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Home , Cathinone, Phentermine, Psychological dependence

International Journal of (2014) 38, 292–298 & 2014 Macmillan Publishers Limited All rights reserved 0307-0565/14 www.nature.com/ijo

ORIGINAL ARTICLE potential of prescribed during long-term treatment of obesity

EJ Hendricks1, M Srisurapanont2, SL Schmidt3, M Haggard1, S Souter1, CL Mitchell1, DG De Marco1, MJ Hendricks1, Y Istratiy1 and FL Greenway4

OBJECTIVE: To investigate if phentermine treatment induces phentermine , psychological dependence (addiction) or phentermine craving in overweight, obese and weight loss maintenance patients. To investigate whether -like withdrawal occurs after abrupt cessation of long-term phentermine treatment. DESIGN: Clinical intervention trial with interruption of phentermine treatment in long-term patients. SUBJECTS: 269 obese, overweight or formerly obese subjects (age: 20–88 years, BMI: 21–74 kg m À 2) treated with phentermine long-term (LTP, N ¼ 117), 1.1–21.1 years, or short-term (ATP, N ¼ 152), 4–22 days, with phentermine doses of 18.75–112.5 (LTP) and 15–93.75 (ATP) mg per day. MEASUREMENTS: Module K of the Mini International Neuropsychiatric Interview modified for phentermine (MINI-SUD), Severity of Dependence Scale (SDS), 45-item Craving Questionnaire-NOW (CCQ-NOW) modified for phentermine (PCQ-NOW), and Amphetamine Withdrawal Questionnaire (AWQ) modified for phentermine (PWQ). RESULTS: 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. CONCLUSIONS: 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.

International Journal of Obesity (2014) 38, 292–298; doi:10.1038/ijo.2013.74 Keywords: phentermine; weight loss; addiction; abuse; dependence; withdrawal

INTRODUCTION To determine whether concerns of addiction resulting from As the worldwide obesity epidemic continues unabated, phentermine treatment are reasonable, we carried out this pharmacotherapy remains an underutilized modality in treating addiction potential of phentermine prescribed during long-term obesity.1 Of course a major reason for this is that there is a treatment of obesity (APPLO) trial, which aimed to examine if paucity of approved effective , but another reason is that psychological dependence, abuse, craving and withdrawal actu- use of certain drugs has been marginalized.2 Among the older ally did occur in obese patients receiving long-term treatment drugs, approved before the US Food and Drug Administration with phentermine. (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.3–9 Although PATIENTS AND METHODS long-term, FDA-supervised, clinical trials have never been Patient recruitment conducted for phentermine, 97% of US obesity treatment Patients were recruited in two cohorts from a private fee-for-service specialists use phentermine as their agent-of-choice drug obesity medicine specialty practice. Overweight, obese and weight loss 10 maintenance patients in this practice are typically treated with antiobesity for treating obesity. The use of this drug for obesity 8,11 treatment by other physicians throughout the world has long drugs over a long term. Patients were recruited for the long-term phentermine-treated (LTP) cohort if they had been treated with been curtailed because of what we believe to be misapprehensions 2 phentermine for a minimum of 1 year, while patients for the acute- regarding phentermine safety. Concerns of phentermine-induced term phentermine (ATP) cohort were recruited after they had been on addiction and of adverse cardiovascular reactions are two fears phentermine for 7–14 days. All patients were 18 years of age or older; there that have had a profound negative impact on phentermine were no other age restrictions. Patients who had taken cumulative prescribing. phentermine drug holidays exceeding 60 days in the previous 12 months

1Center for Weight Management, Roseville, CA, USA; 2Department of Psychiatry, Chiang Mai University, Chiang Mai, Thailand; 3Department of Endocrinology, Metabolism & Diabetes, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA and 4Pennington Biomedical Research Center of the Louisiana State University System, Baton Rouge, LA, USA. Correspondence: Dr EJ Hendricks, Center for Weight Management, 2510 Douglas Boulevard, Suite 200, Roseville, CA 95661, USA. E-mail: [email protected] Received 11 February 2013; revised 7 April 2013; accepted 10 April 2013; accepted article preview online 17 May 2013; advance online publication, 11 June 2013 Investigation for phentermine dependence EJ Hendricks et al 293 or who had taken any drug holiday in the previous 30 days were excluded  The Severity of Dependence Scale (SDS),13 a four-point, Likert-type from the LTP cohort. Patients with current Axis I psychiatric diagnoses were (score 0–3), five-question psychometric scale used for assessing the included provided these were stable and under treatment. Patients with severity of was modified by replacing the word dependence on drugs other than were excluded, as phentermine ‘drug’ with ‘phentermine.’ The SDS used for the LTP patients is shown in was not prescribed for such patients. Ethical and Independent Review Table 2. The SDS used for the ATP patients was identical except the time- Services, Independence, Missouri, a commercial Independent Review frame was weeks rather than years. Board, approved the study procedures and informed consent document.  The Cocaine Craving Questionnaire NOW (CCQ-NOW), a seven-point After the risks of the study had been fully explained, all participating Likert-type (score 1–7) 45-question psychometric scale14 originally patients provided informed consent. Participants were given no remunera- developed for assessment of cocaine drug craving, but also used for tion for participation in the study; each paid the clinic’s customary fees for craving in methamphetamine-dependent subjects,15 their care without discount. Beginning in August 2011, patients newly was modified for phentermine by replacing the words ‘cocaine’ and started on phentermine were recruited for the ATP cohort as they ‘coke’ with ‘phentermine,’ to create a PCQ-NOW. appeared for follow-up examinations after 7–14 days of treatment. At the  The Amphetamine Withdrawal Questionnaire (AWQ),16 a five-point same time eligibility of returning patients for inclusion in the LTP cohort Likert-type (score 0–4), ten-question psychometric scale for assessing was determined as the patients appeared at the clinic. Those eligible were the severity of amphetamine withdrawal in addicted subjects was invited to participate. Few ATP and LTP eligible candidates declined modified to a Phentermine Withdrawal Questionnaire (PWQ) by participation. Patient demographics are detailed in Table 1. This clinical changing the word ‘amphetamine’ to ‘phentermine.’ trial is registered at clinicaltrials.gov as NCT01402674.

Examination procedures Examination schedule  The Mini International Neuropsychiatric Interview (MINI)12 is a structured ATP patients were tested once in the clinic with SDS and PCQ-NOW upon interview guide for making a DSM-IV-TR diagnosis of mental recruitment. disorders, including substance dependence and abuse. Module K, for LTP patients were tested in the clinic with MINI-SUD, SDS, PCQ-NOW and diagnosing non- psychoactive (MINI- PWQ (Day 0 or D0) upon recruitment. LTP patients were instructed to SUD), was used and modified by restricting questioning to phentermine. continue to take their usual dose of phentermine until 1 day prior to their Module K is for assessing over the 12 months prior next office visit when they were to skip their phentermine, and self- to assessment. Module K, version 5.0.0 of the MINI was modified for examine with the PWQ (D1) at B24 h after their last phentermine dose at this study. home. They were instructed to skip their phentermine again the following

Table 1. Demographic and clinical characteristics of patients

APT (N ¼ 152) LPT (N ¼ 117) Significant differencea Asked, consented, completed, (LTP) withdrawal completed 158, 152, 152 124, 117, 117, 76 Mean (s.d.) Mean (s.d.)

Age 44.18 (12.39) 51.18 (11.40) t ¼À4.757, df ¼ 267, Po0.001 BMI 34.88 (7.31) 33.79 (7.59) t ¼ 1.198, df ¼ 267, P ¼ 0.232 Days of phentermine treatment 9.30 (3.35) Years of phentermine treatment 8.35 (5.16) Rx Duration, Range (days/years) 4–22 1.1–21.5 Phentermine-HCl (mg) 34.46 (9.23) 53.43 (19.46) t ¼À9.732, df ¼ 267, Po0.001 Phentermine dose range (mg/d) 15–93.75 18.75–112.5 Number of office examinations 72.1 (51.7) Patients who had taken treatment hiatuso1 month 117 (100%) Patients who had taken treatment hiatus41 month 70 (60%) Average treatment hiatus (mo) 19.5 (19.9) N (%) N (%) Sex (female) 134 (88.2) 108 (92.3) w2 ¼ 1.261, df ¼ 1, P ¼ 0.261

Race White 138 (90.8) 103 (88.0) w2 ¼ 1.812, df ¼ 3, P ¼ 0.612 Hispanic 10 (6.6) (7.7) Black 1 (0.7) (2.6) Asia 3 (2.0) 2 (1.7) Concomitant 2 (1.3) 24 (20.5) 3 Citalopram 5 1 Duloxetine 1 Escitalopram 5 Fluoxetine 4 Paroxetine 1 Sertraline 2 Trazodone 3 1 Other antiobesity medications 0 6 (5.1) 4 Diethylpropion 2 LPT patients were older and received higher doses of phentermine. aOnly the differences of age, BMI, phentermine dose, sex and race between groups were compared.

& 2014 Macmillan Publishers Limited International Journal of Obesity (2014) 292 – 298 Investigation for phentermine dependence EJ Hendricks et al 294 day, the day of their scheduled office visit. Upon arrival at the clinic they in duration of treatment in the LTP cohort ranging from 1.1 years were again tested with the PWQ (D2) at B48 h after their last dose of to 21.1 years with a median value of 7.2 years. phentermine, after which they resumed phentermine treatment. Mini International Neuropsychiatric Interview Data analysis MINI-SUD interviews for each of the 117 LTP patients examined Mean and standard deviation were calculated for patient age, BMI, were negative for phentermine dependence or abuse. These long- phentermine dose, duration of phentermine treatment and number of term patients were well known at the clinic as indicated by the office visits. Scores for SDS, PCQ-NOW and PWQ are ordinal data. Ordinal mean number (±s.d.) of clinical examination visits for the LTP data statistical methods, including Mann–Whitney, Kruskal–Wallis, Wil- patients of 72.1 (51.7). In reviewing the LTP patient records, we coxen signed rank, and Friedman tests calculated by SPSS V17.0 ( SPSS Inc., found no suggestion that any of the LTP patients had ever Chicago, IL, USA) for Windows, were employed for statistical analysis for exhibited maladaptive drug use symptoms listed as the criteria the psychometric scale scores. 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 RESULTS significant impairment or distress as a result of their phentermine Phentermine dose and duration distribution use. The finding that 100% of the LTP MINI-SUD examinations were negative for either phentermine abuse or psychological Phentermine doses and durations of treatment are listed in dependence is consistent with the clinic’s 24 years experience in Table 1. Patients were treated variously with 15 or 30 mg capsules treating obesity with phentermine. 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 hydro- Severity of Dependence Scale chloride. As has been previously reported,8 phentermine doses for SDS data collected from the 152 ATP patients were compared with clinic patients may be adjusted over time using dose-to-effect that collected from the 117 LTP patients using the Mann–Whitney titration where the effect monitored is control of eating behavior. U test. LTP patients’ mean SDS scores were slightly higher (0.50 Because of use of this method of ‘dose-to-effect’ titration of (0.91)) than the ATP patients’ mean scores (0.42 (0.75)), but the phentermine dosage, we find average phentermine doses of clinic difference was not significant (P ¼ 0.528). The distribution of patients gradually increase with duration of treatment. Among the patients’ individual question and total scores is shown in Table 3. ATP cohort phentermine doses were: 19.1% on 15–18.75, 78.9% Note that the majority of both ATP and LTP had total scores of 0 or on 30–37.5 and 2% on greater than 37.5 mg per day. The 1 corresponding to answering never or sometimes, respectively. distribution of doses in the LTP cohort was: 41% at 18.75–37, The range of total scores among the ATP patients was 0–3. The 24.8% at 45–56.25, 30.8% at 60–75 and 3.4% at 475 mg per day. range of total scores among the LPT patients was 0–5, with one Duration of treatment among the ATP cohort varied slightly patient scoring 5 and one patient scoring 4. Examination of the with a median value of 8.0 days. More striking were the variations individual question scoring for these two subjects revealed that

Table 2. Severity of Dependence Scale—SDS.

Never/ Sometimes Often Always/ almost nearly never always

1. Do you think your use of phentermine was out of control? 0 1 2 3 2. Did the prospect of missing a dose make you anxious or worried? 0 1 2 3 3. Did you worry about your use of phentermine? 0 1 2 3 4. Did you wish you could stop? 0 1 2 3 Not Quite Very Impossible difficult difficult difficult 5. How difficult did (or would) you find it to stop or go without 0123 phentermine? The above questions are about your phentermine during the last year. Please indicate your response to each question by drawing a circle around the number in the box with your answer. The SDS is in the public domain and may be downloaded from the Alcohol and Drug Abuse Institute Library of the University of Washington: http:// adai.washington.edu/instruments/pdf/Severity_of_Dependence_Scale_397.pdf.

Table 3. Distribution of patient scores for each SDS question and SDS total for ATP and LTP patients

Scores ATP ATP ATP ATP ATP ATP LTP LTP LTP LTP LTP LTP Q1 Q2 Q3 Q4 Q5 Total Q1 Q2 Q3 Q4 Q5 Total

0 149 140 128 150 134 107 115 96 104 106 108 78 1 3 12 20 2 18 31 2 21 13 11 7 28 2 00300 9 000015 3 00100 5 000014 4 00000 0 000001 5 00000 0 000001

Values tabulated are number of patients. ATP, N ¼ 152; LTP, N ¼ 117. The sum of each column is 152 for ATP and 117 for LTP.

International Journal of Obesity (2014) 292 – 298 & 2014 Macmillan Publishers Limited Investigation for phentermine dependence EJ Hendricks et al 295 the patient with a total of 5 answered sometimes for a score of P ¼ 0.046) in which the peak and bottom-most of withdrawal 1 on each of the five SDS questions, while the patient with a total states were found on D1 and D2, respectively (Z ¼À2.50, of 4 answered sometimes, scoring 1 for questions 2, 3, 4 and 5. P ¼ 0.013). When the three PWQ component syndromes were Twenty-four of the 117 LTP or 20.5% of patients had a diagnosis compared, scores for the hyperarousal and syndromes of , and were taking an antidepressant medication were not significantly different, but the reversed vegetative when recruited as indicated in Table 1. There was no significant syndrome score was different (Friedman test, P ¼ 0.011). Again, difference in mean total SDS scores between the 24 patients the peak of withdrawal was found on D1 (Z ¼À2.478, P ¼ 0.013). on antidepressant medicines, 0.54 (1.18) and the 93 LTP patients The reversed vegetative syndrome score is a combination of three who were not, 0.49 (0.83) (Mann–Whitney U test: Z ¼À0.419, symptoms: fatigue, hyperphagia and sleepiness. Individual ques- P ¼ 0.676). tion scores for fatigue and sleepiness did not differ significantly among D0, D1 and D2 scores. Thus the hyperphagia score was the Phentermine Craving Questionnaire—NOW only PWQ question significantly different within the reversed In scoring the PCQ-NOW we followed the scoring conventions vegetative syndrome score among the D0, D1 and D2 scores suggested by Heinz et al.17 in which total a score for 41 of the 45 (P ¼ 0.027). Nine-item total PWQ scores, omitting scores for the questions is calculated and scores subtotaled for four domains. hyperphagia question, were not significantly different for D0, D1 The four domains as suggested by Heinz et al.17are: factor 1, and D2. 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 DISCUSSION are significantly lower than the corresponding scores for the ATP The results of the MINI-SUD structured interviews were unambig- patients. There was no significant difference in PCQ-NOW mean uous with no hint of either phentermine abuse or psychological total scores between the 24 patients on antidepressant medicines dependence in any LTP subject. (2.06 (0.69)) and the 93 LTP patients who were not (1.90 (0.63)) The SDS is considered a measure of compulsive drug use13 that (Mann–Whitney U test, Z ¼À0.915, P ¼ 0.360). has been used as a screening tool to identify drug users at risk for addiction.18 Total SDS scores 44 are thought to indicate Phentermine Withdrawal Questionnaire problematic amphetamine use in known amphetamine users19 LTP patients were tested with the PWQ three times. The first test requiring further investigation. Suggested SDS cutoff values for was done on a day they had taken phentermine (D0). They were other drugs are 43 for cocaine,20 and 43 for .21 Gossop also tested at B24 h after cessation (D1) and again at 48 h after et al.,13 in a study of the SDS in drug users, found that the mean cessation (D2). PWQ scoring is shown in Table 5. Ten-item PWQ SDS scores in two samples from abusers were 5.2 (5.0), total scores for D0, D1 and D2 differed significantly (Friedman test, N ¼ 222, and 8.7 (4.0), N ¼ 408. The range of values in each sample

Table 4. Scores from PCQ-NOW, a 45-item, Likert-type, psychometric scale adapted from the Cocaine Craving Questionnaire NOW of Tiffany by replacing the words ‘cocaine’ and ‘coke’ with ‘phentermine’

APT (N ¼ 152) LPT (N ¼ 117) Significant differencea

PCQ-NOW desire 1.30 (0.53) 1.17 (0.42) Z ¼À3.155, P ¼ 0.002 PCQ-NOW lack of self- efficacy 3.29 (1.29) 2.74 (1.31) Z ¼À3.549, Po0.001 PCQ-NOW relief 1.74 (0.67) 1.58 (0.66) Z ¼À2.391, P ¼ 0.017 PCQ-NOW compulsivity 2.55 (0.97) 2.13 (0.89) Z ¼À3.716, Po0.001 PCQ-NOW total 2.25 (0.71) 1.93 (0.64) Z ¼À3.668, Po0.001 Comparison of the PCQ-NOW total scores and 4 PCQ-NOW domain scores obtained from the APT (N ¼ 152) and LPT (N ¼ 117) patients. aMann–Whitney U tests (PCQ-NOW scores treated as ordinal data).

Table 5. Phentermine Withdrawal Questionnaire (PWQ) scores obtained while on phentermine (D0), one day after the last dose of phentermine (D1) and two days after the last dose of phentermine (D2)

Measure Mean PWQ score (s.d.) Significant differencea

D0 D1 D2

Total score (10 items) 3.39 (3.48) 3.55 (3.05) 2.99 (2.65) w2 ¼ 6.146, df ¼ 2, P ¼ 0.046b Hyperarousal syndrome score 0.51 (0.86) 0.43 (0.825) 0.37 (0.85) w2 ¼ 1.852, df ¼ 2, P ¼ 0.396 Anxiety syndrome score 0.57 (0.96) 0.49 (1.01) 0.43 (0.82) w2 ¼ 1.776, df ¼ 2, P ¼ 0.412 Reversed vegetative syndrome score 1.85 (2.0) 2.35 (1.72) 2.09 (1.79) w2 ¼ 8.941, df ¼ 2, P ¼ 0.011c Fatigue symptom score 0.86 (0.88) 0.91 (0.91) 0.75 (0.80) w2 ¼ 2.849, df ¼ 2, P ¼ 0.241 Hyperphagia symptom score 0.77 (0.97) 1.16 (1.02) 1.03 (1.09) w2 ¼ 7.260, df ¼ 2, P ¼ 0.027d Sleepiness symptom score 0.25 (0.59) 0.32 (0.62) 0.30 (0.67) w2 ¼ 1.000, df ¼ 2, P ¼ 0.607 nine-item PWQ total scoree 2.65 (3.01) 2.35 (2.60) 1.95 (2.38) w2 ¼ 4.962, df ¼ 2, P ¼ 0.084 aFriedman test, if significantly difference found, followed by Wilcoxon Signed Rank test. bMean D2 score significantly lower than mean D1 score (Z ¼À2.50, P ¼ 0.013). cMean D1 score significantly higher than mean D0 score (Z ¼À2.478, P ¼ 0.013). dMean D1 significantly higher than mean D0 score (Z ¼À2.829, P ¼ 0.005). ePWQ total score—PWQ hyperphagia symptom score.

& 2014 Macmillan Publishers Limited International Journal of Obesity (2014) 292 – 298 Investigation for phentermine dependence EJ Hendricks et al 296 was 0–15, the latter being the maximum possible SDS score.13 taken into account, the nine-item PWQ total scores obtained from In the same study the mean SDS scores in two cohorts of those three time points were not significantly different. amphetamine abusers were 3.7 (4.0), N ¼ 231, and 4.3 (3.2), In addition, the mean nine-item PWQ total scores on D1 (2.35) N ¼ 301. The range of values in the two amphetamine user and on D2 (1.95) were actually lower than that on D0 (2.65), which samples was 1–15 and 0–14, respectively. The mean SDS score in a were contrast to the concept of withdrawal. cohort of cocaine-using patients (N ¼ 15) was 4.2 (3.3) with a range Thus, the only amphetamine-like withdrawal symptom we of 0–13. The mean SDS scores and the range of SDS scores in our found after abrupt phentermine cessation was an increase in study patients were substantially lower than those reported for or an increase in eating. This represents a loss of amphetamine-addicted subjects. One LTP patient did have a SDS phentermine therapeutic effect rather than an amphetamine-like score of 5, scoring 1 in each of the five questions, and one LTP withdrawal symptom. As seen in Table 1, 100% of LTP subjects patient had a SDS score of 4, scoring 1 in questions 2, 3, 4 and 5. had discontinued phentermine and stayed off it for less than However, these two subjects had been patients for 10.4 and 1 month. Most of these episodes were patient initiated in an effort 13.2 years, and had negative MINI-SUD interviews; neither had to see if they could continue to lose weight or could maintain shown drug-seeking behavior nor any sign of compulsive use of a weight loss without continuing phentermine. Occasionally phentermine. The SDS individual and total question scoring in this the clinician initiated these episodes in an attempt to ascertain study is evidence that the addiction potential of phentermine is efficacy or to determine if phentermine was the cause of an vanishingly low in a clinical setting. unfavorable reaction. These patients invariably reported return of The PCQ-NOW was included as a measure of phentermine appetite, increased hunger, increased craving or increased eating, craving. Drug craving is considered a hallmark symptom of either singly or in combination. Typically weight gain slowly addiction and relapse.22,23 The CCQ-NOW has been used as a ensued within a month of phentermine cessation, but occasional measure of cocaine and other drug craving intensity in known patients reported successful weight maintenance for longer drug users.17 Addictive drugs and substances vary in their intervals. 70% of LTP patients gave a history of having addictive potential and the number of exposures required to discontinued phentermine for 41 month. The majority of these induce addiction. Variation in onset of addiction and drug craving returned after having regained weight during the hiatus. Hence, also depends on how rapidly peak drug levels are reached, and reluctance to enroll as an LTP subject was rare because these this varies by route of administration. Thus, addiction occurs patients had all tried abrupt cessation of phentermine many times, quickly with few exposures to inhaled crystal methamphetamine, knew well the symptoms that would ensue, and were unafraid of while multiple exposures are required to induce addiction to abrupt cessation because they were confident they could avoid hydrocodone via the oral route. Our rationale in comparing weight gain during a brief treatment hiatus. phentermine-craving intensity between the ATP and LTP cohorts Evidence supporting the concept that phentermine is an was that if orally-administered phentermine has any addiction addictive substance is missing in the medical literature. The potential it is of a very low order, and that one would not expect idea that phentermine has addiction potential appears to stem phentermine craving to appear after 1–2 weeks of phentermine from early work in rats25 and from the fact that phentermine treatment. We found that both total and domain subtotal is a substituted , a large group of compounds PCQ-NOW scores were significantly higher in the ATP patients with widely varying effects that includes addicting substances than in the LTP patients. This is the opposite result from the one such as methamphetamine, , MDMA (3,4-methylene- expected if long-term phentermine treatment is indeed addicting dioxymethamphetamine or ‘Ecstasy’) and DOM (2,5-dimethoxy-4- and induces phentermine craving. methylamphetamine or ‘STP’), but also compounds without addiction The AWQ is a measure of severity of the ten major symptoms potential such as (N-methyl-b-hydroxyamphetamine) found to occur in amphetamine-addicted subjects after abrupt and bupropion (3-chloro-teri-butyl-b-ketoamphetamine). cessation of amphetamine.16 The ten questions assess drug There are no published reports that orally administered craving, , , anxiety, motor retardation, phentermine treatment for obesity has been associated with agitation, fatigue, increased appetite or eating, vivid or abuse or psychological dependence (addiction) as defined by the unpleasant dreams, and craving for sleep or hypersomnia. Each DSM-IV TR. Although methamphetamine abuse, addiction and question has five possible answers ranging from ‘‘not at all’’ to withdrawal syndromes are now well described and characterized ‘very much’ with a range of scores of 0–4. AWQ total score is the in the peer-reviewed medical literature,24,26–28 no comparable total of all ten questions with a possible range of 0–40. One can syndrome for phentermine has been described. also analyze AWQ by calculating three syndrome scores: Prior to our addiction medicine study of abrupt phentermine hyperarousal syndrome, a combination of scores for drug craving, cessation in patients who had taken it long-term as treatment for agitation, and vivid or unpleasant dreams; reversed vegetative obesity,11 there were only a few reports of human studies of syndrome, combined scores for fatigue, increased appetite, and phentermine abuse liability.29–31 None of the latter studies were craving for sleep or hypersomnia; and anxiety syndrome, conducted in subjects being phentermine-treated for obesity. combined scores for anhedonia, anxiety and motor retardation. Subjects tested in a laboratory environment were found to ‘like’ In one study of the AWQ in hospitalized amphetamine abusers phentermine to varying degrees or to have subjective effects the total scores were highest at D0, then fell slightly on D1 and similar in some ways to those the same subjects experienced with again on D2.24 As seen in panel 1, page 1323, the total AWQ scores amphetamine. for the inpatients appear to be approximately D0E17, D1E15 Two reports indicated that phentermine had been found and D2E13. Also depicted are AWQ scores for a comparison in urine drug screening samples from truck drivers32 and in group of healthy nondependent individuals, which followed that hair samples from Korean drug suspects.33 In 1979, Jain et al.34 same pattern but were substantially lower: D0E3.0, D1E1.5 and had reported that 3.4% of over 10 000 urine specimens from D2E1.7. PWQ scores in LTP patients were also low and were the Los Angeles County probation department and methadone comparable to the scores of the comparison group. maintenance programs tested positive for amphetamine. and that As seen in Table 5, different PWQ scores among those obtained 1.7% of the 10 000 specimens tested positive for phentermine on D0, D1 and D2 found on the total, reversed vegetative using a gas-liquid chromatography technique.34 These reports syndrome and hyperphagia scores suggested the possibility of suggest that although apparently phentermine abuse does occur, phentermine withdrawal. However, in examining the syndrome it may be limited to subjects who abuse other . and symptom related to the withdrawal effect, hyperphagia was In a recently conducted telephone survey of 23 drug the only withdrawal symptom found. If hyperphagia was not rehabilitation centers in Kentucky these centers reported that

International Journal of Obesity (2014) 292 – 298 & 2014 Macmillan Publishers Limited Investigation for phentermine dependence EJ Hendricks et al 297 during 2010 and 2011 they had treated B24 000 patients but that phentermine are exaggerated and present a needless barrier to not one had been admitted or treated for phentermine use or better care for overweight and obese patients worldwide. 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 CONFLICT OF INTEREST hospital emergency rooms in each of 50 US states, no physician could recall ever having diagnosed or treated phentermine abuse, Dr Hendricks has received honoraria from Akramax Pharmaceuticals, Eurodrug addiction or withdrawal (personal communication, David Bryman, Laboratories, Citius Pharmaceuticals and Vivus pharmaceuticals. Dr Greenway has received honoraria from Baronova, Basic Research, Citius, Diabetic Living, Eisai, GNC, D.O., Scottsdale, Arizona). Jenny Craig, Lithera, Merck, Naturalpha, Nume Health, Orexigen, Plensat, Takeda, The drug has now been in use for more than 50 years and Thetis, Unigene and Zafgen. The remaining authors declare no conflict of interest. although a few anecdotes suggesting phentermine is abused have appeared,32–34 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 REFERENCES potential.35 Research in addiction medicine has undergone 1 Samaranayake NR, Ong KL, Leung RY, Cheung BM. in the noteworthy development since 1959. Concepts of addiction National Health and Nutrition Examination Survey (NHANES), 2007-2008. 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International Journal of Obesity (2014) 292 – 298 & 2014 Macmillan Publishers Limited