Naltrexone Maintenance Decreases Cannabis Self-Administration and Subjective Effects in Daily Cannabis Smokers.
Open accessAbstract
Given that cannabis use is increasing in the United States, pharmacological treatment options to treat cannabis use disorder are needed. Opioid antagonists modulate cannabinoid effects and may offer a potential approach to reducing cannabis use. In this double-blind, placebo-controlled human laboratory study, we assessed the effects of naltrexone maintenance on the reinforcing, subjective, psychomotor, and cardiovascular effects of active and inactive cannabis. Nontreatment-seeking, daily cannabis smokers were randomized to receive naltrexone (50 mg: n=18 M and 5 F) or placebo (0 mg; n=26 M and 2 F) capsules for 16 days. Before, during, and after medication maintenance, participants completed 10 laboratory sessions over 4-6 weeks, assessing cannabis' behavioral and cardiovascular effects. Medication compliance was verified by observed capsule administration, plasma naltrexone, and urinary riboflavin. Relative to placebo, maintenance on naltrexone significantly reduced both active cannabis self-administration and its positive subjective effects ('good effect'). Participants in the placebo group had 7.6 times (95% CI: 1.1-51.8) the odds of self-administering active cannabis compared with the naltrexone group. This attenuation of reinforcing and positive subjective effects also influenced cannabis use in the natural ecology. Naltrexone had intrinsic effects: decreasing ratings of friendliness, food intake, and systolic blood pressure, and increasing spontaneous reports of stomach upset and headache, yet dropout rates were comparable between groups. In summary, we show for the first time that maintenance on naltrexone decreased cannabis self-administration and ratings of 'good effect' in nontreatment-seeking daily cannabis smokers. Clinical studies in patients motivated to reduce their cannabis use are warranted to evaluate naltrexone's efficacy as a treatment for cannabis use disorder.
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Acute administration of naltrexone potentiated the positive subjective effects of cannabis, but repeated administration decreased such effects.
“It has been reported that the acute administration of naltrexone potentiated the positive subjective effects of cannabis but that repeated administration decreased such effects 74, 75.”
From Psychosocial and pharmacological interventions for the treatment of cannabis use disorder (2018) · cites this paper as [74]
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“Naltrexone maintenance decreased cannabis self-administration and euphoric effects in daily cannabis smokers [21].”
BackgroundAlayoubi, M., Henry, B. A., Cahill, C. M., & Cooper, Z. D. (2024) · Drugs · doi:10.1007/s40265-024-02098-1 · Cited by 7 · see citing works
“However, when naltrexone (50 mg) was administered for 16 days to nontreatment-seeking people who use cannabis it reduced the positive subjective ratings of cannabis and cannabis self-administration compared to placebo [48].”
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Human Laboratory Models of Cannabis Use Disorder
Arout, C. A., Herrmann, E. S., & Haney, M. (2018) · Springer eBooks · doi:10.1007/978-3-319-90365-1_9 · Cited by 6 · see citing works
Self-citationMiranda, A. H., Roberts, B. Z., Holloway, B. M., Peek, E. M., Rosberg, H., Ayoub, S. M., Piomelli, D., Jung, K., Barnes, S. A., Rossi, S. S., et al. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03718-4 · Cited by 5 · see citing works
“Both BD and HC participants were recruited based on two groupings: no CU (less than 5x lifetime use and no use in the past 90 days) or + CU (4x/week or more for the past 90 days [42 – 45]).”
The Treatment of Cannabis Use Disorder
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“, 1999; Welch & Eads, 1999), data from human studies examining the analgesic efficacy and abuse liability of cannabinoid/opioid combinations are just now emerging (Cooper et al., 2018; Haney et al., 2015), and there are no controlled data on how chronic pain states affect risk for developing Cannabis Use Disorder.”
BackgroundEffects of repeated cue exposure on cannabis craving
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“Other studies have shown that naltrexone maintenance decreases cannabis selfadministration and subjective VAS ratings of “Good Effect” (Haney et al., 2015).”
BackgroundSubjective drug-effect ratings predict cannabis self-administration in people who use cannabis daily
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Pharmacotherapy for Cannabis Use Disorder: Preclinical and Clinical Models
Bedillion, M. F., Moore, C. F., Weerts, E. M., Arout, C. A., Harris, H. M., & Haney, M. (2025) · Current topics in behavioral neurosciences · doi:10.1007/7854_2025_598 · Cited by 1 · see citing works
Self-citationThe Treatment of Cannabis Use Disorder Among Individuals With a Psychotic Disorder
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Translation of CUD Therapeutics from Drug Discovery to the Clinic
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Emerging pharmacotherapy for the treatment of cannabis use disorder
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“[32], participants received naltrexone 50 mg ( n = 18) or placebo ( n = 26) for 16 days.”
MethodMu-opioid antagonism in the treatment of cannabis use disorder
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“sativa and their subjective positive effects in chronic plant users [79].”
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Chapter 17. Treatment of Cannabis-Related Disorders
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Treatment of Co-occurring Psychiatric Disorders and Cannabis Use in the Outpatient Setting
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Gabapentinoids for the treatment of cannabis use disorder: A focus on human laboratory research
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“This decreased reward has also been reported in CanUD with NTX [25], though the effectiveness of NTX for CanUD needs further investigation.”
Chapter 4. Cannabis and Cannabinoids
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“Nal-trexone maintenance (50 mg) over 4 to 6 weeks reduced the positive subjective effects of cannabis as well as self-administration during laboratory sessions [42].”
Self-citationPharmacotherapy for Cannabinoid Use Disorder
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Evidence for pro-cognitive benefits of cannabinoids in people with bipolar disorder
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“Both HC and BD participants were recruited based on two groupings: CU − (no more than four previous exposures to cannabis and no use within the past 90 days) or CU+ (CU ≥ 4 times/week over the past 90 days [32 – 35]).”
Human behavioral pharmacology of cannabis: Insights on cannabis use disorder
Haney, M., Arout, C. A., & Bedillion, M. F. (2026) · Preventive Medicine · doi:10.1016/j.ypmed.2026.108663
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Self-citation
- Authors
- Haney, M., Ramesh, D., Glass, A., Pavlicova, M., Bedi, G., & Cooper, Z. D.
- Affiliations
- Columbia University Irving Medical Center (US)
- Virginia Commonwealth University (US)
- Corresponding author
- Haney, Margaret
- Venue
- Neuropsychopharmacology
- Published
- 2015-04-16
- Volume
- 40
- Issue
- 11
- Pages
- 2489-2498
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4569951
- OpenAlex
- W1988829530
- Cited by
- 73
- References
- 55
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 5 · 2020: 4 · 2019: 4 · 2018: 14 · 2017: 9 · 2016: 7 · 2015: 1 · 2014: 1
- FWCI
- 7.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse (DA-09236, R01DA019239, DA 19239, K23DA034877, P50DA009236)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Keywords
- naltrexone, cannabis use disorder, opioid antagonists, reinforcement effect, cardiovascular effects, psychomotor effects, treatment seeking
- MeSH terms
- Adult, Affect, Blood Pressure, Cannabis, Double-Blind Method, Eating, Female, Humans, Male, Marijuana Smoking, Middle Aged, Naltrexone, Narcotic Antagonists, Patient Compliance, Random Allocation, Riboflavin, Self Administration, Young Adult
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