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Nicotine patch for cannabis withdrawal symptom relief: a randomized controlled trial

Abstract

Rationale

Given that tetrahydrocannabinol (THC) and nicotine have similar effects on negative affect (NA), we hypothesized that a 7-mg nicotine patch (NP) would reduce NA-related cannabis (CAN) withdrawal symptoms in cannabis-dependent (CD) individuals who were not nicotine dependent.

Objective

We sought to determine whether NP reduces NA across 15 days of CAN abstinence in two groups: non-tobacco smokers (NTS) and light tobacco smokers (LTS).

Methods

CD participants (N = 127; aged 18–35) who used CAN at least 5 times/week for the past 12 + months were randomized to (1) NP or (2) a placebo patch (PP) and received $300 for sustained biochemically verified CAN abstinence. Of those randomly assigned, 52 of 63 NP, and 56 of 64 PP maintained biochemically verified CAN abstinence and 51 NP and 50 PP participants complied with all aspects of the study. Affect and other withdrawal symptoms were measured every 48 h across 15 days of CAN abstinence.

Results

After controlling for age, tobacco use, baseline THC concentration, and baseline measurements of the dependent variable, NP reduced NA symptoms across the 15-day treatment relative to PP. Differences in NA and CAN withdrawal symptoms were not moderated by tobacco user status.

Conclusions

The findings provide the first evidence that NP may be able to attenuate NA-related withdrawal symptoms in individuals with cannabis use disorder who are not heavy users of tobacco or nicotine.

Clinical trials registry

NCT01400243 http://www.clinicaltrials.gov

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References

  1. Agosti V, Nunes E, Levin F (2002) Rates of psychiatric comorbidity among U.S. residents with lifetime cannabis dependence. Am J Drug Alcohol Abuse 28:643–652. https://doi.org/10.1081/ADA-120015873

  2. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, fourth edition, text revision (DSM-IV-TR). American Psychiatric Association, Arlington, VA

  3. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (DSM-5®), 5th edn. American Psychiatric Association, Washington, DC

  4. Arendt M, Rosenberg R, Foldager L, Sher L, Munk-Jørgensen P (2007) Withdrawal symptoms do not predict relapse among subjects treated for cannabis dependence. Am J Addict 16:461–467. https://doi.org/10.1080/10550490701640985

  5. Arrindell W (2001) Changes in waiting-list patients over time: data on some commonly-used measures. Beware! Behav Res Ther 39:1227–1247. https://doi.org/10.1016/S0005-7967(00)00104-2

  6. Badiani A, Boden JM, De Pirro S et al (2015) Tobacco smoking and cannabis use in a longitudinal birth cohort: evidence of reciprocal causal relationships. Drug Alcohol Depend 150:69–76. https://doi.org/10.1016/j.drugalcdep.2015.02.015

  7. Barik J, Wonnacott S (2006) Indirect modulation by α7 nicotinic acetylcholine receptors of noradrenaline release in rat hippocampal slices: interaction with glutamate and GABA systems and effect of nicotine withdrawal. Mol Pharmacol 69:618–628. https://doi.org/10.1124/mol.105.018184

  8. Benowitz NL, Jacob P III, Ahijevych K et al (2002) Biochemical verification of tobacco use and cessation. Nicotine Tob Res 4:149–159. https://doi.org/10.1080/14622200210123581

  9. Blackford AL, Yang G, Hernandez-Avila M et al (2006) Cotinine concentration in smokers from different countries: relationship with amount smoked and cigarette type. Cancer Epidemiol Biomark Prev 15:1799–1804. https://doi.org/10.1158/1055-9965.EPI-06-0427

  10. Blum K, Braverman ER, Holder JM et al (2000) The reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive and compulsive behaviors. J Psychoactive Drugs 32:1–112. https://doi.org/10.1080/02791072.2000.10736099

  11. 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. https://doi.org/10.1001/archpsyc.58.10.917

  12. Budney AJ, Moore BA, Vandrey RG, Hughes JR (2003) The time course and significance of cannabis withdrawal. J Abnorm Psychol 112:393–402. https://doi.org/10.1037/0021-843X.112.3.393

  13. Budney AJ, Vandrey RG, Hughes JR, Thostenson JD, Bursac Z (2008) Comparison of cannabis and tobacco withdrawal: severity and contribution to relapse. J Subst Abus Treat 35:362–368. https://doi.org/10.1016/j.jsat.2008.01.002

  14. 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

  15. Center for Behavioral Health Statistics and Quality (2015) Behavioral health trends in the United States: results from the 2014 National Survey on Drug Use and Health

  16. Corrigall WA, Coen KM, Adamson KL (1994) Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res 653:278–284. https://doi.org/10.1016/0006-8993(94)90401-4

  17. First MB, Spitzer RL, Gibbon M, Williams JBW (2002) Structured clinical interview for DSM-IV-TR axis I disorders, research version, non-patient edition. 94–101

  18. Gelfand EV, Cannon CP (2006) Rimonabant: a cannabinoid receptor type 1 blocker for management of multiple cardiometabolic risk factors. J Am Coll Cardiol 47:1919–1926. https://doi.org/10.1016/j.jacc.2005.12.067

  19. Gerdeman GL, Partridge JG, Lupica CR, Lovinger DM (2003) It could be habit forming: drugs of abuse and striatal synaptic plasticity. Trends Neurosci 26:184–192. https://doi.org/10.1016/S0166-2236(03)00065-1

  20. Gilbert DG, Pergadia ML (2017) Nicotine withdrawal and depression. In: Hall FS, Young JW, Der-Avakian A (eds) Negative affective states and cognitive impairments in nicotine dependence. Elsevier, Philadelphia, pp 289–310

  21. Gilbert DG, McClernon FJ, Rabinovich NE et al (1998) Effects of smoking abstinence on mood and craving in men: influences of negative-affect-related personality traits, habitual nicotine intake and repeated measurements. Pers Individ Dif 25:399–423. https://doi.org/10.1016/S0191-8869(98)00003-8

  22. Gilbert DG, McClernon FJ, Rabinovich NE et al (2002) Mood disturbance fails to resolve across 31 days of cigarette abstinence in women. J Consult Clin Psychol 70:142–152. https://doi.org/10.1037/0022-006X.70.1.142

  23. Gilbert DG, Rabinovich NE, Rosenberger S (2003) Effects of fast and slow blood-rise nicotine patches on nausea and feeling states in nonsmokers. In: Ninth Annual Scientific Sessions of the Society for Research on Nicotine. New Orleans, LA

  24. Gilbert DG, Rabinovich NE, Gilbert-Matuskowitz EA et al (2019) Smoking abstinence symptoms across 67 days compared with randomized controls—moderation by nicotine replacement therapy, bupropion, and negative-affect traits. Exp Clin Psychopharmacol. https://doi.org/10.1037/pha0000278

  25. Green B, Kavanagh D, Young R (2003) Being stoned: a review of self-reported cannabis effects. Drug Alcohol Rev 22:453–460. https://doi.org/10.1080/09595230310001613976

  26. Gupta SK, Benowitz NL, Jacob P III et al (1993) Bioavailability and absorption kinetics of nicotine following application of a transdermal system. Br J Clin Pharmacol 36:221–227. https://doi.org/10.1111/j.1365-2125.1993.tb04221.x

  27. 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. https://doi.org/10.1007/s002130000657

  28. Haney M, Hart CL, Vosburg SK, Comer SD, Reed SC, Foltin RW (2008) Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse. Psychopharmacology 197:157–168. https://doi.org/10.1007/s00213-007-1020-8

  29. Haney M, Cooper ZD, Bedi G, Vosburg SK, Comer SD, Foltin RW (2013) Nabilone decreases marijuana withdrawal and a laboratory measure of marijuana relapse. Neuropsychopharmacology 38:1557–1565. https://doi.org/10.1038/npp.2013.54

  30. Hart CL (2005) Increasing treatment options for cannabis dependence: a review of potential pharmacotherapies. Drug Alcohol Depend 80:147–159. https://doi.org/10.1016/j.drugalcdep.2005.03.027

  31. Hasin DS, Shmulewitz D, Sarvet AL (2019) Time trends in US cannabis use and cannabis use disorders overall and by sociodemographic subgroups: a narrative review and new findings. Am J Drug Alcohol Abuse 45:1–21. https://doi.org/10.1080/00952990.2019.1569668

  32. Huestis MA, Gorelick DA, Heishman SJ, et al (2001) Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry 58:322. https://doi.org/10.1001/archpsyc.58.4.322

  33. Jorenby DE, Hays J, Rigotti N, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR, Varenicline Phase 3 Study Group (2006) Efficacy of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 296:56–63. https://doi.org/10.1001/jama.296.1.56

  34. Koller M (2016) Robustlmm : an R package for robust estimation of linear mixed-effects models. J stat Softw 75:1–24. https://doi.org/10.18637/jss.v075.i06

  35. Koller M, Stahel WA (2011) Sharpening wald-type inference in robust regression for small samples. Comput Stat Data Anal 55:2504–2515. https://doi.org/10.1016/j.csda.2011.02.014

  36. Kouri EM, Pope HG (2000) Abstinence symptoms during withdrawal from chronic marijuana use. Exp Clin Psychopharmacol 8:483–492. https://doi.org/10.1037/1064-1297.8.4.483

  37. Kreek MJ (2000) Methadone-related opioid agonist pharmacotherapy for heroin addiction. History, recent molecular and neurochemical research and future in mainstream medicine. Ann N Y Acad Sci 909:186–216

  38. Levin FR, Mariani JJ, Pavlicova M, et al (2016) Dronabinol and lofexidine for cannabis use disorder: A randomized, double-blind, placebocontrolled trial. Drug Alcohol Depend 159:53–60. https://doi.org/10.1016/j.drugalcdep.2015.11.025

  39. Lupica CR, Riegel AC (2005) Endocannabinoid release from midbrain dopamine neurons: a potential substrate for cannabinoid receptor antagonist treatment of addiction. Neuropharmacology 48:1105–1116. https://doi.org/10.1016/j.neuropharm.2005.03.016

  40. Lynskey MT, Heath AC, Nelson EC, Bucholz KK, Madden PA, Slutske WS, Statham DJ, Martin NG (2002) Genetic and environmental contributions to cannabis dependence in a national young adult twin sample. Psychol Med 32:195–207. https://doi.org/10.1017/S0033291701005062

  41. Martens KM, Gilbert DG (2008) Marijuana and tobacco exposure predict affect-regulation expectancies in dual users. Addict Behav 33:1484–1490. https://doi.org/10.1016/j.addbeh.2008.07.002

  42. McNair DM, Lorr M, Droppleman LF (1971) Manual for the POMS. Educ. Ind. Test. Serv

  43. Mentha H (2001) Getting out of it: how to cut down or quit cannabis. Australia: Inner East Community Health Service, Hawthorn

  44. Pacek LR, Vandrey R, Dermody SS, Denlinger-Apte RL, Lemieux A, Tidey JW, McClernon F, Bangdiwala AS, Drobes DJ, al'Absi M, Strasser AA, Koopmeiners JS, Hatsukami DK, Donny EC (2016) Evaluation of a reduced nicotine product standard: moderating effects of and impact on cannabis use. Drug Alcohol Depend 167:228–232. https://doi.org/10.1016/j.drugalcdep.2016.08.620

  45. Perkins KA, Stitzer M, Lerman C (2006) Medication screening for smoking cessation: a proposal for new methodologies. In: Psychopharmacology

  46. Sánchez-Merino JA, Marin J, Balfagón G, Ferrer M (1995) Involvement of α2-adrenoceptors and protein kinase C on nicotine-induced facilitation of noradrenaline release in bovine cerebral arteries. Gen Pharmacol Vasc Syst 26:827–833. https://doi.org/10.1016/0306-3623(94)00259-P

  47. Scherma M, Muntoni AL, Melis M, Fattore L, Fadda P, Fratta W, Pistis M (2016) Interactions between the endocannabinoid and nicotinic cholinergic systems: preclinical evidence and therapeutic perspectives. Psychopharmacology 233:1765–1777. https://doi.org/10.1007/s00213-015-4196-3

  48. Schuster RM, Hanly A, Gilman J, Budney A, Vandrey R, Evins AE (2016) A contingency management method for 30-days abstinence in non-treatment seeking young adult cannabis users. Drug Alcohol Depend 167:199–206. https://doi.org/10.1016/j.drugalcdep.2016.08.622

  49. Schwilke EW, Gullberg RG, Darwin WD, Chiang CN, Cadet JL, Gorelick DA, Pope HG, Huestis MA (2011) Differentiating new cannabis use from residual urinary cannabinoid excretion in chronic, daily cannabis users. Addiction 106:499–506. https://doi.org/10.1111/j.1360-0443.2010.03228.x

  50. Sharpe JP, Gilbert DG (1998) Effects of repeated administration of the beck depression inventory and other measures of negative mood states. Pers Individ Dif 24:457–463. https://doi.org/10.1016/S0191-8869(97)00193-1

  51. Solinas M, Scherma M, Fattore L et al (2007) Nicotinic 7 receptors as a new target for treatment of cannabis abuse. J Neurosci. https://doi.org/10.1523/jneurosci.0027-07.2007

  52. Stephens RS, Curtin L, Simpson EE, Roffman RA (1994) Testing the abstinence violation effect construct with marijuana cessation. Addict Behav 19:23–32. https://doi.org/10.1016/0306-4603(94)90048-5

  53. Tiffany ST, Drobes DJ (1991) The development and initial validation of a questionnaire on smoking urges. Addiction 86:1467–1476. https://doi.org/10.1111/j.1360-0443.1991.tb01732.x

  54. Valjent E, Mitchell JM, Besson M-J et al (2002) Behavioural and biochemical evidence for interactions between Δ9-tetrahydrocannabinol and nicotine. Br J Pharmacol 135:564–578. https://doi.org/10.1038/sj.bjp.0704479

  55. Vandrey R, Umbricht A, Strain EC (2011) Increased blood pressure after abrupt cessation of daily cannabis use. J Addict Med 5:16–20. https://doi.org/10.1097/ADM.0b013e3181d2b309

  56. Viveros M-P, Marco EM, File SE (2006) Nicotine and cannabinoids: parallels, contrasts and interactions. Neurosci Biobehav Rev 30:1161–1181. https://doi.org/10.1016/j.neubiorev.2006.08.002

  57. Vlahov D, Galea S, Resnick H, Ahern J, Boscarino JA, Bucuvalas M, Gold J, Kilpatrick D (2002) Increased use of cigarettes, alcohol, and marijuana among Manhattan, New York, residents after the September 11th terrorist attacks. Am J Epidemiol 155:988–996. https://doi.org/10.1093/aje/155.11.988

  58. Wonnacott S (1997) Presynaptic nicotinic ACh receptors. Trends Neurosci 20:92–98. https://doi.org/10.1016/S0166-2236(96)10073-4

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Acknowledgments

We thank Quincy Scott, our study physician, John D. Lindt, and the dozens of undergraduate and graduate research assistants who helped conduct this study, and without whom, it would have been impossible to complete.

Funding

The study was supported by NIH grant R01DA031006 awarded to David Gilbert.

Author information

The study was designed by DGG and NER. The data were acquired by DGG and NER. The analyses were conducted by DGG and JTM. The manuscript was drafted by DGG, NER, and JTM. Each author contributed to critical revisions and approval of the final version of the manuscript. Funding was obtained by DGG. Supervision of the study was done by DGG and NER.

Correspondence to David G. Gilbert.

Ethics declarations

DGG, NER, and JTM had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of interest

David Gilbert ended grant funding and all other connections with or benefits from R. J. Reynolds Tobacco Company in 1997 and has not received funding from any source other than the National Institutes of Health since that time. Prior to 2000 the first author received free nicotine and placebo patches from Glaxo-Smith Kline and received a consultation fee in 2003 and co-authorship on two manuscripts from Pfizer in 2004 and 2007 dealing with tobacco smoking withdrawal symptoms. Norka Rabinovich worked with several grant projects from R. J. Reynolds prior to the termination of funding from RJR in 1997. Justin McDaniel has no conflict of interest.

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Gilbert, D.G., Rabinovich, N.E. & McDaniel, J.T. Nicotine patch for cannabis withdrawal symptom relief: a randomized controlled trial. Psychopharmacology (2020). https://doi.org/10.1007/s00213-020-05476-1

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Keywords

  • Cannabis
  • Marijuana
  • Withdrawal symptoms
  • Negative affect
  • Nicotine
  • Smoking
  • Testing effect
  • THC