This systematic review (n=93 cases) found that psychedelic-induced psychosis, primarily caused by LSD and MDMA, lasted an average of 1.8 weeks and responded much better to second-generation antipsychotics (91% response rate) than first-generation antipsychotics (27% response rate), though one-third of patients later developed schizophrenia spectrum disorders.
Psychedelics are increasingly used in the general population, yet they are associated with increased risk of psychosis in a minority of users that can experience psychedelic-induced psychosis (<1% in controlled trial settings). In contrast, the evidence regarding the treatment of psychedelics-induced psychosis remains to date scarce.We conducted a PRISMA 2020-compliant systematic review (CRD42023399591), searching electronic databases (inception-August 2024) for interventional, observational studies, case series, or case reports on the treatment of psychedelic-induced psychosis. Frequencies of population, treatment, and outcome characteristics were analyzed. We included 14 case series, 20 case reports, and one prospective study, reporting on 93 cases of psychedelic-induced psychosis, between 1955 and 2024. The primary substances implicated were LSD (47.3%) and MDMA (38.7%), and the average patient age of 23.7+6.3 years, with a predominance of male subjects (88%). Psychosis lasted an average of 1.8 weeks. We identified two main treatment categories: first-generation antipsychotics (n=37) and second-generation antipsychotics (n=57). Electroconvulsive therapy was used in a minor subset of cases (n=9). The response rate for first-generation antipsychotics (27%) was significantly lower than that for second-generation agents (91.3%) and electroconvulsive therapy (91%). Follow-up data indicated 34% of patients later developed schizophrenia spectrum disorders, and 20.4% were diagnosed with bipolar disorder. However, the lack of comprehensive follow-up limits the interpretation of findings In conclusion, the evidence supporting treatment options remains limited, primarily based on case reports. Our findings suggest that second-generation antipsychotics seem to be more beneficial in managing psychedelic-induced psychosis, warranting further investigation into optimized treatment protocols.
Papers cited by this study that are also in Blossom
Nielson, E. M., Guss, J. · Journal of Psychedelic Studies (2018)
Pereira, L. · European Neuropsychopharmacology (2023)
Sabé, M., Sulstarova, A., Glangetas, A. et al. · Molecular Psychiatry (2024)
Strassman, R. J. · Journal of Nervous and Mental Disease (1984)
Sulstarova and colleagues frame the review against a backdrop of rising psychedelic use and renewed interest in therapeutic applications of a diverse group of compounds (LSD, psilocybin, ayahuasca/DMT, mescaline, MDMA and others). The authors note that, although psychedelics can produce prominent perceptual and mood effects via serotonin 5-HT2A mechanisms and other systems, psychedelic-induced psychosis appears to be uncommon in controlled settings and population studies. They emphasise that substance-induced psychotic disorder is a diagnosis of exclusion and that the literature lacks a systematic synthesis of how such episodes are treated when they do occur. This systematic review therefore aims to evaluate existing reports of treatment approaches and their efficacy for psychedelic-induced psychosis. The stated objectives include describing the substances implicated, the clinical course and duration of psychotic symptoms, the treatments administered (pharmacological and non-pharmacological), and subsequent diagnostic outcomes, with the goal of informing clinical decision-making and identifying gaps for future research.
The study is a PRISMA-compliant systematic review registered on PROSPERO (CRD42023399591). Database searches (PubMed, Embase, PsycINFO) were conducted from inception through August 2024, limited to English-language human studies. Two reviewers screened titles and abstracts independently using the Rayyan platform. Eligible reports included randomised trials, clinical trials, case-control studies, prospective and retrospective cohorts, population surveys/registries, case series and case reports addressing treatment of psychedelic-induced psychosis after use of serotoninergic and related classical psychedelics (LSD, DMT, psilocybin, mescaline, MDMA, Salvia divinorum, Hawaiian Baby Woodrose, Angel's trumpet). The authors excluded cases involving cannabis, PCP, ketamine and certain novel substances on the basis that these agents have different dopaminergic or NMDA-related mechanisms. The operational definition of psychedelic-induced psychosis drew on earlier adverse-reaction literature and DSM‑V substance-induced psychosis criteria; hallucinogen-persisting perception disorder (HPPD) was excluded. Data extracted into a spreadsheet included study identifiers, patient mental health history, substance(s) and doses when reported, prior use, clinical course, treatments administered (with antipsychotic doses converted to risperidone-equivalents where possible), and outcomes. Response categories (no response, partial response, good response) were determined from author reports and case details; two reviewers assessed response classification with reported inter-rater agreement. Evidence quality was graded using the Oxford Centre for Evidence-Based Medicine levels. The analysis mainly describes frequencies and characteristics across included reports rather than quantitative meta-analysis.
The review included 35 studies published between 1955 and 2024: 14 case series, 20 case reports and one prospective (non-randomised) cohort study, comprising 93 individual cases of psychedelic-induced psychosis. The most commonly implicated substances were LSD (44 cases; 47.3%) and MDMA (36 cases; 38.7%), with smaller numbers for salvia divinorum (5 cases; 5.3%), ayahuasca/DMT (3 cases; 3.2%), psilocybin (2 cases; 2.1%), Hawaiian Baby Woodrose (2 cases; 2.1%) and Angel's trumpet (1 case; 1%). Information on prior psychedelic exposure and concomitant substances was frequently missing (56 cases, 60.3%); among the cases with data, 4 were psychedelic‑naïve, 9 reported psychedelics as the primary substance, and 24 involved at least one additional substance (11 cases reported regular cannabis use). Demographically, the mean age reported was 23.7 ± 6.3 years (n=67), with a predominance of male patients (88%). For the subset with available timing data (N=45), the mean duration of psychotic symptoms including pharmacological treatment was 1.8 ± 4.2 weeks. Treatments fell into two main immediate categories: first‑generation antipsychotics (FGAs; n=37) and second‑generation antipsychotics (SGAs; n=57); electroconvulsive therapy (ECT) was used in a small number of cases (n=9). Reported mean risperidone-equivalent dosing for FGAs was 8.1 mg (the authors report an equivalence to 818 mg/day of chlorpromazine) over an average treatment duration of 26 days (N=21). For SGAs the mean risperidone-equivalent dose was 4 mg/day (N=56) over about 21 ± 5 days. Chlorpromazine was the most commonly used FGA (62% of FGA cases) and olanzapine the most common SGA (75.4% of SGA cases). Response, classified by the reviewers from case descriptions, showed a markedly different pattern between classes: a 'good' response rate for FGAs of 27% versus 91.3% for SGAs. ECT, used as add-on second‑line therapy (average four sessions), also had a reported 91% good response rate (N=9). Other treatments were infrequently used: benzodiazepines (N=1), antiepileptics (N=5) and antidepressants (N=2) showed generally low efficacy for psychotic symptoms, though valproic acid was reported to yield a 'good response' in about 55% of the limited cases treated. Symptom presentations included psychosis alone in 85 individuals and combined psychotic and manic symptoms in 36 cases; mood stabilisers were reported in only six cases. Follow-up data were sparse: the prospective cohort (32 MDMA/ecstasy cases) treated with olanzapine reported remission of most severe positive symptoms within three months and less than 30% had depressive mood or anxiety after that period. Overall evidence quality was low: most reports were Level 4 (case reports/series) and the single non-randomised cohort provided Level 3 evidence supporting olanzapine for ecstasy-induced psychotic disorder.
Sulstarova and colleagues interpret the assembled case literature as indicating that LSD and MDMA account for most reported instances of psychedelic-induced psychosis, which mirrors their prevalence in wider use. They stress that the overall evidence base for treatment is limited and heterogeneous, precluding definitive guidance, but that their synthesis suggests superior clinical responses to second‑generation antipsychotics and to add‑on ECT compared with first‑generation antipsychotics. The authors discuss diagnostic difficulties: distinguishing substance-induced psychosis from transient acute reactions, mood or anxiety states, or the unmasking of an underlying psychotic disorder is often problematic because of variable timing of presentation, incomplete clinical descriptions and frequent pre-treatment with medications. They note that spontaneous improvement within days to a week occurs in some patients, which complicates assessment of treatment necessity and efficacy. In considering mechanisms, the discussion highlights that different psychedelics interact with distinct neurobiological systems—most classic psychedelics act at 5‑HT2A receptors but may indirectly affect glutamatergic and dopaminergic signalling, whereas MDMA primarily increases monoamine release and salvinorin A targets kappa‑opioid receptors. The authors therefore argue for system‑specific treatment considerations: serotonin–dopamine antagonists (SGAs) may be more effective for many serotonergic psychedelics, while dopamine‑focused antagonists could be preferable for substances with stronger dopaminergic effects. Experimental and clinical data cited in the discussion include trials where risperidone or ketanserin attenuated psilocybin effects, whereas haloperidol was less effective and in some instances increased anxiety or thought disorder. Existing guideline practice is reviewed briefly: acute management commonly emphasises supportive care and benzodiazepines to manage agitation, but the authors suggest SGAs may be preferable in many cases based on the case literature. Practical scenarios are proposed for clinical decision‑making: short-term treatment with monitoring for patients without prior psychosis, more sustained management for those with early-stage or familial risk of psychosis, and standard protocols for patients with established schizophrenia spectrum disorders. The authors acknowledge major limitations of the evidence, including attribution uncertainty (psychedelics may reveal pre-existing vulnerability rather than cause chronic psychosis), selection and reporting bias inherent in case reports, inconsistent outcome definitions, confounding from combined treatments, and scarce follow-up data. These constraints temper the strength of any treatment recommendations and motivate calls for higher-quality observational studies and randomised trials.
The authors conclude that typical (first‑generation) antipsychotics appear to have limited effectiveness for psychedelic-induced psychosis based on the predominantly case‑report literature. Second‑generation antipsychotics, and in some cases electroconvulsive therapy, showed higher reported response rates and may be more suitable treatment options, with olanzapine receiving specific support from a non-randomised cohort of ecstasy-induced cases. Given the sparse and low‑quality evidence, Sulstarova and colleagues recommend further observational research and randomised controlled trials to better define diagnosis, optimal pharmacological and non‑pharmacological treatments, and follow-up strategies for psychedelic-induced psychosis.
The utilization of psychedelics has seen a significant increase in recent years, particularly broadening their application for health-related issues, especially among individuals living with mental health conditions. This varied spectrum of psychedelics, encompassing lysergic acid diethylamide (LSD), psilocybin, ayahuasca/dimethyltryptamine (DMT), mescaline, and 3,4methylenedioxymethamphetamine (MDMA), introduces a multitude of compounds, each with distinct pharmacological properties and effects. The growing interest in psychedelics is underscored by their potential therapeutic applications, extending from treatment-resistant depression to substance use disorders, anxiety, and PTSD. Despite the growing popularity of these substances, there is a noticeable absence of a corresponding increase in admissions related to psychedelic-induced psychosis. In a recent meta-analysis, it was found that the occurrence of psychedelic-induced psychosis J o u r n a l P r e -p r o o f following the use of psychedelics in various patient groups was generally comparable to that observed in the general population, with a prevalence below 4%. Notably, in that meta-analysis, studies excluded patients with a history of personal or familial psychosis. In the, substance-induced psychotic disorder refers to a condition characterized by the presence of prominent hallucinations and/or delusions that are judged to be directly attributable to the physiological effects of a substance (Supplementary Information 1). The substance implied may encompass medications, recreational drugs, or toxins. It is crucial to note that substance-induced psychotic disorder is a diagnosis per exclusion, implying that other primary psychotic disorders must be ruled out before attributing the symptoms solely to substance use. Moreover, the specific substance involved and its impact on the central nervous system play a pivotal role in the diagnosis and considerations for treatment. The term "psychedelic-induced psychosis" identifies a spectrum of altered states of consciousness with psychotic symptoms lasting >24 hours induced by psychedelic drugs that primarily operate through serotoninergic mechanisms. On the neurobiological level, 5-HT2A receptors seem to be central to the hallucinogenic effects of most psychedelics, albeit with some exceptions such as MDMA and Salvia divinorum. LSD primarily exerts its hallucinogenic effects through 5-HT2A receptor activation, which induces alterations in serotonin signaling, leading to profound changes in perception, mood, and cognitionMDMA, on the other hand, primarily causes the release of serotonin and dopamine, which accounts for its stimulant effects, emotional openness, and empathogenic properties. In contrast, Salvia divinorum predominantly targets the kappa-opioid receptor (KOR), leading to unique dissociative and hallucinatory effects. While these receptors mediate the acute hallucinogenic effects, it is suggested that the development of long-lasting psychotic symptoms could be linked to elevated levels of serotoninergic and dopamine activity, with a possible role of glutamate systems. While concerns have been raised about the systematic exclusion of patients with a history of psychosis from trials, the rise in the use of psychedelics is not mirrored by a proportional increase in of admission to emergencies or to hospitalization due to psychedelic-induced psychosis. Crucially, a critical examination of the treatment approaches employed for individuals experiencing psychedelicinduced psychosis and the overall efficacy of these interventions is currently lackingThe present systematic review seeks to bridge this gap by comprehensively evaluating existing literature on treatment approaches and their efficacy in the context of psychedelic-induced psychosis. In addition to synthesizing current knowledge, we aim to provide insights into the duration of psychotic symptoms associated with different psychedelics and delineate the clinical aspects and characteristics that could be associated with underlying disorders.
This systematic review was conducted according to the Preferred Reported Items for Systematic Reviews and Meta-Analysis (PRISMA). The review protocol was registered on PROSPERO in April 2023 (CRD 42023399591). The literature search was updated in August 2024.
Two reviewers (AS and MS) independently reviewed titles and abstracts using Rayyan, a research collaboration web platform for systematic reviews in PubMed, Embase, and PsycINFO, using specific search terms (CRD 42023399591). Results were restricted to articles in English and on human studies.
We retained RCT, clinical trials, case-control studies, prospective and retrospective cohorts, populationsurvey/register studies, and case reports that explored the treatment of cases of psychedelic-induced psychosis following serotoninergic psychedelic consumption (e.g. LSD, DMT, mescaline and psilocybin) and other recreational classical psychedelics (e.g., MDMA, Salvia divinorum, Hawaiian Baby Woodrose, Angel's trumpet). However, cannabis, PCP, ketamine, and new psychedelicsubstances from our analysis were excluded. These substances are strongly linked to the occurrence of psychoses due to their specific neurobiological effects on dopamine and are not classical psychedelics.
We considered any pharmacological and non-pharmacological intervention for addressing psychedelicinduced psychosis. Given that the concept of 'psychedelics-induced psychosis' remains somewhat undefined, our criteria for including studies in this review were informed by Strassman's seminal article on adverse reactions to psychedelic drugs, that we combined with the definition of substance-induced psychosis as outlined in the DSM-V (Supplementary Information 1). We also decided to exclude cases of Hallucinogen-Persisting Perception Disorder (HPPD), as HPPD typically does not involve delusions, hallucinations, or disorganized thinking, but rather sensory and perceptual symptoms indicative of alterations in the brain's visual processing pathways.
We extracted from each study the authors; title, publication year, mental health history, and study type, as well as various details on the substances consumed by patients, in particular dosages, prior consumption, and the evolution of symptoms when available. These elements were systematically organized into an Excel table, with subsequent entries detailing the number of patients exhibiting prolonged psychosis, a thorough description of their pre-treatment condition, the specific treatments administered -primarily focusing on antipsychotic medications-the treatment dosages, where applicable, and the definitive outcomes observed. When available, we converted all antipsychotic doses to risperidone equivalent using Leucht et al.'s daily dose method. Tablereports the demographic and diagnosis characteristics of included patients. Finally, we used the Oxford Centre for Evidence-based Medicinerating to grade evidence.
Our systematic review retained 35 studies published between 1955 and 2024, including 14 case seriesJ o u r n a l P r e -p r o o f 2003), 20 case reports, and one prospective study(see Fig.: PRISMA flowchart), detailing a total of 93 cases of psychedelic-induced psychosis (Table). The average year of publication was 1997. The list of the 93 excluded studies can be found in the supplements (Supplementary Information 2). The primary psychedelics associated with clinical symptoms of psychosis included LSD (44 cases; 47.3%), MDMA (36 cases; 38.7%), salvia divinorum (5 cases; 5.3%), ayahuasca/DMT (3 cases; 3.2%), psilocybin (2 cases; 2.1%), Hawaiian Baby Woodrose (2 cases; 2.1%), and Angel's trumpet (1 case; 1%). Although the majority of cases (56, 60.3%) had missing information, we identified 4 cases (4.3%) involving individuals who were psychedelic-naïve, 9 cases (9.6%) where psychedelics were the primary substance of use, and 24 cases (25.8%) involving individuals who used at least one other substance in addition to psychedelics. Among these, 11 cases (11.8%) reported regular cannabis use (Table). Among the 93 patients analyzed, 32 were included in a prospective study focusing on MDMA-induced psychotic symptoms. The mean age was 23.7 ± 6.3 years (n=67), with the majority being male (88%). The average duration of psychedelic-induced psychosis, including pharmacological treatment was 1.8 ± 4.2 weeks (N=45). We identified two main types of immediate treatment for psychedelic-induced psychosis: firstgeneration antipsychotics (n=37) and second-generation antipsychotics (n=57) (Table). The average publication year for cases involving first-generation antipsychotics was 1985, while for secondgeneration antipsychotics, it was 2010. All patients were hospitalized during treatment. The mean risperidone equivalent dose for first-generation antipsychotics was 8.1 mg (equivalent to 818 mg/day of chlorpromazine) over an average treatment duration of 26 days (N=21). For second-generation antipsychotics, the mean dose was 4 mg/day of risperidone equivalent (N=56) over a mean duration of 21±5 days. Chlorpromazine was the most commonly used first-generation antipsychotic (62%), while olanzapine was the most frequently administered atypical antipsychotic (75.4%). Response to treatment J o u r n a l P r e -p r o o f was categorized as no response, partial response, or good response, as reported by the authors and with joint examination of detailed reported in the cases, conduct independently by two reviewers (AS and MS). The achieved rate of agreement was 78%. The two reviewers then jointly reviewed the remaining cases to reach a consensus. Overall, the response rate classified as 'good' for first-generation antipsychotics was significantly lower than that for second-generation antipsychotics (mean of 27% vs. mean of 91.3%). Add-on electroconvulsive therapy (ECT) was employed as a second-line treatment, averaging four sessions, and demonstrated an excellent response rate (N=9; 91%). Some reports mentioned the use of benzodiazepines (N=1), antiepileptics (N=5), and antidepressants (N=2), but these treatments showed low efficacy regarding psychotic symptoms. Only valproic acid appeared to have some efficacy, yielding a 'good response' in 55% of cases, while other molecules presented no response or partial response. In terms of symptoms, 85 individuals exhibited psychotic symptoms, while a smaller subset (N=36) presented with both psychotic and manic symptoms. The presence of manic symptoms explains the use of mood stabilizer in only 6 cases. Additionally, depressive symptoms were noted in a minority of cases, which led to the use of antidepressants; however, these treatments were ineffective, yielding 'no response' in two cases. Follow-up data were available for only a subset of patients.
According to the Oxford Centre for Evidence-based Medicine, the majority of articles identified, consisting of case reports and case series, only propose a very weak level of evidence (Level 4). Only one non-randomized controlled cohort study with a six-month follow-up period was identified, supporting a Level 3 grade of evidence. In this study, 32 ecstasy consumers who were treated in outpatient centers and who were diagnosed with ecstasy-induced psychotic disorder according to DSM-IV criteria and all received olanzapine. Most severe positive symptoms remitted in the first 3 months. A lesser proportion of patients (<30%) presented a depressive mood or anxiety after this period. Olanzapine was considered safe and effective J o u r n a l P r e -p r o o f by the authors. Thus, the only evidence emerging from our work is the potential efficacy of this secondgeneration antipsychotic for the case of ecstasy-induced psychotic disorder. We found grade 4 evidence recommending a specific class of antipsychotics for LSD, DMT, and psilocybin (Table). For MDMA, a follow-up study suggested olanzapine, allowing for a grade 3 evidence classification. While most of classical psychedelics primarily interact with 5-HT2A receptors, they also involve the glutamatergic and dopaminergic systems, highlighting the unique properties of each substance.
Our findings indicate that most cases of psychedelic-induced psychotic disorder involve LSD or MDMA, which aligns with the significant prevalence of these substances in the general population. A minority, though significant, of the identified cases were also regular users of other substances, primarily cannabis. However, the evidence supporting the treatment of psychedelic-induced psychoses in our systematic review is limited, making it difficult to draw definitive conclusions. Nevertheless, our results suggest a potential correlation between the effectiveness of second-generation antipsychotics and addon electroconvulsive therapy in alleviating psychedelic-induced psychotic symptoms. Additionally, we observed that the total dosage of first-generation antipsychotics prescribed was approximately twice as high as that of second-generation antipsychotics, while not being effective in reducing psychotic symptoms.
The diagnosis of psychedelic-induced psychosis remains challenging as individuals can present various comorbid diagnoses. A key aspect of psychedelic-induced psychosis is the temporal relationship between the onset of symptoms following psychedelic use and their persistence beyond 24 hours. However, in many instances, acute stress reactions last only a few days to a week. This makes it challenging to distinguish between psychedelic-induced psychosis, psychedelic-induced mood disorders J o u r n a l P r e -p r o o f or psychedelic-induced anxiety disorders, which typically persist for more than one to two days, especially since patients often receive medications before this period has elapsed. Moreover, the spontaneous improvement observed in some patients during the week after psychedelic reduces the necessity for antipsychotics in these specific cases. In most reviewed articles, the absence of clear clinical descriptions and the use of substance-induced diagnostic criteria for psychedelicinduced psychosis significantly limit the interpretation of our findings. Furthermore, authors did not recommend any length for antipsychotic treatment.
Our findings align with existing literature, which suggests that first-generation antipsychotics are generally ineffective in treating psychedelic-induced psychosis. While these medications may offer partial symptom relief due to their sedative properties, the common side effects associated with first-generation antipsychotics could contribute to an overall worsening of the clinical picture. Some elements of response can, however, be found in a few studies focusing on individuals with no psychiatric history. These studies examine the effect of antipsychotics during psychedelic experiences, particularly with serotonergic psychedelics. In a randomized-control trial with healthy individuals, Vollenweider and colleagues found that both a pretreatment administration of ketanserin (20-40 mg P.O.) or risperidone (0.5-1.0 mg P.O.) significantly attenuated the immediate psychedelic effects of psilocybin (0.25 mg/kg). Only 1 mg of risperidone effectively blocked the development of psilocybin-induced acute psychotic symptoms. In contrast, pretreatment with haloperidol (0.021 mg/kg I.V.) only moderately reduced the immediate effect of psilocybin, although the given dose of each antipsychotic was chosen to occupy 55-65% of dopamine D2 receptors. The authors even found that the pretreatment with haloperidol mainly increased thought disorder and anxiety measured as 'dread of ego-dissolution' experience. Moreover, the same group of authors propose that first-generation antipsychotics can attenuate ecstasyinduced positive and mania-like moods through a partial dopaminergic mediation of the euphoriant effects of ecstasy.
A study conducted earlier by Giannini and colleagues compared haloperidol to chlorpromazine in the treatment of phencyclidine psychosis. In this study, haloperidol (5mg I.M.) or chlorpromazine (50 mg I.M.) were effective in reducing psychotic symptoms. However, phencyclidine psychosis is thought to be much more related to the direct alteration of the dopaminergic system than the serotoninergic psychedelic considered in our work. Of interest, in mouse models, only sulpiride was not effective against the effect of phenethylamine hallucinogen, probably due to a paucity of 5-HT2 antagonists activity in vivo. In a recent case report, Sabé and colleagues found that a patient with schizoaffective disorder with amisulpride treatment (400 mg/day) was able to lead to the decrease of both negative and depressive symptoms following psilocybin-assisted therapy.
Overall, first-generation antipsychotics, and more largely, antipsychotics with main D2 antagonist properties, are not effective for preventing the occurrence of psychotic symptoms associated with psilocybin. Second-generation antipsychotics, primarily serotonin-dopamine antagonists, appear to be more effective in managing psychedelic-induced psychotic symptoms, even at subthreshold D2 receptor occupancy levels. However, psychedelics are thought to induce psychotic symptoms through various mechanisms involving not only the serotonergic system but also the glutamatergic and dopaminergic systems, particularly at higher doses. Therefore, when treating psychedelic-induced psychotic disorders, it is crucial to consider the specific properties of each psychedelic to optimize antipsychotic treatment. We summarize in Tablethe main mechanisms associated with several psychedelics for further insight regarding potential antipsychotic treatments. LSD, for instance, modulates dopaminergic transmission through TAAR1 receptors, which may partially explain the pathogenesis of psychosis. The interaction of LSD with the dopaminergic system appears to be dose-dependent, potentially accounting for the efficacy of serotonin-dopamine antagonists. Conversely, DMT does not directly interact with dopamine receptors, and substances like psilocybin, peyote/mescalineand bufoteninshow J o u r n a l P r e -p r o o f relatively low affinity for dopamine receptors. However, they may indirectly affect dopamine pathways through their serotonergic activity. Ibogaine exhibits a similar mechanism, primarily binding to 5-HT2A receptors while also inhibiting dopamine reuptake, although it directly involves D2 receptors. MDMA occupies a unique position, as it is not classified as a classical psychedelic. Furthermore, it is a more potent inhibitor of serotonin than norepinephrine or dopamine, which may explain the significant efficacy of olanzapine for treating MDMA-induced psychosis, as suggested by one follow-up study. Phencyclidine (PCP), primarily an NMDA receptor antagonist, produces dissociative and hallucinogenic effects while also increasing dopamine release, contributing to its stimulant and psychotomimetic effects. Therefore, dopamine antagonists may be more suitable for managing PCP-induced psychosis, while serotonin-dopamine antagonists may be more effective for other psychedelics. Lastly, Salvinorin A, is rather unique as it does not act on serotonin receptors like most classic psychedelics. Instead, Salvinorin A is a potent agonist of kappa-opioid receptors (KOR). The mechanisms of Salvinorin A remain enigmatic, with some researchers proposing its moodregulating properties and influence on dopamine transporters.
While no universal guidelines specifically address psychedelic-induced psychosis in the latest American Psychiatric Association Practice Guidelines, treatment of generally involves supportive care, and use of pharmacological medication. For the acute management of a substance-induced psychotic episode, sedation with benzodiazepines is commonly employed to calm the individual and alleviate agitation or anxiety. In the context of substance-induced psychosis, supportive care combined with benzodiazepines is typically preferred over antipsychotics to avoid exacerbating serotonin receptor activity. However, according to our findings, the use of second-generation antipsychotic might be more suitable than the use of benzodiazepines.
In a 1984 review, Strassman noted that administering chlorpromazine prophylactically at the conclusion of LSD studies was effective in preventing further prolonged adverse reactions. However, based on our findings and more recent research, we suggest the use of second-and thirdgeneration antipsychotics to mitigate potential mesolimbic dopaminergic overactivity associated with positive symptoms. If psychotic symptoms persist, or if they are severe, this may indicate a confirmed psychedelic-induced psychotic disorder, antipsychotics should then be considered (Table). Long-term psychosis may necessitate ongoing psychiatric care, similar to the management of other psychotic disorders. In cases of psychedelic-induced psychosis, three clinical scenarios should be carefully considered. First, for patients with no prior history of psychosis, treatment may be short-term, lasting a few months, followed by long-term monitoring. Second, when psychedelic-induced disorder occurs in individuals with early-stage psychosis or a family history of psychotic disorders, treatment may resemble that for patients experiencing a first episode of psychosis. Finally, for individuals with co-occurring schizophrenia spectrum disorders, treatment should align with standard protocols for managing new psychotic episodes. We summarize these different features in Figure
One major limitation of our work is the challenge of attributing psychedelic-induced psychoses solely to psychedelics. From a phenomenological perspective, it is crucial to recognize that psychedelics do not directly trigger clinical psychosis; rather, they often reveal pre-existing vulnerabilities in certain individuals that become evident upon consumption. In many clinical cases reviewed, it is difficult to attribute the entire clinical picture to psychedelics, especially when information about concomitant substance use or the patient's personal history is incomplete. The clinical definition of substance-induced psychosis has evolved significantly over the decades and remains a topic of ongoing debate. A key, yet often overlooked, factor is the temporal proximity between symptom onset and psychedelic use, which typically occurs within one week timeframe. However, this criterion is not consistently present in the majority of cases reviewed. Additionally, only few reports clarify whether individuals had prior experience with other substances, indicating that many may not J o u r n a l P r e -p r o o f have been entirely naive to psychedelics or under the effect of concomitant substances. Considering that the vast majority of gathered materials are case reports, the evidence in the hierarchy of evidence-based medicine is of low-quality. Indeed, published cases likely represent only a fraction of psychedelicinduced psychosis incidents, as many affected individuals may hesitate to seek medical care, reflecting a selection and an observer bias which greatly limit the generalizability of evidence. Furthermore, most studies lack a clear definition of treatment response, and the assessment of psychotic or concomitant manic/disorganized symptoms is often incomplete. Important cofounding factors are also present in cases using combined treatment approaches, such as ECT and antipsychotics given the short timeframe reported. Finally, the absence of follow-up data in most cases, and information on subsequent diagnoses significantly limits the robustness of our findings.
Our findings, drawn largely from case reports, indicate that typical antipsychotics may have limited to no effectiveness in improving the clinical presentation of psychedelic-induced psychosis. Some studies suggest that second-generation antipsychotics may offer greater efficacy in alleviating symptoms associated with these disorders. Nevertheless, the evidence remains sparse. To strengthen our understanding of diagnosis and treatment for psychedelic-induced psychosis -and related conditions such as psychedelic-induced mood and anxiety disorders-further observational studies and randomized controlled trials should be conducted. All other authors report no conflicts of interest.
-First systematic review on treatment approaches of psychedelic induced-psychosis. -Second-generation antipsychotics showed significantly higher efficacy than first-generation. -Electroconvulsive therapy demonstrated excellent response rates in treating psychosis. -MDMA-induced psychosis may benefit from olanzapine treatment, with good outcomes. -Treatment of psychedelic-induced psychosis requires tailored approaches based on substance type.
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Ermentrout, G. B., Vis, P. J., Goudriaan, A. E. et al. · Frontiers in Neuroscience (2021)
Vollenweider, F. X., Kometer, M. · Nature Reviews Neuroscience (2010)
Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A. et al. · NeuroReport (1998)
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