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

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)

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