Legal highs : staying on top of the flood of novel psychoactive substances, David Baumeister et al., 2015

Legal highs : staying on top of the flood of novel psychoactive substances

David Baumeister, Luis M. Tojo and Derek K. Tracy

Therapeutic Advances in Psychopharmacology, 2015, Vol. 5, (2), 97–132

DOI: 10.1177/2045125314559539


Abstract :

There has been growing clinical, public, and media awareness and concern about the availability and potential harmfulness of so-called ‘legal highs’, which are more appropriately called new or novel psychoactive substances (NPS). A cat-and-mouse process has emerged wherein unknown chemists and laboratories are producing new, and as yet nonproscribed, compounds for human consumption; and as soon as they are banned, which they inevitably are, slightly modified analogues are produced to circumvent new laws. This rapidly changing environment, 81 new substances were identified in 2013 alone, has led to confusion for clinicians, psychopharmacologists, and the public at large. Our difficulties in keeping up with the process has had a two-fold negative effect: the danger of ignoring what is confusing; and the problem that some of the newer synthesized compounds appear ever more potent. This review aims to circumscribe a quick moving and growing field, and to categorize NPS into five major groups based upon their ‘parent’ compounds: stimulants similar to cocaine, amphetamines and ecstasy; cannabinoids; benzodiazepine based drugs; dissociatives similar to ketamine and phencyclidine (PCP); and those modelled after classic hallucinogens such as LSD and psilocybin. Pharmacodynamic actions, subjective and physical effects, harmfulness, risk of dependency and, where appropriate, putative clinical potentials are described for each class. Clinicians might encounter NPS in various ways: anecdotal reportage; acute intoxication; as part of a substance misuse profile; and as a precipitant or perpetuating factor for longer-term physical and psychological ill health. Current data are overall limited, and much of our knowledge and treatment strategies are based upon those of the ‘parent’ compound. There is a critical need for more research in this field, and for professionals to make themselves more aware of this growing issue and how it might affect those we see clinically and try to help: a brave new world of so-called ‘psychonauts’ consuming NPS will also need informed ‘psychotherapeutonauts’. The paper should serve as a primer for clinicians and interested readers, as well as provide a framework into which to place the new substances that will inevitably be synthesized in the future.

Keywords : legal highs, novel psychoactive substances



‘Alas, poor man! You have enough necessary ills without increasing them by your invention’
(Montaigne, Essays, III, 5, On Some Verses of Virgil)

Recent years have seen a surge in the availability of new or novel psychoactive substances (NPS)
sold variously as ‘legal highs’, ‘bath salts’ or ‘research chemicals’, with ambiguous names such as ‘K2’, ‘Spice’ or ‘NRG-1’. These are often pharmacological analogues of compounds prohibited under current drug laws such as amphetamines and cannabis, and consumed as legal or quasilegal alternatives available from online vendors or in so-called ‘head shops’. Very little is known about their psycho-pharmacological effects or acute and long-term risks, although typically governmental responses have been to ban them as soon as possible.

However, drug laboratories have responded to prohibition of one agent with the introduction of another, leaving lawmakers engulfed in largely futile, Sisyphean legislative efforts as new substances hit the market in rapid succession. This problem is exemplified by the synthetic cannabinoid JWH-018, which was identified as a main ingredient of ‘Spice’ in Germany in 2009 and subsequently banned. Only 4 weeks thereafter, another sample of ‘Spice’ was obtained, that, whilst not showing traces of JWH-018 anymore, now contained the unregulated homologue JWH- 073 [Lindigkeit et al. 2009]. Not only does this back-and-forth lead to significant financial costs and wasted efforts, but it may lead to increased
risks for substance users who are willing to try an increasing number of unknown and potentially harmful substances. Furthermore, nascent data indicate that some agents may be more harmful than their more established parent compound in terms of risk of dependency, overdose and longterm health impacts. The United Nations Office on Drugs and Crime (UNODC) implemented the Synthetics Monitoring: Analyses, Reporting and Trends (SMART) global collaborative programme in 2008 to assess, report and manage NPS; but the speed of their synthesis has meant it has proven difficult for professionals and services to keep abreast of new developments. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) operates the European Union’s ‘Early Warning System’ (EWS) for NPS, monitoring over 350 NPS: their most recent report (see, published in May 2014, stated that 81 NPS were notified for the first time to the EWS in 2013, and that this system was ‘coming under increasing pressure from the volume and variety of new drugs appearing on the market’.

This review aims to provide professionals and interested readers an overview in which to consider the most common current NPS, their pharmacodynamics, subjective and physiological effects, risks and impact, as well as a framework by which to categorize the novel compounds that will undoubtedly be synthesized in the future.

Categorizing ‘legal highs’

Five major categories of NPS will be reviewed in this article, based on their ‘parent’ compound: those modelled after psychostimulants such as amphetamine, 3,4-methylenedioxy-N-methylamphetamine (MDMA) and cocaine; those that mimic the effects of cannabis; those based upon benzodiazepines; those that produce dissociate effects similar to ketamine or phencyclidine (PCP); and those developed as analogues of ‘classical’ hallucinogens such as LSD or psilocybin.

Pharmacodynamic mechanisms; associated psychological and physical effects; associated health risks as well as risks of dependency and addiction; and potential pharmacotherapeutic potential will be discussed for each class.


2015 legal highs