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What the Science Says
It can be difficult to locate information about the safety and therapeutic value of cannabis. An unfortunate result of the federal prohibition of cannabis has been limited clinical research to investigate the safety and efficacy of cannabis to control symptoms of serious and chronic illness. Many scientists have noted research is “hindered by a complicated federal approval process, limited availability of research grade marijuana, and the debate over legalization.”1
Nonetheless, the documented use of cannabis as a safe and effective therapeutic botanical dates to 2700 BC. Between 1840 and 1900, European and American journals of medicine published more than 100 articles on the therapeutic use of cannabis. In fact, cannabis was part of the American pharmacopoeia until 1942, and is currently available by prescription in Canada, the Netherlands, Israel, and Germany.
The political interference with cannabis research and its use as a medicine originated with the Marihuana Tax Act of 1937. Over the objections of the American Medical Association,2 the United States Congress passed the first federal law restricting access to cannabis, even for medical and research purposes. Since then, numerous reviews by local, federal and international commissions have confirmed the relative safety and efficacy of cannabis as a medicine. And in recent decades, research studies have further shown cannabis has the potential to treat a variety of debilitating conditions for which conventional treatments are lacking. Yet the use of cannabis remains completely prohibited by federal law—even for medical purposes.
- The Endocannabinoid System
- Emerging Clinical Data
- The Clinical Trials
- Cannabis-based Medicines
- Investigative Roadblocks
- Government Studies and Programs
The Endocannabinoid System (ECS)
Humans have used drugs derived from the opium poppy for thousands of years to lessen pain and produce euphoria. In 1973, scientists discovered the brain receptors that interact with these opiates, which include opium, morphine, and heroin. In 1975, the first of the brain's natural chemicals that bind with these receptors was identified. The similarity of this chemical, enkephalin, to morphine suggested opiate drugs work primarily by mimicking natural opiate-like molecules. These discoveries helped explain the effects of opiate drugs and opened the door to the development of powerful new therapeutic drugs that revolutionized pain management.
Similarly, humans have used the cannabis plant for thousands of years to reduce pain, control nausea, stimulate appetite, control anxiety, and produce feelings of euphoria. Since 1964 when the first cannabinoid was identified, researchers have made new discoveries that help us better understand not just why and how cannabis works so well for so many people but its full therapeutic potential.
The therapeutic benefits of cannabis are derived from the interactions of cannabinoids and the human body's own endocannabinoid system, first identified in 1988. The endocannabinoid system (ECS) is a sophisticated group of neuromodulators, their receptors, and signaling pathways involved in regulating a variety of physiological processes including movement, mood, memory, appetite, and pain.
One of the leading modern cannabinoid researchers, Dr. Ethan Russo, offers this comprehensive description of the ECS and its importance to a variety of physiological functions:
The analgesic and palliative effects of the cannabis and cannabinioid preparation have been amply reported over the past generation.... In essence, the effects result from a combination of receptor and non-receptor mediated mechanisms. THC and other cannabinoids exert many actions through cannabinoid receptors, G-protein coupled membrane receptors that are extremely densely represented in central, spinal, and peripheral nociceptive pathways. Endogenous cannabinoids (endocannabinoids) even regulate integrative pain structures such as the periaqueductal gray matter. The endocannabinoid system also interacts in numerous ways with the endogenous opioid and vanillio systems that that can modulate analgesia and with a myriad of other neurotransmitter systems such as the serotonergic, dopaminergic, glutameatergic, etc, pertinent to pain. Research has shown that the addition of cannabinoid agonists to opiates enhances analgesic efficacy markedly in experimental animals, helps diminish the likelihood of the development of opiate tolerance, and prevents opiate withdrawal. The current author has suggested that a clinical endocannabinoid deficiency may underlie the pathogenesis of migraine, fibromyalgia, idiopathic bowel syndrome, and numerous other painful conditions that defy modern pathophysiological explanation or adequate treatment.9
In the little more than 20 years since researchers began developing an understanding of the ECS, two types of cannabinoid receptors, CB1 and CB2, have been identified, setting the stage for discoveries that have dramatically increased our understanding of how cannabis and its many constituent cannabinoids affect the human body.10-11
CB1 receptors are found in the central nervous system, particularly the brain, and in other organs and tissues such as the eyes, lungs, kidneys, liver and digestive tract. In fact, the brain's receptors for cannabinoids far outnumber its opiate receptors, perhaps by as much as ten to one. The relative safety of cannabis is explained by the fact that cannabinoid receptors are virtually absent from those regions at the base of the brain that are responsible for such vital functions as breathing and heart control. CB2 receptors are primarily located in tissues associated with immune function, such as the spleen, thymus, tonsils, bone marrow, and white blood cells.
Research is helping scientists and physicians understand the role of the endocannabinoid system in regulating a variety of bodily functions. As noted by the researcher who first identified THC, Raphael Mechoulam, the discovery of the endocannabinoid system has generated a great deal of interest in identifying opportunities for the development of a wide variety of cannabis-based and other cannabinoid therapeutic drugs.12
In the meantime, physicians are developing protocols for treating patients with cannabis medicines. Doctors at the University of California Center for Medicinal Cannabis Research, which has completed a series of randomized clinical trials with patients, recently published guidelines for medical care. They note that the decision to use cannabis therapeutics, like other treatment modes, should be based on careful assessment of the patient's condition with consideration for other possible treatments. They propose a possible treatment decision-tree for physicians, using neuropathic pain as an example, as reproduced below.
This is similar to the guidelines established by the California Medical Board for doctors. They indicate that physicians recommending medical cannabis should:
- Take a history and conduct a good faith examination of the patient;
- Develop a treatment plan with objectives;
- Provide informed consent, including discussion of side effects;
- Periodically review the treatment’s efficacy;
- Obtain consultations, as necessary; and
- Keep proper records supporting the decision to recommend the use of medical marijuana.
Emerging Clinical Data
The Therapeutic Potential of Cannabis
While research in the United States has been sharply restricted by the federal prohibition on cannabis in the past, recent discoveries have increased interest among scientists in the more than 100 different cannabinoids so far identified in the cannabis plant. The International Cannabinoid Research Society (ICRS) was formally incorporated as a scientific research organization in 1991, and since its incorporation the membership has more than tripled. The International Association for Cannabis as Medicine (IACM), founded in 2000, publishes a bi-weekly newsletter and holds a bi-annual symposium to highlight emerging clinical research concerning cannabis therapeutics. The University of California established the Center for Medical Cannabis Research (CMCR) in 2001 to conduct scientific studies to ascertain the general medical safety and efficacy of cannabis products and examine alternative forms of cannabis administration. In 2010, the CMCR issued a report on the 14 clinical studies it has conducted, most of which were FDA-approved, double-blind, placebo-controlled clinical studies that have demonstrated that cannabis can control pain, in some cases better than the available alternatives.13
To date, more than 15,000 modern peer-reviewed scientific articles on the chemistry and pharmacology of cannabis and cannabinoids have been published, as well as more than 2,000 articles on the body's natural endocannabinoids. In recent years, more placebo-controlled human trials have also been conducted.
A 2009 review of clinical studies conducted over a 38-year period, found that “nearly all of the 33 published controlled clinical trials conducted in the United States have shown significant and measurable benefits in subjects receiving the treatment.”14 The review's authors note that cannabinoids have the capacity for analgesia through neuromodulation in ascending and descending pain pathways, neuroprotection, and anti-inflammatory mechanisms—all of which indicates that the cannabinoids found in cannabis have applications in managing chronic pain, muscle spasticity, cachexia, and other debilitating conditions.
Currently, cannabis is most often recommended as complementary or adjunct medicine. But there is a substantial consensus among experts in the relevant disciplines, including the American College of Physicians, that cannabis and cannabis-based medicines have therapeutic properties that could potentially treat a variety of serious and chronic illness. What follows is a brief, annotated compilation of the emerging clinical data that support the therapeutic use of cannabis.
Cannabis and Cancer
People with cancer who must undergo radiation and chemotherapy frequently stop treatments rather than suffer the nausea, pain, and other unpleasant side effects. Years before any state had authorized the medical use of cannabis, a 1991 Harvard Medical School study revealed that nearly half (44%) of U.S. oncologists were recommending cannabis to their patients as a way of mitigating the side effects of cancer treatments.15
In its 1999 review, the Institute of Medicine concluded that cannabis could be a valid alternative for many people living with cancer. Specifically, the IOM notes, “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.”16
Since the release of the IOM report, new research has been published which supports the use of cannabis to curb the debilitating effects of cancer treatment. In 2001, a review of clinical studies conducted in several states during the past two decades revealed that, in 768 individuals with cancer, cannabis was a highly effective anti-emetic in chemotherapy.17 Other studies have concluded that the active components in cannabis produce palliative effects in cancer patients by preventing nausea, vomiting and pain and by stimulating appetite.
The tumor-fighting properties of cannabinoids have also been demonstrated in numerous laboratory studies, though not yet in human clinical trials. Researchers have observed that “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.”18
Cannabis is used most often to combat nausea induced by chemotherapy agents and pain caused by various cancers. More than 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 1986.19-20 In reviewing this literature, scientists have concluded that, “THC 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.”21
A 1998 review by the British House of Lords Science & Technology Select Committee concluded that “cannabinoids are undoubtedly effective as anti-emetic agents in vomiting induced by anti-cancer drugs. Some users of both find cannabis itself more effective.”22 The House of Lords review builds upon data provided in a 1997 inquiry by the British Medical Association that determined cannabis is, in some cases, more effective than Marinol.23
Recent scientific advances in the study of cannabinoid receptors and endocannabinoids have produced exciting new leads in the search for anti-cancer treatments. In the past decade, scores of studies, both in vivo and in vitro, have demonstrated that various cannabinoids have a significant effect fighting cancer cells. To date, studies have shown that cannabinoids arrest many kinds of cancer growths through promotion of apoptosis (programmed cell death) in tumors and by arresting angiogenesis (increased blood vessel production). Cannabinoids have also been shown to halt the proliferation or spread of cancer cells in a wide variety of cancer types. Unlike conventional chemotherapy treatments that work by creating a toxic environment in the body that frequently compromises overall health, cannabinoids have been shown to selectively target tumor cells.
Cannabinoids and Tumor Reduction
The direct anti-tumor and anti-proliferation activity of cannabinoids, specifically CB1 and CB2 agonists, has now been demonstrated in dozens of studies across a range of cancer types, including brain (gliomas), breast, liver, leukemic, melanoma, phaeochromocytoma, cervical, pituitary, prostate and bowel.24-40 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).41-45 A 2009 review of recent studies on the role of cannabinoids and cannabinoid receptors in the treatment of breast cancer notes that research on the complex interactions of endogenous cannabinoids and receptors is leading to greater scientific understanding of the basic mechanisms by which cancers develop.46
Cannabinoids have been shown to inhibit tumor growth in laboratory animals in multiple studies.47-52 In one study, injections of synthetic THC eradicated malignant brain tumors in one-third of treated rats, and prolonged life in another third by as long as six weeks.53 Other research on pituitary cancers suggests that cannabinoids may be the key to regulating human pituitary hormone secretion.54-57
Research published in 2009 found that the non-psychoactive cannabinoid cannabidiol (CBD) inhibits the invasion of both human cervical cancer and human lung cancer cells. By manipulating cannabidiol's up-regulation of a tissue inhibitor, researchers may have revealed the mechanism of CBD's tumor-fighting effect. A further in vivo study demonstrated “a significant inhibition” of lung cancer metastasis in mice treated with CBD.58 The mechanism of the anti-cancer activity of CBD and other cannabinoids has also been repeatedly demonstrated with breast cancers.59-63
Scientists have also demonstrated the anti-tumor effects of the cannabinoid THC on cholangiocarcinoma cells, an often-fatal type of cancer that attacks the liver's bile ducts. A 2009 study found that “THC inhibited cell proliferation, migration and invasion, and induced cell apoptosis.” At low levels, THC reduced the migration and invasion of cancer cells, while at high concentrations, THC triggered cell-death in tumors. In short, THC reduced the activity and number of cancer cells. 64 This dose-dependent action of cannabinoids on tumors has also been demonstrated in animal studies.
Research on cannabinoids and gliomas, a type of aggressive brain cancer for which there is no cure, holds promise for future treatments for this disease. A study that examined both animal and human glioblastoma multiforme (GBM) tumors, the most common and aggressive form of brain cancer, describes how cannabinoids controlled glioma growth by regulating the blood vessels that supply the tumors.65 In another study, researchers demonstrated that the administration of the non-psychoactive cannabinoid cannabidiol (CBD) significantly inhibited the growth of subcutaneously implanted U87 human glioma cells in mice. The authors of the study noted 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.66
The targeted effects of cannabinoids on GBM were further demonstrated in 2005 by researchers who showed that the cannabinoid THC both selectively inhibited the proliferation of malignant cells and induced them to die off, while leaving healthy cells unaffected.67 While CBD and THC have each been demonstrated to have tumor-fighting properties in isolation, research published in 2010 shows that they work better in combination, as CBD enhances the inhibitory effects of THC on GBM cell proliferation and survival.68
Similarly, researchers reported in 2010 that the way cannabinoid and cannabinoid-like receptors in brain cells “regulate these cells' differentiation, functions and viability” suggests cannabinoids and other drugs that target cannabinoid receptors can “manage neuroinflammation and eradicate malignant astrocytomas,” a type of glial cancer.69 These recent studies confirm the findings of multiple studies that indicated the effectiveness of cannabinoids in fighting gliomas, some of the deadliest forms of brain cancer.70-77
Indications of the remarkable potential of cannabinoids to fight cancer in humans have also been seen in three recent large-scale population studies. The studies were designed to find correlations between smoking cannabis and cancers of the lung, throat, head and neck. Instead, the researchers discovered that the cancer rates of cannabis smokers were at worst no greater than those who smoked nothing at all or even significantly better.78 One study found that 10-20 years of cannabis use reduced the incidence of head, neck and throat cancers by 62%.79 Researchers suggest that cannabinoids my produce a prophylactic effect against cancer development, as seen in the anti-proliferation effect that has been demonstrated in vitro and in vivo.
Cannabis, HIV/AIDS and Hepatitis-C
Cannabis helps to improve the lives of many people living with HIV/AIDS. It's effects help manage appetite loss, wasting, nausea, vomiting, pain, anxiety, stress, depression and other symptoms of both the disease and the anti-retroviral regimes used to treat it. As many as one in four people living with HIV/AIDS use cannabis for medical purposes.80
An international group of nursing researchers has determined from a longitudinal, multi-country, multi-site, randomized-control clinical trial that cannabis is frequently used to manage the six common symptoms of HIV/AIDS. The 2009 study found that a significant percentage of those with HIV/AIDS find cannabis effective for anxiety, depression, fatigue, diarrhea, nausea, and peripheral neuropathy. Researchers note that “those who did use marijuana rate it as effective as prescribed or over the counter medicines for the majority of common symptoms….”81
In addition to symptoms of the disease, cannabis has proven to be effective in controlling unpleasant effects of the drugs used to treat HIV/AIDS. People living with HIV/AIDS who use cannabis to combat the side-effects of HAART therapy are approximately three times more likely to remain on their prescribed drug therapies than those who do not use cannabis, according to a 2007 study.82
In the 1970s, a series of human clinical trials established that cannabis stimulates food intake and weight gain in healthy volunteers, a finding confirmed by numerous subsequent studies. In a randomized trial in people living with AIDS, THC significantly improved appetite and nausea in comparison with placebo. There were also trends towards improved mood and weight gain. Unwanted effects—dry mouth, drowsiness and anxiety—were generally mild or moderate in intensity.83-85
The Institute of Medicine’s comprehensive review in Marijuana and Medicine concluded, “For patients such as those with AIDS or who are undergoing chemotherapy and who suffer simultaneously from severe pain, nausea, and appetite loss, cannabinoid drugs might offer broad-spectrum relief not found in any other single medication.”
An FDA-approved preliminary safety trial of smoked cannabis, conducted in 2003 at the University of California at San Francisco, concluded that neither synthetic THC nor inhaled cannabis had any significant effect on the immune system or viral load. Moreover, the researchers noted that study participants who used cannabis gained weight.86
Cannabinoids may also inhibit the spread of the HIV virus within the body by acting on CD4+ T cells, which are critical to immune function and a target of the virus. A 2012 study found that a cannabinoid that activates CB2 receptors produced a dose-specific reduction of HIV infection of up to 50%, leading the researchers to suggest that the therapeutic use of cannabinoids may help fight the spread of the virus to uninfected T cells in late stages of HIV-1 infection.87
Previous research has shown that the use of cannabinoid drugs in patients with HIV is associated with an increase in CD4+ T cell number and has been shown to reduce viral load in an animal model of HIV.
The Clinical Trials
More than one-third of people living with HIV/AIDS suffer from excruciating nerve pain in the hands or feet, frequently in response to the antiretroviral therapies that constitute the first line of treatment for HIV/AIDS. This neuropathic pain is extremely difficult to treat, and as a result, many individuals reduce or discontinue their HIV/AIDS therapy because they cannot tolerate or get adequate relief from the debilitating side effects of the antiretroviral medications.
The effectiveness of cannabis and cannabinoids in relieving neuropathic pain has been demonstrated in more than three dozen preclinical and clinical trials. A 2009 review noted that “a large number of research articles have demonstrated the efficacy of cannabinoids” and concluded that “cannabinoids show promise for treatment of neuropathic pain.”88
A series of double-blind, placebo-controlled studies of people living with HIV/AIDS have demonstrated that cannabis can reduce neuropathic pain and promote weight gain without immunological compromise.89 One randomized, placebo-controlled clinical trial of 50 people who had experienced neuropathic pain for an average of six years showed that smoked cannabis was well-tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy, according to researchers at the University of California, San Francisco.90 Other double-blind, placebo-controlled clinical trials with people living with HIV who experience neuropathy pain not adequately controlled by other pain-relievers, including opiates, found that cannabis provided pain relief.91
More recent randomized clinical trials conducted by the University of California Center for Medicinal Cannabis Research (CMCR) also demonstrated that smoked cannabis is effective in treating neuropathic pain.92 Researchers found that over half of patients with painful HIV peripheral neuropathy experienced pain reduction of more than 30% when treated with cannabis, a level of relief pain researchers correlate with improved life quality. That improvement occurred in two CMCR trials of patients with HIV peripheral neuropathy and in a separate trial of patients with mixed neuropathic pain due to peripheral or central dysfunction of the nervous system.93,94
Additional double-blind, placebo-controlled clinical trials indicate cannabis medicines may improve neuropathic pain associated with multiple sclerosis and mixed neuropathies resulting from herpes, trauma and vascular problems.95,96 This research is also important for people with cancer, as many of them also experience neuropathic pain.
While at least one study found that the effectiveness of cannabis as an analgesic was dose specific, with lower doses decreasing pain and higher doses increasing pain,97 other studies have indicated that low- and high-dose cannabis produced similar levels of pain relief, reducing both the intensity and unpleasantness of unbearable nerve pain.
Researchers have found that cannabinoids such as THC work in concert with opiate-based painkillers to increase their effectiveness, particularly in neuropathic pain, allowing patients to reduce their opiate dosage.98-99 That synergistic or entourage effect extends to cannabinoids, with multiple studies finding isolated synthetic cannabinoids such as THC (dronabinol) did not provide the same degree of efficacy as a whole-plant preparation of cannabis.100
Cannabis may improve the effectiveness of drug therapy for the hepatitis C virus (HCV), a potentially deadly viral infection that affects more than 3 million Americans. Treatment for Hepatitis-C virus (HCV) involves months of therapy with two powerful drugs, interferon and ribavirin, both of which have severe side effects, including extreme fatigue, nausea, muscle aches, loss of appetite and depression. Due to these side effects, people often do not finish treatment, which worsens their symptoms and can promote harm to the liver.
Researchers from the University of California, San Francisco medical school and the Organization to Achieve Solutions in Substance-Abuse (OASIS) found that “modest cannabis use may offer symptomatic and virological benefit to some patients undergoing HCV treatment by helping them maintain adherence to the challenging medication regimen.”101 Other research found that people combating HCV who used cannabis while undergoing combination ribavirin and interferon treatment were about three times more likely to complete their conventional medical treatment than those participants who did not use cannabis.
While cannabis may have a positive biomedical effect on the immune system similar to that demonstrated with HIV, these studies indicate that for people fighting HCV it improves appetite and offers psychological benefits such as reduced depression that help them tolerate the treatment's unpleasant side effects.
According to the American Academy of Pain, nearly 50 million Americans suffer from persistent pain. Unfortunately, it is estimated that four out of every ten people living with moderate-to-severe pain have yet to experience relief. 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.”102
Although a wide variety of prescription analgesic drugs are available to treat pain-from aspirin to oxycontin-none of these drugs are completely adequate and many cause severe side-effects with continued use. Opiate painkillers are notorious for causing severe nausea, disorientation and drowsiness, while prolonged use can increase tolerance and, in some cases, result in severe dependence or addiction. Even milder analgesics can pose serious risk. Drugs such as aspirin can cause stomach irritation and in some cases ulceration. Prolonged use of acetaminophen can result in liver damage. Ibuprofen can cause kidney failure. Each of these analgesics can produce fatal overdose.
By contrast, the safety record of cannabis is remarkable, and its centuries of use as an analgesic well documented.103,104 In their meta-analysis of the available data, the Institute of Medicine acknowledged the wide use of cannabis for pain, noting that “after nausea and vomiting, chronic pain was the condition cited most often to the IOM study team as a medicinal use for marijuana.”105 Currently, pain relief is by far the most common condition for which physicians recommend the use of cannabis.
Many well-designed, double-blind placebo-controlled clinical trials clearly demonstrate that cannabis can reduce neuropathic pain, as previously noted. Years of clinical studies confirm that the active ingredients in cannabis have powerful analgesic effects, sometimes equivalent to codeine or morphine.106-109 A review of the body of scientific research concerning the analgesic effects of cannabis concluded that “[t]here is now unequivocal evidence that cannabinoids are antinociceptive [capable of blocking the transmission of pain] in animal models of acute pain.”105
Research shows that cannabinoids also produce an entourage effect that enhances the effectiveness of opiate painkillers. One animal study 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.106 Human and animal studies have repeatedly shown that cannabinoids work synergistically with opioid drugs in relieving neuropathic pain. Researchers suggest that direct and indirect interactions between opioid and cannabinoid receptors not only enhance analgesia but also reduce the development of tolerance to opiates. These interactions hold promise for developing therapeutic strategies that provide better pain relief with fewer of the dangerous and debilitating side effects that patients reliant on opiate pain killers experience.107-111
Decades of research on cannabis' effectiveness in pain management include clinical human trials and volumes of anecdotal evidence, as well as new understanding of how activation of the cannabinoid system in the central nervous system reduces sensitivity to pain.112-118 Some of the most encouraging clinical data on the effects of cannabinoids on pain involve the treatment of intractable cancer pain and hard-to-treat neuropathic pain. Somewhere between 25% and 45% of cancer patients experience neuropathic pain, a type of chronic nerve pain that resists conventional treatment.
The effectiveness of cannabis and cannabinoids in relieving neuropathic pain has been demonstrated in more than three dozen preclinical and clinical trials. A 2009 review notes that “a large number of research articles have demonstrated the efficacy of cannabinoids” for treating neuropathic pain and concludes that “cannabinoids show promise for treatment.”119
Multiple clinical trials have shown that a dosage-controlled whole-plant extract of cannabis (Sativex) relieves intractable cancer pain, and does so better than THC alone. A recent double blind, randomized, placebo-controlled trial of 360 cancer patients in 14 countries found that pain scores improved significantly with a cannabis extract. Researchers report that the combination of natural cannabinoids in Sativex “is an efficacious adjunctive treatment for cancer-related pain” for patients who do not get relief from opiate painkillers such as Oxycontin or Vicodin.120, 121
Pain from spinal injuries may also be treatable with cannabis. Several sets of researchers have recently published findings on the efficacy of cannabinoids in treating pain resulting from spinal cord injuries (SCI). A French team, noting that “very few pharmacological studies have dealt specifically with neuropathic pain related to SCI,” suggests that for “refractory central pain, cannabinoids may be proposed on the basis of positive results in other central pain conditions (e.g. multiple sclerosis).”122 Researchers have demonstrated in an animal model of SCI pain that cannabinoids yield more consistent positive results than conventional analgesics such as opiates, which “decrease in efficacy with repeated treatment over time,” concluding that drugs targeting the body's cannabinoid receptors “hold promise for long-term use in alleviating chronic SCI pain.”123
Researchers have also determined that neuropathic pain may be treatable via bolstering the body's natural cannabinoids. A study that inhibited the two enzymes that break down the body's natural cannabinoids found that preserving them “reduces neuropathic pain through distinct receptor mechanisms of action” that “present viable targets” for developing new analgesic drugs.124
Drugs which can selective target CB2 cannabinoid receptors, which are almost completely absent from the central nervous system, have also been shown to have therapeutic potential for both inflammatory and neuropathic pain control. 125
One survey of people living with multiple sclerosis reported that more than 40 percent of respondents used cannabis to relieve symptoms of the disease. Among them, nearly three quarters said that cannabis mitigated their muscle spasms, and more than half said it alleviated their pain. A similar survey found that 96% of Canadians living with MS believe cannabis is therapeutically useful for treating the disease. Of those who admitted using cannabis to treat symptoms of MS, the majority cited relief of chronic pain, spasticity, and depression.126
In addition, numerous studies have reported improvement in tremor, sexual dysfunction, bowel and bladder dysfunctions, vision dimness, dysfunctions of walking and balance (ataxia), and memory loss, as well as pain and spasticity.127-131
In fact, cannabinoids have been shown in animal models to not just measurably lessen MS symptoms but may also slow or halt the progression of the disease. Cannabinoids have demonstrated effects on immune function that may reduce the autoimmune neuroinflammatory response which drives relapsing neurological attacks and increasing disability.132-136 Clues as to why may lie in research that discovered that persons with multiple sclerosis have increased levels of endocannabinoids in their blood, indicating that the endocannabinoid system “may be dynamically modulated depending on the subtype of the disease.”137
Previous studies of the pharmacology of cannabis have identified effects on motor systems of the central nervous system that have the potential of affecting tremor and spasticity. A controlled study of the efficacy of THC in the animal model of MS, experimental allergic encephalomyelitis (EAE), demonstrated significant amelioration of these two MS symptoms. A review of six randomized controlled trials of a cannabis extracts that combines delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) finds “a trend of reduced spasticity in treated patients” and “evidence that combined THC and CBD extracts may provide therapeutic benefit for MS spasticity symptoms.”138
One such dosage-controlled THC-CBD whole-plant extract—GW Pharmaceuticals' sublingual spray, Sativex®—has been shown in numerous clinical trials to ease pain, decrease spasm frequency, and improve bladder control and sleep. Clinical trials of Sativex® found that it “demonstrated a statistically significant and clinically relevant improvement in spasticity and was well tolerated in MS patients.”139 As of June 2012, Sativex® is available by prescription in the UK, Spain, Germany and Denmark for the symptomatic relief of spasticity, neuropathic pain, or both in adults with multiple sclerosis. It has been approved for distribution in Italy, Sweden, Austria and the Czech Republic, with recommendations for approval in Belgium, Finland, Iceland, Ireland, Luxembourg, the Netherlands, Norway, Poland, Portugal and Slovakia.
MS patients frequently report cannabis helps with bladder control, and a review of studies on cannabinoid receptors in the bladder notes that non-psychoactive cannabinoids are effective, and psychotropic effects of THC can be mitigated by delivering cannabinoids directly into the bladder.140
The distribution of CB1 cannabinoid receptors in the brain suggests that they may play a role in movement control. Only recently have scientists identified EAE as an animal model for MS, allowing testing for symptom suppression. While objective measures of spasticity in humans have not consistently shown benefit from cannabinoid treatment, a randomized clinical trial with 189 MS patients being treated with a cannabis extract showed 40% achieved a greater than 30% improvement.141
In addition to studying the potential role of cannabis and its derivatives in the treatment of MS-related symptoms, scientists are exploring the potential of cannabinoids to inhibit neurodegeneration. A 2003 study that the National MS Society called “interesting and potentially exciting” demonstrated that cannabinoids were able to slow the disease process in mice by offering neuroprotection against EAE.142 Neurodegeneration is implicated in a host of debilitating conditions.
Other Movement Disorders
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 relief for spasticity. 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 people find intolerable.
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.”143 Contemporary animal and human clinical studies reveal that cannabis and its constituent cannabinoids may effectively treat movement disorders affecting older patients, such as tremors and spasticity, because cannabis has antispasticity, analgesic, antitremor, and antiataxia actions.144-155
As mentioned, the contemporary understanding of the actions of cannabis was advanced by the discovery of an endogenous cannabinoid system in the human body. This system appears to be intricately involved in regulating normal physiology.156-158 Central cannabinoid receptors are densely located in the basal ganglia, the area of the brain that controls 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 others, 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 endogenous cannabinoid “tone” participates in the control of movements.160-161
Endocannabinoids have modulating effects on the 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 endocannabinoids, it is becoming clear that these chemicals may be involved in the pathology of several neurological diseases. This means 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.162
The neuroprotective qualities of cannabis mean it has enormous potential for protecting the brain and central nervous system from the damage from disease or injury that creates various disorders. Researchers have found that cannabinoids fight the effects of strokes, brain trauma, and spinal cord injury, as well as multiple sclerosis and neurodegenerative diseases. More than 100 research articles have been published on how cannabinoids act as neuroprotective agents that slow the progression of Huntington's, Alzheimer's, and particularly Parkinson's, a condition that affects more than 52% of people over the age of 85.163-165
According to the Arthritis Foundation, arthritis is one of the most prevalent chronic health problems and the nation's leading cause of disability among Americans over age 15. A 2006 report estimated that 46 million Americans-nearly 1 in 5 adults-live with chronic joint pain and arthritis.
The use of cannabis as a treatment for musculoskeletal pain in western medicine dates to the 1700s.166 Modern research confirms that cannabis and related therapies can relieve the pain associated with arthritis and the other rheumatic and degenerative hip, joint and connective tissue disorders. Not only is cannabis an effective pain reliever and anti-inflammatory in its own right, it also has the potential to enhance the efficacy of opiate painkillers, allowing for better pain relief at reduced dosages. In their 1999 meta-analysis of the data then available, the Institutes of Medicine specifically noted that the anti-inflammatory properties of cannabinoids could have therapeutic application in preventing or reducing pain caused by swelling (such as arthritis).167
Research has shown that cannabis and its constituent cannabinoids have powerful immune-modulation and anti-inflammatory properties that may treat chronic inflammatory diseases directly.168-170 Many patients and doctors report cannabis has proven an effective treatment for rheumatoid arthritis, and it is one of the recognized conditions for which many states permit medical use. Specifically, cannabis has a demonstrated ability to improve mobility and reduce morning stiffness and inflammation, and research suggests that individuals can reduce their use of potentially harmful Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) when using cannabis as an adjunct therapy.171,172
One of the non-psychoactive cannabinoid components of cannabis, cannibidol (CBD), has also been shown to have numerous medical applications as an anti-inflammatory and neuroprotective agent, including as a treatment for rheumatoid arthritis.173-175 Research indicates that CBD 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.176,177
Alzheimer's disease is a neurodegenerative condition for which cannabis and cannabinoid therapies show promise, both for treating the symptoms and the underlying disease.
Agitation is the most common behavioral management problem in people with Alzheimer's and affects an estimated 75 percent of people with the disease. It can include symptoms ranging from physical or verbal abusive behavior to pacing and restlessness, as well as disruptive behaviors such as screaming and repetitive requests for attention. Clinical research involving THC indicates that the cannabinoid reduced the agitation common to Alzheimer's sufferers.178,179 THC is also proven effective in combating anorexia or wasting syndrome, a common problem for people with Alzheimer's disease.180
Alzheimer's disease is widely held to be associated with oxidative stress due, in part, to the membrane action of beta-amyloid peptide aggregates. Recent studies have indicated that one of the cannabis plant's primary components, cannabidiol (CBD), combats that problem through a combination of neuroprotective, anti-oxidative and anti-apoptotic effects by inhibiting the release of the toxic beta-amyloid peptide.181,182
This new research, coupled with the extensive work done on other neuroprotective qualities of cannabis and its components, indicates that cannabis or cannabis-based therapy may become the source of the most effective treatments for battling the Central Nervous System diseases that afflict millions of elderly Americans.183-186
The 'Pharmaceuticalization' of Cannabis
Dr. Lester Grinspoon, a professor emeritus at Harvard Medical School and author of several books on the medical use of cannabis, has defined the “pharmaceuticalization of cannabis” as the development of isolated individual cannabinoids, synthetic cannabinoids, and cannabinoid analogs. While this process is characteristic of medical research, it also represents what Dr. Grinspoon describes as the U.S. federal government's desire to introduce a cannabis-like pill to replace natural cannabis use.187 The first efforts to “pharmaceuticalize” cannabis came to fruition in 1985 when a synthetic form of THC known as dronabinol (or Marinol) was approved by the FDA.
Dronabinol (Marinol) is an encapsulated synthetic preparation of delta-9-tetrahydrocannabinol, the primary psychoactive cannabinoid found in the cannabis plant, suspended in sesame oil. Designed and marketed by Solvay Pharmaceuticals and its subsidiary Unimed, Marinol was first indicated for treatment of nausea and vomiting associated with cancer chemotherapy in people who failed to respond adequately to conventional antiemetic treatments; it was later made available for the treatment of anorexia associated with weight loss for people living with HIV/AIDS.
When first approved for medical use, dronabinol was tightly controlled as a Schedule II drug under the Controlled Substances Act, meaning it was classified as a drug with a “high potential for abuse” that could “lead to severe psychological or physical dependence.” In 1999, in response to a rescheduling request by Unimed to make dronabinol more widely available, it was moved by administrative rule to Schedule III, meaning it was now classified as having a lower potential for abuse and only a low or moderate likelihood of physical dependency. Currently Marinol is available in three dosage strengths: 2.5, 5, and 10mg. Despite the well-documented therapeutic value of THC, dronabinol has enjoyed only moderate success.
Marinol's oral route of administration hampers its effectiveness because of slow absorption and difficulty in controlling dosing. In their review of Marinol, the Institute of Medicine specifically noted that only about 10-20% of an oral dose is absorbed by the human body, and onset of action is not obtained until two and four hours after dosing. By contrast, inhalation yields very rapid onset of therapeutic effects, allowing for both more immediate relief and control over dosage. People prescribed dronabinol for severe nausea and vomiting also frequently report difficulty keeping the pills down, a problem not shared by inhalation delivery methods.
Nabilone (Cesamet) is a synthetic derivative of THC with a slightly modified molecular structure from dronabinol. Currently available for medical use in Canada, United Kingdom, and Mexico, it was approved by the FDA in 1985 for treatment of chemotherapy-induced nausea and vomiting that has not responded to conventional medication. Although nabilone was approved more than twenty years ago, it has only been marketed in the United States since 2006 as a treatment of nausea and vomiting caused by cancer chemotherapy.
Cannabis Extract Oral-mucosal Spray (Sativex®)
THC or delta-9-tetrahydrocannabinol is the most familiar cannabinoid, and its therapeutic effects have been well established. However, at least 100 other cannabinoids have been identified in cannabis, including CBD, which not only offset the psychoactive effect of THC, but may contain therapeutic benefits of their own. In fact, research suggests that the therapeutic effect of cannabis might be linked to what researchers call an “entourage effect,” the synergistic relationship between multiple cannabinoids which may make them more therapeutically beneficial in combination then they are individually.
Researchers affiliated with GW Pharmaceuticals, a company founded in the United Kingdom in 1998 to develop cannabis-based medicines, have noted that in practice medicines or extracts derived from the cannabis plant provide greater relief of pain than the equivalent amount of synthetic cannabinoid given as a single chemical entity like dronabinol.
Sativex® is GW Pharmaceuticals' lead cannabinoid product, and in 2005 became the world's first prescription medicine derived from extracts of the cannabis plant. Specifically, Sativex® is a cannabis extract containing equal amounts of dronabinol (THC) and cannabidol (CBD), which is administered as an oral spray absorbed in the patient's mouth.
Sativex® is available by prescription for varying conditions in Canada, the UK, Spain, New Zealand, and Germany. It has been approved for distribution in the Czech Republic and Denmark, and regulatory approval is pending in Italy, Sweden and Austria. It is currently undergoing late stage clinical trials in the United States. Upon approval in the United States, Sativex will be marketed by Otsuka Pharmaceuticals.
The primary indication for which Sativex® has been approved is for the treatment of spasticity due to multiple sclerosis. In Canada, it is also approved for symptomatic relief of neuropathic pain in multiple sclerosis and as adjunctive analgesic treatment in people with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background pain.
According to Dr. Grinspoon's theory, the “pharmaceuticalization” of cannabis will only succeed if the pharmaceutical derivatives and extracts displace cannabis as medicine. Although a few individuals will prefer dose-consistent pharmaceutical alternatives, it seems unlikely that these drugs will completely replace the use of organic cannabis, especially given the plant's negligible toxicity, easy availability, and low cost of production relative to pharmaceuticals. New vaporization devices that replace smoking as an easy and rapid delivery method that allows better dosage control than oral ingestion of pills or oralmucosal sprays such as Sativex® are expanding the plant's remarkable medical versatility.
The U.S. Research Experience
Over the past three decades, there has been an explosion of international research on the therapeutic applications of cannabis and cannabinoids. But restrictions on cannabis research in the U.S. have resulted in very few clinical trials conducted domestically. Meanwhile, scientific teams in Great Britain, Spain, Italy, Israel, and elsewhere have confirmed-through case studies, basic research, pre-clinical and clinical investigations-the medical value of cannabis for treating a wide variety of conditions. Equally important, numerous studies have provided strong indications of the potential for more targeted drugs, whole-plant cannabis derivatives and synthetic cannabinoids. The current research challenge is to conduct controlled human clinical trials that can establish protocols for cannabis-based treatments of specific medical conditions.
That challenge was identified in Marijuana and Medicine, the Institute of Medicine's 1999 report, but there has been no additional U.S. government effort to fully implement the IOM's recommendations or review the vast amount of research conducted since then. Worse, the federal prohibition of cannabis continues to limit clinical research that could investigate the safety and efficacy of cannabis to treat serious and chronic conditions or control their symptoms. In the United States research is stalled, and in some cases blocked, by a complicated federal approval process and restricted access to research-grade cannabis, despite the order of a federal administrative law judge to allow other production sites to meet research demands.
A Movement in Public Health
Despite barriers to research, a growing body of clinical data supports the use of cannabis for medical purposes, as it has been for millennia. While there is still much to learn, the medical value of cannabis is indisputable. As a result, a growing number of public health organizations have endorsed the therapeutic use of cannabis and programs that advance medical and scientific research. Here are some of the more prominent ones.
In 1994 the Federation of American Scientists recommended that the President instruct the National Institutes of Health and the FDA to reopen Investigational New Drug (IND) protocols that would provide federal research cannabis to seriously ill patients who physicians believed would be helped by it. The following year, the American Public Health Association passed a resolution that encourages vigorous research and “urges the Administration and Congress to move expeditiously to make cannabis available as a legal medicine.”
In 1996 the American Academy of Family Physicians offered their support for using medical cannabis to treat specific conditions under the supervision of a licensed medical professional. And, in 1997, two years prior to the publication of the Institute of Medicine's report, the New England Journal of Medicine, one of the world's leading medical publications, published an editorial that said:
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... [because] there is no risk of death from smoking marijuana.
Citing the 1999 Institute of Medicine report and studies published since which indicate that the use of cannabis can alleviate the debilitating symptoms of cancer chemotherapy and wasting, the Lymphoma Foundation of America passed a resolution urging Congress and the President to enact legislation to reschedule cannabis to allow doctors to prescribe cannabis for their patients in accordance with need. The Leukemia & Lymphoma Society also “supports legislation to remove criminal and civil sanctions for the doctor-advised, medical use of marijuana by patients with serious physical medical conditions” and has encouraged “the federal government to authorize the Drug Enforcement Administration to license privately funded production facilities that meet all regulatory requirements to produce pharmaceutical-grade marijuana for use exclusively in federally approved research.”
Following the lead of several state nurses organizations, the American Nurses Association passed a resolution in support of health care providers who recommend the use of cannabis and further acknowledged that “the right of patients to have safe access to therapeutic cannabis.” The ANA specifically called for more research and urged the removal of cannabis from the list of Schedule I controlled substances.
The Assembly of the American Psychiatric Association unanimously approved a strongly worded statement championing legal protections for individuals using cannabis in accordance with a physician's recommendation. The American Psychiatric Association is the main professional organization for psychiatrists in the United States, representing 40,000 members and 16 allied organizations (including the American Academy of Psychiatry and the Law, American Academy of Child and Adolescent Psychiatry, American Association for Social Psychiatry, American Academy of Addiction Psychiatry, and the American Association of Emergency Psychiatrists).
Other professional health organizations that have endorsed the medical use of cannabis include the American Public Health Association, the American Academy of Family Physicians, the National Association of Boards of Pharmacy, the California Medical Association, the American Preventive Medical Association, the American Society of Addiction Medicine, the Iowa Board of Pharmacy, and many more.
In 2008, the American College of Physicians (ACP) published a position paper underscoring the therapeutic value of cannabis and specifically recommending the federal government consider “reclassification [of cannabis] into a more appropriate schedule, given the scientific evidence regarding marijuana's safety and efficacy in some clinical conditions.” The ACP is the second largest physician group in the United States with 124,000 members and publishes the the most widely-cited medical specialty journal in the world. Prominent public health organizations such as the American Medical Association, the American Cancer Society, the British Medical Journal and many others have issued statements of support for cannabis research.
Regarding the growing support by public health organization, former Surgeon General Dr. Jocelyn Elders observed that “large medical associations are by their nature slow and cautious creatures that move only when the evidence is overwhelming.” She continued, “The evidence is indeed overwhelming that, as ACP put it, there is 'a clear discord' between what research tells us and what our laws say about medical marijuana.”
The current acceptance of cannabis as medicine in the US is further evidenced by the thousands of American doctors who have recommended its use to their patients, the tens of thousands of individuals who are using it safely and effectively, and millions of American voters and many state legislatures—representing more than 1/3 of the U.S. population—that have approved its legal use as medicine.
Government Studies and Programs
LaGuardia Report (1944)
The 1937 Marihuana Tax Act may have ended safe and legal access, but it did not end the debate about cannabis policy. In 1939, New York Mayor Fiorello LaGuardia appointed a blue-ribbon panel of renowned physicians, psychiatrists, clinical psychologists, pharmacologists, chemists and other researchers from the New York Academy of Medicine to review claims that smoking cannabis resulted in criminal behavior and a deterioration of physical and mental health.
A summary of the preliminary findings published in 1942 by the American Journal of Psychiatry concluded that “prolonged use of marihuana does not lead to physical, mental or moral degeneration, nor have we observed any permanent deleterious effects from its continued use. Quite the contrary, marihuana and its derivatives and allied synthetics have potentially valuable therapeutic applications which merit further investigation.”3 The final LaGuardia report expanded on those findings, noting that cannabis is not addictive, does not provide a gateway to other drugs of abuse, and is not associated with increased criminal behavior or juvenile delinquency.
The National Commission on Marihuana and Drug Abuse (1972)
The Comprehensive Drug Abuse Prevention and Control Act of 1970 included a provision to study the abuse of cannabis in the United States. President Richard Nixon appointed Pennsylvania Governor Raymond Shafer to chair the National Commission on Marihuana and Drug Abuse. On March 22, 1972, the commission presented to Congress its report, “Marihuana: A Signal of Misunderstanding.”
The Shafer report, like the LaGuardia report before it, concluded that cannabis use does not jeopardize health, lead to experimentation with other drugs, or cause criminal activity. It recommended the decriminalization of cannabis for personal use. President Nixon rejected the Shafer report because it conflicted with many of the provisions of both the Comprehensive Drug Abuse Prevention and Control Act and the Controlled Substances Act. Instead of accepting the findings of scientists and doctors, Nixon declared a “War on Drugs.”
Investigational New Drug Compassionate Access (1978)
In 1975, shortly after discovering that smoking cannabis could relieve symptoms of his severe glaucoma, Washington, DC resident Robert Randall was arrested for cultivating cannabis in his home. Randall successfully used the common law “Doctrine of Necessity” to fight the charges. In November 1976, Judge James Washington ruled that “[w]hile blindness was shown by competent medical testimony to be the otherwise inevitable result of the defendant's disease, no adverse effects from the smoking of marijuana have been demonstrated. Medical evidence suggests that the medical prohibition is not well-founded.”
Randall petitioned the federal government to provide him with access to medical cannabis in accordance with his medical necessity and shortly thereafter became the first American to receive a government-supplied source of cannabis. When Randall went public with his victory, the federal government retaliated with threats to withdraw his access to cannabis. In 1978, Randall filed suit, and federal agencies settled immediately by agreeing to provide free cannabis through a local pharmacy. The Randall settlement helped create the FDA's Investigational New Drug (IND) Compassionate Access Program, which continues to supply a handful of individuals who suffer from severe or chronic illness with a free monthly supply of federally grown cannabis, up to nine pounds annually.
Though only 30 patients were ever enrolled in the program at any one time, in 1992 an overwhelming number of applications from people suffering the effects of AIDS led President George H.W. Bush to close the program to new applicants, citing concerns that the program undermined prohibition.
In 2002, a study of the remaining individuals in the federal IND program found cannabis to have long-term clinical effectiveness in treating chronic musculoskeletal pain, spasm and nausea, and spasticity associated with multiple sclerosis. Assessment of their physiological systems using MRI scans of the brain, pulmonary function tests, chest X-ray, neuropsychological tests, hormone and immunological assays, electroencephalography, P300 testing and neurological clinical examinations found no functionally significant health problems after 11 to 27 years consuming up to 12 joints a day.4
Institute of Medicine (1982, 1999)
In 1982, the Institute of Medicine (IOM), a division of the National Academy of Sciences, published the report “Marijuana and Health.” The IOM noted that “[p]reliminary studies suggest that marijuana and its derivatives or analogues might be useful in the treatment of the raised intraocular pressure of glaucoma, in the control of the severe nausea and vomiting caused by cancer chemotherapy, and in the treatment of asthma.”5
More than a decade later, in response to new state laws that permitted the use of cannabis on the recommendation of a licensed physician, the White House Office of National Drug Control Policy commissioned another report from the IOM to assess the medical and scientific value of cannabis. In 1999 the IOM published Marijuana as Medicine: Assessing the Science Base, a comprehensive meta-analysis of existing research concerning the therapeutic value of cannabis.6 In describing the findings of the IOM review, the Congressional Research Service observes that “[f]or the most part, the IOM Report straddled the fence and provided sound bites for both sides of the medical marijuana debate.”7
Both IOM reports conclude that there is a sound medical and scientific basis for using cannabis as treatment for a variety of serious or chronic medical conditions. Both reports emphasize the need for continued research with a focus on well-designed clinical trials aimed at developing rapid-onset, reliable, and safe delivery systems. Congress and executive agencies have largely ignored these findings and have never convened a panel to oversee the full implementation of recommendations.
The House of Lords Select Committee on Science & Technology Report (1998)
In 1998, the British House of Lords Select Committee on Science and Technology issued a comprehensive report on cannabis that includes testimony from people with serious illness, scientific researchers, and physicians. The report recommended immediately rescheduling cannabis so that doctors could prescribe cannabis to their patients and pharmacies could safely distribute cannabis. This recommendation was made in part because the committee acknowledged that individuals using cannabis for therapeutic purposes “are caught in the front line of the war against drug abuse. This makes criminals of people whose intentions are innocent, it adds to the burden on enforcement agencies, and it brings the law into disrepute. Legalizing medical use on prescription, in the way that we recommend, would create a clear separation between medical and recreational use, under control of the health care professions.”8
The report says further “that clinical trials of cannabis for the treatment of MS and chronic pain should be mounted as a matter of urgency.” Specifically, the committee recommended that research focus on alternative modes of administration that “would retain the benefit of rapid absorption offered by smoking, without the adverse effects.”
Since then, a variety of vaporizing systems have been developed and commercially marketed that allow for rapid-onset delivery of cannabis via inhalation without smoking. A sublingual cannabis spray is now also available from GW Pharmaceuticals and has been approved as of 2011 for use by prescription in the UK, Canada, Spain, Germany, Denmark, and the Czech Republic.
1. American College of Physicians. 2008. Supporting Research into the Therapeutic Role of Marijuana.http://www.acponline.org/advocacy/where_we_stand/other_issues/medmarijuana.pdf
2. Woodward C. 1937. Statement of Dr. William C Woodward, Legislative Council, American Medical Association, before the House of Representatives, Committee on Ways and Means, May 4, 1937. Dr. Woodard warned Congress that a prohibition "loses sight of the fact that future investigation may show that there are substantial medical uses for cannabis." http://www.druglibrary.org/schaffer/hemp/taxact/woodward.htm (accessed June 22, 2012).
3. Allentuck S, Bowman K. 1942. The Psychiatric Aspects of Marihuana Intoxication. American Journal of Psychiatry , 99(2).
4. Russo E et al. Chronic Cannabis Use in the Compassionate Investigational New Drug Program: An Examination of Benefits and Adverse Effects of Legal Clinical Cannabis. Journal of Cannabis Therapeutics, Vol. 2(1) 2002.
5. Institute of Medicine. 1982. Marijuana and Health: Report of a Study by a Committee of the Institute of Medicine, Division of Health Sciences Policy. National Research Council of the National Academy of Science.
6. Joy JE et al. 1999. Marijuana and Medicine: Assessing the Science Base. Division of Neuroscience and Behavioral Research, Institute of Medicine. Washington, DC: National Academy Press.
7. Eddy M. 2010. Medical Marijuana: Review and Analysis of Federal and State Policies. Congressional Research Service. http://www.fas.org/sgp/crs/misc/RL33211.pdf (accessed June 22, 2012).
8. House of Lords Select Committee on Science and Technology. 1998. Cannabis: The Scientific and Medical Evidence. London, The Stationery Office, Parliament.
9. Russo E. 2007. The Solution to the Medicinal Cannabis Problem. Ethical Issues in Chronic Pain Management. Informa Healthcare. New York.
10. Mechoulam, R. Ed. 2005. Cannabinoids as Therapeutics. Milestones in Drug Therapy. Birkhäuser Basel.
11. Breivogel CS et al. 1998. The functional neuoanatomy of brain cannabinoid receptors. Neurobiol Dis; 5:417-431.
12. Makriyannis A, Mechoulam R, Piomelli D. Therapeutic opportunities through modulation of the endocannabinoid system. 2005. Neuropharmacology 48:1068-1071.
13. Grant I, et al. 2010. Report to the Legislature and Governor of the State of California. Center for Medicinal Cannabis Research. Results of only five of the 14 studies conducted have been published to date, with a sixth completed but not yet published. Two showed that smoked cannabis was effective for hard-to-treat pain in HIV patients. One demonstrated that cannabis is effective for relieving neuropathic pain related to spinal cord injuries and other conditions. Another study found that higher doses of cannabis produced more relief in subjects who had pain induced via chemical heat. The remaining studies have not yet been completed. Studies appear in the peer-reviewed journals Neurology, Journal of Pain, Anesthesiology, Neuropsychopharmacology, and Clinical Pharmacology & Therapeutics. www.cmcr.ucsd.edu/CMCR_REPORT_FEB17.pdf (accessed June 22, 2012).
14. Aggrawal S et al. 2009. Medicinal use of cannabis in the United States: historical perspectives, current trends, and future directions. J Opioid Manag. May-Jun;5(3):153-68.
15. Doblin R. 1991. Marijuana as Antiemetic Medicine: A Survey of Oncologists' Experiences and Attitudes. AK. Journal of Clinical Oncology.
16. Joy JE. Op Cit.
17. Musty R, Rossi R. 2001. Effects of smoked cannabis and oral D9-tetrahydrocannabinol on nausea and emesis after cancer chemotherapy: a review of state clinical trials. Journal of Cannabis Therapeutics 1:29-42.
18. Guzman M. 2003. Cannabinoids: potential anticancer agents. Nat Rev Cancer. 3(10): 745-55.
19. Machado. 2008. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur J cancer Care Sep;17(5):431-43.
20. Gieringer D. 1996. Review of the Human Studies on the Medical Use of Marijuana. norml.org/medical/medmj.studies.shtml. See state studies at www.drugpolicy.org/
21. Hall W et al. 1994. The Health and Psychological Consequences of Cannabis Use, Canberra, Australian Government Publishing Service: 189. www.druglibrary.org/
22. House of Lords. Op cit.
23. British Medical Association. 1997. Therapeutic Uses of Cannabis. Harwood Academic Pub.
24. Sarfaraz et al. 2005. Cannabinoid receptors as a novel target for the treatment of prostate cancer. Cancer Research 65: 1635-1641.
25. Mimeault et al. 2003. Anti-proliferative and apoptotic effects of anandamide in human prostatic cancer cell lines. Prostate 56: 1-12.
26. Ruiz et al. 1999. Delta-9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism. FEBS Letters 458: 400-404.
27. Pastos et al. 2005. The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase-2. Gut 54: 1741-1750.
28. Casanova et al. 2003. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. Journal of Clinical Investigation 111: 43-50.
29. Powles et al. 2005. Cannabis-induced cytotoxicity in leukemic cell lines. Blood 105: 1214-1221
30. Guzman et al. 2003. Inhibition of tumor angiogenesis by cannabinoids. The FASEB Journal 17: 529-531.
31. Jia et al. 2006. Delta9-tetrahydrocannabinol-induced apoptosis in Jurkat leukemia T cells is regulated by translocation of Bad to mitochondria. Molecular Cancer Research 4: 549-562.
32. Preet et al. 2008. Delta9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo. Oncogene 10: 339-346.
33. Baek et al. 1998. Antitumor activity of cannabigerol against human oral epitheloid carcinoma cells. Archives of Pharmacal Research: 21: 353-356.
34. Carracedo et al. 2006. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Research 66: 6748-6755.
35. Michalski et al. 2008. Cannabinoids in pancreatic cancer: correlation with survival and pain. International Journal of Cancer 122: 742-750.
36. Ramer, Hinz. 2008. Inhibition of cancer cell invasion by cannabinoids via increased cell expression of tissue inhibitor of matrix metalloproteinases-1. Journal of the National Cancer Institute 100: 59-69.
37. Whyte et al. 2010. Cannabinoids inhibit cellular respiration of human oral cancer cells. Pharmacology 85: 328-335.
38. Leelawat et al. 2010. The dual effects of delta(9)-tetrahydrocannabinol on cholangiocarcinoma cells: anti-invasion activity at low concentration and apoptosis induction at high concentration. Cancer Investigation 28: 357-363.
39. Gustafsson et al. 2006. Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212 is associated with ceramide accumulation and p38 activation in Mantle Cell Lymphoma. Molecular Pharmacology 70: 1612-1620.
40. Gustafsson et al. 2008. Expression of cannabinoid receptors type 1 and type 2 in non-Hodgkin lymphoma: Growth inhibition by receptor activation. International Journal of Cancer 123: 1025-1033.
41. Liu et al. 2008. Enhancing the in vitro cytotoxic activity of Ä9-tetrahydrocannabinol in leukemic cells through a combinatorial approach. Leukemia and Lymphoma 49: 1800-1809.
42. Torres S, et al. 2011. THC and cannabidiol (CBD) remarkably reduced the growth of gliomas. A combination of cannabinoids and temozolomide (TMZ) produced a strong anti- tumoural action in both TMZ-sensitive and TMZ-resistant tumours. Mol Cancer Ther ;10(1):90-103.
43. Galve-Roperph I, et al. 1998. Delta-9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Letters 436: 6-10.
44. Guzman et al. 2000. Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nature Medicine 6: 313-319.
45. Guzman et al. 2003. Inhibition of tumor angiogenesis by cannabinoids. The FASEB Journal 17: 529-531.
46. Alexander A, et al. 2009. Cannabinoids in the Treatment of Cancer. Cancer Lett Nov 18:285(1):6-12.
47. Olea-Herrero N et al. 2009. Inhibition of human tumour prostate PC-3 cell growth by cannabinoids R(+)-Methanandamide and JWH-015: Involvement of CB2. British Journal of Cancer. 101, 940-950.
48. Blazquez C et al (2003) Inhibition of tumor angiogenesis by cannabinoids. FASEB J. 17(3): 529-31.
49. Sanchez C et al. 2001. Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res. 61(15): 5784-9.
50. Casanova ML et al. Op Cit.
51. Jacobsson SO, et al. 2001. Inhibition of rat C6 glioma cell proliferation by endogenous and synthetic cannabinoids. Relative involvement of cannabinoid and vanilloid receptors. J Pharmacol Exp Ther. Dec;299(3): 951-9.
52. Galve-Roperph I et al. Op Cit.
53. ACM Bulletin. "THC destroys brain cancer in animal research." http: //www.acmed.org/english/2000/eb000305.html
54. Gonzalez S et al. 2000. Decreased cannabinoid CB1 receptor mRNA levels and immunoreactivity in pituitary hyperplasia induced by prolonged exposure to estrogens. Pituitary. 3(4):221-6.
55. Pagotto U et al. 2001. Normal human pituitary gland and pituitary adenomas express cannabinoid receptor type 1 and synthesize endogenous cannabinoids: first evidence for a direct role of cannabinoids on hormone modulation at the human pituitary level. J Clin Endocrinol Metab. 86(6):2687-96
56. Bifulco M et al. 2001. Control by the endogenous cannabinoid system of ras oncogene-dependent tumor growth. FASEB J. 15(14): 2745-7. Epub 2001 Oct 29.
57. Rubovitch V et al. 2002. The cannabinoid agonist DALN positively modulates L-type voltage-dependent calcium-channels in N18TG2 neuroblastoma cells. Brain Res Mol Brain Res. 101(1-2):93-102.
58. Ramer R. 2010. Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1. Biochem Pharmacol. Apr 1;79(7):955-66. Researchers found that the non-psychoactive cannabinoid cannabidiol (CBD) inhibited the invasion of both human cervical cancer and human lung cancer cells. By manipulating cannabidiol's upregulation of a tissue inhibitor, researchers may have revealed the mechanism of CBD's tumor-fighting effect. A further in vivo study demonstrated "a significant inhibition" of lung cancer metastasis in mice treated with CBD.
59. McAllister et al. 2007. Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells. Molecular Cancer Therapeutics 6: 2921-2927.
60. Cafferal et al. 2010. Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition. Molecular Cancer 9: 196.
61. De Petrocellis et al. 1998. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 95: 8375-8380.
62. Cafferal et al. 2006. Delta-9-Tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation. Cancer Research 66: 6615-6621.
63. Di Marzo et al. 2006. Anti-tumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. Journal of Pharmacology and Experimental Therapeutics Fast Forward 318: 1375-1387.
64. Leelawat et al. 2010. Op Cit.
65. Guzman et al. 2004. Cannabinoids inhibit the vascular endothelial growth factor pathways in gliomas (PDF). Cancer Research 64: 5617-5623.
66. Massi P et al. 2004. Antitumor effects of cannabidiol, a nonpsychoative cannabinoid, on human glioma cell lines. JPET 308:838-845.
67. Allister et al. 2005. Cannabinoids selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells. Journal of Neurooncology 74: 31-40.
68. Marcu J et al (2010). Cannabidiol enhances the inhibitory effects of Delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Molecular Cancer Therapeutics 9(1):180-9
69. Stella N. 2010. Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia. Jul;58(9):1017-30.
70. Guzman et al. 1998. Delta-9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Letters 436: 6-10.
71. Massi et al. 2004. Antitumor effects of cannabidiol, a non-psychotropic cannabinoid, on human glioma cell lines. Journal of Pharmacology and Experimental Therapeutics Fast Forward 308: 838-845.
72. Guzman et al. 2004. Cannabinoids inhibit the vascular endothelial growth factor pathways in gliomas. Cancer Research 64: 5617-5623.
73. Allister et al. 2005. Cannabinoids selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells. Journal of Neurooncology 74: 31-40.
74. Guzman et al. 2006. A pilot clinical study of delta-9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. British Journal of Cancer (E-pub ahead of print).
75. Parolaro and Massi. 2008. Cannabinoids as a potential new drug therapy for the treatment of gliomas. Expert Reviews of Neurotherapeutics 8: 37-49
76. Galanti et al. 2007. Delta9-Tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells. Acta Oncologica 12: 1-9.
77. Calatozzolo et al. 2007. Expression of cannabinoid receptors and neurotrophins in human gliomas. Neurological Sciences 28: 304-310.
78. Tashkin D. 2006. Paper presented at American Thoracic Society 102nd International Conference, San Diego, May 23, 2006.
79. Lang C et al. 2009. A population-based case-control study of marijuana use and head and neck squamous cell carcinoma. Cancer Prev Res, 2(8): 759-68.
80. Prentiss D et al. 2004. Patterns of Marijuana Use Among Patients With HIV/AIDS Followed in a Public Health Care Setting. J Acquir Immune Defic Syndr, 35(1): 38-45.
81. Corless IB et al. 2009. Marijuana Effectiveness as an HIV Self-Care Strategy. Clinical Nursing Research, 18(2): 172-193.
82. Bouke C. de Jong et al. 2007. Marijuana Use and Its Association with Adherence to Antiretroviral Therapy Among HIV-Infected Persons With Moderate to Severe Nausea . J. Acquir Immune Defic Syndr, 38(1): 43-46.
83. Hollister L. 1971. Hunger and appetite after single doses of marihuana, alcohol, and dextroamphetamine. Clinical Pharmacology and Therapeutics. 12 44-49.
84. Greenberg I et al. 1976. Effects of marihuana use on body weight and caloric intake in humans. Journal of Psychopharmacology (Berlin). 49 79-84.
85. Foltin R et al. 1988. Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory. Appetite 11: 1-14.
86. Abrams DI, et al. 2003. Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo-controlled clinical trial. Annals of Internal Medicine139(4):258-266.
87. Costantino CM, et al. 2012. Cannabinoid Receptor 2-Mediated Attenuation of CXCR4-Tropic HIV Infection in Primary CD4+ T Cells. PLoS ONE 7(3): e33961.
88. Rahn EJ Hohmann AG. 2009. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics. Oct;6(4):713-37.
89. Abrams DI et al. 2003. Op Cit.
90. Abrams DI et al. 2007. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology, 68(7), 515-521.
91. Karst M et al. 2003. Analgesic Effect of the Synthetic Cannabinoid CT-3 on Chronic Neuropathic Pain A Randomized Controlled Trial. JAMA. 290:1757-1762.
92. Ellis RJ, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacol 2009; 34(3): 672-80.
93. Wilsey B. 2007. A Randomized, Placebo-Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic Pain. Journal of Pain; (9)6, 506-521.
94. Ware MA, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ 2010;182(14): E694-701.
95. Rog DJ, et al. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 2005; 65(6):812-9.
96. Nurmikko TJ, et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain 2007 ;133(1-3): 210-20.
97. Wallace M, Schulteis G, Atkinson JH, et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology 2007;107(5):785-96.
98. Lucas P. 2012. Cannabis as an adjunct to or substitute for opiates in the treatment of chronic pain.J Psychoactive Drugs Apr-Jun;44(2):125-33.
99. Welch SP, Eads M. 1999. Synergistic interactions of endogenous opioids and cannabinoid systems. Brain Res. Nov. 27;848 (1-2): 183-90.
100. Russo EB. 2011. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol Aug;163(7):1344-64.
101. Sylvestre DL, Clements BJ, Malibu Y. 2006. Cannabis use improves retention and virological outcomes in patients treated for hepatitis C. European Journal of Gastroenterology and Hepatology 18:1057-1063.
102. Deadwyler S, et al. 1997. Marijuana & Analgesia. Press Conference, Society for Neuroscience 27th Annual Meeting, New Orleans. October 26, 1997. http://www.druglibrary.org/olsen/MEDICAL/POT/analgesia.html (accessed June 22, 2012); "Marijuana-Like Drugs May Be Effective Painkillers." Los Angeles Times. 26 Oct. 1997.
103. O'Shaughnessy WB. 1838. On the preparations of the Indian hemp, or gunjah (Cannabis indica); their effects on the animal system in health, and their utility in the treatment of tetanus and other convulsive diseases. Transactions of the Medical and Physical Society of Bengal. 18; 40: 71-102, 421-61.
104. Russo EB. 2001. Cannabis and Cannabinoids: Their Roles in Pain Management. Weiner RS (ed.) Pain Management: A Clinical Guide for Clinicians, 6th edition, CRC Press, Boca Raton, FL.
105. Joy JE. Op Cit.
106. Richardson J et al. 1998. Cannabinoids Reduce Hyperalgesia and Inflammation via Interaction with Peripheral CB1 Receptors. Pain. 75(1): 111-119.
107. Abrams DI, et al. 2011. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther. Dec;90(6):844-51.
108. Cichewicz DL, McCarthy EA. 2003. Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. J Pharmacol Exp Ther. 2003 Mar;304(3):1010-5.
109. Cox ML, Haller VL, Welch SP. 2007. Synergy between delta9-tetrahydrocannabinol and morphine in the arthritic rat. Eur J Pharmacol. 2007 Jul 12;567(1-2):125-30.
110. Cichewicz DL. 2004. Synergistic interactions between cannabinoid and opioid analgesics. Life Sci. Jan 30;74(11):1317-24.
111. Smith PA, Selley DE, Sim-Selley LJ, Welch SP. 2007. Low dose combination of morphine and delta9-tetrahydrocannabinol circumvents antinociceptive tolerance and apparent desensitization of receptors. Eur J Pharmacol. 2007 Oct 1;571(2-3):129-37.
112. Meng I et al. 1998. An analgesic circuit activated by cannabinoids. Nature 395 381-383.
113. Klarreich E. 2001. Cannabis spray blunts pain: Early trials suggest cannabis spritz may give relief to chronic pain sufferers. British Association for the Advancement of Science. 4 Sept.
114. Holdcroft A et al. 1997. Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia, 5 483-486.
115. Grinspoon L, Bakalar JB. 1997. Psychedelic Drugs Reconsidered. New York: The Lindesmith Center.
116. Randall R. 1991. Marijuana, Medicine and the Law, Vol. II. Washington DC: Galen Press.
117. Noyes R, Baram DA. 1974. Cannabis analgesia. Comprehensive Psychiatry 1974;15:531-535.
118. Iverson, L. 2008. The Science of Marijuana. Oxford University Press.
119. Rahn EJ et al. 2009. Cannabinoids as pharmacotherapies for neuropathic pain. Neurotherapeutics. 6(4):713-37.
120. Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manag 2010; 39(2): 167-79.
121. GW Pharmaceutical. 2009. Phase IIb Cancer Pain Trial Data. gwpharm.com/Phase%20IIb%20Cancer%20Pain%20Trial%20Data.aspx (accessed June 22, 2012).
122. Attal N et al. Chronic neuropathic pain management in spinal cord injury patients. Ann Phys Rehabil Med. 52(2):124-41.
123. Hama A et al. 2009. Sustained antinociceptive effect of cannabinoid receptor agonist WIN 55,212-2 over time in rat model of neuropathic spinal cord injury pain. J Rehabil Res Dev. 46(1):135-43.
124. Kinsey SG. Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain. J Pharmacol Exp Ther. 330(3):902-10.
125. Guindon J, et al. 2008. Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br J Pharmacol. 2008 January; 153(2): 319-334.
126. Baker D et al. 2000. Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature. Mar 2;404(6773):84-7.
127. Petro DJ. 1980. Marihuana as a therapeutic agent for muscle spasm and spasticity. Psychosomatics, 21: 81-85.
1288. Petro DJ. 2002. Cannabis in multiple sclerosis: Women's health concerns. Journal of Cannabis Therapeutics, 2(3-4):161-175.
129. Musty RE, Consroe P. 2002. Spastic disorders. In: Grotenhermen F, Russo EB, editors. Cannabis and cannabinoids: Pharmacology, toxicology, and therapeutic potential. Binghamton, NY. Haworth Press. p. 195-204.
130. Clifford D. 1983. Tetrahydrocannabinol for Tremors in Multiple Sclerosis. Annals of Neurology, 13: 669-671.
131. Meinck H et al. 1989. Effects of cannabinoids on spasticity and ataxia in multiple sclerosis. Journal of Neurology, 226: 120-122.
132. Achiron A et al. 2000. Dexanabinol (HU-211) effect on experimental autoimmune encephalomyelitis: implications for the treatment of acute relapses of multiple sclerosis. Journal of Neuroimmunology, 102: 26-31.
133. Pryce G et al. 2003. Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain. Oct. 126(Pt 10): 2191-202.
134. Baker D, et al. 2007. Cannabinoid control of neuroinflammation related to multiple sclerosis. Br J Pharmacol; 152(5): 649-654.
135. Malfitano AM, Proto MC, Bifulco M. 2008. Cannabinoids in the management of spasticity associated with multiple sclerosis. Neuropsychiatr Dis Treat. 2008 October; 4(5): 847-853.
136. Zhang M, et al. 2009. Modulation of Cannabinoid Receptor Activation as a Neuroprotective Strategy for EAE and Stroke. J Neuroimmune Pharmacol. 2009 June; 4(2): 249-259.
137. Baker D, Pryce G. 2008. The endocannabinoid system and multiple sclerosis. Curr Pharm Des;14(23):2326-36.
138. Lakhan S et al. 2009. Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review. BMC Neurol. 9(1):59.
139. GW Pharma. 2009. Positive Sativex Data Presented at ECTRIMS European Multiple Sclerosis Congress. http://www.gwpharm.com/14september2009.aspx
140. Tyagi J et al. 2010. Functional role of cannabinoid receptors in urinary bladder. Indian J Urol. 26(1):26-35.
141. Collin C, et al. 2007. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol. 2007 Mar;14(3):290-6.
142. Achiron A et al. 2000. Dexanabinol (HU-211) effect on experimental autoimmune encephalomyelitis: implications for the treatment of acute relapses of multiple sclerosis. Journal of Neuroimmunology, 102: 26-31.
143. O'Shaughnessy WB. 1838. On the preparations of the Indian hemp, or gunjah (Cannabis indica); their effects on the animal system in health, and their utility in the treatment of tetanus and other convulsive diseases. Transactions of the Medical and Physical Society of Bengal. 18; 40: 71-102, 421-61.
144. Zajicek J et al. 2003. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet. Nov 8;362(9395): 1517-26.
145. Muller-Vahl KR et al. 1999. Cannabis in movement disorders. Forsch Komplementarmed. Oct;6 Suppl 3:23-7.
146. Amtmann D et al. 2004. Survey of cannabis use in patients with amyotrophic lateral sclerosis. Am J Hosp Palliat Care. Mar-Apr;21(2):95-104.
147. Baker D et al. 2000. Op Cit.
148. Lorenz R. 2004. On the application of cannabis in paediatrics and epileptology. Neuroendocrinol Lett. Feb-Apr;25(1-2):40-4.
149. Malec J et al. 1982. Cannabis effect on spasticity in spinal cord injury. Arch Phys Med Rehabil. Mar;63(3):116-8.
150. Dunn M, Ross D. 1974. The Perceived Effects of Marijuana on Spinal Cord Injured Males. Paraplegia, 12, 175.
151. Hanigan WC et al . 1986. The Effects of Delta-9-THC on Human Spasticity. Journal of the American Society of Clinical Pharmacology & Therapeutics, 198
152. Manno J E et al. 1970. Comparative Effects of Smoking Marihuana or Placebo on Human Motor & Mental Performance. Clinical Pharmacology & Therapeutics, 11:6, 808-815.
153. Meinck HM et al. 1989. Effect of Cannabinoids on Spasticity and Ataxia in Multiple Sclerosis. Journal of Neurology, 236: 120-22 .
154. Petro D & Ellenberger C. Jr.. 1981. Treatment of Human Spasticity with Delta-9-Tetrahydrocannabinol. Journal of Clinical Pharmacology, 21:8&9, 413S-416S.
155. Petro D. 1980. Marijuana as a Therapeutic Agent for Muscle Spasm or Spasticity. Psychosomatics. 21:1, 81-85
156. Howlett AC. 1995. Pharmacology of cannabinoid receptors. Annu Rev Pharmacol Toxicol. 35:607-634.
157. Abood ME and Martin BR. 1996. Molecular neurobiology of the cannabinoid receptor. Intl Rev Neurobiol. 39:197-221.
158. Devane WA et al. 1992. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 258: 1946-1949.
159. Barg J et al. 1995. Cannabinomimetic behavioral effects of and adenylate cyclase inhibition by two new endogenous anandamides. Eur J Pharmacol. 287:145-152.
160. Lastres-Becker I et al. 2003. Effects of cannabinoids in the rat model of Huntington's disease generated by an intrastriatal injection of malonate. Neuroreport. May 6;14(6):813-6.
161. Mechoulam R, Lichtman AH. 2003. Endocannabinoids. Stout guards of the central nervous system. Science. Oct 3;302(5642):65-7
162. Garcia-Arencibia, M. 2009. Cannabinoids and Parkinson's Disease. Current Drug Targets-CNS and Neurological Disorders.
163. Venderoza et al. 2004. Survey on cannabis use in Parkinson's disease: Subjective improvement of motor symptoms. Movement Disorders, 19: 1102-1106.
164. Carroll et al. 2004. Cannabis for dyskinesia in Parkinson's disease: a randomized double blind crossover study. Neurology 63(7):1245-1250.
165. De Lago et al. 2007. Cannabinoids and neuroprotection in motor-related disorders. CNS & Neurological Disorders- Drug targets, 6:377-387.
166. Russo EB. 2002. Op cit.
167. Joy JE. Op cit.
168. Formukong E et al. 1988. Analgesic and Antiinflammatory Activity of Constituents of Cannabis Sativa L. Inflammation 12: 361.
169. Barret ML et al. 1985. Isolation from Cannabis sativa L. of Cannflavon - a novel inhibitor of prostaglandin production. Biochem. Pharmacol. 34: 2019
170. Sofia RD. 1989. Antiedemic and analgesic properties of delta-9-THC compared with three other drugs. Eur. J. Pharamacol. 41: 705-9
171. James JS. 1998. Marijuana, inflammation, and CT-3. DMH-11C): cannabis leads to new class of antiinflammatory drugs. AIDS Treat News. Jan 23;(No 287):1, 5.
172. Straus SE. 2000. Immunoactive cannabinoids: Therapeutic prospects for marijuana constituents. Proc Natl Acad Sci U S A. Aug 15 97(17):9563.
173. Mechoulam R et al. 2002. Cannabidiol: an overview of some pharmacological aspects. J Clin Pharmacol. 2002 Nov;42(11 Suppl):11S-19S.
174. Russo. 2003. Op Cit.
175. Malfait et al . 2000. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci U S A. Aug 15 97(17): 9561-6.
176. Costa B et al. 2004. Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn Schmiedebergs Arch Pharmacol. Mar;369(3):294-9. Epub 2004 Feb 12.
177. Malfait AM et al. 2000. Op Cit.
178. Campbell and Gowran. 2007. Alzheimer's disease; taking the edge off with cannabinoids? British Journal of Pharmacology 152: 655-662.
179. Walther et al. 2006. Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia. Physcopharmacology 185: 524-528.
180. Volicer et al. 1997. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease. International Journal of Geriatric Psychiatry 12: 913-919.
181. Eubanks et al. 2006. A molecular link between the active component of marijuana and Alzheimer's disease pathology. Molecular Pharmaceutics 3: 773-777.
182. Ramirez et al. 2005. Prevention of Alzheimer's Disease pathology by cannabinoids. The Journal of Neuroscience 25: 1904-1913.
183. Marchalant et al (2009) Cannabinoids attenuate the effects of aging upon nueroinflammation and neurogenesis. Neurobiology of Disease 34, 300-307.
184. Julian HV. 2010. "Israeli research shows cannabidiol may slow Alzheimer's disease." Israel National News. December 16, 2010. http://www.israelnationalnews.com/News/News.aspx/125564 (accessed June 24, 2012).
185. Marchalant et al. 2007. Anti-inflammatory property of the cannabinoid agonist WIN-55212-2 in a rodent model of chronic brain inflammation. Neuroscience 144: 1516-1522.
186. Hampson et al. 1998. Cannabidiol and delta-9-tetrahydrocannabinol are neuroprotective antioxidants. Proceedings of the National Academy of Sciences 95: 8268-8273.
187. Grinspoon. 2001. Commentary: On the Pharmaceuticalization of Marijuana. International Journal of Drug Policy, 12 (5-6); 377-383.
188. Iverson, L. Op cit.
189. Young FL. 1988. In the matter of marijuana rescheduling. United States Department of Justice, Drug Enforcement Administration. Docket #86-22. Sept 6, 1988.
190. Joy JE. Op cit.
191. Grinspoon L. 1995. Marijuana as medicine - reply. JAMA;274(23):1838
192. Joy JE. Op cit.
193. Iverson. Op cit.
194. Tashkin DP, et al. 1987. Respiratory systems and lung function in habitual heavy smokers of marijuana alone, smokers of marijuana and tobacco, smokers of tobacco alone, and non-smokers. Am Rev Respir Dis.; 135: 209-216.
195. Hall W, Solowij N. 1998. Adverse effects of cannabis. Lancet. 1998; 352:1611-1616.
196. Marijuana use and cancer incidence. Sidney S, Quesenberry CP, Friedman GD, Tekawa IS.; Cancer Causes Control. 1997; 8: 722-728.
197. Melamede RJ. 2005. Cannabis and tobacco smoke are not equally carcinogenic. Harm Reduction Journal. 2:21.
198. Tashkin D. 2006. Marijuana Use and Lung Cancer: Results of a Case-Control Study. American Thoracic Society International Conference. May 23, 2006, San Diego, California
199. Hashibe M, et al. 2006. Marijuana use and the risk of lung and upper aerodigestive tract cancers: results of a population-based case-control study. Cancer Epidemiol Biomarkers Prev. 2006 Oct;15(10):1829-34.
200. Rosenblatt KA, et al. 2004. Marijuana use and risk of oral squamous cell carcinoma. Cancer Res 2004;64(11):4049-4054.
201. Joy JE. Op cit.
202. Grant I et al. 2003. "Non Acute Neurocognitive Effects of Cannabis Use: A Meta-analytic Study". J Intl Neuropsy Soc.
203. Joy JE. Op cit.
204. Gieringer D. 1988. Marijuana, driving, and accident safety. J Psychoactive Drugs; 20: 93-101.
205. Iverson. Op Cit.
206. Cabral G. 2001. Marijuana and cannabinoids: effects on infections, immunity,and AIDS. Cannabis Ther. 2001; 1: 61-65
207. Klein T. 2001. Cannabinoids and the immune system. Pain Res Manag. 2001 Summer;6(2):95-101.
208. Cabral GA, Staab A. 2005. Effects on the immune system. Cannabinoids. Abood ME et al (eds.).
209. Abrams DI. 2003. Op cit.
210. Kosel BW, et al. 2002. The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir. AIDS. 16:543-550.
211. Costantino CM, et al. Op Cit.