The article's abstract (published online: 22 May 2005) from the peer-reviewed journal Nature Medicine stated:
"Accelerated osteoclastic bone resorption has a central role in the pathogenesis of osteoporosis and other bone diseases. Identifying the molecular pathways that regulate osteoclast activity provides a key to understanding the causes of these diseases and to the development of new treatments.
Here we show that mice with inactivation of cannabinoid type 1 (CB1) receptors have increased bone mass and are protected from ovariectomy-induced bone loss.
Pharmacological antagonists of CB1 and CB2 receptors prevented ovariectomy-induced bone loss in vivo and caused osteoclast inhibition in vitro by promoting osteoclast apoptosis and inhibiting production of several osteoclast survival factors.
These studies show that the CB1 receptor has a role in the regulation of bone mass and ovariectomy-induced bone loss and that CB1- and CB2-selective cannabinoid receptor antagonists are a new class of osteoclast inhibitors that may be of value in the treatment of osteoporosis and other bone diseases."
May 2005 - Nature Medicine
.al Neuropharmacology reported:
"Gliomas, in particular glioblastoma multiforme or grade IV astrocytoma, are the most frequent class of malignant primary brain tumours and one of the most aggressive forms of cancer. Current therapeutic strategies for the treatment of glioblastoma multiforme are usually ineffective or just palliative.
During the last few years, several studies have shown that cannabinoids — the active components of the plant Cannabis sativa and their derivatives — slow the growth of different types of tumours, including gliomas, in laboratory animals.
Cannabinoids induce apoptosis of glioma cells in culture via sustained ceramide accumulation, extracellular signal-regulated kinase activation and Akt inhibition. In addition, cannabinoid treatment inhibits angiogenesis of gliomas in vivo....
Remarkably, cannabinoids kill glioma cells selectively and can protect non-transformed glial cells from death. These and other findings reviewed here might set the basis for a potential use of cannabinoids in the management of gliomas."
Sep. 2004 - Neuropharmacology
Researchers with the Department of Biochemistry and Molecular Biology, School of Biology, Complutense University, Spain, in a study of the use of cannabis-based ointment on skin tumors, published Jan. 2003 in the Journal of Clinical Investigation (JCI) stated:
"Local administration induced a considerable growth inhibition of malignant tumors generated by inoculation of epidermal tumor cells into nude mice. Cannabinoid-treated tumors showed an increased number of apoptotic cells...
These results support a new therapeutic approach [cannabis-based ointment] for the treatment of skin tumors."
Jan. 2003 - Journal of Clinical Investigation
Additionally, studies have also implied that cannabis may be neuroprotective against alcohol-induced cognitive deficits. A 2009 study by investigators at the University of California at San Diego reported that binge drinkers who also used cannabis experienced significantly less white matter damage to the brain as compared to subjects who consumed alcohol alone.
http://www.ncbi.nlm.nih.gov/pubmed/19631736
http://www.ncbi.nlm.nih.gov/pubmed/21749524
"Study turns pot wisdom on its head," pronounced the Globe and Mail in October. News wires throughout North America and the world touted similar headlines -- all of which were met with a monumental silence from federal officials and law enforcement. Why all the fuss? Researchers at the University of Saskatchewan in Saskatoon found that the administration of synthetic cannabinoids in rats stimulated the proliferation of newborn neurons (nerve cells) in the hippocampus region of the brain and significantly reduced measures of anxiety and depression-like behavior. The results shocked researchers -- who noted that almost all other so-called "drugs of abuse," including alcohol and tobacco, decrease neurogenesis in adults -- and left the "pot kills brain cells" crowd with a platter of long-overdue egg on their faces.
While it would be premature to extrapolate the study's findings to humans, at a minimum, the data reinforce the notion that cannabinoids are unusually non-toxic to the brain and that even long-term use of marijuana likely represents little risk to brain function. The findings also offer further evidence that cannabinoids can play a role in the alleviation of depression and anxiety, and that cannabis-based medicines may one day offer a safer alternative to conventional anti-depressant pharmaceuticals such as Paxil and Prozac.
(Reference: Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic and depressant-like effects. The Journal of Clinical Investigation. 2005)
Not only has modern science refuted the notion that marijuana is neurotoxic, recent scientific discoveries have indicated that cannabinoids are, in fact, neuroprotective, particularly against alcohol-induced brain damage. In a recent preclinical study -- the irony of which is obvious to anyone who reads it -- researchers at the US National Institutes of Mental Health (NIMH) reported that the administration of the non-psychoactive cannabinoid cannabidiol (CBD) reduced ethanol-induced cell death in the brain by up to 60 percent. "This study provides the first demonstration of CBD as an in vivo neuroprotectant ... in preventing binge ethanol-induced brain injury," the study's authors wrote in the May 2005 issue of the Journal of Pharmacology and Experimental Therapeutics. Alcohol poisoning is linked to hundreds of preventable deaths each year in the United States, according to the Centers for Disease Control, while cannabis cannot cause death by overdose.
Of course, many US neurologists have known about cannabis' neuroprotective prowess for years. NIMH scientists in 1998 first touted the ability of natural cannabinoids to stave off the brain-damaging effects of stroke and acute head trauma. Similar findings were then replicated by investigators in the Netherlands and Italy and, most recently, by a Japanese research in 2005. However, attempts to measure the potential neuroprotective effects of synthetic cannabinoid-derived medications in humans have so far been inconclusive.
(References: Comparison of cannabidiol, antioxidants and diuretics in reversing binge ethanol-induced neurotoxicity. Journal of Pharmacology and Experimental Therapeutics. 2005 | Cannabidiol prevents cerebral infarction. Stroke. 2005 | Post-ischemic treatment with cannabidiol prevents electroencephalographic flattening, hyperlocomotion and neuronal injury in gerbils. Neuroscience Letters. 2003 | Neuroprotection by Delta9-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity. Journal of Neuroscience. 2001 | Cannabidiol and Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proceedings of the National Academy of Sciences. 1998)
Of all cancers, few are as aggressive and deadly as glioma. Glioma tumors quickly invade healthy brain tissue and are typically unresponsive to surgery and standard medical treatments. One agent they do respond to is cannabis.
Writing in the August 2005 issue of the Journal of Neurooncology, investigators at the California Pacific Medical Center Research Institute reported that the administration of THC on human glioblastoma multiforme cell lines decreased the proliferation of malignant cells and induced apoptosis (programmed cell death) more rapidly than did the administration of the synthetic cannabis receptor agonist, WIN-55,212-2. Researchers also noted that THC selectively targeted malignant cells while ignoring healthy ones in a more profound manner than the synthetic alternative. Patients diagnosed with glioblastoma multiforme typically die within three months without therapy.
Previous research conducted in Italy has also demonstrated the capacity of CBD to inhibit the growth of glioma cells both in vitro (e.g., a petri dish) and in animals in a dose dependent manner. As a result, a Spanish research team is currently investigating whether the intracranial administration of cannabinoids can prolong the lives of patients diagnosed with inoperable brain cancer.
Most recently, a scientific analysis in the October issue of the journal Mini-Reviews in Medicinal Chemistry noted that, in addition to THC and CBD's brain cancer-fighting ability, studies have also shown cannabinoids to halt the progression of lung carcinoma, leukemia, skin carcinoma, colectoral cancer, prostate cancer and breast cancer.
(References: Cannabinoids selectively inhibit proliferation and induce cell death of cultured human glioblastoma multiforme cells. Journal of Neurooncology. 2005 | Cannabinoids and cancer. Mini-Reviews in Medicinal Chemistry. 2005 | Anti-tumor effects of cannabidiol, a non-psychotropic cannabinoid, on human glioma cell lines. Journal of Pharmacology and Experimental Therapeutics. 2003)
Emerging evidence also indicates that cannabinoids may play a role in slowing the progression of certain neurodegenerative diseases, such as Multiple Sclerosis, Parkinson's disease, Alzheimer's, and Amyotrophic Lateral Sclerosis (a.k.a. Lou Gehrig's Disease). Recent animal studies have shown cannabinoids to delay disease progression and inhibit neurodegeneration in mouse models of ALS, Parkinson's, and MS. As a result, the Journal of Neurological Sciences recently pronounced, "There is accumulating evidence ... to support the hypothesis that the cannabinoid system can limit the neurodegenerative processes that drive progressive disease," and patient trials investigating whether the use of oral THC and cannabis extracts may slow the progression of MS are now underway in the United Kingdom.
(References: Cannabinoids and neuroprotection in CNS inflammatory disease. Journal of the Neurological Sciences. 2005. Amyotrophic lateral sclerosis: delayed disease progression in mice by treatment with a cannabinoid. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders. 2004 | Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain. 2003)
But what about claims of cannabis' damaging effect of cognition? A review of the scientific literature indicates that rumors regarding the "stoner stupid" stereotype are unfounded. According to clinical trial data published this past spring in the American Journal of Addictions, cannabis use -- including heavy, long-term use of the drug -- has, at most, only a negligible impact on cognition and memory. Researchers at Harvard Medical School performed magnetic resonance imaging on the brains of 22 long-term cannabis users (reporting a mean of 20,100 lifetime episodes of smoking) and 26 controls (subjects with no history of cannabis use). Imaging displayed "no significant differences" between heavy cannabis smokers compared to controls, the study found.
Previous trials tell a similar tale. An October 2004 study published in the journal Psychological Medicine examining the potential long-term residual effects of cannabis on cognition in monozygotic male twins reported "an absence of marked long-term residual effects of marijuana use on cognitive abilities." A 2003 meta-analysis published in the Journal of the International Neuropsychological Society also "failed to reveal a substantial, systematic effect of long-term, regular cannabis consumption on the neurocognitive functioning of users who were not acutely intoxicated," and a 2002 clinical trial published in the Canadian Medical Association Journal determined, "Marijuana does not have a long-term negative impact on global intelligence."
Finally, a 2001 study published in the journal Archives of General Psychiatry found that long-term cannabis smokers who abstained from the drug for one week "showed virtually no significant differences from control subjects (those who had smoked marijuana less than 50 times in their lives) on a battery of 10 neuropsychological tests." Investigators further added, "Former heavy users, who had consumed little or no cannabis in the three months before testing, [also] showed no significant differences from control subjects on any of these tests on any of the testing days."
(References: Lack of hippocampal volume change in long-term heavy cannabis users. American Journal of Addictions. 2005 | Neuropsychological consequences of regular marijuana use: a twin study. Psychological Medicine. 2004 | Non-acute (residual) neurocognitive effects of cannabis use: A meta-analytic study. Journal of the International Neuropsychological Society. 2003 | Current and former marijuana use: preliminary findings of a longitudinal study of effects on IQ in young adults. Canadian Medical Association Journal. 2002 | Neuropsychological Performance in Long-term Cannabis Users. Archives of General Psychiatry. 2001)
Several longitudinal studies have established that even long-term use of marijuana (via smoking) in humans is not associated with elevated cancer risk, including tobacco-related cancers or with cancer of the following sites: colorectal, lung, melanoma, prostate, breast, cervix. A more recent (2009) population-based case-control study found that moderate marijuana smoking over a 20 year period was associated with reduced risk of head and neck cancer (See Liang et al). And a 5-year-long population-based case control study found even long-term heavy marijuana smoking was not associated with lung cancer or UAT (upper aerodigestive tract) cancers.[6]
At some doses, marijuana affects perception and psychomotor performance – changes which could impair driving ability. However, in driving studies, marijuana produces little or no car-handling impairment – consistently less than produced by low to moderate doses of alcohol and many legal medications. In contrast to alcohol, which tends to increase risky driving practices, marijuana tends to make subjects more cautious. Surveys of fatally injured drivers show that when THC is detected in the blood, alcohol is almost always detected as well. For some individuals, marijuana may play a role in bad driving. The overall rate of highway accidents appears not to be significantly affected by marijuana's widespread use in society.[10]
Drugged Driving: True Threat Or False Panic?
Survey data indicates that approximately 112 million Americans (46 percent of the US population) have experimented with the use of illicit substances.2 Of these, more than 20 million (8.3 percent of the population) self-identify as “current” or “monthly” users of illicit drugs,3 and more than 10 million Americans say that they’ve operated a motor vehicle while under the influence of an illicit substance in the past year.4 These totals, while far from negligible, suggest that the prevalence of illicit drug use among US drivers is far less than the prevalence of alcohol among this same population.5
To date, “[The] role of drugs as a causal factor in traffic crashes involving drug-positive drivers is still not well understood.”6 While some studies have indicated that illicit drug use is associated with an increased risk of accident, a relationship has not been established regarding the use of psychoactive substances and crash severity.7 Drivers under the influence of illicit drugs do experience an enhanced fatality risk compared to sober drivers. However, this risk is approximately three times lower than the fatality risk associated with drivers who operate a vehicle above or near the legal limit for alcohol intoxication.8 According to one recent review: “The risk of all drug-positive drivers compared to drug-free drivers is similar to drivers with a blood alcohol concentration of 0.05%. The risk is also similar to drivers above age 60 compared to younger drivers [around age 35].”9
Marijuana is the most common illicit substance consumed by motorists who report driving after drug use.10 Epidemiological research also indicates that cannabis is the most prevalent illicit drug detected in fatally injured drivers and motor vehicle crash victims.11 Reasons for this are twofold. One, pot is by far the most widely used illicit drug among the US population, with nearly one out of two Americans admitting having tried it.12 Two, marijuana is the most readily detectable illicit drug in toxicological tests. Marijuana’s primary psychoactive compound, THC, may be detected in blood for several hours, and in some extreme cases days after past use,13 long after any impairing effects have worn off. In addition, non-psychoactive byproducts of cannabis, known as metabolites, may be detected in the urine of regular users for days or weeks after past use.14 (Other common drugs of abuse, such as cocaine or methamphetamine, do not possess such long half-lives.) Therefore, pot’s prevalence in toxicological evaluations of US drivers does not necessarily indicate that it is a frequent or significant causal factor in auto accidents. Rather, its prevalence affirms that cannabis remains far more popular and is far more easily detectable on drug screening tests than other controlled substances.
Cruising On Cannabis: Clarifying The Debate
While it is well established that alcohol consumption increases accident risk, evidence of marijuana’s culpability in on-road driving accidents and injury is far less clear. Although acute cannabis intoxication following smoking has been shown to mildly impair psychomotor skills, this impairment is seldom severe or long lasting.15 In closed course and driving simulator studies, marijuana’s acute effects on psychomotor performance include minor impairments in tracking (eye movement control) and reaction time, as well as variation in lateral positioning, headway (drivers under the influence of cannabis tend to follow less closely to the vehicle in front of them), and speed (drivers tend to decrease speed following cannabis inhalation).16 In general, these variations in driving behavior are noticeably less consistent or pronounced than the impairments exhibited by subjects under the influence of alcohol.17 Also, unlike subjects impaired by alcohol, individuals under the influence of cannabis tend to be aware of their impairment and try to compensate for it accordingly, either by driving more cautiously18 or by expressing an unwillingness to drive altogether.19
As a result, cannabis-induced variations in performance do not appear to play a significant role in on-road traffic accidents when THC levels in a driver's blood are low and/or cannabis is not consumed in combination with alcohol.20-21 For example, a 1992 National Highway Traffic Safety Administration review of the role of drug use in fatal accidents reported, “There was no indication that cannabis itself was a cause of fatal crashes” among drivers who tested positive for the presence of the drug.22 A more recent assessment by Blows and colleagues noted that self-reported recent use of cannabis (within three hours of driving) was not significantly associated with car crash injury after investigators controlled for specific cofounders (e.g., seat-belt use, sleepiness, etc.)23 A 2004 observational case control study published in the journal Accident, Analysis and Prevention reported that only drivers under the influence of alcohol or benzodiazepines experience an increased crash risk compared to drug-free controls. Investigators did observe increased risks – though they were not statistically significant – among drivers using amphetamines, cocaine and opiates, but found, “No increased risk for road trauma was found for drivers exposed to cannabis.”24
A handful of more recent studies have noted a positive association between very recent cannabis exposure and a gradually increased risk of vehicle accident. Typically, these studies reveal that drivers who possess THC/blood concentrations above 5ng/ml – implying cannabis inhalation within the past 1-3 hours25-26 – experience an elevated risk of accident compared to drug-free controls.27-28 (Motorists who test positive for the presence of THC in the blood at concentrations below this threshold typically do not have an increased risk compared to controls.29) However, this elevated risk is below the risk presented by drivers who have consumed even small quantities of alcohol.
Two recent case-controlled studies have assessed this risk in detail. A 2007 case-control study published in the Canadian Journal of Public Health reviewed 10-years of US auto-fatality data. Investigators found that US drivers with blood alcohol levels of 0.05% – a level well below the legal limit for intoxication – were three times as likely to have engaged in unsafe driving activities prior to a fatal crash as compared to individuals who tested positive for marijuana.30 A 2005 review of auto accident fatality data from France showed similar results, finding that drivers who tested positive for any amount of alcohol had a four times greater risk of having a fatal accident than did drivers who tested positive for marijuana in their blood.31 In the latter study, even drivers with low levels of alcohol present in their blood (below 0.05%) experienced a greater elevated risk as compared to drivers who tested positive for high concentrations of cannabis (above 5ng/ml). Both studies noted that overall few traffic accidents appeared to be attributed to driver’s operating a vehicle while impaired by cannabis.
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