Acceptance of two variants of medical cannabis by psychotic patients: a randomised cross-over study (N=12).

Problem statement
Cannabis provokes psychotic symptoms, but is also used by psychotic patients to
dampen symptoms of the disease and side effects of the treatment. The ratio of
THC:CBD in the cannabis smoked may be decisive for either induction or
inhibition of psychotic symptoms. Cannabis varieties used in the Netherlands
are often characterized by a high THC:CBD ratio and this may increase the
probability of a psychotic relapse in patients with schizophrenia

Cannabis as causal agent in schizophrenia
Substantial epidemiological evidence shows that cannabis dose-dependently
increases the risk of and provokes psychosis (Zammit et al., 2002; Fergusson et
al., 2005; Henquet et al., 2005). The occurrence of schizophrenia in people
smoking cannabis is increased (Moore et al., 2007) and chronic cannabis smokers
show cognitive deficits similar to those seen in schizophrenic patients
(Solowij and Michie, 2007). Moreover, cannabis use is associated with early
onset of schizophrenia; young people with genetic vulnerability to
schizophrenia are particularly sensitive to the physical and mental effects of
cannabis (Degenhardt and Hall, 2006; Hollis et al., 2008). Nevertheless, the
associations found in longitudinal cohort studies are difficult to interpret
because of methodological problems, in particular the reliability of
self-reported data and the possible role of (not measured) confounders.
Finally, it seems the strong increase in the use of cannabis is not accompanied
to have gone with a higher incidence of schizophrenia (Anonymous, 2011; van
Amsterdam et al., 2004).

Cannabis as self-medication in schizophrenia
A substantial number of schizophrenic patients seem to use cannabis to
self-medicate negative symptoms and anxiety. Therefore, a higher prevalence of
cannabis use and cannabis dependence is seen in these patients as compared to
the healthy population.
Studies, using self-report questionnaires to investigate motives of cannabis
use among psychotic patients, indicate that the principal motives for use in
this group are enhancement of positive affect, social acceptance and coping
with negative affect (Spencer et al., 2002). Additional evidence that patients
may use cannabis to self-medicate distress was reported in a population-based
study where vulnerability for psychosis predicted future cannabis use in those
who had never used cannabis before the onset of psychotic symptoms (Ferdinand
et al., 2005).
Daily cannabis use predicted increases in positive affect in patients and
controls, but decreases in negative affect and increases in hallucinatory
experiences in patients only. Mood-enhancing properties of cannabis were acute,
whereas psychosis-inducing effects were sub-acute. There was no direct evidence
for self-medication effects in daily life. (Henquet et al., 2010).
These findings corroborated well with a meta-analysis, which looked at the
results of nine studies in which psychotic patients (N = 725) with and without
a comorbid substance use disorder (SUD) were compared for the presence of each
other positive and negative symptoms (Talamo et al., 2006). Psychotic patients
with SUD had more positive symptoms, but less negative symptoms on the Positive
and Negative Syndrome Scale (PANSS). Although tobacco and alcohol were
primarily used for social reasons, cannabis was 64 psychotic patients, mainly
used because of the pleasure-enhancing effects
In psychotic patients with co-morbid substance use disorders (SUD), Talamo et
al. showed that in 9 studies (N=725 subjects), SUD+ patients abused alcohol >
cannabis > cocaine. Considering the PANSS score (Positive and Negative Syndrome
Scale Scores), SUD+ patients had significantly higher PANSS-positive, and lower
PANSS-negative scores. A study in 64 psychotic patients confirmed the pleasure
enhancing effects of cannabis. Although tobacco was primarily used by them for
coping motives and alcohol for social motives, cannabis was mainly taken for
pleasure enhancement motives (Thornton et al., 2012).
Patients with psychosis are therefore more sensitive to both the
psychosis-inducing and mood-enhancing effects of cannabis. The temporal
dissociation between acute rewarding effects and sub-acute toxic influences may
be instrumental in explaining the vicious circle of deleterious use in these
patients (Henquet et al., 2010). Henquet et al. further showed that cannabis
improved mood, particularly in psychotic patients. The combination of
differential sensitivity in patients to the acute rewarding effects and the
sub-acute negative influences of cannabis on psychotic symptoms (despite the
fact that the majority of patients were using antipsychotic medication) may be
helpful in explaining the model of cannabis use in patients with psychosis, as
proposed by Spencer et al. (Spencer et al., 2002) According to this model, use
of cannabis is driven by expectations that individuals may have about the
(acute) effects of cannabis. The sub-acute negative psychotic effects may then
be experienced as evidence that more use is necessary to bring about the
anticipated rewarding effects. Hallucinatory experiences are strongly
associated with negative affect (Delespaul et al., 2002), fuelling further use
in order to experience acute improvement in mood. Other epidemiological work,
however, has suggested that cannabis may reduce negative and affective symptoms
in patients with schizophrenia (Compton et al., 2004). The reason for these
differences in results is not clear.
Reports in the literature are, however, not conclusive about the effects of
cannabis use by psychotic patients, because both positive (less negative and
positive episodes) and negative (e.g. increases number of psychotic episodes)
clinical outcomes have been reported (see below).

Cannabis use in high risk subjects and patients with schizophrenia
Negative outcome
The use of cannabis can trigger psychotic episodes in schizophrenic patients,
which has been ascribed to THC. When given in very high dose (intravenously) to
healthy humans, THC produces psychotic-like and anxiogenic effects (D'Souza et
al., 2004; D'Souza et al., 2008). Indeed, most data demonstrate an unfavourable
outcome in patients with schizophrenia and cannabis abuse, as indicated by more
severe and refractory symptoms, poorer treatment-response, higher relapse rates
and an overall worse prognosis (Linszen et al., 2004; Compton et al., 2004),
including more hospitalisations (van Dijk et al., 2012).
In 1982, it was found that schizophrenic patients in South Africa experienced
an increased frequency of acute psychotic episodes i.e. more hypomania and
agitation after the use of a variety of cannabis sativa virtually devoid of CBD
(Rottanburg et al., 1982). Several studies confirmed that cannabis use is
associated with a worsening of symptoms in subjects with psychotic disorder and
have a negative impact on the course of the disease (Degenhardt et al., 2007;
D'Souza et al., 2009).
Van der Meer et al. (van der Meer et al., 2012) recently conducted a systematic
review of studies measuring the impact of cannabis use in a clinical high-risk
(CHR) population on the transition to a first psychotic episode. Of 729
potentially relevant papers, 11 met inclusion criteria. The results of these
studies were contradictory. In some studies, cannabis use was associated with
more severe symptoms at baseline (the prodromal stage), increased pre-psychotic
symptoms immediately after intoxication, and earlier onset of certain high-risk
symptoms. In others, no significant association between cannabis use and
baseline symptomatology was found. In one study, cannabis use was even
significantly associated with a decrease in pre-psychotic negative symptoms,
and with fewer symptoms of depression and anxiety. Four out of five studies
reported no significant effect of cannabis use on transition to psychosis. It
was concluded that cannabis use seems to provoke and enhance sub-clinical
symptoms in CHR subjects. However, the results provide no consistent evidence
for an association between cannabis use and transition to a first psychosis in
CHR subjects (van der Meer et al., 2012). In a 4-year follow-up study of a
small sample of 119 patients with recent onset of psychosis it was demonstrated
that those patients who persisted in the use of cannabis had more positive (but
not negative) symptoms and a more continuous illness at follow-up (Grech et
al., 2005).
About the relationship between cannabis use and the development of psychotic
disorder several studies have shown that co-morbid cannabis use disorder (CUD)
affected the course of the disease in patients with schizophrenia negatively.
Psychosocial functioning ("confusion" and "hostility") had deteriorated
(Caspari, 1999), more severe psychotic symptoms occurred (Foti et al., 2010),
more and earlier psychotic relapses were reported, more hospitalizations were
noted (Caspari, 1999), and the patients showed less compliance (Linszen et al.,
1994; Zammit et al., 2008). A retrospective study in schizophrenic patients
(N=455) showed that those with a history of cannabis use disorder (CUD+; N=175)
performed better on measures of processing speed, verbal fluency, verbal
learning and memory than the CUD- group (N=280). The CUD+ group also scored
better in Global Assessment of Functioning (GAF) scale than the CUD- group
(DeRosse et al., 2010), suggesting that schizophrenic patients with co-morbid
CUD may represent a higher functioning subgroup of schizophrenic patients (see
also below).
Other studies on psychosocial functioning (eg in GAF scores) (Scheller-Gilkey
et al., 2002; Dervaux et al., 2003; Machielsen et al., 2010) found no
significant differences between patients with and without CUD. In patients with
first-episode psychosis with CUD Compton et al. (Compton et al., 2004) found no
difference in positive symptoms and general psychopathology, but they
experienced less prominent negative symptoms than comparable patients without
CUD.
Cannabis and alcohol use was associated with an increased risk of psychosis and
delusions (Nunn et al., 2001). The results of a systematic review also
suggested a link between cannabis use and psychosis, with the higher use
associated with a higher risk (RR 2.09) (Moore et al., 2007). When administered
in very high doses (intravenously) to healthy people THC induced psychosis-like
and anxiogenic effects (D'Souza et al., 2004; D'Souza et al., 2008).

Conclusion
It seems that cannabis use in psychotic patients may lead to fewer negative
symptoms and less anxiety, while there is a greater chance of positive symptoms
(psychosis) and related admissions due to relapse. The positive relationship
between cannabis use and psychosocial functioning that was sometimes found is
probably a result of selection, where the better functioning patients are more
able to obtain cannabis.

Pharmacological profile of THC and CBD
The psychotic effect of cannabis is closely related to the THC:CBD ratio: a
higher proportion of THC is linked to the psychosis-facilitating potential.
THC, the principal psychoactive constituent of the Cannabis sativa plant,
stimulates the central cannabinoid CB1 receptor thereby inducing the
characteristic psychomotor effects, and provokes (already existing) psychosis.
CBD, the second most abundant psychoactive constituent of Cannabis sativa, has
weak partial antagonistic properties at the CB1 receptor. CBD inhibits the
reuptake and hydrolysis of anandamide, the most important endogenous CB1
receptor agonist. As such, CBD (partly) reverses many of the physiological and
behavioural effects of CB1 receptor agonists, like THC, and more importantly
CBD lacks the unwanted psychotropic characteristics of THC (and commonly used
cannabis). Like SR141716, a selective CB1 receptor antagonist, CBD even retains
anti-psychotic properties (Zuardi et al., 2006; Schier et al., 2012) which
resemble that of atypical anti-psychotic drugs (Roser et al., 2010). Due to its
antipsychotic property (recently critically reviewed by Zuardi c.s. (Zuardi et
al., 2012)), CBD may be a therapeutic option in psychosis in general and in
schizophrenia in particular (Zuardi et al., 2012).
A double-blind study, conducted in eight healthy volunteers by Zuardi c.s. in
1982 (Zuardi et al., 1982), demonstrated interactions between THC and CBD, with
CBD (1 mg/kg) suppressing THC-induced anxiety and subjective alterations, like
alertness, and feelings of being incompetent, discontent, clear minded and
clumsy. This observation was later confirmed by various studies (Zuardi et al.,
2006; Fusar-Poli et al., 2010; Bhattacharyya et al., 2010), case reports and in
a clinical trial of Leweke et al. (Leweke et al., 2007). In the latter trial in
42 patients with acute paranoid schizophrenia, 200 mg CBD given during 2-4
weeks induced a similar decrease of symptoms as treatment with the
antipsychotic drug amisulpiride, but showed fewer side effects. Bhattacharyya
c.s reported that pre-treatment of 15 healthy men with minimal earlier exposure
to cannabis with CBD (10 mg p.o.) prevented the acute induction of psychotic
symptoms by THC (Bhattacharyya et al., 2010). Some 20 clinical trials are
registered in 2012 for the use of synthetic CBD for a variety of medical
conditions (finalised or on-going) (Clinical trials, 2012). Possibly, these
results indicate that the CBD may suppress the negative effects of THC in
patients with schizophrenia.
Finally, CBD seems to counteract some of the drug-seeking effects of THC in
humans. This was shown in smokers of high CBD:THC cannabis strains who when
intoxicated showed reduced attentional bias to drug and food stimuli compared
with smokers of low CBD:THC. Note that those smoking higher CBD:THC strains
also showed lower self-rated liking of cannabis stimuli on both test days
(Morgan et al., 2010a). The low reinforcing potency of CBD was confirmed in
rodent studies (Vann et al., 2008), where CBD reversed the conditioned place
preference effect induced by THC in CBD:THC ratios of 1:1 and 1:10 (Vann et
al., 2008).

THC:CBD ratio in cannabis strains
The geographic origin and growing conditions (temperature, inside, outside) can
make considerable difference in terms of the THC content in cannabis. For
example, cannabis produced in the Netherlands (Nederwiet) contains about 15-16%
THC (imported cannabis 5.7%) and virtually no CBD (0.3%), whereas hash imported
from Nepal, Afghanistan or Morocco contained a slightly higher proportion of
THC (17%), but also contained up to 9% CBD (mean 6.9%) (Niesink and Rigter,
2012).
Despite the negative effects of cannabis in psychotic patients mentioned above,
there are also indications that the composition of cannabis i.e. the THC:CBD
ratio is decisive for the clinical outcome. Associations between the use of
certain strains of cannabis and the occurrence of psychotic symptoms have been
found in three 'naturalistic' studies in the United Kingdom and the Netherlands
in 2010 and 2011 (Schubart et al., 2011; Morgan et al., 2010b; Morgan et al.,
2011). These studies did, however, not clarify the effect of different strains
of cannabis on psychotic symptoms in chronic psychotic patients.
High THC:CBD ratio*s have also been associated with a higher risk of a first
psychotic episode (Di Forti et al., 2009), while cannabis with high CBD content
was associated with fewer psychotic experiences (Schubart et al., 2011).
Cognitive deficits emerged in individuals who smoked cannabis with a low-CBD
content, whereas high-CBD cannabis smokers tested in memory tasks under acute
intoxication performed similarly than when tested in a drug-free environment
(Morgan et al., 2010b).
The impact of the ratio THC:CBD was nicely demonstrated by Morgan and Curran
(Morgan and Curran, 2008) who analysed hair samples to examine levels of THC
and CBD in 140 individuals. Three clear groups emerged: *THC only*, *THC+CBD*
and those with no cannabinoid in hair. The THC only group showed higher levels
of schizophrenia-like symptoms (anhedonia, hallucinations, and delusions)
compared with the no cannabinoid and *THC+CBD* group. Except a lower score for
anhedonia for 'THC + CBD' group compared with no cannabinoids, the two groups
did not differ from each other.
Patients with schizophrenia frequently encounter difficulties initiating or
maintaining sleep are encountered. Depending on the degree of psychotic
symptomatology, disturbed sleep can be found in 30-80% of schizophrenic
patients (Cohrs, 2008). Cannabis is known to induce sleepiness, but only few
data could be retrieved from literature. The hypnotic effects of THC were
evaluated in the 1970s, and it was shown that THC increased Stage 3 sleep and
reduced REM sleep (Feinberg et al., 1975). Smoked marijuana and oral
Delta-9-tetrahydrocannabinol (THC) reduce REM sleep. Moreover, acute
administration of cannabis appears to improve deep sleep (stage 3 and 4)
(Schierenbeck et al., 2008).

Conclusion
The use of cannabis is detrimental for patients with chronic psychotic
disorders, but the degree of damage is probably related to the ratio of THC and
CBD in cannabis. To improve the treatment of these patients it is necessary to
understand the effects of cannabis products with different THC: CBD ratio on
well-being of these patients.

Problem analysis
In the Utrecht mental health institutions Altrecht and Victas there are
reportedly some 80 patients with chronic psychotic disorder and severe cannabis
dependence are treated who:
1. hardly respond to currently available interventions,
2. (almost) daily visit the coffee shops, and
3. use considerable quantities of cannabis, including cannabis with a
composition which provokes rather than prevents psychotic episodes.

Various studies (Barnes et al., 2006; Mauri et al., 2006; Talamo et al., 2006;
Wade et al., 2007) have shown that many patients with a psychotic disorder and
substance use (these studies did not specifically examine cannabis but also to
other psychotropic substances) are able to become abstinent which initiates
better functioning. Especially patients with a first psychotic episode benefit
from stopping substance use. Conversely, they may, for reasons of compliance
and side effects of medications, also benefit from controlled use of cannabis
with a high CBD content (see studies of Leweke). This raises the need for a
clinical trial to investigate the therapeutic potency of CBD-enriched cannabis.
A meta-analysis of the available studies on substance use and psychotic
disorders (Mullin et al., 2012), however, showed no significant reduction of
symptoms in patients with a prolonged psychotic disorder who discontinued
substance use. Although the authors also raised methodological arguments (too
small number of enrolled longitudinal studies, limitations of cross-sectional
studies and poor quality of many studies), it can not be excluded that quitting
substance use is only effective when it occurs in the early phase of the
disease. Those who use cannabis may, however, benefit from the prescription of
cannabis with a different composition (i.e. a low THC:CBD ratio).

For literature references see Dutch section

The proposed experimental pilot study focuses on harm reduction in a specific
subpopulation, i.e. in patients with schizophrenia (long-term psychotic
disorder) with a suboptimal response to the currently available interventions,
smoking a lot of cannabis. Cannabis variants with lower THC / CBD ratios would
be significantly better for these patients than the coffeeshop variant (with a
high THC content and a relatively low CBD content) that is usually used by this
group of patients. This relates to anxiety and panic effects and more psychotic
symptoms. Before starting a RCT on the effects of replacement of cannabis with
high THC / CBD ratio by cannabis with a low THC / CBD ratio it must first be
examined whether the latter variant is accepted by these patients. In addition,
with this pilot study a first impression about the possible differences in the
(sub) acute effects of the two variants offered cannabis will be obtained.
The primary aim of this pilot study was therefore to determine the degree of
acceptance of cannabis varieties with different THC / CBD ratios by patients
with schizophrenia who (almost) daily use cannabis. Secondary readouts are
self-reporting of (sub) acute onset of fear, anxiety, pleasure / enjoyment and
psychotic symptoms. Under (sub) acute effects are thought to effects that occur
after use within 2 hours, with probably the CBD antianxiety effects likely to
occur (approximately 15 minutes) than the THC dissociative effects (60 minutes).

Hypotheses
Patients with schizophrenia prefer smoking cannabis with relatively low THC /
CBD ratio, because it has a favorable effect profile with less anxiety, panic
and unrest and a beneficial effect on dissociative and prepsychotic symptoms.
Therefore, it is expected that patients with schizophrenia are willing to
replace the cannabis which they commonly use by variants with a lower THC / CBD
ratio.

In a randomized and blinded design 12 male patients with schizophrenia (the
participants) smoke two types of cannabis; of each kind two joints (total of
four joints; 0.25 grams of cannabis per joint). The two use cannabis strains
are:
A. Medicinal cannabis I: Bedrobinol (13.5% THC, CBD 0%). This species is very
similar to the coffee shop cannabis and serves as a reference.
B. Medicinal cannabis II: Bediol (6.3% THC, 7.5% CBD)
Smoking takes place in hostels of the addiction institution Victas in Utrecht.
In addition, participants will be asked which cannabis he usually smokes. A
sample of this cannabis will be purchased by the researcher at the coffee-shop
to assay the content of THC and CBD in this cannabis.

Study Medication
The Slotervaart-pharmacy (head: Prof. JH Beijnen) buys the two medicinal
cannabis varieties Bedrobinol® and Bediol® at the firm Fagron Pharmaceuticals,
Nieuwerkerk aan de IJssel; the producer is Bedrocan). Bediol is sold in
granular form (the dried flowers are ground into particles having a size of up
to 5 millimeters). The Bedrobinol is granulated in the pharmacy, so both types
of cannabis look the same (for blinding). The Slotervaart pharmacy is
responsible for drug accountability. Bedrobinol® and Bediol® are according to
Dutch law registered as medicinal raw material. Both products are batch
analysis certificates and (highly confidential) IMPD files available.
Bedrobinol and Bediol already off label prescribed several years by doctors
prescription to patients for medical purposes, and is reimbursed by various
health ensurance companies.
After approval by the METC in Leiden and Erasmus METC in the Netherlands
earlier clinical trials conducted with the medicinal cannabis Bedrocan®
variant, which has the same legal status as Bedrobinol®. Trial Registry number
Bedrocan (Erasmus University) NTR783. Title Influence of Medicinal Cannabis
(Bedrocan) on the pharmacokinetics of irinotecan and docetaxel in cancer
patient's (METC 2003-171 Erasmus MC).
http://www.trialregister.nl/trialreg/admin/rctsearch.asp?Term=bedrocan
METC Leiden protocol number P11.007 and P13.262.

Blinding, randomization and issuance
The study has a randomized design with a classic cross-over model (6 x AABB en
6x BBAA). After purchasing the two types of medicinal cannabis and granulating
Bedrobinol by the Slotervaart pharmacy both cannabis strains are dispensed in
portions of 0.25 grams in sealed jars (with open tear strip) and stickered.
This total of 12 x 2 x 2 = 48 pots are randomized and blinded investigator. The
48 jars are randomized and transferred in three rounds to the researcher, to
each record on the transfer form. The latter has to do with the fact that the
treatment institution may have no more than 5 grams of cannabis at stock.
On the examination day, the participant of the research employee receives a
coded jar of cannabis. The participant rolls himself with his own tobacco,
rolling papers and "turn technique" the joint and smokes in the hostel of the
institution attended by the research assistant.

timeline

T1 T2 AB C. Analysis Description Reporting
I I I I I I I I I

T1
Pre-selection, recruitment and inclusion after informed consent.
Purchase of 0.5 gram of cannabis the coffee shop that is normally used by the
participants for the determination of the content of THC and CBD. Up to this
are 12 different weed samples.
Purchase of the two types of medicinal cannabis by Slotervaart pharmacy.

T2
Baseline assessment. Participants complete questionnaires on demographic,
physical and psychological characteristics and medical treatment of psychosis
(see Questionnaire F1-F8).

A
Processing of medicinal cannabis by the Slotervaart pharmacy (grinding,
weighing, distribute evenly, blinding, randomization, labeling). Transfer of 12
x 2 x 2 = 48 servings medical cannabis from 0.25 grams to the researcher (a
total of 12 grams of cannabis) on three different days, to capture transfer
forms.

Week B and C
In these two weeks are smoked in total four joints (two joints per week, each
on one morning). The research assistant and the participant are unaware (blind)
of the contents of the joint.

The participant smokes his joint in the room (hostel of the institution) and
just before (t = -5 min) and three times after smoking (t = 15, 60 and 120
minutes after smoking) questioned by the research assistant on the feelings and
experiences of smoke (see Questionnaires F9 and F10). The participant will also
be asked to write down how he feels a day later (questionnaire F9).

Sizes (baseline)
Self-report at the start of the study (baseline assessment) on the basis of the
following set of questionnaires (F1 - F8; fall time: 45-60 minutes):
F1. Demographic, physical and psychological characteristics and medical
treatment, incl. Drug use
F2. Smoking cannabis in the last month and last week (number of joints smoked,
cannabis type, price per gram of cannabis, spent amount) and use of other
resources.
F3. Motivation cannabis use and the relationship between cannabis smoking and
eliciting positive and negative symptoms.
F4. Questionnaire to smoke (QSU)
F5. Questions List psychotic symptoms (CAPE)
F6. Questionnaire measured anxiety and depression (HADS)
F7. sleep disturbance; shortened questionnaire
F8. Quality of Life (QOL)

Just before each smoking session.
F9. Did you use drugs in the last 24 hrs. If yes, how much?

Decrease 5 min before and 4 x after smoking
F10 Sense and drug effect, incl. Liking, high, stoned, relaxation, anxiety
(VAS). The participant will also be asked to write down a day later how he
feels.

At 2 hours after smoking
F11 rating and acceptance of this joint. Four short questions.

12 patients receive frpm the investigator in total 4 joints (two with Bediol
and two with Bedrobinol) that they smoke in the presence of the researcher on
four different days.

No risk and no special burden.
Participants complete questionnaires and smoking a joint on four different days
(a total of four joints). The joints consist of two different types of
medicinal cannabis.
Except for some nausea or dizziness - no problems or side effects are
anticipated. All participating patients are experienced cannabis users with a
(very) high THC and low CBD (particularly "Dutch weed" with an average content
of 15% THC). The two medical cannabis variants (Bedrobinol® and Bediol®) have a
similar or lower THC content of 13.5% and 6.3% respectively. Therefore, there
are no specific risks to be expected with the use of these variants. All
participants smoke the cannabis under the supervision of the researcher in the
treatment center, where medical staff can help quickly if (unexpected) that
would have serious side effects. If the result of the study is positive, it is
possible to launch a follow-up study into the potential clinical benefit of
high CBD / low THC cannabis for this group to determine patients.