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Article history: Marijuana (cannabis) is the most widely used illicit substance globally, and cannabis use is associated with a
Received 16 July 2010 range of adverse consequences. Currently, no medications have been proven to be effective for the treatment
Received in revised form 3 December 2010 of cannabis addiction. The goals of this study were to examine the safety and efcacy of a potential treatment
Accepted 13 December 2010
medication, modanil, in combination with oral 9-tetrahydrocannabinol (THC). Twelve male and female
Available online 21 December 2010
occasional cannabis users participated in an outpatient double-blind, placebo-controlled, crossover study.
Keywords:
Across four sessions, participants were randomly assigned to a sequence of four oral treatments: (1) 400 mg
Cannabis modanil + placebo, (2) 15 mg THC + placebo, (3) 400 mg modanil + 15 mg THC, or (4) placebo + placebo.
Modanil Outcome measures included heart rate, blood pressure, performance on the Rapid Visual Information
Marijuana Processing (RVIP), and the Hopkins Verbal Learning Test (HVLT), and subjective measures. Oral THC increased
THC heart rate, and produced increased subjective ratings of feeling high and sedated, as well as increased
Addiction ratings of euphoria. Modanil alone increased the Proles of Mood States (POMS) subscales of vigor and
tension. These ndings support the safety of modanil in combination with THC. The effects of modanil in
combination with a range of doses of THC need to be determined in future studies.
Published by Elsevier Inc.
Modanil's potential utility for cannabis dependence has not yet 2.3. THC and modanil administration
been evaluated. The cognitive enhancing effects of modanil may
alleviate cognitive decits associated with cannabis use, and its mood- The oral form of THC (Marionol) was obtained from Unimed
elevating effects could potentially help to alleviate cannabis with- Pharmaceuticals, Inc. (Buffalo Grove, IL). Oral THC is used in the
drawal, which include depressed mood, irritability, anxiety, and anger treatment of anorexia associated with weight loss, in patients with AIDS,
(Budney and Hughes, 2006). In addition, modanil has been shown to and for nausea and vomiting associated with chemotherapy. The typical
attenuate some of the positive subjective effects from cocaine, dose associated with these treatments is in the 2.5 to 20 mg/day range.
methamphetamine and nicotine in humans (Dackis et al., 2003b; De We used 15 mg of THC, which has been shown to be well-tolerated by
La Garza et al., 2010; Malcolm et al., 2006; Sofuoglu et al., 2008). Since cannabis users (Chesher et al., 1990; Haney et al., 2003; Hart et al.,
increasing dopamine release in the nucleus accumbens is a shared 2005). After oral administration, THC has an onset of action of
mechanism for the rewarding effects of stimulants (Pich et al., 1997) approximately 0.5 to 1 h with peak effects at 2 to 4 h. The duration of
as well as cannabis (Cheer et al., 2004; Robledo et al., 2007), it is action for any psychoactive effects is 4 to 6 h, with appetite stimulation
plausible that modanil may also attenuate the rewarding effects of continuing for up to 24 h. Modanil (Provigil) was obtained from
cannabis. Cephalon (145 Brandywine Parkway, West Chester, PA 19380).
The goals of this study were twofold. First, we examined the Although a single daily 200 mg dose of modanil is recommended for
safety and tolerability of modanil treatment in combination with the treatment of narcolepsy or sleep apnea (Murray, 2004), doses
oral 9-tetrahydrocannabinol (THC), as a potential treatment medica- between 200 and 400 mg have been examined in combination with
tion in cannabis users. Second, we examined modanil's effects on the cocaine (Dackis et al., 2003a, 2005a; Hart et al., 2008; Vosburg et al.,
THC-induced physiological, subjective, and cognitive performance 2010). Doses between 200 and 600 mg have been safely tolerated by
responses. We hypothesized that modanil would attenuate the cocaine users (Dackis et al., 2005b; Vosburg et al., 2010), and doses
subjective and cognitive effects of oral THC. between 200 and 400 mg have been used for the treatment of
methamphetamine dependence (Heinzerling et al., 2010; McGaugh et
al., 2009). Previous laboratory studies examining the combination of
2. Materials and methods
cocaine and modanil found that both 200 mg and 400 mg doses of
modanil were equivalent in attenuating the cardiovascular effects of
2.1. Participants
cocaine (Hart et al., 2008), and both doses were not associated with any
medical risk in combination with cocaine (Dackis et al., 2005a; Hart et
A total of 18 occasional cannabis users between the ages of 18 to 55
al., 2008). The one study that examined 200 mg of modanil for
were recruited from the New Haven area by newspaper advertise-
methamphetamine dependence did not nd an effect for modanil over
ments and yers. The inclusion criteria included: (a) cannabis use at
placebo for methamphetamine use (Shearer et al., 2009b). However, at
least once in last two months and at least 10 times in lifetime, and
higher doses, modanil can produce hypertension and tachycardia
(b) a urine sample positive for cannabis. Participants were excluded if
(Wong et al., 1999). Since this is the rst study to assess modanil in
they met DSM-IV criteria for cannabis abuse or dependence, or were
combination with THC, we wanted to maximize the possibility of having
seeking treatment for substance abuse or dependence. The sample
an effective dose, while minimizing side effects. Therefore, we chose the
was limited to occasional cannabis users because heavy cannabis use
400 mg dose of modanil. Following oral administration, modanil is
is associated with tolerance to the acute effects of cannabis (D'Souza
rapidly absorbed, reaching peak plasma levels within 24 h. The half-life
et al., 2008; Lichtman and Martin, 2005; Ramaekers et al., 2009). Data
of modanil is 715 h. Modanil and THC were administered at the
from the rst three participants were used to determine the duration
same time.
and medication effects for safety, which led to a revised protocol. Data
from these three participants were not used since the revisions
2.4. Measures
included changes to the schedule of assessments. In addition, three
participants did not complete the study due to drug use (n = 2), and
The outcome measures included physiological, subjective, and
personal reasons (n = 1). Of the 12 participants who completed the
cognitive performance measures. The physiological measures con-
study (eight African-Americans, three Caucasian, and one Hispanic),
sisted of systolic and diastolic blood pressure and heart rate. The
11 were male and one was female, with an average age (SD) of
subjective measures were comprised of the Drug Effects Question-
33.7 years (7.7). All participants had normal physical, laboratory, and
naire (DEQ), the Addiction Research Center Inventory-Short Form
psychiatric examinations, and none were dependent on alcohol or
(ARCI), and the Prole of Mood States (POMS). The DEQ assessed the
other drugs except nicotine (n = 7). All participants provided
acute subjective effects of THC, and asked subjects to rate stimulat-
informed consent prior to study entry and were paid for participation.
ed, high, anxious, sedated, down, feeling the drug strength,
Experimental sessions were conducted in the Biostudies Unit located
feel good drug effects, feel bad drug effects, want more drug, and
at the VA Connecticut Healthcare System, West Haven campus. This
like the drug on a scale from 0 (not at all) to 10 (extremely). The
study was approved by the VA Connecticut Healthcare System Human
ARCI (Martin et al., 1971) 49-item version consists of true-or-false
Subjects Subcommittee.
questions with ve subscales: drug-induced euphoria (Morphine
Benzedrine Group; MBG), stimulant-like effects (Amphetamine; A),
2.2. Design and procedures intellectual efciency and energy (Benzedrine Group; BG), dysphoria
(Lysergic Acid; LSD), and sedation (PentobarbitalChlorpromazine;
In this double-blind, placebo-controlled, crossover study, subjects PCAG) (Martin et al., 1971). We also included the ARCI M scale,
had four separate outpatient experimental sessions. Across four which consists of four questions specic to marijuana (Chait et al.,
sessions, subjects were randomly assigned to a sequence of four 1985). The POMS is a 65-item rating scale used to measure the effects
treatment conditions which included placebo + placebo, modanil of medication treatments on mood using six subscales: Tension,
(400 mg) + placebo, THC (15 mg) + placebo, or modanil (400 mg) + Depression, Anger, Vigor, Fatigue, and Confusion (McNair et al., 1971).
THC (15 mg). In each session, after baseline measures were obtained, The POMS is widely used as a research tool in behavioral pharmacol-
subjects received the study medication followed by a light meal. The ogy (Fischman and Foltin, 1991). It has been found to be sensitive to
sessions started at 8:00 am and lasted for approximately 7 h. Sessions the mood-altering effects of drugs including cannabis and modanil.
were separated by a minimum of four days to minimize the carryover Cognitive performance was assessed with the Hopkins Verbal
effects from modanil and THC. Learning Test-Revised (HVLT-R) and a module from the Cambridge
96 D.E. Sugarman et al. / Pharmacology, Biochemistry and Behavior 98 (2011) 94100
Neuropsychological Test Automated Battery (CANTAB): the Rapid measure of the tendency to respond regardless of whether a target is
Visual Information Processing (RVIP). The HVLT-R is a brief verbal present). Subjective assessments were completed at baseline, then at
learning and memory test with six alternate forms, making it ideal for 30, 60, 90, 150,180, 210, 240, 270, and 300 min after the study
repeated neuropsychological examinations such as this study. The medications administration. Heart rate and blood pressure measure-
revised version also includes a delayed recall trial (Benedict et al., ments were obtained at the same time points, as well as at 120 and
1998), which is the type of recall that appears most sensitive to the 360 min after medication administration. Cognitive assessments were
effects of cannabis (Hooker and Jones, 1987). For the HVLT-R we used given to participants two hours after medication administration.
total recall, delayed recall, and the Recognition Discrimination Index
as the main outcome measures. The Total Recall is the sum of correct 2.5. Statistical analysis
responses for Trial 1, 2, and 3. Delayed Recall is the number of correct
responses for Trial 4 (after 2025 min). The Recognition Discrimina- We conducted two types of mixed-effects repeated-measures
tion Index is the total number of true positives minus the total number analyses using SAS Proc Mixed, version 9.2. All models included xed
of false positives on delayed recognition trial (given right after trial 4 main-effect estimates for THC (0 mg or 15 mg), modanil (0 mg or
recall). The RVIP is widely used as a measure of sustained attention 400 mg) and their interaction, as well as a blocking factor for
with a working memory component. In this task, subjects are asked to treatment sequence. For the rst analyses, all data collected at each
respond to any of three digit sequences in a continuous stream of time point were included in the model. For the second analyses,
digits lasting for 7 min. A white box appears in the center of the change-from-baseline scores were used as outcome measures.
computer screen, inside which digits from 2 to 9 appear in a pseudo- Change scores, maximum post-dose measurement minus the pre-
random order at the rate of 100 digits per minute. Subjects are dose measurement at baseline, are commonly used summary
instructed to detect consecutive odd or even sequences of digits (e.g., measures that capture the magnitude of the response. Change scores
246, 357, 468, 579, etc.) and to register responses using a were calculated for the physiological and subjective scales, where
press-pad. Impairments in attention have long been recognized in multiple measurements were obtained at different time points.
cannabis users (Harvey et al., 2007; Ranganathan and D'Souza, 2006). Signicant treatment or treatment-by-treatment interactions
For the RVIP key measures were mean latency, A (target sensitivity, a (p b 0.05) were followed by post hoc group comparisons using Fisher's
measure of the ability to detect sequences), and B (response bias, a LSD.
130
70
125
65
mmHg
mmHg
120
115 60
110
55
105
100 50
0 30 60 90 150 180 210 240 270 300 0 30 60 90 150 180 210 240 270 300
Time (Minutes) Time (Minutes)
80
75
bpm
70
65
60
55
50
0 30 60 90 150 180 210 240 270 300
Time (Minutes)
Fig. 1. Systolic (a) and diastolic (b) blood pressure, and heart rate (c) responses under 15 mg active THC plus 400 mg active modanil (THC + MOD), 15 mg active THC plus placebo
(THC + PLA), placebo plus 400 mg active modanil (PLA + MOD), or placebo plus placebo (PLA + PLA) conditions. Systolic blood pressure was signicantly lower for active THC and
modanil conditions compared to placebo. Diastolic blood pressure was a signicantly greater for active modanil conditions. Heart rate was signicantly greater for active THC and
modanil conditions compared to placebo.
D.E. Sugarman et al. / Pharmacology, Biochemistry and Behavior 98 (2011) 94100 97
3. Results p b 0.001]), compared to placebo (see Fig. 3). The THC plus modanil
condition had signicantly lower ratings on the MBG (drug-induced
3.1. Physiological responses euphoria) subscale (THC by modanil effect; [F (1, 461)= 5.3; p b 0.05]),
compared to other conditions. In addition, the THC plus modanil
As shown in Fig. 1, THC increased heart rate (THC main effect; condition had signicantly lower ratings on the BG (intellectual
[F (1, 461)= 18.6; p b 0.0001]) and lowered systolic blood pressure efciency and energy) subscale (THC by modanil effect; [F (1, 461) =
(THC main effect; [F (1, 461) = 4.6; p b 0.05]), compared to placebo. 6.1; p b 0.05]), compared to modanil placebo or THC-placebo conditions
Modanil, compared to placebo, increased heart rate (modanil main (see Fig. 3). For change score analysis of the ARCI, THC increased the
effect; [F (1, 461) = 48.8; p b 0.0001]), increased systolic blood pressure marijuana M-scale [F (1, 30) = 6.2; p b 0.05]. THC plus modanil,
(modanil main effect; [F (1, 461) = 6.5; p b 0.05]) and increased compared to modanil alone had greater score in the marijuana scale
diastolic blood pressure, (modanil main effect; [F (1, 461) = 12.2; (THC by modanil effect; [F (1, 30) = 4.4; p b 0.05]).
p b 0.001]). For change scores in heart rate, modanil plus THC, THC reduced scores for the depressed (THC main effect; [F (1, 461) =
had greater increases in heart rate than THC alone [THC by modanil 4.1; p b 0.05]) and vigor (THC main effect; [F (1, 461) = 30.7; p b 0.001]),
effect; F (1, 30) = 4.2; p b 0.05]. subscales of the POMS, compared to placebo. Modanil increased
ratings of tension (modanil main effect; [F (1, 451)= 10.8; p b 0.005])
3.2. Subjective responses and vigor (modanil main effect; [F (1, 461) = 4.1; p b 0.05]), and
decreased depressed ratings (main effect modanil; [F (1, 461)= 7.2;
THC increased subjective ratings of feel high (THC main p b 0.01]), on the POMS. There were no signicant modanil-by-THC
effect; [F (1, 460) = 6.7 p b 0.05]), feel sedated (THC main effect; interactions for any of the POMS scales. For change score analyses, no
[F (1, 460) = 5.5; p b 0.05]), and feel the drug strength (THC main signicant treatment differences were found.
effect; [F (1, 460) = 5.9; p b 0.05]) scales of the DEQ, compared to
placebo (see Fig. 2). There were no signicant modanil-by-THC 3.3. Cognitive performance assessments
interactions for any of the DEQ scales. For the change score
analyses, modanil treatment reduced the rating of feel sedated There were no signicant treatment effects for the RVIP, and the
(modanil main effect; [F (1, 30) = 4.3; p b 0.05]) and THC treat- HVLT. Fig. 4 graphically represents the means for the three subscales
ment increased the rating of feel the bad effects (THC main of the RVIP and the three subscales of the HVLT, by condition.
effect; [F (1, 30) = 4.3; p b 0.05].
For ratings on the ARCI, THC increased ratings on the PCAG (sedation) 4. Discussion
subscale (THC main effect; [F (1, 461)= 14.0; p b 0.001]), the LSD
(dysphoria) subscale (THC main effect; [F (1, 461) = 7.2; p b 0.001]), and In this study 15 mg oral THC treatment increased subjective
the M (marijuana) subscale (THC main effect; [F (1, 461) = 5.4; ratings on the ARCI subscales of PCAG (sedation), LSD (dysphoria),
1.5 1.5
Rating
Rating
1 1
0.5 0.5
0 0
0 30 60 90 150 180 210 240 270 300 0 30 60 90 150 180 210 240 270 300
Time (Minutes) Time (Minutes)
1.5
Rating
0.5
0
0 30 60 90 150 180 210 240 270 300
Time (Minutes)
Fig. 2. Subjective responses to selected items on DEQ under 15 mg active THC plus 400 mg active modanil (THC + MOD), 15 mg active THC plus placebo (THC + PLA), placebo plus
400 mg active modanil (PLA + MOD), or placebo plus placebo (PLA + PLA) conditions. There were signicantly greater ratings of feel high, feel sedated, and feel the drug
strength for the two active THC conditions.
98 D.E. Sugarman et al. / Pharmacology, Biochemistry and Behavior 98 (2011) 94100
Rating
4 4
3 3
2 2
1 1
0 0
0 30 60 90 150 180 210 240 270 300 0 30 60 90 150 180 210 240 270 300
Time (minutes) Time (minutes)
Rating
4 4
3 3
2 2
1 1
0 0
0 30 60 90 150 180 210 240 270 300 0 30 60 90 150 180 210 240 270 300
Time (minutes) Time (minutes)
Fig. 3. Subjective responses to selected items on ARCI under 15 mg active THC plus 400 mg active modanil (THC + MOD), 15 mg active THC plus placebo (THC + PLA), placebo plus
400 mg active modanil (PLA + MOD), or placebo plus placebo (PLA + PLA) conditions. There were signicantly greater ratings of sedation, dysphoria, and marijuana for active THC
conditions. Compared to other conditions, the THC + MOD condition had signicantly lower ratings of drug-induced euphoria. Compared to THC + PLA and PLA + MOD conditions,
the THC + MOD condition has signicantly lower ratings on the intellectual efciency and energy subscale.
and M (marijuana). These ndings are consistent with previous consistent with many previous studies that administered oral THC
research that has showed the oral THC increased ratings on the ARCI (Chesher et al., 1990; McDonald et al., 2003; Wachtel et al., 2002).
LSD, PCAG, and M subscales (Kirk and de Wit, 1999; Makela et al., In contrast to oral THC, modanil alone did not affect the ratings on
2006; McDonald et al., 2003; Wachtel et al., 2002). Results also the ARCI or DEQ scales. However, modanil had signicant effects on
showed that THC increased DEQ item ratings of feel high, feel mood, assessed by the POMS. Participants had greater ratings for
sedated, and feel the drug strength, and THC reduced ratings of tension and vigor, and lower responses for depressed. In previous
vigor and depression on the POMS subscales. These ndings are studies, modanil treatment has been shown to decrease fatigue and
Score
14
12 0.5
10 0.4
8
0.3
6
0.2
4
2 0.1
0 0
Condition Target Sensitivity Response Bias
Fig. 4. Total recall on the HVLT (a) and target sensitivity and response bias on the RVIP (b) under 15 mg active THC plus 400 mg active modanil (THC + MOD), 15 mg active THC plus
placebo (THC + PLA), placebo plus 400 mg active modanil (PLA + MOD), or placebo plus placebo (PLA + PLA) conditions.
D.E. Sugarman et al. / Pharmacology, Biochemistry and Behavior 98 (2011) 94100 99
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