Preface
Less than 20 years ago the field of cannabis and the cannabinoids was still con-
sidered a minor, somewhat quaint, area of research. A few groups were active in
the field, but it was already being viewed as stagnating. The chemistry of cannabis
was well known,∆^9 -tetrahydrocannabinol (∆^9 -THC), identified in 1964, being the
only major psychoactive constituent and cannabidiol, which is not psychoactive,
possibly contributing to some of the effects. These cannabinoids and several syn-
thetic analogs had been thoroughly investigated for their pharmacological effects.
Their mode of action was considered to be non-specific. The reasons for this as-
sumption were both technical and conceptual. On the technical side, it had been
shown that THC was active in both enantiomeric forms (though with a different
level of potency) and this observation was incompatible with action on biological
substrates—a receptor, an enzyme, an ion channel—which react with a single
stereoisomer only. The conceptual problem related to THC activity. This had been
pointed out by several highly regarded research groups that had shown that many
of the effects seen with cannabinoids were related to those of biologically active
lipophiles, and that many of the effects of THC, particularly chronic ones, were
comparable to those seen with anaesthetics and solvents. The technical problems
were eliminated when it was found, by several groups, that cannabinoid action is
actuallystereospecificandmostofthepreviouswork,whichhadpointedtoadiffer-
ent conclusion, was based on insufficiently purified samples. Theconceptual hurdle
was overcome when Allyn Howlett’s group in 1988 brought out the first evidence
that a specific cannabinoid receptor exists in the brain. This receptor was cloned
shortly thereafter and a second receptor, which is not present in the brain, was
identified in the periphery. As, presumably, receptors do not exist in mammalian
brains for the sake of a plant constituent, several groups went ahead looking for
endogenous cannabinoids. The first such endocannabinoid, named anandamide,
was reported in 1992, and a second major one, 2-arachidonoylglycerol (2-AG), was
discovered in 1995. Several additional, apparently minor ones are now known.
A research flood followed. Antagonists to both receptors have been synthesized,
specific enzymes, which regulate endocannabinoid levels, have been found, and the
biosynthetic and degradation patterns have been established. The endocannabi-
noid system has turned out to be of major biochemical importance. It is involved in
many of our physiological processes—in the nervous, digestive, reproductive, pul-
monary and immune systems. Endocannabinoids enhance appetite, reduce pain,
act as neuroprotectants and regulators of cytokine production and are somehow
involved in the extinction of memories—to mention just a few of their effects.