MARIJUANA REALLY MIGHT MAKE YOU COOL

Marijuana use may confer health benefits by lowering overall body
temperature, according to Tod Mikuriya, MD. It has been observed by his
office staff -and confirmed anecdotally by colleagues-that people seeking
physician approval to medicate with cannabis usually register body
temperatures markedly below 98.6. Just as lower calorie consumption is
associated with greater longevity, lower temperature could confer an
advantage by slowing down metabolism! (Sometimes "great ideas" are simple
and obvious. All history is the story of class struggle. In addition to our
conscious thoughts we have unconscious thoughts that can be glimpsed in
dreams...) Mikuriya writes in the new O'Shaughnessy's:

Hypothermia in the mouse is one of the "classic tetrad" of symptoms
indicating activation of the cannabinoid system. The genesis of hypothermia
requires further study. The Indian Hemp Drugs Commission observed that one
of the reputed benefits was to help laborers tolerate the heat. Cannabis
was described as used to cool the passions -in contrast with alcohol, which
heated them.

Clinically, cannabis appears to actually lower temperature and a couple of
patients have described a sense of cold with transient shivering. The
question could be answered readily by comparing temperatures of persons who
have THC metabolites in their urine and people who don't. If there turns
out to be a significantly lower temperature in the cannabis-using
population, one might posit a slower metabolic rate which, over time, might
have implications for longevity. Temperature has a significant effect on
metabolic rate. We have to understand the mechanism of hypothermogenesis.

If there is a hypothermia, what influence is there on the HPA (Hypothalamus
Pituitary Adrenal networks) and all of the interactions affecting levels of
circulating cortisol and epinephrine, etc.? With management of diabetes,
cannabis decreases blood sugar by diminishing gluconeogenesis, which plays
out in decreased insulin requirement and improved stability.

This hypothermogenic effect appears to be dose-related and could contribute
to a neuroprotective effect after trauma. The optimum delivery method will
require study. Hopefully, we will see a vaporizer on ambulances for
treatment of head injury and seizures, and at the bedside of pre- and
post-neurosurgery patients.

In addition to external cooling, cannabis quiets the irritable CNS. A
combination of inhaled and oral cannabis would be appropriate for acute CNS
trauma from internal or external etiology. I predict this will become
accepted and mainstream in the future.

Raphael Mechoulam's lab published a paper in 2003 showing that hypothermia
appears to be an important factor as to why the synthetic THC analog HU-210
was protective in an animal model of stroke. [Leker, R.R., Gai, N.,
Mechoulam, R. and Ovadia, H. (2003) Drug-induced hypothermia reduces
ischemic damage: effects of the cannabinoid HU-210. Stroke 34,
2000-2006]... If a patient presents to an ER with a stroke, the first thing
they will do is put the patient's head in a cooler and pump them full of
antioxidants (vitamin E).

There's many a pothead thinks their drug of choice makes them cooler than
the general population. Wait till they find out how much cooler!
O'Shaughnessy's is the journal of sorts that I produce for California's
small but growing group of pro-cannabis doctors. It is not available by
subscription, but a contribution of any amount to the CCRMG (California
Cannabis Research Medical Group) will get you on the mailing list for Fall
'05 and future issues. The CCRMG is a 501(c)3 non-profit; contributions are
tax deductible. It was founded in 1999 by Mikuriya, whose pioneering
clinical research has been rewarded by the Medical Board of California with
a $75,000 fine (to pay for the cost of his own prosecution; the liberal
equivalent of being made to dig your own grave). The CCRMG is not
supported by a generous grant from MPP, Green Aid, DPA or any other reform
bureaucracy. It is BY FAR the best way to support the medical marijuana
movement (as opposed to the medical marijuana industry, which does not
really need external support). Please send what you can to CCRMG, po box
9143, Berkeley CA 94709... But wait, there's more! If you order now, you'll
also receive a never-before published transcript of the 1937 Congressional
Hearing that led to the Prohibition of Marijuana, with commentary by your
correspondent.

Some more nuggets from the new O'Shaughnesy's

THC- V (tetrohydrocannabivarin)

The big news at this year's meeting of the International Cannabinoid
Research Society, as reported here and almost nowhere else, alas, was the
conclusion by Donald Tashkin, MD, and colleagues at UCLA, that marijuana
smoking -"even heavy, longterm use"- does not cause cancer of the lung,
upper airways, or esophagus. Among the other talks of apparent
significance was one by Roger Pertwee, MD, of the University of Aberdeen,
who described experiments using a cannabis strain bred by G.W.
Pharmaceuticals to be high in THC-V (tetrohydrocannabivarin).

It turns out that THCV strongly antagonizes anandamide -one of the body's
own cannabinoids- while hardly antagonizing the plant cannabinoid 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 THC-V to achieve homeostasis. If the
endocannabinoid system needs a boost, the THC provides it (while the THCV
shuts down the endocannabinoid system, giving it a rest as it were). The
key to relief, apparently, is not high cannabinoid levels but proper gradients.

Geoffrey Guy, MD, expounded in an interview: "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
endocannabnioid 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."

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 the 2005 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."

Goldberg's Monkeys Bat Last

A researcher named Steven Goldberg maintains a colony of monkeys in
Baltimore, Maryland that have been trained to self-administer THC (by
injection). Goldberg presented a poster co-authored by Zuzana Justinova
on "The Abuse Potential of the Endocannbinoid Transport Inhibitor AM404:
Self-Administration by Squirrel Monkeys."

AM404 is one of the many compounds that corporate- and government-funded
scientists are developing in hopes of achieving higher cannabinoid levels
by indirect means. Goldberg's monkeys liked AM404 enough to self-administer
it, which means, in NIDA's terms, that AM404 is a drug with potential for
abuse. After all their effort to create an alternative to the illegal herb,
the drug companies will have to run their products by Goldberg's monkeys!

The Goldberg-Justinova poster concluded "AM404 functioned as an effective
reinforcer (comparable to THC, anadamide and cocaine under identical
conditions) in non-human primates under a fixed-ratio schedule of drug
injection. Our findings suggest that medications which promote the actions
of endocannabinoids throughout the brain by inhibiting their membrane
transport have a potential for abuse. It remains to be seen whether
medications such as FAAH inhibitors, which augment CB1 signaling only in
certain regions of the nervous system, would be self-administered in a
similar manner."

I'd always heard that monkeys couldn't be trained to self-administer THC,
and mentioned this to Goldberg. Other researchers had used "Old World
monkeys," he said, sounding somewhat disdainful, whereas he used squirrel
monkeys from South America (as if our New World monkeys are inherently
hipper). But the real key to his success, he added, was the very low doses
with which he rewarded the monkeys. This made sense -most of the primates
I know prefer a slight alteration of mood to getting knocked-out-loaded. It
also resonated with a talk on neuroprotection by Italian investigators in
which they found that a synthetic cannabinoid was beneficial only at the
lowest concentrations tested, and detrimental at high concentrations.

It appears that when the name of the game is Cannabinoids, less can be more.

Prohibition Dialog

The poor people abandoned by the federal government in New Orleans are the
heirs, literally and figuratively, of those against whom the anti-marijuana
hysteria was whipped up in the 1920s and '30s. The following exchange
between Rep. John McCormack of Massachusetts and Harry Anslinger of the
Bureau of Narcotics is from the 1937 House Ways and Means Committee Hearing
that culminated in the Marijuana Tax Act, the cumbersome mechanism by which
prohibition was imposed. They cite Eugene Stanley, the longtime district
attorney of New Orleans, an ambitious prosecutor who needed a scapegoat to
explain away an extended wave of robberies that were actually a result of
the alcohol prohibition. (This same Stanley, in the early '20s, had closed
the clinics at which doctors had been treating opium addicts by giving them
maintenance doses.)

McCORMACK Are you acquainted with the report of the public prosecutor at
New Orleans in 1931? ANSLINGER: Yes, sir. I am going to introduce it into
the record. McCORMACK: That was a case where 125 out of 450 prisoners
were found to be marijuana addicts, and slightly less than one half of the
murderers were marijuana addicts, and about 20 percent of them were charged
with being addicts of what they called "merry wonder." ANSLINGER That is
the same thing. MCCORMACK: You are acquainted with that? ANSLINGER: Yes,
sir. That is one of the finest reports that has been written on
marijuana... by the district attorney, Eugene Stanley. (reads from it)
"The United States government, unquestionably, will be compelled to adopt a
consistent attitude towards this drug, and... to give Federal aid to the
states in their effort to suppress a traffic as deadly and destructive to
society as the traffic in the other forms of narcotics now prohibited by
the Harrison Act."