Sustained interest in K2 Spice, JWH-018, and related currently-legal cannabimimetic products

Just a quick post this morning as I am performing my professional responsibility to our nation’s health research agency.
In yesterday’s issue of USA Today (which I only read on the iPhone app or when staying at a hotel that gives it to us free), Donna Leinwand wrote about a currently legal substitute for marijuana called by various names such as K2, Spice, Black Mamba.

Nearly a dozen states and several cities are banning or debating bans on K2 — a packet of herbs coated with a synthetic chemical that mimics a marijuana high when it’s smoked — amid fears that its use is spreading among young people.

Each of these products is comprised of a generic plant material fortified with one of more marijuana mimics, or cannabimimetics, originally synthesized in the 1990s by Clemson University organic chemist John W. Huffman and his graduate students. These compounds generally go by JWH followed by the lab’s code number for the compound. The most popular of these is JWH-018.
These compounds are not considered cannabinoids since they are synthetic and do not bear obvious structural similarity to Δ9THC or other naturally-occurring cannabinoids. However, these compounds do bind cannabinoid receptors in the brain and appear to produce psychoactive effects similar to that of marijuana. Descriptions of various K2 Spice products, and now pure JWH compounds that have become available, are richly described by our commenters to the February post. In fact, a comment received this week, speaks of the risks of the variable levels of JWH compounds that might be sprayed on different products.
The primary driver of K2 use appear to be by cannabis enthusiasts who are either on probation or otherwise subject to urinary drug screening tests that detect THC but not (yet) the JWH compounds. Others simply wish to purchase a still-legal high rather than risk the variable ire of law enforcement officials around the US.
For much more on the pharmacology and risks of dependence on K2 or pure JWH-018, you can read two posts written under the ScienceBlogs masthead in February, one by me and one by my blog brother, DrugMonkey.
Brother Drug and I have been completely blown away by the sustained interest in each of our posts that has actually grown over the last 100 days. In both of our cases, approximately 50% of our readership lands on our February K2 posts. Perhaps this is no surprise given that each of our posts show up at the top, or at least the first page, of Google search results for “K2 Spice.” On top of this, I was the beneficiary yesterday of Reddit member Travesura who recommended his followers to us with the teaser:

“Heard of that “K2 Spice” that everyone has their shorts in a wad over? Here is the best explanation that I have seen about what it is, and how it works.”

Thanks to Travesura and the timeliness of Leinwand’s USA Today article, our February K2 Spice was the landing site of 2,853 of our last 4,000 visitors.
Holy moly.
But I learned possibly of another trend: we received a fair number of hits yesterday from various US military IP addresses, some coming via search terms involving detection of JWH-018.
For our military readers, has any directive come down the pike that soldiers will now be screened for JWH-018 use? Or is this just a coincidence?
But I still have no explanation as to why both DrugMonkey and I are getting such sustained interest in this topic, even more than for previous posts that had short-term high readership such as herbal products adulterated with erectile dysfunction drugs and the Evolv water/M.D. Anderson kerfuffle.
Update: The always-excellent Erowid site has information on the approach to K2 Spice by the US military. The US Army has banned the substance and this January 23, 2010 article by Hope Hodge at the Jacksonville (NC) Daily News on the possible discharge of two Marines at Camp Lejune:

Marine Corps officials did not immediately respond to queries about working policies surrounding spice or how Marines aboard Camp Lejeune are briefed about it. Base officials said that, in place of specific guidance, the use of spice is illegal under SecNav Instruction 5300.28d and OpNav Instruction 5350.4c, which broadly regard substance abuse prevention and control.

Hodge followed up on February 5 with a report that the US Marines has issued a ban of 10 substances that include Spice and Salvia divinorum, the source of the disturbing hallucinogen, salvinorin A.

What’s the buzz?: Synthetic marijuana, K2, Spice, JWH-018

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Welcome to those of you arriving via Reddit from a very kind referral by Travesura. Please feel free to make any comments or ask any questions in the comment box at the end of this post.

My field of natural products pharmacology was founded by indigenous cultures who recognized that plants and fungi contain compounds that produce altered states of consciousness, leading to their most common use in religious ceremonies. While we may most often associate these naturally-occurring drugs with hallucinogens, the arguably most common natural product in use today is marijuana or Cannabis sativa. Indigenous to India and China, Cannabis has been the subject of increasing decriminalization worldwide due in part to its clinical, medicinal effects in multiple sclerosis, cancer, and AIDS.
K2 assortment.jpg

Over the last few months, I’ve seen reports of a so-called “synthetic marijuana” being sold on the internet with stories most commonly coming from England and Germany and, in the US, from Kansas, Missouri, and Arizona. In fact, the St. Louis Post-Dispatch reports today that a bill has been brought before the Missouri House Public Safety Committee seeking to add this product to the state’s list of illegal drugs.

I became intrigued as to why anyone would go through the trouble of making a synthetic marijuana when the real thing is so readily cultivated worldwide, albeit illegally in most locales.

So what is it?

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University of Colorado student died of opium tea overdose

After writing this post, I came across Alex’s obituary and guestbook on By all accounts, Alex was a great kid – loved and admired by many – an accomplished hockey player and musician with a love for the mountains. This could have been you or I, or worse, one of our own children.
Breaking my heart this morning is news from Boulder that last month’s death of 20-year-old CU student, Alexander McGuiggan, was from consumption of “opium tea.”

Police department spokeswoman Sarah Huntley said investigators believe McGuiggan and others had acquired poppy plants — which are available legally over the Internet — and were boiling pods to make intoxicating tea.
Police believe McGuiggan knew that the tea he was drinking was made of opiates, Huntley said.
“What he may not have been as aware of was the dangers of what he was ingesting,” she said.
The Boulder County Drug Task Force is investigating other people who may have been involved in “the procurement of the tea, and the making of the tea,” Huntley said. Those people could face charges, she said.

A previous report has been that the student and friends were boiling up poppy seeds, but I was suspicious as those lack significant amounts of opiates. Instead, as Ryan Morgan of The Boulder Daily Camera reports accurately, the students appear to have obtained seeds for Papaver somniferum, and grown plants, and extracted the latex from mature pods. Opium is an alcoholic tincture of the pod latex and is comprised of approximately 10% morphine, 0.5% codeine, and other lesser naturally-occurring opioids (the plant synthesizes these opiates of the “benzomorphan” class in a biosythetic pathway beginning with the amino acid, L-tyrosine.).
The sad fact is that we’ve known for over 200 years that this is a bad idea: based upon growing conditions, harvest time, and extraction method, the resulting concoction can provide an extremely variable dose of these compounds. Used medicinally as one of the strongest analgesics (“painkillers”) we know, in higher doses the opiates can impart a warming sense of euphoria but, at even higher doses, suppresses the respiratory control center of the brain stem, resulting in death.

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Century-old rule of chemistry overturned? Meh, not so fast

A couple of colleagues turned me on the other morning to a press release by researchers at the University of Warwick who recently published in PNAS that their data apparently overturns the Meyer-Overton Rule regarding solubility of a compound in olive oil and its propensity for crossing biological membranes. I’m having trouble understanding exactly why their conclusions are earth-shattering.
At the turn of the last century, Meyer (1899) and Overton (1901) independently conducted experiments to demonstrate that the longer the carbon chain of a molecule, the better it partitioned into olive oil relative to water, and the more potent it would be as a general anesthetic (I’m almost certain that Meyer did his anesthetic work in tadpoles). This is back when we thought that general anesthetics worked primarily by disrupting ion channel function by altering cell membrane structure (it’s actually more complicated than that, involving anesthetic molecules directly interacting with hydrophobic surfaces on ion channels, but the bottom line is that the better a molecule partitions into the lipid portion of the cell membrane, the greater its anesthetic potency. This point only holds true for inhaled gases from nitrous oxide to halogenated hydrocarbons like isoflurane and is unrelated to sedative/hypnotics used in anesthesia that have discrete molecular actions such as benzodiazepines like diazepam or opiates like fentanyl).
The press release from the University of Warwick describes what appear to be really cool electrochemical experiments with ultramicroelectrodes and confocal microscopy that are to be published in the 26 August 2008 issue of the Proceedings of the National Academy of Sciences (PNAS). The research team apparently provides direct evidence that increasing carbon chain length of carboxylic acids (acetic, butanoic, valeric, and hexanoic) cause them to pass through membranes progressively more slowly.
But instead of being at odds with the Meyer-Overton correlation, this is exactly what one would expect from the Meyer-Overton experiments.
The point is that membrane-disrupting anesthetics act primarily by staying in the membrane. (I might add that the press release is vexing to me because it fails to refer to the work of Meyer, calling it the Overton rule, and uses the term “cell wall” instead of “cell membrane.”)

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A celebration of life-saving natural products

The statin class of cholesterol-lowering agents is rich with history and lessons in the power of natural products, the potential of the prepared mind, and just how precarious the path of drug development can be.
American Scientist, the official publication of the scientific research society Sigma Xi, hosts this issue an absolutely lovely article entitled, “Statins: From Fungus to Pharma.”
Expertly and engagingly written by University of Pennsylvania biology professor Dr Philip A Rea, the article launches with the story of a then-young Japanese biochemist, Akira Endo. (Evidence of my longstanding admiration for Dr Endo goes back beyond my 10 Jan 2006 post, “All hail, Dr Akira Endo.”).

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Detecting ESA (EPO) doping in sports

Jake Young, the MD/PhD student blogging at Pure Pedantry, has a great post this week on the detection of a novel formulation of the erythropoiesis stimulating agent (ESA) erythropoietin in Riccardo Riccó, the Italian cyclist who was thrown out of the Tour de France. Jake’s post is a superb primer on the use of this peptide hormone as a therapeutic agent (in the anemia caused by kidney failure and in cancer chemotherapy).
His essay also reminds me that I commented on this issue at DrugMonkey’s a post exactly a week ago (and from this same couch at my local coffee shop while waiting for PharmKid to finish her Saturday morning dance lesson.). Drug thought it would be a good post but the week got away from me. So go read Jake’s comprehensive post first and then consider my comments (also below) on how this novel formulation of Epo might have been detected:

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Can academic drug discovery programs improve on pharma’s relative stagnation?

A paper in last month’s issue of Nature Reviews Drug Discovery reported that US drug approvals during 2007 were the lowest number since 1983. (17 new molecular entities and 2 biologicals; see this figure for 1996-2007 data.) The review cites increased regulatory action as a factor in this reduction, especially following high-profile post-marketing safety issues with blockbuster drugs like Vioxx or Avandia. But other commentators have noted other problems such as the science of drug discovery in pharma being overridden by managers or the reluctance to develop agents for diseases that afflict less-than-blockbuster-sized patient populations.
I mention this in light of an article earlier this week by Sabine Vollmer of the Raleigh News & Observer on the establishment of drug discovery centers at Duke University and the University of North Carolina at Chapel Hill, each of which are led by former pharmaceutical company scientist/managers. Vollmer notes that Emory and Vanderbilt University have established similar programs. I believe that Vanderbilt has even invested in its own GMP drug manufacturing facility and was probably one of the first to have such a concerted effort.

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Looking for expert commentary on generic “follow-on” biologics

Last week we spent some time discussing the shortcomings of the generic vs. brand name drug debate, focusing on an example of non-bioequivalence between the antidepressant Wellbutrin XL and its generic competitors.
Three days later, I then received an e-mail from one John Procter about a movement to get Washington to move forward on the approval of lower-priced generic biotechnology drugs now that original branded products are facing patent expiration. One source indicates that a $20 billion market value of biological products will be coming off patent by 2015. The US FDA has been reluctant to approve general formulations of biological agents that include protein hormones like erythropoietin and other protein-based therapeutics such as antibodies or antibody-toxin/radionuclide conjugates.

Dear Friend:
A virtual monopoly has limited access to biotechnology drugs for too long, costing our families billions at a time when healthcare costs continue to rise. Recent studies show Americans could save $378 billion over 20 years if generic biologics-costly drugs made by manipulating proteins-were available in the United States as they are in Europe. Although biologics are more than 20 times more expensive than traditional drugs, Washington has yet to approve generic versions in the U.S.
It is time for Washington to give us a choice of generic biotech drugs to treat diseases such as diabetes, cancer, and Alzheimer’s.
We need your help!
Watch our YouTube video [or see below the fold] to Congress, and post your own video or message to lawmakers on why access to safe, affordable biotechnology drugs should happen now!

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Don’t drink the denture cleanser, don’t swallow the inhalation capsules

The safety and effectiveness of medicines and other health products is dependent upon their proper use, particularly the proper route of administration. There are reasons why products are labeled as “for topical use only” or “do not swallow” – two recent warnings from the US FDA illustrate these issues.
Allergic Reactions with Use/Misuse of Denture Cleansers
The FDA recently announced reports of one death and 72 other adverse reactions in individuals who ingested denture cleansers meant to be used in a container with one’s dentures removed. A crucial oxidizing agent, salts of persulfate, can cause allergic reactions in susceptible individuals when swallowed, when swished in the mouth or, more alarmingly, even when residual cleanser solution remains on the dentures when reinserted.
[All sorts of biologists will recognize persulfate (ammonium salt) as the oxidizing agent used to catalyze the crosslinking of acrylamide monomers to make gels for the resolution of proteins and nucleic acids – that is, if you don’t have the luxury of purchasing per-poured gels]

An allergic reaction to persulfates may not occur after the first use or even until after many years of use. Symptoms of an allergic reaction may not appear for several minutes or even hours after actual use. Symptoms may include irritation, tissue damage, rash, hives, gum tenderness, breathing problems, and low blood pressure.

As a result of these cases, FDA is recommending that denture cleanser manufacturers clarify product instructions and offer a consumer education campaign (FDA’s PDF here). Moreover, FDA is recommending that manufacturers begin to investigate the potential for replacing persulfate with other oxidizing/bleaching agents that do not cause these hypersensitivity reactions:

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Are generic drugs inferior to the corresponding brand names?

This issue was brought up by my fellow blogger, Joseph at Corpus Callosum, following an article in yesterday’s LA Times.
For those not familiar with the concept or countries other than the US where laws may differ, generic drugs are those with the same active chemical as the originally-approved “brand name” drug. The original drug manufacturer is the one that conducts all of the preclinical and clinical safety and efficacy testing, natural product isolation and/or chemical synthesis, formulation with inactive ingredients to assure dissolution and reproducible release of the drug, etc. In return for all this work and an investment of about $800 million, the company produces a “brand name” drug for which they have a period of marketing exclusivity of roughly 17 years from the date the drug was first patented (in some cases this can now be extended another 5 years). While that sounds like a monopolistic proposition, many drugs take up to 12 years from patenting to be approved by the US FDA, meaning that the company has to recoup its investment in a rather compressed time period.
When a drug patent is about to expire, companies specializing in the manufacture of drug products compete to gain FDA approval to market a generic version of the drug without all of the huge investment made by the brand name developer of the drug. Hence, generic versions of brand name drugs are priced much lower. However, the generic company[ies] must demonstrate the so-called bioequivalence of their drug, meaning that the active component must be absorbed into the bloodstream within 80% to 125% that of the brand name drug, without any regard for the time course of that process. These studies rarely require more than a few dozen patients given a single dose of a drug. In many cases, this is adequate.

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