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Cannabinoid tetrad effects of oral Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in male and female rats: sex, dose-effects and time course evaluations

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Abstract

Rationale

The legalization of medicinal use of Cannabis sativa in most US states and the removal of hemp from the Drug Enforcement Agency (DEA) controlled substances act has resulted in a proliferation of products containing Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) for oral consumption (e.g., edibles, oils, and tinctures) that are being used for recreational and medicinal purposes.

Objective

This study examined the effects of cannabinoids THC and CBD when administered orally on measures of pain sensitivity, body temperature, locomotor activity, and catalepsy (i.e., cannabinoid tetrad) in male and female Sprague Dawley rats.

Methods

Rats (N = 24, 6 per sex/drug group) were administered THC (1–20 mg/kg), CBD (3–30 mg/kg), or sesame oil via oral gavage. Thermal and mechanical pain sensitivity (tail flick assay, von Frey test), rectal measurements for body temperature, locomotor activity, and the bar-test of catalepsy were completed. A separate group of rats (N = 8/4 per sex) was administered morphine (5–20 mg/kg; intraperitoneal, IP) and evaluated for pain sensitivity as a positive control.

Results

We observed classic tetrad effects of antinociception, hypothermia, hyper- and hypolocomotion, and catalepsy after oral administration of THC that were long lasting (> 7 h). CBD modestly increased mechanical pain sensitivity and produced sex-dependent effects on body temperature and locomotor activity.

Conclusions

Oral THC and CBD produced long lasting effects that differed in magnitude and time course when compared with other routes of administration. Examination of cannabinoid effects administered via different routes of administration, species, and in both males and females is critical to enhance translation.

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Abbreviations

THC:

Δ9-Tetrahydrocannabinol

CBD:

Cannabidiol

CB1R:

Cannabinoid receptor 1

IP:

Intraperitoneal

SC:

Subcutaneous

IV:

Intravenous

TF:

Tail flick

MPE:

Maximum possible effect

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Funding

All experiments were supported by the National Institute on Drug Abuse of the National Institutes of Health grant numbers R21DA046154 (EW) and the Johns Hopkins University Dalio Fund in Decision Making and the Neuroscience of Motivated Behaviors (EW).

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Authors and Affiliations

  1. Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Research Campus, Behavioral Biology Research Center, 5510 Nathan Shock Drive, Suite 3000, Baltimore, MD, 21224, USA

    Catherine F. Moore & Elise M. Weerts

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  1. Catherine F. Moore
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  2. Elise M. Weerts
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Correspondence to Catherine F. Moore.

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Moore, C.F., Weerts, E.M. Cannabinoid tetrad effects of oral Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in male and female rats: sex, dose-effects and time course evaluations. Psychopharmacology 239, 1397–1408 (2022). https://doi.org/10.1007/s00213-021-05995-5

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