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 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/

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/