Cannabis sativa vs. Cannabis indica: Science or Folklore?

Golden Goat or  Sour Diesel?

The bland assurances from medical marijuana dispensaries about the physical and psychological effects of the bewildering array of hybrid plant strains on offer is mostly bunk, claim a growing number of cannabis scientists.

Ethan Russo, a neurologist and pharmacology researcher, as well as the medical director of a biotechnology company, author of numerous books about herbal medicine, and a former faculty member at the University of Washington and the University of Montana, has something to say to marijuana connoisseurs: “There are biochemically distinct strains of Cannabis, but the sativa/indica distinction as commonly applied in the lay literature is total nonsense and an exercise in futility.”

How’s that again? The much-vaunted divide between the cerebral sativa strains, and the sedating, body-oriented effects of indica, are an integral part of marijuana lore and legend. Cannabis growers and biologists endlessly debate the hybridization of new strains. Extolling the virtues of a sativa plant crossed with a plant redolent of indica is a common sales pitch.

In an interview with Dr. Daniele Piomelli for the January 2016 issue of the journal Cannabis and Cannabinoid Research, Russo detailed his disagreement with the assumption that hard evidence exists for this distinction. Dr. Piomelli notes that “sativa is often described as being uplifting and energetic, whereas indica as being relaxing and calming.” Folklore, says Russo. Of course different strains have different effects. But in recent years, says Russo, almost all marijuana has been coming from high-THC strains, with a slight increase in CBD-predominant strains:

"The differences in observed effects in Cannabis are due to their terpenoid content, which is rarely assayed, let alone reported to potential consumers. The sedation of the so-called indica strains is falsely attributed to CBD content when, in fact, CBD is stimulating in low and moderate doses. Rather, sedation in most common Cannabis strains is attributable to their myrcene content, a monoterpene with a strongly sedative couch-lock effect that resembles a narcotic."

And, as for sativa strains: “A high limonene content (common to citrus peels) will be uplifting on mood, while the presence of the relatively rare terpene in Cannabis, alpha-pinene, can effectively reduce or eliminate the short-term memory impairment classically induced by THC.”

Well. I for one do not wish to be caught in the firing line between Dr. Russo and the legions of growers who will beg to differ with his conclusions. For years, it has been accepted wisdom that cannabis comes in two different forms, essentially considered two different species even though they readily interbreed. Even Jean-Baptiste Lamarck, the legendary naturalist of the 18th Century, agreed with the indica and sativa concepts.

But Russo will have none of it: “To paraphrase and expropriate an old Yiddish expression: 12 botanical taxonomists, 25 different opinions…. One cannot in any way currently guess the biochemical content of a given Cannabis plant based on its height, branching, or leaf morphology. The degree of interbreeding/hybridization is such that only a biochemical assay tells a potential consumer or scientist what is really in the plant.”

And finally: “I would strongly encourage the scientific community, the press, and the public to abandon the sativa/indica nomenclature and rather insist that accurate biochemical assays on cannabinoid and terpenoid profiles be available for cannabis in both the medical and recreational markets. Scientific accuracy and the public health demand no less than this.”

Russo’s interview is strong evidence of a viewpoint brought to public attention a few years ago by several others, including the controversial cannabis chemist Jeffrey Raber.

Raber told the L.A. Weekly in 2013 that there was no compelling scientific evidence for the claims routinely made by cannabis dispensaries about the effects of a given colorfully named strain of marijuana. “We took a popular [strain] name, Jack Herer, and found that most didn’t even look like each other. OG whatever, Kush whatever, and the marketing that goes along with it—it’s not really medically designed.”

And the difference between sativa and indica? The cerebral, bracing “mental” high vs. the sleepy, couch-lock “body” high? Forget it, said Raber. The two sub-species are distinguished by morphology only—different structures and appearance, but no hard and fast rules about the quality of the smoking experience. They look different, but that’s no guide to the distribution of THC, CBD, and numerous terpenes that determine the actual quality of the marijuana experience. Moreover, extensive crossbreeding by growers and dealers has helped to obliterate any consistent, meaningful distinctions between sativa and indica highs. (The so-called “skunk” varieties are simply high quality female plants that are prevented from going to seed, which dramatically pushes up the THC content. Almost all of the high-quality weed sold in the U.S., Canada, and the U.K. is skunkweed, so the definition is virtually useless.)

Sativa plants are characteristically tall and rangy, with long branches and long, thin leaves. They evolved, scientists believe, in humid jungle climates. Indica plants are shorter, more compact, and stubbier-looking, with shorter branches and fatter leaves designed for a hot, desert-like climate. It has been assumed that sativas originally came from India, and indicas from Afghanistan. However, indica is the term meant to indicate a plant from India, so right away we find that the situation is all muddled up: the plant from Afghanistan is known by the name of the plant from India. Blame this one on esteemed plant drug investigator Richard Evans Schultes, who apparently mislabeled the plants grown in Afghanistan as C. indica when he drew up the first cannabis taxonomy in the 1970s.

It gets worse. In 2014, at a meeting of the International Cannabis Research Society, research John McPartland with GW Pharmaceuticals announced  the results of his study of genetic markers on the three subspecies of cannabis: C. sativa, C. indica, and a third wild variety, known as C. ruderalis, with very little THC. Any of the three subspecies can be bred as hemp or marijuana, said McPartland. Cannabis sativa should really be known as Cannabis indica, being the Indian variety, while the formerly misnamed indica subspecies should now be called Cannabis afghanica. The name of C. sativa, the high-end connoisseur favorite, would now go to the lowly C. ruderalis, otherwise known as ditch weed, under his new classification scheme.

Quite a lot of changes to a decades-old nomenclature, but it means we are finally getting some serious genetic information about one of the most popular drugs in the world. As Jeremy Daw of The Leaf Online writes: “Starbucks, for example, sources coffee beans from farmers spread across four continents…. In an astonishing feat of global supply chain logistics, Starbucks can now claim to have the ability to trace 94% of its coffee beans all the way back to the exact farm where they were produced.” The cannabis industry, he concludes, still has “a lot of growing up to do.”

Krymon deCesare, chief research director at Steep Hill Halent Lab in Oakland, California, a company developing more sophisticated tests for identifying the various compounds found in marijuana, told AlterNet  that “sativa and indica are only really valid for describing the physical characteristics of the cannabis strain in a given environment. They are not nearly as reliable as terms for making assumptions about energy versus couch lock.” To the extent that there is a grain of truth in the basic division between the mind high of sativa and the body high of indica, as traditionally classified, deCesare believes the culprit is myrcene. Based on the analysis of more than 100,000 samples, deCesare says that his team found “consistently elevated levels of the terpenoid myrcene in C. indica as compared to C. sativa. Myrcene is the major ingredient responsible for ‘flipping’ the normal energetic effect of THC….”

Ethan Russo invokes his notion of the “entourage effect,” in which the distinctive highs normally associated with indica and sativa are in fact the result of a complex combination of many different cannabinoids and terpenes working in harmony. Teasing that apart in the lab is not a cheap or easy affair. If you don’t know your terpene levels, says Russo, than you can’t compute your relative chances of full couch-lock. And even if terpene levels are known, the same pot plant, when smoked, can still cause one person to become energized and talkative, while another person may just fall asleep. Same chemicals, different metabolisms. One person’s happy, giggly high is another person’s paranoid bad trip.

The result of this recent research is to bolster the general suspicion about medical marijuana dispensaries: The names of various marijuana varieties are not only stupid and immature, but also completely misleading and unhelpful. Coherent labeling will require much more than listing relative THC percentages. We’ve only just begun.

Marijuana Deconstructed

What's In Your Weed?

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 climbed to THC levels in 2008 of almost 9%. By 2015, marijuana with THC levels of 20% were for sale in Colorado and Washington.

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

(First published at Addiction Inbox Sept. 3 2013)

Graphics Credit: https://budgenius.com/marijuana-testing.html

The Chemistry of Modern Marijuana

Is low-grade pot better for you than sinsemilla?

First published September 3, 2013.

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  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 ordinary marijuana evolved into sinsemilla. Think Luther Burbank and global chemistry geeks. 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.”

Graphics Credit: http://www.ironlabsllc.co/view/learn.php

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

Hunting For the Marijuana-Dopamine Connection

Why do heavy pot smokers show a blunted reaction to stimulants?

Most drugs of abuse increase dopamine transmission in the brain, and indeed, this is thought to be the basic neural mechanism underlying the rewarding effects of addictive drugs. But in the case of marijuana, the dopamine connection is not so clear-cut. Evidence has been found both for and against the notion of increases in dopamine signaling during marijuana intoxication.

Marijuana has always been the odd duck in the pond, research-wise. Partly this is due to longstanding federal intransigence toward cannabis research, and partly it is because cannabis, chemically speaking, is damnably complicated. The question of marijuana’s effect on dopamine transmission came under strong scrutiny a few years ago, when UK researchers began beating the drums for a theory that chronic consumption of strong cannabis can not only trigger episodes of psychosis, but can be viewed as the actual cause of schizophrenia in some cases.

It sounded like a new version of the old reefer madness, but this time around, the researchers raising their eyebrows had a new fact at hand: Modern marijuana is several times stronger than marijuana in use decades ago. Selective breeding for high THC content has produced some truly formidable strains of pot, even if cooler heads have slowly prevailed on the schizophrenia issue.

One of the reports helping to bank the fires on this notion appeared recently in the Proceedings of the National Academy of Sciences (PNAS). Joanna S. Fowler of the Biosciences Department at Brookhaven National Laboratory, Director Nora Volkow of the National Institute on Drug Abuse (NIDA), and other researchers compared brain dopamine reactivity in healthy controls and heavy marijuana users, using PET scans. For measuring dopamine reactivity, the researchers chose methylphenidate, better known as Ritalin, the psychostimulant frequently prescribed for attention-deficit hyperactivity disorder (ADHD). Ritalin basically functions as a dopamine reuptake inhibitor, meaning that the use of Ritalin leads to increased concentrations of synaptic dopamine.

In the study, heavy marijuana users showed a blunted reaction to the stimulant Ritalin due to reductions in brain dopamine release, according to the research. “The potency of methylphenidate (MP) was also reported to be stronger by the controls than by the marijuana abusers." And in marijuana abusers, Ritalin caused an increase in craving for marijuana and cigarettes.

 “We found that marijuana abusers display attenuated dopamine responses to MP including reduced decreases in striatal distribution volumes,” according to the study’s conclusion. “The significantly attenuated behavioral and striatal distribution volumes response to MP in marijuana abusers compared to controls, indicates reduced brain reactivity to dopamine stimulation that in the ventral striatum might contribute to negative emotionality and drug craving.”

Down-regulation from extended abuse is another complicated aspect of this: “Although, to our knowledge, this is the first clinical report of an attenuation of the effects of MP in marijuana abusers, a preclinical study had reported that rats treated chronically with THC exhibited attenuated locomotor responses to amphetamine. Such blunted responses to MP could reflect neuroadaptations from repeated marijuana abuse, such as downregulation of DA transporters.”

 Animal studies have suggested that these dopamine alterations are reversible over time.

Another recent study came to essentially the same conclusions. Writing in Biological Psychiatry, a group of British researchers led by Michael A.P. Bloomfield and Oliver D. Howes analyzed dope smokers who experienced psychotic symptoms when they were intoxicated. They looked for evidence of a link between cannabis use and psychosis and concluded: “These findings indicate that chronic cannabis use is associated with reduced dopamine synthesis capacity and question the hypothesis that cannabis increases the risk of psychotic disorders by inducing the same dopaminergic alterations seen in schizophrenia.” And again, the higher the level of current cannabis use, the lower the level of striatal dopamine synthesis capacity.  As for mechanisms, the investigators ran up against similar causation problems: “One explanation for our findings is that chronic cannabis use is associated with dopaminergic down-regulation. This might underlie amotivation and reduced reward sensitivity in chronic cannabis users. Alternatively, preclinical evidence suggests that low dopamine neurotransmission may predispose an individual to substance use.”

The findings of diminished responses to Ritalin in heavy marijuana users may have clinical implications, suggesting that marijuana abusers with ADHD may experience reduced benefits from stimulant medications.

Photo Credit: http://www.biologicalpsychiatryjournal.com/

Does Strong Marijuana Cause Addiction?

Strong pot matters, but maybe not the way we think.

Colorado, Washington, and some 20 additional states have now made various provisions for legal transactions involving marijuana. And since time immemorial, there has been an illegal market for marijuana. But try getting your hands on some marijuana straightforwardly, through appropriate channels, for purposes of medical research, and, well, most researchers have just said forget it.

Because in the U.S., a bizarre system of drug classification has led to the ludicrous situation of a virtual government monopoly on cannabis for experimental purposes. Can’t researchers just walk around this roadblock and procure pot in some manner that is legal in their state? No, they cannot—not if they want any serious research grants, or publication in refereed journals. Without the federal government imprimatur, marijuana research isn’t kosher, and could put researchers at legal risk. Researchers who go through channels report frequent and unpredictable delays, and this has been true for decades. Yet millions of recreational marijuana users can secure a supply of the drug, often accompanied by specific genetic information, often with relatively little effort.

The Drug Enforcement Administration (DEA) has refused to budge on its opposition to petitions for reclassification of cannabis. A recent Washington Post article  attributed the problem to “stigma associated with the drug, lack of funding and legal issues…. Scientists say they are frustrated that the federal government has not made any efforts to speed the process of research.”

However, as almost everyone knows, things are different in The Netherlands. It isn’t a big problem for researchers at the University of Amsterdam and elsewhere in that country to engage in behavioral studies of actual marijuana smokers. Participants in a recent study, the results of which appear in Addiction, were even allowed to use their own weed. (Thanks to Ivan Oransky for bringing this study to my attention.) The thesis being tested by Peggy van der Pol and colleagues is a familiar one: Do marijuana smokers “titrate” very strong pot—that is, do they modify their smoking/dosing behavior accordingly, in order to reduce overall THC exposure? If so, just because a cannabis user is ingesting high-THC plant material doesn’t mean that his or her THC blood levels are that much higher than smokers of less potent weed. But if this is NOT true—if smokers of strong pot are boosting their THC exposure significantly, the results could conceivably include impaired driving and greater rates of marijuana addiction.

Most studies that attempt to estimate the risk of cannabis dependence in pot smokers rely on a familiar yardstick—the number of days a smoker smokes per month. Dosing behavior, and other behavioral aspects of marijuana smoking that affect THC exposure, are usually ignored. The Dutch researchers found that, in a group of 600 frequent cannabis users, some smokers did in fact show “shorter puff duration and inhaled lower smoke volumes when joints with a higher THC concentration were used.” So, yes, users did engage in partial titration when they smoked stronger marijuana. However, this did not translate into the expected results. In a final sample of 98 participants, the scientists discovered that “users of stronger cannabis generally used larger amounts of cannabis to prepare their regular joint.” (The study participants smoked marijuana European-style, mixing their marijuana with tobacco.) And even though subjects smoking joints with higher THC levels did inhale at slightly lower volumes and at a slower pace, the average user of pot with THC levels of 12% or higher definitely inhaled more liters of smoked THC per month than users of less potent pot. But just to confound matters, total THC exposure over a month’s time turned out to be “a weak predictor of dependence severity, and did not remain significant after adjustment for baseline dependence severity.”

Nonetheless, even with some degree of titration, “a positive association between total puff volume and withdrawal/craving was found, indicating that a larger inhaled volume may increase the THC exposure sufficiently to result in significant effects on clinical outcomes.” (Here is the UK National Health Service take on the research.) 

It is always difficult to say for certain in a prospective, cross-sectional study of behavior whether participants are acting the way they would act in “real life,” although efforts were made to allow smoking at home, or in Dutch coffee shops, as well as the laboratory. Interestingly, the one behavior that seemed to predict dependence in post-hoc analyses was a simple one. Smokers were allowed to mix a joint however they wished, and smoke however much of it they wanted to. Smokers who finished their joints, rather than leaving a portion of it for later, were the smokers more likely to be associated with dependence in the follow-up studies. In fact, “percentage of the joint smoked may be a simple proxy for risky smoking behavior.”

In addition, certain withdrawal symptoms correlated with dependence: “Increased somatic withdrawal symptoms are predictive of relapse, and…. increased physical tension is a significant predictor of relapse.”

As with alcohol, it seems that it is not necessarily how much you smoke or drink. It is how you smoke or drink. Strong marijuana doesn't cause addiction. The way certain people use strong pot can result in addiction, however.

Earlier research has shown that higher levels of cannabis dependence are associated with greater functional impairment, and that "the average level of impairment caused by cannabis, while mild for most users, can rise to the level of tobacco withdrawal which is of well established clinical significance.”

 Physical distress, a “somatic” variable, often matters more, in terms of relapse, than the amount of marijuana smoked, or any other symptom on the roster of functional impairments—including mood and other negative affect variables.  In an earlier study published in PLOS ONE,  investigators found that “cannabis withdrawal is clinically significant because it is associated with elevated functional impairment to normal daily activities, and the more severe the withdrawal is, the more severe the functional impairment is. Elevated functional impairment from a cluster of cannabis withdrawal symptoms is associated with relapse in more severely dependent users.”

van der Pol P., Liebregts N., Brunt T., van Amsterdam J., de Graaf R., Korf D.J., van den Brink W. & van Laar M. (2014). Cross-sectional and prospective relation of cannabis potency, dosing and smoking behaviour with cannabis dependence: an ecological study, Addiction,   n/a-n/a. DOI: 10.1111/add.12508

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/

Drug News in Brief

Short takes on matters various.

Taking Aim at Pot—Researchers have recently made clinical efforts to test three drugs that might help during marijuana withdrawal to keep pot abstainers on the straight and narrow. Researchers at Columbia University, led by Margaret Haney, have been testing a synthetic THC compound called nabilone. The drug is designed to address sleep and appetite problems during withdrawal.  Whether it is any better tolerated by users than Marinol, Uncle Sam’s widely unpopular version of synthetic THC, remains to be seen. This approach can be viewed rather like methadone or buprenorphine substitution therapy. Meanwhile, work goes on with lofexidine, a drug sometimes used in combination with naltrexone for opiate detoxification. A 2008 study in Psychopharmacology showed a modest improvement over placebo when lofexidine was used for marijuana abstinence, but it worked much better when combined with, yes, synthetic THC. Finally, velafaxine, better known as the antidepressant Effexor, was used in a randomized, double-blind, placebo controlled trial of marijuana-dependent outpatients recently published in Addiction. Not only did velafaxine fail to help the patients with their cannabis dependence, but in fact “may lead to an increase in cannabis use.”

Smoking is Bad to the Bone—The Journal of Adolescent Health reports that cigarette smoking dramatically impacts the rate of bone density growth in teenage girls. Young women may be smoking their way toward a future of osteoporosis, the loss of bone density that often plagues older women. “This age group is when you should gain about 50 percent of your bone accrual,” reports study author Lorah Dorn at Cincinnati Children’s Hospital Medical Center, in Science News. A 2001 study of adult smokers found that smoking increased the risk of hip fracture by 31% in women. In addition, at the recent annual meeting of the American Academy of Orthopedic Surgeons, researchers reported on a study of 6,779 patients undergoing treatment for spinal disorders with severe pain. Those who quit smoking during treatment reported greater pain improvement than patients who didn't stop smoking. 

Dr. Google Will See You Now—Researchers are starting to data-mine the Internet to identify unanticipated side effects and interactions between prescription drugs. According to an article in Science by Sean Treacy, one study in 2011 data-mined reports to the FDA from doctors, nurses, and patients, and “uncovered a hidden drug interaction: When taken together the antidepressant paroxetine and the cholesterol suppressant pravastatin can cause hyperglycemia, or high blood sugar.”  Bioinformatics researcher Nigam Shah of Stanford told the magazine that “if a lot of people are concerned about a symptom, that in itself is valuable information.”

Fetal Health—Scientists have traced out a molecular signaling pathway that appears to play a crucial role in the development of fetal alcohol spectrum disorders (FASD). According to the researchers, whose study was published in the Proceedings of the National Academy of Sciences, “ethanol may cause FASD in part by decreasing the adhesion of the developmentally critical L1 cell adhesion molecule through interactions with an alcohol binding pocket on the extracellular domain.” In English, it means that the research points to strong candidate genes, therefore identifying a specific locus of action for future drugs designed to block alcohol neurotoxicity in the womb. A group led by Michael Charness at Harvard Medical School did the work, building on previous studies that identified the alcohol sensitivity of L1 adhesion molecules. “Prenatal alcohol exposure is the leading preventable cause of birth defects and developmental disorders in the United States,” according to perennial Acting NIAAA Director Kenneth Warren, in an NIH news release.

Photo Credit:  http://jimbaker.wordpress.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

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/

Marijuana, Vomiting, and Hot Baths

A case history of cannabinoid hyperemesis.

Cannabinoid hyperemesis, as it's known, is an extremely rare but terrifying disorder marked by severe episodic vomiting that can only be relieved by hot baths. (see earlier post). Sufferers are heavy, regular cannabis users, most of them. And hot baths? Where did THAT come from?

The syndrome was first brought to wider attention last year by the anonymous biomedical researcher who calls himself Drugmonkey, who documented cases of hyperemesis that had been reported in Australia and New Zealand, as well as Omaha and Boston in the U.S. "There were two striking similarities across all these cases," Drugmonkey reported. "The first is that patients had discovered on their own that taking a hot bath or shower alleviated their symptoms. So afflicted individuals were taking multiple hot showers or baths per day to obtain symptom relief. The second similarity is, as you will have guessed, they were all cannabis users."

The reports haven't stopped. This summer, an intriguing account appeared on the official blog of New York University's Division of General Internal Medicine, where med students offered a formal definition: "A clinical syndrome characterized by intractable vomiting and abdominal pain associated with the unusual learned behavior of compulsive hot water bathing, occurring in the setting of long-term heavy marijuana use."

Still skeptical? I received this heartfelt comment on my original post a few days ago:

Listen, doubters. My son has this. He has been cyclical vomiting and spending hours in boiling hot baths since last Autumn. It's getting worse and he has lost a hell of a lot of weight. He is 21 and an addicted, heavy cannabis user who started at 15. He has tried cutting down but every other joint of weed brings on the obsession. He refuses to co operate with medical staff who try to treat him.
He has been taken to numerous hospitals as an emergency for non-stop vomiting and begs medical staff to let him sit in a very hot bath. They try the best anti-vomiting drugs instead, to no effect, and then some let him go in a hot shower for an hour plus. He always ends up on a drip and as soon as he feels well enough, discharges himself, often the same day.

At the weekend he went to a sports event in the city with friends, realised on the way he was going to have an episode, so left friends and made his way into a hotel room and locked himself in. Police were called and got him out of a boiling hot bath against his will. Cue vomiting attack so bad police called an ambulance. Once again discharged himself from hospital, demanding drip be removed or he would do it himself. Has sat in bath at house he shares with girlfriend for at least 12 hours today, she tells me. She says water is so hot she has no idea how he bears it.

He says he has no pain in stomach, just a sensation that drives his head mad and he KNOWS it will not go, or the vomiting stop, until he gets in boiling hot bath and stays there. He has even done this while abroad on holiday and ended up on a drip before being flown home.

All of this is true. A mother.

I was intrigued, and discussed this briefly with the mother, who lives in the U.K. She added a number of details in an email exchange, and agreed to let me publish her comments:

“I am a mother in the UK whose son definitely has this, but is not officially diagnosed as he ‘escapes’ medical attention by discharging himself from various hospitals.

When it happens he is desperate to get in a hot bath. He lives with his girlfriend. I only realised what the hell was really going on when she insisted on telling me, and have since been regularly involved in the hospitals saga.

When I discovered the truth I put ‘cannabis’ ‘vomiting’ and ‘hot baths’ ‘showers’ in google and up came a perfect description of what my son does.

I am trying to get him to agree to go for counselling and psychiatric help as he has reached the stage where this obsessive vomiting and bathing is wrecking his life. But every time he gets a little better he believes he can ‘control it’ which is not the case at all.

Yes – we end up in the hospitals and the first young emergency doctor who has ever smoked a joint and/or thinks he knows everything, tells G “Oh no it can’t be that, cannabis stops vomiting, not starts it.” Of course, they have never heard of this condition and just think he is being irrational because of the constant need to vomit. They are sure it is food poisoning or some kind of spasm and take basic blood tests.

They find nothing, insist on giving him the best anti-sickness drugs usually for cancer patients and so on…, saying “this will definitely stop it” and still he vomits. He is not in pain, just rapidly dehydrating and panicking and complaining of a weird sensation in his stomach. He tells them “I know it’s in my head doing this” and desperately demands to get in a bath. Even when he has arrived at hospital because police found him in a boiling hot bath, this makes no sense to the medics who only give in when none of their drugs work. He then immediately stops vomiting but is petrified of getting out of the bath. Eventually, when he says it is under control, he agrees to get out, and is put on a drip. Approx an hour later, while the doctors are planning follow-up procedures like scans and more complex blood tests etc, he starts an argument with a nurse, insists the drip is removed and phones a friend to collect him, avoiding seeking a lift from me if he can. The over-pressed doctors here (the British system is like a cattle market) are left mystified and move onto the next emergency in their pile up of admissions. And so it goes on, and will do, until G accepts even the odd joint can set him off.”
----

Researchers speculate that it has something to do with CB-1 cannabinoid receptors in the intestinal nerve plexus--but nobody really knows for sure. Low doses of THC might be anti-emetic, whereas in certain people, the high concentrations produced by long-term use could have the opposite effect.

Marijuana and Memory

Do certain strains make you more forgetful?

Cannabis snobs have been known to argue endlessly about the quality of the highs produced by their favorite varietals: Northern Lights, Hawaiian Haze, White Widow, etc. Among dedicated potheads, debates about the effects of specific cannabis strains are often overheated, and, ultimately, kind of boring. It's a bit like listening to a discussion of whether the wine in question evinces a woody aftertaste or is, instead, redolent of elderberries. For most people, the true essence of wine drinking is pretty straightforward: a drug buzz, produced by a 12 to 15 % concentration of ethyl alcohol derived from grapes, which can be had in a spectrum of varietal flavors.

However, there is no doubting that, unlike the case of wine, different strains of marijuana can have markedly different psychoactive effects. With weed, it's not just a matter of taste.

Over the past couple of years, the cannabis debate has taken a nasty turn, after British scientists published several controversial studies suggesting that high-THC "skunk" cannabis was responsible for increased mental problems among young people--including an increased risk of developing the symptoms of schizophrenia. British drug policy makers have continued to lead the charge on this, with mixed results. See my earlier post.

Recently, a study published in the British Journal Of Psychiatry concluded that marijuana
high in THC--including so-called "skunk" cannabis--caused markedly more memory impairment than varieties of marijuana containing less THC.

In an article at Nature News, Arran Frood spelled out the details of the study:

"Curran and her colleagues traveled to the homes of 134 volunteers, where the subjects got high on their own supply before completing a battery of psychological tests designed to measure anxiety, memory recall and other factors such as verbal fluency when both sober and stoned. The researchers then took a portion of the stash back to the laboratory to test how much THC and cannabidiol it contained....  Analysis showed that participants who had smoked cannabis low in cannabidiol were significantly worse at recalling text than they were when not intoxicated. Those who smoked cannabis high in cannabidiol showed no such impairment."

The two main ingredients in cannabis are THC and cannabidiol (CBD). 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."

So, CBD specifically does not produce the usual marijuana high with accompanying euphoria and forgetfulness and munchies. What the researchers found was that pot smokers suffering memory impairment and those showing normal memory "did not differ in the THC content of the cannabis they smoked. Unlike the marked impairment in prose recall of individuals who smoked cannabis low in cannabidiol, participants smoking cannabis high in cannabidiol showed no memory impairment."

As far as memory goes, THC content didn't seem to matter. It was the percentage of CBD that controlled the degree of memory impairment, the authors concluded. "The antagonistic effects of cannabidiol at the CB1 receptor are probably responsible for its profile in smoked cannabis, attenuating the memory-impairing effects of THC. In terms of harm reduction, users should be made aware of the higher risk of memory impairment associated with smoking low-cannabidiol strains of cannabis like 'skunk' and encouraged to use strains containing higher levels of cannabidiol."

The idea that cannabidiol may protect against THC-induced memory loss is still quite speculative.  Other research has suggested that a paucity of CB1 receptors may be protective against memory impairment. Marijuana growers select for high-THC strains, not high-CBD strains, and thus there is little data available about the CBD levels of most marijuana.

An earlier study in Behavioural Pharmacology by Aaron Ilan and others at the San Francisco Brain Research Institute did not find any connection between memory and CBD content. However, Ilan speculated in the Nature News article that the difference might have been due to methodology: In Britain, the subjects were studied using marijuana of their own choosing.  In the U.S., National Institute of Health research policy has decreed that marijuana for official research must be supplied by the National Institute on Drug Abuse (NIDA). And if there is one thing many researchers seem to agree on, it is that NIDA weed "is notorious for being low in THC and poor quality."

But CBD still does something, and that something just might be pain relief.  Lester Grinspoon, a long-time marijuana researcher at Harvard Medical School, thinks that if the study proves out, it could have an important impact on the medical use of marijuana. Also quoted in Nature News, Grinspoon said: "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."

Morgan, C., Schafer, G., Freeman, T., & Curran, H. (2010). Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study The British Journal of Psychiatry, 197 (4), 285-290 DOI: 10.1192/bjp.bp.110.077503

Graphics Credit: http://sites.google.com