Autumn 2005
O'Shaughnessy's
Journal of the California Cannabis Research Medical
Group
|
Smoking Cannabis Does Not Cause
Cancer Of Lung or Upper Airways, Tashkin FInds; Data Suggests Possible
Protective Effect
By Fred Gardner
Marijuana smoking —“even heavy longterm use”— does
not cause cancer of the lung, upper airways, or esophagus, Donald Tashkin,
MD, reported at this year’s meeting of the International
Cannabinoid Research Society.
Coming from Tashkin, this conclusion had extra significance
for the assembled drug-company and university-based scientists (most
of whom
get funding from the U.S. National Institute on Drug Abuse).
Over the years, Tashkin’s lab at UCLA has produced irrefutable
evidence of the damage that marijuana smoke wreaks on bronchial
tissue.
With NIDA’s support, Tashkin and colleagues have
identified the potent carcinogens in marijuana smoke, biopsied and
made
photomicrographs of pre-malignant cells, and studied the molecular
changes occurring
within them.
It is Tashkin’s research that the Drug Czar’s
office cites in ads linking marijuana to lung cancer. Tashkin himself
has long believed
in a causal relationship, despite a study in which Stephen
Sidney, MD, examined the files of some 64,000 Kaiser patients and
found
that marijuana users did not develop lung cancer at a higher
rate or die
earlier than non-users.
Of five smaller studies on the question, only two —involving
a total of about 300 patients— concluded that marijuana
smoking causes lung cancer.
Tashkin decided to settle the question by conducting
a large, population-based, case-controlled study. “Our major hypothesis,” he told
the ICRS, “was that heavy, longterm use of marijuana
will increase the risk of lung and upper-airways cancers.”
The Los Angeles County Cancer Surveillance program provided
Tashkin’s
team with the names of 1,209 L.A. residents aged 59 or younger
with cancer (611 lung, 403 oral/pharyngeal, 90 laryngeal,
108 esophageal).
Interviewers collected extensive lifetime histories of
marijuana, tobacco, alcohol and other drug use, and data on diet, occupational
exposures,
family history of cancer, and various “socio-demographic
factors.”
Exposure to marijuana was measured in “joint years” —average
number of joints per day x years that number smoked. Thus if a person
had smoked two joints a day for 15 years they’d have
consumed for 30 j-yrs.
Controls were found based on age, gender and neighborhood.
Among them, 46% had never used marijuana, 31% had used for
less than one joint
year, 12% had used for 1-10 j-yrs, 5% had used 10-30 j-yrs,
2% had used for 30-60 j-yrs, and 3% had used for more than
60 j-yrs.
Tashkin controlled for tobacco use and calculated the
relative risk of marijuana use resulting in lung and upper airways
cancers. A relative
risk ratio of .72 means that for every 100 non-users who
get lung cancer, only 72 people who smoke get lung cancer.
All
the odds
ratios in Tashkin’s
study turned out to be less than one!
Compared with subjects who had used less than one joint year,
the estimated odds ratios for lung cancer were .78 for 1-10
j-yrs [according to the
abstract book and .66 according to notes from the talk];
.74 for 10-30 j-yrs; .85 for 30-60 j-yrs; and 0.81 for more
than
60 j-yrs.
The estimated odds ratios for oral/pharyngeal cancers
were 0.92 for 1-10 j-yrs; 0.89 for 10-30 j-yrs; 0.81 for 30-60
j-yrs; and
1.0 for
more than 60 j-yrs. “Similar, though less precise results were
obtained for the other cancer sites,” Tashkin reported. “We
found absolutely no suggestion of a dose response.”
The data on tobacco use, as expected, revealed “a very potent effect and
a clear dose-response relationship —a 21-fold greater risk of developing
lung cancer if you smoke more than two packs a day.” Similarly high odds
obtained for oral/pharyngeal cancer, laryngeal cancer and esophageal cancer. “So,
in summary” Tashkin concluded, “we failed to observe
a positive association of marijuana use and other potential confounders.”
There was time for only one question, said the moderator,
and San Francisco oncologist Donald Abrams, M.D., was already at the
microphone: “You don’t see
any positive correlation, but in at least one category, it almost looked like
there was a negative correlation, i.e., a protective effect. Could you comment
on that?” (Abrams was referring to Tash-kin’s lung-cancer
data for marijuana-only smokers, 1-10 j-yrs.)
“
Yes,” said Tashkin. “The odds ratios are less than
one almost consistently, and in one category that relationship
was significant,
but I think that it
would be difficult to extract from these data the conclusion that
marijuana is protective
against lung cancer. But that is not an unreasonable hypothesis.”
Abrams’s Favorable Results
Abrams had results of his own to report at the ICRS meeting. He
and his colleagues at San Francisco General Hospital had conducted
a
randomized, placebo-controlled
study involving 50 patients with HIV-related peripheral neuropathy.
Over
the course of five days, patients recorded their pain levels in
a diary after smoking
either NIDA-supplied marijuana cigarettes or cigarettes from which
the THC had been extracted. About 25% didn’t know or guessed
wrong as to whether they were smoking the placebos, which suggests
that the
blinding
worked.
Abrams’s results show marijuana providing pain
relief comparable to Gaba-pentin, the most widely used treatment for
a condition
that afflicts some 30% of patients
with HIV.
After Abrams’s presentation, a questioner bemoaned the difficulty of “separating
the high from the clinical benefits.” Abrams responded: “I’m
an oncologist as well as an AIDS doctor and I don’t think that a drug that
creates euphoria in patients with terminal diseases is having an adverse effect.” His
study was funded by the University of California’s Center
for Medicinal Cannabis Research.
Add ICRS Notes
The 15th annual meeting of the ICRS was held at the Clearwater, Florida,
Hilton, June 24-27. Almost 300 scientists attended. R. Stephen Ellis,
MD, of San Francisco, was the sole clinician from California. Medical
student Sunil Aggarwal, Farmacy operator Mike Ommaha and therapist/cultivator
Pat Humphrey audited the proceedings.
Some of the younger European scientists expressed consternation over
the recent U.S. Supreme Court ruling and the vote in Congress re-enforcing
the cannabis prohibition. “How can they dispute that it has medical
effect?” an investigator working in Germany asked us earnestly.
She had come to give a talk on “the role of different neuronal
populations in the pharmacological actions of delta-9 THC.”
For most ICRS members, the holy grail is a legal synthetic drug that
exerts the medicinal effects of the prohibited herb. To this end
they study the mechanism
of action by which the body’s own cannabinoids are assembled, function,
and get broken down. A drug that encourages production or delays dissolution,
they figure, might achieve the desired effect without being subject to “abuse.”
News on the scientific front included the likely identification of a third
cannabinoid receptor expressed in tissues of the lung, brain, kidney, spleen
and smaller branches of the mesenteric artery. Investigators from GlaxoSmith-Kline
and AstraZeneca both reported finding the new receptor but had different versions
of its pharmacology. It may have a role in regulating blood pressure.
Several talks and posters described the safety and efficacy of Sativex,
G.W. Pharmaceuticals’ plant extract containing high levels of THC and cannabidiol
(CBD) formulated to spray in the mouth. See “Dr. X’s Top Talks,” on
page 11.
G.W. director Geoffrey Guy seemed upbeat despite the slide his company’s
stock took this spring when UK regulators withheld permission to
market Sati-vex pending another clinical trial. Canada recently granted
approval
for doctors
to prescribe Sativex, and five sales reps from Bayer (to whom G.W.
sold Canadian marketing rights) are promoting it to neurologists.
Sativex was approved
for treatment of neuropathic pain in multiple sclerosis, but can
be prescribed
for other purposes as doctors see fit.
Most of the work being done with CBD and CBN is done with materials provided
by GW, and some two dozen papers and posters gave them acknowledgment. At last
there is a realistic alternative to NIDA for the young researchers to look
to for support (and plant cannabinoids to study). GW has contributed to a significant
shift in attitude.
On numerous occasions during the meeting a NIDA-funded researcher would describe
the negative effects of THC, and immediately a scientist with a British accent
would be at the mike pointing out that such a high dose injected into the stomach
of a rat had nothing to do with the human experience with cannabis. It must
have happened five or six times. The Brits were always very diplomatic, but
they functioned like a truth squad.
Roger Pertwee of the University of Aberdeen reported intriguing results from
experiments using a cannabis strain bred by GW to be high in THCV (tetrohydrocannabivarin).
It turns out that THCV strongly antagonizes anandamide while hardly
antagonizing THC! It’s as if the cannabis plant contains
and makes available to the body a choice of drugs and the body
uses those
it needs to achieve
a balanced
state (homeostasis). If the body is producing endocannabinoids
in excess, it can use the plant cannabinoid THCV to achieve homeostasis.
If the
endocannabinoid
system needs a boost, the THC provides it (while the THCV shuts
down
the EC
system, giving it a rest as it were). The key to relief, apparently,
is not high cannabinoid levels but proper gradients.
Guy explained, “It’s as if the plant contains a first-aid kit giving
the body everything it needs to get bettter, and the body decides which components
to employ... The endocannibnoid system begins to kick in in abnormality, in
pathology. Perhaps it kicks in whether the pathology is an increase in something
or a decrease in something. What it’s trying to do is get
whatever that abnormality is back to homeostasis.
“
The antagonist may be working to restore function back to the center, and the
agonist might be working to restore function back to the center, and once they’ve
achieved the norm, they don’t go any further. The endocannabinoid system
is the supeme modulator. Its job is done once you’re back to the norm.
Most endocannabinoid modulators simply won’t drive the physiology or
biochemistry —whatever they’re controlling— past
the norm to a detrimental effect.”
Rimonabant Comes Closer
Which might explain the apparent benignity of Rimonabant, a drug that
works by blocking the CB1 receptor system. Rimonabant is being tested
by Sanofi-Aventis for weight loss and smoking cessation. Originally
known as SR-141716, it was developed in the early 1990s as an antagonist
drug for use by researchers. At the 2004 ICRS meeting, Sanofi researchers
described favorable results from clinical trials of Rimonabant as
a diet drug. They informally predicted regulatory approval in Europe
and the U.S. within a year. Some observers warned that blocking the
CB1 receptor system could result in unforeseen longterm side effects
and noted that at least one MS patient had experienced an exacerbation
after taking Rimonabant.
Although regulatory approval has not yet
been granted, Sanofi reported good news at this meeting regarding
side-effects: no more MS cases in a smoking-cessation study study
involving more than 1,000 patients worldwide. “Both the 5mg
and 20mg doses continued to show efficacy in the maintenance of abstinence
from smoking,” reported Gerard Le Fur. “The 20mg dose
also demonstrated efficacy in the reduction of weight gain as well
as significantly increasing the HDL-Cholesterol levels.”
A Sanofi team also reported favorable results from studies using
Rimonabant to treat various rodent models of “metabolic syndrome” —obesity-related
high blood pressure, high insulin levels, excessive triglycerides and “bad” cholesterol
and other problems increasing the risk of diabetes, heart attack and
stroke. There is growing acceptance of the notion that the body can
adjust to even a heavy blockade of the CB1 system. Perhaps when the
CB1 receptor is blocked, the endocannabinoids are redirected to other
targets. At times the layman is struck by how rudimentary the biochemists’ understanding
of the body’s mechanism of action really is.
“
We’re on plateau one or two and the answer is on plateau 12,” said
Guy. “ We could spend the next 30 years on receptors and still
not fully understand them. When we talk about receptors and agonists
and antagonists we should be talking in the same breath about functionality —real
functionality, not models in non-pathological situations. We need
an understanding of the clinical outcome.”
Osteopathic Manipulation Boosts Endocannabinoid
System
John McPartland of GW Pharmaceuticals reported that osteopathic manipulative
treatment (OMT) works via the endocannabinoid system. McPartland and
co-workers conducted a randomized, placebo-controlled study involving
31 patients of a New Zealand osteopath.
“
Cannabimimetic effects” were measured by patients filling
out a questionnaire before and after treatment defining levels
of light-headedness,
hunger, alterness, etc. Anandamide levels in the blood were also
measured before and after treatments.
The “sham” manipulation mimicked a new technique called “biodynamic
osteopathy in the cranial field.” The sham practitioner sabotaged her
own concentration and mental healing intention by silently reciting “backwards
serial sevens” while she applied light manual contact to the patient’s
head.
Subjects receiving OMT indeed reported feeling cannabi-mimetic effects (more
creativity, less coherence, for example) and their serum anandamide levels
increased 168% over pre-treatment levels. Subjects receiving sham manipulation
reported no changes in the questionnaire and there was no change in their serum
anandamide levels.
McPartland et al noted that patients receiving OMT often experience
an improved sense of well-being, sedation and euphoria —effects
similar to those brought on by cannabis consumption. Previous studies
indicated
these psychotropic
effects are not elicited by endorphins (as once had been assumed).
A recent study by Andrea Giuffrida, who contributed to the OMT
study, showed that “runner’s high” correlated
with elevated anandamide and not endorphins. Patients receiving
chiropractic, massage,
acupuncture,
and energy healing also experience parallel psychotropic effects.
The authors conclude that the endocannabinoid system may be mediating
a
widespread but heretofore unrecognized therapeutic phenomenon.