Open-label pilot study of quetiapine treatment for cannabis dependence

Article (PDF Available)inThe American Journal of Drug and Alcohol Abuse 40(4):280-284 · July 2014with48 Reads
DOI: 10.3109/00952990.2014.884102 · Source: PubMed
Abstract
Abstract Background: There are no efficacious pharmacotherapies for cannabis dependence. The effects of quetiapine are well matched to the symptoms of cannabis withdrawal and could be useful in the treatment of cannabis dependence. Objectives: To evaluate quetiapine for the treatment of cannabis dependence and determine the optimal dosing. Methods: In an eight-week open-label outpatient pilot trial, we evaluated the feasibility of quetiapine treatment for cannabis dependence in 15 outpatients. Quetiapine was gradually titrated to 600 mg or the maximum tolerated dose. Results: The mean study retention was 6.5 weeks (±2.3), with 67% of participants completing all eight weeks of the trial. The mean maximum dose achieved was 197 mg/day (range: 25-600 mg/day). Only two of the 15 participants were able to achieve the target dose of 600 mg daily. There were no serious adverse events and no participants were discontinued from the trial due to adverse effects. The most common reported adverse effects were fatigue (80% of participants) and somnolence (47%). From baseline to week 8, the modeled overall decrease in daily dollar value of marijuana was 76.3% (CI: 63.4%, 84.7%). Over the eight weeks of the study, there was a 46.9% (CI: 11%, 68.3%) decrease in urine tetrahydrocannabinol-9-carboxylic acid (THCOOH) levels. Conclusions: These preliminary results are promising in that quetiapine treatment was tolerated by cannabis-dependent patients and associated with decreased cannabis use. The recommended maximum target dose for cannabis-dependent patients is 300 mg daily. These preliminary data support further evaluation of quetiapine as a treatment for cannabis dependence.
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Am J Drug Alcohol Abuse, 2014; 40(4): 280–284
!2014 Informa Healthcare USA, Inc. DOI: 10.3109/00952990.2014.884102
ORIGINAL ARTICLE
Open-label pilot study of quetiapine treatment for cannabis
dependence
John J. Mariani, MD
1,2
, Martina Pavlicova, PhD
3
, Agnieszka K. Mamczur, BS
1
, Adam Bisaga, MD
1,2
,
Edward V. Nunes, MD
1,2
, and Frances R. Levin, MD
1,2
1
New York State Psychiatric Institute, Division of Substance Abuse, New York,
2
Department of Psychiatry, College of Physicians and Surgeons of
Columbia University, New York, and
3
Department of Biostatistics, Columbia University, New York, USA
Abstract
Background: There are no efficacious pharmacotherapies for cannabis dependence. The effects
of quetiapine are well matched to the symptoms of cannabis withdrawal and could be useful in
the treatment of cannabis dependence. Objectives: To evaluate quetiapine for the treatment of
cannabis dependence and determine the optimal dosing. Methods: In an eight-week open-label
outpatient pilot trial, we evaluated the feasibility of quetiapine treatment for cannabis
dependence in 15 outpatients. Quetiapine was gradually titrated to 600 mg or the maximum
tolerated dose. Results: The mean study retention was 6.5 weeks (±2.3), with 67% of participants
completing all eight weeks of the trial. The mean maximum dose achieved was 197 mg/day
(range: 25–600 mg/day). Only two of the 15 participants were able to achieve the target dose of
600 mg daily. There were no serious adverse events and no participants were discontinued from
the trial due to adverse effects. The most common reported adverse effects were fatigue (80%
of participants) and somnolence (47%). From baseline to week 8, the modeled overall decrease
in daily dollar value of marijuana was 76.3% (CI: 63.4%, 84.7%). Over the eight weeks of the
study, there was a 46.9% (CI: 11%, 68.3%) decrease in urine tetrahydrocannabinol-9-carboxylic
acid (THCOOH) levels. Conclusions: These preliminary results are promising in that quetiapine
treatment was tolerated by cannabis-dependent patients and associated with decreased
cannabis use. The recommended maximum target dose for cannabis-dependent patients is
300 mg daily. These preliminary data support further evaluation of quetiapine as a treatment
for cannabis dependence.
Keywords
Cannabis, dependence, pharmacotherapy,
quetiapine, treatment
History
Received 4 July 2013
Revised 4 January 2014
Accepted 6 January 2014
Published online 25 June 2014
Introduction
Marijuana is the most widely-used illicit drug in the United
States with approximately 17.4 million individuals reporting
past-month use (1). The estimated past-year and lifetime
prevalence of marijuana abuse is thought to be 1.1% and
7.2%, respectively, and past-year and lifetime marijuana
dependence to be 0.3% and 1.3% (2,3). The use of abstinence-
based voucher incentives combined with cognitive-behavioral
therapy is associated with rates of abstinence of up to 40%
(4,5), and cognitive behavioral therapy up to 27% (6–8).
There have been a number of negative double-blind
trials of putative cannabis dependence pharmacotherapy
agents (9–12), and while some preliminary work with
N-actetylcysteine (13) and gabapentin (14) is promising,
there is still no clearly efficacious pharmacotherapy agent
available for cannabis dependence.
The psychotropic effects of cannabis are produced mainly
by delta-9-tetrahydrocannabinol (THC), although other can-
nabinoids may modify its effects (15). When a regular user of
cannabis reduces or ceases use, the development of a
withdrawal syndrome may occur. Cannabis withdrawal symp-
toms are common and clinically significant among regular
users of cannabis (16), and include insomnia, irritability,
anorexia, craving, restlessness, anxiety, and depression.
Quetiapine is an atypical antipsychotic effective for the
treatment of schizophrenia, bipolar disorder and as an
adjunctive treatment for major depressive disorder.
Quetiapine is a dibenzothiazepine that acts as an antagonist
at serotonin 5HT
1A
and 5HT
2
, dopamine D
1
and D
2
,
histamine H
1
, and adrenergic a
1
and a
2
receptors (17). Its
weak D
2
receptor binding (18,19) most likely accounts for the
low incidence of extrapyramidal side effects associated with
quetiapine as compared to other atypical antipsychotic agents.
Post-marketing surveillance has demonstrated that quetiapine
is generally safe and well-tolerated (20).
Address correspondence to: John J. Mariani, MD, New York State
Psychiatric Institute, Division of Substance Abuse, 1051 Riverside
Drive, Unit 66, New York, New York 10032, USA. Tel: +1 (212) 543
5987. Fax: +1 (212) 543 6018. E-mail: jm2330@columbia.edu
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The known clinical effects of quetiapine – mood stabil-
ization, anxiolysis, appetite stimulation, and sedation – are
well matched for the symptoms of cannabis withdrawal,
which include dysphoria, irritability, anxiety, and insomnia.
We hypothesized that by reducing craving and other symp-
toms of cannabis withdrawal, quetiapine would reduce
cannabis consumption and promote abstinence. Our goal
was to titrate participants to the highest tolerable dose up to
600 mg daily in order to explore the feasibility of quetiapine
treatment for cannabis dependence and determine the optimal
dosing range.
Materials and methods
Subjects
The clinical trial was conducted at the Substance Treatment
and Research Service (STARS) of Columbia University
Medical Center/New York State Psychiatric Institute.
Recruitment occurred from August or 2009 through May of
2010, and data collection completed in August of 2010.
During the screening period, a comprehensive psychiatric and
medical evaluation including history, physical and laboratory
examinations, and the Structured Clinical Interview (SCID)
for DSM-IV Axis I disorders (21) interview were performed.
Self-reported cannabis use for the prior 28 days was measured
using the timeline followback method (22) adapted for
marijuana (23). All participants were seeking outpatient
treatment for problems related to marijuana use and were
recruited by local advertising (internet, print, radio, televi-
sion, and subway) or by clinical referrals in the New York
City metropolitan area.
Treatment-seeking participants were 18–65 years old; met
Diagnostic and Statistical Manual of Mental Disorders Fourth
Edition, Text Revision (DSM-IV-TR) criteria for cannabis
dependence; and reported using cannabis at least an average
of five days per week during the 28 days prior to study entry.
Participants were excluded if they had: a DSM-IV-TR
diagnosis of major depressive disorder, bipolar disorder, or
schizophrenia; a DSM-IV-TR Axis I psychiatric disorder that
was unstable or likely require treatment during the study
period; physiological dependence on any substances (other
than nicotine or cannabis) that would require medical
intervention; were prescribed psychotropic medication; were
at significant risk for suicide; coronary vascular disease as
indicated by clinical history or electrocardiogram; unstable
physical condition such as poorly controlled hypertension or
acute hepatitis; diabetes, hyperglycemia, obesity or elevated
lipids; history of an allergic reaction to quetiapine; were
pregnant or lactating; or were compelled to receive treatment
to avoid imprisonment or other penalties. This study was
reviewed and approved by the Institutional Review Board of
the New York State Psychiatric Institute, and all participants
gave written informed consent.
Treatment
All participants were assigned to quetiapine treatment under
open-label conditions. Quetiapine was administered in 25 and
100 mg tablets and was gradually titrated to 600 mg or the
maximum tolerated dose (see Table 1) in twice-daily divided
dosing. Study medication was dispensed weekly. Dosing was
flexible, with reductions made for tolerability problems.
All participants received a manualized behavioral treat-
ment, the ‘‘Brief Counseling for Marijuana Dependence:
A Manual for Treating Adults,’’ (24) which combines the use
of motivational enhancement therapy (MET) and cognitive
behavior therapy (CBT). Study visits occurred twice weekly
during the study period. One visit per week was with the
research psychiatrist to perform study assessments and to
monitor medication effects. The second visit each week was
for manualized therapy sessions.
Measures
Cannabis use was assessed by self-report confirmed by urine
toxicology. On a weekly basis, self-reported cannabis use data
was collected using the timeline followback method for
marijuana (23) for each day of the study period. Urine
samples were collected two times per week and creatinine-
corrected quantitative tetrahydrocannabinol-9-carboxylic acid
(THCOOH) levels were determined.
We used a calendar-based structured pill count interview
(timeline followback) to measure medication compliance with
a weekly financial incentive for medication bottle return. This
procedure provided a modest monetary incentive ($10) for
returning the prior week’s pill bottle. Participants were paid
$4 for each screening visit and $5 for each study visit to cover
transportation costs. Subjects earned an additional $15 during
Week 1, Week 4, and Week 8 upon completing additional
assessment measures. The total compensation a patient may
have earned for completion of the screening process and the
entire study was $276. The frequency of adverse events
during the study period was assessed each week by a modified
version of the SAFTEE (25). Female participants had serum
pregnancy tests performed monthly.
Data analyses
All analyses were conducted on the intent-to-treat sample of
all participants. All statistical tests were two-tailed and
employed at a significance level of 5%, unless otherwise
stated. The distributions of all continuous outcome variables
(if not normal) were properly identified and correctly
modeled in the analysis stage with corresponding link
functions.
The primary outcome in this study was the mean highest
tolerated dose of quetiapine achieved. Retention, adverse
effect reports, and discontinuation of treatment due to adverse
Table 1. Open-label quetiapine dosing.
Open-label quetiapine dosing
Study week 1 1 1223345678
Study day 1–2 3–4 5–7 8–10 11–14 15–17 18–21 22–28 29–35 36–42 43–56
Total daily dose quetiapine 25mg 50mg 75 mg 100 mg 150 mg 200 mg 250 mg 300 mg 400 mg 500 mg 600 mg
DOI: 10.3109/00952990.2014.884102 Quetiapine treatment of cannabis dependence 281
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effects were measured to assess tolerability. The measures of
marijuana use analyzed in this study were: (i) marijuana use;
(ii) daily dollar value of marijuana used; (iii) number of non-
using days; and (iv) creatinine-corrected quantitative urine.
Except the variable ‘number of non-using days per week’, the
variables were analyzed using longitudinal mixed effect
model for negative binomial distribution with log link
function. The weekly time correlations within subject were
modeled using autoregressive function and subjects were
modeled as random factors. The variable ‘number of non-
using days’ were modeled with a linear spline procedure (26)
with a ‘‘knot’’ at week 4 in order to appropriately model the
changing trend of non-using days per week, which increases
until week 4 and then stabilizes.
Longitudinal mixed effects models account for unobserved
data and do not require the complete measurement data to
estimate the outcome variable. The inferences from analyses
with missing data are valid provided that they are MAR
‘‘missing at random’’ (i.e. the missing mechanism does not
depend on the value of the unobserved outcome). This is un-
testable in most medical research and in our study as well.
Results
We enrolled 15 participants (11 males; mean age 28.2 years
[±8.1]; 46% black), who were daily marijuana smokers. The
mean study retention was 6.5 weeks (±2.3), with 87% of
participants completing four weeks, and 67% of participants
completing all eight weeks of the trial. The mean maximum
dose achieved was 197 mg/day (range: 25–600 mg/day). Only
two of the 15 participants were able to achieve the target dose
of 600 mg daily. Participants who requested dose reductions
generally preferred to reduce or eliminate the morning dose.
Longitudinal outcome measures of marijuana use decreased
significantly over the eight-week period (see Figures 1 and 2).
The observed daily dollar value of marijuana used at baseline
was on average $33.56 (SD ¼$34.28) and at week 8 was on
average $7.98 (SD ¼$6.74). The observed average number of
abstinence days at baseline was 0 days, at week 1 was on
average 1.13 days (SD ¼2.07) and at week 8 was on average
3.44 days (SD ¼2.60).
Using a mixed-effects model
The daily dollar value of marijuana used over a one-week
period significantly decreased by 16.5% each week
(CI: 11.8%, 20.9%, p50.0001); From baseline to week 8,
the modeled overall decrease in daily dollar value was 76.3%
(CI: 63.4%, 84.7%); Non-using days per week significantly
increased by a 41.2% each week (CI: 18.4%, 68.4%,
p¼0.0002) up to week 4, at which time the abstinent days
per week were stabilized through week 8; From baseline to
week 4, there was a 3.97 (CI: 1.97, 8.05) times increase in the
rate of non-using days. Creatinine-corrected quantitative urine
THCOOH levels per week were significantly decreased by
7.6% each week (CI: 1.4%, 13.4%, p¼0.0170). Overall, over
the 8 weeks of the study, there was a 46.9% (CI: 11%, 68.3%)
decrease in the THCOOH levels.
There were no serious adverse events and no patients were
discontinued due to adverse effects. Participants who did not
complete the trail were lost to follow-up. The most common
reported adverse effects were fatigue (80% of participants)
and somnolence (47%). Other adverse effects that were
reported by more than one participant include appetite change
(19%), constipation (13%), and dry mouth (31%), During the
trial, 11 participants gained weight and four participants lost
weight; the mean weight gain was 1.6 lbs (range:5.0–11.5
lbs). However, no participants gained more than 7% of their
baseline weight, developed a BMI greater than 30, developed
persistently elevated glucose levels, or developed hyperchol-
esterolemia or hypertriglyceridemia.
Discussion
The primary goals of the study were to determine the
feasibility of quetiapine treatment for cannabis dependence
and the optimal dosing range. The average tolerated
quetiapine dose in this study was approximately 200 mg per
day. However, the mean dose achieved was likely depressed
by participant drop-out during the titration phase (six weeks)
for reasons other than tolerability and future studies should
exceed this dose. Only two of the 15 participants were able to
achieve a dose of 600 mg daily, suggesting poor tolerability
of this dose. We suggest a target dose of 300 mg daily for
future studies of quetiapine treatment of marijuana depend-
ence. Quetiapine dosing was twice daily in this pilot study.
Participants who requested dose reductions generally
preferred to reduce or eliminate the morning dose due to
sedation. Based on this experience, we would recommend a
single evening dose.
Figure 1. Observed average daily dollar amount of marijuana per week. Figure 2. Observed average days of abstinence per week.
282 J. J. Mariani et al. Am J Drug Alcohol Abuse, 2014; 40(4): 280–284
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While this study was not designed to assess the efficacy of
quetiapine treatment for cannabis dependence, these prelim-
inary results seem promising in that quetiapine treatment was
associated with reductions in marijuana use. Retention rates
were similar to other cannabis dependence pharmacotherapy
clinical trials (12).
The pharmacodynamic actions of quetiapine provide a
theoretical rationale for why it may be beneficial in treating
marijuana dependence. The low and transient level of
dopamine D
2
receptor affinity of quetiapine (27) combined
with 5-HT
2A
antagonism (28), may be beneficial for
stabilizing dysregulation of the mesostriatal dopaminergic
pathway ‘‘reward circuit.’’ Preclinical data suggests that
quetiapine may attenuate reward through antagonism of
dopamine and non-dopamine neurotransmission (29). An
alternative proposed mechanism is the high affinity of
quetiapine for noradrenergic alpha-1 receptors (29), since
noradrenergic pathways may be critical to rewarding effects
of substances of abuse (30). The clinical effects of quetiapine,
including anxiolysis, mood stabilization, sedation, and appe-
tite stimulation are potentially well matched to the symptoms
of marijuana withdrawal. Most adults seeking treatment for
marijuana dependence report experiencing marijuana with-
drawal symptoms of moderate severity (31), including,
depression, irritability, anxiety, insomnia and anorexia (32).
Quetiapine was well tolerated during the trial. There were
no serious adverse events and no participants discontinued
due to medication intolerability or development of metabolic
abnormalities. Reports of sedation were very common, but
these symptoms were not severe, and did not lead to study
drop out and overall retention was similar to other pharma-
cotherapy trials for cannabis dependence. Weight gain, which
is a known adverse effect due to quetiapine, was modest
during the trial, with a mean weight gain over the entire study
period of 1.6 lbs. This may be due to the relatively brief
course of treatment or a finding related to treating patients
potentially in cannabis withdrawal, which is associated with
weight loss. Quetiapine is associated with metabolic, psychi-
atric, and neurological risks with chronic administration.
A potential model for treating cannabis dependence is a short
course of quetiapine to manage withdrawal symptoms and
facilitate reductions or discontinuation of cannabis use. This
approach could potentially maximize the benefit of the
medication during the phase of cannabis dependence it would
theoretically be most effective, while limiting exposure to the
risks of ongoing quetiapine treatment.
While quetiapine did not induce prolonged abstinence in
this small sample over an eight-week period, abstinence from
cannabis use is difficult to achieve in daily smokers of
marijuana. A medication that could help alleviate cannabis
withdrawal symptoms and facilitated reductions in cannabis
use, could be usefully clinically, particularly in combination
with behavioral strategies. A human laboratory study of
14 non-treatment-seeking (i.e. not motivated to reduce or
abstain from cannabis) marijuana smokers found that
quetiapine improved sleep quality and appetite and reduced
weight loss as compared to placebo (33). However, quetiapine
increased marijuana craving and self-administration during a
laboratory model of relapse, which is inconsistent with the
results of this open-label trial. One possible explanation for
these divergent results is that motivation and treatment goals
are important determinants of outcome, and non-treatment-
seeking laboratory participants may respond differently to
pharmacotherapy than treatment seeking clinical trial
participants.
A limitation of this study is the open label design. While
conducting the trial under open label conditions facilitated
tailoring a tolerable dosing schedule for each participant, the
lack of a control group and the unblinded nature of the
investigation limits the interpretation of the effect of
quetiapine on cannabis use. While cannabis use declined
among participants, this effect could be due entirely to the
psychosocial intervention or other factors other than quetia-
pine administration. Another limitation of the study is that
participants received an active psychosocial treatment during
the trial, which presumably affected cannabis use. However,
this psychosocial approach in the context of a pharmacother-
apy clinical trial for near-daily marijuana users has demon-
strated only limited benefit (12), where only 15.6% of the
placebo group achieved a two-week period of end-of-trial
abstinence. Other limitations include a lack of objective
medication compliance data and a small sample size.
The results of this open-label pilot study suggest that
quetiapine is well-tolerated and is associated with decreased
cannabis use in cannabis-dependent outpatients. The optimal
target dose for cannabis-dependent patients appears to be
approximately 300 mg daily in a single evening dose to
minimize daytime sedation. These preliminary data support
the further evaluation of quetiapine as a treatment for
cannabis dependence.
Acknowledgements
This research was supported by NIDA grants: K23-DA021209
(Mariani), P50-DA09236 (Kleber), K24-DA022412 (Nunes),
K24 029647 (Levin). The authors would like to thank the staff
at the Substance Treatment and Research Service (STARS) of
the Columbia University Medical Center/New York State
Psychiatric Institute for their assistance in conducting this
research.
Declaration of interest
The authors report no conflicts of interest. The authors alone
are responsible for the content and writing of this paper.
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    • "In a 12-month study comparing ziprasidone (n = 16) to clozapine (n = 14), those dually diagnosed with schizophrenia and CUD saw a reduction in cannabis use as measured by self-reported frequency of use for both antipsychotics, but neither drug was significantly more efficacious than the other [19] . Additionally, open-label administration of quetiapine, an atypical antipsychotic that broadly acts as an antagonist at serotonin, dopamine, histamine, and adrenergic receptors, reduced money spent on cannabis and increased non-using days over an 8-week period but did not induce prolonged abstinence [20] . A single case report suggested complete and sustained abstinence from cannabis use in patients with borderline personality disorder given the D 2 partial agonist aripiprazole [21] . "
    [Show abstract] [Hide abstract] ABSTRACT: Cannabis use disorder is associated with a variety of consequences, and treatment outcomes are no better than for other substances of abuse. To date, no medications have been approved for the treatment of cannabis use disorder. Based on the available literature, standard psychotropic agents such as antidepressants, antipsychotics, and anticonvulsants do not appear to be effective. Somewhat promising findings have been reported with the anxiolytic buspirone, and the glutamate modulating drug N-acetylcysteine. Gabapentin showed positive effects for cognition and cannabis use, while cannabinoids may decrease cannabis withdrawal symptoms. Several promising agents to test in humans were identified. The neurosteroid pregnenolone blocks the behavioral effects of tetrahydrocannabinol in an animal model. Cognition may be a domain to target to reduce cannabis use. Thus, medications that modulate cholinergic systems may offer promising treatments. Finally, hypocretin/orexin receptor-1, NMDA receptor, and G-protein-coupled receptor-modulating agents might decrease cannabis craving or withdrawal symptoms. These recent approaches and hypotheses suggest more novel approaches to treating CUD and may be vital in finding treatments for cannabis use disorder.
    Article · Apr 2016
  • [Show abstract] [Hide abstract] ABSTRACT: The Side Effects of Drugs Annuals is a series of volumes in which the adverse effects of drugs and adverse reactions to them are surveyed. The series supplements the contents of Meyler's Side Effects of Drugs: the International Encyclopedia of Adverse Drug Reactions and Interactions. This review of publications on adverse reactions to antipsychotic drugs from July 2013 to December 2014 covers amisulpride, aripiprazole, asenapine, blonanserin, chlorpromazine, chlorprothixene, clozapine, cyamemazine, droperidol, fluphenazine, haloperidol, iloperidone, levomepromazine (methotrimeprazine), loxapine, lurasidone, olanzapine, paliperidone, perazine, perospirone, perphenazine, pimozide, prochlorperazine, quetiapine, risperidone, sertindole, sulpiride, thioridazine, ziprasidone, zotepine, and zuclopenthixol.
    Chapter · Dec 2015