A systematic review of the effects of novel psychoactive substances ‘legal highs’ on people with severe mental illness

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.