 Food intake and feeding behaviour  Obesity  Nausea and vomiting  IBD  Stress  Cancer Role of EC’s in the gut

 CB1 receptor agonists including Δ9-THC  “munchies” or craving for high fat diets  promote body weight gain Food intake Bellocchio et al., 2008,Kunos, 2007 Matias and Di Marzo, 2007

 CB1 receptors located on vagal afferent neurons  may be involved in CB-induced modulation of appetite  anandamide might act as a “hunger signal” in the intestine  OEA -related compound, stimulates appetite Storr & Sharkey, 2007 Role in obesity

 peripherally restricted CB1 receptor antagonist (URB447)  effective at suppressing food intake  reducing body weight in genetically obese ob/ob mice. Role in obesity Lo Verme et al.,2009

 Food intake and feeding behavior  Obesity  Stress  Nausea and vomiting  IBD  Cancer Role of EC’s in the gut

 Anandamide (AEA) and 2- AG  ↓ anadamide in motion sickness  ↓ CB1 receptor activity  ↓ 2-AG in major depression Effects of endocannabinoids

 CBs inhibit emesis in animal models  acute cisplatin and delayed emesis  morphine  radiation-induced emesis  anticipatory nausea and vomiting  FAAH inhibitor URB597  suppressed cisplatin  nicotine-induced vomiting (in the house musk shrew through CB1 receptors) Nausea and vomiting Van Sickle et al., 2001, 2003, 2005; Darmani et al., 2007 Ray et al., 2009

 CB1 receptor antagonist  effective weight loss agent  withdrawn from the market in 2008  increased risk of depression and vomiting Rimonabant : A new Pill To Combat Obesity Van Gaal et al., 2005 Pi-Sunyer et al., 2006 Van Gaal et al.,2008

What is stress? Role of the ECS in stress

“People are disturbed not by a thing, but by their perception of a thing.” Epictetus  Difficult to define  Hence difficult to measure  Highly subjective  First coined in the 1930’s by “Hans Selye”

Stress… Unpredictable Uncontrollable

Psychological stress induces endocrine, sympathetic, and behavioral responses that allow the individual to cope with stress The endocannabinoid/CB1 receptor signaling system (ECS) serves to oppose these stress-induced changes Role of the ECS in stress

 Stress produces an increase in circulating endocannabinoids  inversely related to stress-induced physiological effects, including sympathetic activation and circulating glucocorticoid concentrations  Enables the host to adapt to stress and terminates ongoing sympathetic and hypothalamic-pituitary- adrenal (HPA) axis activation Role in stress

 Studies with CB1 receptor antagonists, such as rimonabant used in Europe for obesity support the role of the ECS in stress-related disorders  Rimonabant was associated with significant depression and nausea as a side effect Role in stress

And so …. EC’s make you happy, fat and dumb ! Laurel and Hardy

BUT And so does weed !

Problems with marijuana