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Lithium carbonate in the management of cannabis withdrawal: a randomized placebo-controlled trial in an inpatient setting

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Abstract

Rationale

Preclinical studies suggest that lithium carbonate (lithium) can reduce precipitated cannabinoid withdrawal in rats by stimulating release of the neuropeptide oxytocin, while two open-label studies indicate lithium may ameliorate cannabis withdrawal symptoms in humans.

Objectives

This study was conducted to examine the efficacy and safety of lithium in the inpatient management of cannabis withdrawal and to determine whether lithium affects plasma oxytocin and the rate of elimination of plasma cannabinoids during abstinence.

Methods

Treatment-seeking cannabis-dependent adults (n = 38) were admitted for 8 days to an inpatient withdrawal unit and randomized to either oral lithium (500 mg) or placebo given twice a day under double-blind randomized controlled trial (RCT) conditions. Primary outcomes included withdrawal severity [cannabis withdrawal scale (CWS)], rates of detoxification completion, and adverse events. Plasma cannabinoids, plasma oxytocin and serum lithium levels were measured repeatedly over admission. Follow-up research interviews were conducted at 14, 30, and 90 days postdischarge.

Results

Lithium did not significantly affect total CWS scores relative to placebo, although it significantly reduced individual symptoms of “loss of appetite,” “stomach aches,” and “nightmares/strange dreams.” No significant group differences were found in treatment retention or adverse events. Lithium did not increase plasma oxytocin levels nor influence the rate of elimination of cannabinoids. Both placebo- and lithium-treated participants showed reduced levels of cannabis use (verified by urinalysis) and improved health and psychosocial outcomes at 30- and 90-day follow-up relative to pretreatment baselines.

Conclusions

Despite the strong rationale for the present study, the efficacy of lithium over placebo in the management of cannabis withdrawal was not demonstrated.

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References

  • AIHW (2012) Alcohol and other drug treatment services in Australia 2010–11: report on the national minimum data set drug treatment series no 18. Australian Institute of Health and Welfare, Canberra

    Google Scholar 

  • Allsop DJ, Norberg MM, Copeland J, Fu S, Budney AJ (2011) The cannabis withdrawal scale development: patterns and predictors of cannabis withdrawal and stress. Drug Alcohol Depend 119:123–129

    Article  PubMed  Google Scholar 

  • Allsop DJ, Copeland J, Norberg MM, Fu S, Molnar A, Lewis J, Budney AJ (2012) Quantifying the clinical significance of cannabis withdrawal. PLoS ONE 7:e44864

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Allsop DJ, Dunlop AJ, Sadler C, Rivas GR, McGregor I, Copeland J (2014a) Changes in cigarette and alcohol use during cannabis abstinence. Drug Alcohol Depend 138:54–60

    Article  CAS  PubMed  Google Scholar 

  • Allsop DJ, Copeland J, Lintzeris N, Dunlop AJ, Montebello M, Sadler C, Rivas GR, Holland RM, Muhleisen P, Norberg MM, Booth J, McGregor I (2014b) A randomized controlled trial of nabiximols (Sativex®) as an agonist replacement therapy during cannabis withdrawal. JAMA Psychiatry 71(3):281–291

    Article  CAS  PubMed  Google Scholar 

  • American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, 4th edn, text rev. American Psychiatric Association, Washington, DC

    Google Scholar 

  • Bell ML, Fairclough DL (2013) Practical and statistical issues in missing data for longitudinal patient reported outcomes. Stat Methods Med Res 19 February 2013

  • Bergamaschi MM, Karschner EL, Goodwin RS, Scheidweiler KB, Hirvonen J, Queiroz RH, Huestis MA (2013) Impact of prolonged cannabinoid excretion in chronic daily cannabis smokers’ blood on per se drugged driving laws. Clin Chem 59:519–526

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bowen R, McIlwrick J, Baetz M, Zhang X (2005) Lithium and marijuana withdrawal. Can J Psychiatry 50:240–241

    PubMed  Google Scholar 

  • Budney AJ, Moore BA et al (2003) The time course and significance of cannabis withdrawal. J Abnorm Psychol 112(3):393–402

    Article  PubMed  Google Scholar 

  • Carson DS, Bosanquet DP, Carter CS, Pournajafi-Nazarloo H, Blaszczynski A, McGregor IS (2012) Preliminary evidence for lowered basal cortisol in a naturalistic sample of methamphetamine polydrug users. Exper Clin Psychopharmacol 20:497–503

  • Caswell A (2005) MIMS annual 2005. CMPMedica, Sydney

    Google Scholar 

  • Copeland J, Swift W (2009) Cannabis use disorder: epidemiology and management. Int Rev Psychiatry 21:96–103

    Article  PubMed  Google Scholar 

  • Copeland J, Gilmour S, Gates P, Swift W (2005) The cannabis problems questionnaire: factor structure, reliability, and validity. Drug Alcohol Depend 80:313–319

    Article  PubMed  Google Scholar 

  • Copersino ML, Boyd SJ, Tashkin DP, Huestis MA, Heishman SJ, Dermand JC, Simmons MS, Gorelick DA (2006) Cannabis withdrawal among non-treatment-seeking adult cannabis users. Am J Addict 15:8–14

    Article  PubMed  Google Scholar 

  • Cui S, Bowen RC, Gu G, Hannesson DK, Yu PH, Zhang X (2001) Prevention of cannabinoid withdrawal syndrom by lithium: involvement of oxytocinergic neuronal activation. J Neurosci 21:9867–9876

    CAS  PubMed  Google Scholar 

  • Danovitch I, Gorelick DA (2012) State of the art treatments for cannabis dependence. Psychiatr Clin North Am 35:309–326

    Article  PubMed Central  PubMed  Google Scholar 

  • EMCDDA (2012) Annual Report 2012: the state of the drugs problem. European Monitoring Centre for Drugs and Drug Addiction, Luxembourg

  • Gossop M, Darke S, Griffiths P, Hando J, Powis B, Hall W, Strang J (1995) The severity of dependence scale (SDS): psychometric properties of the SDS in English and Australian samples of heroin, cocaine and amphetamine users. Addiction 90:607–614

    Article  CAS  PubMed  Google Scholar 

  • Grandjean EM, Aubry JM (2009) Lithium: updated human knowledge using an evidence-based approach: Part III. Clinical safety. CNS Drugs 23:397–418

    Article  CAS  PubMed  Google Scholar 

  • Haney M, Cooper ZD, Bedi G, Vosburg SK, Comer SD, Foltin RW (2013) Nabilone decreases marijuana withdrawal and a laboratory measures of marijuana relapse. Neuropsychopharmacology 2013 Feb 26

  • Hasin DS, Keyes KM, Alderson D, Wang S, Aharonovich E, Grant BF (2008) Cannabis withdrawal in the United States: results from NESARC. J Clin Psychiatry 69:1354–1363

    Article  PubMed Central  PubMed  Google Scholar 

  • Kagerbauer SM, Martin J, Schuster T, Blobner M, Kochs EF, Landgraf R (2013) Plasma oxytocin and vasopressin do not predict neuropeptide concentrations in human cerebrospinal fluid. J Neuroendocrinol 25:668–673

    Article  CAS  PubMed  Google Scholar 

  • Karschner EL, Schwilke EW, Lowe RH, Darwin WD, Herning RI, Cadet JL, Huestis MA (2009) Implications of plasma Delta9-tetrahydrocannabinol, 11-hydroxy-THC, and 11-nor-9-carboxy-THC concentrations in chronic cannabis smokers. J Anal Toxicol 33:469–477

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Keck PE Jr, McElroy SL (2002) Clinical pharmacodynamics and pharmacokinetics of antimanic and mood-stabilizing medications. J Clin Psychiatry 63(Suppl 4):3–11

    CAS  PubMed  Google Scholar 

  • Levin FR, Mariani J, Brooks DJ, Pavlicova M, Nunes EV, Agosti V, Bisaga A, Sullivan MA, Carpenter KM (2013) A randomized double-blind, placebo-controlled trial of venlafaxine-extended release for co-ocurring cannabis dependence and depressive disorders. Addiction 108:1084–1094

    Article  PubMed Central  PubMed  Google Scholar 

  • Lovibond SH, Lovibond PF (1995) Manual for the depression anxiety and stress scales, 2nd edn. Psychology Foundation, Sydney

    Google Scholar 

  • Maddock C, Babbs M (2006) Interventions for cannabis misuse. Adv Psychiatr Treat 12:432–439

    Article  Google Scholar 

  • Mallinckrodt CH, Clark SW, Carroll RJ, Molenbergh G (2003) Assessing response profiles from incomplete longitudinal clinical trial data under regulatory considerations. J Biopharm Stat 13:179–190

    Article  PubMed  Google Scholar 

  • Martin G, Copeland J, Gates P, Gilmore S (2006) The severity of dependence scale (SDS) in an adolescent population of cannabis users: reliability, validity and diagnostic cut-off. Drug Alcohol Depend 83:90–93

    Article  PubMed  Google Scholar 

  • Mason BJ, Crean R et al (2012) A proof-of-concept randomized controlled study of gabapentin: effects on cannabis use, withdrawal and executive function deficits in cannabis-dependent adults. Neuropsychopharmacology 37(7):1689–1698

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McCullough ME, Churchland PS, Mendez AJ (2013) Problems with measuring peripheral oxytocin: can the data on oxytocin and human behavior be trusted? Neurosci Biobehav Rev 37:1485–1492

    Article  CAS  PubMed  Google Scholar 

  • McGregor IS, Bowen MT (2012) Breaking the loop: oxytocin as a potential treatment for drug addiction. Horm Behav 61:331–339

    Article  CAS  PubMed  Google Scholar 

  • McGregor IS, Callaghan PD, Hunt GE (2008) From ultrasocial to antisocial: a role for oxytocin in the acute reinforcing effects and long-term adverse consequences of drug use? Br J Pharmacol 154:358–368

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McRae-Clark AL, Carter RE, Killeen T, Carpenter MJ, Wahlquist AE, Simpson SA, Brady KT (2009) A placebo-controlled trial of buspirone for the treatment of marijuana dependence. Drug Alcohol Depend 105:132–138

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McRae-Clark AL, Baker NL, Maria MM, Brady KT (2013) Effect of oxytocin on craving and stress response in marijuana-dependent individuals: a pilot study. Psychopharmacology (Berl) 228:623–631

    Article  CAS  Google Scholar 

  • Pedersen CA, Smedley KL, Leserman J, Jarskog LF, Rau SW, Kampov-Polevoi A, Casey RL, Fender T, Garbutt JC (2013) Intranasal oxytocin blocks alcohol withdrawal in human subjects. Alcohol Clin Exp Res 37:484–489

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Preuss UW, Watzke AB et al (2010) Cannabis withdrawal severity and short-term course among cannabis-dependent adolescent and young adult inpatients. Drug Alcohol Depend 106(2–3):133–141

    Article  CAS  PubMed  Google Scholar 

  • Quality Metric (2002) Short form (SF) — 12 version 2. Quality Metric, Lincoln, RI

    Google Scholar 

  • Ramaekers JG, Kauert G et al (2009) Neurocognitive performance during acute THC intoxication in heavy and occasional cannabis users. J Psychopharmacol 23(3):266–277

    Article  CAS  PubMed  Google Scholar 

  • Rubin D (1976) Inference and missing data. Biometrika 63:581–592

    Article  Google Scholar 

  • SAMHSA (2009) Treatment episode data set (TEDS): 1997–2007. National admissions to substance abuse treatment services. Substance Abuse and Mental Health Services Administration Office of Applied Studies, Rockville, MD

  • Saunders JB, Aasland OG, Babor TF, de la Puente JR, Grant M (1993) Development of the alcohol use disorders screening test (AUDIT). WHO collaborative project on early detection of persons with harmful alcohol consumption. Addiction 88:791–804

    Article  CAS  PubMed  Google Scholar 

  • Schafer JL (1999) Multiple imputation: a primer. Stat Methods Med Res 8:3–15

    Article  CAS  PubMed  Google Scholar 

  • Szeto A, McCabe PM, Nation DA, Tabak BA, Rossetti MA, McCullough ME, Schneiderman N, Mendez AJ (2011) Evaluation of enzyme immunoassay and radioimmunoassay methods for the measurement of plasma oxytocin. Psychosom Med 73:393–400

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Thams P, Geisler A (1980) Dissociation by lithium of hormone-induced formation of cyclic AMP and release of glycerol in isolated rat fat cells. Acta Pharmacol Toxicol (Copenh) 46:382–387

    Article  CAS  Google Scholar 

  • UNODC (2011) World Drug Report United Nations Publications, No E 11 XI 10. United National Office of Drugs and Crime, Vienna

  • Weinstein AM, Gorelick DA (2011) Pharmacological treatment of cannabis dependence. Curr Pharm Des 17:1351–1358

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • WHO (2000) Australian WHOQOL-100, WHOQOL-BREF and CA-WHOQOL instruments: user’s manual and interpretation guide (the WHOQOL study). Melbourne WHOQOL Field Study Centre, University of Melbourne Department of Psychiatry, St Vincent’s Mental Health Service, Melbourne

  • WHO (2004) The World Health Organization quality of life (WHOQOL) — BREF. WHO, Geneva

    Google Scholar 

  • Winstock A, Lea T, Copeland J (2009) Lithium carbonate in the management of cannabis withdrawal in humans: an open-label study. J Psychopharmacol (Oxf) 23:84–93

    Article  CAS  Google Scholar 

  • Zaragosi LE, Wdziekonski B, Fontaine C, Villageois P, Peraldi P, Dani C (2008) Effects of GSK3 inhibitors on in vitro expansion and differentiation of human adipose-derived stem cells into adipocytes. BMC Cell Biol 9:11

    Article  PubMed Central  PubMed  Google Scholar 

  • Zhang P (2003) Multiple imputation: theory and method. Int Stat Rev 71:581–592

    Article  Google Scholar 

  • Zhang G, Zhang Y, Fast DM, Lin Z, Steenwyk R (2011) Ultra sensitive quantitation of endogenous oxytocin in rat and human plasma using a two-dimensional liquid chromatography-tandem mass spectrometry assay. Anal Biochem 416:45–52

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was funded by the National Health and Medical Research Council (NHMRC Project Grant 556301) and sponsored by The University of Sydney, Camperdown, NSW, Australia. The NHMRC played no role in the design of the study, collection, and analysis of data nor the decision to publish. The authors declare no conflict of interest.

The authors are grateful to the staff and participating clients from Riverlands Drug and Alcohol Centre, Lismore, NSW, Australia.

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Authors and Affiliations

  1. Discipline of Addiction Medicine, University of Sydney, Camperdown, NSW, 2050, Australia

    Jennifer Johnston, Nicholas Lintzeris & David J. Allsop

  2. The Langton Centre, Drug and Alcohol Services, South Eastern Sydney Local Health District, Surry Hills, NSW, 2010, Australia

    Nicholas Lintzeris

  3. School of Psychology, University of Sydney, Sydney, NSW, 2006, Australia

    David J. Allsop, Anastasia Suraev, Jessica Booth, Dean S. Carson & Iain S. McGregor

  4. Riverlands Drug and Alcohol Centre, Lismore, NSW, 2480, Australia

    David Helliwell

  5. Institute of Psychiatry, Kings College, London, SE5 8AF, UK

    Adam Winstock

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  1. Jennifer Johnston
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Correspondence to Nicholas Lintzeris.

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Johnston, J., Lintzeris, N., Allsop, D.J. et al. Lithium carbonate in the management of cannabis withdrawal: a randomized placebo-controlled trial in an inpatient setting. Psychopharmacology 231, 4623–4636 (2014). https://doi.org/10.1007/s00213-014-3611-5

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  • DOI: https://doi.org/10.1007/s00213-014-3611-5

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