Endocannabinoids

Marijuana from Within

Dr. Robert Melamede http://www.uccs.edu/~rmelamed/

INTRODUCTION

Marijuana has been used medicinally for thousands of years, having been documented in the world’s first pharmacopeia, written around 2700 BC in China, as well as on clay tablets from the ancient Assyrians 1.

Historically, cannabis preparations have been used to treat a wide variety of illnesses, including: pain, seizures, spasticity, and cholera. Today thousands of peer-reviewed articles, from researchers around the world, explain the underlying science responsible for the many biological activities of the plant. Not surprisingly, plant derived cannabinoids uniquely mimic the recently discovered endocannabinoid system (marijuana from within). Endocannabinoids are an exploding topic of research. As a result, this chapter will examine only bits of the huge database of new scientific knowledge, specifically those that exemplify the endocannabinoid connection with underlying physical principles of the physics of life.

All body systems, and the components from which they are made, are functionally regulated in a manner analogous to how a thermostat maintains temperature in a building, they must be turned on and off appropriately to maintain dynamic stability, i.e. balanced flow, heat gain and heat loss. Dynamic balance is a fundamental property of living systems. In contrast, a penny lying on a table or balanced on its side is stable in the absence of any flowing quantity such as energy. In biological systems, enzymes made from proteins are ultimately responsible for the synthesis of ligands. These are chemical compounds that bind to receptors, also proteins, serve as switches for initiating biochemical responses to biochemical signals that often reflect the status of a cell with respect to its environment. Biochemical signals must also be turned off, therefore, other appropriately controlled enzymes must be available, which can break down the original initiating signals, or turn off the response to them. This biochemical-balancing act is known as homeostasis. It occurs at all levels of life: within cells and between cells, within organs and between organs, on up the scale to include individuals with their environment, and their societies. What is amazing, and not commonly known, is that dynamic steady states naturally result from flowing energy and matter, they self-organize. In other words, the thermostat makes sets itself (mathematically, there is an attractor)

The sum of an individual’s homeostatic activities is represented by one’s health. It is now known that the endocannabinoid system is an all-pervasive modulator of biochemistry. Basic principles of modern physics can provide a scientific foundation that explains life’s physical operational mechanisms, and the important role that the endocannabinoid system plays in maintaining them. Based on far from equilibrium thermodynamic principles, characterized by emergent behavior (new forms of organization that cannot be directly mapped to their causes in a linear mechanistic manner, such as self-assembling enzymatic circuits), the endocannabinoid system regulates biochemical flow across many scales of organization. An as yet largely unstudied area concerns the impact of various endocannabinoids on society. The prevalence of these physical processes in the real world suggests that consciousness itself is an emergent phenomenon that is critically regulated by the endocannabinoid system. Following this line of thinking, it appears that the endocannabinoid system may participate the mind/body connection, perhaps even regulating the placebo effect, were the mind appears to directly control health.

WHAT ARE ENDOCANNABINOIDS?

Endocannabinoids are a group of lipid compounds (fat-like) that are produced by some invertebrates 2 and all vertebrates including humans . Their classification 4 is based on their biological activity, which is often similar to that of the main psychoactive phytocannabinoid (plant cannabinoid) delta-9 tetrahydrocanabinol (THC) found in the marijuana plant.

The first endocannabinoid discovered was, arachidonyl ethanolamine, and was named anandamide (ananda is Sanskrit for bliss, hence the blissful amide) . Subsequently, 2- arachidonoyl glycerol was isolated from canine gut and identified as a second endocannabinoid . Both of these chemicals are ultimately made from essential fatty acids such as are found in fish and seed oils 9. An as yet unanswered question is how much of the health benefits attributed to essential fatty acids such as omega 3’s are due to their products, endocannabinoids (see section on cardio-protection below)? When cannabinoid receptors are activated, various biochemical properties in cells are altered, as is communication with other cells. The Pandora’s Box of endocannabinoids and their modes of action has been opened. Today a number of additional endocannabinoids have been reported and their possible therapeutic applications are under investigation .

AEA and 2-AG are the most studied, and most abundant, endocannabinoids. However, numerous other related molecules also appear to be, or to have, related endocannabinoid like activity, including N-arachidonoylglycine , stearoylethanolamide , Narachidonoyldopamine, homo-g-linolenylethanolamide and 7,10,13,16- docosatetraenylethanolamid virodhamine , and noladin ether.
Some molecules indirectly promote endocannabinoid activity 20, for example, instead of acting directly on cannabinoid receptors they inhibit the activity of enzymes that breakdown endocannabinoids thus effectively increasing the activity of existin endocannabinoids, the entourage effect . New compounds that inhibit endocannabinoid breakdown are under development for therapeutic application. For example, URB597 is under study as a treatment for nausea , as a treatment for emotional disorders such as depression , and to promote vasodilation .

Endocannabinoids are typically synthesized on demand in a calcium dependant manner by hydrolysis of phospholipid precursors . However, despite decades of effort, the biosynthetic pathways for endocannabinoid biosysnthesis are not firmly established . A novel pathway for the synthesis of anandamide has recently been published 29. Their catabolic metabolism by cyclooxygenase 2 (COX2) 30 yields a novel class of bioactive lipids known as prostamides . Prostamides are chemically similar to prostagandins, however they have a longer lifespan in the serum 32. Typically they mediate antiinflammatory events that help to balance the pro-inflammatory effects of many prostaglandins. Pharmaceutical companies have developed COX2 inhibitors to turn off the pro-inflammatory action of prostaglandins. However, these drugs also turn off the production of cardio-protective prostamideswhich has resulted in thousands of deaths. Hence, while endocannabinoids are often produced for local action, their metabolic products can have wide spread activities, often affect global homeostasis.

HOW DO ENDOCANNABINOIDS FUNCTION?

Amazingly, endocannabinoids regulate all body systems including cardiovascular, digestive, endocrine, excretory, immunological, nervous, musculo-skeletal, respiratory, reproductive, tegumentary (skin) where they often exert health-promoting properties 34. The first modern scientific proof of the endocannabinoid system came with the discovery that a potent radioactive analogue of THC uniquely bound to specific areas in the brain, hence suggesting the presence of a THC receptor . Soon after the receptor was discovered in the nervous system (CB1 receptor), it was cloned and found to belong to the large family of G-coupled protein receptors (GCPR) . A few years later a second receptor was cloned from immunological cells (CB2 receptor) . The CB2 receptor is 44% homologous to the CB1 receptor , and since it was found outside the central nervous system, it became known as the peripheral receptor. Ongoing cannabinoid research suggested the existence of additional endocannabinoid receptors. A recent patent application by a pharmaceutical company identified GPR55 as a new cannabinoid receptor . The CB1, CB2 and GPR55 receptors are typically found on the cell surface, but their local lipid environment and internalization affect their functionality.

Endocannabinoid biochemical circuitry is extremely complicated since endocannabinoids also bind other important receptors and channels either directly, or after enzymatic processing. For example, AEA is also an endovanilloid that acts on vanilloid (TRVP1) receptors . TRVP1 channels are non-selective cation channels that belong to the TRP family of proteins. They are found not only on nerve cells, but also on a variety of other cell types . TRVP1 receptors regulate pain and are responsive to heat, acid and pressure. The complexity of cannabinoids and their closely related circuitry is again apparent. Recent work shows that AEA inhibits 2-AG synthesis by activating TRVP1 receptors. Additionally, AEA on the one hand promotes lipogenesis by activating CB1 receptors, while on the other hand it inhibits lipogenesis through TRVP1 receptors . Also, TRPA1 channels, which are responsible for deep cooling activated pain are inhibited by TRVP1 activation through activation by cannabinoids . The complexity of endocannabinoid action is further underscored by the fact that the often have biphasic affects, meaning a particular response is elicited at a low dose, and the opposite affect may result from a high dose .
The regulation of lipid metabolism is a common denominator for much cannabinoid and related molecular activities. Peroxisome Proliferator Activated Receptors (PPARs) are regulators of lipid metabolism. PPAR alpha and delta promote lipid oxidation , whereas PPAR gamma promotes lipogenesis . Cannabinoids activate peroxisome PPAR alpha and PPAR delta thus increasing fat burning. They also activate PPAR gamma 53 receptors that increase fat deposition. Thus, endocannabinoids promote both fat deposition and fat oxidation. Which process dominates and under what conditions is not yet fully understood; yet genetics is certain to play a crucial role in this balancing act.

Endocannabinoids also regulate serotonin action through their effects on the 5-HT receptors , opiod receptors , nicotinic acetylcholine receptors , glycine receptors, and sodium, potassium and calcium channels 57. Together, these interwoven biochemical circuits control a significant number biochemical processes up to and including consciousness. Thus, varying levels of cannabinoid activity in a population must have social consequences 58.

Presently, it is not known if the spectrum of cannabinoid activities found in the different sub species of cannabis (Cannabis sativa, indica, and ruderalis), as well as the differences in the biological activities of different cultivars 59 encompass the various biological properties of endocannabinoids. The varying chemical profiles found in different strains of cannabis may explain strain-specific therapeutic benefits claimed by medical marijuana patients. Currently, an little explored possibility is that strain differences may reflect an individual’s need to supplement specific endocannabinoid deficiencies that characterize specific illnesses 60. As a result of the complexity exhibited the endocannabinoid system, many aspects of biology must be integrated when trying to develop a comprehensive understanding of the endocannabinoid system’s biological properties. It is therefore interesting to consider that emergent behavior must be a natural phenomenon intrinsic to the endocannabinoid system. Thus, while a reductionism approach provides tremendous details regarding the specifics of endocannabinoid biochemistry, this perspective cannot predict the higher levels of organization and complexity that are non-linearly related to their underlying causes emergent behavior. The perspective guiding this chapter is that health and consciousness of an individual are emergent phenomena. Hence we must look at both the details and the big picture in order to appreciate the unique therapeutic benefits associated with manipulating the endocannabinoid system.

THE PHYSICS OF LIFE

In order understand the great complexity of the endocannabinoid system, and its central role in human health, it must be viewed from a scientific framework that specifically deals with complexity. Sans details, the common thread running through this chapter is the integration of modern endocannabinoid science with the physics that provides a scientific perspective of what life is. Simplistically, when energy flows through large collections of molecules, they acquire a creative quality that results in dynamic selforganization, a phenomenon that is thought to be responsible for life and the evolutionary process 61 62 Using physical and biochemical concepts as a foundation, life/death, health/illness, and social, political and economic principles can be examined from underlying physics, and how, at all levels, these processes are uniquely regulated by the endocannabinoid system 58.

 

CREATIVE ENERGY FLOW AND LIFE

In order to appreciate the medical opportunities provided by manipulating the endocannabinoid system, we must consider the basic properties of life itself. For the first time in mankind’s history, we can look at life from a truly scientific prospective, using tools that will enable us to understand its basic properties. The details of the physics of life will not be examined, but we will describe some of the basic characteristics of life from the perspective of far from equilibrium thermodynamics. For our purposes, these ominous terms can be easily understood.

Let’s start with equilibrium. Scientifically, equilibrium is a state of maximum disorder (entropy), and simultaneously, a state of minimum potential (the ability to do work). In other words, equilibrium is the opposite of life. Thermodynamics refers to the flow of energy. A unique characteristic of matter driven further from equilibrium is that it possesses a natural tendency to create new forms of organization. From the human prospective, moving further from equilibrium can mean promoting or regaining one’s health and increasing one’s organization and energy flow. An example is physical training, where changes occur that span biochemical to behavioral levels. Similarly, learning and enhanced thinking skills (including one’s state of mind) also represent movement from equilibrium. Again, our endocannabinoid system is a master regulator of each of these processes. With such wide-ranging, multi-scaled regulatory activities, the endocannabinoid system is likely to play an important role in connecting the mind and body.

A basic far from equilibrium characteristic is that of dynamic balances. An additional on is that when there is enhanced energy/mass flow through as system of balanced opposing forces, stable steady state can undergo a dramatic shift over a short period of time and can result in cyclic and chaotic behaviors. The consequences of these non-linear rearrangements (phase changes) can be dramatic. For example, endocannabinoids are known to regulate the balance of open/closed-mindedness (the ability to learn new things and replace the old), depression/euphoria, stress/reduced stress, pain/reduced pain, hunger/satiety. Think of the impact that these macroscopic biological activities have on an organism’s interaction with its environment, and that they all emerge from organized underlying biochemical phenomena.

LIFE AND EVOLUTION ARE A SERIES EMERGENT PHENOMENA

Regulated energy and mass flow keeps life away from equilibrium. The movement towards equilibrium is characterized by aging, illness and death. On community, species, individual, cellular and sub-cellular levels, living systems maintain the critical flow of organizing energy by extracting it from their environment, and by dumping their waste products back into the environment. Endocannabinoids play crucial roles in each of these processes.
In addition to distance from equilibrium, in fact a result of it, another fundamental characteristic of living systems is that the whole is greater than the sum of its parts (emergent behavior). Pieces of a system work together and create something new and different, something that would not have been predicted by observing the individual components in isolation. How do these phenomenon impact on the health of cells, individuals, communities and society, and what role is played by the endocannabinoid system? Are consciousness and health emergent phenomenon, with the endocannabinoid system being a critical player in the emergence process? Are endocannabinoids critical components of the mind-body link, and is the endocannabinoid system involved with the placebo affect?

ENDOCANNABINOIDS: PRO-LIFE ANTI-AGING MOLECULES

Before considering the role of endocannabinoids in the aging process, we should consider what aging is. As mentioned above, life is intrinsically a far from equilibrium phenomenon 62,63. Hence we can equate health with an organism’s distance from equilibrium, and both aging and age-related illnesses as an organism’s movement towards equilibrium. Again, equilibrium is when disorder is maximized. From this perspective, the role that cannabinoids play in the aging process can be restated as how do cannabinoids impede and organism’s movement towards equilibrium, and what are biochemical events responsible for the movement towards equilibrium?It is generally accepted that free radicals are critical contributors to the aging process 64.

Free radicals are highly reactive compounds that react with all biologically important molecules including carbohydrates, lipids, nucleic acids (RNA and DNA), and proteins, as well as their building blocks. Mitochondria, specialized energy producing organelles of eukaryiotic cells, are responsible for producing most free radicals . This line of thinking has progressed from viewing proteins as the critical targets, to viewing nucleic acids, in particular DNA, as the critical target, to taking a more systematic view from which all the biological components must work together in an harmonious, integrated fashion, and thus they are all critical targets. Thus the question becomes, can cannabinoids, both endo and exo, impact on the biological consequences of free radicals? Two important studies address this question without examining the specific mechanisms.

The first hint that activating the endocannabinoid system might have anti-aging properties came from a study done within the NIH itself in which after 2 years of THC administration to rodents, “Survival of all dosed groups was generally significantly greater than that of the controls”. In contrast, when the ability of a mouse strain to produce the CB1 receptor was genetically “knocked out”, the mice died significantly younger .The anti-aging properties of cannabinoids could result from their direct capacity to scavenge free radicals , or from their impact on free radical generating, proinflamatory metabolic pathways . In essence, free radical damage to living systems can be considered to be biological rust 72, whereas endo and exo cannabinoids are the oil of life that reduces biochemical friction 34.

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