As anticipated in newsletter four, different compounds have been isolated from cannabis: the cannabinoids. The two most significant are cannabidiol (CBD) and delta-9-tetrahydrocannabinol (the most common variant of THC). CBD was the first cannabinoid that was isolated, and its chemical structure was reported in 1963 [1]. One year later, the structure of THC was determined by an Israeli biochemist, Raphael Mechoulam [1]. After obtaining five kilograms of seized cannabis from the police, he managed to separate a few compounds and tested them on monkeys [1]. He found one of these compounds -THC- to be psychoactive! He also tested this compound on healthy volunteers by feeding them cake containing THC. What he observed may not be surprising to us now: the volunteers experienced a variety of reactions that changed depending on the subjects’ personalities [1]. These included laughing, panic attacks, and openness to discussion. Mechoulam’s discovery triggered the exploration of a new biological system: the endocannabinoid system (ECS).  

The ECS is made of chemical compounds that bind to cannabinoid receptors (CBRs), and cannabinoid receptor proteins that are produced in the nervous system (fig. 1). While many different cannabinoid receptors exist, CB1, and CB2 are the most well established ones in research, with CB1 being predominantly expressed in cells found in the brain and CB2 in the immune system. The three principal cannabinoids that bind to these receptors are: tetrahydrocannabinol (THC), anandamide (AEA), and 2-arachidonoylglycerol (2-AG), with the latter naturally being at higher levels than AEA, in the central nervous system.

THC acts by binding the CB1 receptors in the brain, more specifically the nuclei in the hypothalamus. It is thought that these neurons produce endocannabinoids that work to regulate hunger. The more of these endocannabinoids are produced, the less leptin (a hormone that regulates energy balance) there is in blood [5]. A study on mice showed that the absence of leptin resulted in obesity and in high levels of hypothalamic endocannabinoids, likely as compensation [6]. When the mice were treated with a compound that binds CB (without activating it), food intake was reduced, proving that CB1 has a role in the regulation of hunger [6]. Another important physiological process in which endocannabinoids play a crucial role is sleep. In fact, the endocannabinoid system plays a role in modulating sleep-inducing biochemical behaviors! It was shown that increased endocannabinoid activity within the nervous system promotes sleep-inducing effects. Notably, the administration of AEA decreases wakefulness and increases REM sleep (the deepest phase of sleep) in rats [7]. Moreover, AEA increases adenosine levels , which plays a crucial role in promoting sleep [8]. In another study on rats, it was also shown that when deprived of REM sleep, CB1 receptors numbers increase in the nervous system tissue, thus boosting AEA’s binding potential to CB1, making the rats more susceptible to sleep [9].