1.2.1 Objectives of NEPTUNE

This document is the 2022 update of the 2015 guidance on the harms and management of NPS and club drugs, developed by NEPTUNE (Novel Psychoactive Treatment UK Network). This edition has been funded and supported by EU-Action Against Drugs and Organised Crime (EU-Act).⁵

The aim of the guidance is to improve confidence, competence, and skills of clinicians in the detection, assessment, and management of the harms associated with the use of NPS.

Specific areas addressed include:

• Detection/identification. Recognising the significant psychological, physical, and social risks which can be associated with club drugs and NPS, and equipping professionals to be able to recognise problematic use, associated harms, and dependence.

• Assessment. Assessment of the problems related to the use of club drugs and NPS, including the assessment of both direct and indirect harms.

• Management. Clinical management of acute and chronic harms related to the use of club drugs and NPS – based on the best available evidence.

• Harmr eduction. Interventions aimed at preventing morbidity and mortality among individuals presenting to clinical settings, including measures to reduce the harms of club drugs and NPS for individuals and communities and to help patients achieve and sustain recovery and well-being.

This document provides guidance, not guidelines. The implementation of NEPTUNE at national levels must take place within the principles of national and international guidelines, national and local protocols, as well as the international standards and broad principles for the treatment of substance misuse disorders.^{6, 7}

The implementation of NEPTUNE learning into clinical practice must adapt the learning to take into account factors specific to the region, country or sector where they are implemented. This includes the needs, priorities, legislation, policies, systems of healthcare delivery and resources of the various countries. Adaptation should be carried out without undermining the validity of the evidence-based training. Local and national protocols, including prescribing protocols, should be used.

For up-to-date information, it is also recommended that clinicians contact the Poisons Centres in their region, where available. These are specialised units that advise on, and assist with, the prevention, diagnosis, and management of poisoning. Their structure and function varies around the world; however, at a minimum, a poisons centre is an information service. Some centres may also include a toxicology laboratory and/or a clinical treatment unit.⁸

1.2.2 Why Produce Guidance on Club Drugs and Novel Psychoactive Substances?

The underlying principles of good clinical practice in relation to the users of club drugs and NPS are the same as for harmful and dependent drug misuse in general.

Clinicians’ existing experience of the treatment of other commonly used drugs (such as heroin, alcohol or cannabis for example) is very relevant to the treatment of club drugs and NPS.

However, good assessment and management of the harms of club drugs and NPS must also consider the particular challenges posed by novel drugs and address them directly. These include challenges posed by:

• New drugs (rapidly changing profile and ever-increasing numbers of substances, with poorly understood harms);

• New populations in treatment (including new patterns of drug use and contexts of harm);

• New harms (some club drugs are associated with harms not previously linked to illicit drug use, e.g. ketamine-related ulcerative cystitis);

• New manifestation of drug-related harms which are familiar to clinicians (e.g. dependence and withdrawal associated with gamma-hydroxybutyrate (GHB).

NEPTUNE therefore aims to improve clinicians’ knowledge of the specific issues relating to NPS and to support evidence-based practice at local levels. It also aims to help improve clinicians’ confidence in working with patients who use NPS, by providing the following:

• ‘Technical’ knowledge (what the drugs are and how they work);

• ‘Cultural’ knowledge (who is using them, and how);

• ‘Clinical’ knowledge (how to clinically manage both acute and chronic presentations).

1.3.1 Primary Audience

This guidance is aimed primarily at a clinical audience and most specifically clinicians who manage physical and mental health problems associated with harmful or/and dependent drug use and ensuing acute or chronic problems.

These will include clinicians working in specialist drug treatment and recovery services, as well as in emergency departments. The document is also relevant to professionals working with populations at risk of drug-related harms and associated poorer treatment outcomes, such as mental health services, prison health services, primary care, sexual health services, HIV treatment, hepatology and others.

1.3.2 Other Audiences

Although not directly aimed at them, this document is also a resource for funders/commissioners and policy-makers in developing local, national or regional services. It also provides patients and carers with information on what interventions should be available.

1.4.1 Method for the Literature Review

This document is based on a comprehensive review of the English language literature on the harms and the clinical management of a range of club drugs and NPS, using systematic methods. A multi-disciplinary group of people were involved in developing the NEPTUNE framework and the guidance document was independently peer reviewed.

The first edition of this guidance was published in March 2015.This edition also includes a review of the research literature published until 2021.

For the review of the evidence, studies were identified using electronic searches of Medline, Medline Plus, the Cochrane Library, CINAHL, Current Content, Embase, PUBMED, PsychINFO, Google Scholar and the Science Citation Index. In addition, bibliographies of articles were screened for additional relevant studies.

The outputs of searches were considered against sets of inclusion and exclusion criteria. The citations produced by these searches were then screened via their abstract. Those considered relevant were identified and subjected to critical assessment.

The critical assessment of the evidence was based on the framework developed by the British Association for Psychopharmacology for the development of guidelines for the management of substance misuse.Reference Lingford-Hughes, Welch, Peters and Nutt⁹ This classifies the strength of evidence as follows:

• Strong research evidence (e.g. Cochrane reviews, meta-analyses, high-quality randomised controlled trials);

• Research evidence (e.g. controlled studies or semi-experimental studies);

• Emerging research evidence (e.g. descriptive or comparative studies, correlation studies, evaluations or surveys and non-analytic studies, e.g. case reports, case series);

• Expert panel evidence/consensus;

• Expert by experience evidence (service users/patients);

• Lack of evidence (no evidence, for or against);

• Conflicting evidence.

The 2021 update of the 2015 NEPTUNE guidance document continues to suggest that the evidence base on NPS remains relatively small, albeit exp-anding.Reference Santos-Toscano R, Guirguis A and Davidson D.¹⁰

In particular, studies on the toxicity and management of the harms of NPS and risks associated with long-term use and dependence liability are few, partly because most NPS have limited or no medical use, and partly because some of these substances have only recently emerged.

Overall, a review of the evidence shows that there continues to be limited robust evidence, in particular from meta-analyses or high-quality randomised controlled trials, and even controlled and semi-experimental studies are few. The bulk of the research available provides what is referred to as emerging research evidence, as it is based principally on non-experimental descriptive studies, consisting mainly of case reports and series and a small number of prospective observational studies, retrospective cohort studies and analysis of patient records.

This document therefore does not give definitive answers on the clinical management of NPS, but broad guidance based on the current best available evidence.

1.4.2 Substances and Drug Groups Covered by This Guidance

1.4.2.1 Classifying Novel Psychoactive Substances

Just over psychoactive drugs (NPS) have been reported for the first time in the last decade or so. Because of the very large number of NPS that have been detected and those that will emerge in the future, it is not possible to cover them all in any detail within the confines of this work. Nor is it realistic for clinicians to remember information on all NPS.

In order to deal with these large numbers of NPS and to future-proof this guidance, a two-pronged approach has been adopted.

Categorising Groups of Novel Psychoactive Substances

In order to understand the harms of NPS and how to manage them, it is useful to be able to classify them into different categories. Classification of NPS could be achieved using a variety of approaches, including chemical structure or pharmacological effect.

However, a useful method of categorising NPS is according to their primary psychoactive, physical and psychiatric effects and to use categories that clinicians working with the effects of substance misuse are already familiar with (see Figure 1.1).

Figure 1.1 Categorising substances by their primary psychoactive effects

A drug’s primary effects will provide a conceptual framework for NPS, which will help clinicians navigate the hundreds of new substances detected in recent years, while allowing them to draw on their existing experience of substance misuse.

This classifies NPS and club drugs into the following groups:

• Primarily stimulants

• Primarily depressants

• Primarily hallucinogens

• Synthetic Cannabinoid Receptor Agonists (SCRAs) are put in a category of their own and are classified as a fourth separate category, as they do not fit easily into the other groups. This is because they are such a chemically and pharmacologically diverse group that their specific harms and clinical management also varies widely.

Although these classifications provide a useful framework for this guidance, it is important to note that they are not rigid categories. In reality, many drugs have a combination of effects, often dose-related, e.g. a primarily depressant drug can have stimulant effects at low doses. In addition, people will sometimes use NPS as part of a wider repertoire of illegal drugs and alcohol. The co-ingestion of more than one drug is common.

Most NPS are designed to provide legal alternatives to controlled substances, and have harms similar to those associated with the controlled drugs they have been manufactured to mimic.

The proximal mechanisms of most of these effects (as far as they are known) are shown in Table 1.1.

Table 1.1 Proximal mechanisms of drug effects

Drug	Primary (proximal) target	Brain effect
Alcohol	Agonist at GABA and antagonist at glutamate receptors	Increases GABA; blocks NMDA glutamate receptors
Benzodiazepines	Agonists at benzodiazepine site on GABA-A receptor	Increase GABA
GHB	GHB and GABA-B receptor agonist	Mimics GABA; inhibits dopamine release
Ketamine	NMDA glutamate receptor antagonist	Blocks glutamate
Khat (natural cathinone)	Releases ephedrine, a dopamine releaser	Mild increase in noradrenaline and dopamine
Mephedrone (synthetic cathinone)	Releases dopamine and blocks reuptake
Natural cannabis	Cannabis CB1 receptor agonist	Stimulates endo-cannabinoid signalling, leading to a change in cortical and memory function
Cocaine	Blocks dopamine reuptake site	Greatly increases dopamine
Amphetamines (dexamphetamine and methyl)	Release dopamine and block reuptake	Greatly increase dopamine and noradrenaline
MDMA	Blocks serotonin and dopamine reuptake	Increases serotonin and dopamine functioning
Hallucinogens	Agonists at serotonin 5-HT2A receptors	Change across-cortex signalling
Opioids	Agonists at endorphin receptors	Produce euphoria, reduce pain

Agonist = drug that activates or stimulates a receptor; Antagonist = drug that blocks a receptor.

1.5.1 What Is a Club Drug?

‘Club drugs’ is a short-hand term used for convenience to refer to a group of psychoactive substances typically used in dance venues, house parties, music festivals and sometimes in a sexual context. The term therefore describes a diverse group of substances with different actions.

1.5.2 What Is a Novel Psychoactive Substance?

The term ‘novel psychoactive substance’ (NPS) has been used to describe a diverse group of substances that rapidly emerged from the early to mid-2000s.Reference Peacock A, Bruno R and Gisev N¹¹

The UNODC defines NPS as ‘substances of abuse, either in a pure form or a preparation, that are not controlled by the 1961 Single Convention on Narcotic Drugs or the 1971 Convention on Psychotropic Substances, but which may pose a public health threat’.

Most NPS are thought to be manufactured to mimic the effects of controlled drugs. NPS were developed initially as ‘legal’ replacements to established controlled drugs such as cannabis, heroin, cocaine and MDMA. They are sold openly, in some countries at least, as well as on the Internet in branded products advertised as ‘legal highs’ or ‘research chemicals’ or as ‘food supplements’, in attempts to make these substances attractive to users.

Many hundreds of NPS have been reported for the first time in the last decade. There is no doubt that the producers of novel NPS and ‘legal highs’ are well aware of the legal framework surrounding illicit substances and are continuously replacing controlled compounds with an array of compounds, which are modified to avoid legal control. Given the very numerous possibilities for altering the structure of chemicals, the list of substances produced is likely to grow continuously.¹² New substances are produced very quickly to replace those that are placed under legal control by various states.¹³

As the number of NPS grew rapidly, by 2013 the number of NPS already exceeded the number of psychoactive substances controlled at the international level.¹⁴ By December 2021, a total of 1,124 unique new substances have been reported to the UNODC Early Warning Advisory (EWA) on NPS by Governments, laboratories and partner organisations. These can be grouped as follows: stimulants 36%, SCRAs 29%, classic hallucinogens 15%, opioids 9%, dissociatives 3%, sedatives/hypnotics 3% and not yet assigned 5%.^{15, 16}

In Europe, 830 new psychoactive substances were being monitored by the end of 2020 by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), 46 of which were detected for the first time in Europe in 2020.¹⁷

Not all NPS detected continue to be available over time, as some appear for the first time and then disappear from the market. The World Drug Reports suggest that the overall number of NPS present on the market has stabilised at approximately 500 substances per year over the period 2015–2019.

In terms of the use of NPS and despite the continuing increase in the emergence of new NPS, one study suggested that a core group of over 80 NPS have become established as recreational drugs, supplementing traditional drugs that are misused and becoming part of the repertoire of substances available for consumption.Reference Corkery, Guirguis, Papanti, Orsolini, Schifano and Zawilska¹⁸

Currently, most NPS are stimulants, followed by synthetic cannabinoid receptor agonists and a smaller number of hallucinogenics and opioids.^{19, 20} It has been noted that the increase in the number of opioid NPS and benzodiazepine NPS potentially signals that new psychoactive substances are increasingly more targeted at the long-term and more problematic drug users.²¹

Novel psychoactive substances are generally produced in bulk quantities by chemical and pharmaceutical companies often in China or India, or in clandestine laboratories in Europe. They are then shipped to Europe, where they are processed into products, packaged and marketed.²²

It has been argued that these substances are not ‘legal’ but are instead ‘not prohibited’. Their non-controlled status does not reflect their safety, but rather the lack of regulation over their production, distribution and use.Reference Reuter^23, Reference McNabb, Russell, Caprioli, Nutt, Gibbons and Dalley²⁴ Many are untested and have unknown psychological and toxicological effects.Reference Peters and Martinez-Ramirez^25, Reference Maurer²⁶

Not all NPS are ‘novel’. ‘New’ does not always mean a new invention but could refer to substances that have recently been made available for recreational use, e.g. mephedrone was reportedly first synthesised in 1929, but emerged as a recreational substance of misuse as late as 2007.²⁷ Other ‘new’ substances were synthesised and patented in the 1970s or earlier, but recently their chemistry has been modified slightly to produce psychoactive effects similar to those of well-established illicit substances.

1.5.3 Changes in Legal Control of Novel Psychoactive Substances

The legal position of some NPS has changed over time.  At the international level, up to March 2019, the Commission on Narcotic Drugs placed 48 NPS under international control. These control measures have to be implemented into the national legal framework of each country.²⁸

Other NPS continue to be outside International Drug Control Conventions. However, their legal status differs widely from country to country. To date, approximately 60 countries have implemented legal responses to control NPS by amending existing legislation or through innovative legal instruments.

Some countries have adopted controls on entire substance groups of NPS using a so-called generic approach, or have introduced analogue legislation that invokes the principal of ‘chemical similarity’ to an already controlled substance to control substances not explicitly mentioned in the legislation.²⁹

These controls have limited the open sale of these products. They may also have played a role in reducing the number of NPS detected for the first time. However, challenges remain.

1.5.4 Development and Spread of Large Numbers of Novel Psychoactive Substances

Although the number of NPS has been growing at a very fast pace, it has been noted that this yearly increase appears to be slowing down in recent years. In Europe, it has been reported that the number of new substances identified for the first time each year peaked in 2014–2015, but has since stabilised at levels comparable to 2011–2012.³⁰

The causes of this are unclear, however may reflect the results of sustained efforts to control new substances in Europe and legislation in some countries. This may have resulted in reducing the incentive for producers to keep ahead of legal controls and develop new compounds. In addition, control measures and law enforcement operations in China targeting laboratories producing NPS may also have played a role.^{31, 32}

Nonetheless, and despite reduction in yearly number of NPS detected, challenges continue and new ones emerge. NPS continue to appear at the rate of one per week. There is also no evidence that the overall availability of NPS has reduced and the drugs may still be available more covertly on the illicit market.³³

Some NPS are also now well-established in the drugs market, most particularly SCRAs and synthetic cathinones.³⁴ There is also some evidence the tightening of regulation may have sometimes led to the decrease in the number of people using NPS, but users instead switched to other types of drugs.Reference Tanibuchi, Matsumoto, Shimane and Funada³⁵

There are also changes in the type of substances being detected for the first time globally, with new substances increasingly targeted at long-term and more problematic drug users, particularly NPS synthetic opioids and benzodiazepines.^{36, 37, 38, 39, 40} Problematic NPS use is also increasingly found in some vulnerable groups in Europe, e.g. people who inject drugs and homeless people, and has been associated with increased levels of physical and mental health problems.⁴¹

1.6.1 Overall Drug Use

Novel psychoactive substances have not replaced traditional illicit drugs, but exist alongside them.

Data from European countries on NPS are available from half the countries, but are often not comparable. Existing information suggests that use of NPS is overall low in comparison to traditional illicit club drugs. NPS nonetheless are consumed and are more likely to be used by some population sub-groups.

1.6.2 Club Drug Users and Contexts of Use

Different people will use substances for different reasons and each chapter in this text will look at the subjective effects of a substance desired by people who use it.

There is some research that has looked at why people use NPS specifically, which includes the fact that users turn to NPS as a substitute to traditional drugs when these are prohibited or when there is reduced supply or perceived drop in quality.Reference Measham, Moore, Newcombe and Welch⁴²

There is also evidence that the motives for using NPS are curiosity, enhancement of social situations, the enjoyable effects, a desire to ‘get high’, and a belief that NPS are safer and more convenient.Reference Corazza, Simonato, Corkery, Trincas and Schifano^43, Reference Sande^44, Reference Winstock, Lawn, Deluca and Borschmann^45, Reference Measham, Moore, Newcombe and Welch⁴⁶

Novel psychoactive substances were also used because they were seen as facilitating a novel and exciting adventure, as promoting self-exploration and personal growth, functioning as coping agents, enhancing abilities and performance, fostering social bonding and belonging, and acting as a means for recreation and pleasure.Reference Soussan C and Andersson M⁴⁷

It has been argued that the motives for NPS use may be associated with both the groups of users and the specific types of NPS being consumed. Benshop et al.’s (2020) exploratory and confirmatory factor analysis identified five factors across a number of countries: coping, enhancement, social, conformity and expansion motives. Overall, marginalised users scored higher on coping and conformity motives. Nightlife groups showed higher endorsement of social motive, whereas online community users showed higher scores on expansion motives. Various types of NPS were also associated with different motives. Motives for use of the specific substances are also discussed in the relevant sections throughout this chapter.Reference Benschop, Urbán and Kapitány-Fövény^48, Reference Corazza, Simonato, Corkery, Trincas and Schifano^49, Reference Johnson, Johnson and Portier^50, Reference Measham, Moore, Newcombe and Welch^51, Reference Sande^52, Reference Werse and Morgenstern^53, Reference Winstock, Lawn, Deluca and Borschmann⁵⁴

Some NPS, e.g. mephedrone, are also used for sexual enhancement, including by gay and bisexual men who use it in the context of ‘chemsex’.Reference Maxwella S and Shahmanesh M⁵⁵

1.6.3 Population Groups Most Likely to Use Novel Psychoactive Substances

There is evidence that levels of NPS- and drug use are higher among particular populations. These are the following:

1.6.4 New Markets and User Communication about Drugs

‘Traditional’ methods remain the most common ways to acquire drugs (dealers, friends, family), both classic drugs and NPS. However, the Internet now occupies a growing role in the sale of drugs, with significant drug sales on the darknet and the potential to grow.

Novel psychoactive substances can sometimes be bought on the ‘clearnet’ (a part of the Internet accessible to standard search engines) or from the ‘dark web’ (a part of the Internet only accessible through specialist anonymising web browsers), with the ‘darknet’ also selling controlled substances.^103, Reference Corazza, Schifano and Farre^104, Reference Corazza, Schifano and Simonato^105, Reference Corazza, Valeriani, Bersani and Spice^{106, 107} It has been reported that when compared with current estimates of the annual retail value of the overall EU drug market, sales volumes on darknet markets are currently modest, but growing.¹⁰⁸

For a growing number of people, the Internet is now the first place they look when searching for recreational drugs and their related information, especially when faced with the rapid and baffling proliferation of NPS.¹⁰⁹ A study carried out in the Netherlands has shown that online customers are sometimes willing to pay more for the convenience of purchasing drugs online.¹¹⁰

The Internet has also had an impact on drug use patterns and behaviours. A UNODC 2020 publication has reported that more than a quarter of people who started using drugs before they began buying drugs on the darknet, then consumed a wider range of drugs, and approximately 10% reported that that they consumed a different class of drugs.¹¹¹

Especially when not controlled, NPS have been marketed as ‘plant food’, ‘bath salts’, ‘research chemicals’, ‘incense’ or ‘herbal highs’ and are typically labelled as ‘not for human consumption’.^112, Reference Hout¹¹³

There is also some evidence that NPS, as well as traditional drugs, are sometimes acquired through social media. The most commonly used technology to acquire drugs is that of mobile phones. Phone-based drug delivery services, sometimes known as ‘ring and bring drug phone lines’ or ‘dial-a-drug’ are increasingly common. This is true for NPS as well as traditional illicit substances, and the European market for cocaine has been described as undergoing a process of ‘Uberisation’, where more sellers provide ‘fast delivery anywhere at any time’.¹¹⁴

1.7.1 How Drugs Work

Most NPS are designed to provide legal alternatives to controlled substances, and have effects similar to those associated with the controlled drugs they have been manufactured to mimic.

As mentioned previously, drugs can be classified in various ways – according to chemical structure, pharmacological activity or psychological effects.Reference Werse and Morgenstern^53, Reference Winstock, Lawn, Deluca and Borschmann54^, Reference Schifano^115, Reference Schifano, Orsolini, Duccio Papanti and Corkery¹¹⁶

1.7.2 Toxicity and Other Acute Harms

The harms associated with club drugs and NPS can, as with ‘traditional’ drugs including alcohol, be ranked based on the relative harms.Reference van Amsterdam, Nutt, Phillips and van den Brink¹¹⁷

‘Toxicity’ generally refers to the extent to which a substance causes functional or systemic damage to a living organism.Reference Gable^118, Reference Gable¹¹⁹

Our knowledge of the effects and toxicity of many NPS remains limited, as it is often mainly based on user reports and clinical intoxication cases, with very limited pharmacological and toxicological data available.Reference Luethia D, Kolaczynskaa KE, Doccia L, Krähenbühla S, Hoenerb MC and Liechti ME.¹²⁰

There is nonetheless enough evidence to show that club drugs and NPS are associated with a range of harms.¹²¹ The growing market for new substances has been linked to an increase in the number of serious adverse events – particularly non‐fatal and fatal poisonings.Reference Elliott S and Sedefov R^{122, 123,} Reference Evans‐Brown and Sedefov¹²⁴

There are wide variations in the toxicity of the various club drugs and NPS, including their single-dose lethal toxicity.Reference Gable¹²⁵ An index for fatal toxicity has been developed, showing differences between the various NPS and demonstrating that GHB/GBL, AMT, synthetic cannabinoid receptor agonists (SCRAs) and benzofurans had a higher fatal toxicity than other NPS.Reference King LA and Corkery JM.¹²⁶ In recent years, benzodiazepine NPS have also been linked with fatalities, such as the case of etizolam and other ‘street’ benzodiazepines.¹²⁷ Similarly, new opioids including fentanyl NPS have been associated with high levels of acute toxicity.

The harm associated with any drug of potential misuse may include: the physical and mental health harms to the individual user caused by the drug; overdose; the dependence-inducing potential of the drug; and the effects of drug use on families, communities and society.Reference Nutt, King, Saulsbury and Blakemore¹²⁸ All aspects need to be considered when assessing the impact of a drug.

In addition, individuals vary greatly with respect to metabolism and vulnerability to physical and mental health problems. A number of other factors are also linked to acute toxicity:

• The consumption of more than one substance will increase the chances of acute toxicity, particularly when drugs with similar physiological effects are combined (e.g. sedatives such as GHB and alcohol, or stimulants such as cocaine and amphetamine).

• The risk of overdose is increased by repeated administration of the drug.

• The safety ratio of drugs does not reflect the metabolic or functional tolerance that a user may have developed.

• Non-drug variables can alter toxic reactions significantly (e.g. the psychological effects of the environment, diet, stress, expectation etc.).Reference Bonaccorso S, Metastasio A and Ricciardi A^58, Reference Gable¹²⁹

• The mode of administration, with injecting not only exposing the user to the risk of bacterial infections but also increasing the risk of overdose and dependence.¹³⁰

• Drug purity and adulterants can affect toxicity.

Club drugs and NPS pose a particular challenge to clinicians and constitute a public health challenge for the following reasons:Reference Corazza, Schifano and Farre¹³¹

• these substances are not approved for human consumption;

• they are associated with a number of unknown adverse effects;

• insufficient information is available in peer-reviewed scientific journals on harms;

• they appear in increasingly sophisticated (i.e. non-powder) forms and remain unregulated;

• they are often synthesised in underground laboratories by modifying the molecular structure of controlled drugs, raising concerns over the presence of contaminating agents;

• they are largely available online to everyone, ‘just a click away’.

Whereas all users of club drugs face the risk of acute toxicity, the harms caused by club drugs encompass a wide range of different patterns. Club drugs are associated with harmful use, which can be physical harms (e.g. ketamine can lead to ulcerative cystitis) or mental (e.g. psychosis associated with synthetic cannabinoids).

Although still limited, we have an increasing understanding of the harms associated with NPS through animal and human studies.Reference Costa, De Luca, Piras, Marongiu, Fattore and Simola¹³²

Recently, information has been provided through the Tox-Portal, an online tool developed in collaboration with The International Association of Forensic Toxicologists (TIAFT) that collects data on toxicology and harm related to the use of NPS at a global level.¹³³ This has shown the following:

• synthetic cannabinoids, synthetic opioids and synthetic stimulants account for the majority of NPS reported to the UNODC EWA Toxicology Portal.

• Synthetic cannabinoids in particular remain harmful, persistent and prevalent.

• Poly-drug use continues to be a factor and an important consideration in NPS fatalities.

• Benzodiazepine-type NPS feature highly in cases of driving under the influence of drugs.¹³⁴

Some NPS have also been shown to have a liability to produce dependence and some have been associated with a withdrawal syndrome, which can be severe, for example in the case of GHB/GBL.

1.7.3 Particular Challenges of Novel Psychoactive Substances

1.8.1 Novel Psychoactive Substance and Drug-Related Presentations to Hospital Emergency Departments

Accurate data on emergency hospital admissions resulting from club drug and NPS use in the UK were difficult to obtain for a variety of reasons, not least because ICD-10 codes did not include specific codes for NPSReference Wood DM, De La Rue L and Hosin AA^169, Reference Wood, Conran and Dargan^170, Reference Shah, Wood and Dargan¹⁷¹ and because coding is generally based on clinical condition at presentation.Reference Wood DM, De La Rue L and Hosin AA¹⁷²

More recently, the new classification of substance use disorders and problems in ICD-11 includes a range of diagnostic categories that cover a broad spectrum of health conditions reflecting different levels and patterns of substance use.¹⁷³ ICD-11 also covers some NPS and club drugs, for example synthetic cathinones,¹⁷⁴ SCRAs¹⁷⁵ and MDMA.¹⁷⁶

It has been suggested that these changes may in part help with some of the coding issues, enabling better understanding of the burden of healthcare utilisation related to the use of a wider range of substances.Reference Wood DM, De La Rue L and Hosin AA¹⁷⁷ However, in clinical practice, clinicians may not record drug-related codes, but codes based on clinical presentation. In addition, the rapidly emerging number of NPS means that some may not codeable under existing ICD-10 and even ICD-11 codes.

Data on acute drug-related hospital presentations associated with NPS continue to be limited,¹⁷⁸ but have been improving. Interventions have taken place in Europe for a number of years now, including the European Drug Emergencies Network (Euro-Den), in order to address this current paucity of reliable data.Reference Wood, Heyerdahl and Yates¹⁷⁹

Euro-Den data from 31 sentinel sites in 21 countries reported that there were 23,947 acute drug toxicity presentations reported by the Euro-DEN Plus centres over the four-year period between January 2014 and December 2017. These represented a median of 0.3% of all emergency presentations to the sentinel hospitals. Amongst those, NPS were seen in 9% of presentations over the four-year period, with significant geographical variation in the involvement of NPS in presentations.¹⁸⁰

Data on deaths associated with club drugs and NPS also remain limited, and it has been argued that the absence of European forensic toxicology guidelines for drug-related death investigations is a barrier to improving monitoring and practice in this area.¹⁸¹

However, there is evidence that NPS, including synthetic opioids, synthetic cannabinoid receptor agonists and synthetic cathinones continue to be associated with acute intoxications and deaths. As with all drug-related deaths, fatalities often involve the use of more than one substance (poly-drug use).¹⁸²

Emergency medicine physicians and other clinicians should seek advice on the diagnosis, treatment and care of patients who may have been poisoned with a club drug or an NPS, including from national or regional poisons information services. Interventions provided must be based on local, national and international protocols and guidelines.

1.8.2 Sexual Health Services

The association between substance misuse, including alcohol use, and high-risk sexual behaviours is well established, although evidence of a causal relationship is limited.

There is also some evidence from some countries that the prevalence of drug use is higher among the patients of sexual health services than the general population and most particularly patients who identify as men who have sex with men (MSM). For example, one study of patients at a London sexual health clinic reported significantly higher rates of past month drug use than in the general adult population in England and Wales. This was particularly so among MSM.Reference Hunter, Dargan, Benzie, White and Wood¹⁸³

Patients of sexual health services who misuse alcohol and drugs have also been identified as higher-risk groups for poor sexual health outcomes. Substance misuse interventions in these settings have been recommended.^{184, 185, 186, 187}

It has therefore been argued that sexual health services may provide opportunistic encounters to identify patterns of recreational drug use, explore motivations for use and implement strategies to reduce harms related to drug use.Reference Hunter, Dargan, Benzie, White and Wood^{188, 189, 190, 191} It has been suggested that patient assessment in sexual health services should include a history of alcohol and recreational drug use.¹⁹² Integrated services have also been suggested.¹⁹³

1.8.3 Substance Misuse Treatment Services

International Standards for Treatment of Drug Use Disorders have been developed by the UNODC-WHO, and provide the rules and minimum requirements for clinical practice and the generally accepted principles of patient management in any healthcare system.¹⁹⁴

A set of best practice principles that should underlay drug dependence treatment has been identified and defined by the United Nations Office for Drugs and Crime (UNODC) and the World Health Organization (WHO), and are listed in Box 1.1.¹⁹⁵

Building on these principles, at a practical level, drug treatment services and systems can consider the following to improve their understanding:

• Amending data recording tools to ensure NPS use and associated adverse health effects are accurately recorded

• Engaging in research to build the evidence base for treatment interventions

1.8.4 Overview of the Interventions for the Screening, Identification and Management of Drug Harms in the Target Settings

The different target organisations (treatment settings) of the NEPTUNE guidance have different roles in the detection, identification and management of chronic harms and/or dependence resulting from the use of club drugs and NPS. This is determined by the competence of clinicians to deliver substance misuse treatment and particular pharmacological, psychosocial and recovery interventions.

Table 1.2 provides a summary of the role of each of the target settings and the aims of the interventions provided in terms of the screening, identification, assessment and management of the harms linked to the use of club drugs. Further information on the level of intervention needed is also presented in Chapter 2.