Effects of oral THC maintenance on smoked marijuana self-administration

Drug and Alcohol Dependence 67 (2002) 301 /309
www.elsevier.com/locate/drugalcdep
Effects of oral THC maintenance on smoked marijuana selfadministration
Carl L. Hart *, Margaret Haney, Amie S. Ward, Marian W. Fischman, Richard
W. Foltin
Division on Substance Abuse, New York State Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons of Columbia
University, 1051 Riverside Dr., Unit 120, New York, NY 10032, USA
Received 29 October 2001; received in revised form 16 April 2002; accepted 18 April 2002
Abstract
Studies have shown that the D9-tetrahydrocannabinol (D9-THC) concentration in marijuana cigarettes is an important factor for
the maintenance of marijuana self-administration. Yet, the impact of oral D9-THC treatment on marijuana self-administration is
unknown. Because other agonist therapies have been demonstrated to be effective for the treatment of substance use disorders, the
objective of this study was to evaluate the influence of oral D9-THC maintenance on choice to self-administer smoked marijuana.
During this 18-day residential study, 12 healthy research volunteers received one of three doses of oral D9-THC capsules (0, 10, 20
mg QID) for 3 consecutive days, followed by 3 consecutive days of matching placebo. The order of active D9-THC administration
was counterbalanced. Each morning, except on days 6, 12, and 18, participants smoked the ‘sample’ marijuana cigarette (1.8% D9THC w/w) and received a $2 voucher (redeemable for cash at study’s end). Following the sample, volunteers participated in a fourtrial choice procedure during which they had the opportunity to self-administer either the dose of marijuana they sampled that
morning or to receive the $2 voucher. Relative to placebo D9-THC maintenance, participants’ choice to self-administer marijuana
was not significantly altered by either of the two active D9-THC maintenance conditions. Some ‘positive’ subjective drug-effect
ratings following the sample marijuana cigarette were reduced: by day 3 of active oral D9-THC maintenance, participants’ rating of
‘Good Drug Effect’ and ‘High’ were significantly decreased. Smoked marijuana-related total daily caloric intake was not
significantly altered under any maintenance conditions. Finally, the effects of smoked marijuana on psychomotor task performance
were only minimally affected by oral D9-THC maintenance. These data indicate that participants’ choice to self-administer
marijuana was unaltered by the oral D9-THC dosing regimen used in the present investigation. # 2002 Elsevier Science Ireland Ltd.
All rights reserved.
Keywords: Marijuana; Subjective effects; Choice; Self-administration; Food intake; Delta-9-tetrahydrocannabinol
1. Introduction
Marijuana remains the most widely used illicit drug in
the United States; D9-tetrahydrocannabinol (D9-THC), a
psychopharmacologically active constituent of marijuana smoke, is thought to be essential for the maintenance of chronic marijuana smoking behavior. For
example, oral D9-THC has been shown to serve as a
positive reinforcer in humans under experimental conditions (Chait and Zacny, 1992). In addition, several
* Corresponding author. Tel.: /1-212-543-5884; fax: /1-212-5435991
E-mail address: [email protected] (C.L. Hart).
studies have provided experimental data supporting D9THC’s integral role in the reinforcing effects of smoked
marijuana (Mendelson and Mello, 1984; Chait and
Burke, 1994; Kelly et al., 1994, 1997). In these studies,
participants ‘sampled’ two marijuana cigarettes, each
containing different D9-THC concentrations, and subsequently were given an option to choose between the
cigarettes. Marijuana cigarettes containing a higher
concentration of D9-THC were consistently preferred
to those containing a lower D9-THC concentration.
Moreover, data from this laboratory have demonstrated
that even when the choice between marijuana cigarettes
varying in D9-THC content is not mutually exclusive,
participants chose higher concentration D9-THC con-
03765-8716/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 3 7 6 - 8 7 1 6 ( 0 2 ) 0 0 0 8 4 - 4
302
C.L. Hart et al. / Drug and Alcohol Dependence 67 (2002) 301 /309
centration cigarettes more often than those containing
lower D9-THC concentrations (Haney et al., 1997; Ward
et al., 1997). Volunteers in those studies were presented
with a choice between one marijuana cigarette and an
alternative reinforcer (e.g. snack food, money). Three
different D9-THC concentration cigarettes were compared to the alternative reinforcers repeatedly. While
choice to self-administer marijuana was sensitive to
alternative reinforcers, volunteers overwhelmingly selected more cigarettes containing higher D9-THC content than placebo and low D9-THC cigarettes. Together,
these data bolster the hypothesis that marijuana selfadministration is related to D9-THC content.
Previous laboratory research has shown that tobacco
cigarette and heroin self-administration can be significantly decreased when research participants are maintained on agonist treatments (Mello and Mendelson,
1980; Benowitz et al., 1998; Comer et al., 2001).
Employing non-treatment seeking daily cigarette smokers, Benowitz et al. (1998) reported that 63 mg of
transdermal nicotine (the major psychoactive constituent of tobacco smoke) reduced the daily number of
cigarettes smoked by nearly 30% and decreased the
amount of nicotine obtained from each cigarette by 36%
in comparison to a placebo patch. Similarly, in a recent
laboratory investigation of buprenorphine’s (a partial m
opioid agonist) ability to impact heroin self-administration by humans, Comer et al. (2001) found that
progressive ratio (PR) break point values for heroin
and ratings of subjective heroin effects were markedly
lowered (/40 and 60%, respectively), during 16 mg
buprenorphine maintenance compared to 8 mg. Additionally, although the effects of methadone maintenance
on human heroin self-administration has yet to be
assessed under laboratory conditions, the ability of
methadone maintenance to substantially decrease illicit
heroin use in a clinical setting has been well-documented
(for review, see Kreek, 2000). These findings argue that
agonist medications can be effective tools for decreasing
drug-taking behavior.
Given these considerations, the purpose of this study
was to evaluate the effectiveness of oral D9-THC
maintenance to modify choice to self-administer smoked
marijuana by humans under controlled laboratory
conditions. Using a double-blind, within-participant
design, experienced marijuana smokers were maintained
on oral D9-THC (0, 10, 20 mg QID) for 3 consecutive
days. Choice to self-administer a marijuana cigarette
(1.8% D9-THC w/w) or receive a $2 voucher (redeemable
for cash at study’s end) was compared during different
D9-THC maintenance conditions. Our hypothesis was
that marijuana-related reinforcing and subjective effects
would be significantly attenuated during active oral D9THC maintenance, relative to placebo. Because the
number of individuals seeking treatment for marijuana
dependence has increased in the past decade (SAMHSA,
1998) and because marijuana withdrawal (a syndrome
that, in theory, should be mitigated by oral D9-THC
administration) may be one factor maintaining continued marijuana use, the findings from the current
investigation could have important clinical implications.
2. Methods
2.1. Participants
Twelve healthy research volunteers, ranging in age
from 21 to 45 years (mean/31.7), completed this 18day residential study. Of these participants, two were
female (Black-American, White-American) and 10 were
male (eight Black-American, two Hispanic-American).
They were solicited via word-of-mouth referral and
newspaper advertisement in New York City. All reported smoking marijuana every day, averaging 12
‘joints’ per day (ranging between 1 and 35 joints per
day). An important caveat for self-reported marijuana
use history is that it is difficult to absolutely quantify the
number of marijuana joints research participants
smoked per day because many individuals in the New
York City area report smoking ‘blunts.’ A blunt is
comprised of approximately four joints rolled in tobacco
cigar wrapping paper. In addition, most of the current
research participants reported smoking with other
individuals regularly. As a result, the likelihood of
some participants underestimating or overestimating
their daily marijuana consumption is fairly high. Seven
participants reported current caffeine use (ranging
between 2 and 5 cups per week), eight reported current
alcohol use (ranging between 1 and 10 drinks per week)
and seven reported current tobacco cigarette use (ranging between 2 and 20 cigarettes per day). Several urine
toxicology screens during the screening process confirmed the absence of other illicit drug use, as D9-THC
was the only drug metabolite present. During screening,
all volunteers passed comprehensive medical and psychological evaluations, and were within normal weight
ranges according to the 1983 Metropolitan Life Insurance Company height/weight table. Female volunteers
were given a serum pregnancy test during the screening
process, and subsequent random urine pregnancy tests
throughout the experimental protocol.
Participants were informed that they would have the
opportunity to smoke one marijuana cigarette on five
occasions daily for 15 days, and each 5-day period of
marijuana availability would be separated by a day
during which no marijuana would be available. They
were also informed that they would be administered
four capsules containing a FDA-approved medication at
different times each day. Participants were told that the
D9-THC concentration in the marijuana cigarettes and
doses contained in the capsules could change at anytime
C.L. Hart et al. / Drug and Alcohol Dependence 67 (2002) 301 /309
during the study. All volunteers were told that the
purpose of the study was to evaluate the interactions of
smoked marijuana and medications on ongoing behavior in a relatively naturalistic setting. Each participant
signed a consent form approved by the New York State
Psychiatric Institute’s Institutional Review Board. The
consent form described the study and detailed any
possible risks. At study completion and prior to
discharge, participants were fully informed about experimental and drug conditions. For completing the
entire study, research participants were compensated at
a rate of $70 per day, which was paid in 2 weekly
installments.
2.2. Laboratory
Three groups of participants (each group consisting of
four individuals) resided in a residential laboratory
designed for the continuous observation of behavior
over extended time periods (Foltin et al., 1996). Located
within the New York State Psychiatric Institute, the
facility consists of 11 rooms. The common social area,
where participants were free to engage in recreation
activities, is a large room that contains two couches,
chairs, two video game machines, two television monitors for viewing videotaped films, free-weight exercise
equipment, art supplies, reading materials, board games,
and two washers/dryers. Participants were individually
housed in four private bedrooms, each of which is
furnished with a bed, desk, Macintosh LC computer
system, microwave, toaster, refrigerator, food preparation space, and bar-code scanner (Worthington Data
Solutions, Santa Cruz, CA). The bar-code scanner was
used for food reporting and requesting. From 08:15 to
24:00, food (including caffeinated beverages) was available ad libitum, except during the work sessions when
meals that required extended food preparation time
were not allowed. Additionally, during this time period,
participants had free monitored access to tobacco
cigarettes. Immediately outside of bedrooms were two
single-occupancy bathrooms and two single-occupancy
showers. In addition, two vestibules located adjacent to
the common social area were used for supervised
medication administration and for daily exchange of
all personal items and food. For the purpose of
continuous observation of behavior, cameras and microphones were located throughout the common social
area and in bedrooms. However, no microphones or
cameras were located in bathrooms, showers or private
dressing areas. Communication between the staff and
participants was kept to a minimum and was primarily
accomplished via a continuous on-line computer network system consisting of the computers in each
participant’s bedroom and the control room computer.
303
2.3. Procedure
Prior to residing in the laboratory, participants
completed two 3/4 h training sessions in order to
familiarize them with the computerized psychomotor
tasks, subjective-effects visual analog questionnaire, and
other study procedures. On 2 different days participants
were administered a ‘sample’ of the substances used in
the study: on the first day they smoked a marijuana
cigarette (1.8% D9-THC concentration) and the second
day they were given an oral D9-THC capsule (20 mg).
The purpose of administering marijuana and oral D9THC before the study began was to provide volunteers
with experience with the study marijuana and oral D9THC prior to study onset and to monitor any potential
unusual reaction to them. Volunteers moved into the
laboratory the day before the study began, received
further training on the computerized psychomotor
tasks, and were acclimated to experimental conditions.
Each study day, participants were awakened at 08:15
and were instructed to submit urine samples, which were
randomly tested for drug metabolites (amphetamines,
cocaine, D9-THC, and morphine derivatives): D9-THC
was the only drug metabolite present. Participants
completed a visual analog sleep questionnaire, which
consisted of 7 100-mm lines anchored with ‘not at all’ at
the left end and ‘extremely’ at the right end, labeled
with: ‘I slept well last night,’ ‘I woke up early this
morning,’ ‘I fell asleep easily last night,’ ‘I feel clearheaded this morning,’ ‘I woke up often last night,’ ‘I am
satisfied with my sleep last night,’ and a fill-in question
estimating how many hours participants thought they
slept the previous night (Haney et al., 2001). Additionally, they completed a 50-item subjective-effects visual
analog questionnaire, which was a series of lines, each
100 mm long and labeled ‘not at all’ at one end and
‘extremely’ at the other end, presented one at a time
(Haney et al., 1999b; Hart et al., 2001a). These lines are
labeled with adjectives describing a mood (e.g. I feel. . .
‘Anxious,’ ‘Angry,’ ‘Frustrated’), a drug effect (e.g. I
feel. . . ‘High,’ ‘Good Drug Effect,’ ‘Bad Drug Effect’),
or a physical symptom (e.g. I feel. . . ‘Headache,’
‘Stomach Upset,’ ‘Muscle Pain’). Participants were
also weighed after voiding, but were not informed of
their weight.
Eight 30-min computerized task batteries, composed
of a subjective-effects questionnaire, a drug-effect questionnaire, and psychomotor tasks were completed each
day. Participants were given a 15-min break between
each task battery. From 09:15 to 11:15, participants
completed three task batteries, followed by a lunch
period in which they had access to activities available in
the social/recreational area until 12:30. The final five
task batteries were completed from 13:00 to 17:00.
On the drug-effect questionnaire, participants were
required to rate ‘Good Effects’ and ‘Bad Effects’ from
C.L. Hart et al. / Drug and Alcohol Dependence 67 (2002) 301 /309
304
secutive days of placebo D9-THC administration was
included in order to examine residual D9-THC effects
and as a washout period. The dose of oral D9-THC
during the first 3 days of each block of sessions was
counterbalanced. The oral D9-THC dosing order for the
first four participants (1 /4) was 0, 10, and 20 mg (QID:
total daily dose of 40 or 80 mg); participants 5/8
received 0, 20, and 10 mg (QID); and participants 9/12
received 10, 0, and 20 mg (QID). Because the recommended clinical dose of oral D9-THC (2.5 /5 mg BID:
total daily dose of 5 /20 mg) is well below doses used in
this study, as a safety precaution, the 20 mg dose was
never administer during the first block of sessions. Each
5-day period of marijuana availability was followed by 1
day during which no marijuana was available.
the drug on a five-point scale: 0/‘not at all’ and 4 /
‘very much.’ They were also asked to rate how ‘Strong’
the drug-effect was as well as their desire ‘to take the
drug again.’ Lastly, participants were ask to rate how
much they liked the drug effect on a nine-point scale: /
4 indicated ‘disliked very much,’ 0 indicated ‘feel
neutral, or feel no drug-effect,’ and 4 indicated ‘liked
very much.’ The drug-effect questionnaire was administered 45 min after each marijuana dosing occasion and
participants were instructed to rate their responses based
on the marijuana cigarette most recently, smoked. Only
the drug-effect questionnaire completed after the sample
marijuana dose was included in the data analysis.
Psychomotor tasks (Haney et al., 1999b) consisted of a
3-min Digit-Symbol Substitution Task (McLeod et al.,
1982), a 3-min repeated-acquisition task (Kelly et al.,
1993), a 10-min divided attention task (Miller et al.,
1988), a 10-min rapid information task (Wesnes and
Warburton, 1983), an immediate and delayed digitrecall task, followed by a 15-min rest period. Beginning
at 17:00 h, participants had access to activities available
in the social/recreational area. Two videotaped films
were shown nightly, beginning at 18:15 and 21:30.
Lights were turned out at 24:00.
2.5. Food monitoring
A food box, which contained various meal items,
conventional snacks, and beverages, was distributed to
each participant daily at 08:30. Food boxes did not
contain frozen food items; these items were kept in a
freezer in an adjacent room and were available via
request. To facilitate choice of frozen meals, participants
were provided with a book containing package pictures
of each item. Between 08:15 and 24:00, participants were
free to request additional units of any items as desired
and could consume food items ad libitum. Water could
be consumed at any time. Participants were informed
that their food intake was monitored continuously, and
were instructed to scan custom-designed bar codes
whenever they ate or drank, specifying substance and
portion. Research monitors in the adjacent control
room acknowledged the report and also kept a handwritten record of food consumption. Participants could
cancel a food report, or change portion size, using the
customized bar codes. Wrappers for each item were
color-coded by participant to facilitate data collection.
Trash was removed and examined daily to validate
verbal reports and observer records of food intake, and
to control for the possibility of food hoarding.
2.4. Experimental design
A representative study design is shown in Table 1.
This study consisted of three 6-day blocks of sessions.
At 09:45 during the first 5 days of each block (days 1/5,
7 /11, and 13 /17), participants sampled the reinforcers
available that day: they smoked one marijuana cigarette
(1.8% D9-THC cigarettes were the only cigarettes available throughout the study) and were given a $2 money
voucher, which was redeemable for cash at the end of
the study. For the remaining marijuana-dosing times
(12:35, 16:00, 19:00, 22:00), participants were given the
option to smoke the sampled marijuana cigarette or to
receive the $2 money voucher. Additionally, one of three
doses of oral D9-THC capsules (0, 10, 20 mg QID; 09:00,
12:30, 17:00, 21:00) were administered during the first 3
days of each block of sessions, followed by 3 consecutive
days of placebo D9-THC administration. The 3 con-
Table 1
Representative study design for assessing the effects of oral D9-THC on smoked marijuana (MJ)
Block number
1
2
3
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Oral D9-THCa
MJ choiceb
0
Y
0
Y
0
Y
0
Y
0
Y
0
N
10
Y
10
Y
10
Y
0
Y
0
Y
0
N
20
Y
20
Y
20
Y
0
Y
0
Y
0
N
First marijuana dose on each choice day was a sample. During all other opportunities, participants were presented with a choice between one
marijuana cigarette (1.8% D9-THC) and a $2 voucher. Y Choice day. N No choice day.
a
Oral THC dosing times (09:00, 12:30, 17:00, 21:00).
b
Choice/marijuana times (09:45, 12:35, 16:00, 19:00, 22:00).
C.L. Hart et al. / Drug and Alcohol Dependence 67 (2002) 301 /309
2.6. Drug
During sample dosing and when smoked marijuana
was the selected option, participants smoked a single 1-g
marijuana cigarette (1.8% D9-THC w/w, provided by the
National Institute on Drug Abuse), while under video
observation, using a paced-puffing procedure previously
shown to produce concentration-dependent changes in
heart rate and subjective-effects ratings (Hart et al.,
2001b). They were instructed to take three puffs from
the marijuana cigarette: each puff consisted of a 5-s
preparation interval, followed by 5 s of inhalation, 10 s
of breath-hold, and 40 s of exhalation and rest.
Cigarettes were tightly rolled at both ends and were
smoked through a hollow plastic cigarette holder so that
the contents were not visible. At least 12 h prior to
administration, cigarettes were removed from a freezer,
where they were stored in an airtight container, and
humidified at room temperature. Small tablets of oral
D9-THC (Unimed Pharmaceuticals, Inc.) were repackaged by the Pharmacy Department of the New York
State Psychiatric Institute by placing D9-THC into red
#00 opaque capsules and adding lactose filler. Placebo
D9-THC contained only the filler.
2.7. Data analysis
Data for smoked marijuana choices and the drugeffect questionnaire were analyzed using two-factor
repeated measures analyses of variance (ANOVA): the
first factor was oral D9-THC maintenance condition (0,
10, 20 mg) and the second factor was day of maintenance condition (1 /5). When the ANOVA revealed a
significant dose by day interaction, post hoc analyses
were performed to answer the following question: (1) do
the effects produced by oral D9-THC maintenance differ
from the effects produced by placebo maintenance? To
evaluate potential differences between effects produced
by the oral D9-THC maintenance conditions, each day
of each oral D9-THC maintenance condition was
compared to the corresponding day of each other oral
D9-THC maintenance condition (e.g. placebo oral D9THC, day 1 versus 10 mg oral D9-THC, day 1). Data
from day 6 were not included in the analysis because
marijuana cigarettes were not available on this day.
Data for the subjective-effects visual analog questionnaire and psychomotor performance were analyzed
using three-factor repeated measures ANOVAs: the first
factor was oral D9-THC maintenance condition (0, 10,
20 mg), the second factor was day of maintenance
condition (1 /5), and the third factor was time after the
sample marijuana cigarette (15 and 45 min post the
sample marijuana dose). Analyses were performed only
on subjective ratings and psychomotor performance
data collected after the sample marijuana cigarette for
each oral D9-THC condition because each participant
305
chose to self-administer varying numbers of marijuana
cigarettes during each maintenance condition. Change
from baseline scores for the two subjective-effects
questionnaires and performance scores obtained after
administration of the sample marijuana cigarette were
compared among the various drug conditions. Change
from baseline scores were used because there are subtle
day-to-day differences on some dependent measures and
participants’ task performance often gradually improves
over the course of a study. Data from the subjectiveeffects questionnaire and psychomotor battery that were
completed from 09:15 to 09:45 provided baseline scores
for each day. As stated above, post hoc tests were
performed to evaluate potential differences between
effects produced by the oral D9-THC maintenance
conditions, each day of each oral D9-THC maintenance
condition was compared to the corresponding day of
each other oral D9-THC maintenance condition.
Total caloric intake, gram intake of carbohydrate, fat,
and protein, proportion of caloric intake from each
macronutrient (estimated as kcal from g-intake using
Atwater factors (McLaren, 1976)), mean number of
eating occasions, and eating occasion size were measured. Mean number of eating occasions and eating
occasion size were determined using a minimal interoccasion interval of 10 min: an eating occasion was
defined as beginning with the first report of consuming
an item and ending when there was a pause of greater
than 10 min between food reports. As described above
for smoked marijuana choices, food intake data were
analyzed using two-factor repeated measures ANOVA:
the first factor was oral D9-THC maintenance condition
(0, 10, 20 mg) and the second factor was day of
maintenance condition (1 /5). The same post hoc
analyses were performed. Only those P values B/0.05
were considered statistically significant and HunyhFeldt corrections were used, when appropriate.
3. Results
3.1. Reinforcing effects
Table 2 displays the number of marijuana cigarettes
chosen as a function of the oral D9-THC maintenance
dose. Relative to placebo D9-THC maintenance, participants’ choice to self-administer marijuana was not
significantly altered by either of the two active D9-THC
maintenance conditions as indicated by the lack of a
dose by day interaction (F (8, 88) /1.67, P / 0.12).
3.2. Subjective effects
Fig. 1 shows ratings of ‘Good Drug Effect’ (left panel)
and ‘High’ (right panel) following the sample marijuana
cigarette (1.8% D9-THC) as a function of oral D9-THC
C.L. Hart et al. / Drug and Alcohol Dependence 67 (2002) 301 /309
306
Table 2
Total number of marijuana options selected under each oral D9-THC condition and self-reported drug use by each participant
Selected MJ options under oral D9-THC conditions
Self-reported drug use
Participant Sex Age Daily MJ cigarettesa Daily tobacco cigarettes Weekly alcoholic drinks 0 mg
10 mg
20 mg
1
2
3
4
5
6
7
8
9
10
11
12
12
12
12
12
12
12
8
12
2
4
6
0
7
12
11
12
11
12
9
12
7
12
10
1
M
M
M
M
M
M
F
M
M
M
M
F
21
39
37
33
43
25
27
22
26
38
24
45
3.5
15
25
10
1
10
2
2
25
35
22
3
6
10
0
6
0
2
10
3
0
20
0
0
0
1
0
5
2
2
0
10
0
10
6
2
10
12
12
12
9
10
10
12
7
12
9
11
Maximum number of doses available per participant under each oral D9-THC condition was 12 (four choices across 3 days of active oral D9-THC
maintenance). MJ marijuana.
a
One ‘blunt’ was classified as four ‘joints’ cigarettes.
maintenance dose and day. Analysis of ‘Good Drug
Effect’ data revealed a significant dose by day interaction (F (8, 88) /2.67, P B/ 0.03). On days 1 and 3,
volunteers reported significantly reduced ratings of
‘Good Drug Effect’ following the sample marijuana
cigarette while being maintained on 20 mg oral D9-THC
compared to placebo D9-THC maintenance (P B/ 0.05
and P B/ 0.0001, respectively); on day 3 of 10 mg oral D9THC maintenance, ratings of ‘Good Drug Effect’ were
significantly reduced, relative to placebo maintenance
(P B/ 0.0001). Day 1 was the only day that the active
maintenance conditions differed from each other: ratings were significantly decreased under the high-dose
condition, relative to low-dose condition (P B/ 0.01).
During the period after active oral D9-THC maintenance
(day 4 only), ratings of ‘Good Drug Effects,’ under both
active D9-THC conditions, remained markedly lower
than those under the placebo oral D9-THC condition
(P B/ 0.01).
Analysis of ‘High’ data also revealed a significant
dose by day interaction (F (8, 88) /4.37, P B/ 0.001). On
day 1, participants reported significantly greater ratings
of ‘High’ following the sample marijuana cigarette while
being maintained on 10 mg oral D9-THC, relative to
placebo and 20 mg D9-THC maintenance (P B/ 0.0001).
On day 3 of placebo oral D9-THC maintenance, ratings
of ‘High’ were significantly increased, relative to both
active maintenance conditions (PB/ 0.03). During the
period following active oral D9-THC maintenance (days
4 and 5), ratings of ‘High,’ under 20 mg D9-THC
Fig. 1. Selected mean subjective-effects ratings following the sample marijuana cigarette (1.8% D9-THC) as a function of oral D9-THC maintenance
dose and day. Data are represented as change from baseline scores. Error bars represent one S.E.M. Overlapping error bars were omitted for clarity.
C.L. Hart et al. / Drug and Alcohol Dependence 67 (2002) 301 /309
maintenance, remained significantly lower than those
under the placebo oral D9-THC condition (P B/ 0.01).
No other significant effects were observed for subjectiveeffects visual analog data and no significant effects were
noted for drug-effect questionnaire data.
3.3. Performance effects
There were few performance alterations observed
during D9-THC maintenance. The only significant dose
by day interaction was observed during the immediate
digit-recall task (F (8, 88) /3.05, P B/ 0.02). On day 2,
volunteers correctly recalled more digits under the 20 mg
condition compared to the 10 mg condition (P B/ 0.001).
On day 4, the period following active oral D9-THC
maintenance, participants correctly recalled fewer digits
under the 20 mg condition, relative to the placebo and
10 mg condition (P B/ 0.03 and P B/ 0.02, respectively).
3.4. Food intake
Analysis of mean caloric intake during each meal
revealed a significant dose by day interaction (F (8,
88) /4.67, P B/ 0.001). On day 1, participants’ mean
caloric intake during each meal was significantly increased during both active maintenance conditions
compared to placebo maintenance (P B/ 0.01), whereas
on day 3, mean caloric intake during each meal was
significantly reduced during both active maintenance
conditions, relative to placebo maintenance (P B/ 0.05).
Nevertheless, no significant marijuana-related effects on
daily total caloric intake were observed. The mean daily
total caloric intake for each condition was as follows:
2848 kcal (placebo D9-THC maintenance), 2606 kcal (10
mg D9-THC maintenance), and 2669 kcal (20 mg D9THC maintenance). Additionally, the mean daily total
caloric intake for the 3 days that marijuana was not
available (days 6, 12, and 18) was 2902 kcal. A
significant dose by day interaction was observed when
the mean number of daily eating occasions was analyzed
(F (8, 88) /2.55, PB/ 0.05). Relative to placebo maintenance, on days 1 and 2 the mean number of eating
occasions was significantly decreased by 10 mg D9-THC
maintenance (P B/ 0.03) and on day 2 by 20 mg
maintenance (P B/ 0.001).
3.5. Sleep questionnaire
Active THC maintenance exerted no significant effect
on how participants’ rated the previous night’s sleep.
4. Discussion
Findings from this study show that choice to selfadminister marijuana was not altered during active oral
307
D9-THC maintenance. Only a few positive subjectiveeffects ratings obtained after smoking the sample dose
were reduced under both active D9-THC conditions.
Psychomotor performance after smoked marijuana was
not markedly impaired during active D9-THC maintenance. Consistent with performance, oral D9-THC
maintenance did not substantially alter the effects of
smoked marijuana on participants’ food intake and
rating of the previous night’s sleep.
Smoked marijuana preference was not significantly
altered when volunteers were maintained on oral D9THC. These results were unexpected because of the
substantial body of research indicating a pivotal role for
D9-THC in marijuana’s reinforcing effects and because
of previously reported data demonstrating that nicotineand heroin-associated reinforcing effects are substantially influenced by agonist treatment (Mello and
Mendelson, 1980; Benowitz et al., 1998; Comer et al.,
2001). There are several possible explanations as to why
oral D9-THC did not have a greater effect on marijuana
self-administration in the current study. First, the D9THC maintenance regimen employed consisted of only 3
consecutive days of active treatment, which may have
been an insufficient time frame to produce substantial
reductions in marijuana-related reinforcing effects. Because the volunteers tested in this study reported daily
marijuana use (averaging 12 joints per day) and because
D9-THC directly reinforces marijuana smoking with
each inhalation, the behavior of smoking marijuana
had become well-learned, not only owing to D9-THC’s
primary reinforcement, but also because of conditioned
reinforcers associated with the act of smoking marijuana. That is, smoking-related stimuli repeatedly
paired with marijuana self-administration may elicit
responses similar to those produced by marijuana,
making marijuana-taking behavior difficult to extinguish, even though the amount of D9-THC (the probable
primary reinforcer) obtained from smoking might be
less reinforcing. Evaluating the reinforcing efficacy of
nicotine and de-nicotinized cigarettes in non-treatment
seeking cigarette smokers, Shahan and colleagues reported data consistent with this hypothesis (Shahan et
al., 1999). They showed that the two different types of
cigarettes produced similar reinforcing effects when
cigarette choice was not mutually exclusive, suggesting
that factors other than nicotine were maintaining
cigarette smoking reinforcement. Others have also
demonstrated the reinforcing efficacy of drug-related
conditioned stimuli in laboratory animals (Schuster and
Woods, 1968; Davis and Smith, 1976; Smith et al.,
1977).
A second possible reason that a greater decrease in
marijuana-related reinforcing effects was not observed
during oral D9-THC maintenance is because the selfadministration procedure employed in the current study
was not sufficiently sensitive. Many investigators have
308
C.L. Hart et al. / Drug and Alcohol Dependence 67 (2002) 301 /309
used PR schedules (for review, see Richardson and
Roberts, 1996; Haney et al., 1998), during which
response requirements are systematically increased until
the participant’s performance diminishes below some
criterion level. As a result, the maximum amount of
work a participant is willing to perform in order to
support drug-taking behavior can be estimated. Perhaps
a PR schedule would have revealed a clearer doserelated effect and shown a greater impact of oral D9THC maintenance on smoked marijuana self-administration.
A third possible reason the reinforcing effects of
smoked marijuana were not decreased more by oral
D9-THC maintenance is that the D9-THC doses tested
were too large (oral D9-THC doses used in the current
study were 8/16 times greater than the recommended
clinical doses). Administration of oral D9-THC produces
several behavioral effects, including increased positive
subjective ratings and self-administration (Mendelson
and Mello, 1984; Haney et al., 1999a). In light of this
knowledge, it is conceivable that participants interpreted
oral D9-THC-associated effects as those produced by
smoked marijuana, thus decreasing the likelihood of
observing alterations of smoked marijuana-related reinforcing effects. Positive subjective-effects data obtained after the sample marijuana cigarette, however,
argue against this supposition as the only cause because,
under both active oral D9-THC maintenance conditions,
ratings of ‘Good Drug Effect,’ and ‘High,’ were
significantly decreased following smoking of the sample
marijuana cigarette, indicating that volunteers experienced smoked marijuana’s subjective effects differently
during active oral D9-THC maintenance. This finding is
congruent with a previous investigation, which demonstrated diminished smoked marijuana-associated positive subjective effects during oral D9-THC maintenance
(Jones et al., 1981). Moreover, the dissociation of drugrelated reinforcing and subjective effects has been well
documented by several investigators using different
classes of drugs (e.g. Johanson and Uhlenhuth, 1980;
Fischman et al., 1990; Comer et al., 1997). It may be
that in order to markedly decrease marijuana’s reinforcing effects, pharmacological interventions would have
to decrease marijuana-induced subjective effects substantially more than those decreases observed in the
current study.
Another possible reason choice to smoke marijuana
was not markedly decreased under active oral D9-THC
maintenance is because participants altered their smoking behavior such that they titrated their amounts of
smoked D9-THC exposure while continuing to choose it.
Indeed, the administration of controlled concentrations
of self-inhaled substances to humans is difficult due to
variability in inhalation volume, lung capacity, depth of
hold, etc. However, the current study employed a pacedpuffing procedure, which is designed to decrease the
variability in inhalation parameters. These procedures
have regularly produced D9-THC concentration-dependent changes in mood and cardiovascular activity
following marijuana smoking. For example, in a recent
study, the smoking procedure employed in the current
study produced dose-related heart rate and subjectiveeffects ratings increases, (Hart et al., 2001b). Thus, the
likelihood of changes in participants’ marijuana smoking behavior substantially influencing choice selections
appears to be minimal.
One major caveat of the current study’s design is that
participants in the same group received an identical D9THC maintenance condition order (i.e. oral D9-THC
conditions were not counterbalanced within each
group). This factor potentially functioned as a social
contagion. For example, on average, the third group of
participants studied (participants #9 /12) selected considerably fewer smoked marijuana options than the
other two groups. It is possible that participants’ choice
behavior was influenced by choice selections of their
fellow participants. In an effort to minimize such an
effect, each participant was required to indicate their
choices in the privacy of their room on a personal
computer that was linked to the control room computer
without knowledge of other study participants’ choice.
Nevertheless, future studies should counterbalance
within groups of participants to avoid this potential
social confounder.
The observation that the study drugs did not substantially impair psychomotor performance was not
unexpected given that volunteers tested in this study
were daily marijuana users. There is a growing body of
literature supporting the hypothesis that regular marijuana users have learned (presumably through repeated
practice) to be more cautious when executing challenging activities (e.g. cognitive operations) during intoxication (Ward et al., 1997; Haney et al., 1999b; Hart et
al., 2001b), thereby decreasing the likelihood of observing D9-THC-related cognitive and psychomotor performance impairments in this population. Finally, the
oral D9-THC maintenance doses examined in the current
study did not markedly alter marijuana-related food
intake effects.
In conclusion, although D9-THC is thought to be
integrally involved in smoked marijuana-related reinforcing effects, the majority of participants’ choice to selfadminister marijuana was unaltered by the oral D9-THC
dosing regimen used in the present investigation. These
data suggest that other factors (e.g. conditioned reinforcers) may also be critically involved in the maintenance of smoked marijuana-taking behavior and they
underscore the need for further study of mechanisms
involved in marijuana reinforcement. Future studies
should increase the length of the oral D9-THC maintenance period in an effort to extinguish the effects of
C.L. Hart et al. / Drug and Alcohol Dependence 67 (2002) 301 /309
marijuana-related conditioned stimuli, and employ
other self-administration procedures.
Acknowledgements
This research is dedicated to the memory of our
mentor Dr Marian Fischman, who died before publication of this manuscript. We thank the National Institute
on Drug Abuse for financial support (DA-09236). The
assistance of Shannon Lewis, Rachelle Reis-Larson,
Christine Figueroa, Nicole Cain, Mabel Torres, Tom
Melore, and Drs Cindy M. Pudiak, Evaristo Akerele
and Jeffrey Wilson are gratefully acknowledged.
References
Benowitz, N.L., Zevin, S., Jacob, P. 1998. Suppression of nicotine
intake during ad libitum cigarette smoking by high-dose transdermal nicotine. J. Pharmacol. Exp. Ther. 287, 958 /962.
Chait, L.D., Burke, K.A. 1994. Preference for high- versus lowpotency marijuana. Pharmacol. Biochem. Behav. 49, 643 /647.
Chait, L.D., Zacny, J.P. 1992. Reinforcing and subjective effects of
oral D9-THC and smoked marijuana in humans. Psychopharmacology 107, 255 /262.
Comer, S.D., Collins, E.D., Fischman, M.W. 1997. Choice between
money and intranasal heroin in morphine-maintained humans.
Behav. Pharmacol. 6, 677 /690.
Comer, S.D., Collins, E.D., Fischman, M.W. 2001. Buprenorphine
sublingual tablets: effects of IV heroin self-administration by
humans. Psychopharmacology 154, 28 /37.
Davis, W.M., Smith, S.G. 1976. Role of conditioned reinforcers in the
initiation, maintenance and extinction of drug-seeking behavior.
Pavlov. J. Biol. Sci. 11, 222 /236.
Fischman, M.W., Foltin, R.W., Nestadt, G., Pearlson, G.D. 1990.
Effects of desipramine maintenance on cocaine self-administration
by humans. J. Pharmacol. Exp. Ther. 253, 760 /770.
Foltin, R.W., Haney, M., Comer, S.D., Fischman, M.W. 1996. Effects
of fluoxetine on food intake of humans living in a residential
laboratory. Appetite 27, 165 /181.
Haney, M., Collins, E.D., Ward, A.S., Foltin, R.W., Fischman, M.W.
1998. Effects of pergolide on intravenous cocaine self-administration in men and women. Psychopharmacology 137, 15 /24.
Haney, M., Comer, S.D., Ward, A.S., Foltin, R.W., Fischman, M.W.
1997. Factors influencing marijuana self-administration by humans. Behav. Pharmacol. 8, 101 /112.
Haney, M., Ward, A.S., Comer, S.D., Foltin, R.W., Fischman, M.W.
1999a. Abstinence symptoms following oral THC to humans.
Psychopharmacology 141, 385 /394.
Haney, M., Ward, A.S., Comer, S.D., Foltin, R.W., Fischman, M.W.
1999b. Abstinence symptoms following smoked marijuana in
humans. Psychopharmacology 141, 395 /404.
Haney, M., Ward, A.S., Comer, S.D., Hart, C.L., Foltin, R.W.,
Fischman, M.W. 2001. Bupropion SR worsens mood during
marijuana withdrawal in humans. Psychopharmacology 155,
171 /179.
309
Hart, C.L., Ward, A.S., Haney, M., Foltin, R.W., Fischman, M.W.
2001a. Methamphetamine self-administration by humans. Psychopharmacology 157, 75 /81.
Hart, C.L., van Gorp, W.G., Haney, M., Foltin, R.W., Fischman,
M.W. 2001b. Effects of acute smoked marijuana on complex
cognitive performance. Neuropsychopharmacology 25, 757 /765.
Johanson, C.E., Uhlenhuth, E.H. 1980. Drug preference and mood in
humans: d -amphetamine. Psychopharmacology 71, 275 /279.
Jones, R.T., Benowitz, N.L., Herning, R.I. 1981. Clinical relevance of
cannabis tolerance and dependence. J. Clin. Pharmacol. 21, 143s /
152s.
Kelly, T.H., Foltin, R.W., Emurian, C.S., Fischman, M.W. 1993.
Performance-based testing for drugs of abuse: dose and time
profiles of marijuana, amphetamine, alcohol, and diazepam. J.
Anal. Toxicol. 17, 264 /272.
Kelly, T.H., Foltin, R.W., Emurian, C.S., Fischman, M.W. 1994.
Effects of D9-THC on marijuana smoking, dose choice, and verbal
report of drug liking. J. Exp. Anal. Behav. 61, 203 /211.
Kelly, T.H., Foltin, R.W., Emurian, C.S., Fischman, M.W. 1997. Are
choice and self-administration of marijuana related to D9-THC
content? Exp. Clin. Psychopharmacol. 5, 74 /82.
Kreek, M.J. 2000. Methadone-related opioid agonist pharmacotherapy for heroin addiction. History, recent molecular and neurochemical research and future in mainstream medicine. Ann. NY
Acad. Sci. 909, 186 /216.
McLaren, D.S. 1976. Nutrition and its Disorders, second ed..
Churchill Livingstone, New York.
McLeod, D.R., Griffiths, R.R., Bigelow, G.E., Yingling, J. 1982. An
automated version of the digit symbol substitution test (DSST).
Behav. Res. Meth. Instr. 14, 463 /466.
Mello, N.K., Mendelson, J.H. 1980. Buprenorphine suppresses heroin
use by heroin addicts. Science 207, 657 /659.
Mendelson, J.H., Mello, N.K. 1984. Reinforcing properties of oral D9tetrahydrocannabinol, smoked marijuana, and nabilone: influence
of previous marijuana use. Psychopharmacology 83, 351 /356.
Miller, T.P., Taylor, J.L., Tinklenberg, J.R. 1988. A comparison of
assessment techniques measuring the effects of methylphenidate,
secobarbital, diazepam, and diphenhydramine in abstinent alcoholics. Neuropsychobiology 19, 90 /96.
Richardson, N.R., Roberts, D.C.S. 1996. Progressive ratio schedules
in drug self-administration studies in rats: a method to evaluate
reinforcing efficacy. J. Neurosci. Meth. 66, 1 /11.
Schuster, C.R., Woods, J.H. 1968. The conditioned reinforcing effects
of stimuli associated with morphine reinforcement. Int. J. Addict.
3, 223 /231.
Shahan, T.A., Bickel, W.K., Madden, G.J., Badger, G.J. 1999.
Comparing the reinforcing efficacy of nicotine containing and denicotinized cigarettes: a behavioral economic analysis. Psychopharmacology 147, 210 /216.
Smith, S.G., Werner, T.E., Davis, W.M. 1977. Alcohol-associated
conditioned reinforcement. Psychopharmacology 53, 223 /226.
Substance Abuse and Mental Health Services Administration, 1998.
National Admissions to Substance Abuse Treatment Services: The
Treatment Episode Data Set (TEDS), 1992 /1996. US Department
of Health and Human Services, Rockville, Md.
Ward, A.S., Comer, S.D., Haney, M., Foltin, R.W., Fischman, M.W.
1997. The effects of a monetary alternative on marijuana selfadministration. Behav. Pharmacol. 8, 275 /286.
Wesnes, K., Warburton, D.M. 1983. Effects of smoking on rapid
information processing performance. Neuropsychobiology 9, 223 /
229.