Research Article 134 Ved ABSTRACT Although Canada legalized cannabis beverages in 2019, most available research on acute cannabis intoxication derives from dried flower and edible products. The distinct bioavailability and pharmacokinetic properties of phytocannabinoids ingested from beverages, however, contribute to significantly different acute and long-term effects that need to be better understood to ensure consumer safety. Objective: This review investigates existing cannabis beverage literature, with a particular focus on acute intoxication effects. Method: PubMed, PsycINFO and Web of Science databases were systematically searched. A structured search generated 29 eligible studies, comprising studies of consumption patterns and beliefs, advertisements and marketing, acute effects in human models, and drink composition. Results: Human studies report aversive acute subjective and physiological effects induced by cannabis beverages in healthy, infrequent users. Beverages also showed inaccurate cannabinoid labeling, posing potential risks to consumers. This review highlights the paucity and inconsistency of available research, further exacerbated by the sheer diversity of formulations investigated, while beginning to address some questions surrounding the safety and risks associated with cannabis beverages. Conclusions: Given the extensive differences in effects across cannabis-infused beverages, and the growing ‘drinkables’ market, it is essential that more studies directly examine both acute and long-term impacts of cannabis beverage consumption. Key words: = cannabis beverages; cannabis; acute intoxication; cannabinoids; systematic review Canada legalized recreational cannabis in October 2018 to improve safety regulations and reduce associated health risks (Health Canada, 2022a). By October 2019, the Canadian government expanded the provision of quality- controlled cannabis products to include both edible and concentrate products such as topicals, extracts, and beverages (Department of Justice, 2021; Rubin-Kahana et al., 2022). Recent amendments to the Cannabis Act now allow adults to possess up to 17.1L of cannabis-infused beverages for recreational purposes while maintaining controls to prevent overconsumption (Health Canada 2022a). Other regulations implemented for the sale of cannabis edibles include child-resistant packaging, prominent Anna Marie Froude1,2,3*, Nikki Pangborn1,2,3*, Phillip Britz- McKibbin4,5, James MacKillop1,2,5, & Iris Balodis1,2,5 1Peter Boris Centre for Addictions Research, St. Joseph’s Healthcare Hamilton and McMaster University 2Department of Psychiatry and Behavioural Neurosciences, McMaster University 3Neuroscience Graduate Program, McMaster University 4Department of Chemistry and Chemical Biology, McMaster University 5Michael G. DeGroote Centre for Medicinal Cannabis Research * These two authors contributed equally to this work. Cannabis 2024 © Author(s) 2024 researchmj.org 10.26828/cannabis/2024/000271 Volume 7, Special Issue 3 Potential Risks from Cannabis- Infused Beverages: A Critical Review Corresponding Author: Iris M. Balodis, PhD, McMaster University, 100 West 5th Street, Hamilton, Ontario, L8S 4L8. Phone: (905) 522-1155 ext. 39703.Email: balodisi@mcmaster.ca Cannabis, A Publication of the Research Society on Marijuana 135 health warning labels, serving size, and nutritional information (Ventresca & Elliott, 2022). Improved manufacturing standards are critical to ensure consistent phytocannabinoid content labeling and consistent dosing for consumers (Miller et al., 2022). The onset and duration of Δ9- tetrahydrocannabinol (THC), the primary psychotropic phytocannabinoid constituent with affinity to bind to cannabinoid receptor 1 (Kendall & Yudowski, 2017), effects differ across cannabis products. For instance, THC bioavailability and pharmacokinetics are highly dependent on the route of administration and vehicle composition, with edible products often metabolising more slowly than inhaled smoked or vaporised cannabis (Thayer et al., 2019; Vandrey et al., 2017). Thus, despite single drinkable cannabis beverages maintaining a 10 mg THC limit (Health Canada, 2022a), the neurocognitive effects resulting from their consumption will differ from dried flower or non-beverage edibles (Thayer et al., 2019; Vandrey et al., 2017). Individuals consuming cannabis edibles, including beverages, can experience delayed intoxication relative to smoking/vaping due to slower delivery and bioactivation, increasing overdose risk (Russel et al., 2018). Effects on cognition, memory, and driving performance are modulated by variable amounts of cannabidiol (CBD) and THC:CBD ratios (Arkell et al., 2020), and memory deficits may be further exacerbated by psychotropic constituents in cannabis-infused energy drinks, such as caffeine (Panlilio et al., 2012). However, despite the growing popularity of cannabis beverages in Canada, most acute cannabis effects research derives from dry cannabis flower inhalation or non-beverage edibles (Russel et al., 2018). Considering the novelty of cannabis beverages as a consumable product, a broader examination of research pertaining to their consumer reach, acute effects, and composition is necessary to address potential risks for consumers and guide future research avenues. Thus, the current review provides a critical review of empirical findings on cannabis-infused beverages across the aforementioned domains. METHODS Search Strategy Table 1. Search Phrases Employed for PsycINFO, PubMed and WoS Article Search Database Boolean Search Phrase Number of Results PsycINFO (via OVID) (DE "Cannabis Infused Drink" OR DE "Cannabinoid Infused Drink" OR DE "Cannabis Drink" OR DE "Cannabinoid Drink" OR DE "CBD Drink" OR DE "Tetrahydrocannabinol Infused Drink" OR DE "THC Infused drink" OR DE "Weed Drink" OR DE "Weed Infused Drink" OR DE "Marijuana Drink" OR DE "Marijauna Infused Drink" OR DE "Cannabis Infused Beverage" OR DE "Cannabinoid Infused Beverage" OR DE "Cannabis Beverage" OR DE "Cannabinoid Beverage" OR DE "CBD Beverage" OR DE "Tetrahydrocannabinol Infused Beverage" OR DE "THC Infused Beverage" OR DE "Weed Beverage" OR DE "Weed Infused Beverage" OR DE "Marijuana Beverage" OR DE "Marijauna Infused Beverage") 884 PubMed ("Cannabis Infused Drink" OR "Cannabinoid Infused Drink" OR "Cannabis Drink" OR "Cannabinoid Drink" OR "CBD Drink" OR "Tetrahydrocannabinol Infused Drink" OR "THC Infused drink" OR "Weed Drink" OR "Weed Infused Drink" OR "Marijuana Drink" OR "Marijauna Infused Drink" OR "Cannabis Infused Beverage" OR "Cannabinoid Infused Beverage" OR "Cannabis Beverage" OR "Cannabinoid Beverage" OR "CBD Beverage" OR "Tetrahydrocannabinol Infused Beverage" OR "THC Infused Beverage" OR "Weed Beverage" OR "Weed Infused Beverage" OR "Marijuana Beverage" OR "Marijauna Infused Beverage") 5523 Potential Risks from Cannabis-Infused Beverages 136 Web of Science (Core collection) TS=((cannabis* OR cannabinoid* OR CBD OR infused OR tetrahydrocannabinol OR tetra- hydrocannabinol OR marihuana* OR marijuana* OR THC OR weed) NEAR/3 (beverage* OR drink*)) TI=((cannabis* OR cannabinoid* OR CBD OR infused OR tetrahydrocannabinol OR tetra- hydrocannabinol OR marihuana* OR marijuana* OR THC OR weed) NEAR/3 (beverage* OR drink*)) AB=((cannabis* OR cannabinoid* OR CBD OR infused OR tetrahydrocannabinol OR tetra- hydrocannabinol OR marihuana* OR marijuana* OR THC OR weed) NEAR/3 (beverage* OR drink*)) 925 Table 2. Search Phrases Employed for PsycINFO, MEDLINE and WoS Article Search Database Boolean Search Phrase Number of Results PsycINFO (via OVID) ((Cannabis/ OR exp Cannabinoids/) AND exp Beverages/) use medall (exp Cannabis/ AND exp "Beverages (Nonalcoholic)"/) use psyh ((bhang? OR cannabi* OR ganja? OR hashish? OR hemp? OR marihuana? OR marijuana? OR txid1302822 OR txid3482 OR txid3483 OR CBD OR THC) AND (beverage* OR drink OR drinks OR thandai OR lassi)).ti. ((bhang? OR cannabi* OR ganja? OR hashish? OR hemp? OR marihuana? OR marijuana? OR txid1302822 OR txid3482 OR txid3483 OR CBD OR THC) ADJ5 (beverage* OR drink OR drinks OR thandai OR lassi)).ab,kf,kw,id. ((bhang-infus* OR cannabis-infus*) AND (beverage* OR drink OR drinks OR thandai OR lassi)).tw,kf,kw,id. or/1-5 42 MEDLINE (via OVID) ((Cannabis/ OR exp Cannabinoids/) AND exp Beverages/) use medall (exp Cannabis/ AND exp "Beverages (Nonalcoholic)"/) use psyh ((bhang? OR cannabi* OR ganja? OR hashish? OR hemp? OR marihuana? OR marijuana? OR txid1302822 OR txid3482 OR txid3483 OR CBD OR THC) AND (beverage* OR drink OR drinks OR thandai OR lassi)).ti. ((bhang? OR cannabi* OR ganja? OR hashish? OR hemp? OR marihuana? OR marijuana? OR txid1302822 OR txid3482 OR txid3483 OR CBD OR THC) ADJ5 (beverage* OR drink OR drinks OR thandai OR lassi)).ab,kf,kw,id. ((bhang-infus* OR cannabis-infus*) AND (beverage* OR drink OR drinks OR thandai OR lassi)).tw,kf,kw,id. or/1-5 309 Web of Science (Core collection) TI=(((bhang? OR cannabi* OR ganja? OR hashish? OR hemp? OR marihuana? OR marijuana? OR txid1302822 OR txid3482 OR txid3483 OR CBD OR THC) AND (beverage* OR drink OR drinks OR thandai OR lassi))) AK=(((bhang? OR cannabi* OR ganja? OR hashish? OR hemp? OR marihuana? OR marijuana? OR txid1302822 OR txid3482 OR txid3483 OR CBD OR THC) AND (beverage* OR drink OR drinks OR thandai OR lassi))) TS=(((bhang? OR cannabi* OR ganja? OR hashish? OR hemp? OR marihuana? OR marijuana? OR txid1302822 OR txid3482 OR txid3483 OR CBD OR THC) NEAR/2 (beverage* OR drink OR drinks OR thandai OR lassi))) ALL=(((bhang-infus* OR cannabis-infus*) AND (beverage* OR drink OR drinks OR thandai OR lassi))) #4 OR #3 OR #2 OR #1 319 Cannabis, A Publication of the Research Society on Marijuana 137 A systematic literature search was conducted in September 2022 using PsycINFO, PubMed, and Web of Science, resulting in 7,332 articles (Table 1). An additional search of the beverage ‘Bhang’ was conducted in May 2023 using the same databases (Table 2), producing 670 results. Title and abstract screening identified articles meeting inclusion criteria; full-text review determined their eligibility. Our inclusion criteria comprised English- written, peer-reviewed primary research articles examining cannabis, hemp, or Bhang beverages. Acute effect articles in animal models were included, so long as the cannabis beverages were consumed by choice and not injected. There was no limit on age, sex, or the presence of comorbid disorders. Meta-analyses and review articles were excluded; however, their reference lists were screened to identify other relevant articles. RESULTS This review broadly explores the current state of available cannabis beverage literature. Our search identified 8,002 articles, with 29 meeting inclusion criteria (Figures 1 and 2). Results describe studies examining consumption patterns and beliefs (n = 11), marketing tactics (n = 1), acute effects in humans (n = 6), and compositional aspects of cannabis and hemp beverages (n = 11). Figure 1. Inclusion Flowchart from Initial Search Potential Risks from Cannabis-Infused Beverages 138 Figure 2. Inclusion Flowchart from Secondary Search Consumption Patterns and Beliefs Studies exploring consumption patterns are summarized in Table 3. Although cannabis drinks were consistently chosen less often than smokeable or edible cannabis products (Donovan et al., 2022; Dowd et al., 2023; Dunbar et al., 2022; Fedorova et al., 2021; Goodman et al., 2020; Kerr et al., 2019; Schauer et al., 2020; Sikorski et al., 2021; Sullivan et al., 2022), use rates varied significantly. Consumption of cannabis beverages was particularly low among youth, observed in less than 0.1% of participants over four years (Sullivan et al., 2022). Adult past-month cannabis users reported greater beverage use in a Canadian study, where 27.3% reported lifetime consumption and 14.3% reported past-year consumption (Sikorski et al., 2021). Among past- year consumers (Sikorski et al., 2021), 51.8% reported monthly use, averaging 2.8 drinks monthly, and 19.1% consumed beverages weekly, with drinks primarily being sourced from family or friends (25.7%). Still, only 13.8% and 10% could accurately estimate the amount of THC and CBD present in their products, respectively. In US populations, 4.3% of adult past-month users reported consuming beverages (Schauer et al., 2020). Legal beverage purchasing grew from 71.4% in 2020 to 81.6% in 2021 (Wadsworth et al., 2023), and purchasing was 1.5-2.5X higher in legal compared to illegal markets (Goodman et al., 2020). Legal sourcing did vary by sex, however, as males had significantly greater odds of sourcing “some” drinks illegally (Wadsworth et al., 2023). Clinical populations in the US reported low consumption of cannabis beverages; 1.1% of cancer patients endorsing past-year cannabis use consumed beverages and 0.8% of lifetime users consumed beverages (Donovan et al., 2022). Among epilepsy patients, cannabis beverages were consumed less than all other modalities (7.7%), but were the most prevalent method consumed by patients 51-60 years old (Kerr et al. 2019). Among CBD-only consumers (Dunbar et al., 2022), 10.2% reported past-year beverage use, 8.6% reported lifetime use, and 9.8% reported past-month use, 14.7% of which exclusively used Cannabis, A Publication of the Research Society on Marijuana 139 CBD beverages and 8.4% combined other cannabis products. Alternatively, 2.6% consumed alcoholic CBD beverages in their lifetime, and 3.1% reported past-year consumption. Preferences for major cannabinoids were reportedly inconsistent across studies. Cannabis consumers from one study reported a preference for CBD-dominant (endorsed by n = 18 participants) over THC-dominant beverages (endorsed by n = 6 participants; Fedorova et al., 2021). The opposite has been observed in other research; among n = 38 cannabis beverage consumers, 34% were more likely to use THC- dominant products, while 18% preferred CBD- dominant products (Dowd et al., 2023). Users noted “enjoyment” and “wanting something to do” as primary motivations for consumption on the Comprehensive Marijuana Motives Questionnaire (CMMQ; Lee et al., 2009) Short Form, and reported that beverages took an average of 19 minutes for acute effects to onset – significantly quicker than edibles. Interest in replacing alcohol with a cannabis beverage dropped to 15.8% from 26.6% in 2017 (Charlebois et al., 2020), and substitution motivations were attributed to therapeutic reasons (31.8%), curiosity (25.8%), and psychoactive effects (17.9%) Potential Risks from Cannabis-Infused Beverages 140 Table 3. Summary of Findings on Cannabis Beverage Consumption Patterns and Beliefs Author(s) Year Purpose Subjects Protocol Summary of Results Charlebois et al. 2020 Measure perceptions surrounding edible use in Canada. General Canadian population - N = 1051 participants received the survey, and 94% responded - Age range ≥18 years old - An online survey was administered to randomly selected individuals in 2019 to measure aspects of cannabis use, including: perception of legalisation, legal consumption patterns, social stigma, and perceptions of cannabis edibles. - 15.8% of respondents would replace an alcoholic drink with a cannabis-infused drink (dropping from 26.6% in 2017). - 14.8% of respondents would be willing to substitute a conventional alcoholic drink with cannabis. - Reasons for substituting alcohol with cannabis beverages included therapeutic reasons (31.8%), curiosity (25.8%), and psychoactive effects (17.9%). Donovan et al. 2022a Measure cannabis use patterns in a population of young adults with cancer. Cancer patients -Age range = 18–39 years old - n = 144 males; n = 328 females; n = 4 unspecified gender - An online questionnaire was administered to patients to measure aspects of cannabis use, including: motives, consumption methods, effectiveness, side effects, source of products, and medical licence status. - Among weekly cannabis users, 49% reported eating or drinking cannabis. - Of past-year cannabis consumers (n = 352), four indicated they were using cannabis beverages purchased from a legal storefront. - Of the patients endorsing cannabis use prior to the last year (n = 127), one reported consuming cannabis beverages. Dowd et al. 2023 Examine various factors related to oral cannabis use. Cannabis users in the US - Mean age=32 years old - n = 174 males; n = 185 females Administered online survey program to participants measuring aspects of cannabis use, including: prevalence, motives, formulation, THC/CBD dose, perceived subjective effects, co-use (alcohol), and advice received about reducing use symptoms. - n = 38 (10%) of users consumed cannabis beverages, making it the second least prevalence mode reported. - Beverages, baked goods, gummies, hard and chocolate candy users reported significantly greater "enjoyment" motives compared to oils/tinctures. - Beverages, baked goods, and chocolate candy users reported significantly greater "wanting something to do" motives compared to oils/tinctures. - Beverage users displayed a trend toward the highest scores for using "to replace the use of another drug/medicine", though this was not significant. Cannabis, A Publication of the Research Society on Marijuana 141 - 34% (n =13) of cannabis beverage consumers used THC-dominant products, 24% (n = 9) used a 1:1 ratio of THC:CBD, 18% (n = 7) used CBD-dominant products, and 24% (n = 9) were unsure about the cannabinoid composition. - Using only data from 35 cannabis beverage consumers, participants reported that beverages took approximately 19 minutes (SD = 15) for their effects to onset, which was a significantly lower onset duration compared to baked-good and gummy candy consumers. Dunbar et al. 2022 Explore patterns and correlates of cannabidiol product and marijuana co-use in a sample of young US adults. Young adults in the US - Mean age(SD) = 22.6(0.8) years old - N = 2534 males and females - Examined cross-sectional survey data collected from wave 12 of the CHOICE-STRATA cohort study. - The survey assessed for lifetime, past-year, and past-month frequency, as well as the type of CBD products used, frequency and amount of cannabis consumed, and indicators of problematic cannabis use. - Differences in CBD use between participants reporting past-month use of CBD but not marijuana products (“CBD-only”) and those who co-use both CBD and marijuana products. Alcohol Containing Cannabis Beverages - 2.6% reported lifetime use of CBD beverages - 3.1% reported past-year use of CBD beverages - 3.1% reported past-month CBD beverages - 1.5% reported past-month use of CBD- only beverages - 3.6% reported past-month CBD and marijuana use - No significant differences in rates of use between past-month CBD-only and past- month CBD and marijuana groups for those who consumed alcoholic cannabis beverages. Alcohol-free Cannabis Beverages - 8.6% reported lifetime use of CBD beverages - 10.2% reported past-year use of CBD beverages - 9.8% reported past-month CBD beverages - 14.7% reported past-month use of CBD- only beverages Potential Risks from Cannabis-Infused Beverages 142 - 8.4% reported past-month CBD and marijuana use - No significant differences in rates of use between past-month CBD-only and past- month CBD and marijuana groups for those who consumed alcohol-free cannabis beverages. Fedorova et al. 2021 Measure cannabis use patterns and cannabinoid preferences. Recent cannabis users (past 90 days) - Mean age(SD) = 25.3(2.5) years old - n = 147 males; n = 92 females Data from year 5 of a longitudinal quantitative survey was analysed which measured aspects of cannabis use, including: CBD versus THC-dominant use frequency, mode of administration, general use frequency, and motives. - Cannabis users were classified as either CBD dominant users or THC dominant users. These groups were further divided into four subgroups: (1) (CBD dominant): CBD-only (2) (CBD dominant): Mostly CBD (3) (CBD dominant): Half CBD/half THC (4) (THC dominant): Some CBD The following rates of cannabis beverage consumption were recorded in each subgroup: - CBD-only: n = 11 (19.3%) - Mostly CBD: n = 0 (0%) - Half CBD/half THC: n = 7 (26.9%) - Some CBD: n = 6 (8.7%) - Therefore, the CBD-only users had the largest number of people using cannabis beverages (n = 11), but the half CBD/THC subgroup had the greatest proportion of beverage consumers (26.9%). - Drinks and edibles were tied for highest overall prevalence in the half CBD/THC subgroup, compared to all other modes of use. Goodman et al. 2020 Examine associations between the legal status of non-medical cannabis and patterns of consumption in Canada and legal and illegal regions of the US. Male and Female participants from Canada and the US - Age range = 16-65 years old - N = 27,042 Canada (n = 9976) Illegal US states (n = 9686) - Data was collected using self- completed web-based surveys assessing aspects of cannabis use, including: measurement windows (lifetime, most recent and current use), frequency and prevalence of cannabis use, type of cannabis products used, and age of first using cannabis. Prevalence of use of cannabis beverages % (n) - Canada: 8.1% (224), - Illegal US states: 8.7% (201) - Legal US states: 17.0% (430) Regular (daily and weekly) use of cannabis beverages among past 12-month cannabis users - Canada: 38.4% - Illegal US states: 58.9% - Legal US states: 30.0% Cannabis, A Publication of the Research Society on Marijuana 143 Legal US states (n = 7362) Frequency of use and prevalence of regular cannabis beverage use among past 12-month users % (n) 10% than labelled was determined to be “under labeled”, anything <10% less than labelled was determined to be “over labelled”. - A total of 75 products (from 47 different brands) were included in the analysis. 13 of the 75 products analysed were cannabis beverages. - Only 3 (23.1%) cannabis beverages had accurately labelled amounts of THC in the product (the product’s true amount was within 10% of its label). - 2 (15.4%) beverages were under labelled (>10% more THC than indicated on the label), and 8 (61.5%) were over labelled (<10% THC than indicated on the label). - Comparatively, 9.1% of baked goods were accurately labelled, and 20% of candy/chocolate products were accurately labelled. Note. Abbreviations: ARfD = Acute Reference Dose; CBC = Cannabichromene; CBCA = Cannabichromenic Acid; CBD = Cannabidiol; CBDA = Cannabidiolic Acid; CBDV = Cannabidivarin; CBDVA = Cannabidivarinic Acid; CBG = Cannabigerol; CBGA = Cannabigerolic Acid; CBLA = Cannabicyclolic Acid; CBN = Cannabinol; D8-THC = Δ8- Tetrahydrocannabinol; GC = Gas Chromatography; GC-MS = Gas Chromatography–Mass Spectrometry; HPLC = High Performance Liquid Chromatography; HPLC-DAD = High Performance Liquid Chromatography–Diode-Array Detection; HPLC-MS = High Performance Liquid Chromatography–Mass Spectrometry; ICP-MS = Inductively Coupled Plasma–Mass Spectrometry; LC = Liquid Chromatography; LC-DAD = Liquid Chromatography–Diode Array Detection; LC-MS = Liquid Chromatography–Mass Spectrometry; LC-MS/MS = Liquid Chromatography–Tandem Mass Spectrometry; LOAEL = Lowest Observed Adverse Effect Level; LOD = Limit of Detection; LOQ = Limit of Quantification; OH-THC = 11-Hydroxy-Δ9-Tetrahydrocannabinol; OTA = Ochratoxin A; RSD = Relative Standard Deviation; SPE = Solid-Phase Extraction; THC = Tetrahydrocannabinol; THCA = Tetrahydrocannabinolic Acid; THC-COOH = 11-Nor-9-Carboxy-Tetrahydrocannabinol; THCV = Tetrahydrocannabivarin; THCVA = Tetrahydrocannabivarinic Acid; UAE = Ultrasound-Assisted Extraction aIn the interest of brevity, cannabinoids of interest that were not detected through extraction processes are not reported in the table. bThe LOAEL dosage corresponds to 36 µg/kg of body weight in a 70 kg person. Potential Risks from Cannabis-Infused Beverages 158 DISCUSSION Consumption Patterns and Beliefs Consumption rates and attitudes across studies provide limited insight into beverage intake prevalence and perceptions. All but one of these studies (Sikorski et al., 2020) were conducted in the US; however, numbers are relatively consistent with the 2022 Canadian Cannabis Survey, where 19% of past-year cannabis users consumed beverages and 8% of past-month users drank cannabis (Health Canada, 2022b). Clinical populations residing in the US also mirror low Canadian consumption rates; 1.1% of cancer patients and 7.7% of epilepsy patients consumed cannabis beverages (Donovan et al., 2022; Kerr et al., 2019), while 8% of Canadians reported using cannabis beverages for medical purposes in the past year (Health Canada, 2022b). Legalizing beverages showed a trend toward increasing consumption, with legal purchasing growing 10.2% between 2020–2021 (Wadsworth et al., 2023), and consumers being 1.5-2.5X more likely to purchase drinks in legal than illegal markets (Goodman et al., 2020). Although cannabis beverages before legalization could have been made by consumers at home, availability in stores likely increased their accessibility and thus the ease of consumption. Differences in the legal status of cannabis beverages may partially explain varied reports of cannabis beverage prevalence identified in this review, considering some studies were conducted where cannabis was illegal (Dowd et al., 2023; Goodman et al., 2020; Schuaer et al., 2020; Sikorski et al., 2021). Heterogeneity could also be influenced by mean age; many studies were conducted in young adults (Dunbar et al., 2022; Fedorova et al., 2021; Sikorski et al., 2021; Sullivan et al., 2022) consistent with the mean age of cannabis use initiation (Health Canada, 2022b). These cohort effects make it difficult to draw clear consumption patterns across studies, and more research is necessary across wider population demographics to obtain more potential cohort effects. Studies on beverage preferences and attitudes suggest low reports of alcohol replacement, since 15.8% reported desire to replace alcohol with a cannabis drink (Charlebois et al., 2020). Both medical and recreational motives for cannabis beverage consumption are reported (Dowd et al., 2023; Fedorova et al., 2021); while some consumers may be CBD-only users and others prefer THC-dominant products, it is possible that the appeal of these beverages may be in unique cannabinoid effects, which cannot be substituted with alcohol. Advertisement and Marketing The Marijuana Retail Surveillance Tool (MRST) in Colorado dispensaries suggest that most dispensaries investigated follow appropriate security guidelines (Berg et al., 2017), including cannabis beverages offered across all dispensaries, with relatively consistent prices. Comprehensive marketing and promotion regulations should be widely applied across markets as novel products continue to emerge, including standardised cannabis surveillance tools, such as the MRST, to identify public health risks and monitor responsible marketing practices. Acute Effects in Human Models Human studies elucidated aversive cannabis beverage effects in emergency care settings and following acute administration, including increased pulse rate, anxiety, symptoms of mania, and inaccurate time perception (Cao et al., 2016; Chaudry et al., 1991; Karniol et al., 1974; Zuardi et al., 1982). However, these effects were often mitigated when THC was combined with CBD doses or when participants were administered CBD alone. Only one of these four studies reported including chronic or frequent cannabis users. Notably, infrequent cannabis users are more susceptible to psychoactive and physiological effects induced by THC and the blunting effects of cannabinoid interactions (Colizzi et al., 2018; Solowij et al., 2019). Thus, the frequency of cannabis use should be considered an important variable when understanding reported acute effects in these studies. Aversive outcomes of consumption and THC+CBD interactions may be heightened due to participants’ infrequent consumption rates, and may therefore not be generalizable to all consumers’ experiences with cannabis beverages. Furthermore, new cannabis users should take caution with the cannabinoid dosage and makeup when consuming to limit any potential health-related and psychological harm. Cannabis, A Publication of the Research Society on Marijuana 159 One study reported greater bioavailability of water-soluble CBD beverages relative to fat- soluble drinks (Hobbs et al., 2020). This may have occurred due to the prior fasting of participants, which alters phytocannabinoid bioavailability and pharmacokinetics enhanced by the fat content of meals (Birnbaum et al., 2019). Future investigations should therefore require control of participants’ fed status – ideally following a standardised meal. Potential adverse drug interactions when consuming cannabis-infused beverages with variable THC and CBD content also require greater attention given CBD inhibition of CYP2C9-mediated oral THC clearance (Bansal et al., 2023). Hobbs and colleagues (2020) also reported no changes in interleukin-10 or tumour necrosis factor levels following the consumption of water- and fat- soluble CBD drinks, contrasting previous findings indicating suppressive effects of CBD administration on inflammation in human and rat models (El-Remessy et al., 2006; Han et al., 2009). Thus, broader investigations are required to determine whether CBD beverages can reduce inflammation and be used as a viable medical treatment. Administration of hemp beverages produced a positive THC screen in some participants (Steinagle et al., 1999). In this case, cannabis plants with low residual THC content < 0.3% on a dry weight basis are classified as hemp from a regulatory framework in North America and Europe. Although this could only be detected using a precise analytic method, these findings highlight trace cannabinoid amounts still present in hemp products, which is important to highlight to consumers who may not be knowledgeable of their presence. Drink Composition Two studies observed that changes to tea preparation techniques altered cannabinoid composition (Hazekamp et al., 2007; Pacifici et al., 2017), albeit with conflicting results. Despite both studies using the same cannabis:water ratios in their standard preparations, trending decreases and significant increases in cannabinoid levels at increasing boiling times were observed. Regardless of these inconsistencies, potential differences in phytocannabinoid concentrations can vary depending on preparation techniques; thus, it is essential for consumers to be knowledgeable of these effects to minimize risks for overconsumption. Inconsistent labeling accuracy observed across current research (Lindsay et al., 2021; Miller et al., 2022; Vandrey et al., 2015) may partially occur due to the illicit or criminalized nature of cannabis in certain regions. Specifically, these studies were conducted in the US and Jamaica, where cannabis has not yet been nationally legalized, and thus, packaging and label requirements either vary between states or are nonexistent (Kruger et al., 2022; Lindsay et al., 2021). Labeling inaccuracy still occurs for other cannabis products within regulatory frameworks, and another systematic review has identified five studies reporting between 17 and 86% packaging accuracy. Thus, while the Canadian government has implemented strict packaging requirements (Health Canada, 2022c), consumers should still take caution when consuming cannabis products. Inaccurate reports of cannabis content can pose serious risks for overconsumption, and it is therefore essential to inform consumers of these risks. Considering cannabis has been legalized in Canada since 2018, more research should examine label and packaging accuracy, including minor cannabinoids, terpenes, caffeine, and other psychoactive constituents, to directly observe the influence of cannabis legalization and regulations. Regulated cannabis products require validated analytical methods to determine cannabinoid potency and ensure product efficacy, safety, and consistency. Surveillance testing for adulterated cannabis products is warranted, as accidental exposure can lead to injury or death, such as emerging synthetic cannabinoid receptor agonists (Krotulski et al., 2021). Minor cannabinoids, such as CBN, cannabichromene (CBC) and cannabigerol (CBG; Walsh et al., 2021), were not consistently reported in most studies involving drinkable cannabis products. Importantly, two acidic variants of THC and CBD, THCA and CBDA, are widely overlooked constituents of cannabis that have unique physiological properties and therapeutic applications (Kim et al., 2023), but these were only targeted in four of 11 studies (Ciolino et al., 2018; Hazekamp et al., 2007; Pacifici et al., 2017; Song et al., 2023). Thus, the inclusion of THCA and CBDA information (rather than total THC Potential Risks from Cannabis-Infused Beverages 160 and CBD) in cannabis beverages is important to accurately assess product formulation. Terpene profiles are widely used to classify cannabis strains, as they impact aroma attributes and generate synergistic effects with phytocannabinoids (Kaur et al., 2023); however, their analysis in cannabis-infused beverages is sparse. Reversed-phase LC with UV absorbance or DAD detection is frequently used for phytocannabinoid potency testing with improved selectivity and lower detection limits achieved by LC-MS/MS; however, different extraction and/or sample cleanup methods may be applied to various cannabis products, which might yield variable recovery rates. For instance, Christodoulou et al. (2023) demonstrated that solid-phase extraction increased recovery for accurate determination of cannabis-infused beverages (e.g., cannabis coffee, beer, energy drinks, and hemp tea) prior to LC-MS analysis compared to ultrasound-assisted extraction. Therefore, optimising pre-analytical protocols to process distinct cannabis products is critical for reliable determination of phytocannabinoid content without bias. Limitations and Future Directions This review highlights a dearth of available research on cannabis beverages, particularly acute intoxication. A lack of standard dosing produces limitations across studies. From a policy perspective, maximum legal dosages are vague; although the Canadian government enforces a legal limit of 10 mg/THC per beverage and a possession limit of 17.1 L of cannabis beverages (Health Canada, 2022a), it is not stated how much liquid must be present per 10 mg of THC. Thus, there is no government-determined standard size for cannabis beverages, which range from 30 mL ‘shots’ to over 500 mL. Considering the amount of liquid may affect the speed at which someone consumes their beverage, this may affect the onset and duration of intoxication. This issue is not specific to cannabis drinks, as standard cannabis doses across modes do not yet exist (Volkow & Weiss, 2020). Although a standard of 5 mg per product has been proposed (Freeman & Lorenzetti, 2020), this may not produce consistent intoxication effects (Cloutier et al., 2022; Hughes et al., 2014; Russel et al., 2018; Thayer et al., 2019). Therefore, effects observed in human and animal models may not be indicative of real-world effects. Importantly, THC bioavailability and pharmacokinetics are highly dependent on the specific formulation of the cannabis beverage and whether it is consumed with meals and/or use of other drugs co-metabolized by cytochrome P450 enzymes. Future work should seek to replicate findings using consistent dosages, including considerations of phytocannabinoid profiles, mode of consumption, and individual consumer characteristics. Most methods to date have been developed for the analysis of cannabis dried flowers and concentrates/resins rather than edibles or beverages that have different matrix interferences. Recently, the Association of Official Agricultural Chemists have issued Standard Method Performance Requirements in 2022 for the quantification of five phytocannabinoids in beverages within a recommended analytical range (0.002-10% w/w), recovery (< 70-130%) and reproducibility (CV < 12%), namely CBD, CBDA, THC, THCA and CBN (Audino et al., 2017); moreover, nine additional minor phytocannabinoids were named in a desirable list for quantification, including CBG, cannabigerolic acid (CBGA), CBC, cannabichromenic acid (CBCA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), Δ8-THC, tetrahydrocannabivarin (THCV), and tetrahydrocannabivarinic acid (THCVA). With the exception of Song et al. (2023), few studies have performed comprehensive potency testing of up to sixteen phytocannabinoids in cannabis beverages using LC-MS/MS that also allows for chromatographic resolution of isomeric phytocannabinoids, such as Δ8-/Δ9-THC. While the global cannabis beverage market is expanding to include drugs, such as caffeine, herbal extracts, taurine, and alcohol, few systematic studies exist for these blends. The US National Alcohol Survey reports that most cannabis users simultaneously consume alcohol (Subbaraman & Kerr, 2015), increasing the likelihood of consuming greater quantities of alcohol, drinking more frequently, reporting more alcohol-related consequences than alcohol-only users, and increasing odds of drunk driving, social consequences, and personal harms. A systematic review (Gunn et al., 2022) reported heightened behavioural and cognitive effects and increased plasma THC following low dose alcohol consumption among individuals concurrently Cannabis, A Publication of the Research Society on Marijuana 161 consuming alcohol and cannabis. Higher alcohol doses can also blunt subjective THC effects, which may encourage overconsumption, thereby highlighting the need for explorations of blended drinks. Given the historical and cultural significance that the cannabis beverage Bhang holds, particularly in eastern countries such as India (Karki & Rangaswamy, 2023), our review conducted a secondary search to uncover more on this drink. However, despite its widespread use, no additional studies assessing acute Bhang effects were revealed. While one study highlighted the potential psychotic effects of Bhang (Chaudry et al., 1991), more research should apply similar systematic and controlled explorations of Bhang consumption. Conclusion While the Canadian government made amendments to the Cannabis Act in December 2022 to facilitate better access to cannabis beverages for research (Health Canada, 2022c), there are minimal investigations of acute intoxication effects. Current evidence also makes it difficult to draw conclusive statements, due to limited systematic comparisons of subjective, physiological, and cognitive effects across cannabis products. 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Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology, 76(3), 245–250. https://doi.org/10.1007/BF00432554 Funding and Acknowledgements: This work was supported by the Michael G. DeGroote Centre for Medicinal Cannabis Research and the Peter Boris Centre for Addictions Research. JM is supported by the Peter Boris Chair in Addictions Research and a Canada Research Chair in Translational Addiction Research (CRC-2020- 00170). PB-M acknowledges support from the Natural Sciences and Engineering Research Council of Canada, Canada Foundation for Innovation, and Genome Canada. The authors have no conflicts of interest to report. IB has received funding from the International Centre for Responsible Gaming and the Gambling Research Exchange Ontario as well as consulting fees from Bausch. JM is a principal and senior scientist in Beam Diagnostics Inc and has served as a consultant to Clairvoyant Therapeutics Inc. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. We thank Kaitryn Campbell, MLIS (St. Joseph's Healthcare Hamilton, ON) for formulation and refinement of Boolean search phrases and Karin Dearness, MLIS (St. Joseph's Healthcare Hamilton, ON) for peer review of the Ovid search strategy. Copyright: © 2024 Authors et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction, provided the original author and source are credited, the original sources is not modified, and the source is not used for commercial purposes. https://creativecommons.org/licenses/by/4.0/ Potential Risks from Cannabis-Infused Beverages 166 Citation: Froude, A. M., Pangborn, N., Britz- McKibbin, P., MacKillop, J., & Balodis, I. (2024). Potential risks from cannabis-infused beverages: A critical review. Cannabis, 7(3), 134–166. https://doi.org/10.26828/cannabis/2024/000271 Issue Date: December 12, 2024