Let’s Get Cellular: Meth Metabolism

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

Methland: Book Review

Cooking crystal in the heart of the Heartland.

It’s summer, and I’ve been catching up on my reading. In an earlier post, I reviewed Joshua Lyon’s memoir of prescription drug addiction, Pill Head. This time, we travel to the opposite end of the spectrum and take a look at Methland, Nick Reding’s journalistic account of crystal meth addiction in the small farming community of Oelwein, Iowa.

This is a tale not far from my heart or home. I was born in Iowa and lived there until I was 21. A few years ago, the small Iowa town where my parents live was rocked by a series of revelations about a local lawyer’s ties to a major methedrine operation. Money had flowed through my parent’s small town in ways never seen before.

Also a few years ago, a Chippewa Indian was bound to a chair in the woods, tortured, and finally murdered in a dispute with meth dealers over some missing money. This happened about 30 miles from my home in rural Minnesota. It happened about an hour’s drive from the birthplace of Bob Dylan. It happened in a place where such things just don’t happen.

In a bleak nutshell, Reding lays out how it went down: During the lifetime of the average Baby Boomer, the amphetamine picture has evolved from the classic long-haul trucker’s Benzedrine and Dexedrine to the tweaker’s bathtub crank and crystal meth. “Not only in Oelwein, but all across Iowa, meth had become one of the leading growth sectors of the economy. No legal industry could, like meth, claim 1,000 percent increases in production and sales in the four years between 1998 and 2002, a period in which corn prices remained flat and beef prices actually fell.” In 2004, law enforcement officials busted a total of 1,370 methamphetamine labs in Iowa.

We learn about Jarvis, an Oelwein meth cook who became a local legend by staying awake on speed for 28 days, or, as Reding puts it, “an entire lunar cycle.” We hear about two-year old Buck, Iowa’s most famous meth baby, whose hair, when tested at the behest of the state Department of Human Services, recorded the highest cell follicle traces of speed ever found in an Iowa child (“At least 7,000 kids were living every day in homes that produce five pounds of toxic waste, which is often just thrown in the kitchen trash, for each pound of usable methamphetamine”). And there is the local doctor, forced to deal with meth addicts while battling his own alcohol and nicotine addictions. The doctor refers to the town’s many bars as “unsupervised outpatient stress-reduction clinics that serve cheap over-the-counter medications with lots of side effects.”

The local prosecuting attorney, we learn, has turned to Kant for solace. “So you can put a tweaker in prison,” he tells the author, “and the whole time he’s in there, he’s thinking of only one thing: how he’s going to get high the day he’s out. He’s not even thinking about it, actually. He’s like, rewired to KNOW that everything in life is about the drug. So you say, ‘What good does prison do?’”

The switch from ephedrine to pseudoephedrine as a main ingredient—an artful end run around loophole-ridden legislation—was the “blockbuster moment in the modern history of the meth epidemic,” Reding writes. “This, really, is the genius of the meth business. Cocaine and heroin are linked to illegal crops—coca and poppies respectively. Meth on the other hand is linked in a one-to-one ratio with fighting the common cold.” Moreover, half of the world’s pseudoephedrine supply is manufactured in China, far from the effective reach of U.S. law enforcement.

Not all of Iowa’s meth is homemade. California is the link between Iowa meth and the Drug War. A DEA officer tells Reding: “Our success with Medellin and Cali essentially set the Mexicans up in business, at a time when they were already cash-rich thanks to the budding meth trade in Southern California.”

The connection between Iowa meth, immigration problems, and the food industry is a bit subtler. Agribusiness consolidation in food packaging and processing—particularly meat packing--led to the demand for cheaper labor, which lead to an influx of south-of-the-border immigrants, legal and illegal, to many of Iowa’s small towns. “The real impetus to walk across the desert: Cargill-Excel in Ottumwa is always hiring,” Reding notes. Narcotics and poverty, says the author, mutually reinforce one another.

Graphics Credit: http://abouttheaddict.wordpress.com/

Speed Causing Strokes?

During the cocaine boom of the 1980s, addiction researchers learned that cocaine was sometimes capable of setting off serious seizures in users. Now, a related effect has been tentatively identified in two methamphetamine abusers-- strokes caused by microscropic tears in major arteries of the neck.

Although the study, published in the journal Neurology by researchers at the University of Texas Southwestern Medical Center, documented only the two cases, both young subjects-- women aged 29 and 36--were free of other risk factors. Stroke neurologists took note. Neurologist Steven Cramer at the University of California, Irvine, quoted at scientificamerican.com, said: “If I ever see any young person with a stroke--that is, anyone under 65--I’ll be sure now to do a toxicology screen.”

Stimulants like speed and cocaine markedly increase blood pressure while constricting blood vessels. According to Wengui Yu, one of the authors of the study, such work may help doctors “to better diagnose, treat, and prevent stroke in young adults.”

Sources:

--Choi, Charles Q. “Strokes in Young People Could be Due to Meth.” scientificamerican.com. December 26, 2006.

--McIntosh A., Hungs M., Kostanian V., Yu W. “Carotid artery dissection and middle cerebral artery stroke following methamphetamine use.” Neurology. 2006 Dec 26;67(12):2259-60.