Monday, August 25, 2014

Alcohol and Your Heart

Health benefits of moderate drinking come under fire.

One of those things that “everybody knows” about alcohol is that a drink or two per day is good for your heart. But maybe not as good for your heart as no drinks at all.

Joint first authors Michael V. Holmes of the Department of Epidemiology and Public Health at University College in London, and Caroline E. Dale at the London School of Hygiene & Tropical Medicine in London, recently published a multi-site meta-analysis of epidemiological studies centering on a common gene for alcohol metabolization. The report, published in the UK journal BMJ, brings “the hypothesized cardioprotective effect of alcohol into question,” according to the authors.

People who are born with a particular variant in the gene controlling for the expression of alcohol dehydrogenase, the major enzyme involved in converting alcohol into waste products, will show the familiar flush reaction when they drink. Alcohol, literally, can make many of them sick. This genetic variant, in combination with other enzymes, can be strongly protective against alcohol, and is much more commonly found among Asian populations. Roughly 40% of Japanese, Korean, and Northeastern Chinese populations show the characteristic “Asian glow” to one degree or another if they choose to drink.  (One reason why this effect isn't better known is that the condition is close to nonexistent in Westerners).

 People with this alcohol dehydrogenase deficiency, the researchers found, not only consume less alcohol, for obvious reasons, but “had lower, not higher, odds of developing coronary heart disease regardless of whether they were light, moderate, or heavy drinkers.”  Here are the conclusions in detail: “Carriers of the rs1229984 A-allele had lower levels of alcohol consumption and exhibited lower levels of blood pressure, inflammatory biomarkers, adiposity measures, and non-HDL cholesterol, and reduced odds of developing coronary heart disease, compared with non-carriers of this allele.”

The authors conclude that "reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.”

How does this work? The researchers aren’t completely sure, but note that the “most widely proposed mechanism” is an increase in high-density lipoprotein (HDL) cholesterol. “Although an HDL cholesterol raising effect of alcohol has been reported in experimental studies, the small sample size and short follow-up means existing studies may be prone to bias,” thereby limiting their usefulness. Moreover, the BMJ study itself found “no overall difference between allele carriers and non-carriers in HDL concentration.”

Like most meta-studies, this one has its strengths and weaknesses. The study used a large sample size, used detailed alcohol phenotypic data, and didn't have to deal with the inherent biases of observational-type studies. On the minus side, the lack of a connection between the allele in question and HDL levels is troubling, and stroke data was lacking.

But overall, the authors believe that "social pressure in heavier drinking cultures is unlikely to override the effect of the genetic variant on alcohol consumption."

In retrospect, there have been some trouble spots along the way: A 2008 study in Current Atherosclerosis Reports concluded:

In the absence of large randomized trials of moderate alcohol consumption and heart failure, we cannot exclude residual confounding or unmeasured confounding as possible explanations for the observed relationships. Thus, for patients who do not consume any alcohol, it would be premature to recommend light-to-moderate drinking as a means to lower the risk of heart failure, given the possible risk of abuse and resulting consequences.

At present, the American Heart Association does not recommend drinking any amount of wine or other alcoholic beverages in order to gain potential health benefits.

Holmes M.V.,  L. Zuccolo,  R. J. Silverwood,  Y. Guo,  Z. Ye,  D. Prieto-Merino,  A. Dehghan,  S. Trompet,  A. Wong &  A. Cavadino &  (2014). Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data, BMJ, 349 (jul10 6) g4164-g4164. DOI:

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Wednesday, August 20, 2014

The Chemistry of Modern Marijuana

Is low-grade pot better for you than sinsemilla?

First published September 3, 2013.

Australia has one of the highest rates of marijuana use in the world, but until recently, nobody could say for certain what, exactly, Australians were smoking. Researchers at the University of Sydney and the University of New South Wales  analyzed hundreds of cannabis samples seized by Australian police, and put together comprehensive data on street-level marijuana potency across the country. They sampled police seizures and plants from crop eradication operations. The mean THC content of the samples was 14.88%, while absolute levels varied from less than 1% THC to almost 40%.  Writing in PLoS ONE, Wendy Swift and colleagues found that roughly ¾ of the samples contained at least 10% total THC. Half the samples contained levels of 15% or higher—“the level recommended by the Garretsen Commission as warranting classification of cannabis as a ‘hard’ drug in the Netherlands.”

In the U.S., recent studies have shown that THC levels in cannabis from 1993 averaged 3.4%, and then soared to THC levels in 2008 of almost 9%. THC loads more than doubled in 15 years, but that is still a far cry from news reports erroneously referring to organic THC increases of 10 times or more.

CBD, or cannabidiol, another constituent of cannabis, has garnered considerable attention in the research community as well as the medical marijuana constituency due to its anti-emetic properties. Like many other cannabinoids, CBD is non-psychoactive, and acts as a muscle relaxant as well. CBD levels in the U.S. have remained consistently low over the past 20 years, at 0.3-0.4%. In the Australian study, about 90% of cannabis samples contained less than 0.1% total CBD, based on chromatographic analysis, although some of the samples had levels as high as 6%.

The Australian samples also showed relatively high amounts of CBG, another common cannabinoid. CBG, known as cannabigerol, has been investigated for its pharmacological properties by biotech labs. It is non-psychoactive but useful for inducing sleep and lowering intra-ocular pressure in cases of glaucoma.

CBC, yet another cannabinoid, also acts as a sedative, and is reported to relieve pain, while also moderating the effects of THC. The Australian investigators believe that, as with CBD, “the trend for maximizing THC production may have led to marginalization of CBC as historically, CBC has sometimes been reported to be the second or third most abundant cannabinoid.”

Is today’s potent, very high-THC marijuana a different drug entirely, compared to the marijuana consumed up until the 21st Century? And does super-grass have an adverse effect on the mental health of users? The most obvious answer is, probably not. Recent attempts to link strong pot to the emergence of psychosis have not been definitive, or even terribly convincing. (However, the evidence for adverse cognitive effects in smokers who start young is more convincing).

It’s not terribly difficult to track how ordinary marijuana evolved into sinsemilla. Think Luther Burbank and global chemistry geeks. It is the historical result of several trends: 1) Selective breeding of cannabis strains with high THC/low CBD profiles, 2) near-universal preference for female plants (sinsemilla), 3) the rise of controlled-environment indoor cultivation, and 4) global availability of high-end hybrid seeds for commercial growing operations. And in the Australian sample, much of the marijuana came from areas like Byron Bay, Lismore, and Tweed Heads, where the concentration of specialist cultivators is similar to that of Humboldt County, California.

The investigators admit that “there is little research systematically addressing the public health impacts of use of different strengths and types of cannabis,” such as increases in cannabis addiction and mental health problems. The strongest evidence consistent with lab research is that “CBD may prevent or inhibit the psychotogenic and memory-impairing effects of THC. While the evidence for the ameliorating effects of CBD is not universal, it is thought that consumption of high THC/low CBD cannabis may predispose users towards adverse psychiatric effects….”

The THC rates in Australia are in line with or slightly higher than average values in several other countries. Can an increase in THC potency and corresponding reduction in other key cannabinoids be the reason for a concomitant increase in users seeking treatment for marijuana dependency? Not necessarily, say the investigators. Drug courts, coupled with greater treatment opportunities, might account for the rise. And schizophrenia? “Modelling research does not indicate increases in levels of schizophrenia commensurate with increases in cannabis use.”

One significant problem with surveys of this nature is the matter of determining marijuana’s effective potency—the amount of THC actually ingested by smokers. This may vary considerably, depending upon such factors as “natural variations in the cannabinoid content of plants, the part of the plant consumed, route of administration, and user titration of dose to compensate for differing levels of THC in different smoked material.”

Wendy Swift and her coworkers call for more research on cannabis users’ preferences, “which might shed light on whether cannabis containing a more balanced mix of THC and CBD would have value in the market, as well as potentially conferring reduced risks to mental wellbeing.”

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Swift W., Wong A., Li K.M., Arnold J.C. & McGregor I.S. (2013). Analysis of Cannabis Seizures in NSW, Australia: Cannabis Potency and Cannabinoid Profile., PloS one, PMID: 23894589

Tuesday, August 12, 2014

Synthetic Cannabis Can Cause Cyclic Vomiting

Another reason to skip "Spice."

Cannabinoid hyperemesis,  as it is known, was not documented in the medical literature until 2004. Case studies of more than 100 patients have been reported since then. The biomedical researcher who blogs as Drugmonkey has documented cases of hyperemesis that had been reported in Australia and New Zealand, as well as Omaha and Boston in the U.S.

As Drugmonkey reported, patients who are heavy marijuana smokers, and who experience cyclic nausea and vomiting, “discovered on their own that taking a hot bath or shower alleviated their symptoms. So afflicted individuals were taking multiple hot showers or baths per day to obtain symptom relief.”

A recent report in Mayo Clinic Proceedings by Dr. Benjamin L. Bick and colleagues documents the 3rd reported case of the syndrome in a regular user of synthetic Spice-style products, rather than marijuana. It’s now clear that THC isn’t necessary for triggering the rare but highly unpleasant vomiting cycle in a small fraction of users.

“A 29-year-old man presented with a 2-year history of recurrent episodes of severe nausea and vomiting with epigastric pain,” according to the authors. Drug tests were negative, including tests for THC. “For his more recent symptoms, he was evaluated multiple times in the primary care setting and emergency department. At each visit he denied use of any ‘illicit substances or drugs’ since he quit using marijuana.”

“Hot showers for up to an hour provided relief. He reported experiencing similar symptoms more than 5 years previously when he was regularly smoking marijuana, and these symptoms resolved with the cessation of cannabis.”

The patient eventually admitted to regularly smoking products sold as K2 and Kryptonite, containing “unidentified and uncertain synthetic cannabinoid agonists marketed as ‘legal’ herbal incense.”

The Mayo clinicians offer diagnostic criteria for cannabis hyperemesis, which include “long-term cannabis use, cyclic nausea and vomiting, resolution with cessation of cannabis, relief of symptoms with hot showers, abdominal pain, and weekly use of marijuana.” And theirs is the third published report of cannabis hyperemesis in a male patient after synthetic cannabinoid use. “After 6 months abstinence,” they report, “he noted complete resolution of symptoms.”

The researchers conclude that “synthetic cannabinoids can be potent agonists of the cannabinoid CB1 receptors, which are the same receptors by which THC produces its effects.” While only three Spice-related incidents of hyperemesis syndrome have thus far been identified, it may go unrecognized in patients using synthetic cannabinoids:

 A urine drug screen negative for THC may point physicians away from this syndrome, and patients may not report use if they believe they are using herbal products rather than illicit drugs. Therefore, regardless of negative urine drug screen results and patient denial of cannabis use, physicians should have a high index of suspicion for synthetic CH syndrome in patients who present with classic symptoms of cyclic emesis.

Sarah A. Buckley and Nicholas M. Mark at the NYU School of Medicine, after reviewing 16 published papers on the syndrome,  asked the obvious question: "How can marijuana, which is used in cancer clinics as an anti-emetic, cause intractable vomiting? And why would symptoms abate in response to high temperature?"

We don't know the answer, but Buckley and Mark note that "cannabis disrupts autonomic and thermoregulatory functions of the hippocampal-hypothalamic-pituitary system," which is loaded with CB-1 receptors. The researchers conclude, however, that the link between marijuana and thermoregulation "does not provide a causal relationship" for what they refer to as "this bizarre learned behavior.”

Bick B.L. &  Thomas F. Mangan (2014). Synthetic Cannabinoid Leading to Cannabinoid Hyperemesis Syndrome, Mayo Clinic Proceedings, 89 (8) 1168-1169. DOI:

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