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.

The 2011 Global ATS Assessment estimates that in 2009, some 14 to 57 million people aged 15-64 took an amphetamine-type substance during the year.  The category includes methamphetamine, synthetic stimulants known as bath salts, and Ecstasy. For ecstasy, which is grouped with the ATS family because of its speed-like qualities, “global annual prevalence” stood at only 11-28 million past-year users in 2009, basically unchanged.  Not so for the use of the new synthetic methamphetamines—compounds such as mephedrone, 4-methylmethcathinone (4-MMC) and MDPV, which first took off in the UK, Canada, and New Zealand. In fact, bath salts in the form of mephedrone are competing with ecstasy as the club drug of the moment. (Ecstasy seizures are currently at a 5-year high in the United States, so the window for alternatives is currently wide open.) Meanwhile, recorded worldwide use of heroin, cocaine, and marijuana remained essentially steady from 2005 to 2009.

So what’s behind the global surge in production of amphetamine-type drugs? What advantages do these stimulants hold over time-tested drugs like heroin and coke?  And why is it happening now?

                                                      Emerging Markets

The seismic changes in worldwide drug production begin with geography. Amphetamine-type stimulants are spreading to new regions, and are now being manufactured in places previously off the radar—Iran, Malaysia, and West Africa, for starters. The UNODC report notes that synthetic stimulants “offer criminals a new entry into unexploited and fresh markets.” The locus of activity is no longer the opium fields of Afghanistan, or the coca plantations of Columbia. In absolute numbers, the report claims, “most ATS users live in Southeast Asia, the most populous subregion the world.”

The growing number of methamphetamine pills seized in Southeast Asia is staggering: “The 93.3 million methamphetamine pills seized in 2009 in China, Lao People’s Democratic Republic, Myanmar and Thailand represent a three-fold increase in comparison with 2008 figures,” the UN report alleges. “In 2010, total seizures surpassed 133 million pills.” Not since the Japanese amphetamine scourge of the post-World War II years has East Asia seen anything like this.

 The UN report singles out two new countries—Lao People’s Democratic Republic, and Malaysia—as nations reporting, for the first time, “the injecting use of crystalline methamphetamine in 2008 and 2009.” And a massive increase in production has been documented in northern Burma. Voice of America News reports that amphetamine-type drug seizures in Burma went from one million pills in 2008 to a mind-blowing 23 million pills a year later.

A regional representative for the UNODC in East Asia said that the seizures “reflect a dramatic increase in production in the Shan State” in Northern Burma. The production of methamphetamine is a primary source of income for the Shan, whose territory is near the borders of China and Thailand. “What we are worried about,” said the UNODC rep, “is the nexus of drugs, of weapons, of money that is moving around that region at a time when elections are pending and the political situation is quite fragile.” At the same time, Burma remains a major supplier of opiates, though competition with Afghanistan may have helped encourage the production of illegal stimulants. UNODC Executive Director Yury Fedotove explained that the market for synthetic stimulants “has evolved from a cottage-type industry typified by small-scale manufacturing operations to more of a cocaine or heroin-type market with a higher level of integration and organized crime groups involved throughout the production and supply chain.“

                                                    Homegrown vs. Manmade

Amphetamines, in all their synthetic forms, have several production advantages over plant-based addictive drugs like heroin and cocaine. In recent years, the U.S. and other countries have cracked down on amphetamine precursor drugs like ephedrine and pseudoephedrine. Once these tried and true compounds for amphetamine manufacture—found in cold and allergy medications—were registered and controlled, traffickers made the switch to different chemical approaches. New building blocks like phelylacetic acid and l-phenylacetylcarbinol (l-PAC) have been found in labs from Canada to Mexico. Growers of opium and coca have no such alternatives available to them. Pharmacologist David Kroll, Professor and Chair of Pharmaceutical Science at North Carolina Central University in Durham, who has been following the new synthetic drug products on his blog, Terra Sigillata, said that ome of the latest precursors have a problematic history. “Phenylacetate and phelylacetic acid have been investigated in clinical trials for cancer and in the treatment of sickle cell disease,” said Dr. Kroll. “But they didn’t fare well in large clinical trails because they required such high doses, and patients had side effects.”

While this is definitely not a reliable class of compounds from which to fashion new recreational stimulants, Dr. Kroll noted that rendering synthetic drugs illegal can sometimes play havoc with efforts to develop the same drugs for therapeutic purposes. “If these precursors become more strictly regulated, there might be an untoward effect on the prices of other drugs” that use the same compound as a building block, he said.

                                                               New Players

Drug lab seizures in Jordan, Syria, and the United Arab Emirates have also reached new highs—particularly the clandestine manufacture of a form of amphetamine called phenethylline, marketed under the brand name Captagon. Very little in the way of equipment or startup capital is required, which facilitates new players in this market. Captagon, said Dr. Kroll, “makes pretty good sense. The body can metabolize it to amphetamine itself—it’s an amphetamine pro-drug. The other metabolite of the drug is theophylline, the old asthma drug that also acts as a mild stimulant. But it’s potentially as dangerous as amphetamine, depending on how efficient one’s metabolism is.” This is, of course, a huge problem: One bath salts user might have an acceptable drug experience, while another might find that a few whiffs of the same synthetic stimulant will land him or her in the emergency room, with a dangerously elevated heart rate or other complications.

What drug designers, drug manufacturers, and drug suppliers have come to realize is that methamphetamine and other ATS drugs appear to fill the lifestyle void left by the uncertain supply and pricing situation associated with cocaine. Everywhere they land, synthetic stimulants—from biker crank to mephedrone—wreak instant havoc. They simply are not predictable compounds. One bath salts user compared the experience to “a shot of methamphetamine with a PCP chaser." From any kind of rational sociocultural point of view, these are not safe drugs. And it hardly needs repeating that they are highly addictive for many people. The legalization of amphetamine is not a cause likely to gain much momentum any time soon.

Even though the United States has a long history of dealing with amphetamine, this is manifestly not true of every country in the world. And now these untapped markets are fair game for cheaper, longer lasting amphetamine-type stimulants, which “seem to appeal to the needs of today’s societies and have become part of what is perceived to be a modern and dynamic lifestyle,” according to the UNODC report.

We don’t know with complete certainty that the drug data coming out of several key areas—Southeast Asia, Africa, and the Middle East in particular—is accurate. Authorities have captured and dismantled ATS labs in Central and South America as well. In all likelihood, drug production and use in all these regions is underreported. The UNODC document laments that “household and other surveys are lacking or are outdated in some countries in several of the most affected regions.” This is a particular problem in China and India, where no serious national survey of amphetamine-type stimulants has ever been undertaken.

We have a long way to go before we know the outcome of the current craze for synthetic stimulants. The historical wreckage caused by injected methedrine in the 60s and 70s, and smokable ice in the 90s and the aughts, is a grisly matter of public record. Now we are confronted with a baffling cornucopia of designer concoctions whose track record for safe recreation is, thus far, not so good. Amphetamine drugs have sent thousands to their deaths, and countless others to the emergency rooms. And now this deadly deck of stimulants has many more cards in it than it did just a few years ago. Pick a card, any card. First one’s free.

Photo Credit: http://teens.drugabuse.gov/

Drugs for Cocaine Addiction

Researchers target GABA, noradrenaline.

According to Catalyst Pharmaceutical Partners, a company conducting research on drugs for the treatment of addiction, "The U.S. Food and Drug Administration has recognized that cocaine addiction is a 'serious, life-threatening condition for which there is no current drug treatment,' and the National Institute on Drug Abuse (NIDA) has stated that finding a pharmacological treatment for cocaine addiction is their number one research priority."

Other researchers view it differently, however. Allan Parry, a drug counsellor in Liverpool, U.K., told New Scientist that such work was "only likely to be relevant to a tiny minority of people. People often give up cocaine because their lifestyle changes or they just grow up."

Fighting fire with fire--using drugs to treat drug addiction--will likely remain a controversial approach for years to come.

What is the rationale for the use of drugs in the treatment of drug addiction? There are two basic approaches. Scientists look for medications that help patients initiate abstinence, and they look for drugs that help prevent relapse once the patient has achieved abstinence. The categories are not hard and fast. For example, a drug that effective reduces the reinforcing effects of cocaine by reducing the intensity of withdrawal can theoretically perform both functions at once. On the other hand, a drug that blunts the euphoric effects of cocaine--a drug that takes away the best of the buzz, no matter how much cocaine is ingested--can also succeed at the twin tasks of abstinence initiation and relapse prevention.

The search for medications with which to treat cocaine addiction has been in progress much longer than equivalent efforts aimed at methamphetamine addiction. One research target of long standing is modafinil, an odd-duck drug sold as Provigil for the treatment of narcolepsy. A mild stimulant, modafinil does a little bit of everything, pharmacologically tweaking dopamine, noradrenaline, anandamide and GABA receptor systems. Perhaps for this reason, the drug seemingly has been tried for almost everything, from Alzheimer's to atypical depression to jet lag. The U.S. military has reportedly shown some interest in it.

According to published research by Kyle M. Kampman in the June 2008 Addiction Science and Clinical Practice (PDF), modafinil-treated human subjects used less cocaine than placebo-using counterparts did in several recent small-scale studies. "In a double blind pilot trial with 62 cocaine-dependent patients, those who received modafinil submitted more cocaine-metabolite-free urine samples than placebo-treated patients (42 vs. 22 percent; Dackis et al., 2005)."

Propranolol, better known as the beta-blocker Inderal, works primarily by suppressing adrenaline and noradrenaline levels. In human studies to date, propranolol has shown itself most effective with the most severely cocaine-addicted patients. Studies by Kampman have shown that propanolol-treated patients stay in treatment longer than patients in control groups do.

Specific research on relapse prevention strategies has focused on GABA-enhancing drugs that inhibit cocaine reinforcement by secondarily blocking the dopamine surge characteristic of cocaine intoxication. In addition to vigabatrin, discussed in the previous post, topiramate is another particularly well-suited candidate for relapse prevention. Known as Topamax, and prescribed for seizures and migraines, the drug has shown early promise: "In a 13-week, double-blind, placebo-controlled pilot trial of topiramate involving 40 cocaine-dependent patients.... more of those on topiramate achieved at least 3 weeks of continuous abstinence (59 vs. 26 percent)."

Surprisingly, the granddaddy of all anti-addiction drugs--Antabuse--has made a comeback as a subject of study for cocaine addiction, even though it has never been spectacularly effective in its original application as a relapse prevention drug for alcoholics. Disulfiram, as it is known chemically, causes unpleasant physical sensations, including vomiting, when combined with even small amounts of alcohol. It does so by inhibiting the enzymes responsible for degrading alcohol. Even a little becomes too much. In similar fashion, disulfiram retards the breakdown of cocaine, leading to extremely high levels that induce paranoia and anxiety rather than a pleasurable, if extreme, high. At least four published trials have demonstrated reduced cocaine use in disulfiram-treated patients, according to Kampman's paper . One important downside to using Antabuse for cocaine addiction is that serious complications might occur if alcohol is added to the mix.

Finally, and still well into the future, is the prospect of relapse prevention therapy by means of a vaccine--an entirely different mechanism of approach. Research has shown that it is possible to produce "cocaine-specific antibodies that bind to cocaine molecules and prevent them from crossing the blood-brain barrier, thereby blunting the drug's euphoric and reinforcing effects," Kampman's paper asserts. A vaccine called TA-CD has tested well in preliminary studies.