International Journal of Molecular Sciences
September 23, 2018
Domenico de Berardis, Michele Fornaro, Alessandro Valchera et al.
171 citations
Suicide remains difficult to predict despite advances in neuroscience. The World Health Organization reports one million suicide deaths annually, with one every 40 seconds. Recent genomic studies suggest genetics influence suicide risk. Combining genomic and clinical assessments has identified biomarkers for suicidal ideation involved in neural connectivity, mood, and immune response, including the mammalian target of rapamycin (mTOR) signaling pathway. This provides a neurobiological basis for drugs like ketamine, an NMDA antagonist, which has shown rapid antidepressant and anti-suicidal effects. This review examines preclinical and clinical evidence for ketamine's efficacy in treating suicidal ideation in mood disorders, addressing the neurobiological processes of suicide and potential therapeutics.
Brain Sciences
March 16, 2018
Giovanni Martinotti, Rita Santacroce, Mauro Pettorruso et al.
171 citations
Hallucinogen Persisting Perception Disorder (HPPD) is a rare condition linked to hallucinogenic drug use, often diagnosed in individuals with prior psychological issues or substance misuse, but it can occur after a single exposure. This review of 45 original studies examines proposed etiologies, the hallucinogens involved, clinical features of HPPD types I and II, psychiatric comorbidities, and available or potential treatments. The findings suggest that HPPD remains poorly understood, with limited therapeutic options, highlighting the need for further research.
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.
CNS Spectrums
June 25, 2020
Giovanni Martinotti, Luisa de Risio, Chiara Vannini et al.
102 citations
About 25% of first-episode psychoses are substance-induced. The DSM-5 definition assumes symptoms are transient and disappear after sustained abstinence, but this does not account for persistent cases. A new diagnostic framework is needed to differentiate comorbid conditions from substance-related psychoses. The authors propose a novel clinical entity called substance-related exogenous psychosis (SREP), covering both transient and persistent psychoses linked to substance use. SREP is distinct from schizophrenia, characterized by altered consciousness, persecutory delusions, visual and cenesthetic hallucinations, impulsivity, psychomotor agitation, affective and negative symptoms, a pervasive feeling of unreality, and intact insight. Delusions are secondary to abnormal perception from a 'sensorialization' of the world. Longitudinal studies are needed to validate this category.
BioMed Research International
January 1, 2014
Francesco Saverio Bersani, Ornella Corazza, Gabriella Albano et al.
98 citations
25C-NBOMe, sold online as legal LSD or under names like 'N-bomb' and 'Pandora', is a partial agonist of 5-HT2A receptors that carries a high risk of overdose, with acute toxicity and fatalities reported. It is taken orally, sublingually, nasally, by injection, vaginally, rectally, or smoked, producing effects such as sublingual numbing, stimulation, hallucinations, dissociation, and anxiety. Its use is an emerging phenomenon increased by low-cost online availability, and health professionals should be informed about this trend.
Human Psychopharmacology Clinical and Experimental
September 19, 2003
Fabrizio Schifano, Adenekan Oyefeso, John Corkery et al.
93 citations
Between August 1996 and April 2002, 202 deaths related to ecstasy use occurred in England and Wales, with a steady annual increase. Most victims were young men: the male-to-female ratio was 4:1, and three-quarters were under age 29. In 17% of cases ecstasy was the only drug involved; the rest involved other substances, most often alcohol, cocaine, amphetamines, and opiates. MDMA was detected in 86% of cases and MDA in 13%; MDEA and PMA caused single deaths. This is the largest sample of ecstasy-related deaths reported at the time. The authors propose possible explanations for the rising trend and a rationale for the observed polypharmacy combinations.
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.
Journal of psychopharmacology (Oxford, England)
November 1, 2005
Fabrizio Schifano, Paolo Deluca, Lisa Agosti et al.
70 citations
The compound 2C-T-7 ('Blue Mystic'), which resembles MDMA and other designer drugs, has rarely been identified in the EU, yet online discussion among experimenters has recently grown. A review of cyber and street market information found that 2C-T-7 was first synthesized in 1986 and produces desired effects of empathy and well-being, with anecdotal reports of hallucinations, nausea, anxiety, panic attacks, and paranoid ideation. Street-level availability in Europe appears very low, though one US death from mono-intoxication is documented. From an initial 360 websites, 118 were analyzed: 14 (11.9%) described synthesis, and 5 (4.2%) offered the drug for sale.
Comprehensive Psychiatry
April 20, 2006
Giovanni Martinotti, Sara Andreoli, Emanuela Giametta et al.
67 citations
Pathologic gamblers show higher novelty seeking and self-transcendence, and lower self-directedness and cooperativeness, compared with both non-pathologic gamblers and control subjects. A positive correlation exists between gambling severity and both novelty seeking and self-transcendence scores. Pathologic gamblers with a family history of gambling have even higher novelty seeking. These personality dimensions may help identify individuals at risk for problem gambling and inform treatment approaches.
CNS & Neurological Disorders - Drug Targets
April 17, 2017
Giovanni Martinotti, Rita Santacroce, Duccio Papanti et al.
62 citations
Synthetic cannabinoids are the most widespread class of novel psychoactive substances, yet their health risks are often unknown to users and health professionals. This review synthesizes recent insights on the pharmacology, clinical, and psychopathological aspects of synthetic cannabinoids. A structured search of PubMed and Scopus yielded 162 relevant results, mainly epidemiological, forensic, toxicologic, or analytical. Fifteen synthetic cannabinoid-related fatality cases were reviewed. The findings confirm the need for prompt, reliable information for health professionals, along with more specific analytic techniques and preventive strategies to address the synthetic cannabinoid challenge.
Annals of General Psychiatry
November 26, 2023
Giuseppe Maina, Marina Adami, Giuseppe Ascione et al.
56 citations
A Delphi panel of 60 Italian psychiatrists found wide variation in how treatment-resistant depression (TRD) is managed in Italy, highlighting a need for standardized strategies and treatments specifically approved for TRD. High consensus emerged on adding lithium or antipsychotics as augmentation therapies and on the need for long-term maintenance therapy. Esketamine nasal spray was identified as the best option for TRD patients, with agreement that it can be administered in a community outpatient setting given appropriate educational support for patients.
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.
Current Topics in Medicinal Chemistry
January 31, 2020
Domenico de Berardis, Carmine Tomasetti, Maurizio Pompili et al.
38 citations
Abnormalities in glutamatergic neurotransmission are hypothesized to play a role in mood disorders, prompting investigation of NMDA receptor modulators for Major Depressive Disorder (MDD). Intranasal esketamine, an NMDA receptor antagonist, has been developed for treatment-resistant depression (TRD) and for rapidly reducing depressive symptoms, including suicidal ideation, in MDD patients at imminent suicide risk. A systematic review of literature up to October 2019 found that intravenous esketamine elicits rapid and sustained antidepressant effects in refractory patients. Phase II studies showed intranasal esketamine had rapid onset and persistent efficacy in TRD and MDD patients at suicide risk, though phase III data had discrepancies.
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.
NeuroImage
December 1, 2023
Stefano Delli Pizzi, Piero Chiacchiaretta, Carlo Sestieri et al.
27 citations
LSD selectively alters the functional connectivity between specific thalamic nuclei and sensory and associative cortical areas. Using structural and resting-state functional MRI in healthy volunteers under acute LSD administration, researchers found increased coupling of the ventral complex, pulvinar, and non-specific thalamic nuclei with somatosensory and auditory cortices, as well as with associative cortex regions rich in serotonin 2A receptors. At subcortical levels, LSD increased connectivity among these thalamic nuclei but decreased striatal-thalamic connectivity. These nucleus-specific changes help explain LSD's modulation of subcortical-cortical circuits and associated behavioral effects.
Current neuropharmacology
January 1, 2025
Gianluca Rosso, Giacomo d'Andrea, Stefano Barlati et al.
23 citations
Among patients with treatment-resistant depression who continued esketamine nasal spray for at least six months, 76.2% responded or achieved remission. Of those who had not responded by six months, a subset improved by twelve months. Side effects occurred in 71.8% of patients at six months, decreasing to 42% at twelve months; the most common were sedation and dissociation. Only two patients stopped treatment due to tolerability issues. The findings suggest esketamine is effective and safe for mid- to long-term treatment, with a novel observation of late clinical response in some patients. Results require confirmation in larger samples and longer observation periods.
Frontiers in Psychiatry
August 31, 2020
Giovanni Martinotti, Attilio Negri, Stefania Schiavone et al.
22 citations
Recreational drug use among holidaymakers in Ibiza often involves multiple substances, both traditional and novel, leading to acute psychiatric emergencies. The pattern of poly-substance use is linked to a range of psychopathological consequences. Better understanding of the specific effects of individual drugs, clearer diagnostic signs and symptoms, and long-term follow-up studies are needed.
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.
Diseases
November 3, 2023
Kainat Riaz, Sejal Suneel, Mohammad Hamza Bin Abdul Malik et al.
16 citations
Half of patients with post-traumatic stress disorder (PTSD) do not respond to traditional therapies. A review of six phase II randomized controlled trials indicates that MDMA-assisted psychotherapy can reduce PTSD symptoms even in treatment-resistant cases. MDMA appears to work by increasing neurohormones such as dopamine, serotonin, norepinephrine, and oxytocin, and by modulating brain regions involved in fear and anxiety. The FDA has granted MDMA-assisted psychotherapy a "breakthrough therapy" designation. Further research is needed to determine whether the benefits outweigh the risks and how it might fit into existing PTSD treatment options.
Archiv der Pharmazie
March 1, 2025
Giuseppe Floresta, Alberto Granzotto, Vincenzo Patamia et al.
12 citations
Xylazine, a veterinary sedative now used recreationally with fentanyl, interacts with human serotonin 7 (5-HT7R) and kappa-opioid (KOR) receptors. Computational docking and molecular dynamics simulations identified binding motifs and showed that small structural changes can improve xylazine's affinity for these receptors. These findings may help explain xylazine's psychoactive effects and guide treatments for overdoses.
Psychopathology
January 1, 2024
Valerio Ricci, Giuseppe Maina, Giovanni Martinotti
11 citations
Dissociation in addiction involves a fragmented sense of self that extends beyond momentary experiences, creating a persistent discontinuity of identity. This process compresses an individual's vital space and freezes their perception of time, impairing emotion, sensation, and comprehension. The authors construct a framework through historical analysis and phenomenological perspective, exploring trauma and temporality to understand dissociative experiences in addiction.