Psychological Medicine
July 22, 2019
Fabrizio Schifano, Flavia Napoletano, Stefania Chiappini et al.
118 citations
A novel web-crawling tool called NPS.Finder® identified several thousand new psychoactive substances (NPS)—roughly four times more than European and international drug agencies report. Synthetic cannabinoids, new synthetic opioids, ketamine-like dissociatives, novel stimulants, novel psychedelics, and certain prescription and over-the-counter medicines were most commonly linked to psychopathological consequences. The rapid proliferation of recreational psychotropics poses a challenge for psychiatry because the pharmacodynamics and pharmacokinetics of many NPS remain poorly understood. Health and mental health professionals need up-to-date information on the range of NPS, their intake methods, sought-after effects, drug combinations, and associated medical and psychopathological risks.
Brain Sciences
June 27, 2021
Giovanni Martinotti, Stefania Chiappini, Mauro Pettorruso et al.
114 citations
Ketamine and esketamine, N-methyl-D-aspartate receptor antagonists, show promise for treating obsessive-compulsive disorder (OCD), eating disorders, and substance use disorders, which share features like obsessive thoughts and compulsive behaviors. A review of literature up to April 2021, following PRISMA guidelines, found that while small studies indicate remarkable results for treatment-resistant depression, PTSD, and OCD, solid evidence for benefits in OCD spectrum and addiction is still lacking. The use is supported by glutamatergic neurotransmission dysregulation. Preliminary data are optimistic, but further studies are needed to clarify unknowns and long-term effectiveness.
Bipolar Disorders
January 13, 2023
Giovanni Martinotti, Bernardo Dell’osso, Giorgio Di Lorenzo et al.
72 citations
Esketamine nasal spray reduced depressive symptoms in people with treatment-resistant bipolar depression as effectively as in those with unipolar treatment-resistant depression, with no significant differences in response or remission rates after one and three months. The treatment also showed greater anxiety-reducing effects in the bipolar group. No treatment-emergent affective switch occurred, supporting the safety and tolerability of esketamine for bipolar treatment-resistant depression.
Psychiatry Research
July 29, 2023
Mauro Pettorruso, Roberto Guidotti, Giacomo D’andrea et al.
56 citations
Machine learning models predicted which patients with treatment-resistant depression would respond to esketamine nasal spray. In a retrospective study of 149 patients, three random forest classifiers achieved 68.53% accuracy for response at one month and 66.26% at three months, and 68.60% accuracy for remission at three months. Features such as severe anhedonia, anxious distress, mixed symptoms, and bipolarity positively predicted response and remission, while benzodiazepine use and depression severity were linked to delayed responses. The findings suggest machine learning may aid personalized treatment decisions for treatment-resistant depression.
Experimental neurology
May 1, 2021
Fabrizio Schifano, Stefania Chiappini, Andrea Miuli et al.
49 citations
Several new psychoactive substances (NPS) can trigger serotonin syndrome, a dangerous condition of excessive serotonin activity marked by altered mental status, neuromuscular effects, and autonomic hyperactivity. A systematic review of three retrospective studies, two case series, and five case reports identified implicated substances including psychedelic phenethylamines (2C-I, 25I-NBOMe, 5-IT) and synthetic cathinones (mephedrone, MDPV, methylone, butylone, NRG3, AMT, MXP), as well as the antidepressant bupropion when misused at high doses or combined with other serotonergic drugs. Most substances were taken orally, though nasal insufflation and sublingual administration occurred. Psychiatric history was negative for most subjects. Clinicians should recognize NPS risks and diagnostic challenges due to undetectability in routine drug screenings.
European Neuropsychopharmacology
May 4, 2023
Stefania Chiappini, Giacomo D’andrea, Sergio De Filippis et al.
48 citations
Esketamine nasal spray reduces depression symptoms in patients with treatment-resistant depression who also have a substance use disorder. In 26 patients followed for three months, Montgomery-Asberg depression rating scale scores decreased significantly from baseline to one month and from one to three months. Side effects occurred in 73% of patients, most commonly dissociative symptoms and sedation, but none led to lasting harm and no abuse or misuse of the medication was reported. The findings suggest esketamine is effective and safe in this population, though the study is limited by its small sample and short follow-up.
Human Psychopharmacology Clinical and Experimental
July 1, 2015
Stefania Chiappini, Hugh Claridge, John M. Corkery et al.
45 citations
Methoxetamine (MXE), a novel psychoactive substance, was found in eight fatalities in the UK between 2011 and 2013. The median age at death was 27 years; most decedents were White and male. MXE was directly implicated in four deaths and likely contributed to two others, and in seven of eight cases it was used alongside other substances. The report calls for more research into MXE's health effects and toxicity, and for healthcare professionals to be aware of its harms to develop early interventions and reduce poisonings and deaths.
Frontiers in Psychiatry
November 20, 2019
Laura Orsolini, Stefania Chiappini, Duccio Papanti et al.
41 citations
The spread of novel psychoactive substances (NPS), especially among young people, raises concerns about psychosis linked to synthetic drugs. These 'new psychoses' differ clinically from classical psychosis. This mini-review synthesizes clinical and psychopathological features of NPS-induced psychoses and their treatment, based on a PubMed/Medline search for synthetic cannabinoids and cathinones. It contrasts classical psychoses with NPS-induced ones and offers therapeutic guidelines for clinicians in addiction psychiatry.
American Journal of Geriatric Psychiatry
July 8, 2023
Giacomo D’andrea, Stefania Chiappini, Roger S. McIntyre et al.
36 citations
Esketamine nasal spray (ESK-NS) shows preliminary effectiveness for treatment-resistant depression in adults aged 65 and older, with 53.3% of participants responding (MADRS score reduced by at least 50%) and 33.33% achieving remission (MADRS below 10) after three months. Common adverse effects included dizziness (50%), dissociation (33.3%), sedation (30%), and hypertension (13.33%). Twenty percent of participants discontinued treatment. These findings, from a post-hoc analysis of 30 older adults, suggest ESK-NS can be effective but is associated with high rates of treatment-emergent adverse events, most of which did not require stopping treatment.
Current Neuropharmacology
October 20, 2022
Alessio Mosca, Stefania Chiappini, Andrea Miuli et al.
30 citations
Ibogaine and noribogaine, psychedelic substances from plants of the Apocynaceae family, show some efficacy in treating substance use disorders, particularly opiate detoxification. However, their use carries concerning risks of cardiotoxicity and mortality. A meta-analysis of side effects found a significant risk of developing headaches after treatment. The evidence, drawn from case reports, randomized controlled trials, open-label studies, surveys, and observational studies, remains unclear on overall efficacy and toxicity. Further research is needed to evaluate therapeutic benefits and safety.
Human psychopharmacology
May 1, 2020
Laura Orsolini, Stefania Chiappini, Duccio Papanti et al.
27 citations
Ayahuasca, a hallucinogenic plant preparation used in sacred ceremonies by indigenous Amazonian groups, may offer therapeutic benefits for mental health. Evidence from preclinical, observational, and experimental studies suggests it acts as a fast-acting and enduring antidepressant, emotional regulator, anxiolytic, and antiaddictive drug. It appears safe and well tolerated, with nausea and vomiting as the most common transient side effects. However, findings indicate it should not be used in bipolar or psychotic patients due to increased risk of manic switch or psychotic onset. Further research with randomized, double-blind, placebo-controlled trials and neuroimaging is needed to better evaluate its therapeutic potential in mental disorders.
Current Neuropharmacology
January 14, 2021
Stefania Chiappini, Andrea Miuli, Alessio Mosca et al.
19 citations
Benzydamine, an over-the-counter anti-inflammatory drug, is being diverted and used recreationally at high dosages (500–1500 mg) for its hallucinogenic properties. A systematic review of eleven articles from 1997–2019, including case reports, surveys, and case series, along with analysis of European adverse drug reaction reports from 2005–2020, found three reported abuse cases. The findings suggest healthcare professionals should be aware of potential misuse and that emergency physicians should consider benzydamine abuse when patients present with psychotic symptoms.
Expert review of neurotherapeutics
April 1, 2025
Stefania Chiappini, Gaia Sampogna, Antonio Ventriglio et al.
17 citations
Depression involves a wide range of emotional, cognitive, and physical symptoms that disrupt daily life. Societal changes such as technological advances, economic pressures, climate change, and shifting cultural norms have altered how depression appears and is understood, leading to the identification of new depression subtypes. These include depression in adolescents and young adults, depression with social disconnection, depression with alcohol or substance use disorder, depression with gender dysphoria, and depression linked to stressful events and environmental factors. Managing these subtypes requires individualized treatment approaches. While SSRIs and SNRIs remain standard, atypical antidepressants like trazodone, ketamine, neuromodulation, and personalized psychotherapy offer hope for complex or treatment-resistant cases.
Neuroscience & Biobehavioral Reviews
October 19, 2025
Alessio Mosca, Gianluca Mancusi, Stefania Chiappini et al.
6 citations
Synthetic cannabinoids are the novel psychoactive substances most strongly associated with acute psychosis and, in some cases, persistent or relapsing psychotic disorders. Some cases show symptoms overlapping with schizophrenia, suggesting a possible risk of transition to chronic illness. Synthetic cathinones and phenethylamines are also linked to psychotic manifestations including thought disturbances and perceptual abnormalities. While many psychotic episodes are transient, a notable proportion evolve into persistent states, indicating that these substances may unmask latent vulnerabilities or directly contribute to chronic psychotic disorders. Clinicians should systematically assess NPS use in first-episode psychosis patients.
Pharmaceuticals (Basel, Switzerland)
March 31, 2024
Maria Pepe, Marco Di Nicola, Fabrizio Cocciolillo et al.
6 citations
The psychoactive substance 3-MeO-PCP, a type of NMDA receptor antagonist, can cause persistent psychotic symptoms and cognitive impairment. A literature review and case report describe a 29-year-old man who developed substance-induced psychotic disorder after small oral intakes over two weeks, culminating in a high dose. Psychometric tests, neuropsychological assessment, and brain PET-CT imaging revealed lasting effects. Identifying the clinical features and neural substrates of NPS-induced psychoses may help distinguish them from other psychotic disorders and guide tailored treatments.
Psychiatry International
September 20, 2024
Alessio Mosca, Stefania Chiappini, Andrea Miuli et al.
5 citations
Piperazines, synthetic compounds with stimulant and hallucinogenic effects, are linked to acute psychotic episodes. A systematic review of 4 studies found that piperazine abuse frequently triggers symptoms such as paranoia, auditory, and visual hallucinations. The compounds' complex polyreceptor action may explain these effects, similar to other novel psychoactive substances. Recovery is common after cessation and treatment, but data on long-term outcomes are limited. Further research into piperazine abuse and specific treatment protocols for substance-induced psychosis is needed.
Transl Psychiatry
October 31, 2025
Giacomo D’andrea, Stefania Chiappini, Laura Ciavoni et al.
3 citations
Psychedelics and ketamine/esketamine show promise for treating depressive disorders by inducing rapid and sustained antidepressant effects. The review examines their biological mechanisms, including modulation of glutamate and serotonin systems, promotion of neuroplasticity, and changes in brain connectivity and network function. Neuroimaging studies reveal alterations in default mode network, fronto-limbic connectivity, and thalamic activity. Clinical changes are associated with these brain alterations, though the precise relationships remain under investigation. The work synthesizes current evidence on how these compounds produce observable brain changes and symptom improvement, highlighting the need for further research to clarify mechanisms and optimize therapeutic applications.
Current Neuropharmacology
February 20, 2025
Alessio Mosca, Stefania Chiappini, Gianluca Mancusi et al.
3 citations
Abusing certain over-the-counter medications can trigger psychotic symptoms such as paranoia, hallucinations, and thought disorders. Antihistamines, dextromethorphan, and other OTC drugs are implicated. Dextromethorphan misuse is especially linked to chronic psychosis, while other substances more often cause acute substance-induced psychosis. The review analyzed 46 relevant studies from an initial pool of 2,677 articles, highlighting the need for greater awareness and interventions to address OTC drug misuse and its psychiatric consequences.
Clinical Neuropsychopharmacology and Addiction
September 25, 2025
Stefania Chiappini, Clara Cavallotto, Andrea Miuli et al.
2 citations
About 30–50% of patients with major depression do not respond to two or more antidepressant trials, a condition called treatment-resistant depression (TRD). A narrative review of 60 studies found that glutamatergic agents such as intravenous ketamine and intranasal esketamine consistently produce rapid and clinically meaningful reductions in depressive symptoms. Augmentation with atypical antipsychotics also helps partial responders. Psychedelic-assisted therapies show sustained antidepressant benefits and affect biomarkers like BDNF and inflammatory markers. The findings suggest a shift toward personalized, mechanism-driven treatments for TRD, with ketamine and esketamine offering rapid relief for acute high-risk cases and psychedelics remaining experimental but promising as adjunctive options.
Brain Sci
September 17, 2025
Alessio Mosca, Stefania Chiappini, Andrea Miuli et al.
1 citation
Synthetic cannabinoids can cause psychosis that is often severe and difficult to treat. This systematic review examined published case reports and case series to identify effective treatment strategies. The review found that benzodiazepines and antipsychotics are commonly used, but many patients require intensive care and prolonged hospitalization. No single treatment protocol emerged as clearly superior, and outcomes varied widely, with some patients recovering fully while others experienced persistent psychotic symptoms. The authors suggest that early recognition and aggressive management may improve outcomes, but more research is needed to establish standardized treatment guidelines.
The International Journal of Neuropsychopharmacology
February 1, 2025
Clara Cavallotto, Giacomo D’andrea, Andrea Miuli et al.
1 citation
In patients with treatment-resistant depression, combining the antidepressant vortioxetine with esketamine nasal spray was as effective as the standard combination of an SSRI or SNRI with esketamine in reducing depressive symptoms over three months. The vortioxetine combination showed a larger effect in reducing emotional blunting and was linked to fewer treatment-emergent side effects, including dissociative symptoms. These findings suggest vortioxetine plus esketamine may be a valuable alternative, though larger randomized trials are needed to confirm the results.
Journal of Substance Use and Addiction Treatment
July 1, 2026
Alessio Mosca, Stefania Chiappini, Andrea Miuli et al.
Management of ketamine misuse relies on supportive care, psychotherapy, and off-label medications, but robust evidence is lacking. A systematic review of 73 studies found that approaches include symptomatic medical care, psychotherapeutic interventions such as motivational interviewing and cognitive-behavioral therapy, and pharmacological treatments including benzodiazepines, SSRIs, naltrexone, lamotrigine, and gabapentinoids, with varying effectiveness. Multidisciplinary strategies addressing both psychiatric and somatic complications, such as 'K-bladder' and 'K-cramps', are essential. High relapse rates and limited follow-up weaken the evidence, and there is an urgent need for controlled studies and standardized treatment protocols.
Schizophrenia research
March 24, 2026
Valerio Ricci, Stefania Chiappini, Giovanni Martinotti et al.
Treatment response in substance-induced psychotic disorders is predicted by several factors with varying levels of evidence. Acute symptom onset within 24-48 hours of substance use predicts favorable treatment response, while prominent negative symptoms predict slower remission and higher transition to chronic psychotic disorders. Poor premorbid functioning and bimodal response patterns (rapid remission within 30 days versus poor outcomes thereafter) distinguish responders from non-responders. Early age of substance use onset, family history of psychotic disorders, abstinence achievement, and premorbid cognitive capacity may influence outcomes. Cannabis-induced and methamphetamine-induced psychosis warrant particular caution given higher persistence rates and psychiatric comorbidity.