A Chemical Peek at Modern Marijuana

Researchers ponder whether ditch weed is better for you than sinsemilla.

Australia has one of the highest rates of marijuana use in the world, but until recently, nobody could say for certain what, exactly, Australians were smoking. Researchers at the University of Sydney and the University of New South Wales recently analyzed hundreds of cannabis samples seized by Australian police, and put together comprehensive data on street-level marijuana potency across the country. They sampled police seizures and plants from crop eradication operations. The mean THC content of the samples was 14.88%, while absolute levels varied from less than 1% THC to almost 40%.  Writing in PLoS one, Wendy Swift and colleagues found that roughly ¾ of the samples contained at least 10% total THC. Half the samples contained levels of 15% or higher—“the level recommended by the Garretsen Commission as warranting classification of cannabis as a ‘hard’ drug in the Netherlands.”

In the U.S., recent studies have shown that THC levels in cannabis from 1993 averaged 3.4%, and then soared to THC levels in 2008 of almost 9%. THC loads more than doubled in 15 years, but that is still a far cry from news reports erroneously referring to organic THC increases of 10 times or more.

CBD, or cannabidiol, another constituent of cannabis, has garnered considerable attention in the research community as well as the medical marijuana constituency due to its anti-emetic properties. Like many other cannabinoids, CBD is non-psychoactive, and acts as a muscle relaxant as well. CBD levels in the U.S. have remained consistently low over the past 20 years, at 0.3-0.4%. In the Australian study, about 90% of cannabis samples contained less than 0.1% total CBD, based on chromatographic analysis, although some of the samples had levels as high as 6%.

The Australian samples also showed relatively high amounts of CBG, another common cannabinoid. CBG, known as cannabigerol, has been investigated for its pharmacological properties by biotech labs. It is non-psychoactive but useful for inducing sleep and lowering intra-ocular pressure in cases of glaucoma.

CBC, yet another cannabinoid, also acts as a sedative, and is reported to relieve pain, while also moderating the effects of THC. The Australian investigators believe that, as with CBD, “the trend for maximizing THC production may have led to marginalization of CBC as historically, CBC has sometimes been reported to be the second or third most abundant cannabinoid.”

Is today’s potent, very high-THC marijuana a different drug entirely, compared to the marijuana consumed up until the 21st Century? And does super-grass have an adverse effect on the mental health of users? The most obvious answer is, probably not. Recent attempts to link strong pot to the emergence of psychosis have not been definitive, or even terribly convincing. (However, the evidence for adverse cognitive effects in smokers who start young is more convincing).

It’s not terribly difficult to track how ditch weed evolved into sinsemilla. It is the historical result of several trends: 1) Selective breeding of cannabis strains with high THC/low CBD profiles, 2) near-universal preference for female plants (sinsemilla), 3) the rise of controlled-environment indoor cultivation, and 4) global availability of high-end hybrid seeds for commercial growing operations. And in the Australian sample, much of the marijuana came from areas like Byron Bay, Lismore, and Tweed Heads, where the concentration of specialist cultivators is similar to that of Humboldt County, California.

The investigators admit that “there is little research systematically addressing the public health impacts of use of different strengths and types of cannabis,” such as increases in cannabis addiction and mental health problems. The strongest evidence consistent with lab research is that “CBD may prevent or inhibit the psychotogenic and memory-impairing effects of THC. While the evidence for the ameliorating effects of CBD is not universal, it is thought that consumption of high THC/low CBD cannabis may predispose users towards adverse psychiatric effects….”

The THC rates in Australia are in line with or slightly higher than average values in several other countries. Can an increase in THC potency and corresponding reduction in other key cannabinoids be the reason for a concomitant increase in users seeking treatment for marijuana dependency? Not necessarily, say the investigators. Drug courts, coupled with greater treatment opportunities, might account for the rise. And schizophrenia? “Modelling research does not indicate increases in levels of schizophrenia commensurate with increases in cannabis use.”

One significant problem with surveys of this nature is the matter of determining marijuana’s effective potency—the amount of THC actually ingested by smokers. This may vary considerably, depending upon such factors as “natural variations in the cannabinoid content of plants, the part of the plant consumed, route of administration, and user titration of dose to compensate for differing levels of THC in different smoked material.”

Wendy Swift and her coworkers call for more research on cannabis users’ preferences, “which might shed light on whether cannabis containing a more balanced mix of THC and CBD would have value in the market, as well as potentially conferring reduced risks to mental wellbeing.”

Swift W., Wong A., Li K.M., Arnold J.C. & McGregor I.S. (2013). Analysis of Cannabis Seizures in NSW, Australia: Cannabis Potency and Cannabinoid Profile., PloS one, PMID: 23894589

Graphics Credit: http://420tribune.com

“Spiceophrenia”

Synthetic cannabimimetics and psychosis.

Not long ago, public health officials were obsessing over the possibility that “skunk” marijuana—loosely defined as marijuana exhibiting THC concentrations above 12%, and little or no cannabidiol (CBD), the second crucial ingredient in marijuana—caused psychosis. In some cases, strong pot was blamed for the onset of schizophrenia.

The evidence was never very solid for that contention, but now the same questions have arisen with respect to synthetic cannabimimetics—drugs that have THC-like effects, but no THC. They are sold as spice, incense, K2, Aroma, Krypton, Bonzai, and dozens of other product monikers, and have been called “probationer’s weed” for their ability to elude standard marijuana drug testing. Now a group of researchers drawn primarily from the University of Trieste Medical School in Italy analyzed a total of 223 relevant studies, and boiled them down to the 41 best investigations for systematic review,  to see what evidence exists for connecting spice drugs with clinical psychoses.

Average age of users was 23, and the most common compounds identified using biological specimen analysis were the now-familiar Huffman compounds, based on work at Clemson University by John W. Huffman, professor emeritus of organic chemistry: JWH-018, JWH-073, JWH-122, JWH-250. (The investigators also found CP-47,497, a cannabinoid receptor agonist developed in the 80s by Pfizer and used in scientific research.) The JWH family consists of very powerful drugs that are full agonists at CB-1 and CB-2 receptors, where, according to the study, “they are more powerful than THC itself.” What prompted the investigation was the continued arrival of users in hospitals and emergency rooms, presenting with symptoms of agitation, anxiety, panic, confusion, combativeness, paranoia, and suicidal ideation. Physical effects can includes elevated blood pressure and heart rate, nausea, hallucinations, and seizures.

One of the many problems for researchers and health officials is the lack of a widely available set of reference samples for precise identification of the welter of cannabis-like drugs now available. In addition, the synthetic cannabimimetics (SCs) are frequently mixed together, or mixed with other psychoactive compounds, making identification even more difficult. Add in the presence of masking agents, along with various herbal substances, and it becomes very difficult to find out which of the new drugs—none of which were intended for human use—are bad bets.

Availing themselves of toxicology tests, lab studies, and various surveys, the researchers, writing in Human Psychopharmacology’s Special Issue on Novel Psychoactive Substances, crunched the data related to a range of psychopathological issues reported with SCs—and the results were less than definitive. They found that many of the psychotic symptoms occurred in people who had been previously diagnosed with an existing form of mental disturbance, such as depression, ADHD, or PTSD. But they were able to determine that psychopathological syndromes were far less common with marijuana than with SCs. And those who experienced psychotic episodes on Spice-type drugs presented with “higher/more frequent levels of agitation and behavioral dyscontrol in comparison with those psychotic episodes described in marijuana misusers.”

In the end, the researchers can do no better than to conclude that “the exact risk of developing a psychosis following SC misuse cannot be calculated.” What would the researchers need to demonstrate solid causality between designer cannabis products and psychosis? More product consistency, for one thing, because “the polysubstance intake pattern typically described in SC misusers may act as a significant confounder” when it comes to developing toxicological screening tools. Perhaps most disheartening is “the large structural heterogeneity between the different SC compounds,” which limited the researchers’ ability to interpret the data.

This stuff matters, because the use of Spice-type drugs is reported to be increasing in the U.S. and Europe. Online suppliers are proliferating as well. And the drugs are particularly popular with teens and young adults. Young people are more likely to be drug-naïve or have limited exposure to strong drugs, and there is some evidence that children and adolescents are adversely affected by major exposure to drugs that interact with cannabinoid receptors in the brain. 

Graphics credit: http://scientopia.org/blogs/drugmonkey/

LSD Mutates Into NBOMe

What’s on that blotter?

It is a darkly poetic indictment of the War on Drugs that LSD, the first synthetic psychedelic, demonized for decades and the target of extremely expensive law enforcement operations, looks to be far safer than its replacements.

—Earth and Fire Erowid, in Erowid Extracts

It is called 25I-NBOMe, or 2C-I-NBOMe, or SC-B-NBOMe, or, erroneously, 2C-I. It belongs to a group of drugs called the NBOMes, which are derived from phenethylamine-based drug families made infamous by Dr. Alexander Shulgin. The NBOMe part stands for N-Benzyl-Oxy-Methyl. After it was first synthesized in 2003, Purdue University did some research on the chemical structure of NBOMes, but it was not until 2010 that the drugs began to appear in the underground market.  25I-NBOMe, the most common variety, is strongly psychedelic, with vivid visual and sensory effects. It can also cause horrid trips, especially at higher doses, and like LSD, it can cause vasoconstriction in the form of elevated blood pressure.

Earth and Fire Erowid, editors of the well-regarded Erowid drug information site, wrote a special report on the NBOMes for the July Erowid Extracts.  It is worth going over in some detail.

The NBOMes were initially freebase powders, either snorted or held in the mouth, but the authors note that there is still confusion and uncertainty about the relative effectiveness of various forms of administration. In one case noted by Erowid, three friends obtained a bottle of 25-I-NBOMe, marked as 500 micrograms per drop. “Those who took one drop enjoyed the experience,” but one of the friends, “after three drops, became incoherent and frantic, then ran from the house and drove off in his car. He crashed into a tree and woke up in the hospital two days later….”

This suggests both high potency and a rapid ramp-up of negative effects with dosage, making the NBOMes generally unreliable as street drugs. As the article in Erowid Extracts notes, “The unusually high potency makes overdoses more likely. Unfortunately, the risks of 25I (and perhaps other NBOMes) at high doses seem to include delirious, dangerous behavior (with some accidents resulting in death), as well as the possibility of death from direct pharmacological effects. Medically dangerous doses may be as low as 3-5 mg.”

Even worse, 25I and 25C, when sold as powders, makes dosing even more precarious. Drugs this strong in powder form should only be handled by someone wearing Walter White-style hand and eye protection. “Many people have prior experience with insufflating small lines or bumps of a psychedelic or stimulant,” says Erowid. “It’s a fairly new phenomenon that a similarly-sized line of a drug could lead to death.”

On another note, the incredible potency of the NBOMes makes them imminently smuggleable. A single 750-mcg dose equals about 6 grains of table salt. You could hide about 100,000 doses of 25I in a soda pop can.

For historical perspective, the authors point to the DEA’s bust-up of global supply chains for LSD in the early 2000s. Figures from the Monitoring the Future survey show that use of LSD by 18 year-olds has gone from about 8% in 1999 to less than 2% by 2009. What to do with all that perforated blotter paper? One time-honored response from dealers is to dump a different chemical on the paper and sell it as LSD. Erowid reminds us that LSD sold as the more expensive and difficult-to-synthesize mescaline in the hippie heydays was an early example of this practice.  As one Erowid contributor put it, “Which do you think would sell better, blotter sold as ‘25I-NBOMe’ or blotter sold as the now nearly mythical ‘acid’?”

Erowid found that at the online drug  site Silk Road, NBOMes were being offered at prices 5 to 10 times cheaper than LSD. Silk Road sells 25B-NBOMe powder for between $90 and $200 a gram. Hit size is often 1 mg or more, which is definitely a large dose. Vendors at Silk Road also sell perforated blotter paper with classic acid blotter designs from the past, like Albert Hofmann and the Beatle’s Yellow Submarine.

All of this adds up to erroneous reports of death by LSD, amid actual overdoses caused by an incredibly powerful and relatively untested new drug with a murky track record. Acid is not a lethal drug, and no deaths by overdose have ever been clearly and directly attributed to LSD.

The state of Virginia banned the NBOMes last year, and so far this year, several other states and nations have joined in. But Erowid points out that the U.N.’s World Drug Report 2013 concluded that “no sooner is one substance scheduled, than another one replaces it, thus making it difficult to study the long-term impact of a substance on usage and its health effects.” All of which, says Erowid, begs the question of what drugs will pop up to replace 25I-NBOMe once it is banned? Erowid has high hopes for a landmark New Zealand bill calling for a vendor framework in which the drugs are sold legally only if registration, safety testing, and recordkeeping meet certain standards. The bill is expected to become law in New Zealand later this year.

As Erowid notes, other countries will be watching New Zealand closely. A report by the Health Officers Council of British Columbia points out that “Prohibiting a substance does send a message of social disapproval of use… but the value of using prohibition to send a message to dissuade use must be weighed against the harmful consequences of implementing prohibition….”

Photo Credit:  http://ewsd.wiv-isp.be 

Will Power and Its Limits

How to strengthen your self-control.

Reason in man obscured, or not obeyed,
Immediately inordinate desires,
And upstart passions, catch the government
From reason; and to servitude reduce
Man, till then free.
—John Milton, Paradise Lost

What is will power? Is it the same as delayed gratification? Why is will power “far from bulletproof,” as researchers put it in a recent article for Neuron? Why is willpower “less successful during ‘hot’ emotional states”? And why do people “ration their access to ‘vices’ like cigarettes and junk foods by purchasing them in smaller quantities,” despite the fact that it’s cheaper to buy in bulk?

 Everyone, from children to grandparents, can be lured by the pull of immediate gratification, at the expense of large—but delayed—rewards. By means of a process known as temporal discounting, the subjective value of a reward declines as the delay to its receipt increases. Rational Man, Economic Man, shouldn’t behave in a manner clearly contrary to his or her own best interest. However, as Crockett et. al. point out in a recent paper in Neuron “struggles with self-control pervade daily life and characterize an array of dysfunctional behaviors, including addiction, overeating, overspending, and procrastination.”

Previous research has focused primarily on “the effortful inhibition of impulses” known as will power. Crockett and coworkers wanted to investigate another means by which people resist temptations. This alternative self-control strategy is called precommitment, “in which people anticipate self-control failures and prospectively restrict their access to temptations.” Good examples of this approach include avoiding the purchase of unhealthy foods so that they don’t constitute a short-term temptation at home, and putting money in financial accounts featuring steep penalties for early withdrawal. These strategies are commonplace, and that’s because people generally understand that will power is far from foolproof against short-term temptation. People adopt strategies, like precommitment, precisely because they are anticipating the possibility of a failure of self-control. We talk a good game about will power and self-control in addiction treatment, but the truth is, nobody really trusts it—and for good reason.  The person who still trusts will power has not been sufficiently tempted.

The researchers were looking for the neural mechanisms that underlie precommitment, so that they could compare them with brain scans of people exercising simple self-control in the face of short-term temptation.

After behavioral and fMRI testing, the investigators used preselected erotic imagery rated by subjects as either less desirable ( smaller-sooner reward, or SS), or more highly desirable ( larger-later reward, or LL). The protocol is complicated, and the analysis of brain scans is inherently controversial. But previous studies have shown heightened activity in three brain areas when subjects are engaged in “effortful inhibition of impulses.” These are the dorsolateral prefrontal cortex (DLPFC), the inferior frontal gyrus (IFG), and the posterior parietal cortex (PPC). But when presented with opportunities to precommit by making a binding choice that eliminated short-term temptation, activity increased in a brain region known as the lateral frontopolar cortex (LFPC).  Study participants who scored high on impulsivity tests were inclined to precommit to the binding choice.

In that sense, impulsivity can be defined as the abrupt breakdown of will power. Activity in the LFPC has been associated with value-based decision-making and counterfactual thinking. LFPC activity barely rose above zero when subjects actively resisted a short-term temptation using will power.  Subjects who chose the option to precommit, who were sensitive to the opportunity to make binding choices about the picture they most wanted to see, showed significant activity in the LFPC. “Participants were less likely to receive large delayed reward when they had to actively resist smaller-sooner reward, compared to when they could precommit to choosing the larger reward before being exposed to temptation.”

Here is how it looks to Molly Crockett and her fellow authors of the Neuron article:

Precommitment is adaptive when willpower failures are expected…. One computationally plausible neural mechanism is a hierarchical model of self-control in which an anatomically distinct network monitors the integrity of will-power processes and implements precommitment decisions by controlling activity in those same regions. The lateral frontopolar cortex (LFPC) is a strong candidate for serving this role.

None of the three brain regions implicated in the act of will power were active when opportunities to precommit were presented.  Precommitment, the authors conclude, “may involve recognizing, based on past experience, that future self-control failures are likely if temptations are present. Previous studies of the LFPC suggest that this region specifically plays a role in comparing alternative courses of action with potentially different expected values.” Precommitment, then, may arise as an alternative strategy; a byproduct of learning and memory related to experiences “about one’s own self-control abilities.”

There are plenty of caveats for this study: A small number of participants, the use of pictorial temptations, and the short time span for precommitment decisions, compared to real-world scenarios where delays to greater rewards can take weeks or months. But clearly something in us often knows that, in the immortal words of Carrie Fisher, “instant gratification takes too long.” For this unlucky subset, precommitment may be a vitally important cognitive strategy. “Humans may be woefully vulnerable to self-control failures,” the authors conclude, “but thankfully, we are sometimes sufficiently far-sighted to circumvent our inevitable shortcomings.” We learn—some of us—not to put ourselves in the path of temptation so readily.

Crockett M., Braams B., Clark L., Tobler P., Robbins T. & Kalenscher T. (2013). Restricting Temptations: Neural Mechanisms of Precommitment, Neuron, 79 (2) 391-401. DOI: 10.1016/j.neuron.2013.05.028

Photo Credit: http://tommyboland.com/2011/05/27/white-knuckle-living/

Peyote and the White Man’s Gin

Aldous Huxley reflects on drugs in 1958.

In the Brave New World of my fable there was no whisky, no tobacco, no illicit heroin, no bootlegged co­caine. People neither smoked, nor drank, nor sniffed, nor gave themselves injections. Whenever anyone felt depressed or below par, he would swallow a tablet or two of a chemical compound called soma....

In small doses it brought a sense of bliss, in larger doses it made you see visions and, if you took three tablets, you would sink in a few minutes into refreshing sleep. And all at no physiologi­cal or mental cost. The Brave New Worlders could take holidays from their black moods, or from the familiar annoyances of everyday life, without sacrificing their health or permanently reducing their efficiency....

But this most precious of the subjects' inalienable privileges was at the same time one of the most powerful instruments of rule in the dictator's armory. The systematic drugging of individuals for the benefit of the State (and inciden­tally, of course, for their own delight) was a main plank in the policy of the World Controllers. The daily soma ration was an insurance against personal malad­justment, social unrest and the spread of subversive ideas....

For example, the classical tranquillizer is opium. But opium is a dangerous drug which, from neolithic times down to the present day, has been making addicts and ruining health. The same is true of the classical euphoric, alco­hol -- the drug which, in the words of the Psalmist, "maketh glad the heart of man." But unfortunately alcohol not only maketh glad the heart of man; it also, in excessive doses, causes illness and addiction, and has been a main source, for the last eight or ten thou­sand years, of crime, domestic unhappiness, moral deg­radation and avoidable accidents....

Among the classical stimulants, tea, coffee and maté are, thank goodness, almost completely harmless. They are also very weak stimulants. Unlike these "cups that cheer but not inebriate," cocaine is a very powerful and a very dangerous drug. Those who make use of it must pay for their ecstasies, their sense of unlimited physical and mental power, by spells of agonizing depression, by such horrible physical symptoms as the sensation of being infested by myriads of crawling insects and by paranoid delusions that may lead to crimes of violence. Another stimulant of more recent vintage is amphetamine, better known under its trade name of Benzedrine. Amphetamine works very effec­tively -- but works, if abused, at the expense of mental and physical health. It has been reported that, in Ja­pan, there are now about one million amphetamine ad­dicts....

Of the classical vision-producers the best known are the peyote of Mexico and the southwestern United States and Cannabis sativa, consumed all over the world under such names as hashish, bhang, kif and marihuana. According to the best medical and anthro­pological evidence, peyote is far less harmful than the White Man's gin or whisky.

--From Aldous Huxley’s essay, "Chemical Persuasion," which appeared in Brave New World Revisited. Also cited in Moksha by Michael Horowitz and Cynthia Palmer.

Photo credit: http://therevealer.org 

Methamphetamine: An Excerpt

There’s more than one kind of monster.

Type and I pass the pipe.  The overhead light flickers and the wind picks up even more. It’s coming from the north because with each exhale, the smoke slips past my face, back toward the Twin Cities and my dead parents.
 
But for a brief moment, I’m not thinking about all that. I’m feeling the closest thing I can think of to God and he’s playing the samba inside of my body, his fingers gentle, as they press on the backs of my retinas, my spine, the tendons along my hip flexors. I’m thinking that I love drugs more than anything. That they are the one and only constant in my life. Yeah, they demand a lot of attention and effort, but their love is legendary, their compassion endless. I hold each hit for hours, exhale for decades. The determination that comes with the onset of a high rushes back and I’m all about conquering the world and making money and finding happiness in the form of a loving woman who knows when it’s time to brush the backs of her nails across my cheek and then I’m thinking about this being the same thing as what God is doing to me now.

I love it when my heart rattles against my uvula.

I love it when my vision is a camera shutter.

I love it when I know that someday, I will do great things.

I love it when methamphetamines make things okay.

But I don’t love it when I start to hallucinate because the line between knowing it’s only the drugs and knowing your psyche is about to snap the fuck apart like a high wire is oh so delicate....

—From Fiend, a novel by Peter Stenson

From “The Pleasures and Pains of Coffee”

By Honore de Balzac, translated by Robert Onopa.

Coffee is a great power in my life; I have observed its effects on an epic scale….

Coffee affects the diaphragm and the plexus of the stomach, from which it reaches the brain by barely perceptible radiations that escape complete analysis; that aside, we may surmise that our primary nervous flux conducts an electricity emitted by coffee when we drink it. Coffee's power changes over time. [Italian composer Gioacchino] Rossini has personally experienced some of these effects as, of course, have I. "Coffee," Rossini told me, "is an affair of fifteen or twenty days; just the right amount of time, fortunately, to write an opera." This is true. But the length of time during which one can enjoy the benefits of coffee can be extended.

For a while - for a week or two at most - you can obtain the right amount of stimulation with one, then two cups of coffee brewed from beans that have been crushed with gradually increasing force and infused with hot water.

For another week, by decreasing the amount of water used, by pulverizing the coffee even more finely, and by infusing the grounds with cold water, you can continue to obtain the same cerebral power.

When you have produced the finest grind with the least water possible, you double the dose by drinking two cups at a time; particularly vigorous constitutions can tolerate three cups. In this manner one can continue working for several more days....

Finally, I have discovered a horrible, rather brutal method that I recommend only to men of excessive vigor... It is a question of using finely pulverized, dense coffee, cold and anhydrous, consumed on an empty stomach. This coffee falls into your stomach, a sack whose velvety interior is lined with tapestries of suckers and papillae. The coffee finds nothing else in the sack, and so it attacks these delicate and voluptuous linings; it acts like a food and demands digestive juices; it wrings and twists the stomach for these juices, appealing as a pythoness appeals to her god; it brutalizes these beautiful stomach linings as a wagon master abuses ponies; the plexus becomes inflamed; sparks shoot all the way up to the brain. From that moment on, everything becomes agitated. Ideas quick-march into motion like battalions of a grand army to its legendary fighting ground, and the battle rages. Memories charge in, bright flags on high; the cavalry of metaphor deploys with a magnificent gallop; the artillery of logic rushes up with clattering wagons and cartridges; on imagination's orders, sharpshooters sight and fire; forms and shapes and characters rear up; the paper is spread with ink - for the nightly labor begins and ends with torrents of this black water, as a battle opens and concludes with black powder.

I recommended this way of drinking coffee to a friend of mine, who absolutely wanted to finish a job promised for the next day: he thought he'd been poisoned and took to his bed, which he guarded like a married man. He was tall, blond, slender and had thinning hair; he apparently had a stomach of papier-mache. There has been, on my part, a failure of observation…."