Tetrahydrocannabinol and endocannabinoids in feeding and appetite

Abstract

The physiological control of appetite and satiety, in which numerous neurotransmitters and neuropeptides play a role, is extremely complex. Here we describe the involvement of endocannabinoids in these processes. These endogenous neuromodulators enhance appetite in animals. The same effect is observed in animals and in humans with the psychotropic plant cannabinoid Δ⁹-tetrahydrocannabinol, which is an approved appetite-enhancing drug. The CB₁ cannabinoid receptor antagonist SR141716A blocks the effects on feeding produced by the endocannabinoids. If administered to mice pups, this antagonist blocks suckling. In obese humans, it causes weight reduction. Very little is known about the physiological and biochemical mechanisms involved in the effects of Δ⁹-tetrahydrocannabinol and the cannabinoids in feeding and appetite.

Introduction

The physiological control of appetite and satiety in animals is extremely complex, involving a balance of neurotransmitters and neuropeptides that interact reciprocally to stimulate and inhibit feeding behavior (York, 1999). Several reviews have addressed these interrelations (see, for example, Schwartz et al., 2000). In humans, the control of feeding behavior is, in addition, complicated by the effects of psychological and cultural cues that may override normal physiology, as in the extreme case of anorexia nervosa.

In this article, we review the effects and medical uses of Δ⁹-tetrahydrocannabinol (THC) in feeding and appetite and consider the role of the newly discovered endocannabinoid system as a further level of modulation of feeding in animals and in humans.

So far, two principal receptors have been found to be part of the endocannabinoid system: CB₁, which is present mainly in the brain (Devane et al., 1988, Matsuda et al., 1990; for a review, see Di Marzo et al., 1998) and to a lesser extent in the periphery, and CB₂, which is located mainly in the immune system (Munro et al., 1993; for a review, see Pertwee, 1997). Three types of endocannabinoids have been identified. The first endocannabinoid to be discovered, arachidonoyl ethanolamide (anandamide), is the most widely investigated representative of the class of endocannabinoid polyunsaturated fatty acid ethanol amides (Devane et al., 1992). The two further types are represented by 2-arachidonoylglycerol (2-AG) Mechoulam et al., 1995, Sugiura et al., 1995 and 2-arachidonyl glyceryl ether (Noladin ether) (Hanus et al., 2001). For recent reviews, see Mechoulam et al. (1998), with emphasis on pharmacology, Mechoulam and Ben-Shabat (1999), with emphasis on chemistry, and Chaperon and Thiebot (1999), summarizing behavioral effects.

Both anandamide and 2-AG, as well as the cannabinoid CB₁ receptor, are present in the hypothalamus, a brain area known to be associated with feeding. The exact role of the endocannabinoid system in feeding is not known, but it must have an important function, since it is well conserved in evolution from hydra to Homo sapiens, and endocannabinoids are present in mothers' milk.

Dissecting out the dynamics of appetite regulation by endocannabinoids is of potential importance, as it might lead to novel therapies for the treatment of anorexia and other eating disorders, human immunodeficiency virus (HIV) infection, and cancer cachexia on the one hand, while on the other hand, endocannabinoid antagonists might help in the management of obesity as appetite suppressors Colombo et al., 1998, Le Fur et al., 2001. However, it may be that the endocannabinoids are selective for certain nutrients, such as carbohydrates or alcohol (Arnone et al., 1997), in a manner resembling the effects of galanin on fat ingestion and metabolism (Leibowitz et al., 1998). For a detailed recent review on cannabinoids and appetite, see Kirkham and Williams (2001b).