Download A Study of Abrupt Phentermine Cessation in Patients in

American Journal of Therapeutics 0, 000–000 (2010)
A Study of Abrupt Phentermine Cessation in
Patients in a Weight Management Program
Ed J. Hendricks, MD1* and Frank L. Greenway, MD2
Phentermine is the most widely used antiobesity drug in the United States. Although no evidence of
phentermine addiction has been published, fear that phentermine has addiction potential has
contributed to curtailment of its worldwide use in clinical practice. The aim of this study was to
evaluate the abuse and addiction potential of long-term phentermine pharmacotherapy in patients in
a weight management program. Thirty-five patients in a weight management program who abruptly
stopped taking prescribed phentermine on their own initiative were examined using the 18-item
Kampman Cocaine Selective Severity Assessment scale modified for phentermine. The Kampman
Cocaine Selective Severity Assessment scale has also been modified by McGregor for amphetamines
to assess withdrawal from amphetamine in amphetamine-addicted subjects. For comparison, 35 new
patients were examined with the same scale before any treatment was initiated. Data from the treated
and untreated groups were compared by t test with each other and with published data from
amphetamine-addicted subjects. There were no significant differences in individual items or total
scores between the patients who stopped phentermine abruptly and the patients who had never
taken phentermine. There was a striking and significant difference in individual and total scores
between the phentermine-treated subjects and the amphetamine-dependent subjects. Cravings for
the substance abused, the hallmark characteristic of substance dependence and withdrawal, were
entirely absent in the phentermine-treated subjects. Abrupt cessation of long-term phentermine
therapy does not induce amphetamine-like withdrawal. Long-term phentermine therapy does not
induce phentermine cravings. Symptoms observed after abrupt phentermine cessation represent loss
of therapeutic effect and are not withdrawal.
Keywords: obesity, obesity treatment, phentermine, addiction, addiction scale
INTRODUCTION
Amphetamine was first synthesized in the late 19th
century but its psychopharmacologic properties were
not described until the late 1920s. These properties
included decreased fatigue, wakefulness, alertness,
euphoria, and increased energy. Clinical testing of
amphetamines for the treatment of depression and
1
Center for Weight Management, a private obesity medicine
practice, Sacramento and Roseville, CA; and 2Pennington Biomedical Research Center, Louisiana State University System,
Baton Rouge, LA.
Supported by the Center for Weight Management.
*Address for correspondence: Center for Weight Management,
2310 Professional Drive, Roseville, CA 95661. E-mail: [email protected]
1075–2765 ! 2010 Lippincott Williams & Wilkins
narcolepsy began in the late 1930s, and it was noted
that patients taking amphetamines lost weight.1,2 Less
than 1 year later, it was demonstrated that amphetamines could be used for the treatment of obesity3
and subsequent clinical trials showed it to be effective
in decreasing weight in both adults and children.4,5
Amphetamines were shown in dogs and humans to
decrease body weight by reducing food intake.6 After
the introduction of amphetamines to clinical practice in
1944, a number of agents were developed to modify the
unwanted stimulation of the central nervous system
observed with amphetamines.7
The basic chemical structure of amphetamines is
phenylethylamine consisting of a phenyl ring and a
side chain. Certain substitutions are capable of decreasing the central nervous system stimulation of amphetamine. In the case of phentermine, the methyl addition
to the alpha position of the side chain of the molecule
www.americantherapeutics.com
2
reduced stimulation of the central nervous system to
a greater extent than its effect on appetite but still
caused insomnia in 20% of subjects.8 There is a report of
assessment of the potential for abuse and addiction of
amphetamine and its chemically related anorectic
agents made through the assessment of the stimulatory
properties of these various agents. This stimulation
was assessed using the spontaneous activity in rats
given the drug compared with amphetamines or a
placebo. A dose of 3.16 mmol/kg of amphetamine
reduced food intake by 57% and increased spontaneous activity by 400%, whereas a dose of 17.8 mmol/kg
of phentermine reduced food intake by 52% but
increased spontaneous activity only 257%. Thus,
phentermine increased spontaneous activity 46% less
than amphetamine at a dose that had a similar effect on
food intake.9 As a result of this simulation, phentermine has been considered to have the potential for
abuse and addiction. Although the Drug Enforcement
Administration considers the risks of abuse and addiction of amphetamines significant and places it in
Category II, phentermine is in the lowest category for
addiction and abuse, Category IV.
Although drug abuse has been reported for amphetamines, methamphetamines, and phenmetrazine, claims
for drug abuse of other anorectic agents are less frequent. In fact, amphetamines are 10-fold as potent as
phentermine in maintaining self-administration behavior
in baboons,10 and phentermine has been demonstrated
to decrease cocaine self-administration behavior in
baboons.11 Nevertheless, concern exists regarding phentermine abuse and addiction as a result of its stimulatory properties. We hypothesize that the stimulatory
effects seen in animal studies10 and human studies12
have been overinterpreted as an indicator of potential
abuse of phentermine in humans undergoing treatment
for obesity and that in fact, the abuse potential of
therapeutic phentermine is very low in this particular
patient group.
Stimulant substance addiction and withdrawal
have been investigated extensively in the 40 years
since these compounds were classified. The characteristics of cocaine, the prototypical stimulant of abuse,
and amphetamine addiction and withdrawal are now
well described. Psychometric scales have been created
and validated for use in assessing the nature and
severity of cocaine addiction and withdrawal. These
scales have been modified for use in amphetamineaddicted subjects.
We hypothesized that if phentermine does indeed
have abuse and addiction potential in subjects being
treated for obesity, any symptoms of phentermine
addiction or of withdrawal should include some of
those described in amphetamine addiction and
American Journal of Therapeutics (2010) 0(0)
Hendricks and Greenway
withdrawal. In this study, we used a psychometric
scale, modified for phentermine, to examine patients in
a weight management program who stopped taking
their phentermine abruptly on their own initiative.
The prototypical stimulant of abuse is cocaine.
Abrupt cessation of cocaine use in subjects addicted
to cocaine is consistently followed by a characteristic,
well-described withdrawal symptom complex. Kampman has devised a psychometric scale to assess these
typical withdrawal symptoms, the Cocaine Selective
Severity Assessment (CSSA).13 The Kampman scale
has been modified and used as a metric to assess and
characterize amphetamine cessation in amphetamine
addicts.14–16 Studies have shown that abrupt cessation
of amphetamine use in subjects who are amphetamineaddicted consistently produces a characteristic withdrawal syndrome.
In our study, the Kampman CSSA has been modified
by substituting the word phentermine for the word
cocaine to produce a Phentermine Selective Severity
Assessment (PSSA) in a similar manner to the way
that amphetamine was substituted for cocaine in
the Kampman scale in McGregor’s studies with
amphetamine.
MATERIALS AND METHODS
Patients in weight management programs who are on
therapeutic phentermine often discontinue phentermine on their own initiative. Some patients decide they
should be able to lose or maintain weight without
phentermine. Others, having observed diminution in
the strength of appetite suppression, decide the phentermine is not working. Still others miss scheduled
appointments for any of a wide variety of reasons and
simply run out of phentermine. Typically, patients who
discontinue phentermine then observe an increase or
a return of hunger, cravings, or both. After a variable
time lag, such patients find it increasingly difficult to
maintain control of their food intake and most of them
gain weight. Some patients on long-term phentermine
(more than 90 days) have discontinued phentermine
repeatedly. Such patients, having concluded phentermine had been helpful, often return to the weight
management program after an interval of variable
duration. This study was designed to investigate
symptoms these patients experienced and to compare
and contrast the symptoms with those in new patients
who had never been on phentermine and with symptoms observed in amphetamine-dependent subjects
after abrupt cessation of amphetamines.
Patients in a private fee-for-service medical bariatric
medicine practice who had been on phentermine
www.americantherapeutics.com
Abrupt Phentermine Cessation
T1
monopharmacotherapy continuously for more than 90
days who had abruptly stopped taking phentermine
were candidates for inclusion. Candidates were included
only if the phentermine dose had not been tapered
before cessation and if the candidate had a good
memory of events and symptoms in the week after
cessation. Patients who had tapered their dose, whose
recollection of symptoms and events in the week after
cessation was poor, or who were on medications for
any psychiatric diagnosis were excluded. Comparison
subjects were new patients who had never taken
phentermine.
The scale used in this study, the PSSA (Table 1), was
adapted from the Kampman CSSA with the word
‘‘phentermine’’ replacing the word ‘‘cocaine’’ in Items 4
and 5. McGregor in studying amphetamine cessation in
amphetamine-dependent subjects modified the CSSA
by substituting the word ‘‘amphetamine’’ for ‘‘cocaine’’
creating an Amphetamine Selective Severity Assessment scale (ASSA). Thus, the only difference among
these three scales is the drug name in Items 4 and 5 of
each scale; every other scale examination item in the
three scales is identical.
Subjects were asked to indicate their phentermine
craving intensity and frequency, Items 4 and 5, on the
Likert scale beneath Table 1. All other items were
scored by the examiner, who was not blinded to treatment condition. Memory scores for subjects treated
with phentermine were also assessed by the examiner
who assigned a 0 to 7 score. Subjects with memory
scores lower than 5 were excluded.
RESULTS
T2
The baseline characteristics of study the subjects
are listed in Table 2. Although treated subjects and
comparison untreated subjects were not intentionally
age- and sex-matched, the two groups had characteristics similar to each other and to the population within
the medical practice. The amphetamine-dependent
subjects in McGregor’s study were younger and had
a higher percentage of males. The range of time on
phentermine therapy and the dose range are within
phentermine pharmacotherapy durations and dose
ranges commonly used in bariatric medicine practice in
the United States.17
Results were compared by t tests. Statistical significance was defined as by a two-sided P value less
than 0.05.
There was no significant difference between treated
and untreated groups in individual item scores or in
total scores. Means for individual item scores of
subjects treated with phentermine and untreated
www.americantherapeutics.com
3
subjects were greater than 1 for hyperphagia, carbohydrate craving, and low energy level. Higher scores
for hyperphagia, carbohydrate craving, and for low
energy level are not surprising because obese patients
presenting at weight loss clinics often have these
symptoms. Some obese or overweight patients report
low activity levels and some report inattention or a
poor ability to concentrate. The latter may be attributed
to a high incidence of attention deficit disorder and
attention deficit hyperactivity disorder in the obese.18
Scores for inattention or inability to concentrate were
greater than 0 in six treated subjects and in six
untreated subjects suggesting that some of the clinic
patients had undiagnosed adult attention deficit.
Cravings for phentermine after cessation were
uniformly absent; this is reflected in the zero scores
for phentermine cravings for both treated and untreated subjects. The scores for treated subjects were
significantly different from those previously reported
in the literature for amphetamine-dependent subjects
in all items except hyperphagia.
DISCUSSION
Phentermine, the most widely used antiobesity drug,
is classified as a Category IV controlled substance.
Because of this classification, many believe phentermine to have abuse and addiction potential similar to
that of amphetamine, although of lesser degree or
intensity, because amphetamine is a Category II
controlled substance.
Stimulant substance addiction and withdrawal have
been investigated extensively in the 40 years since these
compounds were classified in response to the US
Controlled Substances Act of 1970. The characteristics
of cocaine, the prototypical stimulant of abuse, and
amphetamine addiction and withdrawal are now well
described. Psychometric scales have been created and
validated for use in assessing the nature and severity
of cocaine addiction and withdrawal. The CSSA scale
of Kampman has been validated as an accurate
measure of cocaine withdrawal in cocaine-dependent
subjects.13,19–21 McGregor modified the Kampman
scale for amphetamines (ASSA) and used it for assessing abrupt cessation of amphetamine in amphetaminedependent subjects.14,15 Recognizing that the symptoms
attendant to abrupt cessation of phentermine have
never been assessed using any modern addiction
medicine scale, we modified the CSSA for phentermine
(PSSA) and used it to investigate symptoms after
abrupt cessation of phentermine pharmacotherapy in
the context of a weight management program.
American Journal of Therapeutics (2010) 0(0)
4
Hendricks and Greenway
Table 1. Phentermine symptom severity assessment scale.
American Journal of Therapeutics (2010) 0(0)
www.americantherapeutics.com
Abrupt Phentermine Cessation
5
Table 2. Baseline subject characteristics.
No.
Sex
Age (years; mean 6 standard deviation)
Age range (years)
Body mass index (kg/m2;
mean 6 standard deviation)
Race
Days on prescription
Range of years: prescription/abuse
Days off drug
Phentermine dose (mg/day)
Dosage range (mg/day)
Memory score
Phentermine-treated
subjects
New phentermine-untreated
subjects.
McGregor’s
ASSA
35
9:26; M:F
45.1 6 11.1
23–62
33.6 6 5.1
35
8:27; M:F
45.3 6 12.3
20–66
35.3 6 8.5
20
9:11; M:F
30
19–45
?
W 89%
576 6 719
0.25–11
61.4 6 79.5
46 6 12.5
30–75
6.91 6 0.37
W 84%
0
0
0
0
0
6.94 6 0.34
Australian
2–13 years
Days 1–7
0
0
ASSA, amphetamine selective severity assessment; M, male; F, female; W, white.
In this study, we discovered that nearly all of the
symptoms observed after amphetamine cessation in
amphetamine-dependent subjects were absent in the
subjects treated with phentermine. Most notably absent
AU2
were phentermine cravings. Substance-dependent
subjects experience intense cravings for the substance
during use and after cessation; cravings are considered a hallmark of both addiction and relapse.22
Table 3. PSSA scores in treated and untreated patients compared with ASSA scores in
amphetamine-dependent subjects.
Item
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Description
Hyperphagia
Hypophagia
Carbohydrate craving
PHEN/A craving intensity
PHEN/A craving frequency
Bradycardia
Hyposomnia
Hypersomnia
Anxiety
Energy level
Activity level
Tension
Attention
Paranoia
Anhedonia
Depression
Suicidality
Irritability
Total scores
Range of total scores
Maximum possible score
Phentermine-treated
subjects
Mean 6 SD
1.86
0.06
1.71
0
0
0
0
0.20
0.09
1.09
0.51
0.06
0.34
0
0.03
0.09
0
0.12
6.14
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
1.57
0.34
1.81
0
0
0
0
0.41
0.51
1.62
0.98
0.34
0.84
0
0.17
0.37
0
0.32
5.12
0–19
126
Untreated
subjects
Mean 6 SD
1.91
0.03
2.49
0
0
0.14
0.03
0.11
0.43
1.63
0.54
0.29
0.23
0
0.03
0.26
0
0.23
8.34
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
1.72
0.17
2.13
0
0
0.60
0.17
0.40
1.04
1.85
0.92
0.67
0.55
0
0.17
0.56
0
0.49
4.51
0–21
126
McGregor’s
amphetamine
dependent
Mean 6 SEM
P, t test*
0.30
.0.05
0.20
,0.1
0.32
,0.01
0.28
,0.01
0.26
,0.01
0.06
,0.05, .0.05
0.23
,0.01
0.31
,0.01
0.27
,0.01
0.30
,0.01
0.28
,0.01
0.27
,0.01
0.26
,0.01
0.23
,0.01
0.31
,0.01
0.30
,0.01
0.21
,0.01
0.27
,0.01
5 day 1
,0.1
39 6 9 day 7
42 day 4
126
2.30
0.68
3.51
3.90
4.14
0.10
1.41
2.27
3.98
3.87
3.51
3.71
2.22
1.42
3.70
2.68
0.89
3.70
55
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
*P values compare columns 2 and 3 with column 4. columns 2 and 3 are not different.
PSSA, phentermine selective severity assessment; ASSA, amphetamine selective severity assessment; SD, standard deviation; SEM,
standard error of mean; PHEN, phentermine.
www.americantherapeutics.com
American Journal of Therapeutics (2010) 0(0)
6
Amphetamine cravings were present in varying
degrees in each and every amphetamine-dependent
subject examined by McGregor.14 Prior investigations
indicate within 24 hours after amphetamine-dependent
users stop using amphetamine abruptly, as many as
97% experience a withdrawal syndrome characterized
by severe dysphoria, irritability, melancholia, anxiety,
hypersomnia, marked fatigue, paranoia, and intense
craving for the drug.23 Typically, abrupt cessation after
a period of heavy amphetamine use is followed by
a ‘‘crash’’ lasting 3 days or more during which the
subject is profoundly depressed, sleeps up to 20 hours
a day, and eats little, followed by days or weeks of
insomnia, carbohydrate cravings, and hyperphagia.24
Most symptoms of amphetamine withdrawal fade
within the first week after cessation but other
symptoms may persist for several months. The ASSA
scale has been shown to assess the intensity of
amphetamine withdrawal and has been used to further
describe the clinical characteristics of abrupt amphetamine cessation.14,15 The data presented here with the
PSSA scale, an exact replica of the ASSA except with
the word amphetamine replaced with phentermine in
two items, clearly demonstrates that abrupt phentermine cessation in the patients studied did not produce
amphetamine-like withdrawal symptoms.
It should also be pointed out that the type and
severity of adverse effects produced by any drug is
influenced by the dose, route and duration of administration. Amphetamine abusers typically self-administer
the drug by either the inhalational or intravenous
route. These routes of administration typically produce
very high plasma drug levels very quickly,25 increasing
the probability of producing serious adverse effects
such as addiction, stroke, and cardiotoxicity. Patients
taking oral stimulants, as prescribed by a physician, do
not achieve the very high plasma drug levels needed to
produce serious adverse effects. This fact is yet another
likely explanation for the overall very low rate of
serious adverse effects seen with the use of stimulants
for the treatment of obesity and of attention deficit
disorder.
This investigation suggests that if therapeutic
phentermine has an addiction potential, the potential
must be very much lower than that seen with illicit
amphetamine use. Perhaps a more cogent comparison
would be to compare the potential for addiction of
therapeutic phentermine for treating obesity versus the
addiction potential of oral amphetamines in treating
attention deficit disorder. The incidence of substance
abuse in adults with attention deficit disorder is said
to be high, from 9% to 30%, but these figures do not
discriminate between substance abuse with therapeutic
amphetamine agents for attention deficit and other
American Journal of Therapeutics (2010) 0(0)
Hendricks and Greenway
substances of abuse.26 In fact, the reported evidence
supports the conclusion that oral amphetamine stimulant therapy in attention deficit disorder does not
increase, but rather reduces the incidence of substance
abuse.27–29 If therapeutic oral amphetamine, a Category
II drug, is associated with a lower incidence of
inducing addiction in patients with attention deficit
disorder, it is reasonable to expect that therapeutic oral
phentermine for the treatment of obese patients would
have an even lower addiction potential.
The focus in this study was to show that phentermine cessation in phentermine-treated subjects did
not show amphetamine-like withdrawal symptoms;
therefore, we did not attempt to quantify symptoms
uncharacteristic for amphetamine withdrawal. As
a result, this investigation does not describe symptoms
unique to phentermine cessation nor describe phentermine therapeutic effects or their disappearance on
phentermine cessation. Typically, the focus of the
numerous phentermine clinical trial reports is weight
loss, and other therapeutic effects such as amelioration
of cravings or improvements in mood and energy level
have been either ignored or not quantified.
Although we did not measure these symptoms
systematically, the most notable symptoms reported in
this trial should be mentioned. Some study patients
reported an initial mild decline in energy level after
stopping phentermine, which persisted only if weight
gain ensued. Hyperphagia and carbohydrate cravings, which had been suppressed on phentermine
therapy, often recurred when these patients stopped
therapy. This was true even in patients who had been
on phentermine for years. The average time lapse
between phentermine cessation and examination for
this study was 61 days, but some of the study patients
had been off phentermine for as long as 10 months
before being examined with the PSSA. However, most
of the patients had abruptly stopped taking phentermine and had experienced cessation symptoms on
numerous occasions. These subjects typically had
very vivid memories of the symptoms occurring in
the week after cessation. On the other hand, subjects
who had stopped taking phentermine abruptly only
one or two times had less detailed recollection; these
patients with memory scores graded by the examiner
of less than 5 were excluded. Binge use of phentermine has never been reported nor was it observed
during this study.
Our hypothesis in undertaking this study was that
the phentermine stimulatory effects seen in animal
studies have been overinterpreted as an indicator of
potential abuse of phentermine in humans being
treated for obesity. The question of whether phentermine has addiction potential in this group of patients is
www.americantherapeutics.com
Abrupt Phentermine Cessation
AU1
an important one in the face of a growing obesity
epidemic, because obesity afflicts the socioeconomically disadvantaged to a disproportionate degree and
the majority of third-party payers do not cover obesity
drugs. Phentermine, approved in 1959, is now available in generic form and is therefore much less
expensive than drugs like Orlistat and Sibutramine,
which are approved for chronic obesity treatment.
This study demonstrates that long-term phentermine
pharmacotherapy in the context of a weight management program does not induce amphetamine-like
withdrawal symptoms. The study also indicates that
long-term phentermine pharmacotherapy does not
induce phentermine cravings. This is true even in
patients who had been on phentermine therapy for
as long as 11 years and in patients on doses higher
than recommended in the package insert. This report
provides data supporting other authors’ assertions
that long-term phentermine therapy in the context of
obesity treatment does not induce phentermine abuse,
addiction, or inappropriate use.30,31 Patients who stop
taking phentermine abruptly do experience symptoms,
but these appear indicative of loss of phentermine
therapeutic effect and are not amphetamine-like
withdrawal symptoms.
ACKNOWLEDGMENTS
We gratefully acknowledge the assistance of Richard B.
Rothman in designing the study and the constructive
comments of Manit Srisurapanont.
REFERENCES
1. Nathanson MH. The central action of betaaminopropylbenzine (Benzadrine) clinical observations.
J Am Med Assoc. 1937;108:528–531.
2. Ulrich H. Narcolepsy and its treatment with Benzedrine
sulfate. N Engl J Med. 1937;217:696–701.
3. Lesses M, Myerson A. Human autonomic pharmacology
XVI. Benzedrine sulfate as an aid in the treatment of
obesity. N Engl J Med. 1938;218:119–124.
4. Ersner JS. The treatment of obesity due to dietary
indiscretion (over-eating) with benzedrine sulfate. Endocrinology. 1940;27:776–780.
5. Kalb SW. The effect of amphetamine (Benzedrine) sulfate
and thyroid hormone in the treatment of obesity:
observations on 500 cases. J Med Soc NJ. 1942;39:74–75.
6. Harris SC, Ivy AC, Searle LM. The mechanism of
amphetamine-induced loss of weight. J Am Med Assoc.
1947;134:1468–1475.
7. Albrecht FK. The use of Benzedrine sulfate in obesity. Ann
Intern Med. 1944;21:983–989.
www.americantherapeutics.com
7
8. Steel JM, Munro JF, Duncan LJP. A comparative trial
of different regimens of fenfluramine and phentermine in
obesity. The Practitioner. 1973;211:232–236.
9. Rossum JMV, Simon F. Locomotor activity and anorexigenic action. Psychopharmacologia. 1969;14:248–254.
10. Griffiths RR, Winger G, Brady JV, et al. Comparison of
behavior maintained by infusions of eight phenylethylamines in baboons. Psychopharmacology (Berl). 1976;50:
251–258.
11. Wojnicki FHE, Rothman RB, Rice KC, et al. Effects of
phentermine on responding maintained under multiple
fixed-ratio schedules of food and cocaine presentation
in the rhesus monkey. J Pharmacol Exp Ther. 1999;288:
550–560.
12. Jain NC, Budd RD, Sneath TC. Frequency of use or abuse
of amphetamine-related drugs. Am J Drug Alcohol Abuse.
1979;6:53–57.
13. Kampman KM, Volpicelli JR, McGinnis DE, et al. Reliability and validity of the Cocaine Selective Severity
Assessment. Addictive Behaviors. 1998;23:449–461.
14. McGregor C. Amphetamine Withdrawal: Nature, Time
Course, and Treatment. PhD thesis. Adelaide: University
of Adelaide; 2005.
15. McGregor C, Srisurapanont M, Jittiwutikarn J, et al.
The nature, time course and severity of methamphetamine withdrawal. Addiction (Abingdon, England). 2005;
100:1320–1329.
16. McGregor C, Srisurapanont M, Mitchell A, et al. Psychometric evaluation of the Amphetamine Cessation Symptom Assessment. J Subst Abuse Treat. 2008;34:443–449.
17. Hendricks EJ, Greenway FL, Westman EC, et al. A survey
of prescribing practices of medical bariatricians. Obesity.
2008;16:S292–S293.
18. Pagoto SL, Curtin C, Lemon SC, et al. Association
between adult attention deficit/hyperactivity disorder
and obesity in the US population. Obesity. 2009;17:
539–544.
19. Ahmadi J, Kampman K, Dackis C. Outcome predictors in
cocaine dependence treatment trials. Am J Addict. 2006;15:
434–439.
20. Ahmadi J, Kampman K, Dackis C, et al. Cocaine
withdrawal symptoms identify ’Type B’ cocaine-dependent patients. Am J Addict. 2008;17:60–64.
21. Ahmadi J, Kampman KM, Oslin DM, et al. Predictors
of treatment outcome in outpatient cocaine and alcohol
dependence treatment. Am J Addict. 2009;18:81–86.
22. Heinz AJ, Epstein DH, Schroeder JR, et al. Heroin and
cocaine craving and use during treatment: measurement
validation and potential relationships. J Subst Abuse Treat.
2006;31:355–364.
23. Topp L, Darke S. The applicability of the dependence
syndrome to amphetamine. Drug Alcohol Depend. 1997;48:
113–118.
24. Shoptaw SJ, Kao U, Heinzerling K, et al. Treatment for
amphetamine withdrawal. Cochrane Database Syst Rev.
2009:CD003021.
25. Evans SM, Cone EJ, Henningfield JE. Arterial and venous
cocaine plasma concentrations in humans: relationship to
American Journal of Therapeutics (2010) 0(0)
8
route of administration, cardiovascular effects and subjective effects. J Pharmacol Exp Ther. 1996;279:1345–1356.
26. Wilens TE. Attention Deficit Hyperactivity Disorder
and Substance Use Disorders. Am J Psychiatry. 2006;163:
2059–2063.
27. Wilens TE, Adamson J, Monuteaux MC, et al. Effect of
prior stimulant treatment for attention-deficit/hyperactivity disorder on subsequent risk for cigarette smoking
and alcohol and drug use disorders in adolescents. Arch
Pediatr Adolesc Med. 2008;162:916–921.
28. Wilens TE, Faraone SV, Biederman J, et al. Does stimulant
therapy of attention–deficit/hyperactivity disorder beget
American Journal of Therapeutics (2010) 0(0)
Hendricks and Greenway
later substance abuse? A meta-analytic review of the
literature. Pediatrics. 2003;111:179–185.
29. Wilens TE, Monuteaux MC, Snyder LE, et al. The clinical
dilemma of using medications in substance-abusing adolescents and adults with attention-deficit/hyperactivity
disorder: what does the literature tell us? J Child Adolesc
Psychopharmacol. 2005;15:787–798.
30. Frank A. The long-term management of obesity
with continuing pharmacotherapy. Obes Res. 2004;12:
1821–1827.
31. Bray GA, Greenway FL. Current and potential drugs for
treatment of obesity. Endocr Rev. 1999;20:805–875.
www.americantherapeutics.com