Psychiatria Danubina, 2019; Vol. 31, Suppl.

2, pp S162-170 Conference paper

© Medicinska naklada - Zagreb, Croatia

CLINICAL CHALLENGES IN PATIENTS WITH FIRST

EPISODE PSYCHOSIS AND CANNABIS USE:
MINI-REVIEW AND A CASE STUDY
Josefina Gerlach1, Barbara Koret1, Natko Gereš1, Katarina Matiü1, Diana Prskalo-ýule1,
Tihana Zadravec Vrbanc1, Vanja Lovretiü1, Katarina Skopljak1, Tin Matoš1,
Ivona Šimunoviü Filipþiü2 & Igor Filipþiü1,3,4
1
Psychiatric Hospital "Sveti Ivan", Zagreb, Croatia
2
University Hospital Center Zagreb, Zagreb, Croatia
3
Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
4
School of Medicine, University of Zagreb, Zagreb, Croatia

SUMMARY
The influence of cannabis use on the occurrence, clinical course and the treatment of the first psychotic episode (FEP) is well
documented. However, the exact link is still not clearly established. The aim of this article is to review and report the noticed
increase in the number of hospitalizations of young people with a clinical appearance of severe psychotic decompensation following
cannabis consumption and to show the clinical challenges in treatment of the FEP. The case study describes the clinical course of a
five selected patients with a diagnosis of the FEP and positive tetrahydrocannabinol (THC) urine test who were hospitalized in a
similar pattern of events. They all have a history of cannabis consumption for at least 6 years in continuity and were presented with
severe psychomotor agitation, disorganisation, confusion and aggression at admission. Although the chosen drug to treat all patients
was atypical antipsychotic and benzodiazepines, the course of the disorder and the clinical response to therapy were noticeably
different in each patient. The clinical presentation of FEP in cannabis users can be atypical and highly unpredictable from mild
psychotic symptoms to severe substance intoxication delirium. In clinical practice clinicians treating new onset psychosis need to be
watchful for cannabis and synthetic cannabinoids induced psychosis. Pharmacotherapeutic interventions include prompt and
adequate use of the benzodiazepine, second-generation antipsychotic, and mood-stabilizers. Further research in the pharmaco-
therapy of cannabis-induced psychosis is required.

Key words: cannabis - synthetic cannabinoids - psychosis - first episode psychosis - early-phase psychosis - schizophrenia - case study

* * * * *

INTRODUCTION bis at age 15 or younger may lead to earlier onset of

psychosis, and increase the odds for the psychotic
Cannabis and psychosis disorder but not independently of frequency or the
There is a growing body of evidence that daily use potency of the cannabis used. (Di Forti et al. 2019,
of cannabis and the use of high-potency cannabis is 2014, Mustonen et al. 2018). Some studies suggest that
associated with an increased odds of developing non an earlier onset of psychosis may be due to a toxic
affective psychotic disorders, especially for those with a effect of cannabis rather than a severe mental illness
pre-existing vulnerability and elevated familial risk for alone (Mustonen et al. 2018). Estimated time between
psychosis (Di Forti et al. 2019, Gage et al. 2016, Kend- first cannabis use and psychosis onset is around six
ler et al. 2019, Mustonen et al. 2018). Yet, ascertaining years (Leeson et al. 2012). Furthermore, studies show
causation is more challenging (Gage et al. 2017). About that higher levels of cannabis use are associated with
a third of all patients with first-episode psychosis (FEP) greater risk of psychosis, giving an odds ratio of 3.90
are also cannabis users (Meng et al. 2017, Myles et al. for the risk of a psychotic event among the heaviest
2016). Overall, there is around 34% prevalence of clini- cannabis users versus nonusers (Marconi et al. 2016).
cally significant cannabis consumption in FEP, while Additionally, there is also a firm argument that subjects
the odds of continued cannabis use at the follow-up who had been using high-potency cannabis (tetrahydro-
period declines by approximately 50% over time. cannabinol (THC) •10%) on a daily basis had the
(Myles et al. 2016). Many studies have found that the earliest onset, approximately six years earlier than
use of cannabis is connected with an earlier onset of nonusers and it’s the strongest independent predictors of
psychotic illness and that this connection is based on whether any given individual would have a psychotic
several factors. A psychotic episode may occur almost disorder or not (Di Forti et al. 2019, 2014).
three years earlier in the life of those who use cannabis Although the connection between THC and psycho-
when compared with nonusers (Myles et al. 2012) and sis has been explored for decades, the relationship bet-
there is an apparent linear connection between age of ween novel synthetic cannabinoids (SCs) and psychosis
first cannabis use and age of the FEP, but also pro- is in its infancy. SCs products are “herbal” mixtures
dromal symptoms (Leeson et al. 2012). Starting canna- laced with various compounds that are sold around the

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 Josefina Gerlach, Barbara Koret, Natko Gereš, Katarina Matiü, Diana Prskalo-ýule, Tihana Zadravec Vrbanc, Vanja Lovretiü, Katarina Skopljak,
Tin Matoš, Ivona Šimunoviü Filipþiü & Igor Filipþiü: CLINICAL CHALLENGES IN PATIENTS WITH FIRST EPISODE PSYCHOSIS
AND CANNABIS USE: MINI-REVIEW AND A CASE STUDY Psychiatria Danubina, 2019; Vol. 31, Suppl. 2, pp 162-170

world under a variety of brand names to be smoked or there is no wonder combining these two factors will
consumed in other ways (Advisory Council on the contribute to the risk of agitation and aggression. How-
Misuse of Drugs, 2014). In general, most biological ever, the link between cannabis use and violent beha-
effects of SCs mimic those of ǻ9-THC; although the viour in FEP is unclear (Moulin et al. 2018). Although
greater potency of SCs at cannabinoid-1 receptors some research and reviews indicate that psychiatric pa-
produces stronger pharmacodynamics effects. The role tients who use cannabis show a higher risk of aggressive
of SCs in psychosis is complex, and whether prior SC and violent behaviour (Carabellese et al. 2013, Della-
use has a role in developing chronic psychotic disorders zizzo et al. 2019, Dugré et al. 2017, Moulin et al. 2018).
such as schizophrenia is still unclear (Deng et al. 2018). Furthermore, a clinical presentation of SCs use is
highly unpredictable (Kronstrand et al. 2013, Deng et al.
Clinical manifestation 2018, Kolla & Mishra 2018). A recent observational
study of a relatively large cohort of 594 SC users found
There is a lot of evidence that patients with psy- that they were more severely psychotic than cannabis
chosis who are regular cannabis users have more posi- users. In particular, the SC users were more often
tive symptoms, more frequent relapses, and require diagnosed with psychotic disorders, were treated with
more hospitalization (Hall & Degenhardt 2008, Patel et higher doses of antipsychotic medications, and required
al. 2016). However, recent research presented no signi- longer hospitalizations (Bassir Nia et al. 2016). Charac-
ficant associations between continuation and cessation teristic symptoms of SC not seen in cannabis intoxi-
of cannabis use and positive and negative symptoms cation include enhanced aggression and agitation, seizu-
over the 2-year follow-up, while the depressive res, hypertension, emesis, hypokalemia, and kidney
symptoms were significantly higher in patients who injury (Deng et al. 2018, Gray et al. 2016, Kolla &
continued using cannabis (Hadden et al. 2018). When Mishra 2018).
presented with a patient with psychotic symptoms and
history of cannabis use, we may ask ourselves a
question – ''Is there a clear difference between clinical Cannabis and medication
manifestation of a primary psychotic disorder with Both medication non-adherence and co-morbid can-
concurrent substance abuse (PPD+SA) and a substance- nabis abuse are associated with poor clinical outcome in
induced psychotic disorder (SIPD)?''. Distinguishing FEP, more frequent hospitalizations, increased rate of
these entities can be diagnostically challenging. A compulsory hospital admission and a greater number of
recent systematic review did not reveal many days spent in hospital (Patel et al. 2016). The potential
differences in the psychopathology. However, the reason for such outcomes was a possible failure of anti-
findings indicate that patients with SIPD had both fewer psychotic treatment, indicated by the number of unique
positive and negative symptoms, but more depression antipsychotics prescribed up to the 5 years follow up
and anxiety than patients with PPD+SA. Logically, (Patel et al. 2016). This could mean that patients were
patients with SIPD had a weaker family history of either resistant to the given antipsychotic or poorly ad-
psychotic disorder but also a higher degree of insight herent to the treatment or that there were overwhelming
(Wilson et al. 2017) and faired worse regarding side effects. Some patients could have had reduced do-
occupational outcomes (O’Connell et al. 2018). Hence, pamine synthesis capacity, which could reduce response
O’Connell and colleagues found that 35.7% of those to the antidopaminergic effect of antipsychotics (Bloom-
with SIPD had a change of diagnosis to a schizophrenia field et al. 2014. Howes & Kapur 2014). Another pos-
spectrum or bipolar disorder after a median of 84 weeks sible reason for treatment failure could be the phar-
(O’Connell et al. 2018). But from a psychopathological macokinetic interactions between cannabis and other
point of view, „cannabis psychosis“ may not be quali- medications. For example, the main psychoactive part
tatively any different than any other type of psychosis of cannabis, tetrahydrocannabinol (THC) and canna-
(Baldacchino et al. 2012, O’Connell et al. 2018, Thomp- bidiol (CBD) are both metabolized by cytochrome P450
son et al. 2016). A recent prospective cohort study came enzymes CYP3A4 and CYP2C9. Consequently, the
up with the results showing higher excitement symp- CYP3A4 inhibitors may slightly increase THC levels,
toms at baseline in patients who used cannabis before while CYP3A4 inducers slightly decrease THC and
FEP, as well as a better response for excitement and CBD levels (Stout & Cimino 2014). THC is a CYP1A2
positive symptoms (Meng et al. 2017). inducer, and it can theoretically decrease serum con-
Excitement symptoms are often presented in the centrations of some psychiatric drugs such as cloza-
form of agitation which follows the fact that psychiatric pine, duloxetine, olanzapine, haloperidol, and chlor-
patients are generally considered as potentially dange- promazine. Although there is extensive evidence about
rous and aggressive, but despite the overall opinion, the effects of antipsychotic medications in FEP gene-
there isn’t such a great connection between mental ill- ral, the efficacy and safety of antipsychotics on
ness and violence (Fazel & Grann 2006). Since sub- psychotic symptoms in patients with comorbid can-
stance use has a clear relationship with violent beha- nabis use is not clear, as such patients are usually
viour in healthy individuals as well as in mentally ill, excluded from clinical trials.

S163
 Josefina Gerlach, Barbara Koret, Natko Gereš, Katarina Matiü, Diana Prskalo-ýule, Tihana Zadravec Vrbanc, Vanja Lovretiü, Katarina Skopljak,
Tin Matoš, Ivona Šimunoviü Filipþiü & Igor Filipþiü: CLINICAL CHALLENGES IN PATIENTS WITH FIRST EPISODE PSYCHOSIS
AND CANNABIS USE: MINI-REVIEW AND A CASE STUDY Psychiatria Danubina, 2019; Vol. 31, Suppl. 2, pp 162-170

Intrigued by all the literature findings and questions His inpatient medication regimen with risperidone a
raised by everyday clinical practice, we decided to 2mg/day, lorazepam a 3 mg/day and sodium valproate
assess the practical issues of cannabis use in patients 600 mg/day was effective for his psychotic symptoms,
with FEP from both psychopathological and psycho- but within few days, he developed bilateral tremors, and
pharmacological point of view. rigidity on upper limbs, which were manifestations of
extrapyramidal symptoms (EPS). A probable diagnosis
SUBJECTS AND METHODS of risperidone-induced EPS was, made and the drug was
withdrawn. He was started on 10 mg aripiprazole for his
This study describes a case series of five FEP psychotic symptoms and was discharged after 13 days
patients with positive THC urine test who were on LAI aripiprazole a 400 mg monthly in complete
presented with severe agitation at admission, besides resolution of symptoms.
other psychotic symptoms, and was pharmacologically Case 2#
challenging to treat. They were all treated at the Centre A 27-year-old man, with no history of psychiatric
for Integrative Psychiatry in Psychiatric Hospital “Sveti illness, was brought into hospital’s ER by an ambulance
Ivan”, Croatia. The data was collected from electronic and accompanied by three policemen, after being found
documentation for each patient individually and based wandering in a psychotic state on a highway near the
medical history information, as well as psychiatric state border. On admission, he is present with agitation,
interviews, conducted multiple times during the hos- disruptive, and unpredictable behavior, irritable, shou-
pitalization, laboratory blood and urine tests, nurse ting, and threatening staff members. He developed in-
documentation, psychological and neurological exami- creasing paranoid concerns that his family has turned
nations. against him and that an assassin was sent to kill him. He
was frightened and went to the state border to escape to
RESULTS another country where his suspicions about the conspi-
racy would be heard. He has been treated with risperi-
Clinical cases done a 2 mg/day and lorazepam a 3 mg/day.
Case 1# He grew up in a dysfunctional family. At the age of
A 26-year-old man, with no history of psychiatric 16, he begins to consume cannabis. Gradually, the con-
illness, is brought into hospital’s emergency room dition stabilizes for 3 days, but two days after the ini-
(ER) by an ambulance and police, and his brother after tial stabilization, the patient becomes restless, confu-
he punched his mentor because he thought he was sed and disorganized, extremely demanding, presents a
working on a machine that would destroy the world. variety of delusional ideas, and a paranoid concerns.
On admission, he is present with extreme agitation, Diazepam IV 20 mg was administered, and the dose of
confusion, and disorganization. He is leaping, running, risperidone was increased to 4 mg/day due to poor
shouting, laughing, crying, and insulting the policemen symptom control. Following the modification of the-
and the medical stuff, vulgar, noncompliant and un- rapy, the patient is quickly calmed down. After 15
aware of his condition. After initial clinical assess- days of treatment in the acute ward, he is eventually
ment, he remains uncooperative and disruptive, sub- transferred to the psychotherapeutic department. After
sequently, he was physically restrained and given a total of 50 days of hospitalization, the patient is
intramuscular (IM) haloperidol 10 mg, and intravenous discharged in a compensated mental state on paliperi-
(IV) diazepam 20 mg was administered, to prevent done palmitate 100 mg monthly, diazepam 5 mg/day
harm to himself or others. Next day after admission, and zolpidem 10 mg/day.
the psychotic production fades, mood, psychosis, and Case 3#
aggression improve, and the patient is calmer and A 21-year-old female, with no history of psychiatric
compliant. He had tested positive for THC, other illness, is brought into hospital’s ER accompanied by
laboratory studies completed during he’s hospitali- emergency medical services after her boyfriend called
zation are unremarkable. the police because she manically ran around the apart-
He grew up in a dysfunctional family, and he was ment, threatened with suicide, and locked herself in the
often subjected to mockery and mistreatment by peers. toilet. Upon arrival in the hospital, she starts to resist,
At the age of 15, he began smoking marijuana inten- paranoid interpretation of reality was present, she was
sively, which continued to date. After the breakup of extremely aggressive, unmanageable. She took medica-
only emotional relationship, two years ago, he became tions after long persuasion. To address her symptoms,
more consumed by cannabis, and he experimented with she received olanzapine 5mg/day, and diazepam IV 20
psilocybin mushrooms. A week before hospitalization, mg was administered.
the patient describes that something "clicked in him," She was born in a dysfunctional family where there
and he started believing in God, reading hidden was often physical violence, and she was often found
messages from random conversations, realizing that the fleeing from home. From the age of 15, she is regularly
universe works at 430Hz. using cannabis. Three months before being admitted,

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 Josefina Gerlach, Barbara Koret, Natko Gereš, Katarina Matiü, Diana Prskalo-ýule, Tihana Zadravec Vrbanc, Vanja Lovretiü, Katarina Skopljak,
Tin Matoš, Ivona Šimunoviü Filipþiü & Igor Filipþiü: CLINICAL CHALLENGES IN PATIENTS WITH FIRST EPISODE PSYCHOSIS
AND CANNABIS USE: MINI-REVIEW AND A CASE STUDY Psychiatria Danubina, 2019; Vol. 31, Suppl. 2, pp 162-170

she began to behave bizarrely. According to the sister, He received a combination of paliperidone palmitate
she often smoked weed, had dramatic mood oscillations, 100 mg and clozapine 250 mg with augmentation from
religious delusions, and was physically aggressive. sodium valproate 600 mg. Gradually his sleep is
Three days after admission, she is calm and coope- regulated, the psychotic symptoms are paling; he is
rative, agrees to therapy, states that she believes that her critical to THC consumption, and negates craving. After
medication helps her, and realizes she needs treatment. 18 days of treatment in the acute ward, he had been
On the fifth day, the psychotic symptoms exacerbate, transferred to the psychotherapeutic department. After
she again refuses therapy, is paranoid and aggressive two weeks of psychotherapy treatment the patient and
towards the medical staff. She received diazepam IV 20 his family insist on discharged. He was released in an
mg and starts risperidone 2 mg/day, and oral clonaze- uncompleted remission with a recommendation to con-
pam 0.5 mg was also added to relieve anxiety and tinue with the following medication: paliperidone pal-
sedate the patient. Despite the modification of therapy, mitate 100 mg, clozapine 250 mg, sodium valproate
the patient's psychological state was oscillating day by 600 mg, and lorazepam a 3 mg.
day. Clonazepam is switched to quetiapine, 25 to 50 mg
Case 5 #
as needed, to address ongoing mood oscillation and in-
somnia and to reduce the risk of dependency on clona- A 24-year-old man, with no history of psychiatric
zepam. All laboratory studies completed during she’s illness, was brought into the hospital’s ER by an ambu-
hospitalization are unremarkable. Urine drug screen was lance and accompanied by ten policemen for inadequate
positive for THC. She does not undergo any head and bizarre behavior in public. On admission, he is
imaging. During hospitalization, quetiapine dose was present with religious delusions, calling himself an
increased to 200 mg/day. Over the next few days, her omnipotent god. He is disorganized, restless, verbally,
mood, psychosis, and aggression improve. The tenth and physically aggressive toward staff members. He
day of treatment, her condition stabilized After 16 days received IV diazepam 20 mg and risperidone 2 mg/day,
of hospitalization she is calm and cooperative, mood, which helps to alleviate his disruptive behaviors.
psychosis, and aggression improve. She denies suicidal He has always had problems adapting to a new
or homicidal ideation and is deemed safe for discharge. environment and has a feeling that he does not belong
She was discharged on LAI risperidone 25 mg bi- anywhere. He begins with the consumption of various
monthly and quetiapine 200 mg/day. drugs at the age of 17 of which only cannabis is con-
sumed regularly. Half a year before arriving at our
Case 4 # hospital, he feels excess energy and frequent mood
A 24-year-old man was brought to the ER with changes.
emergency medical services. He was disorganized, The next day, after he sleeps through the night, he
refuses contact, prays, and wants to talk only with the does not remember the events that preceded his admit-
Pope. Upon arrival, he becomes physically aggressive tance. He was calm, cooperative, accepts medications
towards the staff, and had to be restrained. He refused and treatment. Over time and with adequate treatment
therapy, and IM haloperidol 10 mg and IM diazepam (risperidone 4 mg/day and clonazepam 0.5 to 1 mg as
10mg are applied after which he calmed down. needed) resulted in gradual normalization of vital signs
In childhood, he had problems with a stutter and along with psychotic symptoms and behavioral control
involuntary body movements, which is why peers teased such that he returned to his baseline mental status and
him, and often physically abused him. He started to was discharged on hospital day 12.
consume cannabis when he was 16-year-old. His family
and friends describe him as passive, withdrawn, obe-
Case review
dient. The day before the reception to the hospital, the
patient began to behave differently; he was in an In this case study, the status of five selected patients
elevated mood, quick and extensive in contact, agitated, is monitored, four male and one female, aged between
which was unusual for him. His father tried to get him 21 and 26 admitted at the hospital under the clinical
to the ER, but he ran away from the car. The second day appearance of the FEP and a positive THC urine test.
after admission, he was still agitated, aggressive, and They are hospitalized after a similar pattern of events,
uncooperative, he displayed significant disorganization following police intervention and emergency medical
and thought blocking. He received IM olanzapine 10 mg assistance and arrive disorganized, confused and hostile,
but in the evening he became aggressive, hostile and with disruptive and unpredictable behavior. Upon arri-
disorganized again. His agitation resolved following val, initial assessment and routine laboratory processing
acute administration of IV diazepam 20 mg, and anti- were performed. After patients, acute symptoms were
psychotic treatment was change to risperidone stabilized, a neurological, and psychological exami-
2 mg/day. All laboratory studies completed during he’s nation was performed. The patients` laboratory findings
hospitalization are unremarkable. A urine drug screen were within normal limits, and in all cases, acute neuro-
was positive for THC. His mental state oscillated, at logical events were excluded. Interestingly, all patients
times he was uncooperative, and his psychotic symp- come from dysfunctional primary families with negative
toms remained fluctuant and have sleep disturbances. psychiatric history with experience of early childhood

S165
 Josefina Gerlach, Barbara Koret, Natko Gereš, Katarina Matiü, Diana Prskalo-ýule, Tihana Zadravec Vrbanc, Vanja Lovretiü, Katarina Skopljak,
Tin Matoš, Ivona Šimunoviü Filipþiü & Igor Filipþiü: CLINICAL CHALLENGES IN PATIENTS WITH FIRST EPISODE PSYCHOSIS
AND CANNABIS USE: MINI-REVIEW AND A CASE STUDY Psychiatria Danubina, 2019; Vol. 31, Suppl. 2, pp 162-170

trauma. They all have a history of cannabis al. 2019). In our study, all the presented patients had
consumption for at least 6 years in continuity together no previous medical record of psychiatric illness, as
with occasional experimentation with other well as no family history of schizophrenia or other
psychoactive substances. On average, the onset of psychotic disorders. All this information is in accor-
cannabis use is at the age of 16. According to psycho- dance with the observations from the relevant litera-
logical testing and responses in the Applied Personality ture, which indicates that cannabis use may induce
Questionnaire (PAI), it is common for everyone to acute psychotic experiences and affect the severity of
emphasize impulsiveness, an inclination to beware and psychotic symptoms. There have been reports of a 2-
risk behavior, aggressive coping with problems, weak fold increase in the risk to develop a psychotic dis-
control of hostile reaction in relationships, and wea- order in average cannabis users compared to nonusers
kened tolerance on frustration in the personality domain. as well as approximately a 4-fold increase in risk for
Although the chosen drug to treat all patients was an the heaviest users (Henquet et al. 2005, Marconi et al.
atypical antipsychotic course of the disease and the 2016, Moore et al. 2007, Semple et al. 2005) Accor-
clinical response to therapy was noticeably different in ding to one study, SIPD patients experienced sig-
each patient. The duration of hospitalizations was from nificantly more severe symptoms of mania and distur-
13 to 50 days. Two out of five patients continued treat- bed behaviour compared to those with PPD + SA, but
ment at the psychotherapeutic department after treat- these findings were only significant on admission to
ment in the acute department. Two out of five patients hospital and symptoms diminished rapidly (Dawe et al.
experienced a relapse within a year after being released 2011). Our patients also followed this pattern and were
from our hospital, notably both of them did not continue presented with severe symptoms of agitation, aggres-
to take antipsychotic medications and continued with sive behaviour, hostility, delusions, visual and auditory
cannabis use. hallucinations, and persecution ideas when admitted to
The clinical presentation differs significantly among the hospital. However, the response to the applied
patients. In two patients, it was noted that within 12 therapy was variable, from rapid improvement within
hours of application of the drugs, the psychotic substrate 12 hours, through the oscillation of the symptoms
fades and rapid recovery occurs. Meanwhile, in the daily to the gradual stabilization of the mental state in
other three patient’s mental state highly oscillated for the following ten days. This could lead us to a few
days followed by gradual improvement of the mental very different paths. If we observe described patients
state. As mentioned, the drug of choice was atypical through the loop of cannabis-induced psychotic
antipsychotic, and depending on the clinical appearance, disorder, one of the possible explanations of such a
a mood stabilizer, anxiolytic, and other atypical anti- dramatic clinical appearance is the fact that nowadays
psychotics at low doses. The response to therapy is cannabis has higher potency and the level of THC
noticeably different in each patient, and the clinical (tetrahydrocannabinol) in illicit cannabis samples has
appearance of the FEP is atypical, although we notice grown from around 4% during 1995 to almost 12% in
the significant agitation improvement upon admini- 2014, while the level of CBD (cannabidiol) fell. In
stration of a high dose of IV benzodiazepines. other words, cannabis is stronger now than it was
twenty years ago (ElSohly et al., 2016). Surely we
DISCUSSION didn’t have the opportunity to analyse the cannabis
samples and to examine the potency of it, but high
Based on our observation and experience, the clini- potency cannabis could be one of the reasons for
cal manifestation of FEP in patients who are also severe agitation in presented patients. The other reason
cannabis users can be unpredictable. As seen from for more aggressive symptoms in patients with FEP is
given examples, symptoms may vary from well-known a relatively high percentage of use of novel psycho-
psychotic signs such as delusions, hallucinations, or active substances (NPS) among people between ages
negative symptoms to the severe psychomotor agita- 18 and 50 in our country. One of the epidemiological
tion, irritability, or aggression. Some studies found studies revealed that 19.1% of people in Croatia who
that duration of untreated psychosis (DUP) is shorter goes to the night clubs had tried some of the NPS at
among substance-induced psychotic disorders (SIPD) least once in a lifetime (Glavak Tkaliü et al. 2018).
than in primary psychotic disorders with concurrent Psychopathological symptoms associated with NPS, in
substance abuse (PPD+SA) (Wilson et al. 2017). With particular with SC use in comparison with natural
all the given information, we might ask ourselves - cannabis include severe sleep problems, hypomanic
does the cannabis use affects the incidence rates of symptoms, somatization, depression, anxiety, hostility,
psychotic disorders? One of the recent studies found a phobic anxiety, paranoid ideation and psychoticism
correlation between the incidence rates for psychotic (Mensen et al. 2019). Since the possibilities to detect
disorder and the prevalence of daily cannabis use in synthetic cannabinoids in organic samples such as
controls. The incidence rates were highest in areas urine are very limited, we cannot be sure if some of the
where an everyday use and use of high-potency patients could use some of the unknown and unde-
cannabis (THC •10%) was more prevalent (Di Forti et tected NPS.

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 Josefina Gerlach, Barbara Koret, Natko Gereš, Katarina Matiü, Diana Prskalo-ýule, Tihana Zadravec Vrbanc, Vanja Lovretiü, Katarina Skopljak,
Tin Matoš, Ivona Šimunoviü Filipþiü & Igor Filipþiü: CLINICAL CHALLENGES IN PATIENTS WITH FIRST EPISODE PSYCHOSIS
AND CANNABIS USE: MINI-REVIEW AND A CASE STUDY Psychiatria Danubina, 2019; Vol. 31, Suppl. 2, pp 162-170

Table 1.
Brief Psychotic Episode* Delirium* Symptoms Of Described Patients
Presence of one (or more) of the A disturbance in attention (i.e., Extreme agitation, hostility,
following symptoms: delusions, reduced ability to direct, focus, disorientation, disorganization, attention
hallucinations, disorganized speech sustain, and shift attention) and disorders, delusions, and hallucinations,
(e.g., frequent derailment or awareness (reduced orientation to lost the ability to test reality, verbal and
incoherence), grossly disorganized the environment). physical aggression were present.
or catatonic behavior.
Duration of an episode of the The disturbance develops over a The course of the disease was different
disturbance is at least 1 day but less short period of time (usually hours in each patient. In some, the disturbance
than 1 month, with to a few days), represents a change developed in a short period of time, and
eventual full return to premorbid from baseline attention and awa- in others for a longer period. Further-
level of functioning. reness, and tends to fluctuate in more, an episode of the disturbance had
severity during the course of a day. a different duration in each patient; from
one day to a week with fluctuation in the
severity of symptoms during the course
of that week.
The disturbance is not better explai- An additional disturbance in cogni- According to medical history data,
ned by major depressive or bipolar tion (e.g., memory deficit, disorien- psychological and neurological
disorder with psychotic features or tation, language, visuospatial ability, examinations in all patients were not
another psychotic disorder such as or perception). registered any other neurological or
schizophrenia or catatonia, and is mental illness
not attributable to the physiological
effects of a substance (e.g., a drug
of abuse,a medication) or another
medical condition.
These disturbances are not better The patients` laboratory findings were
explained by another preexisting, within normal limits, and in all cases,
established, or evolving neuro- acute neurological events were
cognitive disorder and do not occur excluded.
in the context of a severely reduced
level of arousal, such as coma.
There is evidence from the history, All of the patients had positive tetra-
physical examination, or laboratory hydrocannabinol (THC) urine test.
findings that the disturbance is a
direct physiological consequence
of another medical condition, sub-
stance intoxication or withdrawal
(i.e., due to a drug of abuse or to a
medication), or exposure to a toxin,
or is due to multiple etiologies.
* Diagnostic criteria based on a DSM-V

Another interesting question could be observed from period of time and tends to fluctuate in severity during
a diagnostic point of view, and a clinician could find the day, often with worsening at night when external
himself in doubt when presented with a patient with stimuli decrease. Besides that, there are disturbances in
obvious psychotic symptoms. But when we carefully cognition such as perception disruption which may
scroll through diagnostic criteria, psychotic symptoms include misinterpretations, illusions, or hallucinations
may occur in many different mental states, beside (American Psychiatric Association 2013). However,
psychotic disorders on its own. For example, psychotic there is always clear evidence that all these symptoms
symptoms can occur in a substance intoxication or are a consequence of another medical condition,
substance withdrawal delirium. According to the fifth intoxication, or withdrawal. Other symptoms associated
edition of Diagnostic and statistical manual of mental with delirium are a disturbance in the sleep-wake cycle
disorders (DSM-V) (American Psychiatric Association with excessive nighttime agitation and rapid shifts in
2013) delirium is characterized by the disturbance in emotional states which can be manifested in screaming,
attention and awareness which develops over a short calling out or making strange sounds. All these

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 Josefina Gerlach, Barbara Koret, Natko Gereš, Katarina Matiü, Diana Prskalo-ýule, Tihana Zadravec Vrbanc, Vanja Lovretiü, Katarina Skopljak,
Tin Matoš, Ivona Šimunoviü Filipþiü & Igor Filipþiü: CLINICAL CHALLENGES IN PATIENTS WITH FIRST EPISODE PSYCHOSIS
AND CANNABIS USE: MINI-REVIEW AND A CASE STUDY Psychiatria Danubina, 2019; Vol. 31, Suppl. 2, pp 162-170

symptoms can be sometimes difficult to distinguish link between cannabis use and psychosis. It is not
from acute psychosis since individuals with the brief irrelevant to mention the effect of the environmental
psychotic disorder (BPD) also usually experience factor as well as the influence of personality traits on the
anxiety or overwhelming confusion, and they may have course of the treatment. This can be one of the reasons
rapid shifts from one intense effect to another. Diffe- for therapeutic non-adherence and relapse of the disease.
rential diagnosis between a BPD and psychotic disorder
due to another medical condition, delirium, or substan- CONCLUSION
ce-related disorders can be determined when there is
clear evidence from the medical history, physical exa- The clinical presentation of FEP in cannabis users
mination, laboratory or other diagnostic tests that symp- can be atypical and highly unpredictable from mild
toms are the consequence of one of these conditions psychotic symptoms to severe substance intoxication
(American Psychiatric Association, 2013). Table 1. delirium. In clinical practice clinicians treating new
shows the differences in diagnostic criteria for the BPD onset psychosis need to be watchful for cannabis and
and delirium based and DSM-V in compare with symp- synthetic cannabinoids induced psychosis. Pharmaco-
toms our five described patients were presented with. therapeutic interventions include prompt and adequate
The findings of 2012 meta-analysis support the hypo- use of the benzodiazepine, second-generation antipsy-
thesis that cannabis consumption plays a causal role in chotic, and mood-stabilizers. Further research in the
the development of psychotic disorders in some pharmacotherapy of cannabis-induced psychosis is
patients. This also invites new treatment possibilities for required
people with schizophrenia, where the main target could
be endo-cannabinoid receptors (Newall et al. 2012).
Areas for the future study also include how cannabis use Acknowledgements:
might interact with psychiatric medications since there
The study was funded by Psychiatric Hospital “Sveti
are little data investigating how cannabis may acutely
Ivan”, Zagreb, Croatia.
affect the efficacy of antipsychotics. In our study, all
patients were given the same medication, but the Conflict of interest: None to declare.
clinical response in each patient was different. Also,
during the hospitalization period, especially in the early Contribution of individual authors:
acute phase with severe aggressive symptoms, patients
All authors contributed to the conception of this manu-
were treated with high doses of anxiolytics in order to
script, the literature search, the interpretation of the
effectively and quickly reduce their unpredictable and obtained results, participated in drafting and revi-
hostile behaviour. It is interesting to draw the line across sing the article critically.
delirium treatment in which patients also promptly
response to given anxiolytics, so our patients can be
somehow compared to acute confused state such as References
delirium. If we could gain a better understanding of how
cannabis could affect psychiatric medications, we might 1. American Psychiatric Association: Diagnostic Statistical
be able to adjust the medicine prescribed to a specific Manual of Mental Disorders, American Journal of
patient (Johnson et al. 2016). Current evidence supports Psychiatry, 2013.
the fact that high levels of cannabis use can increase the https://doi.org/10.1176/appi.books.9780890425596.744053
2. Baldacchino A, Hughes Z, Kehoe M, Blair H, Teh Y, Win-
risk for psychotic outcomes in a dose-dependent way.
deatt S, Crome IB: Cannabis psychosis: examining the evi-
Although a causal link cannot be established, there is dence for a distinctive psychopathology in a systematic and
sufficient proof to justify harm reduction prevention narrative review. Am J Addict 2012; 21(Suppl 1):S88-98.
programs (Henquet et al. 2005). A pilot version of such https://doi.org/10.1111/j.1521-0391.2012.00295.x
programme has taken a leap under the slogan “Clear 3. Bassir Nia A, Medrano B, Perkel C, Galynker I, Hurd YL:
head without weed” within the Centre for integrative Psychiatric comorbidity associated with synthetic canna-
psychiatry (CIP) multimodal Early Intervention Servi- binoid use compared to cannabis. J Psychopharmacol
ces in the form of the Day Hospital for Addictive Dis- 2016; 30:1321–1330.
orders in “Sveti Ivan” Psychiatric Hospital in Zagreb, https://doi.org/10.1177/0269881116658990
Croatia. The programme consists of eight psycho- 4. Bloomfield MAP, Morgan CJA, Egerton A, Kapur S,
Curran HV, Howes OD: Dopaminergic function in
educational workshops in the form of a group with
cannabis users and its relationship to cannabis-induced
between 10-12 patients who experienced FEP triggered psychotic symptoms. Biol Psychiatry 2014; 75:470–8.
by cannabis consumption. It is focused to change https://doi.org/10.1016/j.biopsych.2013.05.027
problematic cannabis use in those patients, to prevent 5. Carabellese F, Candelli C, Martinelli D, La Tegola D,
subsequent episodes and further impairment. It is based Catanesi R: Cannabis use and violent behaviour: a
on several psychotherapies, and psychoeducational psychiatric patients cohort study in Southern Italy. Riv
approaches and every single workshop covered one Psichiatr 2013; 48:43–50.
specific area, with hope to help patients to recognize the https://doi.org/10.1708/1228.13614

S168
 Josefina Gerlach, Barbara Koret, Natko Gereš, Katarina Matiü, Diana Prskalo-ýule, Tihana Zadravec Vrbanc, Vanja Lovretiü, Katarina Skopljak,
Tin Matoš, Ivona Šimunoviü Filipþiü & Igor Filipþiü: CLINICAL CHALLENGES IN PATIENTS WITH FIRST EPISODE PSYCHOSIS
AND CANNABIS USE: MINI-REVIEW AND A CASE STUDY Psychiatria Danubina, 2019; Vol. 31, Suppl. 2, pp 162-170

6. Dawe S, Geppert L, Occhipinti S, Kingswell W: A psychosis. Early Interv Psychiatry 2018; 12:848–855.
comparison of the symptoms and short-term clinical https://doi.org/10.1111/eip.12377
course in inpatients with substance-induced psychosis and 18. Hall W, Degenhardt L: Cannabis use and the risk of
primary psychosis. J Subst Abuse Treat 2011; 40:95–101. developing a psychotic disorder. World Psychiatry 2008;
https://doi.org/10.1016/j.jsat.2010.08.002 7:68–71. https://doi.org/10.1503/cmaj.080585
7. Dellazizzo L, Potvin S, Beaudoin M, Luigi M, Dou BY, 19. Henquet C, Murray R, Linszen D, van Os J: The environ-
Giguère C-É, Dumais A: Cannabis use and violence in ment and schizophrenia: the role of cannabis use.
patients with severe mental illnesses: A meta-analytical Schizophr Bull 2005; 31:608–12.
investigation. Psychiatry Res 2019; 274:42–48. https://doi.org/10.1093/schbul/sbi027
https://doi.org/10.1016/j.psychres.2019.02.010 20. Howes OD, Kapur S: A neurobiological hypothesis for the
8. Deng H, Verrico CD, Kosten TR, Nielsen DA: Psychosis classification of schizophrenia: type A (hyperdopami-
and synthetic cannabinoids. Psychiatry Res 2018; nergic) and type B (normodopaminergic). Br J Psychiatry
268:400–412. 2014; 205:1–3. https://doi.org/10.1192/bjp.bp.113.138578
https://doi.org/10.1016/j.psychres.2018.08.012 21. Johnson JM, Wu CY, Winder GS, Casher MI, Marshall
9. Di Forti M, Quattrone D, Freeman TP, Tripoli G, Gayer- VD, Bostwick JR: The Effects of Cannabis on Inpatient
Anderson C, Quigley H, Rodriguez V, Jongsma HE, Agitation, Aggression, and Length of Stay. J Dual Diagn
Ferraro L, La Cascia C, La Barbera D, Tarricone I, 2016; 12:244–251.
Berardi D, Szöke A, Arango C, Tortelli A, Velthorst E, https://doi.org/10.1080/15504263.2016.1245457
Bernardo M, Del-Ben CM, Menezes PR, Selten J-P, Jones 22. Kendler KS, Ohlsson H, Sundquist J, Sundquist K: Predic-
PB, Kirkbride JB, Rutten BP, de Haan L, Sham PC, van tion of Onset of Substance-Induced Psychotic Disorder
Os J, Lewis CM, Lynskey M, Morgan C, Murray RM, EU- and Its Progression to Schizophrenia in a Swedish Na-
GEI WP2 Group: The contribution of cannabis use to tional Sample. Am J Psychiatry 2019.
variation in the incidence of psychotic disorder across appiajp201918101217.
Europe (EU-GEI): a multicentre case-control study. The https://doi.org/10.1176/appi.ajp.2019.18101217
lancet Psychiatry 2019; 6:427–436. 23. Kolla NJ, Mishra A: The Endocannabinoid System,
https://doi.org/10.1016/S2215-0366(19)30048-3 Aggression, and the Violence of Synthetic Cannabinoid
10. Di Forti M, Sallis H, Allegri F, Trotta A, Ferraro L, Stilo Use, Borderline Personality Disorder, Antisocial Perso-
SA, Marconi A, La Cascia C, Reis Marques T, Pariante C, nality Disorder, and Other Psychiatric Disorders. Front
Dazzan P, Mondelli V, Paparelli A, Kolliakou A, Prata D, Behav Neurosci 2018; 12:41.
Gaughran F, David AS, Morgan C, Stahl D, Khondoker https://doi.org/10.3389/fnbeh.2018.00041
M, MacCabe JH, Murray RM: Daily use, especially of 24. Leeson VC, Harrison I, Ron MA, Barnes TRE, Joyce EM:
high-potency cannabis, drives the earlier onset of psycho- The effect of cannabis use and cognitive reserve on age at
sis in cannabis users. Schizophr Bull 2014; 40:1509–17. onset and psychosis outcomes in first-episode schizo-
https://doi.org/10.1093/schbul/sbt181 phrenia. Schizophr Bull 2012; 38:873–80.
11. Dugré JR, Dellazizzo L, Giguère C-É, Potvin S, Dumais A: https://doi.org/10.1093/schbul/sbq153
Persistency of Cannabis Use Predicts Violence following 25. Marconi A, Di Forti M, Lewis CM, Murray RM, Vassos E:
Acute Psychiatric Discharge. Front psychiatry 2017; Meta-analysis of the Association Between the Level of
8:176. https://doi.org/10.3389/fpsyt.2017.00176 Cannabis Use and Risk of Psychosis. Schizophr Bull 2016;
12. ElSohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, 42:1262–9. https://doi.org/10.1093/schbul/sbw003
Church JC: Changes in Cannabis Potency Over the Last 2 26. Meng H, Johnston B, Englesakis M, Moulin DE, Bhatia A:
Decades (1995-2014): Analysis of Current Data in the Selective Cannabinoids for Chronic Neuropathic Pain: A
United States. Biol Psychiatry 2016; 79:613–9. Systematic Review and Meta-analysis. Anesth Analg 2017;
https://doi.org/10.1016/j.biopsych.2016.01.004 125:1638–1652.
13. Fazel S, Grann M: The population impact of severe mental https://doi.org/10.1213/ANE.0000000000002110
illness on violent crime. Am J Psychiatry 2006; 163:1397– 27. Moore THM, Zammit S, Lingford-Hughes A, Barnes
403. https://doi.org/10.1176/ajp.2006.163.8.1397 TRE, Jones PB, Burke M, Lewis G: Cannabis use and
14. Gage SH, Hickman M, Zammit S: Association Between risk of psychotic or affective mental health outcomes: a
Cannabis and Psychosis: Epidemiologic Evidence. Biol systematic review. Lancet (London, England) 2007;
Psychiatry 2016; 79:549–56. 370:319–28.
https://doi.org/10.1016/j.biopsych.2015.08.001 https://doi.org/10.1016/S0140-6736(07)61162-3
15. Gage SH, Jones HJ, Burgess S, Bowden J, Davey Smith G, 28. Moulin V, Baumann P, Gholamrezaee M, Alameda L,
Zammit S, Munafò MR: Assessing causality in associa- Palix J, Gasser J, Conus P: Cannabis, a Significant Risk
tions between cannabis use and schizophrenia risk: a two- Factor for Violent Behavior in the Early Phase Psychosis.
sample Mendelian randomization study. Psychol Med Two Patterns of Interaction of Factors Increase the Risk
2017; 47:971–980. of Violent Behavior: Cannabis Use Disorder and Impul-
https://doi.org/10.1017/S0033291716003172 sivity; Cannabis Use Disorder, Lack of Insight and
16. Gray R, Bressington D, Hughes E, Ivanecka A: A syste- Treatmen. Front psychiatry 2018; 9:294.
matic review of the effects of novel psychoactive sub- https://doi.org/10.3389/fpsyt.2018.00294
stances “legal highs” on people with severe mental 29. Mustonen A, Niemelä S, Nordström T, Murray GK, Mäki
illness. J Psychiatr Ment Health Nurs 2016; 23:267–81. P, Jääskeläinen E, Miettunen J: Adolescent cannabis use,
https://doi.org/10.1111/jpm.12297 baseline prodromal symptoms and the risk of psychosis.
17. Hadden KL, LeDrew K, Hogan K, Thomas B: Impact of Br J Psychiatry 2018; 212:227–233.
comorbid cannabis use on outcome in first episode https://doi.org/10.1192/bjp.2017.52

S169
 Josefina Gerlach, Barbara Koret, Natko Gereš, Katarina Matiü, Diana Prskalo-ýule, Tihana Zadravec Vrbanc, Vanja Lovretiü, Katarina Skopljak,
Tin Matoš, Ivona Šimunoviü Filipþiü & Igor Filipþiü: CLINICAL CHALLENGES IN PATIENTS WITH FIRST EPISODE PSYCHOSIS
AND CANNABIS USE: MINI-REVIEW AND A CASE STUDY Psychiatria Danubina, 2019; Vol. 31, Suppl. 2, pp 162-170

30. Myles H, Myles N, Large M: Cannabis use in first episode 34. Semple DM, McIntosh AM, Lawrie SM: Cannabis as a
psychosis: Meta-analysis of prevalence, and the time risk factor for psychosis: systematic review. J Psycho-
course of initiation and continued use. Aust N Z J pharmacol 2005; 19:187–94.
Psychiatry 2016; 50:208–19. https://doi.org/10.1177/0269881105049040
https://doi.org/10.1177/0004867415599846 35. Stout SM, Cimino NM: Exogenous cannabinoids as
31. Myles N, Newall H, Nielssen O, Large M: The association substrates, inhibitors, and inducers of human drug
between cannabis use and earlier age at onset of metabolizing enzymes: a systematic review. Drug Metab
schizophrenia and other psychoses: meta-analysis of Rev 2014; 46:86–95.
possible confounding factors. Curr Pharm Des 2012; https://doi.org/10.3109/03602532.2013.849268
18:5055–69 36. Thompson A, Marwaha S, Winsper C, Everard L, Jones
32. O’Connell J, Sunwoo M, McGorry P, O’Donoghue B: PB, Fowler D, Amos T, Freemantle N, Singh SP, Marshall
Characteristics and outcomes of young people with sub- M, Sharma V, Birchwood M: Short-term outcome of
stance induced psychotic disorder. Schizophr Res 2018; substance-induced psychotic disorder in a large UK first
6–11. https://doi.org/10.1016/j.schres.2018.11.007 episode psychosis cohort. Acta Psychiatr Scand 2016;
33. Patel R, Wilson R, Jackson R, Ball M, Shetty H, Broadbent 134:321–8. https://doi.org/10.1111/acps.12623
M, Stewart R, McGuire P, Bhattacharyya S: Association 37. Wilson L, Szigeti A, Kearney A, Clarke M: Clinical charac-
of cannabis use with hospital admission and antipsychotic teristics of primary psychotic disorders with concurrent
treatment failure in first episode psychosis: an observa- substance abuse and substance-induced psychotic dis-
tional study. BMJ Open 2016; 6:e009888. orders: A systematic review. Schizophr Res 2017;
https://doi.org/10.1136/bmjopen-2015-009888 197:78–86. https://doi.org/10.1016/j.schres.2017.11.001

Correspondence:
Josefina Gerlach, MD
Psychiatric Hospital “Sveti Ivan”
Jankomir 11, pp 68, HR-10 090 Zagreb, Croatia
E-mail: josefina.gerlach @pbsvi.hr

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