Women, Cigarettes, and Meth

More bad news for young female addicts.

A blizzard of research findings this year continues to demonstrate that women have gender-specific issues to deal with when it comes to cigarettes and speed. None of the findings have anything to do with the old canard that women cannot “hold their liquor,” or do drugs like men do. Women hold their liquor fine, on a pound for pound basis. And women are well represented, presently, among the ranks of alcoholics. That is unfortunate, since a great deal of research has shown that alcohol causes neurological damage in women more quickly than in men. And now comes more evidence that women don’t respond metabolically to cigarettes and speed the same as men, either.

Start with cigarettes: Women who begin smoking have a great risk of heart attack than men who take up the addiction—but scientists don’t know exactly why. Cardiovascular diseases remain the leading cause of female deaths in the developed world. One theory is that smoking lowers levels of “good” cholesterol more markedly in women than in men. This is not news, but preliminary research in the Journal of Clinical Endocrinology and Metabolism now appears to show that teenaged girls in Australia were more sensitive to the effects of second-hand smoke than teenaged boys. If true, it could mean that “childhood passive smoke exposure may be a more significant cardiovascular risk factor for women than men,” lead author Chi Le-Ha said in a press release. 

And there’s more bad news: Research published in Diabetologia, the journal of the European Association for the Study of Diabetes, suggests that women who continue to smoke during pregnancy increase the risk for obesity and diabetes in their unborn daughters. Kristin Mattsson of Lund University in Sweden, along with Matthew Longnecker and members of the National Institute on Environmental Health Sciences in North Carolina, reported that data from the Medical Birth Register of Sweden showed that the risk (odds ratio) of gestational diabetes increased 52-62 per cent for women exposed to moderate or heavy smoking while in the womb. After adjusting the data for a host of outside factors, the researchers also concluded that women exposed to moderate amounts of smoking while in the womb were 36 per cent more likely to become obese, while the daughters of heavy smokers during pregnancy were 58 per cent more likely to be obese compared to non-smokers in the study.

Again, researchers are not quite sure what accounts for this effect. The researchers suggest a variety of possible answers: Alterations in appetite regulation, death of insulin-producing cells in the pancreas, gene transcription changes causing the formation of fat cells, and epigenetic changes. But it may be that other factors—undetected differences in nutrition, extent of prenatal care, neglect, abuse, and many other variables—make it difficult to determine the major difference in outcomes between smoking and non-smoking families. Nailing down these risk factors becomes all the more important as young women in countries all around the world take up daily smoking in greater numbers than ever. The authors emphasize the importance of recognizing such long-term detrimental effects on offspring.

As for methamphetamine: A study in the Journal of Adolescent Health, conducted by the UCLA Center for Behavioral and Addiction Medicine, followed a group of adolescents in treatment for methamphetamine addiction. They found that girls were more likely to continue using meth during treatment than boys. Overall, boys returned twice as many meth-free urine samples as the girls in the program. Lead author Keith Heinzerling said in a prepared statement that the findings may have significant implications for treatment: “The greater severity of methamphetamine problems in adolescent girls compared to boys, combined with results of studies in adults that also found women to be more susceptible to methamphetamine than men, suggests that the gender differences in methamphetamine addiction observed in adults may actually begin in adolescence.” The small NIDA-funded study, involving only 19 teenagers, also found that the antidepressant Wellbutrin, used effectively in many smoking cessation programs, was not effective in curbing use among the teen meth addicts.

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

The Black Market for Seroquel

Speed freaks, coke heads, and antipsychotics.

Last week, writing on the Daily Beast web site, reporter Jeff Deeney profiled a startling underground market for the antipsychotic medication Seroquel (quetiapine). Deeney described street transactions in North Philadelphia for Quells or Suzie-Qs, as the drug is sometimes called. Seroquel, a drug developed for the treatment of schizophrenia and bipolar disorder, has developed an additional reputation as a “comedown” drug for stimulant abusers.

Seroquel, a so-called atypical antipsychotic, works by altering levels of dopamine. While some addicts have claimed that the drug is perfect for a cocaine or speed comedown, Seroquel has also been studied for its anti-craving properties when used for cocaine abstinence.

Why would a speed freak or a coke addict want to take a drug that might decrease their desire for their stimulant of choice? For the same reason that ecstasy users often take a morning-after dose of Prozac in a misguided attempt to compensate for possible damage to serotonin receptor arrays. Or because the drug is mildly sedating for some users. However, there may be more to it. Perhaps Seroquel is an effective anti-craving medication for cocaine and methamphetamine addicts, who misuse it as a drug to ease them through enforced periods of detox or lack of availability.

One high-traffic drug discussion site has shut down a long-standing thread on Seroquel with the warning: “Do not use Seroquel for a cocaine comedown.”

The fact that prescription Seroquel is available as a street drug, at least in some parts of the country, demonstrates the likelihood that physicians and psychiatrists are increasingly using it for off-prescription purposes—like drug detox. Deeney strongly suggests that this is the case: “Drug dealers, mandated to treatment as a condition of their probation or parole, are given off-label prescriptions for Seroquel, then sent right back to the street, where the pills can be sold for cash to users and other dealers.”

Increasing its appeal is Seroquel’s reputation for combining well with cocaine in a mixture known as a Q-Ball, or Rosemary’s Dolly—a variation on the heroin/cocaine mix known as a Speedball, to which Seroquel can also be added. An anonymous med student on a medical blog noted that “certain people say they love Seroquel when doing a speed-ball. Makes sense, think about it. It heightens the high of the heroin, it eases the crash of the cocaine.”

Seroquel’s ability to modulate the effect of illegal drugs means that the medication can possibly find a market both as a detox drug for stimulant abusers, and as an ingredient in the very stimulants they abuse.

By itself, Seroquel is not considered addictive. Some addicts told Deeney that the drug simply put them to sleep more quickly after a long meth run. Indeed, Seroquel is considered to be more sedating than similar antipsychotics such as Olanzapine and Aripiprazole. The larger issue, as the Daily Beast post makes clear, is that “Seroquel can have serious side effects including diabetes, a permanent Parkinson’s-like palsy called tardive dyskinesia, and sudden cardiac death.”

All of this confusing and sometimes contradictory input is coming well ahead of the clinical data, although a study in 2001, presented at the 4th International Conference on Bipolar disorder, found that quetiapine caused a significant reduction in cocaine use among a small group of cocaine-dependent subjects who also suffered from bipolar disorder. A report last year in the Journal of Clinical Psychopharmacology also showed positive results with cocaine users. Studies of quetiapine for the reduction of cocaine use are currently being undertaken by the Seattle Institute for Biomedical and Clinical Research.

drugs dopamine

Another Round of Trials for Vigabatrin

Firm secures funding for anti-craving tests.

A Florida pharmaceutical company has secured financing for additional testing of the anti-addiction drug vigabatrin, despite the drug’s poor performance in earlier trials. Patrick J. McEnany, chairman and CEO of Catalyst Pharmaceuticals (CPRX) in Coral Gables, said the company would continue developing CPP-109 , its version of vigabatrin, for the treatment of cocaine and methamphetamine addiction.

Vigabatrin garnered early publicity on the basis of early trials suggesting it might be effective against stimulant addiction. Unlike alcohol and heroin, cocaine and speed have proven particularly resistant to treatment with other drugs designed to diminish craving. A drug that effectively reduced craving in abstinent cocaine and methamphetamine addicts would open up a potentially large and lucrative market.

Catalyst said it raised $3.97 million in a recent common stock offering from a group of investors including Federated Kaufmann Funds. Catalyst owns exclusive licensing rights to several patents related to vigabatrin from Brookhaven National Laboratory, reports Genetic Engineering and Biotechnology News. The company also owns patents or patent applications in more than 30 countries. Catalyst recently acquired worldwide rights to a related patent held by Northwestern University.

Earlier, the U.S. Food and Drug Administration (FDA) had given Fast Track designation to vigabatrin. The drug increases brain levels of GABA, an inhibitory transmitter. However, CPP-109 failed in a mid-stage treatment for cocaine addiction. Brian Bandell of the South Florida Business Journal reported that during the 12-week study, the drug did not help addicts stay cocaine-free, compared to a placebo group. In July, the company’s stock was trading at a 52-week low of 39 cents.

Last week, Catalyst said its decision to renew testing and development efforts with vigabatrin was due to a reanalysis of data from the earlier test. The company said the review showed that overall test subject compliance rates during the clinical trial may have been as low as 40 %. The company also said that early results with methamphetamine addiction were promising, but not statistically significant due to the small number of test subjects.

Last year, there was also a flurry of interest in vigabatrin as a weight loss drug. (See my earlier post). The FDA has yet to approve the drug for use in the U.S., citing concerns about reports of retinal damage in patients overseas. Catalyst said it had not uncovered any clinically significant visual abnormalities in its CPP-109 testing programs.

Vigabatrin, or gamma vinyl-GABA, is marketed in Europe as Sabril, and has existing clinical uses for the treatment of specific types of epilepsy and infant spasms.

Graphics Credit: www.dosewatch.com


addiction drugs

Addiction Assumptions: The Meth Epidemic

Who is really at risk?

A simple question: Has meth use in the United States truly reached “epidemic” levels, as is commonly stated by health authorities and drug experts?

The answer depends on how you slice the data, according to sociologist Herbert Covey. For women, unemployed men, and residents of the Western United States, the answer is yes. For African-Americans and citizens of the Northeast, not so much.

In “Prevalence of Use and Manufacture of Methamphetamine in the United States,” published in the Praeger International Collection on Addictions, Dr. Covey first notes that the spread of methamphetamine use is by no means unique to the United States. In Thailand, Covey writes, more than 70 percent of the addict population is composed of meth users.

In the U.S., meth lab busts increased 4,000 percent from 1995 to 2001, according to the Office of National Drug Control Policy. Treatment numbers also soared, but it is not clear whether this trend represents more meth users, or more court-mandated treatment for offenders.

The short answer to the question of who is at primary risk is: women. According to Covey, women of childbearing age represent a severely problematic risk group. Women report using meth at an earlier age, have significantly longer first treatment experiences, and have greater difficulty than men with related issues of employment, child-raising, and job opportunities. (See my post on “Rehab and the Working Mother.”)

Perhaps the most unwelcome finding of all is that “The majority of women [in a major study of gender differences] had children under 18, but most did not live with their children within the last 30 days.”

However, there is a tendency in the media to leap ahead of the data with stories of this sort. Covey and other researchers question the validity of media references to “meth babies” and “ice babies,” recalling the overblown coverage of the “crack baby” epidemic of the 1980s—an epidemic for which, more than two decades later, there is almost no solid evidence. As Covey cautions, “that meth use by pregnant women results in severe health consequences for infants has not been established by medical research.”

As Covey sums it up: “Meth accounts for a small percentage of the total number of people affected by drug and alcohol problems. However, almost all of the data... reveal that meth use, manufacturing and distribution are increasing throughout much of the nation.” In the future, he writes, “The other question is whether meth use will grow in prevalence in minority populations. To date Latino, Hispanic, and African American populations have not embraced meth to the extent that Anglos have. If this changes, the negative effects could be substantial.”

Covey concludes: “Whether the upward spiral of meth use and manufacture continues remains to be seen.”

Photo Credit: The Curvature

addiction drugs

The Pharmacokinetics of Speed

Meth lingers longer than coke, targets different brain areas.

Scientists at the Brookhaven National Laboratory, already famous for their work on positron emission tomography (PET) scans, have traced the pathways by which methamphetamine lingers in the brain longer than cocaine. The Brookhaven Lab, managed by the U.S. Department of Energy (DOE) tested non-drug abusing volunteers. The results will be published in the November 1 issue of Neuroimage.

The researchers injected the 19 volunteers with radioactively tagged doses of the drugs. Scanning cameras then recorded the concentration and distribution of the tagged molecules. Both cocaine and methamphetamine enter the brain quickly—part of the reason why the two drugs are so reinforcing. However, cocaine clears the brain just as quickly, while meth does not. Moreover, the study demonstrated that methamphetamine is much more widely distributed throughout the brain than cocaine, which tends to exclusively target the dopamine-rich limbic reward pathways. “This slow clearance of methamphetamine from such widespread brain regions may help explain why the drug has such long-lasting behavioral and neurotoxic effects,” said Joanna Fowler, lead author of the study.

The researchers also looked at a more controversial hypothesis—widespread reports that methamphetamine abuse among African Americans is markedly lower than it is among Caucasians. These reports lead Fowler and her colleagues to question “whether biological or pharmacokinetic differences might explain this difference.”

The answer? Evidently not. According to a Brookhaven press release, “Surprisingly, the researchers found significant differences in cocaine pharmacokinetics between African Americans and Caucasians, with the African Americans exhibiting higher uptake of cocaine, a later rise to peak levels, and slower clearance.” When it came to speed, however, the scientists failed to detect any racial differences in uptake.

Fowler’s conclusion: “Variables other than pharmacokinetics and bioavailability account for the lower prevalence of methamphetamine abuse in African Americans.”

She added that “the differences observed for cocaine pharmacokinetics are surprising considering there are no differences in cocaine abuse prevalence between these two ethnic groups.”

This may come as a surprise to people who have been taught by news coverage and crime dramas to think of the crack problem as a “black problem.” But it may also indicate an inherent physiological preference for cocaine among African Americans, regardless of stated levels of abuse prevalence. As usual, more studies are needed.

Image Credit: Brookhaven National Laboratory News

dopamine

No Pill for Stimulant Addiction

Meth and cocaine continue to elude researchers.

Despite promising trials of several compounds, methamphetamine addiction remains largely impervious to anti-craving pills and other forms of drug treatment. According to a paper in the June issue of Addiction Science and Clinical Practice, "currently, no medications are approved by the FDA for the treatment of stimulant dependence. However, recent advances in understanding... have allowed researchers to identify several promising candidates."

The paper's author, Dr. Kyle Kampman of the University of Pennsylvania School of Medicine and Treatment Research Center, notes that "the demand for treatment for cocaine dependence remained roughly level from 1992 to 2005, while the demand for treatment for amphetamine dependence increased about eight-fold." (See chart above).

As I wrote earlier ("FDA Puts Coke/Meth Treatment on Fast Track"), the U.S. Food and Drug Administration (FDA) in January gave Fast Track designation to vigabatrin, sold as Sabril by Ovation Pharmaceuticals. Ovation is collaborating with the NIDA on Phase II studies to evaluate the safety of Sabril, with Phase III trials scheduled for the end of this year.

Vigabatrin, an anti-epilepsy drug called Gamma-vinyl-GABA, or GVG for short, showed early promise for use with cocaine addicts in a 60-day study and appears to increase GABA transmission. GABA has an inhibitory effect on dopamine and serotonin release.

Another entry in the vigabatrin sweepstakes, Catalyst Pharmaceuticals, is also testing its version of the drug, dubbed CPP-109, for the treatment of methamphetamine addiction in Phase II double-blind, placebo-controlled studies. Patrick J. McEnany, chief executive officer of Catalyst, commented, "We are excited to follow up on our cocaine trial with the initiation of our second, large-scale U.S. Phase II trial with CPP-109, this time as a potential treatment for methamphetamine addiction. As with cocaine, we believe that CPP-109 may offer the potential to provide patients suffering from methamphetamine addiction, as well as the physicians and clinicians that treat them, with a safe and effective pharmacotherapy option."

What, in essence, are such pills designed to accomplish? The primary avenue of research has centered upon medications that decrease the addict's experience of withdrawal and craving. According to Kampan, "several studies have demonstrated that patients who experience severe cocaine withdrawal symptoms... are twice as likely to drop out of treatment and less likely to attain abstinence in outpatient programs."

However, questions remain about the safety of vigabatrin. Although available abroad, it is not approved for use in the U.S., due to an association with serious visual effects after long-term use. The use of vigabatrin for stimulant addiction, if approved, might require associated eye examinations.

Buproprion, a drug that has shown some promise in the treatment of cocaine addiction, is also a candidate for meth addiction. The drug inhibits the reuptake of dopamine, thus allowing more dopamine to circulate in the brain. In addition, there are plans to test other drugs being investigated for cocaine craving, such as topiramate and modafinil.

According to the 2005 SAMHSA Survey on Drug Use and Health, an estimated 10.4 million people age 12 or older (4.3 percent of the population) have tried methamphetamine at some time in their lives. Approximately 1.3 million reported past-year methamphetamine use, and 512,000 reported current (past-month) use. Approximately 535,000 patients sought treatment for methamphetamine and other stimulant abuse in 2006.

Next post: Drugs for cocaine craving

Photo Credit: National Drug Intelligence Center

dopamine

Vote of No Confidence For Prometa

Addiction drug loses major funding.

It is composed of three common and inexpensive drugs used for other purposes. It has never been subjected to clinical double blind testing. It costs thousands of dollars for the full treatment package, and the company that markets it says it cures about 80 percent of the drug addicts who use it.

If that description sounds familiar—if it seems to give off a faint whiff of blue-green algae and multi-level marketing—such concerns have not stunted the promotion and acceptance of the anti-addiction drug Prometa. But MSNBC reported last week that Prometa, the drug “cocktail” designed to combat addiction to cocaine and methamphetamine, was dealt a severe blow when accountants in Pierce County, Washington froze the funding for an $800,000 pilot program, citing irregularities in testing.

The treatment involves intravenous infusions of Flumazinil, a reversal agent for benzodiazepines like Valium and Klonopin. The second drug, hydroxyzine, is an antihistamine, and the third, sold as Neurontin, as an anti-seizure medication frequently used “off prescription” as a treatment for a number of ailments, including alcoholism and hearing loss.

The treatment does not require approval by the Food and Drug Administration (FDA) because all three ingredients are already in common use in clinics and hospitals. The Prometa Regimen marketed by Hythium involves formulating the protocol and contracting with doctors to deliver the medications.

To date, there is no published clinical data to support treatment for addiction with these three drugs in proprietary combination.

Marketed heavily by anecdote and personal testimonials, the Prometa marketing campaign included ads in 2006 featuring the late comedian Chris Farley, who died of a drug overdose.

Hythiam, the company that markets Prometa, has touted the treatment with claims of success rates as high as 98 per cent, but Pierce County Councilman Shawn Bunney found the results of the county audit “alarming,” according to MSNBC. “It’s clear to me that we are much more involved in a marketing scheme…”

Hythiam Executive Vice President Richard Anderson disagreed. “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.”

The dispute centers on the manner in which dropouts were counted in surveys done by Hythiam’s non-profit arm, the Pierce County Alliance. The Alliance had been responsible for administering the Prometa program in Pierce County drug courts. According to county auditors, dropouts and no-shows (patients who fail to show up for drug testing) were not included in the Alliance’s final report on 35 patients over a 14-month period. In Pierce and neighboring counties of Washington, drug courts record no-shows as equivalent to positive drug tests. This was not how the alliance scored it, although alliance spokespeople have insisted that county officials have misunderstood the mechanics of the study.

An investigation by the Tacoma News Tribune threw more cold water on the Prometa numbers. “According to the multiple public statements by the alliance,” wrote Sean Robinson, 86 percent of the Prometa clients ‘remained drug-free’ at the end of the 14-month program. According to county auditors, the number was 50 percent.”

Furthermore, the alliance “defined success in the Prometa program as 60 or more days of clean drug tests…. In Pierce County, drug-court clients must show 90 days of clean drug tests… In Snohomish and Thurston counties, drug-court clients must show six months.”

Investors in Hythiam, which is publicly traded, were counting on the Pierce program after similar programs in Fulton County, Georgia, and in Idaho 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,” claimed Lori Karan of the Drug Dependence Research Laboratory at the University of California-San Francisco.

Double-blind studies of Prometa are underway at the University of California-Los Angeles and at the University of South Carolina.