). believe that the content of endocannabi- indicate that only 1.6–5% of the orally 5. Mechoulam, R. et al. Nature 389, 25–26 (1997). noids in foods, and in cocoa in particular, is administered compounds enter the blood- 6. Bisogno, T. et al. Eur. J. Biochem. 254, 634–642 (1998). not sufficient to produce cannabis-like stream, probably owing to the high levels in 7. Cook, H. W. Biochemistry of Lipids, Lipoproteins and Membranes effects in mammals. the gastrointestinal tract of the enzyme fatty 141–169 (Elsevier, Amsterdam, 1991). 10 8. Martin, B. R. et al. Pharmacol. Biochem. Behav. 40, 471–478 (1991). We purified NAEs and 2-AG from acid amide hydrolase , which catalyses the 9. Fride, E. & Mechoulam, R. Eur. J. Pharmacol. 231, 313–314 (1993). various foods (including mature human, hydrolysis of both compounds. Therefore, it 10. Katayama, K. et al. Biochim. Biophys. Acta 1347, 212–218 (1997). bovine and goat milk, and cocoa at various is unlikely that the amounts of anandamide stages of processing) and quantified them and 2-AG found in food are sufficient to Beltramo and Piomelli reply — The two by gas chromatography and mass spectrom- produce observable psychotropic effects. most abundant N-acylethanolamines etry. Milk was the only food analysed in We did not test other unsaturated NAEs (NAEs) found in chocolate (N-oleyl- which an endocannabinoid, 2-AG, was that have been suggested to enhance ethanolamine and N-linoleylethanolamine) found in relatively high concentrations endogenous anandamide activity by do not activate brain cannabinoid receptors (0.3350.11 mg ml11 in human milk, for inhibiting its inactivation2, but instead but effectively inhibit anandamide degrada- example). The level of NAEs varied between assayed oleamide — for which this kind of tion1,2. This observation suggested to us that 0.003 and 0.024 mg ml11, with anandamide action is also supported by pharmacological these compounds might contribute to the being the least abundant compound. data5,6. High oral doses are again necessary hedonic properties of chocolate by causing Oleamide, a sleep-inducing substance4 that for activity to be observed in vivo (Table 1). non-metabolized anandamide to accumu- inhibits the hydrolysis of anandamide5,6, Our results show that the amounts of late at its sites of action2. was also present (0.055–1.27 mg ml11). anandamide, 2-AG and oleamide in foods, How can this hypothesis be tested? One In cocoa-derived samples, we detected including milk and cocoa, are several orders possibility is to determine whether antago- Table 1 Effects of test substances on performance of behavioural tests in mice nists of cannabinoid receptors prevent or Olive oil Anandamide 2-AG D9-THC Oleamide reduce chocolate craving. However, because (vehicle) (300 mg kg11) (400 mg kg11) (90 mg kg11) (200 mg kg11) cannabinoid antagonists also reduce the Ambulation 77511 5158* 1359** 3457** 3956** intake of other palatable foods and drinks3–5, Rearing 2955 1754* 352** 353** 1252** the results of this experiment would be diffi- Immobility 2257 70520* 157519** 146518** 85519* cult to interpret. Another approach would Analgesia 1250.4 1653 1051 2552** 1553 be to test whether N-oleyl-ethanolamine Hypothermia 10.250.25 12.3050.42** 13.250.5** 14.151.0** 12.850.56** and N-linoleylethanolamine act as reinforc- Effects of orally administered olive oil, anandamide, 2-AG, D9-THC and oleamide on mouse ambulation (number of ing stimuli in behavioural experiments. It is square crossings) and rearing (number of offspring reared) in an open field, immobility (time spent motionless on a ring, in seconds), analgesia (response latency to hind paw lick on a hot plate (54 °C), in seconds), and hypothermia possible, for example, to determine in ani- (decrease in rectal temperature, in °C)6,7,9,10. The procedures are not harmful to mice and meet with NIH ethical mals whether these compounds possess dis- standards. Substances were administered to Sabra female mice by mouth by gavaging. Doses lower than those shown did not produce any statistically significant effect. Results are mean5s.e.m. from 4–9 mice. *, P*0.01; criminative properties, a measure of their **, P*0.005; assessed by analysis of variance followed by Newman–Keuls post-hoc tests for group differences. ‘subjective’ effects. In either case, the aim is 636 Nature © Macmillan Publishers Ltd 1998 NATURE | VOL 396 | 17 DECEMBER 1998 | www.nature.com scientific correspondence to ascertain what component of the psycho- yellow exit. When the entrance was lemon pharmacological effects of chocolate, if any, scented, they preferred the blue exit (Fig. is mediated by an indirect activation of the Honeybees link sights 1b, experiment 1). The scent of mango evi- endogenous cannabinoid system. dently evoked recall of yellow, and lemon Di Marzo and co-workers have tested to smells triggered recall of blue. Bees could also be the role of endogenous cannabinoids in trained to make the opposite associations: chocolate craving by investigating the It is common for a smell or a sound to trig- yellow with lemon, and blue with mango extent to which NAEs and anandamide ger a vivid recollection of an associated event (Fig. 1b, experiment 2). reach the bloodstream and exert their phar- in the past, even if it involves a different sen- Bees trained on this task sometimes hes- macological effects after oral administra- sory modality and the episode occurred a itate to choose a colour in chamber B, the8n tion. To test whether anandamide or long time ago1,2. The human brain displays return to the entrance of chamber A and oleamide (which is not an NAE, but inhibits impressive cross-modal associative recall.
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