http://www.sciencenews.org/view/feature/id/59872/title/Not_just_a_high
Scientists test medicinal marijuana against MS, inflammation and cancer
By Nathan Seppa
June 19th, 2010
In science's struggle to keep up with life on the streets, smoking
cannabis for medical purposes stands as Exhibit A.
Medical use of cannabis has taken on momentum of its own, surging
ahead of scientists' ability to measure the drug's benefits. The pace
has been a little too quick for some, who see medicinal joints as a
punch line, a ruse to free up access to a recreational drug.
But while the medical marijuana movement has been generating
political news, some researchers have been quietly moving in new
directions testing cannabis and its derivatives against a host of
diseases. The scientific literature now brims with potential uses for
cannabis that extend beyond its well-known abilities to fend off
nausea and block pain in people with cancer and AIDS. Cannabis
derivatives may combat multiple sclerosis, Crohn's disease and other
inflammatory conditions, the new research finds. Cannabis may even
kill cancerous tumors.
Many in the scientific community are now keen to see if this
potential will be fulfilled, but they haven't always been.
Pharmacologist Roger Pertwee of the University of Aberdeen in
Scotland recalls attending scientific conferences 30 years ago, eager
to present his latest findings on the therapeutic effects of
cannabis. It was a hard sell.
"Our talks would be scheduled at the end of the day, and our posters
would be stuck in the corner somewhere," he says. "That's all changed."
Underlying biology
The long march to credibility for cannabis research has been built on
molecular biology. Smoking or otherwise consuming marijuana Latin
name Cannabis sativa has a medical history that dates back
thousands of years. But the euphoria-inducing component of cannabis,
delta-9-tetrahydrocannabinol, or THC, wasn't isolated until 1964, by
biochemist Raphael Mechoulam, then of the Weizmann Institute of
Science in Rehovot, Israel, and his colleagues. Within two decades,
other researchers had developed synthetic THC to use in pill form.
The secrets of how THC worked in the body lay hidden until the late
1980s, when researchers working with rats found that the compound
binds to a protein that pops up on the surface of nerve cells.
Further tests showed that THC also hooks up with another protein
found elsewhere in the body. These receptor proteins were dubbed CB1 and CB2.
A bigger revelation came in 1992: Mammals make their own compound
that binds to, and switches on, the CB1 receptor. Scientists named
the compound anandamide. Researchers soon found its counterpart that
binds mainly to the CB2 receptor, calling that one 2AG, for
2-arachidonyl glycerol. The body routinely makes these compounds,
called endocannabinoids, and sends them into action as needed.
"At that point, this became a very, very respectable field," says
Mechoulam, now at Hebrew University of Jerusalem, who along with
Pertwee and others reported the anandamide discovery in Science. "THC
just mimics the effects of these compounds in our bodies," Mechoulam
says. Although the receptors are abundant, anandamide and 2AG are
short-acting compounds, so their effects are fleeting.
In contrast, when a person consumes cannabis, a flood of THC
molecules bind to thousands of CB1 and CB2 receptors, with
longer-lasting effects. The binding triggers so many internal changes
that, decades after the receptors' discovery, scientists are still
sorting out the effects. From a biological standpoint, smoking pot to
get high is like starting up a semitruck just to listen to the radio.
There's a lot more going on.
Though the psychoactive effect of THC has slowed approval for
cannabis-based drugs, the high might also have brought on a
serendipitous discovery, says neurologist Ethan Russo, senior medical
adviser for GW Pharmaceuticals, which is based in Porton Down,
England. "How much longer would it have taken us to figure out the
endocannabinoid system if cannabis didn't happen to have these
unusual effects on human physiology?"
Beyond the pain
Today smoked cannabis is a sanctioned self-treatment for verifiable
medical conditions in 14 U.S. states, Canada, the Netherlands and
Israel, among other places. It usually requires a doctor's
recommendation and some paperwork.
People smoke the drug to alleviate pain, sleep easier and deal with
nausea, lack of appetite and mood disorders such as anxiety, stress
and depression. Patients not wanting to smoke cannabis can seek out
prescriptions for FDA-approved capsules containing cannabis compounds
for treatment of some of these same problems.
Research now suggests that multiple sclerosis could join the growing
list of cannabis-treated ailments. More than a dozen medical trials
in the past decade have shown that treatments containing THC (and
some that combine THC with another derivative called cannabidiol, or
CBD) not only ease pain in MS patients but also alleviate other
problems associated with the disease. MS results from damage to the
fatty sheaths that insulate nerves in the brain and spinal cord.
"MS patients get burning pain in the legs and muscle stiffness and
spasms that keep them awake at night," says John Zajicek, a
neurologist at the Peninsula College of Medicine and Dentistry in
Plymouth, England. Patients can take potent steroids and other
anti-inflammatory drugs, but the effects of these medications can be
inconsistent.
Pertwee has analyzed 17 trials in which MS patients received some
form of cannabis or its derivatives. Reports from the patients
themselves, who didn't know if they were getting real cannabinoids or
a placebo in most of the trials, show improvements in muscle
spasticity, sleep quality, shakiness, sense of well-being and
mobility. Pertwee, who is also a consultant for GW Pharmaceuticals
which makes a cannabinoid drug that is delivered in spray form,
called Sativex reviewed the findings in Molecular Neurobiology in 2007.
Sativex was approved in Canada for MS in 2005 after studies (some
included in Pertwee's analysis) showed its success in relieving
symptoms of the disease.
GW Pharmaceuticals expects clearance for MS treatment in the United
Kingdom and Spain this year. Later, the company plans to seek U.S.
approval of Sativex for cancer pain.
Zajicek's team has also compared MS patients who received a placebo
with patients receiving either a capsule containing THC or one with
THC and CBD. Both of the cannabis-based drugs outperformed a placebo,
and the researchers are now working on a multiyear MS trial.
Calming symptoms such as muscle spasticity and pain is useful,
Zajicek says, but the true value of cannabinoids may exceed that. "To
me, the really exciting stuff is whether these drugs have a much more
fundamental role in changing the course of MS over the longer term,"
he says. "We've got nothing that actually slows progression of the disease."
Fighting inflammation
CBD, the same cannabis component that proved beneficial alongside THC
for MS, may also work on other hard-to-treat diseases. Tests on cell
cultures and lab animals have revealed that CBD fights inflammation
and mitigates the psychoactive effects of THC.
Crohn's disease, which can lead to chronic pain, diarrhea and
ulcerations, could be a fitting target for CBD. In Crohn's disease,
inflammatory proteins damage the intestinal lining, causing leaks
that allow bacteria in the gut to spread where they shouldn't. This
spread leads to a vicious cycle that can trigger more inflammation.
Karen Wright, a pharmacologist at Lancaster University in England,
and her colleagues have found that CBD inhibits this inflammation and
can reverse the microscopic intestinal leakiness in lab tests of
human cells. Adding
THC doesn't seem to boost the benefit, Wright reported in December
2009 in London at a meeting of the British Pharmacological Society.
The results bolster earlier findings by Wright's team showing that
cannabinoids could improve wound healing in intestinal cells.
CBD's anti-inflammatory effect may work, at least in some cases,
through its antioxidant properties the ability to soak up highly
reactive molecules called free radicals, which cause cell damage.
In the brain and eye, CBD slows the action of microglia, immune cells
that can foster harmful inflammation when hyperactivated by free
radicals. Working with rats whose retinas were induced to have
inflammation, biochemist Gregory Liou of the Medical College of
Georgia in Augusta and his team found that CBD neutralized free
radicals, preventing eye damage. This finding could have implications
for people with diabetes who develop vision loss.
Apart from being an anti-inflammatory and antioxidant, CBD tones down
the psychoactive effect of THC without eliminating its medical
properties. CBD also mutes the occasional anxiety and even paranoia
that THC can induce. This has been welcome news to scientists, who
consider the "buzz" of cannabis little more than psychoactive baggage.
But CBD has paid a price for this anti-upper effect. "CBD has
essentially been bred out of North American black market drug
strains," Russo says. People growing cannabis for its recreational
qualities have preferred plants high in THC, so people lighting up
for medical purposes, whether to boost appetite in AIDS patients or
alleviate cancer pain, may be missing a valuable cannabis component.
Cannabis versus cancer
With or without CBD, cannabis may someday do more for cancer patients
than relieve pain and nausea. New research suggests THC may be lethal
to tumors themselves.
Biochemists Guillermo Velasco and Manuel Guzmán of Complutense
University in Madrid have spent more than a decade establishing in
lab-dish and animal tests that THC can kill cancer of the brain, skin
and pancreas.
THC ignites programmed suicide in some cancerous cells, the
researchers reported in 2009 in the Journal of Clinical
Investigation. The team's previous work showed that THC sabotages the
process by which a tumor hastily forms a netting of blood vessels to
nourish itself, and also keeps cancer cells from moving around.
THC achieves this wizardry by binding to protein receptors on a
cancerous cell's surface. Once attached, the THC induces the cell to
make a fatty substance called ceramide, which prompts the cell to
start devouring itself. "We see programmed cell death," Velasco says.
What's more, noncancerous cells don't make ceramide when they come
into contact with THC. The healthy cells don't die.
Many compounds kill cancer in a test tube and even in animals, but
most prove useless because they cause side effects or just don't work
in people. The Madrid team is now seeking funding to test whether
cannabis derivatives can kill tumors in cancer patients. In an early
trial of nine brain cancer patients whose disease had worsened
despite standard therapy, the scientists found that THC injections
into tumors were safe to give.
Early reports from other research groups suggest that THC also fights
breast cancer and leukemia. "I think the cancer research is extremely
promising," Russo says. "Heretofore, the model for cancer was to use
an agent that's extremely toxic to kill the cancer before it kills
you. With cannabinoids, we have an opportunity to use agents that are
selectively toxic to cancer cells."
Looking ahead
Testing of cannabis and its derivatives has also begun on type 1
diabetes, rheumatoid arthritis, stroke, Tourette syndrome, epilepsy,
depression, bipolar disorder and schizophrenia. Pertwee is
particularly optimistic that cannabis will help people with
post-traumatic stress disorder. Experiments in rats show that THC
"speeds up the rate at which the animals forget unpleasant
experiences," he says. And a recent study in people with PTSD showed
that THC capsules improved sleep and stopped nightmares.
Despite these heady beginnings, medical cannabis still faces an
uphill climb. Although some states have sanctioned its use, no smoked
substance has ever been formally approved as a medicine by U.S.
regulatory agencies. Smoking cannabis can lead to chronic coughing
and bronchitis, and smoking renders a drug off-limits for children,
Mechoulam notes.
THC pills don't have these downsides, but the drugs have received
only lukewarm acceptance. Despite smoking's drawbacks, "it is seen as
better because you can regulate the amount of THC you're getting by
not puffing as much," says pharmacologist Daniele Piomelli of the
University of California, Irvine. Capsules can cause dizziness and
make it hard to focus. "Patients suffering from neuropathic pain or
depression don't want to be stoned they want relief," he says.
Controlled, randomized trials that seek to clarify whether smoked
cannabis delivers on its medical promise with acceptable side
effects have been hard to come by. But scientists in California
have recently concluded several studies in which patients with severe
pain received actual cannabis cigarettes or cannabis cigarettes with
the cannabinoids removed.
In one trial, researchers randomly assigned 27 HIV patients to get
the real thing and 28 to get fake joints. All the patients had
neuropathic pain, in which neurons can overreact to even mild
stimuli. About half of the people getting real cannabis experienced a
pain reduction of 30 percent or greater, a standard benchmark in pain
measurement. Only one-quarter of volunteers getting the placebo
reported such a reduction.
"That's about as good [a reduction] as other drugs provide," says
Igor Grant, a neuropsychiatrist at the University of California, San
Diego, who is among the scientists overseeing the trials.
While such studies provide evidence that smoked marijuana has medical
benefits, future trials are more likely to explore the benefits of
cannabis derivatives that don't carry the baggage that smoking does.
Ultimately, the fate of medical cannabis and its derivatives will
rest on the same make-or-break requirements that every experimental
medicine faces whether it cures a disease or alleviates its
symptoms, and whether it's tolerable.
"We have to be careful that marijuana isn't seen as a panacea that
will help everybody," Grant says. "It probably has a niche.… We can't
ignore the fact that cannabis is a substance of abuse in some people."
Getting cannabis in
When most people think of medicinal cannabis, smoking comes to mind.
Though smoking works quickly and allows users to regulate their
intake, it's hardly a scientific approach: Cannabis quality is often
unknown, and inhaling burned materials is bad for the lungs. These
and other drawbacks have spawned new ways to consume medical marijuana.
Some people inhale cannabis by using a device that heats the plant
without igniting it. This vaporization unleashes many of the same
cannabinoid compounds as smoking does, without the combustion
by-products, researchers say. Anecdotally, patients report that the
effect is prompt, on a par with smoking.
Because cannabis derivatives can pass through the lining of the mouth
and throat, a company called GW Pharmaceuticals has devised a spray
product called Sativex. This drug contains roughly equal amounts of
two key cannabinoids THC and CBD plus other cannabis components
in an alcohol solution. A dose of Sativex is sprayed under the
tongue; no smoking required.
In the face of these options, the "pot pill" seems almost passé. But
capsules of synthetic THC exist. One called Marinol has been approved
in the United States since 1985, and another called Cesamet was
cleared more recently. Doctors can prescribe the drugs for nausea,
vomiting, loss of appetite and weight loss. Though sales of capsules
have increased recently, many users complain of psychoactive side
effects and slow action.
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