Cannabis And Aging

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Cannabis has been found to help many patients suffering from conditions that afflict older patients, including arthritis, chronic pain, cancer, Alzheimer's disease, diabetes, and spasticity associated with such diseases as Parkinson's.

Cannabis and Arthritis

More than 31 million Americans suffer from arthritis. There are two common types of arthritis, rheumatoid arthritis and osteoarthritis, but both affect the joints, causing pain and swelling, and limiting movement.

Rheumatoid arthritis is caused by a malfunction of the immune system. Instead of fighting off intruders such as bacteria or viruses, the body attacks the synovial membranes, which facilitate the movement of joints, eventually destroying cartilage and eroding bones. Rheumatoid arthritis is most common among the aged, whose immune systems are no longer as robust or efficient. Osteoarthritis, or arthritis of the bones, is also found primarily among the elderly, whose cartilage has been worn away through use. Arthritis may also manifest as chronic inflammation of the joints as the result of injuries.

INSTITUTE of MEDICINE

"Nausea, appetite loss, pain and anxiety . . all can be mitigated by marijuana For patients, such as those with AIDS or undergoing chemotherapy, who suffer simultaneously from severe pain, nausea, and appetite loss.cannabinoid drugs might offer broad spectrum relief not found in any other single medication."

Marijuana and Medicine: Assessing the Science Base, 1999

Recent research is accumulating evidence that cannabis therapies are effective for arthritis and the other rheumatic and degenerative hip, joint and connective tissue disorders. Since these are frequently extremely painful conditions, the ability of cannabis to combat chronic pain makes it useful for that aspect, both on its own and as an adjunct therapy that enhances the efficacy of opiod painkillers. The use of cannabis as a treatment for musclo-skeletal pain in western medicine dates to the 1700s.12 "

But cannabis has also been shown to have powerful immune-modulation and anti-inflammatory properties,1417 indicating it may treat chronic inflammatory diseases directly. In fact one of the earliest records of medical use of cannabis—a Chinese text dating from ca. 2000 BC—notes that cannabis is effective in treating rheumatism, suggesting that ancient societies long ago recognized its anti-inflammatory and analgesic properties.18

Modern research on cannabidiol (CBD)—one of the non-psychoactive components of cannabis—has found that it suppresses the immune response in mice and rats that is responsible for a disease resembling arthritis, protecting them from severe damage to their joints, and markedly improving their condition.1920

Human studies have shown cannabis to be an effective treatment for rheumatoid arthritis, and it is one of the recognized conditions for which many states allow legal medical use. Cannabis has a demonstrated ability to improve mobility and reduce morning stiffness and inflammation. Research has also shown that patients are able to reduce their usage of potentially harmful Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) when using cannabis as an adjunct therapy.2122

Medical researchers investigating Cannabidiol at Hebrew University in Jerusalem discovered an acid with potent anti-inflammatory action compa rable to the drug indomethacin, but without the considerable gastrointestinal side effects associated with that drug.23

In addition, when the body metabolizes tetrahydrocannabinol (THC, one of the primary components of cannabis) it produces a number of related chemicals. At least one of these metabolites has anti-inflammatory and pain-relieving effects. By modifying this metabolite, researchers at the University of Massachusetts Medical Center have produced a synthetic car-boxylic acid known as CT-3 (also called DMH-11C, chemical name dimethyl-heptyl-THC-11 oic acid), which is more powerful than the natural metabolite and can be given in smaller doses. Animal tests found CT-3 effective against both chronic and acute inflammation; it also prevented destruction of joint tissue from chronic inflammation. The long safety record of marijuana (no one has ever died of an overdose) and the discovery that a metabolite with the desired anti-inflammatory effect is produced in the body when marijuana is used, strongly suggest that safe and effective antiinflammatory drugs may be developed from cannabinoids.24

In addition, CT3 has demonstrated analgesic effects in animals. In some cases, the dose-dependent effect of THC was equivalent to morphine, but with a much greater duration of action.25 26 In contrast to the NSAIDs commonly prescribed arthritis sufferers, CT3 did not cause ulcers at therapeutically relevant doses. Moreover, it does not depress respiration, produce dependence, induce body weight loss or cause mutations. Studies on its mechanism of action are currently underway, and cytokine synthesis is one of the pathways being investigated.27

Cannabis may also help combat rheumatoid arthritis by way of its established immune-modulation properties.28 Rheumatoid arthritis is characterized by dysregulation of the immune system in response to an initial infection or trauma. Over-activity of the immune system's B-cells causes antibodies to attack and destroy the synovial tissues located in the joint.

The immuno-modulatory properties of a group of fats found in cannabis, known as sterols and sterolins, have been used as natural alternatives to conventional rheumatoid arthritis treatments, which typically employ highly toxic drugs to either suppress the entire immune response of the body or to palliate pain and the inflammatory process without correcting the underlying immune dysfunction.

Cytokines play a role in either fueling or suppressing the inflammation that causes damage in rheumatoid arthritis and some other diseases. The release of selected cytokines is impaired by cannabis, but the findings differ by cell type, experimental conditions, and especially the concentration of the cannabinoids examined.29 32 A sterol/sterolin combination has been experimentally demonstrated to reduce the secretion of the pro-inflammatory cytokines controlled by the TH2 helper cells and to increase the number of TH helper cells that regulate the secretion of antibodies from the B cells. This selective activation and inhibition of the immune system is effective in controlling the dysfunctional auto-immune response.

Similarly, another non-psychoactive cannabinoid, ajulemic acid, has been found by UMass Medical Center researchers to reduce joint tissue damage in rats with adjuvant arthritis." Tests on human tissue done in vitro showed a 50% suppression of one of the body chemicals (interleukin-1beta) central to the progression of inflammation and joint tissue injury in patients with rheumatoid arthritis.34

Cannabis and Chronic Pain

Many older patients suffer from persistent and disabling pain, which can have numerous and sometimes multiple causes. These include cancer; arthritis and other rheumatic and degenerative hip, joint and connective tissue disorders; diabetes; AIDS; sickle cell anemia; multiple sclerosis; defects or injuries to the back, neck and spinal cord; and severe burns. Pain is not a primary condition or injury, but is rather a severe, frequently intolerable symptom that varies in frequency, duration, and severity according to the individual. The underlying condition determines the appropriate curative approach, but does not determine the proper symptom management. It is the character, severity, location and duration of the pain that determines the range of appropriate therapies.

For patients in pain, the goal is to function as fully as possible by reducing their pain as much as possible, while minimizing the often debilitating side effects of the pain therapies. Failure to adequately treat severe and/or chronic pain can have tragic consequences. Not infrequently, people in unrelieved pain want to die. Despair can also cause patients to discontinue potentially life-saving procedures (e.g., chemotherapy or surgery), which themselves cause severe suffering. In such dire cases, anything that helps to alleviate the pain will prolong these patients' lives.

Cannabis can serve at least two important roles in safe, effective pain management. It can provide relief from the pain itself (either alone or in combination with other analgesics), and it can control the nausea associated with taking opiod drugs, as well as the nausea, vomiting and dizziness that often accompany severe, prolonged pain.

Opioid therapy is often an effective treatment for severe pain, but all opiates have the potential to induce nausea. The intensity and duration of this nausea can cause enormous discomfort and additional suffering and lead to malnourishment, anorexia, wasting, and a severe decline in a patient's health. Some patients find the nausea so intolerable that they are inclined to discontinue the primary pain treatment, rather than endure the nausea.

Inhaled cannabis provides almost immediate relief for this, with significantly fewer adverse effects than orally ingested Marinol. Inhalation allows the active compounds in cannabis to be absorbed into the blood stream with greater speed and efficiency. It is for this reason that inhalation is an increasingly common, and often preferable, route of administration for many medications. Cannabis may also be more effective than Marinol because it contains many more cannabinoids than just the THC that is Marinol's active ingredient. The additional cannabinoids may well have additional and complementary antiemetic qualities. They have been conclusively shown to have better pain-control properties when taken in combination than THC alone.

Research on cannabis and pain management

Cannabis has historically been used as an analgesic,35 36 and patients often report significant pain relief from marijuana.3"2 Some of the most encouraging clinical data on the effects of cannabinoids on chronic pain are from studies of intractable cancer pain and hard-to-treat neuropathic pain.4344

After reviewing a series of trials in 1997, the U.S. Society for Neuroscience concluded that "substances similar to or derived from marijuana could benefit the more than 97 million Americans who experience some form of pain each year."45

A 1999 study commissioned by the White House and conducted by the Institute of Medicine recognizes the role that cannabis can play in treating chronic pain. "After nausea and vomiting, chronic pain was the condition cited most often to the IOM study team as a medicinal use for marijuana."46

The study found that "basic biology indicates a role for cannabinoids in pain and control of movement, which is consistent with a possible therapeutic role in these areas. The evidence is relatively strong for the treatment of pain and intriguingly, although less well established, for movement disorder." According to the report, a number of brain areas that have an established role in sensing and processing pain respond to the analgesic effect of cannabis, such that cannabinoids have been used successfully to treat cancer pain, which is often resistant to treatment with opiates.

The Report further notes that cannabinoids serve as an anti-inflammatory agent, and so have therapeutic potential in preventing and reducing pain caused by the swelling of body tissues (such as arthritis).

In addition to its analgesic properties, the Report indicates that cannabis, like its synthetic cousin Marinol, can help treat the nausea often induced by

opiate therapy, especially when other antiemetics prove ineffective. In short, the IOM Report recognizes the potential benefits of cannabis for certain patients, including:

• Chemotherapy patients, especially those being treated for mucositis, nausea, and anorexia.

• Postoperative pain patients (using cannabinoids as an opioid adjunct to reduce the nausea and vomiting).

• Patients with spinal cord injury, peripheral neuropathic pain, or central post-stroke pain.

• Patients with chronic pain and insomnia.

• AIDS patients with cachexia, AIDS neuropathy, or any significant pain problem.

Britain's House of Lords reached similar conclusions and called for legalized cannabis by prescription.47

Several studies have found that cannabinoids have analgesic effects in animal models, sometimes equivalent to codeine.48 52 Cannabinoids also seem to synergize with opiods, which often lose their effectiveness as patients build up tolerance. One study in rats found morphine was 15 times more active with the addition of a small dose of THC. Codeine was enhanced on the order of 900 fold.53

In 1990, researchers conducted a double-blind study comparing the antispasmodic and analgesic effects of THC, oral Codeine, and a placebo on a single patient suffering from a spinal cord injury.54 Their findings confirmed the analgesic effects of THC being "equivalent to codeine." A 1997 study made similar findings related to morphine.55

A 1999 article reviewing the body of scientific animal research concerning the analgesic effects of marijuana concludes that "[tjhere is now unequivocal evidence that cannabinoids are antinociceptive [capable of blocking the appreciation or transmission of pain] in animal models of acute pain."56

In 2001, British researchers reported that cannabis extract sprayed under the tongue was effective in reducing pain in 18 of 23 patients who were suffering from intractable neuropathic pain.57

CANNABIS and CANCER

Cannabis has been found to help cancer patients with pain and nausea, and recent research indicates it has tumor-reducing and anti-carcinogenic properties as well. It has proven highly effective at controlling the nausea associated with chemotherapy, and its appetite-stimulation properties help com bat wasting. Cannabis can also help control the pain associated with some cancers, as well as that resulting from radiation and chemotherapy treatment.

Cannabis and chemotherapy side effects

One of the most widely studied therapeutic applications for cannabis and the pharmaceutical drugs derived from cannabinoids is in the treatment of nausea and vomiting associated with cancer chemotherapy. Numerous clinical studies have reported that the use of cannabis reduces nausea and vomiting and stimulates appetite, thereby reducing the severity of cachexia, or wasting syndrome, in patients receiving chemotherapy treatment.

The 1999 Institutes of Medicine report concluded: "In patients already experiencing severe nausea or vomiting, pills are generally ineffective, because of the difficulty _

in swallowing or keeping a pill down, and slow onset of the drug effect. Thus an inhalation (but, preferably not smoking) cannabinoid drug delivery system would be advantageous for treating chemotherapy-induced nausea.

NEW ENGLAND JOURNAL of MEDICINE

"A federal policy that prohibits physicians from alleviating suffering by prescribing marijuana to seriously ill patients is misguided, heavy-handed, and inhumane It is also hypocritical to forbid physicians to prescribe marijuana while permitting them to prescribe morphine and meperidine to relieve extreme dyspnea and pain...there is no risk of death from smoking marijuana To demand evidence of therapeutic efficacy is equally hypocritical"

A 1997 inquiry by the British Medical Association found cannabis more effective than Marinol, and a 1998 review by the House of Lords Science &

Technology Select Committee concluded that "cannabinoids are undoubt edly effective as anti-emetic agents in vomiting induced by anti-cancer drugs. Some users of both find cannabis itself more effective." 59 60

Jerome P. Kassirer, MD, editor N Engl J Med 336:366-367,1997

In the last three years, there have been major advances in both cannabinoid pharmacology and in understanding of the cancer disease process. In particular, research has demonstrated the presence of numerous cannabinoid receptors in the nucleus of the solitary tract, a brain center important in control of vomiting.

Although other recently developed anti-emetics are as effective or more effective than oral THC, nabilone or smoked cannabis, for certain individuals unresponsive to conventional anti-emetic drugs, the use of smoked cannabis can provide relief more effectively than oral preparations which may be difficult to swallow or be vomited before taking effect, as the IOM report notes.

The psychoactive euphoriant effects of THC or inhaled cannabis may also provide an improvement in mood. By contrast, several conventional medications commonly prescribed for cancer patients, e.g. phenothiazines such as haloperidol (known as "major tranquillizers"), may produce unwanted side effects such as excessive sedation, flattening of mood, and/or distressing physical "extrapyramidal" symptoms such as uncontrolled or compulsive movements.

While clinical research on using cannabis medicinally has been severely limited by federal prohibition, the accumulated data speaks strongly in favor of considering it as an option for most cancer patients, and many oncologists do. Survey data from a Harvard Medical School study in 1990, before any states had approved medical use, shows that 44% of oncologists were then recommending cannabis to at least some of their patients. Nearly half said they would do so if the laws were changed. According the American Cancer Society's 2003 data, more than 1,300,000 Americans are diagnosed with cancer each year.61 At least 300,000 of them will undergo chemotherapy, meaning as many as 132,000 patients annually may have cannabis recommended to them to help fight the side effects of conventional treatments.

As the Institutes of Medicine report concluded, "nausea, appetite loss, pain and anxiety ... all can be mitigated by marijuana."

Research on cannabis and chemotherapy

Cannabis is used to combat pain caused by various cancers and nausea induced by chemotherapy agents. Over 30 human clinical trials have examined the effects of cannabis or synthetic cannabinoids on nausea, not including several U.S. state trials that took place between 1978 and 1986.62 In reviewing this literature. Hall et al. concluded that "... THC [delta-9-tetrahydrocannabinol] is superior to placebo, and equivalent in effectiveness to other widely-used anti-emetic drugs, in its capacity to reduce the nausea and vomiting caused by some chemotherapy regimens in some cancer patients."63 A 2003 study found "Cannabinoids—the active components of Cannabis sativa and their derivatives—exert palliative effects in cancer patients by preventing nausea, vomiting and pain and by stimulating appetite. In addition, these compounds have been shown to inhibit the growth of tumor cells in culture and animal models by modulating key cell-signaling pathways. Cannabinoids are usually well tolerated, and do not

produce the generalized toxic effects of conventional chemotherapies."64 Authors of the Institute of Medicine report, "Marijuana and Medicine: Assessing the Science Base," found that there are many cancer patients for whom cannabis should be a valid medical option.65

A random-sample anonymous survey conducted in the spring of 1990 measured the attitudes and experiences of oncologists concerning the antiemetic use of cannabis in cancer chemotherapy patients. Of the respondents expressing an opinion, a majority (54%) thought cannabis should be available by prescription.66

Cancer-fighting properties of cannabis

Recent scientific advances in the study of cannabinoid receptors and endo-cannabinoids have produced exciting new leads in the search for anti-cancer treatments. More than twenty major studies published between 2001 and 2006 have shown that the chemicals in cannabis known as cannabinoids have a significant effect fighting cancer cells. We now know cannabinoids arrest many kinds of cancer growths (brain, breast, leukemic, melanoma, phaeochromocytoma, etc.) through promotion of apoptosis (programmed cell death) that is lost in tumors, and by arresting angiogenesis (increased blood vessel production).

There is growing evidence of direct anti-tumor activity of cannabinoids, specifically CB1 and CB2 agonists, in a range of cancer types including brain (gliomas), skin, pituitary, prostate and bowel. The anti-tumor activity has led in laboratory animals and in-vitro human tissues to regression of tumors, reductions in vascularisation (blood supply) and metastases (secondary tumors), as well as the direct destruction of cancer cells (apoptosis). Indeed, research on the complex interactions of endogenous cannabinoids and receptors is leading to greater scientific understanding of the basic mechanisms by which cancers develop.

The findings of these studies are borne out by the anecdotal reports of such patients as Steve Kubby, whose cannabis use is credited with keeping rare, terminal cancers in a state of remission for decades beyond conventional expectations.

Research on Tumor Reduction

Although cannabis smoke has been shown to have precancerous-causing effects in animal tissue, epidemiological studies have failed to link cannabis smoking with cancer.67 68 If smoke inhalation is a concern, cannabis can be used with a vaporizer, orally in baked goods, and topically as a tincture or a suppository.

Cannabinoids, the active components of cannabis, have been shown to exhibit anti-tumor properties. Multiple studies published between 2001 and 2003 found that cannabinoids inhibit tumor growth in laboratory animals.69

73 In another study, injections of synthetic THC eradicated malignant brain tumors in one-third of treated rats, and prolonged life in another third by as much as six weeks.74 Other journals have also reported on cannabinoids' antitumoral potential.75 81 Italian research teams reported in 1998 and 2001 that the endocannabinoid anandamide, which binds to the same brain receptors as cannabis, "potently and selectively inhibits the proliferation of human breast cancer cells in vitro" by interfering with their DNA production cycle.82 84 Cannabis has been shown in recent studies to inhibit the growth of thyroid, prostate and colorectal cancer cells.85 87 THC has been found to cause the death of glioma cells.88 89 And research on pituitary cancers shows cannabinoids are key to regulating human pituitary hormone secretion.90 93

In 2004 an Italian research team demonstrated that the administration of the non-psychoactive cannabinoid cannabidiol (CBD) to nude mice significantly inhibited the growth of subcutaneous-ly implanted U87 human glioma cells. The authors of the study concluded that "... CBD was able to produce a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent (an agent that inhibits the growth of malignant cells.)"94

FEDERATION of AMERICAN SCIENTISTS

"Based on much evidence, from patients and doctors alike, on the superior effectiveness and safety of whole cannabis compared to other medications,... the President should instruct the NIH and the FDA to make efforts to enroll seriously ill patients whose physicians believe that whole cannabis would be helpful to their conditions in clinical trials"

FAS Petition on Medical Marijuana, 1994

More recently, investigators at the California Pacific Medical Center Research Institute reported that the administration of THC on human glioblastoma multiforme cell lines decreased the proliferation of malignant cells and induced apoptosis (programmed cell death) more rapidly than did the administration of an alternative synthetic cannabis receptor agonist.95

Cannabis and Movement Disorders

Movement disorders and neuro-degenerative diseases, which are sometimes interlinked, are among the conditions cannabis is particularly well suited to treat.

The therapeutic use of cannabis for treating muscle problems and movement disorders has been known to western medicine for nearly two centuries. In 1839, Dr. William B. O'Shaughnessy noted the plant's muscle relaxant and anti-convulsant properties, writing that doctors had "gained an anti-convulsive remedy of the greatest value."96 In 1890 Dr. J. Russell Reynolds, physician to Queen Victoria, noted in an article in The Lancet that for "organic disease of a gross character in the nervous centers. . . India hemp (cannabis) is the most useful agent with which I am acquainted."97

Muscular spasticity is a common condition, affecting millions of people in the United States. It afflicts individuals who have suffered strokes, as well as those with multiple sclerosis, cerebral palsy, paraplegia, quadriplegia, and spinal cord injuries. Conventional medical therapy offers little help for spasticity problems. Phenobarbital and diazepam (Valium) are commonly prescribed, but they rarely provide complete relief, and many patients develop a tolerance, become addicted, or complain of heavy sedation. These drugs also cause weakness, drowsiness and other side effects that patients find intolerable.

Extensive modern studies in animals and various clinical states have shown that cannabis can treat movement disorders affecting older patients, such as tremors and spasticity, because cannabis has antispasticity, analgesic, antitremor, and antiataxia actions.98110

In the federal court brief they filed in support of physicians' right to recommend cannabis, the American Public Health Association stated that "Marijuana is effective in treating muscle spasticity." They point out that the government's own Institutes of Medicine report on medical use of cannabis found that "current treatments for painful muscle spasms. . . have only limited effectiveness and their use is complicated by various adverse side effects." They go on to note that "a survey of British and American MS patients reports that after ingesting marijuana a significant majority experienced substantial improvements in controlling muscle spasticity and pain. An extensive neurological study found that herbal cannabis provided relief from both muscle spasms and ataxia (loss of coordination), a multiple benefit not achieved by any currently available medications" (amicus brief in Conantv. McCaffrey, 2001 filing).

Cannabis also has enormous potential for protecting the brain and central nervous system from the damage that creates various movement disorders. Researchers have found that cannabinoids fight the effects of strokes, as well as brain trauma, spinal cord injury, and multiple sclerosis. More than 100 research articles have been published on how canna-binoids act as neuroprotective agents to slow the progression of such neurodegenerative diseases as Huntington's, Alzheimer's and particularly Parkinson's, which affects more than 52% of people over the age of 85.

The contemporary understanding of the actions of cannabis was spurred by the discovery of an endogenous cannabinoid system in the human body. This system appears to be intricately involved in normal physiology, specifically in the control of movement.111115 Central cannabinoid receptors are densely located in the basal ganglia, the area of the brain that regulates body movement. Endogenous cannabinoids also appear to play a role in the manipulation of other transmitter systems within the basal ganglia— increasing transmission of certain chemicals, inhibiting the release of oth ers, and affecting how still others are absorbed. Most movement disorders are caused by a dysfunction of the chemical loops in this part of the brain. Research suggests that an endo-genous cannabinoid tone participates in the control of movements.116120

Endocannabinoids have paradoxical effects on the mammalian nervous system: Sometimes they block neuronal excitability and other times they augment it. As scientists are developing a better understanding of the physiological role of those natural cannabinoids, or endocannabinoids, it is becoming clear that these chemicals may be involved in the pathology of several neurological diseases. Researchers are identifying an array of potential therapeutic targets within the human nervous system. They have determined that various cannabinoids found in the cannabis plant interrupt the synthesis, uptake or metabolism of the endocannabinoids that drive the progression of Huntington's disease, Parkinson's disease, and tremor.121122

Parkinson's disease has been linked to dysfunction in the body's dopamine system, specifically the production of too much of the neurotransmitter glu-tamate and oxidative damage to dopaminergic neurons. Studies have found a tight association between cannabinoids and dopamine, and recent research has produced anatomical, biochemical and pharmacological evidence supporting a role for the endogenous cannabinoid system in the modulation of dopaminergic transmission. Cannabinoid receptors switch between blocking and enhancing dopamine signaling. Cannabinoids neuroprotective action appears to result from their ability to inhibit reactive oxygen species, glutamate and tumour necrosis factor.

Cannabis and Alzheimer's Disease

Alzheimer's disease is another neuro-degenerative condition for which cannabis and cannabinoid therapies show promise, both for treating the symptoms and the underlying disease.

Alzheimer's disease is widely held to be associated with oxidative stress due, in part, to the membrane action of beta-amyloid peptide aggregates. A laboratory study published in 2004 indicates that one of the cannabis plant's primary components, cannabidiol (CBD), exerts a combination of neuroprotective, anti-oxidative and anti-apoptotic effects by inhibiting the release of the toxic beta-amyloid peptide.123

Another cannabinoid, THC, has also has been shown to reduce the agitation common to Alzheimer's sufferers, according to findings presented in 2003 at the American Society of Consultant Pharmacists' 34th annual meeting.124 Agitation is the most common behavioral management problem in patients with Alzheimer's and affects an estimated 75 percent of people with the disease. It may lead to a variety of symptoms ranging from physical and/or verbal abusive postures, physically non-aggressive conduct including pacing and restlessness, as well as verbally disturbed behaviors such as screaming and repetitive requests for attention.

This study and the Institutes of Medicine report also showTHC to be effective in combating the anorexia or wasting syndrome common to Alzheimer's sufferers, since food refusal is a common problem in patients who suffer from Alzheimer's-type dementia. The appetite-stimula-tion properties of cannabis are some of the most well established in clinical research.125

This new research on cannabis and Alzheimer's disease, coupled with the extensive work done on other neuroprotective qualities of cannabis and its components, indicates that cannabis may become the source of the most effective treatments for battling the Central Nervous System diseases that afflict millions of elderly Americans.

HOW CANNABIS COMPARES TO OTHER TREATMENTS Arthritis Medications

Nearly 100 medications are listed by the Arthritis Foundation website for use with arthritis or other related conditions, such as fibromyalgia, psoriasis, osteoporosis and gout. These medicines include aspirin, ibuprofen and other oral and topical analgesics that dull pain. The most commonly used analgesic, acetaminophen (aspirin-free Anacin, Excedrin, Panadol, Tylenol) is usually not associated with side effects, though long-term use of acetaminophen is thought to be one of the common causes of end-stage renal disease. To effectively control arthritis, aspirin must be taken in large, continuous doses (1000-5400 mg daily), which can cause stomach pain or damage; it is believed to cause more than 1,000 deaths annually in the United States. For that reason, some doctors prescribe one of several chemical variations referred to as nonacetylated salicylates, such as CMT, Tricosal, and Trilisate, which can cause deafness or ringing in the ears in large doses.

Much stronger analgesics are also prescribed for arthritis, sometimes along with acetominophen. These are: codeine (Dolacet, Hydrocet, Lorcet, Lortab, Vicodin); morphine (Avinza, Oramorph); oxycodone (Oxycontin, Roxicodone); propoxyphene (Percocet, Darvon, Darvocet) and tramadol (Ultram, Ultracet). These medicines can cause psychological and physical dependence, as well as constipation, dizziness, lightheadedness, mood changes, nausea, sedation, shortness of breath and vomiting. Taking high doses or mixing with alcohol can slow down breathing, a potentially fatal condition.

Analgesics don't treat the inflammation that can cause severe arthritis pain. For inflammation, steroids, nonsteroidal antiinflammatory drugs (NSAIDs) and newer COX-2 inhibitors are prescribed. Corticosteroids (Cortisone), prednisone and related medications can cause bruising, cataracts, elevated blood sugar, hypertension, increased appetite, indigestion, insomnia, mood swings, muscle weakness, nervousness or restlessness, osteoporosis, susceptibility to infection and thin skin.

Twenty NSAIDs are available with a doctor's prescription, with three of those also available over the counter. They are diclofenac (Arthrotec, Cataflam, Voltaren); diflunisal (Dolobid); etodolac (Lodine); fenoprofen calcium (Nalfon); flurbiprofen (Ansaid); ibuprofen (Advil, Motrin IB, Nuprin); indomethacin (Indocin); ketoprofen (Orudis); meclofenamate sodium (Medomen); mefenamic acid (Ponstel); meloxicam (Mobic); nabumetone (Relafen); naproxen (Naprosyn, Naprelan); naproxen sodium (Anaprox, Aleve); oxaprozin (Daypro); piroxicam (Feldene); sulindac (Clinoril); and tolmetin sodium (Tolectin).

Side effects of NSAIDs include abdominal or stomach cramps, edema (swelling of the feet), pain or discomfort, diarrhea, dizziness, drowsiness or lightheadedness, headache, heartburn or indigestion, nausea or vomiting, gastric ulcers, stomach irritation, bleeding, fluid retention, and decreased kidney function. This is because NSAIDs act on arthritis by inhibiting prostaglandins, which protect the stomach lining, promote clotting of the blood, regulate salt and fluid balance, and maintain blood flow to the kidneys. The gastrointestinal complications of NSAIDS are the most commonly reported serious adverse drug reaction, though NSAIDs cause more than 7,600 annual deaths and 70,000 hospitalizations.

The newer group of arthritis drugs is known as cyclo-oxygenase-2 inhibitors (COX-2), which include Celebrex, Bextra and Vioxx. These medications have the same side effects as NSAIDS, except they are less likely to cause bleeding stomach ulcers and susceptibility to bruising or bleeding.

Non-selective NSAIDS have been associated with an increased risk of con

gestive heart failure. Less is known or has been concluded about the cardiovascular effects of COX-2 inhibitors, though a retrospective analysis of the risk of hospital admission for heart failure done by the Institute for Clinical Evaluative Sciences in Toronto, Canada suggests some may have serious side effects. The study of 130,000 older patients found that those using Vioxx had an 80% increased risk of hospital admission for congestive heart failure. Those using non-selective NSAIDS had a 40% increased risk, and those using Celebrex had the same rate of heart failure as people who had never used NSAIDS.

Antipyretic and anti-inflammatory effects of NSAIDs can mask the signs and symptoms of infection. Their use can interfere with the pharmacologic control of hypertension and cardiac failure in patients who take beta-adrenergic antagonists, angiotensin-converting enzyme inhibitors, or diuretics. Long-term use may damage chondrocyte (cartilage) function.

Only about 60% of patients will respond to any single NSAID. Approximately 10% of rheumatoid arthritis patients will not respond to any NSAID.

Biologic response modifiers such as adalimumab (Humira); etanercept (Enbrel); infliximab (Remicade), and anakinra (Kineret)) are prescribed to either inhibit or the supplement the immune system components called cytokines. Rare reports of lupus (with symptoms such as rash, fever and pleurisy) have been linked to treatment with adalimumab, etanercept and infliximab. Lupus symptoms resolve when the medication is stopped. Multiple sclerosis has rarely developed in patients receiving biologic response modifiers. Seizures have been reported with etanercept.

Chronic Pain Medications

According to the Institute of Medicine, "All of the currently available analgesic (pain-relieving) drugs have limited efficacy for some types of pain. Some are limited by dose-related side effects and some by the development of tolerance or dependence."

The opioid analgesics commonly used to combat pain include codeine (Dolacet, Hydrocet, Lorcet, Lortab); morphine (Avinza, Oramorph); oxycodone (Vicodin, Oxycontin, Roxicodone, Percocet, Roxicet); propoxyphene (Darvon, Darvocet) and tramadol (Ultram, Ultracet). These medicines can cause psychological and physical dependence, as well as constipation, dizziness, lightheadedness, mood changes, nausea, sedation, shortness of breath and vomiting. Taking high doses or mixing with alcohol can slow down breathing, a potentially fatal condition.

In addition, patients in pain are often prescribed muscle relaxants such as Robaxin and Flexeril; anti-anxiety agents such as Valium, Sinequan, Vistaril, Ativan and Xanax; hypnotics such as Halcion, Restoril, Chloralhydrate, Dalmane and Doral and anti-emetics such as Zofran, Compazine, Phenergan, Tigan and Marinol.

Robaxin's side effects include abnormal taste, amnesia, blurred vision, confusion, dizziness, drop in blood pressure and fainting, drowsiness, fever, flushing, headache, hives, indigestion, insomnia, itching, light-headedness, nasal congestion, nausea, pinkeye, poor coordination, rash, seizures, slowed heartbeat, uncontrolled eye movement, vertigo, vomiting and yellow eyes and skin.

Flexeril can cause abnormal heartbeats, aggressive behavior, agitation, anxiety, bloated feeling, blurred vision, confusion, constipation, convulsions, decreased appetite, depressed mood, diarrhea, difficulty falling or staying asleep, difficulty speaking, disorientation, double vision, excitement, fainting, fatigue, fluid retention, gas, hallucinations, headache, heartburn, hepatitis, hives, increased heart rate, indigestion, inflammation of the stomach, itching, lack of coordination, liver diseases, loss of sense of taste, low blood pressure, muscle twitching, nausea, nervousness, palpitations, paranoia, rash, ringing in the ears, severe allergic reaction, stomach and intestinal pain, sweating, swelling of the tongue or face, thirst, tingling in hands or feet, tremors, unpleasant taste in the mouth, urinating more or less than usual, vague feeling of bodily discomfort, vertigo, vomiting, weakness, and yellow eyes and skin

AMERICAN ACADEMY of FAMILY PHYSICIANS

"The American Academy of Family Physicians [supports] the use of marijuana ... under medical supervision and control for specific medical indications."

1996-1997 AAFP Reference Manual

The newer antiemetics, Anzamet, Kytril and Zofran, are serotonin antagonists, blocking the neurotransmitter that sends a vomiting signal to the brain. Rare side effects of these drugs include fever, fatigue, bone pain, muscle aches, constipation, loss of appetite, inflammation of the pancreas, changes in electrical activity of heart, vivid dreams, sleep problems, confusion, anxiety and facial swelling.

Reglan, a substituted benzamide, increases emptying of the stomach, thus decreasing the chance of developing nausea and vomiting due to food remaining in the stomach. When given at high doses, it blocks the messages to the part of the brain responsible for nausea and vomiting. Side effects include sleepiness, restlessness, diarrhea and dry mouth. Rarer side effects are rash, hives and decreased blood pressure

Haldol and Inapsine are tranquilizers that block messages to the part of the brain responsible for nausea and vomiting. Possible side effects include decreased breathing rate, increased heart rate, decrease in blood pressure when changing position and, rarely, change in electrical activity of the heart.

Compazine and Torecan are phenothiazines, the first major anti-nausea drugs. Both have tranquilizing effects. Common side effects include dry mouth and constipation. Less common effects are blurred vision, restlessness, involuntary muscle movements, tremors, increased appetite, weight gain, increased heart rate and changes in electrical activity of heart. Rare side effects include jaundice, rash, hives and increased sensitivity to sunlight.

Benadryl, an antihistamine, is given along with Reglan, Haldol, Inapsine, Compazine and Torecan to counter side effects of restlessness, tongue protrusion and involuntary movements. Its side effects include sedation, drowsiness, dry mouth, dizziness, confusion, excitability and decreased blood pressure.

Benzodiazepine drugs Ativan and Xanax are prescribed to combat the anxiety associated with chronic pain. Ativan causes amnesia. Abruptly stopping the drug can cause anxiety, dizziness, nausea and vomiting, and tiredness. It can cause drowsiness, confusion, weakness and headache when first starting the drug. Nausea, vomiting, dry mouth, changes in heart rate and blood pressure and palpitations are possible side effects.

Cancer Medications

The American Cancer Society lists 269 medicines currently prescribed to treat cancer and its symptoms, and to treat the side effects of other cancer drugs. Some drugs are prescribed for pain caused by cancer, and cancer patients report pain relief with cannabis therapy. Many chemotherapy agents cause severe nausea and 13 drugs are currently prescribed to treat nausea, including Marinol, a synthetic form of delta-9-THC, one of the active ingredients in cannabis.

Antiemetic medications used for treating nausea, and medications such as antihitamines that are sometimes prescribed in combination with antiemetics, are all discussed above, under pain medications.

Decadron (dexamethasone), a corticosteroid, is given with other chemotherapy drugs as an adjunct medication. Common side effects include increased appetite, irritation of stomach, euphoria, difficulty sleeping, mood changes, flushing, increased blood sugar, decreased blood potassium level. Possible side effects upon discontinuing the drug include adrenal insufficiency, weakness, aches, fever, dizziness, lowering of blood pressure when changing position, difficulty breathing, and low blood sugar.

Benzodiazepine drugs Ativan and Xanax are also prescribed to combat the effects of chemotherapy. Ativan causes amnesia. Abruptly stopping the drug can cause anxiety, dizziness, nausea and vomiting, and tiredness. It can cause drowsiness, confusion, weakness, and headache when first starting the drug. Nausea, vomiting, dry mouth, changes in heart rate and blood pressure, and palpitations are possible side effects.

In addition, in April 2003 the FDA approved the drug Emend (aprepi-tant) to help control delayed-onset nausea. It is given along with two other anti-nausea drugs. A regimen of three pills costs $250. The most common side effects with Emend are fatigue, nausea, loss of appetite, constipation and diarrhea.

Spasticity And Movement Medications

Benzodiazepines, baclofen, dantrolene sodium, and tizanidine are the most widely used agents for reduction of spasticity. At high dosages, oral medications can cause unwanted side effects that include sedation, as well as changes in mood and cognition.

Benzodiazepines, which include Diazepam (Valium) and Clonazepam (Klonopin, Rivotril) are centrally acting agents that increase the affinity of GABAto its receptor. Diazepam is the oldest and most frequently used oral agent for managing spasticity. Benzodiazepine side effects include sedation, weakness, hypotension, Gl symptoms, memory impairment, incoordination, confusion, depression and ataxia. Tolerance and dependency may occur and withdrawal on cessation. Tolerance may also lead to unacceptable dosage escalation.

Baclofen (Lioresal) has been widely used for spasticity since 1967. It is a GABA agonist. Tolerance to the medication may develop. Baclofen must be slowly weaned to prevent withdrawal effects such as seizures, hallucinations and increased spasticity. It must be used with care in patients with renal insufficiency as its clearance is primarily renal. Side effects are predominantly from central depressant properties including sedation, ataxia, weakness and fatigue. May cause depression when combined with tizanidine or benzodiazepines.

Dantrolene Sodium (Dantrium) acts peripherally at the level of the muscle fiber and works best for cerebral palsy and traumatic brain injury. Because the action of dantrolene sodium is not selective for spastic muscles, it may cause generalized weakness, including weakness of the respiratory muscles. The side effects include drowsiness, dizziness, weakness, fatigue and diarrhea. In addition, hepatotoxicity (liver damage) occurs in < 1% of patients who take dantrolene sodium.

Tizanidine (Zanaflex) facilitates short-term vibratory inhibition of the H-reflex. Tizanidine in conjunction with baclofen or benzodiazepines has potential additive effects, including sedation and the possibility of liver toxicity. Dry mouth, somnolence, asthenia and dizziness are the most common side effects. Liver function problems and hallucinations may also occur.

Cannabis vs. Other Medications

Cannabis: By comparison, the side effects associated with cannabis are typically mild and are classified as "low risk." Euphoric mood changes are among the most frequent side effects. Cannabinoids can exacerbate schizophrenic psychosis in predisposed persons. Cannabinoids impede cognitive and psychomotor performance, resulting in temporary impairment. Chronic use can lead to the development of tolerance. Tachycardia and hypotension are frequently documented as adverse events in the cardiovascular system. A few cases of myocardial ischemia have been reported in young and previously healthy patients. Inhaling the smoke of cannabis cigarettes induces side effects on the respiratory system. Cannabinoids are contraindicated for patients with a history of cardiac ischemias. In summary, a low risk profile is evident from the literature available. Serious complications are very rare and are not usually reported during the use of cannabinoids for medical indications.

Is cannabis safe to recommend?

"The smoking of cannabis, even long term, is not harmful to health " So began a 1995 editorial statement of Great Britain's leading medical journal. The Lancet. The long history of human use of cannabis also attests to its safety—nearly 5,000 years of documented use without a single death. In the same year as the Lancet editorial. Dr. Lester Grinspoon, a professor emeritus at Harvard Medical School who has published many influential books and articles on medical use of cannabis, had this to say in an article in the Journal of the American Medical Association (1995):

"One of marihuana's greatest advantages as a medicine is its remarkable safety. It has little effect on major physiological functions. There is no known case of a lethal overdose; on the basis of animal models, the ratio of lethal to effective dose is estimated as 40,000 to 1. By comparison, the ratio is between 3 and 50 to 1 for secobarbital and between 4 and 10 to 1 for ethanol. Marihuana is also far less addictive and far less subject to abuse than many drugs now used as muscle relaxants, hypnotics, and analgesics. The chief legitimate concern is the effect of smoking on the lungs. Cannabis smoke carries even more tars and other particulate matter than tobacco smoke. But the amount smoked is much less, especially in medical use, and once marihuana is an openly recognized medicine, solutions may be found; ultimately a technology for the inhalation of cannabinoid vapors could be developed."

The technology Dr. Grinspoon imagined in 1995 now exists in the form of "vaporizers," (which are widely available through stores and by mail-order) and recent research attests to their efficacy and safety.35 Additionally, pharmaceutical companies have developed sublingual sprays and tablet forms of the drug. Patients and doctors have found other ways to avoid the potential problems associated with smoking, though long-term studies of even the heaviest users in Jamaica, Turkey and the U.S. have not found increased incidence of lung disease or other respiratory problems. As Dr. Grinspoon goes on to say, "the greatest danger in medical use of marihuana is its illegality, which imposes much anxiety and expense on suffering people, forces them to bargain with illicit drug dealers, and exposes them to the threat of criminal prosecution." This was the same conclusion reached by the House of Lords report, which recommended rescheduling and decriminalization, both of which were enacted in Great Britain in 2004.

Cannabis or Marinol?

Those committed to the prohibition on cannabis frequently cite Marinol, a Schedule III drug, as the legal means to obtain the benefits of cannabis. However, Marinol, which is a synthetic form of THC, does not deliver the same therapeutic benefits as the natural herb, which contains at least another 60 cannabinoids in addition to THC.

Recent research conducted by GW Pharmaceuticals in Great Britain has shown that Marinol is simply not as effective for pain management as the whole plant; a balance of cannabinoids, specifically CBC and CBD with THC, is what helps patients most. In fact, Marinol is not labeled for pain, only appetite stimulation and nausea control. But studies have found that many severely nauseated patients experience difficulty in getting and keeping a pill down, a problem avoided by use of inhaled cannabis.

Clinical research on Marinol vs. cannabis has been limited by federal restrictions, but a New Mexico state research program conducted from 1978 to 1986 provided cannabis or Marinol to about 250 cancer patients for whom conventional medications had failed to control the nausea and vomiting associated with chemotherapy.

At a DEA hearing, a physician with the program testified that cannabis was clearly superior to both Chlorpromazine and Marinol for these patients. Additionally, patients frequently have difficulty getting the right dose with Marinol, while inhaled cannabis allows for easier titration and avoids the negative side effects many report with Marinol. As the House of Lords report states, "Some users of both find cannabis itself more effective."

THE EXPERIENCE OF PATIENTS Dorothy Gibbs

In 1911, at the age of one, I contracted the polio virus.. The early onset of polio caused permanent damage in my legs, spine, and back, resulting in significant weakness and atrophy in my legs. As a result, I have never been able to walk without the assistance of crutches and braces or a wheelchair. Approximately 30 years ago, my condition began to deteriorate. I began to suffer from increasing levels of pain and weakness in my legs and back as well as severe osteoarthritis in my hands, arms, and joints. Over time, my deteriorating medical condition has been exacerbated by my pain, leaving me increasingly immobilized..

By May, 1996, my physician [Dr. Arnold Leff, M.D.] had tried various prescription medications to relieve my pain, including: Tylenol #3, Ultram, Daypro, Tegretol, Soma, Valium, steroid injections into the trigger point, Dilantin, Duragesic, Zofran and Comapazine for the nausea caused by the opioid pain relievers, and Doloboid and Lodine as nonsteroids. Nothing seemed to work, and the pain persisted. I was growing increasingly depressed by the inability of anything to relieve my pain.

During this period it was clear to me, my caretaker and my physician that nothing was working to combat my pain. My caretaker, Pat, had heard of the success some people experience with the medicinal use of marijuana for pain management. Sometime during the end of 1997, she obtained a sample for me. Although I had never used marijuana in my previous eighty-seven years of life, I was willing to try anything that could alleviate even part of the pain.

The relief I experienced from medical marijuana was almost immediate. I was so pleased with the result that I wrote to Dr. Leff about my use of medical marijuana and we talked about the benefits of the medicine. Dr. Leff examined me and noted that medical marijuana helped me experience less chronic pain and nausea, leading him to recommended medical marijuana as part of my daily pain care regimen

I strongly feel that I should have the right to use anything that may relieve any or some of my pain, and my last days should not be spent suffering. . . .

Ever since trying medical marijuana, my life has drastically improved. Although chronic pain, related to my post-polio syndrome will always be a part of my life, medical marijuana had helped me manage this pain by providing fast and effective relief for my muscle spasms, acute pains, and arthritis..

Since I began using medical marijuana, my pain is no longer persistent or debilitating. When I do suffer from pain, I am usually able to "get ahead of it" by using medical marijuana and make it manageable..

Judith Cushner

In 1989, I was diagnosed with breast cancer. After a brief period of recovery from the surgeries, I was placed on an aggressive protocol of chemotherapy, which lasted for eight months. That protocol was referred to as "CMF," because it consisted of heavy doses of Cytoxan, methotraxate, and 5 fluo-rouracil.

The treatment caused severe and persistent side effects which were thoroughly disabling: chronic nausea, joint pain and weakness; a debilitating lack of energy and motivation; loss of appetite and a resulting unwanted weight loss; sleep disruption; and eventually my withdrawal from social situations and interpersonal relationships. The cumulative effect of these symptoms often rendered it impossible (or painfully difficult) to take the huge number of medications essential to my treatment regimen.

Right from the start, I was given Compazine as part of my chemotherapy protocol. I took it both orally (in pill form) and intravenously, but it too caused severe adverse side effects, including neuropathy. Moreover, the Compazine provided little, if any, relief from the nausea that had persisted since my treatment began. Hoping for better results, my doctor discontinued the Compazine and prescribed Reglan. That, too, had no effect on the nausea and we decided to discontinue it after a fairly short time.

By then, I had developed chronic mouth sores (also from the chemotherapy), which made it extremely painful to take pills or swallow anything. Rather than providing relief, the Reglan increased my discomfort and pain.

Yet another drug I tried was Marinol, which gave me no relief from the unrelenting nausea. If anything, taking yet another pill increased my discomfort. The pills themselves irritated the sores in my mouth. It also made me quite groggy, yet my sleep disturbance persisted, in part because my nausea and anxiety were so distracting.

During this time, a friend of mine (who happened to be a nurse) gave me a marijuana cigarette. She had seen my suffering and thought it might help. I took her advice and it worked. I took just a few puffs and within minutes, the nausea dissipated. For the first time in several months, I felt relief. I also felt hope. I smoked small amounts of marijuana for the remainder of my chemotherapy and radiation treatment. It was not a regular part of my day, nor did it become a habit. Each time I felt nausea coming on, I inhaled just two or three puffs and it subsided.

As my nausea decreased, my ability to eat and retain food increased. I saw a marked weight gain and my energy increased. As my general health improved, my sleeping habits also improved. In retrospect, one of the greatest benefits from the marijuana was that it decreased my use of other, more disabling and toxic medications, including the Compazine, Reglan and Lorazepam.

My cancer has been in remission now for just under a year. I lived to see my son's Bar Mitzvah, and I am proud to say that the risks I took to save my life, while technically illegal, have earned me the respect of both my children. They have learned the difference between therapeutic treatment and substance abuse, and (unlike many of their peers) that knowledge has helped them resist the temptations of recreational drugs. My decision to use marijuana and save my own life has educated many, including my rabbi and my congregation.

Sworn testimony by Judith Cushner in Conant v. McCaffrey, 2/14/1997

Jo Daly

In 1980, I was appointed by Dianne Feinstein, then Mayor of San Francisco, to serve as police commissioner for the city of San Francisco, an office which I held for six years. On May 24, 1988, I was diagnosed with Phase IV cancer of the colon. By the time it was diagnosed, it had already spread to my ovaries and lymph nodes. My oncologist at the UCSF Hospital prescribed an aggressive regimen of chemotherapy, which lasted

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