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  • The International Journal of Neuropsychopharmacology, Volume 17, Issue 2
  • February 2014, pp. 223-233

Safety and efficacy of varenicline to reduce positive subjective effects produced by methamphetamine in methamphetamine-dependent volunteers


Methamphetamine use is increasing in the US. Although there are no Food and Drug Administration (FDA)-approved medications for methamphetamine dependence, preclinical and clinical studies suggest that methamphetamine users may benefit from treatments that enhance cholinergic neurotransmission. Consequently, we determined the safety and the efficacy of varenicline treatment, a partial agonist at α4β2 and a full agonist at α7 nicotinic acetylcholine receptors, to reduce positive subjective effects produced by smoked methamphetamine. Additionally, the effects of treatment with varenicline on the cardiovascular and reinforcing effects of methamphetamine were determined. We conducted a double-blind, placebo-controlled, within-subjects trial of varenicline vs. placebo in methamphetamine-dependent volunteers who were not seeking treatment. Participants were randomly assigned to receive one dose of varenicline (0, 1, or 2 mg) po BID, titrated up to the target dose over days 1–7, during each of three separate inpatient phases. Safety measures included the frequency, duration, severity, and relatedness of adverse events reported. Positive subjective effects included ‘Any drug effect’, ‘High’, ‘Good effects’, ‘Stimulated’, and ‘Drug liking’, which were rated by participants before and for 1 h after smoking methamphetamine (0, 10, and 30 mg). There were no serious adverse events and no differences in adverse events reported during the three phases. Varenicline (2 mg) significantly reduced ratings of ‘Any drug effect’ and ‘Stimulated’, as well as attenuated ratings of ‘High’, ‘Drug liking’, and ‘Good effects’, produced by methamphetamine (30 mg). The ability of varenicline to attenuate the positive subjective effects of methamphetamine in the laboratory suggests that varenicline should continue to be explored as a treatment for methamphetamine dependence.

Corresponding author
Address for correspondence: C. D. Verrico, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, 1977 Butler Blvd. Suite E4.163, Houston, Texas 77030, USA. Tel.: (713) 791-1414 x6849Fax: (713) 794-7833Email:
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M Brensilver , KG Heinzerling , AN Swanson , D Telesca , BA Furst , SJ Shoptaw (2013) Cigarette smoking as a target for potentiating outcomes for methamphetamine abuse treatment. Drug Alcohol Rev 32:9699.

J Cohen (1988) Statistical power analysis for the behavioral science, 2nd edn.Hillsdale, NJ: L. Erlbaum Associates.

CC Cruickshank , KR Dyer (2009) A review of the clinical pharmacology of methamphetamine. Addiction 104:10851099.

R De La Garza II, JJ Mahoney III, C Culbertson , S Shoptaw , TF Newton (2008a) The acetylcholinesterase inhibitor rivastigmine does not alter total choices for methamphetamine, but may reduce positive subjective effects, in a laboratory model of intravenous self-administration in human volunteers. Pharmacol, Biochem, Behav 89:200208.

R De La Garza , S Shoptaw , TF Newton (2008b) Evaluation of the cardiovascular and subjective effects of rivastigmine in combination with methamphetamine in methamphetamine-dependent human volunteers. Int J Neuropsychopharmacol 11:729741.

R De La Garza II, T Zorick , ED London , TF Newton (2010) Evaluation of modafinil effects on cardiovascular, subjective, and reinforcing effects of methamphetamine in methamphetamine-dependent volunteers. Drug and Alcohol Depend 106:173180.

R De La Garza II, TF Newton , CN Haile , JH Yoon , CS Nerumalla , JJ Mahoney III, A Aziziyeh (2012) Rivastigmine reduces “likely to use methamphetamine” in methamphetamine-dependent volunteers. Prog Neuropsychopharmacol Biol Psychiatry 37:141146.

LK Dobbs , GP Mark (2008) Comparison of systemic and local methamphetamine treatment on acetylcholine and dopamine levels in the ventral tegmental area in the mouse. Neuroscience 156:700711.

LK Dobbs , GP Mark (2012) Acetylcholine from the mesopontine tegmental nuclei differentially affects methamphetamine induced locomotor activity and neurotransmitter levels in the mesolimbic pathway. Behav Brain Res 226:224234.

AM Elkashef , RA Rawson , AL Anderson , SH Li , T Holmes , EV Smith (2008) Bupropion for the treatment of methamphetamine dependence. Neuropsychopharmacology 33:11621170.

MW Fischman , RW Foltin (1991) Utility of subjective-effects measurements in assessing abuse liability of drugs in humans. Br J Addict 86:15631570.

T Franklin , Z Wang , JJ Suh , R Hazan , J Cruz , Y Li (2011) Effects of varenicline on smoking cue-triggered neural and craving responses. Arch Gen Psychiatry 68:516526.

AA Grace , SB Floresco , Y Goto , DJ Lodge (2007) Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci 30:220227.

M Haney , ED Collins , AS Ward , RW Foltin , MW Fischman (1999) Effect of a selective dopamine D1 agonist (ABT-431) on smoked cocaine self-administration in humans. Psychopharmacology 143:102110.

CL Hart , AS Ward , M Haney , RW Foltin , MW Fischman (2001) Methamphetamine self-administration by humans. Psychopharmacology 157:7581.

CL Hart , M Haney , SK Vosburg , E Rubin , RW Foltin (2008) Smoked cocaine self-administration is decreased by modafinil. Neuropsychopharmacology 33:761768.

T Hiranita , Y Nawata , K Sakimura , K Anggadiredja , T Yamamoto (2006) Suppression of methamphetamine-seeking behavior by nicotinic agonists. Proc Natl Acad Sci U S A 103:85238527.

T Hiranita , Y Nawata , K Sakimura , T Yamamoto (2008) Methamphetamine-seeking behavior is due to inhibition of nicotinic cholinergic transmission by activation of cannabinoid CB1 receptors. Neuropharmacology 55:13001306.

SJ Kish , KS Kalasinsky , Y Furukawa , M Guttman , L Ang , L Li (1999) Brain choline acetyltransferase activity in chronic, human users of cocaine, methamphetamine, and heroin. Mol Psychiatry 4:2632.

NK Lee , RA Rawson (2008) A systematic review of cognitive and behavioural therapies for methamphetamine dependence. Drug Alcohol Rev 27:309317.

M Longo , W Wickes , M Smout , S Harrison , S Cahill , JM White (2010) Randomized controlled trial of dexamphetamine maintenance for the treatment of methamphetamine dependence. Addiction 105:146154.

JJ Mahoney , CN Haile , TF Newton , CD Verrico , B Shapiro , R De La Garza (2013) A comparison of the subjective and cardiovascular effects produced by exposure to intravenous vs. smoked methamphetamine in the laboratory. Boston, MA: Abstract presented at the annual meeting of ASPET.

M Mameli-Engvall , A Evrard , S Pons , U Maskos , TH Svensson , JP Changeux (2006) Hierarchical control of dopamine neuron-firing patterns by nicotinic receptors. Neuron 50:911921.

MC McElhiney , JG Rabkin , R Rabkin , EV Nunes (2009) Provigil (modafinil) plus cognitive behavioral therapy for methamphetamine use in HIV+ gay men: a pilot study. Am J Drug Alcohol Abuse 35:3437.

C McGregor , M Srisurapanont , A Mitchell , W Wickes , JM White (2008) Symptoms and sleep patterns during inpatient treatment of methamphetamine withdrawal: a comparison of mirtazapine and modafinil with treatment as usual. J Subst Abuse Treat 35:334342.

TF Newton , JD Roache , R De La Garza II, T Fong , CL Wallace , SH Li (2005) Safety of intravenous methamphetamine administration during treatment with bupropion. Psychopharmacology 182:426435.

TF Newton , JD Roache , R De La Garza II, T Fong , CL Wallace , SH Li (2006) Bupropion reduces methamphetamine-induced subjective effects and cue-induced craving. Neuropsychopharmacology 31:15371544.

T Ohmori , T Abekawa , T Koyama (1995) Scopolamine prevents the development of sensitization to methamphetamine. Life Sci 56:12231229.

N Omelchenko , SR Sesack (2006) Cholinergic axons in the rat ventral tegmental area synapse preferentially onto mesoaccumbens dopamine neurons. J Comp Neurol 494:863875.

M Perez-Reyes , WR White , SA McDonald , JM Hill , AR Jeffcoat , CE Cook (1991) Clinical effects of methamphetamine vapor inhalation. Life Sci 49:953959.

JG Plebani , KG Lynch , Q Yu , HM Pettinati , CP O'Brien , KM Kampman (2012) Results of an initial clinical trial of varenicline for the treatment of cocaine dependence. Drug Alcohol Depend 121:163166.

KS Rau , E Birdsall , JE Hanson , KL Johnson-Davis , FI Carroll , DG Wilkins (2005) Bupropion increases striatal vesicular monoamine transport. Neuropharmacology 49:820830.

CR Rush , WW Stoops , JA Lile , PE Glaser , LR Hays (2011) Subjective and physiological effects of acute intranasal methamphetamine during d-amphetamine maintenance. Psychopharmacology 214:665674.

J Shearer , S Darke , C Rodgers , T Slade , I van Beek , J Lewis (2009) A double-blind, placebo-controlled trial of modafinil (200 mg/day). for methamphetamine dependence. Addiction 104:224233.

S Shoptaw , KG Heinzerling , E Rotheram-Fuller , T Steward , J Wang , AN Swanson (2008) Randomized, placebo-controlled trial of bupropion for the treatment of methamphetamine dependence. Drug Alcohol Depend 96:222232.

D Siegal , J Erickson , H Varoqui , L Ang , KS Kalasinsky , FJ Peretti (2004) Brain vesicular acetylcholine transporter in human users of drugs of abuse. Synapse 52:223232.

M Sofuoglu , S Brown , DA Babb , PR Pentel , DK Hatsukami (2000) Carvedilol affects the physiological and behavioral response to smoked cocaine in humans. Drug Alcohol Depend 60:6976.

Substance Abuse and Mental Health Services Administration (2011) Treatment episode data set (TEDS) 1999–2009. Rockville, MD: National Admissions to Substance Abuse Treatment Services, DASIS Series: S-56, HHS Publication No. (SMA) 11-4646.

Substance Abuse and Mental Health Services Administration (2012) Results from the 2011 national survey on drug use and health: summary of national findings. Rockville, MD: NSDUH Series H-44, HHS Publication No (SMA)12-4713.

K Taguchi , J Atobe , M Kato , T Chuma , T Chikuma , T Shigenaga (1998) The effect of methamphetamine on the release of acetylcholine in the rat striatum. Eur J Pharmacol 360:131137.

J Tiihonen , K Kuoppasalmi , J Fohr , P Tuomola , O Kuikanmaki , H Vorma (2007) A comparison of aripiprazole, methylphenidate, and placebo for amphetamine dependence. Am J Psychiatry 164:160162.

ND Volkow , L Chang , GJ Wang , JS Fowler , M Leonido-Yee , D Franceschi (2001) Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiatry 158:377382.

ND Volkow , GJ Wang , Y Ma , JS Fowler , C Wong , YS Ding (2005) Activation of orbital and medial prefrontal cortex by methylphenidate in cocaine-addicted subjects but not in controls: relevance to addiction. J Neurosci 25:39323939.

ND Volkow , JS Fowler , J Logan , D Alexoff , W Zhu , F Telang (2009) Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. JAMA 301:11481154.

GJ Wang , L Smith , ND Volkow , F Telang , J Logan , D Tomasi (2012) Decreased dopamine activity predicts relapse in methamphetamine abusers. Mol Psychiatry 17:918925.

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