A preclinical model of THC edibles that produces high-dose cannabimimetic responses

  1. Departments of Pharmacology
  2. UW Center of Excellence in Neurobiology of Addiction, Pain, and Emotion (NAPE)
  3. Center for Cannabis Research, University of Washington, Seattle WA 98195
  4. Department of Anatomy & Neurobiology, University of California Irvine, Irvine CA
  5. Psychiatry & Behavioral Sciences, University of Washington, Seattle WA 98195

Editors

  • Reviewing Editor
    Robert Laprairie
    University of Saskatchewan, Canada
  • Senior Editor
    Kate Wassum
    University of California, Los Angeles, Los Angeles, United States of America

Reviewer #1 (Public Review):

Summary:

This manuscript describes the development of an oral THC consumption model in mice where THC is added to a chocolate flavored gelatin. The authors compared the effects of THC consumed in this highly palatable gelatin (termed E-gel) to THC dissolved in a less palatable gelatin (CTR-gel), and to i.p. injections of multiple doses of THC, on the classic triad of CB1R dependent behaviors (hypolocomotion, antinociception, and body temperature).

The authors found that they could achieve consumption of higher concentrations of THC in the E-gel than the CTR-gel, and that this led to larger total dose exposure and decreases in locomotor activity, antinociception, and body temperature reductions similar to 3-4 mg/kg THC when tested after 2 hour consumption and roughly 10 mg/kg if tested immediately after 1 hour consumption. The majority of THC E-gel consumption was found to occur in the first hour on the first exposure day. THC E-gel consumption was lower than VEH E-gel consumption and this persisted on a subsequent consumption day, suggesting that the animals may form a taste aversion and that THC at the dose consumed likely has aversive properties, consistent with the literature on i.p. dosing. The authors also report the pharmacokinetics in brain and plasma of THC and metabolites after 1 or 2 hour consumption, finding high levels of THC in the brain that begins to dissipate at 2.5 hours is gone 24 hours later. Finally, the authors tested THC effects on the acoustic startle response and found an inverted dose response that was more pronounced in males than females after i.p. dosing and a greater startle response in males after E-gel dosing.

Overall, the authors find that voluntary oral consumption of THC can achieve levels of intake that are consistent with the present and prior reported literature on i.p. dosing.

Strengths:

The strengths of the article include a direct comparison of voluntary oral THC consumption to noncontingent i.p. administration, the use of multiple THC doses and oral THC formulations, the inclusion of multiple assays of cannabinoid agonist effects, and the inclusion of males and females. Additional strengths include monitoring intake over 10 minute intervals and validating that effects are CB1R dependent via antagonist studies.

Weaknesses:

1. The abstract does not discuss the reduction of E-gel consumption that occurs after multiple days of exposure to the THC formulation, but rather implies that a new model for chronic oral self-administration has been developed. Given that only two days of consumption was assessed, it is not clear if the model will be useful to determine THC effects beyond the acute measures presented here. The abstract should clarify that there was evidence of reduced consumption/aversive effects with repeated exposures.
2. In the results section, the authors sometimes describe effects in terms of the concentration of gel as opposed to the dose consumed in mg/kg, which can make interpretation difficult. For example, the text describing Figure 1i states that significant effects on body temperature were achieved at 4 mg CTR-gel and 5 mg THC-gel, but were essentially equivalent doses consumed? It would be helpful to describe what average dose of THC produced effects given that consumption varied within each group of mice assigned to a particular concentration.
3. The description of the PK data in Figure 3 did not specify if sex differences were examined. Prior studies have found that males and females can exhibit stark differences in brain and plasma levels of THC and metabolites, even when behavioral effects are similar. However, this does depend on species, route, timing of tissue collection. It would be helpful to describe the PK profile of males and females separately.
4. In Figure 5, it is unclear how the predicted i.p. THC dose could be 30 mg/kg when 30 mg/kg was not tested by the i.p. route according to the figure, and if it had been it would have likely been almost zero acoustic startle, not the increased startle that was observed in the 2 hr gel group. It seems more likely that it would be equivalent to 3 mg/kg i.p. Could there be an error in the modeling, or was it based on the model used for the triad effects? This should be clarified.

Reviewer #2 (Public Review):

Summary:
The work fruitfully adds to the tools to study cannabinoid action and pharmacology specifically, but also this method is applicable to other drugs, in particular, if lipophilic in nature.

Strengths:
The addition of chocolate flavor overcomes aversive reactions which are often experienced in pharmacological treatments, leading to possible caveats in the interpretation of the behavioral outcomes.

Weaknesses:
Certainly, more THC mediated behavioral outcomes could have been tested, but the work presents a proof-of-concept study to investigate acute THC treatment.
It would have been interesting if this application form is also possible for chronic treatment regimen

Reviewer #3 (Public Review):

Summary: This manuscript explores the development of a rodent voluntary oral THC consumption model. The authors use the model to demonstrate that similar effect levels of THC can be observed to what has previously been described for i.p. THC administration.

Strengths: Overall this is an interesting study with compelling data presented. There is a growing need within the field of cannabinoid research to explore more 'realistic' routes of cannabinoid administration, such as oral consumption or inhalation. The evidence presented here shows the utility of this oral administration model.

Weaknesses: The main weaknesses of the manuscript revolve around clarification of the Methods section. All of these weaknesses are described in the "Recommendations to authors" section. Revising the manuscript would account for many of these weaknesses.

  1. Howard Hughes Medical Institute
  2. Wellcome Trust
  3. Max-Planck-Gesellschaft
  4. Knut and Alice Wallenberg Foundation