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.
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.
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.
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.
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.
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.
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.
Psychopathology
January 1, 2024
Valerio Ricci, Giuseppe Maina, Giovanni Martinotti
8 citations
The twilight state of consciousness involves a narrowed yet expanded awareness, marked by perceptual shifts in time and space. New psychoactive substances can induce this state by deconstructing core components of consciousness, potentially triggering exogenous psychosis. This paper uses a phenomenological approach to explore how these substances alter spatial and temporal perception during the twilight phase, highlighting an overlooked aspect of psychopathology.
Frontiers in psychiatry
January 1, 2025
Miriam Olivola, Filippo Mazzoni, Barbara Tarantino et al.
7 citations
In treatment-resistant depression, esketamine—a glutamatergic modulator approved in 2019—may improve not only depressive symptoms but also key psychological factors such as mentalization, psychache, social cognition, suicidality, and cognitive-emotional rigidity. In a six-month observational study of 36 patients with treatment-resistant depressive episodes, depressive symptoms significantly decreased, as measured by the Montgomery-Åsberg Depression Rating Scale. By six months, 69% of patients achieved remission, indicating a robust and sustained response. The findings suggest esketamine may be particularly beneficial in reducing cognitive rigidity and improving mentalization, potentially breaking the inflexible thinking patterns that sustain depression. Personalized treatment approaches are emphasized.
Frontiers in psychiatry
January 1, 2025
Valerio Ricci, Maria Celeste Ciavarella, Carlotta Marrangone et al.
7 citations
Substance-induced psychoses (SIPs) triggered by novel psychoactive substances differ from endogenous psychoses like schizophrenia in three key ways: dissociation, mental automatism, and temporality. Dissociation in SIPs causes fragmentation of consciousness and identity detachment, distinct from the spaltung seen in schizophrenia. Mental automatism, as described by De Clerambault, appears early in SIPs with cognitive disruptions preceding delusions. Temporally, SIPs trap individuals in an eternal present, disconnected from past and future, unlike the fragmented temporality in schizophrenia. The paper argues that a phenomenological approach aids clinical differentiation and targeted interventions.
Journal of affective disorders
December 15, 2024
Giacomo d'Andrea, Andrea Miuli, Mauro Pettorruso et al.
6 citations
In patients with treatment-resistant depression, combining vortioxetine with esketamine nasal spray reduces depressive symptoms as effectively as the standard combination of an SSRI or SNRI with esketamine. The vortioxetine combination also showed a larger reduction in emotional blunting after three months and had fewer treatment-emergent side effects. These findings come from a post-hoc analysis of twenty patients, ten in each group. The authors suggest the vortioxetine-plus-esketamine regimen may be a valuable alternative, but they call for larger randomized controlled trials to confirm the results.
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.
Journal of psychoactive drugs
January 8, 2025
Valerio Ricci, Domenico De Berardis, Sheikh Shoib et al.
4 citations
Frequent recreational ketamine use among young adults is linked to more psychotic-like experiences, such as unusual thoughts and perceptions. In ten participants aged 18–24 who used ketamine multiple times weekly, higher use frequency correlated with more such experiences, while other drugs like THC, MDMA, and alcohol did not significantly contribute. The findings suggest ketamine's action on NMDA receptors may produce symptoms resembling schizophrenia. The small sample and reliance on self-report limit the conclusions, and more research is needed to confirm causality and long-term effects.
Asian journal of psychiatry
June 1, 2026
Fabiola Raffone, Filippo Mazzoni, Arianna De Ciechi et al.
3 citations
In a six-month observational study of 90 outpatients with treatment-resistant depression receiving intranasal esketamine, those with and without comorbid borderline personality disorder showed sustained reductions in suicidal ideation, suicidal behavior, and deliberate self-harm. Improvements were significant from month one onward. Self-harm episode frequency in the borderline group dropped from a mean of 30.8 at baseline to 2.4 at six months. Baseline impulsivity correlated with self-harm and suicidal measures, but these associations weakened by six months. No serious adverse events, treatment discontinuations, or increases in suicidality occurred. Controlled studies are needed to confirm durability, especially for patients with borderline personality disorder.
Brain Sciences
February 7, 2026
Miriam Olivola, Tiziano Prodi, Giada Versaci et al.
2 citations
During intranasal esketamine treatment for treatment-resistant depression, patients describe four distinct types of dissociative experiences: sensory alteration and perceptual flow (27.8%), time suspension and chronological drift (58.3%), body and space alteration (55.6%), and psychic distance from suffering (83.3%). Most patients frame these experiences as neutral or meaningful, often linked to temporary relief from rumination and depressive distress, though a minority report transient distress or loss of control. The findings suggest dissociation functions as a transitional subjective state whose clinical relevance depends on anticipation, framing, monitoring, and integration, supporting structured psychoeducation and in-session support in esketamine programs.
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.
Psychiatry Research
August 18, 2025
Ilenia Rosa, L. Padula, Francesco Semeraro et al.
2 citations
Treatment-resistant depression (TRD) challenges standard approaches, prompting a shift toward non-monoaminergic interventions like neuromodulation and glutamatergic agents. This narrative review examines the endocannabinoid system (ECS) as a potential common pathway for these treatments. Evidence indicates that repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT) increase endocannabinoids anandamide and 2-arachidonoylglycerol, correlating with clinical improvement. Ketamine and esketamine modulate CB1 receptors, while psilocybin restores 2-AG and enhances CB1 expression in mood-related brain regions. These findings suggest ECS modulation may unify diverse antidepressant mechanisms in TRD, offering a promising target for novel therapies.
Psychopathology
January 1, 2026
Valerio Ricci, Massimiliano Aragona, Giuseppe Maina et al.
1 citation
Hallucinations in schizophrenia, substance-induced psychosis (SIP), and substance-related persistent psychosis (PP) differ qualitatively. Schizophrenic hallucinations typically occur in clear consciousness with variable sensory vividness. SIP hallucinations arise in an oneiroid (dreamlike) state with increased vividness and multisensory integration. PP hallucinations occur in a twilight state of consciousness, often simpler but intrusive. These phenomenological differences provide a conceptual framework for more accurate diagnosis and treatment, especially in substance-related psychopathologies.
Current neuropharmacology
April 7, 2025
Marika Alborghetti, Luana Lionetto, Ginevra Lombardozzi et al.
1 citation
In patients with treatment-resistant depression receiving intranasal esketamine (56 mg) alongside another antidepressant, those taking antidepressants that inhibit cytochrome-P450 isoforms (paroxetine, fluoxetine, duloxetine, venlafaxine) had significantly higher serum esketamine levels 20 minutes after dosing and over 72 hours compared to patients on sertraline, citalopram, escitalopram, or vortioxetine. Salivary esketamine levels were several-fold higher than serum levels at all time points and showed high variability. These pharmacokinetic differences did not affect clinical outcomes, but changes in systolic blood pressure positively correlated with serum esketamine levels, suggesting dose reduction may be warranted for patients with cardiovascular comorbidity on those CYP450-inhibiting antidepressants. Small subgroup sizes limit strong conclusions.