Molecule of the Year: Cannabiodiol

Via NY Transfer News Collective * All the News that Doesn't Fit

Counterpunch - Dec 22, 2007

http://www.counterpunch.org/gardner12222007.html

Pot Shots

Molecule of the Year: Cannabiodiol

By Fred Gardner

THC -delta-9 tetrahydrocannabinol- is not the only active
ingredient in cannabis. At least five other cannabinoids
exhibit biological activity, and so do some terpenes and
flavonoids. All these compounds are found in the resin
stored in the plant's glandular trichomes. They are
chemically related.

THC predominates in plants bred for psychoactivity (as
cannabis plants have been bred for generations in
California and elsewhere). Cannabidiol -CBD- is the
predominant cannabinoid in plants typically bred for fiber.
There are only trace quantities of CBD in high-THC plants
because one form of the same gene codes for THC synthase
and the other codes for CBD synthase. Thus growers
selecting for high THC content get low CBD.

California growers hoping to develop plants with a high
CBD-to-THC ratio have been stymied by lack of access to an
analytical test lab. In surreptitious tests, "high grade"
buds were reportedly in the range of 15-20%% THC and 0.1%%
CBD.

The U.S. Drug Enforcement Administration has placed CBD on
Schedule I even though CBD has no known adverse effects and
doesn't induce "euphoria." The most dire effects attributed
to marijuana -tachycardia (accelerated heartbeat), panic,
confusion, anxiety, even psychosis- are effects of THC that
CBD has been shown to mitigate!

By listing CBD as a Schedule 1 substance and denying
growers the means to develop high-CBD plant strains, the
government is protecting the American people from an
immunomodulator with anti-inflammatory, anti-convulsant,
anti-psychotic, anti-oxidant, and neuro-protective
properties. In whose interests could that possibly be?

BF Mechoulam on CBD END BF

The chemist who worked out the precise structure of CBD 45
years ago, Raphael Mechoulam, gave a "review talk" at this
year's meeting of the International Association for
Cannabis as Medicine. Mechoulam had just gotten his PhD in
chemistry in the Fall of '62 and was looking for a research
project that might lead to tenure at the Weizmann
Institute. He chose to analyze the components of cannabis,
he said, thinking "it's a minor project, it will be
finished off in six months."

Hashish of Lebanese origin was obtained from the police -
"There is a fantastic collaboration between Arabs and Jews
in smuggling," Mechoulam observed- and a dozen constituents
were then identified by two types of chromatography. (Some
cannabis constituents had been identified previously,
including CBD, which Roger Adams of the University of
Illinois isolated in the early 1940s.)

It was generally assumed throughout the '60s and '70s that
the cannabinoids exerted effects not by binding to a
specific receptor but "nonspecifically" by altering the
lipid structure of cellular membranes. Mechoulam
established that the action was specific by purifying THC
and showing that only the natural version of the molecule -
and not its synthetic mirror image- was exerting the
effect. In 1988 Alynn Howlett found that THC was indeed
activating a receptor. It was dubbed "CB1" and was found in
those areas of the brain involved in movement, stress,
cognitive function - "everywhere it would be expected,"
said Mechoulam, given what was known about the effects of
cannabis on people.

Unlike THC, CBD hardly binds to the CB1 receptor. It binds
to a second cannabinoid receptor -CB2-originally found in
spleen cells by S. Munro of Cambridge University in 1993
and subsequently found in the stomach, liver, heart,
kidney, lymph and immune cells, bones, endocrine glands,
and throughout the peripheral nervous system.

In his IACM talk Mechoulam reviewed research in recent
years that has shed light on aspects of CBD's mechanism of
action. Its lipid-solubility enables it to get into places
in the brain that conventional neurotransmitters cannot
reach. It is a potent anti-oxidative agent. It turns out to
be an antagonist to a recently discovered receptor called
GPR-55 to which THC and 2-AG bind as agonists. It blocks
the uptake of adenosine, an inhibitory neurotransmitter
that may promote sleep. It blocks the formation of various
cytokines (signaling compounds not released by nerves or
glands) under certain circumstances. It activates the
serotonin receptors. No wonder, then, that CBD plays a role
in many clinical conditions.

Conditions treatable by CBD

Mechoulam described an experiment led by Paul Consroe and
colleagues in Brazil in which CBD was tested as a treatment
for intractable epilepsy. Patients stayed on the
anticonvulsants they had been on (which hadn't eliminated
their seizures) and added 200mg/day of CBD or a placebo. Of
the seven patients getting CBD over the course of several
months, only one showed no improvement; three became
seizure-free; one experienced only one or two seizures,
Mechoulam recalled; and two experienced reduced severity
and occurrence of seizures.

"So it seemed a very promising approach," said Mechoulam,
"but unfortunately, nothing has been done ever since. To
the best of my knowledge, nobody has done any work on
cannabidiol in the clinic on epilepsy, and I wonder why."

A colleague of Mechoulam's, Marc Feldman at Imperial
College, London, tested CBD on mice who had a version of
rheumatoid arthritis and found that it reduced inflammation
by almost 50%% at the right dose -5mg/kg of body weight. But
this "beautiful antiinflammatory reaction was lost if we
went up to, say, 25 mg/kg," Mechoulam said. Drug developers
must bear in mind and cope with the fact that cannabinoids
have a finite "therapeutic window" -they are ineffective at
low and high doses.

Mechoulam has been testing CBD on mice bred to have a
version of type-1 diabetes that manifests around age 14
weeks. He and his co-workers treated these mice with CBD
for their first 6-7 weeks of life, then tested them 6-7
weeks later and found that only 30%% had developed diabetes
(compared to 90-100%% given placebo).

In a follow-up experiment the mice weren't given a course
of CBD until age 14 weeks, when they were developing
diabetes. They were then tested at age 24 weeks, and again
only 30%% of the treated mice were found to have diabetes.
In other words, CBD did not just prevent onset but blocked
development of diabetes.

Examination of the insulin-producing islets showed that
only 8%% were intact in the untreated diabetic mice, whereas
77%% were intact in the mice treated with CBD. "I believe
that here we have something very promising," Mechoulam
said. "We plan to have a clinical trial starting next week
treating patients, and hopefully at the next meeting I will
tell you that all of them are cured."

Cardiologists working with mice at Hebrew University have
found that CBD treatment at the time of a heart attack can
reduce infarct size by about 66%%. "So now they're pushing
me, 'let's have more CBD,'" Mechoulam said. "We should try
it with humans in a few years."

He went on: "What about sleep? I'm jumping from thing to
thing to show you that CBD does quite a lot of things and
I'm not sure that all of them are according to the same
mechanism." Mechoulam was part of a group led by Eric
Murillo-Rodriguez that administered CBD to rats and
determined that while THC caused sleepiness, CBD increased
wakefulness and significantly decreased REM sleep.
According to Mechoulam, "When one says 'cannabis causes
sleep,' one should think really of two compounds, one that
causes sleep and one that causes awakening."

The anti-nausea and memory extinction effects of CBD "seem
to be closely related," Mechoulam said. He described the
problem of anticipatory nausea, for which no good drugs are
available. (The effects of chemotherapy can be so
nauseating that patients start vomiting when they see the
doctor or nurse who is going to administer the treatment.)
Linda Parker at the University of Guelph conditioned shrews
to start vomiting by administering lithium fluoride at a
certain location. When the shrews were subsequently placed
in that location they began vomiting. But if given CBD,
they could be moved to the dreaded location without
vomiting. "The conditioned-wretching reaction was
completely abolished," Mechoulam declared. [THC is anti-
emetic, too; the advantage of CBD in this instance may be
legal rather than medical.]

Mechoulam is hopeful that CBD can help tone down other
kinds of conditioning. He described an experiment in which
rats had a choice of two paths, one leading to cocaine, one
to no reward. Rats like cocaine (and amphetamine) and will
learn to choose the path leading to it. But if injected
with CBD, they no longer show a preference for cocaine!
Mechoulam characterized post-traumatic stress disorder,
certain phobias and forms of chronic pain as "human
situations which are conditioned" and might be amenable to
treatment with CBD. "I know that many patients with PTSD
take cannabis, self administered," Mechoulam said. He has
been trying to interest the Israeli Ministry of Health in
testing CBD and THC at various ratios to treat PTSD.

[Fred Gardner can be reached at fred@plebesite ]

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