Original Investigation

Psychopharmacology

, Volume 198, Issue 4, pp 587-603

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

  • Deepak Cyril D’SouzaAffiliated withSchizophrenia Biological Research Center, VA Connecticut Healthcare SystemAbraham Ribicoff Research Facilities, Connecticut Mental Health CenterDepartment of Psychiatry, Yale University School of MedicinePsychiatry Service, 116A, VA Connecticut Healthcare System Email author 
  • , Gabriel BraleyAffiliated withSchizophrenia Biological Research Center, VA Connecticut Healthcare SystemDepartment of Psychiatry, Yale University School of Medicine
  • , Rebecca BlaiseAffiliated withSchizophrenia Biological Research Center, VA Connecticut Healthcare SystemDepartment of Psychiatry, Yale University School of Medicine
  • , Michael VendettiAffiliated withSchizophrenia Biological Research Center, VA Connecticut Healthcare SystemDepartment of Psychiatry, Yale University School of Medicine
  • , Stephen OliverAffiliated withSchizophrenia Biological Research Center, VA Connecticut Healthcare SystemDepartment of Psychiatry, Yale University School of Medicine
  • , Brian PittmanAffiliated withAbraham Ribicoff Research Facilities, Connecticut Mental Health Center
  • , Mohini RanganathanAffiliated withSchizophrenia Biological Research Center, VA Connecticut Healthcare SystemDepartment of Psychiatry, Yale University School of Medicine
  • , Savita BhaktaAffiliated withSchizophrenia Biological Research Center, VA Connecticut Healthcare SystemDepartment of Psychiatry, Yale University School of Medicine
  • , Zoran ZimoloAffiliated withSchizophrenia Biological Research Center, VA Connecticut Healthcare SystemDepartment of Psychiatry, Yale University School of Medicine
    • , Thomas CooperAffiliated withDepartment of Psychiatry, College of Physicians and Surgeons, Columbia University
    • , Edward PerryAffiliated withSchizophrenia Biological Research Center, VA Connecticut Healthcare SystemDepartment of Psychiatry, Yale University School of Medicine

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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.

Keywords

Schizophrenia Cannabinoids Dopamine Antipsychotic Cognition Memory Addiction Attention Haloperidol Endocrine