Endocannabinoids 

Humans and animals alike naturally synthesize endocannabinoids, chemical compounds that activate the same receptors as delta-9-tetrahydrocannabinol (THC), the active component of marijuana (Cannabis sativa). Cannabis is famous for its significant psychoactive effects. Its ability to provide relief to chronic pain sufferers, to induce an increase in appetite, to alleviate nausea, and to ease anxiety are only some of the common uses for hemp.

History of endocannabinoid research

When Mechoulam and colleagues isolated THC in 1964, they made it possible to further understand the complex nature of the endocannabinoid system.^[1] Other important events in endocannabinoid research are as follows:

• 1988 - Cannabinoid-binding sites in rat brains identified
• 1991 - Human cannabinoid receptor CB1 successfully cloned
• 1992 - Discovery of the first endocannabinoid, arachidonoyl ethanolamide, later named anandamide (a Sanskrit word for “internal bliss”)^[2]
• 1993 - Peripheral CB2 receptor cloned
• 1995 - Discovery of a second endocannabinoid, 2-arachidonoyl glycerol (2-AG)

In the 21^st century, new discoveries of other endocannabinoids, their site distributions, and roles are deepening our understanding of the endocannabinoid system.

Further investigation

Endocannabinoids are crucial to bioregulation. With scientific evidence suggesting their role in inflammation, insulin sensitivity, and fat and energy metabolism, inhibition of endocannabinoids may be a tool in reducing the prevalence of metabolic syndrome. Furthermore, modulation of the endocannabinoid system may be a cure for more chronic neurologic and immune conditions. Many questions are left unanswered about this relatively newly discovered regulatory system. Further investigation into this exciting field promises to shed insights into the mechanisms of health and disease and provide new therapeutic options.

Multiple human and animal studies support that endocannabinoids play a key role in memory, mood, brain reward systems, drug addiction, and metabolic processes, such as lipolysis, glucose metabolism, and energy balance.^[3]

Through postsynaptic neuronal depolarization and an influx of calcium, the body activates N- acylphosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) and diacylglycerol (DAG) lipase, which then build anandamide and 2-AG, respectively. Due to their lipophilic nature, the endocannabinoids act locally and are not synthesized until needed. Central nervous system messengers that act in a retrograde fashion, the endocannabinoids are agonists to CB1 and CB2.

CB1 and CB2 are G-protein receptors. CB1 receptors are abundant in the brain, specifically the mesocorticolimbic system, the spinal cord, and the peripheral neurons. CB1 receptors are particularly concentrated on gamma-aminobutyric acid (GABA) – releasing neurons (inhibitory neurons). Hence, activation of CB1 leads to retrograde suppression of neurotransmitter release. CB2 receptors are located peripherally, with a high density on immune-modulating cells and activated microglial.

CB1 receptor roles

CB1 receptor activation modulates food intake and energy metabolism through coordination of the mesolimbic reward system and the hypothalamus’ appetite control pathway. With fasting or starvation, anandamide and 2-AG levels increase in the limbic forebrain and, to a less significant extent, in the hypothalamus.

CB1 receptors aid in modulating hepatic lipogenesis. Activation in the liver leads to fatty acid synthesis, causing hepatic steatosis and diet-induced obesity.

CB1 activation aids in vasodilation and cardiac contractility, regulating blood pressure and improving left heart function. Activation of CB-1 receptors and, to a lesser extent, CB2 receptors by anandamide also reduces gastrointestinal motility and secretions. CB1 receptor activation inhibits proinflammatory responses in the colon. Moreover, hyperactivity of the endocannabinoid-signaling pathway contributes to the pathophysiology of Parkinson disease.^{[4, 5]}

Obese and overweight individuals may have a mutation in fatty acid amide hydrolase, the enzyme that degrades anandamide.

Even in wild-type mice who develop diet-induced obesity, there is a hyperactive endocannabinoid system, with an increase in receptor availability and an increase in circulation endocannabinoids. In presatiated mice, an intrahypothalamic injection of anandamide induced substantial hyperphagia. Inactivation of CB1 receptors decreases plasma insulin and leptin levels, ultimately leading to more efficient energy metabolism.^{[6, 7]}

CB2 receptor roles

CB2 selective agonists have proven to be helpful in reducing inflammation and undoing established inflammation hypersensitivity involved in peripheral pain and skin disorders. By reducing inflammatory cell infiltration and lipid peroxidation, CB2 receptor activation is protective against hepatic ischemia-reperfusion injury.

In addition to immunomodulatory pathways, CB2 receptors are involved in maintaining proper bone mass.^[8] CB2 receptors are abundant in osteocytes, osteoclasts, and osteoblasts. CB2 agonists enhance endocortical osteoblast reproduction and activation, while inhibiting osteoclastogenesis.

Endocannabinoid degradation

Once their job is done at the presynaptic membrane, the endocannabinoids are quickly degraded through transport protein reuptake and hydrolyzation by fatty acid amide hydrolase (FAAH) and monoacylglycerol (MAG) lipase.^[9]

Cannabinoid receptor agonists

Tetrahydrocannabinol and cannabidiol (which together make up the drug Sativex) are active components of Cannabis sativa that bind to CB1 and CB2 receptors. Their bioavailability is unknown. A buccal spray is approved for use for neuropathic pain associated with multiple sclerosis in Canada only.^{[10, 11]}

Dronabinol (Marinol), a synthetic THC, is a CB1 and CB2 receptor agonist that has been approved by the US Food and Drug Administration (FDA) for use as an antiemetic for chemotherapy and an appetite stimulant for persons with acquired immunodeficiency syndrome (AIDS). Its Bioavailability is 10%.^{[12, 13]}

Nabilone (Cesamet) is a synthetic analogue of THC; it is a CB1 and CB2 receptor agonist that has been FDA approved as an antiemetic in chemotherapy patients in whom all other therapy has failed. Unapproved use is employed in patients with upper motor neuron syndrome who have spasticity-related pain not controlled by conventional treatment.^[14]

CB1 receptor antagonist

Rimonabant (Acomplia or Zimulti) is a selective CB1 receptor antagonist, SR141716, with an affinity to centrally acting CB1 receptors. Rimonabant is currently being sold in the United Kingdom, Germany, and a few other countries around the world under the name Acomplia, as an anti-obesity drug. In the United States, rimonabant was rejected by an expert panel of the FDA. However, evidence exists to support the use of rimonabant in the treatment of obesity, its comorbidities, and drug dependence.^{[15, 16, 17]}

A large downside of rimonabant is that with larger doses, such as 20 mg, nausea and mood changes, especially depression, have frequently been experienced. Other reported adverse effects include arthralgias, insomnia, dizziness, fatigue, nasopharyngitis, and increased incidence of upper respiratory tract infections.

The 4 phase III randomized, controlled trials of Rimonabant in Obesity (RIO) yielded promising results for obesity treatment. After evaluating placebo with rimonabant 5 mg and 20 mg, along with a hypocaloric diet for all groups, rimonabant was proven to be effective in aiding weight reduction. Subjects in the 20 mg group lost an average of 6.3 kg, which is 4.7 kg greater than the average loss experienced with placebo after 1 year. Administration of rimonabant 5 mg resulted in a modest loss of 2.9 kg. Rimonabant ingestion also resulted in a 12-16% decrease in triglycerides and a 7-9% increase in high-density lipoprotein (HDL). More significantly, rimonabant modified body weight by changing the body's regulation of energy metabolism.^[16]

CB1 receptors activate the dopaminergic reward system. Commonly abused drugs, such as nicotine, opiates, THC, and alcohol share a common pathway, the dopaminergic surge in the nucleus accumbens. Independent studies involving humans and mice respectively reported an increase in smoking cessation rates, decreased alcohol intake, and a reduction in cocaine-seeking behavior with rimonabant administration.