International Clinical Psychopharmacology 2002, 17:141–143 CASE REPORT

Tobacco and cannabis smoking cessation can

lead to intoxication with clozapine or olanzapine
D.F. Zullino, D. Delessert, C.B. Eap, M. Preisig and P. Baumann
Unit of Biochemistry and Clinical Psychopharmacology, University Department of Adult
Psychiatry, Prilly, Lausanne, Switzerland
Correspondence to Daniele Zullino, Unite¤ de Biochimie et Psychopharmacologie Clinique,
De¤partement Universitaire de Psychiatrie Adulte, Clinique de Cery, CH-1008 Prilly,
Lausanne, Switzerland
Tel: +41 21 643 64 04; fax: +41 21 643 64 44; e-mail: daniele.zullino@inst.hospvd.ch

Received 30 January 2002; accepted 21February 2002

Plasma levels of clozapine and olanzapine are lower in smokers than in nonsmokers, which is mainly due to induction of cytochrome
P4501A2 (CYP1A2) by some smoke constituents. Smoking cessation in patients treated with antipsychotic drugs that are CYP1A2
substrates may result in increased plasma levels of the drug and, consequently, in adverse drug effects. Two cases of patients who
smoked tobacco and cannabis are reported. The first patient, who was receiving clozapine treatment, developed confusion after
tobacco and cannabis smoking cessation, which was related to increased clozapine plasma levels. The second patient, who was
receiving olanzapine treatment, showed important extrapyramidal motor symptoms after reducing his tobacco consumption. The
clinical implication of these observations is that smoking patients treated with CYP1A2 substrate antipsychotics should regularly be
monitored with regard to their smoking consumption in order to adjust doses in cases of a reduction or increase in smoking. Int Clin
Psychopharmacol 17:141–143 r 2002 Lippincott Williams & Wilkins

Keywords: antipsychotic agents, cannabis, cytochrome P-450, enzyme induction, smoking, smoking cessation

INTRODUCTION cokinetic effect is mainly due to induction of cyto-

Nicotine dependence is the most common substance
use disorder among individuals with psychiatric
disorders and the prevalence of cigarette smoking in
schizophrenic patients is more than twice that of the
general population (Hughes et al., 1986; Tanskanen
et al., 1998; Kelly and McCreadie, 1999; Bron et al.,
2000). Schizophrenia is also associated with low
smoking cessation rates (Ziedonis and George, 1997;
Addington et al., 1998; Bron et al., 2000).
One explanation of the high association between
schizophrenia and cigarette smoking is that smoking
may counterbalance some side-effects associated with
antipsychotic medications. This may be through
nicotine effects (e.g. improvement of cognitive symp-
toms, or through a reduction of plasma concentrations
of antipsychotic drugs) (Rihs et al., 1996).
Plasma levels of clozapine and olanzapine have been
shown to be lower in smokers than in nonsmokers
(Haring et al., 1989; Ereshefsky, 1996). This pharma-
chrome P4501A2 (CYP1A2) by some smoke
constituents. Many components found in tobacco
smoke belong to the polycyclic aromatic hydrocar-
bons, which are the classical inducers of the pathway
involving the aryl hydrocarbon (Ah) receptor. The
binding of inducers to the intracellular Ah receptors,
together with another protein, the Ah receptor nuclear
translocator, increases enzyme expression by binding
to an enhancer/promoter region (Fuhr, 2000). N-
demethylation by CYP1A2 is the main metabolic
pathway for both clozapine and olanzapine. It has
previously been reported that a high CYP1A2 activity
in smokers can be related to low clozapine plasma
levels and, subsequently, to therapy refractoriness
(Bender and Eap, 1998).
Induction occurs within a few hours (Fuhr, 2000)
but little is known about the duration during which the
induction is effective after elimination of the inducing
agent. After smoking cessation, CYP1A2 activity is
expected to decrease due to the cessation of enzyme

0268-1315 r 2002 Lippincott Williams & Wilkins International Clinical Psychopharmacology 2002, Vol 17 No 3 141
 ZULLINO ET AL.

induction, resulting in an increase of CYP1A2 sub-
strate (e.g. clozapine or olanzapine) plasma concentra-
tions and, consequently, an increased risk for toxic
reactions. Two cases of grand mal seizure have been
reported for clozapine-treated patients, which occurred
2 weeks (McCarthy, 1994) and 3 weeks (Skogh et al.,
1999), respectively, after smoking cessation. In both
cases, measurement of the change of tobacco con-
sumption was not objective.
To date, no cases have been reported regarding
olanzapine or with respect to cannabis smoking
cessation.
CASE REPORTS
Case 1
The patient, a 37-year-old man, had an 8-year history
of treatment for paranoid schizophrenia and was
hospitalized at the last time at the age of 35 years.
Subsequently, he has been living in a therapeutic
community. He was a smoker since early adolescence
and began to smoke cannabis at the age of 23 years,
which rapidly increased to smoking daily. His con-
sumption was regularly measured objectively through
urine drug screenings in the therapeutic community
(Fig. 1). The screenings were always negative for other
drugs. Following the last hospitalization, the patient
was treated with clozapine 600 mg/day. Due to
intensifying paranoid ideas, the dose was raised to
700 mg, which clearly improved the paranoid sympto-
matology. Lorazepam was occasionally given as
concomitant medication only. Clozapine plasma levels
were regularly controlled, confirming good patient
compliance (Fig. 1).
Three months after the clozapine dose augmenta-
tion, the patient decided to stop smoking both tobacco
Clozapine dose600 mg/d 700 mg/d
THC Urine
Screening + + + + + + + - - - - - -
1400
and cannabis (day 0). Cannabis smoking cessation
subsequently was measured objectively by urine drug
screenings. Approximately 1 month after smoking
cessation, the patient appeared increasingly agitated,
complaining about acoustic hallucinations and mani-
festing clear paranoid ideas. The symptoms worsened
over the following 2 months, with the patient increas-
ingly being confused. Three and a half months after
smoking cessation, his clozapine plasma level was
1328 ng/ml and norclozapine was 715 ng/ml. The
clozapine dose was reduced to 500 mg/day and the
psychotic symptomatology disappeared within 1 week
with plasma concentrations returning to the pre-
smoking cessation level.
Case 2
The patient, a 25-year-old man, had been treated for a
bipolar disorder since the age of 21 years. He was
known to abuse alcohol during manic and depressive
episodes and to consume cannabis regularly. For more
than 2 years, he was treated with lithiumsulfate
1980 mg/day and sodium valproate 3500 mg/day.
Following a manic episode, olanzapine 30 mg/day
was introduced without any subjective or objective
side-effect.
After 5 weeks of olanzapine treatment, the patient
decided to reduce his daily tobacco consumption from
40 cigarettes to 10 cigarettes as an initial strategy for
smoking cessation. After 4 days, he began to develop
akathisia and, increasingly over the following days,
akinesia and bradyphrenia. Ten days after smoking
reduction, the patient consulted our outpatient facility
and showed an important Parkinson’s syndrome with
bradykinesia, stooped posture, small steps, hypomi-
mia, cogwheel rigidity, seborrhea and positive naseo-
palpebral reflex.
The olanzapine dose was reduced to 20 mg/day and
the symptomatology improved during the following
500 mg/d week, with the patient’s olanzapine plasma concentra-
- - -
tion being 15 ng/ml.

1200

1000
DISCUSSION
800
600
Nicotine modulates the release of dopamine in
400
mesencephalic dopaminergic pathways. Activation of
200
nicotinic acetylcholine receptors on dopaminergic
neurones stimulates central dopamine release and
-152
-145
-131
-117
-94
-79
-38
-17
-3
24
40
59
61
68
96
103
104
110
112
117
123
124

Day turnover and increases the release of dopamine in the

Clozapine
Norclozapine
nucleus accumbens (Balfour, 1994). Mesolimbic struc-
tures, such as the nucleus accumbens and ventral
Figure 1. Impact of cannabis smoking cessation on clo- tegmental area-regions, are implicated in the regulation
zapine and norclozapine plasma levels. of emotional expression, drug reinforcement, reward

142 International Clinical Psychopharmacology 2002, Vol 17 No 3

SMOKING CESSATION CAN LEAD TO INTOXICATION
and motivation (Gamberino and Gold, 1999). As
anergia and amotivation are phenomena frequently
observed in depression, and in the negative syndrome
of schizophrenia, it has been suggested that alterations
in the reward system could be associated with the
disposition of some subjects to develop these symp-
toms. Numerous studies have confirmed that smoking
is perceived by smokers to improve negative symp-
toms, to provide stress reduction and to enhance
positive affects. Smoking may also be used as a means
to distract attention away from disturbing stimuli
(Glassman, 1993). It is interesting to note that patients
who receive antipsychotic drugs that block dopamine
receptors experience more negative symptoms (Crow,
1980). High levels of smoking, as observed in schizo-
phrenic patients treated by typical neuroleptics, may
partially overcome this blockade and produce reward
effects. This hypothesis is corroborated by the ob-
servation that smokers smoke less when treated with
clozapine than when treated with conventional anti-
psychotics (McEvoy et al., 1999).
Although the prevalence of smoking in psychiatric
patients is higher and smoking cessation rates lower
compared to the general population, some patients
may decide to stop tobacco or cannabis consumption.
Smoking cessation in patients treated with drugs that
are CYP1A2 substrates may result in increased plasma
levels of the drug and, consequently, in adverse drug
effects, as has previously been reported (McCarthy,
1994; Skogh et al., 1999). In addition to being smokers,
our two patients were cannabis users, which raises the
question of the effect of cannabis smoking on CYP1A2
induction. As the first patient stopped tobacco and
cannabis smoking simultaneously, which was docu-
mented by cannabis urine drug screenings, a role for
cannabis cannot be ruled out.
Our second case suggests that not only total smoking
cessation, but also a substantial reduction of the
number of cigarettes smoked can be associated with
the appearance of formerly absent side-effects. This is
the first case report on this phenomenon implicating
olanzapine.
The clinical implication of these observations is that
patients who smoke and who are treated with CYP1A2
substrate antipsychotics should be monitored regularly
with regard to their smoking cessation plans, and
possibly also to any potentially large increase in
smoking. In the case of smoking cessation, appropriate
dose adjustments should be made, combined with
regular therapeutic drug monitoring, in order to ensure
that clozapine concentrations remain within the
therapeutic range.
International Clinical Psychopharmacology 2002, Vol 17 No 3
Acknowledgement
This study comprises part of the AMSP drug safety
program (Arzneimittelsicherheit in der Psychiatrie):
cases LAU-01-017 and LAU-01-029.
REFERENCES
Addington J, el-Guebaly N, Campbell W, Hodgins DC,
Addington D (1998) Smoking cessation treatment for
patients with schizophrenia. Am J Psychiatry 155:974–976.
Balfour DJK (1994) Neural mechanisms underlying
nicotine dependence. Addiction 89:1419–1423.
Bender S, Eap CB (1998) Very high cytochrome P4501A2
activity and nonresponse to clozapine. Arch Gen
Psychiatry 55:1048–1049.
Bron C, Zullino D, Besson J, Borgeat F (2000) Le
tabagisme en psychiatrie, un problème négligé. Praxis
89:1695–1699.
Crow TJ (1980) Positive and negative schizophrenic
symptoms and the role of dopamine. Br J Psychiatry
137:383–386.
Ereshefsky L (1996) Pharmacokinetics and drug interac-
tions: update for new antipsychotics. J Clin Psychiatry
57:12–25.
Fuhr U (2000) Induction of drug metabolizing enzymes.
Clin Pharmacokinet 38:493–504.
Gamberino WC, Gold MS (1999) Neurobiology of
tobacco smoking and other addicitve disorders. Psychiatr
Clin North Am 22:301–312.
Glassman AH (1993) Cigarette smoking: implications for
psychiatric illness. Am J Psychiatry 150:546–553.
Haring C, Meise U, Humpel C, Saria A, Fleischhacker
WW, Hinterhuber H (1989) Dose-related plasma levels
of clozapine: influence of smoking behaviour, sex and
age. Psychopharmacology 99:S38–S40.
Hughes JR, Hatsukami DK, Mitchell JE, Dahlgren LA
(1986) Prevalence of smoking among psychiatric out-
patients. Am J Psychiatry 143:993–997.
Kelly C, McCreadie RG (1999) Smoking habits, current
symptoms, and premorbid characteristics of schizophre-
nic patients in Nithsdale, Scotland. Am J Psychiatry
156:1751–1757.
McCarthy RH (1994) Seizures following smoking cessation
in a clozapine responder. Pharmacopsychiatry 27:210–211.
McEvoy JP, Freudenreich O, Wilson WH (1999) Smoking
and therapeutic response to clozapine in patients with
schizophrenia. Biol Psychiatry 46:125–129.
Rihs M, Müller C, Baumann P (1996) Caffeine
consumption in hospitalized psychiatric patients. Eur
Arch Psychiatry Clin Neurosci 246:83–92.
Skogh E, Bengtsson F, Nordin C (1999) Could
discontinuing smoking be hazardous for patients admi-
nistered clozapine medication? A case report. Ther Drug
Monit 21:580–582.
Tanskanen A, Viinamäki H, Koivuma-Honkanen HT,
Jääskeläinen J, Lehtonen J (1998) Smoking among
psychiatric patients. Eur J Psychiatry 12:109–118.
Ziedonis DM, George TP (1997) Schizophrenia and
nicotine use: Report of a pilot smoking cessation
program and review of neurobiological and clinical
issues. Schizophr Bull 23:2247–2254.
143