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." - --- MAP posted-by: Jay Bergstrom