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

Book Review of "Drunken Angel"

A hipster gets his shit straight—sort of.

Addiction memoirs remain one of the most popular forms of autobiography on the shelves. But now, when considering a new addition to the genre, it’s impossible not to wonder whether the claims being made by the author are genuine. Since serious drunks often end up visiting the lower circles of hell during the course of their disease, hair-raising and improbable scenes are lamentably common—that is part of the genre’s charm, if that is the right word for it. But how are we to react now? The answer is, you can’t know, and you never really could, that bastard James Frey notwithstanding.

But read them we do. Alan Kaufman, the author of the lively but exasperating autobiography of alcoholism, Drunken Angel, sweetens the pot considerably. He drops so many names, and finds himself involved in so many improbably episodes of transnational mayhem and kinky sex, that the escapades could almost fill a Bond novel. But to be fair, there’s nothing debonair going on here; not from a man who describes himself at one stage as “filthy, nauseous, hungover, astonished at my gargantuan appetite for the abyss.” And a willing suspension of disbelief, an attitude of innocent until proven guilty, must hold sway in the end, else why read them at all?

Alan Kaufman is more Jack Kerouac than James Bond: One of the founding members of California’s Spoken Word scene, editor of The Outlaw Bible of American Poetry, Kaufman bounced through the beat/hippie/downtown scenes in New York, and San Francisco and Israel, writing for Jewish publications, treating his wives shabbily, and blacking out all over whatever town he happened to be in. It’s not pretty, and it’s not meant to be. The deep layer of poverty and grunge that settles over the author’s existence between bouts of the literary high life caused Kirkus Reviews to complain that “Drunken Angels” was marred by the author’s tendency to whip schizophrenically “between manic moments of literary self-aggrandizing and deeply depressive moments of shocking wreckage.” That’s true—but Kaufman is also a classic case of dual diagnosis, an alcoholic who also suffers from delusions, hallucinations, and Post Traumatic Stress Disorder after his time spent in the Israeli Army. (It’s complicated.) Also known as co-morbidity, this combination often makes for complicated, even potentially fatal difficulties, as on a bus ride with his wife one night, when he “realized that certain passengers were Satanists who had singled out Anna and me for human sacrifice.” Not good.

Down and almost out, he is scooped from the gutter by an acceptance letter from the Columbia University Master of Fine Arts program, where he hobnobs with Tama Janowitz and Steve Jobs’ sister, the writer Mona Simpson. But always, there are “the nightmares, the operatives, the unfolding skein of sinister designs” that Kaufman must negotiate as his mental health deteriorated. And the drinking never really stopped.

Finally, in order to both prove he’s sick and to signal his distress, Kaufman slit his wrists, then “staggered to the bathroom, wrapped white towels around the bloody wounds, and with a sense of exhilaration, called 911.” Perhaps the reader may be forgiven for not sharing in the exhilaration at this stage of the narrative, after reading about the author being ejected from crash pads by acid dealers for bad debts, dodging alimony and child support, neglecting a daughter on another continent, veering into sadomasochistic sex (in considerable detail), sleeping in filthy gutters, on warm street grates, on park benches. Kaufman made a habit of sitting down at restaurant tables to finish off the leftovers. “Ate donuts from garbage cans, pizza crusts from sidewalks, half-rotten fruit found in doorways. I kept my cash for booze…” In one excruciating scene, he tracks down an ex-girlfriend in her class at Columbia, calls her a whore in front of the class, and hits her in the face. A roomful of witnesses to that one, presumably. “In all this,” he tells us,” I never once lost my grip on the scotch bottle. Not a drop lost.”

So, that was it for Columbia. “All my life,” Kaufman writes, “ I had been going, fleeing. Leaving. Home, friends, jobs. Cities, countries, armies. Marriages, families—everything…. Anything but this, anyone but you, anywhere but here.” That was also about it for common sense from our anti-hero. We are pretty safe, it seems to me, in assuming that only a blackout alcoholic with severe mental problems is likely to wake up with a cruel hangover, married to the total stranger he finds lying in bed next to him. And then proceed to try and make the marriage work.

But in time, the story arc swings toward redemption, and Kaufmann falls in with AA and the Twelve Steppers.  “You’re allergic to alcohol and obsessed with it at the same time," an AA companion tells him. “The combination is fatal and unstoppable. Once booze hits your system, the jig’s up: you must drink.” And, to his immense credit, at long last, Kaufman gets straight, and eventually stays that way, even if the sordid circumstances of his life do not instantly change for the better. One of the most valuable lessons Kaufman takes away from AA (one of the most valuable lessons many people learn there) is a hoary old maxim called HALT: Don’t get too Hungry, Angry, Lonely, or Tired. All serious trigger conditions for relapse in freshly abstinent alcoholics and other drug addicts.

His book is a reminder that all of an addict’s life problems do not blessedly vanish the instant he or she stops drinking or using, any more than a regular schedule of insulin injections ends all problems for diabetics—the more so in cases where addiction is mixed with diagnosable mental illness. Getting clean and sober does not eliminate Kaufman’s sexual aggression, his tendency to lie to his wives, or bring back his ability to write steadily for a living.

In the end, Kaufman met a lot of famous people, managed to get published in some very hip venues, helped spark a poetry movement in San Francisco—and has now been clean and sober for more than 20 years. So what does he have to say about the prime mover of this amped-up narrative, alcoholism itself? It happened in the usual way—a formative alcohol experience at a young age. In early high school, a football player, Kaufman went out with some school buddies and without much thought began passing around those big gallon jugs of cheap Gallo wine. “I felt the universe swim into view. I stumble, drunk, to the grass and lay with arms and legs akimbo, like an altar sacrifice smiling at the blazing stars. For the first time in my life, I felt connected, happy, sure that life belonged to me and I to it. And I drank myself unconscious.”

Travelling alone in Germany, late in the book, after a nightmarish tableaux of temptation arranged for him by a cadre of Russian soldiers ready to pour vodka down his gullet in the spirit of macho brotherhood, Kaufman breaks away and finds a quiet spot in a deserted train car, and holds his own AA meeting in his head. “My name is Alan, I’m an alcoholic,” he says silently to himself. And then he says the Serenity Prayer, “then the 12 steps, and, appointing myself as guest speaker, shared about the experience I’d just had with Russian soldiers and endless vodka.” The phantom faces of his AA friends “kept me company right until I reached Berlin. And they are always with me, to this day, the meeting that I carry in my soul.”

Photo credit: http://www.booksmith.com/

Drug Fact Not Fiction

National Drug Facts Week is upon us.

Yes, kids, times does fly, and it’s time again to do a CyberShoutout for National Drug Facts Week, which kicks off on Monday, October 31, and runs through November 6. (Check the map for related events in your neck of the woods.)

Sponsored by the National Institute on Drug Abuse (NIDA), National Drug Facts Week is an official health observance designed to shatter myths and spread the facts about drug abuse and addiction. (Information booklet available here). And, okay, let’s face it: Most programs, textbooks, and videos that attempt to instill an anti-drug message in our nation’s youth are lame beyond belief. From “Reefer Madness” to “This is Your Brain on Drugs,” adults have managed to inculcate one overriding message in the nation’s young people: When it comes to drugs and alcohol, you can’t count on older people to tell you what you really need to know.

So, in honor of National Drug Facts Week, it is with pleasure that I point to the Sara Bellum Blog,  maintained by NIDA, and dedicated to the proposition that tweens and teens might just be as interested in straightforward drug facts as anybody else. Here you will find such goodies as Brain Games (my personal favorite), informative videos by actual scientists, and Peerx, a new section about prescription drugs. Not to mention the actual blog for underagers by Sara herself, which is refreshingly science-oriented for that sort of thing, covering everything from alcopops to nanotechnology.

Addiction Inbox is pleased to join the CyberShout again this year, because cigarette smoking among 12th graders reached it’s lowest point in history in 2010—and also because, in the same year, about 10% of high school seniors reported abusing Vicodin. Good things are happening, more truth is being told—but there is a lot of hard work yet to do.

Decoding Dope

Why marijuana gets you high, and hemp doesn’t.

Cannabis sativa comes in two distinct flavors—smokeable weed, and headache-inducing hemp. The difference between hemp and smokeable marijuana is simple: Hemp, used for fiber and seed, contains only a tiny amount of THC, the primary active ingredient in the kind of cannabis that gets you high. I am old enough to recall the sad saga of California hippies driving through my natal state of Iowa, and filling their trunks with “ditch weed”—wild hemp that grows commonly along Iowa rural fencerows, and while it cannot get you high, it could, back then, get you arrested.

But the California hippies who ran afoul of the law in Iowa were not so stupid as it might seem. Even a marijuana connoisseur can have a hard time telling the difference between strong sinsemilla and wild hemp. Both varieties look similar, have similar growth patterns and flowering schedules, and a fresh bud of ditch hemp can look and smell enticingly like the real thing. Even the trichomes—the thousands of sticky, microscopic stalks that grow on the female flowers, each containing a bead of resin, like a crystal golf ball on a tee, containing mostly THC, in the case of pot, and mostly CBD, in the case of hemp—are also similar in appearance and growth behavior.

A study by a group of Canadian researchers, just published in Genome Biology, lays out the draft genome of marijuana, containing all of the plant’s hereditary information as encoded in DNA and RNA.In their article, Timothy Hughes, Jonathan Page and co-workers reported “a draft genome and transcriptome sequence of C. sativa Purple Kush.” (The genome and transcriptome can be browsed or downloaded at The Cannabis Genome Browser.) More than 20 plant genomes have now been sequenced, including corn and rice, but Cannabis sativa marks the first genomic sequencing of a traditional medicinal plant.

So how does it happen that one version of cannabis comes power packed, while the other version shoots blanks, so to speak? The researchers began with the modern facts of the matter: The THC content of medical and recreational marijuana is “remarkably high.” Research shows that median levels of THC in dried female flowers of Purple Kush (the strain used in the study) and other high-end variants now approach 11%, with some strains achieving a stratospheric 23% THC content by dry weight. Why can’t breeders pull any buzz out of ditch weed? How did cannabis split into two distinct subtypes? In an accompanying editorial entitled “how hemp got high,” Naomi Attar calls Cannabis sativa “a plant with a ‘split personality,' whose Dr. Jekyll, hemp, is an innocent source of textiles, but whose Mr. Hyde, marijuana, is chiefly used to alter the mind.” In brief, what are the biological reasons for the psychoactive differences between marijuana and hemp?

Co-lead author Jon Page, a plant biologist at the University of Saskatchewan, along with Tim Hughes of the Department of Molecular Genetics at the University of Toronto, compared the genomic information of Purple Kush, a medical marijuana favorite, with a Finnish strain of hemp called Finola, which was developed for oil seed production and contains less than 1% THC content. That is not enough THC to be mind-altering in any way. Instead, what Finola has in abundance is cannabidiol, or CBD, the other major ingredient in cannabis.

CBD isn’t considered psychoactive, but it does produce a host of pharmacological activity in the body. CBD shows less affinity for the two main types of cannabis receptors, CB1 and CB2, meaning that it attaches to receptors more weakly, and activates them less robustly, than THC.  The euphoric effects of marijuana are generally attributed to THC content, not CBD content. In fact, there appears to be an inverse ratio at work. According to a paper in Neuropsychopharmacology, "Delta-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD's ability to block the psychotogenic effects of delta-9-THC."

The kind of cannabis people want to buy has a high THC/low CBD profile, while the hemp chemotype is just the reverse—low THC/high CBD. While the medical marijuana movement has concentrated on Purple Kush and other high-THC breeds, medical researchers have often tilted towards the CBD-heavy variants, since CBD seems to be directly involved with some of the purported medicinal effects of the plant. So, CBD specifically does not produce the usual marijuana high with accompanying euphoria and forgetfulness and munchies. What other researchers have discovered is that pot smokers who suffer the most memory impairment are the ones smoking cannabis low in cannabidiol, while people smoking cannabis high in cannabidiol—cheap, seedy, brown weed—show almost no memory impairment at all. THC content didn't seem to matter. It was the percentage of CBD that controlled the degree of memory impairment, the authors of earlier studies concluded.

 The researchers found evidence in Purple Kush for “upregulation of cannabinoid ‘pathway genes’ and the exclusive presence of functional THCA synthase.” That means the reason hemp doesn’t get you high is because it is lacking the crucial enzyme—THCA synthase—that limits production of CBD and allows the production of THC to go wild. In contrast, cannabis strains producing high levels of THC—the Kushes and Hazes and White Widows and other seriously spendy variants—do have high levels of the enzyme that limits the production of CBD. Purple Kush gets you high because it has a built-in chemical brake on the production of CBD. Hemp doesn’t.

In a press release from the University of Saskatchewan, the researchers explain how they think this divergence came about: “Over thousands of years of cultivation, hemp farmers selectively bred Cannabis sativa into two distinct strains—one for fiber and seed, and one for medicine.” This intensive selective breeding resulted in changes in the essential enzyme for THC production, which “is turned on in marijuana, but switched of in hemp,” as Page put it. Furthermore, says co-leader Tim Hughes of the Department of Molecular Genetics at the University of Toronto, an additional enzyme responsible for removing materials required for THC production was “highly expressed in the hemp strain, but not the Purple Kush.” The loss of this enzyme in Purple Kush eliminated a substance “which would otherwise compete for the metabolites used as starting material” in THC production.

Without knowing the mechanics of it, underground growers and breeders have been steadily maximizing the cultivation of strains of cannabis high in THCA synthase, the result of which is a molecular blocking maneuver that maximizes THC production. This is great for getting high, but may not be the optimal breeding strategy for producing plants with medicinal properties.  Raphael Mechoulam, the scientist who first isolated and synthesized THC, has referred to plant-derived cannabinoids as a “neglected pharmacological treasure trove.”  The authors of this study agree, and have already identified some candidate genes that encode for a variety of cannabinoids with “interesting biological activities.” Such knowledge, they say, will “facilitate breeding of cannabis for medical and pharmaceutical applications.”

But cannabis of this kind may turn out to be low-THC weed. And that may be a good thing, some researchers believe. Marijuana expert Lester Grinspoon told Nature News: "Cannabis with high cannabidiol levels will make a more appealing option for anti-pain, anti-anxiety and anti-spasm treatments, because they can be delivered without causing disconcerting euphoria." (We’ll leave definitional issues about the effects of euphoria for another post.)

Finally, the authors strongly suggest that if it were not for “legal restrictions in most jurisdictions on growing cannabis, even for research purposes,” we would have known all of this stuff years ago, and would have been well on our way to developing “finer tailoring of cannabinoid content in new strains of marijuana,” as Nature News Blog describes it.

van Bakel H, Stout JM, Cote AG, Tallon CM, Sharpe AG, Hughes TR, & Page JE (2011). The draft genome and transcriptome of Cannabis sativa. Genome biology, 12 (10) PMID: 22014239
Photo Credit:http://www.medicinalgenomics.com/