To investigate if phentermine treatment induces phentermine abuse, psychological dependence (addiction) or phentermine drug craving in overweight, obese and weight loss maintenance patients. To investigate whether amphetamine-like withdrawal occurs after abrupt cessation of long-term phentermine treatment.
Clinical intervention trial with interruption of phentermine treatment in long-term patients.
269 obese, overweight or formerly obese subjects (age: 20–88 years, BMI: 21–74 kg m−2) treated with phentermine long-term (LTP, N=117), 1.1–21.1 years, or short-term (ATP, N=152), 4–22 days, with phentermine doses of 18.75–112.5 (LTP) and 15–93.75 (ATP) mg per day.
Module K of the Mini International Neuropsychiatric Interview modified for phentermine (MINI-SUD), Severity of Dependence Scale (SDS), 45-item Cocaine Craving Questionnaire-NOW (CCQ-NOW) modified for phentermine (PCQ-NOW), and Amphetamine Withdrawal Questionnaire (AWQ) modified for phentermine (PWQ).
MINI-SUD interviews were negative for phentermine abuse or psychological dependence in all LTP patients. SDS examination scores were low for all LTP and ATP patients, indicating they were not psychologically dependent upon phentermine. PCQ-NOW scores were low for all LTP and ATP patients, indicating neither short-term nor long-term phentermine treatment had induced phentermine craving. Other than an increase in hunger or eating, amphetamine-like withdrawal symptoms did not occur upon abrupt phentermine cessation as measured by sequential PWQ scores.
Phentermine abuse or psychological dependence (addiction) does not occur in patients treated with phentermine for obesity. Phentermine treatment does not induce phentermine drug craving, a hallmark sign of addiction. Amphetamine-like withdrawal does not occur upon abrupt treatment cessation even at doses much higher than commonly recommended and after treatment durations of up to 21 years.
As the worldwide obesity epidemic continues unabated, pharmacotherapy remains an underutilized modality in treating obesity.1 Of course a major reason for this is that there is a paucity of approved effective drugs, but another reason is that use of certain drugs has been marginalized.2 Among the older drugs, approved before the US Food and Drug Administration (FDA) began to require long-term trials for obesity drugs, phentermine is known to be effective, both for short-term weight loss and for long-term weight maintenance.3, 4, 5, 6, 7, 8, 9 Although long-term, FDA-supervised, clinical trials have never been conducted for phentermine, 97% of US obesity treatment specialists use phentermine as their agent-of-choice drug for treating obesity.10 The use of this drug for obesity treatment by other physicians throughout the world has long been curtailed because of what we believe to be misapprehensions regarding phentermine safety.2 Concerns of phentermine-induced addiction and of adverse cardiovascular reactions are two fears that have had a profound negative impact on phentermine prescribing.
To determine whether concerns of addiction resulting from phentermine treatment are reasonable, we carried out this addiction potential of phentermine prescribed during long-term treatment of obesity (APPLO) trial, which aimed to examine if psychological dependence, abuse, craving and withdrawal actually did occur in obese patients receiving long-term treatment with phentermine.
Patients and methods
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 antiobesity drugs over a long term.8, 11 Patients were recruited for the long-term phentermine-treated (LTP) cohort if they had been treated with phentermine for a minimum of 1 year, while patients for the acute-term phentermine (ATP) cohort were recruited after they had been on phentermine for 7–14 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, as phentermine was not prescribed for such patients. Ethical and Independent Review Services, Independence, Missouri, a commercial Independent Review Board, approved the study procedures and informed consent document. After the risks of the study had been fully explained, all participating patients provided informed consent. Participants were given no remuneration for participation in the study; each paid the clinic’s customary fees for their care without discount. Beginning in August 2011, patients newly started on phentermine were recruited for the ATP cohort as they appeared for follow-up examinations after 7–14 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. Patient demographics are detailed in Table 1. This clinical trial is registered at clinicaltrials.gov as NCT01402674.
The Mini International Neuropsychiatric Interview (MINI)12 is a structured interview guide for making a DSM-IV-TR diagnosis of mental disorders, including substance dependence and abuse. Module K, for diagnosing non-alcohol psychoactive substance use disorder (MINI-SUD), was used and modified by restricting questioning to phentermine. Module K is for assessing addictive behavior over the 12 months prior to assessment. Module K, version 5.0.0 of the MINI was modified for this study.
The Severity of Dependence Scale (SDS),13 a four-point, 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.’ The SDS used for the LTP patients is shown in Table 2. The SDS used for the ATP patients was identical except the time-frame was weeks rather than years.
The Cocaine Craving Questionnaire NOW (CCQ-NOW), a seven-point Likert-type (score 1–7) 45-question psychometric scale14 originally developed for assessment of cocaine drug craving, but also used for methamphetamine craving in methamphetamine-dependent subjects,15 was modified for phentermine by replacing the words ‘cocaine’ and ‘coke’ with ‘phentermine,’ to create a PCQ-NOW.
The Amphetamine Withdrawal Questionnaire (AWQ),16 a five-point Likert-type (score 0–4), ten-question psychometric scale for assessing the severity of amphetamine withdrawal in addicted subjects was modified to a Phentermine Withdrawal Questionnaire (PWQ) by changing the word ‘amphetamine’ to ‘phentermine.’
ATP patients were tested once in the clinic with SDS and PCQ-NOW upon recruitment.
LTP patients were tested in the clinic with MINI-SUD, SDS, PCQ-NOW and PWQ (Day 0 or D0) upon recruitment. LTP patients were instructed to continue to take their usual dose of phentermine until 1 day prior to their next office visit when they were to skip their phentermine, and self-examine with the PWQ (D1) at ∼24 h after their last phentermine dose at home. They were instructed to skip their phentermine again the following day, the day of their scheduled office visit. Upon arrival at the clinic they were again tested with the PWQ (D2) at ∼48 h after their last dose of phentermine, after which they resumed phentermine treatment.
Mean and standard deviation were calculated for patient age, BMI, phentermine dose, duration of phentermine treatment and number of office visits. Scores for SDS, PCQ-NOW and PWQ are ordinal data. Ordinal data statistical methods, including Mann–Whitney, Kruskal–Wallis, Wilcoxen signed rank, and Friedman tests calculated by SPSS V17.0 ( SPSS Inc., Chicago, IL, USA) for Windows, were employed for statistical analysis for the psychometric scale scores.
Phentermine dose and duration distribution
Phentermine doses and durations of treatment are listed in Table 1. Patients were treated variously with 15 or 30 mg capsules of phentermine hydrochloride or 37.5 mg tablets of phentermine hydrochloride. The latter tablets are scored enabling patients to take one-half tablet of 18.73 milligrams of phentermine hydrochloride. As has been previously reported,8 phentermine doses for clinic patients may be adjusted over time using dose-to-effect titration where the effect monitored is control of eating behavior. Because of use of this method of ‘dose-to-effect’ titration of phentermine dosage, we find average phentermine doses of clinic patients gradually increase with duration of treatment. Among the ATP cohort phentermine doses were: 19.1% on 15–18.75, 78.9% on 30–37.5 and 2% on greater than 37.5 mg per day. The distribution of doses in the LTP cohort was: 41% at 18.75–37, 24.8% at 45–56.25, 30.8% at 60–75 and 3.4% at >75 mg per day.
Duration of treatment among the ATP cohort varied slightly with a median value of 8.0 days. More striking were the variations in duration of treatment in the LTP cohort ranging from 1.1 years to 21.1 years with a median value of 7.2 years.
Mini International Neuropsychiatric Interview
MINI-SUD interviews for each of the 117 LTP patients examined were negative for phentermine dependence or abuse. These long-term patients were well known at the clinic as indicated by the mean number (±s.d.) of clinical examination visits for the LTP patients of 72.1 (51.7). In reviewing the LTP patient records, we found no suggestion that any of the LTP patients had ever exhibited maladaptive drug use symptoms listed as the criteria for drug abuse or dependence in the DSM-IV TR. Nor did any of these patients exhibit drug-seeking behaviors, manifest signs of compulsive phentermine use, or have apparent clinically significant impairment or distress as a result of their phentermine use. The finding that 100% of the LTP MINI-SUD examinations were negative for either phentermine abuse or psychological dependence is consistent with the clinic’s 24 years experience in treating obesity with phentermine.
Severity of Dependence Scale
SDS data collected from the 152 ATP patients were compared with that collected from the 117 LTP patients using the Mann–Whitney U test. 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). The distribution of patients’ individual question and total scores is shown in Table 3. Note that the majority of both ATP and LTP had total scores of 0 or 1 corresponding to answering never or sometimes, respectively. The range of total scores among the ATP patients was 0–3. The range of total scores among the LPT patients was 0–5, with one patient scoring 5 and one patient scoring 4. Examination of the individual question scoring for these two subjects revealed that the patient with a total of 5 answered sometimes for a score of 1 on each of the five SDS questions, while the patient with a total of 4 answered sometimes, scoring 1 for questions 2, 3, 4 and 5.
Twenty-four of the 117 LTP or 20.5% of patients had a diagnosis of depression, and were taking an antidepressant medication when recruited as indicated in Table 1. There was no significant difference in mean total SDS scores between the 24 patients on antidepressant medicines, 0.54 (1.18) and the 93 LTP patients who were not, 0.49 (0.83) (Mann–Whitney U test: Z=−0.419, P=0.676).
Phentermine Craving Questionnaire—NOW
In scoring the PCQ-NOW we followed the scoring conventions suggested by Heinz et al.17 in which total a score for 41 of the 45 questions is calculated and scores subtotaled for four domains. The four domains as suggested by Heinz et al.17are: factor 1, desire, factor 2, lack of self-efficacy, factor 3, compulsivity, and factor 4, relief. PCQ-NOW scoring results are presented in Table 4. The total and each of the four domain scores for the LTP patients are significantly lower than the corresponding scores for the ATP patients. There was no significant difference in PCQ-NOW mean total scores between the 24 patients on antidepressant medicines (2.06 (0.69)) and the 93 LTP patients who were not (1.90 (0.63)) (Mann–Whitney U test, Z=−0.915, P=0.360).
Phentermine Withdrawal Questionnaire
LTP patients were tested with the PWQ three times. The first test was done on a day they had taken phentermine (D0). They were also tested at ∼24 h after cessation (D1) and again at 48 h after cessation (D2). PWQ scoring is shown in Table 5. Ten-item PWQ total scores for D0, D1 and D2 differed significantly (Friedman test, P=0.046) in which the peak and bottom-most of withdrawal states were found on D1 and D2, respectively (Z=−2.50, P=0.013). When the three PWQ component syndromes were compared, scores for the hyperarousal and anxiety syndromes were not significantly different, but the reversed vegetative syndrome score was different (Friedman test, P=0.011). Again, the peak of withdrawal was found on D1 (Z=−2.478, P=0.013). The reversed vegetative syndrome score is a combination of three symptoms: fatigue, hyperphagia and sleepiness. Individual question scores for fatigue and sleepiness did not differ significantly among D0, D1 and D2 scores. Thus the hyperphagia score was the only PWQ question significantly different within the reversed vegetative syndrome score among the D0, D1 and D2 scores (P=0.027). Nine-item total PWQ scores, omitting scores for the hyperphagia question, were not significantly different for D0, D1 and D2.
The results of the MINI-SUD structured interviews were unambiguous with no hint of either phentermine abuse or psychological dependence in any LTP subject.
The SDS is considered a measure of compulsive drug use13 that has been used as a screening tool to identify drug users at risk for addiction.18 Total SDS scores >4 are thought to indicate problematic amphetamine use in known amphetamine users19 requiring further investigation. Suggested SDS cutoff values for other drugs are >3 for cocaine,20 and >3 for cannabis.21 Gossop et al.,13 in a study of the SDS in drug users, found that the mean SDS scores in two samples from heroin abusers were 5.2 (5.0), N=222, and 8.7 (4.0), N=408. The range of values in each sample was 0–15, the latter being the maximum possible SDS score.13 In the same study the mean SDS scores in two cohorts of amphetamine abusers were 3.7 (4.0), N=231, and 4.3 (3.2), N=301. The range of values in the two amphetamine user samples was 1–15 and 0–14, respectively. The mean SDS score in a cohort of cocaine-using patients (N=15) was 4.2 (3.3) with a range of 0–13. The mean SDS scores and the range of SDS scores in our study patients were substantially lower than those reported for amphetamine-addicted subjects. One LTP patient did have a SDS score of 5, scoring 1 in each of the five questions, and one LTP patient had a SDS score of 4, scoring 1 in questions 2, 3, 4 and 5. However, these two subjects had been patients for 10.4 and 13.2 years, and had negative MINI-SUD interviews; neither had shown drug-seeking behavior nor any sign of compulsive use of phentermine. The SDS individual and total question scoring in this study is evidence that the addiction potential of phentermine is vanishingly low in a clinical setting.
The PCQ-NOW was included as a measure of phentermine craving. Drug craving is considered a hallmark symptom of addiction and relapse.22, 23 The CCQ-NOW has been used as a measure of cocaine and other drug craving intensity in known drug users.17 Addictive drugs and substances vary in their addictive potential and the number of exposures required to induce addiction. Variation in onset of addiction and drug craving also depends on how rapidly peak drug levels are reached, and this varies by route of administration. Thus, addiction occurs quickly with few exposures to inhaled crystal methamphetamine, while multiple exposures are required to induce addiction to hydrocodone via the oral route. Our rationale in comparing phentermine-craving intensity between the ATP and LTP cohorts was that if orally-administered phentermine has any addiction potential it is of a very low order, and that one would not expect phentermine craving to appear after 1–2 weeks of phentermine treatment. We found that both total and domain subtotal PCQ-NOW scores were significantly higher in the ATP patients than in the LTP patients. This is the opposite result from the one expected if long-term phentermine treatment is indeed addicting and induces phentermine craving.
The AWQ is a measure of severity of the ten major symptoms found to occur in amphetamine-addicted subjects after abrupt cessation of amphetamine.16 The ten questions assess drug craving, dysphoria, anhedonia, anxiety, motor retardation, agitation, fatigue, increased appetite or eating, vivid or unpleasant dreams, and craving for sleep or hypersomnia. Each question has five possible answers ranging from “not at all” to ‘very much’ with a range of scores of 0–4. AWQ total score is the total of all ten questions with a possible range of 0–40. One can also analyze AWQ by calculating three syndrome scores: hyperarousal syndrome, a combination of scores for drug craving, agitation, and vivid or unpleasant dreams; reversed vegetative syndrome, combined scores for fatigue, increased appetite, and craving for sleep or hypersomnia; and anxiety syndrome, combined scores for anhedonia, anxiety and motor retardation.
In one study of the AWQ in hospitalized amphetamine abusers the total scores were highest at D0, then fell slightly on D1 and again on D2.24 As seen in panel 1, page 1323, the total AWQ scores for the inpatients appear to be approximately D0≈17, D1≈15 and D2≈13. Also depicted are AWQ scores for a comparison group of healthy nondependent individuals, which followed that same pattern but were substantially lower: D0≈3.0, D1≈1.5 and D2≈1.7. PWQ scores in LTP patients were also low and were comparable to the scores of the comparison group.
As seen in Table 5, different PWQ scores among those obtained on D0, D1 and D2 found on the total, reversed vegetative syndrome and hyperphagia scores suggested the possibility of phentermine withdrawal. However, in examining the syndrome and symptom related to the withdrawal effect, hyperphagia was the only withdrawal symptom found. If hyperphagia was not taken into account, the nine-item PWQ total scores obtained from those three time points were not significantly different. In addition, the mean nine-item PWQ total scores on D1 (2.35) and on D2 (1.95) were actually lower than that on D0 (2.65), which were contrast to the concept of stimulant withdrawal.
Thus, the only amphetamine-like withdrawal symptom we found after abrupt phentermine cessation was an increase in appetite or an increase in eating. This represents a loss of phentermine therapeutic effect rather than an amphetamine-like withdrawal symptom. As seen in Table 1, 100% of LTP subjects had discontinued phentermine and stayed off it for less than 1 month. Most of these episodes were patient initiated in an effort to see if they could continue to lose weight or could maintain a weight loss without continuing phentermine. Occasionally the clinician initiated these episodes in an attempt to ascertain efficacy or to determine if phentermine was the cause of an unfavorable reaction. These patients invariably reported return of appetite, increased hunger, increased craving or increased eating, either singly or in combination. Typically weight gain slowly ensued within a month of phentermine cessation, but occasional patients reported successful weight maintenance for longer intervals. 70% of LTP patients gave a history of having discontinued phentermine for >1 month. The majority of these returned after having regained weight during the hiatus. Hence, reluctance to enroll as an LTP subject was rare because these patients had all tried abrupt cessation of phentermine many times, knew well the symptoms that would ensue, and were unafraid of abrupt cessation because they were confident they could avoid weight gain during a brief treatment hiatus.
Evidence supporting the concept that phentermine is an addictive substance is missing in the medical literature. The idea that phentermine has addiction potential appears to stem from early work in rats25 and from the fact that phentermine is a substituted phenethylamine, a large group of compounds with widely varying effects that includes addicting substances such as methamphetamine, cathinone, MDMA (3,4-methylene-dioxymethamphetamine or ‘Ecstasy’) and DOM (2,5-dimethoxy-4-methylamphetamine or ‘STP’), but also compounds without addiction potential such as ephedrine (N-methyl-β-hydroxyamphetamine) and bupropion (3-chloro-teri-butyl-β-ketoamphetamine).
There are no published reports that orally administered phentermine treatment for obesity has been associated with abuse or psychological dependence (addiction) as defined by the DSM-IV TR. Although methamphetamine abuse, addiction and withdrawal syndromes are now well described and characterized in the peer-reviewed medical literature,24, 26, 27, 28 no comparable syndrome for phentermine has been described.
Prior to our addiction medicine study of abrupt phentermine cessation in patients who had taken it long-term as treatment for obesity,11 there were only a few reports of human studies of phentermine abuse liability.29, 30, 31 None of the latter studies were conducted in subjects being phentermine-treated for obesity. Subjects tested in a laboratory environment were found to ‘like’ phentermine to varying degrees or to have subjective effects similar in some ways to those the same subjects experienced with amphetamine.
Two reports indicated that phentermine had been found in urine drug screening samples from truck drivers32 and in hair samples from Korean drug suspects.33 In 1979, Jain et al.34 had reported that 3.4% of over 10 000 urine specimens from the Los Angeles County probation department and methadone maintenance programs tested positive for amphetamine. and that 1.7% of the 10 000 specimens tested positive for phentermine using a gas-liquid chromatography technique.34 These reports suggest that although apparently phentermine abuse does occur, it may be limited to subjects who abuse other stimulants.
In a recently conducted telephone survey of 23 drug rehabilitation centers in Kentucky these centers reported that during 2010 and 2011 they had treated ∼24 000 patients but that not one had been admitted or treated for phentermine use or addiction (personal communication, Julie Swindler, M.D., Lexington, Kentucky). In another recently conducted telephone survey of medical directors of 50 drug treatment centers and 50 major hospital emergency rooms in each of 50 US states, no physician could recall ever having diagnosed or treated phentermine abuse, addiction or withdrawal (personal communication, David Bryman, D.O., Scottsdale, Arizona).
The drug has now been in use for more than 50 years and although a few anecdotes suggesting phentermine is abused have appeared,32, 33, 34 there is still no clinical evidence in the peer-reviewed medical literature to support the hypothesis that phentermine is addicting or has any significant human addiction potential.35 Research in addiction medicine has undergone noteworthy development since 1959. Concepts of addiction have shifted from an early focus on tolerance and withdrawal to a current emphasis on psychological components of dependence.13 Standardized diagnostic criteria for drug abuse, addiction and withdrawal were agreed upon among the American Psychiatric Association, and adopted for the Diagnostic and Statistical Manual of Mental Disorders—IV.36 Although there was agreement on definition of addiction, the label for this condition was changed to dependence, a change which has created considerable confusion as there is a clinical difference between psychological dependence, meaning a compulsive drug-taking condition or addiction, and physical dependence, which can occur in anyone taking a medicine affecting the central nervous system.37 In this paper we use the terms ‘psychological dependence’ and ‘addiction’ synonymously. Psychometric testing methods have been developed, validated and applied clinically for measurements of psychological dependence, drug craving and withdrawal for a wide variety of substances of abuse including cocaine, heroin, amphetamine and others.16, 17, 24, 38, 39 Currently drug craving is considered a characteristic symptom of both drug abuse, and psychological dependence or addiction.22, 23
We are aware of two studies that compared the addiction potential of phentermine with the addiction potential of other drugs using drug liking scales.30, 31 Both studies found that when experimental subjects were given phentermine some liked the drug. Neither of these studies was conducted in subjects given phentermine for obesity treatment. The only study we are aware of that has investigated phentermine addiction potential in phentermine-treated patients using modern addiction medicine metrics is one we recently conducted looking for amphetamine-like withdrawal symptoms in patients treated with long-term phentermine in a weight management program who ceased taking phentermine abruptly.11 We used a psychometric scale originally developed for use in evaluating withdrawal symptoms in cocaine abusers occurring after abrupt cocaine cessation.38 The scale has been used to characterize cocaine withdrawal,40, 41 and has also been modified for use in characterizing amphetamine withdrawal.15, 24 We found patients on long-term phentermine who ceased phentermine abruptly did not develop an amphetamine-like withdrawal symptom complex. Significantly we also found no evidence that long-term phentermine use induced phentermine craving.
This report is the first clinical trial conducted in which patients treated with phentermine for obesity have been examined with validated, currently used addiction medicine metrics. The study was conducted among patients in a fee-for-service obesity medicine specialty practice that has existed over two decades. Our data strongly suggest that long-term phentermine pharmacotherapy for obesity for up to 21.5 years and at doses up to 112.5 mg per day does not induce abuse or psychological dependence (addiction), that long-term phentermine pharmacotherapy does not induce phentermine drug craving, and that abrupt treatment cessation does not induce amphetamine-like withdrawal. These trial 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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Dr Hendricks has received honoraria from Akramax Pharmaceuticals, Eurodrug Laboratories, Citius Pharmaceuticals and Vivus pharmaceuticals. Dr Greenway has received honoraria from Baronova, Basic Research, Citius, Diabetic Living, Eisai, GNC, Jenny Craig, Lithera, Merck, Naturalpha, Nume Health, Orexigen, Plensat, Takeda, Thetis, Unigene and Zafgen. The remaining authors declare no conflict of interest.
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Hendricks, E., Srisurapanont, M., Schmidt, S. et al. Addiction potential of phentermine prescribed during long-term treatment of obesity. Int J Obes 38, 292–298 (2014). https://doi.org/10.1038/ijo.2013.74
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