Synthetic Cannabis Can Cause Cyclic Vomiting

Another reason to skip "Spice."

Cannabinoid hyperemesis,  as it is known, was not documented in the medical literature until 2004. Case studies of more than 100 patients have been reported since then. The biomedical researcher who blogs as Drugmonkey has 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 who are heavy marijuana smokers, and who experience cyclic nausea and vomiting, “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 recent report in Mayo Clinic Proceedings by Dr. Benjamin L. Bick and colleagues documents the 3rd reported case of the syndrome in a regular user of synthetic Spice-style products, rather than marijuana. It’s now clear that THC isn’t necessary for triggering the rare but highly unpleasant vomiting cycle in a small fraction of users.

“A 29-year-old man presented with a 2-year history of recurrent episodes of severe nausea and vomiting with epigastric pain,” according to the authors. Drug tests were negative, including tests for THC. “For his more recent symptoms, he was evaluated multiple times in the primary care setting and emergency department. At each visit he denied use of any ‘illicit substances or drugs’ since he quit using marijuana.”

“Hot showers for up to an hour provided relief. He reported experiencing similar symptoms more than 5 years previously when he was regularly smoking marijuana, and these symptoms resolved with the cessation of cannabis.”

The patient eventually admitted to regularly smoking products sold as K2 and Kryptonite, containing “unidentified and uncertain synthetic cannabinoid agonists marketed as ‘legal’ herbal incense.”

The Mayo clinicians offer diagnostic criteria for cannabis hyperemesis, which include “long-term cannabis use, cyclic nausea and vomiting, resolution with cessation of cannabis, relief of symptoms with hot showers, abdominal pain, and weekly use of marijuana.” And theirs is the third published report of cannabis hyperemesis in a male patient after synthetic cannabinoid use. “After 6 months abstinence,” they report, “he noted complete resolution of symptoms.”

The researchers conclude that “synthetic cannabinoids can be potent agonists of the cannabinoid CB1 receptors, which are the same receptors by which THC produces its effects.” While only three Spice-related incidents of hyperemesis syndrome have thus far been identified, it may go unrecognized in patients using synthetic cannabinoids:

 A urine drug screen negative for THC may point physicians away from this syndrome, and patients may not report use if they believe they are using herbal products rather than illicit drugs. Therefore, regardless of negative urine drug screen results and patient denial of cannabis use, physicians should have a high index of suspicion for synthetic CH syndrome in patients who present with classic symptoms of cyclic emesis.

Sarah A. Buckley and Nicholas M. Mark at the NYU School of Medicine, after reviewing 16 published papers on the syndrome,  asked the obvious question: "How can marijuana, which is used in cancer clinics as an anti-emetic, cause intractable vomiting? And why would symptoms abate in response to high temperature?"

We don't know the answer, but Buckley and Mark note that "cannabis disrupts autonomic and thermoregulatory functions of the hippocampal-hypothalamic-pituitary system," which is loaded with CB-1 receptors. The researchers conclude, however, that the link between marijuana and thermoregulation "does not provide a causal relationship" for what they refer to as "this bizarre learned behavior.”

Bick B.L. &  Thomas F. Mangan (2014). Synthetic Cannabinoid Leading to Cannabinoid Hyperemesis Syndrome, Mayo Clinic Proceedings, 89 (8) 1168-1169. DOI: http://dx.doi.org/10.1016/j.mayocp.2014.06.013

Photo credit: http://www.aquaticcreationsnc.com/custom.htm

“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: 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

Spice, K2, Other “Fake Pot” Illegal as of March 1

DEA makes synthetic marijuana a Schedule 1 drug.

The U.S. Drug Enforcement Administration (DEA) exercised its emergency scheduling authority yesterday to outlaw the use of “fake pot” products.

Sixteen states have already passed a mishmash of legislation outlawing one or more of the drugs in question, which are typically sold as Spice, K2 or Red X.

The DEA had already announced its intention to put 5 new drugs--JWH-018, JWH-073, JWH-200, CP-47, 497, and cannabicyclohexanol--on the official list of scheduled substances. “These products consist of plant material that has been coated with research chemicals that claim to mimic THC, the active ingredient in marijuana, and are sold at a variety of retail outlets, in head shops, and over the Internet,” the DEA said in a prepared statement. “The temporary scheduling action will remain in effect for at least one year while the DEA and the United States Department of Health and Human Services (DHHS) further study whether these chemicals should be permanently controlled."

According to the DEA, “Emergency room physicians report that individuals that use these types of products experience serious side effects which include: convulsions, anxiety attacks, dangerously elevated heart rates, increased blood pressure, vomiting, and disorientation.”

The smokable herbal products were designated as Schedule 1 substances, the federal government’s most restrictive category, ostensibly reserved for drugs with “no accepted medical use for treatment in the United States and a lack of accepted safety for use of the drug under medical supervision.” Marijuana is also a Schedule 1 drug, along with heroin, Ecstasy, and LSD. The supposedly less dangerous Schedule 2 drugs, bizarrely, contain the most problematic drugs of all in terms of human health and addictive potential: methamphetamine, oxycontin, and cocaine. Schedule 3 is so confusing as to defy coherent description, while Schedule 4 is the valium category and Schedule 5 is the Robitusson category.

One problem with the whack-a-mole approach to drug enforcement is that developers of designer drugs can easily stay one jump ahead of the law. What many drug officials and agencies, including the International Narcotics Control Board, want to see is sweeping, generic bans on whole categories of chemicals, in order to win the game of leapfrog.

However, as reported by Maia Szalavitz at Time Healthland, broad-spectrum drug bans “could have the unintended effect of keeping potential cures for diseases like Alzheimer’s out of the pharmaceutical pipeline.” As Szalavitz notes, “getting a drug out of Schedule 1 is much harder than getting it into that legal category, as supporters of medical marijuana and MDMA have discovered.”

And if clinical researchers wish, say, to pursue JWH-133--a chemical compound closely related to the newly banned drugs—for its ability to reduce the inflammation associated with plaque buildup in the brains of people with Alzheimer’s, they are going to find that research almost impossible to do, as more and more chemicals escape the lab or emerge from the work of underground chemists and ultimately become illegal substances.

Notice of Intent to Temporarily Control Five Synthetic Cannabinoids

Graphics Credit: http://newsbythesecond.com/

DEA Slaps Temporary Ban on Spice and Other “Fake Pot” Products

Synthetic cannabis now illegal for one year.

The material below is excerpted directly from the official press release of the U.S Drug Enforcement Administration Public Affairs Office:

The United States Drug Enforcement Administration (DEA) is using its emergency scheduling authority to temporarily control five chemicals (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) used to make “fake pot” products.  Except as authorized by law, this action will make possessing and selling these chemicals or the products that contain them illegal in the U.S. for at least one year while the DEA and the United States Department of Health and Human Services (DHHS) further study whether these chemicals and products should be permanently controlled. 

A Notice of Intent to Temporarily Control was published in the Federal Register today to alert the public to this action. After no fewer than 30 days, DEA will publish in the Federal Register a Final Rule to Temporarily Control these chemicals for at least 12 months with the possibility of a six-month extension. They will be designated as Schedule I substances, the most restrictive category, which is reserved for unsafe, highly abused substances with no medical usage.

Over the past year, smokable herbal blends marketed as being “legal” and providing a marijuana-like high, have become increasingly popular, particularly among teens and young adults.  These products consist of plant material that has been coated with research chemicals that mimic THC, the active ingredient in marijuana, and are sold at a variety of retail outlets, in head shops and over the Internet.  These chemicals, however, have not been approved by the FDA for human consumption and there is no oversight of the manufacturing process.  Brands such as “Spice,” “K2,” “Blaze,” and “Red X Dawn” are labeled as incense to mask their intended purpose.

Graphics Credit: http://thefreshscent.com/

The New Cannabinoids

Army fears influx of synthetic marijuana

It’s a common rumor: Spice, as the new synthetic cannabis-like products are usually called, will get you high--but will allow you to pass a drug urinalysis. And for this reason, rumor has it, Spice is becoming very popular in exactly the places it might be least welcomed: Police stations, fire departments—and army bases.

What the hell is this stuff?

Little is known about spice and other synthetic twists on basic cannabinoid molecules. We do know that the near-cannabis compounds are hard to detect, and even harder to legislate against without closing down avenues of legitimate research. It appears evident that a number of cannabinoid compounds are in circulation, and the precise nature of any given dose is difficult to determine. Much like trying the brown acid, or the joint laced with PCP, the effects vary widely. There are numerous anecdotal reports that spice and its cousins are extremely dose dependent.

The best coverage of Spice, K2, and similar “legal highs” has been generated by science bloggers—especially David Kroll at Terra Sigillata, DrugMonkey at DrugMonkey blog,  and Dr. Leigh at Neurodynamics.  Readers are advised to consult these links for the most comprehensive coverage of this emerging drug issue.

David Kroll  aptly summarized what we know about the "fake weed."

"Synthetic marijuana, marketed as K2 or spice, is an herbal substance sold as an incense or smoking material that remains legal in much of the United States but is being increasingly banned at the state and local levels. The products contain one or more synthetic compounds that behave similarly to the primary psychoactive constituent of marijuana, delta nine tetrahydrocannabinol or THC.”

Kroll writes that JWH–018 is "one of over 100 indoles, pyrroles, and indenes synthesized by the Huffman laboratory to develop cannabimimetics, drugs that mimic the effect of cannabinoids such as THC.”

Furthermore: “The compound most commonly found in these products is a chemical first synthesized by the well-known Clemson University organic chemist, Prof. John W Huffman: the eponymous JW H–018. Another compound, found in spice products sold in Germany, is an analog of CP-47, 497, a cannabinoid developed by Pfizer over 20 years ago."

The cannabimimetics are back.

Unfortunately, the chemical compositions vary, as do the effects, all of which is unpleasantly reminiscent of PCP problems in the past. To gain a better perspective on the matter, I spoke with Joe Gould, a staff writer for the Army Times  who has been covering the issue of Spice use in the Armed Forces. Gould has written extensively on the case of Spc. Bryan Roudebush, who attacked his girlfriend in Hawaii while under the influence of Spice. Roudebush had been home from an Iraq deployment for a year when the incident occurred. Two earlier experiences with spice had produced marijuana-like effects. But for Roudebush, the third time was not the charm: He beat his girlfriend and tried to throw her out a window while experiencing what he described as a trance-like state.

“What we were told by the folks at the Army Criminal Investigation Lab is that it started showing up on bases,” said Gould, “and the investigators on the bases were baffled, and the crime lab wasn’t sure what it was at first.”

What investigators discovered was “all that really defines a synthetic cannabinoid is that it activates cannabinoid receptors. We know what THC does. But the chemical composition is not THC. There are all these different strains. Some of the state laws we’ve been seeing, they’re targeting specific varieties of this stuff, but there are other varieties that the law doesn’t know about yet. So I think what the Army has done, intentionally or not, it has sort of skirted this whole question by just calling it all Spice.”

As for the Roudebush case, Gould said: “The first two times he tried it, it was very much like pot. And then the third time, by his and his girlfriend’s description, he goes into a violent trance. They think it was just a different variety. It’s kind of a mystery. What was in that batch? Why did it affect him the way it did? It just goes to how little is known about the drug. You don’t know from one batch to another.”

The U.S. Army currently has no specific testing program in place for Spice. Can you pass a drug test on Spice? “That’s what we heard,” Gould told me. “A researcher from NIH told us exactly that—they believe that the reason it’s popular, the reason they’ve seen officials using it, is because it can’t be tested for.” Despite this, Gould said he knew of “at least nine Commands that have individually passed regulations to target Spice.”

Gould downplayed any talk of an epidemic of usage, and made clear that his research shows that Spice usage is not rampant. “It’s not entirely clear how many soldiers are using Spice. The Army’s not really tracking the use of Spice. Each of these commands passed these regulations either because they saw a problem, or because they were trying to get out in front of what could potentially be a problem.”

Too far out in front for Phillip Cave, a Virginia attorney who has represented military personnel in cases involving Spice. Gould quotes Cave calling the whole thing a “witch hunt,” noting that alcohol is freely available on base, and that researchers do not yet knew whether Spice and its analogs are unsafe or addictive—and they are illegal in only a handful of states at present. Cave also objects to the fact that most cases have been resolved by an Article 15 discharge from service.

“The European Union study says there is the potential for abuse,” said Gould. “How bad it gets, we won’t know until we see more studies.”

Hand-in-hand with restrictions on Spice have come crackdowns on the use of Salvia, a plant responsible for brief but intense bouts of hallucinogenic effects. “The state laws have tended to tackle the two at once,” according to Gould.  “Like the state legislatures, the Army has a patchwork of bans they’re putting out there, and there also hitting Salvia. But what I was told by the folks at the lab was that they’re not seeing it in the same kinds of numbers. It’s been sporadic at best.”