Spice: A never ending story?
Introduction
Tracking the World Wide Web, the appearance of “Spice” can be traced back to the year 2006. The popularity of “Spice” and analogous herbal blends peaked in the second half of 2008 after several reports in German television and local newspapers covered the issue. Shortly after these reports, these products had sold out and were only available online. To our knowledge, these herbals were sold in many western European countries. Although declared as incense and not for human consumption, these blends are consumed as herbal drugs via smoking, much like cannabis (as for instances documented, on www.youtube.com). In several internet blogs consumers described cannabis-like effects after smoking, although preliminary chemical and botanical analysis showed no indication of cannabis in the mixtures. The list of ingredients indicated a mixture of plant components like “Lion's Tail”, “Indian Warrior” etc., with very vaguely described intoxicating effects, but no clinical evidence. Based on these accounts these products were not banned by the authorities. Instead their popularity as “legal drugs” rapidly increased based their reputation of being potent herbal intoxicants and “legal” alternatives to the strictly regulated cannabis. Towards the end of 2008 at least eight effectively similar products were available on the German market demonstrating both the popularity and financial lucrativity of these products.
However, there was strong suspicion that added synthetic compounds or plant extracts are the real source of the described narcotic pharmacological effects.
In December 2008 the German company THC Pharma (Frankfurt, Germany) reported JWH-018 as an active ingredient in “Spice”. Shortly afterwards two research groups at the University of Freiburg (Germany) [1] and at the National Institute of Health Sciences, Japan [2] concurrently identified and characterized the CP 47,497-C8 homolog (and its isomer as a synthetic byproduct) in these incenses (Fig. 1). Both substances are among the dozens of synthetic cannabinoids already described and in vitro tested for cannabinoid-action in scientific journals. As a consequence, on January 22nd 2009, the German Health Authorities prohibited the detected synthetic cannabinoids JWH-018 and CP 47,497-C8 [3]. While the German regulation included several homologues of CP 47,497-C8 (alkyl side chain C6 to C9), only one representative of the alkylaminoindoles (JWH-018) was banned. In the meantime some European countries have undertaken similar steps. However, in vitro data suggest that JWH-018 analogues (especially the side chain length C4 to C6; 1b–1d) possess equal or higher affinity to the CB1 and CB2 receptor than Δ9-THC [4]. The same is true for compounds that lack the carbonyl functionality [5]. Here, only in vitro data for 2c is available and shows receptor affinity in the same range as reported for Δ9-THC.
During the last 15 years several dozens of alkylaminoindols were synthesized to study structure–activity relationships and receptor affinities for the CB1 and CB2 receptors [5], [6], [7], [8]. While CB1 is primarily expressed in the central nervous system and exhibits the typical cannabinoid pharmacology, CB2 is also found in peripheral immune cells and seems to be involved in pain perception. Hence, it seems especially desirable to discover compounds with strong binding affinity towards CB2 but low affinity for CB1 [9].
Because of the ease of synthesis analogues of JWH-018 could easily be used as legal “Spice replacement products”. In order to provide a resource for facilitating the analysis of these potentially narcotic substances we synthesized several JWH-018 analogues. The structures were verified by NMR and characterized by mass spectrometry to provide the chemical information needed for rapid target screening. The gathered information were then used to analyze the second generation of “Spice-like-products” that were available on the German market as of March 2009.
Section snippets
General experimental procedures
GC–MS parameters: An Agilent 6890 gas chromatograph equipped with a 30 m analytical column (ZB5MS, Phenomenex, 30 m × 0.32 mm ID, ft = 0.25 μm) and helium as carrier gas (1.0 ml/min; constant flow mode). Temperature program 70 °C (3 min)–10 °C/min–330 °C (5 min). The GC was coupled directly to a JMS-T100GC (GCAccuTOF, JEOL, Japan) time of flight mass spectrometer in electron ionization (EI) mode at 70 eV and JEOL MassCenter™ workstation software was used. The source and transfer line temperature were set at
Results
The 13C and 1H NMR data and the signal assignments for 1a–2e are given in Table 1, Table 2, respectively. The NMR spectra of JWH-018 (1c) and of its analogue 2c were fully assigned by means of two-dimensional H,H-COSY and -NOESY and H,C-HSQC and -HMBC experiments, which provided definite proof of the structures. Due to the high similarity of the spectra of these compounds with the remaining ones of the respective series, the NMR spectra of the latter could be assigned by analogy.
The GC–MS data
Discussion
The recent success of “Spice” and related products reflects the large demand for “legal-drugs” in our society, but the observed phenomena show some additional peculiarities. Up to the legal ban, “Spice” was probably the most popular product defining a new class of so-called “herbal highs” with high popularity in user circles because of its obvious psychoactive properties. In retrospect, the trade name “Spice” together with the imprinted symbol of a wide open eye seems a blatant allusion to
Acknowledgements
M. Pütz and Dr. H.M. Schiebel are thanked for fruitful discussions. E. Stauber for language polishing on short notice and B. Beuerle for persistent patience.
References (14)
- et al.
Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding
Drug Alcohol. Depend.
(2000) - et al.
Design, synthesis and pharmacology of cannabimimetic indoles
Bioorg. Med. Chem. Lett.
(1994) - et al.
Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding
Drug. Alcohol Depend.
(2000) - et al.
3-Indolyl-1-naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB1 cannabinoid receptor
Bioorg. Med. Chem.
(2003) - et al.
1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles
Bioorg. Med. Chem. Lett.
(2005) - et al.
Spice and other herbal blends: harmless incense or cannabinoid designer drugs?
J. Mass Spectrom.
(2009) - et al.
Identification of a cannabinoid analog as a new type of designer drug in a herbal product
Chem. Pharm. Bull.
(2009)