POSTED 2 JUN 2005
Cannabis: good reception
For many years, friends of marijuana argued that it had medical benefits, but the science was slippery -- when the government even permitted the research at all. In 1990, CB(1), the first cannabinoid receptor was discovered. Then endogenous cannabinoids -- body-made chemicals that activated the receptors -- were identified, and everything changed (see "Structure of a Cannabinoid ..." in the bibliography).
Photo: US Dept of Justice
The second cannabinoid receptor, CB(2), was found in 1993. While CB(2) resides mainly in the immune system, CB(1) is largely a nervous Nellie -- living on nerve cells. Roger Pertwee, a cannabis expert at the University of Aberdeen, says the receptor is "distributed widely throughout the central nervous system and the peripheral nervous system... They are present in their greatest concentration around the hippocampus, cortex, olfactory areas, basal ganglia, cerebellum and spinal cord. This pattern accounts for the effects of cannabinoids on memory, emotion, cognition and movement" (see "Pharmacological Actions..." in the bibliography).
Eyes have it
CB(1)s are also found in the eye, of all places. In 2001, researchers at the University of Arizona found the receptor and anandamide, the most-studied endogenous cannabinoid, in structures that control eye pressure (see "Cannabinoid CB(1) Receptor Expression..." in the bibliography). The researchers said that the signaling system explains why marijuana compounds can reduce eye pressure, and suggest that marijuana derivatives could reduce eye pressure and perhaps treat the blinding disease glaucoma which high pressure causes.
Dense groups of CB(1) receptors also appear in the light-sensing retinal cells of monkeys, mice, rats, chickens, goldfish and salamanders. When the cannabinoid receptor was activated, it changed the electrical activity of retinal cells, suggesting, according to the study authors, "a substantive role for an endogenous cannabinoid signaling system in retinal physiology, and perhaps vision in general" (see "Cannabinoid CB1 Receptors and Ligands..." in the bibliography).
Cannabinoid receptors occur on nerves that detect pain, where they may even outnumber the opiate receptors. That could explain rodent experiments that show that cannabinoids can increase the pain-killing activity of opiates (see "Pharmacological Actions..." in the bibliography.)
Another surprising location for anandamide and the CB(1) receptor is the male and female reproductive tract. Herbert Schuel, a professor of anatomy and cell biology at the State University at Buffalo, discovered that the system regulates changes in sperm activity just before fertilization. At low anandamide concentrations, sperm swim more vigorously; when the concentration rises, they slow down. This variable response, Schuel says, enables the reproductive tract in both sexes to turn sperm on and off to meet changing situations: "When human sperm are swimming up from the vagina, through the uterus, into the first portion of the oviduct, they seem to be held there for a period of time, and some are gradually released to swim upstream to where the egg is going to be."
Anandamide also plays a role in the sperms' second challenge: penetrating the egg's external protein coat. In mammalian and human sperm, a tiny structure on the sperm head releases enzymes that help the sperm enter the egg. In the sea urchin, an animal often used to study reproduction, Schuel said, "that process was blocked by anandamide, as well as by THC, the substance responsible for the high produced by marijuana smoke."
Overall, Schuel says, anandamide seems to play a major role in the timing and sequence of reproduction. "We have this very finely tuned series of exchanges of chemical signals between eggs and sperm in sea urchins that regulates the process of fertilization, and in humans we have evidence that anandamide produced by cells that line the male and female reproductive tract regulates sperm functions required for fertilization."
No hurling allowed
One of the surest medical uses for marijuana compounds is for controlling nausea and vomiting after cancer chemotherapy. Typical chemo drugs kill fast-dividing cells in the gut, leading to the release of signaling compounds that can cause nausea and vomiting. During the 1960s, says Nissar Darmani, chair of basic medical sciences at Western University of Health Sciences, hippies noticed that smoking grass would reduce this nasty side effect of chemo, and a synthetic medicine called dronabinol that entered the market in 1985 contains delta 9-THC, one of marijuana's many active ingredients.
The discovery of the first cannabinoid receptor in 1990 was a key to proving that marijuana compounds reduce the urge to purge. When Darmani and colleagues gave cisplatin, a chemotherapy drug, to a lab animal called the least shrew, they found that cannabinoid compounds such as delta 9-THC would activate the CB(1) receptor and reduce vomiting (see "Delta 9-THC Differentially..." and "Cannabinoids Inhibit Emesis..." in the bibliography).
Chemotherapy can cause two phases of vomiting, and the drugs used for reducing retching are less effective against the second phase, which starts 24 hours after chemotherapy, Darmani says. In May, the maker of dronabinol announced a new study showing that it could enhance the effectiveness of standard anti-nausea medicines, suggesting that delta 9-THC could combine with existing drugs to control second-phase vomiting.
Delta-9 THC could also -- and we're deep in speculative territory now -- be used to kill cancer cells. Manuel Guzman, an associate professor of biochemistry and molecular biology at Madrid Complutense University (Spain), has begun a clinical trial of the cannabis compound against glioblastoma, a difficult-to-treat brain cancer. The rationale for the trial, he wrote, is the observation that, in the laboratory, delta-9 THC is toxic to tumor cells but not normal cells.
How did it start?
We do not deny that cannabis chemicals are illegal, and even aside from incarceration, they have other ill effects: reducing body temperature, interfering with movement or memory, and causing addiction or anxiety. But better knowledge of the pharmacology of cannabinoids may lead to compounds that maximize the positive effects while minimizing the negative ones.
We predict you will hear more about cannabinoid receptors, if only because they are so common. CB(1) is "one of the densest receptors in the brain, even including neurotransmitter receptors such as dopamine and serotonin," says Darmani. "CB(1) is found practically everywhere in nerve terminals, where it controls the release of other neurotransmitters."
Can we make sense of the opiate and cannabis receptors?
Megan Anderson, project assistant; Terry Devitt, editor; S.V. Medaris, designer/illustrator; David Tenenbaum, feature writer; Amy Toburen, content development executive