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

So, Like, We’re Watching the LSD Episode of The Fringe...

Lysergic Acid Diethylamide

So this guy I know? Like really, really well? He’s over at my place and we’re watching The Fringe on TV and smoking a bowl, excuse me, we’re vaping a bowl, he’s an older guy and all concerned with his health and shit. So we’re watching the Lysergic Acid Diethylamide episode of The Fringe, and Walter’s rapping away like a drunken monkey as usual, and they’re hardly underway before my friend is jumping up off the couch and saying no, that’s not what LSD was like…. I said how would I know, and anyway the clothes in those Sixties photos always looked so bad, they must have looked even worse when you were tripping on that stuff. The closest thing I’ve ever had to a psychedelic experience was that time that guy slipped a roofie in my Mimosa. But I digress. My friend says no, no, see, when you took acid, you didn’t suddenly get hurled into somebody else’s consciousness, which in this case seems to resemble some crowded city out of Inception, with your tripping buddy perched on a bus, waving at you. That’s just not fucking how it went. So then he pauses, gets kind of sheepish, says, well, actually, that did happen once, but that’s not the point. And then blah blah happened. And everybody could read everybody else’s mind. And from then on everything was blah blah blah. And peace reigned forevermore. Okay, that’s not fair, he’s really just complaining that they aren’t telling it straight, about how LSD really feels, and what you really see and shit. This notion about taking drugs and ending up in cities full of people wearing black clothing really cracked him up. So I go, when was the last time you took a walk down Lake Street and saw somebody wearing some other color? But he loved the black guy who accidentally dosed himself and then started comparing his stick of red licorice to Bernini's spiral altar at St. Peter's. But car chases? Elevators? The Twin Towers, for God’s sake? Where are the colors, the tracers, the melting edges, the fractal glow of a universe in constant motion? Or something like that. My friend wants to know how they thought they were going to get away with it. Turning it all into a cartoon. And not just any cartoon, but that awful rotoscoping shit that made him seasick when we rented “A Scanner Darkly.”  Like they thought nobody who had ever taken the stuff was going to watch their crappy show, anyway? Whatever. But I thought that last part was cool, the cartoon guys were running to catch a giant purple blimp, like an episode of the Teenage Mutant Ninja Turtles—and chased by zombies!  And more car chases! Too cool! And my friend is laughing, and then he says yeah, well, something like that happened to him once, too….

Photo Credit:http://clatl.com/

Medical Cigarettes

Is it “Inhumane” to Take Cigarettes Away from Schizophrenics?

In an article for Brain Blogger a couple of years ago, I looked into the astonishing fact that, as a typical study of in-patient smoking among schizophrenics in Britain revealed, about 80-90% of the patients diagnosed with schizophrenia were cigarette smokers. Given that the running rate in the general population hovers around 20-25% on average, this is really quite amazing. It seems clear that nicotine is doing something for a schizophrenic that makes cigarettes into a form of self-medication that almost all schizophrenics apparently discover at one time or another.

A review of relevant studies through 1999, undertaken by Lyon and published in Psychiatric Services, shows unequivocally that schizophrenic smokers are self-medicating to improve processing of auditory stimuli and to reduce many of the cognitive symptoms of the disease. “Neurobiological factors provide the strongest explanation for the link between smoking and schizophrenia,” Lyons writes, “because a direct neurochemical interaction can be demonstrated.” According to Lyon, “Several studies have reported that smokers require higher levels of antipsychotics than nonsmokers. Smoking can lower the blood levels of some antipsychotics by as much as 50%…. For example, Ziedonis and associates found that the average antipsychotic dosage for smokers in their sample was 590 mg in chlorpromazine equivalents compared with 375 mg for nonsmokers.”

In particular, smoking seems to help quell auditory and visual hallucinations. The process known as “sensory gating” refers to lower response levels to repeated auditory stimuli. A schizophrenic’s response to a second stimulus is greater than a normal person’s, and this is also impacted by cigarettes. Sensory gating may be involved in the auditory hallucinations common to schizophrenics. Receptors for nicotine are involved in sensory gating, and several studies have shown that sensory gating among schizophrenics is markedly improved after smoking.

There is an additional reason why smoking is an issue of importance for health professionals. Dr. Bill Yates at Brain Posts recently examined a small study by Michael Allen and colleagues in the American Journal of Psychiatry in which 40 schizophrenic patients were admitted to a psychiatric emergency service, where they were given standard antipsychotic therapy. In addition, the researchers randomly assigned either a 21mg nicotine patch or a placebo patch to the subjects upon admission. As Dr. Yates summarized the results:

--Nicotine patches reduced agitation by 33% in the first four hours and 23% at 24 hours. And the reduction was greater than with either the antipsychotic alone, or in conjunction with the placebo patch.

--Subjects with lower nicotine dependence scores tended to show the most response compared to placebo.

--The effect of nicotine replacement on agitation reduction approached the level seen with standard antipsychotic therapy.

As Yates notes, this finding is “pretty dramatic.” It seems to show that acute nicotine withdrawal only makes the situation worse in a clinical setting. The study authors also argue that stronger patches combined with nicotine gum might quell agitation more quickly and effectively. “Encouraging patients with psychotic disorders and mood disorders to quit smoking is an important general health strategy,” Dr. Yates writes. “However, this study suggests that attempting this during an acute psychotic break is probably counter productive and may be inhumane.”

Photo Credit:http://drugabuse.gov/

Drug Czar Kerlikowske Interviewed in Foreign Policy Magazine

Drug War goes international in a big way.

Gil Kerlikowske, Director of the Office of National Drug Control Policy--a.k.a. the Drug Czar--finds himself in a curious position. Kerlikowske can be forgiven for feeling a little like J. Edgar Hoover, when the FBI director found that domestic security at home seemed to require some rather active investigations into Cubans and other Communists abroad. Kerlikowske is now riding a horse he never had much say in buying. The U.S. is in the midst of launching a new international drug strategy consisting of “interlocking plans” in Central and South America aimed at “transnational criminal groups.”

AFP reporter Jordi Zamora wrote that “the strategy will merge a handful of existing programs, including Plan Colombia, which has received more than $6 billion in U.S. aid since it was launched in 2000, and the Merida Initiative for Mexico, for which Congress has appropriated $1.5 billion since 2008.” Kerlikowske said that the global nature of the drug threat “requires a strategic response that is also global in scope.” With various crackdowns and battles over smuggling routes, the drug trade in the region has led to thousands of deaths, and has created “complex and evolving threats” from crime syndicates,” according to Assistant Secretary of State William Brownfield.  However, “progress in Central America will only push drug traffickers elsewhere if we do not support strong institutions throughout the hemisphere,” he said.  It seems like the Office of National Drug Control Policy continues to be internationalist in scope.

With all that as background, Foreign Policy magazine spoke with Kerlikowske in search of more detail, and got some--including a strange paean to America’s ability to produce and distribute its own illegal drugs, with no help from Mexico, thank you very much. Kerlikowske seems almost to be bragging. And if he’s right, what are all those border killings about, anyway?

FP: What's your big-picture sense of the drug situation in Latin America?

GK: It used to be fairly easy to categorize countries as production countries, transit countries, or consumer countries. I think those lines have been--if not completely obliterated--generally blurred. The amount of drug use in Mexico is significant. It's also clear from my most recent trip to visit drug treatment centers in Colombia that they're concerned as well. 

FP: U.S. Ambassador Carlos Pascual was forced to leave his position in Mexico two weeks ago because of comments he made in WikiLeaks cables about the perception that the drug war in Mexico is failing and about pervasive corruption in Mexican law enforcement. Are those concerns you share?

GK: As a police officer, I can say that cynicism just comes with the territory, and it's pretty easy to adapt that kind of attitude to Mexico. I'm not overly optimistic, but I think there has been some progress and we have an administration that's courageously taking on these criminal organizations, who are now involved in so many other kinds of crimes.

FP: It does seem that there have been a number of recent scandals involving U.S.-Mexico drug partnership: the Pascual resignation, the reports of the ATF allowing cross-border gunrunning, the controversial use of drones over Mexican territory. Has that relationship become more difficult lately?

GK: In my two years of dealing with this on a closer level, I'd say these last two months are more strained than during the rest of the time I've been here, but I don't see it as a significant bump in the road or a glitch that's going to stop things.

FP: What do you say to those in Latin America who say that it’s useless to crack down on the drug trade as long as the demand persists from the United States?

GK: For one thing, we've become much better at producing drugs in the United States: hydroponic marijuana with a very high THC content -- public lands produce a lot of marijuana. And we don't get any prescription drugs smuggled in to any great extent--which, right now, are our No. 1 growing drug problem in the United States, and also methamphetamine. We're getting much better at making our own, albeit in small amounts.

FP: How do you respond to the growing number of former Latin American leaders--former Mexican President Vicente Fox, most recently--who have come out in favor of legalization or at least a radical overhaul of the current policy?

GK: Isn't it funny how people who no longer have responsibility for anyone's safety or security suddenly see the light? I think it's not a lot different from what we've heard in recent years in the United States, which is: We've had a war on drugs for 40 years and we don't see success. If we have a kid in high school, they can still get drugs or there's drugs on the street corner. So legalization must be an answer…. Heaven knows, we're not very successful with alcohol. We don't collect much in tax money to cover the costs. We certainly can't keep it out of the hands of teenagers or people who get behind the wheel. Why in heaven’s name do we think that if we legalize marijuana, we'd have a system where we could collect enough tax revenue to cover the increased health-care costs? I haven't seen that grand plan. “

Photo Credit: www.fs.fed.us

Marijuana, Vomiting, and Hot Baths

A case history of cannabinoid hyperemesis.

Cannabinoid hyperemesis, as it's known, is an extremely rare but terrifying disorder marked by severe episodic vomiting that can only be relieved by hot baths. (see earlier post). Sufferers are heavy, regular cannabis users, most of them. And hot baths? Where did THAT come from?

The syndrome was first brought to wider attention last year by the anonymous biomedical researcher who calls himself Drugmonkey, who documented cases of hyperemesis that had been reported in Australia and New Zealand, as well as Omaha and Boston in the U.S. "There were two striking similarities across all these cases," Drugmonkey reported. "The first is that patients had discovered on their own that taking a hot bath or shower alleviated their symptoms. So afflicted individuals were taking multiple hot showers or baths per day to obtain symptom relief. The second similarity is, as you will have guessed, they were all cannabis users."

The reports haven't stopped. This summer, an intriguing account appeared on the official blog of New York University's Division of General Internal Medicine, where med students offered a formal definition: "A clinical syndrome characterized by intractable vomiting and abdominal pain associated with the unusual learned behavior of compulsive hot water bathing, occurring in the setting of long-term heavy marijuana use."

Still skeptical? I received this heartfelt comment on my original post a few days ago:

Listen, doubters. My son has this. He has been cyclical vomiting and spending hours in boiling hot baths since last Autumn. It's getting worse and he has lost a hell of a lot of weight. He is 21 and an addicted, heavy cannabis user who started at 15. He has tried cutting down but every other joint of weed brings on the obsession. He refuses to co operate with medical staff who try to treat him.
He has been taken to numerous hospitals as an emergency for non-stop vomiting and begs medical staff to let him sit in a very hot bath. They try the best anti-vomiting drugs instead, to no effect, and then some let him go in a hot shower for an hour plus. He always ends up on a drip and as soon as he feels well enough, discharges himself, often the same day.

At the weekend he went to a sports event in the city with friends, realised on the way he was going to have an episode, so left friends and made his way into a hotel room and locked himself in. Police were called and got him out of a boiling hot bath against his will. Cue vomiting attack so bad police called an ambulance. Once again discharged himself from hospital, demanding drip be removed or he would do it himself. Has sat in bath at house he shares with girlfriend for at least 12 hours today, she tells me. She says water is so hot she has no idea how he bears it.

He says he has no pain in stomach, just a sensation that drives his head mad and he KNOWS it will not go, or the vomiting stop, until he gets in boiling hot bath and stays there. He has even done this while abroad on holiday and ended up on a drip before being flown home.

All of this is true. A mother.

I was intrigued, and discussed this briefly with the mother, who lives in the U.K. She added a number of details in an email exchange, and agreed to let me publish her comments:

“I am a mother in the UK whose son definitely has this, but is not officially diagnosed as he ‘escapes’ medical attention by discharging himself from various hospitals.

When it happens he is desperate to get in a hot bath. He lives with his girlfriend. I only realised what the hell was really going on when she insisted on telling me, and have since been regularly involved in the hospitals saga.

When I discovered the truth I put ‘cannabis’ ‘vomiting’ and ‘hot baths’ ‘showers’ in google and up came a perfect description of what my son does.

I am trying to get him to agree to go for counselling and psychiatric help as he has reached the stage where this obsessive vomiting and bathing is wrecking his life. But every time he gets a little better he believes he can ‘control it’ which is not the case at all.

Yes – we end up in the hospitals and the first young emergency doctor who has ever smoked a joint and/or thinks he knows everything, tells G “Oh no it can’t be that, cannabis stops vomiting, not starts it.” Of course, they have never heard of this condition and just think he is being irrational because of the constant need to vomit. They are sure it is food poisoning or some kind of spasm and take basic blood tests.

They find nothing, insist on giving him the best anti-sickness drugs usually for cancer patients and so on…, saying “this will definitely stop it” and still he vomits. He is not in pain, just rapidly dehydrating and panicking and complaining of a weird sensation in his stomach. He tells them “I know it’s in my head doing this” and desperately demands to get in a bath. Even when he has arrived at hospital because police found him in a boiling hot bath, this makes no sense to the medics who only give in when none of their drugs work. He then immediately stops vomiting but is petrified of getting out of the bath. Eventually, when he says it is under control, he agrees to get out, and is put on a drip. Approx an hour later, while the doctors are planning follow-up procedures like scans and more complex blood tests etc, he starts an argument with a nurse, insists the drip is removed and phones a friend to collect him, avoiding seeking a lift from me if he can. The over-pressed doctors here (the British system is like a cattle market) are left mystified and move onto the next emergency in their pile up of admissions. And so it goes on, and will do, until G accepts even the odd joint can set him off.”
----

Researchers speculate that it has something to do with CB-1 cannabinoid receptors in the intestinal nerve plexus--but nobody really knows for sure. Low doses of THC might be anti-emetic, whereas in certain people, the high concentrations produced by long-term use could have the opposite effect.

When Smokers Move

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.

New Addiction/Recovery Web Site

Daily news blog is part of "The Fix."

I’m pleased to announce that I'll be writing and editing a new blog, “This Just In,” for the recently-launched addiction and recovery site, The Fix. Some top-notch writers are involved, like Susan Cheever and Walter Armstrong. Big take-down of Narconon in the current issue. I encourage you to take a look.

Addiction Inbox will continue to appear without change. Apologies in advance if the pace of posting tends to slow a bit in the immediate future.