This systematic review (mostly case reports) found scarce but consistent evidence that novel psychoactive substances can precipitate new or worsening psychotic symptoms, marked behavioural disturbance (agitation, aggression) and physiological changes in people with severe mental illness. Findings are limited by the reliance on case studies, and the authors call for clinicians to ask directly about NPS use and for further research into long‑term mental and physical effects.
Accessible summaryWhat is known on the subject? Novel psychoactive substances (NPS) include synthetic drugs mimicking the effects of illicit drugs, e.g. synthetic cannabinoids, and herbs such as Salvia divinorum. NPS are substances that can trigger hallucinations and other effects altering the mind, and are currently uncontrolled by the United Nations' 1961 Narcotic Drugs/1971 Psychotropic Substances Conventions. NPS affect brain chemistry that induces the psychoactive effects, such as hallucinations and feeling ‘high’. It is unknown what effects such drugs have on people with severe mental illness (i.e. psychotic illnesses). What this paper adds to existing knowledge? Our review demonstrates that little is known about the effects of various NPS on people with severe mental illness. Almost nothing is known about the long‐term consequences of NPS use on the mental and physical health of SMI patients. Patients may lack understanding that NPS are psychoactive drugs that can impact on their mental and physical wellbeing. What are the implications for practice? Some patients might be reluctant or do not think it is relevant to disclose NPS use. Commonly used illicit drug screening is unlikely to detect the presence of NPS, therefore health and mental health professionals should directly enquire about NPS and actively encourage patients with severe mental illness to disclose any substance use. Patient and public involvement in the research There was no significant patient and public involvement in the development and conduct of this study .AbstractIntroductionNovel psychoactive substances (NPS) are synthetic substances that have been developed to produce altered states of consciousness and perceptions. People with severe mental illness (SMI) are more likely to use NPS than people without mental illness, but the short‐ and long‐term effects of NPS are largely unknown.
Method
We systematically reviewed the literature about the effects of NPS on people with SMI.
Results
We included 12 case reports, 1 cross‐sectional survey and 1 qualitative study. Participants included mostly males aged between 20 and 35 years. A variety of NPS were used, including synthetic cathinones and herbs such as Salvia. The most commonly reported effects of NPS were psychotic symptoms (in some cases novel in form and content to the patients' usual symptoms) and significant changes in behaviour, including agitation, aggression and violence. Patients' vital signs, such as blood pressure, pulse rate and temperature, were also commonly affected.
Conclusion
NPS potentially have serious effects on people with SMI, but our findings have limited generalizability due to a reliance on case studies. There is a paucity of evidence about the long‐term effects of these substances. Further research is required to provide a better understanding about how different NPS affect patients' mental and physical health.
People with severe mental illness (SMI), such as schizophrenia and bipolar disorder, are known to have high rates of comorbid substance misuse and worse clinical outcomes when substance use co-occurs. Novel psychoactive substances (NPS) — a heterogeneous group that includes synthetic cannabinoids, synthetic cathinones (so-called "bath salts"), MDMA analogues and psychoactive herbs such as Salvia divinorum — have emerged in recent years and are available widely, often via the internet. While NPS intoxication in the general population has been associated with hallucinations, agitation, cardiovascular instability, seizures, organ injury and death, their effects specifically in people with pre-existing SMI have not been systematically reviewed and may be of particular concern given possible interactions with underlying neuropathology and psychotropic medications. Gray and colleagues therefore set out to synthesise the available evidence on how NPS affect the mental and physical health of adults with SMI. The stated aim was to identify and describe reported changes in psychiatric symptomatology and other health-related effects after recent NPS exposure in people with documented SMI, and to characterise the quality of that evidence to inform clinical practice and future research priorities.
The review followed PRISMA reporting guidance and the protocol was registered on PROSPERO (CRD42015026944). A broad electronic search was conducted across multiple databases including EMBASE, MEDLINE, CINAHL, The Cochrane Library, Scopus and PubMed, covering records to October 2015. The search combined terms for NPS (for example "novel psychoactive substances", "legal highs", "designer drugs") with terms for SMI (for example "schizophrenia", "bipolar disorder", "psychosis"). Reference lists of key articles and serendipitous citations were also screened. Inclusion criteria specified adults (aged 18+) with a documented diagnosis of SMI (schizophrenia spectrum or bipolar disorder) and a history of NPS use. Any study design was eligible provided it reported effects of NPS on mental or physical health; only English-language, peer-reviewed studies available by October 2015 were included. The primary outcome was change in psychiatric symptomatology related to recent NPS use; secondary outcomes covered other health effects. Study selection and data extraction were undertaken using Endnote and a piloted extraction tool. Two reviewers independently extracted study characteristics, participant demographics and clinical data, and reported outcomes of NPS exposure. Because varied designs were expected, risk of bias and methodological quality were assessed with appropriate validated tools: a Newcastle-Ottawa adaptation for non-comparative case reports, and CASP tools for qualitative and observational studies. Assessments of quality informed interpretation but were not used to exclude studies. Data synthesis followed narrative synthesis principles rather than meta-analysis due to heterogeneity of designs and outcomes.
The searches yielded 550 records in total; after deduplication and removal of non-English records, 367 titles/abstracts were screened and 133 full texts assessed. Fourteen reports met inclusion criteria (12 full studies and 2 conference abstracts) published between 2011 and 2015. Most included reports were non-comparative: 10 single case reports, 2 case series, 1 qualitative interview study and 1 questionnaire-based study comparing head-shop purchasing between people with and without mental illness. Geographically, seven studies were from Europe (three UK, three Ireland, one Slovenia), three from the United States, one from India and two from other/unreported locations; four studies were set in inpatient or acute psychiatric services. Risk-of-bias appraisal indicated generally high risk across studies, largely because most were case reports with small, convenience samples and incomplete clinical detail. Diagnosis verification was often not reported, substance exposure was commonly self-reported, and few studies performed laboratory confirmation. The qualitative and questionnaire studies also exhibited sampling and recall biases and limited reporting of methods. Across the case reports there were 19 participants described, of whom 17 had prior SMI (schizophrenia n = 10; bipolar disorder n = 4; one with unspecified psychiatric history). The majority were male (14/17, 82%) and the mean age reported for case series was 31 years (SD = 7). The qualitative study (Every-Palmer 2011) contributed 21 participants, 15 of whom met the review criteria (all male, mean age 34, SD = 8). The questionnaire study enrolled 608 participants overall, with 135 reporting psychotic disorders; of these 135, 23 (17%) reported purchasing NPS in "head shops". Types of NPS reported varied. Among case reports, exposures included unspecified "bath salts" (n = 5), the synthetic cannabinoid AM-2201 (n = 4), and other agents such as Datura stramonium, Salvia divinorum, a product called "el blanco", mixtures containing MDPV and flephedrone, and benzylpiperazine (BZP). In the qualitative sample all included participants had used JWH-018; the survey group reported a range of synthetic cannabinoids and stimulant-type NPS (e.g. mephedrone, methcathinone, methylone) and piperazine derivatives. Short-term mental health effects were prominent: of 17 SMI cases, 15 developed psychotic symptoms after NPS use, including new delusions, auditory/visual/haptic hallucinations, severe thought disorder and altered mental state. Two patients were unconscious on presentation. Behavioural disturbance was frequent: nine of 17 exhibited bizarre or chaotic behaviours (repetitive movements, disinhibited actions), five were agitated (three required chemical or physical restraint), and three displayed violent or assaultive behaviour. One case involved use of pepper spray during restraint and the patient subsequently died weeks later. Physical effects commonly involved marked changes in vital signs: nine of 17 cases showed tachycardia, hypertension, hyperthermia and profuse sweating, with some authors describing features consistent with serotonin syndrome. Renal impairment (elevated creatine kinase and/or creatinine) was reported in six patients and two experienced liver function damage requiring intensive care. Recovery times varied greatly: six recovered within 2–12 hours, two returned to baseline by day 3–4, three remained symptomatic at one month, and four studies did not detail duration. One death was reported among the cases. Objective confirmation of NPS was limited. Substance use was identified by self-report in nine cases, captured by staff observation in five, and by possession in two. Only five authors reported any testing of substances; routine urine toxicology screens were often negative for the NPS implicated, and three samples were sent to specialised laboratories for analysis.
The review found that the published evidence on NPS effects in people with SMI is sparse and dominated by case reports and small observational studies, but the available reports indicate potentially serious acute mental and physical consequences. Across heterogeneous substances, the common clinical picture in the included cases was rapid alteration of mental status with psychotic symptoms and notable behavioural disturbance; significant autonomic and systemic effects, including signs compatible with serotonin syndrome, renal and hepatic injury, were also reported. Gray and colleagues note that many of the physical harms seen are consistent with reports in the general population, but that mental health effects may differ for people with pre-existing psychotic disorders. Behavioural disturbance, agitation requiring restraint and aggression appeared relatively frequent in the SMI cases reviewed; the authors compare this to a Japanese emergency department series where aggression was less common (11% violent/aggressive, 24% irritable or agitated). They suggest that in SMI patients such drug-related behavioural change could be misattributed to the underlying psychiatric diagnosis, with possible consequences for future treatment and stigma. The authors acknowledge several key limitations affecting the confidence and generalisability of their conclusions. Most included studies had high inherent risk of bias (case reports, convenience sampling), diagnostic verification was often absent, exposure confirmation was frequently reliant on self-report with limited toxicological testing, and studies were small in number. Language restriction to English may have missed additional reports. The review therefore cannot estimate prevalence or quantify risk and is likely influenced by reporting bias towards severe or unusual presentations. In terms of clinical implications, the authors advise that clinicians should actively enquire about NPS use because patients may perceive these substances as "natural" or less harmful and may not volunteer use; routine drug screens often miss NPS. They also highlight uncertainty about interactions between NPS and prescribed psychotropic medications. For research, the paper recommends higher-quality observational and prevalence studies, investigation of health professionals' ability to recognise NPS intoxication in psychiatric settings, and comparative work to determine whether NPS effects differ between people with and without SMI. The authors further suggest utilising poison/toxicology registries to improve case ascertainment and understanding of outcomes.
such as Salvia. The most commonly reported effects of NPS were psychotic symptoms (in some cases novel in form and content to the patients' usual symptoms) and significant changes in behaviour, including agitation, aggression and violence. Patients' vital signs, such as blood pressure, pulse rate and temperature, were also commonly affected. Conclusion: NPS potentially have serious effects on people with SMI, but our findings have limited generalizability due to a reliance on case studies. There is a paucity of evidence about the long-term effects of these substances. Further research is required to provide a better understanding about how different NPS affect patients' mental and physical health.
People with severe mental illness (SMI) such as schizophrenia and bipolar disorder are at increased risk of suffering co-morbid conditions including substance misuse. For example, a study based on Danish national data showed that between 28% and 35% of people with psychotic disorders also have a co-existing substance use disorder. At the same time, substance misuse, especially cannabis use, is a known risk factor for developing psychosis. There is also evidence that people with a dual diagnosis (substance use and SMI) have worse clinical outcomes in terms of symptom control, adherence to treatment and rates of violence and aggression. In recent years, new drugs and drug substitutes have emerged, possibly in response to the increased control of illicit drugs. The use of so-called 'legal highs' or novel psychoactive substances (NPS) is becoming increasingly common and NPS have been tried by at least 5% of young people aged 15-24 in the EU. There is some evidence of considerable variation in the prevalence of use between countries, e.g. 1% of young people in Italy and 16% in Ireland are reported to have tried NSPs. The UK government has introduced the Novel Psychoactive Substances 2015 bill in an attempt to ban all new and future substances with psychoactive effects intended for humans (excluding nicotine, caffeine, alcohol, food and medicines) in an attempt to keep up to date with new and emerging substances. NPS are defined as narcotic or psychotropic drugs that are not currently controlled by the United NationsPsychotropic Substances Conventions, but which might pose a public health threat comparable to that posed by substances listed in these conventions. Examples include synthetic cannabimimetics containing molecules that bind to cannabinoid receptors, synthetic cathinones that are similar to amphetamines such as 'bath salts' or methylenedioxypyrovalerone (MDPV), new drugs mimicking the effects of MDMA ('Ecstasy') and other substances including herbs like Salvia divinorum, which can cause a state of delirium and hallucinations. Such substances are currently uncontrolled, but hundreds of drugs with variable ingredients and untested effects/risks are available for purchase on the Internet). Within the general population, intoxication with NPS can pose significant health and mental health risks to their users, including but not limited to hallucinations, agitation, tachycardia, hypertension, vomiting, seizures, stroke, rhabdomyolysis (uncontrolled breakdown of muscle), kidney injuries and death. The effects of NPS on people with existing SMI are largely unknown. The use of NPS appears to be significantly more common in people with psychiatric illnesses compared to healthy people. It is therefore imperative to understand what effects NPS have on health and mental health, and specifically on people with co-existing mental illnesses. Dopamine is a neurotransmitter with an established role in psychosis. Studies involving PET scans of acutely psychotic patients show increased pre-synaptic levels of dopamine. Dopamine is a neurotransmitter involved in controlling behaviours and thought processes. In a review of the literature,reported that dopamine function is disturbed when certain NPS (e.g. synthetic cathinones, synthetic cocaine substitutes and some novel stimulants such as methiopropamine) are used, triggering their psychoactive effects. It might be hypothesized that NPS use in people with SMI could have stronger and more severe effects. However, the link between psychosis and NPS has not been examined. While various mental health complications have been described in people who have taken NPS, to the best of our knowledge, there has not been a systematic review that has examined the effects of NPS on patients with SMI.
The aim of this systematic review is to explore the effects of NPS on the mental and physical health of people with SMI.
We have followed the PRISMA guideline for reporting systematic reviews. The protocol is registered on Prospero International Prospective Register of Systematic Reviews (PERO/:2015 registration number: CRD42015026944.
We used a broad search strategy to identify the relevant studies from the following electronic databases: • EMBASE/OVID (1947-2015) • MEDLINE/OVID (1961-2015) • Cumulative Index to Nursing and Allied Health (CINAHL with Full Text) (1904-2015) • The Cochrane Library (1900-2015) • Scopus
We also reviewed the reference lists of important articles in order to identify further potentially relevant papers, and we included papers identified serendipitously. Our search string consisted of two main concepts. We searched the following keywords or key concept terms (as appropriate) related to novel psychoactive substances: 'new psychoactive substances' OR 'novel psychoactive substances' OR 'legal highs' OR 'designer drugs' OR 'research chemicals' OR 'smart drugs' OR 'emerging drugs of abuse'. They were subsequently combined using 'AND' with the search terms related to the concept of SMI: 'schizophrenia' OR 'manic depressive psychosis' OR 'bipolar disorder' OR 'psychosis' OR 'psychotic disorders' OR 'schizoaffective psychosis' OR 'mania' OR 'mixed mania and depression' OR 'bipolar mania' OR 'bipolar affective disorder' OR 'depressive psychosis' OR 'affective psychosis'. The search strategy was adapted accordingly for each database.
This review is concerned with adults (aged 18 years or over) with a diagnosis of SMI and a history of NPS use. We included studies using any research design, reporting on how exposure to NPS affects mental and physical health of people with a current diagnosis of SMI. We included studies published in English with no restriction of context (i.e. any country, inpatients or outpatients), published in peer-reviewed professional journals (including conference proceedings) before or electronically available in October 2015.
Studies were included if the participant(s) are described in the publication as being diagnosed with a SMI. SMI is defined as a documented diagnosis of schizophrenia or delusional/ psychotic illness (ICD 10 F20.9 & F22 or DSM-equivalent) or bipolar disorder (ICD F31 or DSM-equivalent). The SMIinclusive diagnosis was established by either a gold-standard structured clinical interview for establishing a DSM-IV/ DSM-V or ICD-10 diagnosis (e.g. Structured Clinical Interview for DSM-IV/DSM-V), or made by a mental health professional and documented in the medical record.
We included studies where participants were reported to have used NPS, which are narcotic or psychotropic drugs that are not currently controlled by the United Nations' 1961 Narcotic Drugs/1971 Psychotropic Substances Conventions, but might pose a public health threat as defined by the European Monitoring Centre for Drugs and Drug Addiction. No comparator was defined for this review.
The primary outcome was change in psychiatric symptomatology of an existing SMI diagnosis in relation to recent use of NPS. Secondary outcomes were any other health-related effects caused by the use of NPS in people with SMI.
Articles identified in the literature searches were exported into reference management software (Endnote TM ). Duplicate records were excluded (using Endnote and manually) and the titles and abstracts of the individual articles were screened for eligibility based on inclusion criteria. We developed a data extraction tool for this review and piloted it on a sample of studies to check its utility. The relevant information about each study was recorded by two reviewers independently (AI and DB). We recorded the study characteristics, information about the study design and methodology, participant characteristics (including the demographic and clinical characteristics) and the outcomes of the NPS exposure (i.e. the effects of NPS on health and mental health of the participants).
We anticipated inclusion of studies using various designs. Their risk of bias (ROB) and methodological quality were therefore assessed using different validated ROB assessment tools, as appropriate. Qualitative research articles were assessed using a Critical Appraisal Skills Programme (CASP) tool, case studies were assessed using a Newcastle-Ottawa quality assessment scale for case-control studies) and other observational studies were assessed using a CASP tool for cohort studies. The assessment of the ROB or quality of studies was not used to decide eligibility or inclusion of the relevant papers. Instead, the assessed ROB/quality was reported to inform the interpretation of the findings.
Information gathered from the included studies was synthesized according to the main principles of narrative synthesis.
Figureshows the flow of the articles through the review process. In the electronic database search and through other sources, we identified a total of 550 papers. After removing duplicates and non-English papers, we screened 367 titles and abstracts, and excluded 234 records. We assessed 133 articles for eligibility, excluding a total of 119, mostly because their focus was not on SMI (n = 67) but were reviews (n = 8) or commentary articles (n = 15). One paper was excluded as we were unable to retrieve a full text copy of the manuscript from the British Library. We included 12 full studies and 2 conference abstracts that met our inclusion criteria. Included studies were published between 2011 and 2015.
Thirteen of the 14 studies included in this review were non-comparative reports. Specifically, we identified 10 single case reports, 2 case series and 1 study involving qualitative interviews with NPS users about their experiences with the substances. One study, was an explorative questionnaire study comparing the prevalence of using 'head shops' to buy NPS by people with mental illness and people without. A total of seven studies were conducted in Europe (three in UK, three in Ireland, one in Slovenia), three in the United States, one in India and two studies were in other countries (unre- ported). Four studies were conducted in inpatient or acute psychiatric clinics.
The ROB and quality of the 12 case studies (including the conference abstract reports) were assessed using the Newcastle-Ottawa quality assessment scale for case-control studies, due to a lack of appropriate assessment tools for noncomparative case reports. Since the studies did not involve control participants, we determined that three out of the eight questions in the tool were applicable for case reports. Case reports are subject of relatively high inherent ROB due to involving a small number of participants who are often selected conveniently, without an opportunity to compare the identified effects with a control group. The case reports included between one and four participants, making their samples unrepresentative of any given population. In addition to the high inherent ROB, all but two studies included in this review reported patient's diagnosis but do not indicate how it was obtained. No study reported the number of other potential cases within their institution in any given time period. Patients' exposure to NPS was in most cases determined by self-report, providing further opportunity for bias. We also included one qualitative study (Every-Palmer 2011) and one cross-sectional survey. Their ROB was assessed using the Critical Appraisal Skills Programme (CASP) tool for qualitative and cohort studies respectively.was deemed to have a risk of sampling bias due to recruiting all presentations rather than only new cases within the eight local hospitals. The risk of recall bias was also present due to reliance on patients' self-reports over the past 12 months. The authors identified-but did not measure and/or take account of-confounding factors such as alcohol use, employment and socioeconomic status, which again increased the study's ROB. The qualitative study (Every-Palmer 2011) also had a relatively high ROB. The authors provided scant details of the study. The study aims were not clearly stated, making it difficult to determine how appropriate the research design was. Not enough detail was provided regarding the recruitment process, explo-ration of the relationship between the researcher and participants during data collection and how the thematic analysis was undertaken.
Tableshows the key characteristics of the participants involved in the studies included in this review. The case studies involved a total of 19 participants, of whom 17 had prior SMI. This is because one of the case series described two participants with a history of SMI and two people without mental illness, we only included the two participants with SMI. Participants in the case studies had diagnoses of schizophrenia (n = 10) and bipolar disorder (n = 4), and in one study the authors mentioned a patient had a psychiatric history without providing further details of their diagnosis. The majority of the patients in the studies were male (n = 14; 82%) and the mean age was 31 years (SD = 7). The qualitative study (Every-Palmer 2011) included 21 participants. Of which, 15 were eligible for this review. All were male with mean age of 34 years (SD = 8). The study using questionnaires) involved 608 participants, of whom 135 had psychotic disorders. Of the 135 patients, 23 (17%) had purchased NPS in specialized drug shops called 'head shops'. Further demographic information about the sample in this survey was only provided for the whole group of 608 participants.
Tableshows that most of the case study participants had used substances described as 'bath salts' without further specification (n = 5), four had used same type of synthetic cannabinoid called [1-(5-fluoropentyl)-3-(1naphthoyl)] indole (AM-2201) and six had used other types of substances. The others included herbs Datura stramonium, Salvia divinorum, a substance called 'el blanco', an amphetamine type stimulant containing a mixture of methylenedioxypyrovalerone (MDPV) and flephedrone, and benzylpiperazine (BZP). All of the questionnaire study participants had used the same type of synthetic cannabinoid, called JWH-018 (n = 15). Participants in the survey studyhad used a number of different substances that included synthetic cannabinoids (e.g. 'Spice' and 'Smoke XXX'), benzylpiperazine and piperazine derivates mephedrone, methcathinone and methylone among others. Outcomes: Health and mental health effects of NPS Tablesummarizes the mental and physical effects of NPS reported in the included studies. In all of the case studies, the authors reported that the NPS taken had a significant impact on the patients' mental state.
Out of a total of 17 cases, 15 reported a range of psychotic symptoms after taking NPS. Two were reported as being unconscious as a result of NPS use on admission to hospital intensive care unit/emergency department. The psychotic symptoms most commonly reported included delusions, hallucinations (including haptic, auditory, visual and tactile), severe thought disorder (including incoherent speech and tangential thought processes) and altered mental status (specific details not provided). Authors of a study involving four already hospitalized patients observed that all patients demonstrated new psychotic symptoms with no exacerbation of their previously known symptoms). In the qualitative study (Every-Palmer 2011), all patients reported the onset of psychotic symptoms following the use of NPS. Psychotic symptoms were also identified by users as an effect of NPS in a survey study. Participants in the qualitative study appeared to perceive NPS as less harmful or 'natural' substances, which 'make you high' in a faster and safer way, compared to illicit drugs (Every-Palmer 2011). Patients' behaviour after the use of NPS was also severely affected. In 9 of the 17 cases, bizarre or chaotic behaviour was observed, which included repetitive movements, crawling on the floor or running naked in the streets. Five patients were described as agitated with three requiring chemical and/or physical restraint, and three patients displaying violent, aggressive or assaultive behaviour. In one case this led to the use of pepper spray by security personnel with a subsequent severe adverse reaction that resulted in the patient's death.
Of the 17 cases, nine were reported to show considerable change in vital signs, most often elevated heart rate, blood pressure, increased temperature and profuse sweating, symptoms reported to be consistent with serotonin syndrome. Serotonin syndrome is a potentially life-threatening condition involving sudden onset of mental and neurological symptoms caused by an overstimulation of serotonergic receptors in the brain. In one person the vital signs returned to normal after 1 h, while several patients improved after 6-12 h, others after a considerably longer time (ranging between several days to several weeks). Three studies did not provide information about any physical effects of NPS and one patient had no significant physical symptoms due to the drug taken. In addition to directly affecting the vital signs as a result of neurological effects, NPS can also seriously disturb kidney and liver function. Six patients showed the signs of renal impairment based on increased levels of phosphokinase and/or creatinine (in one case creatinine was increased without renal impairment) and two patients subsequently experienced liver function damage requiring treatment in intensive care.
The duration of the effects caused by NPS varied considerably in the case studies. Six patients were reported as recovered within 2-12 h of intoxication or admission. Two persons returned to their mental state baseline on day 3 and 4 (consequently). Three patients were still unwell or just improved after 1 month of intoxication. Four studies did not provide detail about the time needed to recover. No patients were reported to have long-term kidney or liver damage. Out of the 17 cases, one death was reported. The authorshypothesized that this could have been caused by a severe reaction (i.e. respiratory arrest) to the agent in pepper spray that was used to subdue the patient because of their aggressive and violent behaviour. The patient never regained consciousness and died several weeks after the incident.
The case studies generally provided little or no detail about how NPS use was objectively confirmed. In most cases, NPS use was identified based on self-report (n = 9), although two patients denied drug use at first and admitted taking drugs only after several weeks of treatment resistanceor after repeated hospitalization. Five patients were reported to have been seen taking drugs by clinical staff, in two cases patients were found to be in possession of NPSand in one case the authors did not report any details about how drug use was determined. Only 5 of the 12 authors reported having done any testing of the substances used. In seven cases a standard urine drug/toxicology screen was performed, usually negative for the NPS taken by the patient. In three cases the substance was sent to specialized laboratories for detailed testing. Authors of one study reported that poison control was contacted without providing any further detailsand in four studies no substance testing was reported.
This review aimed to investigate evidence of the effects of NPS for people with serious mental illness. Through electronic databases search, of an initial 367 studies, we included 14 studies that met the inclusion criteria. Twelve of these were case studies focusing on reporting the acute effects of NPS. While the substances used by participants varied considerably, the majority experienced significant changes in vital signs and often significant and rapid alteration of mental status, involving psychotic symptoms and bizarre behaviour. A very common symptom across patients with all diagnoses and NPS was violent, assaultive or aggressive behaviour requiring restraint. The particular symptoms participants experienced were diverse, ranging from sedation and loss of consciousness, to bizarre repeated motions, to erratic running. The wide range of effects was most apparent in a study involving four hospitalized patients with schizophrenia who had smoked the same substance but exhibited very different symptoms. The authors mentioned that the four patients experienced psychotic symptoms that were not typical of earlier presentations, which may suggest that these were 'new symptoms' rather than an exacerbation of previous symptoms. Overall, our findings of the NPS effects are consistent with the effects reported in the general population. This may be because we do not yet understand the interaction between psychosis, brain dysfunction, prescribed medication and NPS. The changes in vital signs, mental status and behaviour were also observed in a Japanese retrospective survey of 518 patients (not specific MH patients) brought to emergency departmentand in a New Zealand overdose database analysis). We did not identify any studies that described positive effects of NPS. We suggest that NPS can have a relatively severe effect on people with psychotic disorders. Although the limited available evidence suggests that the adverse physical health issues resulting from NPS use are likely to be similar in both the general population and the SMI population, the effects on mental health may differ. For example, one of the common effects of NPS in people with SMI was significant behaviour change. Agitation requiring restraint was reported in around a third of the case study patients, with one in five being aggressive or violent. For comparison, only 56 (11%) of 518 patients brought to emergency departments in Japan for NPS intoxication, demonstrated violent and aggressive behaviour to self or others and 24% were irritable or agitated. Most (96%) of the people in the Japanese study recovered completely and did not require any further treatment. Episodes of extreme agitation in the general population who have taken NPS may be likely to be solely attributed to the use of the drugs, whereas in people with SMI it is possible that levels of behavioural disturbance could be viewed by professionals as being part of the SMI diagnosis. In such circumstances it is possible that NPS-related aggression in people with SMI might negatively influence their future mental health treatment (i.e. in terms of types and doses of prescribed medications) or hinder their recovery (i.e. resulting from stigma associated with having a history of violent/dangerous behaviour). It is very likely that the full extent of NPS use by people with SMI is under-recognized and may only be reported in the literature when this use results in extremely agitated behaviours and other serious health concerns. Due to this, it is also quite possible that there may be people with a SMI diagnosis who take NPS and do not come to the attention of health professionals because they may experience little harm. The beliefs of people with SMI that NPS are less harmful than illegal substances or are 'natural' (Every-Palmer 2011) have also been reported in some studies conducted in the general population. These ideas may result in people with SMI believing it is unnecessary to mention that they have used them during mental health assessments. This issue, coupled with the fact that commonly used illicit drug screening often fails to detect NPS use, indicates that mental health and other healthcare professionals should routinely enquire about the use of NPS by people with SMI in order to obtain a comprehensive picture of factors affecting mental illness. To date, this is the first systematic review of the evidence about the effects of NPS on the mental and physical health of people with SMI. The studies included in this review provide some indication that for some people with serious mental illness, NPS can have potentially serious effects on both physical and mental health.
This review had several limitations. First, the papers included in this review were mostly case studies and a cohort and qualitative study, which are inherently more likely to be of a lower quality and high ROB. Our findings, therefore, might not be applicable for, or generalizable to the wider population of people with SMI. For practical reasons we excluded papers that were not written in English, and this may have resulted in us over-look-ing some relevant material. Reporting in the case studies was also frequently lacking details about patients' clinical history and long-term follow-up, which might not be crucial for emergency purposes but are necessary for a better understanding of NPS effects on people with SMI. One study) also lacked details about the patient's psychiatric history and provided no specific diagnosis. Similarly to several other reports, the patient's diagnosis was not independently verified, which seriously limits the generalizability of the review findings. Another limitation is the small number of studies included in the review. Despite the reports of NPS use being relatively common among people with SMI (Martinotti et al. 2014), we were only able to identify 14 studies focusing on this population. This observation suggests that the issue may be under-reported and/or underresearched and more evidence is needed to inform clinical decisions and policy making. It might also indicate reporting bias, i.e. medical professionals selecting only severe and clinically interesting cases for publication, rather than reporting all cases of NPS intoxication. Due to the small number of studies and included patients, it is also difficult to directly compare the prevalence of the NPS effects in people with SMI and the effects within the general population published previously.
Patients might not always perceive NPS use as 'drug use' and may have a lack of knowledge and understanding of the likely effects and risks involved in their use. In order to make appropriate treatment choices, health professionals need to know what substance the patient had taken. To encourage truthful self-report, health professionals should have an understanding of how patients perceive NPS in terms of their origin, effects and risks. No studies examined medical and nursing staff knowledge and perceptions of NPS. It is also unclear how the different NPS interact with other drugs and medicines used in practice, although some of the drug interactions could potentially have serious consequences. When coupled with patients' reluctance to disclose all substance use, health professionals should be particularly vigilant and actively enquire about illicit as well as NPS drug use by people with SMI.
Our review suggests that NPS may have serious and potentially lethal consequences for at least some people with SMI. However, more research of higher quality is required to provide a better understanding of the short-and long-term effects of NPS. This in turn will aid in detection of use, management of intoxication as well as health education regarding effects and risks of such substances. The small number of publications about NPS use in the SMI population could potentially be related to the health professionals' lack of knowledge about NPS, but the understanding and attitude of health professionals about NPS is largely unknown. Future research should therefore provide more information about the ability of health professionals in emergency rooms and psychiatric departments, to recognize and address the NPS intoxication by people with SMI. More observational and prevalence research is needed to provide a better evidence base about the effects of NPS on the vulnerable population of people with SMI. It would also be valuable to determine whether and to what extent the effects of NPS differ between people with SMI and people without psychiatric illness. Future research could also focus on the entries into medical registers for reporting drug use, e.g. Toxbase (www.toxbase.org).
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