Table 2 Narrative reviews and systematic reviews reporting potential psychedelic-induced psychosis.

Cohen [37]

Lysergic acid diethylamide: side effects and complications

LSD

Narrative review and report of a UCT

Follow-up cohort

Case reports. A total of 62 physicians who had experience with prescription of LSD or mescaline were asked on psychiatric side effects of treatments. (n.a)

*Four adverse reactions following LSD use were identified: ‘prolonged psychotic reactions’, ‘acting out behavior’, ‘abuse of euphoriant’, ‘multihabituation’.

*Rate of 1.8 prolonged reactions per 1000 patients.

*Suicide attempts and completed suicides occurred at a rate of 1.2 and 0.4 per 1000 patients.

*No case of HPPD were detect on this sample of 5000 LSD users.

MQ; n.m.

Level 2

Smart & Bateman [154]

Unfavorable reactions to LSD: a review and analysis of the available case reports.

LSD

Narrative review

21 case-reports which contained the details of 225 adverse reactions. Additional citation of longitudinal studies

*The most serious complications include prolonged psychotic reactions, recurrent LSD experiences, disturbed non-psychotic reactions, and, less frequently, suicide, homicide, and convulsions.

*Data on the frequency of illicit use are unavailable, so prevalence rates of adverse reactions cannot be estimated

*Baker [76] (conference) precipitated four psychoses lasting three or four days in 150 patients who received up to 10 LSD sessions.

*Leuner [155] (conference) found three prolonged psychotic reactions among 82 patients given an average of 27 LSD sessions.

LQ; n.m.

Level 2

Panhuysen [156]

[Undesirable side effects of LSD administration]

LSD

Narrative review

Authors discuss side-effects associated with LSD use

*Illegally manufactured LSD can be contaminated with atropine-like acting substances

*Patients with the following conditions should only be eligible for LSD trials after intense clinical examination:

-Patients with neurotic ego-defense mechanisms at work

-Patients with psychasthenic symptoms, psychopathic traits, with bipolar disorders, schizoaffective disorders and schizophrenia.

LQ; n.m.

Level 3

Strassman [7]

Adverse reactions to psychedelic drugs. A review of the literature

LSD

Narrative review

Good quality narrative review including case series, cohorts’ studies and clinical trials

*Strassman distinguish from acute, time-limited panic reactions during administration, through transient psychoses lasting several days, to recurrent flashbacks and chronic undifferentiated psychotic and treatment-resistant cases.

*Potential risk are: poorer premorbid adjustment, a history of psychiatric illness and/or treatment, a greater number of exposures to psychedelic drugs and correlatively, a greater average total cumulative dosage taken over time, drug-taking in an unsupervised setting, a history of polydrug abuse, and self-therapeutic and/or peer-pressure-submission motive

*Discussion of the potential of LSD to trigger underlying illness

HQ; n.m.

Level 2

Novak [79]

LSD before Leary: Sidney Cohen’s critique of 1950s psychedelic drug research

LSD

Narrative review

Narrative review on historical concepts

*Reports a long-lasting psychosis ( > 48H) at a rate of 1 case out of 247 individuals who received LSD

LQ; n.m.

Level 3

Paparelli et al. [86]

Drug-induced psychosis: how to avoid star gazing in schizophrenia research by looking at more obvious sources of light

LSD

Narrative review

Narrative review on mechanism of drug-induced psychosis

*Authors discuss the link between cannabis use and psychosis

*Authors propose that stimulants and THC are more likely to induce paranoia beliefs, in particular following repeated use, whereas LSD is more closely associated with visual hallucinations

H.Q.; no coi

Level 2

Boutros & Bowers [147]

Chronic substance-induced psychotic disorders: state of the literature.

LSD

Systematic review

Case series, cohorts’ studies and case controls studies

*Psychostimulants, hallucinogens, marijuana, and possibly industrial inhalants can cause or increase the susceptibility for a state of chronic psychosis

CL n.m.

Level 1

De Gregorio et al. [157]

d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology

LSD

Systematic review

Systematic review on preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD

*LSD’s exert effects on serotonin, dopamine, glutamate and TAAR systems

*LSD’s mechanism of action is pleiotropic, primarily mediated

by the serotonergic system in the Dorsal Raphe, binding the 5-HT2A receptor as a partial agonist and 5-HT1A as an agonist.

*LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D2, Trace Amine Associate receptor 1 (TAAR1) and 5-HT2

CL no coi

Level 1

Perez et al. [22]

Psilocybin-assisted therapy for depression: A systematic review and dose-response meta-analysis of human studies

Psilocybin

Meta-analysis

A total of 366 patients included in several RCt were included in this meta-analysis. Doses of psilocyin varied from 3 mg to 40 mg. 366(46.8%)

*The determined 95% effective doses per day (ED95) were 8.92, 24.68, and 36.08 mg/70 kg for patients with secondary depression, primary depression, and both subgroups, respectively.

*Authors found found significant dose-response associations for various side effects, including physical discomfort, blood pressure increase, nausea/vomiting, headache/migraine, and the risk of prolonged psychosis

LR; p.f.

Level 1

Jacob & Presti [158]

Endogenous psychoactive tryptamines reconsidered: an anxiolytic role for dimethyltryptamine

DMT

Narrative review

Narrative review on the role of DMT

*Authors hypothesis that the action of endogenous DMT at the TA receptor is to produce a calming, anxiolytic effect, which may suppress, rather than promote, symptoms of psychosis.

MQ; n.m.

Level 4

Grammenos & Barker [159]

On the transmethylation hypothesis: stress, N,N-dimethyltryptamine, and positive symptoms of psychosis

DMT

Narrative review

Narrative review on the role of DMT

*Stress has been found to elevate DMT levels in rodents and DMT levels have been associated with positive features of psychosis.

*Healthy participants treated with exogenous DMT experience predominantly positive symptoms of psychosis. Authors hypothesize that increased DMT reactivity as a response to stress could possibly underlie positive symptoms of psychosis in a subgroup of patients with schizophrenia.

MQ; no coi

Level 4

Gable [160]

Risk assessment of ritual use of oral dimethyltryptamine (DMT) and harmala alkaloids

DMT

Systematic review and presentation of case reports

Narrative review on the role of DMT

*DMT is capable of inducing aversive psychological reactions or transient psychotic episodes that resolve spontaneously in a few hours.

*The dependence potential of oral DMT and the risk of sustained psychological disturbance are minimal.

*DMT or ayahuasca experience has a substantial degree of unpredictability with respect to both aversive and positive aspects, depending on variables such as dosage, participant’s intention and setting.

CL; npo

Level 2

Dos Santos et al. [55]

Ayahuasca, dimethyltryptamine, and psychosis: a systematic review of human studies

DMT

Systematic review and presentation of one case report

Systematic review on DMT and psychosis

*Authors suggest that the incidence of psychotic episodes associated with ayahuasca/DMT intake is a rare phenomenon, and these rare instances appear be associated with previous premorbid characteristics of the individuals, previous and possibly concurrent drug abuse, and lack of a supervised setting

*Individuals with personal or family history of schizophrenia or schizophreniform disorders, psychotic depression or mania, or with ongoing manic or psychotic symptomatology, should avoid ayahuasca/DMT intake

CL; no coi

Level 2

Orsolini et al. [87]

How does ayahuasca work from a psychiatric perspective? Pros and cons of the entheogenic therapy

Ayahuasca

Systematic review

Systematic review on preclinical, observational, and experimental studies in healthy volunteers and in clinical samples

*Ayahuasca appears to be safe and well tolerated, nausea and emesis being the most reported and transient side effects.

*Findings suggest not to use ayahuasca in bipolar or psychotic patients because of an increased risk of manic switch -based on 2 case-reports- and/or psychotic onset -based on one epidemiological survey- that do not drive clear conclusion on this association (see Lima & Tófoli, 2011)

LQ; no coi

Level 1

Studerus et al. [75]

Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies

Psilocybin

Review of different clinical trials

Narrative review of the prospective follow-up of patients included in different clinical trials. 227 subjects experimented psilocybin with follow-up of possible adverse events

*Authors identified a pool of 8 RCTs published between 1999 and 2008

*The analysis included 110 healthy subjects who had received 1–4 oral doses of psilocybin (45-315 µg/kg body weight)

*Acute adverse drug reactions, characterized by strong dysphoria and/or anxiety/panic, occurred only in the two highest dose conditions in a relatively small proportion of subjects (2/110)

*Authors found no indication for subsequent drug abuse, persisting perception disorders, prolonged psychosis or other long-term impairments of functioning in any of our subjects.

LR; npo, pf

Level 1

Skryabin [161]

Hallucinogen persisting perception disorder: A literature review and three case reports

MDMA

Ecstasy

Narrative review

Narrative review on the phenomena of HPPD with case report presentation

*Authors discuss HPPD II occurrence in users of ecstasy and MDMA.

*Treatments with tofisopam, lamotrigine and sertraline showed possible partial response.

HQ; no coi

Level 3

McGuire et al. [162]

Long term psychiatric and cognitive effects of MDMA use.

MDMA

Narrative review

Narrative review gathering 16 case reports and case series

*In rare cases, MDMA use may be associated with chronic psychiatric symptoms, which persist long after the cessation of MDMA use, such as psychotic features, panic disorder, depression, and obsessive-compulsive symptoms

*These subjects might already be predisposed to psychiatric disorders.

*50% of cases in a series of MDMA users with chronic psychiatric symptoms had a first degree relative with a psychiatric illness, and 50% had previously experienced transient psychiatric symptoms following use of other illicit drugs.

*Severe long-term psychiatric disturbances following MDMA use seem uncommon relative to the large numbers of people who use MDMA

*It is difficult to determine whether MDMA use is directly responsible, triggers symptoms in subjects predisposed to mental illness, or is incidental.

HQ; n.m.

Level 2

Soar et al. [163]

Psychiatric disorders in Ecstasy (MDMA) users: A literature review focusing on personal predisposition and drug history.

MDMA

Ecstasy

Narrative review

This narrative review present 38 case reports of side-effects following MDMA or ecstasy use

*Authors estimate that 5 million individuals have tried Ecstasy in UK

*29% of cases showing psychiatric symptoms after MDMA consumption involved psychotics symptoms, with 65% of psychotic symptoms among presented case-reports

*Authors propose that MDMA could cause long-term neurotoxicity

*24% of the patients had a previously diagnosed psychiatric history and 34% had a family psychiatric history

HQ; n.m.

Level 3

Smith et al. [164]

MDMA-Assisted Psychotherapy for Treatment of Posttraumatic Stress Disorder: A Systematic Review With Meta-Analysis

MDMA

Systematic review and meta-analysis

This meta-analysis included 5 RCTS of MDMA-assisted psychotherapy

*Therapy was generally safe and well tolerated, bruxism, anxiety, jitteriness, headache, and nausea are commonly reported.

*Moderate to high dose of MDMA could expose to panic attacks and anxiety, in particular in a non-controlled psychotherapeutic setting

LQ; no coi

Level 1

Mogar & Aldrich [165]

The use of psychedelic agents with autistic schizophrenic children.

LSD, Psilocybin and UML

Narrative review

Narrative review on 7 studies gathering 91 patients with severe autism resistant to treatments

*80% of patients presented some improvement with LSD

*Doses ranged from 50 to 400 μg. The most effective dose was of 100 μg with improved speech behavior in mute children; increased emotional response to other children and adults; elevation in positive mood, decreases in compulsive ritualistic behavior.

MQ; n.m.

Level 2

Glass [166]

Psychedelic drugs, stress, and the ego. The differential diagnosis of psychosis associated with psychotomimetic drug use

Mescaline and LSD

Narrative review and case series

Narrative review including case series, with the case report of a patients with chronic psychosis associated with 200 LSD trips in a 2-year period

*Clinical entities to distinguish psychotic onset and psychedelic induced lasting symptoms: past personal history, current and past drug use, prepsychotic level of functioning, mode of onset of long-lasting symptoms, nature of external precipitating factors and presenting mental status

*Occasional drug use in patients with schizophrenia may have no significant impact on the patients overall clinical course or response to treatment

LQ; n.m.

Level 3

McCabe [167]

Psychedelic Drug Crises: Toxicity and Therapeutics

All psychedelics

Narrative review

Narrative review of psychedelic mechanisms

*The author propose that obsessive and paranoid personality orientations represent the defensive styles most at risk under the influence of psychedelics.

*The author proposes a typical sequence that occurs during the psychedelic trip: altered perceptions of external and internal physical stimuli; a loosening of psychological defenses, often after an intensification or caricaturization of those defenses, with a resulting release of conflictual unconscious material; and dissolution of rational, logical, and problem-solving functions (“ego”), with an alteration in the perception of time, space, and subject-object dichotomies.

LQ; n.m.

Level 3

Vollenweider et al. [9]

Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action.

Psilocybin

LSD

Review of two clinical trials

Authors describes two experiments in healthy human volunteers, to examine the psychotomimetic effects of psilocybin and its response to antipsychotic.

*D2 antagonist haloperidol attenuated psilocybin-induced depersonalisation, derealisation and euphoria

*Haloperidol had virtually no effect on psilocybin-induced hallucinations (VUS) and even increased anxious ego-dissolution (AIA) in psilocybin subjects,

*Ketanserin, a preferential 5-HT2A receptor antagonist, dose-dependently prevented psilocybin psychosis

MQ; pf

Level 1

Wolf et al. [8]

Could psychedelic drugs have a role in the treatment of schizophrenia? Rationale and strategy for safe implementation

All psychedelics

Narrative review

Narrative review of the potential of psychedelics in the treatment of schizophrenia

*Psychedelics could have a therapeutic potential on reducing primary negative symptoms due to the ability to enhance neural plasticity and its effects on inflammatory processes

HQ; pf, npo

Level 1

Hermle et al. [168] (Article in German)

Hallucinogen-induced psychological disorders

All hallucinogens

Systematic review

Narrative review on Hallucinogen-induced disorders

*The authors reported that adolescent intoxication with psychedelic drugs rarely produced acute psychotic syndromes

M.Q.; n.m.

Level 2

Trope et al. [169]

Psychedelic-assisted group therapy: A systematic review

RCTs settings

Systematic review

Authors discuss psychedelic-assisted individual psychotherapy modalities

*Authors discuss group therapies for “neurotics” that include patients with psychosis. Most studies excluded chronically psychotic patients, however patients with comorbid psychosis were frequently included

*In most studies, the assessment and reporting of adverse events is inconsistent

* No studies reported any cases of prolonged psychosis, suicide, or other serious adverse events directly attributable to psychedelic administration

CL; pf

Level 1

Fiorentini et al. [27]

Substance-Induced Psychoses: An Updated Literature Review

All hallucinogens

Systematic review

Authors present and discus substance-induced psychoses for different hallucinogens

*The propensity to develop psychosis seems to be a function of the severity of use and addiction

* There remains a striking paucity of information on the outcomes, treatments, and best practices of substance-induced psychotic episodes.

LQ; pf

Level 2

McCabe [167]

Psychedelic drug crises: toxicity and therapeutics.

All psychedelics

Narrative review

Authors discuss mechanisms, psychedelic experiences, risks, and potential treatments of adverse effects

*Acute panic reactions and spontaneous recurrent experiences seem to

be more common with psychedelic amphetamines

*Author comment of a specific bad trip due to negative emotions and psychosomatic symptoms, that can last beyond the session

LQ; n.m.

Level 3

Lerner et al. [170]

Flashback and hallucinogen persisting perception disorder: clinical aspects and pharmacological treatment approach.

LSD

Narrative review

Narrative review on the phenomena of HPPD

*Flashback is a usually short-term, non-distressing, spontaneous, recurrent, reversible and benign condition accompanied by a pleasant affect

*HPPD is a generally long-term, distressing, spontaneous, recurrent, pervasive, either slowly reversible or irreversible, non-benign condition accompanied by an unpleasant dysphoric affect.

*Pharmacological agents such as clonidine, perphenazine and clonazepam some efficacy on HPPD

MQ; n.m.

Level 3

Litjens et al. [171]

Hallucinogen persisting perception disorder and the serotonergic system: A comprehensive review including new MDMA-related clinical cases.

MDMA

Narrative review

Narrative review on the phenomena of HPPF with presentation of case-reports

*Authors present 31 HPPD cases that implicated MDMA as a causative agent for HPPD-like symptoms, alongside classical hallucinogens.

*According to authors HPPD symptoms may be a result from a misbalance of inhibitory-excitatory activity in low-level visual processing and GABA-releasing inhibitory interneurons may be involved

HQ; pf

Level 3

Halpern & Pope [172]

Hallucinogen persisting perception disorder: what do we know after 50 years?

LSD

Systematic review

Systematic review on the phenomena of HPPD

*The term ‘flashbacks’ is poorly defined. Most studies provide little information to judge how cases could meet DSM-IV criteria for HPPD

*Information about risk factors for HPPD, possible etiologic mechanisms, and potential treatment modalities must be interpreted with great caution

*HPPD appears to be a genuine but uncommon disorder, sometimes persisting for months or years after hallucinogen use and causing substantial morbidity. It is reported most commonly after illicit LSD use, but less commonly with LSD administered in research or treatment settings, or with use of other types of hallucinogens

CL; npo, pf

Level 2

Orsolini et al. [173]

The “Endless Trip” among the NPS Users: Psychopathology and Psychopharmacology in the Hallucinogen-Persisting Perception Disorder. A Systematic Review

LSD

Systematic review

Authors gathered 45 papers on the HPPD phenomena, and discuss risk factors and treatment options

*Authors distinguish HPPD I (short term) and HPPD II (long-lasting)

*A vast list of psychoactive substances has been identified and linked with the development of this condition

LQ; pf

Level 2

Martinotti et al. [174]

Hallucinogen Persisting Perception Disorder: Etiology, Clinical Features, and Therapeutic Perspectives

LSD

Cannabis

Systematic review

Systematic review on the phenomena of HPPD

*The current prevalence estimates are unknown, but DSM-5 suggests 4.2%

*The condition is more often diagnosed in individuals with a history of previous psychological issues or substance misuse and can occur even after a single use of LSD or other psychedelics

*Controlled clinical investigations are mostly needed in order to better understand the etiology, mechanisms of action, clinical issues, and pharmacological treatment

CL; no coi

Level 2

Murrie et al. [20]

Transition of Substance-Induced, Brief, and Atypical Psychoses to Schizophrenia: A Systematic Review and Meta-analysis

Multiple substances

Systematic review and meta-analysis

Systematic review on the risk of substance-induced psychosis. Authors included 3 studies (n = 208) for hallucinogens.

*Authors propose a transition rate of ‘hallucinogens-induced psychosis’ of 26% (95%CI 14-43)(p = 0.0211; I² = 74)

*The rate of transition to schizophrenia was higher following cannabis-induced psychosis (34%) than other substance-induced psychoses, including those associated with amphetamines (22%) and hallucinogens (26%).

*Of importance, one study concerned phencyclidine

HQ; no coi

Level 1

Doyle et al. 2022 [175]

Hallucinogen persisting perceptual disorder: a scoping review covering frequency, risk factors, prevention and treatment

LSD

Scoping review

Scoping review on the phenomena of HPPD

*HPPD appears to be an uncommon, yet serious event associated with prior hallucinogen exposure.

*One theory suggests that cell death of cortical GABAergic inhibitory

neurons expressing serotonergic 5HT2A receptors, induced by

toxicity related to the actions of LSD as well as other hallucinogens on these receptors, leads to disinhibition of the visual system at the cortical level, resulting in the onset of HPPD symptoms

CR; pf, pi

Level 2