How globalization and market innovation challengehow we think about and respond to drug use:‘Spice’ a case studyadd_2874 951..953

‘Spice’ is a herbal mixture sold on the internet, samplesof which have been found to contain new syntheticdrugs which produce effects similar to cannabis. TheEuropean Monitoring Centre for Drugs and DrugAddiction (EMCDDA)’s early warning system onnew drugs provides an important case study in howglobalization and innovation present challenges todrug control.

The story of ‘Spice’ provides an important case study inhow globalization and innovation in the drug market pre-sents a growing challenge to current approaches tomonitoring, responding to and controlling the use of newpsychoactive substances. ‘Spice’ is a herbal mixture soldprincipally on the internet, and in some countries inspecialist shops offering legal alternatives to controlledsubstances. The packaging is sophisticated, and many dif-ferent mixtures have been released under the generic‘Spice’ brand. These often exotically named mixtures,such as ‘Spice Gold’, ‘Diamond’ and ‘Silver’, purportedlycontain different combinations of herbs, some of whichmay have psychoactive properties. The products haveprobably been available in Europe since 2004, if notearlier, but they only started to attract wider attention in2007, and began to be monitored by the European earlywarning system on new drugs during the first months of2008 [1]. This mechanism is part of a Europe-wide three-step approach of information exchange/early warning;risk assessment; and decision-making for the detectionand possible control of new psychoactive substances.

‘Spice’ is sold under a number of guises, commonly asan exotic incense blend, and usually contains a warningnote stating that it is not for human consumption. Thisinformation is juxtaposed with sophisticated marketingthat would suggest that it may have other uses. The useand marketing of herbal mixtures is not new, and a rangeof non-controlled plants and fungi are sometimes usedfor their psychoactive or supposedly psychoactive effects.

‘Spice’ stands out not only because of the sophistica-tion of the packaging and the complicated blends of sub-stances that it is purported to contain. It also stands outbecause some of those who used the drug reported effectssimilar to or even stronger than those obtained bysmoking cannabis. The veracity of these reports was dif-ficult to judge, as they came mainly from online forums.However, this underlines the importance of the internet,

not only as a source for ‘Spice’ but also for marketing andraising awareness about the product. A parallel can bedrawn here with modern viral marketing techniques,which attempt to use social networking as a tool forencouraging new brands to be adopted, especially bywhat are regarded as socially influential individuals, earlyadopters and trend leaders.

Although non-controlled plant products are clearlyattractive to some users—khat and salvia (Salvia divi-norum) spring to mind—in general, many of the productsmarketed as legal highs struggle to compete with con-trolled drugs [khat is controlled in some jurisdictions butthe plant is not listed in the international drug controlconventions and in many countries is not subject tocontrol]. This is arguably because they often do notmeet users’ expectations, perhaps because they deliverunpleasant or only mild effects. However, in 2008 thesuggestion that ‘Spice’ was different slowly began toattract attention, first from the media and then frompolicy makers and researchers. Initially, concern about‘Spice’ was focused on a few central European countries,although internet monitoring would suggest that con-sumer interest had spread far wider than this, extendingbeyond the European Union and even into Russia. Adetailed review of the identification, availability and mar-keting of ‘Spice’ can be found at EMCDDA [2].

The initial problem facing the analysis of ‘Spice’ wasto determine exactly what was in it. ‘Spice’ purported tocontain up to 15 different herbs, of which wild dagga(Leonotis leonurus) and Indian warrior (Pedicularis densi-flora) were viewed as the most likely candidates forcausing a psychoactive effect. In a self-administrationexperiment, German researchers were surprised at thepotency of the sample tested [3]. However, detailedchemical analysis failed to find any of the herbal sub-stances expected from the product labelling. What theydid eventually manage to identify, on 16 December 2008,using nuclear magnetic resonance spectroscopy, was thepresence of a synthetic cannabinoid, the cyclohexylphe-nol CP 47 497 and one of its active homologues [2,4,5].Just one day earlier a company undertaking analysis ofthe product for the city council of Frankfurt had alsoidentified the synthetic cannabinoid naphthoylindole,JWH-018 [3,6]. This was a lucky break, as it resultedfrom comparing one of the unknown mass spectra gen-erated by a ‘Spice’ sample to a JWH-018 reference sample

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they happened to have in stock. Since then nine syntheticcannabinoids have been found in ‘Spice’ or ‘Spice’-relatedproducts in Europe [2,7] and in the United States [8]and Japan [9]. A review of these compounds can befound at http://www.emcdda.europa.eu/publications/drug-profiles. Identification of these products has beenhampered by the lack of reference samples of theseobscure chemicals. It is also possible that masking agentssuch as tocopherol (vitamin E) were added to confounddetection [2].

The appearance of synthetic cannabinoids can beseen as a new phase in the development of what is some-times known as the ‘designer drug’ market. Attempts todevelop legal alternatives to controlled substances are notnew, but they have evolved considerably. ‘Designer drugs’based on fentanyl appeared in the early 1980s, followedby ring-substituted phenethylamines in the late 1980sand tryptamines in the 1990s. Since 2000, we haveincreasingly seen piperazines and cathinone derivativesexploited for this purpose. However, in 2008, with JWH-018, for the first time ever a synthetic cannabinoid wasreported to the European early warning system. Thismechanism monitors trends in the availability of non-controlled substances, and can trigger a more formal riskassessment and legal control response. This is a worryingdevelopment, as there are more than a hundred com-pounds with cannabinoid activity. The cannabinoidsfound in ‘Spice’ are just two among a large number ofobscure chemicals with CB1 or CB2 receptor agonist activ-ity, and which can be expected to produce cannabis-likeeffects. Some of these may be full agonists and consider-ably more potent than natural cannabinoids—with theconsequence that they can produce the same effect aslarger doses of tetrahydrocannabinol (THC). Virtuallynothing is known about the health implications of con-suming these drugs, either in man or animals. However,serious consequences [10], including the possibility ofoverdose, cannot be ruled out. More generally, the emer-gence of these substances points to the fact that recentdevelopments that permit cheap organic chemical syn-thesis are being exploited by chemists seeking out attrac-tive new substances for the recreational drug market.

In contrast to the undeclared ingredients of ‘Spice’,the psychoactive plants listed on the product label havehardly been detected. Although some herbal mixturesmay contain the plants stated, most samples of ‘Spice’tested appear to contain inert vegetable matter. Althoughlittle is known about the manufacture of ‘Spice’, the syn-thetic compounds that are sometimes present seem tohave been added surreptitiously to the mixtures at theirproduction sites, which appear to be in Asia. This raisesthe difficult question for policy makers, both practicallyand morally, of whether ‘Spice’ should be addressed as aconsumer protection or drug control issue.

Most of the attention received by ‘Spice’ has been inEuropean Union (EU) countries, in part because of themechanism that exists to respond to potential new drugthreats. Nevertheless, it is very much a global phenom-enon. Any control measures considered are faced withthe regulatory difficulties presented when products areavailable from the internet, where national jurisdictionscan be circumvented easily. This can also lead to anoma-lies. Internet retailers of ‘Spice’ based in the Netherlands,for example, can supply ‘Spice’ products to other EUcountries but not their own. Moreover, the developmentand production of ‘Spice’, as far as we are able to ascer-tain, took place in countries in the developing and tran-sitional world—again where regulatory mechanismsmay be weak or difficult to enforce.

The ‘Spice’ case study poses difficult questions abouthow we monitor and respond to drug use. Europe hasinvested in developing an early warning system on newdrugs and information exchange is now possible in a waythat would have been difficult in the past. However, nocentral reference laboratory exists or mechanism formaking reference samples is available. This is important,as identification of the active ingredients in ‘Spice’ wascomplicated by the lack of reference material. Also, asthere is no current proactive testing of this type ofproduct, it was only after a considerable time that itbecame visible to the authorities and sufficient concernwas generated to launch an investigation. That this typeof product falls into a grey area between commercialproducts, medicines and illicit substances also meant thatthere was a lack of clarity regarding which agenciesshould take responsibility for this issue. This conceptualissue is also mirrored in the attempts that some countrieshave made to control ‘Spice’ by using a variety of instru-ments, including medicines legislation and formal drugcontrol measures [11,12]. Even if one adopts the viewthat ‘Spice’ should be viewed simply as a consumerproduct, the fact that a substance was being consumedwhich contained a unlisted psychoactive ingredient,which is largely untested and not known to be safe, isclearly a cause for concern. A minimum public healthresponse would be to warn consumers that the productcontained unlisted compounds. However, this course ofaction is not uncontested, as concerns have been raisedthat drawing attention to this fact may increase interestin the product.

Some of the synthetic chemicals that had been addedclandestinely to ‘Spice’ mixtures have, in a few months,gone from being virtually unknown research chemicals,for which forensic science laboratories had difficulties inidentifying and obtaining reference samples, to beingcommercially marketed in their own right. For those withthe right knowledge, significant amounts of highly psy-choactive chemicals can be obtained cheaply and legally

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with a few clicks of a mouse. The speed and sophisticationof innovation in this area is impressive and also serves tohighlight the sluggishness and clumsiness of mostattempts at control. ‘Spice’ itself may be a transientproduct, but it provides an excellent case study of how theglobally connected world in which we now live is chal-lenging existing models of drug control.

Acknowledgements

The authors would like to thank Peter Fay for his helpfulcomments on the text and acknowledge the work of thosescientists who attended the EMCDDA’s expert meeting on‘Spice’ held in Lisbon, on 6 March 2009, the deliberationsof which were the inspiration for this piece.

Declarations of interest

None.

Keywords Drug control, internet, ‘Spice’, syntheticcannabinoids.

PAUL GRIFFITHS, ROUMEN SEDEFOV,

ANA GALLEGOS & DOMINIQUE LOPEZ

European Monitoring Centre for Drugs and Drug Addiction(EMCDDA), Lisbon, Portugal.

E-mail: paul.griffiths@emcdda.europa.eu

References

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2. European Monitoring Centre for Drugs and Drug Addiction(EMCDDA) Thematic Papers—Understanding the ‘Spice’Phenomenon. Lisbon: EMCDDA; 2009. Available at: http://

www.emcdda.europa.eu/html.cfm/index90917EN.html(accessed 23 October 2009).

3. Auwärter V., Dresen S., Weinmann W., Müller M., Pütz M.,Ferreirós N. Spice and other herbal blends: harmless incenseor cannabinoid designer drugs? J Mass Spectrom 2009; 44:832–7.

4. Compton D. R., Johnson M. R., Melvin L. S., Martin B. R.Pharmacological profile of a series of bicyclic cannabinoidanalogs: classification as cannabimimetic agents. J Pharma-col Exp Ther 1992; 260: 201–9.

5. Compton D. R., Rice K. C., de Costa B. R., Razdan R. K.,Melvin L. S., Johnson M. R. et al. Cannabinoid structure–activity relationships: correlation of receptor binding and invivo activities. J Pharmacol Exp Ther 1993; 265: 218–26.

6. Huffman J. W. Cannabimimetic indoles, pyrroles, andindenes: structure–activity relationships and receptor inter-actions. In: Reggio P. H., editor. The Cannabinoid Receptors.Totowa, NJ: Humana Press; 2009, 49–116.

7. Lindigkeit R., Boehme A., Eiserloh I., Luebbecke M., Wigger-mann M., Ernst L. et al. Spice: a never ending story? ForensicSci Int 2009; 191: 58–63.

8. United States Drug Enforcement Administration, Office ofForensic Sciences. ‘Spice’—plant material(s) laced with syn-thetic cannabinoids or cannabinoid mimicking compounds.Microgram Bulletin, March 2009. Available at: http://www.justice.gov/dea/programs/forensicsci/microgram/mg0309/mg0309.html (accessed 7 January 2010).

9. Uchiyama N., Kikura-Hanajiri R., Kawahara N., HaishimaY., Goda Y. Identification of a cannabinoid analog as a newtype of designer drug in a herbal product. Chem Pharm Bull2009; 57: 439–41.

10. Zimmermann U. S., Winkelmann P. R., Pilhatsch M., Nees J.A., Spanagel R., Schulz K. Withdrawal phenomena anddependence syndrome after the consumption of ‘spice gold’.Dtsch Arztebl Int 2009; 106: 464–7.

11. McLachlan G. Taking the spice out of legal smoking mix-tures. Lancet 2009; 374: 600.

12. Advisory Council on the Misuse of Drugs. Consideration ofthe Major Cannabinoid Agonists. 2009. Available at: http://drugs.homeoffice.gov.uk/drugs-laws/acmd/ (accessed 23October 2009).

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