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Psychological Medicine
cambridge.org/psm
Original Article
*These authors contributed equally to this
work.
Cite this article: Trotta G et al (2023).
Cannabis use as a potential mediator between
childhood adversity and first-episode
psychosis: results from the EU-GEI
case–control study. Psychological Medicine
1–10. https://doi.org/10.1017/
S0033291723000995
Received: 17 August 2022
Revised: 21 February 2023
Accepted: 27 March 2023
Keywords:
Cannabis use; childhood experience;
mediation; psychotic disorders; trauma
Corresponding author:
Giulia Trotta; E-mail: giulia.trotta@kcl.ac.uk
© The Author(s), 2023. Published by
Cambridge University Press. This is an Open
Access article, distributed under the terms of
the Creative Commons Attribution licence
(http://creativecommons.org/licenses/by/4.0),
which permits unrestricted re- use,
distribution and reproduction, provided the
original article is properly cited.
Cannabis use as a potential mediator between
childhood adversity and first-episode
psychosis: results from the EU-GEI
case–control study
Giulia Trotta1, Victoria Rodriguez2, Diego Quattrone1, Edoardo Spinazzola2,
Giada Tripoli2, Charlotte Gayer-Anderson3, Tom P Freeman4,
Hannah E Jongsma5, Lucia Sideli6, Monica Aas1, Simona A Stilo2,
Caterina La Cascia7, Laura Ferraro7, Daniele La Barbera7, Antonio Lasalvia8,
Sarah Tosato8, Ilaria Tarricone9, Giuseppe D’Andrea2, Andrea Tortelli10,
Franck Schürhoff11, Andrei Szöke11, Baptiste Pignon11, Jean-Paul Selten12,
Eva Velthorst13, Lieuwe de Haan14, Pierre-Michel Llorca15, Paulo Rossi Menezes16,
Cristina M Del Ben17, Jose Luis Santos18, Manuel Arrojo19, Julio Bobes20,
Julio Sanjuán21, Miquel Bernardo22, Celso Arango23, James B Kirkbride5,
Peter B Jones24, Alexander Richards25, Bart P Rutten26, Jim Van Os2,
Isabelle Austin-Zimmerman1, Zhikun Li1, Craig Morgan3, Pak C Sham27,
Evangelos Vassos1, Chloe Wong1, Richard Bentall28, Helen L Fisher1,
Robin M Murray2, Luis Alameda2,*, Marta Di Forti1*and EU-GEI WP2 Group1
Abstract
Background. Childhood adversity and cannabis use are considered independent risk factors
for psychosis, but whether different patterns of cannabis use may be acting as mediator
between adversity and psychotic disorders has not yet been explored. The aim of this study
is to examine whether cannabis use mediates the relationship between childhood adversity
and psychosis.
Methods. Data were utilised on 881 first-episode psychosis patients and 1231 controls from
the European network of national schizophrenia networks studying Gene–Environment
Interactions (EU-GEI) study. Detailed history of cannabis use was collected with the
Cannabis Experience Questionnaire. The Childhood Experience of Care and Abuse
Questionnaire was used to assess exposure to household discord, sexual, physical or emotional
abuse and bullying in two periods: early (0–11 years), and late (12–17 years). A path decom-
position method was used to analyse whether the association between childhood adversity and
psychosis was mediated by (1) lifetime cannabis use, (2) cannabis potency and (3) frequency
of use.
Results. The association between household discord and psychosis was partially mediated by
lifetime use of cannabis (indirect effect coef. 0.078, S.E. 0.022, 17%), its potency (indirect effect
coef. 0.059, S.E. 0.018, 14%) and by frequency (indirect effect coef. 0.117, S.E. 0.038, 29%).
Similar findings were obtained when analyses were restricted to early exposure to household
discord.
Conclusions. Harmful patterns of cannabis use mediated the association between specific
childhood adversities, like household discord, with later psychosis. Children exposed to par-
ticularly challenging environments in their household could benefit from psychosocial inter-
ventions aimed at preventing cannabis misuse.
Introduction
A growing body of literature has investigated the nature of the association between childhood
adversity and psychosis (Belbasis et al., 2018; Morgan & Gayer-Anderson, 2016). In recent
years multiple possible mediating mechanisms have been suggested in the adversity–psychosis
association, including the role of mood, PTSD-related symptoms, negative schemas about the
self, the world and others (Alameda et al., 2020). Identifying possible treatable factors that con-
tribute to this association may have important clinical implications, as they can constitute the
https://doi.org/10.1017/S0033291723000995 Published online by Cambridge University Press
object of specific interventions that may decrease the negative
impact of adversity in those with a psychotic disorder
(Bebbington, 2015).
Both childhood adversity and cannabis use increased the risk
of psychosis independently [OR 2.8 for the former (Varese
et al., 2012) and 3.9 for the latter (Marconi, Di Forti, Lewis,
Murray, & Vassos, 2016)]. There is also evidence showing that
the coexistence between both risk factors have an interactive effect
on the risk of the disorder (Bentall, Wickham, Shevlin, & Varese,
2012; Harley et al., 2010; Houston, Murphy, Adamson, Stringer, &
Shevlin, 2008; Konings et al., 2012; Sideli et al., 2018). Moreover,
some reports have suggested that cannabis use may be a conse-
quence of childhood adversity exposure (Morgan et al., 2014;
Van Nierop et al., 2014). This leads to the possible scenario
where some individuals at risk for the disorder who have been
exposed to childhood adversity may use cannabis as a maladap-
tive coping strategy to cope with the unpleasant emotions led
by trauma. In this line, some studies have examined whether can-
nabis may be a mediator between adversity and psychotic symp-
toms (Etain et al., 2017; Frydecka et al., 2020; Van Nierop et al.,
2014). An online survey conducted in Poland investigated the
relationship between early trauma, cognitive biases, cannabis
use and risk of psychosis among young adults from the general
population (Frydecka et al., 2020). The results showed an import-
ant mediating role of cannabis use and cognitive biases in the
association between childhood traumatic events and the develop-
ment of psychotic-like experiences. Van Nierop et al. aimed to
elucidate the effect of social defeat, cannabis use and affective dys-
regulation on the association between childhood trauma and
psychosis in a large population-based sample (van Nierop et al.,
2014). While both social defeat and affective dysregulation acted
as separate mediators, cannabis use did not mediate this associ-
ation. Another study found no evidence of mediation between
various childhood adversities and bipolar disorder, via cannabis
use (Etain et al., 2017).
To the best of our knowledge, there are no studies testing this
hypothesis in patients with a psychotic disorder, and none explor-
ing detailed measures of cannabis use such as the potency and fre-
quency of use, and taking into account the varying influence of
different forms of childhood adversity. Given that cannabis use
can potentially be modified by prevention or treatment (Lees
et al., 2021), more large epidemiological studies testing its possible
mediating contribution between adversity and psychosis are of
great interest, as preventing or reducing cannabis use could poten-
tially reduce the harmful effect of childhood adversity on psychosis.
Based on the above, using data from the European network of
national schizophrenia networks studying Gene–Environment
Interactions (EU-GEI) case–control study of first-episode psych-
osis, we tested whether the relationship between childhood adver-
sity and psychotic disorder is mediated by (i) lifetime cannabis
use, (ii) cannabis potency and (iii) frequency of using cannabis.
We hypothesised that cannabis use indirectly underlined the
link between different types of childhood adversity and psychosis.
If our hypothesis is confirmed, it would help clinicians to identify
‘at-risk’individuals that could be targeted for specific preventive
and therapeutic interventions.
Methods
The ‘first-episode’work package of the EU-GEI study consists of a
multicentre incidence and case–control study of genetic and
environmental determinants of psychotic disorders (Jongsma
et al., 2018), including 17 catchment areas across six countries:
England (n= 2; southeast London, Cambridgeshire and
Peterborough), France (n= 3; 20th arrondissement of Paris,
Val-de-Marne, Puy-de-Dôme), the Netherlands (n= 2; central
Amsterdam, Gouda and Voorhout), Italy (n= 3; part of the
Veneto region, Bologna municipality and the city of Palermo),
Spain (n= 6; Madrid, Barcelona, Valencia, Oviedo, Santiago and
Cuenca) and Brazil (n= 1; Ribeirão Preto).
Participants
All individuals who contacted mental health services in the 17
catchment areas over a median case ascertainment period of 25
months (interquartile range: 24–36 months) (Jongsma et al.,
2018), between 1 May 2010 and 1 April 2015, with a suspected
first episode of psychosis (FEP) were identified by trained
researchers, and included if they met the following criteria: (i)
being a resident within the catchment area at first presentation;
(ii) aged 18–64 years and (iii) presented to services with a clinical
diagnosis of psychosis (International Statistical Classification of
Diseases, Tenth Revision [ICD-10] codes F20–33) (World Health
Organization, 1992). Patients were excluded if they had previous
contact with mental health services for psychosis, evidence of
psychotic symptoms precipitated by an organic cause or resulting
from acute intoxication, as defined by the ICD-10 (codes F1x.5).
Controls were recruited from the general population living in
the same catchment areas using a quota sampling approach
to maximise representativeness by age, sex and ethnicity
(Gayer-Anderson et al., 2020). Controls were excluded if they
had received a diagnosis of, or treatment for, psychotic disorder.
The authors assert that all procedures contributing to this work
comply with the ethical standards of the relevant national and
institutional committees on human experimentation and with
the Helsinki Declaration of 1975, as revised in 2008. All partici-
pants provided informed, written consent; and ethical approval
was provided by research ethics committees in each site: South
London and Maudsley and Institute of Psychiatry Research Ethics
Committee; National Research Ethics Service Committee East of
England–East Cambridge; Medisch-Ethische Toetsingscommissie
van het Academisch Centrum te Amsterdam; Comité Ético de
Investigación Clínica Hospital Gregorio Marañón; Comité Ético
de Investigación Clínica del Hospital Clinic de Barcelona; Comité
Ético de Investigación Clínica del Hospital Clinic Universitari de
Valencia; Comité Ética de la Investigación Clínica del Principado
de Asturias; Comité Ético de Investigación Clínica de Galicia;
Comité Ético de Investigación Clínica del Hospital Virgen de la
Luz de Cuenca; Comité de Protéction des Personnes–CPP Île de
France IX; Comitato Etico Policlinico S Orsola Malpighi;
Comitato Etico Azienda Ospedaleria Universitaria di Verona;
Comitato Etico Palermo 1, Azienda Ospedaliera Policlinico ‘Paolo
Giaccone’and Research Ethics Committee of the clinical Hospital
of Ribeirão Preto Medical School, University of São Paulo, Brazil.
Given that our aim is to explore the relation between early
childhood adversity and later cannabis use, in order to reduce
the influence of reverse causality, we excluded subjects that had
used cannabis before the age of 12 years old.
Measures
Sociodemographic data
We obtained sociodemographic data during interviews with par-
ticipants using the Medical Research Council Sociodemographic
2 Giulia Trotta et al.
https://doi.org/10.1017/S0033291723000995 Published online by Cambridge University Press
Schedule (Mallett, 1997). In this study, we used age, sex, ethnicity
(white, black, Mixed, Asian, north African and other), country
and years of education.
Childhood adversity
The Childhood Experience of Care and Abuse (CECA) and a spe-
cific questionnaire on bullying were read out to participants during
a face-to-face interview. The CECA is an instrument developed to
retrospectively assess childhood adversity that occurred before 18
years of age. In this study, we focused on experiences of childhood
abuse (sexual, physical and psychological) and household discord
reported as occurring between ages 0 and 17 years (Roy & Perry,
2004). Psychological abuse comprised humiliation, degradation,
extreme rejection, emotional blackmail, terrorizing by a caregiver
or deprivation of basic needs. Physical abuse was defined as bodily
harm inflicted by a caregiver that resulted in at least bruising.
Sexual abuse was defined as the participant’s report of any
unwanted sexual incident. Household discord was defined as the
amount of fighting between the caregivers and/or with the child.
For bullying, the participants were asked if they had experienced
any of the following from peers before 17 years of age: having
been verbally abused or made fun of; having been ignored,
excluded or left out on purpose; having been hit, kicked, shoved
or locked in a room; having been told lies or been the subject of
false rumours; having been a victim of any other type of bullying.
For the analyses, each childhood adversity subtype was dichoto-
mised based on severity cut-off thresholds: ‘absent’–(0) if none
or some –or ‘present’–(1) if moderate or marked.
Sensitivity analyses were conducted using age at the time of the
first exposure which was categorised as follows: (1) early adversity
refers to exposure between birth and age 11 years, (2) late adver-
sity refers to exposure between ages 12 and 17 years, as has been
done previously (Alameda et al., 2017).
Cannabis use
We utilised an updated version of the modified Cannabis
Experience Questionnaire (CEQ
EU−GEI
) to collect a detailed his-
tory of cannabis use from participants (Di Forti et al., 2009).
Following from the EUGEI study cannabis core paper (Di Forti
et al., 2019), we included three measures of cannabis use in the
analyses: (i) lifetime cannabis use (which in this paper includes
those starting cannabis from age 12), (ii) lifetime frequency of
use and (iii) cannabis potency. Among cannabis users, we selected
subjects who started using cannabis in adolescence (i.e. after
age 12) in order to clarify the temporal relationship among child-
hood adversity and later exposure to cannabis.
Lifetime frequency of use was categorised as (1) used never or
occasionally, (2) used more than once a week and (3) daily. The
cannabis potency was dichotomised based on the expected amount
of THC that subjects reported to have used: (1) low potency can-
nabis with less than 10% of THC, and (2) high potency more
than 10% of THC (see online Supplementary Methods).
Diagnostic assessment
We obtained research-based diagnoses based on the Operational
Criteria Checklist algorithm (OPCRIT), with good inter-rater reli-
ability across catchment areas (κ= 0.7). The OPCRIT system
allows researchers to: (i) assess the pre-morbid history and current
mental state; and (ii) establish the diagnosis of psychotic disorders
based on algorithms for several diagnostic classification systems.
It consists of a 96-item checklist which can be filled based on a
semi-structured clinical interview or review of clinical notes and
other relevant information (McGuffin, Farmer, & Harvey,
1991). Where OPCRIT assessment was not possible, we relied
on clinical diagnoses.
Statistical analysis
Case–control comparisons on sociodemographics and primary
outcomes measures (cannabis use and childhood adversity)
were made with χ
2
, Student tor Wilcoxon–Mann–Whitney
tests depending on normality of data distribution. We used medi-
ation analyses to test whether the relationship between childhood
adversities and psychosis is direct or whether putative mediator
variables (i.e. lifetime cannabis use, cannabis potency and lifetime
frequency of use) account for the relationship between them
(see online Supplementary Fig. S1). Sensitivity analyses were
conducted examining the mediational role of cannabis in the
association between early/late exposure to different types of
adversity and first-episode psychosis.
Following Baron and Kenny’s (Baron & Kenny, 1986) criteria,
running logistic regressions we first ascertained that: (i) there is an
association between different subtypes of childhood adversity and
psychotic disorder (pathway c); (ii) the putative mediator vari-
ables are associated with psychotic disorder (pathway b) and
(iii) there is an association between childhood adversity and can-
nabis use (pathway a). We then performed mediation modelling
using the Karlson, Holm and Breen method as framed in the
khb package in Stata 15. Each putative mediator was entered in
separate models to investigate their individual impact on the over-
all relationship. If the entry of the mediator was accompanied by a
statistically significant effect on the dependent variable together
with a reduction of the childhood adversity effect, mediation
can be deduced. On the other hand, if the effect of the mediator
lacked statistical significance, all that can be inferred is a direct
effect of childhood adversity on psychosis. Analyses were con-
trolled for age, sex, ethnicity, years of education, country and
other childhood adversities. All statistical tests were two-tailed
and significance was determined at the 0.05 level.
Results
Sample
From the original sample of 1130 cases and 1499 controls, we
excluded 491 subjects (229 first-episode psychosis patients and
262 patients) for missing data on the variables of interest, and
26 participants (20 controls and six cases) for starting using can-
nabis before 12, leaving a final sample composed of 1231 controls
and 881 cases (see online Supplementary results for more detailed
recruitment flow-charts).
Rates of childhood adversities, cannabis use and
sociodemographic characteristics
Sociodemographic characteristics, rates of childhood adversities
and cannabis use are described in Table 1.
As a whole, the mean age of cases was 30.88 (S.D. 10.55), 61.98%
of which were male. There were differences in terms of sociodemo-
graphic characteristics between psychosis cases and controls.
Patients were younger, more often men, with a lower level of edu-
cation, and from ethnic minorities (all p’s <0.05). Among the 2112
participants, 1362 (69.00%) had been exposed to at least one of the
selected adversities (breakdown of prevalence by each subtype is
Psychological Medicine 3
https://doi.org/10.1017/S0033291723000995 Published online by Cambridge University Press
presented in Table 1); of these 851 (62.48% of exposed participants)
had been exposed before age 12 (early adversity) and 511 (37.52%
of exposed participants) between age 12 and 17 (late adversity).
Patients reported a higher rate of childhood adversities considering
all different subtypes, i.e. household discord, psychological abuse,
physical abuse, sexual abuse and bullying (all p’s<0.05).Ahigher
proportion of cases than controls significantly reported having
ever used cannabis, 64.13% and 46.22%, respectively. We also
found differences between cases and controls in terms of pattern
of use (see Table 1) and age at first tried cannabis (see Fig. S4)
(p< 0.05). Indeed, cases often reported a more harmful pattern
of use (i.e. high potency and weekly/daily use) and started using
cannabis earlier in adolescence.
Associations between childhood adversity and cannabis use
with psychotic disorder
Results of logistic regression analyses of both childhood adversity
and cannabis use on psychosis are shown in Table 2 (panel A).
Regarding different subtypes of childhood adversity, house-
hold discord, psychological abuse, sexual abuse and bullying
were significantly associated with having an FEP. When consider-
ing early exposure to adversity, we obtain similar results with only
early sexual abuse not being significantly associated with psych-
osis, whereas for later adversities, only sexual abuse and bullying
remained strongly associated. All cannabis use measures were sig-
nificantly related to psychotic disorder.
Associations between childhood adversity and cannabis use
Associations between childhood adversity, total and early, and
cannabis use are reported in Table 2 (panel B).
In our sample, household discord, both overall and early
adversity, was significantly and positively associated with all mea-
sures of cannabis misuse. Early psychological abuse was signifi-
cantly associated with lifetime cannabis use and cannabis
potency, as well as total sexual abuse. Interestingly, exposure to
Table 1. Sociodemographics, childhood adversities and cannabis use across all included first-episode psychosis cases and unaffected controls
Total,
n=2112
Controls,
n=1231
Cases,
n=881
Controls
v. cases
Age in years, M(S.D.) 33.97 (12.58) 36.19 (13.43) 30.88 (10.55) U= 8.749*
Sex, male, N(%) 1124 (53.23) 578 (46.99) 546 (61.98) χ
2
=46.2906*
Ethnicity, N(%)
White
Black
Mixed
Asian
North African
Other
1447 (68.61)
277 (13.13)
215 (10.19)
64 (3.03)
65 (3.08)
41 (1.94)
927 (75.43)
115 (9.36)
112 (9.11)
33 (2.69)
23 (1.87)
19 (1.55)
520 (59.09)
162 (18.41)
103 (11.70)
31 (3.52)
42 (4.77)
22 (2.50)
χ
2
=72.9084*
Years of education, M(S.D.) 15.24 (10.37) 15.32 (7.43) 15.12 (13.43) U= 8.462*
Country, N(%)
UK
Holland
Spain
France
Italy
Brazil
571 (27.04)
402 (19.03)
143 (6.77)
214 (10.13)
292 (13.83)
490 (23.20)
334 (27.13)
210 (17.06)
75 (6.09)
147 (11.94)
165 (13.40)
300 (24.37)
237 (26.90)
192 (21.79)
68 (7.72)
67 (7.60)
127 (14.42)
190 (21.57)
χ
2
=19.7118*
Childhood trauma, N(%)
Household discord
Psychological abuse
Physical abuse
Sexual abuse
Bullying
932 (44.81)
259 (12.50)
556 (26.77)
206 (9.94)
732 (36.08)
481 (39.27)
111 (9.09)
291 (23.79)
102 (8.33)
371 (31.02)
451 (52.75)
148 (17.39)
265 (31.03)
104 (12.26)
361 (43.34)
χ
2
=30.8554*
Childhood trauma, N(%)
Early trauma
Late trauma
851 (43.11)
511 (25.89)
488 (41.22)
273 (23.06)
363 (45.95)
238 (30.13)
χ
2
=32.8989*
Lifetime cannabis use, yes N(%) 1133 (45.07) 568 (46.22) 565 (64.13) χ
2
=69.6654*
Age first tried cannabis, M(S.D.) 17.51 (4.58) 18.04 (4.60) 16.97 (4.50) U= 5.416*
Cannabis potency, N(%)
Non-users
Low potency (THC <10%)
High potency (THC ⩾10%)
951 (48.05)
631 (31.88)
397 (20.06)
648 (55.86)
341 (29.40)
171 (14.74)
303 (37.00)
290 (35.41)
226 (27.59)
χ
2
=80.5330*
Cannabis frequency, N(%)
Never or occasional
More than once a week
Daily
604 (53.88)
190 (16.95)
327 (29.17)
398 (70.19)
90 (15.87)
79 (13.93)
206 (37.18)
100 (18.05)
248 (44.77)
χ
2
=148.7712*
Early trauma refers to exposure between birth and age 11; late trauma refers to exposure between ages 12 and 17; THC, Δ⁹-tetrahydrocannabinol; U, Mann–Whitney Utest; χ
2
, Chi-squared
test; *pvalue ⩽0.05.
4 Giulia Trotta et al.
https://doi.org/10.1017/S0033291723000995 Published online by Cambridge University Press
bullying during adolescence was negatively associated with life-
time cannabis use (see online Supplementary Table S2).
Mediating effects of cannabis use between childhood adversity
and psychosis
The results of the mediation analyses (see Table 3) indicate that
the relationship between household discord and psychosis is par-
tially mediated by all measures of cannabis use, i.e. lifetime can-
nabis use (indirect effect coef. 0.078 S.E. 0.022, 17%), cannabis
potency (indirect effect coef. 0.059 S.E. 0.018, 14%) and frequency
of use (indirect effect coef. 0.117 S.E. 0.034, 42%). Lifetime
cannabis use (indirect effect coef. 0.082 S.E. 0.045, 18%) and can-
nabis potency (indirect effect coeff. 0.078 S.E. 0.078, 19%) also
mediated the relationship between sexual abuse and later
psychosis.
From the sensitivity analyses restricted to early (prior to age 12)
exposure to adversity we obtained the following findings.
Consistently, the association between early household discord and
psychosis was mediated by lifetime cannabis use (indirect effect
coef. 0.083 S.E. 0.026, 14%), cannabis potency (indirect effect coef.
0.050 S.E. 0.022, 10%) and cannabis frequency (indirect effect coef.
0.126 S.E. 0.46, 24%). Both lifetime cannabis use (indirect effect
coeff. 0.108 S.E. 0.045, 29%) and cannabis potency (indirect effect
Table 2. Associations between childhood adversities and cannabis use with psychotic disorder (panel A) and associations between childhood adversity and
cannabis use (panel B)
Panel A. Logistic regressions between childhood adversities, cannabis use and psychotic disorder
aOR (95% CI) pvalue
Household discord
Total adversity
Early adversity
1.53 (1.25–1.88)
a
1.67 (1.31–2.14)
a
<0.001
a
<0.001
a
Psychological abuse
Total adversity
Early adversity
1.79 (1.30–2.47)
a
1.59 (1.02–2.47)
a
<0.001
a
0.039
a
Physical abuse
Total adversity
Early adversity
0.86 (0.67–1.10)
a
0.84 (0.62–1.14)
a
0.240
a
0.250
a
Sexual abuse
Total adversity
Early adversity
1.42 (1.01–2.00)
a
1.43 (0.90–2.27)
a
0.042
a
0.133
a
Bullying
Total adversity
Early adversity
1.57 (1.27–1.96)
a
1.54 (1.17–2.02)
a
<0.001
a
0.002
a
Lifetime cannabis use 2.04 (1.62–2.58)
b
<0.001
b
Cannabis potency 1.53 (1.32–1.76)
b
<0.001
b
Cannabis frequency 2.93 (2.24–3.84)
b
<0.001
b
Panel B. Logistic regressions between childhood adversities and cannabis use
Lifetime cannabis use Cannabis potency Cannabis frequency
aOR (95% CI)
a
pvalue
a
aOR (95% CI)
a
pvalue
a
aOR (95% CI)
a
pvalue
a
Household discord
Total adversity
Early adversity
1.76 (1.37–2.25)
1.80 (1.33–2.44)
<0.001
<0.001
1.47 (1.19–1.83)
1.33 (1.02–1.74)
<0.001
0.033
1.71 (1.30–2.25)
1.79 (1.27–2.53)
<0.001
0.001
Psychological abuse
Total adversity
Early adversity
1.33 (0.89–1.98)
1.92 (1.10–3.38)
0.168
0.023
1.39 (0.98–1.97)
1.86 (1.14–3.04)
0.067
0.013
1.29 (0.85–1.96)
1.71 (0.95–3.09)
0.241
0.076
Physical abuse
Total adversity
Early adversity
1.07 (0.79–1.44)
0.71 (0.48–1.104)
0.664
0.076
0.95 (0.73–1.24)
0.81 (0.58–1.15)
0.693
0.208
1.45 (1.03–2.04)
1.43 (0.92–2.23)
0.032
0.116
Sexual abuse
Total adversity
Early adversity
1.89 (1.24–2.88)
1.69 (0.97–2.95)
0.003
0.063
2.04 (1.41–2.96)
1.55(0.95–2.53)
<0.001
0.081
0.84 (0.54–1.32)
0.68 (0.36–1.30)
0.453
0.248
Bullying
Total adversity
Early adversity
0.95 (0.73–1.25)
1.12 (0.80–1.58)
0.729
0.515
1.12 (0.89–1.42)
1.28 (0.95–1.72)
0.324
0.110
0.99 (0.74–1.33)
1.03 (0.73–1.45)
0.967
0.862
Early adversity refers to exposure between birth and age 11; late adversity refers to exposure between ages 12 and 17; CI, confidence interval; aOR, adjusted odds ratio. Bold text indicates
associations where p< 0.05.
a
Adjusted for age, sex, ethnicity, years of education, country and other childhood adversities.
b
Adjusted for age, sex, ethnicity, country and years of education.
Psychological Medicine 5
https://doi.org/10.1017/S0033291723000995 Published online by Cambridge University Press
coeff. 0.104 S.E. 0.041, 31%) mediated the effect of early psychological
abuse. The different mediation models are illustrated in Fig. 1.
Mediation analyses on late exposure to adversity (12–17 years) are
reported in the online Supplementary Materials (see Table S3 and
Fig. S5). Although not reaching the statistical significance threshold,
it is still worth noticing the negative effect that lifetime cannabis use
seems to have on the association between late bullying and psychosis
(indirect effect coeff. −0.082 S.E.0.044,−14%).
Discussion
Using data from a large multicentre case–control study of first-
episode psychosis, we examined whether cannabis use, in different
forms, mediated the relationship between childhood adversity
subtypes and the risk of developing a psychotic disorder.
Our findings suggest that around a fifth of the association
between household discord before 18 and psychosis (% of total
effect mediated ranging from 14% to 29%) was mediated by can-
nabis use, high potency cannabis and frequency of use, with
slightly smaller mediating effects found when household discord
was considered as occurring before age of 12 (% of total effect
mediated ranging from 10% to 24%). The risk of developing
psychosis after being exposed to psychological abuse was
mediated by lifetime cannabis use and cannabis potency, when
the adversity occurred early (around 30% of total effect mediated).
Lifetime cannabis use and cannabis potency also mediated around
18% of the link between sexual abuse and psychotic disorder.
Surprisingly, lifetime cannabis use had a slightly negative mediat-
ing effect on the relationship between late bullying and psychosis.
This is due to a negative link between those individuals that have
faced such adversity and risk of using cannabis. No mediation
models could be tested for physical abuse, because interestingly
no association between such type of trauma and psychosis was
found in our sample. This might depend on a too broad definition
utilised which did not allow us to discriminate whether exposure
to physical abuse might lead to an increased risk of developing
psychosis.
Strengths and limitations
The relationship between childhood adverse experiences and later
substance misuse has received growing attention in the last few
years, providing evidence of increased drug use in patients who
were exposed to abuse in childhood (Schäfer & Fisher, 2011).
Some recent studies focused on the interaction between childhood
adversity, cannabis use and psychosis, reporting a significantly
greater risk for psychotic outcomes (Houston et al., 2008; Sideli
et al., 2018). However, the novelty and major strength of the cur-
rent study is the use of mediation analysis to elucidate the
mechanisms underlying the nature of the association. To demon-
strate mediation, one must establish strong relationships between
the predictor, the mediator and a criterion variable, and previous
studies failed to do so (Bebbington et al., 2011).
Furthermore, the specific questionnaire we used allows a
detailed assessment of lifetime patterns of cannabis use, including
age at first use, frequency and duration of use, and the specific
type of cannabis used. Although a clear dose–response association
has consistently been shown between cannabis use and the risk of
Table 3. Mediation analyses displaying the total, direct, indirect effects and the percentage of total effect mediated between advertises and psychosis, via cannabis
use patterns
Panel A. Main analyses on total exposure to adversity
Childhood adversities
and potential mediators
Total Direct Indirect
Coef. (S.E.) pvalue Coef. (S.E.) pvalue Coef. (S.E.) % Mediated pvalue
Household discord –total
Lifetime cannabis use
Cannabis potency
Cannabis frequency
0.451 (0.115)
0.411 (0.106)
0.404 (0.146)
<0.001
<0.001
0.006
0.373 (0.116)
0.352 (0.106)
0.287 (0.146)
0.001
0.001
0.050
0.078 (0.022)
0.059 (0.018)
0.117 (0.038)
17.25
14.37
28.94
<0.001
0.001
0.002
Sexual abuse –total
Lifetime cannabis use
Cannabis potency
0.460 (0.201)
0.418 (0.180)
0.022
0.020
0.377 (0.201)
0.338 (0.181)
0.061
0.061
0.082 (0.034)
0.078 (0.029)
17.83
19.12
0.016
0.005
Panel B. Sensitivity analyses restricted to early exposure to adversity
Childhood adversities
and potential mediators
Total Direct Indirect
Coef. (S.E.) pvalue Coef. (S.E.) pvalue Coef. (S.E.) % Mediated pvalue
Household discord –early
Lifetime cannabis use
Cannabis potency
Cannabis frequency
0.581 (0.137)
0.518 (0.128)
0.530 (0.178)
<0.001
<0.001
0.003
0.498 (0.138)
0.468 (0.128)
0.404 (0.178)
<0.001
<0.001
0.023
0.083 (0.026)
0.050 (0.022)
0.126 (0.046)
14.26
9.63
23.77
0.002
0.024
0.006
Psychological abuse –early
Lifetime cannabis use
Cannabis potency
0.369 (0.256)
0.331 (0.229)
0.149
0.148
0.261 (0.256)
0.228 (0.230)
0.308
0.321
0.108 (0.045)
0.104 (0.041)
29.16
31.28
0.017
0.011
Following Baron and Kenny criteria, mediation analyses have been conducted when the mediator is both associated with the predictor (adversities) and with the outcome simultaneously,
based on analyses shown in Tables 1 and 2. Panel A refers to total exposure to adversity, while panel B shows the results of the sensitivity analyses restricted to early exposure to adversity
(0–12 years).
Total effect, direct effect + indirect effect; direct effect, effect of the independent variable to the outcome variable; indirect effect, effect of the independent variable to the mediator and of
the mediator on the outcome variable.
SE, standard error. Bold text indicates associations where p< 0.05.
6 Giulia Trotta et al.
https://doi.org/10.1017/S0033291723000995 Published online by Cambridge University Press
developing psychosis, only few studies have collected detailed data
on the pattern of cannabis use or its potency (Di Forti et al.,
2019). Similarly, the measure utilised to assess childhood adver-
sity allows the characterisation of different types of adversity
stratified by age of exposure.
Moreover, the sample utilised in the present study was a well-
characterised sample of recent-onset patients presenting for the
first time with psychosis and representative controls. Among can-
nabis users, we selected participants who started using cannabis
after age 12 in order to decrease the risk of reverse causation
between cannabis use and exposure to adversity.
Having acknowledged these strengths, it is also important to
recognise the limitations of our work. Most importantly, although
we tried to diminish the risk of reverse causation between expos-
ure to adversity cannabis use by looking at childhood and adoles-
cence separately and excluding cannabis used prior to age 12, we
cannot exclude the possibility that some exposures (i.e. late ado-
lescent bullying or abuse) occurred slightly after or at the same
than cannabis initiation. Case–control data are also collected
retrospectively, and like all such data, may be subject to some
level of recall bias, especially in the collection of traumatic experi-
ences in people with psychosis (Howard, 1993). Given the inher-
ent limitations of using case–control data to investigate mediation,
we did not attempt to implement more sophisticated mediation
models, such as causal mediation models in the present paper.
Prospective, longitudinal studies are thus required to disentangle
the directions of these associations using stronger causal inference
methods. Additionally, we were unable to undertake bootstrap-
ping, limiting our understanding of the accuracy of our inference.
Another limitation regards the range of confounders that have
been taken into account. We could not account for cognitive func-
tion which in multiple studies has shown to be associated with
Figure 1. Proportion of the total effect of specific types of adversity on psychosis mediated via lifetime cannabis use, cannabis potency, and frequency of using
cannabis. The blue portion of each bar indicates the percentage of the effect mediated (indirect effect). Panel A refers to the main analyses on total exposure to
childhood adversity (0–17 years), Panel B refers to the sensitivity analyses restricted to early exposure to childhood adversity (0–12 years).
Psychological Medicine 7
https://doi.org/10.1017/S0033291723000995 Published online by Cambridge University Press
childhood adversity exposure (Vargas et al., 2019). Although we
adjusted by the most relevant confounders in the field of trauma,
cannabis and psychosis literature, the interplay between trauma
and other environmental variables such as migration or discrim-
ination is difficult to disentangle and was not the focus of the cur-
rent paper. A recent publication on this topic from our group is
already available (D’Andrea et al., 2022). We hope other factors
such as the genetic influence in the form of family history and
polygenic risk scores can be explored in the future and has not
been focus of the current work either.
Finally, the number of statistical tests carried out was signifi-
cantly essential; thus, we cannot confidently rule out the possibil-
ity that some of the associations might have been due to type I
errors.
Specific role of cannabis consumption in those exposed to
household discord
The mediational role of cannabis use was particularly robust for
experiences of household discord, especially when the exposure
occurred in childhood, relative to other types of adversity, such
as psychological, physical and sexual abuse. However, the risk
of developing psychosis tends to be higher in those exposed to
more severe experiences of abuse (Varese et al., 2012). Thus,
this suggests that the association with psychosis in those exposed
to such experiences might be mediated by other variables that we
did not explore in this study, such as low mood, PTSD-related
symptoms, negative schemas about the self, the world and others
(Alameda et al., 2020).
Cannabis use during adolescence, an important insult in a
critical period of vulnerability
Growing evidence has pointed out adolescence as a particularly
vulnerable developmental period during which exposure to can-
nabis might lead to deleterious consequences, such as developing
psychosis (Arseneault, Cannon, Witton, & Murray, 2004; Hall,
2006). The maturational processes occurring during puberty
and adolescence are necessary for adult behaviour. Thus, it is
not surprising that immature individuals seem to be particularly
susceptible to the exposure of cannabis. Cannabis exposure dur-
ing pubertal development can lead to abnormal social behaviour
and anhedonia in adulthood (Skumlien et al., 2021), which are
also symptoms of psychosis. Although the association between
early cannabis use and subsequent problems may be due, in
part, to common risk factors, monitoring the age of initial canna-
bis use remains important.
Future perspective and clinical implications
These results have important therapeutic implications suggesting
that cannabis use may be a useful preventive intervention target in
children exposed to household discord, particularly in those
exposed prior to the age of 12. At a clinical level, our results sup-
port the need for a comprehensive assessment of childhood adver-
sity and cannabis use history in first-episode psychosis patient.
Young people with a history of household discord could poten-
tially be targeted for psychotherapeutic or psycho-educational
interventions regarding the risks of cannabis use, particularly dur-
ing adolescence. Current findings outline the need for future
research on the role of cannabis use in the association between
childhood adversity and psychosis. The results should be
replicated using a prospective design to clarify the temporal rela-
tionship between risk factors and psychosis, excluding the effect
of reverse causality and recall bias.
In addition, research analysing the interaction between envir-
onmental risk factors (including migration, urbanicity, substance
misuse and recent life events) and genetics is needed to better
investigate the aetiology of psychosis. For instance, direct mea-
sures of genetic variation and family history may help in evaluat-
ing adversity and cannabis-related risk of psychosis in the context
of genetic susceptibility. This has potential implications for pre-
vention, for example, in predicting those at risk of psychosis
who can ultimately benefit from specific clinical interventions.
Supplementary material. The supplementary material for this article can
be found at https://doi.org/10.1017/S0033291723000995.
Data. The data that support the findings of this study is available on request
from the corresponding author, G. T.
Acknowledgements. The accomplishment of this work could not have been
possible without all those who participated in the study and generously gave up
their time, and the hard work of the wider EU-GEI team.
Author contributions. G. T., V. R., L. A., M. D. F. and R. M. contributed to
the conception and design of the study. G. T., V. R. and L. A. analysed the
data. M. D. F. and R. M. took part in the interpretation of the data. All authors
contributed to the drafting and revision of the manuscript.
Financial support. EU-GEI is the acronym of the project ‘European network
of National Schizophrenia Networks Studying Gene-Environment
Interactions’. The research leading to these results has received funding
from the European Community’s Seventh Framework Programme under
grant agreement No. HEALTH-F2-2010-241909 (Project EU-GEI). Brazilian
data included in the EU-GEI consortium were funded by the São Paulo
Research Foundation –FAPESP, Brazil (grant number 2012/05178-0).
G. T. and M. D. F. were supported by the Medical Research Council (MRC) –
UKRI [MR/T007818/1]. This work represents independent research part sup-
ported by The Swiss National Science Foundation (no 171804 to LA).
C. M. and H. L. F. were supported by the Economic and Social Research
Council (ESRC) Centre for Society and Mental Health at King’s College
London [ES/S012567/1]. J. B. K. was supported by National Institute for
Health Research (NIHR), University College London Hospital, Biomedical
Research Centre (BRC), and E. V. was supported by the NIHR Maudsley
BRC at South London and Maudsley NHS Foundation Trust and King’s
College London. The views expressed in this publication are those of the
authors and not necessarily those of the ESCR, the NHS, the NIHR, the
Department of Health and Social Care or King’s College London. C. A. was sup-
ported by the Spanish Ministry of Science and Innovation. Instituto de Salud
Carlos III (SAM16PE07CP1, PI16/02012, PI19/024), co-financed by ERDF
Funds from the European Commission, ‘A way of making Europe’,
CIBERSAM. Madrid Regional Government (B2017/BMD-3740 AGES-CM-2),
European Union Structural Funds. European Union Seventh Framework
Program under grant agreements FP7-4-HEALTH-2009-2.2.1-2-241909
(Project EU-GEI), FP7- HEALTH-2013-2.2.1-2-603196 (Project PSYSCAN)
and FP7- HEALTH-2013-2.2.1-2-602478 (Project METSY); and European
Union H2020 Program under the Innovative Medicines Initiative 2 Joint
Undertaking (grant agreement No 115916, Project PRISM, and grant agreement
No 777394, Project AIMS-2-TRIALS), Fundación Familia Alonso and
Fundación Alicia Koplowitz.
Conflict of interest. R. M. M. reports personal fees from Janssen, Lundbeck,
Sunovion and Otsuka, outside of the submitted work. M. D. F. reports personal
fees from Janssen, outside the submitted work. M. B. reports grants and personal
fees from Adamed, Janssen-Cilag, Otsuka and Abbiotics; personal fees from
Angelini and Casen Recordati; and grants from Lundbeck and Takeda, outside
of the submitted work. C. A. has been a consultant to or has received honoraria
or grants from Acadia, Angelini, Boehringer, Gedeon Richter, Janssen Cilag,
Lundbeck, Minerva, Otsuka, Roche, Sage, Servier, Shire, Schering Plough,
8 Giulia Trotta et al.
https://doi.org/10.1017/S0033291723000995 Published online by Cambridge University Press
Sumitomo Dainippon Pharma, Sunovion and Takeda. M. Q. has been a consult-
ant for, received grant/research support and honoraria from, and been on the
speakers/advisory board of Adamed, Angelini, Casen Recordati, Janssen-Cilag,
Lundbeck, Otsuka, Menarini and Takeda.
1
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry,
Psychology and Neuroscience, King’s College London, London, UK;
2
Department of Psychosis Studies, Institute of Psychiatry, Psychology and
Neuroscience, King’s College London, London, UK;
3
Health Service and
Population Research, Institute of Psychiatry, Psychology, and Neuroscience,
King's College London, London, UK;
4
University of Bath Department of
Pharmacy and Pharmacology: University of Bath Department of Life Sciences,
Bath, UK;
5
PsyLife Group, Division of Psychiatry, University College London,
London, UK;
6
Department of Human Science, LUMSA University, Rome, Italy;
7
University of Palermo Department of Biomedicine Neuroscience and Advanced
Diagnostics: Universita degli Studi di Palermo Dipartimento di Biomedicina
Neuroscienze e Diagnostica avanzata, Palermo, Italy;
8
Section of Psychiatry,
Department of Neuroscience, Biomedicine and Movement, University of Verona,
Verona, Italy;
9
University of Bologna Department of Medical and Surgical
Sciences: Universita degli Studi di Bologna Dipartimento di Scienze Mediche e
Chirurgiche, Bologna, Italy;
10
Establissement Public de Sante, Maison Blanche,
France;
11
Univ Paris Est Creteil (UPEC), AP-HP, Hopitaux Universitaires ‘H.
Mondor’, DMU IMPACT, INSERM, IMRB, Translational Neuropsychiatry,
Fondation FondaMental, F-94010 Creteil, France;
12
Institute for Mental Health,
GGZ Rivierduinen, Leiden, The Netherlands;
13
Mount Sinai School of Medicine
Department of Psychiatry: Icahn School of Medicine, New York, NY, USA;
14
Early
Psychosis Section, Department of Psychiatry, Amsterdam UMC, Amsterdam, The
Netherlands;
15
EA 7280 Npsydo, Universite Clermont Auvergne, Clermont-
Ferrand, France;
16
Department of Preventive Medicine, Faculdade de Medicina,
Universidade de São Paulo, São Paulo, Brazil;
17
Department of Neuroscience
and Behaviour, Division of Psychiatry, Ribeirao Preto Medical School, University
of São Paulo, São Paulo, Brazil;
18
Department of Psychiatry, Hospital ‘Virgen de
la Luz’, Cuenca, Spain;
19
Department of Psychiatry, Psychiatric Genetic Group,
Instituto de Investigation Sanitaria de Santiago de Compostela, Complejo
Hospitalario Universitario de Santiago de Compostela, Spain;
20
Department of
Medicine, Psychiatry Area, Universidad de Oviedo, ISPA, INEUROPA, CIBERSAM,
Oviedo, Spain;
21
Department of Psychiatry, Centro de Investigation Biomedica
en Red de Salud Mental, School of Medicine, Universidad de Valencia, Spain;
22
Barcelona Clinic Schizophrenia Unit, Hospital Clinic, Department of Medicine,
Neuroscience Institute, University of Barcelona, Institute d’investigations
Biomediques, August Pi I Sunyer, Centro de Investigation Biomedica en Red de
Salud Mental, Barcelona, Spain;
23
Department of Child and Adolescent
Psychiatry, Institute of Psychiatry and Mental Health, Hospital General
Universitario Gregorio Maranon, School of Medicine, Universidad Complutense,
ISGM, CIBERSAM, Madrid, Spain;
24
CAMEO Early Intervention Service,
Cambridgeshire and Peterborough National Health Service Foundation Trust,
Cambridge, England;
25
Division of Psychological Medicine and Clinical
Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics,
Cardiff University, Cardiff, UK;
26
Department of Psychiatry and
Neuropsychology, School for Mental Health and Neuroscience, Maastricht
University, Maastricht, The Netherlands;
27
Hong Kong University: University of
Hong Kong, Hong Kong and
28
The University of Sheffield Department of
Psychology, Sheffield, UK
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