July 10, 2015, 03:35 PM
Medical Marijuana: Where's the Evidence?
Medical Marijuana: Where's the Evidence?
Medscape Medical News
July 06, 2015
NB: Bolding of the words Tourette Syndrome for Forum purposes only
With many US states now having laws in place to facilitate access to medical marijuana for a variety of medical conditions, two new reviews have highlighted the lack of evidence to support its use in most indications.
An editorial also raises questions about the legal implications for doctors prescribing such products.
The reviews, published in the June 23/30 issue of JAMA, note that 23 states and the District of Columbia have enacted laws to allow prescription of medical marijuana for certain medical conditions.
Reviewing the medical literature on medical marijuana, the two papers come to similar conclusions — that some evidence supports the use of marijuana for nausea and vomiting related to chemotherapy, specific pain syndromes, and spasticity from multiple sclerosis. But for most other indications such as hepatitis C, Crohn's disease, Parkinson's disease, or Tourette's syndrome, they found that the evidence supporting its use is of poor quality.
A third paper in the same issue of JAMA highlights the large variability in specific cannabinoids in various medical marijuana products and finds that contents did not conform to what was advertised on the labelling.
In an accompanying editorial, Deepak Cyril D'Souza, MBBS, and Mohini Ranganathan, MD, Yale University School of Medicine, New Haven, Connecticut, note that for most of the conditions that qualify for medical marijuana use, the evidence fails to meet US Food and Drug Administration (FDA) standards.
They call for government support to conduct high-quality trials. Until such trials are available, they suggest it may be prudent to wait before widely adopting use of marijuana. "Perhaps it is time to place the horse back in front of the cart," they conclude.
Legal implications Unclear
The editorialists point out that for physicians, the legal implications of certifying patients for medical marijuana remain unclear given the differences between the views of state vs federal government.
They emphasize that the prescription, supply, or sale of marijuana is illegal by federal law, and it is not known to what extent a physician who certifies a patient for medical marijuana may be liable for negative outcomes, and whether malpractice insurance will cover any liability.
In one of the review papers, Kevin P. Hill, MD, McLean Hospital, Belmont, Massachusetts, examined 28 randomized clinical trials of cannabinoids in various indications.
He notes that there are two cannabinoids (dronabinol and nabilone), which are FDA approved for nausea and appetite stimulation.
Apart from these two indications, Dr. Hill found that use of marijuana for chronic pain, neuropathic pain, and spasticity due to multiple sclerosis is supported by high-quality evidence.
Six trials that included 325 patients examined chronic pain, 6 trials that included 396 patients investigated neuropathic pain, and 12 trials that included 1600 patients focused on multiple sclerosis. Several of these trials had positive results, suggesting that marijuana or cannabinoids may be efficacious for these indications.
The other review paper, by a team led by Penny F. Whiting, PhD, University Hospitals Bristol NHS Foundation Trust, United Kingdom, evaluated 79 trials of cannabinoids in a total of 6462 participants. Indications included nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette's syndrome.
There was better evidence of efficacy in nausea and vomiting (with 47% of patients showing a complete response vs 20% placebo in 3 trials), pain (with 37% of patients reporting a reduction vs 31% on placebo in 8 trials), and spasticity (with an average reduction in the Ashworth spasticity scale of –0.36 in 7 trials).
Both reviews report an increased risk for short-term adverse effects, including dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, hallucination, addiction, and worsening of psychiatric illnesses, such as anxiety and mood disorders.
For the dosing paper, a team led by Ryan Vandrey, PhD, Johns Hopkins University School of Medicine in Baltimore, Maryland, report that of 75 products purchased (47 different brands), 17% were accurately labeled, 23% were underlabeled, and 60% were overlabeled with respect to tetrahydrocannabinol content.
"Edible cannabis products from 3 major metropolitan areas, though unregulated, failed to meet basic label accuracy standards for pharmaceuticals," the authors write. "Because medical cannabis is recommended for specific health conditions, regulation and quality assurance are needed," they conclude.
In their editorial, Dr D'Souza and Dr Ranganathan note inconsistencies in how medical conditions are qualified for medical marijuana use within a state and between states. For example, in Connecticut, psoriasis and sickle cell disease but not Tourette's syndrome qualify, even though the supporting evidence for all three conditions is uniformly of very low quality. Similarly, post-traumatic stress disorder is approved as a qualifying condition in some, but not all, US states.
They also point out that marijuana is a complex of more than 400 compounds, including up to 70 cannabinoids that have individual or interactive effects, and that the composition of cannabis preparations can vary substantially.
The editorialists advise that because of the risk for psychosis with marijuana, there needs to be explicit contraindications for use in patients with schizophrenia, bipolar disorder, or substance dependence, along with measures to minimize their access to it. They suggest that follow-up programs should be introduced to monitor long-term outcomes in patients taking medical marijuana.
Given that cannabinoid exposure during critical periods of brain development is associated with long-lasting changes in behavior and cognition, they say careful consideration is needed to determine at what age exposure to medical marijuana is justifiable.
JAMA. 2015;313:2474-2483, 2456-2473, 2491-2493, 2431-2432.
Hill review paper
Whiting review paper
September 2, 2015, 10:39 AM
Re: Medical Marijuana: Where's the Evidence?
Marijuana and the Brain: More Research, More Questions
Medscape Medical News
August 27, 2015
How cannabis use might affect the brain of young people is the subject of two major studies published this week.
One study finds no significant effect of cannabis use on brain volume, but rather hints that the brains of users may be smaller to begin with.
The other study suggests that marijuana may alter brain structure in young men at high genetic risk of developing schizophrenia, which can be triggered by cannabis use.
Both studies were published online August 26 in JAMA Psychiatry.
In a related editorial, David Goldman, MD, of the National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland, cautions that it "would be wrong to conclude that it is safe to use cannabis" or that it "would be safe for people with the right genetic makeup or women, in particular, to use cannabis."
No Cause-and-Effect Conclusions
In the first study, researchers studied 483 twin/siblings aged 22 to 35 years, of whom 262 reported a history of cannabis use. On MRI, cannabis users had smaller left amygdala volume (roughly 2.3%; P = .007) and smaller right ventral striatum volume (about 3.5%; P < .005) than nonusers. These volumetric differences, however, were in the range of normal variation.
"Importantly," say the researchers, brain volumes did not differ between sex-matched siblings discordant for cannabis use (P = .35). Both exposed and unexposed siblings in pairs discordant for cannabis use showed reduced amygdala volumes relative to members of concordant unexposed pairs (P = .003).
"Our study shows that the relationship between a simple index of cannabis use (ever using it during one's lifetime) and amygdala volume is attributable to common predisposing factors, such as those shared by members of twin and sibling pairs," study investigator Arpana Agrawal, PhD, associate professor, Department of Psychiatry, Washington University School of Medicine in St. Louis, told Medscape Medical News.
She noted that although other studies have suggested causal effects of cannabis use on brain volumes, this study provides an alternative explanation for that association.
"We can conclude that factors that predispose individuals to use cannabis may also be associated with variations in their amygdala volume," Dr Agrawal explained. "These factors may be genetic or relate to early rearing environment, are shared by brothers and sisters, and influence both our likelihood of using cannabis and variations in amygdala volume. However, we cannot draw any definitive conclusions about causation nor infer what results might be seen when studying heavier, more involved levels of cannabis use and other regions of the brain."
In the second study, researchers asked whether cannabis use influences brain maturation differently in adolescents with low vs high genetic risk for schizophrenia, as estimated from 108 genetic locations identified by the Psychiatric Genomics Consortium.
"Note that all 1577 participants were recruited from the general population ― not selected because of their substance use or mental health. As such, it provides a snapshot of what might be going on in the brain of an average teenager," study investigator Tomáš Paus, MD, PhD, Tanenbaum Chair in Population Neuroscience, the Rotman Research Institute, and professor of psychology and psychiatry, University of Toronto, Ontario, Canada, told Medscape Medical News.
The researchers observed a negative correlation between cannabis use in early adolescence (by age 16 years) and cortical thickness in male participants with a high polygenic risk score. This was not the case for low-risk male participants or for the low- or high-risk female participants.
"Our findings suggest that cannabis use might interfere with the maturation of the cerebral cortex in male adolescents at high risk for schizophrenia by virtue of their polygenic risk score," the authors write.
Any Effect a "Serious Concern"
Dr Paus told Medscape Medical News, "Although we cannot make any cause-and-effect conclusions about the associations between cannabis use and brain maturation, it seems that cannabis- related differences are particularly pronounced in cortical regions with high density of cannabinoid receptor 1. This suggests that chemicals inhaled when smoking cannabis may have something to do with what we see.
"Whether or not this is the case, the fact that we observed the link between early cannabis use and brain maturation only in boys with high polygenic risk score tells us that the brains of these boys may be more susceptible to adverse experiences," Dr Paus said.
"Any effect on brain structure is a serious concern," writes Dr Goldman in his editorial. "If replicated, these genotype-mediated effects of cannabis use are of special concern in young men made vulnerable by genetic background."
Dr Goldman also notes that people using cannabis often and in potent forms are more apt to suffer negative consequences.
"Yet, data on the effects of heavy exposures are lacking, even as access to potent cannabis is becoming easier. The burden of cannabis' effects may fall more heavily on people who, because of genetic makeup or early life exposures, are at greatest risk for brain structural changes, psychosis or addiction. It is safer not to expose people to psychoactive drugs," Dr Goldman concludes.
Neither study had commercial funding. Several authors have disclosed relevant financial relationships, which are listed in the original articles.
JAMA Psychiatry. Published online August 26, 2015. Agrawal et al, abstract; Paus et al, abstract; Editorial
September 27, 2015, 09:27 AM
Re: Medical Marijuana: Where's the Evidence?
Medical Benefits of Marijuana Unclear
Researchers at the University of Bristol, UK, have carried out an analysis of dozens of trials of the medical benefits of cannabis or marijuana.
Dr. Penny Whiting and her team looked at 79 randomized trials including 6,462 participants. Overall, this contained “moderate-quality evidence” to support the use of cannabinoids (chemical compounds that are the active principles in cannabis or marijuana) for chronic pain or spasticity due to multiple sclerosis.
But the evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, sleep disorders, and Tourette syndrome was “lower-quality,” they report. The evidence that cannabinoids could improve anxiety, depression, or psychosis was “very low-quality.”
The evidence for a beneficial effect on psychosis was “low-quality,” and there was “very low-level evidence” for an effect on depression. Neither the type of cannabinoids used, nor mode of administration, appeared to affect the results.
They explain in the Journal of the American Medical Association that most studies suggested cannabinoids were associated with improvements in symptoms, but these associations did not reach statistical significance in all studies.
Despite the introduction of laws to permit the medical use of cannabis in 23 states and Washington, D.C., “their efficacy for specific indications is not clear,” according to the team.
Short-term side effects of cannabinoids included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.
The authors write, “Further large, robust, randomized clinical trials are needed to confirm the effects of cannabinoids, particularly on weight gain in patients with HIV/AIDS, depression, sleep disorders, anxiety disorders, psychosis, glaucoma, and Tourette syndrome are required.
“Further studies evaluating cannabis itself are also required because there is very little evidence on the effects and side effects of cannabis,” the authors write.
Deepak Cyril D’Souza, M.B.B.S., M.D. of the Yale University School of Medicine, New Haven, Connecticut, commented on the findings in an editorial.
He writes, “There is some evidence to support the use of marijuana for nausea and vomiting related to chemotherapy, specific pain syndromes, and spasticity from multiple sclerosis. However, for most other indications that qualify by state law for use of medical marijuana, such as hepatitis C, Crohn disease, Parkinson disease, or Tourette syndrome, the evidence supporting its use is of poor quality.”
He points out, “For most qualifying conditions, approval has relied on low-quality scientific evidence, anecdotal reports, individual testimonials, legislative initiatives, and public opinion. Imagine if other drugs were approved through a similar approach … For most of the conditions that qualify for medical marijuana use, the evidence fails to meet FDA standards.
“If the states’ initiative to legalize medical marijuana is merely a veiled step toward allowing access to recreational marijuana, then the medical community should be left out of the process, and instead marijuana should be decriminalized.
“Conversely, if the goal is to make marijuana available for medical purposes, then it is unclear why the approval process should be different from that used for other medications. Evidence justifying marijuana use for various medical conditions will require the conduct of adequately powered, double-blind, randomized, placebo/active controlled clinical trials to test its short- and long-term efficacy and safety. The federal government and states should support medical marijuana research.
“Since medical marijuana is not a life-saving intervention, it may be prudent to wait before widely adopting its use until high-quality evidence is available to guide the development of a rational approval process.”
In his work as a psychiatrist, D’Souza has extensively studied the impact of marijuana on mental health. He is concerned about how routine daily use may affect the body and the brain over the long term.
Dr. Suzi Gage, also from the University of Bristol, studied this issue and concludes, “Overall, evidence from epidemiologic studies provides strong enough evidence to warrant a public health message that cannabinoids can increase the risk of psychotic disorders.
“However, further studies are required to determine the magnitude of this effect, to determine the effect of different strains on risk, and to identify high risk groups particularly susceptible to the risk of psychosis.”
D’Souza adds, “We don’t fully understand why some people appear to be more vulnerable to these effects, but that is a devastating mental disorder for anyone to have.”
He agrees that cannabinoids are difficult to study because there are hundreds of different components in different strains, and he calls on federal and state health officials to remove any legal or financial obstacles to further investigation.
Whiting, P. F. et al. Cannabinoids for Medical Use: A Systematic Review and Meta-Analysis. The Journal of the American Medical Association, 24 June 2015 doi:10.1001/jama.2015.6358
Gage, S. H. et al. Association Between Cannabis and Psychosis: Epidemiologic Evidence. Biological Psychiatry, 12 August 2015 doi: 10.1016/j.biopsych.2015.08.001
February 28, 2017, 12:18 PM
Marijuana Not Benign: Warn Teens, Parents, AAP Says
Marijuana Not Benign: Warn Teens, Parents, AAP Says
Medscape Medical News
February 27, 2017
As the legal status of marijuana evolves, pediatricians should counsel teenagers and their parents about its potential for harm, write the authors of a new clinical report from the American Academy of Pediatrics.
Despite the impression among many teenagers and their parents that marijuana is a fairly benign drug, it has some real risks that can have a longstanding effect on an individual's health and function, write Sheryl A. Ryan, MD, and Seth D. Ammerman, MD, and colleagues in the clinical report published online February 27 in Pediatrics.
A key area of concern is "the effect of its use on brain development," Dr Ammerman told Medscape Medical News.
There is also the concern that younger children may be exposed to marijuana in the form of edibles such as brownies that may be in the home, he noted. Already, there have been a few reports of children overdosing in this fashion in states where marijuana is legal.
As a result, "a lot of pediatricians now are being asked, 'is marijuana safe?' " he said.
The report arms clinicians with some information to answer that question. It addresses the effects of adolescent marijuana use and offers suggestions for conducting brief, office-based interventions aimed at identifying problem users and helping them stop.
It also provides a list of 10 talking points for pediatricians to remember when talking with parents and teenagers. The points stress the addictive nature of marijuana and its effect on the brain, the dangers of driving under the influence of marijuana, the toxicity of secondhand marijuana smoke, and the influence parents can exert as role models for their children.
Well-Documented Adverse Effects
The view of marijuana as a harmful substance has diminished among adolescents in recent years, the authors explain.
According to the National Survey on Drug Use and Health conducted by the US Department of Health and Human Services, only 41% of participants 12 to 17 years of age perceived "great risk" in smoking marijuana once or twice a week in 2015, down from 55% in 2007.
Yet many of its adverse effects are "well-documented," such as impaired short-term memory and concentration; alterations in judgment, coordination, and motor control; diminished lung function; and a heightened risk for mental health disorders such as depression and psychosis.
In addition, some studies have shown alterations in brain development in areas such as the amygdala, hippocampus, and prefrontal cortex, said Dr Ammerman, clinical professor, Division of Adolescent Medicine, Department of Pediatrics, Stanford University School of Medicine and Lucille Packard Children's Hospital, Stanford, California.
The clinical implications of these findings are unclear, he added, "but they're probably not good."
There is also clear evidence that marijuana is addictive, Dr Ryan, professor of pediatrics and associate clinical professor of nursing, Yale School of Medicine, New Haven, Connecticut, and colleagues write in the report. Overall, 9% of people who try marijuana become addicted, but that rises to 17% of people who try it during adolescence and anywhere from 25% to 50% of adolescents who smoke marijuana daily.
The risk is especially high among adolescents who are regular or heavy users of cannabis. Regular use is defined as 10 to 19 times per month, and heavy use is defined as 20 or more times per month.
Office Screening Suggested
The report urges pediatricians to screen adolescent patients for substance use, as recommended in the previously published Screening, Brief Intervention, and Referral for Treatment policy statement.
Screening should occur at all well-teen visits, or "whenever there is a concern that marijuana use might be an issue," Dr Ammerman said. He also suggested that even before they start screening, pediatricians should raise the issue with patients in an age-appropriate way.
Motivational interviewing techniques can be used either to support patients who have chosen to abstain or to discourage use among adolescents who do smoke marijuana. Some patients may require one or more follow-up visits or a referral to a mental health counselor, the authors write.
Clinicians can use the talking points to emphasize the drawbacks of marijuana: not only the adverse mental and physical effects, but also the fact that its use by people younger than 21 years is still illegal. Prosecution may result "in a permanent criminal record, affecting schooling, jobs, etc.," the authors state.
In addition, the talking points remind parents that they are role models for their children. "Actions speak louder than words," Dr Ammerman warned. "It's very clear that if parents use marijuana in front of their kids, those kids are more likely to use it themselves, regardless of what the parent says."
Adults who view marijuana as relatively harmless may be thinking of the product they used in the 1970s and 1980s, he added. Back then, the average dose of marijuana had about 4% tetrahydrocannabinol, or THC, the compound that gives marijuana its euphoric properties.
However, today's marijuana has 16% THC. "So the drug that we experienced is much less potent than what our children are using, and we know much more today about its potential problems."
On average, adolescents who become addicted to marijuana remain addicted for about 10 years, Dr Ammerman said. "So you've lost 10 years of your life, perhaps doing poorly in school or on the job, or in your relationships. We don't want anyone to throw their life away like that."
Pediatrics. Published online February 27, 2017. Full text
PDF copies of the Medscape article and the full text source Pediatrics article are attached for download.