Pharmacology, Biochemistry and Behavior 98 (2011) 94100

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Pharmacology, Biochemistry and Behavior

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p h a r m b i o c h e m b e h

The safety of modanil in combination with oral 9-tetrahydrocannabinol in humans

Dawn E. Sugarman , James Poling, Mehmet Sofuoglu
Yale University School of Medicine, Department of Psychiatry, 300 George St., New Haven, CT 06511, USA
VA Connecticut Healthcare System, 950 Campbell Ave., Bldg. 36/116A4, West Haven, CT 06516, USA

a r t i c l e i n f o a b s t r a c t

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.

1. Introduction Evidence shows that chronic exposure to cannabis is associated

with dose-related cognitive impairments, most consistently in
Marijuana (cannabis) is the most widely used illicit substance attention, working memory, verbal learning and memory functions
globally and in the United States (Compton et al., 2004; Ofce of (Bolla et al., 2002; Pope et al., 1995; Pope and Yurgelun-Todd, 1996;
National Drug Control Policy, 2008; SAMHSA, 2008). It is estimated that Solowij, 1995; Solowij et al., 1995, 2002). Recently, we proposed that
one out of 12 cannabis users will eventually become dependent targeting cognitive impairment associated with chronic cannabis use
(Wagner and Anthony, 2002). Increased treatment-seeking has been by cognitive-enhancing medications may be a promising novel
observed among cannabis users (Stephens et al., 2002), making strategy for the treatment of cannabis addiction (Sofuoglu et al.,
cannabis one of the most common illicit drugs of use among admissions 2010). We suggested that medications enhancing cognitive function
to treatment programs in the US (SAMHSA, 2008). Marijuana smoking is may be effective either alone or in combination with behavioral
associated with a range of adverse consequences, including respiratory treatments for cannabis addiction (Sofuoglu et al., 2010). One
ailments, and impairments in memory, concentration, motivation, self- cognitive enhancer that has been evaluated for other addictive
esteem, employment, and interpersonal relationships (Stephens et al., disorders is modanil. Modanil is a wakefulness-promoting medi-
2002). Currently, there are no effective medications for the treatment of cation, approved for the treatment of narcolepsy, sleep-apnea and
cannabis addiction and available behavioral treatments are only shift-work induced sleep disorder (Ballon and Feifel, 2006). Modanil
modestly effective (Nordstrom and Levin, 2007). For example, behav- has been shown to improve cognitive performance in sleep deprived
ioral treatments including cognitivebehavioral therapy (CBT), moti- individuals, as well as in those with attention decit hyperactivity
vational enhancement therapy (MET), and contingency management disorder (ADHD) and schizophrenia (Muller et al., 2004; Turner et al.,
(CM) have shown promise in the short-term, but one year abstinence 2003; Wesensten et al., 2002). Modanil's mechanism of action is
rates with a combination of these behavioral treatments have ranged complex and may include enhancement of glutamate release and
from 9 to 29% (Budney et al., 2007). Thus, development of effective inhibition of GABA release in various brain regions (Ferraro et al.,
treatment strategies, specically for cannabis use disorders (depen- 1998, 1999), as well as dopamine and norepinephrine transporter
dence or abuse), is urgently needed. inhibition (Madras et al., 2006), which results in increased synaptic
levels of dopamine and norepinephrine (Murillo-Rodriguez et al.,
Corresponding author. VA Connecticut Healthcare System, 950 Campbell Ave., Bldg.
2007; Volkow et al., 2009). Modanil is currently being examined for
36/116A4, West Haven, CT 06516, USA. Tel.: + 1 203 937 4804; fax: + 1 203 937 3478. the treatment of cocaine and methamphetamine addiction (Dackis et
E-mail address: [email protected] (D.E. Sugarman). al., 2005a; Hart et al., 2008; Morgan et al., 2010; Shearer et al., 2009a).

0091-3057/$ see front matter. Published by Elsevier Inc.

doi:10.1016/j.pbb.2010.12.013
 D.E. Sugarman et al. / Pharmacology, Biochemistry and Behavior 98 (2011) 94100 95

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.

(a) Systolic Pressure (b)

Diastolic Pressure
THC+MOD THC+MOD
THC+PLA THC+PLA
PLA+MOD 75 PLA+MOD
135 PLA+PLA PLA+PLA

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)

(c) Heart Rate

THC+MOD
90 THC+PLA
PLA+MOD
85 PLA+PLA

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),

DEQ: I feel high DEQ: I feel sedated

2.5 THC+MOD 2.5 THC+MOD
THC+PLA THC+PLA
PLA+MOD PLA+MOD
2 PLA+PLA 2 PLA+PLA

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)

DEQ: I feel the drug strength

2.5
THC+MOD
THC+PLA
PLA+MOD
2
PLA+PLA

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

ARCI: Sedation ARCI: Marijuana

THC+MOD THC+MOD
THC+PLA THC+PLA
8 PLA+MOD 8 PLA+MOD
PLA+PLA PLA+PLA
7 7
6 6
5 5
Rating

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)

ARCI: Euphoria ARCI: Intellectual efficiency and energy

THC+MOD
THC+MOD THC+PLA
8
THC+PLA 8 PLA+MOD
PLA+MOD PLA+PLA
7
PLA+PLA 7
6
6
5 5
Rating

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

(a) HVLT: Total Recall

(b) RVIP: Target Sensitivity and Response Bias
THC+MOD THC+MOD
THC+PLA THC+PLA
24 PLA+MOD PLA+MOD
1
PLA+PLA PLA+PLA
22 0.9
20
0.8
18
16 0.7
0.6
Score

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

enhance vigor especially in sleep-deprived individuals, while in- References

creased anxiety and aggression has also been reported as a result of
modanil treatment (MacDonald et al., 2002; Rush et al., 2002; Ballon JS, Feifel D. A systematic review of modanil: potential clinical uses and
mechanisms of action. J Clin Psychiatry 2006;67:55466.
Wesensten, 2006). In a more recent study with healthy adults, Benedict R, Schretlen D, Groninger L, Brandt J. Hopkins Verbal Learning Test-Revised:
modanil increased both the negative and positive scales of the normative data and analysis of inter-form and test-retest reliability. Clin
PANAS (Taneja et al., 2007). It has been suggested that the arousing Neuropsychol 1998;12:4355.
Bolla KI, Brown K, Eldreth D, Tate K, Cadet JL. Dose-related neurocognitive effects of
effect of modanil may be interpreted as negative by some marijuana use. Neurology 2002;59:133743.
individuals. Budney AJ, Hughes JR. The cannabis withdrawal syndrome. Curr Opin Psychiatry
We also observed a signicant modanil-by-THC interaction, with 2006;19:2338.
Budney AJ, Roffman R, Stephens RS, Walker D. Marijuana dependence and its treatment.
lower attenuated ratings on the euphoria subscale of the ARCI, Addict Sci Clin Pract 2007;4:4-16.
compared to other treatment conditions. Given that the single dose of Chait LD, Fischman MW, Schuster CR. Hangover effects the morning after marijuana
THC in this study had very little effect, this minor interaction cannot smoking. Drug Alcohol Depend 1985;15:22938.
Cheer JF, Wassum KM, Heien ML, Phillips PE, Wightman RM. Cannabinoids enhance
be meaningfully interpreted. Moreover, these effects were not
subsecond dopamine release in the nucleus accumbens of awake rats. J Neurosci
signicant when the change scores, rather than the all the time 2004;24:4393400.
points, were analyzed. Chesher GB, Bird KD, Jackson DM, Perrignon A. The effects of orally administered 9-
As expected, THC increased heart rate. The cardiovascular effects of tetrahydrocannabinol in man on mood and performance measures: a dose-
response study. Pharmacol Biochem Behav 1990;35:8614.
THC are mediated by sympathetic activation and cholinergic inhibi- Compton WM, Grant BF, Colliver JD, Glantz MD, Stinson FS. Prevalence of marijuana use
tion (Jones, 2002). In our study, 400 mg modanil increased disorders in the United States: 19911992 and 20012002. JAMA 2004;291:
participants' heart rate and systolic and diastolic blood pressure. 211421.
Dackis CA, Lynch KG, Yu E, Samaha FF, Kampman KM, Cornish JW, et al. Modanil and
These ndings are consistent with previous studies where modanil cocaine: a double-blind, placebo-controlled drug interaction study. Drug Alcohol
increased the resting heart rate and blood pressure in healthy controls Depend 2003a;70:2937.
(Taneja et al., 2005) and abstinent smokers (Sofuoglu et al., 2008). The Dackis CA, Lynch KG, Yu E, Samaha FF, Kampman KM, Cornish JW, et al. Modanil and
cocaine: a double-blind, placebo-controlled drug interaction study. Drug Alcohol
increased blood pressure and heart rate induced by modanil have Depend 2003b;70:2937.
been attributed to noradrenergic activation (Taneja et al., 2005). In Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP. A double-blind, placebo-
our study, modanil did not enhance the heart rate and blood controlled trial of modanil for cocaine dependence. Neuropsychopharmacology
2005a;30:20511.
pressure induced by oral THC. These ndings support the safety of Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP. A double-blind, placebo-
modanil in combination with THC. controlled trial of modanil for cocaine dependence. Neuropsychopharmacology
In this study, the cognitive effects of oral THC or modanil were 2005b;30:20511.
De La Garza 2nd R, Zorick T, London ED, Newton TF. Evaluation of modanil effects on
not signicant. There was a trend for a THC-induced impairment on
cardiovascular, subjective, and reinforcing effects of methamphetamine in
the HVLT. This lack of treatment effect on cognitive outcomes could be methamphetamine-dependent volunteers. Drug Alcohol Depend 2010;106:
due to several limitations of this study. First, we only used one dose 17380.
(400 mg) of modanil in this study. Since this is the rst study to D'Souza DC, Ranganathan M, Braley G, Gueorguieva R, Zimolo Z, Cooper T, et al. Blunted
psychotomimetic and amnestic effects of delta-9-tetrahydrocannabinol in frequent
assess modanil in combination with THC, we based our dosage on users of cannabis. Neuropsychopharmacology 2008;33:250516.
other studies in the literature that have examined modanil in Ferraro L, Antonelli T, O'Connor WT, Tanganelli S, Rambert FA, Fuxe K. The effects of
combination with illicit drug use (i.e. cocaine and methamphet- modanil on striatal, pallidal and nigral GABA and glutamate release in the
conscious rat: evidence for a preferential inhibition of striato-pallidal GABA
amine). Future research should examine the combination of THC and transmission. Neurosci Lett 1998;253:1358.
modanil in cannabis users using multiple doses in order to more fully Ferraro L, Antonelli T, Tanganelli S, O'Connor WT, Perez de la Mora M, Mendez-Franco J,
understand modanil's effects. Second, the treatment duration was et al. The vigilance promoting drug modanil increases extracellular glutamate
levels in the medial preoptic area and the posterior hypothalamus of the conscious
brief, and only one relatively small dose of THC was administered. It is rat: prevention by local GABAA receptor blockade. Neuropsychopharmacology
possible that higher doses of THC would show effects on cognitive 1999;20:34656.
performance. Third, the cognitive assessment in this study involved Fischman MW, Foltin RW. Utility of subjective-effects measurements in assessing abuse
liability of drugs in humans. Br J Addict 1991;86:156370.
only two tasks, did not include a comprehensive assessment, and was Haney M, Bisaga A, Foltin RW. Interaction between naltrexone and oral THC in heavy
limited by small sample sizes. Fourth, the exclusion of heavy cannabis marijuana smokers. Psychopharmacology 2003;166:7785.
users limits the ability to generalize these results to future examina- Hart CL, Haney M, Vosburg SK, Comer SD, Foltin RW. Reinforcing effects of oral 9-THC
in male marijuana smokers in a laboratory choice procedure. Psychopharmacology
tions of modanil for the treatment of cannabis dependence. Finally,
2005;181:23743.
although our sample was limited to occasional users, we did not Hart CL, Haney M, Vosburg SK, Rubin E, Foltin RW. Smoked cocaine self-administration
collect data on specic cannabis use patterns of participants; therefore is decreased by modanil. Neuropsychopharmacology 2008;33:7618.
we cannot rule out the possibility that the effects of THC may differ by Harvey MA, Sellman JD, Porter RJ, Frampton CM. The relationship between non-acute
adolescent cannabis use and cognition. Drug Alcohol Rev 2007;26:30919.
patterns of use. Heinzerling KG, Swanson A-N, Kim S, Cederblom L, Moe A, Ling W, et al. Randomized,
In summary, these results show that modanil can be safely double-blind, placebo-controlled trial of modanil for the treatment of metham-
combined with oral THC. Further studies with larger sample sizes and phetamine dependence. Drug Alcohol Depend 2010;109:209.
Hooker WD, Jones RT. Increased susceptibility to memory intrusions and the Stroop
a range of cannabis doses are warranted to investigate the therapeutic interference effect during acute marijuana intoxication. Psychopharmacol Berl
efcacy of modanil. It is also recommended that future studies 1987;91:204.
examine the effects of modanil with regular marijuana smokers, Jones RT. Cardiovascular system effects of marijuana. J Clin Pharmacol 2002;42:
58S63S.
and include a more comprehensive cognitive assessment battery in Kirk JM, de Wit H. Responses to oral 9-tetrahydrocannabinol in frequent and
order to detect possible effects of modanil and THC on cognitive infrequent marijuana users. Pharmacol Biochem Behav 1999;63:13742.
performance. Lichtman AH, Martin BR. Cannabinoid tolerance and dependence. Handb Exp
Pharmacol 2005:691717.
MacDonald JR, Hill JD, Tarnopolsky MA. Modanil reduces excessive somnolence and
enhances mood in patients with myotonic dystrophy. Neurology 2002;59:
Acknowledgments 187680.
Madras BK, Xie Z, Lin Z, Jassen A, Panas H, Lynch L, et al. Modanil occupies dopamine
and norepinephrine transporters in vivo and modulates the transporters and trace
This research was supported by the Veterans Administration amine activity in vitro. J Pharmacol Exp Ther 2006;319:5619.
Mental Illness Research, Education and Clinical Center (MIRECC) and Makela P, Wakeley J, Gijsman H, Robson PJ, Bhagwagar Z, Rogers RD. Low doses of 9-
the National Institute on Drug Abuse (NIDA) grant K02-DA021304 tetrahydrocannabinol (THC) have divergent effects on short-term spatial memory
in young, healthy adults. Neuropsychopharmacology 2006;31:46270.
(MS). We would like to thank Ellen Mitchell, R.N. and Stacy Minnix for Malcolm R, Swayngim K, Donovan JL, DeVane CL, Elkashef A, Chiang N, et al. Modanil
technical assistance. and cocaine interactions. Am J Drug Alcohol Abuse 2006;32:57787.
100 D.E. Sugarman et al. / Pharmacology, Biochemistry and Behavior 98 (2011) 94100

Martin W, Sloan J, Sapira J, Jasinski D. Physiologic, subjective, and behavioral effects of Shearer J, Darke S, Rodgers C, Slade T, van Beek I, Lewis J, et al. A double-blind, placebo-
amphetamine, methamphetamine, ephedrine, phenmetrazine, and methylphenidate controlled trial of modanil (200 mg/day) for methamphetamine dependence.
in man. Clin Pharmacol Ther 1971;12:24558. Addiction 2009b;104:22433.
McDonald J, Schleifer L, Richards JB, de Wit H. Effects of THC on behavioral measures of Sofuoglu M, Waters AJ, Mooney M. Modanil and nicotine interactions in abstinent
impulsitivity in humans. Neuropsychopharmacology 2003;28:135665. smokers. Hum Psychopharmacol 2008;23:2130.
McGaugh J, Mancino MJ, Feldman Z, Chopra ME, Gentry WB, Cargile C, et al. Open-label Sofuoglu M, Sugarman DE, Carroll KM. Cognitive function as an emerging treatment
pilot study of modanil for methamphetamine dependence. J Clin Psychopharmacol target for marijuana addiction. Exp Clin Psychopharmacol 2010;18:10919.
2009;29:48891. Solowij N. Do cognitive impairments recover following cessation of cannabis use? Life
McNair D, Lorr M, Dropperman L. Manual for prole of mood states. Educational and Sci 1995;56:211926.
Industrial Testing Services, Educational and Industrial Testing Services; 1971. Solowij N, Michie PT, Fox AM. Differential impairments of selective attention due to
Morgan PT, Pace-Schott E, Pittman B, Stickgold R, Malison RT. Normalizing effects of frequency and duration of cannabis use. Biol Psychiatry 1995;37:7319.
modanil on sleep in chronic cocaine users. Am J Psychiatry 2010;167:33140. Solowij N, Stephens RS, Roffman RA, Babor T, Kadden R, Miller M, et al. Cognitive
Muller U, Steffenhagen N, Regenthal R, Bublak P. Effects of modanil on working functioning of long-term heavy cannabis users seeking treatment. [comment]
memory processes in humans. Psychopharmacol Berl 2004;177:1619. [erratum appears in JAMA2002 Apr 3;287(13):1651]JAMA 2002;287:112331.
Murillo-Rodriguez E, Haro R, Palomero-Rivero M, Millan-Aldaco D, Drucker-Colin R. Stephens RS, Babor TF, Kadden R, Miller M, MTP Research Group. The marijuana
Modanil enhances extracellular levels of dopamine in the nucleus accumbens and treatment project: rationale, design, and participant characteristics. Addiction
increases wakefulness in rats. Behav Brain Res 2007;176:3537. 2002;97:10924.
Murray L. Physician's Desk Reference. Thomson PDR; 2004. Taneja I, Diedrich A, Black BK, Byrne DW, Paranjape SY, Robertson D. Modanil elicits
Nordstrom BR, Levin FR. Treatment of cannabis use disorders: a review of the literature. sympathomedullary activation. Hypertension 2005;45:6128.
Am J Addict 2007;16:33142. Taneja I, Haman K, Shelton RC, Robertson D. A randomized, double-blind, crossover trial
Ofce of National Drug Control Policy. Marijuana: The Greatest Cause of Illegal Drug of modanil on mood. J Clin Psychopharmacol 2007;27:769.
Abuse The Marijuana Factbook. Washington, DC: Executive Ofce of the President; Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ. Cognitive enhancing
2008. 20503. effects of modanil in healthy volunteers. Psychopharmacol Berl 2003;165:2609.
Pich EM, Pagliusi SR, Tessari M, Talabot-Ayer D, Hooft van Huijsduijnen R, Chiamulera C. Volkow ND, Fowler JS, Logan J, Alexoff D, Zhu W, Telang F, et al. Effects of modanil on
Common neural substrates for the addictive properties of nicotine and cocaine. dopamine and dopamine transporters in the male human brain: clinical
Science 1997;275:836. implications. JAMA 2009;301:114854.
Pope Jr HG, Yurgelun-Todd D. The residual cognitive effects of heavy marijuana use in Vosburg SK, Hart CL, Haney M, Rubin E, Foltin RW. Modanil does not serve as a
college students. Jama 1996;275:5217. reinforcer in cocaine abusers. Drug Alcohol Depend 2010;106:2336.
Pope Jr HG, Gruber AJ, Yurgelun-Todd D. The residual neuropsychological effects of Wachtel SR, ElSohly MA, Ross SA, Ambre J, de Wit H. Comparison of the subjective effects of
cannabis: the current status of research. Drug Alcohol Depend 1995;38:2534. 9-tetrahydrocannabinol and marijuana in humans. Psychopharmacology 2002;161:
Ramaekers JG, Kauert G, Theunissen EL, Toennes SW, Moeller MR. Neurocognitive 3319.
performance during acute THC intoxication in heavy and occasional cannabis users. Wagner FA, Anthony JC. From rst drug use to drug dependence; developmental periods of
J Psychopharmacol 2009;23:26677. risk for dependence upon marijuana, cocaine, and alcohol. Neuropsychopharmacology
Ranganathan M, D'Souza DC. The acute effects of cannabinoids on memory in humans: 2002;26:47988.
a review. Psychopharmacol Berl 2006;188:42544. Wesensten NJ. Effects of modanil on cognitive performance and alertness during sleep
Robledo P, Trigo JM, Panayi F, de la Torre R, Maldonado R. Behavioural and deprivation. Curr Pharm Des 2006;12:245771.
neurochemical effects of combined MDMA and THC administration in mice. Wesensten NJ, Belenky G, Kautz MA, Thorne DR, Reichardt RM, Balkin TJ. Maintaining
Psychopharmacol Berl 2007;195:25564. alertness and performance during sleep deprivation: modanil versus caffeine.
Rush CR, Kelly TH, Hays LR, Wooten AF. Discriminative-stimulus effects of modanil in Psychopharmacol Berl 2002;159:23847.
cocaine-trained humans. Drug Alcohol Depend 2002;67:31122. Wong Y, Simcoe D, Hartman L, Laughton W, King S, McCormick G, et al. A double-blind,
Substance Abuse and Mental Health Services Administration (SAMHSA). Results from placebo-controlled, ascending-dose evaluation of the pharmacokinetics and
the 2007 National Survey on Drug Use and Health: national ndings; 2008. tolerability of modanil tablets in healthy male volunteers. J Clin Pharmacol
Shearer J, Darke S, Rodgers C, Slade T, van Beek I, Lewis J, et al. A double-blind, placebo- 1999;39:3040.
controlled trial of modanil (200 mg/day) for methamphetamine dependence.
Addiction 2009a;104:22433.