Psychopharmacology (1999) 141 : 395–404© Springer-Verlag 1999

ORIGINAL INVESTIGATIONMargaret Haney · Amie S. Ward · Sandra D. Comer
Richard W. Foltin · Marian W. Fischman

Abstinence symptoms following smoked marijuana in humans

Received: 2 June 1998 / Final version: 11 September 1998

Abstract Symptoms of withdrawal after oral *9tetrahydrocannabinol (THC) administration have beenreported, yet little is known about the development ofdependence on smoked marijuana in humans. In a 21day residential study, marijuana smokers (n = 12)
worked on five psychomotor tasks during the day(0915–1700 hours), and in the evening engaged in recreational activities (1700 –2330 hours); subjective-effects
measures were completed 10 times/day. Food and beverages were available ad libitum from 0830 to 2330
hours. Marijuana cigarettes (0.0, 1.8, 3.1% THC) were
smoked at 1000, 1400, 1800, and 2200 hours. Placebo
marijuana was administered on days 1– 4 . One of theactive marijuana doses was administered on days 5–8,
followed by 4 days of placebo marijuana (days 9–12).
The other concentration of active marijuana cigarettes
was administered on days 13–16, followed by 4 daysof placebo marijuana (days 17–20); the order in which
the high and low THC-concentration marijuana cigarettes were administered was counter-balanced between
groups. Both active doses of marijuana increased ratings of “High,” and “Good Drug Effect,” and increasedfood intake, while decreasing verbal interaction compared to the placebo baseline (days 1–4). Abstinencefrom active marijuana increased ratings such as“Anxious,” “Irritable,” and “Stomach pain,” andsignificantly decreased food intake compared to baseline. This empirical demonstration of withdrawal fromsmoked marijuana may suggest that daily marijuana
use may be maintained, at least in part, by the alleviation of abstinence symptoms.

M. Haney (*) · A.S. Ward · S.D. Comer · R.W. Foltin
M.W. Fischman
Division on Substance Abuse, New York State PsychiatricInstitute and Department of Psychiatry, College of Physiciansand Surgeons of Columbia University, 722 West 168th Street,
Unit 54, New York, NY 10032, USAe-mail : mh235@columbia.edu, Fax:+1-212-543-5991

Key words 3Marijuana · Dependence · Withdrawal ·Human · Tolerance · Subjective effect ·Performance · Residential laboratory

Introduction
The recent sharp rise in marijuana smoking, particularly in young men and women, has been accompanied
by an increase in the number of people seeking treatment for marijuana abuse. Approximately 5% of highschool seniors in the United States are reporting thatthey smoke marijuana daily (Johnston et al. 1995, 1997;
Frank and Galea 1995). As with other “harder” drugsof abuse, a subset of marijuana users are also reporting uncontrolled marijuana use that is interfering with
their daily lives. A significant proportion of individuals responding to advertisements targetting marijuanausers report that they have been unable to stop smoking marijuana when they want to, and that they experience symptoms of withdrawal when they abstain frommarijuana (Roffman et al. 1998; Stephens et al. 1993,
1994).
One possible reason that a subset of marijuanasmokers are seeking treatment is that daily marijuana
use can result in the development of physical dependence. In the United States, 7.4% of adult and 14.4%
of adolescent marijuana users meet DSM-IV diagnostic criteria for marijuana dependence within the past
year (Budney et al. 1997). Further, the development of
cannabinoid dependence has been substantiated by laboratory studies. Precipitated withdrawal from *9tetrahydrocannabinol (THC), the major psychoactive
component in marijuana, has been demonstrated inrats using the cannabinoid receptor antagonist,
SR141716A (Rinaldi-Carmona et al. 1994): rats
repeatedly exposed to THC showed dramatic symptoms of withdrawal, e.g., ptosis, wet-dog shakes, “anxiety” reactions, and disorganized patterns of motor

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activity, when injected with SR141716A (Aceto et al.
1995; Tsou et al. 1995; de Fonseca et al. 1997). Abstinence from THC following a regimen of THC maintenance has also been shown to produce withdrawal
signs. In rhesus monkeys, abstinence from intravenous(IV) THC resulted in aggression, hyperirritability,
anorexia (Kaymakcalan 1973) and disruptions in operant behavior (Beardsley et al. 1986); the specificity ofthis latter effect was demonstrated by its reversal with
IV THC administration.
In human laboratory studies, maintenance of highdoses of oral THC (210 mg/day for 10–20 days), produced both tolerance and dependence (Jones et al.
1976, 1981). During THC administration, there was aprogressive decline in THC’s cardiovascular and subjective effects. After abrupt cessation of THC administration, the majority of volunteers reported
irritability, restlessness, decreased appetite, and sleep
disturbances; re-administration of oral THC diminished most of these symptoms. Recent studies from thislaboratory (Haney et al. 1999) demonstrate that abstinence symptoms also occur when human participants
are exposed to lower daily doses of oral THC(80–120 mg/day) for a briefer period of time (3– 4 days)
than used in the Jones et al. studies (1976, 1981).
During THC administration, there was a progressive
decline in subjective effects ratings, while abstinencefrom THC increased ratings of anxiety, depression, andirritability, decreased the reported quantity and quality of sleep, and decreased food intake by 20–30% compared to baseline (Haney et al. 1999; Ward et al., in
preparation).
Although the effects of oral THC cannot be expected
to generalize fully to those of smoked marijuana, laboratory studies have demonstrated that abstinence
following repeated marijuana smoking is also associated with a range of withdrawal symptoms. One
research participant, who averaged nine marijuana cigarettes/day (1.8% THC) for 21 days, experienced symptoms of anxiety, dysphoria, anorexia and sweating uponcessation of marijuana use (Mendelson et al. 1984).
Long-term inpatient studies of marijuana also provide
clinical descriptions of irritability, hostility, restlessness,sleeplessness and loss of appetite during periods of marijuana abstinence (Georgotas and Zeidenberg Nowlan
1979; and Cohen 1977). Finally, a study using a laboratory model of human aggression (point-subtraction
aggression paradigm; Cherek 1981), provides evidence
that marijuana abstinence is associated with increased
aggressive behavior. Frequent marijuana smokers abstinent from marijuana for up to 7 days showed greaterlevels of aggressive responding when provoked, compared to when they were still using marijuana (Kouri
et al. 1998). These data suggest that the irritability manifested during marijuana abstinence may translate into
aggressive behavior in the natural ecology.
The purpose of the present study was systematicallyto determine the effect of marijuana abstinence whenmarijuana is smoked at levels comparable to thosereportedly used in natural settings. Specifically, theeffects of marijuana and marijuana abstinence on a
range of behaviors, mood, food intake, sleep, social
behavior, and performance on psychomotor and memory tasks, were measured.

Materials and methods
Participants
Twelve male (seven African-American, three Non-Hispanic
Caucasian, two Hispanic) healthy research volunteers ranging inage from 21 to 44 years (mean: 28), participated in a 21-day experiment. Prior to study participation, volunteers provided a detailed
drug and medical history, received complete medical and psychiatric evaluations, and signed consent forms detailing all aspects of
the research. Participants reported smoking marijuana 5.8 ± 0.4
days/week (mean ± SD), averaging 6.7 ± 1.6 marijuana cigarettes
per day. Most participants also reported drinking alcohol weekly(mean: 2 day/week, two drinks/occasion). Eight reported smoking
tobacco cigarettes, and continued to do so during the experiment.
Other drug use was infrequent, although one subject reported occasional cocaine use. Participants did not diet, were within accepted
weight ranges for their heights [69.8 ± 1.7kg (Metropolitan
Life Insurance Company 1983)], and had no self-reported eating
abnormalities.
Participants were instructed that they were participating in astudy of the behavioral effects of marijuana. They were told thatthe strength of the marijuana cigarettes might change at any time.
Prior to discharge, participants were fully informed about the experimental and drug conditions. All procedures were approved by the
New York State Psychiatric Institute’s Institutional Review Board.

Laboratory
Participants, in three groups of four, lived in a residential laboratory designed for the continuous observation of human behavior
over extended periods of time. The residential laboratory consistsof 11 rooms in the New York State Psychiatric Institute: four private participant rooms, a common recreational area, two singleoccupancy bathrooms, two single-occupancy shower rooms, andtwo vestibules used for exchanging supplies (see Haney et al. 1998,
for a more detailed laboratory description).
Output from a video and audio monitoring system terminated in
an adjacent control room. Participants were observed continuously
except while in the bathroom or in private dressing areas. No video
or audio recordings were made. Communication between participants and experimenters was accomplished using a networked computer system, linking each participant’s computer with the computerin the main control room and allowing for a continuous on-line
interaction between participants and experimenters, but not
between participants.

Procedure
Prior to residence, participants received two training sessions(3– 4 h/session) on the computerized tasks and on a separate day,smoked a marijuana cigarette (3.1% THC). Participants moved into
the laboratory on the day before the study, during which theyreceived additional training on tasks and experimental procedures.
The first experimental day began at 0830 hours the following
morning. The St Mary’s Hospital Sleep Questionnaire, rating the397
previous night’s sleep, was completed each morning. Participants
first completed a 50-item visual analog scale (VAS), which consistedof a 100-mm line anchored with “not at all” at the left end and“extremely” at the right end, labeled with “I feel...” “High,”“Stimulated,” “Anxious,” “Sedated,” “Depressed,” “Hungry,”“Friendly,” “Miserable,” “On edge,” “Alert,” “Tired,” “Talkative,”“Self-confident,” “Social,” “Irritable,” “Confused,” “A good drug
effect,” “A bad drug effect,” “Dizzy,” “Sleepy,” “Like yawning,”“Energetic,” “Jittery,” “Content,” “Unmotivated,” “Restless,”“Nauseated,” “Like vomiting,” “Suicidal,” “Forgetful,” “Mellow,”“Clumsy,” “Numbness or tingling in my extremities,”“Withdrawn,” “I have...”. “An upset Stomach,” “Muscle pain,” “Arunny nose,” “A headache,” “Flu-like symptoms,” “Chills,” “Goose
flesh,” “Stomach pain,” “I’m having difficulty concentrating,” “I
am sweating,” “I’m having difficulty sleeping,” “I am dreaming
more,” “My heart is pounding or beating faster that usual,” “Noises
or sounds seem louder than usual,” “My vision is blurred,” and“My limbs feel heavier than usual.’’ Participants were then weighed
and given time to eat breakfast. Three work periods occurred eachday: The first work period (0915–0945 hours), consisted of one
task battery, composed of five computer tasks and the VAS.
Marijuana was first smoked at 1000 hours each day. Participants
then began their second work period (1015–1315 hours), composedof four task batteries; each task battery consisted of the same fivetasks and the VAS. The Drug-Effects Questionnaire was completed
on the computer 90min after each administration of marijuana. The
second administration of marijuana occurred at 1400 hours. The
final work period (1415–1615 hours) consisted of another three task
batteries. Beginning at 1715 hours, participants had access to activities available in the recreation area. Marijuana was smoked for thethird time each day at 1800 hours. Two video-taped films wereshown, one beginning at 1815 hours and the other at 2115 hours.
The final marijuana administration occurred at 2200 hours. At 2330
hours, the recreation area was no longer available. A final VAS anda marijuana withdrawal checklist (modified from a cocaine withdrawal checklist; Brower et al. 1988), in which participants answered
if they did or did not experience a range of symptoms, were completed at 2330 hours. Lights were turned off no later than 2400
hours.

Food
Every morning at 0830 hours each participant received a box offood containing a variety of meal items, snacks and beverages which
could be consumed at any time within the day. Frozen meal items
were also continuously available by request. To facilitate choice offrozen meals, participants were provided with a book containing
package pictures of each item. Additional units of any item were
freely available upon request. Participants were instructed to scancustom-designed bar codes whenever they ate or drank, specifying
substance and portion. At 2330 hours, participants returned theirfood box to a staff member. Food items were not available between
2330 hours and 0830 hours the following morning, although water
was available at all times.

Task battery
Each task battery consisted of a 3-min digit-symbol substitution
task (DSST), a 3-min repeated acquisition task, a 10-min divided
attention task (DAT), a 10-min rapid information task (RIT), an
immediate and delayed digit-recall task, and a VAS. The battery
measures various aspects of learning, memory, vigilance and psychomotor ability (see Foltin et al. 1996, for description of the tasks).
Participants were instructed to complete each task as quickly andas accurately as possible.

Social behavior
A computerized observation program was used to record behavior
categorically every 2.5 min during each evening recreation period.
Behaviors were divided into two categories: private and social.
Private behaviors occurred in each participant’s private room or in
the bathroom/shower room. Social behaviors occurred in the recreation area. Social behavior was further categorized as being either
verbal or non-verbal.

Marijuana administration
Participants received two marijuana cigarettes (0, 1.8, 3.1% THC
weight/weight, provided by the National Institute on Drug Abuse)prior to each scheduled smoking occasion. Marijuana was administered using a cued-smoking procedure, which has been shown to
produce reliable increases in heart-rate and plasma levels of *9THC (Foltin et al. 1987). Colored lights (mounted on the ceiling of
the social area) signalled “light the cigarette” (30 s), “get ready”(5 s), “inhale” (5 s), “hold smoke in lungs” (10 s) and “exhale”.
Participants smoked five puffs (three puffs on one cigarette, two on
the other) in this manner, with a 40-s interval between each puff.
Participants were instructed that they could signal that they wanted
to stop smoking by raising their left hand, yet no participant did.
Since participants can discriminate THC content by the color of
the plant material (Chait and Pierri 1989), cigarettes were tightly
rolled at both ends and were smoked through a hollow plastic cigarette holder so the marijuana was not visible. Cigarettes were stored
frozen in an airtight container and humidified at room temperaturefor 24 h prior to use.

Tobacco cigarette smoking
The social and private areas are equipped with pressure-activatedsensors through which all tobacco cigarettes are smoked. The sensors are connected to color-coded plastic cigarette holders with PVC
tubing in order to allow recording of each cigarette puff by eachparticipant.

DesignMarijuana cigarettes were administered four times/day at 1000,
1400, 1800 and 2200 hours. During the first 4 inpatient days, participants received placebo marijuana. On days 5–8, one of the active
marijuana concentrations was administered, followed by 4 days ofplacebo marijuana (days 9–12). The other active marijuana concentration was administered on days 13–16, followed by 4 days ofplacebo (days 17–20); the order in which the 1.8% and 3.1% THC
concentration marijuana cigarettes were administered was counterbalanced between studies. Participants moved out on day 21.

Data analysis
Repeated measures analyses of variance (ANOVA) with planned
comparisons were used to address two issues: The first was to determine the effect of repeated marijuana exposure and abstinence frommarijuana on subjective effects (peak daily ratings), drug effects(peak daily ratings), task performance, social behavior, food intake[total energy intake, g-intake of carbohydrate, fats and protein, percent of energy intake derived from each macronutrient estimatedas kcal from g-intake using Atwater factors (McLaren 1976)], andbody weight. The first 4 days of placebo baseline (days 1– 4) werecompared to 4 days of each later condition. Thus, there were two
within-group factors [Condition (baseline, 1.8%, 3.1%, post-1.8%,

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post-3.1%) and Day of Condition (1, 2, 3, 4)]. Sixteen planned comparisons were completed for each measure: baseline was comparedto each THC concentration (1.8%, 3.1%) and baseline was compared to each abstinence condition (post-1.8%, post-3.1%) for the
4 days of each condition. Analysis of certain food data included an
additional within-group condition: time of day: 0–1259 (including
breakfast); 1300–1659 (including lunch) and 1700–2330 hours(including dinner). For these data, 16 planned comparisons between
baseline and each dose condition were made at the three times ofday; the days of each condition were collapsed. A second objective
was to determine if tolerance developed to the effects of repeatedmarijuana administration. For this comparison, two planned comparisons were made : peak ratings occuring on the first and last dayof the 1.8% THC and the 3.1% THC condition were compared.
Given the large number of planned comparisons overall, only thosewith P values less than 0.01 were considered statistically significant,in an effort to control for type I error. Hunyh-Feldt corrections
were used, when appropriate.

Results
Subjective-effects ratings
Each figure and table portrays the peak baseline measure averaged across the 4-day initial placebo period,
followed by the peak data for each day of active marijuana administration, and each day of marijuana abstinence. Fig. 1 illustrates that both concentrations of
THC significantly increased ratings of “Good Drug
Effect,” “High” and “Stimulated” compared to baseline. Tolerance developed to the effects of the 3.1% THC
cigarettes, evidenced by a significant diminution ofpeak ratings of “Good Drug Effect” and “High” on
day 4 of its administration compared to day 1 of administration. During abstinence from either marijuana conFig. 1 Selected peaksubjective-effects ratings undereach active marijuanacondition and during theabstinence period that
followed each active marijuanacondition as a function of dayof condition. The single open
triangle on each graphrepresents the mean peakrating observed during the 4days of the initial baseline.
Number signs indicate asignificant difference between
days 1 and 4 within eachcondition (#P < 0.01;##
P < 0.005), and asterisks
indicate a significant difference
between that day and baseline(*P < 0.01; **P < 0.005).
Error bars represent ±standard error of the mean
(SEM). ∆ Baseline, o 1.8%
THC, 䊏 3.1% THC, 䊊
Abstin 1.8% THC, l Abstin
3.1% THC

dition, participants rated the placebo cigarettes as giving them less of a “Good Drug Effect,” and making
them less “Stimulated” compared to the placebo cigarettes at baseline.
As shown in Fig. 2, ratings of “Anxiety” weresignificantly increased on the third and fourth day of
abstinence from the 1.8% THC cigarettes compared tothe baseline condition. Ratings of “Stomach Pain” and“Irritability” were increased on day 4 of abstinencefrom the 1.8% and 3.1% THC cigarettes, respectively.
Additional significant effects of drug condition onmood are portrayed in Fig. 3: Both active marijuanaconditions increased ratings of “Mellow” on each dayof administration, while abstinence from either active
concentration decreased ratings of “Mellow” on days
3 and 4 of abstinence. Similarly, ratings of “Content”
and “Friendly” were significantly decreased during
abstinence from either marijuana condition.
Additional significant effects are reported inTable 1. Both active marijuana conditions decreased
ratings of “On Edge” (Table 1) and increased ratingsof “Clumsy” [1.8%, day 1: F1,12= 11.81; day 2 :F1,12=13.01; day 4; 3.1%, day 2: F1,12 =14.49,
P<0.01 (data not shown)] compared to baseline. The
1.8% THC cigarettes increased ratings of “Talkative,”
while the 3.1% THC cigarettes increased ratings of“Noises seem Louder than Usual,” “Heart Pounding
more than Usual (Table 1),” and “Blurred Vision” [day3 : F1,12 =10.21, P< 0.01 (data not shown)]; marijuana
had significantly less of an effect on heart pounding by
day 4 of administration compared to day 1 (Table 1).
During abstinence from the 3.1% THC condition, ratings of “Talkative” were decreased, while ratings of“Social” and “Energetic” were significantly decreased

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Fig. 2 Selected peaksubjective-effects ratings. See
Fig. 1 legend for details

Fig. 3 Selected peaksubjective-effects ratings. See
Fig. 1 legend for details

during abstinence from either marijuana condition(Table 1).
Drug-effects questionnaire
Figure 4, portraying ratings on the Drug-Effects
Questionnaire, shows that marijuana significantly
increased ratings of marijuana strength, willingness to
smoke that concentration cigarette again, and liking
for the concentration of marijuana. During abstinencefrom marijuana, participants were less willing to smoke
the placebo marijuana cigarettes again compared tobaseline (Fig. 4). Ratings of marijuana strength, andliking (Fig. 4) were also significantly less during marijuana abstinence than at baseline.
Marijuana withdrawal checklist
There were no significant changes in response as a function of drug condition.

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Table 1 Means (± SEM) of
peak subjective-effects ratings
following 4 days of marijuanaadministration or abstinencefrom 4 days of marijuanaadministration

Days

1

2

3

‘‘On Edge’’
1.8%
3.1%
Abstinence 1.8%
Abstinence 3.1%

17.5 (8.3)
23.1 (10.1)
16.4 (5.6)
11.2 (7.1)

6.2
6.2
19.5
17.0

(2.9)**(4.7)**
(6.7)
(8.7)

13.9
2.7
24.3
19.9

(6.9)
(1.7)**
(9.1)
(9.4)

Placebo = 25.8 (4.5)
11.2 (4.9)
4.6 (3.6)**
23.4 (11.1)
26.7 (10.5)‘‘Talkative’’
1.8%
3.1%
Abstinence 1.8%
Abstinence 3.1%

68.6
55.5
49.7
44.2

(9.0)*(8.9)(8.5)(9.2)**

63.9
51.0
47.2
49.2

(8.6)
(9.3)
(9.2)
(8.4)

59.2
54.7
53.2
50.9

(7.4)
(8.6)
(8.6)
(7.5)

Placebo = 57.4 (3.5)
59.6 (7.8)
50.9 (9.2)
57.7 (8.2)
49.3 (8.0)‘‘Noises seem Louder’’
1.8%
3.1%
Abstinence 1.8%
Abstinence 3.1%

14.4
27.1
5.3
7.2

(6.6)
(9.3)**
(4.1)
(4.5)

8.8 (4.8)
19.1 (7.3)*
3.7 (3.4)
14.6 (8.8)

11.7
21.2
2.8
7.1

(5.7)
(9.4)*(2.60)(4.7)

Placebo = 8.5 (2.1)
11.9 (6.5)
18.1 (9.1)
4.6 (3.3)
7.2 (4.6)‘‘Heart Pounding’’
1.8%
3.1%
Abstinence 1.8%
Abstinence 3.1%

11.1 (5.3)
20.2 (8.5)**
2.9 (2.2)
5.9 (3.6)

3.5
8.0
1.4
2.5

4.2
11.9
0.4
2.1

(2.3)
(5.8)
(0.4)
(1.9)

Placebo = 3.6 (1.3)
7.3 (4.2)
2.1 (1.7)##
0.3 (0.3)
1.5 (1.0)‘‘Energetic’’
1.8%
3.1%
Abstinence 1.8%
Abstinence 3.1%

61.3 (10.1)
58.8 (10.8)
41.3 (9.6)**
47.5 (9.3)

52.2 (9.8)
54.4 (10.9)
49.6 (10.2)
47.2 (6.9)

48.6 (8.4)
55.7 (8.9)
47.6 (10.1)
47.1 (8.9)

Placebo = 55.0 (3.9)
45.6 (9.1)
54.1 (10.4)
59.2 (10.0)
42.2 (8.8)**‘‘Social’’
1.8%
3.1%
Abstinence 1.8%
Abstinence 3.1%

68.8 (7.5)
55.3 (10.5)
48.8 (9.8)
44.0 (11.1)**

58.3 (9.9)
58.2 (9.1)
48.4 (10.3)*
48.6 (10.0)*

62.6
50.0
48.2
53.7

Placebo = 61.0 (3.8)
57.4 (9.1)
51.3 (9.8)
50.4 (9.6)
50.2 (8.9)

(1.8)
(4.3)
(0.9)
(2.0)

4

(9.2)
(9.7)
(9.5)*(9.2)

Asterisks indicate a significant difference between the day of each condition and baseline (*P<0.01,** P<0.005). Number signs indicate a significant difference between days 1 and 4 within each condition (# P<0.01, ## P<0.005)

St. Mary’s Hospital Sleep Questionnaire
There were no significant changes in response as a function of drug condition.
Food intake
As shown in Fig. 5, daily caloric intake was increased
by both the 1.8% and 3.1% THC cigarettes on eachday of administration; food intake was significantly
increased in the evening for 1.8% THC cigarettes[F1,8 =15.17, P< 0.0002 (data not shown)]. Fig. 5 also
shows that the mechanism by which marijuana
influenced daily caloric intake was by increasing thenumber of eating occasions, defined as beginning withthe first report of an item to be consumed and ending
when there was a pause of greater than 10 min between
food reports (Foltin et al. 1996). Abstinence from either
active marijuana condition decreased total daily caloric
intake by decreasing the number of eating occasions
throughout the day. During abstinence from the 1.8%
THC cigarettes, caloric intake in the evening was
significantly decreased (data not shown), and partici-

pants derived a significantly larger percentage of their
total caloric intake from proteins (13.1% versus 11.8%)
compared to baseline [day 1: F1,12=7.55, P < 0.01
(data not shown)].
Body weight significantly increased during active
marijuana conditions compared to baseline : weights
ranged from 71.2 to 71.7 kg on days 3 and 4 of eachactive marijuana condition, which were significantly
higher than the average baseline weight of
69.6 ± 0.8 kg. Body weight did not significantly differ
from baseline during either abstinence condition. By
the end of the study, participants averaged a 0.9 kg
weight gain compared to baseline levels.
Social behavior
Both the 1.8% (day 3: F1,132=16.11; day 4 :F1,132 = 14.64, P < 0.006) and the 3.1% THC (day 2 :F1,132 = 15.19; day 3 : F1,132 = 30.59, day 4:
F1,132 = 36.20, P < 0.006) cigarettes significantly
decreased the amount of time participants spent talking while they were in the social area. Under baseline
conditions, participants spent an average of 30.9 ± 2.6%

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Fig. 4 Selected peak ratings
on the Drug-Effects
Questionnaire. See Fig. 1
legend for details

Fig. 5 Mean daily caloric
intake and mean number of
eatings occasions. See Fig. 1
legend for detailsof their time in the social area talking, while underactive marijuana conditions, the percentage of timespent talking ranged from 4.2 to 13.6%, depending on
the day of the condition. Abstinence from THC did
not have a significant effect on time spent talking compared to the baseline condition.
Performance effects
Performance on the DSST was impaired following
administration of the 3.1% THC cigarettes: partici-

pants entered fewer patterns correctly compared tobaseline [day 1 : F1,132 = 12.28; day 2: F1,132 =12.54; day 4: F1,132 = 16.92, P < 0.01 (data notshown)]. Performance on the DAT was improved on
the first day the 1.8% THC cigarettes were administered, with participants achieving a higher maximum
speed of entering the patterns than during baseline (day1 : F1,132 = 7.64, P < 0.006). Participants were lessaccurate in tracking the DAT’s moving target whenabstinent from either the 1.8% (day 4 : F1,132 = 23.58,
P < 0.002) or the 3.1% (day 2: F1,132 = 16.70; day 4:

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F1,132 = 16.50, P < 0.007 (data not shown)] THC
cigarettes, compared to baseline.
Tobacco cigarette smoking
Data on only six of the eight cigarette smokers wereavailable, due to equipment malfunction. The numberof puffs cigarette smokers took on tobacco cigarettes
did not vary as a function of drug condition : an average of 97 ± 39 cigarette puffs were taken over the courseof the 4-day baseline condition. On days of 1.8% THC
cigarette administration, 102±36 puffs were taken,
while in the 3.1% THC condition, 111 ± 33 puffs weretaken. An average of 111 ±34 puffs were taken during
abstinence from 1.8% THC cigarettes, and an averageof 87 ± 28 puffs during abstinence from 3.1% THC
cigarettes.

Discussion
The present study provides empirical evidence that
abstinence from marijuana is associated with increases
in anxiety, irritability and stomach pain, and decreases
in the amount and frequency of food intake. These
symptoms are similar to the pattern of abstinence
effects following oral THC administration (Jones et al.
1976, 1981; Haney et al. 1999), and are similar to theeffects seen in laboratory participants smoking marijuana repeatedly for at least 3 weeks (Nowlan and
Cohen 1977; Georgotas and Zeidenberg 1979;
Mendelson et al. 1984). The present findings are also
consistent with interview data obtained in daily marijuana smokers, who report feeling ‘‘nervous, tense, andrestless’’ when abstinent from marijuana (Wiesbeck
et al. 1996).
Although there were no significant self-reports ofsleep disturbance during marijuana abstinence, we haverecently completed a study with portable sleep monitors (Respironics, Atlanta, Go., USA), showing that
abstinence following exposure to four to five marijuana
cigarettes/day (1.8–3.1% THC) for even a shorter
period of time (3 days) was associated with a substantially increased latency to fall asleep and latency torapid eye movement (Ward et al., in preparation). These
data, using a more sensitive measure of sleep than selfreport, suggest that sleep disruption may be an additional consequence of marijuana abstinence.
For most measures, the mood changes during marijuana abstinence became statistically significant on thethird or fourth day since the last marijuana cigarette,
while changes in food intake occurred on day 1 andwere statistically significant through day 4 of abstinence. How long these symptoms persist is unclear,since the abstinence condition was not maintained
longer than 4 days. Although earlier data with oral

THC and smoked marijuana indicated that abstinence
symptoms abated within 4 days (Jones et al. 1976;
Mendelson et al. 1984), the fact that most symptoms
observed in this study were peaking on day 4 suggests
they would persist for a longer period of time.
Further, aggressive behavior is heightened for at least
7 consecutive days of marijuana abstinence (Kouri
et al. 1998), supporting the idea that some symptoms,
such as irritability, persist longer than 4 days of abstinence from marijuana.
Given the negative mood and behavioral symptoms
associated with marijuana abstinence following daily
marijuana exposure, it appears likely that the onset of
abstinence symptoms may partly maintain chronic
marijuana use, i.e. people continue to smoke marijuanaeach day because abruptly stopping is associated withnegative mood. A similar pattern has been reportedwith nicotine : data from cigarette smokers indicate that
nicotine deprivation leads to smoking in order toreverse the effects of withdrawal (USDHHS 1988;
Heishman 1994). It may be that individuals who havea history of using drugs such as marijuana to modulate mood are particularly likely to increase their drug
use as a consequence of even subtle changes in mood.
It is important to note that the subtle symptoms ofmarijuana abstinence observed in the present study
could be dissociated from the development of tolerance. The literature is replete with studies, including
our own, demonstrating that repeated exposure to highlevels of marijuana results in tolerance to certain of its
effects (Babor et al. 1975; Nowlan and Cohen 1977;
Haney et al. 1997b). Similarly, in the present study,
repeated exposure to high THC concentration marijuana cigarettes resulted in a significant decrease inthree subjective-effects ratings (‘‘High,’’ ‘‘Good Drug
Effect,’’ ‘‘Heart Pounding’’). However tolerance to the
low THC concentration cigarettes did not develop
under these conditions, although abstinence from thelow THC concentration cigarettes also resulted insymptoms of withdrawal, such as anxiety and stomach
pain. These data demonstrate that when behavior iscarefully and continuously monitored, evidence of marijuana withdrawal can be detected even at levels of marijuana exposure that do not produce tolerance.
It is possible that this population of near-daily marijuana smokers were tolerant to many of marijuana’s
behavioral effects even before starting the experimental protocol. Supporting this idea is the demonstrationthat marijuana had relatively minor effects on task performance (and in fact improved performance on theDAT). Studies directly comparing different populationsof marijuana smokers have shown that heavy marijuanausers show fewer performance decrements after smoking marijuana compared to light users (Meyer et al.
1971; Rickles et al. 1973; Cohen and Rickles 1974),
presumably because the heavy users are tolerant to theimpairing effects of marijuana. It is also probable thatthe present group of marijuana users were already403

dependent on marijuana when they started the study.
Thus, the period considered ‘‘baseline’’ was actually aperiod of marijuana abstinence. It was difficult to avoid
this problem, since we did not want to expose lighter
marijuana users to the dose regimen used in the present study, and increasing the length of the baseline
placebo period would have made the duration of theresidential study prohibitively long to most of our subject pool. Our rationale was that this design was in fact
conservative, since it would minimize rather thanamplify the likelihood that we would see a significant
difference between the initial ‘‘baseline’’ period and theabstinent condition. In fact, initial baseline ratings of‘‘Anxiety’’ and ‘‘Irritability’’ were 3– 6 times higher inthe present study compared to previous studies in thislaboratory in individuals who did not smoke marijuana(Haney et al. 1997a, unpublished data) or in marijuanausers who did not undergo a period of abstinence(Haney et al. 1997b, unpublished data), suggesting that
there may be some indication of abstinence symptoms
during the ‘‘baseline’’ period. We postulate that participants were experiencing some abstinence symptoms
in the initial baseline period, but the symptoms became
more robust when the amount and frequency of marijuana smoking was experimentally controlled between
individuals, thereby decreasing variability.
To conclude, a distinct withdrawal syndrome can beobserved following a relatively brief period of controlled marijuana administration in regular users ofmarijuana. Although adolescents are reporting a lower
perceived risk of regular marijuana use compared toolder adults (Johnston et al. 1997), the present datasuggest that dependence may in fact be an importantconsequence to repeated, daily exposure to cannabi-noids. While not as dramatic as the withdrawal syndrome observed in individuals dependent on opioids,
alcohol or barbiturates, this pattern of symptoms may
still be significant to the individual marijuana user. Thisempirical demonstration of withdrawal from smokedmarijuana, in combination with the epidemiological evidence for increased marijuana use, suggests that
effective treatments targeting marijuana abuse may beneeded.
Acknowledgements The assistance of Shannon Lewis, Joaquin
Morales, Jessica Keitlen, Paul Toth, and Drs. Adam Bisaga, Maria
Sullivan, Eric Collins, and Eric Rubin are gratefully acknowledged.
This research was supported by US National Institute on Drug
Abuse grant DA03476–11 (M.W.F.) and the Aarn Diamond
Fellowship Foundation (M.H.).

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