Metamorphosis

Warning: rare self-indulgent post.

Blogging has been and will be light over the next few days while we are packing up things around here to move to our next, more permanent home.

In the meantime, you may have noticed here and on Twitter that part of my big news is that I will begin writing under my PharmMom-given name.

My dilemma has been that I have two Twitter accounts. @AbelPharmboy has been the one I use for all blog-related stuff as well as any other gems of my mind that can fit into 140 characters.  Thanks to you, I have 1,600 followers at that account. However, I also have a real name Twitter account that I used for my now-fledgling-and-almost-nonexistent music career and local banter with folks in the Durham-Chapel Hill area. That one only had 200 followers until I began announcing my metamorphosis.

With the pending blog move and melding of my IRL and online identities, one of my mentors, Twitter follower, writer, editor, and Johns Hopkins journalism professor, Mary Knudson, asked what I was going to do regarding the two avatars I use for each Twitter account.

One of my dear friends was enthusiastic about me coming up with a new avatar for the real name account but I’ve been worried about losing old followers who might not recognize the real name avatar.

But coming to the rescue from across the pond is my devoted reader and neuropharmacology enthusiast, Synchronium – world-famous for showing not one but both nipples in the British press.

Here is my metamorphosis:

Follow me now @davidkroll on Twitter.

More news on our move as it becomes available.

Louisiana K2 ban hurts convenience stores, but is there a homeopathy loophole?

I’m trying not to make this the synthetic marijuana blog but the news on K2, Spice, and other “herbal incense” products keeps coming fast and furious.

This weekend, I saw a Lake Charles, Louisiana story from KPLC-TV coincident with the statewide ban on synthetic marijuana products that took effect on August 15th following legislation signed by Gov. Bobby Jindal in June. One convenience store owner remarked on how the ban will affect her business:

Patricia Maynard, co-owner of Westlake’s Quick Stop, said selling the herbal substances has allowed her to stay in business and keep her electricity on.

Now, that the state has banned synthetic cannabinoid, Maynard is worried her business will suffer. [APB: should be "cannabimimetic" not "cannabinoid" because the active compounds differ structurally from cannabinoids]

“Look how much revenue the state’s going to lose,” said Maynard. “I really don’t understand it. I really don’t understand their reasoning behind it and yeah, it’s definitely going to hurt my business.”

But the final sentence is what caught my eye:

Synthetic cannabinoid is still legal if prescribed by a doctor as a homeopathic drug.

Today’s our first day of classes so it’ll take me some time to dig into the laws governing homeopathics in Louisiana. Technically, a K2 or Spice product cannot possibly a homeopathic remedy because it actually contains measurable amounts of active components. I wonder how long it will take K2 manufacturers to take advantage of this loophole and how much  homeopathic “physicians” might charge “patients” for such a referral.

K2 Spice associated with death of young Indiana mother of two

Welcome to readers arriving via Adam Brown’s referral from Cracked.com. I’ve since moved my blog where I have written extensively on the fake weed phenomenon over the last year-and-a-half.

Click here to read my compilation of synthetic marijuana posts at the new home of this blog.
 


 

From the overnight e-mail referrals of PharmGirl, MD, whose insomnia fuels much of my blogging, comes a story from Middletown, Indiana, on the death of a 28-year-old woman from smoking a synthetic marijuana product.

From WXIN-TV in Indianapolis:

A mother of two is dead after using a synthetic-marijuana laced incense known as “Spice.”

Now her friends and family want the drug outlawed since more and more people appear to be dying from it.

“Yesterday I lost one of the most important people in my life,” says Heather Hogan, blinking back tears, still trying to make sense of a life taken so suddenly.

A common brand of "herbal incense" or "synthetic marijuana."

Several “herbal incense” products sold as K2 or Spice (usually Spice Gold) have permeated the media over the last year, in the US at least, as legal alternatives to marijuana. These products contain one or more synthetic chemicals designed to bind the same cannabinoid receptors in the brain as those affected by the active compounds in marijuana.  These synthetic compounds, called cannabimimetics, do not have the same chemical structure as marijuana’s THC but still have equal or greater potency and effectiveness. Most recognized among these chemicals is JWH-018, so named by the research team of Clemson University professor emeritus, John W. Huffman, who worked on these molecules as biological probes in the mid-1990s together with some of the best behavioral pharmacologists in the US.

For more reading, go to these posts by us, DrugMonkey, and Dr. Leigh.

However, if these compounds do indeed behave like those in marijuana, deaths associated with their use might not be expected.  However, there is at least one other Indiana death from May that is associated with Spice use. Unlike the current article, the May case has a statement from the coroner:

“Given that it was reported that the decedent may have used an unknown substance call “K 12 spice”, a synthetic drug being used by some smokers as a legal substitute to marijuana, we will review the toxicology results to determine what chemicals are involved. We know that there are current studies being done to determine the effects of this substance. We will follow this case closely and watch for other related types of unexpected deaths.”

The coroner probably meant K2, not K12. But regardless, could this stuff cause death?

DrugMonkey, Leigh, and I have been monitoring the literature and our comment threads but most of what we see are from users who report, at worst, some very unpleasant experiences with K2 or Spice use.  However, a couple of our commenters have noted that the products can cause seizures. And if severe enough, a seizure can cause death. (P.S. Leigh has started writing a new blog at Scientopia.org called Neurodynamics.)

This particular commenter of ours who purchased pure JWH-018 to make his own herbal blend reports that while one cannot usually overdose on marijuana, high doses of this compound are very different. Other habitual marijuana users report that some high-dose effects of K2 Spice reported sound similar to those of very strong strains of cannabis.

More and more of these kinds of products are popping up under other names such as Colorado Chronic, Dragon Spice, HUSH, and others.

So, what’s the story here? Let’s assume for a moment that these deaths can be causally linked to synthetic marijuana use.

Could lethal effects of K2 Spice be due to a synthetic contaminant?

My hypothesis is driven by pharmacology/toxicology history. In the early 1980s, young people started showing up in San Francisco hospitals with symptoms of shaking and muscle rigidity that looked just like Parkinson’s disease that usually afflicts folks in the 60s or, in the early-onset version, their 40s. The cases were traced back to an East Coast chemistry graduate student who had been trying to synthesize MPPP an analog of the synthetic opioid drug, meperidine, to prepare a “synthetic heroin.”

In this 1983 Science paper, J William Langston and other colleagues at Stanford identified the presence and activity of a neurotoxic by-product of illicit MPPP syntheses called MPTP. Langston’s group reviewed that case of the Maryland chemistry graduate student who had presented with similar symptoms in 1976 while using this 1947 synthetic scheme, part of a series of four piperidine synthesis papers in that issue of the Journal of Organic Chemistry. Davis et al. reported on this case in 1979 in Psychiatry Research that the student noted the onset of parkinsonian side effects when injecting the compound made after taking some synthetic shortcuts following several successful batches. The student, now known as Barry Kidston, died after a cocaine overdose and his brain slices are those shown in the Davis paper.

Langston’s group later reported in Neuroscience Letters that MPTP is metabolized in the brain of non-human primates to the highly-reactive neurotoxin, MPP+ (interestingly, an equally high ratio of MPP+ to MPTP was observed in the heart but I’ve not read anything about cardiac effects of MPTP). I should also note that the use of non-human primates for this work was critical to understanding how this toxin caused parkinsonism – the effects were not seen in rats given MPTP.

Production of this highly-reactive pyridinium ion was later shown to result form neuronal metabolism by monoamine oxidase B, the same enzyme we normally use to inactivate dopamine. The MPP+ caused selective death of dopamine neurons in the substantia nigra, “comparable in severity to that usually seen in idiopathic parkinsonism.” (Quote from Langston et al, Science 1983; 219:979-80 about Kidston’s pathology)

For more reading on this topic, Langston co-authored a 1995 book entitled, The Case of the Frozen Addicts, that also fueled a NOVA special. A New England Journal of Medicine review of the book appears here.

MPPP, the intended illicit compound, and MPTP, the proneurotoxin that is oxidized in the brain to MPP+.

This remains an active area of research today because environmental causes of parkinsonism may be mediated similar by compounds we encounter daily – in the 1980s, Sol Snyder’s group at Hopkins showed that MPP+ is made in and exported from astrocytes to kill surrounding neurons and just last year another group at Rochester and Columbia showed that identified an organic cation transport protein, oct3, that’s responsible for this export.

In the case of JWH-018 and related compounds, they are not piperidine (a six-membered saturated ring containing nitrogen) but rather indoles, a five-membered nitrogen-containing ring connected to a benzyl ring. Both are heterocycles, meaning they are carbon rings with nitrogen and, like the methyl on the pyridine nitrogen in MPTP, the nitrogen in JWH-018 is modified with an aliphatic group (a five-carbon pentyl group, in this case).

The cannabimimetic, JWH-018, sold pure and in K2, Spice, and other "synthetic marijuana" or "herbal incense" products.

My question to my chemistry colleagues is whether something could happen in the JWH-018 synthesis to create a situation on the indole that could allow this to be activated to a reactive cation. I’m not sure how the carbonyl electrons one carbon off from the indole might influence things. But then again, we have indoles everywhere endogenously – in tryptophan and serotonin.

Just thinking out loud here – although I’m happy to partner with one of my chemistry colleagues to suss this out – but the cases of deaths reported with K2 Spice, if causally associated, seem too sporadic to be a general theme. The fact that these two cases (and perhaps three) in Indiana smells to me like a locally-restricted distribution of a “bad batch.” I anticipate that poison control centers and forensic analytical chemists in Indiana are on the case.

But here’s a case where I really wish I knew chemistry better. But, in true blog tradition, I’d rather open up this discussion to chemists of the blogosphere rather than try and be all secretive and see if this hypothesis can be quietly tested with my colleagues.

I see that some of my chemist friends have followed me over here from the old digs at ScienceBlogs – what say you, o learned ones?

From Mind Hacks: Illegal drugs found in legal highs sold in the UK

I’ve been kind of tied up with work things this week so my apologies for lack of original content. But I just had to share this with you because it was so reminiscent of the herbal adulteration story I brought you just a few days ago.

Many times when I post something on drugs that affect the central nervous system, I’ll get a tweet from Dr Vaughan Bell at Mind Hacks pointing me to his coverage on the same topic a few weeks ago. This time, he shares with us a report where dietary supplements sold in England have been found to contain newly-illegal psychoactives and related compounds.

For example, before the ban, a legal pill sold as ‘Doves Original’ was advertised as containing a blend of amino acids and ketones but actually contained the psychedelic drugs mephedrone and butylone. Both were completely legal but were simply not mentioned by the manufacturers.

Interestingly, after the ban, it seems that several companies just changed their packaging without changing their ingredients.

Out of the six products tested, all advertised as being legal, five included recently banned substances – including mephedrone, 4-fluoromethcathinone and methylone – and the other contained dimethocaine, a legal but unmentioned local anaesthetic (presumably to emulate the nose-numbing effect of cocaine).

Drugmonkey, newly installed at Scientopia.org, has in his archives a nice series of posts on mephedrone for your further reading on these compounds.

Read Vaughan’s full post here.

Previous K2 Spice/synthetic marijuana coverage in The Washington Post

In remarking Sunday on coverage of the synthetic marijuana products in The New York Times, I totally missed that a more detailed article appeared the day before in The Washington Post.
With contributions from Aaron C. Davis, the article by writer Michael W. Savage provided an insight into Spice use in Adams Morgan and around the District. The second page of the online article goes into much more detail than the NYT article by addressing the pros and cons of state approaches to outlaw the compounds and products.
Savage also included commentary by Marilyn Huestis, chief of chemistry and drug metabolism at the National Institute on Drug Abuse (NIDA), and focused in on a problem we discussed Sunday, namely, that the content of active components in the synthetic products and dosing with the pure compound(s) can vary wildly and account for reports of safe use vs. those of intense anxiety, cardiac disturbances, and seizures.
Savage quotes Dr. Huestis:

“These different, synthetic compounds are up to 100 times more potent than THC and have not been tested on humans,” she said. “When people take it, they don’t know how much they’re taking or what it is they’re taking.”

It’s a really nice overview and it won’t take you terribly long to read it.
As more states move toward regulating JWH-018, related compounds, and incense products that contain one or more of the compounds, we will be seeing more of these kinds of articles in the legacy media.
By the way, if you are looking for more science writing, check out Carl Zimmer’s fantastic article, How Microbes Defend and Define Us, in today’s NYT Science Times section on the microbes that live in our bodies and how “fecal transplants” have proven effective in treating infectious diseases – I kid you not.

K2 Spice, JWH-018, and synthetic marijuana make The New York Times

Overnight, Malcolm Gay posted an article that appears in this morning’s Sunday edition of The New York Times regarding synthetic marijuana products.
“Incense” blends such as K2, Spice, Black Mamba, and Wildfire Extreme are sold legally in most states in the US but have been illegal in Europe for over a year. These herbacious products are sprayed with one or more compounds originally synthesized in the laboratory of Dr. John W. Huffman at Clemson University. The compounds carry his initials followed by a number, such as JWH-018. The chemical structure of the compounds are different from the active constituents in marijuana but they bind to the same receptors in the brain. In recent months, JWH compounds have become available on the internet in their pure form, allowing users to make their own products.
While brief, the article notes some poison control data that do not surprise me based upon anecdotal experiences left here and at DrugMonkey’s blog since we wrote parallel posts on the topic in early February:

The American Association of Poison Control Centers reports that so far this year there have been 567 K2-related calls, up from 13 in 2009. But investigators add that no one is really certain what is in K2, and people are arriving at emergency rooms with symptoms that would not normally be associated with marijuana or a synthetic form of the drug.
“I don’t know how many people are going for a box of doughnuts after smoking K2, but they’re sure getting some other symptoms,” said Dr. Anthony Scalzo, a professor of emergency medicine at the St. Louis University who first reported a rise in K2-related cases and is collaborating with Dr. Rosenbaum in researching K2’s effects. “These are very anxious, agitated people that are requiring several doses of sedatives.”

Gay notes that these reports have led to Missouri’s Gov. Jay Nixon to sign a ban on these products this past Tuesday. Earlier this month, Gov. Mike Beebe in neighboring Arkansas signed a similar emergency measure and bans.
“Similar prohibitions are pending in at least six other states, including Illinois, Louisiana, Michigan, New Jersey, New York and Ohio, according to the National Conference of State Legislatures,” notes Gay.
Why do people use Spice? For some kids, it is simply easier to get – on the internet, at gas stations – and, until recently, legal to do so. The products have also been popular among people on parole or anyone else subject to urinary drug screening. Depending on the drug screen, the JWH compounds may not be detected. However, the US military’s drug screening method does detect them and these products have been banned from use by soldiers.
I’m looking forward to reading a compilation of these poison control center reports because the trend I’ve observed in the comments of readers who report using the products is that truly unpleasant effects did not begin emerging until pure JWH-018 became available. As a result, users can easily overdose on the substance due to its potency and homemade “incense” products can vary wildly in their JWH-018 content.
Pure JWH-018, or any powdered drug for that matter, is also difficult to “dose” without a balance having milligram sensitivity. I suspect that some users may overdose simply because they don’t know what a 10 mg “looks” like – if a pharmaceutical tablet is one’s frame of reference, one may not realize that much of a “10 mg” tablet is mostly excipient or solubilizing agent and may be 50 or even 100 mg in weight. So, it’s easy to portion out five or ten times as much compound as one thinks.
British psychoactive drug blogger, Synchronium, posted on the in vitro toxicology of JWH-018 and received 444 comments before he closed the thread, with one comment saying that, “JWH is like giving a noob driver a drag racer as their first vehicle.”
Unlike well-documented, poison control reports that are largely compiled from emergency room visits, the comments received there, here and at the DrugMonkey blog are non-scientific and unsubstantiated. Nevertheless, here is a sampling of some of the comments we’ve seen:

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Hallucinations and hospitalizations: Angel’s Trumpet

Toxicity reports are re-emerging in southern California this week after a dozen hospitalizations of kids using teas made from a fragrant flowering plant called Angel’s Trumpet. A tea made from the plants is used to produce hallucinations, but they can progress to extremely unpleasant experiences. Moreover, Angel’s Trumpet can be deadly, accelerating the heart rate and causing fatal cardiac rhythmic disturbances and bronchoconstriction that can trigger asthma attacks in sensitive individuals.
220px-Atropine.svg.pngAngel’s Trumpet is one of a series of plants in the Brugmansia genus that make a variety of muscarinic cholinergic antagonists such as atropine (dl-hyoscyamine, pictured to the right) and scopolamine (l-hyoscine). These compounds are also known chemically as tropane alkaloids or belladonna alkaloids, the latter derived from their classical isolation from Atropa belladonna. The belladonna name derives from the use of eye drops made from the plants that prevent constriction of the pupils (mydriasis), back when the size of a woman’s pupils was a sign of beauty and arousal.
The tropane alkaloids are ubiquitous in plants and fungi and act as classic hallucinogens when used in high doses. Their legend goes back to witches brews, which we discussed here, and beyond. A wonderfully colorful history of tropane alkaloids by Robert S. Holzman of Children’s Hospital and Harvard Medical School was offered in this free 1998 paper in the journal, Anesthesiology (1998; 89:241-249).
However, the aftermath of Angel’s Trumpet use isn’t all fun and games. In cases like these, I like to turn to the Erowid site, a respected, user-supported site that offers non-judgmental information on plant-derived and synthetic psychoactive agents. The Erowid Experience Vault has several descriptions of the use of Angel’s Trumpet but this one is the most detailed and representative of the downsides of this plant. (Note that the colloquial term for Angel’s Trumpet in Australia is sometimes “Tree Datura,” although Brugmansia is a closely-related but distinct genus from Datura within the Solanaceae family.)

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Exposing quackery and abuse in the addictions treatment industry

The 75th anniversary of Alcoholics Anonymous has brought out a spate of legacy media articles about the organization, most singing the praises of an unscientific movement begun during The Great Depression that still forms the basis of many clinical drug and alcohol addiction treatment programs.
My post Thursday on Brendan Koerner’s Wired article brought out a very thoughtful commenter and sharp writer, friendthegirl. I learned that ftg writes the blog, Stinkin’ Thinkin': Muckraking the 12-Step Industry.

Stinkin’ Thinkin’ was started with the intention highlighting the quackery and abuse that is the foundation of the addictions treatment industry – with a view toward building community among people who are questioning the only game in town.
We will post news stories; expose how the inmates treat each other in their asylum, provide resources and information. While Stinkin’ Thinkin’ is not specifically an addictions recovery support board (we don’t endorse any methods), we support you wholeheartedly in your quest to find your way.

For those readers unfamiliar with addictions treatments of various types, Alcoholics Anonymous is one of the most polarizing organizations out there. Some people, like Robert Ebert, hold that their decades of sobriety are due to AA while others, like my Dad, despised AA as some sort of brainwashing cult.
ftg has also made me think about another point: many of us in the science and medical blogging communities routinely take apart pseudoscience movements in vaccine paranoia and dubious cancer therapies, yet I don’t know of one of my compatriots who’ve looked closely at pseudoscience in the addictions treatment industry. [Addendum: I'm wrong - Harriet Hall had a great post in May 2009 at Science-Based Medicine entitled, AA Is Faith-Based, Not Evidence-Based.]
Stinkin’ Thinkin’ has some great articles with pithy writing and revealing experiences of those who tried AA but found it not to be for them – some funny, some devastating. I recommend that one start reading from their greatest hits page.
As another example of the value of this site for alternative thinking about AA, ftg commented here and posted there about a rebuttal by addictions psychologist Dr. Stanton Peele to and David Brooks’s NYT commentary on AA that was seeded by Koerner’s Wired piece.

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Brendan Koerner in Wired how, why, and if Alcoholics Anonymous works

The last two days (here and here), you lovely commenters and I have been bantering about legacy media’s reluctance to use the original literature citation in print or online coverage of science, medicine, and health stories. The discussion has drawn input from working writers as well as scientists and bloggers and I also draw your attention to the comments at the impetus for these posts over at The White Coat Underground with PalMD.
But remember, my dear ink- and pixel-stained friends, I am also a graduate advisory board member and instructor in a science and medical journalism program at a major state university. So, I hope those new to the blog understand that my comments and objections arose from my concerns and love for journalism and journalists.
To further emphasize my admiration for superb sci/med/health writing, I wish today to add another writer to my growing blog category of “Journalists, Awesome.”
Via my drug abuse research colleague, DrugMonkey, my attention was drawn to a new Wired magazine article by Brendan I. Koerner entitled, Secret of AA: After 75 Years, We Don’t Know How It Works.
I strongly recommend this long-form article for anyone in the field of substance abuse and dependence research, psychology and general clinical research, students of excellent science writing, alcoholics and their family members, and anyone who thinks that good science writing no longer exists.
I don’t want to influence your views any further other than to say that since poured my first whiskey and water for my grandmother when I was around 7, I’ve had a longstanding interest in why Alcoholics Anonymous helps so many alcohol-dependent folks kick the disease for decades while others trying the approach continue to crash and burn or otherwise abhor its very tenets, especially the “Higher Power” focus. The reader comments there also reflect this bipolar view of the unorganized organization.
Regular readers will also recall that PharmDad died of alcoholism at age 58 after two rounds of inpatient rehab at a nationally-renowned facility – he despised AA even though we had been ardent churchgoers when I was a kid.

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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.