Endocannabinoids: Molecular, Pharmacological, Behavioral and Clinical Features

The ubiquitous cannabinoid receptors (CBRs) – probably the most abundant binding sites in the CNS - are known to be involved in a number of neuropsychiatric disturbances. CBRs are coded in human chromosomes 1 and 6 and activated by endocannabinoids, phytocannabinoids and marijuana use (medical/recreational use).


For me, personally, the year 2013 has a special significance. Exactly 50 years ago I published my first paper on cannabinoids. At that time, in 1963, research on the constituents of Cannabis sativa had mostly come to a stop. Although investigation on cannabis in its various forms –hashish, marijuana, bhang – had been reported over a century, its psychoactive constituent(s) had not been isolated in a pure form and its structure – or possibly structures – was unknown. And yet, there was no research going on in either North America or the UK – the major research countries at the time. The major reason for this neglect was possibly legal.
Cannabis was an illicit substance and was not readily available to scientists. And even if it were obtained legally, research with it would have been impossible in an academic laboratory, due to strict security regulations for work with such substances. Luckily I was not aware of these problems. Through the research institute I worked at the time – the Weizmann Research Institute – I obtained 5kg of confiscated hashish from the police, who apparently were also unaware of the international agreements on cannabis. First, my colleagues, the late Yuval Shvo, Yehiel Gaoni and I reisolated cannabidiol, a non-psychoactive constituent. This compound had been obtained previously by Lord Todd, a Nobel Prize winner, and by Roger Adams but its structure had not been elucidated. By use of then modern methods – NMR and mass spectrometry – we established its structure and published the results in 1963 – 50 years ago. At this point I asked for a grant from the US National Institute of Health (NIH). My application never went beyond the administrative office. Their answer was that cannabis use was not an American problem. Would I, they wrote, apply with a more relevant topic. Nevertheless Yehiel Gaoni and I went ahead and by 1964 had isolated several cannabinoids – a term I coined several years later – and had elucidated their structures. Dr. Habib Edery and Yona Grunfeld, colleagues at a nearby biological research station, tested these constituents for psychoactivity in monkeys. Only one compound caused such activity. At that time we called the compound delta-1-tetrahydrocannabinol, but later it was renamed delta-9 –tetrahydrocannabiol (Δ9 THC) and many thousands of publications on it have been published. Suddenly NIH decided that cannabinoid research is a relevant topic for research. A prominent NIH pharmacologist flew over, took with him the entire supply of pure THC and for the next few years most of the research on this compound in the US was done with it. And NIH has supported my work ever since. 
Over the next 2 decades we, and many other groups, worked on the chemistry, biochemistry, pharmacogy and even some clinical effects of the cannabinoids. We learned how the cannabinoids are formed in the body, how they are metabolized and what effects they cause in vitro and in vivo. Some clinical work was also published. THC was approved as a drug for enhancement of appetite (mostly in cancer and AIDS patients) and for prevention of vomiting and nausea in patients undergoing cancer chemotherapy. But, surprisingly, the mechanism of THC action remained unclear. It was believed that it had something to do with possible action on lipid membranes due to its lipophilic properties. In the mid-1980's Allyn Howlett's group showed that a specific receptor exists. Stimulation of this receptor, known now as the CB1 receptor today, leads to the well known marijuana effects. Later a second receptor, CB2, was discovered in the immune system. We assumed that these receptors are stimulated by endogenous constituents and went ahead looking for them. As THC is a lipid, we assumed that the endogenous constituents are also lipophilic compounds, In 1992 we isolated the first such endocannabinoid and named it anandamide. Later a second endocannabinoid, 2-AG, was identified. The present, outstanding eBook describes in considerable detail the enormous amount of research done on the endocannabinoids, the endocannabinoid receptors, the unique endocannabinoid signaling system and the advances in the clinic. 
Where is endocannabinoid research going now? I shall try to put forward several areas, which I believe will lead to major advances:


Pal Pacher and I have speculated in a recent review that "The mammalian body has a highly developed immune system which guards against continuous invading protein attacks and aims at preventing, attenuating or repairing the inflicted damage. It is conceivable that through evolution analogous biological protective systems have evolved against nonprotein attacks. There is emerging evidence that lipid endocannabinoid signaling through CB2 receptors may represent an example/part of such a protective system” Indeed over the last few years numerous groups have reported protective action through the CB2 receptors in numerous physiological systems. We can expect this trend to continue.

Over the last few years several groups have shown that endocannabinoid signaling is involved in progenitor/stem cell development, thus leading to regulation of their proliferation, differentiation and survival. In view of the importance of stem cells in human health and disease, we should expect to see a major research effort in this fascinating field.


Many dozens of fatty acid amides of ethanol amines and amino acids, as well as esters of fatty acids with glycerol (endocannabinoid-like compounds) are present in the brain and possibly in other organs. Those that have been investigated have been shown to cause various physiological effects – lowering of pain, vasodilation, anti-osteoporotic and anti-cancer activity. It is quite possible that this type of compounds may represent a valuable treasure throve of physiological mediators.
Linda Parker and I have speculated that "If subtle chemical disparity is one of the causes for the variability in personality—an area in psychology that is yet to be fully understood—we may have to look for a large catalog of compounds in the brain with distinct CNS effects. Is it possible that the above-described large cluster of chemically related anandamide-type compounds in the brain is related to the chemistry of the human personality and the individual temperamental differences? 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. If this intellectual speculation is shown to have some factual basis, it may lead to major advances in molecular psychology". Will the endocannabinoid system be the key to this yet unexplored niche of science?

Hebrew University Institute for Drug Research
R. Mechoulam
Medical Faculty Jerusalem Israel

Hiroki Ishiguro, Claire M. Leonard, Susan Sgro and Emmanuel S.

Yamanashi University, Japan,  William Paterson University, Wayne NJ 07470,
USA and 3 NIDA-NIH Baltimore MD 21224, USA
Abstract: The ubiquitous cannabinoid receptors (CBRs) – probably the most abundant binding sites in the CNS - are known to be involved in a number of neuropsychiatric disturbances. CBRs are coded in human chromosomes 1 and 6 and activated by endocannabinoids, phytocannabinoids and marijuana use (medical/recreational use).

The components of the endocannabinoid system (ECS) include CNR1 and CNR2 genes encoding these CBRs (CB1Rs and CB2Rs), endocannabinoids (eCBs), and their synthesizing and degradation enzymes are major targets of investigation for their impact in neuropsychiatry. Hence we have continued to study the influence of CBR variants in neuropsychiatric disorders. Many studies have shown that CNR1 and FAAH single nucleotide polymorphisms (SNPs) may contribute to drug addiction, depression, eating disorders, schizophrenia, and multiple sclerosis. But little attention has been paid to the neuronal and functional expression of CB2Rs in the brain and their role in neuropsychiatric disorders has been much less well characterized. Indeed our studies provided the first evidence for neuronal CNS effects of CB2Rs and their possible role in drug addiction, eating disorders, psychosis, depression and autism spectrum disorders (ASDs).
In the current ongoing studies many features of CBR gene structures, SNPs, copy number variations (CNVs), CpG islands, microRNA regulation and the impact of CBR gene variants in neuropsychiatry and where possible in rodent models have been assessed. Although CNR1 gene has more CpG islands than CNR2 gene, both have CPG islands less than 300 bases, but they may be regulated by DNA methylation. MicroRNA binding to the 3′ untranslated region of the CNR1 gene with two polyadenylation sites may also potentially regulate CB1R expression. CNR1 gene has 4 exons and there are 135 SNPs reported in more than 1% of the population with no common SNP that changes amino acids of CB1R currently known or reported. A copy number variant (CNV) which is 19.5kb found in 4 out of 2026 people covers exons 3 and 4 and codes amino acid that could alter the expression of CB1Rs. CNR2 has 4 exons with CB2A with 3 exons and CB2B with 2 exons; and there are about 100 SNPs found in more than 1% of the population, which include common cSNPs that change amino acids of the CB2R, including R63Q, Q66R and H316Y. CNVs in Asian and Yoruba population have been reported. We also report on the identification of novel human and rodent CB2R isoforms, their differential tissue expression patterns and regulation by CBR ligands. Our findings also indicate increased risk of schizophrenia, depression, drug abuse, and eating and autism spectrum disorders in low CB2R function. Therefore, studying the CBR genomic structure, its polymorphic nature, subtype specificity, its variants and associated regulatory elements that confer vulnerabilities to a number of neuropsychiatric disturbances may provide deeper insight in unraveling the underlining mechanisms. Thus, understanding CBR variants and other components of the ECS may provide novel targets for the effects of cannabinoids in neuropsychiatry. Support R15DA032890 and WPUNJ.