Investigating a not-so-natural high
Researchers identify synthetic cannabinoids in herbal incense.
ould you do something wrong if University Medical Center Freiburg from all the symptomsOstarting from
Wyou knew you weren t going to get (Germany), together with the Bundes- red conjunctivae, dry mouth, and very
caught? This prospect tempted thousands kriminalamt (BKA), Germany s federal high pulse rate, says Auwärter. But
of people as word spread about a again, the scientists did not de-
 legal high Oherbal incense that tect THC or other common psy-
could be smoked like marijuana. Re- chotropic substances in the clini-
searchers in several countries failed to cal samples. The researchers did,
find evidence of any common psy- however, see some unidentified
chotropic compounds when they peaks in the GC/MS analysis of
tested these herbal mixtures. And the blood; these peaks were traced
urine of people who appeared to back to unidentified substances
have overdosed on the substance did also detected in extracts of the
not contain known drug metabolites. herbal mixtures.
But with a lot of analytical chemistry,
some Internet research, and a little
Synthetic cannabinoids
serendipity, researchers in Germany
Next, the investigators turned to
eventually identified synthetic can-
the Internet, where they found
nabinoids in several different types of
rumors that the herbal mixtures
herbal incense; they recently re-
had been spiked with synthetic
ported their results in the Journal of
compounds that could not be de-
Mass Spectrometry (2009, DOI
tected by drug screens. So the
10.1002/jms.1558).
group shifted focus and began to
look for synthetic cannabinoid
A public service announce-
agonists. The researchers tested
ment backfires?
criminal police office, performed more seven different products and analyzed
Reporters for German television prob-
extensive testing for psychotropic extracts from the herbal mixtures via
ably thought that they were doing soci-
compounds in the clinical samples GC/electron impact MS, LC/MSn, UV
ety a favor when they broadcast a news
from the overdose patients but found spectroscopy, and TLC, but they still
story about herbal incense that pro-
nothing. Baffled, Auwärter and col- couldn t determine the identity of three
duced a marijuana-like high but
leagues decided to do a controlled peaks. Auwärter points out that the
couldn t be detected by common drug
self-experiment with one type of laboratories could not identify the un-
screens. But after the August 2008
herbal incense so they would have known compounds quickly because the
broadcast, the popularity of the incense
clinical samples after a known con- compounds weren t in any of their mass
soared in Germany. Young people began
sumption of the substance.  First, we spectra libraries.
to show up at emergency rooms across
wanted to know is there a real effect, According to Auwärter, a critical
the country with psychosis-like panic
and if there is a real effect, there has to step in the group s analyses was the
attacks and heart and circulatory prob-
be a substance that is responsible for isolation of milligram quantities of the
lems; these patients admitted to smok-
it, says Auwärter. The group wanted unknowns via silica gel chromatogra-
ing or ingesting products marketed as
to collect enough clinical samples over phy so that they could perform struc-
 herbal incense . Despite all signs point-
an extended period to be able to per- tural analysis by NMR.  We had some
ing to marijuana overdose, no delta-9-
form preliminary kinetic analyses on information from each method, and
tetrahydrocannabinol (THC) or any of
any metabolites, which are often the that had to be puzzled together, he
its metabolites were detected in clinical
only components detectable in urine. says. For example, TLC of extracts
samples from the patients.
Much to the researchers surprise, a from three varieties of one brand of
low dose (0.3 g of the mixture smoked incense showed that the amount of
The guinea pigs by two of the researchers) produced a two unknown compounds increased
Volker Auwärter s laboratory at the psychotropic effect that lasted for 5 6 with the price of the product; this was
Institute of Forensic Medicine at the hours.  It was really cannabis-like a pretty good indication that the com-
10. 1021/ AC900564U © XXXX AMERI CAN CHEMI CAL SOCI ETY MONTH XX, XXXX / ANALYTI CAL CHEMI STRY A
JULIE FARRAR/PHOTODISC
pounds were intentionally added to The nature of the herbal incense ary 2009. Within days, Germany
the herbal mixtures. Eventually, the products has changed over time. Origi- banned CP 47,497 and its pharmaco-
group pieced together a structure for nally, Auwärter thought that the first logically active homologues and JWH-
one of those unknowns, but the 018. France outlawed all of those
structure was not related to THC. compounds plus another synthetic
cannabinoid, HU-210, in February
Serendipity knocks 2009.
But spiked herbal incense is not
In mid-December 2008, the col-
just a European phenomenon. The
laborators were still trying to deduce
U.S. Customs and Border Protec-
the structures of the unknown com-
tion (CBP) announced in mid-Janu-
pounds when they got lucky. A
ary 2009 that it had seized herbal
commercial laboratory in Frankfurt
incense shown to contain HU-210.
announced that it had identified
When CBP officers at the Ohio fa-
JWH-018, one of several cannab-
cility of an international express
inoid agonists synthesized at Clem-
courier saw the dried plant material
son University, in samples of herbal
inside a shipment, they performed a
incense. The city of Frankfurt had
field test for the presence of THC,
asked THC Pharm, a company pro-
but it was negative. Further analysis
ducing pharmaceuticals based on One of the herbal mixtures tested, Spice Gold.
at the CBP laboratory in Chicago
natural cannabinoids, to analyze the
products sold did not contain canna-
confirmed the presence of HU-210.
herbal incense. The firm s scientists were
binoids. But after laboratories knew
Over a three-month period, CBP seized
able to match the GC/MS spectrum of
what to look for and reanalyzed the ear-
100 lb of HU-210-laced herbal mix-
one peak to spectra they d previously
lier batches of incense, they detected the
tures in five separate shipments. (Inter-
collected on JWH-018. Auwärter says
spiked cannabinoids. Auwärter says,  It
estingly, a narcotics detector dog led
that the Frankfurt laboratory did see
seems like the labs doing the analyses at
authorities to the substance in at least
another unidentified peak in the
that time were just not suspicious
one of the cases.)
GC/MS spectrum.  They didn t know
enough. And batch-to-batch reproduc-
Brett Sturgeon, a CBP public liai-
what it was, but they just suspected it
ibility was an issue as well. In one brand
son officer, says that the agency has
may be some kind of aroma compo-
of herbal incense, sometimes JWH-018
made seizures of this substance in
nent, he says.
was detected and sometimes it wasn t.
other U.S. ports as well. And a couple
Armed with this new knowledge, Au-
After publishing their paper, the re-
of weeks after the CBP announcement,
wärter and colleagues combed through
searchers found yet another synthetic
scientists at Japan s National Institute
the literature on other synthetic canna-
cannabinoid in a batch of incense.
of Health Sciences published a paper
binoids, such as the CP and HU series
But the spiked compounds are not
in the Chemical and Pharmaceutical
of compounds synthesized at Pfizer and
the only thing changing.  In the begin-
Bulletin (2009, 57, 439 441) identi-
Hebrew University (Israel), respectively.
ning, the Swiss labs were able to find at
fying the same C8 homologue of CP
The group quickly matched its data with
least some of the herbs which are de-
47,497 in herbal incense; they did not
published data on cannabinoid agonists.
clared on the back side of the package,
report the presence of JWH-018 or
By comparing the NMR spectra, the
says Auwärter. He says that by the time
the diastereomer that Auwärter s
scientists realized that the structure they
the herbal mixtures laced with canna-
group found, however.
had previously pieced together was a
binoids became popular in Germany, the
homologue of CP 47,497Oa compound
mixtures did not even contain the herbs
How do they do it?
known to bind to the brain cannabinoid
listed in the ingredients.  [The manu-
receptor. In the seven products tested, Auwärter hypothesizes that the produc-
facturers] just took any kind of plant
the researchers identified CP 47,497; ers buy cannabinoids from laboratories
material that is cheap, says Auwärter.
the C8 homologue of CP 47,497 and its in China or other countries that offer
trans diastereomer; JWH-018; and ole- cheap organic syntheses, dissolve the
Going global
amide. The CP 47,497 homologue compounds in a solvent, spray the solu-
and its diastereomer were the major Starting in December 2008, countries tion on the plant material, and evaporate
components for five out of the seven including Austria and Switzerland the solvent before packaging the herbal
products tested; for the other two banned the herbal incense. Auwärter s mixtures. At a price of 20 30 euros
products, JWH-018 was the major group and the BKA issued a press re- ( $25 40) for a 3-g packet, the in-
component. lease about their findings in mid-Janu- cense is significantly more expensive
B ANALYTI CAL CHEMI STRY / MONTH XX, XXXX
COURTESY OF VOLKER AUWÄRTER
than marijuana. Nevertheless, its popu- for national authorities to trace back the compounds, which are just fakes. The
larity has spreadOprobably in no small whole thing. researchers will also work on finding me-
part because word travels quickly on the So the group next plans to do profiling tabolites in urine that could be used to
Internet. experiments to help pinpoint the source(s) detect consumption, even days after the
How do the vendors sell so much of of the synthetic compounds.  Now, al- last intake. But with such a variety of syn-
their product without getting caught?  I most daily, we get new products which are thetic cannabinoids, that will be a chal-
guess it s the same like with all these phar- also declared as herbal incense, with differ- lenge.  Now that JWH-018 is controlled,
maceutical products like Viagra that are ent names, different packaging.... Always, then next on the market may be  butyl-
sold over the Internet, Auwärter says. you have some plant material and some- or  hexyl- instead of  pentyl- and so on,
 They have a whole system of distribu- times you have cannabinoids that are al- says Auwärter.  [Tracing these com-
tion. Commonly, they have a base over- ready known, says Auwärter.  And of pounds is] now a rat race.
seas ... and from there, they send it from course, there are some products which do  Christine Piggee
one country to the other. It s very difficult not contain any pharmacologically active
MONTH XX, XXXX / ANALYTI CAL CHEMI STRY C