1. Long-term Phentermine Pharmacotherapy: An
Investigation for Amphetamine-like Abuse
Potential
EJ Hendricks, FL Greenway, M Srisurapanont,
SL Schmidt, D De Marco, MJ Hendricks, Y Istratiy
ABSTRACT
Introduction: A commonly held presumption is
that phentermine therapy can induce abuse or
dependence, at a lower incidence rate, with
similar symptoms, but of lesser severity than
amphetamine and methamphetamine-induced
dependence. No human data supporting these
presumptions has ever been published. Intense
cravings for amphetamine are a hallmark
symptom of amphetamine abuse and
dependence. If phentermine-induced abuse
occurs, phentermine cravings could be
expected to occur during long-term use.
Methods: 117 patients phentermine-treated for
8.4 (±5.2) years with 53.4 (±19.5) mg/day
(Long-Term Patients, LTP) and 152 patients
phentermine-treated for 9.3 (±3.4) days with
34.5 (±9.5) mg/day (Acute-Term Patients, ATP)
were examined. LTP were interviewed using
Module K (Non-alcohol psychoactive substance
use disorders) of the Mini International
Neuropsychiatric Interview (MINI) modified for
phentermine, then examined using the Severity
of Dependence Scale (SDS) modified for
phentermine, and Tiffany’s 45-question cocaine
craving questionnaire modified for phentermine
(PCQ). ATP were examined with SDS and
PCQ. SDS and PCQ scores were analysed
using Mann-Whitney U tests.
Results: Based on the MINI, no LTP had
phentermine abuse or dependence. SDS mean
total scores were not significantly different: LTP
0.42 (±0.75); ATP 0.50 (±0.91), P = 0.528.
(Typically SDS scores for amphetaminedependent subjects are >4.) PCQ total mean
scores: LTP 1.93 (±0.64); ATP 2.25 (±0.71), P
<0.001, but ATP>LTP, reverse the ratio
expected if phentermine induced cravings.
Conclusions: Patients treated with
phentermine for averages of 8.4 years and 53.4
mg/day had no sign of amphetamine-like abuse
or dependence. Long-term phentermine
treatment did not induce phentermine cravings.
BACKGROUND
In 1959 when the US FDA approved
phentermine for treating obesity the only
evidence that phentermine could induce abuse
or addiction came from studies in rats. The facts
that rats “liked” phentermine, that phentermine is
a stimulant, and that phentermine is a
substituted phenethylamine with a structure
similar to amphetamine led to the presumption
that phentermine abuse and addiction might
occur. Although there was no evidence of
human addiction potential, the US DEA decided
phentermine should be classed as a category IV
controlled substance.
After 53 years of widespread use,
phentermine addiction has never been reported.
Nor have there been reports of investigations of
the human addiction potential for phentermine.
Phentermine is a mild stimulant. A few
laboratories have reported finding phentermine
in samples from long-haul truck drivers and in
subjects in drug treatment programs, but
absence of clinical reports suggests
phentermine abuse, if it indeed occurs, is rare.
We used validated modern addiction
medicine metrics to examine phenterminetreated patients for signs or symptoms of
amphetamine-like abuse, addiction
(psychological dependence), or phentermine
cravings. Cravings for the drug or substance in
question are now considered a hallmark sign of
abuse or addiction.
DEMOGRAPHICS
OBJECTIVE
To examine patients treated with
phentermine long-term for signs of
phentermine abuse, addiction
(psychological dependence), or
phentermine cravings
RECRUITMENT
Patients were recruited in two cohorts from
a private fee-for-service obesity medicine
specialty practice. Overweight, obese, and
weight loss maintenance patients in this
practice are typically treated with anti-obesity
drugs long-term. Patients were recruited for
the Long-Term Phentermine-treated (LTP)
cohort if they had been treated with
phentermine for a minimum of one year while
patients for the Acute-Term Phentermine
(ATP) cohort were recruited after they had
been on phentermine for 7 to 14 days.
All patients were 18 years of age or older;
there were no other age restrictions. Patients
who had taken cumulative phentermine drug
holidays exceeding 60 days in the previous 12
months or who had taken any drug holiday in
the previous 30 days were excluded from the
LTP cohort. Patients with current Axis I
psychiatric diagnoses were included provided
these were stable and under treatment.
Patients with dependence on drugs other than
nicotine were excluded since phentermine
was not prescribed for such patients.
Beginning in August 2011, patients newly
started on phentermine were recruited for the
ATP cohort as they appeared for follow-up
examinations after 7 to 14 days of treatment.
At the same time eligibility of returning
patients for inclusion in the LTP cohort was
determined as the patients appeared at the
clinic. Those eligible were invited to
participate. Few ATP and LTP eligible
candidates declined participation.
This clinical trial is registered at
clinicaltrials.gov as NCT01402674.
METHODS
Mini International Neuropsychiatric
Interview (MINI): a structured interview guide
for making a DSM-IV-TR diagnosis of mental
disorders, including substance dependence
and abuse. Module K, for diagnosing nonalcohol psychoactive substance use disorder
(MINI-SUD), was used and modified by
restricting questioning to phentermine.
Severity of Dependence Scale (SDS): a
Likert-type (score 0-3), five-question
psychometric scale used for assessing the
severity of substance dependence was
modified by replacing the word “drug” with
“phentermine.”
Cocaine Craving Questionnaire NOW (CCQNOW): a seven-point Likert-type (score 1-7)
forty-five-question psychometric scale originally
developed for assessment of cocaine drug
cravings, but also used for methamphetamine
cravings in methamphetamine dependent
subjects, was modified for phentermine by
replacing the words “cocaine” and “coke” with
“phentermine,” to create a PCQ-NOW.
APT (N=152)
LPT (N=117)
Mean (SD)
Mean (SD)
Age, Years
44.18 ±12.39) 51.18 ±11.40)
BMI
34.88 (±7.31)
Treatment Duration
9.30 (±3.35) D 8.35 (±5.16)Y
Rx Range (Days/Yrs)
Phentermine (mg/d)
4 – 22 Days
33.79 (±7.59)
1.1 – 21.5 Yrs
34.46 (±9.23) 53.43(±19.46)
Dosage range (mg/d)
15 - 93.75
18.75 – 112.5
Office examinations
72.1 (±51.7)
Rx hiatus < 1 month
117 (100%)
Rx hiatus > 1 month
70 (60%)
Avg. Rx hiatus (mo)
19.5 (19.9)
RESULTS
Mini International Neuropsychiatric Interview
(MINI-SUD)
MINI-SUD interviews for each of the 117 LTP
patients examined were negative for phentermine
dependence or abuse.
Severity of Dependence Scale (SDS)
LTP patients’ mean SDS scores were slightly
higher, 0.50 (0.91) than the ATP patients’ mean
scores, 0.42 (0.75) but the difference was not
significant (p = 0.528).
Phentermine Craving Questionnaire – NOW
(PCQ-NOW)
Total scores for the LTP patients were significantly
lower than the corresponding scores for the ATP
patients. (p<0.001) Domain scores were also
significantly lower: desire (p=0.002), lack of selfefficacy (p<0.001), compulsivity (p<0.001), and
relief (p=0.017)
CONCLUSIONS
These data strongly suggest that long-term
phentermine pharmacotherapy for obesity for up to
21.5 years and at doses up to 112.5 milligrams per
day does not induce abuse, or addiction
(psychological dependence), and that long-term
phentermine pharmacotherapy does not induce
phentermine drug cravings.
These data suggest fears of causing addiction
with long-term phentermine are exaggerated and
present a needless barrier to better care for
overweight and obese patients worldwide.
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