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Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse

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Abstract

Introduction

Individuals seeking treatment for their marijuana use rarely achieve sustained abstinence.

Objectives

The objectives of the study are to determine if THC, a cannabinoid agonist, and lofexidine, an α2-adrenergic receptor agonist, given alone and in combination, decreased symptoms of marijuana withdrawal and relapse, defined as a return to marijuana use after a period of abstinence.

Materials and methods

Nontreatment-seeking, male volunteers (n = 8), averaging 12 marijuana cigarettes/day, were maintained on each of four medication conditions for 7 days: placebo, tetrahydrocannabinol (THC) (60 mg/day), lofexidine (2.4 mg/day), and THC (60 mg/day) combined with lofexidine (2.4 mg/day); each inpatient phase was separated by an outpatient washout phase. During the first three inpatient days, placebo marijuana was available for self-administration (withdrawal). For the next 4 days, active marijuana was available for self-administration (relapse). Participants paid for self-administered marijuana using study earnings. Self-administration, mood, task performance, food intake, and sleep were measured.

Results

THC reversed the anorexia and weight loss associated with marijuana withdrawal, and decreased a subset of withdrawal symptoms, but increased sleep onset latency, and did not decrease marijuana relapse. Lofexidine was sedating, worsened abstinence-related anorexia, and did not robustly attenuate withdrawal, but improved sleep and decreased marijuana relapse. The combination of lofexidine and THC produced the most robust improvements in sleep and decreased marijuana withdrawal, craving, and relapse in daily marijuana smokers relative to either medication alone.

Conclusions

These data suggest the combination of lofexidine and THC warrant further testing as a potential treatment for marijuana dependence.

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References

  • Ajilore O, Stickgold R, Rittenhouse CD, Hobson JA (1995) Nightcap: laboratory and home-based evaluation of a portable sleep monitor. Psychophysiology 32:92–98

    Article  PubMed  CAS  Google Scholar 

  • Anggadiredja K, Yamaguchi T, Tanaka H, Shoyama Y, Watanabe S, Yamamoto T (2003) Prostaglandin E2 attenuates SR141716A-precipitated withdrawal in tetrahydrocannabinol-dependent mice. Brain Res 966:47–53

    Article  PubMed  CAS  Google Scholar 

  • Anthony JC, Warner LA, Kessler RC (1994) Comparative epidemiology of dependence on tobacco, alcohol, controlled substances and inhalants: basic findings from the National Comorbidity Survey. Exp Clin Psychopharmacol 2:244–268

    Article  Google Scholar 

  • Balerio GN, Aso E, Berrendero F, Murtra P, Maldonado R (2004) Delta9-tetrahydrocannabinol decreases somatic and motivational manifestations of nicotine withdrawal in mice. Eur J Neurosci 20:2737–2748

    Article  PubMed  Google Scholar 

  • Bearn J, Gossop M, Strang J (1996) Randomized double-blind comparison of lofexidine and methadone in the in-patient treatment of opiate withdrawal. Drug Alcohol Depend 43:87–91

    Article  PubMed  Google Scholar 

  • Bearn J, Gossop M, Strang J (1998) Accelerated lofexidine treatment regimen compared with conventional lofexidine and methadone treatment for inpatient opiate detoxification. Drug Alcohol Depend 50:227–232

    Article  PubMed  CAS  Google Scholar 

  • Beswick T, Best D, Rees S, Bearn J, Gossop M, Strang J (2003) Major disruptions of sleep during treatment of the opiate withdrawal syndrome: differences between methadone and lofexidine detoxification treatments. Addict Biol 8:49–57

    Article  PubMed  CAS  Google Scholar 

  • Boyd S, Gorelick D, Huestis M, Heishman S, Dermand JC, Nides MA et al (2002) Prevalence and persistence of withdrawal symptoms reported by a non-treatment sample of marijuana smokers. Drug Alcohol Depend 66:S19

    Google Scholar 

  • Brower KJ, Aldrich MS, Hall JM (1998) Polysomnographic and subjective sleep predictors of alcoholic relapse. Alcohol Clin Exp Res 22:1864–1871

    PubMed  CAS  Google Scholar 

  • Budney AJ, Radonovich KJ, Higgins ST, Wong CJ (1998) Adults seeking treatment for marijuana dependence: A comparison with cocaine-dependent treatment seekers. Exp Clin Psychopharmacology 6:419–426

    Article  CAS  Google Scholar 

  • Budney AJ, Novy PL, Hughes JR (1999) Marijuana withdrawal among adults seeking treatment for marijuana dependence. Addiction 94:1311–1321

    Article  PubMed  CAS  Google Scholar 

  • Budney AJ, Hughes JR, Moore BA, Novy PL (2001) Marijuana abstinence effects in marijuana smokers maintained in their home environment. Arch Gen Psychiatry 58:917–924

    Article  PubMed  CAS  Google Scholar 

  • Budney AJ, Moore BA, Vandrey RA, Hughes JR (2002) Onset, magnitude, and duration of abstinence effects following heavy marijuana use. Drug Alcohol Depend 66:S23

    Google Scholar 

  • Budney AJ, Hughes JR, Moore BA, Vandry R (2004) Review of the validity and significance of the cannabis withdrawal syndrome. Am J Psychiatry 11:1967–1977

    Article  Google Scholar 

  • Budney AJ, Vandrey RG, Hughes JR, Moore BA, Bahrenburg B (2007) Oral delta-9 tetrahydrocannabinol suppresses cannabis withdrawal symptoms. Drug Alcohol Depend 86:22–29

    Article  PubMed  CAS  Google Scholar 

  • Carter AJ (1997) Hippocampal noradrenaline release in awake, freely moving rats is regulated by alpha-2 adrenoceptors but not by adenosine receptors. J Pharmacol Exp Ther 281:648–654

    PubMed  CAS  Google Scholar 

  • Compton WM, Grant BF, Colliver JD, Glantz MD, Stinson FS (2004) Prevalence of marijuana use disorders in the United States: 1991–1992 and 2001–2002. JAMA 291:2114–2121

    Article  PubMed  CAS  Google Scholar 

  • Copeland J, Swift W, Roffman R, Stephens R (2001) A randomized controlled trial of brief cognitive-behavioral interventions for cannabis use disorder. J Subst Abuse Treatment 21:55–64

    Article  CAS  Google Scholar 

  • Covey LS, Sullivan MA, Johnston JA, Glassman AH, Robinson MD, Adams DP (2000) Advances in non-nicotine pharmacotherapy for smoking cessation. Drugs 59:17–31

    Article  PubMed  CAS  Google Scholar 

  • Dole VP (1988) Implications of methadone maintenance on theories of narcotic addiction. JAMA 260:3025–3029

    Article  PubMed  CAS  Google Scholar 

  • Donny EC, Dierker LC (2007) The absence of DSM-IV nicotine dependence in moderate-to-heavy daily smokers. Drug Alcohol Depend 89:93–96

    Article  PubMed  CAS  Google Scholar 

  • Evans SM, Foltin RW, Levin FR, Fischman MW (1995) Behavioral and subjective effects of DN-2327 (pazinaclone) and alprazolam in normal volunteers. Behav Pharmcol 6:176–186

    CAS  Google Scholar 

  • Foltin RW, Fischman MW, Pedroso JJ, Pearlson GD (1987) Marijuana and cocaine interactions in humans: cardiovascular consequences. Pharmacol Biochem Behavior 28:459–464

    Article  CAS  Google Scholar 

  • Foltin RW, Haney M, Comer SD, Fischman MW (1996) Effects of fenfluramine in food intake, mood, and performance of humans living in a residential laboratory. Physiol Behav 59:295–305

    Article  PubMed  CAS  Google Scholar 

  • Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW (1999a) Abstinence symptoms following oral THC administration to humans. Psychopharmacology 141:385–394

    Article  PubMed  CAS  Google Scholar 

  • Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW (1999b) Abstinence symptoms following smoked marijuana in humans. Psychopharmacology 141:395–404

    Article  PubMed  CAS  Google Scholar 

  • Haney M, Ward AS, Comer SD, Hart CL, Foltin RW, Fischman MW (2001) Bupropion SR worsens mood during marijuana withdrawal in humans. Psychopharmacology 155:171–179

    Article  PubMed  CAS  Google Scholar 

  • Haney M, Hart CL, Ward AS, Foltin RW (2003) Nefazodone decreases anxiety during marijuana withdrawal in humans. Psychopharmacology 165:157–165

    PubMed  CAS  Google Scholar 

  • Haney M, Hart CL, Vosburg SK, Nasser J, Bennett A, Zubaran C et al (2004) Marijuana withdrawal in humans: effects of oral THC or Divalproex. Neuropsychopharmacology 29:158–170

    Article  PubMed  CAS  Google Scholar 

  • Hart CL (2005) Increasing treatment options for cannabis dependence: a review of potential pharmacotherapies. Drug Alcohol Depend 80:147–159

    Article  PubMed  CAS  Google Scholar 

  • Hart C, Ward AS, Haney M, Comer SD, Foltin RW, Fischman MW (2002) Comparison of smoked marijuana and oral d9-tetrahydrocannabinol in humans. Psychopharmacology 164:407–415

    Article  PubMed  CAS  Google Scholar 

  • Herman BH, O’Brien CP (1997) Clinical medications development for opiate addiction: focus on nonopioids and opioid antagonists for the amelioration of opiate withdrawal symptoms and relapse prevention. Semin Neurosci 9:158–172

    Article  CAS  Google Scholar 

  • Kahn A, Mumford JP, Rogers GA, Beckford H (1997) Double-blind study of lofexidine and clonidine in the detoxification of opiate addicts in hospital. Drug Alcohol Depend 44:57–61

    Article  PubMed  CAS  Google Scholar 

  • Kouri EM, Pope HG Jr (2000) Abstinence symptoms during withdrawal from chronic marijuana use. Exp Clin Psychopharm 8:483–492

    Article  CAS  Google Scholar 

  • Lang E, Engelander M, Brooke T (2000) Report of an integrated brief intervention with self-defined problem cannabis users. J Subst Abuse Treat 19:111–116

    Article  PubMed  CAS  Google Scholar 

  • Levin FR, McDowell D, Evans SM, Nunes E, Akerele E, Donovan S et al (2004) Pharmacotherapy for marijuana dependence: a double-blind, placebo-controlled pilot study of divalproex sodium. Am J Addict 13:21–32

    Article  PubMed  Google Scholar 

  • Lichtman AH, Fisher J, Martin BR (2001) Precipitated cannabinoid withdrawal is reversed by Delta(9)-tetrahydrocannabinol or clonidine. Pharmacol Biochem Behav 69:181–188

    Article  PubMed  CAS  Google Scholar 

  • Lin SK, Strang J, Su LW, Tsai CJ, Hu WH (1997) Double-blind randomised controlled trial of lofexidine versus clonidine in the treatment of heroin withdrawal. Drug Alcohol Depend 48:127–133

    Article  PubMed  CAS  Google Scholar 

  • Moore BA, Budney AJ (2003) Relapse in outpatient treatment for marijuana dependence. J Subst Abuse Treat 25:85–89

    Article  PubMed  Google Scholar 

  • Roffman RA, Stephens RS, Simpson EE, Whitaker DL (1988) Treatment of marijuana dependence: preliminary results. J Psychoactive Drugs 20:129–137

    PubMed  CAS  Google Scholar 

  • Shaham Y, Shalev U, Lu L, De Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168:3–20

    Article  PubMed  CAS  Google Scholar 

  • Shiffman S, Johnston JA, Khayrallah M, Elash CA, Gwaltney CJ, Paty JA et al (2000) The effect of bupropion on nicotine craving and withdrawal. Psychopharmacology 148:33–40

    Article  PubMed  CAS  Google Scholar 

  • Sinha R, Kimmerling A, Doebrick C, Kosten TR (2007) Effects of lofexidine on stress-induced and cue-induced opioid craving and opioid abstinence rates: preliminary findings. Psychopharmacology 190:569–574

    Article  PubMed  CAS  Google Scholar 

  • Stephens RS, Roffman RA, Simpson EE (1993) Adult marijuana users seeking treatment. J Consult Clin Psychology 61:1100–1104

    Article  CAS  Google Scholar 

  • Stephens RS, Roffman RA, Simpson EE (1994) Treating adult marijuana dependence: a test of the relapse prevention model. J Consult Clin Psychology 62:92–99

    Article  CAS  Google Scholar 

  • Stephens RS, Roffman RA, Curtin L (2000) Extended versus brief treatment for marijuana use. J Consult Clin Psychology 68:898–908

    Article  CAS  Google Scholar 

  • Strang J, Bearn J, Gossop M (1999) Lofexidine for opiate detoxification: review of recent randomized and open controlled trials. Am J Addict 8:337–348

    Article  PubMed  CAS  Google Scholar 

  • The Consensus Committee of the American Autonomic Society and the American Academy of Neurology (1996) Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. Neurology 46:1470

    Google Scholar 

  • Uhde TW, Redmond DE Jr, Kleber HD (1980) Clonidine suppresses the opioid abstinence syndrome without clonidine-withdrawal symptoms: a blind inpatient study. Psychiatry Res 2:37–47

    Article  PubMed  CAS  Google Scholar 

  • Yu E, Herman BH, Miotto K, Montgomery A, Fudala PJ, Fisher C et al (2000) In-patient safety evaluation of lofexidine, an alpha-2 adrenergic agonist, as a medication for opiate withdrawal. NIDA Research Monograph 180:227

    Google Scholar 

Download references

Acknowledgment

The U.S. National Institute on Drug Abuse (NIDA) supported this research (DA19239). We also thank NIDA for supplying the marijuana cigarettes and US WorldMeds for supplying the lofexidine. We are grateful to Brooke Roe, Diana Paksarian, Michael Rubin, and Liah Barnett for their superb assistance in data collection.

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Authors and Affiliations

  1. Division on Substance Abuse, New York State Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons of Columbia University, 1051 Riverside Drive, Unit 120, New York, NY, 10032, USA

    Margaret Haney, Carl L. Hart, Suzanne K. Vosburg, Sandra D. Comer, Stephanie Collins Reed & Richard W. Foltin

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  1. Margaret Haney
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  2. Carl L. Hart
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  3. Suzanne K. Vosburg
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  4. Sandra D. Comer
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  5. Stephanie Collins Reed
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  6. Richard W. Foltin
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Correspondence to Margaret Haney.

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Haney, M., Hart, C.L., Vosburg, S.K. et al. Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse. Psychopharmacology 197, 157–168 (2008). https://doi.org/10.1007/s00213-007-1020-8

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  • DOI: https://doi.org/10.1007/s00213-007-1020-8

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