Lex Pelger's Endocannabinoid System & Cannabinoids #3: Anandamide
Lex Pelger's Endocannabinoid System & Cannabinoids #3: Anandamide
In 2014, the hardworking drug journalist David Jay Brown questioned Dr. Raphael Mechoulam in an interview, “You once said that ‘Whatever THC does, anandamide does as well.’ What is the reason that synthetic anandamide isn’t used therapeutically as an alternative THC?”
The co-discoverer of anandamide answered, “That’s a very touchy subject. Many years ago when insulin was discovered–I think it was in the early twenties–it was in the clinic within six months. When cortisone was discovered fifty years ago it was in the clinic within two years, and it became a very successful drug. We discovered anandamide twelve years ago, and it still has never been officially administered to a human.”
With the CB1 receptor identified in the late ‘80’s, scientists suspected there must already be cannabinoids present to trigger it because at the biochemical level, nature is a thrifty housekeeper. They knew that this receptor wouldn’t be found in all creatures with spinal cords in the happenchance that some migratory apes stumbled into an obscure Central Asian shrub carrying these compounds. There must be a physiological molecule binding to these newly discovered and widespread cannabinoid receptors.
It took until 1992 - 30 years after THC’s discovery - for Dr. Mechoulam, his colleague Dr. Lumír Hanuš and the NIMH research fellow Dr. William Devane to identify the slippery long-chain polyunsaturated fatty acid amide they sought. For the naming, they decided to use the root of the Sanskrit word for bliss - ananda. When asked why he used an Eastern word for work that occurred in Israel, Dr. Mechoulam still jokes that “we wanted to use a Hebrew word for joy - but they didn’t have any.”
In any case, bliss turned out to be not quite the right shorthand descriptor for anandamide. If lazy science journalists call serotonin the neurotransmitter of happiness, oxytocin the molecule of relationships and dopamine for addiction, the best pat phrase for anandamide is the neurotransmitter of balance.
Because, it’s not only found in the brain. It’s found in the body and it activates the CB2 receptors spread across almost every organ. There’s a clear biochemical reason that hemp showed up in all the world’s apothecaries for such a vast swathe of diseases. The endocannabinoid system seems to operate as a homeostasis system for the body, calming an overwrought organ or down-regulating a biochemical process gone haywire. The long lists of cannabis treated diseases gathered by sober doctors writing pot books are not just blowing smoke. Many mouse studies have made it clear that the endocannabinoid system is intricately embedded in both the hormonal and immune systems of the body - though the exact relationship is murky because of the extreme complexity of these systems.
All of this interaction speaks to the ideas of Dr. Candace Pert, a legendary neuroscientist who had a run-in with academia after openly protesting a lack of due credit for her discovery of the brain’s opiate receptor while only a grad student. Later in her colorful career, she theorized in her book ‘The Molecules of Emotion’ that generations to come will look back oddly at our false divisions between the neuronal, immune and hormonal systems of the body. She postulates that white blood cells will be recognized as migrating neurons, hormones as slower messengers. The field of our microscope will expand to grasp an inclusive neuro-immuno-endocrine system consisting of many moving parts - the axis of which is the newly discovered endocannabinoid system that initiates profound changes in the entirety of this complex integrated system .
Its sheer range of effects allows anandamide to act as a modulator across the entire organism. It’s been found to regulate appetite, memory, our sensations of pleasure and pain, our sleep patterns and our immune system. As one old grower confessed to a scientist in an unguarded moment at a conference, “If you told me that the endocannabinoid system is where the body meets the mind, I’d believe you.”
At the biochemical level, besides the obvious importance of binding to CB1 and CB2, anandamide also binds to PPARs - receptors on the nucleus of the cell responsible for changing the RNA transcription of genes via manipulation of the protein Egr-1, often described as a “master regulator of gene transcription”. Anandamide also regulates the activity of multiple important enzymes and some of the protein transporter molecules that allow gap junctions between cells or cause the phenomenon of multidrug resistance. It even affects the ion channel receptors regulating the flow of electrically charged ions into the cell. This changes the excitability of the cell and the voltage gates that control neuronal firings and underpins its ability to change neural plasticity.
High levels of endocannabinoids like anandamide occur after a stroke or other neural insult and signal the endocannabinoid system’s function as a neuroprotectant. Furthermore, the reports of NFL players using CBD to protect their brains dovetails strongly with the preclinical research, but it has more jobs than just protection. In this article about CBD’s effect on schizophrenia, it explains how CBD might not bind to the CB1 and CB2 receptors but it does inhibit the degradation of anandamide that’s carried out by the the FAAH molecule in the intracellular space. The presence of CBD consequently boosts the brain’s natural cannabinoid, anandamide.
As Dr. John M. McPartland explains in his review, ‘The Endocannabinoid System: An Osteopathic Perspective’, “In fact, the endocannabinoid system organizes a broad array of developmental processes in the embryonic brain. Proliferation and differentiation of neural stem cells are shaped by extracellular cues provided by endocannabinoids. Indeed, once stem cells commit to neurogenesis, endocannabinoids regulate neuronal migration and synaptogenesis. Lastly, axon guidance is shaped by axon growth cones, and endocannabinoids are part of the molecular “soup” that guides growth cones to their destinations.”
UNKNOWN:
Learning the above took decades of work and ten of thousands of dead mice - but what we know still pales in comparison to the mysteries of unknown biochemical functions and entanglements. As Mechoulam points out in his review of the endocannabinoid system and the brain, unlike most neurotransmitters like dopamine and serotonin, anandamide is not stored away in vesicles for release but instead is synthesized on demand by the cell itself.
According to Hill and Gorzalka’s article ‘The endocannabinoid system and the treatment of mood and anxiety disorders’, “To date, three distinct and independent mechanisms have been found to generate AEA [anandamide]; however, the pathway that is primarily responsible for neuronal AEA synthesis is not currently known…” Once created, the levels of anandamide are regulated by cellular uptake and metabolism (biochem speak for “search & destroy”) but the transporter for capturing this slippery lipid and moving it to the place of degradation by FAAH has been a subject of much controversy.
In the mere thirty-two years since its discovery, anandamide’s range of action is already known to be widespread and as the research continues, more neurotransmitters and receptors will surely be discovered and push the endocannabinoid system into prominence as one of the key signaling systems of the human body.