Mi Pvs SCH Oz Phrenia 2019

REVIEW
published: 10 October 2018

doi: 10.3389/fpsyt.2018.00491
A Comparison of
Methamphetamine-Induced
Psychosis and Schizophrenia: A
Review of Positive, Negative, and
Cognitive Symptomatology
Travis A. Wearne 1,2 and Jennifer L. Cornish 1*
1
Department of Psychology, Macquarie University, Sydney, NSW, Australia, 2 School of Psychology, University of New South
Wales, Sydney, NSW, Australia
Methamphetamine is a potent psychostimulant that can induce psychosis among

recreational and chronic users, with some users developing a persistent psychotic
syndrome that shows similarities to schizophrenia. This review provides a comprehensive
critique of research that has directly compared schizophrenia with acute and
chronic METH psychosis, with particular focus on psychiatric and neurocognitive
Edited by: symptomatology. We conclude that while there is considerable overlap in the behavioral
Julia M. Lappin, and cognitive symptoms between METH psychosis and schizophrenia, there appears
University of New South Wales,
Australia
to be some evidence that suggests there are divergent aspects to each condition,
Reviewed by:
particularly with acute METH psychosis. Schizophrenia appears to be associated with
Domenico De Berardis, pronounced thought disorder, negative symptoms more generally and cognitive deficits
Azienda Usl Teramo, Italy mediated by the parietal cortex, such as difficulties with selective visual attention, while
Fleur Margaret Howells,
University of Cape Town, South Africa visual and tactile hallucinations appear to be more prevalent in acute METH-induced
*Correspondence: psychosis. As such, acute METH psychosis may represent a distinct psychotic disorder
Jennifer L. Cornish to schizophrenia and could be clinically distinguished from a primary psychotic disorder
jennifer.cornish@mq.edu.au
based on the aforementioned behavioral and cognitive sequelae. Preliminary evidence,
Specialty section: on the other hand, suggests that chronic METH psychosis may be clinically similar to
This article was submitted to that of primary psychotic disorders, particularly with respect to positive and cognitive
Addictive Disorders,
symptomatology, although negative symptoms appear to be more pronounced in
a section of the journal
Frontiers in Psychiatry schizophrenia. Limitations of the literature and avenues for future research are also
Received: 28 June 2018 discussed.
Accepted: 19 September 2018
Keywords: methamphetamine, psychosis, schizophrenia, positive symptoms, negative symptoms, cognition
Published: 10 October 2018
Citation:
Wearne TA and Cornish JL (2018) A METHAMPHETAMINE
Comparison of
Methamphetamine-Induced
Amphetamines refer to a class of chemically related compounds that have been used extensively
Psychosis and Schizophrenia: A
Review of Positive, Negative, and
over the last century in both recreational and medicinal settings, with various amphetamine
Cognitive Symptomatology. analogs used in the treatment of narcolepsy, attention deficit hyperactivity disorder (ADHD) and
Front. Psychiatry 9:491. obesity (1, 2). Methamphetamine (METH; N-methyl-alpha-methylphenethylamine) is a highly
doi: 10.3389/fpsyt.2018.00491 potent amphetamine derivative that is frequently abused worldwide and has significant effects
Frontiers in Psychiatry | www.frontiersin.org 1 October 2018 | Volume 9 | Article 491

Wearne and Cornish Methamphetamine Psychosis With Schizophrenia Comparison
on physical, behavioral, cognitive and psychiatric output (3). visual hallucinations, persecutory delusions, ideas of reference,
It is a cationic molecule and chiral compound based around and disorganized speech (31–33). The idea that METH use
a phenylethylamine core (4), and distinguishable from its could induce a psychotic state has long been recognized by
amphetamine analogs by an additional methyl group. This clinicians in Japan, who increasingly observed psychosis in their
methyl addition reportedly makes METH highly lipophilic, METH-dependent patients (34). The early identification of this
thereby allowing it to increasingly penetrate the blood-brain relationship was due, in part, to the high prevalence of METH
barrier (5). This causes changes to dopaminergic, serotonergic, use together with the absence of polydrug use, thereby enabling
and noradrenergic systems via the stimulated release of clinicians to isolate the link between METH and psychosis
monoamines, the inhibition and reversal of monoamine without the confound of additional substance use (35).
reuptake, inactivation of presynaptic vesicular monoamine Research has shown that METH psychosis is a prevalent
transporter 2, and by reducing the efficacy of monoamine health concern among recreational users. Studies on prevalence
metabolic enzymes (6–10). Although all three monoamine rates have varied between 7% (32) up to 76% (36), with a
systems are involved, the behavioral and reinforcing properties recent meta-analysis indicating that the prevalence of METH-
of METH have typically been associated with dopaminergic induced psychotic disorder was 36.5% (37) and these rates
neurotransmission, particularly in the mesocorticolimbic were higher for lifetime prevalence (42.7%) and for those with
pathway (11, 12). METH use disorder (43.3%). In an Australian study of non-
Epidemiological studies place amphetamine-type stimulants treatment seeking METH users, 13% of the sample population
as the most widely used illicit drug in the world after cannabis were positive for psychosis at the time of assessment (32) while
(13, 14), with up to 51 million users globally between 15 and 64 23% reported ‘clinically significant’ symptoms of psychosis over
years old (15–17). Worldwide statistics on METH use describe the previous year. Another study found that 60% of METH-
it as a global phenomenon, with METH consumption reportedly dependent individuals sampled in the USA reported at least one
independent of wealth, geographical location, and culture (18). type of psychotic symptom (38). Overall, recreational METH
Recent reports suggest an increased production of METH around users are two to three times more likely to experience psychotic
the world and an increasing popularity of METH over the last symptoms than the general population (39), with their risk
5–15 years, which has been linked to increased ease and cost- increasing if they began using METH at a younger age or if
effective synthesis in clandestine laboratories and augmented large amounts of METH are administered (40). Regular METH
importation of METH from Mexico and Asia (16, 19). Indeed, users, on the other hand, are 11 times more likely to experience
worldwide seizures relating to METH have been greater than any psychosis than the general population (41), with the average
other drug category (17). Additionally, admissions to treatment time between first use and onset of psychosis being 1.7 years
programs for METH use increased 255% from 1997 to 2007 in (42). Furthermore, users of crystallized METH are more likely to
the USA (20, 21), although there is some evidence that the rate report psychotic symptoms compared to other forms of METH
of admissions for METH in the USA have remained stable or (43), suggesting that the type and route of administration may
slightly declined from 2004 to 2014 (22). In Australia, there has be important factors in determining the likelihood of psychotic
been a 233% increase in demand for METH related treatment symptoms.
and a 274% increase in METH related hospital admissions since Users are more susceptible to the psychotic effects of METH
2010 (23, 24), with Queensland specifically witnessing a 20-fold whilst they are using the drug. McKetin et al. (15) found that
increase in METH related hospital admissions from 2009 to chronic METH users were 5 times more likely to experience
2015 (25). psychotic symptoms during periods of METH use than during
METH is available in various forms and at different levels periods of abstinence. They also found a dose-response effect
of chemical purity. When injected, snorted, or inhaled, METH between the frequency of METH use and psychotic symptoms,
has direct access to the circulatory system and therefore has with psychosis reaching a peak likelihood of 48% following 16
more immediate effects on the brain (26, 27). Given that the days or more of chronic use. Importantly, these findings were
negative consequences of METH are associated with the use still significant after controlling for polydrug use, suggesting that
of more potent forms of the drug and with hazardous routes the psychotic symptoms were attributable to the effects of METH
of administration (i.e., injection), the increased availability of and not due to the interaction of additional drug consumption.
crystalline METH on the illegal market had resulted in a Overall, these findings suggest that METH use is associated with
significant increase in METH’s popularity amongst dependent a high prevalence of psychotic symptoms, which may present
and intravenous drug-taking populations (28). Indeed, while 22% a significant burden on the healthcare system due to increased
of METH users reported that crystallized METH was their drug demand for care and management of METH-related psychoses.
of choice in 2010 (29), this had increased to 50% by 2013 (30). Indeed, METH psychosis accounted for 10% of admissions to
These trends are salient given the potential for addiction and psychiatric facilities in Thailand (44), and in Australia, METH
overdose with more potent forms of METH administration. psychosis was responsible for 10.3 hospital admissions per
1,000 (45). More recent data has also suggested an increase
ACUTE METHAMPHETAMINE PSYCHOSIS in METH psychosis admissions to hospital emergency rooms
and psychiatric facilities over recent years. For example, the
Dependency to METH, together with high doses and number of admissions to psychiatric units for METH psychosis
recreational METH use, have all been associated with the in Queensland has increased significantly from 2012 (25) while in
induction of psychotic symptoms, including auditory and New South Wales, Australia, the number of hospital admissions

for METH psychosis declined in the mid-2000s but have steadily diagnosed with schizophrenia, there are particular symptoms
increased again since 2010 (46). These findings also appear to be that aid in differential diagnosis. “Positive symptoms” refer to
independent of geographical location, with increased emergency symptoms that are usually not present but are experienced by
department admissions for METH psychosis reported in the those with schizophrenia, and include distortions in perceptions
Americas (47) and the middle east (48). (hallucinations), false beliefs or distorted thought content
(delusions), unclear or confused thinking (thought disorder),
and disorganized speech. These symptoms are generally
CHRONIC METHAMPHETAMINE interpreted as a loss of touch with reality and are present at
PSYCHOSIS discrete times during “psychotic episodes,” which are considered
a core feature of the disorder (61). While these symptoms can also
METH psychosis typically follows a transient course, with be present during remission, medication serves to suppress the
symptoms subsiding once the user has stopped taking the drug severity and chronicity of these symptoms. “Negative symptoms,”
(3). Some consumers, however, can experience a prolonged on the other hand, refer to symptoms or experiences that are
psychosis that persists even after the drug has cleared from usually absent or diminished in individuals with schizophrenia.
the body, with the majority of psychotic symptoms resolving These include social withdrawal, anhedonia, flattened affect,
within 1 month (34, 49). Some research has further indicated motor retardation, and poverty of speech (62, 63). Negative
that METH psychosis can develop into an enduring form of symptoms have a significant bearing on functional engagement
psychosis. Reports have suggested that up to 30% of those with and independence, with negative symptoms shown to predict the
METH psychosis may have symptoms that continue up to 6 status of future functioning, employment, independence, and
months following abstinence (49), with specific studies reporting social contact (64).
15–28% of patients admitted to hospital with METH psychosis While both positive and negative symptoms are established
needing hospitalization for more than 2–3 months following as core symptom dimensions and criteria for schizophrenia
admission (50, 51). Additionally, others have reported that 10– diagnosis in the DSM-5 (65), a third core domain reported is
28% of patients with METH psychosis continued to display cognitive dysfunction. A wide range of cognitive domains appear
psychosis for more than 6 months (35, 50), while in another to be compromised in schizophrenia, with many reviews and
study, 28% of METH-users continued to display “schizophrenia- meta-analyses concluding moderate to severe deficits in general
like symptoms” 8–12 years following abstinence (52). Outside of intelligence, attention, working memory, verbal learning and
Japan, McKetin et al. (15) reported that even abstinent METH memory, speed of information processing, visuospatial deficits,
users had a 7% risk of experiencing psychotic symptoms and and executive dysfunction (66–71). The cognitive deficits in
another group found that 5% of abstinent METH-dependent schizophrenia are stable across the course of the disorder (72–
users met criteria for a psychotic disorder at 3 years follow-up 75) and are consistent between those with first episode psychosis
(53). Furthermore, METH can induce a chronic psychosis in and chronic schizophrenia (76–78). However, there is some
those with no premorbid psychiatric risk factors (54), suggesting evidence that those with earlier onset schizophrenia may have
that METH use can induce persistent physiological changes a decline in cognitive function throughout the progression of
consistent with psychosis that are independent to genetic and the illness (79). Furthermore, antipsychotic medication appears
personality predispositions. It is recommended that readers to have minimal positive impact, if at all, on the cognitive
examine many of the comprehensive review articles available difficulties associated with schizophrenia (80). Executive function
for further information on the clinical profiles, correlates, and appears to be the most compromised and conserved cognitive
recovery of METH-induced psychosis (55–60). Overall, METH deficit across patients with schizophrenia (81, 82), with executive
psychosis can result in a persistent psychotic syndrome that is deficits shown to be the most pervasive amongst older adults
resistant to spontaneous recovery, and in light of the high use of with schizophrenia (83) and negatively impacted by number of
METH use globally, chronic METH psychosis will undoubtedly psychotic episodes (84). Additionally, the fact that the cognitive
continue to be an issue for health-care professionals. As such, issues in schizophrenia are deleterious to social functioning,
understanding the factors that subserve the neurobiology and functional outcomes (85, 86), independence (87, 88), recovery
maintenance of chronic psychosis induced by METH abuse will (89), and well-being (90) has prompted the argument that
be important for delineating diagnostic markers and avenues for cognitive dysfunction should be regarded as one of the core
treatment. dimensions in the disease, particularly with respect to DSM-5
diagnostic criteria (61).
SCHIZOPHRENIA
Schizophrenia is a severe, complex and debilitating THE RELATIONSHIP BETWEEN
neuropsychiatric disorder that is traditionally associated with METH-INDUCED PSYCHOSIS AND
poor treatment outcomes relative to other psychiatric disorders. SCHIZOPHRENIA
It is a significantly heterogeneous disorder, with symptoms
so diverse and idiosyncratic from patient to patient that the While a subset of METH users can experience an enduring
clinical profile has to be “clustered” into different domains. form of psychosis, there is uncertainty of the diagnostic
While there is no symptom that is sufficient for a person to be status of chronic METH psychosis as a primary psychotic

disorder. That is, METH-induced and other substance-induced syndrome. More recently, however, there has been discussion
psychoses are clearly distinguished from schizophrenia and other surrounding the possibility that METH use could actually
primary psychoses in the Diagnostic and Statistical Manual. In cause the onset of schizophrenia (54, 94, 99), potentially by
fact, any psychosis during the withdrawal from a substance inducing schizophrenia pathology. Even though this does not
requires the diagnosis of “substance-induced psychotic disorder” explain why only a percentage of users develop a persistent
according to the Diagnostic and Statistical Manual (65) and psychotic syndrome, both explanations suggest that METH
the International Classification of Diseases, Tenth Revision psychosis and schizophrenia may be the same disorder on
(ICD-10). Diagnostic guidelines, however, become ambiguous a continuum of pathology, converging with the idea that
should the psychosis persist for an extended period of time. schizophrenia is a neurobiological disorder with multiple
The DSM-5 outlines that any psychosis that persist longer etiologies.
than 6 months should warrant the diagnosis of a primary Alternative explanations for METH-induced psychosis may
psychotic illness (65). Indeed, a Thai study of METH abusers, be possible. As such, it could be that METH psychosis
who were initially hospitalized for METH psychosis found that and schizophrenia represent distinct disorders, and indeed,
38.8% had been diagnosed with schizophrenia due to persistent several researchers have proposed that METH use in isolation
psychosis at 5 years follow up (91), and 5.0% of Chinese can produce a persistent psychotic syndrome that should be
patients with METH-induced psychosis had their diagnosis diagnosed and treated as a distinct syndrome to schizophrenia
changed to schizophrenia (49). Longitudinal analyses have (100, 101). Therefore, given that any persistent psychosis
also found that 19.1% (92) to 30% (93) of patients initially beyond a 6-month period should be considered as a primary
admitted for amphetamine-induced psychosis had transitioned psychotic disorder, based on the current diagnostic criteria in
to a schizophrenia diagnosis at follow-up. Furthermore, a the DSM-5, METH psychosis may be routinely misdiagnosed
large study conducted over a 10 year period in the USA and treated as schizophrenia. Therefore, the diagnosis of
determined that individuals who were hospitalized for METH- schizophrenia secondary to METH use described in the
related causes had a higher risk of receiving a subsequent aforementioned studies may merely reflect adherence to
schizophrenia diagnosis (94). Therefore, while the potential for diagnostic protocol and may not be a true reflection of the
METH to induce an acute psychosis is well recognized, the status and prevalence of chronic METH psychosis in the
development of an enduring-form of psychotic disorder, and general population. That is, individuals who present with METH
its potential to transition into a primary psychotic disorder, psychosis may be diagnosed with schizophrenia, which may
such as schizophrenia, is not as well understood. As these therefore underestimate the degree to which METH use results
studies propose that stimulant-induced psychoses represents in a persistent psychotic disorder in epidemiological research
a significant precursor to the development of more enduring studies.
forms of psychotic disorders, these findings should guide the Overall, there appears to be uncertainty about whether
management, early intervention and policy related to METH- METH use causes schizophrenia or whether chronic METH
related psychoses to circumvent the progression of these psychosis represents a symptomatically distinct disorder that
conditions. should be distinguished from other primary psychoses. While
While the above findings support that METH use is there appears to be similarity between the two conditions,
associated with an enduring psychosis, there are several there is limited research that has explicitly compared the
interpretations of the link between METH use and schizophrenia. behavioral and cognitive markers between the disorders. To
Firstly, METH could induce schizophrenia by eliciting an understand the similarities and distinguishing features of METH
underlying vulnerability/predisposition to a primary psychotic psychosis and schizophrenia is of benefit. Not only will this
disorder. Early research on amphetamine psychosis attributed assist in determining the diagnostic entity of METH psychosis,
the continuation of psychotic symptoms to “latent paranoia” but will also help develop differential diagnostic markers
(95). Additionally, a growing body of literature has examined for clinicians, better treatment options for long-term METH
the role of genetic and environmental interactions in the psychosis suffers, and will help to delineate common biological
development of METH psychosis, with some studies showing markers across syndromes that may initiate and maintain a
convergence of genetic risk factors for METH psychosis with persistent vulnerability to psychosis. This will enable a deeper
those for schizophrenia (58, 96). Additionally, one study found theoretical understanding of the specific biological factors that
a significant enrichment of singe nucleotide polymorphisms subserve the symptoms that are commonly observed across
(SNPs) for METH psychosis risk in patients with schizophrenia psychotic disorders.
(97) while another found that a family history of schizophrenia
was a risk factor for the development of METH psychosis
(40, 42, 98). These findings suggest that the development of a OVERVIEW OF REVIEW
persistent psychotic syndrome, such as schizophrenia, may be
the complex interaction between a predetermined vulnerability Aims
and/or the direct effects of METH as an environmental The current review will describe and critique the literature
trigger (i.e., the two hit hypothesis), and may provide an that has compared the clinical profile of schizophrenia with (i)
explanation as to why only a small percentage of those with acute METH psychosis and (ii) chronic METH psychosis, with
METH psychosis go on to develop a persistent psychotic particular focus on positive, negative and cognitive symptoms.

While several reviews have examined the clinical profiles, risk schizophrenia can be found in Table 1. The methodological
factors, and correlates of METH-psychosis (55, 59, 60) and considerations of this research are detailed in Table 2.
cognitive deficits associated with METH use (102–104), the aim
of this study was to provide a comprehensive overview of research
that has directly compared METH psychosis (acute and chronic) Acute Meth Psychosis vs. Schizophrenia
with schizophrenia. Furthermore, while (55) have reviewed Early findings on METH induced psychosis reported
the relationship between METH psychosis and schizophrenia, hallucinations and delusions as a predominant presenting
we wished to extend this review by differentiating between factor (34, 118), with later findings acknowledging that the
acute and persistent forms of METH psychosis. If the use similarities between METH psychosis and schizophrenia
of METH does cause a primary psychotic disorder, then the were largely directed toward positive symptoms. McKetin
presentation and symptoms of chronic METH psychosis should et al. (32) found that unusual thoughts, hallucinations
match those typically reported in schizophrenia. Consequently, and suspiciousness were present in one-quarter of chronic
persistent METH psychosis could be regarded as the same consumers of METH diagnosed with acute METH psychosis.
diagnostic entity and could allude to similar neurobiology and Indeed, Bousman et al. (119) examined the variation
etiological mechanisms. However, if METH psychosis represents in positive symptoms across individuals with METH
a biologically and clinically distinct disorder there should be psychosis. While they found three distinct sub-profiles,
divergence in the behavioral, cognitive and biological markers delusions were common amongst all individuals with
between METH psychosis and schizophrenia. METH-induced psychosis. Additional studies have also
reported that METH psychosis is associated with a high
Inclusion Criteria prevalence of persecutory delusions, auditory and visual
Prior to conducting the literature search, inclusion criteria were hallucinations, odd speech, and delusions of reference
formulated from the aims, not only to determine which studies (15, 40, 60, 113, 119–122).
would be suitable but to provide a unique perspective to the Of studies that have directly compared acute METH
review and to also minimize the occurrence of methodological psychosis with schizophrenia (Table 1), researchers have found
flaws. These included: (1) studies had to based on people, no difference in the type and severity of positive symptoms
aged 16 years and older; (2) the current review focused using the Positive and Negative Syndrome Scale (PANSS)
specifically on research relating to methamphetamine (rather (110, 117) or the Brief Psychiatric Rating Scale (BPRS) (111).
than amphetamine or other psychostimulants); (3) studies had There is also research demonstrating that the longitudinal
examined profiles associated with METH psychosis (i.e., no changes of positive symptoms between METH psychosis and
studies looking at the cognitive effects of METH without schizophrenia are similar. For example, Hajebi et al. (117)
psychosis); (3) studies had to have directly compared METH conducted a prospective study on individuals with METH-
psychosis with schizophrenia or primary psychotic disorder (4) induced psychosis and found that there was no significant
METH usage had to precede the presentation of psychosis in difference in the severity of positive symptoms (using the
order to focus on METH-induced psychotic syndromes; (5) PANSS) between acute METH psychosis and non-affective
only original research studies were included (i.e., reviews were psychosis (e.g., schizophrenia) groups on admission, at discharge,
omitted); (6) Case studies were omitted [for a review and and at 6 and 12-month follow-up. These findings suggest
examination of historical case studies of METH psychosis, please that the progression of positive symptoms following METH
see (59)]. psychosis is comparable to that of schizophrenia. However,
given that those with METH-induced psychosis continued to
Search Approach experience symptoms of psychosis following discharge, it is
To identify potential studies for inclusion in this review, uncertain whether this group represents acute or chronic METH
the computerized databases of PubMed, PsychINFO and psychosis. Furthermore, it should be considered that the non-
ScienceDirect were searched. Additionally, reference lists from affective psychosis group was a heterogeneous sample, consisting
retrieved articles were screened to identify omitted articles of participants diagnosed with schizophrenia, schizoaffective
from the database search. Lastly, a Google Scholar search disorder and brief psychotic disorder. Collectively, these findings
was conducted to ensure that no main article escaped suggest that the positive symptoms of acute METH-induced
detection in the literature search. The following search terms psychosis are qualitatively and quantitatively comparable to the
were used to identify potential articles: (methamphetamine positive symptoms of schizophrenia, with the initial presentation
psychosis OR methamphetamine-induced psychosis) AND of acute METH psychosis indistinguishable from schizophrenia-
(schizophrenia OR primary psychotic disorder) AND (negative related psychosis (113).
symptoms OR positive symptoms OR psychiatric symptoms OR Despite the considerable overlap in positive symptoms
cognition). between acute METH psychosis and schizophrenia, there
are several differences across both conditions. For example,
POSITIVE SYMPTOMS Srisurapanont et al. (113) found that while there were no
difference in the type and severity of positive symptoms between
An overview of the design and findings of individual research METH psychosis and schizophrenia, the METH psychosis
studies that have directly compared METH psychosis with group tended to have more severe hallucinations and delusions

TABLE 1 | Summary of experimental studies that have compared METH psychosis with schizophrenia.
Study Design n Sample characteristics Groups Psychosis type Measures used Findings
(105) Cross sectional, 252 Sample consisted of 160 5 groups: Control group (n Both Diagnostic Interview for Genetic BPRS Total: Schiz = Persistent MAP,
case-control study METH users and 54 patients = 67), METH users (n = 25), Studies (Chinese Version; Both Schiz and Persistent MAP >
Wearne and Cornish
with schizophrenia. They Acute MAP (n = 50), DIGS-C, BPRS and BACS Acute MAP. BPRS Positive
were recruited from various Persistent MAP (n = 56) Symptoms: Schiz = Persistent MAP,
detention centers, hospitals, and Schizophrenia (n = 54). Both Schiz and Persistent MAP >
psychiatric facilities and in- Acute MAP.BPRS Negative
and outpatient clinics in Symptoms: Schiz > Persistent MAP
Taiwan. The control group > Acute MAP. BACS: Schiz =
were recruited from Persistent MAP across all cognitive
Frontiers in Psychiatry | www.frontiersin.org

community volunteers. measures. Schiz +Persistent MAP <
Acute MAP +METH users across all
cognitive measures. No differences
between Acute MAP, METH users
and Controls across all cognitive
measures.
(106) Cross sectional 90 Clinical participants were 3 groups: MAP (n = 30), Acute MAP Wisconsin Card Sorting Test MAP + Schizophrenia < Controls on
study between recruited from the schizophrenia (n = 30) and (WCST), Stroop Test, Visual WCST, Stroop, VSAT and WMS. No
MAP and Schiz emergency ward of the Iran healthy controls (n = 30) Search and Attention Test (VSAT) sig differences between MAP And
Psychiatric Hospital and and Wechsler Memory Scale Schizophrenia for WCST, Stroop and
enrolled into the study after (WMS) WMS. Schiz performed worse than
stabilization. Diagnoses MAP on VSAT.
were obtained from patient
6
files.
(107) Cross-sectional 198 Current METH users (61% Psychotic (51%) and Acute MAP BPRS No sig differences between
study as part of male). Average age of 31.65 non-psychotic disorder substance-induced psychosis and
12-month years. METH was primary groups (49%). Psychotic primary psychotic disorder on total
prospective study. drug of choice. Recruited disorder separated into BPRS scores, positive symptoms,
via needle syringe programs lifetime (39%) and current negative symptoms, mania, and
in Australia diagnoses (61%) and depression-anxiety.
subdivided into those with
substance-induced and
those with primary
psychotic disorders
(108) Cross sectional 39 Chart review was used to MAP (n=19) and paranoid Likely acute MAP, Wechsler Abbreviated Scale of No significant differences were
study between select participants for the schizophrenia (n = 20) although Intelligence (WASI), Repeatable observed between groups on any
MAP and Schiz study. Schizophrenia abstinence or time Battery for the Assessment of cognitive domain examined.
diagnosis was confirmed by since admission Neuropsychological Status
hospital records. was not reported (RBANS), Delis Kaplan Executive
Functioning System (DKEFS)
Color-word Interference Test,
Continuous Performance Test of
Attention, Grooved Pebgoard,
Wide Reading Achievement Test
(WRAT) reading subtest and
Trailmaking Tests (TMT)
(Continued)
October 2018 | Volume 9 | Article 491

Methamphetamine Psychosis With Schizophrenia Comparison
TABLE 1 | Continued
(109) Cross-sectional 284 Derived from a later study, 4 groups: METH users (n = Both BPRS and CIDI Transient MAP > Control group on
Wearne and Cornish
study as part of the Methamphetamine 110), Acute MAP (n = 85), lifetime persecutory delusions and
larger longitudinal Treatment Evaluation Study Persistent MAP (n = 37), tactile hallucinations. Persistent MAP
study (MATES). Participants had a Primary Psychosis (n = 52) > Transient MAP on lifetime delusions
mean age of 31.6 years and of reference, thought interference,
71% male. complex auditory hallucinations and
hallucinations in various modalities
(visual, olfactory and tactile). Primary

psychosis > Transient MAP on
delusions of reference, thought
projection, erotomania, passivity, and
auditory, olfactory and tactile
hallucinations. No sig difference
between persistent MAP and primary
psychoses on any positive symptom.
(110) Cross-sectional 285 Participants were admitted METH negative diagnosed Acute MAP Urine and/or blood analysis to No sig difference between MAP and
study between to two psychiatric wards in with schizophrenia (n = 33) confirm the presence of METH. Schizophrenia on any positive
MAP and Schiz public hospitals in Norway. vs. METH positive with PANSS symptom
52% were men and average psychosis (n = 9)
age was approximately
38-39 years.
7
(111) Experimental 56 Participants were recruited 3 groups: MAP (n = 21), Acute MAP GAF, PANSS,JART, Stop-signal No sig difference between MAP and
study between from the University of Tokyo schizophrenia (n= 14) and Task and NIRS Schizophrenia groups on the Positive
MAP and Hospital and Tokyo healthy controls (n = 21) and Negative subscales of the
schizophrenia Metropolitan Matsuzawa PANSS. Using the PANS 5-factor
Hospital. model, MAP group had higher
Excitement scores compared to
schiz. Trend (p = 0.052) for Schiz to
have lowest percent correct on
stop-signal task compared to MAP
and controls. Both MAP and Schiz
showed reduced activation in the
ventrolateral prefrontal cortex
compared to controls. MAP had
reduced activation in the frontopolar
prefrontal cortex compared to
schizophrenia
(Continued)

TABLE 1 | Continued
Wearne and Cornish
(112) Cross sectional 102 Data was collected from MAP (n = 33) and Acute METH SCID-I-RV (Structured Clinical Thought broadcasting was more
study between two larger cross-sectional schizophrenia (n = 69) Psychosis Interview for DSM-IV) prevalent in Schizophrenia (42%) than
MAP and Schiz studies. Data was collected in MAP (24%) and significantly
from patients presents with predicted the diagnosis of
psychotic disorders schizophrenia once controlling for
admitted to a psychiatric age. Auditory hallucinations (voices
facility in Cape Town. heard conversing) were significantly

higher in MAP (48.5%) than in
schizophrenia (20.3%). No difference
in the severity and prevalence of any
other first-rank symptoms between
MAP and Schiz.
(113) Cross-sectional 61 Data for both groups was MAP group (n =168) and Acute MAP Mini-International No significant differences between
study on taken from the WHO-MAIP schizophrenia (n = 169) neuropsychiatric Interview- Plus MAP and schiz on the severity of
retrospective data and RLAI-Thai studies. The (MINI-P), Manchester Scale negative symptoms. MAP group had
MAP group had used METH higher positive symptoms scores of
for and average of 3.8 (5.4) delusions, hallucinations and
years. incoherent speech. Differential item
functioning analysis further showed
that MAP and Schiz were able to be
8
differentiated based on incoherent
speech alone. The positive and
negative symptom profiles of MAP
and Schiz were the same.
(114) Cross sectional 22 Chronic MAP group had MAP group (n = 11) and Chronic MAP Scale for the Assessment of Qualitatively, the positive symptom
study between used moderate and/or high paranoid schizophrenia (n = Negative Symptoms (SANS). profile was similar between both MAP
MAP and Schiz doses of MAP intravenously 11) Medical records were examined and Schiz. Overall negative
for an extended period of for positive symptom profiles on symptoms were milder in MAP
time. The MAP group were admission. compared to Schiz. Affective
recruited from inpatient and flattening or blunting and alogia were
outpatient settings in Japan. less severe in the MAP group
The Schiz group were compared to Schiz.
matched to the MAP group
and recruited from the same
hospital
(Continued)

TABLE 1 | Continued
(115) Cross sectional 106 Sample consisted of METH MAP (n = 53) and Chronic MAP BPRS, PANSS and structure No difference in the patterns of
Wearne and Cornish
and case-control users with psychosis and schizophrenia (n = 53) interview questions in the delusions experienced between MAP
study between patients with schizophrenia. DIGS-C and Schiz. Auditory hallucinations
MAP and Schiz They were recruited from were comparable between both MAP
various general hospitals, and Schizophrenia. Visual and Tactile
psychiatric facilities and in- hallucinations were more prevalent in
and outpatient clinics in MAP compared to schizophrenia.
Taiwan. Unusual thought content, blunted

affect, emotional withdrawal and
motor retardation were more
prevalent in Schiz than persistent
MAP. Schiz was associated with
greater negative symptoms overall
than MAP
(116) Experimental 34 Recruited through in- and MAP (n = 15) and Chronic MAP Japanese version of the National No differences between groups on
study between outpatient clinics in Japan. Schizophrenia (n = 19) Adult Reading Test (JART), PANNS total score, positive
MAP and PANNS, Brief Assessment of symptoms and negative symptoms.
schizophrenia Cognition in Schizophrenia No differences between groups on
(BACS), verbal fluency task, tasks of verbal memory, working
NIRS measurements memory, motor speed, verbal fluency,
attention and processing speed,
executive functioning, and total
9
cognition score. Oxyhaemoglobin
changes in the prefrontal cortex were
higher in MAP compared to
schizophrenia, particularly in the right
dorsolateral prefrontal cortex

TABLE 2 | Methodological assessment of studies that have compared METH psychosis with schizophrenia.
Study Methodological considerations
Schizophrenia Healthy control Differentiate METH psychosis Abstinent at time of Other factors controlled Other considerations?
Wearne and Cornish
comparison group? between acute and characteristics assessment? for?

group? chronic psychosis?
(105) Yes Yes Yes Acute group was defined as Yes Those in the METH groups Those in the acute METH psychosis
METH users with brief psychotic could not have a history of were assessed approximately 9
symptoms that disappeared 1 psychosis prior to drug use weeks after experiencing their METH
month after ending METH. and the psychosis had to be psychosis so could not be assessing

Those who continued to clearly linked to drug use. their psychotic symptoms and
experience psychosis 1 month Schizophrenia participants cognitive functioning in the immediate
after abstinence from METH could not have a history of time following their episodes. The
were categorized as METH users drug or alcohol use control group was also not perfectly
with persistent psychosis. disorders. matched to the METH users.
Neuroleptic medication also differed
between groups
(106) Yes Yes No MAP group were recruited from Not stated, although Matched on age, gender 66% of MAP group had history of
emergency room so recruited via emergency and education. Those in other drug use. Those in the MAP and
experiencing psychosis at the room so likely to have been Schiz group had no history Schiz group were taking neuroleptic
time. Could represent those with active METH users at time of METH use. medication. Small sample sizes
acute MAP. of enrolment.
(117) Yes (NFP group) No No Psychotic symptoms followed Not stated. Unsure if sample No differences in age, NFP group was a heterogeneous
10
recent METH use or cessation of was abstinent after gender or education. group consisting of a group of
prolonged and heavy METH use discharge too. Polydrug use not schizophrenia (n = 46),
addressed. schizoaffective disorder (n = 1) and
brief psychotic disorder (n = 3). 9
patients in the NFP had a history of
METH use.
(107) Yes No No. Differentiates between lifetime Yes No sig differences between Primary psychotic disorder group
and current psychotic disorder groups on any demographic were also METH users and may not
but not acute and chronic METH variable examined. No represent pure schizophrenia.
psychosis differences between groups
on polydrug use
(108) Yes No No Had to meet diagnostic criteria Not stated METH use had to precede Differences were found between
for METH dependence the onset of psychosis for groups in age, ethnicity and place of
concurrently with psychotic the MAP group. No birth. Small sample sizes.
disorder and the dependence differences were found in
had to precede the psychosis. sex, education, legal status,
and medication.
(Continued)

TABLE 2 | Continued
Study Methodological considerations
Wearne and Cornish
(109) Yes No Yes Acute METH defined as Not stated Details lifetime positive symptoms
participants who experience rather than positive symptoms at the
psychosis symptoms when using time of the assessment. Primary
METH for at least 1 months but psychotic disorder group were also
no during months when METH users and may not represent

abstinent. Persistent MAP was pure schizophrenia.
defined as experiencing
psychotic symptoms during
METH use and for at least 1
months or longer after
abstinence
(110) Yes No No Had to test positive for METH in 13% had taken Those in the schizophrenia 35 of 38 tested positive for METH and
system to be included in the methamphetamine recently group did not test positive Amphetamine. 87% also had at least
study. according to blood and/or for METH one other psychoactive substance in
urine analysis their urine and/or blood. Polydrug use
may be a confounding factor. Small
sample size of those who are METH
positive with psychosis.
11
(111) Yes Yes No 6 MAP subjects were classified Not stated Groups were matched for IQ > in healthy control group. No
with ’Psychotic disorder due to age and gender. Medication analyses were done to look at the
use of METH’ and the remaining dosage no different distinction between acute and
15 were classified with ’residual between MAP and Schiz. persistent MAP due to small sample
and late-onset psychotic size.
disorder due to use of METH’
(112) Yes No No Symptom onset had to be within No greater than 4 weeks Schiz group had exclusion Thought broadcasting was
1 months of METH intoxication criteria of previous significantly only once the age of the
or withdrawal and could not substance use while MAP samples were controlled.
exceed 4 weeks. were excluded if meeting
dependence criteria for any
substance other than
METH. No difference
between groups on
education and gender
distribution
(Continued)

TABLE 2 | Continued
Study Methodological Considerations
Wearne and Cornish
(113) Yes No No MAP group taken from hospitals Had to have used METH in Not matched for age. The schiz group had all been taking
and had to have used METH in the past week Unsure of drug taking habits neuroleptic medication for months
the previous week. Could of those in the Schiz group and/or years while the MAP group
represent both acute and chronic had only recently comment
MAP individuals. antipsychotic medication. Those in

the schiz group were chosen for the
study as they were not responding
well to medication and may not truely
represent schizophrenia.
(114) Yes No No Chronic psychosis. Subjects had Not stated Matched for age and 64% of sample had a history of drug
to have continued to experience gender. dependency besides METH. Positive
delusions and hallucinations for symptoms were documented
more than 1 month after qualitatively from the medical records
abstinence from the drug. from admission. Small sample size.
(115) Yes No Yes Individuals had to have an Greater than 1 months Those in the METH groups
enduring psychosis for more could not have a history of
than 1 month after cessatin of psychosis prior to drug use
METH and the psychosis had to be
12
clearly linked to drug use.
Schizophrenia participants
could not have a history of
drug or alcohol use
disorders.
(116) Yes No No 8.42 years since onset of Not stated No differences in age, Nearly all subjects were on
psychotic symptoms may gender, medication and neuroleptic medication. Trend for
suggest the sample was more premorbid IQ. schizophrenia group to have longer
chronic MAP than acute. No duration of illness. No indication of
evidence of abstinence so acute or chronic. Small sample size.
assumed they are acute MAP

compared to schizophrenia. Further analysis revealed that psychosis. However, these later findings are based on indirect
incoherent speech, a distinguishing marker of thought disorder, comparisons and not on reliable evidence that has directly
was the only symptom to be differentially expressed between compared METH psychosis with schizophrenia.
schizophrenia and METH psychosis. Thought disorder refers to
disorganized thinking and is characterized by the loosening of
associations and fragmented speech (123), and is suggested to Chronic Meth Psychosis vs. Schizophrenia
be a defining and salient feature in schizophrenia (124–127). Researchers have also examined chronic METH psychosis in
Although related to amphetamine, initial work by Bell (125) relation to schizophrenia. In a small study of 11 patients with
distinguished between schizophrenia and amphetamine-induced chronic METH psychosis who had been abstinent from METH
psychosis with the appearance of thought disorder, as this for more than 1 month (114) qualitatively reported that five
symptom was only seen in schizophrenic cases. Additionally, Yui subjects experienced visual hallucinations, seven experienced
et al. (127) found that while individuals with METH psychosis delusions of reference and persecutory delusions while all
experienced paranoid hallucinations and delusions, the same experienced auditory hallucinations. Additionally, Yamamuro
participants did not exhibit thought disorder or disorganized et al. (116) found similar PANSS results in their experimental
speech. Therefore, the absence of thought disorder may be a study examining oxygenation changes in the prefrontal cortex
discriminating feature associated with METH psychosis that in acute METH psychosis and schizophrenia during a verbal
can be used to differentiate this disorder from schizophrenia. fluency task. Furthermore, Wang et al. (115) examined the
However, the use of this potential discriminating feature this positive symptom profile of 52 individuals with chronic METH
is currently based on indirect and inconclusive evidence, and psychosis (who experienced psychosis and had been abstinent
further research is needed to determine the differentiation of from METH for more than 1 month) and compared this to
thought disorder between METH psychoses and schizophrenia. 53 participants with schizophrenia. They found no difference
Studies that have also differentiated the types of hallucinations in the patterns of delusions experienced between those with
and delusions commonly experienced in METH psychosis and chronic METH psychosis and schizophrenia and that auditory
schizophrenia. Shelly et al. (112), in their examination of first- hallucinations were the most common type of hallucination
rank positive symptoms, found that acute METH psychosis and experienced between groups. However, those with chronic
schizophrenia demonstrated comparable positive symptoms but METH psychosis significantly experienced greater visual and
those with acute METH psychosis showed higher frequency of tactile hallucinations relative to schizophrenia while those with
auditory hallucinations (48.5%) in comparison to schizophrenia schizophrenia endorsed greater conceptual disorganization. This
(20.3%). Conversely, thought broadcasting was more prevalent suggests that thought disorder may be specific to schizophrenia
in the schizophrenia (42%) group compared to METH psychosis and not present in either acute or chronic METH psychoses
(24%), although this was only significant once age was controlled while tactile/visual hallucinations, such as formication, may be
for in their analyses. Regardless, these findings are strengthened more reflective of METH-induced psychoses. These findings are
by the exclusion criteria of polydrug use for the METH psychosis strengthened by the fact that those in the METH psychosis group
group and METH use for the schizophrenia group. Also, could only be included if their psychosis occurred after the use
the individuals in the METH psychosis group were deemed of METH, and those in the schizophrenia group could not have a
eligible if they were abstinent for no greater than 4 weeks, history of drug use disorder, meaning that the diagnosis of each
highlighting that this represented a true acute psychosis sample. psychiatric condition was independent to the effect of several
There is also some evidence that persecutory delusions and confounds.
tactile hallucinations may be specific to acute/transient METH The profiles of acute METH psychosis, persistent METH
psychosis as opposed to the chronic psychosis and schizophrenia psychosis and schizophrenia have also been compared. Chen
(109), and indirect comparisons suggest that visual and tactile et al. (105) examined the positive symptoms experienced by
hallucinations appear to be more prominent in METH psychosis those with acute METH psychosis (experienced psychosis for
compared with schizophrenia (4, 125). Chen et al. (40) reported <1 month following abstinence), persistent METH psychosis
that 46.5 and 21.3% of their METH psychosis sample reported (psychosis presents following abstinence from METH > 1
visual and tactile hallucinations, respectively. Additional findings month) and schizophrenia using the PANNS. Those with
have also confirmed visual hallucinations in 68.8% of METH persistent METH psychosis and schizophrenia demonstrated
abstinent individuals (128) while others have reported that visual comparable severity and frequency of positive symptoms, and
hallucinations are the fourth most reported positive symptom both of these groups had PANNS scores that were significantly
in METH psychosis (120). However, visual hallucinations are higher than those in the acute METH psychosis group. These
typically only reported in severe cases in schizophrenia (129), findings may suggest that those with acute METH psychosis
with the prevalence rate ranging from 16 to 27% (129, may not experience positive symptoms to the same frequency
130). Additionally, formication, a tactile hallucination where and severity as those with schizophrenia and chronic METH
individuals believe that one’s skin has been infested by bugs, psychosis. However, it should be noted that those in the acute
is typically only reported in METH psychosis (131). Therefore, METH group were abstinent for an average of 9 weeks at the
while auditory hallucinations appear to be the most common time of assessment, and therefore, the results may not truly reflect
hallucination of both METH psychosis and schizophrenia, visual the severity of these symptoms experienced at the time of their
and tactile hallucinations appear to be more prominent in METH psychotic episodes.

Recently, McKetin et al. (109) classified 284 METH dependent However, some researchers have shown differences in the
participants as experiencing no current psychotic symptoms, severity of negative symptoms experienced between acute
transient psychotic symptoms when using METH, psychotic METH psychosis and schizophrenia. For example, Hajebi et al.
symptoms during METH use and more than 1 month abstinent (117) found that on admission to hospital, those with non-
(i.e., persistent METH psychosis) or as experiencing primary affective psychosis had more severe negative symptoms than
psychosis (i.e., schizophrenia), and examined the lifetime those with acute METH-psychosis. Furthermore, while the
experience of hallucinations and delusions between groups. severity of negative symptoms had improved for both groups
Relative to acute METH psychosis, it was shown that persistent upon discharge, the non-affective psychosis group continued
METH-induced psychosis was associated with greater lifetime to maintain increased severity of negative symptoms relative
experiences of thought interference and delusions of reference to the acute METH-psychosis group. There is also indirect
while primary psychosis was likely to experience the same evidence that negative symptoms are less severe in acute METH
symptoms in addition to thought projection, erotomania, psychosis compared to schizophrenia. Negative symptoms are
olfactory hallucinations and passivity (relative to acute METH common in schizophrenia, with negative symptoms considered
psychosis). Furthermore, those with persistent METH psychosis a central feature of its phenomenology and diagnostic criteria
and schizophrenia also reported reduced symptoms of visual (133, 134). Indeed, 58% of individuals with schizophrenia
and tactile hallucinations relative to those in the transient experience negative symptoms (135), with 50–90% of those
METH psychosis group. Importantly, the lifetime delusion and with schizophrenia displaying negative symptoms in first-episode
hallucination symptom profiles were not significantly different psychosis (136). On the other hand (132) found that only 25% of
between persistent METH psychosis and primary psychosis, individuals hospitalized with METH psychosis exhibited negative
suggesting that the positive symptoms are comparable between symptoms while (122) similarly found that only 21.4% of their
the two conditions. However, it should be noted that those sample met criteria for negative symptoms in a clinical interview
in the primary psychosis group were also METH dependent, using the MINI-plus. While these lower prevalence rates may
suggesting that the results are not independent to drug effects, be attributable to limited research in the area, specifically with
and as the authors indicate, those in the primary psychosis respect to inclusion and appropriate assessment of negative
group may have experienced mania as opposed to schizophrenia. symptoms in research studies, these findings suggest that negative
Furthermore, the authors examined the lifetime prevalence symptoms may be experienced at a considerably lower rate in
of psychotic symptoms, rather than those experienced during acute METH psychosis compared with schizophrenia.
their psychotic episodes, which may explain why there was no
differences between chronic psychotic syndromes. Nevertheless, Chronic Meth Psychosis vs. Schizophrenia
these findings suggest that patients who present with greater Previous research has explicitly compared the negative symptoms
severity and frequency of lifetime delusions and hallucinations between chronic METH psychosis and schizophrenia. Tomiyama
(particularly thought interference, delusions of references and (114) examined the experience of negative symptoms between 11
auditory hallucinations) may be at increased risk for the participants with chronic METH psychosis and 11 participants
development of recurrent psychotic episodes or a primary with schizophrenia using the Scale for the Assessment of Negative
psychotic disorder. Symptoms (SANS). They found that negative symptoms were
milder in chronic METH psychosis overall when compared
NEGATIVE SYMPTOMS to schizophrenia. When examining the individual symptoms,
however, they found that ratings of avolition-apathy, anhedonia-
An overview of the design and findings of individual research asociality, and attentional impairment were similar between both
studies that have directly compared negative symptoms in those groups, but those with schizophrenia demonstrated elevated
with METH psychoses to those with schizophrenia can be symptoms of affective flattening and alogia. Additionally, Wang
found in Table 1. The methodological considerations in the et al. (115) found that schizophrenia was associated with greater
examination of research that has compared symptoms between frequency and severity of negative symptoms compared to
METH psychosis and schizophrenia is shown in Table 2. those with chronic METH psychosis. Specifically, those with
schizophrenia demonstrated elevated scores for blunted affect,
Acute Meth Psychosis vs. Schizophrenia emotional withdrawal and motor retardation. Furthermore, in
While stimulant-induced psychotic disorders have been differentiating between acute and chronic METH psychosis with
predominantly characterized by positive symptoms, negative schizophrenia (105), using the BPRS, found that those with
symptoms such as flat affect, social withdrawal, apathy, loss of schizophrenia demonstrated the greatest severity of negative
drive, anhedonia and poverty of speech have also been reported symptoms compared to those with acute and chronic METH
in METH psychosis samples (4, 40, 113, 123, 132). Srisurapanont psychosis, but the negative symptoms demonstrated by the
et al. (113) showed no difference between METH psychosis chronic METH psychosis group were significantly greater than
and schizophrenia on measures of psychomotor retardation, those in the acute METH group. Therefore, even though negative
flattened affect and poverty of speech using the Manchester scale, symptoms have been reported in both schizophrenia and METH
while other researchers have found no significant differences psychosis, schizophrenia appears to be associated with greater
between METH psychosis and schizophrenia using the BPRS prevalence and severity of negative symptoms compared to
(107) or the PANSS (111). METH psychoses.

COGNITIVE SYMPTOMS the use of distinct cognitive measures. However, despite the
overwhelming similarities in cognitive dysfunction between
An overview of the design and findings of individual research METH psychosis and schizophrenia (106) found that individuals
studies that have directly compared the cognitive symptoms with schizophrenia and METH psychosis demonstrated
associated with METH psychosis to those of schizophrenia can difficulties with sustained visual attention compared to controls,
be found in Table 1. The methodological considerations in the yet those with schizophrenia performed worse than subjects with
examination of research that has compared symptoms between acute METH psychosis. As selective visual attention is primarily
METH psychosis and schizophrenia is shown in Table 2. correlated with the parietal cortex (137), these findings indicate
that dysfunction of the parietal cortex may be more pronounced
Acute Meth Psychosis vs. Schizophrenia in schizophrenia than acute METH psychosis.
Recent work has examined the prevalence and severity of
cognitive dysfunction following acute METH psychosis in Chronic Meth Psychosis vs. Schizophrenia
comparison with schizophrenia. Jacobs et al. (108) in an The above studies were based on recent abstinent METH users
exploratory cross-sectional study, compared the cognitive profile and may not be generalizable to those with chronic METH
of individuals hospitalized with METH psychosis with patients psychosis. However, there is emerging evidence of similarities
with paranoid schizophrenia across eight cognitive domains, between cognitive symptoms in persistent METH psychosis and
including premorbid intellectual ability, learning and memory, schizophrenia in the literature. For example, (116) examined
executive functioning, general intellectual functioning, attention individuals with METH psychosis and schizophrenia on a verbal
and concentration, motor abilities together with non-verbal and fluency tasks while they had their brain blood oxygenation levels
verbal skills. They found no significant differences between recorded using Functional Near-Infrared Spectroscopy (NIRS).
the two groups in any cognitive domain examined, suggesting They also had their cognitive ability measured using the Brief
that both METH psychosis and schizophrenia may have similar Assessment of Cognition in Schizophrenia (BASC). They found
cognitive profiles and may therefore share underlying brain there was no difference between those with METH-psychosis
pathology, particularly with respect to dysfunction of the frontal and schizophrenia on tasks of verbal memory, working memory,
and temporal lobes. However, there are several limitations motor speed, verbal fluency, attention, speed of information
to these findings. Firstly, the groups had small sample sizes. processing, executive functioning and total cognitive ability.
Secondly, there were between-group differences in age, ethnicity However, oxyhaemaoglobin changes in the prefrontal cortex were
and place of birth between those with METH psychosis higher in the METH psychosis group compared to schizophrenia,
and schizophrenia and as such, these factors may have been particularly in the right dorsolateral prefrontal cortex. This
confounds in the study. Additionally, it was not known how suggests that while the cognitive ability may be similarly
long the sample had been abstinent from METH nor was it perturbed across METH psychosis and schizophrenia, there are
reported how long the METH psychosis sample had been taking biological changes that may be used to distinguish between the
METH prior to their participation in the study. Regardless, this two conditions. However, a significant limitation in this study
initial study suggested that METH psychosis may show cognitive is that the length of abstinence for the METH psychosis group
deficits, similar to those typically reported in schizophrenia. was not stated. Given that the sample had been 8.42 years since
Ezzatpanah et al. (106) further compared cognitive function the onset of psychotic symptoms (average of 2.5 hospitalizations
in individuals with METH-induced psychosis and schizophrenia and 8.42 months of hospitalization), the sample likely reflects a
to healthy controls, with all subjects matched for age, sex more persistent METH psychosis, and the researchers referred to
and education. They found that both METH psychosis and the sample as “methamphetamine-induced psychotic disorder.”
schizophrenia were characterized by reduced performance on all However, in the absence of abstinence information, it is uncertain
cognitive tasks examined when compared to healthy controls, whether these findings are applicable to acute or chronic METH
and there were no significant differences in the performance of psychosis, or the sample could reflect a blended representation.
those with acute METH psychosis and schizophrenia across tasks More recent research has shown that cognitive dysfunction
of memory, sustained attention, selective attention and executive is specific to the persistent form of METH psychosis rather
functioning. Specifically, METH psychosis and schizophrenia than acute METH psychosis. For example, Chen et al. (105)
groups demonstrated difficulty in inhibiting, manipulating and conducted a well-designed cross-sectional study on healthy
suppressing information, together with difficulties learning controls, METH users without psychosis, METH users with
and retaining verbal information over time. These findings acute psychosis (METH users who had psychotic symptoms
indicate that both disorders may be characterized by comparable that dissipated within 1 month following abstinence), METH
deficits of cognition mediated by the temporal and frontal users with persistent psychosis (psychosis greater than 1 month),
lobes, specifically the prefrontal cortex, and further extends the and individuals with schizophrenia. They found that METH
findings of Jacobs et al. (108) that both METH psychosis and users with persistent psychosis performed comparably to those
schizophrenia may be the product of similar pattern of brain with schizophrenia across all cognitive domains, with both these
pathology. While both these studies were hampered by small groups performing worse than the other acute METH psychosis,
sample sizes, these similar findings are strengthened by the METH users without psychosis and control groups. These
fact that these two studies were derived from different cultural findings extend the findings of Jacobs et al. (108) and Ezzatpanah
samples - American (108) and Iranian (106)–and through et al. (106) by clearly distinguishing between METH users with

acute and persistent psychoses, suggesting that schizophrenia and METH users with a persistent METH psychosis syndrome appear
only persistent psychosis secondary to METH use are associated to display the cognitive dysfunction typically associated with
with similar cognitive profiles. This may indicate that the samples schizophrenia (105), it is possible that the differences in positive,
used in previous studies could represent a mixture of both negative and cognitive symptoms reported in additional studies
acute and persistent METH psychoses. These findings therefore may refer only to acute METH psychosis. It will be important
suggest that cognitive dysfunction may develop in individuals for future research to examine the effect of persistent METH
who originally had acute symptoms that endured over time, psychosis and how this relates to the behavioral, cognitive and
likely as a secondary consequence to neuropathological changes biological changes typically reported in schizophrenia in order to
that coincide with abstinence. Altogether, these findings indicate elucidate whether chronic METH psychosis represents a distinct
that chronic METH-induced psychosis is associated with brain psychotic disorder and to differentiate the clinical profiles of
changes that may be carefully distinguished from the changes acute vs. chronic psychosis forms.
concomitant with METH use and acute METH psychosis. There are additional limitations to this field of research
that should be addressed. Firstly, many studies are of low
sample size, meaning that many of the similarities between
METHODOLOGICAL LIMITATIONS AND METH psychosis and schizophrenia may be due to low
CONSIDERATIONS statistical power to detect significant difference between groups.
Secondly, many studies do not control for polydrug use,
An overview of the methodological considerations in the meaning that the symptoms of psychosis may not be exclusively
examination of research that has compared symptoms between attributed to METH administration. Thirdly, studies do not
METH psychosis and schizophrenia is shown in Table 2. One actively control for the effect of psychotropic medication,
of the biggest limitations with METH psychosis research is that particularly given that this impacts on the presentation of
little effort is made to distinguish between those with acute behavioral symptoms. Additionally, many studies are reliant
and chronic METH psychosis, with the majority of the findings on hospitalized samples, which are likely concomitant with
portraying a blended representation of all types. Indeed, the more severe psychosis than non-treatment-seeking individuals
majority of studies failed to report the length of time of abstinence with METH psychosis in the community. Lastly, many studies
from METH at the time of the assessment. For the purpose of this compare METH psychosis to schizophrenia using screening
review, therefore, we considered these studies to represent acute or brief assessment tools. A significant limitation of these
METH psychosis studies as there was no evidence to suggest scales is that they do not differentiate the qualitative nature of
that these samples had been abstinent for long enough to be the hallucinations or delusions experienced, as they quantify
considered to be representative of chronic METH psychosis [>1 the status of positive symptoms with a total score, meaning
month abstinence according to published papers, e.g., (105)]. that these scales may be unable to detect differences that
Additionally, few studies indicate whether their samples are may differentiate these conditions. The use of such tools may
abstinent at the time of the assessment. Taken together, the explain why research studies produce such contrasting, and
findings presented in these papers may not be generalizable to at times conflicting, clinical profiles. For example, the positive
samples of chronic METH psychosis, as it is uncertain whether symptoms associated with METH psychosis and schizophrenia
these behavioral outcomes are referable to the direct effects of using the PANSS and BPRS are comparable, but examination
METH, acute METH psychosis or persistent METH psychosis. using more indepth tools, such as the Manchester Scale, revealed
In keeping with this limitation, some studies implement differences in the type of positive symptoms experienced between
diagnostic criteria for chronic METH psychosis that is distinct groups.
by those provided by the DSM-5. That is, these studies
typically categorize those who continue to experience psychosis
after discontinuing METH for more than 1 month as those SUMMARY AND CONCLUSIONS
with persistent METH psychosis. According to the DSM,
however, these patients should be diagnosed with a primary A comparison of the positive, negative and cognitive symptoms
psychotic disorder, and some studies adhere to these guidelines. between schizophrenia and acute/chronic METH psychosis is
Consequently, individuals with chronic METH psychosis may be detailed in Figure 1. Research has shown both similarities and
categorized as participants with schizophrenia. There are several differences in the positive, negative and cognitive symptoms
implications to this procedure. Firstly, chronic METH psychosis between METH-induced psychosis and schizophrenia. There
may be underreported across scientific literature. Secondly, the appears to be a high degree of concordance in the type,
inappropriate allocation of participants to treatment conditions prevalence and severity of positive symptoms between METH-
precludes the examination of distinct clinical and symptom induced psychosis and schizophrenia, confirming that it would
profiles between conditions given the significant heterogeneity be difficult to distinguish between the two conditions in
across various outcome measures. Furthermore, inconsistency the clinical setting based on the positive symptoms alone.
in sample characteristics hinders the ability to pool data and However, while auditory hallucinations appear to be the
conclusions across research studies. Indeed, it is worth noting most common hallucination reported in METH psychosis
that other researchers have proposed similar concerns about this (acute and chronic) and schizophrenia, visual and tactile
approach to METH psychosis research (138). Given that only hallucinations appear to be more prominent in acute/transient

FIGURE 1 | Venn diagram of the overlap in psychiatric and cognitive symptomatology between acute METH psychosis, chronic METH psychosis, and schizophrenia.
The left represents symptoms specific to acute METH psychosis, the right (highlighted blue) represents the symptoms and profile specific to chronic METH psychosis,
while the bottom highlights those associated specifically with a schizophrenia profile. Symptoms that are common across disorders are shown in the overlap. a All
conditions demonstrate some degree of positive, negative and cognitive symptomatology according the specific syndrome scales (e.g., Brief Psychiatric Rating Scale
or the Positive and Negative Severity Scale). b Visual and tactile hallucinations: Acute METH psychosis > Chronic METH psychosis > Schizophrenia c Severity of
negative symptoms: Schizophrenia > Chronic METH psychosis > Acute METH psychosis. d Cognition: Schizophrenia = Chronic METH psychosis > Acute METH
psychosis.
METH psychosis, with thought disorder the most pronounced and phenotypes, acute METH psychosis could represent a
symptom in schizophrenia. While negative symptoms occur in distinct psychotic disorder to schizophrenia and may be
both conditions, some research has indicated that there are clinically distinguished from a primary psychotic disorder
differences in the type, severity and progression of negative based on distinct behavioral and cognitive sequelae. On
symptoms throughout both conditions, with METH psychosis the other hand, preliminary evidence suggests that chronic
associated with reduced frequency and severity of several METH psychosis may be clinically similar to that of primary
negative markers, such as flattened affect (although chronic psychotic disorders, particularly with respect to positive
psychosis is associated with worse negative symptoms than and cognitive symptomatology. However, given the number
acute METH psychosis). Lastly, from a cognitive perspective, of limitations evident in the available studies, particularly
most cognitive domains appear to be similarly perturbed with respective to the paucity of experimental designs
across METH psychosis and schizophrenia. However, recent that differentiate between acute and chronic forms of
findings have highlighted that some functions subserved by METH psychosis, there is insufficient evidence to conclude
the parietal cortex, such as selective visual attention, may whether chronic METH psychosis is clinically distinct from
be more pronounced in schizophrenia that acute METH schizophrenia.
psychosis, and that cognitive dysfunction may be specifically Nevertheless, these findings may have implications for the
comparable to schizophrenia for those with chronic METH longer-term management and treatment of such conditions.
psychosis. For example, concerning the management of acute METH
Overall, while there is considerable overlap in the behavioral psychosis, symptoms will resolve with abstinence from METH
and cognitive symptoms between acute METH psychosis and with the appropriate management of withdrawal. Therefore,
and schizophrenia, research has shown that there are unique for the most part, long-term pharmacological interventions
aspects to each condition. While both disorders may be for acute METH psychoses would not be needed or beneficial
characterized by common underlying biological pathologies (139). However, given the similarity in symptoms between

persistent METH psychosis and schizophrenia, second AUTHOR CONTRIBUTIONS

generation antipsychotic medicines, such as risperidone
and olanzapine, may be appropriate intervention strategies. TW and JC designed the review. TW conducted the review;
While first-generation anti-psychotics (i.e., haloperidol) may TW wrote the initial version of the manuscript with subsequent
useful for the management of schizophrenia, and therefore, contribution from JC.
persistent METH psychosis, such medicines are at elevated
risk of causing extrapyramidal symptoms in individuals with ACKNOWLEDGMENTS
METH induced psychosis, and should therefore be used
carefully (56, 140). However, these suggestions are not clinical TW was in receipt of an Australian Postgraduate
recommendations and should be further examined using Award (APA) and would like to acknowledge the
large randomized clinical trials so that clinical guidelines support of Macquarie University in the form of
on the appropriate treatment of these conditions can be the Psychology Department Higher Degree Research
developed. Grant.
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published: 10 October 2018

Methamphetamine is a potent psychostimulant that can induce psychosis among

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Study Methodological considerations

comparison group? between acute and characteristics assessment? for?

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Study Methodological considerations

group? chronic psychosis?

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October 2018 | Volume 9 | Article 491

Study Methodological Considerations

group? chronic psychosis?

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persistent METH psychosis and schizophrenia, second AUTHOR CONTRIBUTIONS

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