Your Inner Cannabis

June 30, 2006

Lorrie Klosterman, Chronogram

Marijuana-like chemicls are part of our physiology; usurping their cellular pathways for medical research and treatment is decades old.

In the early 1980s, Steven J. Gould, Professor of Zoology at Harvard and curator of its Museum of Comparative Zoology, explained publicly how smoking marijuana was the only thing that made his cancer chemotherapy tolerable. Gould was one of last century's landmark thinkers in evolutionary biology and paleontology. He penned hundreds of essays for the layperson in Natural History magazine, and collected his entertaining musings in The Panda's Thumb, Ever Since Darwin, The Mismeasure of Man, and many other books.

Gould's revelation impressed me, partly because he was admitting to a federal crime, but mostly because one wouldn't mess with a cerebrum like his lightly. Indeed, it is said he shunned drugs, including alcohol, for that reason. Gould won his cancer battle back then, which bought him two more decades; he succumbed to another onslaught in 2002.

Thousands of people have used marijuana to alleviate symptoms of grave illnesses or to quell side effects of treatments, inspiring several panels of medical experts over the years to scrutinize existing clinical trials and testimony of patients and doctors to discern any promise for marijuana or its components as medicine. In 1999, the Institute of Medicine, a part of the revered US National Academy of Sciences, explained its findings in a 250-page document (an exceptionally educational read for lay people about many aspects of health and medicine). The report concluded that marijuana and its most-studied component, THC, were moderately effective for some conditions and in some patients—enough so that more studies were warranted. Further, the suite of drug effects offered multiple benefits that existing drugs did not.

Also in the late 1990s were reports from the American Medical Association, British Medical Association, US National Institutes of Health, World Health Organization, and the British House of Lords Science and Technology Committee; all echoed the Institute's conclusions, noted a dearth of studies, and encouraged more.

But earlier this year, the FDA reiterated its position in response to discussions in Congress about medical marijuana. An April 20 interagency advisory and press release cited a "past evaluation by several Department of Health and Human Services agencies" (including the FDA, Substance Abuse and Mental Health Services Administration, and National Institute for Drug Abuse), which concluded that "no sound scientific studies supported medical use of marijuana for treatment in the United States, and no animal or human data supported the safety or efficacy of marijuana for general medical use." The statement is the second of two recent federal-level punches to the notion of legalization of marijuana for medical use. The first was a 2005 decision by the Supreme Court that marijuana use for any purpose would remain a federal crime, including in those eleven states that allow medical exemptions.

The Institute of Medicine agrees that "there is little future in smoked marijuana as a medically approved medication [emphasis added]," faulting it as "a crude THC delivery system that also delivers harmful substances," meaning the abundant toxins and carcinogens in marijuana smoke. But it clarifies: "The argument against the future of smoked marijuana for treating any condition is not that there is no reason to predict efficacy but that there is risk. That risk could be overcome by the development of a nonsmoked rapid-onset delivery system for cannabinoid drugs." Specifically, an inhaler would be a good idea. Since that could be years and hundreds of millions of research dollars away with our drug approval system, says the report, "there is no clear alternative for people suffering from chronic conditions that might be relieved by smoking marijuana, such as pain or AIDS wasting."

Meet Your Endocannabinoids

There is ample evidence that marijuana and THC (delta-9-tetrahydrocannabinol) influence the body in ways that, for some patients, nothing else can. But how? Does it offer a mellow resignation, perhaps a lethargy that makes it hard to care too much about one's horrific physical state? To some degree, yes. But that's just a preface to a fascinating story that doesn't get much popular press.

Just as studies of heroin's effects on the brain led to the discovery of our own opioid system—the endorphins and cousins—so has marijuana revealed the endocannabinoids. That tongue twister of a name refers to naturally occurring chemicals now suspected to play along with the brain's neurotransmitter elite—dopamine, serotonin, GABA, and epinephrine—in essential brain functions such as mood, cognition, memory, appetite, pain awareness, and emotions. Endocannabinoids are widespread outside the brain as well. They are made from a hairpin-shaped lipid, arachidonic acid, an essential omega-6 fatty acid in the membranes of all cells, and which serves as a precursor to several molecules with diverse activities. This is not to say that all our cells make cannabinoids, but their building blocks are nothing exotic.

Endocannabinoid history begins in the late 1980s, with clear evidence that people (as well as laboratory animals) have special proteins to which THC and related chemicals bind. These proteins were dubbed cannabinoid receptors (CB1) after Cannabis, the marijuana plant's botanical name. By the early 1990s cannabinoid receptor proteins had been purified and their presence in many regions of the brain and other tissues established. Two years later a naturally occurring chemical—the first endogenous cannabinoid—was identified. It was named anandamide, after the Sanskrit word ananda, bliss (the chemical's formal name is arachidonyl ethanolamide). It is about half as potent as THC. Then a second type of receptor (CB2) was located, mostly on immune cells. Other endogenous cannabinoids have since been discovered, with varying degrees of biological activity (most without the psychogenic properties of anandamide). For instance, 2-arachidonyl glycerol (2-AG) is more abundant but less psychoactive than anandamide and binds to both the CB1 and CB2 receptors; cannabidiol attaches most readily to CB2 receptors, and in doing so seems to relieve convulsions, inflammation, anxiety, and nausea.

Medicinal Value of Cannabinoids

The endocannabinoid system is how THC and similar chemicals are presumed to exert their impacts on physiology. Smoked marijuana typically induces relaxation, sleepiness, euphoria, and an increase in appetite. It temporarily impairs memory formation and clear thinking, and can produce visual distortions, dizziness, and even anxiety, panic, or psychotic reactions in rare cases. (The last effects can be too disruptive for some patients to continue.) But there is more to this drug. Accounts exist for nearly two dozen medical conditions for which marijuana (or purified THC) has improved symptoms. Here are the most established:

Pain suppression. While opioid-based pain relievers (e.g., morphine) work well for many kinds of pain, they don't touch others, and people develop drug tolerance that requires ever-higher doses for the same effect. Also, opioids create dependency and, for some people, insurmountable adverse reactions, especially at the high doses required to alleviate their pain. Several clinical trials show cannabinoids offer pain relief while also inducing calm, sleep, and improved appetite. In addition, they can be added to opioids for better pain relief, such as for "breakthrough" pain that eludes ongoing opioid analgesia. Alleviating pain is no small issue; the medical community has long acknowledged that undertreatment of pain is a serious problem. Studies suggest marijuana or THC helps with migraine headaches, for which existing medications don't always work.

Nausea and Vomiting. Nausea and/or vomiting are nearly guaranteed side effects of cancer chemotherapy. More than just unpleasant, vomiting (emesis, medically speaking) can be so debilitating that people forego anything resembling a normal daily existence or choose to stop chemotherapy. Marijuana has helped many of those people (including in Dr. Gould's time), before antiemetic drugs were as effective as they are today. And while only a third or a fourth of patients find marijuana and THC effective, they are an alternative for patients for whom the standard drugs are insufficient or intolerable due to side effects.

Food Intake. Clinical trials demonstrate that marijuana and THC improve appetite and weight gain in AIDS patients, for whom as little as five percent weight loss decreases survival, and in cancer patients with cachexia (tumor-mediated tissue breakdown and weight loss, common in later stage cancer). In fact, it was a study in the early 1990s showing that THC increased body weight in many people with AIDS wasting, that won FDA approval for pharmaceutical THC (called dronabinol, trade name Marinol) in that patient population.

Muscle Spasm Control. People with multiple sclerosis, spinal cord injury, epilepsy, and movement disorders such as Parkinson's disease, Huntington's disease, and Tourette's syndrome have spontaneous muscle contractions that can be extremely debilitating. Marijuana or THC reduces muscle spasms (most studies are for multiple sclerosis), presumably through brain regions related to muscle control that are known to have cannabinoid receptors.

Anti-inflammatory. Ongoing studies in laboratory animals and people show promise for the cannabinoids in treating diseases of the digestive tract, especially those that involve inflammation, such as ulcers, irritable bowel syndrome, Crohn's disease, and gastroesophageal reflux (heartburn). Another application is neuroprotection—sparing brain cells from death after head injury, oxygen deprivation, and inflammation or immune-mediated nerve cell damage.

Plant and Pharm

While virtually every existing drug product was born out of Mother Nature's botanical warehouse, the Institute of Medicine noted in their report that those based on marijuana are "considered to be especially risky, to judge by the paucity of products in development and the small size of the pharmaceutical firms sponsoring them." Still, the work to "pharm" marijuana has been underway for some time. The first synthetic cannabinoids were created in the 1980s (and key in the discovery of the receptors). Today, there are half a dozen agonists (drugs that mimic the effects of THC or endogenous cannabinoids in various ways) and a few antagonists (which block cannabinoid action). Some agonists are many times more potent than THC; certain forms are more specific for one receptor type, aiding the design of drugs to zero in on certain symptoms with the fewest side effects. The antagonist rimonabant is a potential appetite suppressant/weight-loss drug that also improves blood lipid profiles in such a way that would reduce risk of heart disease.

In the US, two oral cannabinoids are available by prescription. Marinol is synthetic THC, approved by the FDA in 1985 specifically to stimulate appetite in AIDS patients who are losing weight, and in 1992 to reduce nausea and vomiting in people undergoing cancer chemotherapy. Nabilone, a THC-like synthetic, was approved just over a month ago to treat nausea and vomiting in cancer patients when other drugs have failed.

There are pros and cons to both smoked marijuana and the pharmaceuticals. The former carries risk of airway irritation in the short term and airway disease and cancer in the long term (though the largest study to date of lung cancer among long-term heavy marijuana smokers found no increase compared to nonsmokers). And of course, it's a criminal act to grow, buy, possess, or use it. Some medical users find it makes them too sleepy, but many learn to adjust their intake to balance benefit of symptom relief with side effects—something easily done because effects are rapid when inhaled. The pharmaceuticals have their own—and many people would argue, worse—problems. Expense is one, though the makers of Marinol have financial programs for reduced cost to qualified patients. The oral delivery mode means it takes two to four hours for maximum effect (and is useless for patients who are vomiting), yet as additional doses are given to reach effect, overdose is possible. Marinol's packaging warns "overdose may occur either with therapeutic doses or with higher, nontherapeutic doses" and "caution should be exercised in dose escalation because the incidence of psychiatric symptoms increases significantly at maximum doses." Overdose symptoms can include blood pressure drop and unconsiousness, extreme agitation, and psychotic or hallucinatory reactions (these are rarely reported by marijuana smokers). Another consideration is that the dried plant contains many other potentially active compounds; this has been argued as a benefit both of using the plant and of using a single-drug pharmaceutical.

Coming Down the Pipe—er, Pike

Other marijuana-inspired drugs are out there. Sativex is an oral spray developed in the UK and recently approved in Canada and Spain to treat pain and muscle spasms of multiple sclerosis. It is billed as the first Cannabis-based drug in the world available by prescription (in the sense that it has THC and cannabinol from the plant, rather than being synthetics). Sativex got the nod in January by the FDA for a two-to-three year clinical trial in the US beginning later this year for pain relief in advanced cancer patients; at least two other studies are underway to test marijuana and THC for neuropathic pain relief in HIV and AIDS patients.

There is also the federal "compassionate use" program, which grants individual people with life-threatening conditions the opportunity to take a drug not yet approved by the FDA as safe or effective. These "n-of-1" (single-person) clinical trials allow a patient who qualifies and complies with requirements to take an "experimental" drug, including marijuana, while under a doctor's supervision.

So while debates on legalization of marijuana continue and opponents fume, scientists have moved on, as best they can, to capitalize on the plant—monetarily and medically. Research into what marijuana's cannabinoids and our endocannabinoids do, in sickness and in health, is forging ahead.

RESOURCES

 

The Institute of Medicine's Marijuana and Medicine: Assessing the Science Base, at  http://fermat.nap.edu/html/marimed

"The Brain's Own Marijuana" about endocannabinoids, in Scientific American (December 2004), online at www.sciam.com

Online audio slide show about cannabinoids, by the makers of Marinol,at www.marinol.com/slides.html



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