Spiced: Synthetic Cannabis Keeps Getting Stronger

Case reports of seizures in Germany from 2008 to 2011.

I wish I could stop writing blog posts about Spice, as the family of synthetic cannabinoids has become known. I wish young people would stop taking these drugs, and stick to genuine marijuana, which is far safer. I wish that politicians and proponents of the Drug War would lean in a bit and help, by knocking off the testing for marijuana in most circumstances, so the difficulty of detecting Spice products isn’t a significant factor in their favor. I wish synthetic cannabinoids weren’t research chemicals, untested for safety in humans, so that I could avoid having to sound like an alarmist geek on the topic.  I wish I didn’t have to discuss the clinical toxicity of more powerful synthetic cannabinoids like JWH-122 and JWH-210. I wish talented chemists didn’t have to spend precious time and lab resources laboriously characterizing the various metabolic pathways of these drugs, in an effort to understand their clinical consequences. I wish Spice drugs didn’t make regular cannabis look so good by comparison, and serve as an argument in favor of more widespread legalization of organic marijuana.

A German study, published in Addiction, seems to demonstrate that “from 2008 to 2011 a shift to the extremely potent synthetic cannabinoids JWH-122 and JWH-210 occurred…. Symptoms were mostly similar to adverse effects after high-dose cannabis. However, agitation, seizures, hypertension, emesis, and hypokalemia  [low blood potassium] also occurred—symptoms which are usually not seen even after high doses of cannabis.”

The German patients in the study were located through the Poison Information Center, and toxicological analysis was performed in the Institute of Forensic Medicine at the University Medical Center Freiburg. Only two study subjects had appreciable levels of actual THC in their blood. Alcohol and other confounders were factored out. First-time consumers were at elevated risk for unintended overdose consequences, since tolerance to Spice drug side effects does develop, as it does with marijuana.

Clinically, the common symptom was tachycardia, with hearts rates as high as 170 beats per minute. Blurred vision, hallucinations and agitation were also reported, but this cluster of symptoms is also seen in high-dose THC cases that turn up in emergency rooms. The same with nausea, the most common gastrointestinal complaint logged by the researchers.

But in 29 patients in whom the presence of synthetic cannabinoids was verified, some of the symptoms seem unique to the Spice drugs. The synthetic cannabinoids caused, in at least one case, an epileptic seizure. Hypertension and low potassium were also seen more often with the synthetics. After the introduction of the more potent forms, JWH-122 and JWH-210, the symptom set expanded to include “generalized seizures, myocloni [muscle spasms] and muscle pain, elevation of creatine kinase and hypokalemia.” The researchers note that seizures induced by marijuana are almost unheard of. In fact, studies have shown that marijuana has anticonvulsive properties, one of the reason it is popular with cancer patients being treated with radiation therapy.

And there are literally hundreds of other synthetic cannabinoid chemicals waiting in the wings. What is going on? Two things. First, synthetic cannabinoids, unlike THC itself, are full agonists at CB1 receptors. THC is only a partial agonist. What this means is that, because of the greater affinity for cannabinoid receptors, synthetic cannabinoids are, in general, stronger than marijuana—strong enough, in fact, to be toxic, possibly even lethal. Secondly, CB1 receptors are everywhere in the brain and body. The human cannabinoid type-1 receptor is one of the most abundant receptors in the central nervous system and is found in particularly high density in brain areas involving cognition and memory.

The Addiction paper by Maren Hermanns-Clausen and colleagues at the Freiburg University Medical Center in Germany is titled “Acute toxicity due to the confirmed consumption of synthetic cannabinoids,” and is worth quoting at some length:

The central nervous excitation with the symptoms agitation, panic attack, aggressiveness and seizure in our case series is remarkable, and may be typical for these novel synthetic cannabinoids. It is somewhat unlikely that co-consumption of amphetamine-like drugs was responsible for the excitation, because such co-consumption occurred in only two of our cases. The appearance of myocloni and generalized tonic-clonic seizures is worrying. These effects are also unexpected because phytocannabinoids [marijuana] show anticonvulsive actions in humans and in animal models of epilepsy.

The reason for all this may be related to the fact that low potassium was observed “in about one-third of the patients of our case series.” Low potassium levels in the blood can cause muscle spasms, abnormal heart rhythms, and other unpleasant side effects.

One happier possibility that arises from the research is that the fierce affinity of synthetic cannabinoids for CB1 receptors could be used against them. “A selective CB1 receptor antagonist,” Hermanns-Clausen and colleagues write, “for example rimonabant, would immediately reverse the acute toxic effects of the synthetic cannabinoids.”

The total number of cases in the study was low, and we can’t assume that everyone who smokes a Spice joint will suffer from epileptic seizures. But we can say that synthetic cannabinoids in the recreational drug market are becoming stronger, are appearing in ever more baffling combinations, and have made the matter of not taking too much a central issue, unlike marijuana, where taking too much leads to nausea, overeating, and sleep.

(See my post “Spiceophrenia” for a discussion of the less-compelling evidence for synthetic cannabinoids and psychosis).

Hermanns-Clausen M., Kneisel S., Hutter M., Szabo B. & Auwärter V. (2013). Acute intoxication by synthetic cannabinoids - Four case reports, Drug Testing and Analysis,   n/a-n/a. DOI: 10.1002/dta.1483

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

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/