“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/

Marijuana and Diabetes: Does Pot Make You Thin?

Teasing out the insulin effect.

On the face of it, the study seems to come out of left field: A group of researchers claimed that marijuana smokers showed 16 per cent lower fasting insulin levels than non-smokers. The study, called “The Impact of Marijuana Use on Glucose, Insulin, and Insulin Resistance among US Adults,”  is in press for The American Journal of Medicine. The authors are a diverse group of medical researchers from Harvard, Beth Israel Deaconess Medical Center, and the University of Nebraska College of Medicine. The study concluded: “We found that marijuana use was associated with lower levels of fasting insulin and HOMA-IR [a measure of insulin resistance], and smaller waist circumference.”

Of course, it was that last tidbit about waist circumference that was picked up by the media. “Why Pot Smokers Are Skinnier,” headlined the Atlantic. However, the important implications are not so much for weight control, or the discovery of some built-in offsetting mechanism for the marijuana munchies, but rather for insulin control and the treatment of diabetes.

But in a clinical study, remarkable observations require remarkable documentation. What does the research actually say?

There are problems with the study worth noting. While researchers took blood samples after a 9-hour fast to determine insulin and glucose levels, they relied on self-reporting for marijuana use data. And self-reporting for alcohol and drug use has its limitations as an investigative tool. Namely, lack of honesty. But let’s get beyond that for a moment: From a database of 4,657 men and women who participated in the National Health and Nutrition Examination Survey, the researchers determined that 579 were current marijuana users, while 1,975 were pot smokers in the past.

The marijuana-smoking cohort tended to be young males who also smoked cigarettes. After running everything through a series of complicated multivariable-adjusted models, marijuana came out associated with lower insulin levels, and “lower waist circumference” than those who reported never using marijuana. And the results didn’t change much after adjusting for BMI numbers and excluding participants who actually had diabetes. Furthermore, the association was strongest in current smokers, “suggesting that the impact of marijuana use on insulin and insulin resistance exists during periods of recent use.” (It should also be noted that other health habits can affect glucose and insulin activity, including cigarettes, alcohol, and lack of physical activity.)

The investigators don’t offer a solution to the increased appetite/decreased waistline conundrum they claim to have identified. “We did not find any significant associations between marijuana use, and triglyceride levels, systolic blood pressure, or diastolic blood pressure,” they concluded.

We know marijuana has a complicated relationship with appetite mechanisms, as evidenced by its use with chemotherapy patients who need to eat. The theory is that the metabolic effects are mediated by a complex mix of cannabinoid type 1 and type 2 receptor interactions, since type 1 receptor antagonists like rimonabant improve insulin resistance in humans, and type 1 knockout mice also show resistance to diet-induced obesity.

Does marijuana smoking protect against diabetes? Wisely, the researchers don’t go that far, on the basis of this one uncontrolled study.  The researchers’ conclusions neatly hedge the bets, suggesting that with recent trends in the direction of marijuana legalization, “physicians will increasingly encounter patients who use marijuana and should therefore be aware of the effects it can have on common disease processes, such as diabetes mellitus.”

As it happens, the findings aren’t entirely new. Anecdotal reports abound. Back in 2010, on the Diabetes Daily support board, there was a long discussion of marijuana’s effect on blood glucose levels in diabetics. And there are several mouse models showing the same effects. In a prepared statement, lead investigator Murray A. Mittleman of Beth Israel Deaconess Medical Center in Boston conceded that previous epidemiological studies have found “lower prevalence rates of obesity and diabetes mellitus in marijuana users compared to people who have never used marijuana, suggesting a relationship between cannabinoids and peripheral metabolic processes.” However, he believes that “ours is the first study to investigate the relationship between marijuana use and fasting insulin, glucose, and insulin resistance.”

Perhaps so. A 2011 study in the American Journal of Epidemiology concluded that “the prevalence of obesity is lower in cannabis users than in nonusers.” And the British Medical Journal featured a finding in 2012 by Los Angeles researchers that marijuana use was “independently associated with a lower prevalence of diabetes mellitus.” But the online patient guide for marijuana offered by Mayo Clinic  says without equivocation that “cannabis may lower blood sugar. Caution is advised in patients with diabetes or hypoglycemia, and in those taking drugs, herbs, or supplements that affect blood sugar.” In fact, Mayo Clinic advises that patients may want to monitor their blood glucose levels if they smoke medical marijuana.

Regarding the current study, the editor-in-chief of the American Journal of Medicine said in a statement that there is a need for “a great deal more basic and clinical research into the short- and long-term effects of marijuana in a variety of clinical settings such as cancer, diabetes, and frailty of the elderly.” Editor Joseph S. Alpert also called on the National Institutes of Health (NIH) and the Drug Enforcement Administration (DEA) to collaborate in “developing policies to implement solid scientific investigations that would lead to information assisting physicians in the proper use and prescription of THC in its synthetic or herbal form.”

Penner E.A., Buettner H. & Mittleman M.A. (2013). The Impact of Marijuana Use on Glucose, Insulin, and Insulin Resistance among US Adults, The American Journal of Medicine,    DOI: 10.1016/j.amjmed.2013.03.002

Photo Credit: http://www.herbalmission.org/

Marijuana and Strokes: Medical Reality or Scare Story?

Heavy tokers may be at higher risk, but alcohol is the hidden confounder.

Young people don’t suffer from strokes, as a rule. And when they do, at least half the time there is no obvious cardiovascular explanation. So it’s not surprising that drugs are often invoked as the culprit.

A New Zealand study earlier this year once again raised the specter of a possible link between stroke and marijuana smoking. As reported by Maia Szalavitz at Time Healthland, the confounding issue, as is typical of such studies, is the coexisting use of other drugs, like alcohol and cigarettes. As Szalavitz writes:

The stroke study, which incorporated preliminary data, is the first trial of its kind to study a possible connection between marijuana use and stroke. It included 160 patients aged 18 to 55 who had suffered a stroke connected to a blood clot in the brain, and who agreed to have their urine tested for marijuana within 72 hours of the stroke.  These results were compared to those from 160 controls who had not had a stroke but came to the hospital for other reasons. They were matched on age, gender and ethnic background, all of which can also affect the risk for this type of stroke. About 16% of the stroke patients showed traces of marijuana in their urine, compared to 8% of those in the control group, suggesting a doubling of the risk of stroke.

However, because of nicotine and other confounding variables, that study was considered inconclusive. In an earlier study published in Stroke, the journal of the American Heart Association, Valerie Wolff and colleagues from the University of Strasbourg in France searched the medical literature and found 59 cases of stroke in which cannabis could be considered a cardiovascular risk factor. The investigators used only cases that had been confirmed by neuroimaging. The researchers focused on cases where a stroke had occurred while smoking marijuana, or within a half hour after the last joint or bong hit.

But proving a cause and effect relationship is tricky. Assuming, for now, that all of the strokes in question were not caused or compounded by alcohol or drugs other than marijuana, the French scientists postulated several mechanisms that could conceivably account for a cannabis-related ischemic stroke (a stroke caused by obstruction of a blood vessel). These include orthostatic hypotension, altered cerebral vasomotor function, major swings in blood pressure, and cardiac arrhythmias. However, the only solid commonality in cannabis-related strokes was that the users were more likely to be heavy smokers.

In the 50 strokes the researchers were able to confirm by cerebral imaging, the patterns in some patients were similar to those observed in a syndrome called reversible cerebral vasoconstriction syndrome (RCVS). RCVS  is marked by severe headaches, strokes, and brain edema, but symptoms typically resolve in a few months.  “Reversibility of the vasoconstriction within 12 weeks is a key point of this syndrome,” the authors write. “The long duration of stenosis [blockage] argues in favor of a drug-induced immunoallergic vasculitis rather than vasospasm. Our point of view is that this disorder may be considered as a variant of RCVS,” rather than as a garden-variety ischemic stroke triggered by excessive use of cannabis.

According to the French study, “The most frequently presented characteristics of cannabis users who experienced a stroke are young male chronic tobacco and cannabis abusers who have had an unusual high consumption of cannabis and alcohol before stroke.” The most convincing mechanism to explain ischemic strokes in young people, the researchers say, is “reversible cerebral angiopathy involving several arteries, associated with cannabis consumption in association with tobacco and alcohol use.”

And there you have it. Smoke weed, and you appear to have a slight risk of suffering stroke, which, under age 50, is an extremely uncommon medical event.  Add tobacco, and the stroke risk goes up. Add alcohol, and the stroke risk ratchets even higher. By itself, marijuana appears to be a minor factor in strokes—but it appears likely that pot is indeed the culprit at least some of the time.

“Cannabis-related stroke is not a myth,” the scientists conclude, “and a likely mechanism of stroke in most cannabis users is the presence of reversible multifocal intracranial stenosis (MIS) induced by this drug. The reality of the relationship between cannabis and stroke is, however, complex, because other confounding factors have to be considered (ie, lifestyle and genetic factors).”

Wolff V., Armspach J.P., Lauer V., Rouyer O., Bataillard M., Marescaux C. & Geny B. (2013). Cannabis-related Stroke: Myth or Reality?, Stroke, 44 (2) 558-563. DOI: 10.1161/STROKEAHA.112.671347

Graphics Credit: http://www.strokegenomics.org/

A Look at the Recent Study of Cannabis and Multiple Sclerosis

Smoked marijuana reduced spasticity in a small trial of MS patients.

The leading wedge of the medical marijuana movement has traditionally been centered on pot as medicine for the effects of chemotherapy, for the treatment of glaucoma, and for certain kinds of neuropathic pain. From there, the evidence for conditions treatable with marijuana quickly becomes either anecdotal or based on limited studies. But pharmacologists have always been intrigued by the notion of treating certain neurologic conditions with cannabis. Sativex, which is sprayed under the tongue as a cannabis mist, has been approved for use against multiple sclerosis, or MS, in Canada, the UK, and some European countries. (In the U.S., parent company GW Pharma is seeking FDA approval for the use of Sativex to treat cancer pain).

There is accumulating evidence that cannabinoid receptors may be involved in controlling spasticity, and that anandamide, the brain’s endogenous form of cannabis, is a specific antispasticity agent.

Additional evidence that researchers may be on to something appeared recently in the Canadian Medical Association Journal. Dr. Jody Corey-Bloom and coworkers at the University of California in San Diego conducted a small, placebo-controlled trial with adult patients suffering from poorly controlled spasticity. Thirty participants were randomly divided into two groups. Those in the first group were given a daily joint, and those in the second group received “identical placebo cigarettes.” After three days, the investigators found that smoked marijuana resulted in a reduction in treatment-resistant spasticity, compared to placebo.

Clearly, it’s hard for a study of this sort to be truly blind: Participants, one presumes, had little trouble distinguishing the medicine from the placebo. And in fact, an appendix to the study shows this to be true: “Seventeen participants correctly guessed their treatment phase for all six visits… For the remaining participants, cannabis was correctly guessed on 33/35 visits.” This raises the question of various kinds of self-selection bias and expectancy effects, and the study authors themselves write that the results “might not be generalizable to patients who are cannabis-naïve.” On the other hand, cannabis-naïve patients were in the minority. The average age of the participants was 50, and fully 80% of them admitted to previous “recreational experience” with cannabis. (I don’t have a good Baby Boomer joke for the occasion, but if I did, this is where it would go).

I asked Dr. Corey-Bloom about this potential problem in an email exchange: “The primary outcome measure was the Ashworth Spasticity Scale, which is an objective measure, carried out by an independent rater,” she wrote. “Their job was just to come in and feel the tone around each joint (elbow, hip, knee), rate it, and leave.  That's why we think it was so important to have an objective measure, rather than just self-report.”

With all this in mind, the study found that “smoking cannabis reduced patient scores on the modified Ashworth scale by an average of 2.74 points.” The authors conclude: “We saw a beneficial effect of smoked cannabis on treatment-resistant spasticity and pain associated with multiple sclerosis among our participants.”

Other studies have found similar declines in spasticity from cannabinoids, but have tended not to use marijuana in smokable form.

Corey-Bloom, J., Wolfson, T., Gamst, A., Jin, S., Marcotte, T., Bentley, H., & Gouaux, B. (2012). Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial Canadian Medical Association Journal DOI: 10.1503/cmaj.110837

Photo Credit: http://blog.amsvans.com/

Marijuana Can Make You Vomit, and Other Stories

Short subjects, various.

First, a recap of an earlier story, and a very strange story at that. Cannabinoid hyperemesis, as it's known, was not documented in the medical literature until 2004, and was first brought to wider attention earlier this year by the biomedical researcher who blogs as Drugmonkey. Episodes of serial vomiting appear to be a very rare side effect of regular marijuana use. Posting on his eponymous blog, Drugmonkey documented cases of hyperemesis that had been reported in Australia and New Zealand, as well as Omaha and Boston in the U.S.

As Drugmonkey reported, “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.”

A year ago, I published a post on this topic, titled "Marijuana, Vomiting, and Hot Baths." Sure enough, a number of people left comments about their own experiences with this unusual and unpleasant effect. Recently, one of my commenters caught drugmonkey’s eye, and he noted it in his new blog post on the phenomenon:

“Dirk Hanson's post on cannabis hyperemesis garnered another pertinent user:

Anonymous said...
My son suffers from this cannabinoid hyperemesis. At this moment he is here at my home on the couch suffering. I have been up with him for 3 days with the vomiting and hot baths. He says this time its over for good. This is our third bout. The first two time we went to ER, they put him on a drip to hydrate him, and gave him some pain medicine and nausea medicine. After a few hours he went home and recovered. This time we went to Urgent Care, put him on a drip, pain med, Benadryl, and Zofran….

Drugmonkey writes: “I reviewed several case reports back in 2010.... and there was considerable skepticism that the case report data was convincing. So I thought I'd do a PubMed search for cannabis hyperemesis and see if any additional case reports have been published…. One in particular struck my eye. Simonetto and colleagues (2012) performed a records review at the Mayo Clinic. They found 98 cases of unexplained, cyclic vomiting which appeared to match the cannabis hyperemesis profile out of 1571 patients with unexplained vomiting and at least some record of prior cannabis use… this is typical of relatively rare and inexplicable health phenomena. The Case Reports originally trickle out... this makes the medical establishment more aware and so they may reconsider their prior stance vis a vis so-called "psychogenic" causes. A few more doctors may obtain a much better cannabis use history then they otherwise would have done. More cases turn up. More Case Reports are published. etc. It's a recursive process. “
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In a story I think of as vaguely related, in the sense that it is a rare drug phenomenon unrecognized by the public, I recently wrote an article  for The Dana Foundation on the subject of “Smoking’s Ties to Schizophrenia.” In addition, check out a story about plans by the Air Force to make their hospitals and clinics smoke-free HERE. In brief: Smoke-free clinics pose major problems for heavy smokers with mental health disorders.
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Speaking of hospitals, Michelle Andrews reports in Kaiser Health News that about half of the patients undergoing treatment in hospital emergency rooms are under the influence of booze. Alcohol screening and counseling can be effective in this context—but there’s a catch. “Regardless of state law, self-insured companies that pay their employee’s health care costs directly can refuse to cover employees for alcohol-related claims.”

Even though the National association of Insurance Commissioners does not recommend it, dozens of states have passed laws allowing health insurers to deny payment for a patient’s injuries if they were incurred while he or she was under the influence of alcohol. About as many states have passed laws prohibiting such exclusions due to alcohol. The result is one big mess, and confusion reigns. As a professor of health law put it: “There’s no reason to think that insurers, eager to hold down costs, wouldn’t continue” to deny payment for alcohol-related injuries.
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And finally, some news about Chantix (varenicline), the drug both patients and doctors love to hate. It often works very well as an anti-craving medication for smoking cessation. But it can also, in some cases, present patients with a bewildering array of psychological side effects, including rare cases of suicidal ideation. A new study  by researchers at the Ernest Gallo Clinic and Research Center at the University of California, San Francisco, suggests that Chantix may have application in the treatment of alcoholism as well. Participants in the study reduced the average number of drinker per week on Chantix, compared to placebo. The study was funded by the National Institutes of Health and the State of California. Pfizer, the company that markets Chantix, did not fund or participate in the study.

Graphics Credit: http://teesdiary.files.wordpress.com/

A Drug For Marijuana Withdrawal?

Researchers get good results with gabapentin.

Marijuana, as researchers and pundits never tire of pointing out, is the most widely used illegal drug in the world, by a serious margin. And while the argument still rages, for some years now drug researchers have been migrating to the camp that sees marijuana as an addictive drug for a minority of people who exhibit a propensity for addiction. The scientific literature supporting the contention of marijuana as addictive for some users is robust and growing, as is the body of anecdotal evidence.  It’s also clear that in many countries, cultures, and subcultures, combining cannabis with tobacco is a common practice that increases health risks all around.

Ongoing work at the Scripps Research Institute’s Pearson Center for Alcoholism and Addiction Research in La Jolla, California, has focused in part on the lack of FDA-approved medical therapies for treating marijuana addiction. Barbara J. Mason and coworkers at Scripps have reported preliminary success in a 12-week, double-blind, placebo-controlled pilot study with 50 treatment-seeking volunteers, using the anti-seizure drug gabapentin. Gabapentin, sold as Neurontin, pops up as a possible treatment for various forms of pain and anxiety, and sharp-eyed readers will recall that gabapentin was one of the ingredients in the now-defunct addiction drug Prometa.

Marijuana addiction numbers are hard to come by, and often inflated, since many small-time pot offenders end up in mandatory treatment programs, where they tend to be classified as marijuana addicts, whether or not that is objectively the case. Nonetheless, there are plenty of people seeking treatment on their own for cannabis dependence. For people strongly addicted to pot, the problems are very real, and withdrawal and abstinence pose serious challenges. People for whom marijuana poses no addictive threat should bear this in mind, the way casual drinkers bear in mind the existence of alcoholism in others.

The study, published recently in Neuropsychopharmacology, says that “activation of brain stress circuitry caused by chronic heavy marijuana use” can lead to withdrawal symptoms that persist “for weeks or even months, as in the case of marijuana craving and sleep disturbances.” A variety of existing medications have been tested in recent years, including buspirone, an anti-anxiety medication; Serzone, an antidepressant; and Wellbutrin, an antidepressant commonly used for smoking cessation. None of these treatments has shown any effect on cannabis use or withdrawal, according to Mason.

Gabapentin, as the name suggests, was modeled after the neurotransmitter GABA, and works via a transporter protein to raise GABA levels. Effective only for partial-onset seizures, common side effects include drowsiness, dizziness, and possible weight gain. It is a popular anti-epileptic drug, because it is relatively safe, with a low side-effect profile, compared to many of the medications in its class. For the same reasons, it is a common treatment for neuropathic pain. In addition to neuralgia, it has found some use as a migraine preventative.

Gabapentin normalizes GABA activation caused by corticotrophin-releasing factor, or CRF. CRF is a major player in the brain’s stress responses. As it turns out, withdrawal from both cannabis and alcohol ramp up anxiety levels by increasing CRF release in the amygdala, animal studies have shown. “Gabapentin had a significant effect in decreasing marijuana use over the course of treatment, relative to placebo,” the authors report. In addition, gabapentin produced “significant reductions in both the acute symptoms of withdrawal as well as in the more commonly persistent symptoms involving mood, craving, and sleep.”

As a bonus, the researchers discovered that “overall improvement in performance across cognitive measures was significantly greater for gabapentin-treated subjects compared with those receiving placebo.” Gabapentin was associated with improvement in “tasks related to neurocognitive executive functioning”—things like attention, concentration, visual-motor functioning, and inhibition. Counseling alone, represented by the placebo group, “resulted in less effective treatment of cannabis use and withdrawal, and no improvement in executive function.”

As in the case of Chantix for cigarette cessation, a treatment, which now requires additional caveats about possible suicidal ideation, researchers looking for a treatment for drug withdrawal, must weigh the benefits of pharmacological treatment against the possible side effects of the treatment itself. Does gabapentin for marijuana withdrawal pass the “Do No Harm” test? According to Mason, it does. “Gabapentin was well tolerated and without significant side effects” in the admittedly small trial study. The two groups did not differ in the number of adverse medical events reported in the first two weeks, when dropout rates due to side effects are highest in these kinds of studies. The investigators were not relying solely on self-reporting, either. They used urine drug screens, and verified that only 3% of the study sample tested positive for other drugs.

In short, the authors report that gabapentin reduced cannabis use and eased withdrawal with an acceptable safety profile and no signs of dependence. Gabapentin, the authors conclude, “may offer the most promising treatment for cannabis withdrawal and dependence studied to date.” Further clinical research is needed, of course, but the positive results of this proof-of-concept study should make funding a bit easier.

Mason, B., Crean, R., Goodell, V., Light, J., Quello, S., Shadan, F., Buffkins, K., Kyle, M., Adusumalli, M., Begovic, A., & Rao, S. (2012). A Proof-of-Concept Randomized Controlled Study of Gabapentin: Effects on Cannabis Use, Withdrawal and Executive Function Deficits in Cannabis-Dependent Adults Neuropsychopharmacology DOI: 10.1038/npp.2012.14

Photo Credit: http://pep3799.hubpages.com/

From Their Mouth to Your Ear: Researchers Talk Drugs

A collection of five-question interviews.

I’ll be away from the Addiction Inbox office this week, attending the big TEDMED health and medicine powwow in Washington, D.C.

In the meantime, here’s a summation (with links) of the interviews I’ve been doing recently in the “five-question interview” series. I’ve been very lucky to nab some state-of-the-art thinkers, working at the top of their fields, from psychiatry to pharmacology to neuroscience.

See below for the story thus far:



David Kroll, former Professor and Chair of Pharmaceutical Science at North Carolina Central University in Durham, is now Science Communications Director for the Nature Research Center at the North Carolina Museum of Natural Sciences.

“The attraction to users was, until recently, that Huffman cannabis compounds (prefixed with "JWH-" for his initials) could not be detected in urine by routine drug testing. Hence, incense products containing these compounds have been called ‘probationer's weed.’" MORE

Vaughan Bell is a Senior Research Fellow at the Institute of Psychiatry, King’s College, London. He is also honorary professor at the Universidad de Antioquia in Medellín, Colombia.

"I was very struck by the appearance of classic Kluver form constants [after taking ayahuasca], geometric patterns that are probably caused by the drug affecting the visual neurons that deal with basic perceptual process (e.g. line detection)." MORE

Jon Simons, a cognitive neuroscientist, is a lecturer in the Department of Experimental Psychology at the University of Cambridge, UK, and principal investigator at the University’s Memory Laboratory.

“If you’re at a party and happen to drunkenly strike up conversation with Angelina Jolie (or Brad Pitt, if you prefer) and, bowled over by your charm and witty repartee, she tells you her phone number, you may well not remember it when you wake up sober the next morning. However, the evidence suggests that you would have a better chance of recalling the number if you got drunk again." MORE

Bankole Johnson is professor and chairman of the University of Virginia’s Department of Psychiatry and Neurobehavioral Sciences.

“With growing and clear acceptance of the neurobiological underpinnings of addiction, our work on pharmacogenetics promises to provide effective medications—such as ondansetron—that we can deliver to an individual likely to be a high responder, based on his or her genetic make up." MORE

Michael Farrell is the director of the National Drug and Alcohol Research Centre (NDARC) at the University of New South Wales in Sydney, Australia. Before that, he was Professor of Addiction Psychiatry at the Institute of Psychiatry at Kings College, London.

“The near complete absence of methadone or buprenorphine treatment in American prisons is hard to understand, when you see what a great contribution US research and treatment with methadone and buprenorphine has had globally. Now there are over 300,000 people on methadone in China as part of HIV and AIDS prevention." MORE

Deni Carise is a clinical psychologist who serves as senior vice president and chief clinical officer at Phoenix House, a leading U.S. non-profit drug treatment organization with more than 100 programs in 10 states.

“Those in recovery see the disease of alcoholism or addiction as a moral obligation to get well. If you know you have this disease and the only way to keep it under control is not to use alcohol or drugs, then that’s what you have to do." MORE


Keith Laws is professor of cognitive neuropsychology and head of research in the School of Psychology at the University of Hertfordshire, UK.

"Some may tolerate 100s or even 1000s of E tablets, but for others far fewer may lead to memory problems. We can predict that 3 in 4 users will develop memory problems, but not which 3 or after how many tablets." MORE

photo credit: http://www.startawritingbusiness.co.uk

The Mysteries of the Blunt

Why do so many smokers combine tobacco with marijuana?

People who smoke a combination of tobacco and marijuana, a common practice overseas for years, and increasingly popular here in the form of “blunts,” may be reacting to some unidentified mechanism that links the two drugs. Researchers believe such smokers would be well advised to consider giving up both drugs at once, rather than one at a time, according to an upcoming study in the journal Addiction.

Clinical trials of adults with cannabis use disorders suggest that “approximately 50% are current tobacco smokers,” according to the report, which was authored by Arpana Agrawal and Michael T. Lynskey of Washington University School of Medicine, and Alan J. Budney of the University of Arkansas for Medical Sciences.  “As many cannabis users smoke a mixture of cannabis and tobacco or chase cannabis use with tobacco, and as conditioned cues associated with smoking both substances may trigger use of either substance,” the researchers conclude, “a simultaneous cessation approach with cannabis and tobacco may be most beneficial.”

A blunt is simply a marijuana cigar, with the wrapping paper made of tobacco and the majority of loose tobacco removed and replaced with marijuana. In Europe, smokers commonly mix the two substances together and roll the combination into a single joint, the precise ratio of cannabis and nicotine varying with the desires of the user. “There is accumulating evidence that some mechanisms linking cannabis and tobacco use are distinct from those contributing to co-occurring use of drugs in general,” the investigators say. Or, as psychiatry postdoc Erica Peters of Yale put it in a press release, “There’s something about tobacco use that seems to worsen marijuana use in some way.” The researchers believe that this “something” involved may be a genetic predisposition. In addition to an overall genetic proclivity for addiction, do dual smokers inherit a specific propensity for smoked substances? We don’t know—but evidence is weak and contradictory so far.

Wouldn’t it be easier to quit just one drug, using the other as a crutch? The researchers don’t think so, and here’s why: In the few studies available, for every dually addicted participant who reported greater aggression, anger, and irritability with simultaneous cessation, “comparable numbers of participants rated withdrawal associated with dual abstinence as less severe than withdrawal from either drug alone.” So, for dual abusers, some of them may have better luck if they quit marijuana and cigarettes at the same time. The authors suggest that “absence of smoking cues when abstaining from both substances may reduce withdrawal severity in some individuals.” In other words, revisiting the route of administration, a.k.a. smoking, may trigger cravings for the drug you’re trying to quit. This form of “respiratory adaption” may work in other ways. For instance, the authors note that, “in addition to flavorants, cigarettes typically contain compounds (e.g. salicylates) that have anti-inflammatory and anesthetic effects which may facilitate cannabis inhalation.”

Studies of teens diagnosed with cannabis use disorder have shown that continued tobacco used is associated with a poor cannabis abstention rate. But there are fewer studies suggesting the reverse—that cigarette smokers fair poorly in quitting if they persist in cannabis use. No one really knows, and dual users will have to find out for themselves which categories seems to best suit them when it comes time to deal with quitting.

We will pass up the opportunity to examine the genetic research in detail. Suffice to say that while marijuana addiction probably has a genetic component like other addictions, genetic studies have not identified any gene variants as strong candidates thus far. The case is stronger for cigarettes, but to date no genetic mechanisms have been uncovered that definitively show a neurobiological pathway that directly connects the two addictions.

There are all sorts of environmental factors too, of course. Peer influences are often cited, but those influences often seem tautological: Drug-using teens are members of the drug-using teens group. Tobacco users report earlier opportunities to use cannabis, which might have an effect, if anybody knew how and why it happens.

Further complicating matters is the fact that withdrawal from nicotine and withdrawal from marijuana share a number of similarities.  The researchers state that “similar withdrawal syndromes, with many symptoms in common, may have important treatment implications.” As the authors sum it up, cannabis withdrawal consists of “anger, aggression or irritability, nervousness or anxiety, sleep difficulties, decreased appetite or weight loss, psychomotor agitation or restlessness, depressed mood, and less commonly, physical symptoms such as stomach pain and shakes/tremors.” Others complain of night sweats and temperature sensitivity.

And the symptoms of nicotine withdrawal? In essence, the same. The difference, say the authors, is that cannabis withdrawal tends to produce more irritability and decreased appetite, while tobacco withdrawal brings on an appetite increase and more immediate, sustained craving. Otherwise, the similarities far outnumber the differences.

None of this, however, has been reflected in the structure of treatment programs: “Emerging evidence suggests that dual abstinence may predict better cessation outcomes, yet empirically researched treatments tailored for co-occurring use are lacking.”

The truth is, we don’t really know for certain why many smokers prefer to consume tobacco and marijuana in combination. But we do know several reasons why it’s not a good idea. Many of the health-related harms are similar, and presumably cumulative: chronic bronchitis, wheezing, morning sputum, coughing—smokers know the drill. Another study cited by the authors found that dual smokers reported smoking as many cigarettes as those who only smoked tobacco. All of this can lead to “considerable elevation in odds of respiratory distress indicators and reduced lung functioning in those who used both.” However, there is no strong link at present between marijuana smoking and lung cancer.

Some researchers believe that receptor cross-talk allows cannabis to modify receptors for nicotine, or vice versa. Genes involved in drug metabolism might somehow predispose a subset of addicts to prefer smoking. But at present, there are no solid genetic or environmental influences consistent enough to account for a specific linkage between marijuana addiction and nicotine addiction, or a specific genetic proclivity for smoking as a means of drug administration.

Agrawal, A., Budney, A., & Lynskey, M. (2012). The Co-occurring Use and Misuse of Cannabis and Tobacco: A Review Addiction DOI: 10.1111/j.1360-0443.2012.03837.x

Photo credit:  http://stuffstonerslike.com

The Black Bag: Odds and Ends

Drug news from the world of science and medicine.


--How Marijuana Impairs Memory

Mo Costandi at the UK Guardian expands on his Nature article about the mechanisms that result in memory impairment when people smoke marijuana. Memory formation depends on the neurotransmitter glutamate. What goes wrong when you smoke pot? Enter the astrocyte…

--Coffee Will Disrupt Your Sleep—Unless You’re a Night Owl

From Scientific American comes the news that your “chronotype”—the chronological patterns you naturally favor—may determine whether or not caffeine keeps you tossing and turning and night. Morning people, or “larks,” had more periods of wakefulness during sleep hours than night people, or “owls.” The findings, published in the journal Sleep Medicine, show that “for the early risers, the more caffeine in their bodies, the more time they spent awake during the night after initially falling asleep. This was not seen in the night owls.”

--Brain Scans Get Better

You wouldn’t know it from all the bad press about moving heads and specious interpretations, but fMRI technology continues to improve. Time Healthland reports that new machines will be able to do a better job spotting traumatic brain injury in military personnel, athletes, and accident victims. High-definition fiber tracking, as this article in the Journal of Neurosurgery explains, will allow medical staff to better assess damage to nerve fibers deep in the brain, due to technological improvements in “assessing white matter injuries that are not apparent in standard anatomical imaging.”

--Cig Makers Trump FDA on Free Speech Grounds

The FDA maybe didn’t think this one through quite as thoroughly as they should have. Reuters reports  that a U.S. judge “sided with tobacco companies on Wednesday, ruling that regulations requiring large graphic health warnings on cigarette packaging and advertising violate free-speech rights under the U.S. Constitution.” Evidently, FDA officials didn’t see the 1st Amendment argument coming. By mandating grisly pictures of diseased lungs, rotting teeth, and dying smokers on cigarette packs, “the government has failed to carry both its burden of demonstrating a compelling interest and its burden of demonstrating that the rule is narrowly tailored to achieve a constitutionally permissible form of compelled commercial speech," U.S. District Judge Richard Leon said.

--Meth Head Burns Down Tree Older Than Jesus

And finally, as if we needed any more evidence, here’s a story about bad decision-making among the meth head crowd: WFTV reports that a female meth addict in Seminole County, Florida, burned down a historic cypress believed to have been the world’s 5th oldest tree. Authorities learned that the woman and a friend had been cooking methamphetamine under the 3,500 year-old tree. Officials said the woman took pictures of the disaster with her cell phone, and was quoted saying: "I can't believe I burned down a tree older then Jesus."

Photo Credit: http://www.squidoo.com 

A Six-Pack of Prior Posts

Don’t fear the chemistry. 

This isn’t a top 10 list, just a compilation of five previous posts here at Addiction Inbox that have continued to draw reader interest since they were first published. If there is a theme running through this set, it is neurochemistry at its most basic level. Take a look, if any of the subjects interests you. (My most popular post of all, on Marijuana Withdrawal, has turned into a self-help message board. I note it here, but leave it off the list, as it has become a blog of its own for all practical purposes.)
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1) Don’t let anyone tell you that the basic notions involved in neurotransmitter action in the brain are over everyone’s head. This post about serotonin and dopamine basics has always been popular, partly because serotonin and dopamine have gone from obscure abstractions to pop buzzwords. But I think it also shows a growing awareness of brain science and its real-world applications among interested readers.

“…. Addictive drugs have molecules that are the right shape for the amine receptors. Drugs like LSD and Ecstasy target serotonin systems. Serotonin systems control feeding and sleeping behaviors in living creatures from slugs to chimps. Serotonin, also known as 5-HT, occurs in nuts, fruit, and snake venom. It is found in the intestinal walls, large blood vessels, and the central nervous system of most vertebrates. The body normally synthesizes 5-hydroxytryptamine, as serotonin is formally known, from tryptophan in the diet….”

Serotonin and Dopamine: A primer on the molecules of reward
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2) Continuing on the chemistry theme, this post on anandamide, the brain’s own form of internal marijuana, has garnered steady attention since 2008. It may be coincidental, but the post also makes mention of serotonin and dopamine.

“…Several years ago, molecular biologists identified the elusive brain receptor where THC, the active ingredient in marijuana, did its work. Shortly after that discovery, researchers at Hebrew University in Jerusalem identified the body’s own form of THC, which sticks to the same receptors, in pulverized pig brains. They christened the internally manufactured substance “anandamide,” after the Sanskrit ananda, or bliss…”

Anandamide, the Brain’s Own Marijuana: Anxiety and the THC receptor.
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3) Interest in the anti-craving drug Topamax, an anti-seizure medication used to treat alcoholism, remains strong with blog readers, although the drug has not become the universal blockbuster many advocates had hoped.

“…Dr. Bankole Johnson, chairman of Psychiatry and Neurobehavioral Sciences at the University of Virginia, told Bloomberg News that Topamax does everything researchers want to see in a pharmaceutical treatment for alcoholism: “First, it reduces your craving for alcohol; second, it reduces the amount of withdrawal symptoms you get when you start reducing alcohol; and third, it reduces the potential for you to relapse after you go down to a low level of drinking or zero drinking…"

Topamax for Alcoholism: A Closer Look. Epilepsy drug gains ground, draws fire as newest anti-craving pill
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4) One of the most popular posts to date was this examination of neurological questions surrounding marijuana and memory loss. Inquiring minds, uh, forget the question. Oh yeah: Does the strain of dope you smoke determine how forgetful you’ll become?

“…As far as memory goes, THC content didn't seem to matter. It was the percentage of cannabidiol (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..." 


Marijuana and Memory: Do certain strains make you more forgetful?
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5) Finally, a popular post focusing on the biochemistry of nicotine in e-cigarettes, the new, smokeless nicotine delivery system. Are they safe? The latest in harm reduction strategies, or starter kits for youngsters?

“…You may never have heard of it—but it’s the newest drug in town. It’s called an electronic cigarette, or “e-cigarette.” Electronic cigarettes use batteries to convert liquid nicotine into a fine, heated mist that is absorbed by the lungs. No smoke, but plenty of what makes cigarettes go, if you don’t account for taste—or ashtrays and smoke rings….”

E-Cigarettes and Health: Smokeless nicotine comes under scrutiny.

Photo Credit: http://www.livingim.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/

Common Field Test for Marijuana is Unreliable, Critics Say

A 75-year old pot assay is due for an update.

We’ve all seen it on cop shows: The little plastic bag, the officer breaking the seal on a small pipette and inserting a bit of marijuana, then a firm shake, and voila, the liquid in the test satchel turns purple: Guilty.

Here’s an interesting twist they don’t tell you about: The so-called Duquenois-Levine test—the dominant method for field-testing marijuana since 1930—is considered by many to be wildly inaccurate, and frequently doesn’t hold up in court. One U.S. Superior Court judge referred to the test as “pseudo-scientific.”

The test itself works fine. The problem is that, in addition to identifying marijuana or hashish, the Duquenois-Levine, or D-L, frequently reads positive for tea, nutmeg, sage, and dozens of other chemicals—including resorcinols, a family of over-the-counter medicines, which, according to John Kelly at AlterNet, includes Sucrets throat lozenges. This does matter, because in New York, Washington, D.C., and elsewhere, inner-city minority kids are getting busted for pot in record numbers. Lacking a reliable test protocol, marijuana is whatever the officer says it is. In a classic case that continues to bedevil the testing industry, a middle-aged woman was busted for marijuana while bird watching. A “leafy substance” turned purple on the Duquenois-Levine (D-L) test, and the woman was arrested. The material turned out to be sage, sweetgrass, and lavender, and the woman was engaging in a Native American purifying ritual using a smudge, a concept with which the arresting officers were unfamiliar.

So, when push comes to shove, a positive D-L rarely establishes the presence of marijuana beyond a reasonable doubt, without further confirmatory testing. For at least 20 years now, a visual inspection and a NarcoPouch, as the D-L field test is called, were enough to bring on the felony charges. State courts have squabbled over the matter, but state legislatures have been reluctant to intervene, in large part because sending samples to a lab for confirmatory testing is prohibitively expensive, particularly when the busts are small. The D-L test saves money.

According to the official drug policy of the United Nations, a positive marijuana ID requires gas chromatography/mass spectrometry analysis. And even this far more sophisticated test has angered courts in Washington and Colorado, the UK Guardian reports, “because the DEA doesn’t have standard lab protocols to govern its use.” In part, the judges are furious because plea-bargaining depends upon valid drug possession evidence. So, the officers themselves, when it comes to testifying in court, become de facto expert witnesses, able to identify illegal drugs on sight. Ah, those were the days. But now, cannabis-based products come in a bewildering variety of sizes, shapes, colors, smells, and chemical compositions.

But c’mon, if it looks like bud and it smells like bud… except that the research shows there are 120 terpenoid-type compounds involved in the odor of marijuana. No two varieties smell exactly alike. There is no characteristic marijuana smell—there are hundreds of characteristic marijuana smells. Nonetheless, in 2009 the National Academy of Sciences called the testing of controlled substances “a mature forensic science discipline,” according to AlterNet.

In a 2008 article for the Texas Tech Law Review, Frederic Whitehurst, Executive Director for the Forensic Justice Project and formerly with the FBI, concluded: “We are arresting vast numbers of citizens for possession of a substance that we cannot identify by utilizing the forensic protocol that is presently in use in most crime labs in the United States.” In another section of the article, Whitehurst asks: “Why is this protocol still being utilized to decide whether human beings should be confined to cages and at times, to death chambers?” And as Stewart J. Lawrence and John Kelly write in the Guardian, “using manifestly flawed drug identification tests to charge defendants, or pressure them to plead guilty, is hard to square with a defendant’s right to due process.”

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