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Anandamide as a Focus for ECS Supplementation

One spectacular benefit of adding full spectrum cannabis extract high in CBD to your diet is it should naturally boost Anandamide levels - contributing to a healthier Endocannabinoid System tone. Let’s investigate Anandamide and the bigger picture together.

What’s an Endo-Cannabinoid?

Anandamide (N-arachidonoylethanolamine - AEA) is one of our core endocannabinoids (ECBs), the other being 2-Arachidonoylglycerol (2-AG). More are being discovered, like b-Caryophyllene (considered a dietary cannabinoid by many due to its cannabinoid receptor binding affinity), but AEA and 2-AG seem to be our dynamic duo.


Endo in this context means endogenous, or, compounds created organically on the cellular level (synthesized from glycerophospholipids) by the human body to act as receptor-mediating signaling agents within the Endocannabinoid System (ECS). Other similar endogenous signaling compounds or neurotransmitters you’re quite familiar with are serotonin, norepinephrine, cortisol, dopamine, GABA, and glutamate.


ECBs like AEA are special though because they work through retrograde inhibition.


Retrograde Inhibition? Instead of being created on the presynaptic neuron and then traveling to receptors on the postsynaptic neuron, ECBs are created on the postsynaptic neuron then travel backwards; modulating activity and helping regulate non-cannabinoid neurotransmitters created by postsynaptic neurons in response to stimuli.


Here’s a great quote from Melissa Moore’s LabRoots article, Endocannabinoid Performance Through Retrograde Signaling, which does a great job summarizing:

“In order to get a neuron to fire, excitatory neurons use anterograde signaling which causes calcium channels to open in the postsynaptic neuron. This alters the charge of the cell and produces an action potential. The calcium that flows into the postsynaptic neuron also activates an enzyme that produces ECBs. When the calcium influx is healthy, 2-AG is produced, if it is not healthy AEA is produced. When one of these ligands are manufactured, it instinctively is released back into the synapse where it travels in the opposite direction. At the axon, it binds to the CB1 receptors and causes the cell to produce an inhibitory response which is created by AEA or an excitatory response which can be generated with 2-AG.

Though published in 2012, one of the best video presentations on the subject was a Master's Research Project submitted for a Master of Science in Biomedical Communications through the Institute of Medical Science, University of Toronto. It's a 5-minute visualization of the endocannabinoid signaling system using pain signaling as the example.


3 Core Anandamide Facts

  1. AEA is a fragile molecule derived from arachidonic acid, a polyunsaturated omega-6 fatty acid (meaning fat-soluble thanks to its long hydrocarbon tail), created by your body to interface with the ECS through primarily CB1 Receptors (cannabinoid receptor 1) which are expressed in the CNS; rich in areas such as basal ganglia, cerebellum, amygdala and hippocampus. Also found in the periphery, including human testis, retina, sperm cells, colonic tissues, peripheral neurons, adipocytes and other organs including the adrenal glands, heart, lungs, prostate, uterus, and ovary. (1)

  2. Phytocannabinoid Cannabidiol (CBD) supplementation increases AEA levels in part through inhibiting Fatty Acid Amide Hydrolase (FAAH), the enzyme your body creates to breakdown AEA which has a short metabolic half-life compared to its mimetic (very similar) plant compound delta-9 THC. Recent studies show strong correlations between an individual’s level of happiness and the presence of the A allele in the FAAH gene variant (rs324420) which helps prevent the chemical degradation of AEA (2). This is where the many FAAH blockers are coming from - a medical desire to increase natural amounts of AEA in the body which has profoundly positive effects.

  3. The ECS is an internal homeostasis regulatory system. Within it, AEA acts as a partial CB1 agonist and a weak CB2 agonist. However, it typically synergizes with other ECBs like 2-AG and conventional signaling agents to produce endogenous entourage effects.

Introduction: Forgetting to Cope with the Human Condition

Before pioneering our journey into AEA and your ECS, let’s begin with a crazy question.


What if you were designed not to forget anything?


And we can go full throttle - ALL sensory-psychological data branded into your grey matter second by second along with everything else shaping your ongoing mental timeline, or memory. Imagine how much shorter your lifespan would be and the rate you’d go bonkers. Sure, a somewhat recent Stanford Study put the number of synapses in your cerebral cortex at 125 trillion (3), while another study conducted by a large assortment of institutes and universities estimated 1 synapse can store 4.7 bits of information (4)...there’d be too much data for any actual ‘thinking’ to take place!


You’d be frozen and frazzled. The prospect is truly frightening; tormenting. Humans would’ve never made it out of the proverbial Garden of Eden in such a state.


Your senses gather 11+ million bits per second from the environment alone (5), not accounting for thoughts, things you read, people you meet, fluttering ideas, scary situations, every regret, action taken or untaken, etc. all colliding from perceived pasts, futures and the present.


What chaos!


Guess how much your surface consciousness ("I") is likely operating on right now...


About 40-50 bits.


Yep, stop a sec to look at your conscious awareness of the ongoing stream of now around you, along with your potential, and realize they’re dependent on about 50bps (really adds perspective to the power of A.I. computational power doesn’t it).


In the last second, your skin sent over a 1 million bits... just your skin! My goodness, the remarkable data compression rates you possess... but, what’s allowing you to forget and remain blissfully unaware of terabytes of information being processed by your brain throughout the day? Furthermore, what’s enabled our species to endure immense trauma and hardship, yet mentally get beyond it and continue moving through the millennia?

Remembering and being able to recall what’s important, while forgetting what the surface intellect doesn’t need.


Well, physiologically speaking, the over 600 million year old ECS in your body that’s evolved to oversee this homeostatic function via its network of cannabinoid receptors throughout your brain and AEA - along with 2-AG which I’m not going to touch on in this article. These processes aren’t well-understood yet, but we know they’re in place so you can function instead of being wholly preoccupied with a freakishly loud haze of information and sensory bombardment.

  • Note: AEA is a central component in the modulation of memory consolidation (6). Meaning, along with learning in general, AEA influence is observed in the intersection where short-term experience can become long-term memory.

Forgetting is critical to maintaining your homeostasis, and AEA is a big part of what the ECS uses to accomplish this feat on the chemical level in every second passing. We know this because of cannabis THC impacts (a phyto-mimetic compound) as well as administered AEA analogues in animal tests. Point being, AEA is part of the reason you’re only going to retain a small portion of what you read in this article on first pass instead of every single word and every finite detail and event that unfolded around you. Depending on your tolerance, if you suddenly put high levels of THC into your body, within a minute the forgetful effects would be magnified and you likely wouldn’t remember anything read afterwards for at least 30-40 minutes.


As a man named William James put it, quoted by Daniel J. Boostin in his book The Discoverers:

“All recollected times undergo foreshortening, and this foreshortening is due to the emission of an enormous number of facts which shield them. We thus reach the paradox of the results that one condition of remembering is that we should forget. Without totally forgetting a prodigious number of states of consciousness and momentarily forgetting a large number, we could not remember at all.”

This truly ancient-majestic biological communication system, our ECS, utilizes AEA - a made on demand, short-acting, retrograde neurotransmitter - to ensure you forget what needs to be forgotten, so you can be you.


After some consideration, thank goodness we don’t transmit pure memory to our children because the vast majority of human existence has been wrought with hardship and brutality. When we sit back to gander at such toils and trials our species weathered to get this far the expanse is overwhelming, laced with both benevolence and cruelty. What evolution (or if you prefer, the Gods) designed to keep us alive and charging on despite it all is to a large degree…the chemical of bliss, sleep, relief and reward...


Anandamide.


Folks, this cannot be overstated, AEA is an integral part of a system that’s been evolving on earth for over 600 million years. It may end up much older... research in progress.


AEA is synthesized most in the areas of your brain where memory (remember & forget), motivation (inhibitory & antagonistic potentials), core cognitive processes (attention, learning, higher reasoning) and movement control are regulated.


In terms of emotionality and forgetfulness, commenting on Nietzsche’s 1876 essay “The Uses and Disadvantages of History of Life” Michael Pollan said in his paper “Cannabis, Forgetting, and the Botany of Desire”,

“It’s a great essay, and he’s talking about how cheerfulness, the good conscience, the joyful deed of doing anything really depends on forgetting.

Mr Pollan also made me aware of this stilling-inspiring Nietzsche quote,

“...those who can act are those who, forget most things, so as to do one thing.”

If it weren’t for the way your ECS utilizes AEA, you’d never have any mental real estate to ponder potential futures and become sentiantly aware of present situations. On the flip-side, AEA is involved with the encoding of long-term memory for both learning and survival.

  • Note: FAAH inhibition has been found to enhance memory acquisition (7). So, as you can see, AEA impacts what we retain and forget to retain. Imagine the impacts on human evolution - how many quirks of fate unleashed! Keep in mind the majority of our ancestors were NOT exposed to high doses of phytocannabinoids like we have access to these days. Most humans got this far on the ECBs we’re genetically designed to create.

Which leads us to the next big role AEA plays in homeostasis and development…


Sleep, Relaxation, and Reward

Speaking of forgetfulness, extrapolate everything our species accomplished over the last 50,000 years, then drink in the fact we snoozed and kicked back through about half the time! As forgetting is to thinking, sleep and relaxation is to our forward momentum.


Per current research, the ECS employs AEA on both sides of this spectrum - to help balance energy metabolism and regulate our primary ‘reward or pleasure system’ - pumping us full of glutamatergic and dopaminergic agents whenever we do/accomplish/attain something (or think we have) beneficial for ourselves, our friends and family, tribe, click, etc. So when you make others you care about happy or proud your AEA levels go up.


Aren’t neurological relationships between cannabinoid receptors and others, along with synergistic neurotransmitters involved in homeostasis fascinating?


Don’t get me started...for example,

The very high expression of A2A [Adenosine receptors] and CB1 receptors in the striatum suggests that direct or indirect interactions between A2A and CB1 receptors are involved in the modulation of motor activity and goal-directed behaviours.” (8)

We’ll get to the striatum in due haste, but first, what’s Adenosine?


Predictably, it’s complex, partially used to determine sleep quality which is ideally a balance of REM and non-REM cycles. Thus the widely-theorized AEA involvement in maintaining a healthy circadian rhythm by helping modulate and synergize with Adenosine to combat impacts of sleep deprivation which is quite common (9) in humans!

Anandamide increased adenosine levels in the basal forebrain and also increased sleep. The soporific effects of anandamide [induces drowsiness or sleep] were mediated by the CB1 receptor, since the effects were blocked by the CB1-receptor antagonist. These findings identify a potential therapeutic use of endocannabinoids to induce sleep in conditions where sleep may be severely attenuated.”(10)
  • Side Note: Listen, too many people are being led to believe cannabis CBD is a sleep-inducing agent. It’s not! Isolated CBD (like its mimetic ECB 2-AG) is technically an energy booster. The sleepiness associated with CBD has FAR more to do with what it’s often combined with in both psychoactive cannabis indica (terpenes like myrcene; cannabinoids like CBN) and non-intoxicant 'hemp' cannabis (added terpenes, and sleepy-agents via essential oils like lavender, etc.).

In other words, Adenosine builds up in your system while you’re awake making you increasingly tired, and also rewards you for accomplishing goals (like well-deserved rest!).


We don’t conserve most of these mini-experiences, like dreams, the litany of little goals we accomplish throughout each day/month/year, conversations around the fire...but, what’s the striatum where CB1 receptors are so dense?

“Functionally, the striatum coordinates multiple aspects of cognition, including motor and action planning, decision-making, motivation, reinforcement, and reward perception....activated by stimuli associated with reward, but also by aversive, novel, unexpected, or intense stimuli, and cues associated with such events. fMRI evidence suggests that the common property linking these stimuli, to which the striatum is reacting, is salience under the conditions of presentation.” (11)

Again AEA makes an appearance when an important goal keeps you up late, and when your body says ‘enough’ and begins beckoning you to sleep - homeostasis! The doctor who discovered AEA, Raphael Mechoulam, published a small library of work on the subject. Many doctors who study it end up seeing AEA as arguably the most perfectly-designed drug by the force of evolution we’re aware of to date.


Rather than going deeper, let’s look at another invaluable reward system AEA plays a mighty role in - eating and metabolism.


Eating into the Top of the Food Chain

First, let’s get this clear,

“The binding of the endocannabinoid to the cannabinoid receptors in the brain stimulates food intake, and the ECS participates in systemic macro-nutrient metabolism where the gastrointestinal system, liver, muscle, and adipose are involved...the ECS was found to be integral in the control of food intake...from an evolutionarily perspective, the primary physiological function of the ECS appears to shift energy balance toward energy storage (Piazza et al., 2007), and thus, can lead to fat accumulation. ” (12)

RARELY will you see depictions of an obese chronic psychoactive cannabis user. As an archetype, the 'Stoner' is skinny. One of the earliest examples for my generation in entertainment was this guy, good'ol Shaggy from Scooby Doo:

He talked, walked, laughed, and acted like a lot of folks do when stoned and was ALWAYS either eating or trying to eat yet never gained a pound somehow.


But I digress, to be specific,

“The endocannabinoid system has important physiological functions not only in the central nervous system but also in peripheral tissues. The activation of central CB1 receptors, particularly in hypothalamic nuclei and in the limbic system, is involved in the regulation of feeding behavior, and especially in the control of the intake of palatable food. In the periphery, cannabinoid receptors are present in adipocytes, skeletal muscle, gastrointestinal tract and liver, modulating energy metabolism.” (13)

The body uses AEA to both stimulate the desire to consume food for nutrition, and harmoniously metabolize it. Most people like Shaggy see this through THC - the munchies! - where THC binds to CB1 receptors and even if you’re completely satiated, full on all needed micro/macro-nutrients, you’ll CRAVE more food and begin eating anything in sight, the more calorically-dense the better (often junk food).


But THC is much stronger than AEA, and as mentioned, lasts longer in the body. Outside THC supplementation AEA was designed to instigate your desire to eat and replenish biological resources.

  • Note: Anecdotally, something reported by CBD consumers is they suddenly experience urges to eat more, yes, but HEALTHIER foods. As though miraculously their brain begins asking for higher-quality fruits, vegetables, and plant food, while the desire for less-local and inorganic meats and junk food either dwindles or stays relatively the same. This is echoed by Williams and Kirkham, 1999; Kirkham et al., 2002 in that AEA is used to reinforce motivation to find and consume food with high incentive value.

In fact, one of the more exciting areas of current ECS science revolves around the ECS and our gut microbiome where we know AEA is produced to help balance a huge assortment of gastrointestinal and immunologically-related processes (hello endocrine system). According to animal studies by Gomez et al, in 2002, after a full 24-hour fast AEA levels in the small intestine were seven times higher than their litter mates who hadn’t fasted.


So, the next time your brain starts telling you you’re hungry and suggest lots of highly-nutritious foods, AEA is helping produce this experience (CBD may intensify it). AEA communicates and seeks balance with your microbiome. It’s also going to be released once you begin eating to chemically reward you. And, if you share nutritious food with someone to receive a warm blissful gut feeling, yep, AEA again...one of our oldest comrades in survival.


Protection & Pain Relief

AEA is bliss, rest, reward and cellular protection - the opposite of pain and inflammation.


The most important thing to know is wherever pain and inflammation exist within the human body, AEA (along with 2-AG) are to a degree being used to temper and ease it by mitigating cellular response (nociception).

“Direct activation of peripheral cannabinoid receptors causes profound analgesic effects in experimental models of pain. Our findings indicate that significant analgesia can also be obtained by magnifying the intrinsic activity of an anandamide-based signaling system involved in the dynamic regulation of nociceptive homeostasis outside the CNS. These findings offer new insights into the intrinsic control of pain and might be exploited therapeutically to develop analgesic agents devoid of central side effects.” (15)

How did this come about?


As mentioned, cannabinoid receptors in nature are insanely OLD. Scientists don’t know exactly how old, but theorize bygone evolutionary predecessors potentially dating back to a time before plants and animals diverged in the primordial soup. At some point we began using cannabis for a large variety of things. According to Hui-Lin Li back in 1974,

“Although Cannabis is generally believed to be of Asiatic origin [used since before the Neolithic times], within this vast geographical area, there is no general agreement as to where the domestication really came about.” (14)

Honestly, we don’t know how old cannabis is (right now estimated at 30-40,000 years thanks to work by doctors like John McPartland and Vincenzo Di Marzo), where it originated from (highly debated), or when our forebears began seriously cultivating it outside what meager evidence we’ve unearthed over the last few centuries...but we do theorize humans immediately recognized the plant’s THC-related analgesic value. Although we must keep in mind the GINORMIC differences between ancient wild cannabis and what’s been cultivated across the planet over the last 10,000+ years.


Look at what we created with cannabis, broken down into two core cultivars:

  • Cannabis Sativa, or Fiber Hemp for seed (food, oil), fiber (rope, canvas, textiles), and extracts which are classically known to contain as high as 40% CBD in the resin.

  • Cannabis Indica, or THC-dominant psychoactive cannabis, for nothing other than the medicinal value (cannabinoids + terpenes) provided by its flowers, buds, and the leaves immediately surrounding them.

Through the study of THC, we’ve built a fairly large amount of both animal and human research to confirm AEA roles in pain. As mentioned, over the years science has produced FAAH blockers to prolong AEA effects and synthetic cannabinoids (some of these have been dangerous) attempting to mimic AEA’s analgesic function, but we’re not smarter than nature.


Cannabinoid-based pain relief comes in three forms:

  1. The natural amount you’re endowed with via your ECS. Based on the level of pain mitigation you’re capable of (immense), this is by no means the lesser of the three.

  2. Introducing psychoactive THC-dominant cannabis extract into the body to bind to CB1 receptors and mimic AEA in conjunction with other cannabinoids and terpenes with their own analgesic values.

  3. Introducing new strains of 'Hemp' cannabis extracts high in CBD which safely inhibit FAAH without negative side effects or THC intoxication.

We could just keep going and going on this subject alone, including science relating to AEA and neurogenesis or cell development, cell regulation and apoptosis (programmed death, for example cancerous cell mitigation), or make the connection with its activation of TRPV-1 vanilloid receptors to ease inflammation...but alas I believe my goal has been served in this article which was to put my two cents out there and help spread the word.


Closing Thoughts

While much of the focus as of late has been on phytocannabinoids like CBD, THC, CBN, and CBG, it’s clear Anandamide isn’t being given enough credit. Far too many consumers using hemp CBD are being left unaware of the fact a percentage of therapeutic impacts aren’t actually coming from CBD at all, but AEA, after the slowing down or inhibition of FAAH so AEA levels can increase and last longer. Through receptors in the ECS, we know where AEA binds and why - the exact ‘hows’ are being figured out with swift resolve.


In brief AEA is...

  • Anxiolytic/Sedative (CB1)

  • Analgesic (CB1)

  • Anticonvulsant (CB1)

  • Appetite Stimulant (CB1)

  • Antiemetic (Nausea) (CB1)

  • Anti-inflammatory / Immune Suppressant (CB2)

Thanks for your time :)




References

1: Endocannabinoid Binding to the Cannabinoid Receptors: What Is Known and What Remains Unknown; Patricia H. Reggio.

2: Genes may contribute to making some nations happier than others; Science Daily, Science News, 01/14/2016.

3: New imaging method developed at Stanford reveals stunning details of brain connections; Stanford Medicine News, 11/17/2010.

4: Nanoconnectomic upper bound on the variability of synaptic plasticity; eLifeSciences, Thomas M Bartol Jr., Cailey Bromer, et al., 11/30/2015.

5: Information Theory, Physiology; Encyclopedia Britannica.

6: Differential role of anandamide and 2-arachidonoylglycerol in memory and anxiety-like responses; Busquets-Garcia, Puighermanal E, et al., Biol Psychiatry, 09/01/2011.

7: Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-α nuclear receptors; Carmen Mazzola, Julie Medalie, et al., Learning Memory, CSH Press.

8: Adenosine–cannabinoid receptor interactions. Implications for striatal function; Sergi Ferré, Carme Lluís, et al., Br J Pharmacol.

9: Sleep homeostasis: a role for adenosine in humans?; Landolt HP, Biochem Pharmacol. 06/01/2008.

10: Anandamide enhances extracellular levels of adenosine and induces sleep: an in vivo microdialysis study; Murillo-Rodriguez, Blanco-Centurion C, Sleep, 12/15/2003.

11: The role of the striatum in social behavior; Raymundo Báez-Mendoza, Wolfram Schultz, Front Neurosci, 12/10/2013.

12: The endocannabinoid system: directing eating behavior and macronutrient metabolism; Bruce A. Watkins, Jeffrey Kim, Front Psychol, 01/06/2015.

13: The multiple functions of the endocannabinoid system: a focus on the regulation of food intake; Tibiriça E, Diabetol Metab Syndr, 01/21/2010,

14: An archaeological and historical account of cannabis in China; Economic Botany October 1973, Volume 28, Issue 4, pp 437–448.

15: Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism; Jason R. Clapper, Guillermo Moreno-Sanz, et al., Nat Neurosci, 10/13/2010.