As the multi-cellular complexity of life evolved, new structures were necessary to support the enhanced dialog between an organism and it’s environment. A primary requirement would be the development of a more organized capacity for greater energy/mass through put, in other words the development of the digestive system. A reliance on simple diffusion for nutrient and waste transfer would limit the far from equilibrium driven mandate for the biosphere to increase entropy production to the environment. Thus, the concerted evolution of a digestive system, sensory organs and the nervous system, would in a concerted manner drive the evolution of the musculoskeletal system, which, as organisms evolved enhanced mobility, would require the protective properties of the evolving immune system. All these biological components work together and mutually enable each other so that an organism can sense it’s environment, determine it’s thermodynamic compatibility with it, and make the necessary adjustments in an attempt to optimize its place in the unfolding universe. Surprisingly, as these body systems synergistically evolved, endocannabinoids became crucial modulators of the multi-dimensional biochemical balancing strategies that characterize living systems. Some representative examples are found below.


From a far from equilibrium perspective, in order for a system of molecules to undergo a nonlinear rearrangement that will increase its complexity, there must be an excess of potential for increased mass and energy flow. Thus, this rule should have driven the evolution of single celled organisms into more complex multi-cellular forms. Hence the first level of complexity that must have been selected for was the capacity to more efficiently intake food and removal wastes. In fact it appears that around the same time that this evolutionary step first occurred, some 600 million years ago, the primitive beginnings of the endocannabinoid system first appeared 73. Today it is obvious that the endocannabinoid system evolved into a fundamental regulator of hunger and the digestive/excretory system 74.

Endocannabinoids regulate many aspects of food acquisition, and processing from one end of our digestive tract to the other. The profound effect that cannabinoids have on eating is well known. The “munchies” result from cannabis consumption because THC mimics the release of endocannabinoids in the brain’s appetite center that results the mental feeling of hunger . Endocannabinoids stimulate hunger both in the brain 76 and in the gut .

An interesting holistic behavioral affect of endocannabinoids is seen in the regulation of song in adult male zebra finch, where courtship, kin recognition, and nest defense are components of mating behavior . When these birds have limited food availability, or are treated with cannabinoids, the transcription of genes involved in the auditory processing of songs is inhibited. Hence endocannabinoids are participating in the integrated regulation of feeding, reproductive behavior, and aggression Dramatically, the significance of endocannabinoid signaling in feeding behavior is underscored by the feeding new born mice a CB1 antagonist (SR141716A, also known as Rimonabant), they die . Since Rimonabant’s (and other CB1 antagonists) inhibit feeding, it has been developed as a treatment for obesity . It has undergone clinical trials in Europe and the USA. Today it is a commercial product in Europe for weight control, however it failed to pass the FDA approval process and remain unavailable in the United States.

When the multi-facetted involvement of the endocannabinoid system in maintaining homeostasis in living systems is considered, turning of the CB1 receptor seems to be a dangerous undertaking. In fact, Rimonanant-induced nausea and depression are common reasons for patients discontinued its use during the clinical trials . Futhermore, in support of the neuroprotective properties of cannabinoids (see section below on the nervous system), a patient, using Rimonabant for obesity, developed multiple sclerosis. The age related accumulation of free radical damages is at least participatory in the etiology of age related illnesses of the digestive tract, as a result, both a scientific studies and anecdotal observation are in agreement. For example, anecdotal observations suggest that cannabinoids are beneficial for treating gastro-intestinal reflux disease, a condition where stomach acid erodes the esophageal wall as a result of the esophageal sphincter failing to fully close. The sphincter closes when it is relaxed, and this process is promoted by endocannabinoids acting on CB1 receptors in the dorsal vagal nerve complex as demonstrated in ferrets.

Another important gastric disorder is ulcers. The main cause of peptic ulcers is now known to be infection with H. pylori, which results in a strong proinflammatory Th1 cytokine response 84, and excessive acid production. Since endocannabinoids turn down the Th1 response, and inhibit acid secretion 85, it makes sense that cannabinoids have anti-peptic ulcer activities. By similar mechanisms of immune cytokine modulation and regulation of neurological activity, endocannabinoids have protective roles in the lower gastrointestinal tract where they protect against colonic inflammation . The latest data indicates that the protective actions of endocannabinoids in the lower gastrointestinal tract is not simply the result of CB1 activity, but also involves TRPV1 and CB2 receptors 88. Interestingly, the latest research indicates that the CB2 are up-regulated during pathology independent of tissue type.


Endocannabinoids are central players in the nervous system, both centrally and peripherally. The CB1 receptor is the most abundant G-coupled protein receptor in the brain 89. When involved in nerve transmission, endocannabinoids are released by postsynaptic neurons and travel retrograde across the synaptic cleft and where they bind to specific receptors . Alternatively, they may be transported 91 into cells for degradation by specific enzymes such as fatty acid amino hydrolase and monoacylglycerol lipase. Endocannabinoids provide important protection for the nervous system, since free radicals again play an important role in nervous system pathologies including ALS, Huntington’s Disease , Alzheimer’s Disease 97.

The detrimental consequences of excessive neurological stimulation as induced by excitotoxins and epileptic seizure, inflammation , as results from traumatic brain injury , stroke and infections, are all reduced by endocannabinoids. However, again demonstrating the critical importance of appropriately balanced biochemical circuits, and the at times contradictory properties of the endocannabinoid system, COX metabolites of the endogenous cannabinoid 2-AG promotes excitatory glutaminergic transmission and associated nerve injury and death. The negative consequences that marijuana has on memory commonly know, and well documented . The important question that arises from these observations is “what is the biological role of the endocannabinoid system with respect to memory?” Possible answers will be examined from a holistic perspective. A healthy individual must have an appropriate balance of remembering and forgetting, imagine if all the things you would rather forget dominated your thoughts. Post-traumatic stress and depression are natural consequences in humans who could not forget unpleasant memories. Again, nature has selected the endocannabinoid system as a critical modulator of balancing remembering and forgetting.

A poignant example that demonstrates consequences of insufficient forgetting comes from behavioral studies with CB1 knockout mice . While both wildtype (normal) mice and knock out mice were able to learn the solution to a water maze (finding a platform to get out of the water), the CB1 deficient knockouts could not relearn the solution when the platform was moved to a new position 102. If cannabinoids regulate similar neurological processes in humans, it is inevitable that this form of relearning will vary in any population with people having abilities above and below the average. The human equivalent of the relearning behavior of mice might be open-mindedness, a quality anecdotally described as enhanced by the use of cannabis. If this analysis is correct, endocannabinoid activity regarding this phenotype could have important implications for the survival of mankind, where open mindedness may be necessary to change human behavior to minimize the consequences of the rapidly changing environment that results from human activities 58.

The Immune SystemThe function of the immune system is simple, to protect an individual from danger. However the mechanisms by which the immune system functions to accomplish this task are incredibly complicated and far-reaching in that they impact on the biochemistry of all other biological systems. The far from equilibrium thermodynamic model of life is based on a multidimensional web of biochemical balance that has pro- and anti- inflammatory processes as a core component. The immune system is a critical regulator of this core. The immune system responds to environmental perturbations impinging on an organism. Free radical production is a universal signal of imbalance between an organism and its environment. However, organisms have evolved the capacity to respond by producing and using free radicals and other reactive oxygen (ROS) and nitrogen (RON) chemicals as sanitizing agents to fight infection. This response, however, must be kept in check due to the highly reactive nature of these chemical species.

By modifying DNA, RNA, proteins and lipids, free radicals reduce an organism’s distance from equilibrium by reducing the efficiency of biochemical flow (the friction of life). The endocannabinoid system critically tries to restore balance by reducing the inflammatory response and promoting the anti-inflammatory response. The health consequences of pro-inflammatory imbalances are all pervasive.Most immune disorders can be attributed to a pro-inflammatory imbalance that results in the immune system attacking inappropriate targets that results in autoimmune disease. Arthritis , Crohn’s Disease 104, diabetes 105, Lupus , and multiple sclerosis all have proinflammatory imbalances that results in tissue destruction. Each of these illnesses is, in part, characterized by excessive pro-inflammatory cytokines (Th1 response), which are protein messengers through which the immune system communicates with itself and the rest of the body. Since the endocannabinoids are important regulators of the Th1 versus the anti-inflammatory Th2 response 108, as well as the development of the immune system itself, some of these illnesses are now being characterized as endocannabinoid deficiencies including melancholic depression 109, multiple scherosis 110, migraines.


Inadequate attempts by the body to use endocannabinoids to mediate protection of the cardiovascular system may be seen in a variety of pathologies. As a result, many illnesses may be characterized by endocannabinoid deficiencies. Excessive pro-inflammatory activity has a profound impact on cardiovascular health. For example, pro-inflammatory TH1 cytokines inhibit the burning of fat by macrophage, which in turn promotes their conversion to fat laden foam cells. Additionally, the Th1 cytokine profile promotes macrophage migration through the walls of blood vessels, where some die and turn into the plaque that results in atherosclerosis, “hardening of the arteries.” Recent work in mice demonstrates that cannabinoids can reverse this process by activating the CB2 receptors.

Additionally, when a cardiac blood vessel blockage is created in mouse models, endocannabinoids acting through the CB2 receptors, protect the heart muscle from the damage that results from oxygen deprivation, as well as when reperfusion replenishes the oxygen supply and generated free radicals . It now appears that remote ischemic preconditioning, when damage at one site protects other sites, occurs through a CB2 mechanism In addition to these protective properties, endocannabinoids, in animal models endocannabinoids also regulate cardiac 115, mesenteric , kidney and cerebral circulation Wagner et al., 2001, Eur J Pharmacol, 423, 203-10} by promoting vasodilation.
It should be noted that while cardiovascular pathologies most seem result from an excessive pro-inflammatory response, there are others that seem to result from an excessive anti-inflammatory/TH2 response. For example, the cardiac contractile dysfunction that is associated with liver cirrhosis is mediated by the CB1 receptors , as is the low blood pressure associated with hemorrhagic shock.


Societal open mindedness, or the lack there of, has important health ramifications when considering pain management especially for cancer patients (see below). The combination of cannabinoids with opiates for pain treatment provides unique benefits in that a positive analgesic synergy has been found between these two drugs . Furthermore, this combined treatment reduces the tolerance that normally develops to opiates . When one considers that pain is often associated with inflammation and tissue degradation as is found with arthritis, cannabinoids become an ideal tool to assist with chronic pain management in that they reduce both inflammation and the associated degradation 122.


The importance of modulating the endocannabinoid system for pain management is underscored with cancer. The use of narcotics, aside from their impact on the quality of life, seems to enhance biological responses that promote tumor metastasis 123. In contrast cannabinoids inhibit metastatic mediators like epithelial growth factor VEGF , adhesion and migration , while also having anti-nausea and anti-depressive activities , although there is also evidence to the contrary . The numerous benefits that cannabinoids can offer cancer patients are underscored by the direct cancer killing properties of cannabinoids. In the 1970’s it was already known that cannabinoids could kill Lewis lung carcinoma cells. We now know that cannabinoids (endo, phyto and synthetics) halt the growth or kill many different types of cancers including glioma, skin cancer , , breast cancer , prostate cancer , lymphoma, melanoma.


This chapter has provided a limited, but holistic overview of the complexity of the endocannabinoid system and its involvement in maintaining healthful homeostasis. We have not covered important areas such as the involvement of endocannabinoids in regulating the skeletal system, the reproductive system, addictive behaviors etc. The field of endocannabinoid research is logarithmically expanding since endocannabinoids regulate an incredibly diverse array of biochemical events that transcend sub-cellular to societal scales. As such, the endocannabinoid system exemplifies the profound creative nature of the physics of life, far from equilibrium thermodynamics, by participating in holistic biochemical behavior that ideally manifests as health. Endocannabinoids, through multiple modes of action, are critical regulators of energy balance 139, and energy flow is essential in maintaining organization of flow dependant structures that result from distance from equilibrium.

From a far from equilibrium perspective, the multifaceted implications of this regulation can be unique to each person as determined by limit cycles, where mass and energy flow result is self-assembling regulatory circuits 140. Hence imbalances characterized by an over active, or under active, endocannabinoid system are functions of the individual (genetics and environmental history) and the tissue or organ under consideration. Typically, since we are all aging, most endocannabinoid imbalances are of insufficiency. Endocannabinoids are unique tools that can help shift biochemical imbalances (inappropriate limit cycles), not by pushing change in isolated areas, but by initiating change through many interrelated components of biochemistry. A movement towards a more healthy state results from establishing new limit cycles driven by energy acquisition that leads to novel multi-scaled communication and cooperation. Our cells, our bodies, our societies are all profoundly impacted by endocannabinoids.

Endocannabinoids have unknowingly been manipulated in an effort to improve health and relieve suffering for decades. The commonly used analgesic, acetaminophen, is metabolized to produce an inhibitor of anandamide transport (AM404), thus effectively raising endocannabinoid levels . The commonly used general anesthetic propofol also inhibits FAAH . Are the anti depressive effect of electro shock therapy due to elevated endocannabinoid levels elicited to protect the brain? Osteopathic manipulation raises anandamide levels 168% . Yogurt induces CB2 levels in the gut . Activities as simple as taking a warm bath to relieve stress and pain are likely to increase endocannabinoid levels since through their action in the hypothalmus they can reduce an elevated body temperature 145.

A person’s life is the progressive unfolding of the interactions of the biological system with its environment. Consciousness has defined possibilities for examining and attempting to control this process. An individual can look backward to what has already happened, look forward to what is projected to happen, or a person can be present and can experience the now. The latter two possibilities are promoted by cannabinoids as a consequence of how cannabinoids typically have a negative impact on memory but favor relearning and novely, thus potentially fostering the anecdotally noted enhancement of creativity by exocannabinoids. Cannabinoid research has come a long way in a relatively short period of time, where it will go remains to be seen, but it certainly appears manipulating the endocannabinoid system will have an expanding role in the future of mankind.

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