DOCSLIB.ORG

Behavioral and Neurochemical Consequences of Long-Term Intravenous Self-Administration of MDMA and Its Enantiomers by Rhesus Monkeys

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Behavioral and Neurochemical Consequences of Long-Term Intravenous Self-Administration of MDMA and Its Enantiomers by Rhesus Monkeys Neuropsychopharmacology (2004) 29, 1270–1281 & 2004 Nature Publishing Group All rights reserved 0893-133X/04 $30.00 www.neuropsychopharmacology.org Behavioral and Neurochemical Consequences of Long-Term Intravenous Self-Administration of MDMA and Its Enantiomers by Rhesus Monkeys ,1,2 3 2 2 4 William E Fantegrossi* , William L Woolverton , Michael Kilbourn , Phillip Sherman , Jie Yuan , 4 4 1 1 George Hatzidimitriou , George A Ricaurte , James H Woods and Gail Winger 1 2 Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA; Cyclotron/PET Facility, Division of Nuclear Medicine, 3 Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Psychiatry, University of Mississippi 4 Medical Center, Jackson, MS, USA; Department of Neurology, Johns Hopkins Medical Institutions, Baltimore, MD, USA The effects of self-administered 3,4-methylenedioxymethamphetamine (MDMA) on behavior and neurochemistry have not been previously studied in laboratory primates. We investigated the capacity of MDMA and its enantiomers to maintain contingent responding over an extended duration, whether any decrements in the reinforcing effects of these compounds would be observed over time, whether such decrements would be MDMA-selective, and whether any neurochemical correlates could be identified. Animals were previously trained to self-administer cocaine, then exposed to periodic substitutions of various doses of racemic MDMA and its enantiomers; full dose–effect curves were generated for each MDMA compound repeatedly over the duration of the study. After approximately 18 months of MDMA self-administration, drug exposure was halted and after at least 2 months drug abstinence, animals were scanned using positron emission tomography (PET) with the vesicular monoamine transporter (VMAT) ligand dihydro- tetrabenazine (DTBZ). Shortly thereafter, animals were euthanized, brains were dissected, and samples were assayed for brain monoamines and their metabolites using high-performance liquid chromatography (HPLC), and for VMAT using DTBZ binding. The reinforcing effects of racemic and R(À)-MDMA were reduced over a long series (months) of individual self-administration access periods; the reinforcing effects of S( þ )-MDMA were more resistant to this effect, but were attenuated for one animal. The reinforcing effects of cocaine were not altered by chronic MDMA self-administration, nor was the VMAT binding potential as assessed by PET. Further, there were no measurable decrements in serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) or VMAT in any brain regions assayed. The reinforcing effects of MDMA are selectively attenuated by chronic MDMA self-administration, although this behavioral change appears to occur in the absence of any frank neurochemical correlates of toxicity. Neuropsychopharmacology (2004) 29, 1270–1281, advance online publication, 24 March 2004; doi:10.1038/sj.npp.1300442 Keywords: MDMA; neurotoxicity; self-administration; neuroimaging; rhesus monkeys INTRODUCTION for this phenomenon have invoked several mechanisms, including loss of novelty, behavioral tolerance, and MDMA- Human ecstasy users have reported that the psychological induced neurotoxicity. With regard to this latter point, the effects of this compound seem to diminish with repeated evidence collected from multiple laboratory animal species drug exposures (Beck and Rosenbaum, 1994), a finding shows that the selective effects of MDMA on brain serotonin which may underlie the high rates (50% or higher) of (5-HT) systems can be quite extensive under particular dose spontaneous abstinence noted in several populations of regimens. For example, large or repeated doses of MDMA youths with varying levels of MDMA use, abuse, and have been shown to deplete 5-HT and its metabolite 5- dependence (von Sydow et al, 2002). Potential explanations hydroxyindoleacetic acid (5-HIAA) in primates and rats, without affecting homovanillic acid (HVA), 3-methoxy-4- *Correspondence: Dr WE Fantegrossi, Department of Pharmacology, hydroxy-phenethylene glycol (MHPG), dopamine (DA), or University of Michigan Medical School, 1150 West Medical Center norepinephrine (NE) (DeSouza et al, 1990). Drive, Ann Arbor, M1 48101-0632, USA, Tel: þ 1 734 615 7755, Fax: þ 1 734 764 7118, E-mail: [email protected] Single bolus MDMA doses as low as 5 mg/kg have been Received 29 August 2003; revised 06 February 2004; accepted 10 shown to produce 5-HT and/or 5-HIAA depletions in some February 2004 regions of the monkey brain 2 weeks later (Ricaurte et al, Online publication: 16 February 2004 at http://www.acnp.org/citations/ 2000), however, the relation of these doses to those used by Npp02160403396/default.pdf humans has been questioned (Saunders, 1995; Kish, 2002). Consequences of long-term administration of MDMA WE Fantegrossi et al 1271 Nonetheless, application of some formulae for interspecies MDMA administration to the human experience (in which scaling places some of these experimental animal doses MDMA is self-administered) must be regarded as unknown. within the range of those commonly administered by In this regard, we have been investigating the long-term humans in recreational settings (Morgan, 2000), implying maintenance of intravenous self-administration of MDMA that there may be no significant margin of safety between and its stereoisomers in rhesus monkeys. Of particular neurotoxic and recreational doses in humans (but see interest to us were the issues of whether or not any Vollenweider et al (2001) for a critique of allometric decrements in the reinforcing effects of these compounds interspecies scaling). Given that the reinforcing effects of would be observed over time, whether or not such MDMA in rhesus monkeys are mediated, at least in part, by decrements would be MDMA-selective, and whether or brain 5-HT systems (Fantegrossi et al, 2002), it seems not neurochemical correlates could be identified. The plausible to postulate that serotonergic neurotoxicity could reinforcing effects of MDMA and its enantiomers were thus alter the reinforcing effects of MDMA in this species. assessed in multiple dose–effect curve determinations over Although multiple measures of serotonergic neurotoxicity a period of approximately 18 months, and compared with (ie decreases in levels of 5-HT, 5-HIAA, 5-HT transporters, behavior maintained by a reference dose of cocaine over vesicular monoamine transporters (VMAT), measures of this same time interval in order to gauge the selectivity of anterograde transport, and tryptophan hydroxylase (TPH) any observed response decrements when MDMA was activity, as well as histological evidence of 5-HT axon available for self-administration. degeneration and the concomitant ‘pruning effect’) have Neurochemical effects of this extended MDMA self- been employed to yield evidence of MDMA-induced administration regimen were assessed by imaging VMAT neurochemical and neuroanatomical changes in laboratory via PET with [11C]dihydrotetabenazine (DTBZ). The use of animals, only rarely have these effects been correlated with DTBZ as a radioligand suitable for studying the potential behavioral deficits in drug-free animals. In this regard, neurodegeneration of monoaminergic neurons in vivo is following the standard multiple MDMA dose regimen, predicated upon this compound’s demonstrated specific alterations in the acoustic startle response (Schmidt and binding to monoaminergic terminals throughout the brain Kehne, 1990), rates of isolation calling (Winslow and Insel, (DaSilva et al, 1993). Further, VMAT may present a more 1992), reduced anxiety-like behavior in the open field and stable target than plasmalemmal proteins due to its lack of elevated plus maze assays (Mechan et al, 2002) and regulation according to varying levels of endogenous impaired thermoregulation (Miller and O’Callaghan, 1995) ligands or chronic treatment with dopaminergic drugs have been noted in rodents, although some of these effects (Vander Borght et al, 1995; Frey et al, 1997; but see have not been particularly robust. More germane to the Sandoval et al, 2003). In addition, VMAT binding has been present experiments, the discriminative stimulus effects of used to provide a highly reliable index of decreased S( þ )-MDMA (Virden and Baker, 1999) and racemic monoaminergic innervation in human striatum among MDMA (Schechter, 1991) were disrupted in the rat Parkinsonian patients (Frey et al, 1996), and has previously following a multiple dose regimen of racemic MDMA, as been shown to be sensitive to noncontingent MDMA were the rewarding effects of racemic MDMA as assessed by administration in baboons (Ricaurte et al, 2000). Following a conditioned place preference assay (Schechter, 1991). euthanasia, VMAT was also measured using radioligand However, it should be noted that similar dose regimens in binding techniques in striatal membrane preparations. the monkey have not previously been shown to produce any Finally, reverse-phase high-pressure liquid chromatography spontaneous behavioral changes in drug-free animals (HPLC) was used to measure levels of DA, 3,4-dihydroxy- (Slikker et al, 1989). Thus, at least in the primate, it appears phenylacetic acid (DOPAC), 5-HT, and 5-HIAA in post- that some neurochemical consequences of MDMA admin- mortem brain. istration can occur in the absence of obvious behavioral correlates, although behavioral consequences may be uncovered by subsequent drug challenges (Ricaurte
Load more

Recommended publications
  • Investigating Interactions Between Phentermine, Dexfenfluramine, and 5-HT2C Agonists, on Food Intake in the Rat
    Psychopharmacology DOI 10.1007/s00213-014-3829-2 ORIGINAL INVESTIGATION Investigating interactions between phentermine, dexfenfluramine, and 5-HT2C agonists, on food intake in the rat Andrew J. Grottick & Kevin Whelan & Erin K. Sanabria & Dominic P. Behan & Michael Morgan & Carleton Sage Received: 2 October 2014 /Accepted: 20 November 2014 # The Author(s) 2014. This article is published with open access at Springerlink.com Abstract Conclusions Dex-phen synergy in the rat is caused by a Rationale Synergistic or supra-additive interactions between pharmacokinetic interaction, resulting in increased central the anorectics (dex)fenfluramine and phentermine have been concentrations of phentermine. reported previously in the rat and in the clinic. Studies with 5- HT2C antagonists and 5-HT2C knockouts have demonstrated Keywords Synergy . BELVIQ® . Lorcaserin . Isobologram . dexfenfluramine hypophagia in the rodent to be mediated by Fen-phen actions at the 5-HT2C receptor. Given the recent FDA approv- al of the selective 5-HT2C agonist lorcaserin (BELVIQ®) for weight management, we investigated the interaction between Introduction phentermine and 5-HT2C agonists on food intake. Objectives This study aims to confirm dexfenfluramine- Fenfluramine (Pondimin) and dexfenfluramine (Redux) are phentermine (dex-phen) synergy in a rat food intake assay, anorectic agents which act to enhance serotonergic transmission to extend these findings to other 5-HT2C agonists, and to both through inhibition of 5-HT reuptake by the parent com- determine whether pharmacokinetic interactions could ex- pounds, and through their major circulating des-ethylated me- plain synergistic findings with particular drug combinations. tabolite, (dex)norfenfluramine, which is a 5-HT reuptake inhib- Methods Isobolographic analyses were performed in which itor, a 5-HT and noradrenaline releasing agent, and a potent phentermine was paired with either dexfenfluramine, the 5- agonist at postsynaptic 5-HT2 receptors (Curzon et al.
    [Show full text]
  • Downloaded Popular in Europe, and the “Rave” (An All Night Dance Party) from the Web [4]
    The Open Forensic Science Journal, 2011, 4, 20-24 20 Open Access A Historical Review of MDMA Steven B. Karch* Berkeley, California 94705, USA Abstract: In less than 50 years the number of MDMA (3,4-Methylenedioxymethamphetamine or Ecstasy) users in the United States has gone from zero to nearly three million. For all of its popularity, very little is known about MDMA’s probable mechanism of action, or the mechanisms by which it causes death and disability. Even less is known about this drug’s checkered past, including dangerous plans by various government agencies to “weaponize” MDMA, and misleading research sponsored and propagated by the U.S. government. Recently, evidence has begun to emerge that MDMA may cause valvular heart disease and possibly myocardial disease as well. These issues have not yet appeared on the media radar. For that reason, an historical review of this fascinating drug was undertaken here. Keywords: Ecstacy, Shulgin, history, MK-Ultra, psychoactive, serotonin, empathogen, myocardial fibrosis, neurotoxicity. MDA, Club drugs, Raves. INTRODUCTION as a precursor compound, and never even evaluated MDMA’s basic physiologic properties until years after the Estimates of the United Nations suggest that in North patent for MDMA was actually awarded. America there are approximately 2.6 million MDMA (3,4- Methylenedioxymethamphetamine or Ecstasy) users, mostly Fifteen years passed before Merck made any effort to in the United States. The annual prevalence of MDMA use systematically evaluate MDMA’s pharmacologic effects in within the general U.S. population is approximately 0.9%, animals. The first experiments were carried out in 1927.
    [Show full text]
  • 212102Orig1s000
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 212102Orig1s000 OTHER REVIEW(S) Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research | Office of Surveillance and Epidemiology (OSE) Epidemiology: ARIA Sufficiency Date: June 29, 2020 Reviewer: Silvia Perez-Vilar, PharmD, PhD Division of Epidemiology I Team Leader: Kira Leishear, PhD, MS Division of Epidemiology I Division Director: CAPT Sukhminder K. Sandhu, PhD, MPH, MS Division of Epidemiology I Subject: ARIA Sufficiency Memo for Fenfluramine-associated Valvular Heart Disease and Pulmonary Arterial Hypertension Drug Name(s): FINTEPLA (Fenfluramine hydrochloride, ZX008) Application Type/Number: NDA 212102 Submission Number: 212102/01 Applicant/sponsor: Zogenix, Inc. OSE RCM #: 2020-953 The original ARIA memo was dated June 23, 2020. This version, dated June 29, 2020, was amended to include “Assess a known serious risk” as FDAAA purpose (per Section 505(o)(3)(B)) to make it consistent with the approved labeling. The PMR development template refers to the original memo, dated June 23, 2020. Page 1 of 13 Reference ID: 46331494640015 EXECUTIVE SUMMARY (place “X” in appropriate boxes) Memo type -Initial -Interim -Final X X Source of safety concern -Peri-approval X X -Post-approval Is ARIA sufficient to help characterize the safety concern? Safety outcome Valvular Pulmonary heart arterial disease hypertension (VHD) (PAH) -Yes -No X X If “No”, please identify the area(s) of concern. -Surveillance or Study Population X X -Exposure -Outcome(s) of Interest X X -Covariate(s) of Interest X X -Surveillance Design/Analytic Tools Page 2 of 13 Reference ID: 46331494640015 1.
    [Show full text]
  • Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans
    molecules Review Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans Paul Cumming 1,2,* , Milan Scheidegger 3 , Dario Dornbierer 3, Mikael Palner 4,5,6 , Boris B. Quednow 3,7 and Chantal Martin-Soelch 8 1 Department of Nuclear Medicine, Bern University Hospital, CH-3010 Bern, Switzerland 2 School of Psychology and Counselling, Queensland University of Technology, Brisbane 4059, Australia 3 Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital of the University of Zurich, CH-8032 Zurich, Switzerland; [email protected] (M.S.); [email protected] (D.D.); [email protected] (B.B.Q.) 4 Odense Department of Clinical Research, University of Southern Denmark, DK-5000 Odense, Denmark; [email protected] 5 Department of Nuclear Medicine, Odense University Hospital, DK-5000 Odense, Denmark 6 Neurobiology Research Unit, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark 7 Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, CH-8058 Zurich, Switzerland 8 Department of Psychology, University of Fribourg, CH-1700 Fribourg, Switzerland; [email protected] * Correspondence: [email protected] or [email protected] Abstract: Hallucinogens are a loosely defined group of compounds including LSD, N,N- dimethyltryptamines, mescaline, psilocybin/psilocin, and 2,5-dimethoxy-4-methamphetamine (DOM), Citation: Cumming, P.; Scheidegger, which can evoke intense visual and emotional experiences. We are witnessing a renaissance of re- M.; Dornbierer, D.; Palner, M.; search interest in hallucinogens, driven by increasing awareness of their psychotherapeutic potential. Quednow, B.B.; Martin-Soelch, C. As such, we now present a narrative review of the literature on hallucinogen binding in vitro and Molecular and Functional Imaging ex vivo, and the various molecular imaging studies with positron emission tomography (PET) or Studies of Psychedelic Drug Action in single photon emission computer tomography (SPECT).
    [Show full text]
  • Neural Control of Dieting Counting Species Names
    SCIENTIFIC CORRESPONDENCE supersensitivity, and also by acting, via its Neural control of dieting principal metabolite ( + )norfenfluramine, as an agonist at 5-HT2c receptors and SIR - Tecott et al. 1 have shown that trans­ 100 thereby directly inducing satiety. The genic mice lacking the receptor for 0 effects of dexfenf!uramine as an anorectic the 5-hydroxytryptamine neurotransmitter 75 agent in humans are abolished by the co­ subtype 5-HT2c become obese through administration of ritanserin 7• overeating, indicating a primary role for ~ These findings emphasize the role of this receptor in the satiety response; these dr 50 5-HT2c receptors in controlling food () animals do not respond to the 5-HT2c intake and satiety, and suggest that dex­ receptor agonist m-chlorophenylpiperazine 25 fenfluramine might reset the balance 2 (mCPP). Cowen et al. emphasized that between 5-HT release and 5-HT2c recep­ antagonists for this receptor, such as cloza­ tor stimulation. Further work is required 0 pine and mianserin, cause troublesome - 5 to define how control of this receptor weight-gain in people; clozapine abolishes system parallels other, recently described, the endocrine responses to mCPP in Cytosolic calcium levels in CHO cells trans­ sytems such as glucagon-like peptide-1 fected with the human recombinant 5-HT2c 3 9 10 humans • These authors showed that diet­ receptor. The concentration-response cu rve (ref. 8) and leptin • , to modulate satiety ing may be difficult because of an imbal­ for (+)norfenfluramine for increase in intracel­ and obesity. In this respect, both the ance of brain 5-HT release and 5-HT2 c lular calcium is expressed as a percentage of leptin receptor and 5-HT2c receptors are receptors: dieting lowers plasma trypto­ the final response to 5-HT (3 µM).
    [Show full text]
  • 2015 Schmid LSD Biol Psych Athor Copy
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by edoc Schmid et al. Effects of LSD Archival report Acute effects of LSD in healthy subjects Yasmin Schmid, Florian Enzler, Peter Gasser, Eric Grouzmann, Katrin H. Preller, Franz X. Vollenweider, Rudolf Brenneisen, Felix Müller, Stefan Borgwardt, Matthias E. Liechti From Psychopharmacology Research, Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Switzerland (YS, FE, MEL), Practice for Psychiatry and Psychotherapy, Solothurn, Switzerland (PG), Biomedicine Service, University Hospital Lausanne, Lausanne, Switzerland (EG) Neuropsychopharmacology and Brain Imaging and Heffter Research Center, Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Psychiatry Zurich, Switzerland (KHP, FXV), Department of Clinical Research, University of Bern, Bern, Switzerland (RB), and Department of Psychiatry, University of Basel, Basel, Switzerland (FM, SB). Short title: Effects of LSD Address correspondence to Prof. Matthias E. Liechti, MD, Clinical Pharmacology, University Hospital Basel, Hebelstrasse 2, Basel, CH-4031, Switzerland; E-mail: [email protected]; Phone: +41 61 328 68 68; Fax: +41 61 265 45 60 Word counts: Abstract: 250; Manuscript: 3940 References : 90 Tables and Figures : Tables: 0; Figures: 6 Supplemental material online: 1 file with 3 tables and 4 figures Keywords: LSD, prepulse inhibition, subjective effects, hormones, adverse effects, sympathomimetic effects 1 Schmid et al. Effects of LSD Summary Background: After no research in humans for more than 40 years, there is renewed interest in using lysergic acid diethylamide (LSD) in clinical psychiatric research and practice. There are no modern studies on the subjective and autonomic effects of LSD and its endocrine effects are unknown.
    [Show full text]
  • Revisão Pharmacological Treatment of Obesity
    Pharmacological Treatment of Obesity revisão ABSTRACT Marcio C. Mancini This review offers an overview of physiological agents, current therapeu- Alfredo Halpern tics, as well as medications, which have been extensively used and those agents not currently available or non-classically considered anti-obesity drugs. As obesity — particularly that of central distribution — represents an important triggering factor for insulin resistance, its pharmacological treatment is relevant in the context of metabolic syndrome control. The authors present an extensive review on the criteria for anti-obesity man- agement efficacy, on physiological mechanisms that regulate central and/or peripheral energy homeostasis (nutrients, monoamines, and pep- tides), on β-phenethylamine pharmacological derivative agents (fenflu- ramine, dexfenfluramine, phentermine and sibutramine), tricyclic deriva- tives (mazindol), phenylpropanolamine derivatives (ephedrin, phenyl- propanolamine), phenylpropanolamine oxytrifluorphenyl derivative (flu- oxetine), a naftilamine derivative (sertraline) and a lipstatine derivative (orlistat). An analysis of all clinical trials — over ten-week long — is also presented for medications used in the management of obesity, as well as data about future medications, such as a the inverse cannabinoid agonist, rimonabant. (Arq Bras Endocrinol Metab 2006;50/2:377-389) Keywords: Obesity; Treatment; Anfepramone; Mazindol; Sibutramine; Endocrinology and Metabology Orlistat; Rimonabant Division, Hospital das Clínicas, University of São Paulo Medical
    [Show full text]
  • 1 441 702 B1
    (19) TZZ__Z _T (11) EP 1 441 702 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/4045 (2006.01) A61P 25/20 (2006.01) 10.05.2017 Bulletin 2017/19 A61K 9/20 (2006.01) (21) Application number: 02760523.7 (86) International application number: PCT/IL2002/000662 (22) Date of filing: 12.08.2002 (87) International publication number: WO 2003/015690 (27.02.2003 Gazette 2003/09) (54) METHOD FOR TREATING PRIMARY INSOMNIA VERFAHREN ZUR BEHANDLUNG PRIMÄRER INSOMNIA METHODE DE TRAITEMENT DE L’INSOMNIE PRIMAIRE (84) Designated Contracting States: • ROTH T ET AL: "Consensus for the AT BE BG CH CY CZ DE DK EE ES FI FR GB GR pharmacological management of insomnia in th IE IT LI LU MC NL PT SE SK TR enew millennium", INTERNATIONAL JOURNAL Designated Extension States: OF CLINICAL PRACTICE, MEDICON LT LV RO SI INTERNATIONAL, ESHER, GB, vol. 55, no. 1, 1 January 2001 (2001-01-01), page 10PAGES, (30) Priority: 14.08.2001 IL 14490001 XP002990688, ISSN: 1368-5031 • PERLIS M L ET AL: "Psychophysiological (43) Date of publication of application: insomnia: the behavioural model and a 04.08.2004 Bulletin 2004/32 neurocognitive perspective", JOURNAL OF SLEEP RESEARCH, BLACKWELL SCIENTIFIC, (60) Divisional application: OXFORD, GB, vol. 6, 1 January 1997 (1997-01-01), 16172415.8 / 3 103 443 pages 179-188, XP002990686, ISSN: 0962-1105, DOI: DOI:10.1046/J.1365-2869.1997.00045.X (73) Proprietor: NEURIM PHARMACEUTICALS (1991) • SILVA J A C E ET AL: "Special report from a LIMITED symposium held by the WHO and the World Tel Aviv 69710 (IL) Federation of sleep research societies: an overview of insomnias and related disorders - (72) Inventor: ZISAPEL, Nava recognition, epidemiology and rational 69355 Tel Aviv (IL) management", SLEEP, ALLEN PRESS, LAWRENCE, KS,US, vol.
    [Show full text]
  • Pharmacotherapies for Obesity: Past, Current, and Future Therapies
    Hindawi Publishing Corporation Journal of Obesity Volume 2011, Article ID 179674, 18 pages doi:10.1155/2011/179674 Review Article Pharmacotherapies for Obesity: Past, Current, and Future Therapies Lisa L. Ioannides-Demos, Loretta Piccenna, and John J. McNeil Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Alfred Centre, Commercial Road, Melbourne, VIC 3004, Australia Correspondence should be addressed to Lisa L. Ioannides-Demos, [email protected] Received 4 August 2010; Accepted 24 September 2010 Academic Editor: A. Halpern Copyright © 2011 Lisa L. Ioannides-Demos et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Past therapies for the treatment of obesity have typically involved pharmacological agents usually in combination with a calorie- controlled diet. This paper reviews the efficacy and safety of pharmacotherapies for obesity focusing on drugs approved for long- term therapy (orlistat), drugs approved for short-term use (amfepramone [diethylpropion], phentermine), recently withdrawn therapies (rimonabant, sibutamine) and drugs evaluated in Phase III studies (taranabant, pramlintide, lorcaserin and tesofensine and combination therapies of topiramate plus phentermine, bupropion plus naltrexone, and bupropion plus zonisamide). No current pharmacotherapy possesses the efficacy needed to produce substantial weight loss in morbidly obese patients. Meta- analyses support a significant though modest loss in bodyweight with a mean weight difference of 4.7 kg (95% CI 4.1 to 5.3 kg) for rimonabant, 4.2 kg (95% CI 3.6 to 4.8 kg) for sibutramine and 2.9 kg (95% CI 2.5 to 3.2 kg) for orlistat compared to placebo at ≥12 months.
    [Show full text]
  • The Pyramid of Recent Trials
    Endoscopic and Minimally Invasive Bariatrics: Medical Management of Obesity September 25, 2017 Judith Korner, MD, PhD Professor, Department of Medicine Division of Endocrinology Director, Weight Control Center Columbia University Medical Center Cornerstone of Weight Loss Treatment • Behavior Therapy, Diet, Exercise Long-Term Weight Loss with Non-Pharmacologic Treatment VLCD: ≤800 kcal/day BMOD: behavior + 1200kcal/day Combined: VLCD + behavior Wadden Annals of Int Med 119:688 1993 Neurohormonal Changes Associated with Weight Loss Korner & Aronne, J Clin Invest 111:565-570 (2003) A Guide to Selecting Treatment: National Institutes of Health (NIH) Guidelines* Body Mass Index (BMI) (kg/m2) Treatment 25–26.9 27–29.9 30–34.9 35–39.9 ≥40 Diet, physical activity, Yes with Yes with Yes Yes Yes behavior comorbidities comorbidities therapy Pharmaco- Yes with Yes Yes Yes therapy comorbidities Weight-loss Yes with *** Yes surgery comorbidities *Yes alone indicates that the treatment is indicated regardless of the presence or absence of comorbidities. The solid arrow signifies the point at which therapy is initiated. *** The FDA has approved use of LAGB for patients with BMI > 30 who also have at least one condition linked to obesity, such as heart disease or diabetes. NIH/NHLBI, NAASO. The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. Bethesda, Md: NIH; 2000. History of Drugs for Weight Loss • 1947: Methamphetamine Phendimetrazine (Bontril) • 1957: Phentermine (Adipex, Suprenza) • 1982: Diethylpropion
    [Show full text]
  • Boris Quednow: Brain Serotonin Function in MDMA (Ecstasy) Users
    BrainBrain serotoninserotonin functionfunction inin MDMAMDMA (( ““ecstasyecstasy ””)) usersusers Boris B. Quednow 1, Felix Hasler 1, Valerie Treyer 2, Matthias T. Wyss 2, Katharina M. Rentsch 3, Gerrit Westera 4, Schubiger PA 4, Alfred Buck 2, Franz X. Vollenweider 1 1University Hospital of Psychiatry, Zurich, Switzerland 2Department of Nuclear Medicine, University Hospital Zurich, Switzerland 3Department of Clinical Chemistry, University Hospital Zurich, Switzerland 4Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland EcstasyEcstasy • The use of Ecstasy is increasingly spreading since the end of the 1980s. • Lifetime prevalence of Ecstasy use in European adolescents and young adults is about 4-5%. • In Europe, Ecstasy is the second most popular illicit drug in adolescents and young adults following cannabis. • Over the past 15 years, in Germany and Switzerland more than 90% of the confiscated Ecstasy pills contained exclusively the substituted amphetamine derivative MDMA. • Ecstasy pills comprise of 60-65 mg MDMA on average, but with a great range (0-360 mg). SerotonergicSerotonergic neurotransmissionneurotransmission Holmes, Neurosci Biobehav 2008 MDMA SelectiveSelective serotonergicserotonergic neurotoxicityneurotoxicity ofof MDMAMDMA Sagittal plane of 5-HT immunoreaktive axons in the frontal cortex of squirrel monkeys after a treatment of 5 mg/kg MDMA 2x/die for 4 days. Control 2 weeks after MDMA 7 years after MDMA Hatzidimitriou et al., J Neurosci 1999 TheThe serotoninserotonin systemsystem
    [Show full text]
  • Introduction Obesity Is a Major Health Problem in Most Developed
    Introduction Obesity is a major health problem in most developed countries around the world. It is estimated that there are approximately 76 million obese people in the United States, thus making 1 in every 3 people obese (1). Furthermore, obesity has bee n labeled the second leading cause of preventable death (the first being smoking) in the United States, contributing to 300,000 deaths annually (1). Health problems associated with obesity primarily involve the cardiovascular system, such as hypertension, hypercholestrolemia, stroke, and myocardial infarction. Physicians are accordingly motivated to help their patients lose weight in order to minimize the impact of obesity on their health. Consequently, many diets, regimens, herbs, and drugs have been intro duced to help in this common endeavor, however none have been as potent as the combination drug therapy commonly known as "fen -phen". Two landmark studies Fen -phen is a combination of fenfluramine or dexfenfluramine (fenfluramine’s d-isomer) and phenterm ine, all of which have been individually approved by the Food and Drug Administration (FDA) as appetite suppressants for short -term use in the medical management of obesity. Fenfluramine is a serotonergic agonist that performs its action of appetite suppre ssion via the activation of serotonergic pathways in the brain, thus giving one the sensation of fullness. Fenfluramine and dexfenfluramine promote the rapid release of serotonin, inhibit its reuptake, and may have receptor-agonist activity, thus making se rotonin more susceptible to metabolism and breakdown (2). Phentermine, on the other hand, is a noradrenergic agent that interferes with the pulmonary clearance of serotonin and also helps in appetite suppression (2).
    [Show full text]