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/

Drug Addiction in 10 Slides or Less

Dr. David Friedman explains it all.

Dr. David Friedman, a professor of physiology and pharmacology at Wake Forest University School of Medicine, is also the co-founder and director of the Addiction Studies Program, a workshop for science journalists in Washington, D. C., funded by the National Institute on Drug Abuse (NIDA).

Sometimes it helps to step back and attempt to make the scientific case for addictive disorders as simply as we are able. Herewith, some highlights from Dr. Friedman’s useful presentation at the recent Addiction Studies Program workshop. Slides reproduced with Dr. Friedman’s kind permission. The comments adjacent to the slides are my own, as are any errors of fact or interpretation.

 There are important distinctions to be made between drug abuse and drug addiction, as Dr. Friedman makes clear in the slide to the right and the slide below. Unfortunately, government agencies have tended to take the position that any drug use is ipso facto drug abuse; a political position not well supported by the relevant science

  As a chronic medical condition, or “brain disorder,” addiction has a fair amount in common with other diseases, like hypertension, asthmas and diabetes, Friedman said. Relapses and setbacks are frequent, but not found in every case. 

  The key questions, indeed: What is different about the brains or the genes or the nerve cells of those who become dangerously addicted, compared to those who can take it or leave it? Scientists have discovered various so-called “markers” over the years in the brains of the children of adult alcoholics, but none of these have been broad enough in scope to point toward anything like an effective near-term treatment. However, the recent shift from chasing genes to studying neurobiological brain processes is a hopeful turn of events.

Again, a crucial distinction must be made between a state of physical dependence (at right) and a state of withdrawal (below). Non-addicts can become physical dependent on a variety of prescription medications. Such physical dependence precedes a full-blown state of addiction, but is not to be confused with addiction itself.

 The symptoms and intensity of drug withdrawal can vary from horrifying to essentially non-existent. It depends upon the drug, the drug taker’s metabolism, the social setting, environment and expectations of the users, etc. Craving and withdrawal represent the basic mechanism responsible for relapse.

 Most people are familiar with the “rebound effect” sometimes produced by over-the-counter nose sprays. Whey you inhale these medications regularly enough, the result of going turkey is… a profoundly stuffed-up nose.

In an effort to expand on the “chronic disease of the brain” label affixed by former NIDA director Alan Leshner, Dr.Friedman directs our attention toward specific brain mechanisms: reward, motivation, and memory.

Addiction is a pediatric disorder, Friedman emphasizes. This is particularly true with marijuana abuse and addiction.  Lke sugar in your blood, you can choose to control the amount of drugs you take, but you cannot choose your reaction to them.

We know for certain these days that adolescent brains are not yet fully formed, and that adolescent brains react to drugs differently than adult brains. For example, recent studies show that the actual composition of adult nicotine receptors in the brain is affected by exposure to nicotine in adolescence.

The net result of all this? Things happen at the biochemical level that change how things play out at the behavioral level.







Photo Credit: http://www.wakehealth.edu/

The Empty Seat at the Holiday Table

Mothers and the War on Drugs.

Guest post by Gretchen Burns Bergman

Gretchen Burns Bergman is Co-Founder and Executive Director of A New PATH (Parents for Addiction Treatment and Healing) and lead organizer of Moms United to End the War on Drugs.

The Holiday season is upon us. At this time, when the weather turns chilly and we move indoors to enjoy the warmth and safety of our homes and the closeness of family and friends, I am acutely aware of those not so fortunate: people who are out in the elements, either because of dire financial situations or mental and addictive illness.

The Holidays are particularly difficult for those who must navigate the mighty and destructive waves of addiction. It is a painful time for families who are separated because of a loved one’s incarceration, whose young person is lost on the streets due to drug problems, whose children are in danger because of the violence of the drug cartels, or those who have lost a loved one to overdose. Often a family member is missing from the festivities because of stigma and shame.

I don’t remember when I started dreading Thanksgiving. It wasn’t after my father or my nephew died, because they were remembered and celebrated at the table, or even after the breakup of my first marriage. It was all of the times that my older son was absent because he was locked behind bars in that cold, concrete jungle, and I couldn’t figure out where I belonged – with him to somehow nurture and sustain him, or in the bosom of the rest of my family. It is the memories of holidays when one of my sons wasn’t included because he was lost in the maze of his addiction, and his name wasn’t even mentioned because of pain, discomfort, and even judgment. Those omissions widened the hole in my heart.

I weep for the countless families who have been torn apart by discriminatory and destructive drug policies that lock up fathers and remove children from their mothers in the name of the war on drugs, which is really a war waged against families and communities.

This season, mothers are banding together and speaking out with human stories of injustice and devastation, to encourage other mothers to join our voices for change. Moms United to End the War on Drugs is a national movement to end the violence, mass incarceration and accidental overdose deaths that are result of these blundering punitive policies. At a time when 2.3 million people are incarcerated in the United States and overdose is a leading cause of accidental death, mothers must lead the way in demanding harm reduction strategies, health-oriented solutions, and restorative justice.

The following are stories written by mothers who have experienced the ravages of the war on drugs, and who honor that empty seat at the holiday table:

The missing seat at the prison visiting table.

It was Thanksgiving and my family and I drove 4 hrs to visit my young son in his California prison for the holiday. He was serving time for drug possession, celled with a murderer, in one of the state’s highest security prisons, so “processing time” including prison official dysfunction, near total disrobing, endless questioning, metal detectors, sally-ports, and guard escorts, took about 4 hours to complete before we got to the highly secure visiting room. Because of this time consuming process, there was only 45 minutes left to visit. On the other side, my inmate son was being strip searched and waiting in a line moving at glacial speed to enter the visiting area. I cried to the guard that, as time ticked by, I was being left with five minutes to see my son for Thanksgiving…but I wanted those five minutes. He waited in his sally-port on the other side, while we all waited at our assigned table for that precious few minutes with my son. That seat remained empty. Alerts sounded that visiting was over.

--Julia Negron, A New PATH Los Angeles, California

Until this war ends, an extra place at my table.

During the holidays, we reflect as we prepare meals, set our tables, and decorate our homes. As I begin planning, with my daughter and husband’s help, I think back to the time when I was addicted to heroin, and missing from my family’s holiday table. Though it was more than 20 years ago, my family experienced extreme grief over my addiction. My father tells me that he is so grateful that I am alive. He didn’t know, in the midst of my homelessness, whether I’d ever be able to attend, let alone host, a Thanksgiving with my own family. I think how lucky I am, because I had the opportunity to get treatment that worked for me. I know someone waited and despaired over me. Now, I wait for those with substance use disorders to be served by our health care system rather than languishing in prison. Until that wait is over, there will always be an extra place setting at my holiday table for those who are locked up, thrown away or left out. The person in prison for a drug crime might not be able to eat with me this year, but perhaps next year, they will.

--Kathie Kane-Willis, Illinois Consortium on Drug Policy, Roosevelt University

Emptiness is everywhere.

Since our son was born, we always picked out the Christmas tree together. It became a tradition and one of the fun parts of the holiday rush. Dad would put the lights on the tree and make clam chowder, while Jeff and I did the ornaments. As years passed, it was sometimes difficult for us all to be together for this tradition, but we were. Our son had addictive illness, and through the many rehabs, the short county incarcerations, the times where he’d isolate because he was using, we somehow were able to keep that tradition. Christmas Eve was spent with our entire family either in our home or my sister’s. The first year without Jeff – just 3 months after he died of an accidental overdose and 2 days after release from 4 months in county jail, was unreal. Jeff had been so much a part of Christmas, sharing Santa duties and passing out gifts to the little ones with the biggest smile on his face. The emptiness was EVERYWHERE. He should have been there. We haven’t had a Christmas tree or decorations in our home since 2007. I don’t think we ever will again. The Holidays bring nothing but pain.

--Denise Cullen, Broken No More, Orange County, California

Photo Credit: http://sisterjohnpaul.blogspot.com/

End of the Line for Prometa?

Controversial meth treatment program fails in major study.

Prometa—the drug cocktail designed to combat addiction to cocaine and methamphetamine—has fallen flat on its face in a double-blind, placebo-controlled 108-day study just published in the journal Addiction. Dogged all along by a lack of published clinical data as well as major doubts about its success rates, Prometa has been a controversial treatment right from the start. In 2006, marketed heavily by anecdote and personal testimonials, the Prometa campaign included ads featuring the late comedian Chris Farley, who died of a drug overdose.

Hythiam,  the company that markets Prometa, had touted reports that 80% or more of Prometa users experienced “significant clinical benefit.” But MSNBC reported in 2008 that accountants in Pierce County, Washington froze the funding for an $800,000 pilot program, citing irregularities in testing. Investors in Hythiam, which is publicly traded, had been counting on the Pierce program after similar programs in Fulton County, Georgia, and in Idaho had failed to get off the ground. Things only got worse when the Tacoma News Tribune revealed that several county officials who had gotten behind the program also owned Hythiam stock.

Small rural communities that have felt the impact of meth sales and production in their communities are looking for help, and represent a significant market for an anti-addiction medication. However, in the case of Prometa, “The marketing is way ahead of the science,” said Lori Karan of the Drug Dependence Research Laboratory at the University of California-San Francisco. At the same time, Hythiam Executive Vice President Richard Anderson voiced strong objections to the Pierce County decision: “The people who are using it,” he said, “the doctors, patients, administrators, and drug court judges—are seeing an impact with it, so I think the treatment will carry it at the end of the day.”

But the day has ended, and the treatment did not carry it. The study in Addiction by a team of researchers at UCLA found no difference between Prometa and placebo in a group of 120 methamphetamine-addicted adults. The Prometa regimen, which can cost as much as $12,000 to $15,000 a month, “appears to be no more effective than placebo in reducing methamphetamine use, retaining patients in treatment or reducing methamphetamine craving,” the investigators conclude.

Ironically, the study was funded by Hythiam, as a response to complaints from the scientific community about a lack of rigorous testing. When it first launched the treatment, Hythiam was able to skim past the pesky drug approval process by exploiting a loophole in the FDA’s regulatory system that allows combinations of previously approved drugs to be marketed without formal review. Prometa was a blend of three existing medications: Neurontin (gabapentin) for epilepsy, Vistaril (hydrozyzine) for allergies, and Romazicon (flumazenil) for reversing benzodiazepine overdoses.

Ling, W., Shoptaw, S., Hillhouse, M., Bholat, M., Charuvastra, C., Heinzerling, K., Chim, D., Annon, J., Dowling, P., & Doraimani, G. (2011). Double-blind placebo-controlled evaluation of the PROMETA™ protocol for methamphetamine dependence Addiction DOI: 10.1111/j.1360-0443.2011.03619.x

Researchers Eye a Cheap, Organic Alternative to Chantix for Smokers

Meet cytisine, available in Bulgaria for 25 cents a pill.

A clear majority of American smokers say they want to quit. But each year, only a small percentage of them manage to do it. For individual smokers, the will is there, but what’s sometimes missing is the money.

For many smokers, cessation aids like nicotine patches and anti-craving medication are effective. But they are relatively costly, and insurance coverage for such products varies widely. Chantix, the top-of-the-line smoking cessation aid introduced by Pfizer five years ago as a very expensive prescription drug, was discovered by modifying the chemical attributes of an existing plant substance called cytisine.

But what if cytisine itself, found in various plants, including the golden rain tree, a small shrub native to the Alps—worked almost as well as Chantix, but for only pennies a day? Cytisine, packaged as Tabex and marketed by a Bulgarian firm, has already been on the market in Central Europe and Russia for more than 40 years. In Russia, a four-week course of Tabex costs $6.  Chantix will cost smokers about $250 for a 12-week run, or about $3-$4 per pill. In Poland, Tabex sells for about 25 cents per pill.

Moreover, as David Biello pointed out in Scientific American, when Chantix (known as Champix in the U.K.) was first approved for use against cigarettes, “the leaves of Cytisus laburnum, or the golden rain acacia tree, were used as a tobacco substitute by soldiers in World War II.” Later, clinicians in the U.S. paid scant attention to reports of a cheap Bulgarian plant-based supplement that smokers in Russia and Central Europe were using to help break their nicotine addiction. Instead, researchers structurally modified cytisine to produce varenicline, or Chantix. It makes for a more effective drug, but there are always tradeoffs: It is expensive and time-consuming to produce drugs through a process of total syntheses, and they will always come at a considerable cost premium relative to their organic originals. That is partly how pharmacology works, and it’s a good thing, providing you have the money or the health insurance to be able to afford the finished product.

Recently, a group of researchers at a smoking cessation clinic in Poland studied the effect of cytisine, a “partial nicotine agonist,” in a clinical trial published
 in the New England Journal of Medicine. The double-blind trial showed that cytisine was not as effective as Chantix, but significantly more effective than a placebo. Dr. Robert West of University College, London, and lead author of the study, said the “net improvement in the abstinence rate with cytisine was 6 percentage points. The relative rate of abstinence in the cytisine group as compared with that in the placebo group was 3.4.”

“It wasn't compared head-to-head against the Rx drugs, but its reasonable efficacy makes it sound like a cheaper alternative,” said Dr. David Kroll, Professor and Chair of Pharmaceutical Science at North Carolina Central University. “Like nicotine, it can cause side effects like headaches and nausea,” he added.

So is cytisine an eventual possibility in the U.S., where it is not currently licensed and available? Is it something that the National Institute on Drug Abuse is interested in? When I asked NIDA director Nora Volkow that question in an interview last week, the answer was yes. “The data look very interesting,” Volkow said, referring to the New England Journal of Medicine Study.  “The beauty of cytisine is that it’s not just inexpensive, you can also get a response in three weeks.” She added that “we don’t know yet whether we can improve it,” by, for example, combining it with other cessation aids. “The main side effect of cytisine is nausea, but not suicidal ideation,” she said.

An earlier survey in the Archives of Internal Medicine of the admittedly sparse research showed similar results in several placebo-controlled double-blind studies. Cytisine, the Marxist-Socialist answer to cigarette addiction, works about as well as standard nicotine replacement therapy, like patches and gums.

“I hope this drug will be available throughout the world at a cost that every smoker can afford,” said West. And that might be a problem. Cytisine is not currently legal in the U.S. or Canada. Tabex itself was withdrawn from some of the European countries in which it was formerly available, after several Central and Eastern European countries joined the European Union and began adhering to stricter licensing rules.

Meanwhile, a third of the world is still out there smoking tobacco. It seems sensible to have some modest help available for smokers in poverty who want to quit and financially need to quit. “I have long been concerned that effective treatments to help smokers to stop are not affordable by the majority of smokers in the world,” West said. “There are still regulatory hoops to go through, but I hope that before long this drug will be available throughout the world at a cost that every smoker can afford. It should be cheaper to take this drug than to smoke, wherever you are in the world. It is not a magic cure by any means; stopping is still extremely difficult for many people. But it could save many hundreds of thousands of lives, if not millions, which is quite a thought.”

As Dr. Volkow put it: “We urgently need medications for smoking. Five million people die per year” from smoking-related causes in the U.S.

West R, Zatonski W, Cedzynska M, Lewandowska D, Pazik J, Aveyard P, & Stapleton J (2011). Placebo-controlled trial of cytisine for smoking cessation. The New England journal of medicine, 365 (13), 1193-200 PMID: 21991893

Judge Rules Against Graphic Cigarette Packs

District Court says FDA mandate would violate First Amendment.

Consumers may yet be spared graphic images of diseased lungs and smokers with holes in their throats, after R.J. Reynolds, Lorillard, and other tobacco companies prevailed over the Food and Drug Administration in the U.S. District Court for the District of Columbia today. Judge Richard Leon ruled that forcing cigarette manufacturers to offer their products only in gruesome packages was a violation of free speech, and therefore unconstitutional. The companies were granted a preliminary injunction, while the FDA regroups and lawyers rehuddle.

The judge wrote that “plaintiffs raise for the first time in our Circuit the question of whether the FDA's new and mandatory graphic images, when combined with certain textual warnings on cigarette packaging, are unconstitutional under the First Amendment. Upon review of the pleadings, the parties' supplemental pleadings, oral argument, the entire record, and the applicable law, the Court concludes that plaintiffs have demonstrated a substantial likelihood that they will prevail on the merits of their position that these mandatory graphic images unconstitutionally compel speech, and that they will suffer irreparable harm absent injunctive relief pending a judicial review of the constitutionality of the FDA's Rule.” (Complete ruling available here).

As Josh Gerstein reported at POLITICO, Leon “found that the new warnings, which occupy 50% of the front and back of cigarette packs, convert them into "mini-billboards...for [the FDA's] obvious anti-smoking agenda." Both Health and Human Services Secretary Kathleen Sebelius and FDA Commissioner Margaret Hamburg were also named in the lawsuit.

Judge Leon foresees a slippery constitutional slope if such mandates are allowed to bloom:

When one considers the logical extension of the Government's defense of its compelled graphic images to possible graphic labels that the Congress and the FDA might wish to someday impose on various food packages (i.e., fast food and snack food items) and alcoholic beverage containers (from beer cans to champagne bottles), it becomes clearer still that the public's interest in preserving its constitutional protections - and, indeed, the Government's concomitant interest in not violating the constitutional rights of its citizens - are best served by granting injunctive relief at this preliminary stage.

Graphics Credit: http://pubcit.typepad.com

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.

The new forms of synthetic cannabis tickle the same brain receptors as THC does, and are sometimes capable of producing feelings of well-being, empathy, and euphoria—in other words, pretty much the same effects that draw people to pot. But along the way, users began turning up in the emergency room, something that very rarely happens in the case of smoked marijuana. The symptoms were similar to adverse effects some people experience with marijuana, but greatly exaggerated: extreme anxiety and paranoia, and heart palpitations.

As it turns out, there is a very real difference between smoking Purple Kush and snorting “Banana Cream Nuke” out of a metallic packet. The difference lies in the manner in which the brain’s receptors for cannabinoids are stimulated by the new cannabis compounds. When things goes wrong at the CB1 and CB2 receptors, and the mix isn’t right, the results may not be euphoria, giggles, short-term memory loss, and the munchies, but rather “nausea, anxiety, agitation/panic attacks, tachycardia, paranoid ideation, and hallucinations.” Furthermore, the Spice variants do not contain cannabidiol, a cannabis ingredient that has been shown to reduce anxiety in animal models, and reduces THC-induced anxiety in human volunteers. The authors of a recent study suggest that the “lack of this cannabinoid in Spice drugs may exacerbate the detrimental effects of these herbal mixtures on emotion and sociability.”

What concerned the researchers was that, in addition to reports of cognitive deficits and emotional alterations and gastrointestinal effects, emergency room physicians were reporting wildly elevated heart rates, extremely high blood pressure, chest pains, and fever. Fattore and Fratta report that “two adolescents died in the USA after ingestion of a Spice product called ‘K2,’” one due to a coronary ischemic event, and the other due to suicide. What’s going on?

In a paper for Frontiers in Behavioral Neuroscience called “Beyond THC: the new generation of cannabinoid designer drugs,” Liana Fattore and Walter Fratta of the University Of Cagliari in Monserrato, Italy, identified more than 140 different products marketed as Spice, and laid out the extreme variability found in composition and potency. Like a mutating virus, they came to the U.S., starting in early 2009, a new strain seemingly every week: Spice, K2, Spice Gold, Silver, Arctic Spice, Genie, Dream, and dozens of others, the naming and renaming suggesting nothing so much as the proliferating strains of high-end marijuana: Skunk, Haze, Silver Haze, Amnesia, AK-47. Synthetic marijuana comes mainly from manufacturers in Asia, and second generation chemicals have already been put on a to-be-banned list by the DEA. States have jumped all over the problem with duplicate legislation, despite the fact that experts believe a majority of sales take place over the Internet. A third generation of synthetic cannabis variants, which are sprinkled on an herbal base and meant to be snorted, are openly sold and touted as legal. And they are legal, depending upon which one you buy, and where you buy it. Synthetic cannabis is still readily available, affordably packaged, and right on the shelf, or ready for purchase online—unlike the frequently vague and sometimes shady process of scoring a bag of weed. In the beginning, at least, the new drugs were perceived by youthful users as safer than other drugs.

But the most crucial attribute of Spice and related products is that they are not detectable in urine and blood samples. You can cruise all night on Spice, and test clean the next day at work. The kind of cannabis in Spice doesn’t read out on anybody’s drug tests as marijuana. That requires the presence of THC—and the new synthetics don’t have any.

There are four different categories of chemicals used in the manufacture of “cannabimimetic” drugs. The first and best known is the so-called JWH series of “novel cannabinoids” synthesized by John W. Huffman at Clemson University in the 1980s. The most widely used variant is an extremely potent version known as JWH-018.  While JWH-018 is, chemically speaking, not structurally like THC at all, it snaps onto CB1 and CB2 receptors more fiercely than THC itself. The CP-compounds, the second class of synthetic compounds, were developed back in the 1970s by Pfizer, when that firm was actively engaged in testing cannabis-like compounds for commercial potential, a program they later dropped. The best-known example is CP-47,497. While CP-47,497 lacks the chemical structure of classic cannabinoids, it is anywhere from 3 to 28 times more potent than THC, and shows classic THC-like effects in animal studies. The next group is known as HU-compounds, because they originated at Hebrew University, where much of the early work on the mechanisms of THC took place. The last category consists of chemicals in the family of benzoylindoles, which also show an affinity for cannabinoid receptors.

JWH-018, the most common form of synthetic cannabis, and now widely illegal, is considerably more potent than THC—4 times stronger at the CB1 receptor, and 10 times stronger at the less familiar CB2 receptor. The CB2 receptor seems to have a lot to do with pain perception and inflammation, which is why researchers continue to investigate it. But CB2 receptors contribute only indirectly to the classic marijuana high, which is all about THC’s affinity for CB1 receptors, and the effects of using drugs with a very strong affinity for CB2 receptors is not well documented. And therein might lie the source of the problem—or, as Fattore and Fratta describe it, “the greater prevalence of adverse effects observed with JWH-018-containing products relative to marijuana.” A popular compound of the second kind, HU-210, has frequently been found in herbal mixtures available in the U.S. and U.K. According to the study, “the pharmacological effects of HU-210 in vivo are also exceptionally long lasting, and in animal models it has been shown to negatively affect learning and memory processes as well as sexual behavior.”

That, in a nutshell, is what the kids are smoking these days. But wait, there’s more: Besides synthetic cannabinoids, herbs and vitamins, researchers have found opioids like tramadol, opioid receptor-active compounds like Kratom (Mitragyna speciosa), and oleamide, a fatty acid derivative with psychoactive properties. (A combination of oleamide and JWH-018 has been sold as “Aroma.”) Indentifying which of these active ingredients is part of any particular packet of “legal highs” is further complicated by manufacturers’ tendency to mix the ingredients together with various organic compounds—everything from nicotine to masking agents like vitamin E. In fact, almost anything that might make it more difficult for forensic labs to pry it all apart: alfalfa, comfrey leaf, passionflower, horehound, etc. Banana Cream Nuke, which was purchased in an American smoke shop, and made two young girls very sick, contained 15 varieties of synthetic cannabis—but none of the herbal ingredients actually listed on the label.

Unlike the partial activation of CB1 receptors by THC, which takes place when people smoke marijuana, “synthetic cannabinoids identified so far in Spice products have been shown to act as full agonists with increased potency, thus leading to longer durations of action and an increased likelihood of adverse effects.” When it comes to cannabis, users are far better off smoking the real thing, from a harm reduction standpoint, and staying clear of these unpredictable synthetic substitutes.

Graphics Credit: http://www.cityblends.info/2011/10/beyond-thc.html

Fattore, L., & Fratta, W. (2011). Beyond THC: The New Generation of Cannabinoid Designer Drugs Frontiers in Behavioral Neuroscience, 5 DOI: 10.3389/fnbeh.2011.00060