In the early 1990s, researchers around the globe began investigating the human body’s network of cellular receptors that have been proven, in the decades since, to bind with the health-giving chemicals produced by the cannabis plant. In the process, these researchers learned something interesting: The human body produces its own—and almost identical—set of wellness molecules.
Called endocannabinoids, these special molecules bind, or interact, with the same network of cellular receptors within the body that accommodates wellness chemicals from cannabis called phytocannabinoids and terpenes. These molecules have proven to provide health-giving therapeutic value for patients who suffer a wide variety of diseases and conditions.
Made by the Endocannabinoid System
A full understanding of the potential medicinal and wellness benefits of endocannabinoids is best gained when readers comprehend the basic environment and underlying mechanisms involved when the human body produces and metabolizes these unique and seemingly beneficial molecules.
Any serious consideration of this topic necessarily includes how endocannabinoids relate to phytocannabinoids and important patient issues, such as how those who exhibit deficiencies in their production of endocannabinoids may gain particular benefit from supplementation via their molecular cousins, the phytocannabinoids produced by the flowers of mature female cannabis plants.
Endocannabinoid production is handled by something called the endocannabinoid system, or ECS. The ECS is a network of microscopic cellular receptors, also categorized as neurotransmitters, strewn throughout literally every organ and tissue of the body. It is found in not only humans, but all vertebrates (including all mammals).
Phytocannabinoids = Mimetic Molecules
Two major endocannabinoids have been identified to date: Anandamide (often cited in research studies as AEA, arachidonylethanolamide, or N-arachidonoylethanolamine) and 2-Arachidonoylglycerol (more commonly known as 2-AG).
Research has indicated that both molecules play an important role in modulating the ECS and maintaining overall health. The concept of the optimal health of the ECS is expressed by researchers and scientists as homeostasis. This is the theoretical state of an optimally tuned ECS — including improvements in the many bodily systems that it manages. A human whose ECS is considered in homeostasis is assumed to be balanced and, thus, operating in a state of “maximum health.”
The two major phytocannabinoids from cannabis are tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the infamous molecule that produces sometimes significant psychotropic effects and euphoria in users. Despite its reputation for psychoactivity, THC also conveys a range of medicinal benefits, including appetite stimulation, reduced anxiety and depression, and even anti-cancer efficacy.
Scientists have determined that THC mimics anandamide, with both molecules providing similar effects, including emotional and psychological benefits (such as reduced anxiety), lower systemic inflammation (of benefit to literally thousands of diseases and conditions), and other significant health improvements.
CBD is one of the phytocannabinoids that has shown a wide range of efficacy for humans and mammals, including decreased depression and anxiety, pain relief, and improvements in sleep.
Anandamide: Discovery & Investigation
In 1992, a research team working at Hebrew University in Jerusalem isolated and identified anandamide. The team consisted of American pharmacologist William Devane and Czech analytical chemist Lumir Hanuš, along with pioneering cannabinoid and terpene researcher Dr. Raphael Mechoulam. It was Devane and Hanuš who, after discovering the ability of this molecule to improve the emotional state of patients, chose the name anandamide, which is derived from ancient Sanskrit and means “joy” and “bliss.”
Devane and Hanuš published their discoveries in a research paper entitled “Isolation and Structure of a Brain Constituent that Binds to the Cannabinoid Receptor” that was published in the journal Science. “The structure of this compound, which has been named ‘anandamide,’ was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis,” reported the researchers.
In 1995, Mechoulam’s team at Hebrew University discovered a second endocannabinoid that they named 2-Arachidonoylglycerol, more commonly known as 2-AG. Together, anandamide and 2-AG have prompted researchers to further investigate the dynamics of the ECS and the critical role that it appears to play in the regulation of a variety of important bodily systems, including immune function, mood, appetite, sleep, energy level and metabolism, cognition, skin quality, vision, motor skills, and even libido.
The Medicinal Efficacy of Anandamide
Anandamide has been revealed through hundreds of research studies to deliver a wide range of benefits. These encompass appetite stimulation and emotional and mental improvements, including reduced anxiety and depression. This makes anandamide of special value in the treatment of Post-Traumatic Stress Disorder (PTSD), pain relief, and reductions in systemic inflammation — of benefit to diseases such as arthritis, Crohn’s disease, and multiple sclerosis.
General Efficacy Studies
A 2017 study entitled “Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years” investigated the overall role and underlying mechanisms involved in the production of anandamide, its interaction with the ECS, and its overall ability to improve health and treat disease.
The study observed that anandamide plays a critical role in nearly all systems and mechanisms of the body. “Such a multifaceted ability of AEA to impact on virtually every system of the human body (and well beyond humans along the phylogenetic tree) depends on a multiplicity of receptor targets that includes…CB1 and CB2….,” concluded the researchers.
Appetite Stimulation Studies
A 2005 study entitled “Endocannabinoids in the Regulation of Appetite and Body Weight” investigated the ability of endocannabinoids such as anandamide and 2-AG to act as effective treatments for diseases and conditions involving loss of appetite. These include wasting syndromes (HIV/AIDS), liver disease, various forms of dementia, and hypothyroidism.
Because loss of appetite can result in malnutrition, which in turn leads to the degradation of overall bodily function and the immune system (including more difficulty in combating specific diseases), appetite stimulation is an important consideration for millions of patients and their wellness practitioners.
Reported the study’s authors, “It is now confirmed that endocannabinoids, acting at brain CB1 cannabinoid receptors, stimulate appetite and ingestive behaviours….” The research indicated that endocannabinoids like anandamide—as well as the entire body-wide endocannabinoid system—play a role that extends beyond mere appetite control to overall energy level and metabolism. “Moreover, there is strong evidence of an endocannabinoid role in energy metabolism and fuel storage,” reported the study.
A 2001 study entitled “Anandamide Administration into the Ventromedial Hypothalamus Stimulates Appetite in Rats” explored how anandamide may stimulate appetite in humans based on the similarities in the ECS mechanisms of humans and mammals such as rodents.
Reported the study, “Given that cannabinoids have been used clinically to stimulate appetite in HIV and cancer chemotherapy patients, there has been a renewed interest in the involvement of cannabinoids in appetite modulation.”
This study involved the direct injection of anandamide into the brains of rats to detect the changes in “modulating appetitive behavior” that this endocannabinoid caused. In addition to identifying anandamide as an appetite stimulant, the research more clearly explained the role of the endocannabinoid system and, more specifically, CB1 receptors in appetite stimulation.
A 2019 preclinical study entitled “Cannabinoid Regulation of Fear and Anxiety: An Update” explored the role of endocannabinoids such as anandamide and phytocannabinoids in the treatment of psychological conditions like anxiety. The study recognized the lack of effectiveness of many traditional pharmaceutical drugs and therapies.
The researchers surveyed available research studies and found a pattern of CBD and anandamide demonstrating “acute” anti-anxiety (anxiolytic) properties. The study revealed that cannabinoids such as anandamide regulate anxiety responses such as fear “by dampening its expression, enhancing its extinction, and disrupting its reconsolidation.”
A 2014 study entitled “Central Anandamide Deficiency Predicts Stress-induced Anxiety: Behavioral Reversal through Endocannabinoid Augmentation” investigated how anandamide might reduce anxiety that results from environmental and psychological stressors.
The study pointed out the anxiety-reducing role of anandamide for conditions such as PTSD. “Among individuals with posttraumatic stress disorder, those with lower peripheral [anandamide] content exhibit more intrusive symptoms.”
Interestingly, the study concluded that supplementation of the ECS may reduce anxiety levels. “Importantly, our study also demonstrates that pharmacological augmentation of [anandamide] signaling after stress exposure can reverse stress-induced anxiety, which is a necessary feature of novel therapeutics for stress-related psychopathology.”
A 2016 study entitled “Endocannabinoid System: Role in Depression, Reward, and Pain Control” cited the fact that the majority of patients who suffer from depression and pain are not responsive to pharmacological treatments, “making this comorbidity disorder a heavy burden on patients and society.”
The study reported that the specialized receptors of the ECS that bind to phytocannabinoids such as CBD and THC — and that have been shown to play a role in managing pain and depression — also feature a strong binding affinity for endocannabinoids such as anandamide and 2-AG. The research reinforced the concept of phytocannabinoids as mimetic molecules of endocannabinoids, meaning they interact with the human and mammalian ECS in extremely similar ways, often resulting in many of the same efficacies and wellness benefits.
Reported the researchers, “Considerable evidence suggested the involvement of the endocannabinoid system in eliciting potent effects on neurotransmission, neuroendocrine, and inflammatory processes, which are known to be deranged in depression and chronic pain.”
A 2010 study entitled “Anandamide Suppresses Pain Initiation through a Peripheral Endocannabinoid Mechanism” explored the ability of anandamide to act as an analgesic (pain killer) and its potential role in helping patients suffering chronic pain.
The researchers found that anandamide was either directly or indirectly involved in multiple mechanisms of pain modulation (and potential suppression) involving CB1 receptors in the brain and CNS.
How to Boost Anandamide Levels
Given the health benefits of anandamide, including significant potential mental and physical improvements, the issue of either producing more anandamide internally or supplementing with outside sources of this special molecule is of obvious merit.
Plant-based molecules that enhance or mimic anandamide are produced by a variety of sources, including cacao (used to make chocolate) and black truffles. This means that people supplementing their ECS with these natural plants might gain significant health benefits and emotional support. It may also help explain the common human craving for chocolate and cacao; perhaps these people are suffering from a deficiency in their ECS, specifically in their internal production of anandamide and 2-AG.
A research study dating back to 1996 entitled “Marijuana and Chocolate” that was published in the journal AIDS Treatment News investigated how chocolate and, more specifically, the plant cacao, produces human wellness molecules that parrot many of the cannabinoids found in cannabis, including the manner in which they interact with the human ECS.
“Three substances in chocolate and cocoa powder may mimic cannabinoids by activating receptors or increasing anandamide levels,” reported the study. Concluded the researchers, “A practical implication of this finding is that the amount of marijuana needed for medicinal purposes may be decreased by using it with chocolate, reducing… the… cost associated with marijuana.”
Not only does high-quality chocolate derived from cacao boost the human body’s production of anandamide, it also delivers theobromine, a molecular cousin to caffeine that produces the polar opposite effect of relaxation. The study theorizes that theobromine may cause the body (specifically, the brain, where the greatest density of CB1 receptors is found) to produce greater volumes of anandamide.
A 2015 research study entitled “Truffles Contain Endocannabinoid Metabolic Enzymes and Anandamide” explored how sources outside of the human body and the cacao plant produce anandamide. “Since anandamide, a prominent member of the endocannabinoid system (ECS), is responsible for melanin synthesis in normal human epidermal melanocytes, we thought that [an] ECS might be present also in truffles,” reported the researchers.
The study investigated the production of anandamide and “major metabolic enzymes of the ECS” by truffles (the fruiting body of fungi and a type of tuber). The researchers found production of anandamide to be especially great in winter black truffles. They also discovered that, while truffles may produce anandamide (a component of the human ECS), they do not feature receptors (such as CB1 and CB2 in humans) or other elements of a full ECS neurotransmitter system.
Exercise & Anandamide
One of the most effective and beneficial ways to produce more anandamide is exercise. Anandamide is synthesized internally in an effort to deal with physiological or mental stress or disharmony. Although the benefits of anandamide are multifaceted, one of its greatest values is as an analgesic. Thus, this endocannabinoid is produced in the most plentiful quantities during endurance exercise involving significant effort or time periods.
A 2004 study entitled “Endocannabinoids and Exercise” investigated the effect of exercise on “analgesia, sedation, anxiolysis, and a sense of wellbeing.”
“An exercise-induced altered state of consciousness has long been appreciated by endurance athletes. The effect has been well documented in the popular literature and subjected to scientific investigation,” wrote the study’s authors. The research defined runner’s high, which typically is mired in ambiguity and a lack of scientific description, relatively precisely: “The runner’s high has been described subjectively as pure happiness, elation, a feeling of unity with one’s self and/or nature, endless peacefulness, inner harmony, boundless energy, and a reduction in pain sensation.”
The study revealed that the analgesic quality of endocannabinoids such as anandamide is dictated by the type of pain being experienced. “There are particular types of pain against which cannabinoids are particularly effective,” reported the study’s authors.
A 2003 study entitled “Exercise Activates the Endocannabinoid System” discovered that people who exercised for a minimum of an hour produced significantly higher levels of the endocannabinoid anandamide.
The study also concluded that anandamide is the molecule that causes the euphoria called runner’s high, not the hormone endorphin. This research is notable because it was the first to counter the idea that a runner’s high is produced by high levels of endorphin.
The researchers found that the body produces endocannabinoids as a means of self-healing and mitigating pain and other bodily stresses during moderate or intense exercise. Reported the study’s authors: “No other study has ever considered this possibility, which is why the results are so significant.”
For generations, the energized euphoria experienced by many people during endurance exercise — commonly referred to as runner’s high — was credited solely to the hormone endorphin (β-endorphin). Research has revealed, however, that β-endorphin is not responsible for this phenomenon (see the 2015 study “The Blood-Brain Barrier” and the 2015 study entitled “A Runner’s High Depends on Cannabinoid Receptors”).
Anandamide, however, is able to permeate the Blood-Brain Barrier to reach the CB1 receptors that are found most prevalently in the brain and CNS. When anandamide binds with these cellular receptors, it causes improvements in mood and other euphoric effects (a characteristic of obvious value to those suffering psychological conditions such as social anxiety, clinical depression, and PTSD).
Anandamide in Short
The health benefits of endocannabinoids such as anandamide and 2-AG are being proven at an increasingly detailed and convincing level by a wealth of new peer-reviewed research studies.
Evidence is mounting that patients who produce adequate amounts of anandamide within their own bodies — or who supplement their ECS with anandamide from outside sources or mimetic molecules from plants (such as CBD and THC) — may be better equipped to prevent or combat a wide variety of psychological and physical conditions and diseases.