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Effects of haloperidol on the behavioral, subjective, cognitive, motor, and neuroendocrine effects of Δ-9-tetrahydrocannabinol in humans

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Abstract

Introduction

Cannabinoids produce a spectrum of effects in humans including euphoria, cognitive impairments, psychotomimetic effects, and perceptual alterations. The extent to which dopaminergic systems contribute to the effects of Δ-9-tetrahydrocannabinol (Δ-9-THC) remains unclear. This study evaluated whether pretreatment with a dopamine receptor antagonist altered the effects of Δ-9-THC in humans.

Materials and methods

In a 2-test-day double-blind study, 28 subjects including healthy subjects (n = 17) and frequent users of cannabis (n = 11) were administered active (0.057 mg/kg) or placebo oral haloperidol in random order followed 90 and 215 min later by fixed order intravenous administration of placebo (vehicle) and active (0.0286 mg/kg) Δ-9-THC, respectively.

Results

Consistent with previous reports, intravenous Δ-9-THC produced psychotomimetic effects, perceptual alterations, and subjective effects including “high.” Δ-9-THC also impaired verbal recall and attention. Haloperidol pretreatment did not reduce any of the behavioral effects of Δ-9-THC. Haloperidol worsened the immediate free and delayed free and cued recall deficits produced by Δ-9-THC. Haloperidol and Δ-9-THC worsened distractibility and vigilance. Neither drug impaired performance on a motor screening task, the Stockings of Cambridge task, or the delayed match to sample task. Frequent users had lower baseline plasma prolactin levels and blunted Δ-9-THC induced memory impairments.

Conclusions

The deleterious effects of haloperidol pretreatment on the cognitive effects of Δ-9-THC are consistent with the preclinical literature in suggesting crosstalk between DAergic and CBergic systems. However, it is unlikely that DA D2 receptor mechanisms play a major role in mediating the psychotomimetic and perceptual altering effects of Δ-9-THC. Further investigation is warranted to understand the basis of the psychotomimetic effects of Δ-9-THC and to better understand the crosstalk between DAergic and CBergic systems.

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Acknowledgements

The authors wish to acknowledge the critical clinical research contributions of the Biological Studies Unit, VA Connecticut Healthcare System, including Elizabeth O’Donell, R.N; Angelina Genovese, R.N.; Sonah Yoo, R.Ph.; Robert Sturwold, R.Ph., and Mr. Willie Ford. This study was supported by the National Institute of Drug Abuse (DA12382-01 to DCD). In addition, the authors acknowledge support from the (1) Department of Veterans Affairs Schizophrenia Biological Research Center (John Krystal), (2) National Institute of Mental Health (MH61019-02 to DCD), (3) National Institute of Alcohol Abuse and Alcoholism (R03 AA11413-02 to DCD), (4) Stanley Medical Research Institute (DCD), and (5) Donaghue Foundation (DCD).

Disclosure/Conflict of interest

None of the authors have any potential conflict/s of interest relating to the subject of the report.

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Authors and Affiliations

  1. Schizophrenia Biological Research Center, VA Connecticut Healthcare System, West Haven, CT, USA

    Deepak Cyril D’Souza, Gabriel Braley, Rebecca Blaise, Michael Vendetti, Stephen Oliver, Mohini Ranganathan, Savita Bhakta, Zoran Zimolo & Edward Perry

  2. Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT, USA

    Deepak Cyril D’Souza & Brian Pittman

  3. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Deepak Cyril D’Souza, Gabriel Braley, Rebecca Blaise, Michael Vendetti, Stephen Oliver, Mohini Ranganathan, Savita Bhakta, Zoran Zimolo & Edward Perry

  4. Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Thomas Cooper

  5. Psychiatry Service, 116A, VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT, 06516, USA

    Deepak Cyril D’Souza

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Corresponding author

Correspondence to Deepak Cyril D’Souza.

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Table S1

Motor results (means [±SD]) (DOC 36.0 KB)

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D’Souza, D.C., Braley, G., Blaise, R. et al. Effects of haloperidol on the behavioral, subjective, cognitive, motor, and neuroendocrine effects of Δ-9-tetrahydrocannabinol in humans. Psychopharmacology 198, 587–603 (2008). https://doi.org/10.1007/s00213-007-1042-2

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