The original name of the ICRS was “International Cannabis Research Society.” In 1995—after the body’s own cannabinoid receptor system had been discovered and elucidated by ICRS members—the group changed the C-word in its name to “Cannabinoid.” As pharmacologist Dale Deutsch explained in 1998, “The field is moving away from the plant.”
The 2014 ICRS meeting marked the return of the plant to the forefront of the field. Neurologist Ethan Russo was serving as president (the job is held for a year), and he invited the Italian natural product chemist Giovanni Appendino to give the featured talk.
Appendino, a professor at the Università del Piemonte Orientale, noted proudly that he is from Carmagnola, a northern Italian town renowned for its fiber hemp variety of the same name.
Appendino first published research in the cannabinoid field in 2002, when he was co-author of a paper on “Noladin ether—a putative endocannabinoid.” The lead authors were Raphael Mechoulam and Vincenzo DiMarzo. But his “relationship with cannabis as fiber hemp” goes much further back, he said. “My grandfather was growing it and the odor of hemp retting tanks filled the air around Carmagnola during the Fall.”
“Nature has varied on the cannabinoid structure,” Appendino observed. Cannabis researchers have focused almost e. xclusively on THC, CBD, CBC (cannabichromene), and CBG (cannabigerol, precursor to the other three) while not investigating the therapeutic potential of related molecules present in Cannabis — and other plants as well.
Similarly, by defining cannabinoids as drugs that work at the CB1 and CB2 receptors (the canonical cannabinoid receptors concentrated in the central and peripheral nervous system, respectively), researchers may be overlooking beneficial compounds in Cannabis that work by other mechanisms.
In the course of screening more than 200 varieties of fiber hemp, Appendino and colleagues have found significant quantities of obscure compounds whose medical potential he considers “worthy of investigation.”
He touched briefly on canniprene, the cannflavins, cannabinoid esters, and “sesqui-CBG,” which Appendino’s group isolated from a fiber hemp variety.
Appendino has encountered a hemp variety containing two percent canniprene—a compound he called “the Cannabis version of resveratrol” (a beneficial antioxidant compound present in red grapes).
From others varieties of hemp he isolated the prenylated version of cannbigerol—meaning CBG with a prenyl group attached. Prenylation entails the addition of a hydrophobic molecule to a protein or chemical compound, which may facilitate lipid binding to cell membranes.
There is no reason, Appendino said, that marijuana should not also produce the prenylated version of THC—which would have distinct biological activity.
Cannabinoids not unique to Cannabis
Cannabinoids are not unique to cannabis—they have been found in other plants. Appendino reported that a large amount of CBG and its carboxylic precursor (CBGA) had been isolated from a specific Helichrysum variety found only in South Africa.
Studying how Helichrysum makes “non-cannabis” CBG and its related compounds has been difficult for Appendino and his colleagues, because strict South African bio-piracy laws prohibit the collection and export of native species or their seeds. These laws, designed to prevent foreign corporate exploitation of the country’s unique genetic resources, also impede legitimate scientific research. After two years of bureaucratic red tape, Appendino was only able to obtain a small vial of extract from Helichrysum, and has not been able to obtain seeds of the plant to continue his research.
Appendino discovered that cannabinoid-like compounds are made by plants “apart from the normal cannabinoid biosynthetic route. There is a new pathway that starts from an aromatic acid.” Referred to as the “Helichrysum cannabinoids,” these compounds also have been detected in liverwort, a diuretic herb helpful for bronchitis and liver congestion, as well as gallbladder, kidney, and bladder problems.
Helichrysum is used in African ethno-pharmacology, Appendino explains, “like hemp, to make fumes in ritual ceremonies” and that a “psychotropic effect...similar to cannabinoids,” might ensue.
Appendino also discussed some of the therapeutic attributes of terpenoids, the largest class of naturally occurring compounds on the planet. Terpenoids, or terpenes, are the chemicals that give plants their unique smells and flavors. Found in high concentrations in many culinary herbs and spices, terpenes not only provide flavor and scent, they are also important signaling chemicals that plants use to communicate with insects.
Some plants up-regulate specific terpenes when attacked by herbivores to render the plant less palatable to the attacking insect. In a beautiful demonstration of the web that Mother Nature has created, these same terpenes have been shown to recruit parasitic bugs that themselves attack the herbivores which are eating the plant!
Present in black pepper, bitter leafy greens, Echinacea, and many cannabis strains, beta-caryophyllene is one of the terpenes that plants use to defend themselves against predators.
Terpenes are synthesized by the plant from five-carbon isoprene units, two of which come together in specialized cellular compartments to form the 10-carbon monoterpenes (limonene, pinene, linalool, terpinolene, et al). The 15-carbon sesquiterpenes, such as β-caryophyllene, differ from the monoterpenes by the incorporation of an extra isoprene unit. (β is the Greek letter beta.)
Monoterpenes are more volatile at lower temperatures, so when Cannabis is dried, stored for periods of time, or made into extracts, the monoterpenes are generally first to evaporate while the sesquiterpenes like β-caryophyllene are more likely to remain.
Appendino recounted how the wild, ancestral relative of corn, teosinte, grown by the Mayan and Incan farmers in pre-European Central and South America, produced significant amounts of β-caryophyllene before modern breeders selected towards high yielding corn with an increased sugar content. The drive to breed high-yielding varieties of corn for intensive commercial agriculture sacrificed the ability of the plant to produce β-caryophyllene .
At the 2007 ICRS meeting, Jürg Gertsch reported that β-caryophyllene binds specifically to the CB2 cannabinoid receptor, which regulates immune function and is found mainly outside the central nervous system.
Big Pharma has taken note of CB2’s role as an immune cell modulator. But the CB2 receptor has yet to be successfully exploited by the pharmaceutical industry, observed Appendino in 2014: “If drug discovery is a sea, then CB2 is a rock that is surrounded by shipwrecked-projects,” he commented poetically.
Pharmaceutical companies have spent large sums investigating proprietary synthetic CB2-selective compounds that end up showing little clinical efficacy. “But β-caryophyllene is a special lottery ticket,” said Appendino.
β-caryophyllene seems like the Cannabis plant’s own perfect key for nature’s CB2 lock. Appendino described how the β-caryophyllene molecule interacts with the CB2 receptor. It’s an unusual physical relationship for cannabinoid-type agonists. β-caryophyllene does not look like any other molecule that binds to the cannabinoid receptors.
Known to be anti-inflammatory and easy on the stomach lining, plant extracts high in β-caryophyllene have produced analgesic and anti-inflammatory effects in clinical trials. “Maybe the interaction of β-caryophyllene with CB2 is an echo of an ancient dialog between plants and insects,” Appendino mused.
Expanded-Definition Cannabinoids (EDCs)
Just as natural selection tinkers with compounds, so do scientists, hoping to find a useful modification that evolutionary pressure hasn’t induced nature to come up with. Research is underway into some of the unorthodox cannabinoids Appendino discussed.
Appendino’s expanded concept of cannabinoid drugs involves an expanded concept of the endocannabinoid system. In addition to CB1 and CB2, the biological targets of the EDCs include the GPR55 receptor; transcription factors in the mitochondria that switch genes on and off; and TRP (pronounced “trip”) receptors, which function as ion channels with gates that open and close to transmit signals. CBD, CBG, and other phytocannabinoids bind to various TRP receptors.
A Spanish biotech company called VivaCell has developed a drug, VCE-003, in which a quinol group has been attached to CBG. VCE-003 outperforms CBG in activating PPAR receptors, which are situated on the cell’s nucleus and regulate gene expression and metabolic function. VCE-003 has shown efficacy in studies using mouse models of Multiple Sclerosis and Encephalomyelitis.
Drugs like VCE-003 are known as “semi-synthetics.” Hydrocodone and buprenorphine, which have replaced codeine and morphine and most opioid analgesics now sold in the U.S., are well-known semi-synthetics.
The process by which a semi-synthetic drug is created can be patented, whereas a natural product cannot be patented. This raises the question of whether such drugs are in fact superior for medical reasons or for commercial purposes.