Journal of Psychoactive Drugs
February 9, 2019
Lorenzo Moccia, A. Tofani, Marianna Mazza et al.
10 citations
A 23-year-old man developed a substance-induced psychotic disorder after intravenously injecting an unspecified amount of methoxetamine (MXE), a ketamine derivative hallucinogen. Clinically, he showed blunted affect, diminished social drive, loss of sense of purpose, and detachment from the environment. Psychometric tests revealed severe dissociation, lack of motivation, and mild impairments in verbal fluency, working memory, and attention. Brain scans using 18F-FDG PET/CT showed significantly reduced tracer uptake in the dorsolateral prefrontal cortex (DLPFC), a region critical for goal-oriented cognition, working memory, and attention. This case indicates that a single acute MXE intoxication can cause severe brain impairment.
Psychiatry International
October 15, 2024
Valerio Ricci, Giovanni Martinotti, Giuseppe Maina
9 citations
Substance-induced psychosis (SIP) is increasingly common, especially among adolescents and young adults using cannabis, cocaine, and novel psychoactive substances. This review examines how SIP differs from primary psychotic disorders by focusing on two key concepts: Gaëtan de Clérambault's "mental automatism," where involuntary thoughts and sensations feel alien to the self, and the "twilight state" of consciousness, marked by altered perception of space, time, and social interaction. These phenomena help explain how substance use triggers psychotic processes and how SIP can transition to persistent psychosis with frequent, potent use. The review advocates for a clinical–phenomenological approach to improve diagnosis and treatment.
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.
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.
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.
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.
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.
Journal of Psychiatric Research
June 19, 2025
Valerio Ricci, Ilenia di Muzio, Mancusi Gianluca et al.
2 citations
Synthetic cannabinoid users experiencing first-episode psychosis show more severe positive psychotic symptoms, persistent aberrant salience, and limited recovery of alexithymia over six months compared to natural cannabis users and non-users. Dissociative symptoms are more prominent in both user groups, with synthetic cannabinoid users showing minimal improvement. Negative symptoms are higher in non-users but decrease across all groups. Alexithymia correlates with specific aberrant salience subscales, particularly Feelings of Increased Significance and Sense Sharpening. These findings indicate synthetic cannabinoids are associated with more severe and persistent psychotic symptoms and emotional dysregulation than natural cannabis.
Rivista di psichiatria
November 1, 2024
Valerio Ricci, Domenico de Berardis, Giovanni Martinotti et al.
2 citations
Abruptly stopping cannabis use can trigger psychotic symptoms in vulnerable individuals. An analysis of four patients seen between 2019 and 2023 describes psychotic features that emerged after sudden cannabis withdrawal. The report suggests that withdrawal, not only chronic use, may be a risk factor for precipitating psychosis, especially in susceptible patients. Clinicians should be aware of this potential risk.
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.
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.
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.
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.
Psychiatry Research Case Reports
October 18, 2023
Giacomo D’andrea, Ornella di Marco, Francesco Maria Semeraro et al.
1 citation
A 56-year-old man with rapid cycling bipolar disorder, experiencing four or more mood episodes per year, received esketamine nasal spray during a depressive episode and was followed for 18 months. He showed substantial mood stabilization, with only a brief depressive episode when treatment was stopped for three months, which resolved after restarting esketamine. Mild dissociative symptoms occurred with initial doses, but no other serious side effects were reported. This case suggests esketamine nasal spray may have mood-stabilizing effects for rapid cycling bipolar disorder, a condition that often responds poorly to lithium and standard treatments.
Preprints.org
Kainat Riaz, Sejal Suneel, Mohammad Hamza Bin Abdul Malik et al.
1 citation
preprint
Half of patients with post-traumatic stress disorder (PTSD) do not respond to standard pharmacotherapy or psychotherapy. A review of six phase II randomized controlled trials indicates that MDMA-assisted psychotherapy can reduce PTSD symptoms, even in treatment-resistant cases, 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 whether this approach can be integrated into existing treatment options.
Psychiatry research
September 1, 2026
Valerio Ricci, Andrea Paggi, Giovanni Martinotti et al.
In patients with cannabis-induced first-episode psychosis, dissociative symptoms—especially depersonalization and derealization—are strong independent predictors of poor functional recovery over 24 months. Among 72 patients, three recovery trajectories emerged: Rapid Recovery (34.7%, GAF +29.1 points), Gradual Recovery (40.3%, GAF +15.7 points), and Persistent Impairment (25.0%, GAF +4.7 points). A symptom-function discrepancy occurred in 31.9% of patients, where psychotic symptoms improved but functioning did not; these patients had higher baseline dissociation scores (33.8 vs. 18.1). Dissociation mediated 35% of cannabis's negative effect on functional outcomes. A high-risk subgroup (22%) with elevated dissociation, depression, and continued cannabis use showed minimal improvement despite treatment. Routine dissociation assessment and targeted interventions may improve outcomes.