Informing and preventing: a review of novel psychoactive substances in adolescents

Introduction: Novel psychoactive substances (NPS) represent a rapidly evolving neuropsychopharmacological challenge. Designed to mimic controlled drugs whilst evading regulatory frameworks, NPS encompass a range of substances, including synthetic cannabinoids, synthetic cathinones, synthetic opioids (including nitazenes), and alkyl nitrites. Their widespread online availability, frequent adulteration of traditional substances, and evasion of standard urine immunoassays pose significant clinical and diagnostic challenges, particularly given the neurobiological vulnerability of the developing adolescent brain.

Aims: This review aimed to synthesise current European epidemiological data on NPS use in adolescents, characterise the pharmacological profiles and neuropsychiatric toxidromes of the most clinically relevant emerging substances, and identify evidence-based approaches for screening and early intervention.

Methods: A literature review was conducted integrating data from European Union Drugs Agency (EUDA) surveillance reports (2024–2025), the European School Survey Project on Alcohol and Other Drugs (ESPAD) 2024, peer-reviewed publications on adolescent neurodevelopment and substance use disorders, and Portuguese national epidemiological data. Sources were selected to reflect the most recent trends and clinically actionable evidence.

Results: The ESPAD 2024 survey (n=113,882; aged 15–16; 37 European countries) identified NPS lifetime prevalence at approximately 3%, exceeding amphetamines (1.8%), 3,4-methylenedioxymethamphetamine (MDMA) (2.1%), and cocaine (2.3%). By end-2024, EUDA monitored over 1,000 NPS; 47 new substances were detected in 2024 alone, including 20 novel synthetic cannabinoids (18 semi-synthetic). All 7 newly notified synthetic opioids in 2024 were nitazenes - benzimidazole-opioid receptor agonists with µ-receptor affinity potentially exceeding fentanyl - producing rapid-onset respiratory depression, frequently requiring high-dose naloxone infusion and mechanical ventilation. Synthetic cathinones (dopamine, noradrenaline, and serotonin reuptake inhibitors and releasers) accounted for 37 tonnes seized across Europe in 2023, producing sympathomimetic toxidromes including hyperthermia, acute psychosis, and potentially fatal arrhythmias comparable in severity to cocaine or methamphetamine intoxication. The immature prefrontal cortex, with limbic system dominance persisting until approximately age 25, confers specific neurobiological vulnerability: adolescent substance exposure increases lifetime risk of substance use disorder and produces disproportionate prefrontal and working memory impairment relative to adults. Critically, standard urine immunoassays do not detect NPS, rendering diagnosis predominantly clinical. Polydrug use and adulteration - including cannabis adulterated with synthetic cannabinoids and counterfeit opioid and benzodiazepine tablets containing nitazenes - substantially amplify toxicity. The CRAFFT 2.1 (score ≥2 indicating high risk) provides a validated brief screening instrument for adolescent substance use.

Conclusions: NPS constitute a growing and neuropsychiatrically significant threat, with prevalence in European adolescents already surpassing several classical illicit substances individually, though not exceeding cannabis prevalence. The diagnostic gap created by negative standard screens requires heightened clinical suspicion in unexplained neuropsychiatric presentations. Whilst overall illicit drug use trends show modest decline, NPS, e-cigarette, and non-medical prescription drug use are rising. Integration of validated screening tools, awareness of NPS neuropsychiatric toxidromes, and competency-based prevention strategies are warranted. Further research on the long-term neurodevelopmental consequences of adolescent NPS exposure is needed.

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