A Clinician's Guide to Medical Marijuana
Carol Peckham; Bret Stetka, MD; Charles P. Vega, MD
July 30, 2013
Legalize It? A Clinician's Guide to Medical Marijuana
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Trends in Medical Marijuana
As of July 2013, 19 states (New Hampshire the most recent) have instituted laws that legalize marijuana in some form.[1] A recent study addressed physicians' attitudes toward medical marijuana in Colorado, the only state besides Washington that has decriminalized marijuana for both medical and recreational use.[2] Over 60% of physicians in the study thought that marijuana could promote significant physical and mental health risks. In contrast, only 27% of survey respondents thought that marijuana could promote significant benefits to physical health. The evidence regarding the efficacy and safety of medical marijuana is limited but generally supports the conservative views of the physicians surveyed in the current study. Although evidence is weak, many studies are now under way to determine benefits and risks with cannabis and cannabinoids in many conditions.
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Is Cannabis Effective for Chronic Pain?
Marijuana has been used medically for thousands of years, often to treat pain, but the evidence on its benefits is conflicted. A 2009 meta-analysis[3] concluded that cannabis is moderately effective in treating chronic pain but that the benefits could be countered by the potential for serious side effects. Work published in 2011[4] found that in patients taking long-acting opioid analgesics for various chronic pain conditions, the addition of vaporized cannabis reduced their reported pain by 27%, suggesting a potential combination treatment approach and also a possible means of cutting opioid dosing in chronic pain. A systematic review in 2001 found no additional benefit from cannabis in reducing postoperative, cancer, or chronic nonmalignant pain.[5] All medications, and particularly potent analgesics, can promote potentially serious side effects. The drawbacks of marijuana are described in this work. Physicians and patients need to exercise their own judgment as to whether the potential benefits of marijuana outweigh the risks. The evidence does not support marijuana as a superdrug -- a cure-all -- nor does it demonstrate that medicinal marijuana has no therapeutic effect.
Benefits in Neuropathic Pain
There is stronger evidence for the use of cannabis in neuropathic pain and spasticity.[7-9] In a 2003 study, cannabinoid CT-3, a synthetic form of cannabis, was effective in reducing chronic neuropathic pain compared with placebo. No major adverse effects were observed.[6] It is not clear whether smoking or oral administration is more effective. In one small study, 25 mg herbal cannabis with 9.4% tetrahydrocannabinol, administered as a single smoked inhalation 3 times daily for 5 days, significantly reduced average pain intensity compared with placebo.[10] In a comparison between smoked marijuana and oral dronabinol, both reduced pain, although dronabinol's effect was longer-lasting.[11]
Effects on Spasticity and Pain in Multiple Sclerosis
One of the most promising clinical uses of cannabinoid compounds is in the symptomatic treatment of multiple sclerosis (MS).[12] A 2006 study of 13 patients with MS reported that low-dose treatment with the synthetic cannabinoid nabilone reduced pain by a median of 2 points compared with placebo. There was no improvement, however, in spastic muscle tone, dexterity, or functional integrity in daily life.[13] In larger subsequent studies, the cannabinoid nabiximols (Sativex®) achieved improvement in spasticity and is now approved in Canada and several European countries for treatment of MS and spasticity.[14-16] Nabiximols is an oromucosal mouth spray and is derived from cannabis plants rather than a solely synthetic process. There are still concerns related to the relative paucity of data on long-term safety.[17]
Graph from Wissel J, et al.[13]
Benefits in Fibromyalgia
In the first randomized controlled trial to assess the benefit of nabilone, a synthetic cannabinoid, on pain reduction and quality-of-life improvement in patients with fibromyalgia, nabilone improved symptoms and was well tolerated.[18] Another study reported that it improved sleep in patients with fibromyalgia.[19] Therefore, it may be a useful adjunct for managing patients with this condition. There is some concern, however, about patients who self-medicate with marijuana. In one study of 457 fibromyalgia patients, cannabinoids were being used by 13%; among these, there was a higher rate of unstable mental illness, opioid drug-seeking behavior, and being male.[20]
Image from Medscape Slideshow: Fibromyalgia
Effects on Appetite in Patients With Cachexia
In 1986, THC was licensed as an antiemetic drug in cancer patients receiving chemotherapy. Clinical studies on THC have shown significant stimulation of appetite and increase in body weight in HIV-positive and cancer patients. There are some indications that cannabis is better tolerated than THC alone, because cannabis contains several additional cannabinoids that antagonize the psychotropic actions of THC but do not inhibit the appetite-stimulating effect.[21] In a 2006 study, however, patients with cancer-related anorexia-cachexia syndrome and weight loss were randomly assigned to receive cannabis extract, THC, or placebo. There were no differences observed over 6 weeks of treatment for the primary endpoints of appetite and quality of life, for cannabinoid-related toxicity, or for secondary endpoints such as mood and nausea. The study was stopped.[22]
Graph from Cannabis-In-Cachexia-Study-Group, et al[22]
Benefits in Patients With Inflammatory Bowel Disease
Cannabis preparations are being studied in and are considered promising tools for inflammatory bowel disease (IBD) and other gut disturbances because of anti-inflammatory properties and effects on motility.[23-25] In one study of 21 patients with Crohn disease,[26] 8 weeks of smoked cannabis produced significant benefits to 11 patients, with 3 weaned from steroid dependency and all reporting improved appetite and sleep and no significant side effects. The primary endpoint -- induction of remission -- was not achieved. In another small study,[27] patients with long-standing IBD were prescribed cannabis; after 3 months they reported improvement in general health perception, social functioning, ability to work, physical pain, and depression. In addition, they had a weight gain of 4.3 ± 2 kg during treatment and an average BMI increase of 1.4 ± 0.61 kg/m2.
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Use in Patients With HIV/AIDS
A 2013 Cochrane review[28] looked at whether natural or artificially produced cannabis, either smoked or ingested, improves morbidity and/or mortality in patients with HIV. Seven short-term, randomized controlled studies were included in the review, but given the difficulty in blinding patients to marijuana ingestion, the reviewers ultimately considered only 3 of the trials to be adequate for inclusion. Outcomes included changes in weight, body fat, appetite, nausea and vomiting, and mood. One small study (N = 139, of which only 88 were evaluable) found that patients who were administered dronabinol experienced a slight mean weight gain of 0.1 kg vs a 0.4-kg loss in the placebo group, although overall evidence of any significant effect on morbidity or mortality was limited. More encouraging research[29] suggests that cannabinoid receptor type 2 agonism exerts antiviral effects against CXCR4-tropic viruses in late stages of HIV-1 infection, representing a potential therapeutic target in HIV.
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Pulmonary Health
Perhaps surprising, a large longitudinal study spanning 20 years and published in 2012[30] found that smoking marijuana on an occasional basis does not appear to adversely affect pulmonary function. Even more perplexing was the finding that light marijuana smoking correlates with larger lung volumes. Study author Mark J. Pletcher, MD, MPH, University of California, San Francisco, speculated to Medscape Medical News that this might be due to "the way people smoke marijuana, with very large, deep inhalations." Short-term marijuana exposure has also been associated with bronchodilation and reversal of bronchospasm. However, it should be noted that although smoking marijuana appears safer than smoking tobacco, previous work[31,32] has linked long-term frequent marijuana smoking with impaired lung function, respiratory symptomatology such as cough, and precancerous pulmonary lesions (see next slide).
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Risk for Lung Cancer
Although marijuana seems to have less of an effect on pulmonary function than tobacco does, an association with lung cancer is suggestive. An analysis published in 2008 was based on 3 case-control studies and restricted to men in Tunisia, Morocco, and Algeria.[33] Tobacco smokers comprised 96% of the cases and 67.8% of the controls; 15.3% of the cases and 5% of the controls were ever cannabis smokers; and all cannabis smokers used tobacco. The OR for lung cancer was 2.4 for cannabis ever-smokers, which held after adjusting for lifetime tobacco pack-years as a continuous variable. A 2013 cohort study of Swedish men[34] further supported this finding. The men were tracked for 40 years; over that time, heavy cannabis use was associated with a greater than twofold risk of developing lung cancer, even after adjustment for tobacco and alcohol use and other factors.
Graph from Berthiller J, et al.[33]
Is Marijuana Addictive?
The literature suggests that, yes, marijuana can be addictive but is not as addictive as many other abused substances. Up to 9% of marijuana users will become addicted compared with 15% of alcohol users, 17% of cocaine users, 23% of heroin users, and 32% of tobacco users. However, the number is higher in those who begin using marijuana at a young age and in those who smoke it daily. Also, when quitting, long-term marijuana users can experience withdrawal symptoms such as irritability, sleeplessness, decreased appetite, anxiety, and drug craving.[35] Addiction risk with marijuana appears particularly high in youth with potential comorbid mood or anxiety disorders. Among those seeking psychiatric care for such disorders, approximately half of the participants in a recent study[36] were at moderate to high risk for a substance use disorder. The results also suggest an association between cannabis use and being male, age of first cannabis use, recent cigarette use, and functional impairment.
Marijuana and Automobile Accidents
"Pot doesn't affect my driving like alcohol does" -- a common refrain among many marijuana users. However, 2 recent meta-analyses suggest otherwise. The first one pooled data from 9 studies and reported that marijuana use is associated with nearly double the risk of being in a motor vehicle accident, particularly a fatal collision.[37] The second analysis reported a nearly threefold risk.[38] As might be expected, accident risk increases in a dose-dependent fashion.
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Is Marijuana a Gateway Drug?
A significant body of literature supports the "gateway drug" theory, the idea that drug experimentation and use tends to follow a sequential pattern of increasingly potent and/or dangerous substances. Use of "hard drugs" is often preceded by marijuana use, which is often preceded by alcohol and tobacco use. Obviously this pattern represents a generalization, and drug use sequence can vary greatly depending on numerous personal and cultural factors. A 2009 study found that deviation from the typical gateway sequence, particularly earlier-than-usual illicit drug use, did slightly increase the risk of developing dependence. The authors further concluded that deviations are more likely in adolescents with mental illness.[39] A more recent French study found that use of other illicit drugs is 21 times more likely in cannabis experimenters and 124 times higher in daily users compared with nonusers.[40]
Image courtesy of Charles Vega, MD
Marijuana and Risk for Psychosis
The link between marijuana and psychosis is contentious. Evidence supports an association between marijuana use and a higher risk of developing future psychotic symptoms.[41-43] A 2007 meta-analysis[44] reported a 41% increased risk for any psychotic outcome in those who had ever used cannabis and more than twice the risk in frequent users. Furthermore, a recent study reported that in those who had experienced an episode of cannabis-induced psychosis, there was a 21.4% risk of subsequently receiving a c schizophrenia diagnosis.[45] However, causality remains up for debate. In a recent article, Dr. David Castle concludes, "It is likely that cannabis exposure is a 'component cause' that interacts with other factors to 'cause' schizophrenia or other psychotic disorders, but is neither necessary nor sufficient to do so alone." In another recent article, Dr. Suzanne Gage's group, argues that evidence of causality is lacking and that further investigation is required. "Public health models suggest that cannabis use may need to be treated and prevented in many thousands of users in order to prevent one case of schizophrenia," they write.
Effects on Cognition
There is mixed evidence as to the effects of marijuana on cognitive function. Some research has suggested a negative impact on learning and memory, but the findings may have been confounded by the acute effects of marijuana use and withdrawal symptoms. A 2011 study[46] followed nearly 2500 young Australian participants for 8 years, looking for a relationship between change in marijuana use and cognitive performance. They found that marijuana had few long-term effects on learning and memory and that any impairments that had emerged were mostly reversible with use cessation. A 2012 meta-analysis[47] also assessed the long-term neurocognitive impact of marijuana use after abstinence and concluded that "any negative residual effects on neurocognitive performance attributable to either cannabis residue or withdrawal symptoms are limited to the first 25 days of abstinence. Furthermore, there was no evidence for enduring negative effects of cannabis use."
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Conclusions
Marijuana is far from a cure-all; it induces significant short-term cognitive impairment, can be addictive, and appears to be associated with a greater risk of developing lung cancer. Still, the effects of inhaled marijuana on lung function appear less detrimental than those associated with smoked tobacco. Also, there is evidence that the drug may have a role in treating IBD, MS, and certain chronic pain conditions, including neuropathic pain and fibromyalgia. In all cases, the potential negative side effects associated with marijuana should be weighed against any potential benefits.
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