THE ENDOCANNABINOID SYSTEM

· There are many cannabis species and >460 known chemical constituents. ∆9 THC is the principal psychoactive component.

· Therapeutic properties of cannabis were described as early as 200 A.D. in Chinese medicine writings.

· Cannabinol was discovered and synthesized in 1940.

· THC was discovered in 1960 by Dr. Mechoulam of Hebrew University.

· THC binding sites in the nervous system were discovered in 1988.

· The first cannabinoid (CB) receptor (CB1) was cloned in 1990.

· The first endocannabinoid (eCB) was identified in Mechoulam & Partwee (Scotland) in 1992 and named anandamide from the Sanskrit word “anand” (bliss).

· The CB2 receptor was cloned in 1993.

· A 2nd eCB was discovered in 1995 and called 2-AG (2-Arachidonoylglycerol).

· Dr. Gardner and other scientists fully expect the discovery of new eCB receptors, eCBs, eCB enzymes, and therapies.

· A cannabinoid may be defined as a compound that produces cannabinoid psychoactivity, natural or synthetic.

· Note the similar progression here to that seen with the scientific study of the opioid system approximately 10 years earlier: discovery of specific binding sites (receptors) in the central nervous system (CNS, that is, brain and spinal cord), identification and synthesis of specific molecules that bind to these receptors (“agonists” and “antagonists”), cloning of receptors, identification & study of endogenous molecules.

· CB1 & CB2 receptors, like others in the CNS, consist of specific proteins that span nerve cell membranes. The part of the receptor that projects from the cell interacts in a lock and key fashion with molecules that either torn on the receptor (agonists) or turn off the receptor (antagonists). Due to that interaction, the shape and electrical charge of the protein changes in such a way as to affect a specific change in the behavior of the cell.

Characteristics of CB1 & CB2 receptors include:

– Dense distribution throughout the body

– CB1 especially dense in CNS

– CB2 especially dense in periphery, especially in the immune system (!), but also in the CNS with approximate density of μ-opioid receptors

– Located on axon terminals & mediate retrograde signaling (dendrite to axon)

· CB1 localization especially in cortex, hippocampus, basal ganglia, SN, and cerebellum.

· CB1 is “the most widely distributed neurotransmitter system in the nervous system” (!)

· CB1 is also densely present in the VTA (Ventral Tegmental Area, aka the reward & pleasure center, responsible for craving & relapse as well).

· CB1 system activation decreases neurotransmission.

· Endogenous cannabinoids (eCBs): 2 families now known: (1) Amides (e.g. anandamide) and (2) Esters (2-AG). Formed from arachadonic acid (found in cell membranes – Note: also is the source of prostaglandins, which function as local hormones and whose production is blocked by NSAIDs such as ibuprofen. eCBs are “made on demand”.

“Take-Home Messages”

– eCBs are neurotransmitters

– CBs modulate neural activity

– eCBs are involved in synaptic remodeling

Cannabinoids & Pain

· There are peripheral antinociceptive effects (shown in animal studies) that are synergistic with ibuprofen.

· These effects are reversed by application of CB antagonists (AM251 = CB1 antagonist; AM630 = CB2 antagonist).

· CBs are effective in modulating pain in various animal models including: tail flick, hot plate, paw pressure, formalin injection (paw), capsaicin, etc.

Cannabinoids & Addiction

· “There is now an extensive published literature showing anti-addiction efficacy for cannabinoid ligands.”

· AM251 inhibits the cocaine “high” and inhibits cocaine-seeking relapse in animal models.

· “Knock out” animals without the CB1 receptor do not show cocaine psychostimulant effects.

· “Caveats regarding development of cannabinoid agonists as potential pharmacotherapeutic agents”

– CB1 & CB2 receptors are ubiquitous throughout the body leading to the potential for numerous side effects.

– Some CB ligands have poor bioavailability.

– CB1 receptor agonists have addictive potential.

· There is “hard preclinical evidence” for potential treatments for diseases of energy metabolism (e.g. obesity, dyslipidemia, anorexia, diabetes type 2), pain, inflammation, CNS disorders (e.g. traumatic brain injury, neurotoxicity, stroke, spinal cord injury, MS, Alzheimer’s, anxiety, depression, insomnia, PTSD, schizophrenia, addiction), Cardiovascular disease (e.g. hypertension, atherosclerosis), eye disorders (e.g. glaucoma, retinopathy), cancer, GI diseases (e.g. inflammatory bowel disease, hepatitis, cirrhosis), musculoskeletal disorders (e.g. arthritis, osteoporosis, post-fracture bone healing).

· Note: again a similarity to opioids, in that at the proper dose and appropriate time, opioids can produce analgesia; at higher dosage, opioids can produce adverse effects such as sedation, GI problems, decreased cognitive function, decreased respiratory function, death, etc.)

· Note: “Medical marijuana” is not a pharmaceutical agent. Therefore, the dosage of the ingredients is unknown and therefore unpredictable, perhaps dangerous, especially when smoked or used in the presence of other drugs, including prescription drugs!

[1] Eliot L. Gardner, Ph.D., Chief, Neuropsychopharmacology Section, National Institute on Drug Abuse, NIH

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