VOL. 1, No. 1, January 2004

J. C. Sipe [2004] Med Hypotheses Res 1: 1-10.

The Brain Endogenous Cannabinoid System: A Role in
Reward/Craving of Addiction?

Jack C. Sipe*

Department of Molecular and Experimental Medicine, The Scripps Research Institute,
La Jolla, CA 92037, USA

Abstract. Cannabinoid signaling in the central nervous system and periphery of
mammals is controlled through a mechanism known as the endogenous cannabinoid
system (ECS) that consists of the cannabinoid receptors 1 and 2, a growing family of
endogenous neuromodulatory fatty acid amide ligands, the “endocannabinoids”, and their
principal inactivating enzyme, fatty acid amide hydrolase (FAAH). The ECS represents a
product of vertebrate nervous system evolution that is now recognized as an important
retrograde signaling pathway for continuous modulation of the release of many classical
neurotransmitters while also having the potential to influence diverse and at times
profoundly abnormal neurobehavioral consequences under pathological conditions. The
purpose of this review is to summarize some of the recent advances in our knowledge of
the ECS and to propose a hypothesis for a role of the ECS as a risk factor for reward and
craving behaviors in some addictions. Evidence is presented that the ECS influences
addictive behavior in both animal models and human disorders of reward and craving.
These findings support the concept that brain endogenous cannabinoid signaling may be a
useful future target for novel therapeutic strategies in selected addiction disorders.

*Address all correspondence to: Dr. Jack C. Sipe, Department of Molecular and
Experimental Medicine, The Scripps Research Institute (MEM-215), La Jolla, CA 92037
(USA).  E-Mail:

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