Treatment approaches and efficacy in Psychedelic-Induced Psychosis: A systematic review

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.