Pubdate: Wed, 14 Sep 2005
Source: Anderson Valley Advertiser (CA)
Column: Cannabinotes
Copyright: 2005 Anderson Valley Advertiser
Contact:  http://www.theava.com/
Details: http://www.mapinc.org/media/2667
Author: Fred Gardner
Bookmark: http://www.mapinc.org/pot.htm (Cannabis)

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."
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MAP posted-by: Jay Bergstrom