Foreword: Beyond THC and Anandamide
One of the most appealing features of scientific research is the promise of discovery of unexpected new facets of our surroundings or even of our own world. The original aim of cannabis research—like that of morphine, about a century earlier—was to identify the active principle and to make it available for biological and clinical investigations. Indeed, this type of research, which had started in the late nineteenth century, culminated in the 1960s and early 1970s with the elucidation of the chemistry of specific cannabis constituents, which were termed cannabinoids. Although many dozens of plant cannabinoids are now known, surprisingly, there is essentially only one compound, delta-9-tetrahydrocannabinol (THC), which causes the typical “marijuana” effects, although others, such as cannabidiol (CBD), modify its activity. Unexpectedly, the exciting saga of cannabinoid research did not end here, but led to further discoveries of wider importance. THC turned out to be an agonist to two major new receptors, which had their own endogenous agonists—anandamide and 2-arachidonoyl glycerol (2-AG). These endocannabinoids have complicated biosynthetic and degradation pathways. This elaborate new biochemical system, appropriately named the endocannabinoid system, has turned out to be of central importance in physiology. It has both direct biological effects, and effects due to modulation of other neurotransmitter systems. In fact the endocannabinoids are synthesized, when and where needed, in the postsynapse and move to the presynapse, where they affect the release of many of the major known neurotransmitters (Howlett et al. 2002; Pertwee et al. 2010). The present book, edited by Roger Pertwee, one of the early pioneers in the area, presents a picture of our knowledge of the endocannabinoid field, with emphasis on the major biological systems in which the endocannabinoids are involved, with parts dealing with a wide spectrum of topics, stretching from history and international control, through chemistry and pharmacology, to clinical use and clinical promise. The roles of the endocannabinoid system in many central physiological mechanisms are emphasized. It gives us an almost complete picture of the present-day state of knowledge. But a final picture is never possible. There are already tiny slivers of published, unexplained facts, which will presumably open new vistas of which we are not fully aware today. Just two examples: Endocannabinoids and synthetic molecules acting through the type 2 cannabinoid receptor (CB2) have been shown to affect a large number of pathological conditions—cardiovascular, neurodegenerative, reproductive, gastrointestinal, liver, lung, skeletal, and even psychiatric and cancer diseases. This receptor works in conjunction with the immune system and presumably with various other physiological systems. It seems that the CB2 receptor is part of a major general protective entity. We are, of course, aware that the mammalian body has a highly developed immune system, whose main role is to guard against protein attack and prevent, reduce, or repair possible injury. It is inconceivable that through evolution analogous biological protective systems have not been developed against nonprotein attacks. Pál Pacher and I have previously posed the speculative question: “Are there mechanisms through which our body lowers the damage caused by various types of neuronal as well as non-neuronal insults? The answer is of course positive. Through evolution numerous protective mechanisms have evolved to prevent and limit tissue injury. We believe that lipid signaling through CB2 receptors is a part of such a protective machinery and FOREWORD vii CB2 receptor stimulation leads mostly to sequences of activities of a protective nature” (Pacher and Mechoulam 2011). In addition to anandamide and 2-AG there are many dozens, possibly hundreds, of chemically related compounds in the brain and possibly in the periphery. They are mostly fatty acid amides of amino acids (FAAAs) or of ethanol amines, or glycerol esters of fatty acids. More than 50 years ago Godel, in his philosophical work, suggested that everything in the world has meaning, which is analogous to the principle that everything has a cause, on which most of science rests. Along this line of thought: do these compounds play a physiological role? Those constituents that have been evaluated do not bind to the cannabinoid receptors, but possess various activities. Thus, arachidonoyl serine is a vasodilator and lowers brain damage; arachidonoyl glycine is antinociceptive; arachidonoyl dopamine affects synaptic transmission in dopaminergic neurons; oleoyl serine is antiosteoporotic; palmitoyl ethanolamide is anti-inflammatory etc., etc. Numerous papers have shown that in certain pathological conditions the levels of anandamide and 2-AG are modified and recently the levels of some of the FAAAs and related compounds of the types just mentioned have also been shown to change. Can we follow these changes to diagnose early neurological and other diseases? Does this cluster of compounds affect our physiological and psychological reactions, our moods, or even contribute to our personality? Linda Parker and I (Mechoulam and Parker 2013) have previously speculated that “It is tempting to assume that the huge possible variability of the levels and ratios of substances in such a cluster of compounds may allow an infinite number of individual differences, the raw substance which of course is sculpted by experience. The known variants of CB1 and FAAH genes may also play a role in these differences. If this intellectual speculation is shown to have some factual basis, it may lead to major advances in molecular psychology.” I assume that the endocannabinoid system still holds quite a few surprises. I believe that we shall enjoy learning about them soon.