Chemistry News

Issue 23, 2013

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Synthetic drugs of abuse

by Professor Michael Kassiou

The past few years have seen a paradigm shift in recreational drug use throughout the world. There has been a sudden explosion in the availability of many synthetic drugs that mimic the effects of cannabis but are without complete characterisation.

After decades of stable use of a relatively small array of illicit psychoactive substances (e.g. cannabis, cocaine, methamphetamine, MDMA, LSD) there has been a sudden explosion in the availability of novel psychoactives, many with completely uncharacterised potency and toxicity. In 2012, European authorities became aware of more than 70 new compounds, indicative of an exponential increase in the detection of such compounds over time (Fig. 1). The most commonly detected type of new psychoactive substance during 2011 and 2012 were the synthetic cannabinoids (SCs) which are a major health concern.

In America, the Association of Poison Control Centres reported just 13 calls regarding SC exposure in 2009, but this jumped to 6968 in 2011. In Australia, a recent survey of SC users revealed that more than two-thirds (68%) of 300 respondents experienced at least one serious side-effect when last using SCs. The rapid rate of emergence of novel SCs remains an impediment to their systematic evaluation, and the scale and speed of their evolution suggests that it is only a matter of time before a compound arrives that has substantial toxicity.

Figure 1. European Monitoring Centre for Drugs and Drug Addiction (MCDDA)  detection of novel drugs

Figure 1. European Monitoring Centre for Drugs and Drug Addiction (MCDDA) detection of novel drugs

From around 2010, a range of these SC- products became available under brand names such as Spice, Kronic, K2, Tai High and Zeus. These typically consist of non-psychoactive plant material laced with SC. These are available globally from internet-based vendors, and from bricks-and-mortar retailers such as "head shops", adult stores, tobacconists, and convenience stores. Although these products are disingenuously labelled as "incense" or "aromatherapy" products, and "not for human consumption", their branding and packaging indicates that they are intended for smoking as unregulated, and therefore de facto legal, marijuana substitutes. At least 27 uniquely branded SC products have been reported in Australia alone.

Although use of SCs probably started around 2004-06, the popularity of these substances dramatically increased in 2008 in Europe, and in 2010-11 in the USA, Australia, and New Zealand. Even though acute cannabis ingestion itself is rarely associated with serious adverse effects, consumption of many SCs can be associated with severe toxicity. Case reports of serious adverse events are increasingly common, including severe agitation, disorientation, hallucinations, panic, psychotic episodes, suicide attempts, extreme hypertension, tachycardia, myocardial infarction, convulsion, and coma. These effects are rarely associated with the use of cannabis itself. Most recently, a multicentre study conducted by the Centre for Disease Control and Prevention attributed severe oliguric acute kidney injury (AKI) to SC ingestion. Worryingly, no single product brand or confirmed SC explained all cases of AKI, suggesting that multiple SCs may possess previously unrecognised nephrotoxicity.

Shortly after the identification of the "grandfather" SC, JWH-018 (1, Fig. 2) in herbal blends in 2008, many countries placed this SC in the most restrictive regulatory categories. Manufacturers quickly circumvented these control measures by substituting 1 with one or more unscheduled, congeneric SCs possessing similar effects. Indeed, despite the enactment of legislation banning the sale of JWH-018 and several analogues, the 2012 Monitoring the Future Report in the USA showed that SC use amongst 12th graders remain unchanged. Dozens of SCs have now been identified in unregulated commercial products, with perhaps more than 100 SCs currently available but awaiting formal identification.

Figure 2. Several known and predicted SCs identified in illicit products

Figure 2. Several known and predicted SCs identified in illicit products

The banning of JWH-018 was followed by the release of UR-144 (2) in multiple countries, indicating that the aromatic naphthalene group of 1 is not essential for psychoactivity. Our extensive experience exploiting the desirable physicochemical properties of the adamantane cage in drug discovery allowed us to predict that structure 3 would eventually appear on the SC market, a prediction ultimately validated by forensic reports of this compound as "AB-001". Similarly, our analysis of recent cannabinoid chemotypes in the scientific literature suggested that 4 (SDB-001, APICA, 2NE1), a molecular hybrid of 3 and a quinolinecarboxamide cannabinoid scaffold, would likely emerge in SC products and this has since been confirmed. The terminal fluorination of JWH-018 to give AM-2201 (5) was reported by Makriyannis and colleagues in to improve CB1R binding affinity, and resulted in the appearance of AM-2201 in SC products. Anecdotal reports by SC users on internet forums that AM-2201 was more potent than JWH-018 led us to propose that the identification of fluorinated analogues of 2, 3, and 4 in SC products was also inevitable. Indeed, 6 (XLR-11) is one of several fluorinated SCs now reported in the forensic literature, the availability of 7 remains unconfirmed, and 8 is currently offered by online SC vendors as "STS-135" (although it has not been reported in the scientific literature).

The rapid rate of emergence of fluorinated SCs like 5–8 is particularly alarming due to their potential to form highly toxic fluoroalkyl metabolites. Nothing is known about the metabolism of fluorinated SCs. However, XLR-11 was implicated in several (but not all) cases of AKI, suggesting that fluorinated SCs may be nephrotoxic. Moreover, since these products are typically consumed by smoking, there is serious pulmonary risk posed by the pyrrolitic generation of hazardous hydrofluoric acid.

Despite the sheer number of SCs, these compounds possess limited structural diversity. The vast majority of SCs are 1,3-difunctionalised indoles which appear to be generated by clandestine laboratories applying rational drug design techniques to existing structure-activity relationship (SAR) data in the scientific and patent literature. Furthermore, each SC may produce multiple bioactive metabolites, as is the case with one of the first identified SCs of abuse, JWH-018. Several metabolites of JWH-018 have been identified, each possessing different functional activity and pharmacokinetic properties to the parent drug and other metabolites. SCs or their metabolites also interact with non-cannabinoid receptor targets possibly accounting for the cardiotoxicity of these compounds compared to cannabis.

Delay in the conclusive identification and pharmacological characterization of emerging SCs presents a potential danger to the intended consumers, and the pre-emptive identification and thorough assessment of novel "designer drugs" remains an important aspect of proactive public health policy. The implementation of appropriate legal restriction of synthetic cannabinoids is hampered by a scarcity of reference materials and analytical data, a problem that is compounded by the sheer rate of emergence of such compounds.

In collaboration with Prof's Mark Connor and Iain McGregor we are currently identifying structural features of recently identified and predicted SCs, and their metabolites, that contribute to cannabinoid receptor potency and behavioural and toxicological profiles in vivo.


  1. Banister, SD; Wilkinson, SM; Longworth, M and Kassiou, M, et al. The synthesis and pharmacological evaluation of adamantane-derived indoles: Cannabimimetic drugs of abuse. ACS Chemical Neuroscience, 4 (7), 1081-1092, 2013. DOI: 10.1021/cn400035r
  2. Interview with The Daily Examiner. "Worse symptoms than marijuana", 2013. Visit
  3. Radio interview with Richard Bell, Chair, 2NSB - The North Shore's FM99.3, on the effects of the side effects and use of synthetic drugs. Visit

Biography: Professor Michael Kassiou

Michael Kassiou

Professor Michael Kassiou

Michael Kassiou received his PhD in Organic Chemistry in 1992 from the University of NSW. Following this he took up a position as research scientist within the Biomedicine and Health Program at the Australian Nuclear Science and Technology Organisation (ANSTO). In 1993 he was appointed as a visiting scientist at the CEA-Service Hospitalier Frédéric Joliot Life Sciences group in France which peaked his interest in methods for studying the living brain. It was here that he first experienced the use of positron emission tomography (PET) as a technique that allowed for the first time to look inside the living brain to study brain neurochemistry and the effects that therapeutic drugs had on it in a non-invasive manner. Shortly after that Michael took up a postdoctoral position at the Johns Hopkins Medical Institutes in Baltimore USA with Professor Robert Dannals and the late Professor Henry Wagner who was known as the forefather of Nuclear Medicine. Living in Baltimore and studying at Johns Hopkins was a very stimulating time, both academically and socially. During this time he learnt three simple principles about research that he still abides by; "is it new?", "is it true?" and "does it matter?". In 1996 he was awarded a Fogerty Fellowship that saw him take up a position at the NIH National Institute of Drug Abuse (NIDA) USA with Professor Edythe London. Here he developed an interest in looking at the effects of drugs of abuse with a focus on nicotine and the use of PET. He then moved back to Sydney to the Department of PET and Nuclear Medicine at the Royal Prince Alfred Hospital as a Principal Hospital Scientist and in 2006 took up a position at the University of Sydney in which he is currently Professor of Medicinal Chemistry. He has also been elected as a Fellow of the Royal Australian Chemical Institute (RACI) (FRACI, C.Chem) and is currently chair of the Medicinal Chemistry & Chemical Biology Division of RACI.

Michael's research is interdisciplinary and built around the key themes of medicinal chemistry and drug discovery. In this domain a key component is the development of structure-activity relationships of bioactive CNS molecules which allow the rational design of more efficacious treatments for diseases of the brain. In addition, he has a long-standing interest in development of targeted molecular probes for neuropharmacological studies, including the development of pharmacological techniques for the study of receptor-ligand interactions and radioligands to identify brain regions and neural pathways affected in substance abuse, neurodegenerative and psychotic disorders.