Tuesday, June 26, 2012

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 ResearchBlogging.orgAdministration. 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


Anonymous said...

GLARING problem here: Shulgin did not "invent" MDMA. He certainly did massive PR work for it (and the analogues) but he is in no way an inventor of it.

Dirk Hanson said...

You're right. The word I meant to use was "popularize." MDMA was first synthesized in 1912.

mb said...

Shulgin is also yet 'late'.

Dirk Hanson said...

I certainly did Shulgin no favors in the copy editing. Born in 1925. 87 years young.

Dirk Hanson said...

I have corrected these errors of fact in the post 6-26-12.

Anonymous said...

Come on man.....violent thoughts ?? The LAST thing going through my head was harming a fly....

Anonymous said...

Come on man.....violent thoughts ?? The LAST thing going through my head was harming a fly....

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