MDPV Turns Lab Rats Into "Window Lickers"

Popular bath salt drug shown to be highly addictive.

Researchers at the Scripps Research Institute (TSRI) in La Jolla, California, appear to have hammered the last nail into the coffin for the common “bath salt” drug known as MDPV. We can now say with a high degree of certainty that, based on animal models, we know that 3,4-methylenedioxypyrovalerone is addictive—perhaps more strongly addictive than methamphetamine, although such comparisons are always perilous. However, principal investigator Michael A. Taffe, an associate professor at TSRI, said in a prepared release that the research group “observed that rats will press a lever more often to get a single infusion of MPDV than they will for meth, across a fairly wide dose range.”

Like methamphetamine, MDPV works by stalling the uptake of dopamine, and it also has effects on noradrenaline and serotonin.  As cathinone derivatives, MPDV and mephedrone are related to the stimulant drug khat, which is used like cocaine in northeastern Africa.  In earlier research at Scripps under Dr. Taffe, investigators found that lab rats would intravenously self-administer mephedrone and behave in a manner similar to the effects produced when the rats were on methamphetamine. In a paper  for Drug and Alcohol Dependence, the Taffe Lab concluded that “the potential for compulsive use of mephedrone in humans is likely quite high, particularly in comparison with MDMA.”

Now the researchers have zeroed in on the effects of the dirty pharmacology represented by MDPV, the other primary ingredient in many bath salt mixtures. In a new study by Michael Taffe, Tobin J. Dickerson, Shawn M. Aarde, and others, to be published in the August issue of Neuropharmacology, the investigators found that MDPV was a more potent attraction than meth for rats allowed to self-administer the drugs. Very little lab data exists for MDPV, and this study was among the first to directly compare the effect of MDPV to methamphetamine in an animal experiment.

It took some time to tease out the behavioral clues—the cognitive, thermoregulatory, and potentially addictive effects of the drug—but MDPV’s strong affinities with speed can no longer be ignored. The researchers saw the same types of repetitive activities seen in animals on meth, such as excessive grooming, tooth grinding, and skin picking.  Lead author Shawn Aarde said in a prepared statement that “one stereotyped behavior that we often observed was a rat repeatedly licking the clear plastic walls of its operant chamber—a behavior that was sometimes uninterruptable.”

 MDPV, in the jargon of such experiments, had “greater reward value” than methamphetamine. Which is saying something, given the well-publicized addictive threat of speed. When the group boosted the number of lever presses needed for another infusion of MDPV or meth, “we observed that rats emitted about 60 presses on average for a dose of meth but up to about 600 for MDPV—some rats would even emit 3,000 lever presses for a single hit of MDPV,” said Aarde in a press release. “If you consider these lever presses a measure of how much a rat will work to get a drug infusion, then these rats worked more than 10 times harder to get MDPV.”

Excuse me, did he say as many as three thousand bar presses for another bump of intravenous MDPV? He did. Overall, the rats self-administered more MDPV than methamphetamine. In the paper itself, the authors write that “compared with meth, the effect of MDPV on drug-reinforced behavior was of greater potency (more responding under lowest dose under fixed-ratio schedule) and greater efficacy (more responding under optimal dose under a progressive ratio schedule)…”

The conclusion? MDPV’s “abuse liability” may be greater than that of standard methamphetamine. Which is another excellent piece of evidence for approaching the world of new synthetic psychoactives with great caution.

Aarde S.M., Huang P.K., Creehan K.M., Dickerson T.J. & Taffe M.A. (2013). The novel recreational drug 3,4-methylenedioxypyrovalerone (MDPV) is a potent psychomotor stimulant: Self-administration and locomotor activity in rats, Neuropharmacology, 71  130-140. DOI: 10.1016/j.neuropharm.2013.04.003

Popular Synthetics: The Class of 2013

Navigating the new alphabet of intoxication.

You don’t have to be a molecular chemist to know which of today’s recreational drugs are safe. Wait, I take that back. You DO have to be a molecular chemist to navigate today’s synthetic drug market with anything like a modest degree of safety.

It’s hard not to get nostalgic: Back in the day, you had your pot, you had your acid, your coke, your speed, and your heroin. And that, with the exception of a few freak outriders like PCP, was about that. Baby boomers of today, already losing touch with leading-edge music—Macklemore? Tame Impala?—can now consider themselves officially out of touch when it comes to illegal drugs.

That is, unless they are familiar with psychoactive chemicals beyond mere methamphetamine “bath salt” knockoffs like mephedrone, and cannabis “Spice” look-alikes such as JWH-018. We’re talking about drugs like Bromo-DragonFly, Benzo Fury, and 2C-B.  As Vanessa Grigoriadis writes in New York Magazine: “These drug users imagine themselves as amateur chemists, proto-Walter Whites, sampling and resynthesizing drugs to achieve exactly the state of consciousness they find most pleasurable. And there are no end of drugs to play with.”

A big piece of the synthetic drugs movement can be traced to the work of the legendary Alexander Shulgin, a Harvard grad who worked for Dow chemical, and who invented more than 100 entirely novel hallucinogenic compounds over the years. Other than the hallucinogens investigated by Shulgin and his coterie of personal friends, who were willing to take new hallucinogens and report back, none of the drugs on this list were meant for, or tested on, human beings.

Many of them are not, technically, new. Nonetheless, writes Grigoriadis, "almost every drug, from pot to GHB to morphine, has been messed with, as chemists find that removing a methoxy group or adding a benzene ring makes a new drug with different properties: body-grooving with a side helping of visuals, euphoric or speedy, long or short, or administering just the right dose of primal fear. Formerly known as “designer drugs,” they have morphed into “synthetic highs.” The tricky precursor chemical problem has become much easier to solve in the present moment, when any budding entrepreneur can send the official chemical designation of a drug, called its CAS number, to any of dozens of manufacturers in China, who will provide them with whatever weird “research” drug they need.


Herewith, a sampling of a few popular drugs of the day:

• 2C Series

2C-P is an Alexander Shulgin favorite, a hallucinogenic phenethylamine known officially as 2-(2,5-dmethoxy-4-propylphenyl)ethanamine. But your mileage may vary. Phenethylamine is similar in action to amphetamine and acts on dopamine and norepinephrine receptors. Nonetheless, 2C drugs have strong psychedelic effects as well. Other phenethylamine drugs include ephedrine, mescaline, bupropion (Wellbutrin), and venlafaxine (Effexor). There are several drugs in the 2C family, including 2C-B and 2C-I, but 2C-P is considered the strongest in the class, an intense psychedelic with visualizations lasting for up to 16 hours. 2C-B, or 4-bromo-2,5-dimethoxyphenethylamine is another popular hallucinogen, described by some as a cross between LSD and MDMA (Ecstasy)—less “psychedelic” than LSD, with stronger “body effects.” Drugs in this family are generally recognized as non-addictive, but large doses can cause sweating and chills, stomach discomfort, and paranoia or panic. A close cousin, the DOB drugs (2,5-Dimethoxy-4-Bromoamphetamine) are a related family of hallucinogens.

• Bromo-Dragonfly

This synthetic, sold as 3C-Bromo-Dragonfly and DOB-Dragonfly, is a very strong serotonin agonist, and has effects consistent with serotonin 5-HT hallucinogens such as LSD. This one came out of Purdue Pharmaceuticals as a compound for use in serotonin research, and belongs to a class of drugs called benzodifurans, which are related to the phenethylamines. It has been implicated in several deaths since it was first reported in 2007, says drug site Erowid. Positive effects listed at EROWID  included mood lift, visual changes, and increased energy. Negative effects include short-term memory loss, muscle tension, and “unknown risks due to research chemical status.” This is not a drug to take lightly. Dr. Jeff Lapoint, an attending physician at San Diego’s Kaiser Permanente and an expert in toxicology, recently told Tony O'Neill at The Fix that “Bromo-Dragonfly is probably the scariest thing on the list.”

• NBOMe Series

This group of synthetics, now available to underground buyers, is a perfect example of a complicated new series of psychoactive drugs with little or no track record of human use before they appeared online in 2010. When coherently labeled at all, they are sold as 2C-C-NBOMe, 2c-I-NBOMe, 25C-NBOMe, and mescaline-NBOMe, among other designations. The NBOMe series have attributes of both hallucinogens and amphetamines, and are active at very low doses, like LSD. There isn’t even much in the way of animal research on this collection. As with many of these synthetics, reports linking 2C-C-NBOMe to the deaths of young users have surfaced over the past two years.  While hallucinogens always present this Janus-faced aspect, this roll-the-dice-for-a-good-trip-or-a-bad-trip vibe, the ability to actually KNOW what you are taking—always a problem of major significance in the underground drug world—becomes even more acute in the case of research chemicals not intended for human use, let alone Prime Time.  If all goes well, users get a mood lift, visuals, and euphoria. At high doses, the effects can include nausea, paranoia, extreme fear, and panic. It is the essential dilemma at the heart of psychedelic experimentation—there are no guarantees going in, and it is always, at least to a degree, a form of psychic Russian roulette.

• 6-APB (Benzo Fury)

A lot of different drugs are sold as Benzo Fury, but the name comes originally from 6-APB, or 6-(2-aminopropyl)benzofuran. Like so many other designer amphetamines, 6-APB showed up online in 2010. The online drug discussion site Bluelight notes that vendors also peddle it as 6-APDB, 5-APDB, and 4-D as well. To date it has mostly surfaced as a club drug in the UK, and is chemically similar to MDA, another “entactogen” with strong body effects that was popular in the 60s as the “love drug.” Unfortunately Benzo Fury proved to be such a Euro-smash as a brand that drug sellers started packaging any research chemical at hand as Benzo Fury, so that the brand name has already become meaningless.

• MDPV

3,4-methylenedioxypyrovalerone, frequently referred to as bath salts, or sometimes as Molly, which is supposed to mean MDMA, is primarily a methamphetamine-style stimulant, but can induce hallucinations at high doses, EROWID reports, as well as tachycardia and elevated blood pressure. As with speed, withdrawal can be extremely problematic, and increased mental and physical energy make this one highly reinforcing. Redosing is common. Recent studies strongly suggest that it is addictive in humans. A report at EROWID states: “Doing/coming off of MDPV is like winning a Mercedes and being told at the last minute they got your name wrong. Uggh.”

• 5-MeO-DMT

This naturally occurring hallucinogenic tryptamine, 5-methoxy-N,N-dimethyltryptamine by name, has the unfortunate luck of sounding like another drug, simply called DMT. Both have hallucinogenic properties, but vaporized 5-MeO-DMT is active at 5 mg, where DMT is only active at a dosage about 5 times that high. So confusing the two drugs is not wise. High doses of 5-MeO-DMT can cause cardiac problems, convulsions, and mental confusion. Dealers who use them interchangeably are to be avoided. Unlike some of the other drugs in this list, 5-MeO-DMT has a long pedigree, in use since the 1970s, and is thought by some anthropologists to have been an ingredient in “shamanic snuff” used by early civilizations.

Photo Credit: http://legalmann.wordpress.com/

What We Talk About When We Talk About Drugs

Some number crunching at bluelight.ru.

A fantastic set of interactive graphics tracking conversational trends in drugs at the chat board bluelight.ru reveals some surprises, to the delight of data journalists everywhere. Virostatiq, a software package authored by Marko Plahuta, was put to the task of analyzing traffic at the drug discussion site. Various kinds of plots are available, with endless variables to permutate. Bear in mind that the data that got crunched dealt with the subject of messages, and cannot be directly correlated with drug use, trends, distributions, etc. But it is a fascinating glimpse at what illegal drug users are talking about, and from that, some inferences can be hazarded.

Plahuta writes:

I thought it would be nice to visualize these drug groups based on what users of harm-reduction forums say, so I analyzed around 1.2 million posts on bluelight.ru and constructed a simple diagram that tells a lot…. My whole database contains posts from 2010 until March 2013. Here’s an analytical tool to better understand what’s going on in the recreational drug community. Time is on horizontal axis, while the proportion of posts mentioning specific drug relative to all posts in that month is on the vertical axis. Play around with interactive chart to discover emerging trends, or simply to behold the wax and wane of specific chemicals as they compete for users’ neurological apparatuses, while their manufacturers are temporarily evading ever stricter analog laws.

The chart above represents a graphic created for Addiction Inbox using the visual data provided by Virostatiq. I have singled out six drugs of abuse for discussion. Bear in mind that the trend lines for common drugs like LSD, Ecstasy, marijuana, and methamphetamine all show much higher usage than the ones I have chosen to chart.

—Mephedrone, arguably the most common “bath salt” stimulant, was mentioned at bluelight.ru a lot during 2010, when it came to the U.S. in a major way. But comments have been tailing off pretty steeply ever since. This suggests that mephedrone was sampled and found wanting by those who knew what drug they were taking. Or it could simply be old news by now, and less of a topic for discussion. But if the graph is suggestive of interest levels in the drug-using community, mephedrone seems to have a PR problem.

—Surprisingly, at least to me, a hallucinogen name 2c-e was one of the most talked-about designer drugs of all. 2c-e is a research chemical similar to mescaline but with a spotty track record. Linked to deaths and hospitalizations in Oklahoma and Minnesota, it isn’t known for certain whether the medical problems were due to the pure drug or contaminants. 2c-e is one of the drugs to come out of Alexander Shulgin’s infamous laboratories, and has been around for 20 years. As Tony O’Neill wrote at The Fix: “All in all, it doesn’t sound like the best bet for a recreational Saturday night at the dance club.” As with mephedrone, 2c-e was less talked bout in the last year of the graph.

—Kratom retained a steady popularity over the full 3-year period. Kratom has always been hovering in the background of the opiate family, but seems to have undergone an unprecedented surge in underground popularity of late. From a tree native to Southeast Asia, and often used as a tea, Kratom is powered by an active ingredient called mitragynine—a substance capable of partially activating the mu- and delta-opioid receptors. Kratom serves as a weak opium, and some opiate enthusiasts swear by it for use as a withdrawal aid.

—One of the popular synthetic cannabis products to come out of the Huffman labs at Clemson University, jwh-018 seems to have pretty much cratered as a topic of discussion among drug cognoscenti. Perhaps some of the news about synthetic cannabis and correlations with serious liver problems has taken the shine off that apple. Or simply the fact that, over the few years that synthetic cannabis has been available, users have learned that they prefer the real thing, drug tests notwithstanding.

—Hydrocodone, otherwise known as Vicodin, may have lost some popularity lately due to the popularity of oxycontin and other new synthetic opiate formulations. This is the drug that may have cost Rush Limbaugh his hearing. As a legitimate pain drug, it suffers in comparison with oxycontin, aka Percodan.

—Ketamine is a major topic of discussion, which makes sense. Lately it has rebounded as a party drug, and also scored highly in clinical testing of its efficacy as a short-acting treatment for depression. Unfortunately, use of the drug has been linked to bladder problems  lately.

Popular “Bath Salt” Hooks Lab Rats

Mephedrone shows addictive properties in animal models.

Cathinones, like methedrine and other stimulants, are primarily dopamine-active drugs. Though they are now illegal in the U.S., they were formerly of primary interest only to pharmaceutical researchers. The best-known cathinone sold in the form of bath salts and plant food—mephedrone—has both dopamine and serotonin effects. It broke big in the UK a few years ago as a “legal” party drug alternative to MDMA. The idea was to get high without testing dirty, as the saying goes.

Behavioral clues about mephedrone have been teased out of rat studies. The Taffe Laboratory at Scripps Research Institute has been focusing on the cognitive, thermoregulatory, and potentially addictive effects of the cathinones, and mephedrone in particular. Scripps researchers have carried the investigation forward with a recent study in the journal Drug and Alcohol Dependence.

Now comes additional evidence, also from the Taffe Lab at Scripps, that mephedrone, or 4-MMC, looks like an addictive drug. In a paper accepted for publication by Addiction Biology, which Addiction Inbox was allowed to review in advance, Dr. Michael Taffe, along with lead author S.M. Aarde and coworkers, demonstrated in an animal study that lab rats will intravenously self-administer mephedrone under normal lab conditions—roughly analogous to shooting speed.

Without suitable strains of test animals, most genetic and neurobiological research would take centuries, and would involve ethical questions about human testing far stickier than the questions raised by work with animals. Animal models are one of the primary pathways of discovery available to neurobiologists and other researchers.

But it’s tricky. Establishing traditional rodent laboratory conditions is a Goldilocks endeavor: The environment must be not too hot, but not too cold, because this can effect rodent behavior. And the drug must be given at rates that are not too frequent and not too rare.

The curious thing about mephedrone is that it appears to combine the effects of prototypical stimulants like cocaine and methamphetamine, with the trippy, “entactogen” effects of MDMA, aka Ecstasy, in the bargain. The drug rapidly crosses the blood-brain barrier, reaching peak levels two minutes after injection, and full effects last about an hour. In one study, 76% of people who had snorted both cocaine and mephedrone reported that the quality of the mephedrone high was “similar to or better than” cocaine. But the paper also states that “human recreational users report 4-MMC to be subjectively similar to MDMA.”

The investigators ran a series of tests with various groups of rats, and found that 80-100% of the rats would happily reward-press a lever for an infusion of mephedrone. “Under these conditions,” writes Taffe, “methamphetamine and 4-MMC have about equal effect on rat self-administration although the 4-MMC is considerably less potent, requiring about 10 times the per-infusion dose for effect.” Although it wasn’t demonstrated directly in this paper, Ecstasy “is at best unevenly self-administered by rats,” and “despite an MDMA-like serotonin/dopamine neuropharmacological effect, mephedrone has a liability for repetitive intake more similar to the classical amphetamine-type stimulants such as methamphetamine.”

It’s a weaker type of stimulant, mephedrone, but it does the trick. It is highly reinforcing. Mephedrone chemically resembles speed, but also has Ecstasy-like effects. "Furthermore, neurochemical data suggest MDMA-like patterns of relatively greater serotonin versus dopamine accumulation in nucleus accumbens.” Even with its added Ecstasy-like effects, the scientists conclude that “the potential for compulsive use of mephedrone in humans is likely quite high, particularly in comparison with MDMA.”

Photo Credit: Creative Commons

Synthetic Drugs: Collected Posts

Catching up with bath salts and spice.


The Low Down on the New Highs: Not all bath salts are alike.

“You’re 16 hours into your 24-hour shift on the medic unit, and you find yourself responding to an “unknown problem” call.... Walking up to the patient, you note a slender male sitting wide-eyed on the sidewalk. His skin is noticeably flushed and diaphoretic, and he appears extremely tense. You notice slight tremors in his upper body, a clenched jaw and a vacant look in his eyes.... As you begin to apply the blood pressure cuff, the patient begins violently resisting and thrashing about on the sidewalk—still handcuffed. Nothing seems to calm him, and he simultaneously bangs his head on the sidewalk and tries to kick you...” [Go here]


The New Highs: Are Bath Salts Addictive? What we know and don’t know about synthetic speed.

Call bath salts a new trend, if you insist. Do they cause psychosis? Are they “super-LSD?” The truth is, they are a continuation of a 70-year old trend: speed. Lately, we’ve been fretting about the Adderall Generation, but every population cohort has had its own confrontation with the pleasures and perils of speed: Ritalin, ice, Methedrine, crystal meth, IV meth, amphetamine, Dexedrine, Benzedrine… and so it goes. For addicts: Speed kills. Those two words were found all over posters in the Haight Ashbury district of San Francisco, a few years too late to do the residents much good…. [Go here]


“Bath Salts” and Ecstasy Implicated in Kidney Injuries: “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…. [Go here]


The Triumph of Synthetics: Designer stimulants surpass heroin and cocaine.

A troubling report by the United Nations Office on Drugs and Crime (UNODC) shows that amphetamine-type stimulants (ATS) have, for the first time, become more popular around the world than heroin and cocaine. Marijuana remains the most popular illegal drug in the world, and the use of amphetamines has fallen sharply in the U.S., but the world trend represents the worldwide triumph of synthetic drug design over the plant-based “hard drugs” of the past…. [Go here]

Marijuana: The New Generation: 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…. [Go here]


An Interview with Pharmacologist David Kroll: On synthetic marijuana, organic medicines, and drugs of the future.

Herewith, a 5-question interview with pharmacologist David Kroll, Ph.D., Professor and Chair of Pharmaceutical Science at North Carolina Central University in Durham, and a well-known blogger in the online science community. A cancer pharmacologist whose field is natural products—he’s currently involved in a project to explore the potential anticancer action of chemicals found in milk thistle and various sorts of fungi—Dr. Kroll received his Ph.D. from the University of Florida, and completed his postdoctoral fellowship in Medical Oncology and Molecular Endocrinology at the University of Colorado School of Medicine. He went on to spend the first nine years of his independent research and teaching career at the University of Colorado School of Pharmacy, where he taught all aspects of pharmacology, from central nervous system-active drugs, to anticancer and antiviral medications…. [Go here]


Mephedrone, the New Drug in Town: Bull market for quasi-legal designer highs.

Most people in the United States have never heard of it. Very few have ever tried it. But if Europe is any kind of leading indicator for synthetic drugs (and it is), then America will shortly have a chance to get acquainted with mephedrone, a.k.a. Drone, MCAT, 4-methylmethcathinone (4-MMC), and Meow Meow--the latter nickname presumably in honor of its membership in the cathinone family, making it chemically similar in some ways to amphetamine and ephedrine. But its users often refer to effects more commonly associated with Ecstasy (MDMA), both the good (euphoria, empathy, talkativeness) and the bad (blood pressure spikes, delusions, drastic changes in body temperature)…. [Go here]


Tracking Synthetic Highs: UN office monitors designer drug trade.

Produced by the United Nations Office on Drugs and Crime (UNODC), the Global SMART Update  (PDF) for October provides interim reports of emerging trends in synthetic drug use. The report does not concern itself with cocaine, heroin, marijuana, alcohol, or tobacco. “Unlike plant-based drugs,” says the report, “synthetic drugs are quickly evolving with new designer drugs appearing on the market each year.” The update deals primarily with amphetamine-type stimulants, but also includes newer designer drugs such as mephedrone, atypical synthetics like ketamine, synthetic opioids like fentanyl, and old standbys like LSD…. [Go here]


The New Cannabinoids: Army fears influx of synthetic marijuana.

It’s a common rumor: Spice, as the new synthetic cannabis-like products are usually called, will get you high--but will allow you to pass a drug urinalysis. And for this reason, rumor has it, Spice is becoming very popular in exactly the places it might be least welcomed: Police stations, fire departments—and army bases. What the hell is this stuff? [Go here]

Photo credit: http://gizmodo.com/

photo credit 2: http://www.clemson.edu/

The New Highs: Are Bath Salts Addictive?

What we know and don’t know about synthetic speed.

Part II.

Call bath salts a new trend, if you insist. Do they cause psychosis? Are they “super-LSD?” The truth is, they are a continuation of a 70-year old trend: speed. Lately, we’ve been fretting about the Adderall Generation, but every population cohort has had its own confrontation with the pleasures and perils of speed: Ritalin, ice, Methedrine, crystal meth, IV meth, amphetamine, Dexedrine, Benzedrine… and so it goes. For addicts: Speed kills. Those two words were found all over posters in the Haight Ashbury district of San Francisco, a few years too late to do the residents much good.

While the matter of the addictiveness of Spice and other synthetic cannabis products remains open to question, there no longer seems to be much doubt about the stimulant drugs known collectively as bath salts. To a greater or lesser degree, these off-the-shelf synthetic stimulants appear to be potentially addictive. And that’s not good news for anyone.

Last week, the U.S. Congress added 26 additional synthetic chemicals to the Controlled Substances Act, including the designer stimulants mephedrone and MDPV, at the behest of the Drug Enforcement Administration. Mephedrone and MDPV are cathinones, sold as bath salts or plant food, and chemically similar to amphetamine and ephedrine. (Methcathinone, often called MCAT, is to cathinone as methamphetamine is to amphetamine)

The research news on bath salts at the annual meeting of the College on Problems of Drug  Dependence (CPDD) in Palm Springs recently was complex and confusing. For example, the phemonenon of overheating, or hyperthermia, that plagues ravers on MDMA and sends some of them to the hospital is a function of certain temperature-sensitive effects of Ecstasy. But it is not as much of a problem with MDPV and mephedrone. The bath salts, like meth, don’t seem to cause overheating as readily.

On another front, William Fantegrossi, assistant professor in the Department of Pharmacology and Toxicology at the University of Arkansas for Medical Sciences, told the panel audience that at very high doses and very high temperatures, stimulants like Ecstasy and MDPV “can cause self-mutilation in animals.”  Fantegrossi’s statement was the closest anybody has come to providing a possible scientific basis for popular press accounts linking bath salts to flesh-eating frenzies by psychotic users. But this remains speculative, as there are still no reliable toxicological findings available in such cases.

The symposium on bath salts at the CPDD played to a packed conference hall, a sure sign that professional scientists who study addiction for a living were interested in the subject. The panel was titled “A Stimulating Soak in ‘Bath Salts’: Investigating Cathinone Derivative Drugs,” and was co-chaired by Dr. Michael Taffe of the Scripps Research Institute in La Jolla, CA, and pharmacology professor Dr. Annette Fleckenstein of the University of Utah.

Fantegrossi characterized the overall problem of designer stimulants as “dirty pharmacology” on both sides, pointing to the desperate efforts underway by government-funded scientists to “throw antagonists [blocking drugs] at these things.”

Alexander Shulgin, the grandfather of the modern psychedelic movement, popularized MDMA and hundreds of variants in his backyard laboratory in the Bay Area over the years. Shulgin, better than anyone, knew that legitimate research and dirty recreational chemistry are only a molecule away. In their book Pihkal: A Chemical Love Story, Alexander Shulgin and his wife Ana recall that cartoonist Gary Trudeau captured the truth of the situation as far back as 1985, when the MDMA story became front-page news:

Way back in mid-1985, the cartoonist-author of Doonesbury, Gary Trudeau, did a two-week feature on it, playing it humorous, and almost (but not quite) straight, in a hilarious sequence of twelve strips. On August 19, 1985 he had Duke, president of Baby Doc College, introduce the drug design team from USC in the form of two brilliant twins, Drs. Albie and Bunny Gorp. They vividly demonstrated to the enthusiastic conference that their new drug "Intensity" was simply MDMA with one of the two oxygens removed. "Voila," said one of them, with a molecular model in his hands, "Legal as sea salt."

Jeffrey Moran of the Arkansas Department of Health noted that despite the cat-and-mouse game continuously played between illegal drug designers and the law, government bans on mephedrone and MDPV, the two most common forms of designer stimulant, cause only temporary downturns in supply. They are no longer as legal as sea salt, but it doesn’t seem to matter. There are always new ones in the pipeline. Moran told the audience that at least 48 different compounds had been identified in more than 200 distinct bath salt-style products in his state alone.  Sorting out the specific chemistry involves specialized assays designed to detect a bewildering array of molecules: methylone, mephedrone, paphyrone, butylone, 4-MEC, alpha-PVP, and a host of others, some old, some new, some reimagined by underground chemists. 

Terry Boos of the U.S. Drug Enforcement Agency explained that most designer stimulants currently in play are not manufactured stateside. Most originate in Asia and arrive through various ports of call, where they are repackaged for sale in the U.S. Purity of the cathinone ranges from 30 to 95 per cent, Boos said.

Annette Fleckenstein of the University of Utah emphasized that scientists shouldn’t be fooled by overall structural similarities among such drugs as meth, mephedrone, MDMA, and MDPV. In a 2011 study published with her colleagues at the University of Utah, Fleckenstein lamented that mephedrone’s recent emergence on the drug scene had exposed the fact that “there are no formal pharmacodynamic or pharmacokinetic studies of mephedrone.”

But she has managed to show that methamphetamine causes lasting decreases in serotonin functions, as well as the better-known dopamine alterations, and that MDMA and mephedrone are intimately involved in the accumulation of serotonin in the brain’s nucleus accumbens, where addictive drugs produce many of their rewarding effects. “Rats will self-administer mephedrone,” said Fleckenstein—always a troubling clue that the drug in question may have addictive properties.  Since the high in humans only last for three to six hours, there is a tendency to reinforce the behavior through repeated dosings.

Other behavioral clues have been teased out of rat studies. The Taffe Laboratory at Scripps Research Institute has focused on the cognitive, thermoregulatory, and potentially addictive effects of the cathinones. Rats will self-administer mephedrone, MDPV, and of course methamphetamine. However, Dr. Taffe told the audience that MDMA does not produce these classic locomotor stimulant effects at low doses and that it is “more difficult to get them to self-administer” Ecstasy. Nonetheless, Taffe told me he believes that MDMA is, in fact, potentially addictive. “Our data suggest that MDPV is highly reinforcing,” Taffe said in an email exchange after the conference, “and at least as readily self-administered as methamphetamine, at approximately the same per-infusion doses. But it is a very complicated story.”

Scripps researchers have carried the investigation forward with a new study, currently in press at the journal Drug and Alcohol Dependence. Pai-Kai Huang and coworkers studied the differing effects of designer stimulants on voluntary wheel-running activity in rats, adding additional evidence to the basic behavioral split among club drugs of the moment. Taffe, one of the study’s co-authors, said the researchers had predicted that the two drugs with the strongest serotonin activity—MDMA and the mephedrone variants—would decrease wheel running activity in the rats. Methedrine and MDPV, they predicted, would increase activity.

And that’s how it turned out. What that means for human users is still not entirely clear. But MDPV in particular, it now seems evident, has some rather direct and disturbing affinities with crystal meth and cocaine. And the vagaries of the market have led to sharp increases in the percentage of MDPV found in bath salt products in the last two years. Are we seeing the wholesale replacement of MDMA by a more directly addictive, methedrine-like drug? Will we see a rise in psychotic symptoms, and increased visits to the ER, as MDPV becomes more common in bath salts? Ecstasy has been implicated in the death of users as well, but will the surge in cathinone drugs mean there will be additional deaths?

And remember: Researchers are able to distinguish between rats under the influence of either MDMA- or MDPV-based wheel activity—but the research suggests that under blinded conditions, human users aren’t very good at guessing which of those two drugs they’re on. Furthermore, we don’t have the data to say whether users can tell mephedrone from MDPV in a blind test. And even wheel-running rats don’t give away whether they’re running on MDMA or mephedrone. These categorical distinctions are all-important, but still in relative infancy as far as street use is concerned.

The Scripps scientists concluded that their study “underlines the error of assuming all novel cathinone derivative stimulants that become popular with recreational users will share neuropharmacological or biobehavioral properties.” Some of the combinations produce a “unique constellation of desired effects.”

But by 2011, the U.S. media had conflated mephedrone with MDPV and half a dozen other substances, all with differing effects on users. For public health officials, it was a nightmare.

“We know that MDMA users follow the science,” Taffe said, at the close of the bath salts panel.  “So information we make available can have a direct effect on public health for those people.” But for bath salt users, the picture is not as clear. Consider, once again, Arkansas’ finding of 30 or 40 different cathinone derivatives, part of a set of 250 distinct chemicals identified in different combinations of bath salt products. “Slight modifications can change the toxicities,” Taffe said. “Abuse liabilities differ between MDMA and different cathinones. They all confer different health risks.” 

One of the primary drivers of bath salt usage appears to be the desire to finesse drug-testing programs. And if drug-testing programs are pushing people in the direction of more dangerous, unfamiliar, and addictive substances, then perhaps drug testing is part of the problem rather than the solution.

In the short run, emergency treatment of patients with OD symptoms they attribute to bath salts will remain the same, whether the cathinone in question is mephedrone, MDPV, or some other variant. General emergency-department procedures for stimulant intoxication are standardized. People can suffer cardiac arrest from either MDMA or meth. And people can run very high temperatures with overdoses of any of these stimulants.

Are users listening? Do they believe any of the health warnings this time out, or have there been too many over the years, always strident and hysterical and overinflated?

Huang PK, Aarde SM, Angrish D, Houseknecht KL, Dickerson TJ, & Taffe MA (2012). Contrasting effects of d-methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxypyrovalerone, and 4-methylmethcathinone on wheel activity in rats. Drug and alcohol dependence PMID: 22664136

Hadlock GC, Webb KM, McFadden LM, Chu PW, Ellis JD, Allen SC, Andrenyak DM, Vieira-Brock PL, German CL, Conrad KM, Hoonakker AJ, Gibb JW, Wilkins DG, Hanson GR, & Fleckenstein AE (2011). 4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse. The Journal of pharmacology and experimental therapeutics, 339 (2), 530-6 PMID: 21810934

The Low Down on the New Highs

Not all bath salts are alike.

“You’re 16 hours into your 24-hour shift on the medic unit, and you find yourself responding to an “unknown problem” call.... Walking up to the patient, you note a slender male sitting wide-eyed on the sidewalk. His skin is noticeably flushed and diaphoretic, and he appears extremely tense. You notice slight tremors in his upper body, a clenched jaw and a vacant look in his eyes.... As you begin to apply the blood pressure cuff, the patient begins violently resisting and thrashing about on the sidewalk—still handcuffed. Nothing seems to calm him, and he simultaneously bangs his head on the sidewalk and tries to kick you... and his body temperature is 103.2° F. He doesn’t respond with anything other than basic “yes” and “no” answers. Recognizing the probable state of acute stimulant intoxication and the risks associated, you begin further treatment. You turn the patient compartment air conditioning on high and obtain large-bore IV access of normal saline and set an initial infusion rate of 250 cc/hour.... Later in your shift, you return to the same emergency department (ED) and are informed that the patient has been admitted for rhabdomyolysis and has admitted to taking “bath salts” for the past three days.”

This episode, taken from an article in a recent issue of the Journal of Emergency Medical Services by Jon Nevin, a California emergency medical technician and paramedic, aptly demonstrates the dilemmas facing medical workers since the explosion in usage of “bath salts.” A catchall category for a family of designer stimulants centered on chemicals known as cathinones, bath salts, which are of course no such thing, began filtering in from Europe. One of the more popular new club drugs was variously called meph, or CAT, or 4-MMC, or Meow Meow. The drug’s official name was mephedrone. It was a chemical cousin of amphetamine, with effects somewhat similar to those of Ecstasy (MDMA).

In 2011, calls to poison controls centers skyrocketed across the country as new and untested combinations of cathinones came on the market. Bewildered emergency room technicians and toxicologists were hard pressed to identify even basic ingredients. Recreational users never knew what was in the shiny foil packages, only what was purportedly not in them—a laundry list of recently proscribed chemicals, which the marketers proudly noted on the packaging. This endless Mobius strip of designer stimulant development and grey-market sales channels mean a lucrative hit-and-run business for the producers, but a completely unsafe landscape for recreational users, who act as voluntary guinea pigs for new combinations of poorly understood psychoactive compounds. It is from this underground designer milieu that MDMA came to the forefront, courtesy of clandestine work done by neurochemist Alexander Shulgin and associates. 

Mephedrone started showing up in the U.S. in 2010, and quickly spread via word of mouth and the Internet. This was not the synthetic marijuana in powder form being marketed as Spice and K2, although distribution channels were often the same. This was synthetic speed that could be dissolved and injected. The idea was, you could get high and still pass a random drug test, since drug tests didn’t have the sophisticated assays needed to sort out the cathinones. And you could escape the tightening net around Ecstasy use, and still get Ecstasy-like effects. And designer stimulants picked up another strong user base: heroin addicts and methadone users looked for a detection-free boost. They could stay enrolled in their methadone program, and dodge trouble with parole officers, and still party all weekend on bath salts. One big problem became apparent straightaway: The effect of bath salts varied wildly, from gentle stimulant to some sort of death’s-head equivalent of the brown acid at Woodstock.

Bath salts were easy to buy. These unregulated stimulants came in a bewildering array of mixtures, featuring dozens of ingredients and additives. Even when they weren’t blatantly available on the shelves of head shops and convenience stores, many outlets carried them—if you knew the street codes. What law enforcement officer would bust you for buying jewelry cleaner, for example? Cops and drug enforcement officers must long for the clarity of the old days. You had smack, you had crack, you had bathtub Methedrine (methamphetamine).

“Understanding what each of those substances can do physiologically is key to understanding their dangers and to determining how best to treat people who need medical assistance,” wrote Marc Kaufman, with the McLean Imaging Center at Harvard. The trouble is, that knowledge is hard to come by.

It's not hard to understand the allure of stimulants, designer or otherwise. Countless baby boomers and Gen Xers have sampled cocaine and methamphetamine on a recreational basis, and will have no trouble explaining the appeal: It just feels good. In the short run, these drugs boost self-esteem, physical stamina, locomotor skills, and verbal dexterity. The original Dr. Feelgood of New York hipster fame was injecting his ultracool clientele with amphetamines. Nothing felt better than speed, if you want to put it that way.

Cathinones, like methedrine and other form of speed, are primarily dopamine-active drugs. Though they are now illegal in the U.S., they were formerly of primary interest only to pharmaceutical researchers. The best-known cathinone sold as bath salt—mephedrone—has both dopamine and serotonin effects. It broke big in the UK a few years ago as a “legal” party drug alternative to MDMA. Mephedrone came packaged with other chemicals under various marketing guises. And soon, as legal heat came down on the drug, designers switched to near-beer variants, and eventually began flooding the bath salt markets with other cathinone drugs whose effects were equally murky. Users of bath salt products had been seduced, wrote Natasha Vargas-Cooper in Spin magazine, by the idea that they could “get high without testing dirty.”

In 2011, users of bath salt products started turning up in ERs in significant numbers. Some of them were suffering overdoses of MDMA or mephedrone, but last year a new twist on the cathinone molecular structure began to get serious traction in the states. To stay one jump ahead of the law, underground chemists began churning out large quantities of a different amphetamine variant with the tongue-twisting name of methylenedioxypyrovalerone: MDPV, for short. And what were EMTs and paramedics seeing in cases where the drug could be identified as MDPV? In a study in Clinical Toxicology of recent admissions involving self-reports of bath salt use, two regional poison centers reported that exposure to MDPV was becoming more common than mephedrone. And the clinical symptoms of overdose? Agitation, tachycardia, hallucinations, combative behavior, hypertension, chest pain, blurred vision—and at least one death. This synthetic cathinone was evidently capable of producing psychotic episodes requiring sedation. It all sounded eerily similar to the PCP overdoses of the 60s and 70s, when that dissociative veterinary anesthetic enjoyed a period of dubious notoriety.

The arrival of MDPV in the emergency rooms of American changed the picture considerably. Medical workers and drug enforcement officers were forced to admit that they were behind the rolling curve of drug permutations. Nobody knew what was in a given packet of bath salts or plant food, or whatever other disguise was in vogue this week. Nobody knew how much to take, or to determine how much had been taken. Doctors didn’t know enough about cathinones to consistently diagnose an overdose. And what little testing was available for detecting synthetic stimulants was costly and questionable.

As 2012 began, researchers around the world were feeling pressure to find ways of discriminating between the different kinds of cathinones involved in overdoses, as a way of beginning to seriously sort out the fact from the fiction, the dangers from the overblown scare stories.

Various hopeless phrases were bandied about to describe the task of the DEA’s Forensic Sciences labs—“Whack-a-Mole,” “Cat-and-Mouse,” and “losing battle” being among the most common. What has them baffled and demoralized is the fact that these new chemicals under the sun are being created by underground chemists with more than casual kitchen sink skills. And, as one undercover drug officer told Spin Magazine, “when you go out and seize a warehouse full of something packaged as Dragonfly, you really have no idea what it is.” Nor do you know whether you can make a case under the Federal Analog Act, which is supposed to make all this easier by allowing cops and courts to outlaw drugs that are “substantially similar” to drugs already proscribed. But deciding questions of that nature is a matter of sophisticated biochemistry.

Dr. Michael Taffe of the Scripps Research Institute in La Jolla, CA, and pharmacology professor Annette Fleckenstein of the University of Utah have been working on these questions in the lab. Building on previous work, they had begun to conclude from their own animal studies that when it came to cathinones, there could be a big difference in effect without much evidence of a difference in chemistry.

Taffe and Fleckenstein, working separately, had produced evidence of specific behavioral differences between mephedrone and MPDV. As co-chairs of what turned out to be one of the best-attended sessions at the recent annual meeting of the College on Problems of Drug Dependence, the two scientists proceeded to expand the general understanding of a drug running rampant across three continents, and previously associated only with the chewing of Khat, a mild stimulant plant found in Africa.

(End of Part I)

Graphics Credit: http://www.bytrade.com/

“Bath Salts” and Ecstasy Implicated in Kidney Injuries

“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 drugs 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  

Drug Czar “Deeply Concerned” About Synthetic Stimulants

“Bath salts” come under federal scrutiny.

The Director of the Office of National Drug Control Policy issued a warning about the new synthetic stimulants now being clandestinely marketed as bath salts or insecticide.  Admitting that “we lack sufficient data to understand exactly how prevalent the use of these stimulants are,” Drug Czar Gil Kerlikowske nonetheless announced that the marketing of such drugs as mephedrone and MDPV was “both unacceptable and dangerous.”

A growing list of states, now including Michigan, Hawaii, Louisiana, Kentucky, North Dakota, and, recently, Florida, have introduced measures to ban the designer drugs, currently being sold under names like “Ivory Wave” or “Purple Wave.” The United Kingdom has already put mephedrone and related drugs under a blanket ban. The drugs are considered addictive, primarily because they are chemically similar to amphetamine and ephedrine. But users often refer to effects more commonly associated with Ecstasy (MDMA), both the good (euphoria, empathy, talkativeness) and the bad (blood pressure spikes, delusions, drastic changes in body temperature).

“I am deeply concerned  about the distribution, sale, and use of synthetic stimulants—especially those that are marketed as legal substances,” Kerlikowske said. “I ask that parents and other adult influences act immediately to discuss with young people the severe harm that can be caused” by such drugs.

Kerlikowske, who will convene a panel of experts on the subject,  said he was acting in response to recent data from the American Association of Poison Control Centers, which showed that poison control units have received 251 calls related to “bath salts” so far this year, compared to a total of 236 calls in all of calendar year 2010.

An earlier post of mine on mephedrone can be found HERE. Some of the best coverage has come from the anonymous NIH researcher who blogs on science topics as DrugMonkey.  See also coverage of alleged mephedrone deaths by David Kroll HERE.


Photo Credit: http://www.astantin.com/

Khat to the Chase

Of mephedrone, bath salts, and impaired driving.

 Automobile accidents are the ninth leading cause of death worlwide, according to the World Health Organization (WHO). More than a million people are killed on roads annually, and that number could rise to 2.5 million by 2020. WHO estimates that traffic accidents cost developing countries an astonishing 1-2 % of their gross domestic product (GDP).

For years now, police and public health officials have puzzled over the alarming number of traffic accidents in East Africa. In terms of sheer numbers, Asian countries have the highest total traffic fatalities, according to figures compiled by the Global Road Safety Partnership (GRSP), a consortium including the World Bank, the Red Cross and other aid agencies (PDF HERE). That is not surprising, since these nations contain the majority of the world’s drivers.

However, beyond the picture of traffic fatalities in terms of sheer numbers, or on a per population basis, there is another revealing measure—traffic deaths per motor vehicle. And when the GRSP measured nations by that yardstick, the four worst countries in the world for traffic deaths—judging by the number of fatalities per 10,000 licensed vehicles—were Ethiopia, Tanzania, Lesotho, and Kenya—all East African nations.

Moreover, these are all African countries in which the use of khat--an amphetamine-like plant drug that is the natural precursor of the designer drug known as mephedrone--is legal and common. The major khat-using countries in Africa are commonly listed as: Somalia, Kenya, Yemen, Ethiopa, Tanzania, Lesotho. Note the overlap. Khat, as one online article put it, is “the legal high of east Africa.”

On the tiny island nation of Mauritius, just off the southeast African coast, Touria Prayag writes at allAfrica.com that drivers “zoom past you, zigzag on the roads, nervously changing to the left lane to swiftly veer back on your side without any warning…. brazenly flouting the Highway Code in every imaginable dangerous manner…. And the carnage continues….”

In Ethiopia, annual road crash fatalities account for 114 deaths per 10,000 vehicles, compared to one death per 10,000 vehicles in Great Britain, and an average of 60 deaths per 10,000 vehicles across 39 sub-Saharan African countries. A report in the Bulletin of the World Health Organization (PDF HERE)  notes that Ethiopian truck drivers “are regarded as so dangerous that their trucks are commonly referred to across Ethiopia as ‘al Qaeda.’” Anecdotally, Ethiopians told WHO officials that khat “increased driver confidence and vehicle speed while also making drivers irritable and impairing concentration,” and that high levels of khat could lead to hallucinations.

A Kenya forum on TripAdvisor asks: Are matatus [local taxes piloted by khat-chewing Kenyans] safe?” 

Since khat is legally available in most of East Africa, and comprises a significant part of the social fabric of local cultures, the use of khat is similar to the use of alcohol in higher-income nations. But does khat present the same threat of driving impairment as alcohol? Bolivia is now arguing its right to allow citizens to chew coca leaves in the traditional manner. Is it safe to drive and chew coca leaves? In all of these cases, the challenge is to determine what constitutes a “safe” dose of the drug; a dose that does not endanger people on or near the highway. There is not enough research on khat to answer that question. Nor is there a way to administer roadside tests for khat. The best evidence, African police officers say, is green teeth.

The active ingredients in khat—cathine and cathinone—are similar in structure to amphetamines, and chemically similar to the ingredients used in the manufacture of mephedrone powder. Mephedrone is sold as 4-MMC, Meow Meow, M-Cat, and other nicknames. Cathine and cathinone ramp up dopamine, serotonin and noradrenaline levels in a manner very similar to amphetamine, with many of the same positive effects (mild euphoria, reduced hunger, increased energy) and the same negative effects (depression, fatigue, lack of appetite, drug craving). It is thought that chronic use of khat results in dopamine D2 depletion in areas of the brain involved in goal-directed action.

The current fervor over mephedrone being disguised as bath salts or plant food for black market sales purposes in the U.S and U.K. demonstrates that this question is not academic for developed western nations. Sold as Ivory Wave, or Bliss, or White Lightning, mephedrone and other products containing cathinone are increasingly available across the U.S. states. In 2008, police seized 600 pounds of fresh khat—in Fargo, North Dakota.

A recent paper published in Frontiers in Psychology, authored by a group of Dutch and Spanish psychologists, appears to show that khat users exhibit a specific cognitive deficit: On stop-signal tasks, stop signal reaction time (SSRT) was significantly slower for the khat users. Such tests typically involve rapidly pressing a green “go” button upon seeing an arrow in certain positions, or abruptly aborting the response when the arrow turns red. The test measures “individual ability to stop a planned or ongoing motor response in a voluntary fashion.” For example, someone with Parkinson’s disease would score at the very high end of the SSRT scale.

The study itself involved 20 regular khat users recruited from the immigrant populations of Leiden and The Hague, and matched against 20 khat-free controls. All of the khat users met four or more of the 7 DSM-IV criteria for addiction, and did not consume alcohol the night before the test. The investigators speculate that this reduced level of inhibitory control “may even be involved in the emergence of addiction: the more a drug is used, the less able users are to prevent themselves from using it.”

The parallels to traffic signals and stop signs are obvious, and apt. The authors state that the findings of their study are “rather worrying because, first, many real-life situations require active inhibition of prepotent actions, as in the case of traffic lights turning red, or of criminal actions.” The obvious conclusion is that the chronic chewing of khat leaves “may indeed lead to a marked deterioration of cognitive functions (as inhibitory control) implicated in driving behavior.” Studies by NIDA director Nora Volkow and others have show that cocaine users suffer similar reductions in dopamine D2 receptors and “need significantly more time to inhibit responses to stop signals than non-users.” In general, stimulant drugs taken regularly at high doses appear to disrupt response inhibition due to alterations in dopamine functioning. (Although some studies have shown a facilitation of inhibitory control at lower doses).

The usual caveats apply: It is impossible to rule out pre-existing propensities for impulsivity, disinhibition, and the like. Some health researchers do not agree that the case for driving impairment on khat has yet been made. In the Bulletin of the World Health Organization, Anita Feigin of the Centre for Population Health in Australia writes that, so far, much of the information is anecdotal, “and, as yet, there is no clear evidence of a causal relationship between the use of khat and traffic accidents.” African taxi drivers who immigrate to Australia use khat “to stay awake and alert.” However, Feigin notes that the use of khat has deeply divided the members of east African migrant communities.

It is an interesting conundrum. The developed West has its entrenched tradition of alcohol as a legal high, despite its side-effects, which frequently result in mayhem on the highways. On the other hand, the drinking nations must now contend with demands from other cultures for the decriminalization of khat and coca leaf, which, along with coffee and tea, make up a category we might call the “soft” stimulants.

Because of the connection with mephedrone and other amphetamine-like designer drugs, these questions will not be going away until more research provides some solid answers. Such research may not be long in coming: The NIH-funded Khat Research Program (KRP) at the University of Minnesota, for example, brings American researchers together with a broad group of scientists from Yemenese and German universities to study the effects of a common plant drug most Americans have never heard of—but a drug they may be dealing with in synthetic form sooner rather than later.

Colzato, L., Ruiz, M., van den Wildenberg, W., Bajo, M., & Hommel, B. (2011). Long-Term Effects of Chronic Khat Use: Impaired Inhibitory Control Frontiers in Psychology, 1 DOI: 10.3389/fpsyg.2010.00219


Photo Credit: http://blogs.citypages.com

Mephedrone, the New Drug in Town

Bull market for quasi-legal designer highs.

Most people in the United States have never heard of it. Very few have ever tried it. But if Europe is any kind of leading indicator for synthetic drugs (and it is), then America will shortly have a chance to get acquainted with mephedrone, a.k.a. Drone, MCAT, 4-methylmethcathinone (4-MMC), and Meow Meow--the latter nickname presumably in honor of its membership in the cathinone family, making it chemically similar in some ways to amphetamine and ephedrine. But its users often refer to effects more commonly associated with Ecstasy (MDMA), both the good (euphoria, empathy, talkativeness) and the bad (blood pressure spikes, delusions, drastic changes in body temperature).

Some of the best stateside coverage has come from the anonymous NIH researcher who blogs on science topics as DrugMonkey. The whole business of what mephedrone does is complicated, he writes. The cathinone structure is “very similar to amphetamine and supports parallel modifications,” but there is clearly an “MDMA-like component to this mephedrone stuff.” (See additional DrugMonkey coverage here  and here.)

Until earlier this year, mephedrone was in that weird state of limbo LSD found itself occupying in the mid-1960s: legal, but not for long. States are attempting to sweep synthetic drugs of abuse like Spice and other cannabinioid derivatives into a proscribed package that includes mephedrone.  Federal authorities are able to prosecute under The Analogue Drug Act of 1986, which was designed to combat this dilemma in the United States by outlawing drugs “substantially similar” to any drug that is already illegal. However, “chemical experts disagree on whether a chemical is 'substantially similar' in structure to another chemical—so much so that Federal Analogue Act litigation often degenerates into a 'battle of experts,' which is founded more on opinion than on actual scientific evidence,” writes Gregory Kau in an article for the University of Pennsylvania Law Review.

It is clear by now that this cat-and-mouse game is rigged in favor of the designers and suppliers of new drugs under the sun. Exploiting the gray zone of quasi-legality is extremely profitable. One outlaw chemist told Jeanne Whalen of the Wall Street Journal that by the time law enforcement closes in, “we are going to bring out something else.” At which point, prosecutorial mechanisms put in place for mephedrone must be laboriously recreated for the new drug.

This drug entrepreneur, and others like him, makes extensive use of the Internet, especially in Europe, since mephedrone is not universally banned. To keep the business technically legal, sellers label mephedrone “not for human consumption” and market it as anything from plant food to bath salts.  Sometimes they draw unwanted attention to themselves through the purchase of lab equipment, like the rotary evaporator pictured above. 

Mephedrone has lately been covered relentlessly by the British press, after the deaths of three young people in the U.K. and Sweden were attributed to mephedrone. Part of the difficulty in assessing the danger and addictiveness, if any, of these newer substances is that most of them have not been subjected to controlled clinical testing on humans. (One hardy purveyor of mephedrone snorted half a gram of the drug on a Belgian news program to demonstrate his side of the argument.)

Media hysteria in the U.K. led to reports of dozens of deaths due to mephedrone, none of which have thus far proven to be indisputably the result of ingesting mephedrone. As British politicians rushed to enact a ban, Danny Kushlick of the drug charity Transform told the U.K. Guardian in April: “The misreporting of mephedrone deaths is a crass example of the potentially lethal alliance between press and politicians that by default ends in a ban that often creates far greater harms than those caused by use.”  In July, BBC News reported that the mephedrone crackdown was “floundering”, even though the ban had been widened to included a near-beer version of mephedrone called Naphyrone (sold as NRG1). But a spokesperson for Lifeline, another British drug charity, argued that “you can’t just ban your way out of a problem because it could result in far more dangerous chemicals coming onto the market.” According to the European Monitoring Centre for Drugs and Drug Addiction, which operates the EU early-warning system on new drugs in cooperation with Europol,  “24 new psychoactive substances were officially notified for the first time to the two agencies in 2009.”

The National Drug Intelligence Center at the U.S. Department of Justice reported that early in the year, “several individuals in the Bismarck [North Dakota] area ingested or injected illicit products containing mephedrone and required hospitalization. In addition, the Oregon State Police Forensic Laboratory (Bend, Oregon) received two submission of white power that users referred to as ‘sunshine.’ Both submissions tested as mephedrone.”

And now comes a report from North Carolina of two fatalities allegedly linked to the use of mephedrone, as reported by David Kroll at Terra Sigillata.

Narcotics officials and toxicologists say that the raw materials for many of the new drugs appear to be manufactured in China and trans-shipped to other countries in Southeast Asia and the Middle East. DrugMonkey also notes that it will be interesting to see “if actions such as Cambodia, Vietnam, and Thailand finally getting serious about controlling the production of the safrole oil used as a precursor in MDMA manufacture is having a lasting effect on world markets.”

Photo Credit: http://www.ipfw.edu/

Tracking Synthetic Highs

UN office monitors designer drug trade.

Produced by the United Nations Office on Drugs and Crime (UNODC), the Global SMART Update  (PDF) for October provides interim reports of emerging trends in synthetic drug use. The report does not concern itself with cocaine, heroin, marijuana, alcohol, or tobacco. “Unlike plant-based drugs,” says the report, “synthetic drugs are quickly evolving with new designer drugs appearing on the market each year.” The update deals primarily with amphetamine-type stimulants, but also includes newer designer drugs such as mephedrone, atypical synthetics like ketamine, synthetic opioids like fentanyl, and old standbys like LSD.

I have summarized some of the findings below:

The first methamphetamine lab in 15 years has been discovered in Japan. Japanese law enforcement seized a suspected residential methamphetamine laboratory outside of Tokyo, the first such seizure since 1995. Two Iranian nationals were arrested. Given the continuously high price of imported crystalline methamphetamine in Japan, there is an increased likelihood that more domestic manufacturers could emerge.

Record ketamine seizures and use has been reported by Taiwan province of China. The FDA reports that ketamine seizures in the first five months of 2010 alone totaled 1465 KG, nearly 300 KG more than last year. Concurrent increases in use were also noted.

The first methamphetamine laboratory in Turkey was discovered. Local media reported the seizure of the lab, in the southern part of the country. The facility reportedly planned to manufacture 100,000 tablets for retail sale at USD 13.40 apiece. In 2009, Turkey reported its first seizures of methamphetamine totaling 103 KG at Istanbul’s airport, which has become a transit point for methamphetamine traffic from Iran to markets in East Asia.

Law enforcement faces unique challenges when dealing with synthetic drug analogs. Customs officers at Prague’s Ruzyne airport reported arresting a Polish national for transporting a substance initially testing positive for ephedrone, a controlled synthetic stimulant. Confirmatory tests, however, revealed the substance to be mephedrone, an analogue not under international control. The event illustrates the challenges law enforcement face when encountering new synthetic substances not under national or international control.

Amphetamine breathalyzer tests may soon be possible, say Swedish researchers. The June issue of the Journal of Analytical Toxicology report reported that the first breath test for methamphetamine and amphetamine detection was successfully conducted in Sweden. Drugs in the exhaled breath are captured in a filter and analyzed using a combination of liquid chromatography and mass spectrometry. Experimental trials on amphetamine-dependent patients admitted to hospital urgency rooms for overdose provided the same results as traditional drug tests.

The U.S. is expanding controls on precursor chemicals for fentanyl and LSD. The Drug Enforcement Administration (DEA) has designated a compound called ANPP as a precursor chemical for fentanyl, an extremely potent synthetic analgesic. Earlier this year, the DEA proposed new controls over ergocristine, a chemical precursor sometimes used in the manufacture of LSD. Clandestine laboratories in the United States employ it as a substitute for ergotamine and ergometrine, both of which are already under international control.

The U.S. indicts 15 people in one of the largest MDMA busts ever. The U.S. Department of Justice announced that a federal grand jury indicted 15 men linked to one of the country's largest ecstasy manufacturing and trafficking rings. Two storage facilities were also seized during the investigation, yielding about 710,000 MDMA tablets. Law enforcement authorities seized more than 1.1 million tablets in all. Authorities believe that the group had been responsible for the distribution of hundreds of thousands of MDMA tablets each month.

Belize stops large shipments of methamphetamine precursors bound for Mexico. Customs authorities in Belize reportedly stopped two large shipments of phenylacetic acid (PAA), or roughly 46 metric tons. Phenylacetic acid can be used in the manufacture of methamphetamine. Reports suggest the chemical came from China and was ultimately destined for Mexico.

Graphics Credit: http://www.unodc.org/