46 posts · 25,057 views
Dirk Hanson is a freelance science reporter and novelist. He is the author of "The Chemical Carousel: What Science Tells Us About Beating Addiction." He has written two previous books—"The New Alchemists: Silicon Valley and the Microlectronics Revolution," and "The Seventh Level: A Novel." He runs the Addiction Inbox blog.
Addiction Inbox
46 posts
Sort by Latest Post, Most Popular
View by Condensed, Full
- May 20, 2012
- 03:52 PM
- 70 views
Energy Drinks: What’s the Big Deal?
by Dirk Hanson in Addiction Inbox
The sons of Red Bull are sporting record concentrations of caffeine.
Are energy drinks capable of pushing some people into caffeine-induced psychotic states? Some medical researchers think so, under the right set of conditions.
Red Bull, for all its iconic ferocity, is pretty tame, weighing in at approximately half a cup of coffee. Drinks like Monster Energy and Full Throttle push it up to 100-150, or the equivalent of a full cuppa joe, according to USDA figures at Talk About Coffee. That doesn’t sound so bad—unless you’re ten years old. A little caffeine might put you on task, but an overdose can leave you scattered and anxious—or worse. If you cut your teeth on Coke and Pepsi, then two or three energy drinks can delivery an order-of-magnitude overdose by comparison.
Readers are entitled to ask: Are you serious? Can’t we just ignore the inevitable view-this-with-alarm development in normal kid culture, and move on?
My interest began when I ran across a 2009 case report in CNS Spectrums, describing an apparent example of “caffeine-induced delusions and paranoia” in a very heavy coffee drinking farmer. “Convinced of a plot against him,” the psychologists write, “he installed surveillance cameras in his house and on his farm…. He became so preoccupied with the alleged plot that he neglected the business of the farm…. and he had his children taken from him because of unsanitary living conditions.”
The patient was not known to be a drinker, reporting less than a case of beer annually. He had shown no prior history of psychotic behaviors. But for the past seven years, he had been consuming about 36 cups of coffee per day, according to his account. Take that number of cups times 125 milligrams, let’s say, for a daily total of 4500 milligrams. At that level, he should be suffering from panic and anxiety disorders, according to caffeine toxicity reports, and he would be advised to call the Poison Control Center. And that certainly seems to have been the case. “At presentation,” the authors write, “the patient reporting drinking 1 gallon of coffee/day.”
On the one hand, the idea of caffeine causing a state resembling chronic psychosis is the stuff of sitcoms. On the other hand, metabolisms do vary, and the precise manner in which coffee stimulates adenosine receptors can lead to anxiety, aggression, agitation, and other conditions. Could caffeine, in an aberrant metabolism, break over into full-blown psychosis? At the Caffeine Web, where psychiatrists and toxicologists duke it out over all things caffeinated, Sidney Kay of the Institute of Legal Medicine writes: “Coffee overindulgence is overlooked many times because the bizarre symptoms may resemble and masquerade as an organic or mental disease.” Symptoms, he explains, can include "restlessness, silliness, elation, euphoria, confusion, disorientation, excitation, and even violent behavior with wild, manic screaming, kicking and biting, progressing to semi-stupor.”
That doesn’t sound so good. In “Energy drinks: What is all the hype?” Mandy Rath examines the question in a recent issue of the Journal of the American Academy of Health Practitioners.
Selling energy drinks to kids from 6 to 19 years old is a $3.5 billion annual industry, Rath asserts. And while “most energy drinks consumed in moderation do not pose a huge health risk,” more and more youngsters are putting away higher and higher doses of caffeine. At the level of several cans of Coke, or a few cups of strong coffee or, an energy drink or three, students can expect to experience improved reaction times, increased aerobic endurance, and less sleepiness behind the wheel. Most people can handle up to 300 mg of caffeine in a concentrated blast. Certainly a better bargain, overall, than three or four beers.
But first of all, you don’t need high-priced, caffeine-packed superdrinks to achieve that effect. A milligram of caffeine is a milligram of caffeine. But wait, what about the nifty additives in Full Throttle and Monster and Rockstar? The taurine and… stuff. Taurine is an amino acid found in lots of foods. Good for you in the abstract. Manufacturers also commonly add sugar (excess calories), ginseng (at very low levels), and bitter orange (structurally similar to norepinephrine). However, the truly interesting addition is guarana, a botanical product from South America. When guarana breaks down, it’s principal byproduct is, yes, caffeine. Guarana seeds contain twice the caffeine found in coffee beans. Three to five grams of guarana provide 250 mg of caffeine. Energy drink manufacturers don’t add that caffeine to the total on the label because—oh wait, that’s right, because makers of energy drinks, unlike makers of soft drinks, don’t have to print the amount of caffeine as dietary information. And on an ounce-for-pound basis, kids are getting a lot more caffeine with the new drinks than the older, labeled ones.
All of this increases the chances of caffeine intoxication. Rath writes that researchers have identified caffeine-related increases among children in hypertension, insomnia, motor tics, irritability, and headaches. Chronic caffeine intoxication results in “anxiety, emotional disturbances, and chronic abdominal pain.” Not to mention cardiac arrhythmia, seizures, and mania.
So what have we learned, kids? Energy drinks are safe—if you don’t guzzle several of them in a row, or substitute them for dinner, or have diabetes, or an ulcer, or happen to be pregnant, or are suffering from heart disease or hypertension. And if you do OD on high-caffeine drinks, it will not be pleasant: Severe palpitations, panic, mania, muscle spasms, etc. Somebody might even want to take you to the emergency room. Coaches and teachers need to keep a better eye out for caffeine intoxication.
Note: There is a “caffeine calculator” available at the Caffeine Awareness website, designed to determined whether you are a coffee addict. I can by no means swear to its scientific accuracy, but, based on my own, distinctly non-young person daily intake, the test told me that my consumption was likely to manifest itself as “high irritability, moodiness & personality disorders.” Can I blame it all on those endless cokes we had as kids? Growing up in the Baby Boom suburbs, we all drank carbonated caffeine beverages instead of water. Nothing much has changed except the caffeine levels.
Rath, M. (2012). Energy drinks: What is all the hype? The dangers of energy drink consumption Journal of the American Academy of Nurse Practitioners, 24 (2), 70-76 DOI: 10.1111/j.1745-7599.2011.00689.x
Graphics Credit: http://urlybits.com/
... Read more »
Rath, M. (2012) Energy drinks: What is all the hype? The dangers of energy drink consumption. Journal of the American Academy of Nurse Practitioners, 24(2), 70-76. DOI: 10.1111/j.1745-7599.2011.00689.x
- May 16, 2012
- 03:46 PM
- 94 views
A Look at the Recent Study of Cannabis and Multiple Sclerosis
by Dirk Hanson in Addiction Inbox
Smoked marijuana reduced spasticity in a small trial of MS patients.
The leading wedge of the medical marijuana movement has traditionally been centered on pot as medicine for the effects of chemotherapy, for the treatment of glaucoma, and for certain kinds of neuropathic pain. From there, the evidence for conditions treatable with marijuana quickly becomes either anecdotal or based on limited studies. But pharmacologists have always been intrigued by the notion of treating certain neurologic conditions with cannabis. Sativex, which is sprayed under the under-the-tongue as a cannabis mist, has been approved for use against multiple sclerosis, or MS, in Canada, the UK, and some European countries. (In the U.S., parent company GW Pharma is seeking FDA approval for the use of Sativex to treat cancer pain).
There is accumulating evidence that cannabinoid receptors may be involved in controlling spasticity, and that anandamide, the brain’s endogenous form of cannabis, is a specific antispasticity agent.
Additional evidence that researchers may be on to something appeared recently in the Canadian Medical Association Journal. Dr. Jody Corey-Bloom and coworkers at the University of California in San Diego conducted a small, placebo-controlled trial with adult patients suffering from poorly controlled spasticity. Thirty participants were randomly divided into two groups. Those in the first group were given a daily joint, and those in the second group received “identical placebo cigarettes.” After three days, the investigators found that smoked marijuana resulted in a reduction in treatment-resistant spasticity, compared to placebo.
Clearly, it’s hard for a study of this sort to be truly blind: Participants, one presumes, had little trouble distinguishing the medicine from the placebo. And in fact, an appendix to the study shows this to be true: “Seventeen participants correctly guessed their treatment phase for all six visits… For the remaining participants, cannabis was correctly guessed on 33/35 visits.” This raises the question of various kinds of self-selection bias and expectancy effects, and the study authors themselves write that the results “might not be generalizable to patients who are cannabis-naïve.” On the other hand, cannabis-naïve patients were in the minority. The average age of the participants was 50, and fully 80% of them admitted to previous “recreational experience” with cannabis. (I don’t have a good Baby Boomer joke for the occasion, but if I did, this is where it would go).
I asked Dr. Corey-Bloom about this potential problem in an email exchange: “The primary outcome measure was the Ashworth Spasticity Scale, which is an objective measure, carried out by an independent rater,” she wrote. “Their job was just to come in and feel the tone around each joint (elbow, hip, knee), rate it, and leave. That's why we think it was so important to have an objective measure, rather than just self-report.”
With all this in mind, the study found that “smoking cannabis reduced patient scores on the modified Ashworth scale by an average of 2.74 points.” The authors conclude: “We saw a beneficial effect of smoked cannabis on treatment-resistant spasticity and pain associated with multiple sclerosis among our participants.”
Other studies have found similar declines in spasticity from cannabinoids, but have tended not to use marijuana in smokable form.
Corey-Bloom, J., Wolfson, T., Gamst, A., Jin, S., Marcotte, T., Bentley, H., & Gouaux, B. (2012). Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial Canadian Medical Association Journal DOI: 10.1503/cmaj.110837
Photo Credit: http://blog.amsvans.com/... Read more »
Corey-Bloom, J., Wolfson, T., Gamst, A., Jin, S., Marcotte, T., Bentley, H., & Gouaux, B. (2012) Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. Canadian Medical Association Journal. DOI: 10.1503/cmaj.110837
- April 24, 2012
- 05:40 PM
- 124 views
A Drug For Marijuana Withdrawal?
by Dirk Hanson in Addiction Inbox
Researchers get good results with gabapentin.
Marijuana, as researchers and pundits never tire of pointing out, is the most widely used illegal drug in the world, by a serious margin. And while the argument still rages, for some years now drug researchers have been migrating to the camp that sees marijuana as an addictive drug for a minority of people who exhibit a propensity for addiction. The scientific literature supporting the contention of marijuana as addictive for some users is robust and growing, as is the body of anecdotal evidence. It’s also clear that in many countries, cultures, and subcultures, combining cannabis with tobacco is a common practice that increases health risks all around.
Ongoing works at the Scripps Research Institute’s Pearson Center for Alcoholism and Addiction Research in La Jolla, California, has focused in part on the lack of FDA-approved medical therapies for treating marijuana addiction. Barbara J. Mason and coworkers at Scripps have reported preliminary success in a 12-week, double-blind, placebo-controlled pilot study with 50 treatment-seeking volunteers, using the anti-seizure drug gabapentin. Gabapentin, sold as Neurontin, pops up as a possible treatment for various forms of pain and anxiety, and sharp-eyed readers will recall that gabapentin was one of the ingredients in the now-defunct addiction drug Prometa.
Marijuana addiction numbers are hard to come by, and often inflated, since many small-time pot offenders end up in mandatory treatment programs, where they tend to be classified as marijuana addicts, whether or not that is objectively the case. Nonetheless, there are plenty of people seeking treatment on their own for cannabis dependence. For people strongly addicted to pot, the problems are very real, and withdrawal and abstinence pose serious challenges. People for whom marijuana poses no addictive threat should bear this in mind, the way casual drinkers bear in mind the existence of alcoholism in others.
The study, published recently in Neuropsychopharmacology, says that “activation of brain stress circuitry caused by chronic heavy marijuana use” can lead to withdrawal symptoms that persist “for weeks or even months, as in the case of marijuana craving and sleep disturbances.” A variety of existing medications have been tested in recent years, including buspirone, an anti-anxiety medication; Serzone, an antidepressant; and Wellbutrin, an antidepressant commonly used for smoking cessation. None of these treatments have shown any effect on cannabis use or withdrawal, according to Mason.
Gabapentin, as the name suggests, was modeled after the neurotransmitter GABA, and works via a transporter protein to raise GABA levels. Effective only for partial-onset seizures, common side effects include drowsiness, dizziness, and possible weight gain. It is a popular anti-epileptic drug, because it is relatively safe, with a low side-effect profile, compared to many of the medications in its class. For the same reasons, it is a common treatment for neuropathic pain. In addition to neuralgia, it has found some use as a migraine preventative.
Gabapentin normalizes GABA activation caused by corticotrophin-releasing factor, or CRF. CRF is a major player in the brain’s stress responses. As it turns out, withdrawal from both cannabis and alcohol ramp up anxiety levels by increasing CRF release in the amygdala, animal studies have shown. “Gabapentin had a significant effect in decreasing marijuana use over the course of treatment, relative to placebo,” the authors report. In addition, gabapentin produced “significant reductions in both the acute symptoms of withdrawal as well as in the more commonly persistent symptoms involving mood, craving, and sleep.”
As a bonus, the researchers discovered that “overall improvement in performance across cognitive measures was significantly greater for gabapentin-treated subjects compared with those receiving placebo.” Gabapentin was associated with improvement in “tasks related to neurocognitive executive functioning”—things like attention, concentration, visual-motor functioning, and inhibition. Counseling alone, represented by the placebo group, “resulted in less effective treatment of cannabis use and withdrawal, and no improvement in executive function.”
As in the case of Chantix for cigarette cessation, a treatment, which now requires additional caveats about possible suicidal ideation, researchers looking for a treatment for drug withdrawal, must weigh the benefits of pharmacological treatment against the possible side effects of the treatment itself. Does gabapentin for marijuana withdrawal pass the “Do No Harm” test? According to Mason, it does. “Gabapentin was well tolerated and without significant side effects” in the admittedly small trial study. The two groups did not differ in the number of adverse medical events reported in the first two weeks, when dropout rates due to side effects are highest in these kinds of studies. The investigators were not relying solely on self-reporting, either. They used urine drug screens, and verified that only 3% of the study sample tested positive for other drugs.
In short, the authors report that gabapentin reduced cannabis use and eased withdrawal with an acceptable safety profile and no signs of dependence. Gabapentin, the authors conclude, “may offer the most promising treatment for cannabis withdrawal and dependence studied to date.” Further clinical research is needed, of course, but the positive results of this proof-of-concept study should make funding those a bit easier.
Mason, B., Crean, R., Goodell, V., Light, J., Quello, S., Shadan, F., Buffkins, K., Kyle, M., Adusumalli, M., Begovic, A., & Rao, S. (2012). A Proof-of-Concept Randomized Controlled Study of Gabapentin: Effects on Cannabis Use, Withdrawal and Executive Function Deficits in Cannabis-Dependent Adults Neuropsychopharmacology DOI: 10.1038/npp.2012.14
Photo Credit: http://pep3799.hubpages.com/
... Read more »
Mason, B., Crean, R., Goodell, V., Light, J., Quello, S., Shadan, F., Buffkins, K., Kyle, M., Adusumalli, M., Begovic, A.... (2012) A Proof-of-Concept Randomized Controlled Study of Gabapentin: Effects on Cannabis Use, Withdrawal and Executive Function Deficits in Cannabis-Dependent Adults. Neuropsychopharmacology. DOI: 10.1038/npp.2012.14
- March 22, 2012
- 11:37 AM
- 242 views
The Mysteries of the Blunt
by Dirk Hanson in Addiction Inbox
Why do so many smokers combine tobacco with marijuana?
People who smoke a combination of tobacco and marijuana, a common practice overseas for years, and increasingly popular here in the form of “blunts,” may be reacting to some unidentified mechanism that links the two drugs. Researchers believe such smokers would be well advised to consider giving up both drugs at once, rather than one at a time, according to an upcoming study in the journal Addiction.
Clinical trials of adults with cannabis use disorders suggest that “approximately 50% are current tobacco smokers,” according to the report, which was authored by Arpana Agrawal and Michael T. Lynskey of Washington University School of Medicine, and Alan J. Budney of the University of Arkansas for Medical Sciences. “As many cannabis users smoke a mixture of cannabis and tobacco or chase cannabis use with tobacco, and as conditioned cues associated with smoking both substances may trigger use of either substance,” the researchers conclude, “a simultaneous cessation approach with cannabis and tobacco may be most beneficial.”
A blunt is simply a marijuana cigar, with the wrapping paper made of tobacco and the majority of loose tobacco removed and replaced with marijuana. In Europe, smokers commonly mix the two substances together and roll the combination into a single joint, the precise ratio of cannabis and nicotine varying with the desires of the user. “There is accumulating evidence that some mechanisms linking cannabis and tobacco use are distinct from those contributing to co-occurring use of drugs in general,” the investigators say. Or, as psychiatry postdoc Erica Peters of Yale put it in a press release, “There’s something about tobacco use that seems to worsen marijuana use in some way.” The researchers believe that this “something” involved may be a genetic predisposition. In addition to an overall genetic proclivity for addiction, do dual smokers inherit a specific propensity for smoked substances? We don’t know—but evidence is weak and contradictory so far.
Wouldn’t it be easier to quit just one drug, using the other as a crutch? The researchers don’t think so, and here’s why: In the few studies available, for every dually addicted participant who reported greater aggression, anger, and irritability with simultaneous cessation, “comparable numbers of participants rated withdrawal associated with dual abstinence as less severe than withdrawal from either drug alone.” So, for dual abusers, some of them may have better luck if they quit marijuana and cigarettes at the same time. Why? The authors suggest that “absence of smoking cues when abstaining from both substances may reduce withdrawal severity in some individuals.” In other words, revisiting the route of administration, a.k.a. smoking, may trigger cravings for the drug you’re trying to quit. This form of “respiratory adaption” may work in others ways. For instance, the authors note that, “in addition to flavorants, cigarettes typically contain compounds (e.g. salicylates) that have anti-inflammatory and anesthetic effects which may facilitate cannabis inhalation.”
Studies of teens diagnosed with cannabis use disorder have shown that continued tobacco used is associated with a poor cannabis abstention rate. But there are fewer studies suggesting the reverse—that cigarette smokers fair poorly in quitting if they persist in cannabis use. No one really knows, and dual users will have to find out for themselves which categories seems to best suit them when it comes time to deal with quitting.
We will pass up the opportunity to examine the genetic research in detail. Suffice to say that while marijuana addiction probably has a genetic component like other addictions, genetic studies have not identified any gene variants as strong candidates thus far. The case is stronger for cigarettes, but to date no genetic mechanisms have been uncovered that definitively show a neurobiological pathway that directly connects the two addictions.
There are all sorts of environmental factors too, of course. Peer influences are often cited, but those influences often seem tautological: Drug-using teens are members of the drug-using teens group. Tobacco users report earlier opportunities to use cannabis, which might have an effect, if anybody knew how and why it happens.
Further complicating matters is the fact that withdrawal from nicotine and withdrawal from marijuana share a number of similarities. The researchers state that “similar withdrawal syndromes, with many symptoms in common, may have important treatment implications.” As the authors sum it up, cannabis withdrawal consists of “anger, aggression or irritability, nervousness or anxiety, sleep difficulties, decreased appetite or weight loss, psychomotor agitation or restlessness, depressed mood, and less commonly, physical symptoms such as stomach pain and shakes/tremors.” Others complain of night sweats and temperature sensitivity.
And the symptoms of nicotine withdrawal? In essence, the same. The difference, say the authors, is that cannabis withdrawal tends to produce more irritability and decreased appetite, while tobacco withdrawal brings on an appetite increase and more immediate, sustained craving. Otherwise, the similarities far outnumber the differences.
None of this, however, has been reflected in the structure of treatment programs: “Emerging evidence suggests that dual abstinence may predict better cessation outcomes, yet empirically researched treatments tailored for co-occurring use are lacking.”
The truth is, we don’t really know for certain why many smokers prefer to consume tobacco and marijuana in combination. But we do know several reasons why it’s not a good idea. Many of the health-related harms are similar, and presumably cumulative: chronic bronchitis, wheezing, morning sputum, coughing—smokers know the drill. Another study cited by the authors found that dual smokers reported smoking as many cigarettes as those who only smoked tobacco. All of this can lead to “considerable elevation in odds of respiratory distress indicators and reduced lung functioning in those who used both.” However, there is no strong link at present between marijuana smoking and lung cancer.
Some researchers believe that receptor cross-talk allows cannabis to modify receptors for nicotine, or vice versa. Genes involved in drug metabolism might somehow predispose a subset of addicts to prefer smoking. But at present, there are no solid genetic or environmental influences consistent enough to account for a specific linkage between marijuana addiction and nicotine addiction, or a specific genetic proclivity for smoking as a means of drug administration.
Agrawal, A., Budney, A., & Lynskey, M. (2012). The Co-occurring Use and Misuse of Cannabis and Tobacco: A Review Addiction DOI: 10.1111/j.1360-0443.2012.03837.x
Photo credit: http://stuffstonerslike.com ... Read more »
Agrawal, A., Budney, A., & Lynskey, M. (2012) The Co-occurring Use and Misuse of Cannabis and Tobacco: A Review. Addiction. DOI: 10.1111/j.1360-0443.2012.03837.x
- March 18, 2012
- 06:28 PM
- 225 views
“Bath Salts” and Ecstasy Implicated in Kidney Injuries
by Dirk Hanson in Addiction Inbox
“A potentially life-threatening situation.”
Earlier this month, state officials became alarmed by a cluster of puzzling health problems that had suddenly popped up in Casper, Wyoming, population 55,000. Three young people had been hospitalized with kidney injuries, and dozens of others were allegedly suffering from vomiting and back pain after smoking or snorting an herbal product sold as “blueberry spice.” The Poison Review reported that the outbreak was presently under investigation by state medical officials. “At this point we are viewing use of this drug as a potentially life-threatening situation,” said Tracy Murphy, Wyoming state epidemiologist.
It is beginning to look like acute kidney injury from the newer synthetic stimulants may be a genuine threat. And if that wasn’t bad enough, continuing research has implicated MDMA, better known as Ecstasy, as another potential source of kidney damage. Recreational druggies, forewarned is forearmed.
Bath salts first. In the Wyoming case, while the drug in question may have been one of the synthetic marijuana products marketed as Spice, it’s entirely possible that the drug in question was actually one or more of the new synthetic stimulants called bath salts. (Quality control and truth in packaging are not part of this industry). The American Journal of Kidney Diseases recently published a report titled “Recurrent Acute Kidney Injury Following Bath Salts Intoxication.” It features a case history that Yale researchers believe to be “the first report of recurrent acute kidney injury associated with repeated bath salts intoxication.” The most common causes for emergency room admissions due to bath salts—primarily the drugs MDPV and mephedrone—are agitation, hallucinations, and tachycardia, the authors report. But the case report of a 26-year old man showed recurrent kidney injury after using bath salts. The authors speculate that the damage resulted from “severe renal vasospasm induced by these vasoactive substances.” (A vasoactive substance can constrict or dilate blood vessels.)
A possible secondary mechanism of action for kidney damage among bath salt users is rhabdomyolysis—a breakdown of muscle fibers that releases muscle fiber contents into the bloodstream, causing severe kidney damage. Heavy alcohol and drug use, especially cocaine, are also known risk factors for this condition. The complicating factor here is that rhabdomyolysis has also been described in cases of MDMA intoxication, and here we arrived at the second part of the story.
In 2008, the Clinical Journal of the American Society of Nephrology published “The Agony of Ecstasy: MDMA and the Kidney.” In this study, Garland A. Campbell and Mitchell H. Rosner of the University of Virginia Department of Medicine found that “Ecstasy has been associated with acute kidney injury that is most commonly secondary to nontraumatic rhabdomyolysis but also has been reported in the setting of drug-induced liver failure and drug-induced vasculitis.”
Chemically, MDMA is another amphetamine spinoff, like mephedrone and other bath salts. Many people take this club drug regularly without apparent harm, whereas others seem to be acutely sensitive and can experience serious toxicity, possibly due to genetic variance in the breakdown enzyme CYP2D6. The authors trace the first case report of acute kidney injury due to Ecstasy back to 1992, but “because most of these data are accrued from case reports, the absolute incidence of this complication cannot be determined.”
Campbell and Rosner believe that nontraumatic rhabdomyolysis is a likely culprit in many cases, and speculate that the condition is “greatly compounded by the ambient temperature, which in crowded rave parties is usually elevated.” If a physician suspects rhabdomyolysis in an Ecstasy user, “aggressive cooling measures should be undertaken to lower the patient’s core temperature to levels that will lessen further muscle and end-organ injury.” This complication can have far-reaching effects: The authors note the case history of “transplant graft loss of both kidneys obtained from a donor with a history of recent Ecstasy use.”
In addition, there may be undocumented risks to the liver as well. An earlier study by Andreu et. al. claims that “up to 31% of all drug toxicity-related acute hepatic failure is due to MDMA… Patients with severe acute hepatic failure secondary to ecstasy use often survive with supportive care and have successfully undergone liver transplantation.”
But the picture is far from clear: “Unfortunately, no case reports of acute kidney injury secondary to ecstasy have had renal biopsies performed to allow for further elucidation…” And attributing firm causation is difficult, due to the fact that MDMA users often use other drugs in combination, some of which, like cocaine, can cause kidney problem all by themselves.
A study by Harold Kalant of the University of Toronto’s Addiction Research Foundation, published in the Canadian Medical Association Journal, proposed that “dantrolene, which is a drug used to stop the intense muscle contractures in malignant hyperthermia, should also be useful in the hyperthermic type of MDMA toxicity. Numerous cases have now been treated in this way, some with rapid and dramatic results even when the clinical picture suggested the likelihood of a fatal outcome.”
Adebamiro, A., and Perazella, M. (2012). Recurrent Acute Kidney Injury Following Bath Salts Intoxication American Journal of Kidney Diseases, 59 (2), 273-275 DOI: 10.1053/j.ajkd.2011.10.012
Graphics Credit: http://trialx.com ... Read more »
Adebamiro, A., & Perazella, M. (2012) Recurrent Acute Kidney Injury Following Bath Salts Intoxication. American Journal of Kidney Diseases, 59(2), 273-275. DOI: 10.1053/j.ajkd.2011.10.012
- March 4, 2012
- 08:44 PM
- 213 views
Night Owls Get a Coffee Break
by Dirk Hanson in Addiction Inbox
“Morning people” have more caffeine-related sleep problems.
Let me start by saying that I love this caffeine study for personal reasons. As a lifelong night owl, I have been chastised by wife, family, and friends over the years for my regular habit of drinking coffee after 10 pm. (And falling easily asleep two or three hours later, if I choose to.) Other coffee drinkers have told me how rare and weird this is. If we have a cup, they tell me, or even an afternoon sip, we toss and turn all night.
As it turns out, I was talking to the wrong kind of coffee drinkers. I needed to consult my crowd, and that’s what I did. I checked in with a few confirmed fellow night owls, and yes, a few of them reported that they had no problems going to sleep after a late night cup or two.
Anecdotal, of course—but a recent clinical study published in Sleep Medicine backs me up. The study, “Modeling caffeine concentrations with the Stanford Caffeine Questionnaire: Preliminary evidence for an interaction of chronotype with the effects of caffeine on sleep,” sets out to examine the effects of caffeine on the sleep patterns of college students. Researchers at Stanford told the students to keep sleep logs and to wear an actigraphy wristband to record rest/activity cycles. The students filled out daily questionnaires about their caffeine intake at different times of the day, and gave saliva samples for caffeine assessments.
The scientists were able to accurately predict salivary caffeine concentrations based on the questionnaires, which was the primary intent of the study. But in the process, they discovered what they believe to be “a novel relationship between the effects of caffeine on sleep and genotype and chronotype.” What the researchers ended up with was some seriously suggestive evidence about the relationship of caffeine and natural sleep rhythms. (Here’s a nifty little test to determine whether you are a lark or an owl, i.e., your chronotype.)
Typically, clinical trials with caffeine are limited to the basic question: How much coffee did you drink today? But the Stanford researchers wanted to include the many variables that modulate caffeine intake—things like the timing of ingestion, the variations in the amount of caffeine among beverages, individual variations in caffeine metabolism, and the wide differences in half-life that caffeine can exhibit under various circumstances. They attempted to establish the students’ genotypes for adenosine receptors, where caffeine does most of its work, and to select volunteers who had “statistically indistinguishable” differences in adenosine receptor gene frequencies.
As you might expect, even among students, caffeine intake progressively decreased throughout the day in the study group. However, a small number of participants continued their intake of caffeine well into the night. The metric known as “wake after sleep onset,” or WASO, was used as the primary measurement of sleep disruption. “Our data indicate caffeine strongly influences WASO in those who self-identify as morning-type,” the researchers found. “It affects WASO less so in those who are neither type, and does not appear to affect WASO in those who are evening-type. To our knowledge, there have been no previous reports linking the effects of caffeine and chronotype.”
Some warnings on the study: It involved only 50 college students. And they were students, meaning their schedules were highly erratic by definition, and they were chronically sleep-deprived by habit. The study authors attempted to turn this defect into a virtue, noting that “the students were under such homeostatic pressure that their mood had little effect on their sleep.” Nonetheless, we will need to see if the findings hold up using less, er, unpredictable subjects.
If they do hold up, it will make it easier for people to understand the homily delivered by the coffee-drinking grandmother of a friend of mine: “The only time coffee ever kept me awake was when I knew there was another cup in the pot.”
Photo credit: http://www.facebook.com/
Nova, P., Hernandez, B., Ptolemy, A., & Zeitzer, J. (2012). Modeling caffeine concentrations with the Stanford Caffeine Questionnaire: Preliminary evidence for an interaction of chronotype with the effects of caffeine on sleep Sleep Medicine DOI: 10.1016/j.sleep.2011.11.011... Read more »
Nova, P., Hernandez, B., Ptolemy, A., & Zeitzer, J. (2012) Modeling caffeine concentrations with the Stanford Caffeine Questionnaire: Preliminary evidence for an interaction of chronotype with the effects of caffeine on sleep. Sleep Medicine. DOI: 10.1016/j.sleep.2011.11.011
- February 13, 2012
- 11:18 PM
- 223 views
PROMETA™ Postmortem
by Dirk Hanson in Addiction Inbox
How the latest miracle cure for addiction failed to deliver.
PROMETA™: Last seen going down fast, smoke pouring from all engines.
As reported here at Addiction Inbox, a double-blind placebo-controlled evaluation of PROMETA™ by W. Ling and associates, published online last month in the journal Addiction, found that the much-publicized treatment protocol for meth addiction “appears to be no more effective than placebo in reducing methamphetamine use, retaining patients in treatment or reducing methamphetamine craving.” The authors of the journal paper didn’t accuse Hythiam, the company that makes and sells the product, of not telling the truth. They just said that the treatment didn’t work. The study authors did, however, find evidence of “potential financial conflicts of interests among its advocates…”
An earlier CBS News "60 Minutes" news report in 2009 had raised similar questions, but generated a great deal of publicity for PROMETA™. And the only testing available, a small open study from Texas, had shown positive results. Testimonials began mounting, and a few prominent doctors in the addiction field lent their names to the marketing effort. More conservative voices, like Richard Rawson and the University of Pennsylvania’s Tom McClellan, warned that there was insufficient scientific evidence to push forward with the new treatment—but their concerns were swept aside amid the general enthusiasm for a long-sought antidote to the ravages of methamphetamine addiction.
So how did it happen? And what, if anything, does it teach us about the enterprise of addiction research and treatment?
An editorial by Dr. Keith Humphreys of the Stanford University Medical Centers, which accompanied the report of the clinical trial in Addiction, attempted to analyze the saga of how “a former junk bond trader with no medical background raised $150 million in capital to market a combination of three medications (gabapentin, flumazenil and hydroxyzine) as a treatment for methamphetamine addiction.” Bear in mind that only one of the drugs—gabapentin—had ever been involved in clinical trials against addiction, with decidedly mixed results. As for the other ingredients, a prominent neuroscientist who blogs pseudonymously as Neuroskeptic, commented at the time: “What the hell kind of a cocktail is that? Gabapentin—OK, it might reduce anxiety and stabilize mood, although the evidence is poor and if you wanted to do that, there are better drugs. Ditto for hydroxazine. And why you want both of those is unclear. But flumazenil? That doesn't do much if you haven't taken a benzodiazepine. But if it did do anything it would be to antagonize the gabapentin.”
All in all, not a promising analysis.
The three drugs are approved for various uses by the FDA, and there is the rub: Off-label practices allow physicians to prescribe medications for uses other than those listed on the official package insert. As useful as this practice can be, it creates a situation in which a “combination of previously approved medications can be marketed without review as a new treatment protocol, despite the fact that none of the individual medications had any evidence nor were originally approved as a treatment for the condition the new protocol targets.”
Under this directive, Hythiam was free to promote the combination of approved medications as a new addiction treatment advance without any significant testing, Humphreys contends.
If the treatment, in the end, proved to be no better than placebo for meth addiction, what made it seem like such a successful new thing under the sun at the outset? Wishful thinking, Humphreys believes: “Many serious, good-hearted people will be shocked at Ling’s negative results because they believed sincerely… we must not yield to our powerful collective desire to believe before we have hard evidence of effectiveness from disinterested, respected sources. The simpler, faster and more miraculous-seeming the cure, the greater should be our skepticism.”
Furthermore: "As was the case with another would-be ‘miracle cure’—ultra-rapid opiate-detoxification—a manufacturer was able to market an untested treatment protocol to addicted patients…”
Why? Because “off-label use of medications is well-established in medical practice and has significant value in many cases, but a balance must be struck with the risk this creates for evasion of the normal safety and efficacy checks by creators of new treatment protocols."
"We have a huge advantage at this historical moment which was not available to people in prior eras who could not determine whether ‘Dr. Keeley’s Double Chloride of Gold Injections’, ‘Dr. Revaly’s Guaranteed Remedy for the Tobacco Habit’ and ‘Dr. Meeker’s Addiction Antidote’ were effective,” writes Humphreys. Namely, “a well-developed addiction treatment research enterprise." And because of that, we should “point with pride to Ling et.al.’s work as an example of how high-quality science can inform suffering people about what will help them and what will not; and those who set pubic research budgets need look no further for an example of return on investment.”
HUMPHREYS, K. (2012). What can we learn from the failure of yet another ‘miracle cure’ for addiction? Addiction, 107 (2), 237-239 DOI: 10.1111/j.1360-0443.2011.03652.x
Photo Credit: http://blog.nebraskahistory.org ... Read more »
HUMPHREYS, K. (2012) What can we learn from the failure of yet another ‘miracle cure’ for addiction?. Addiction, 107(2), 237-239. DOI: 10.1111/j.1360-0443.2011.03652.x
- January 31, 2012
- 11:20 AM
- 306 views
Reward and Punish: Say Hello to Dopamine’s Leetle Friend
by Dirk Hanson in Addiction Inbox
Dopamine recruits a helper to track drug rewards.
Ah, dopamine. Whenever it seems like researchers have finally gotten a bead on how that tricky molecule modulates pleasure and reward, and the role in plays in the process of drug and alcohol addiction, along come new findings that rearrange its role, deepening and complicating our understanding of brain function.
We know that the ultimate site of dopamine activity caused by drugs is the ventral tegmental area, or VTA, and an associated structure, the nucleus accumbens. But dopamine neurons in the VTA actually perform two distinct functions. They discriminate acutely between the expectation of reward, and the actual reward itself. Pavlov showed how these dual functions are linked, but the manner in which dopamine neurons computed and then dealt with the differences between expectation and reward—a controversial concept known as reward prediction error—was not well understood.
We all know about reward and punishment, however. Years ago, behaviorism’s emphasis on positive and negative reinforcement demonstrated the strong connection between reward, punishment, and learning. As Michael Bozarth wrote in “Pleasure Systems in the Brain,” addictive drugs “pharmacologically activate brain reward mechanisms involved in the control of normal behavior. Thus, addictive drugs may be used as tools to study brain mechanisms involved in normal motivational and reward processes.”
But how does the evolutionary pursuit of pleasure or avoidance of punishment that guarantees the survival of an organism—fighting, fleeing, feeding, and… fornicating, in the well-known “4-F” configuration—become a pathological reversal of this function? To begin with, as Bozarth writes, “the direct chemical activation of these reward pathways does not in itself represent any severe departure from the normal control reward systems exert over behavior…. Simple activation of brain reward systems does not constitute addiction!”
What does, then? Bozarth believes addiction results from “motivational toxicity,” defined as deterioration in the “ability of normal rewards to govern behavior.” In an impaired reward system, “natural” rewards don’t alter dopamine function as strongly as drug rewards. “Direct pharmacological activation of a reward system dominates the organism’s motivational hierarchy at the expense of other rewards that promote survival,” Bozarth writes. The result? Drug addicts who prefer, say, methamphetamine to food.
How does an addict’s mind become so addled that the next hit takes precedence over the next meal? A group of Harvard-based researchers, writing in Nature, thinks it may have a handle on how the brain calculates reward expectations, and how those calculations go awry in the case of heavy drug and alcohol use.
The dopamine system somehow calculates the results of both failed and fulfilled expectations of reward, and uses that data in future situations. Cellular biologists, with some exceptions, believe that dopamine neurons effectively signal some rather complicated discrepancies between expected and actual rewards. Dopaminergic neurons were, in effect, computing reward prediction error, according to the theory. They were encoding expectation, which spiked when the reward was better than expected, and fell when the reward was less than expected. As Scicurious wrote at her blog, Neurotic Physiology “If you can’t predict where and when you’re going to get food, shelter, or sex in response to specific stimuli, you’re going to be a very hungry, chilly and undersexed organism.” (See her excellent and very readable post on dopamine and reward prediction HERE. )
But nobody knew how this calculation was performed at the cellular level.
Enter research mice.
As it turns out, dopamine is not the whole story. (A single neurotransmitter rarely is.) Dopaminergic neurons account for only about 55-65% of total neurons on the VTA. The rest? Mostly neurons for GABA, the inhibitory transmitter. “Many addictive drugs inhibit VTA GABAergic neurons,” the researchers note, “which increases dopamine release (called disinhibition), a potential mechanism for reinforcing the effects of these drugs.” By inhibiting the inhibitor, so to speak, addictive drugs increase the dopamine buzz factor.
The researchers used two strains of genetically altered mice, one optimized for measuring dopamine, the other for measuring GABA. The scientists conditioned mice using odor cues, and offered four possible outcomes: big reward, small reward, nothing, or punishment (puff of air to the animal’s face). Throughout the conditioning and testing, the researchers recorded the activity of neurons in the ventral tegmental area. They found plenty of neurons with atypical firing patterns. These neurons, in response to reward-predicting odors, showed “persistent excitation” during the delay before the reward. Others showed “persistent inhibition” to reward-predicting odors.
It took a good deal of sorting out, and conclusions are still tentative, but eventually the investigators believed that VTA dopamine neurons managed to detect the discrepancy between expected and actual outcomes by recruiting GABA neurons to aid in the dendritic computation. This mechanism may play a critical role in optimal learning, the researchers argue.
Furthermore, the authors believe that “inhibition of GABAergic neurons by addictive drugs could lead to sustained reward prediction error even after the learned effects of drug intake are well established.” Because alcohol and other addictive drugs disrupt GABA levels in the brain’s reward circuitry, the mechanism for evaluating expectation and reward is compromised. GABA, dopamine’s partner in the enterprise, isn’t contributing properly. The ability to learn from experience and to accurately gauge the likelihood of reward, so famously compromised in active addiction, may be the result of this GABA disruption.
Naoshige Uchida, associate professor of molecular and cellular biology at Harvard, and one of the authors of the Nature paper, said in a press release that until now, “no one knew how these GABA neurons were involved in the reward and punishment cycle. What we believe is happening is that they are inhibiting the dopamine neurons, so the two are working together to make the reward error computation.” Apparently, the firing of dopamine neurons in the VTA signals an unexpected reward—but the firing of GABA neurons signals an expected reward. Working together, GABA neurons aid dopamine neurons in calculating reward prediction error.
In other words, if you inhibit GABA neurons through heavy drug use, you screw up a very intricate dopamine feedback loop. When faced with a reward prediction error, such as drug tolerance—a good example of reward not meeting expectations—addicts will continue taking the drug. This seems nonsensical. If the drug no longer works to produce pleasure like it used to do, then why continue to take it? It may be because dopamine-active brain circuits are no longer accurately computing reward prediction errors. N... Read more »
Cohen, J., Haesler, S., Vong, L., Lowell, B., & Uchida, N. (2012) Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature. DOI: 10.1038/nature10754
- November 17, 2011
- 02:10 PM
- 389 views
End of the Line for Prometa?
by Dirk Hanson in Addiction Inbox
Controversial meth treatment program fails in major study.
Prometa—the drug cocktail designed to combat addiction to cocaine and methamphetamine—has fallen flat on its face in a double-blind, placebo-controlled 108-day study just published in the journal Addiction. Dogged all along by a lack of published clinical data as well as major doubts about its success rates, Prometa has been a controversial treatment right from the start. In 2006, marketed heavily by anecdote and personal testimonials, the Prometa campaign included ads featuring the late comedian Chris Farley, who died of a drug overdose.
Hythiam, the company that markets Prometa, had touted reports that 80% or more of Prometa users experienced “significant clinical benefit.” But MSNBC reported in 2008 that accountants in Pierce County, Washington froze the funding for an $800,000 pilot program, citing irregularities in testing. Investors in Hythiam, which is publicly traded, had been counting on the Pierce program after similar programs in Fulton County, Georgia, and in Idaho had failed to get off the ground. Things only got worse when the Tacoma News Tribune revealed that several county officials who had gotten behind the program also owned Hythiam stock.
Small rural communities that have felt the impact of meth sales and production in their communities are looking for help, and represent a significant market for an anti-addiction medication. However, in the case of Prometa, “The marketing is way ahead of the science,” said Lori Karan of the Drug Dependence Research Laboratory at the University of California-San Francisco. At the same time, Hythiam Executive Vice President Richard Anderson voiced strong objections to the Pierce County decision: “The people who are using it,” he said, “the doctors, patients, administrators, and drug court judges—are seeing an impact with it, so I think the treatment will carry it at the end of the day.”
But the day has ended, and the treatment did not carry it. The study in Addiction by a team of researchers at UCLA found no difference between Prometa and placebo in a group of 120 methamphetamine-addicted adults. The Prometa regimen, which can cost as much as $12,000 to $15,000 a month, “appears to be no more effective than placebo in reducing methamphetamine use, retaining patients in treatment or reducing methamphetamine craving,” the investigators conclude.
Ironically, the study was funded by Hythiam, as a response to complaints from the scientific community about a lack of rigorous testing. When it first launched the treatment, Hythiam was able to skim past the pesky drug approval process by exploiting a loophole in the FDA’s regulatory system that allows combinations of previously approved drugs to be marketed without formal review. Prometa was a blend of three existing medications: Neurontin (gabapentin) for epilepsy, Vistaril (hydrozyzine) for allergies, and Romazicon (flumazenil) for reversing benzodiazepine overdoses.
Ling, W., Shoptaw, S., Hillhouse, M., Bholat, M., Charuvastra, C., Heinzerling, K., Chim, D., Annon, J., Dowling, P., & Doraimani, G. (2011). Double-blind placebo-controlled evaluation of the PROMETA™ protocol for methamphetamine dependence Addiction DOI: 10.1111/j.1360-0443.2011.03619.x... Read more »
Ling, W., Shoptaw, S., Hillhouse, M., Bholat, M., Charuvastra, C., Heinzerling, K., Chim, D., Annon, J., Dowling, P., & Doraimani, G. (2011) Double-blind placebo-controlled evaluation of the PROMETA™ protocol for methamphetamine dependence. Addiction. DOI: 10.1111/j.1360-0443.2011.03619.x
- November 14, 2011
- 01:37 PM
- 367 views
Researchers Eye a Cheap, Organic Alternative to Chantix for Smokers
by Dirk Hanson in Addiction Inbox
Meet cytisine, available in Bulgaria for 25 cents a pill.
A clear majority of American smokers say they want to quit. But each year, only a small percentage of them manage to do it. For individual smokers, the will is there, but what’s sometimes missing is the money.
For many smokers, cessation aids like nicotine patches and anti-craving medication are effective. But they are relatively costly, and insurance coverage for such products varies widely. Chantix, the top-of-the-line smoking cessation aid introduced by Pfizer five years ago as a very expensive prescription drug, was discovered by modifying the chemical attributes of an existing plant substance called cytisine.
But what if cytisine itself, found in various plants, including the golden rain tree, a small shrub native to the Alps—worked almost as well as Chantix, but for only pennies a day? Cytisine, packaged as Tabex and marketed by a Bulgarian firm, has already been on the market in Central Europe and Russia for more than 40 years. In Russia, a four-week course of Tabex costs $6. Chantix will cost smokers about $250 for a 12-week run, or about $3-$4 per pill. In Poland, Tabex sells for about 25 cents per pill.
Moreover, as David Biello pointed out in Scientific American, when Chantix (known as Champix in the U.K.) was first approved for use against cigarettes, “the leaves of Cytisus laburnum, or the golden rain acacia tree, were used as a tobacco substitute by soldiers in World War II.” Later, clinicians in the U.S. paid scant attention to reports of a cheap Bulgarian plant-based supplement that smokers in Russia and Central Europe were using to help break their nicotine addiction. Instead, researchers structurally modified cytisine to produce varenicline, or Chantix. It makes for a more effective drug, but there are always tradeoffs: It is expensive and time-consuming to produce drugs through a process of total syntheses, and they will always come at a considerable cost premium relative to their organic originals. That is partly how pharmacology works, and it’s a good thing, providing you have the money or the health insurance to be able to afford the finished product.
Recently, a group of researchers at a smoking cessation clinic in Poland studied the effect of cytisine, a “partial nicotine agonist,” in a clinical trial published
in the New England Journal of Medicine. The double-blind trial showed that cytisine was not as effective as Chantix, but significantly more effective than a placebo. Dr. Robert West of University College, London, and lead author of the study, said the “net improvement in the abstinence rate with cytisine was 6 percentage points. The relative rate of abstinence in the cytisine group as compared with that in the placebo group was 3.4.”
“It wasn't compared head-to-head against the Rx drugs, but its reasonable efficacy makes it sounds like a cheaper alternative,” said Dr. David Kroll, Professor and Chair of Pharmaceutical Science at North Carolina Central University. “Like nicotine, it can cause side effects like headaches and nausea,” he added.
So is cytisine an eventual possibility in the U.S., where it is not currently licensed and available? Is it something that the National Institute on Drug Abuse is interested in? When I asked NIDA director Nora Volkow that question in an interview last week, the answer was yes. “The data looks very interesting,” Volkow said, referring to the New England Journal of Medicine Study. “The beauty of cytisine is that it’s not just inexpensive, you can also get a response in three weeks.” She added that “we don’t know yet whether we can improve it,” by, for example, combining it with other cessation aids. “The main side effect of cytisine is nausea, but not suicidal ideation,” she added.
An earlier survey in the Archives of Internal Medicine of the admittedly sparse research showed similar results in several placebo-controlled double-blind studies. Cytisine, the Marxist-Socialist answer to cigarette addiction, works about as well as standard nicotine replacement therapy, like patches and gums.
“I hope this drug will be available throughout the world at a cost that every smoker can afford,” said West. And that might be a problem. Cytisine is not currently legal in the U.S. or Canada. Tabex itself was withdrawn from some of the European countries in which it was formerly available, after several Central and Eastern European countries joined the European Union and began adhering to stricter licensing rules.
Meanwhile, a third of the world is still out there smoking tobacco. It seems sensible to have some modest help available for smokers in poverty who want to quit and financially need to quit. “I have long been concerned that effective treatments to help smokers to stop are not affordable by the majority of smokers in the world,” West said. “There are still regulatory hoops to go through, but I hope that before long this drug will be available throughout the world at a cost that every smoker can afford. It should be cheaper to take this drug than to smoke, wherever you are in the world. It is not a magic cure by any means; stopping is still extremely difficult for many people. But it could save many hundreds of thousands of lives, if not millions, which is quite a thought.”
As Dr. Volkow put it: “We urgently need medications for smoking. Five million people die per year” from smoking-related causes in the U.S.
West R, Zatonski W, Cedzynska M, Lewandowska D, Pazik J, Aveyard P, & Stapleton J (2011). Placebo-controlled trial of cytisine for smoking cessation. The New England journal of medicine, 365 (13), 1193-200 PMID: 21991893... Read more »
West R, Zatonski W, Cedzynska M, Lewandowska D, Pazik J, Aveyard P, & Stapleton J. (2011) Placebo-controlled trial of cytisine for smoking cessation. The New England journal of medicine, 365(13), 1193-200. PMID: 21991893
- November 2, 2011
- 06:33 PM
- 453 views
Marijuana: The New Generation
by Dirk Hanson in Addiction Inbox
What’s in that “Spice” packet?
They first turned up in Europe and the U.K.; those neon-colored foil packets labeled “Spice,” sold in small stores and novelty shops, next to the 2 oz. power drinks and the caffeine pills. Unlike the stimulants known as mephedrone or M-Cat, or the several variations on the formula for MDMA—both of which have also been marketed as Spice and “bath salts”—the bulk of the new products in the Spice line were synthetic versions of cannabis.
The new forms of synthetic cannabis tickle the same brain receptors as THC does, and are sometimes capable of producing feelings of well-being, empathy, and euphoria—in other words, pretty much the same effects that draw people to pot. But along the way, users began turning up in the emergency room, something that very rarely happens in the case of smoked marijuana. The symptoms were similar to adverse effects some people experience with marijuana, but greatly exaggerated: extreme anxiety and paranoia, and heart palpitations.
As it turns out, there is a very real difference between smoking Purple Kush and snorting “Banana Cream Nuke” out of a metallic packet. The difference lies in the manner in which the brain’s receptors for cannabinoids are stimulated by the new cannabis compounds. When things goes wrong at the CB1 and CB2 receptors, and the mix isn’t right, the results may not be euphoria, giggles, short-term memory loss, and the munchies, but rather “nausea, anxiety, agitation/panic attacks, tachycardia, paranoid ideation, and hallucinations.” Furthermore, the Spice variants do not contain cannabidiol, a cannabis ingredient that has been shown to reduce anxiety in animal models, and reduces THC-induced anxiety in human volunteers. The authors of a recent study suggest that the “lack of this cannabinoid in Spice drugs may exacerbate the detrimental effects of these herbal mixtures on emotion and sociability.”
What concerned the researchers was that, in addition to reports of cognitive deficits and emotional alterations and gastrointestinal effects, emergency room physicians were reporting wildly elevated heart rates, extremely high blood pressure, chest pains, and fever. Fattore and Fratta report that “two adolescents died in the USA after ingestion of a Spice product called ‘K2,’” one due to a coronary ischemic event, and the other due to suicide. What’s going on?
In a paper for Frontiers in Behavioral Neuroscience called “Beyond THC: the new generation of cannabinoid designer drugs,” Liana Fattore and Walter Fratta of the University Of Cagliari in Monserrato, Italy, identified more than 140 different products marketed as Spice, and laid out the extreme variability found in composition and potency. Like a mutating virus, they came to the U.S., starting in early 2009, a new strain seemingly every week: Spice, K2, Spice Gold, Silver, Arctic Spice, Genie, Dream, and dozens of others, the naming and renaming suggesting nothing so much as the proliferating strains of high-end marijuana: Skunk, Haze, Silver Haze, Amnesia, AK-47. Synthetic marijuana comes mainly from manufacturers in Asia, and second generation chemicals have already been put on a to-be-banned list by the DEA. States have jumped all over the problem with duplicate legislation, despite the fact that experts believe a majority of sales take place over the Internet. A third generation of synthetic cannabis variants, which are sprinkled on an herbal base and meant to be snorted, are openly sold and touted as legal. And they are legal, depending upon which one you buy, and where you buy it. Synthetic cannabis is still readily available, affordably packaged, and right on the shelf, or ready for purchase online—unlike the frequently vague and sometimes shady process of scoring a bag of weed. In the beginning, at least, the new drugs were perceived by youthful users as safer than other drugs.
But the most crucial attribute of Spice and related products is that they are not detectable in urine and blood samples. You can cruise all night on Spice, and test clean the next day at work. The kind of cannabis in Spice doesn’t read out on anybody’s drug tests as marijuana. That requires the presence of THC—and the new synthetics don’t have any.
There are four different categories of chemicals used in the manufacture of “cannabimimetic” drugs. The first and best known is the so-called JWH series of “novel cannabinoids” synthesized by John W. Huffman at Clemson University in the 1980s. The most widely used variant is an extremely potent version known as JWH-018. While JWH-018 is, chemically speaking, not structurally like THC at all, it snaps onto CB1 and CB2 receptors more fiercely than THC itself The CP-compounds, the second class of synthetic compounds, were developed back in the 1970s by Pfizer, when that firm was actively engaged in testing cannabis-like compounds for commercial potential, a program they later dropped. The best-known example is CP-47,497. While CP-47,497, the most common variant, lacks the chemical structure of classic cannabinoids, it is anywhere from 3 to 28 times more potent than THC, and shows classic THC-like effects in animal studies. The next group is known as HU-compounds, because they originated at Hebrew University, where much of the early work on the mechanisms of THC took place. The last category consists of chemicals in the family of benzoylindoles, which also show an affinity for cannabinoid receptors.
JWH-018, the most common form of synthetic cannabis, and now widely illegal, is considerably more potent than THC—4 times stronger at the CB1 receptor, and 10 times stronger at the less familiar CB2 receptor. The CB2 receptor seems to have a lot to do with pain perception and inflammation, which is why researchers continue to investigate it. But CB2 receptors contribute only indirectly to the classic marijuana high, which is all about THC’s affinity for CB1 receptors, and the effects of using drugs with a very strong affinity for CB2 receptors is not well documented. And therein might lie the source of the problem—or, as Fattore and Fratta describe it, “the greater prevalence of adverse effects observed with JWH-018-containing products relative to marijuana.” A popular compound of the second kind, HU-210, has frequently been found in herbal mixtures available in the U.S. and U.K. According to the study, “the pharmacological effects of HU-210 in vivo are also exceptionally long lasting, and in animal models it has been shown to negatively affect learning and memory processes as well as sexual behavior.”
That, in a nutshell, is what the kids are smoking these days. But wait, there’s more: Besides synthetic cannabinoids, herbs and vitamins, researchers have found opioids like tramadol, opioid receptor-active compounds like Kratom (Mitragyna speciosa), and oleamide, a fatty acid derivative with psychoactive properties. (A combination of oleamide and JWH-018 has been sold as “Aroma.”) Indentifying which of these active ingredients is part of any particular packet of “legal highs” is further complicated by manufacturers’ tendency to mix the ingredients together with up to 15 organic compounds—everything from nicotine to masking agents like vitamin E. In fact, almost anything that might make it more difficult for forensic labs to pry it all apart: alfalfa, comfrey leaf, passionflower, horehound, etc. Banana Cream Nuke, which was purchased in an American smoke shop, and made two young girls very sick, contained 15 varieties of synthetic cannabis—but none of the herbal ingredients actually listed on the label.
Unlike to the partial activation of CB1 receptors by THC, which takes place when people smoke marijuana, “synthetic cannabinoids identified so far in Spice products have been shown to act as full agonists with increased potency, thus leading to longer durations of action and an increased likelihood of adverse effects.” When it comes to cannabis, users are far better off smoking the ... Read more »
Fattore, L., & Fratta, W. (2011) Beyond THC: The New Generation of Cannabinoid Designer Drugs. Frontiers in Behavioral Neuroscience. DOI: 10.3389/fnbeh.2011.00060
- October 23, 2011
- 06:42 PM
- 345 views
Decoding Dope
by Dirk Hanson in Addiction Inbox
Why marijuana gets you high, and hemp doesn’t.
Cannabis sativa comes in two distinct flavors—smokeable weed, and headache-inducing hemp. The difference between hemp and smokeable marijuana is simple: Hemp, used for fiber and seed, contains only a tiny amount of THC, the primary active ingredient in the kind of cannabis that gets you high. I am old enough to recall the sad saga of California hippies driving through my natal state of Iowa, and filling their trunks with “ditch weed”—wild hemp that grows commonly along Iowa rural fencerows, and while it cannot get you high, it could, back then, get you arrested.
But the California hippies who ran afoul of the law in Iowa were not so stupid as it might seem. Even a marijuana connoisseur can have a hard time telling the difference between strong sinsemilla and wild hemp. Both varieties look similar, have similar growth patterns and flowering schedules, and a fresh bud of ditch hemp can look and smell enticingly like the real thing. Even the trichomes—the thousands of sticky, microscopic stalks that grow on the female flowers, each containing a bead of resin, like a crystal golf ball on a tee, containing mostly THC, in the case of pot, and mostly CBD, in the case of hemp—are also similar in appearance and growth behavior.
A study by a group of Canadian researchers, just published in Genome Biology, lays out the draft genome of marijuana, containing all of the plant’s hereditary information as encoded in DNA and RNA. In their article, Timothy Hughes, Jonathan Page and co-workers reported “a draft genome and transcriptome sequence of C. sativa Purple Kush.” (The genome and transcriptome can be browsed or downloaded at The Cannabis Genome Browser.) More than 20 plant genomes have now been sequenced, including corn and rice, but Cannabis sativa marks the first genomic sequencing of a traditional medicinal plant.
So how does it happen that one version of cannabis comes power packed, while the other version shoots blanks, so to speak? The researchers began with the modern facts of the matter: The THC content of medical and recreational marijuana is “remarkably high.” Research shows that median levels of THC in dried female flowers of Purple Kush (the strain used in the study) and other high-end variants now approach 11%, with some strains achieving a stratospheric 23% THC content by dry weight. Why can’t breeders pull any buzz out of ditch weed? How did cannabis split into two distinct subtypes? In an accompanying editorial entitled “how hemp got high,” Naomi Attar calls Cannabis sativa “a plant with a ‘split personality,' whose Dr. Jekyll, hemp, is an innocent source of textiles, but whose Mr. Hyde, marijuana, is chiefly used to alter the mind.” In brief, what are the biological reasons for the psychoactive differences between marijuana and hemp?
Co-lead author Jon Page, a plant biologist at the University of Saskatchewan, along with Tim Hughes of the Department of Molecular Genetics at the University of Toronto, compared the genomic information of Purple Kush, a medical marijuana favorite, with a Finnish strain of hemp called Finola, which was developed for oil seed production and contains less than 1% THC content. That is not enough THC to be mind-altering in any way. Instead, what Finola has in abundance is cannabidiol, or CBD, the other major ingredient in cannabis.
CBD isn’t considered psychoactive, but it does produce a host of pharmacological activity in the body. CBD shows less affinity for the two main types of cannabis receptors, CB1 and CB2, meaning that it attaches to receptors more weakly, and activates them less robustly, than THC. The euphoric effects of marijuana are generally attributed to THC content, not CBD content. In fact, there appears to be an inverse ratio at work. According to a paper in Neuropsychopharmacology, "Delta-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD's ability to block the psychotogenic effects of delta-9-THC."
The kind of cannabis people want to buy has a high THC/low CBD profile, while the hemp chemotype is just the reverse—low THC/high CBD. While the medical marijuana movement has concentrated on Purple Kush and other high-THC breeds, medical researchers have often tilted towards the CBD-heavy variants, since CBD seems to be directly involved with some of the purported medicinal effects of the plant. So, CBD specifically does not produce the usual marijuana high with accompanying euphoria and forgetfulness and munchies. What other researchers have discovered is that pot smokers who suffer the most memory impairment are the ones smoking cannabis low in cannabidiol, while people smoking cannabis high in cannabidiol—cheap, seedy, brown weed—show almost no memory impairment at all. THC content didn't seem to matter. It was the percentage of CBD that controlled the degree of memory impairment, the authors of earlier studies concluded.
The researchers found evidence in Purple Kush for “upregulation of cannabinoid ‘pathway genes’ and the exclusive presence of functional THCA synthase.” That means the reason hemp doesn’t get you high is because it is lacking the crucial enzyme—THCA synthase—that limits production of CBD and allows the production of THC to go wild. In contrast, cannabis strains producing high levels of THC—the Kushes and Hazes and White Widows and other seriously spendy variants—do have high levels of the enzyme that limits the production of CBD. Purple Kush gets you high because it has a built-in chemical brake on the production of CBD. Hemp doesn’t.
In a press release from the University of Saskatchewan, the researchers explain how they think this divergence came about: “Over thousands of years of cultivation, hemp farmers selectively bred Cannabis sativa into two distinct strains—one for fiber and seed, and one for medicine.” This intensive selective breeding resulted in changes in the essential enzyme for THC production, which “is turned on in marijuana, but switched of in hemp,” as Page put it. Furthermore, says co-leader Tim Hughes of the Department of Molecular Genetics at the University of Toronto, an additional enzyme responsible for removing materials required for THC production was “highly expressed in the hemp strain, but not the Purple Kush.” The loss of this enzyme in Purple Kush eliminated a substance “which would otherwise compete for the metabolites used as starting material” in THC production.
Without knowing the mechanics of it, underground growers and breeders have been steadily maximizing the cultivation of strains of cannabis high in THCA synthase, the result of which is a molecular blocking maneuver that maximizes THC production. This is great for getting high, but may not be the optimal breeding strategy for producing plants with medicinal properties. Raphael Mechoulam, the scientist who first isolated and synthesized THC, has referred to plant-derived cannabinoids as a “neglected pharmacological treasure trove.” The authors of this study agree, and have already identified some candidate genes that encode for a variety of cannabinoids with “interesting biological activities.” Such knowledge, they say, will “facilitate breeding of cannabis for medical and pharmaceutical applications.”
But cannabis of this kind may turn out to be low-THC weed. And that may be a good thing, some researchers believe. Marijuana expert Lester Grinspoon told Nature News: "Cannabis with high cannabidiol levels will make a more appealing option for anti-pain, anti-anxiety and anti-spasm treatments, because they can be delivered without causing disconcerting euphoria." (We’ll leave definitional issues about the effects of euphoria for another post.)
Finally, the authors strongly suggest that if it were not for “legal restrictions in most jurisdictions on growing cannabis, even for research purposes,” we would have known all of this stuff years ago, and would have been well on our way to developing “finer tailoring of cannabinoid content in new strains of marijuana,” as Nature News Blog ... Read more »
van Bakel H, Stout JM, Cote AG, Tallon CM, Sharpe AG, Hughes TR, & Page JE. (2011) The draft genome and transcriptome of Cannabis sativa. Genome biology, 12(10). PMID: 22014239
- August 5, 2011
- 12:56 PM
- 652 views
Cigarette Sadness
by Dirk Hanson in Addiction Inbox
The chemistry of sorrow during nicotine withdrawal.
When you smoke a cigarette, nicotine pops into acetylcholine receptors in the brain, the adrenal glands, and the skeletal muscles, and you get a nicotine rush. Just like alcohol, a cigarette alters the transmission of several important chemical messengers in the brain. “These are not trivial responses,” said Professor Ovide Pomerleau of the University of Michigan Medical School. “It’s like lighting a match in a gasoline factory.”
Experiments at NIDA’s Addiction Research Center in Baltimore have confirmed that nicotine withdrawal not only makes people irritable, but also impairs intellectual performance. Logical reasoning and rapid decision-making both suffer during nicotine withdrawal. Acetylcholine appears to enhance memory, which may help explain a common lament voiced by many smokers during early withdrawal. As summarized by one ex-smoker, “I cannot think, cannot remember, cannot concentrate.”
But there is another, less widely discussed aspect of nicotine withdrawal: profound sadness. Profound enough, in many cases, to be diagnosed as clinical unipolar depression.
Of course, people detoxing from addictive drugs like nicotine are rarely known to be happy campers. But quitting smoking, for all its other withdrawal effects, reliably evokes a sense of acute nostalgia, like saying goodbye to a lifelong friend. The very act of abstinence produces sadness, joylessness, dysphoria, melancholia—all emotional states associated with unipolar depression.
Work undertaken by Dr. Alexander Glassman and his associates at the New York State Psychiatric Institute has nailed down an unexpectedly strong relationship between prior depression and cigarette smoking, and the findings have been confirmed in other work. This sheds important light on the question of why some smokers repeatedly fail to stop smoking, regardless of the method or the motivation. The problem, as Glassman sees it, is “an associated vulnerability between affective [mood] disorders and nicotine.”
Now a group of Canadian researchers, working out of the Centre of Addiction and Mental Health (CAMH), and the Department of Psychiatry at the University of Toronto, believe they have isolated the specific neuronal mechanisms responsible for the profound sadness of the abstinent smoker.
Writing in the Archives of General Psychiatry, the investigators, who had access to what the CAMH proudly calls the only PET scanner in the world dedicated to mental health and addiction research, gave PET scans to 24 healthy smokers and 24 healthy non-smokers. Non-smokers were scanned once, while heavy and moderate cigarette smokers were scanned after smoking a cigarette, and also after a period of acute withdrawal. Earlier research of this kind had focused on nicotine’s effect on dopamine release. But Ingrid Bacher and her coworkers in Toronto were measuring MAO-A levels in the prefrontal and anterior cingulate regions, two areas known to be involved in “affect,” or emotional responses. When patients suffering from major depressive disorders get scanned, they tend to show elevated levels of MAO-A. The so-called MAO-A inhibitors Marplan, Nardil, Emsam, and Parnate are still in use as antidepressant medications. In general, the higher the levels of MAO-A, the lower the levels of various neurotransmitters crucial to pleasure and reward. A high level of MAO-A would suggest that the enzyme was significantly altering the activity of serotonin, dopamine, and norepinephrine in brain regions involved in mood.
The researchers found that smokers in withdrawal had 25-35% more MAO-A binding activity than non-smoking controls. “This finding may explain why heavy smokers are at high risk for clinical depression," says Dr. Anthony Phillips, Scientific Director of the Canadian Institutes of Health Research's (CIHR's) Institute of Neurosciences, Mental Health and Addiction, which funded this study.
Although researchers involved in these kinds of drug studies almost always claim that the work is likely to lead to new pharmacological therapies, the plain truth is that such immediate spinouts are rare. But in this case, it does seem like the study provides a clear incentive to investigate the clinical standing of MAO-A inhibitors as an adjunct therapy in stop-smoking programs. “Understanding sadness during cigarette withdrawal is important because this sad mood makes it hard for people to quit, especially in the first few days,” said Dr. Jeffrey Meyer, one of the study authors.
As one addiction researcher noted, an associated vulnerability to depression “isn’t going to cover everybody’s problem, and it doesn’t mean that if you give up smoking, you’re automatically going to plunge into a suicidal depression. However, for people who have some problems along those lines, giving up smoking definitely complicates their lives.”
Bacher, I., Houle, S., Xu, X., Zawertailo, L., Soliman, A., Wilson, A., Selby, P., George, T., Sacher, J., Miler, L., Kish, S., Rusjan, P., & Meyer, J. (2011). Monoamine Oxidase A Binding in the Prefrontal and Anterior Cingulate Cortices During Acute Withdrawal From Heavy Cigarette Smoking Archives of General Psychiatry, 68 (8), 817-826 DOI: 10.1001/archgenpsychiatry.2011.82
Photo Credit:http://jenniferonmars.wordpress.com
... Read more »
Bacher, I., Houle, S., Xu, X., Zawertailo, L., Soliman, A., Wilson, A., Selby, P., George, T., Sacher, J., Miler, L.... (2011) Monoamine Oxidase A Binding in the Prefrontal and Anterior Cingulate Cortices During Acute Withdrawal From Heavy Cigarette Smoking. Archives of General Psychiatry, 68(8), 817-826. DOI: 10.1001/archgenpsychiatry.2011.82
- July 9, 2011
- 09:11 PM
- 760 views
Teachable Moments in the Life of a Cigarette Smoker
by Dirk Hanson in Addiction Inbox
Child surgery makes smoking parents more likely to try quitting.
Here’s a strange one: Doctors at Mayo Clinic wanted to find out whether children undergoing surgery had any effect on the smoking behavior of their parents. And it did—but the effect appears to be short-lived.
The Mayo researchers began from the already well-tested proposition that smokers who have surgery are more likely to quit smoking. In fact, they quit at twice the rate of smokers who haven’t had surgery. Not hard to understand, intimations of mortality and all that. They pass through a teachable moment, the scientists write in Anesthesiology, defined as “an event that prompts behavioral change.” As for smokers with kids, doctors have always had recourse to two tactics for creating teachable moments for cigarette cessation. First, they could point to increased illness and asthma in the innocent children of smokers. And when that didn’t work, they could throw in the cold fact that children exposed to secondhand smoke have a higher risk of respiratory complications during and after surgical anesthesia. And in a further queasy irony, “the increased frequency of conditions such as middle ear diseases caused by secondhand smoke may also make it more likely that children will require surgery.”
For documentation, the investigators turned to the massive National Health Interview Survey (NHIS), a questionnaire served up annually to 35,000 households by personal interview. About 12% of children in the NHIS survey in 2005 were exposed to secondhand smoke. Of the thousands of children undergoing surgery, there was an increased likelihood that a parent of one of them would inaugurate a no-smoking attempt. But these quitters were no more likely to succeed in their attempt than any other quitters.
However, “parents having surgery within the previous 12 months was associated with more quit attempts, more successful attempts, and a greater intent to quit among those still smoking.” What happened to the indestructable bond between parent and child? It appears that concerns about one’s own health trump concerns about the health of offspring when it comes to quitting cigarettes. “We can only speculate about why surgery was a significant factor associated with sustained abstinence when experienced by the smoker but not the smoker’s child.”
There are plenty of limitations to these kinds of self-reported surveys, but it is hard not to speculate, along with the researchers. One obvious implication: the chances of a smoker quitting are at their maximum when parent and child both have surgeries.
“Our current findings suggest that having a child undergo surgery can serve as a teachable moment for quit attempts,” said Dr. Warner. “The scheduling of children for surgery may present us with an opportunity to provide tobacco interventions to parents, who are apparently more motivated to at least try to quit – but who need assistance to succeed.”
Shi, Y., & Warner, D. (2011). Pediatric Surgery and Parental Smoking Behavior Anesthesiology, 115 (1), 12-17 DOI: 10.1097/ALN.0b013e3182207bde
Photo Credit: http://special-needs.families.com/... Read more »
Shi, Y., & Warner, D. (2011) Pediatric Surgery and Parental Smoking Behavior. Anesthesiology, 115(1), 12-17. DOI: 10.1097/ALN.0b013e3182207bde
- July 5, 2011
- 07:42 PM
- 697 views
The Undiagnosed Epidemic of Incarceration
by Dirk Hanson in Addiction Inbox
Prison once again a place for addicts and the mentally ill.
Readers may remember the dark day of January 1, 2008, when the U.S. set an all-time record: One out of every 100 adults was behind bars. That’s more than 2.3 million people. That’s 25% of all the prisoners in the world—and the world includes some very nasty nations. What gives?
You know the answer: drug crimes. Can it really be a coincidence that over the past 40 years, ever since President Richard Nixon first declared war on drugs, the number of people housed in U.S. prisons has gone up by more than 600%? Are we really just that much more vicious and larcenous than we used to be? 600% more unlawful than we were as a people in 1971? Last month, a group of medical professionals from the Division of Infectious Diseases at Brown Medical School, and the Center for Prisoner Health and Human Rights, both in Providence, Rhode Island, co-authored an article for the New England Journal of Medicine entitled “Medicine and the Epidemic of Incarceration in the United States.” The investigators conclude that the explosion in the prison population is a direct result of “our country’s failure to treat addiction and mental illness as medical conditions. The natural history of these diseases often leads to behaviors that result in incarceration.” Packed prisons are also the result of a broader movement over the past 40 years to shift the burden of care for addiction and mental illness over to the prison system. “Deinstitutionalization of the mentally ill over the past 50 years and severe punishment for drug users starting in the 1970s have shifted the burden of care for addiction and mental illness to jails and prisons,” the authors argue.
Do the social costs of this massive transfer of addicts and the mentally ill to the U.S. prison system outweigh the benefits? According to the NEJM article by Josiah D. Rich and co-workers, “more than 50% of inmates meet the DSM-IV criteria for drug dependence or abuse, and 20% of state prisoners have a history of injection-drug use.” Rich estimates that up to a third of all heroin users pass through the criminal justice system each year. These figures are shockingly high, compared to the general population, even allowing for a higher level of drug use among the criminal population.
“The largest facilities housing psychiatric patients in the United States are not hospitals but jails,” they write. “More than half of inmates have symptoms of a psychiatric disorder… yet correctional facilities are fundamentally designed to confine and punish, not to treat disease.” Furthermore, as most people are aware, the punishment is not meted out equally: “By middle age, black men in the United State are more likely to have spent time in prison than to have graduated from college or joined the military and they are far more likely than whites to be sent to prison for drug offenses despite being no more likely that whites to use drugs.”
And there is one aspect of the sorry situation that receives almost no attention at all: Most prisoners are eventually released. This post-release period, says the NEJM article, “presents extraordinary risks to individuals and costs to society.” In the first two weeks after release, former inmates are 129 times more likely to die from a drug overdose than the average man or woman on the street. They are 12 times more likely to die, period. And here’s a nice touch: Most of them don’t have Medicaid or other medical insurance, and there is usually no primary care follow-up to assure that they have access to affordable medications, if they need them. Inevitably, these are among the people who make the local emergency room their primary care facility, at great cost to everyone involved. As the article states: "Addressing the health needs of this vulnerable population is thus not only an ethical imperative, but also of crucial importance from both a fiscal and a public health perspective."
State spending on correctional institutes is now the second fastest growing sector of government spending, after Medicaid. According to the authors, five states now spend more on prisons than they spend on higher education. “Locking up millions of people for drug-related crimes has failed as a public-safety strategy and has harmed public health in the communities to which these men and women return.”
The authors make it clear that, for addicts, drug and mental health treatment programs are humane and sensible alternatives to incarceration. They are also cost-effective: In Rhode Island, for example, the price for putting someone behind bars for a year is $41,000—or $110,000, if we are talking about the new super maximum-security facilities. Why haven’t politicians seized on all of this as a budgeting issue; as a cost-effective way to address drug and alcohol addiction without clogging up the criminal justice system, and creating embarrassing rates of incarceration? The authors have an answer: the fear of being tagged as “soft on crime.” If addiction is a craven failure of will power leading to the violation of social norms, as so many citizens seem to think, than prison is where addicts belong. The result: political pandering on the drug issue, by politicians suffering from a craven failure of will.
Here is where President Obama’s Affordable Care Act could really end up making a difference. Former prisoners will have a good shot at health coverage, and a policy that links together community health centers and academic medical centers could radically improve care during the critical post-release period. As Rich and colleagues argue: “Such access could redirect many people with serious illnesses away from the revolving door of the criminal justice system, thereby improving overall public health in the communities to which prisoners return and decreasing the costs associated with reincarceration due to untreated addiction and mental illness.”
Rich JD, Wakeman SE, & Dickman SL (2011). Medicine and the epidemic of incarceration in the United States. The New England journal of medicine, 364 (22), 2081-3 PMID: 21631319
Pic http://scrapetv.com ... Read more »
Rich JD, Wakeman SE, & Dickman SL. (2011) Medicine and the epidemic of incarceration in the United States. The New England journal of medicine, 364(22), 2081-3. PMID: 21631319
- June 25, 2011
- 04:46 PM
- 728 views
That Pesky Gambling Question
by Dirk Hanson in Addiction Inbox
The DSM-V is set to label problem gambling an addiction.
Nobody has ever bet enough on the winning horse.
— Unknown wise person
I used to gamble. Back when I did, I was also an active alcoholic and a chain smoker. Camel filters, if you’re wondering. And we had a running joke, my wife and I, although the humor leaked out of it for her pretty quickly. We would breach the doors of the gambling palace, and plunge into the dark, icy interior of a casino at Las Vegas or Tahoe, and stand on the edge of the gaming room, taking it all in for a moment. “Ah,” I would say, surveying the roomful of cigarette smokers with drinks in their hands, making bets or hitting buttons at one o’clock in the morning, “my kind of people.”
Gambling can be defined as an activity in which something of value is put at risk in a situation where the outcome is uncertain. That’s really all there is to it. Howard J. Shaffer and Ryan Martin, whose article in the Annual Review of Clinical Psychology, “Disordered Gambling: Etiology, Trajectory and Clinical Considerations,” takes on all the interesting questions about gambling as an addictive disease, have chosen to favor the term “disordered gambling.” Just as there are divisions between alcoholic drinking, heavy drinking, and social drinking, there are similar states we can call pathological gambling, excessive gambling, and social gambling. On the problematic end of the scale, pathological or problem gambling has proven to be “a more complex and unstable disorder than originally and traditionally thought.” No kidding. Once the neurophysiology of the gambling state of mind came under scrutiny, the parallels with addiction cropped up so rapidly that investigators have been hard pressed to come up with suitable explanations for it all.
The new DSM-V proposes to shift pathological gambling from “impulse control disorder” to the new category of “addiction and related disorders.” So it’s a good time to rethink the question along with the psychiatric community.
In the traditional view, pathological gambling was a matter of exposure to the proper stimuli—it could happen to anyone. But as more and more gambling outlets and opportunities bloomed in Nevada, on reservations and riverboats, and in convenience stores, that view began to fall out of favor, because a funny thing happened. According to Shaffer and Martin, the prevalence of pathological gambling has remained stable over the past 35 years, even as opportunities to gamble have exploded. The lifetime prevalence rate of pathological gambling in the U.S. in the mid-1970s was 0.7%, say the authors, and by 2005, U.S. lifetime rates had actually fallen slightly, to 0.6% or less. Where was the concomitant explosion in the number of pathological gamblers?
Next, researchers got technical, wondering whether certain types of gambling, or certain types of gambling machines, were more “addictive” than others. They quickly ran into the same kind of trouble substance abuse researchers got into when they first tried ranking drugs according to strict hierarchies of addictiveness. In so doing, the staggering metabolic diversity of the human animal got lost in the shuffle, as did the fact that my metabolism and my behavior when taking drugs, or knocking one back, or losing money in a casino, is going to be different from yours.
Then came Internet gambling. In 1996, the first online casino to accept real money began operation, and by 2001, there were more than a thousand. Previously, researchers had to rely mostly on the time-honored but not always accurate system of self-reporting. If you ask people why they gamble, they tend to answer that they do it for the fun, the excitement, the challenge, and the chance to win some money. But what gamblers can’t recall very well are specific patterns of play over time that might benefit researchers. For example, in a 2009 study in which observers actually watched gamblers gambling, one long-standing observation from the self-report literature—gamblers become more liberal risk takers as they approach the end of a gambling session in a behavior called “chasing”—didn’t prove out. When researchers watched actual gamblers in action on the Internet, or playing lotteries, they found that problem gamblers in fact began betting more conservatively as they approached the end of their gambling, the authors write.
Another approach is to consider risk factors of all kinds—neurobiological, psychological, and social—and look for similarities between those for substance addiction, and those for “activity-based expressions of addiction.” The “syndrome model,” or what I usually call the umbrella model, derives from neurobiological research suggesting that “addictive disorders might not be independent: each outwardly unique addiction disorder might be a distinctive expression of the same underlying addiction syndrome…. The specific objects of addiction play a less central role in the development of addiction than previously thought….”
All of this opens the door to some informed speculation about a broader range of disorders that may lurk beneath the umbrella of the addictive disease concept. Among these are such conditions as body dysmorphic disorder, bulimia, depression, and extreme PMS, which are all found more often in addict populations. In addition, impulsivity and low “harm avoidance” are behavioral traits often found in association with addiction. Shaffer and Martin call these “shadow syndromes,” and they are found to be associated with BOTH substance and behavioral addictions.
But what, exactly, is the high in gambling? The researchers believe that, “similar to ingesting stimulants, there is evidence that gambling is associated with autonomic arousal including elevated blood pressure, heart rate, and mood.” That's not very specific, and could also describe a craving for teddy bears. But recently, fascinating evidence of neurobiological influences on gambling arose when Parkinson’s’ patients on strong dopamine agonist treatments, with no history of gambling whatsoever, began behaving for all the world like pathological gamblers. I cannot imagine a better suggestion of neurogenetic involvement than this unexpected finding. Previous research had shown that dopamine-active drugs were capable of increasing the incidence of other addictions, too. Shaffer and Martin list compulsive eating, compulsive sexual behaviors, and compulsive shopping as activities that can also be boosted with dopamine agonists or diminished by lowering dopamine activity.
And it does not strike me as surprising to learn that, yes, gambling problems tend to run in families, or that twins studies show that pathological gambling is higher among twins born to pathological gamblers than twins born to non-gamblers. It is the same evidence anyone can bring forth to bolster the argument for neurobiological influences on alcoholism, heroin addiction, and the like. “In sum” Shaffer and Martin conclude, “genetic influences might not determine the development of specific expression of addiction; however, genetics does influence the risk of addiction in general.”
If all of this is true, we should expect to see a corresponding connection between pathological gambling and substance abuse disorders. Some degree of overlap would be good evidence. And we have it in spades. Pathological gamblers are five and a half times more likely to have suffered from a substance abuse disorder. “75% of PGs (pathological gamblers) have had an alcohol disorder, 38% have had a drug use disorder and 60% have had nicotine dependence.” Also, “PGs are 4 times more likely than non-PGs to experience a mood disorder in their lifetime….”
So when I used to stand on the edge of the casino floor, as an alcoholic and a nicotine addict, casually calling those gamblers my kind of people, I think I was more right than I ever could have guessed.
Does all this mean that playing games on the Internet is an addictive behavior if making bets with real money is involved? The authors crunched the studies on that question, and discovered that maybe 1% of the Internet population has used the Internet for gambling purposes, and that “the case of Internet gambling provides little evidence that exposure is the primary driving force behind the prevalence and intensity of gambling…. The relationship between the extent of gambling ‘involvement’ is a better predictor of disordered gambling than any particular game that people play.”
By gambling involvement, the authors mean the number of different kinds of games a gambler plays. The more he or she plays, the more likely they are, or are likely to become, problem gamblers. However, it’s not hard to see where the online notion came from. Gambling folklore has alw... Read more »
Shaffer HJ, & Martin R. (2011) Disordered gambling: etiology, trajectory, and clinical considerations. Annual review of clinical psychology, 483-510. PMID: 21219194
- June 3, 2011
- 08:45 PM
- 786 views
For Smokers, Nowhere to Run and Nowhere to Hide
by Dirk Hanson in Addiction Inbox
(With love and apologies to Martha and the Vandellas.)
That wonderful song goes on to declare:
'Cause I know
You're no good for me
But you’ve become
A part of me.
The song is not about cigarette addiction, but it could be. Full Disclosure: I smoked cigarettes myself for almost 25 years. And then, after several failed attempts, I quit. I out myself on this subject because a paper from the May 25 issue of the New England Journal of Medicine (NEJM) decries what the authors call the “denormalization” of smoking—and I find myself agreeing with them, smokeless though I may be. I recently visited New York, coincidentally on the day that smoking outdoors in New York City became illegal. Okay, that’s not quite fair to say—it became illegal to smoke in Central Park, or at Brighton Beach, or along the newly pedestrian mallways of Times Square. There is no smoking along the High Line. There is no smoking at any park, beach, or pedestrian mall. As both the tobacco industry and anti-smoking activists well know, this was an iconic victory that has the potential to change smoking laws in virtually every other American city.
It’s a fascinating progression, starting in the 70s when the Civil Aeronautics Board decreed non-smoking sections on domestic airline flights, to the recent New York City Council Decision to ban smoking en plein air, so to speak. Thomas Farley, New York City Health Commissioner, summed it up as follows in a public hearing: “I think in the future, we will look back on this time and say ‘How could we have ever tolerated smoking in a park?’”
I’m not so sure on that, myself. James Colgrove, Ronald Bayer, and Kathleen Bachynski of the Mailman School of Public Health at Columbia University wrote the paper, entitled “Nowhere Left to Hide? The Banishment of Smoking from Public Spaces,” in the NEJM. The authors note that more than 500 towns and cities in 43 different states have already enacted laws banning smoking “in outdoor recreation areas.” At first, as the authors summarize the history, it all seems like a sensible compromise, built on common courtesy. First airplanes and buses, then restaurants and bars, began setting aside seats for non-smokers. By the early 90s, the first data on secondhand smoke was rolling in. Schools, convention centers, and finally even private workplaces either banned smoking or created smoke-free areas. But even then, the primary motivator, according to the researchers, was that secondhand smoke was “unpleasant and annoying,” not deadly. Smokers weren’t being asked to refrain from public smoking for the good of their own health, but as a courtesy to others.
The solid scientific evidence kept accumulating, however—even though tobacco cigarettes were, and still are, completely legal products for adult Americans to purchase and consume if they so choose. Now the arguments shifted to the innocent bystanders, those within the six-foot ring, the immediate smoke zone surrounding a smoker, and the elevated risk of lung cancer, heart disease, and asthma that smokers were subjecting them to. In 1993, the Environmental Protection Agency (EPA) classified secondhand smoke as a Class A carcinogen, and more school, stadiums and offices proscribed smoking.
So far so good, really, from a public health standpoint. But now comes the bend in the road. Suddenly, parks and beaches were being added to the no-smoking roster. “As the zones of prohibition are extended from indoor to outdoor spaces, however, the evidence of physical harm to bystanders grows more tenuous.” In 2008, the authors report, “The editor of the journal Tobacco Control dismissed as ‘flimsy’ the evidence that secondhand smoke poses a threat to the health of nonsmokers in most outdoor settings.”
This confusion was much in evidence at public hearings last fall on the proposed outdoor smoking bans. While Health commissioner Farley argued that 57% of New Yorkers showed nicotine by-products in their blood, he also argued that exposing young children to adults in the carnal act of smoking was detrimental to the public health and welfare. “Families,” he said, “should be able to bring their children to parks and beaches knowing that they won’t see others smoking.” This is really quite an astonishing assertion, given the range of bad habits youngsters are exposed to as they go about a normal day in the adult world. The authors are particularly concerned about this push to stigmatize smokers. “Given the addictive nature of nicotine and the difficultly of quitting smoking, strategies of denormalization raise both pragmatic and ethical concerns.” Furthermore:
The decline in U.S. smoking rates since the 1960s has coincided with the development of a sharp gradient along the lines of socioeconomic status. Whereas about one fifth of all Americans are smokers, about one third of those with incomes below the federal poverty level smoke. These data are especially pertinent to the question of bans in parks. Since smokers are more likely to be poor and therefore dependent on free public spaces for enjoyment and recreation, refusing to allow them to smoke in those places poses potential problems of fairness.
The anti-tobacco movement, frustrated by the slow pace of gains over several years of active efforts, with rates of smoking remaining essentially unchanged, has to face the fact that an outright ban on cigarettes is a ticket to black market, crime syndicate hell. But a de facto ban is something altogether different, and “steadily winnowing the spaces in which smoking is legally allowed may be leading to a kind of de facto prohibition.” More and more employers prohibit smoking in doorways, within ten feet of doorways, anywhere on university campuses, and so on. No one has voted to make cigarette smoking illegal. But the public space in which this legal activity can be pursued is disappearing. And here is where the tough questions start: “In the absence of direct health risks to others, bans on smoking in parks and beaches raise questions about the acceptable limits for government to impose on conduct,” the authors conclude. Not to mention issues of personal autonomy, individual choice, and the stigma attached to addictive behavior. Perhaps the ACLU will soon take an interest in the civil rights of outdoor smokers, where the only health being hazarded is the smokers’ own.
Colgrove J, Bayer R, & Bachynski KE (2011). Nowhere Left to Hide? The Banishment of Smoking from Public Spaces. The New England journal of medicine PMID: 21612464
Photo Credit: www.thinkstock.com... Read more »
Colgrove J, Bayer R, & Bachynski KE. (2011) Nowhere Left to Hide? The Banishment of Smoking from Public Spaces. The New England journal of medicine. PMID: 21612464
- April 22, 2011
- 04:24 PM
- 297 views
Let’s Get Cellular: Meth Metabolism
by Dirk Hanson in Addiction Inbox
Speedy fruit flies metabolize glucose differently.
We know from the work of Nora Volkow and others that meth abusers have chronically low levels of dopamine D2 receptors in their brains. But what is going on in the rest of the body when methamphetamine addiction is running full force? A study of meth-crazed fruit flies, just published at PLoS ONE by researchers at the University of Illinois, Purdue, and elsewhere, took a whole-body approach, tracing the meth-induced cascade of chemical reactions wherever they found it. Most drug research in animal models concentrates on changes in the brain. But this study was looking elsewhere, for changes caused by meth and evidenced along common metabolic pathways. They found that meth exposure had striking effects on insect molecular pathways associated with “energy generation, sugar metabolism, sperm cell formation, cell structure, hormones, skeletal muscle and cardiac muscles.” In other words—and no secret here—speed impacts aging, sexual behavior and cardiovascular health. But how, exactly?
The administration of methamphetamine to Drosophilia melanogaster—a fruit fly with one of the most studies genotypes in history—causes changes in the way certain genes and proteins are expressed. Some of the changes might hold for human users, as well:
-- Meth dysregulates calcium and iron homeostasis.
-- Meth inhibits something called ETC—the mitochondrial electron transport chain. This causes changes in proteins and reduced enzyme activity that, among other things, has been known to make bees more aggressive.
-- Meth alters peptides related to chronic heart failure in humans. The researchers observed that “concentrations of numerous muscle-associated proteins changed in response to METH exposure.”
-- Meth causes various sexual dysfunctions in man and animal, including inhibited sperm motility. Some of the changes in fruit flies caused by meth involved genes known to control sperm maturation. Altogether, the team identified seven meth-responsive genes and proteins associated with male reproductive functions.
-- Meth also caused changes “in whole organism sugar levels” in the fruit flies. Using gas chromatography/mass spectrometry technology, researchers observed decreased levels of trehalose, the primary form of blood sugar in insects. This could reflect “either higher metabolic rates resulting from a METH-induced increase in physical activity or increased carbohydrate consumption resulting from increased glycolysis…. Interestingly, human METH addicts often imbibe large amounts of sugary soft drinks; such dietary studies in Drosophilia lead us to question whether sugar intake in humans helps to alleviate the toxic effects of METH.”
-- “METH impacts pathways associated with hypoxia and/or the Warburg effect, pathways in which cellular energy is predominantly produced by glycolysis rather than by oxidative respiration.” Short version: The Warburg effect is associated with the aberrant energy metabolism characteristic of cancer cells. This certainly doesn’t mean we can conclude that speed causes cancer, but it is one more piece of evidence confirming the notion that methamphetamine’s range of potentially damaging side effects is simply too high to justify. We can argue the merits of legalizing marijuana, but no one who studies meth seriously has ever suggested legalization of this pernicious substance.
Professor Barry Pittendrigh of the University of Illinois, a member of the study team, said: “One could almost call meth a perfect storm toxin because it does so much damage to so many different tissues in the body.”
Sun, L., Li, H., Seufferheld, M., Walters, K., Margam, V., Jannasch, A., Diaz, N., Riley, C., Sun, W., Li, Y., Muir, W., Xie, J., Wu, J., Zhang, F., Chen, J., Barker, E., Adamec, J., & Pittendrigh, B. (2011). Systems-Scale Analysis Reveals Pathways Involved in Cellular Response to Methamphetamine PLoS ONE, 6 (4) DOI: 10.1371/journal.pone.0018215... Read more »
Sun, L., Li, H., Seufferheld, M., Walters, K., Margam, V., Jannasch, A., Diaz, N., Riley, C., Sun, W., Li, Y.... (2011) Systems-Scale Analysis Reveals Pathways Involved in Cellular Response to Methamphetamine. PLoS ONE, 6(4). DOI: 10.1371/journal.pone.0018215
- April 3, 2011
- 06:26 PM
- 756 views
When Smokers Move
by Dirk Hanson in Addiction Inbox
Is your new house a thirdhand smoke reservoir?
In the first published examination of thirdhand smoke pollution and exposure, researchers at San Diego State University discovered that non-smokers who move into homes purchased from smokers encounter significantly elevated nicotine levels in the air and dust of their new homes two months or more after moving in.
100 smoking households and 50 non-smoking households participated in the study, which was published in Tobacco Control. The researchers tested for surface nicotine levels in living rooms and bedrooms, took finger nicotine concentrations, collected dust and air samples, and measured urine concentrations of the nicotine breakdown product cotinine.
So, what faces non-smoking new homeowners when they take up residence in a smoker’s former home? “Air nicotine concentrations were 35-98 times higher than those found in non-smoker homes,” the investigators write. “Dust and surfaces showed nicotine levels approximately 12-21 and 30-150 times higher, respectively, than the reference levels in non-smoker homes.”
The homes had been vacated a median of 62 days, and tests on the new residents were conducted a median of 34 days after the move. “Nicotine levels found on the index fingers of non-smokers residing in former smoker homes were 7-8 times higher” than those residing in non-smoking homes. What makes this even more noteworthy is that most of the smokers’ homes “underwent cleaning and many were repainted and had carpets replaced before new occupants moved in.” In addition, “smoker homes remained vacant for on average an extra month,” all of which suggests that smoking has a host of economic side effects we are only beginning to pin down.
“In summary,” say the researchers, “these findings demonstrate that smokers leave behind a legacy of thirdhand smoke (THS) in the dust and on the surfaces of their homes that persists over weeks and months.” But do these numbers rise to the level of a legitimate health and safety concern? After all, an exposure of 150 times more cigarette smoke than the background nicotine pollution level of essentially zero doesn’t necessarily mean a hazardous layer of leftover smoke.
Unless, possibly, you happen to be a small child who likes to crawl around on everything you can reach, wearing only your diapers, while licking absolutely everything you come across and simultaneously “ingesting non-food items,” as the researchers put it. In that case, your exposure to the nicotine, phenol, cresols, naphthalene, formaldehyde, and tobacco-specific nitrosamines (all combining in unknown ways with other pollutants and oxidants in the home environment), and the potential effect of that exposure on your immature immune system, might be high enough to raise the concern level of your parents.
Matt, G., Quintana, P., Zakarian, J., Fortmann, A., Chatfield, D., Hoh, E., Uribe, A., & Hovell, M. (2010). When smokers move out and non-smokers move in: residential thirdhand smoke pollution and exposure Tobacco Control, 20 (1) DOI: 10.1136/tc.2010.037382
Photo Credit: quit-smoking-central.... Read more »
Matt, G., Quintana, P., Zakarian, J., Fortmann, A., Chatfield, D., Hoh, E., Uribe, A., & Hovell, M. (2010) When smokers move out and non-smokers move in: residential thirdhand smoke pollution and exposure. Tobacco Control, 20(1). DOI: 10.1136/tc.2010.037382
- February 24, 2011
- 03:34 PM
- 888 views
Smoking and Adolescent Attention Deficit
by Dirk Hanson in Addiction Inbox
Are young smokers risking cognitive impairment as adults?
Call it “nicolescence.” It’s that time of life when certain 18-and-unders discover cigarettes. Most adult smokers begin their habit before the age of 19, and a majority of adolescents have tried cigarettes at least once. But for some of them—those who were “born to smoke,” in a sense—early exposure to nicotine may influence adolescent cognitive performance in ways that adult exposure to nicotine does not. Furthermore, early exposure may result in “cognitive impairments in later life.”
These provocative notions are raised by a group of researchers at VU University, Amsterdam, The Netherlands, in a paper for Nature Neuroscience. And while the specifics of glutamate activity they have documented are fascinating, the leaps back and forth between adolescent humans and adolescent lab mice are dizzying. Nonetheless, the bold claims made in the paper prompted the scientists “to reconsider our views on the etiology of attention deficits.”
That may be more than many addiction researchers are willing to countenance, but the study makes an intriguing case for long-term effects on attentional processing. The Dutch researchers exposed adolescent rats to nicotine, assessed visuospatial attention and other markers associated with synaptic activity in the prefrontal cortex, and found impaired measures of attention and signs of increased impulsivity in adulthood after five weeks of abstinence. Adult rats exposed to nicotine for the first time did not show similar long-term consequences.
The molecular underpinnings for this phenomenon appear to be reduced glutamate receptor protein levels in the prefrontal cortex. Glutamate is a neurotransmitter involved in attention, among other cortical tasks. Glutamate levels were “altered specifically by adolescent and not adult nicotine exposure” in the lab animals, the researchers found.
The glutamate receptor mGluR2 is the likely culprit. The researchers report that “a lasting downregulation of mGluR2 on presynaptic terminals of glutamatergic synapses in the prefrontal cortex persists into adulthood causing disturbances in attention…. Restoring mGluR2 activity in vivo in the prefrontal cortex of adult rats exposed to nicotine during adolescence remediated the attention deficit.”
The study concludes: “Not only from a behavioral, but also from a molecular point of view, the adolescent brain is more susceptible to consequences of nicotinic receptor activation.” In other words, there is at least some evidence that the neurotoxic effects of nicotine are potentially more severe in the early developmental stage called adolescence.
The Dutch study is not the only one of its kind. In 2005, Biological Psychiatry published a report on cognition in which adolescent smokers “were found to have impairments in accuracy of working memory performance irrespective of recency of smoking. Performance decrements were more severe with earlier age of onset of smoking.”
And a 2007 study published in Neuropsychopharmocology, based on testing and fMRI scans of 181 male and female adolescent smokers, concluded that “in humans, prenatal and adolescent exposure to nicotine exerts gender-specific deleterious effects on auditory and visual attention…” Boys were more sensitive than girls to attention deficits involving auditory processing, while girls tended to show equal deficits in both auditory and visual attention tasks.
Counotte, D., Goriounova, N., Li, K., Loos, M., van der Schors, R., Schetters, D., Schoffelmeer, A., Smit, A., Mansvelder, H., Pattij, T., & Spijker, S. (2011). Lasting synaptic changes underlie attention deficits caused by nicotine exposure during adolescence Nature Neuroscience DOI: 10.1038/nn.2770
Photo Credit: http://smoking-quit.info/... Read more »
Counotte, D., Goriounova, N., Li, K., Loos, M., van der Schors, R., Schetters, D., Schoffelmeer, A., Smit, A., Mansvelder, H., Pattij, T.... (2011) Lasting synaptic changes underlie attention deficits caused by nicotine exposure during adolescence. Nature Neuroscience. DOI: 10.1038/nn.2770
topics
join us!
Do you write about peer-reviewed research in your blog? Use ResearchBlogging.org to make it easy for your readers — and others from around the world — to find your serious posts about academic research.
If you don't have a blog, you can still use our site to learn about fascinating developments in cutting-edge research from around the world.
