Update on Synthetic Drug Surprises

Spicier than ever.

Four drug deaths last month in Britain have been blamed on so-called “Superman” pills being sold as Ecstasy, but actually containing PMMA, a synthetic stimulant drug with some MDMA-like effects that has been implicated in a number of deaths and hospitalizations in Europe and the U.S. The “fake Ecstasy” was also under suspicion in the September deaths of six people in Florida and another three in Chicago. An additional six deaths in Ireland have also been linked to the drug. (See Drugs.ie for more details.)

PMMA, or paramethoxymethamphetamine, causes dangerous increases in body temperature and blood pressure, is toxic at lower doses than Ecstasy, and requires up to two hours in order to take effect.

In other words, very nearly the perfect overdose drug.

Whether you call them “emerging drugs of misuse,” or “new psychoactive substances,” these synthetic highs have not gone away, and aren’t likely to. As Italian researchers have noted, “The web plays a major role in shaping this unregulated market, with users being attracted by these substances due to both their intense psychoactive effects and likely lack of detection in routine drug screenings.” Even more troubling is the fact that many of the novel compounds turning up as recreational drugs have been abandoned by legitimate chemists because of toxicity or addiction issues.

The Spice products—synthetic cannabinoids—are still the most common of the novel synthetic drugs. Hundreds of variants are now on the market. Science magazine recently reported on a UK study in which researchers discovered more than a dozen previously unknown psychoactive substances by conducting urine samples on portable toilets in Greater London. Call the mixture Spice, K2, Incense, Yucatan Fire, Black Mamba, or any other catchy, edgy name, and chances are, some kids will take it, both for the reported kick, and for the undetectability. According to NIDA, one out of nine U.S. 12th graders had used a synthetic cannabinoid product during the prior year.

“Laws just push forward the list of compounds,” Dr. Duccio Papanti, a psychiatrist at the University of Trieste who studies the new drugs, said in an interview for this article. “The market is very chaotic, bulk purchasing of pure compounds are cheaply available from China, India, Hong-Kong, but small labs are rising in Western Countries, too. Some authors point out that newer compounds are more related to harms (intoxications and deaths) than the older ones. You can clearly see from formulas that newer compounds are different from the first ones: new constituents are added, and there are structural changes, so although we have some clues about the metabolism of older, better studied compounds, we don't know anything about the newer (and currently used) ones."

The problems with synthetic cannabinoids often begin with headaches, vomiting, and hallucinations. At the Department of Medical, Surgical, and Health Sciences at the University of Trieste, researchers Samuele Naviglio, Duccio Papanti, Valentina Moressa, and Alessandro Ventura characterized the typical ER patient on synthetic cannabinoids, in a BMJ article: “On arrival at the emergency department he was conscious but drowsy and slow in answering simple questions. He reported frontal headache (8/10 on a visual analogue scale) and photophobia, and he was unable to stand unassisted. He was afebrile, his heart rate was 170 beats/min, and his blood pressure was 132/80 mm Hg.”

According to the BMJ paper, the most commonly reported adverse symptoms include: "Confusion, agitation, irritability, drowsiness, tachycardia, hypertension, diaphoresis [sweating], mydriasis [excessive pupil dilation], and hallucinations. Other neurological and psychiatric effects include seizures, suicidal ideation, aggressive behavior, and psychosis. Ischemic stroke has also been reported. Gastrointestinal toxicity may cause xerostomia [dry mouth], nausea, and vomiting. Severe cardiotoxic effects have been described, including myocardial infarction…”

In a recent article (PDF) for World Psychiatry, Papanti and a group of other associates revealed additional features of synthetic cannabimemetics (SC), as they are officially known: “For example, inhibition of γ-aminobutyric acid receptors may cause anxiety, agitation, and seizures, whereas the activation of serotonin receptors and the inhibition of monoamine oxidases may be responsible for hallucinations and the occurrence of serotonin syndrome-like signs and symptoms.”

Papanti says researchers are also seeing more fluorinated drugs. “Fluorination is the incorporation of fluorine into a drug,” he says, one effect of which is “modulating the metabolism and increasing the lipophilicity, and enhancing absorption into biological membranes, including the blood-brain barrier, so that a drug is available at higher concentrations. An increasing number of fluorinated synthetic cannabinoids are available, and fluorinated cathinones are available, too.”

A primary problem is that physicians are still largely unacquainted with these chemicals, several years after their current popularity began. This is entirely understandable. In addition to the synthetic cathinones, several new mind-altering substances based on compounds discovered decades ago have also surfaced lately. Papanti provided a partial list of additional compounds that have led to official concern in the EU:

—Synthetic opioids (the best known are AH-7921, MT-45)

—Synthetic stimulants (the best known are MDPV, 4,4'-DMAR)

—New synthetic psychedelics (the NBOMe series)

—New dissociatives (Methoxetamine, Methoxphenidine, Diphenidine)

—New performance enhancing drugs (Melanotan, DNP)

—Gaba agonists (Phenibut, new benzodiazepines)

Most of the new and next-generation synthetics are not readily detected by standard drug screen processes. Spice drugs will not usually show up on anything but the most advanced test screening, using gas chromatography or liquid chromatography-tandem mass spectrometry—high tech tools which are rarely available for anything but serious (and costly) forensic investigations.

“Testing is a big problem,” Papanti declares. “From a clinical point of view, do you need the test to make a diagnosis of intoxication, for following up an addiction treatment, or for forensic purposes? With the new drugs, maybe taken together, with different pharmacology, we are not very sure about this yet. If I want to have confirmation of a diagnosis of SC intoxication, I need two weeks as an average, in order to obtain the result. Your patient has been discharged by that time, or in the worse case, he is dead.”

 Another major problem, according to Papanti, “is that the machines need sample libraries in order to recognize the compound, and samples mean money. Plus, they need to be continuously updated.”

In summary, there is no antidote to these drugs, but intoxication is general less than 24 hours, and the indicated medical management is primarily supportive. If you plan to take a drug marketed as Ecstasy, or indeed any of the spice or bath salt compounds, Drugs.ie notes that there are some basic rules of conduct that will help maximize the odds of a safe trip:

—If you don’t “come up” as quickly as anticipated, don’t assume you need another pill. PMMA can take two hours or more to take effect. Do not “double drop.”

—If you don’t feel like you expected to feel, and are noticing a “pins-and-needles” feeling or numbness in the limbs, consider the possibility that another drug is involved.

—Don’t mix reputed Ecstasy with other drugs, especially alcohol, as PMMA reacts very dangerously with excessive alcohol.

—Remember to hydrate, but don’t overhydrate. If you go dancing, figure on about a pint per hour.

The Media and Drug Policy: Where’s the Science?

Groping blindly toward a new framework.

As states and the federal government clash at the legal, social, and political levels over legalizing marijuana, the science of drugs and addiction has taken a back seat. The dismal state of the addiction treatment business has recently been documented by Anne M. Fletcher in Inside Rehab, while over the past few years, drug policy officials in the U.S. have had to cope with three major developments: the medicalization and legalization of marijuana, the emergence of new synthetic drugs, and the abuse of potent prescription painkillers.

Major media outlets have largely failed to highlight the relevant scientific issues in each case. What we see instead is that journalists and others who are covering drugs and addiction issues are not making connections with solid scientific sources in the neurochemical research community. All too often, media reports of adverse drug events are sourced solely by police officers, or spokespersons on behalf of for-profit rehab centers, who are no more ready to make science-based pronouncements on these matters than anyone else.

States are now in the process of relaxing strictures on the possession and use of cannabis—and they are doing it well before they have put in place a set of evidence-based policies for the implementation of this new state of affairs. Who is in charge of directing policy decisions in Washington and Colorado? What will be the regulatory structure at the level of county and municipal government? Whose voices will actually be heard? Should the feds leave it to the states, and the states leave it to the counties, who then leave it to the cities? To what degree are the two states taking the medical and health aspects of this sweeping change into account? Can evidence be substituted for opinion in such cases? If so, how?

Even if the Department of Justice decides to shut down all efforts at relaxing marijuana statutes, it will need to rely upon a sound collection of scientific evidence to make its argument. The media play a compelling role in drug discussions, but coverage traditionally has been limited to articles about the legal, political, and sociocultural ramifications of the changes. These are all critical parts of the story, but science journalists need to step forward and direct more coverage toward emerging medical issues and the findings of science. Ordinary citizens will want to have at least a partial grasp of the medical and science-based decisions that state and federal governments will be making about personal health and habits as they legislate and adjudicate these concerns.

The federal government will have to begin working with states rather than against them, if public opinion continues to change on legalization issues. At the same time, the feds will be called upon to provide guidance for the states that is consistent with international drug treaties. Congressional committees will have to grapple with the realities of setting forth the limits and logistics of the market for marijuana in coherent and consistent ways. Incredibly, very little of this is pinned down, firmly understood, or even grasped as imminent problems by either legalizers or their opponents. Many of the issues that took years to wrestle down with cigarettes, such as warning labels on cigarette packages, will present themselves with equal and immediate force in the case of states with legalization plans.

In addition, marijuana policy makers in Colorado and Washington will have to render decisions concerning sales to minors, cannabis in the workplace, DUI marijuana laws, addiction issues, sales outlets, tax issues, and the results of ongoing medical research on marijuana. Some states allow private dispensaries, some have banned them. Some allow private cultivation of cannabis, and some do not. 

As for the newer synthetic drugs—the cannabis-like products known as Spice, and designer stimulant drugs known collectively as “bath salts”— these chemicals exist in a twilight zone of ignorance, with very little sound medical information passing to the public. Few people understand with any degree of certainty just what is inside those shiny foil packages. This glaring disconnect between clinical research and media reports leads to unsupported tales of face-eating zombies and dead teenagers on bath salts, well in advance of the drug testing that might factually answer questions about drug-related behavior. Meanwhile, scientists fear that the continuing effort to ban every substance illegally marketed in this category will close off certain valuable avenues of research, including new drug discovery.

Finally, the ongoing battle to lower the soaring use and abuse of oxycontin, Vicodin, and other opiate drugs has caused problems for legitimate pain patients across the country. Yet this medical aspect of the painkiller panic is rarely remarked upon. Some addiction researchers believe that as prescription painkillers are removed from the market or made more difficult to abuse, those with opiate addictions will migrate to heroin in greater numbers. Scientific research on addiction suggests that this may well be the case. 

What is missing specifically from most drug policy debates is the recognition of the vast metabolic variation among individuals. Different drugs affect different people differently, and for the first time, neuroscientists are building a solid body of information that could help policy makers better forecast the results of their actions. Lethality, side effects, tolerance, and susceptibility to addiction all vary widely due to metabolic differences among people.

But some shared reactions, and basic withdrawal parameters, do exist. Congress, the FDA, NIDA, as well as state health agencies and other regulatory bodies, need information about drugs and drug use that scientists have been busily compiling. The public needs this information, too. We need to search for ways media can more effectively inject science-based drug information into current policy debates. 

Science journalists are perfectly situated to serve as potential communicators between warring parties. What can the media do to markedly enhance intelligent, science-based coverage of drug issues?

Photo: Telstar Logistics

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 the College on Problems of Drug Dependence

CPDD holds annual meeting.

I’ll be out of the office for a few days, attending the annual meeting of the College on Problems of Drug Dependence (CPDD), the oldest group in the United States dedicated to addressing problems of drug addiction. The organization functions as an independent body, and is affiliated with other scientific and professional societies involved in the study of drug dependence and abuse. The meeting dovetails with the 2012 NIDA International Forum. A broad selection of the nation’s top drug and addiction researchers will be there, along with Nora Volkow, Director of the National Institute of Drug Abuse (NIDA), and Drug Czar Gil Kerlikowske, director of the Office of National Drug Control Policy.

 I’m pleased to be the recipient of the organization’s 2012 CPDD/NIDA Media Award, which is given each year for “contributions through the media that have enhanced the public understanding of scientific issues concerning drug use disorders.” That’s pretty nice of them, and you can find an interview I did for their CPDD blog HERE.

While in attendance, your faithful correspondent will be attending what looks to be a massively interesting panel discussion called “A Stimulating Soak in “Bath Salts”: Investigating Cathinone Derivative Drugs.” Look for a blog post on that one.

I’m also planning to attend a symposium on “Exercise as a Treatment for Drug Dependence in Humans,” and plan to report back on that topic as well.

“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  

Bath Salts, Graphically

What you need to know about mephedrone.

The Pat Moore Foundation has put together this nifty chart as a primer on mephedrone, the amphetamine-type stimulant marketed as "bath salts." Thanks PMF! 

 Created by Pat Moore Foundation

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