Pharmacodynamic dose effects of oral cannabis ingestion in healthy adults who infrequently use cannabis

Highlights

• Pharmacodynamics were assessed for oral cannabis containing 0, 10, 25, and 50 mg THC.

• 10 mg THC produced discriminable subjective effects but no cognitive impairment.

• 25 mg and 50 mg THC markedly impaired cognitive and psychomotor functioning.

• The onset of drug effects was delayed greatly, peaking 1.5−3 h post-ingestion.

• Blood THC levels were far lower than typically observed after cannabis inhalation.

Abstract

Background

Prior controlled cannabis research has mostly focused on smoked cannabis and predominantly included frequent cannabis users. Oral cannabis products (“edibles”) make up a large and growing segment of the retail cannabis market. This study sought to characterize the pharmacodynamic effects of oral cannabis among infrequent cannabis users.

Methods

Seventeen healthy adults who had not used cannabis for at least 60 days completed four experimental sessions in which they consumed a cannabis-infused brownie that contained 0, 10, 25, or 50 mg THC. Subjective effects, vital signs, cognitive/psychomotor performance, and blood THC concentrations were assessed before and for 8 h after dosing.

Results

Relative to placebo, the 10 mg THC dose produced discriminable subjective drug effects and elevated heart rate but did not alter cognitive/psychomotor performance. The 25 and 50 mg THC doses elicited pronounced subjective effects and markedly impaired cognitive and psychomotor functioning compared with placebo. For all active doses, pharmacodynamic effects did not manifest until 30−60 min after ingestion, and peak effects occurred 1.5−3 h post-administration. Blood THC levels were significantly correlated with some pharmacodynamic drug effects, but were substantially lower than what is typically observed after cannabis inhalation.

Conclusion

Ingestion of oral cannabis dose-dependently altered subjective drug effects and impaired cognitive performance. Unlike inhaled forms of cannabis for which acute effects occur almost immediately, effects of oral cannabis were considerably delayed. In an era of legalization, education about the time course of drug effects for cannabis edibles is needed to facilitate dose titration and reduce acute overdose incidents.

Introduction

Cannabis is one of the most widely used drugs in the world. Recent reforms to the policies governing the medicinal and non-medicinal (i.e., “recreational”) use of cannabis have greatly increased access to cannabis. Inhalation of smoked cannabis is the most common route of self-administration (Borodovsky et al., 2016; Knapp et al., 2018). However, the cannabis retail marketplace contains a vast array of products that can be administered via other routes (Russell et al., 2018; Spindle et al., 2019a). Oral cannabis products (a.k.a. “edibles”) have emerged as a popular alternative method of cannabis administration (Schauer et al., 2016; Steigerwald et al., 2018a). This subset of cannabis products includes cannabis-infused food (e.g., brownies, cookies, gummies) as well as various cannabis-containing beverages (Russell et al., 2018; Spindle et al., 2019a). Cannabis edibles are perceived to be healthier than smoked cannabis and can be used discreetly, which increases their appeal (Kostadinov and Roche, 2017; Lamy et al., 2016).

Δ-9-tetrahydrocannabinol (THC) is the primary psychoactive chemical constituent of the cannabis plant that is responsible for producing subjective “highs,” feelings of euphoria, as well as dysphoric effects such as panic, paranoia, and acute psychosis (Russo, 2011). Previous experimental examinations of the pharmacokinetic and pharmacodynamic effects of oral cannabis have typically administered pure THC, often in the form of dronabinol. These studies have shown that oral THC dose-dependently increases positive subjective drug effects ratings (e.g., ‘like drug effect’), subjective items associated with feelings of intoxication (e.g., ‘stoned’), and heart rate (Curran et al., 2002; Fogel et al., 2017; Lile et al., 2013; Vandrey et al., 2013). These studies also show dose-dependent impairment in attention, memory, and psychomotor performance following oral THC ingestion, but these effects are more consistently observed among less frequent cannabis users (Curran et al., 2002), likely due to the development of tolerance among heavier users. Though informative, these studies have limited ecological validity to current products available on the retail cannabis market. This is because most retail products are made with raw cannabis or whole-plant cannabis extracts and contain food ingredients that may affect drug absorption and alter pharmacodynamic effects relative to pharmaceutical formulations containing only THC (e.g., dronabinol).

Only a small subset of oral cannabis dosing studies have administered cannabis “edibles” (e.g., brownies) containing cannabis plant material (Cone et al., 1988; Newmeyer et al., 2017a; Niedbala et al., 2001; Vandrey et al., 2017; Wachtel et al., 2002). Several of these studies (Newmeyer et al., 2017a; Niedbala et al., 2001; Wachtel et al., 2002) compared the pharmacokinetic and pharmacodynamic effects of oral cannabis to a similar dose(s) of smoked or vaporized cannabis. The fourth study, conducted in our laboratory, examined the acute effects of oral cannabis among participants who were randomly assigned to receive a single oral cannabis dose (Vandrey et al., 2017). Collectively, these studies demonstrate that the acute pharmacodynamic effects of cannabis are substantially delayed following oral cannabis ingestion and often do not peak until several hours after administration, which is in stark contrast to inhaled forms of cannabis (either smoked or vaporized) for which cannabis effects peak within minutes (Newmeyer et al., 2017a; Niedbala et al., 2001; Vandrey et al., 2017; Wachtel et al., 2002). Regarding pharmacokinetic effects, peak concentrations of THC and its metabolites following oral cannabis ingestion are substantially lower compared with inhaled cannabis. The delayed onset of oral cannabis effects makes dose titration more difficult and increases the chances of acute overdose while the pharmacokinetics of oral cannabis make it difficult to identify individuals who are intoxicated based on blood THC concentrations alone (Allen et al., 2017; Barrus et al., 2016; Hudak et al., 2015).

There are some critical limitations of published laboratory studies involving controlled oral cannabis administration. First, most have only administered one or two doses, and as a result, the acute effects of oral cannabis have not been sufficiently characterized for the wide range of doses available in the retail marketplace (Steigerwald et al., 2018b). Participants in oral cannabis studies have included moderate to heavy users (Newmeyer et al., 2017a; Niedbala et al., 2001; Wachtel et al., 2002) whereas infrequent users of oral cannabis products represent a growing proportion of the user market and infrequent use may be associated with greater sensitivity to the acute pharmacodynamic effects of cannabis compared with frequent users that have developed tolerance. Second, prior studies have included male participants predominantly. Last, oral cannabis products represent a growing portion of the market share of cannabis products, which necessitates further understanding of the physiologic, subjective, and cognitive effects of these products.

The present study extends prior research by characterizing the pharmacodynamic effects of multiple oral cannabis doses (0, 10, 25, and 50 mg THC) in a sample of infrequent cannabis users. The current study utilizes a within-subjects crossover design as opposed to the between-subjects design used in our prior oral cannabis study (Vandrey et al., 2017), which allowed us to better control for the considerable inter-individual variability that exists in the pharmacokinetics and pharmacodynamics of oral cannabis because each participant served as their own control. The use of only infrequent cannabis users also minimized the potential that some participants would be tolerant to the effects of cannabis/THC.