Skip to main content

Advertisement

Log in

Effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory model of relapse in cannabis users

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Each year, over 300,000 individuals in the USA enter treatment for cannabis use disorder (CUD). The development of effective pharmacotherapy for CUD is a priority.

Objective

This placebo-controlled study examined the effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory measure of relapse.

Methods

Eleven daily, non-treatment-seeking cannabis users completed three, 8-day inpatient phases; each phase tested a different medication condition in counter-balanced order. On the first day of each phase, participants were administered placebo capsules t.i.d. and smoked experimenter-administered active cannabis (5.6 % Δ9-tetrahydrocannabinol (THC)). On days 2–8, the participants were administered capsules containing either placebo (0 mg at 0900, 1800, and 2300 hours), zolpidem (0 mg at 0900 and 1800, and 12.5 mg at 2300), or zolpidem (12.5 mg at 2300) and nabilone (3 mg at 0900 and 1800). Cannabis withdrawal, subjective capsule effects, and cognitive performance were examined on days 3–4, when only inactive cannabis (0.0 % THC) was available for self-administration. “Relapse” was measured on days 5–8, when participants could self-administer active cannabis.

Results

Both medication conditions decreased withdrawal-related disruptions in sleep, but only zolpidem in combination with nabilone decreased withdrawal-related disruptions in mood and food intake relative to placebo. Zolpidem in combination with nabilone, but not zolpidem alone, decreased self-administration of active cannabis. Zolpidem in combination with nabilone also produced small increases in certain abuse-related subjective capsule ratings, while zolpidem alone did not. Neither medication condition altered cognitive performance.

Conclusions

Clinical testing of nabilone, either alone, or in combination with zolpidem is warranted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Allsop DJ, Copeland J, Norberg MM, Fu S, Molnar A, Lewis J et al (2012) Quantifying the clinical significance of cannabis withdrawal. PLoS ONE 7, e44864. doi:10.1371/journal.pone.0044864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balter RE, Cooper ZD, Haney M (2014) Novel pharmacologic approaches to treating cannabis use disorder. Curr Addict Rep 1:137–143

    Article  PubMed  PubMed Central  Google Scholar 

  • Bedi G, Foltin RW, Gunderson EW, Rabkin J, Hart CL, Comer SD et al (2010) Efficacy and tolerability of high-dose dronabinol maintenance in HIV-positive marijuana smokers: a controlled laboratory study. Psychopharmacology 212:675–686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bedi G, Cooper ZD, Haney M (2013) Subjective, cognitive and cardiovascular dose-effect profile of nabilone and dronabinol in marijuana smokers. Addict Biol 18:872–881

    Article  CAS  PubMed  Google Scholar 

  • Budney AJ, Moore BA, Vandrey RG, Hughes JR (2003) The time course and significance of cannabis withdrawal. J Abnorm Psychol 112:393–402

    Article  PubMed  Google Scholar 

  • Budney AJ, Hughes JR, Moore BA, Vandrey R (2004) Review of the validity and significance of cannabis withdrawal syndrome. Am J Psychiatry 161:1967–1977

    Article  PubMed  Google Scholar 

  • Budney AJ, Moore BA, Rocha HL, Higgins ST (2006) Clinical trial of abstinence-based vouchers and cognitive-behavioral therapy for cannabis dependence. J Consult Clin Psychol 74:307–316

    Article  PubMed  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  CAS  PubMed  Google Scholar 

  • Budney AJ, Vandrey RG, Hughes JR, Thostenson JD, Bursac Z (2008) Comparison of cannabis and tobacco withdrawal: severity and contribution to relapse. J Subst Abuse Treat 35:362–368

    Article  PubMed  PubMed Central  Google Scholar 

  • Carroll KM, Nich C, LaPaglia DM, Peters EN, Easton CJ, Petry NM (2012) Combining cognitive behavioral therapy and contingency management to enhance their effects in treating cannabis dependence: less can be more, more or less. Addiction 107:1650–1659

    Article  PubMed  PubMed Central  Google Scholar 

  • Cooper ZD, Foltin RW, Hart CL, Vosburg SK, Comer SD, Haney M (2013) A human laboratory study investigating the effects of quetiapine on marijuana withdrawal and relapse in daily marijuana smokers. Addict Biol 18:993–1002

    Article  CAS  PubMed  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 Pharmacol 6:176–186

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Fraser AD, Meatherall R (1989) Lack of interference by nabilone in the EMIT® dau cannabinoid assay, Abbott TDx® cannabinoid assay, and a sensitive TLC assay for Δ9-THC-carboxylic acid. J Anal Toxicol 13:240

    Article  CAS  PubMed  Google Scholar 

  • Glass RM, Uhlenhuth EH, Hartel FW, Schuster CR, Fischman MW (1981) Single-dose study of nabilone in anxious volunteers. J Clin Pharmacol 21:383S–396S

    Article  CAS  PubMed  Google Scholar 

  • Gorelick DA, Goodwin RS, Schwilke E, Schwope DM, Darwin WD, Kelly DL et al (2013) Tolerance to effects of high-dose oral Δ9-tetrahydrocannabinol and plasma cannabinoid concentrations in male daily cannabis smokers. J Anal Toxicol 37:11–16

    Article  CAS  PubMed  Google Scholar 

  • Hajak G, Müller WE, Wittchen HU, Pittrow D, Kirch W (2003) Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data. Addiction 98:1371–1378

    Article  CAS  PubMed  Google Scholar 

  • Haney M (2005) The marijuana withdrawal syndrome: diagnosis and treatment. Curr Psychiatr Rep 7:360–366

    Article  Google Scholar 

  • Haney M (2009) Self-administration of cocaine, cannabis and heroin in the human laboratory: benefits and pitfalls. Addict Biol 14:9–21

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Haney M, Hart CL, Vosburg SK, Comer SD, Reed SC, Cooper ZD, Foltin RW (2010) Effects of baclofen and mirtazapine on a laboratory model of marijuana withdrawal and relapse. Psychopharmacology 211(2):233–244

  • Haney M, Cooper ZD, Bedi G, Vosburg SK, Comer SD, Foltin RW (2013a) Nabilone decreases marijuana withdrawal and a laboratory measure of marijuana relapse. Neuropsychopharmacology 38:1557–1565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haney M, Bedi G, Cooper ZD, Glass A, Vosburg SK, Comer SD, Foltin RW (2013b) Predictors of marijuana relapse in the human laboratory: robust impact of tobacco cigarette smoking status. Biol Psychiatry 73:242–248

    Article  PubMed  Google Scholar 

  • Hart CL, Haney M, Ward AS, Fischman MW, Foltin RW (2002) Effects of oral THC maintenance on smoked marijuana self-administration. Drug Alcohol Depend 67:301–309

    Article  CAS  PubMed  Google Scholar 

  • Hasin DS, Saha TD, Kerridge BT, Goldstein RB, Chou SP, Zhang H et al (2015) Prevalence of marijuana use disorders in the United States between 2001–2002 and 2012–2013. JAMA Psychiatry 72:1–9

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Krystal AD, Erman M, Zammi GK, Soubrane C, Roth T (2008) Long-term efficacy and safety of zolpidem extended-release 12.5 mg, administered 3 to 7 nights per week for 24 weeks, in patients with chronic primary insomnia: a 6-month, randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Sleep 31:79–90

    PubMed  PubMed Central  Google Scholar 

  • Lemberger L, Rubin A, Wolen R, DeSante K, Rowe H, Forney R et al (1982) Pharmacokinetics, metabolism and drug-abuse potential of nabilone. Cancer Treat Rev 9:17–23

    Article  PubMed  Google Scholar 

  • Levin FR, Mariani JJ, Brooks DJ, Pavlicova M, Cheng W, Nunes EV (2011) Dronabinol for the treatment of cannabis dependence: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend 116:142–150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lile JA, Kelly TH, Hays LR (2010) Substitution profile of the cannabinoid agonist nabilone in human subjects discriminating δ9-tetrahydrocannabinol. Clin Neuropharmacol 33:235–242

    Article  CAS  PubMed  Google Scholar 

  • Lile JA, Kelly TH, Hays LR (2011) Separate and combined effects of the cannabinoid agonists nabilone and Δ 9-THC in humans discriminating Δ 9-THC. Drug Alcohol Depend 116:86–92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mendelson JH, Mello NK (1984) Reinforcing properties of oral Δ 9-tetrahydrocannabinol, smoked marijuana, and nabilone: influence of previous marijuana use. Psychopharmacology 83:351–356

    Article  CAS  PubMed  Google Scholar 

  • Randall S, Roehrs TA, Roth T (2012) Efficacy of eight months of nightly zolpidem: a prospective placebo-controlled study. Sleep 35:1551–1557

    PubMed  PubMed Central  Google Scholar 

  • Roehrs TA, Randall S, Harris E, Maan R, Roth T (2012) Twelve months of nightly zolpidem does not lead to rebound insomnia or withdrawal symptoms: a prospective placebo-controlled study. J Psychopharmacol 26(8):1088–1095

    Article  CAS  PubMed  Google Scholar 

  • Rush CR, Baker RW, Wright K (1999) Acute behavioral effects and abuse potential of trazodone, zolpidem and triazolam in humans. Psychopharmacology 144:220–233

    Article  CAS  PubMed  Google Scholar 

  • Scharf MB, Rot T, Vogel GW, Walsh JK (1994) A multicenter, placebo-controlled study evaluating zolpidem in the treatment of chronic insomnia. J Clin Psychiatry 55:192–199

    CAS  PubMed  Google Scholar 

  • Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality (2014) Treatment Episode Data Set (TEDS): 2002–2012. National Admissions to Substance Abuse Treatment Services. BHSIS Series S-71, HHS Publication No. (SMA) 14–4850. Rockville, MD

  • Vandrey RG, Budney AJ, Hughes JR, Liguori A (2008) A within-subject comparison of withdrawal symptoms during abstinence from cannabis, tobacco, and both substances. Drug Alcohol Depend 92:48–54

    Article  CAS  PubMed  Google Scholar 

  • Vandrey R, Smith M, McCann UD, Budney AJ, Curran EM (2011) Sleep disturbance and the effects of extended-release zolpidem during cannabis withdrawal. Drug Alcohol Depend 117:38–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vandrey R, Stitzer ML, Mintzer MZ, Huestis MA, Murray JA, Lee D (2013) The dose effects of short-term dronabinol (oral THC) maintenance in daily cannabis users. Drug Alcohol Depend 128:64–70

    Article  CAS  PubMed  Google Scholar 

  • Volkow ND, Baler RD, Compton WM, Weiss SR (2014) Adverse health effects of marijuana use. N Engl J Med 370:2219–2227

    Article  PubMed  PubMed Central  Google Scholar 

  • Ware MA, Arnaud‐Trempe S (2010) The abuse potential of the synthetic cannabinoid nabilone. Addiction 105:494–503

    Article  PubMed  Google Scholar 

  • World Health Organization (n.d.) Management of substance abuse: cannabis. Retrieved from http://www.who.int/substance_abuse/facts/cannabis/en/

Download references

Acknowledgments

This research was supported by P50 DA009236 and T32 DA007294 from the National Institute on Drug Abuse.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Evan S. Herrmann.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Herrmann, E.S., Cooper, Z.D., Bedi, G. et al. Effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory model of relapse in cannabis users. Psychopharmacology 233, 2469–2478 (2016). https://doi.org/10.1007/s00213-016-4298-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-016-4298-6

Keywords

Navigation