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Table of Contents
Year : 2022  |  Volume : 19  |  Issue : 1  |  Page : 75-82

Update on critical issues and current challenges with “newer psychoactive substances: An narrative review”

Department of Psychiatry, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India

Date of Submission08-Apr-2022
Date of Decision20-Apr-2022
Date of Acceptance20-Apr-2022
Date of Web Publication05-Jul-2022

Correspondence Address:
Prof. Raka Jain
Department of Psychiatry, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/iopn.iopn_41_22

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In recent years, new psychoactive substances (NPS) (”legal highs” or “designer drugs”) are increasing worldwide. An increase in NPS is a cause for concern for drug-regulatory authorities and health-care professionals as it poses a threat to public health. Because of their novelty, these drugs go undetected by traditional detection methods, hampering adverse reaction assessment, and increasing challenges for laboratories and the regulatory system. This review aims to provide an update on the current state of NPS at the global level. The article addresses important issues and challenges in the clinical and forensic toxicology laboratories, which deals with testing for substances of abuse, the unclear legal status of NPS, and the limited knowledge of the public about their side effect. These issues and challenges would be important for health-care professionals, toxicologists, law enforcement authorities, and policymakers to take into account an effective response to control the use of NPS.

Keywords: Challenges, critical issues, new psychoactive substances

How to cite this article:
Jain R, Verma K. Update on critical issues and current challenges with “newer psychoactive substances: An narrative review”. Indian J Psy Nsg 2022;19:75-82

How to cite this URL:
Jain R, Verma K. Update on critical issues and current challenges with “newer psychoactive substances: An narrative review”. Indian J Psy Nsg [serial online] 2022 [cited 2023 Apr 2];19:75-82. Available from: https://www.ijpn.in/text.asp?2022/19/1/75/349884

  Introduction Top

New psychoactive substances (NPS) are “substances of abuse,” either in preparation or pure form, which are not regulated by the 1961 Single Convention on Narcotic Drugs or the 1971 Convention on Psychotropic Substances, but may pose a serious safety concern for public health.[1] They have emerged as “legal” alternatives to internationally controlled drugs and are marketed as “legal” replacements for them. They are synthesized to evade drug laws by altering the chemical structure of controlled substances (viz. cannabis, cocaine, heroin, LSD, MDMA, or methamphetamine), to produce a new unscheduled drug that yields a similar effect to their controlled counterparts.[2] The most important characteristics of NPS are that they are psychoactive. They depress or stimulate the central nervous system, create dependence in some users, have a similar potential harm level to internationally controlled drugs, and are newly available but not newly invented. NPS are known by various names in the market such as herbal highs, legal highs, bath salts, designer drugs, research chemicals, or party pills. The list is exhaustive and they are mostly sold in the market with misleading names not describing the exact content. With the rapid progression in both the prevalence of NPS entering the market each year and their unknown toxicity status, NPS has also found a place in the International Classification of Diseases-11. The new classificatory system includes various types of “NPS” in its coverage. These include synthetic cannabinoids and synthetic cathinones. Category of dissociative drugs has also been incorporated separately, which comprise phencyclidine and ketamine.

The focus of this narrative review is to provide an update on critical issues and current challenges with newer psychoactive substances.[3],[4]

  Magnitude of the Problem Top

Currently, 133 countries and territories have reported over 1100 individual NPS to the United Nations Office of Drug Control Early Warning Advisory up to November 2021.[5] The use of NPS is often for reasons of low prices and easy availability and is not detectable by standard toxicology screens.[6] The emergence of New NPS is most prevalent in regions of North America as well as various countries in Europe. According to the EMCDDA 2020,[7] among the categories of NPS reported to the EU early warning system, most common are cannabinoids (25%), followed by cathinones (22%) and various other synthetic compounds. The NPS market is in a constant state of influx and outflow with every passing year certain new NPS get added to the pool and some previously known substances disappear from the market. In the US, in the year 2018 according to UNODC among the 541 different NPS in the market, 48 new substances got added to the pool, and 118 NPS were not reported or disappeared from the market since 2015. According to the UNODC World Drug Report 2020,[8] new potentially harmful synthetic opioids are on increase. Drug markets are complex and these synthetics are replacing opiates in central Asia and the Russian Federation and the methamphetamine market is growing in Afghanistan and Iraq. Limited prevalence studies are available as most of the national survey across the world does not include NPS. In the US, in a Nationwide study, self-reported ever use of NPS was found to be 1.2%.[9] In Germany, in a general population survey, the estimated ever use of NPS was 2.8%.[10] The use of NPS is more prevalent among the youth population. According to estimates, between 1% and 8% of European school students have used NPS at some point in their life. Young people that attend electronic dance music events or nightclubs consume a lot of alcohol.[11]

  Classes of New Psychoactive Substances Top

NPS can be divided into six classes based on the chemical constituent or based on their effect on the body or mechanism of action.[12] These classes are stimulants, hallucinogens, dissociatives, synthetic sedatives/hypnotics, synthetic cannabinoids, and synthetic opioids. These substances act on the body by various mechanisms such as activation of the cannabinoid receptor type 1, acting as an n-methyl-d-aspartate receptor antagonist, actions on GABA receptor, or interaction with the opioid receptors. NPS modulates the levels and actions of the monoamine neurotransmitters dopamine, epinephrine, and serotonin.[13]

  COVID-19 and Effect of New Psychoactive Substances Top

The pandemic and related lockdowns worsened the health situation of many people who use drugs. The infection has kept the world on halt and its effects on the drug market are far-reaching. COVID-19 has special effects on the drug market as well as on the people who are using drugs. Drug use disorders and regular drug use can lead to complications and mortality if users are infected with corona infection. People with drug use disorders are more vulnerable to comorbidities that can lead to poor outcomes. People who use stimulants are particularly susceptible to damage and inflammation to the lung tissue.

Economic difficulties also changed drug consumption for the worse. The economic slowdown may result in state members cutting drug-related budgets, an overall increase in drug usage, a move to cheaper substances, NPS, and a shift in drug consumption patterns toward injecting drugs. People who are already at a socioeconomic disadvantage may be hit harder than others by the economic slowdown caused by the COVID-19 crisis. This could lead to an increase in the number of individuals turning to illegal drug-related activities for a living (manufacturing, transportation, etc.) and/or being recruited into drug trafficking.[8]

The market of addictive substances has been impacted from the production to the distribution and changing consumption patterns. In the COVID-19 pandemic, mental health and substance use have become a growing concern, including concerns related to suicidal thoughts.[14] People all across the world have been influenced by fear, stress, and anxiety, worsening latent psychiatric and psychological problems.[15] Because of the pandemic's overall stress and associated restrictions, there has been a surge in the usage of cannabis products, benzodiazepines, and new designer benzodiazepines.[16] Simultaneously, there was a decrease in the demand for stimulants due to the lack of accessibility to conventional recreational settings.[17] Moreover, drug usage has shifted to alternative substances and homemade NPS, which are made up of compounds such as pharmaceutical drug analogs, research chemicals, and prescription medicines that mimic the psychoactive effects of commonly used illicit or prescription drugs.[18],[19] Furthermore, the unavailability of opioids like heroin may have encouraged frequent users to take other substances with similar characteristics such as fentanyl analogs. Furthermore, the limited supply of heroin could have been contaminated with other psychoactive compounds. In addition, the restricted quantity of heroin could have been tainted with additional psychotropic substances. This, in turn, may have induced a search for more potent drugs, at a lower cost, which resulted in a rise in drug e-commerce.[7],[20] Because of the diversity of regulations used in different nations and the drugs involved, the situation appeared complicated.[21] Catalani et al.[22] performed a study on 94,000 individuals using NPSfinder® software, a navigating, password-protected program, that enables registered researchers only to screen and classify molecules being identified. There were three NPS categories, namely synthetic cannabinoid receptor agonists, synthetic opioids, and cathinones. Out of 229 NPSs discussed during the pandemic, about 18 NPSs were identified for the first time via the NPSfinder®. Ten of those NPSs had not been previously reported to either the UNODC or the EMCDDA. Eighteen NPSs, opioids, and cathinone were the most discussed on social media/Reddit, with the highest number of threads associated.[22]

  Indian Scenario Top

In India, scientific data are limited; data come largely from newspaper reports where NPS forms catchy headlines. Although the data are sparse, it appears that NPS does not seem to be new to the Indian market. Recently, some parts of India have already determined an upsurge in synthetic cathinone use. Synthetic cathinones, like mephedrone, usually referred to as Meow Meow, are far cheaper than other classical stimulants like cocaine. Mephedrone has recently gained popularity among Indian teenagers. Media reports from India claim that Meow Meow is generally used by marginalized adolescents or college-goers who could not afford cocaine.[23]

Seizure data and other indirect measures of use have also raised concerns about the increasing use of NPS in India. According to the annual report of the Indian Narcotics Control Bureau (2017),[24] the country's mephedrone seizures totaled 173 kg in 2017. In addition, the majority of mephedrone seizures were reported in New Delhi in 2017, with smaller amounts reported from other Indian states (Gujarat, Madhya Pradesh, and Maharashtra). It is less expensive than cocaine, costing Rs. 150 per g versus Rs. 3000 per g for cocaine. Mephedrone is manufactured in China and India and is popular at rave parties in Goa. It started in the mid-seventies and is known for its Hippi culture. Furthermore, ecstasy had been tried extensively in clubs in Goa, in recent years. According to Goa police, there are also structured or unstructured channels for ketamine. One of the locally available pills known as CK1 pills currently popular in Goa clubs is being used as a party drug. The pill is a combination of cocaine and ketamine and is sold by its street names Calvin Klein and Blizzard.[25] Recently, amphetamine-type stimulants (ATS), particularly MDMA, have become the major concern in Southeast and Southwest Asia, owing to their low cost as compared to opioids. Although no national survey talked about NPS as a group, a large study on the magnitude of substance use talked about ATS which is used by 19.4 lakh individuals (0.18%) of the general population. States with a sizeable population of ATS users are Maharashtra, Telangana, Uttar Pradesh, Punjab, and Manipur. In addition, Delhi also has an estimated number of about one lakh ATS users.[26] There is a lack of awareness about the pharmacology and harmful consequences of these drugs among health professionals in India.[27],[28]

  Health-Related Issues Top

NPS can cause various harms to the body of the users through its acute or chronic use, which are mostly unknown. The toxicity profile of NPS is also mostly unavailable. Some reports show mortality associated with NPS, but the data may be biased due to preexisting conditions or polysubstance use being present, and the low numbers make it difficult to establish exact data on toxicity.[10],[18] In a study done for fatalities associated with NPS, mephedrone was found to be the most commonly associated with fatalities, but in 84% of samples, alcohol, as well as other drugs, were also present.[29]

The health hazards of NPS can be psychological or physical, including cardiac problems, heart attack, seizures, anxiety, agitation, memory loss, depression, suicide, kidney failure, and psychosis. As the route of administration of NPS also involves needle sharing and intravenous route, thus the risk of having complications such as hepatitis B, hepatitis C, and HIV/AIDS is also present. The complications are more severe if there is concomitant use of alcohol or other drugs. NPS users need frequent hospitalization with severe intoxications. The composition and purity of NPS-consumed products are frequently unknown, putting users at higher risk. Furthermore, the risk of abuse liability and toxicity with long-term use is largely unknown.[30] Statistics on morbidity and mortality may not reflect the actual situation as users may recover, for instance, from a mixed heroin/synthetic opioid overdose when naloxone is administered and the illicit substance reported will then be heroin rather than a synthetic one.[31],[32]

There is no drug approved for management and dependence on NPS. Treatment is symptomatic. No antidote is available. For controlling agitation, benzodiazepines are the agents of choice. The Novel Psychoactive Treatment UK Network (NEPTUNE) recommends diagnosis based on clinical assessment and the clinical toxidrome. It recommends supportive management mostly symptomatic, particularly in the absence of research on the management of toxicity associated with various NPS.[33] Smith and Robert 2014 described that for synthetic cathinones and associated sympathomimetic complications benzodiazepines should be given, and for hyperpyrexia/NMS, active or passive cooling and 5HT antagonist, for example, cyproheptadine should be used. No role of antipyretics or dantrolene is described. A mainstay of management remains supportive care in form of maintaining an airway, breathing, and circulation.[34]

  Popularity and Sale Top

The network of production and distribution of NPS is quite complex. NPS users are more likely to be males and in their late teens/the early twenties and NPS have colorful, attractive packaging with enticing names to attract younger individuals.[35] The production sources are mainly unregulated laboratories in Asia (China and India). The distribution of NPS is carried out through three main channels. These include head shops, the Internet with online sales, and rave parties and music festivals.[9] In addition, NPS keeps changing its chemical composition to evade drug laws, produce more potent substances, avoid drug testing procedures, and ultimately increase profits.

The dark web plays a role in this “supersafe” drug trade through which virtually anybody can buy drugs anonymously and pay for them with a virtual wallet. Facebook is often used for this purpose. There are several drug forums like www.drugs-forum. com and others that allow NPS to share their subjective experiences.[36] The most well-known is the Silk Road hub, which was started by the Federal Bureau of Investigation in October 2013 but shut down soon after but reappeared a month later under the name Silk Road 2.0. In NPS drug forums, users report positive and negative experiences, provide advice on doses and routes of administration, and often discuss their favorite substances using pharmacological language. Users describe how to obtain substances easily. There are now videos of various NPS being ingested live on YouTube. On popular social media sites like Instagram, several unknown profiles regularly post photographs of their products with hashtags. Various smartphone apps are available today, that give easy access to NPS information The ease of access to NPS through the online route has increased its use by users.[12]

  Laboratory Related Challenges Top

Testing for NPS in clinical and forensic settings can be a complex task. Toxicology screens currently used in most clinical toxicology and forensic laboratories are unable to detect all of the newer synthetic drugs. In most laboratories, it is not yet possible to conduct standardized testing for NPS. The expanding number of NPS also poses a challenge to traditional drug testing techniques. Due to the heterogeneity of designer drug product compositions, concentrations, and chemical components, detection has become more challenging.[37] Some designer drugs are designed by modifying their psychoactive components to circumvent the legal system.[38] Standard urine drug screening tests fail to detect drugs, which is a common reason for using NPS.

Generally, the detection and identification of drugs of abuse is a two-tier process, i.e., preliminary screening followed by a confirmation step. Conventionally, screening of drugs of abuse in biological matrices is performed with immunological methods, allowing for faster and low-cost analysis. For designer drug screening, immunoassays are limited by the requirement of developing antibodies specific to a wide array of new chemical structures, posing a challenge to the rapid, and dynamic nature of the NPS market. In addition, immunoassays are limited by their low sensitivity and cross-reactivity, leading to false-positive or false-negative results.

In recent years, more specific and selective techniques such as conventional gas chromatography-mass spectrometry (GC-MS) or liquid chromatography combined with MS (LC/MS) and tandem MS (LC/MS/MS) has become a powerful tool for the identification and characterization of newer psychoactive substances. Among the many methods available, particularly noteworthy is LC coupled with quadrupole time of flight MS (LC-QTOF-MS).[39] LC-QTOF-MS has demonstrated some superiority to GC-MS in detecting most forms of NPS.[12] A unique feature of LC-QTOF-MS is that its chemical formula can be predicted from accurate ion mass measurements and characteristic isotopic patterns. In addition, the sample amount needed for the analysis is very small, and sample preparation is minimal. Moreover, modern LC-QTOF-mass spectrometers also have high chromatographic and mass resolutions, as well as high mass accuracy measurements of both parent and fragment ions. Databases of spectral information from known NPS chemical structures are currently being built and validated, to allow for the identification of known (and potentially unknown).[40]

The available methods are highly specialized and medical centers often do not have access to these methods. Apart from that, the long turnaround time for sample identification would not change clinical decisions. Research and development require an investment of significant capital and are affected by commercial considerations. There are delays in the development of commercial testing as research and development in detection are outpaced by the appearance of new unknown substances.[41]

In addition to the lack of analytical research information on NPS, the inaccessibility of scientific literature and the lack of reference standards from a scientific standpoint as they are still relatively new to the market, pose challenges to the toxicological laboratory in NPS identification.

The introduction of a new legal high necessitates the production and certification of several new reference materials, many of which are not yet available, resulting in a gap in laboratory preparedness. Since drug reference materials must meet quality and purity standards, they take 6–12 months for commercial production. By the time the reference material becomes ready, a modified version of the same drug appears on the market which is undetectable if the readied reference material is used. Furthermore, the gaps in techniques for identifying NPS include general strategies for developing methods of urinalysis, sample preparation for urinalysis, and stability issues of the metabolites. When NPS first appear on the market, little or no information exists about their urinary excretion patterns, making it difficult to develop urinalysis procedures for them. Developing urinalysis procedures for NPS is complicated by the lack of data regarding urinary excretion patterns when such drugs first appear on the market. Moreover, analytical techniques are insufficient to detect drugs of this class. The development of urinalysis procedures for NPS is complicated by the fact that generally little or no information on urinary excretion patterns of such drugs exists when they first appear on the market. There is still insufficient analytical methodology to detect all the NPS present in the samples analyzed, and many laboratories lack the equipment and expertise required for NPS identification, particularly in the interpretation of mass spectral fragmentation patterns. Several laboratories, however, have overcome the problem of inaccessible commercial reference standards by synthesizing them in their laboratories, but due to the lack of organic synthesis expertise and resources in many toxicology laboratories, this approach is not considered an adequate solution. In addition, NPS are also sold as mixtures of various drugs, and there are instances when immunoassay screening results are negative but the presence of these drugs is strongly suspected. Such cases present challenges for the analysis of a respective class of drugs. Furthermore, laboratories lack clarity on licenses for possessing reference drugs standards.[42] Finally, there have been no government-mandated screening and confirmation cutoffs in any biological matrix despite the unprecedented spread of NPS.[43]

The analytical characterization of these NPS is, therefore, crucial to facilitate their detection in biological matrices. Drug analysis helps to answer key drug control policy questions, such as purity of the products, manufacturing methods, route of manufacture and alternative routes of manufacture, use of preprecursors and the effectiveness of precursor control measures, impurity profiles, cutting agents effect, market dynamics, and flow of controlled substances from source to user markets. Cutting agent effects, and how controlled substances travel from sources to users.

  Legal Challenges Top

The place of NPS within the legal system is a matter of debate for most countries and the issue is ambiguous. NPS challenges the international control system. It was in the year 2014 ECDD reviewed NPS for the first time. By 2018, forty NPS had been scheduled under the international drug control conventions. Although some state members prefer many NPS to be scheduled, the Conventions only permit the scheduling of individual substances (e.g., alpha pyrrolidinovalerophenone) rather than broad substance classes (e.g., cathinones). Most of the NPS does not seem to be a part of scheduled International conventions as NPS fall outside the global drug control system, it is tackled by National or Regional responses only. Due to a lack of coordinated International response, the scope for the establishment of a market for drug trafficking has proliferated.[44] NPS is impervious to legal sanctions due to delays in declaring drugs as illegal, imperfect international agreements, and lack of international resolve.[45] Some countries are rapidly legalizing new substances. There is a temporary increase in sales after the scheduling of substances. The number of emergency hospitalizations also increased around the time of legislation. For instance, more than 320 cases of severe poisonings were recorded in Poland after numerous NPS from the different chemical groups were placed in the Schedule of the Controlled Substance Act.[46]

There is a scarcity of scientific evidence on public health risks, amending the law can take time, and the product range is extensive. When more substances are added to the list, law enforcement has to make sure the substances are tested for, but the technical and financial resources required for more tests may not always be increased. As NPS vary in terms of their chemical structure, effects, mimetic properties, as well as market versatility and transience, this can lead to more test costs.

The most important challenge for risk management is the market's rapid emergence or disappearance. The collection of sufficient data for regulatory decisions necessitates time, which legislators do not have. In the case of these new substances putting strict control presents its own set of challenges.

Adding a person's criminal record or imprisonment for possession often be more damaging to an individual and society than the substance itself, especially for young adults. A cautious attitude and the prohibition of a wide range of illegal substances lead to an illegal market and competition that may be harmful to society.[47],[48]

Nationally, NPS has prompted a range of novel legal responses aimed at limiting the open sale of these substances. Globally, a wide range of legislative responses, including generic controls, analog controls, temporary legislation, specific legislation, import controls, and trade restrictions, have been explored. Controls based on consumer safety or medicines legislation, extending and adapting existing laws and processes, as well as developing new legislation to address new substances are the three main methods used by various countries.

EMCDDA provides an important source of data relating to newer NPS in the market. It collaborates with WHO and UNODC for the dissemination of information and helps in the scheduling of substances based on their report. An early warning system has been in place (up to 560 substances understudy). Under the UK Psychoactive Substances Act 2016, all psychoactive substances are now illegal, apart from food, alcohol, nicotine, caffeine, and medicinal products. Personal possession is not deemed criminal, unless “the person is in a custodial institution.”[48]

A problem noted by critics is the law's broad definition of psychoactive substances and its failure to differentiate dangerous from low-harm substances in punishing offenders. Between 2007 and 2015, a total of 940 “new” psychoactive compounds were reported in China, Japan, Korea, and Taiwan, yet only 25 were regulated at the time in four countries, with Japan and Korea being the most proactive in their regulation. In India, only NDPS Act exists, few substances like mephedrone have been added to the existing law. A new strategy has been adopted in New Zealand, a law enacted in July 2013 represents a U-turn from the conventional approach of retroactively banning synthetic drugs. New Zealand will attempt to regulate designer drugs, permitting their sale if they pass rigorous safety testing standards.

New Zealand is also aiming to meet clinicians in the emergency department to look into more thorough means to capture adverse health effects.[49]

To tackle this issue, global strategies need to be developed that include revising international data collection systems, integrating evidence-based interventions, strengthening monitoring systems, and expanding collaboration between researchers and forensic specialists. For the legal, regulatory, and clinical systems to remain dynamic, enforcement agencies should measure their success by breaking up drug networks, as seizures rarely disrupt drugs markets.[50]

  Implications for Health Professionals Top

The use and misuse of NPS have risen dramatically over the world, particularly among young adults. Nurses, doctors, and other health professionals in all settings are more likely to interact with people who abuse drugs and have a range of health problems, including mental health issues.[51] Although there is little evidence on the management of NPS abuse, patients should be treated holistically. Strategies are needed to educate the public about the dangers associated with these substances, to help people who misuse them achieve abstinence, and to treat people who develop health problems as a result of their abuse. Education and training are needed for health-care professionals working in various departments where NPS users are encountered. There is a pressing need for research into early detection and screening interventions and approaches. Furthermore, multidisciplinary and multiagency approaches should be deployed across the country to capture evolving trends in NPS use. More research into the effectiveness of psychosocial therapies is needed, and clinical teams should be aware of local clinical guidance on dealing with NPS abuse.

  Conclusion Top

NPS are an important part of the drug market but data is not sufficient to establish the extent of use of NPS among different populations. Broad classes on NPS are currently established, but new classes may emerge in the future given the rising trends in types of NPS. Very limited information is available on the adverse health effects of newer psychoactive substances. Studies concerning the health effects of NPS usually rely on self-reports, and small case series, which are subject to selection and recall bias. Therefore, health-care professionals and emergency professionals who are likely to encounter NPS use to remain abreast of clinical features and to develop evidence-based approaches to harm-minimization and treatment of dependence syndromes. In some cases, clinicians treating individuals inflicted with harm related to the use of NPS may feel less confident in managing those patients compared with those who are presenting after using classical recreational drugs.[52] NPS continues to pose a challenge to public health and drug policy over the next few years. There is a need to pay particular attention to the speed at which NPS appear on the market and the risks associated with their use. The study of NPS requires multidisciplinary approaches involving epidemiology, pharmacology, and prevention. Early warning systems at the national and regional levels will be vital to the detection of NPS and ensuring timely public health responses. Considering changes in substance use trends, there is a need for increasing awareness. Finally, research-based prevention education will ultimately protect societies from this tidal wave.

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Conflicts of interest

There are no conflicts of interest.

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