Cannabinoids is the term given to the group of compounds found in the resin of cannabis plants. Unlike sesquiterpenoids, which are built from three isoprene units, cannabinoids are biosynthesized from only two activated building blocks, and the ensuing 10-carbon intermediate is then fused with a phenolic compound known as olivetolic acid. In Padma’s time, as reflected in the content of his thesis, it was believed that mevalonic acid was the activated isoprene unit for biosynthesis. It’s now known to be isopentenyl pyrophosphate. Marijuana’s active molecules surprised early investigators because, unlike psychoactive drugs in other plants, those of cannabis are not alkaloids.
Later in the fall, one of my friends, Mike, suddenly took an interest in our lab and asked for a tour. I let him in, showed him around, but he was not exactly captivated by a demonstration of the rotary evaporator. He wanted to know how to turn on an electronic balance, and when I did it for him, he unwrapped some aluminum foil around a big brown lump to verify if his supplier had given him his money’s worth. A characteristic, spicy odor came through the wrapping.
The lump was hashish, a mixture of cannabis trichomes and other plant material. Also found in many other plants, trichomes are hairs that often produce characteristic compounds. For instance, tomato leaf trichomes produce sesquiterpenes; mint and basil ones secrete their characteristicsweet-smelling oils and the antimalarial drug artemisinin, another sesquiterpene, comes from the trichome glands of the Chinese herb sweet wormwood.
In Cannabis, trichomes are found mostly on flower buds but also on various other mature plant parts. As revealed in the images some trichomes are non-productive; the bulbous ones contain annabinoids-secreting glands. There’s a positive correlation between the total number of glands per leaf as compared and the total cannabinoid content of the leaf. At their densest, leaf trichomes, however, produce, at best, only one fourth of the cannabinoids made by those of female flowers.
The presence of an illicit drug in the lab made me pretty nervous, especially in that quantity. I made sure nobody was peering through the glass in the door to our lab, and I told Mike he should leave before he got me kicked out of college. Not yet stoned—his eyes did not have tht common, glazed look—he had a smile suggesting that contrary to my concerns, nothing could possibly go wrong.
Our university was probably where Mike, a non-college student, purchased his stash. One day, in that same year, I was in the hallway, reading on a black couch, when someone walked up to me. Without a book or back pack, he had one of those four o’clock shadows at 11 in the morning, a thick accent, and a couple of look-alikes behind him. He asked me to move over. I obliged. Unknowingly, I had been sitting on a slit of the couch’s fake leather. He slid his hand into it, and from underneath the yellow-brown foam, he pulled out a lump surrounded by foil, much like the one my friend had weighed.
The sneaky behavior and waste of energy is in part due to irrational marijuana laws. In addition, they create tedious paperwork and funding obstacles for motivated researchers who hope to learn more about the medicinal potential of cannabis. In 1838, when it was legal, William B. O’Shaughnessy found clinical evidence for some of the Far Eastern medicinal folk use of marijuana. More recently, in 2009, one of the non-psychoactive ingredients, cannabidiol(CBD), proved to be affective against colitis in mice. For events in between the following outline from a review paper by Vincenzo Di Marzo highlights the most important developments.
The author points out that the British have made the most contributions (highlighted in blue) to the field. The 1980s medicines Marinol and Cesamet , based on cannabinoids, are still used to treat nausea and weight-loss in patients with cancer and AIDS. But some marijuana smokers feel that the plant itself is more effective than the use of isolated compounds. In the next decade, two receptors for cannabinoids were found in humans and other mammals along with two animal compounds(annadamide and 2-4G) that interact with those receptors. The compounds’ molecules have “tails” that are identical to those of tetrahydrocannabinol (THC), cannabis’ psychoactive ingredient. This so-called endocannabinoid research has led to the development of the drugs Sativex and Rimonabant. Sativex is a mouth spray used for symptomatic relief of neuropathic pain in people with multiple sclerosis. The active ingredients are THC and the mouse-colitis-reliever CBD. The appetite suppressant, Rimonabant, did not enjoy the same success, and in 2009 was withdrawn from the market.
New drugs were not the only fruits of endocannabinoid investigations. They led to the elucidation of the previously unknown mechanism of retrograde signalling. If a neuron simultaneously receives different neurotransmitters(GABA and glutamate, specifically) from different presynaptic neurons, it will not fire. But if the postsynaptic neuron releases the cannabinoid 2-4G, it will interact with a cannabinoid receptor on the presynaptic neuron and prevent the release of GABA. The postsynaptic neuron will then be able to signal the next cell.
It is unfortunate that in the public imagination, such intriguing findings are clouded by an atmosphere of information that either exclusively focuses on the unscientific rationalization of existing laws or on the exaggerated claims about what it can cure.
- Francesca Borrelli and al. Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis .J Mol Med (2009) 87:1111–1121 (entire article; free of charge)
- Monika Fellermeier , Wolfgang Eisenreich , Adelbert Bacher and Meinhart H. Zenk. Biosynthesis of Cannabinoids Incorporation Experiments with 13C-labeled glucoses. Eur. J. Biochem. 268, 1596±1604 (2001) (entire article; free of charge)
- Anthony L. Schilmiller and al. Studies of a Biochemical Factory: Tomato Trichome Deep Expressed Sequence Tag Sequencing and Proteomics. Plant Physiology July 2010 vol. 153 no. 3 1212-1223 (entire article; free of charge)
- Di Marzo V. A brief history of cannabinoid and endocannabinoid pharmacology as inspired by the work of British scientists. Trends Pharmacol Sci. 2006 Mar;27(3):134-40. Epub 2006 Feb 13.(entire article; free of charge)
- Nicoll and Bradley. The Brain’s Own Marijuana. Scientific American. December 2004 (entire article; free of charge)
- Turner JC, Hemphill JK, Mahlberg PG. Interrelationships of glandular trichomes and cannabinoid content. II. Developing vegetative leaves of Cannabis sativa L. (Cannabaceae).Bull Narc. 1981;33(3):63-71.
- Newsweek How procedural and legal restrictions make studying the effects of medical marijuana difficult. Nov 3, 2010