ABSTRACT

Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid and hemp derivative increasingly used in food. Illegal in food at the U.S. federal level, but legal in some states, the CBD-infused food product market has grown substantially, prompting government concerns regarding potential safety risks. CBD foods are a growing market that is driven by increasing demand from producers and consumers and that is governed by an inconsistent and evolving legal framework. This systematic review of research and regulations identified how legality relates to safety. The research also included an emphasis on dose, a key factor for determining safety in foods. Statutes and guidance documents were reviewed from a selection of jurisdictions with existing or proposed legalized CBD in food to determine what restrictions are used relative to safety, including dose and related standards for food. A search of scientific literature was conducted to evaluate what is known about safe dose in food applications and determine what information is still needed to inform a standard or regulated limit. Findings were analyzed to determine risks and what research and regulations are needed to address them. Legal jurisdictions do little to safeguard consumers against potential risks associated with CBD in food because they focus primarily on warnings and prohibiting health claims. Warning and labeling requirements lack consistency. More concerning is the absence of standards for dose in food or for the composition of the CBD used. Further, there is limited and incomplete information to inform such standards.

HIGHLIGHTS
  • State and federal jurisdictions are grappling with the legal status of CBD in food.

  • Information on safe quantities of CBD in food is limited and incomplete.

  • Ties to marijuana negated an opportunity to establish safety data for CBD in food.

  • Few safeguards exist to protect consumers from potential risks of CBD in food.

  • Warning and labeling requirements in legal jurisdictions lack consistency.

Cannabidiol (CBD) is a nonpsychoactive derivative of Cannabis sativa L. and the principal cannabinoid of hemp, containing less than 0.3% delta-9-tetrahydrocannabinol (THC), according to United States law (10, 55, 79). This low THC content distinguishes it and its derivatives from marijuana, a different Cannabis sativa L. species and a controlled substance (1, 44). Currently, use of CBD as a food additive or drug supplement is illegal at the federal level in the United States (31). Congress wants the U.S. Food and Drug Administration (FDA) to create guidance for legally marketing hemp-derived CBD in food and supplements and a policy for jurisdictional enforcement discretion (16). H.R.841 has been introduced into the U.S. federal legislature to amend the Food, Drug and Cosmetics Act to approve its use as a dietary supplement (81).

Cultivation of hemp was illegal for decades as a result of laws that linked hemp to marijuana; this has further impacted the legality of CBD and other hemp-derived products (44). The Marijuana Tax Act of 1937 limited production of hemp with taxation on the sale of all Cannabis sativa L., connecting hemp and marijuana legally (44). The Controlled Substances Act, which classified hemp and marijuana as indistinct, required hemp cultivation to be licensed by the U.S. Drug Enforcement Administration (DEA) and placed cannabis on the controlled substance list under Schedule I (i.e., high abuse potential) (44, 50, 82). The Agriculture Improvement Act of 2018 (2018 Farm Bill) removed hemp and hemp seed from controlled substances classification but did not change the authority on the FDA oversight of cannabis products (10). Further confusion regarding CBD resulted from statements by the U.S. Department of Agriculture (USDA), FDA, and DEA, in their attempts to clarify the legality of hemp-derived compounds relative to the 2018 Farm Bill (44). The 2016 Marijuana Extract Rule differentiated the seeds, resin, and compounds (which includes CBD) of Cannabis sativa L. species plants from the stalks, seeds, and cake by defining them as “marijuana,” a controlled substance (44). The resulting implication that CBD derived from hemp was illegal was challenged in the 2018 lawsuit Hemp Industries Association (HIA) v. DEA, but the case was dismissed without creating any clarification (44). Although hemp was one of the earliest crops cultivated in history, its production was virtually halted by regulations driven by uncertainty and limited information until it could be distinguished from marijuana, eventually creating opportunities to market hemp-derived products (44).

The 2018 Farm Bill authorized hemp production in the United States and directed the USDA to regulate it (80). Prior to this law, the 2014 Farm Bill's Hemp Pilot Program legalized hemp cultivation for research purposes, and states are in various stages of transitioning to the 2018 program and its required standards (57, 58). The 2018 Farm Bill preserved the FDA's governance of hemp products, which led to a misconception that all products containing hemp, including CBD, are legal in interstate commerce or are provided a pathway to achieve legality (1, 71). Hemp derivatives such as hemp seed, hemp seed protein powder, and hemp seed oil are generally recognized as safe in foods (84). As the active ingredient in the approved drug Epidiolex, CBD is illegal for food and supplements because federal law states that a food or supplement with a drug added may not be introduced unless it was marketed in a food or supplement prior to approval as a drug (1, 16).

Despite the federal illegal status of CBD, the FDA has observed a variety of food products marketed with CBD over the last 5 years (1). Products include infused beverages, baked goods, candies, and snack food with varying CBD doses (28, 43, 96). CBD products are expected to reach $2 billion in sales in 2022 (19) with projections of $5.98 billion by 2025, attributing $950 million to edibles and $1.7 billion to beverages (27). In 2018, sales of CBD edible product categories grew by 500 to more than 900% (29). Increasing consumer demand is driving producers to enter the market (66). CBD industry growth is motivated by financial gain more than by consumer safety and health (35). Differences in state requirements and standards have created a patchwork of legality among states for producers to navigate (43).

CBD is also a topic of economic opportunity and concern in the animal food and feed industry. The market growth for CBD infused pet products is consistent with that for humans (23). Consumers seek hemp and marijuana products for their pets to address pain, anxiety, noise phobias, and inflammation (54). The Association of American Feed Control Officials states that, because CBD in animal food is governed by the same laws as in human foods, such products are illegal at the federal level (4). However, local jurisdictions have begun to open the legal marketplace for such products. Michigan passed H.B. 5085, which allows veterinarians to discuss CBD options with pet owners (52). Producers are marketing these products despite federal laws that prohibit them, and pet owners may be administering CBD to their pets without consulting a veterinarian (33). Whereas CBD in human food is the focus of this study, CBD use in pet foods provides an opportunity to obtain data on the impacts to animal health that may also be pertinent to human use.

CBD products for human consumption have been brought to market and legalized with inconsistent guidelines and without evidence of effectiveness and safety (14, 36). Abernethy (1) has stated concerns about the widespread availability and use of CBD in foods and dietary supplements without sufficient time to study the health and safety risks. The FDA is concerned that consumers will use CBD to self-treat with products outside of medical supervision before the agency can assess safe dose and risks for special populations such as children and pregnant women (1). Nearly 62% of CBD users report using CBD to treat a medical condition (19). These conditions include pain, anxiety, depression, insomnia, tension headaches or migraines, post-traumatic stress disorder, nausea, cancer, allergies or asthma, multiple sclerosis, chronic obstructive pulmonary disease, Parkinson's disease, and Alzheimer's disease (19). CBD and other cannabinoids bind to receptors in the body's endocannabinoid system, which may be linked to neurodevelopment of the adolescent brain and could impact neural and brain development (10, 11, 34, 70). Further research is needed to understand the possible impact of these risks (70). CBD's inability to impair the brain, as THC does, is also not well understood (30).

Research on CBD dose has been limited historically by the laws that restrict its production and use. The classification of cannabis as a Controlled Substances Act Schedule I substance significantly reduced its research potential because it required strict limitations and DEA registration (47, 50). Whereas research with hemp no longer requires DEA registration, conducting research on CBD using human subjects requires an investigational new drug exemption from the FDA and may not circumvent the lengthy and expensive drug research process by introducing it in food or supplements (50). CBD not meeting the definition of hemp-derived still requires DEA registration for research (16).

To establish safe dosage, the FDA considers short- and long-term testing of toxicity and pharmacokinetics relative to expected intake, cumulative exposure, and method of consumption (67). This is further complicated by variability in extracts, which may include other cannabinoids and may have different safety profiles separately or in combination with one another (12, 13, 45, 68). The United Kingdom and the European Union (EU) are working to address this issue by classifying CBD food products as “novel foods” and requiring preauthorization for such products to be introduced or remain on the market (74, 92). This application process requires a comprehensive risk assessment to include the aforementioned issues (74). Such a process to obtain research is not currently available in the United States (11, 47, 50).

The World Health Organization (98) has published reports that testify to the safety of pure CBD but without quantifying a safe amount. Safe quantity of a food additive is typically derived as a portion of acceptable daily intake, derived from an estimated daily intake from all potential sources (67). However, CBD's current legal use as an approved drug ingredient provides more data in the form of dose.

Illegality in food is not a deterrent for all producers. Numerous companies that have been warned by the FDA for marketing CBD food products via interstate commerce (85) continue to do so regardless of illegality (72). CBD food products may be readily available in jurisdictions where they are illegal because jurisdictional enforcement is lenient or development of policies for addressing the expanding market for these products is ongoing (34). Civil lawsuits related to strict product liability are expected to increase with a rise in consumption (78). Due to foreseeable increases in restrictions, producers are calculating those risks based on regulations within each jurisdiction and are attempting to move forward to claim market share (25).

CBD-infused food has become widely available despite unclear safety parameters for such use. This systematic review of research and regulations identified how legality of CBD foods in the United States corresponds to safety issues. The research also included an emphasis on dose, a key factor for determining safety in foods. Research and analysis first addressed what safety-related restrictions current legal jurisdictions are using, with a review of statutes and guidance. Then, a review of the literature on dosage explores what is known about “safe dose” of CBD as consumed in foods, and whether there is enough information available to inform this quantity in foods within U.S. regulations.

Methodology for researching CBD regulations is described first, followed by the methodology used for researching safe dose.

Regulations

The laws and guidance for hemp-derived CBD in food were researched in the 18 states that have legalized recreational marijuana, as identified from the National Conference of State Legislatures, and states that have a hemp program for regulating the growth and production of hemp products (56) (Table 1). These states have established regulations for selling cannabis extracts, including THC- and CBD-infused food products, to the public through licensed dispensaries (18). Although they vary, state recreational marijuana laws also have established restrictions, including those pertaining to THC dose (38). Current laws and policies for producing food containing hemp derivatives within state departments of agriculture and health (or equivalent agencies governing food) and, if referenced, state agencies charged with regulating production and sales of cannabis products were examined.

TABLE 1

Regulatory status of cannabis in the United States as of December 2021a

Regulatory status of cannabis in the United States as of December 2021a
Regulatory status of cannabis in the United States as of December 2021a

Findings were organized by legal status and restrictions. A subset of legal jurisdictions for CBD in food was identified, and their restrictions are listed in Table 2 for comparison to safety issues relevant to FDA concerns as stated by Abernethy (1).

TABLE 2

Regulations for legalized CBD in food of studied states

Regulations for legalized CBD in food of studied states
Regulations for legalized CBD in food of studied states

Guidance on quantifying CBD in food, how it can be sold (where and who can purchase), and any warnings or prohibitions for use were noted. Findings were compared among jurisdictions and to FDA safety concerns. Gaps in restrictions were identified for safety issues.

Dose research

A Food Science and Technology Abstracts (Web of Knowledge) search was conducted of the Web of Science Core Collection using (cannabidiol AND dose) AND (toxic* OR safe*) AND (food OR oral) NOT (treatment) as terms and narrowed to studies in English within the last 10 years. Terms were selected to identify studies related to safety or toxicity of oral doses potentially relevant to consumption in food. Treatment was excluded in search terms to eliminate studies primarily focused on treatment outcomes rather than dose. For inclusion, articles must have studied and provided insight on safe dose or toxicity of CBD at certain dose levels. Although an important topic, studies on drug interactions were excluded to maintain focus on safe dosages. Treatment of disease and conditions, dosages of THC, and alternative products, such as synthetics, were excluded. Review articles were used only for relevance and for potential references to primary research within them; they were excluded if significant insights into dose were not present. Figure 1 provides additional detail on the selection process of dose studies.

FIGURE 1

Schematic representation showing selection of dose studies through the process of the systematic literature review.

FIGURE 1

Schematic representation showing selection of dose studies through the process of the systematic literature review.

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Findings were reported as an overview of the selected studies' design, scope, analysis, and resulting data. Resulting data were organized by key topics for safety in food observed from the studies: safe dose quantities, safe doses to special populations, and safety in food.

A standard form was used to extract data consistently for each study. Study name, purpose, type, methods, products and dosages tested, time period for dosing and observation, and study results were recorded. Strengths and weaknesses of each study were noted based on evaluation of the study and author-reported limitations.

Reported data were synthesized by evaluating similarities, differences, and gaps in findings and were compared to FDA standards for addressing safety in food. Synthesis addressed what is known and still needs to be researched in terms of safe dose, cumulative exposure, and special populations in the context of usual consumption or self-treatment through food.

Outcomes from research on current CBD regulations at state and federal levels are presented followed by the resulting data from safe dose research.

Regulations

The legal status of CBD in food in the 18 states with legal recreational marijuana, as identified in Table 1, ranges from illegal in any form, as in Massachusetts (46), to legal in foods and dietary supplements, as in Colorado (15), with variable legality in between. Some states allow or imply legality of CBD foods through licensed marijuana dispensaries only. CBD foods may be sold in licensed dispensaries in Illinois, but there is no definitive law or clear policy for CBD in any foods (20). Arizona and New Jersey indicate that jurisdiction of food products falls outside of its hemp program (3, 60).

Massachusetts, Michigan, Montana, Nevada, and Washington have government-issued publications stating the illegality of CBD in food (8, 46, 51, 53, 59, 96). Michigan and Washington allow CBD in food only through their licensed marijuana dispensaries (51, 97). However, Michigan has no approved methods for these facilities to source hemp for such use (51). Montana, having approved recreational marijuana in 2020, only allows CBD in food through its medical marijuana guidelines, but the state has not updated documents to reflect recreational status (53). Nevada's CBD fact sheet states CBD is legal if sold from an approved dispensary in a marijuana product, but it does not indicate if CBD-only products are permitted (59).

Like Illinois and New Mexico, Oregon's laws for CBD in most food are vague, and the legality of hemp in food is stated as “unclear” in published Oregon Department of Agriculture fact sheets (63). However, Oregon does allow CBD in food through its licensed marijuana dispensaries, overseen by the Oregon Liquor Control Commission (63, 64). New Mexico approved recreational marijuana in late 2020 but has no mention of CBD in its regulation and guidance at this time (61).

Alaska, California, Colorado, Connecticut, Maine, New York, Vermont, and Virginia have stated legality of CBD in food either by statute or guidance (2, 9, 15, 17, 42, 62, 88, 93). However, there is significant variability in the regulations among these jurisdictions.

Restrictions placed on CBD foods were researched in the jurisdictions in which these foods are currently legal or have pending legislation to make them legal. States with ambiguous legal status or legality only through cannabis-controlled agencies were excluded to identify specific restrictions placed on CBD food products. The findings of state regulations for legal CBD in food are summarized in Table 2.

Economic gains may be a motivation for promoting legality of CBD foods in some states. Hemp production and the lucrative CBD component provide opportunity to boost the U.S. farming industry (71). California's turn toward legalizing CBD in food has been cited as driven by the agricultural industry's demand for a new value crop (73). Imposed restrictions suggest appeasement of safety concerns, while opening a market with strong financial potential. Given a motivation to capitalize on a lucrative market, it is important to understand what, if anything, these jurisdictions are doing to support public safety through restrictions.

Jurisdictions vary in which food and beverage applications for CBD are allowed. Maine's bill, LD 630, specifically legalizes the use of CBD in foods without any stated restrictions on food applications (42). New York excludes CBD as an additive to any alcoholic beverages (62). CBD is legal in some food products governed by the Vermont Agency of Agriculture, such as dairy and maple products (88). However, foods governed by the Vermont Department of Health have no stated policy (90, 91).

New York has proposed the most comprehensive set of guidance for CBD use in food and beverages to ensure consistency in production and transparency (62). These include validated third-party testing of products to ensure that THC is within the 0.3% limit, good manufacturing practices, and traceability of the product to the hemp from which it is derived (62).

Based on the states observed, most legal jurisdictions prohibit health-related claims for CBD products, which has been an enforcement issue at the federal level (83, 86). This is the most common restriction used; it addresses a current FDA safety concern that consumers will seek such foods as self-treatment based on unsubstantiated claims (1). However, this may not deter consumers who already perceive CBD to be a natural and gentle ingredient associated with wellness for which food is a preferable medium (27, 28, 43).

Warnings on labels attempt to provide some measure of safety. New York, Maine, and Colorado require that labels warn consumers that these products undergo no federal evaluation for safety and effectiveness (15, 42, 62). California and New York require a warning for children and pregnant and breastfeeding women (9, 62). This is consistent with research that indicates that CBD can cross the placenta and is found in breastmilk and with the limited available data on safety in children (39). New York also requires a warning that consumption may result in testing positive for THC in a drug test, unless the extract used is an isolate (95% CBD) or is sourced from its state hemp program (62). However, the lack of consistency in these warnings across all legal jurisdictions could weaken the intended message to consumers.

Sourcing requirements and mandated product registration may enable more data collection and control over the CBD extracts used and products manufactured, while maintaining the distinction as intrastate commerce. All legal jurisdictions require sourcing from an approved hemp program, but only Maine requires that its hemp be sourced within the state (42). Alaska's requirement to obtain product endorsement by its Department of Agriculture facilitates a control over and cataloguing of CBD product offerings in the state, but a recently published warning letter suggests that there are compliance issues (69). In addition to traceability of source hemp and extracts, New York also requires a means for reporting adverse effects related to consumption of the products (62). Maintaining a current list of all products produced in a state, their source extracts, product applications, and quantities of CBD used could enable more research into safety issues pertaining to specific products.

Defining the CBD extract provides more consistent language for regulation. The hemp plant is composed of a combination of cannabinoids, including CBD, THC, cannabigerol (CBG), cannabinol (CBN), and cannabichromene (CBC), and their acidic forms, CBDA, THCA, CBGA, CBNA, and CBCA, and terpenes, the oils that protect the plant and provide fragrance (37, 65). Vermont's law, V.S.A. 6, § 561-570, and New York's guidelines identify the cannabinoids, define the types of extracts used in products, and require that they meet the specified criteria when listed on the label (62, 89). Both states indicate that CBD products may contain whole hemp plant components, full spectrum extracts (all cannabinoids and terpenes, including THC), broad spectrum extracts (all cannabinoids and terpenes except THC), CBD isolates (95% pure CBD), and distillates (a concentration of selected cannabinoids), but they do not allow synthetic extracts to be used in infused products (62, 89). It is unclear whether the differences in the chemical compositions among these types of extracts may warrant defining them as unique articles for the purposes of safety (45).

Most notably absent are restrictions on potency and dose of CBD. States in which recreational marijuana is legal have varying dose restrictions for THC through their marijuana programs (38), and all require a limit of 0.3% THC in CBD extracts. However, only one jurisdiction reviewed has stated dose limits or parameters for the CBD itself. Colorado requires CBD amount to be indicated, along with quantification of other cannabinoids and ratio of CBD to THC (15). Only New York's guidelines indicate a dose restriction of 25 mg of total cannabinoid per package for food and beverage products. The guidelines also require listing THC and CBD in mg per serving and mg per package as well as the identification of other cannabinoids in the product (44). The New York guidelines enable consumers to control the amount of CBD consumed via portioning requirements (62).

Variability in U.S. regulations also impacts Canada. CBD food products made in Canada are heavily regulated, and a federal license is required for production, distribution, and sales (49). Canadian consumer perception of CBD legality in Canada has been influenced by online marketing of products by U.S. producers (49). As a result, many Canadian consumers are unaware that CBD products are federally regulated in Canada to different standards than in the United States (49).

Studies in the United States and the EU have found that many products do not contain the stated amount of CBD claimed on the labels and may contain significantly more or less than claimed (6, 26, 32, 65, 95). Presence of THC in excess of the 0.3% limit for such products in the United States and above the safety limits established in the EU are also concerning (32, 95). Cannabinoid degradation is a complicating factor because heat and light can degrade the cannabinoid acids and increase the potency of their neutral counterparts (37). THCA converts to THC with heat treatment but is not included measurement for THC threshold (37). Thus, when factors that impact CBD dose are not also regulated, stated quantities are potentially inaccurate and the possibility for unintended THC exposure is a considerable risk.

Inconsistency in regulation of CBD in food presents challenges for both producers and consumers. Producers cannot consistently label and market their products when the requirements vary among jurisdictions. This would also require dedicated resources to interpret and comply with each state's specific legal requirements. A lack of consistent information in labeling, warnings, and standards can create confusion in consumers when they are presented with similar products from different jurisdictions. Further, both producers and consumers are unclear about what quantities of CBD are acceptable in foods. Safe dose parameters and availability of information to inform this in regulations will be addressed in this review's dose research.

Dose

The initial search of the literature related to safe dose of CBD yielded 27 studies. The application of inclusion and exclusion criteria yielded six studies for analysis. (See Fig. 1 for the dose study selection process.) Exclusion criteria eliminated one duplicate title, 14 articles based on review of abstracts, and two articles after reading complete articles. The remaining 10 articles included four review articles, none of which provided a relevant specific study to access and include. A summary of the selected studies and their respective contributions is provided in Table 3.

TABLE 3

Summary of selected dose studies

Summary of selected dose studies
Summary of selected dose studies

The selected studies include four in vivo human studies identified as phase I trials (21, 7577), one feline–canine preliminary study (22), and one study that included an in vivo rat and a comparative rat and human in vitro study (99). All studies, except Deabold et al. (22), imply application of dosing in a clinical setting under medical supervision. Two of the studies focused on special populations (renal (77) and hepatic impairment (75)), and two specifically studied food impact (21, 76). Deabold et al. (22) utilized commercially available hemp-infused products from ElleVet Sciences containing a 50/50 ratio of CBD to CBDA in chews for dogs and fish oil for cats. All other studies sourced pure CBD from GW Pharmaceuticals' Epidiolex.

All selected studies stated externally reviewed and approved methods for study design. Study methods were clearly described in detail and review, and approving organizations were referenced. All studies used relevant controls. As a control group, Zgair et al. (99) compared metabolism of intravenous (i.v.) administration to oral with and without lipids in the in vivo study and rat and human plasma for the in vitro study. Deabold et al. (22) compared blood work prior to administration of the same feline and canine trial participants. The hepatic, renal, and multiple and ascending dose studies utilized placebo control groups to compare groups with short-term exposure (7577). Crockett et al. (21) compared variations of meal types in combination with the same dosage of CBD, using fasting as a control. All studies met criteria for two of two potential points in design.

Each study used qualified chemical analysis tools and included quantitative data analysis, qualifying all for two of two points in the data collection and analysis category. The studies measuring adverse reaction assessments included quantifiable elements, such as electrocardiogram, vomiting, and diarrheal incidents. Scaled assessments were used for measuring observed and reported adverse events for all four human studies in which these were monitored. Four studies used validated bioanalysis assessment processes to quantify CBD and its metabolites in blood samples at intervals (21, 7577). These also observed adverse effects through physical evaluation, assessment of vitals, and reported symptoms during initial evaluation periods and at follow-up periods. Deabold et al. (22) outsourced blood chemistry analyses, with adverse effects being evaluated by veterinarians throughout the 12-week study. Zgair et al. (99) followed similar validated protocols for pharmacokinetics analysis in the in vivo study and utilized an established lipolysis model to process treated human and rat tissues to understand mechanisms for absorption in the in vitro study.

Population size and length of study were evaluated based on parameters for phase 0, I, and II trials. Deabold et al. (22) and Zgair et al. (99) were studies with fewer than 20 subjects each. The remaining four studies used populations ranging from 30 to 76. No studies in this review included large enough populations to meet criteria for phase II. Only Deabold et al. (22) studied subjects for months of cumulative exposure, consistent with phase II trial time lines. The remaining studies used either a single dose or multiple doses within a week.

Potential bias was evaluated by reviewing conflicts of interest stated for each of the studies and methods for bias control used in the study design. Of the six selected studies, five disclosed a conflict of interest that at least one author was an employee of the manufacturer of the product used in the study. Only Zgair (99) stated no conflicts of interest. Crockett et al. (21), Taylor et al. (hepatic) (75), and Taylor et al. (multiple and ascending) (76) dose studies utilized a randomized and/or double-blind approach. No other studies stated bias control methods.

The selected studies explore the safety and pharmacokinetics of single and repeated dosing of CBD, the impact of renal and hepatic impairment, and the food effect on metabolism and safety of CBD.

Dosing at a variety of levels that could be consistent with consumption in food products is necessary to determine the safety of such products. The Taylor et al. (76) multiple and ascending dose study is multifaceted in that it studies a variety of single doses, as well as two multiple dose levels over the course of a week in a fasted state prior to and following dosing. Doses at 1,500, 3,000, 4,500, or 6,000 mg were tested against placebo, revealing no severe adverse effects and decreasing proportionality of absorption relative to increase in dose. Taylor et al. (76) offers that the latter may be due to study design but also suggests that a higher dose may be consistent with less absorption. The multiple dose trial consisted of twice daily doses of 750 or 1,500 mg over 7 days (13 total doses) compared with placebo in a fasted state. Pharmacokinetics analysis indicated that absorption rate is more consistent with dose when administered repeatedly. Although no severe adverse effects were observed, a significant rash was noted in three of six of the participants in the 1,500-mg repeated-dose group 5 to 70 h after the last dose. Taylor et al. (76) suggests that single doses of 6,000 mg in a day or 3,000 mg daily over the course of a week would be within safe margins, but adds caution pending further investigation relative to the rash outcome.

Dosing pertinent to special populations, such as those with underlying health conditions, is relevant to warnings and contraindications. The Taylor et al. (75) study on the impact of hepatic impairment on CBD safety mirrors the Tayo et al. (77) study relative to renal damage. Both studies tested a single 200-mg dose of pure CBD among approximately 30 total participants with mild, moderate, and severely impaired kidneys or livers relative to placebo after a low-protein breakfast (75, 77). Results at this dose yielded no significant adverse events relative to placebo for either study. Tayo et al. (77) determined that kidney damage did not have a significant impact on pharmacokinetics of CBD. However, Taylor et al. (75) noted that moderate and severe liver damage limited the conversion of CBD to one of its primary metabolites. Thus, increased CBD exposure is likely, and dose reduction is recommended for this subpopulation.

Studies with nonhuman subjects also point to liver-related issues. Deabold et al. (22) presented the only multiple-week study consisting of twice daily dosages to healthy cats and dogs of commercially available hemp-infused animal products over the course of 84 days. Dosages were established at 2 mg of CBD per kg of animal body weight (22). Elevated liver enzyme levels in one feline were observed throughout the study, and a referenced prior study of higher dosages to canines revealed similar elevated levels (48). Based on this, Deabold et al. (22) determined the dosages to be relatively safe but recommended monitoring liver enzyme levels in future research. This suggests that a 68-kg (150-lb) human may tolerate 136 mg twice daily in food, if this dosage is applied directly interspecies.

Because safe use of CBD in foods is central to this review, it is important to understand how food impacts key pharmacokinetics of CBD consumption and to assess adverse effects. The Crockett et al. (21) study and the food effect arm of the Taylor et al. (77) study provide such analysis. Crockett et al. (21) compared results across a variety of meal types, including high fat and high calorie, low fat and low calorie, milk, and fasted states using a single 750-mg dose. Taylor et al. (75) compared high fat and high calorie and fasted states across its single-dose-level groups, excluding the 6,000-mg group. The results of both studies consistently indicate that higher fat levels increase bioavailability and, thus, increase CBD exposure in combination with fats with no significant increase in adverse effects (21, 76). Alcohol also increased CBD exposure, but to a lesser extent than seen in foods with fats (21). These studies suggest that fat consumption would make CBD more effective in a clinical treatment setting by making it more bioavailable. Whereas there is implication that doses as high as 4,500 mg would be safe even with a high-fat meal (76), it is unclear whether the increased CBD exposure relative to higher fat content would produce a safety concern in self-dosing through infused foods.

The Zgair et al. (99) study attempts to quantify the effect of lipids on CBD bioavailability and to explain how this occurs. The in vivo rat study compared plasma levels of CBD at intervals following i.v. injection, oral administration in a nonlipid solution, and oral administration in a lipid-based solution. This revealed a threefold increase in bioavailability of CBD in lipids relative to that in nonlipid solution. The in vitro study modeling digestion identified lipid activation of the lymphatic transport as the mechanism for increasing exposure of CBD when combined with fats. This was expressed similarly in rat and human blood. Zgair et al. (99) cautions that use of fats should be a factor in determining potency, and the quantity of fat required for such shifts in potency could be easily achieved in a high-fat infused food.

Although this review is not intended to identify a specific safe dose for food, it is meant to reveal enough data to inform dose quantities through food for self-treatment and ordinary consumption. Findings from the selected studies point to gaps in the information necessary to understand safe consumption quantities in food.

Based on data from the studies selected, there is insufficient information to establish safe single and cumulative doses. Cogan (14) points to an absence of phase III studies, which require large sample sizes; the selected studies represent phase I or preliminary studies with small sample sizes. The FDA's food ingredient approval process requires information regarding cumulative exposure of up to 24 months (67); however, Deabold et al. (22) provide the longest study at 12 weeks.

Data from the selected studies provide preliminary information for additional study but not a widely tested threshold of safety. The FDA-approved maximum therapeutic dose level is 20 mg/kg of body weight per day, or 1,400 mg for a 70-kg adult for seizure disorder (7). Single doses up to 6,000- and 3,000-mg daily doses deemed “safe” in the Taylor et al. (76) single ascending and multiple dose study could reveal more safety issues if executed on a larger scale. Some adverse effects, such as rashes observed in the multiple dose setting, may prove more significant over longer exposure and should be investigated (76). Other noted toxicity studies in rats of pure CBD found no adverse effect levels that ranged from 100 to 800 mg/day, but these do not reflect food applications (24, 40). These lower levels may present a more conservative upper limit for a suggested range and could be explored for further testing. However, it is not clear what doses are relevant for testing in food applications because ordinary consumption quantities, estimated daily intake from all potential sources, and cumulative exposure are not available for reference.

The context of the studies is important both in how safety is evaluated and how the product is consumed. All selected studies except Deabold et al. (22) utilized a pharmaceutical-grade pure extract. The Crockett et al. study, the two studies by Taylor et al., and the Tayo et al. study each evaluated outcomes relative to a treatment context (21, 7577). These factors suggest that a mild or moderate adverse effect in a treatment context might be viewed as less significant than in the context of self-treatment or casual consumption. Raised liver enzymes in the Taylor et al. hepatic study (76) could be more concerning in combination with other substances, including foods and drugs, leading to contraindications. Drug–drug interactions have been observed between CBD and some commonly used medications, resulting in an increased risk of side effects of these medications (7, 26). Dose in the clinical studies is significantly higher than that typically found in food products, but a non–peer-reviewed study reported drug interactions at doses as low as 1 mg/kg (11). Some of these drugs also increase the bioavailability of the CBD consumed, amplifying the effects of the CBD (7). It is also important to understand how a threefold increase in CBD exposure could increase this risk factor if it is consumed with or as part of a food (99). Other research estimates a four- to fivefold increase with a high fat or calorie diet, which suggests that exposure varies with different foods (5, 11). Research into CBD consumption in ordinary foods, common in the infused food market, is essential. Further, an estimated daily intake is necessary to understand how much exposure a person is likely to have with routine consumption from all potential sources (67).

There is limited information about CBD products and how their compositions can differ from the form used in approved products that have been tested for adverse effects (85). Only the Deabold et al. study (22) used a commercially available hemp-infused product, which contained a 50/50 mix of CBD and CBDA, another cannabinoid. The remaining studies used purified CBD isolate, yet foods may be infused with one of the several types of extracts noted in Vermont law (89). Purified CBD used in Epidiolex has a different chemical composition than full extracts (6). Studies on how these cannabinoids and terpenes interact suggest an “entourage effect” that may impact potency and safety (6, 12, 13, 68). When the source extracts within products vary, safety standards that apply to one may not apply to another; thus, information on the safety of different extracts is needed to determine whether these should be categorized as unique articles or whether they could be distinguished from the extract used for Epidiolex.

The selected studies point to a wide gap in the knowledge necessary to inform a specific safe dose in the regulation of infused foods. More data is needed to understand the composition of the various CBD extracts used in foods and their safety profiles, the relationship between different food applications and CBD exposure, the cumulative and long-term exposure to larger populations, and estimation of a daily intake from all potential exposures to determine what dose thresholds are relevant to test.

Bias

Selection and interpretation of data were potential bias factors in the legal search and analysis processes. Selection bias was possible because the search process for legal positions and regulations required a targeted approach to investigating each relevant agency. Differences among states in government structure and in where and how legal status is communicated created challenges in finding a legal position; this provided an opportunity for unintentional omission. Interpretation of state policy may also be biased in instances in which no laws were stated and only fact sheets provided information. In some states, policy provided a reference to federal legal status but did not indicate whether enforcement within the state would occur.

Bias is relevant in the dose studies relative to source of study and purpose. Of the six articles selected, only the authors of Zgair et al. (99)  have no declared biases or notable connection to the outcome. One of the authors of Deabold et al. (22) is an employee of ElleVet, the company providing the product for the study. Authors of the remaining studies include employees from GW Pharmaceuticals, maker of the Epidiolex product used in the studies. Bias in these instances may understate risk in terms of subjective factors, such as severity of adverse effects. Of the six selected studies, four share authors with at least one other study, which may skew collective data from multiple studies toward the interpretation of a few authors. The studies, excluding Deabold et al., assess safety relevant to use of CBD as a drug, not as a food ingredient (21, 22, 7577, 99). Consumption monitored under a physician's care is likely assumed versus self-administration through foods.

Selection and interpretation are potential bias factors in this study's approach to the search and selection of research. The specific search tools used in the study may have also contributed to bias by limiting information sources. Limited expertise on the topic may also skew interpretation of the data.

Limitations

State law and guidance is limited in some states. They offer limited or no statements or laws that declare the position on legality, which suggests only the absence of a stated policy. This does not account for policy that may be implied or interpreted by state and local regulatory agencies but not published in specific terms. CBD is also a current and evolving topic with active legislation in process; thus, information will be dated by the time writing of this paper is completed.

This review is limited by the availability of studies and information relevant to dose of CBD in food as an emerging product. Search criteria using available databases may have limited the quantity and quality of the studies. Research of ingested CBD is skewed to its use in drug form due to past regulations, Controlled Substances Act scheduling of CBD, and its current status as a drug (16, 47, 50). Federal approval for CBD use as a drug provides more data on applications for treatment and tolerance in clinical settings. Its use in foods in limited legal jurisdictions, and its illegal use in other jurisdictions, may create barriers for availability, the quality of research, and cooperation of subjects for such studies.

This review of studies identified that a lack of robust data precludes safe dose parameters applicable to ordinary consumption of infused foods to the public-at-large. This can be attributed to the legal restrictions imposed on CBD, which substantially limit its research potential, first with Controlled Substances Act scheduling and then as a drug ingredient (47, 50).

In supervised settings, using pure CBD isolate, a range of single and multiple short-term doses produced no severe adverse effects. However, a lower threshold, such as an acceptable daily intake, informed by a no adverse effect level or lowest adverse effect level with chronic exposure, seems more appropriate for CBD foods available for regular consumption. Current research does not address all potential exposures to provide an accurate estimated daily intake, which is necessary to understand cumulative exposure and what doses are relevant for testing for food consumption. Studies with larger populations over extended periods of time were not available to extrapolate risk to the general population. CBD's increased exposure consumed with fats has been estimated, but a range for the variety of food applications has not been quantified. Current research does not account for variability in extracts that could be used in food, which should be tested for safety. These gaps in data do not inform parameters for regulating dose.

Legal jurisdictions provide limited safety measures for consumers. Some state regulations require safety warnings and exclusion of health-related claims. However, these precautions may do little to deter consumers who have preconceived ideas about the safety and benefits of CBD. A lack of standardization in labeling specific CBD quantities per serving and types of extracts can lead to wide variability of CBD exposure and potential safety risks. Some state regulations provide opportunities for best practices, such as defining extracts and requiring product traceability, but these are not used consistently or clearly for this purpose. With no consistent CBD parameters per serving or standards for communicating the actual type of extract used among jurisdictions, consumers are left to assume safety at any dose and type of extract presented.

Unregulated products can lead to other safety risks. Uncontrolled sources of CBD can be contaminated with chemicals (used to increase plant yield or potency), heavy metals, mold, bacteria, pesticides, solvents for extraction, and synthetic cannabinoids (34, 50). Also, because hemp naturally absorbs heavy metals from soil, control measures are required (50). Products without standardized extracts may contain other cannabinoids that have not been studied for safety, such as CBG, THCV, CBDA, and THCA (34). CBD and synthetic material are subject to degradation in certain storage conditions, which may impact its potency and label accuracy (41).

The growing demand for CBD products could and, in fact, has motivated evasive and misleading business practices, leading to more product safety concerns (94). Companies have added drugs or their equivalents to supplements in the past to enhance benefits of their product (94). Manufacturers of food and supplements may increase dosages of CBD to achieve prescription levels with these widely available products (41). Manufacturers have marketed their products as containing “hemp extracts” instead of cannabinoids, which would serve as a red flag for illegal additives (50). Companies are currently working around the federal patent and trademark laws, which prohibit CBD in food due to the FDA's position, by creating duplicate product lines without CBD to get a patent, trademark, or copyright (71). In the absence of clear and strict regulations or guidelines, producers may make their own rules.

Sheehan and Roy (71) suggest that agencies should focus on regulations that protect consumers with safe, quality products rather than on preventing the inevitable access to them (71). Hemp's questionable regulatory link to marijuana ultimately negated any opportunity for CBD to be a food or dietary ingredient prior to its introduction as a drug (44). Prior to the 2018 Farm Bill, CBD could not be produced legally in foods or supplements, and the introduction of Epidiolex the same year prevented future introduction of these products (44). Such an argument could serve as a rationale for a new regulation allowing the use of hemp-derived CBD in food or supplements.

The cannabinoid market is unrestrained in many regards, and many producers would welcome a regulatory framework that could address quality issues related to CBD products (34, 94). Existing FDA requirements for food, food additives, and supplements include facility registration; compliance with current good manufacturing practices; mandatory recall authority; adulteration and misbranding provisions; and adverse event reporting for dietary supplements (16, 87). Such controls should include labeling requirements that reflect accurate ingredients, the product composition, and how it was manufactured (34).

The FDA could authorize and facilitate a conditional product registration with detailed parameters. Walker et al. (94) recommend a corporate stewardship program that would include third-party verification of adherence to quality and safety standards through current good manufacturing practices, conditional registration, product analysis and testing, adverse events reporting, and sharing of safety data from this process to generate best practices. Such a program could optimize quality and safety control measures and generate more producer transparency and accountability, discouraging unethical and unsafe practices from the market (34).

Conditional registration is used by the Environmental Protection Agency for pesticides for a 2-year period to gather data on the safety profile and adverse effects on pets (94). The agency worked with pesticide industry stakeholders to develop best practices and a path to full registration with a record of safety to support it (94). A similar program for CBD food products could drive more competent manufacturing with greater accountability and establish a surveillance system to monitor safety and lead to more informed regulation (34, 94).

FDA should also provide guidelines for states to promote greater standardization among states and the safety of products under their jurisdictions. These should include clear guidelines for the specific extracts, disclosure of specific and accurate information about CBD quantity and extracts on labels, and product traceability. States with legalized CBD in food should continue to prohibit use of health-related claims and enforce the prohibition. Stronger and more prominent language regarding warnings, including a recommendation to consult a physician before use, is suggested. Medical professionals and the government should be provided with tools to educate consumers about the effects of CBD use and to clear up consumer misconceptions, and to identify adverse events at the local level (30).

Future research

There is significant opportunity for future research to inform safe quantities of CBD for regulation of infused foods. This research should address the type of CBD extract and its applications, quantification and safety of potential consumption, and regulatory best practices for consistency.

Differences in CBD in its various extract forms and food applications should be more clearly defined. The forms of CBD extracts should be compared for chemical compositions, pharmacokinetics, metabolism, and adverse effects to determine whether these should be defined as unique articles with different safety profiles. CBD in typical food applications used for CBD can be compared for variations in bioavailability and adverse effects across a wider span of product categories. Additional research is needed to determine whether dose levels in CBD foods and supplements could generate drug-level effects (11). Research from the pet food and supplement industry and extrapolation of relevant data could be used to speed the research process.

Quantities and time frames of exposure relevant to CBD food consumption should be identified and used for safety studies. Estimated daily intake from all potential sources could be researched among users in legal states to determine what dosages should be tested. Data such as that from phase III trials, using larger populations over longer periods of time, are needed to more accurately assess the safety of those doses. Identifying a no adverse effect level and lowest adverse effect level using these more expansive studies presents another opportunity for research.

New York's current guidelines provide an example of how state regulation of CBD in food and supplements can be used to gather more information about safety of CBD in food. New York's required adverse effect reporting system for cannabinoid-infused foods and supplements can identify dose safety issues relative to its maximum limit for foods (25 mg per package) and supplements (3,000 mg per package and 75 mg per serving) (62). The state's traceback requirement has potential to apprise regulators of dose safety issues related to its hemp source and extract types (62). Recommendation of standard guidelines such as these in other states could generate more robust data to inform dose or acceptable daily intake within U.S. products.

The European Food Safety Authority's risk assessment process for novel foods in the EU and the United Kingdom could provide a model for informing and establishing U.S. safety guidelines, including dose limits with cumulative exposure, for CBD foods. The European application process requests that the applicant provide validation of scientific data related to safety of the food and also requires toxicological studies (92). Because the novel food process applies to all cannabinoids, toxicological data could also be obtained for different types of extracts and their cannabinoid components (92). This process is also designed to review the safety and toxicology of the cannabinoid in its food or beverage application (92). Such data is important in understanding how certain food and beverage applications can impact the bioavailability of the cannabinoids and the potential for increased adverse effects.

The European Food Safety Authority currently provides guidance for an upper limit of daily intake of THC to be 1 mg/kg of body weight per day, equating to 70 mg for a person weighing 70 kg (approximately 154 lb). Reports from the United Kingdom suggest a lowest adverse effect level of CBD in humans of 4 mg/day for a 70-kg adult, based on hepatic toxicity from human and animal research (74). These limits can be validated further with additional data generated from the novel food application process.

Research obtained from the EU novel food process is intended to be publicly available and could increase the amount of toxicological data on CBD in food (35). The establishment of conditional registration with guidelines in the United States and the incorporation of similar elements of this system at the federal level could compound this data to inform safe quantities of CBD in food. Opening the legal path to CBD foods and supplements with such a process and driving producers to it could bridge the research gap significantly for CBD dose, while also addressing safety concerns in an existing and growing market.

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