The current understanding of the benefits, safety, and regulation of cannabidiol in consumer products

Abstract

The popularity of cannabidiol (CBD) in consumer products is soaring as consumers are using CBD for general health and well-being as well as to seek relief from ailments especially pain, inflammation, anxiety, depression, and sleep disorders. However, there is limited data currently in the public domain that provide support for these benefits. By contrast, a significant amount of safety evaluation data for CBD has been obtained recently from pre-clinical and clinical studies of the CBD therapeutic Epidiolex®. Yet some key data gaps concerning the safe use of CBD still remain. Furthermore, current regulations on CBD use in consumer products remain uncertain and often conflict between the state and federal level. In light of the rapidly expanding popularity of CBD-related products in the marketplace, here we review the current understanding of the benefits, safety, and regulations surrounding CBD in consumer products. This review does not advocate for or against the use of CBD in consumer products. Rather this review seeks to assess the state-of-the-science on the health effects and safety of CBD, to identify critical knowledge gaps for future studies, and to raise the awareness of the current regulations that govern CBD use in consumer products.

1. Introduction

Phytocannabinoids represent a class of structurally related compounds produced by Cannabis sativa, also commonly known as marijuana or hemp. Marijuana and hemp are classified under U.S. law based on the quantity of Δ⁹-tetrahydrocannabinol (THC) in cannabis or its derivatives, with hemp containing not more than 0.3% of THC by dry weight. Cannabidiol (CBD) is one of more than one hundred cannabinoids now identified in cannabis (ElSohly et al., 2017). The popularity of CBD in consumer products has significantly increased in the past few years. As of 2018, the estimated retail sales of CBD as an herbal supplement increased by more than 300% in the prior two years, thus making CBD not only the fastest-growing product category but also the top-selling ingredient in the U.S. natural channel (Smith et al., 2019). It has been estimated that the total U.S. CBD market could soon become a multi-billion-dollar industry.

Consumer products containing CBD are available in a variety of forms, including tinctures/oil dropper, gel/capsules, edibles, vapes and topicals. These products are widely available, found online, in smoke shops, specialty outlets, pharmacies, and in retail and grocery outlets. A cross-sectional survey revealed that 38.4% of CBD consumers use CBD for general health and well-being benefits while the remaining 61.6% use CBD to provide relief from pain, inflammation, anxiety, depression and to help improve the quality of sleep (Corroon and Phillips, 2018).

Although CBD-containing products are increasingly popular with consumers, there is a shortage of scientifically derived data in the public domain that provide support for many of the benefits reported by consumers. In addition, a considerable amount of safety evaluation data on CBD have derived from pre-clinical and clinical studies during the development of the CBD therapeutic, Epidiolex®, but there are still data gaps regarding the safe use of CBD. Moreover, quality assurance such as label accuracy and purity have remained a safety- and regulatory-related concern with CBD-containing products. Furthermore, regulations pertaining to CBD use in consumer products are often unclear and still evolving.

Considering the rapidly expanding popularity of CBD-related products in the marketplace, the intent of this review is to summarize current understanding of the benefits, safety, and regulations surrounding the use of CBD in consumer products. This review does not advocate for or against the use of CBD. Rather, this review assesses the state-of-the-science on the health effects and safety of CBD, identifies critical knowledge gaps, and summarizes U.S. regulations pertaining to CBD use in consumer products.

2. Pharmacological properties of CBD

CBD was first isolated in 1940 and its structure was elucidated in1963 (Mechoulam and Shvo, 1963). The chemical structure of CBD is remarkably similar to THC (Fig. 1), the primary psychotropic cannabinoid congener in cannabis that is responsible for producing the euphoria and high associated with cannabis use. Yet, unlike THC, CBD is not psychotropic and exhibits low binding affinity to the canonical cannabinoid receptor type1 (CB1) and type 2 (CB2) (Matsuda et al., 1990; Munro et al., 1993).

Figure 1.

The chemical structure of Δ⁹-tetrahydrocannabinol (THC) (A) and cannabidiol (CBD) (B).

A growing body of evidence in the scientific literature suggests that CBD modulates (activates or inhibits) a variety of biological targets, including transient receptor potential vanilloid type 1 (TRPV1), 5-HT1A serotonin receptor, adenosine A_2A, fatty acid amide hydrolase (FAAH), peroxisome proliferator-activated receptor gamma (PPAR-γ), and G protein-coupled receptor GPR55 (National Academies of Sciences Engineering and Medicine, 2017; Zlebnik and Cheer, 2016). Given these interactions, a diverse assortment of therapeutic properties of CBD have been investigated including anti-epileptic properties, anti-inflammatory activity, anxiolytic properties, neuropathic pain relief, and neuroprotection (National Academies of Sciences Engineering and Medicine, 2017; Pisanti et al., 2017).

Currently, two CBD-containing medications have been approved by regulatory authorities for a narrowly defined set of therapeutic uses. The first is Sativex® (nabiximols), which consists of equal parts of CBD and THC and is used to treat neuropathic pain and spasticity due to multiple sclerosis. Sativex® was approved in 2005 in Canada by Health Canada and in 2010 in United Kingdom by Medicines and Healthcare products Regulatory Agency. Following the approval in United Kingdom, a European Mutual Recognition Procedure (MRP) for Sativex® was completed in 2012 expanding the availability of Sativex® to additional European countries. However, Sativex® has not been approved in the United States by the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER). The other CBD-containing pharmaceutical is Epidiolex®, which was approved by the U.S. FDA CDER in 2018 for the treatment of two rare and severe forms of epilepsy, Dravet syndrome and Lennox-Gastaut syndrome. The other putative therapeutic properties ascribed to CBD are yet to be clinically confirmed. Based on the ClinicalTrials.gov database maintained by the U.S. National Library of Medicine, a search conducted on January 12, 2021 revealed that there were over 200 ongoing clinical trials exploring various pharmacological and therapeutic effects of CBD.

3. The current knowledge and data gaps in supporting consumer benefits of CBD

The soaring popularity of CBD products is primarily attributable to a broad range of consumer-perceived benefits. Recently, a comprehensive survey was conducted to assess the underlying reasons for CBD use in 2409 self-described CBD users most of whom reside in the U.S. (Corroon and Phillips, 2018). This survey revealed that 1483 respondents reported using CBD to relieve at least one ailment, with a total of more than 3963 ailments being reported. The top five most frequently mentioned conditions were chronic pain, arthritis/joint pain, anxiety, depression, and sleep disorders, which accounted for more than two-thirds of conditions for which respondents reported using CBD (Corroon and Phillips, 2018). Similarly, a recent study surveyed 135 CBD users to explore CBD knowledge, attitudes and use among young adults also found that the most prevalent reasons for CBD use included stress relief, relaxation and sleep improvement (Wheeler et al., 2020).

The following sections from 3.1 to 3.4 provide an overview of what is scientifically known about the mechanisms by which CBD could mediate these consumer-perceived benefits. Much of what is known about CBD safety and effectiveness derives from studies conducted to assess the therapeutic benefits of CBD. It is noteworthy that consumer products are not therapeutics and therefore cannot lawfully carry claims that the product is intended to diagnose, treat, cure, prevent, or mitigate disease.

3.1. Pain and inflammation

Cannabis, the source of CBD, has been used to relieve pain for centuries (ElSohly et al., 2017; Tanasescu et al., 2011b). Therefore, this section will start with a brief summary of the effects of cannabis on pain management and then focus on the current knowledge and data gaps regarding the effect of CBD on pain and inflammation. A large body of scientific literature pertaining to the analgesic properties of cannabis exists, primarily comprised of animal studies. In addition, some human clinical trials have also been conducted. In 2017, the National Academies of Science, Engineering and Medicine reviewed published scientific literature and concluded that there was substantial evidence that cannabis is an effective treatment for chronic pain in adults. Meanwhile, it noted that “very little is known about the efficacy, dose, routes of administration, or side effects of commonly used and commercially available cannabis products in the United States.” (National Academies of Sciences Engineering and Medicine, 2017). In terms of medical use, Sativex® (nabiximols), as mentioned earlier, is a cannabis-derived therapeutic with a standardized preparation, composition, and formulation, which contains approximately equal parts of CBD and THC and is prescribed to alleviate neuropathic pain in multiple sclerosis and intractable cancer pain (Tanasescu et al., 2011a).

It is widely recognized that the primary analgesic constituent in cannabis is THC, which produces analgesia by binding CB1 in the central nervous system to block the release of painpropagating neurotransmitters in the brain and spinal cord (Cichewicz, 2004; Wilson and Nicoll, 2002). Although CBD exhibits 2–3 orders of magnitude lower binding affinity (Ki values range from 2860 nM to 27542 nM) for cannabinoid receptors (i.e., CB1 and CB2) as compared to THC (Ki values ranges from 3.1 nM to 80.3 nM) (Pertwee, 2008), an analgesic effect of CBD is suggested by recent studies primarily in animal models (Urits et al., 2019). The potential underlying mechanisms include the modulation of a variety of neural receptor-mediated pathways in the central nervous system, such as the serotonin 1A receptor 5-HT1A and N-methyl-D-aspartate acid receptors (Rodriguez-Munoz et al., 2018; Ward et al., 2014). Studies also suggest that CBD-mediated anti-inflammatory activity plays an important role in mitigating neuropathic pain and arthritis associated pain (Hammell et al., 2016; Malfait et al., 2000; Philpott et al., 2017; Toth et al., 2010).

Inflammation is one of several essential mechanisms by which the immune system destroys invading pathogens to protect the host from infection. However, excessive or unresolved inflammation can cause tissue injury and damage, and contributes to the etiology and progression of many diseases and disorders, including rheumatoid arthritis, neuropathic pain, neurodegenerative disease, obesity and metabolic syndrome, types I and II diabetes, atherosclerosis, hypertension, and depression (Booz, 2011; Burstein, 2015; Nathan and Ding, 2010). As reviewed by Nichols and Kaplan, there is a large historical database, albeit primarily in animal models, overwhelmingly demonstrating that CBD possesses anti-inflammatory properties that might contribute to the attenuation of many inflammation-associated ailments, including arthritis, diabetes, sciatic nerve pain, colitis, ischemic injuries, and autoimmune diseases such as experimental autoimmune encephalomyelitis, multiple sclerosis, experimental autoimmune hepatitis, experimental autoimmune myocarditis and experimental autoimmune diabetes (Nichols and Kaplan, 2019). The potential mechanisms by which CBD suppresses inflammatory responses include activation of CB2 (Castillo et al., 2010; Pazos et al., 2013; Petrosino et al., 2018; Vuolo et al., 2019), TRPV1 (Costa et al., 2004; Costa et al., 2007; Couch et al., 2017; Petrosino et al., 2018), adenosine A_2A (Carrier et al., 2006; Castillo et al., 2010; Liou et al., 2008), PPAR-γ (De Filippis et al., 2011; Esposito et al., 2011; Hind et al., 2016; Sonego et al., 2018), 5-HT1A (Hind et al., 2016; Pazos et al., 2013), and antagonism of GPR55 (Chiurchiu et al., 2015). Given the involvement of inflammation in many, if not most disorders, the anti-inflammatory properties of CBD demonstrated in animal and cell-based studies, albeit remaining to be confirmed in human clinical studies, may be contributing to the popularity of CBD products in the marketplace.

It is noteworthy that currently available studies investigating the effects of CBD on pain and inflammation are mainly based on animal models (Nichols and Kaplan, 2019; Urits et al., 2019). In addition, human clinical trials on pain management using cannabinoids typically contain both THC and CBD, making it difficult to evaluate the effects attributable specifically to CBD (Mucke et al., 2018; White, 2019; Whiting et al., 2015). The scarcity of human studies in the public domain for CBD represents a significant data gap and research opportunity. Clearly there is a need for more randomized controlled clinical trials to evaluate the effects of CBD on pain management and mitigation of inflammation. Likewise, mechanistic studies are needed to define the specific molecular targets responsible for the anti-inflammatory properties of CBD.

3.2. Anxiety

Anxiety is an adaptive reaction that naturally occurs in response to perceived threats; however, excessive anxiety can cause adverse psychological and physical consequences and interfere with activities of daily life (Tovote et al., 2015). Animal studies conducted in the past several decades suggesting that CBD attenuates stress-induced anxiety-like behavior as reviewed by Lee at al. (2017). Multiple pharmacological mechanisms underlying the anxiolytic activity of CBD have been proposed and investigated, and are thought to involve the 5-HT1A serotonin receptor, TRPV1 and endocannabinoid signaling (Lee et al., 2017; Papagianni and Stevenson, 2019). Some studies suggest that moderate doses of CBD attenuate anxiety by activating 5-HT1A receptors, whereas higher doses of CBD result in a loss of anxiolytic effects by concomitantly activating TRPV1, which correlates with the observed bell-shaped dose-response curve of CBD in many animal studies as reviewed by Lee at al. (2017). In addition, cannabinoid receptor signaling also plays a role in the anxiolytic effects of CBD by regulating learned fear processing. Despite low binding affinity to cannabinoid receptors, CB1 and CB2, CBD has been proposed to indirectly activate endocannabinoid signaling by impairing the degradation of anandamide, an endogenous cannabinoid receptor agonist (Blessing et al., 2015; Campos et al., 2012; de Mello Schier et al., 2014; Izzo et al., 2009; Papagianni and Stevenson, 2019; Patel et al., 2017; Skelley et al., 2020). In light of promising effects in animal models, there have been approximately a dozen clinical trials conducted to date assessing the effectiveness of CBD in attenuating anxiety elicited by a variety of stressors, including public speaking, visual and auditory stimuli, electric shock, and 3D virtual reality-provided stressors (Blessing et al., 2015; Larsen and Shahinas, 2020; Lee et al., 2017; Skelley et al., 2020; White, 2019). As reviewed by White (2019), three double-blinded, randomized, and placebo controlled clinical trials with a relatively limited number of participants (ranging from 24 to 60) have shown that a single dose of CBD (ranging from 100 to 900 mg), when administered prophylactically, might relieve anxiety provoked by public speaking. Similar to animal studies, a bell-shaped dose-response curve was also observed for the anxiolytic effects of CBD in these clinical trials. Meanwhile, the results from seven other double-blinded, randomized, and placebo controlled clinical studies with a relatively limited number of participants (ranging from 10 to 48) assessing the anxiolytic effects of CBD under anxiety-provoking situations (aside from public speaking) were inconsistent. Therefore, it is presently unclear whether CBD is effective in reducing anxiety in a non-public speaking anxiety-provoking event (White, 2019). In addition, a number of limitations were identified in the currently available clinical trials assessing the effects of CBD on reducing anxiety, which include small sample size, variety of dosing schedules and routes of administration, lack of a standardized assessment tool, and the heterogeneity of anxiety-provoking stressors (Larsen and Shahinas, 2020; Lee et al., 2017; Skelley et al., 2020; White, 2019). Based on these limitations, additional clinical studies with larger sample size using more defined study designs are needed to further evaluate the anxiolytic efficacy of CBD.

3.3. Depression

Depression is one of the most common mental health disorders characterized by the presence of sad, empty, or irritable mood, accompanied by somatic and cognitive changes that affect the individual’s capacity to function (American Psychiatric Association, 2013). As reviewed by Silote et al. (2019), 14 studies have reported on the antidepressant-like properties of CBD since 2010. Nine of these 14 studies were conducted in animal models employing what is termed the forced swimming test, a testing paradigm widely used to assess antidepressant effects. Potential pharmacological mechanisms responsible for CBD antidepressant activity point to the activation of 5-HT1A serotonin receptor signaling, as CBD-induced antidepressant effects were blocked by 5-HT1A antagonist (Zanelati et al., 2010). Studies also showed that indirect activation of CB1 by CBD, potentially via impairment of the degradation of the endocannabinoid anandamide, plays a role in CBD-induced antidepressant-like effects (Sartim et al., 2016). In addition, CBD increased brain-derived neurotrophic factor in mice and promoted neuronal synaptogenesis, which was also proposed to mediate the antidepressant-like effects of CBD (Sales et al., 2019). Moreover, as noted in several papers, growing evidence, although still limited, has implicated a role for inflammation in the etiology of depression (Majd et al., 2020; Miller and Raison, 2016; Song and Wang, 2011). Given the anti-inflammatory properties of CBD as discussed in section 3.1, it is possible that CBD exerts its antidepressant-like effects, at least in part, by attenuating inflammation and thus protecting neurons and neurogenesis.

Studies investigating the effects of CBD on depression in humans are scarce (Elsaid et al., 2019; Silote et al., 2019). One clinical trial investigating the therapeutic effects of CBD on psychotic-like symptoms in 20 frequent cannabis users revealed improvement in symptoms of depression (Solowij et al., 2018). However, this study had a small sample size and lacked a placebo-control. In addition, the symptoms of depression in this studied cohort were associated with chronic cannabis use; therefore, the findings could not be generalized to patients with depression disorders that are not arising from cannabis use. Beyond the aforementioned study, no other clinical trials have been reported on the effects of CBD on depression. To determine the effects of CBD on depression in humans, additional large scale, randomized, and placebo-controlled clinical trials will need to be conducted.

3.4. Sleep disorders

Cannabis has long been anecdotally used for the treatment of sleep disorders. It is proposed that cannabinoids may play a role in regulating sleep by interacting with the endocannabinoid system. Studies have suggested that the endocannabinoid system is involved in the regulation of circadian rhythm (Hanlon, 2020; Murillo-Rodríguez, 2008; Navarro et al., 2003; Pava et al., 2016). As reviewed by Vaughn et al. (2010), endogenous cannabinoid signaling may serves as a link between circadian regulators (such as the intrinsic clock of the suprachiasmatic nucleus) and physiological processes, including the sleep-wake cycle.

Studies investigating the effect of cannabinoids on sleep have been predominantly focused on THC. This is not surprising since THC is the primary psychotropic ingredient of cannabis and a known agonist of cannabinoid receptors. A recent critical review conducted by Kuhathasan et al. (2019) reported that many clinical studies have suggested that the use of THC and THC-derivatives, alone or in combination with CBD, may improve self-reported sleep quality, reduce sleep disturbances, and decrease sleep onset latency. However, the vast majority of studies (33 out of 41 clinical studies reviewed by Kuhathasan et al.) examined the improvement of sleep as a secondary effect to relieving primary disorders, such as chronic pain, neuropathic pain, and multiple sclerosis. Beyond those studies, research examining the use of cannabinoids specifically for treatment of sleep disorders is relatively limited (Babson et al., 2017; Kuhathasan et al., 2019; National Academies of Sciences Engineering and Medicine, 2017).

Concerning the effect of CBD on sleep, a variety of molecular mechanisms have been investigated, including the inhibition of the enzyme FAAH by CBD. FAAH is well established as being a key enzyme in the breakdown of fatty acid amides including the two most extensively characterized endocannabinoids, anandamide and 2-arachidonylglycerol. An in vitro study showed that 32 μM CBD decreased FAAH enzymatic activity in mouse brain microsomes by 43% (WATANABE et al., 1996; Watanabe et al., 1998). Likewise, a second in vitro study using membranes prepared from rat brain reported a 50% decrease in FAAH activity by 15.2 μM CBD (De Petrocellis et al., 2011). Based primarily on these two studies, it has been proposed that CBD-mediated inhibition of FAAH will lead to an increase in endogenous cannabinoid receptor ligands, activation of neurons in waking-related brain areas such as hypothalamus and dorsal raphe nucleus, and deregulation of circadian rhythm gene expression in microglial cells (Lafaye et al., 2019; Murillo-Rodriguez et al., 2006).

Studies investigating the effect of CBD on sleep in animal models and human subjects have yielded mixed results, which could, at least in part, be attributable to the differential effect of CBD based on the administered dose (Babson et al., 2017; Bonaccorso et al., 2019). It has been reported in a small clinical study with 8 subjects that a single low dose of CBD (15 mg) decreased nocturnal duration of sleep (Nicholson et al., 2004), which was consistent with the finding that perfusion of small amounts of CBD (10 μg in 5 μl) into the rat brain increased wakefulness and decreased sleep (Murillo-Rodriguez et al., 2006; Murillo-Rodriguez et al., 2011). On the other hand, intraperitoneal injection of relatively higher doses of CBD (20–40 mg/kg bw) increased slow-wave sleep time and decreased wakefulness in rats (Monti, 1977). Likewise, in clinical trials carried out according to FDA testing guidelines in support of the registration of the CBD pharmaceutical, Epidiolex®, subjects administered high doses of CBD (10–20 mg/kg bw/day) repeatedly reported sedation and somnolence as a side effect (Devinsky et al., 2018a; Thiele et al., 2018). In addition, several case series studies (higher risk of bias) reported that CBD improved sleep in patients with Parkinson’s Disease and in patients suffering from anxiety (Chagas et al., 2014; Shannon et al., 2019). In the case series reported by Chagas et al. (2014), four Parkinson’s disease patients receiving CBD (75 – 300 mg/day) for 6 weeks reported a reduction in the frequency of rapid eye movement sleep behavior disorder symptoms. In a larger case series, Shannon et al. (2019) reported that 48 out of 72 patients who suffered from sleep or anxiety disorder showed improved sleep scores within the first month of CBD treatment (25–175 mg/day). By contrast, a randomized, double-blind, placebo-controlled crossover study with 70 participants (lower risk of bias) revealed no acute effects of CBD (single dose of 300 mg) on the sleep-wake cycle of healthy subjects (Linares et al., 2018). Overall, the current state-of-the-science on how CBD affects sleep is still in its early stages with limited clinical studies to date examining the use of CBD, specifically for treatment of sleep disorders. This represents a significant data gap that requires large-scale randomized controlled clinical trials with validated objective sleep measures.

4. Current knowledge and data gaps concerning the safety of CBD

Considering the increasing use of CBD as pharmaceutical and consumer products, comprehensive literature reviews have been published summarizing the potential therapeutic effects and toxicity of CBD. In 2011, Bergamaschi et al. reviewed the safety and side effects of CBD in both in vitro and in vivo studies and concluded that CBD is well tolerated in humans based on therapeutic case reports but recommended additional studies to better define observed side effects (Bergamaschi et al., 2011). A subsequent literature survey conducted by Iffland and Grotenhermen in 2017 extended the aforementioned review and confirmed the safety profile of CBD for therapeutic use, especially compared to other drugs used for the treatment of epilepsy and psychotic disorders (Iffland and Grotenhermen, 2017). However, as noted by Bergamaschi et al., many studies that reported the lack of CBD side effects were primarily focused on the pharmacologic activity of CBD rather than comprehensively evaluating the safety of CBD (Bergamaschi et al., 2011). Recently, pre-clinical and clinical studies evaluating the safety of CBD were conducted during the development of Epidiolex®, which have provided valuable insights into the safety profile of CBD. In addition, a recent comprehensive review was conducted by Huestis et al. that primarily focused on the adverse effects and toxicity of CBD (Huestis et al., 2019). Here we provide a brief overview of the current knowledge on the safety of CBD based on several recent key toxicological studies and highlight data gaps for future research.

4.1. The safety evaluation of CBD in pre-clinical studies

Several pivotal repeat-dose oral toxicity studies of CBD have been conducted in mice, rats, and dogs according to FDA guidelines and good laboratory practices (GLP) in support of the Epidiolex® New Drug Application. Results from those studies were reviewed and summarized by FDA CDER (Center for Drug Evaluation and Research, 2018b). In these studies, purified CBD (the exact purity of CBD used in these studies has been redacted in the CDER document) was administered by oral gavage to mice (400, 550, or 700 mg/kg bw/day), rats (15, 50, or 150 mg/kg bw/day), and dogs (10, 50, or 100 mg/kg bw/day) for 13 weeks, 26 weeks, and 39 weeks, respectively. Assessments included mortality, clinical signs, body weight, food consumption, and clinical and anatomic pathology evaluations. As concluded by CDER, the primary target organ for CBD is the liver, as evidenced by hepatocellular hypertrophy accompanied by an increase in alanine aminotransferase (ALT) and alkaline phosphatase in animals treated with medium and high doses of CBD. In addition to the aforementioned Epidiolex® pre-clinical studies, there are other studies evaluating the acute and repeat-dose oral toxicity of CBD. Ewing et al. conducted a hepatoxicity study using CBD-rich extract (CBD: 57.9%; other cannabinoids: <5%) and reported that acute (2460 mg/kg bw/day for 1 day) and subacute (615 mg/kg bw/day for 10 days) oral administration of CBD to mice increased the liver-to-body weight ratio, ALT, aspartate aminotransferase, and total bilirubin, suggesting the potential for hepatotoxicity at high CBD doses (Ewing et al., 2019). Further mechanistic investigations using gene expression endpoints suggested that CBD-induced liver injury might be cholestatic (Ewing et al., 2019). In addition, Marx et al. conducted a battery of OECD-compliant toxicological studies to evaluate the safety of a hemp extract (CBD: 25%; other cannabinoids: 1%; edible fatty acid: 61%) (Marx et al., 2018). Rats were administered hemp extract for 90 days, resulting in estimated CBD exposure levels of 25, 90, or 180 mg/kg bw/day. A comprehensive list of endpoints was assessed including body and organ weights, food consumption, hematology endpoints, clinical chemistry endpoints, and both gross pathological and histopathological examination. It was reported that body weights decreased, and liver and adrenal gland weights increased in animals in the 360 and 720 mg hemp extract/kg bw/day (equivalent to 90 and 180 mg CBD/kg bw/day) groups concomitant with an increase in gamma-glutamyl transferase. Therefore, the no-observed-adverse-effect level for the hemp extract in rat was considered to be 100 mg/kg bw/day with CBD exposure at 25 mg/kg bw/day.

Reproductive and developmental toxicity of CBD has been suggested in the literature as reviewed by Carvalho et al. (Carvalho et al., 2020). For instance, male mice receiving an oral dose of 15 or 30 mg/kg bw/day of CBD (99% purity) for 34 days showed an increase in abnormalities of sperm and a decrease in fertility rate and the number of litters (Carvalho et al., 2018a; Carvalho et al., 2018b). Conversely, a guideline-compliant toxicological study found no effect of CBD on sperm count and sperm morphology in rats administered hemp extract (CBD: 25%; other cannabinoids: 1%; edible fatty acid: 61%. CBD exposures were estimated to be 25, 90, or 180 mg/kg bw/day) for 90 days (Marx et al., 2018). In addition, the effects of CBD on fertility were not observed in the reproductive and developmental toxicity studies conducted following FDA guidelines and GLP in support of the Epidiolex® New Drug Application (Center for Drug Evaluation and Research, 2018b). In one study, rats were administered CBD at 75, 150, or 250mg/kg bw/day for 2 weeks prior to mating and until gestation day 6. A full battery of assessments was conducted including male and female fertility, reproductive performance, and parameters of implantation and fetuses. The researchers concluded that no clear effects of CBD were observed on fertility and reproductive performance in the rat. In addition, the effect of CBD on embryo-fetal development was evaluated in rats (75, 150, or 250 mg/kg bw/day) and rabbits (50, 180, or 125 mg/kg bw/day). Fetuses were evaluated for external, visceral, and skeletal malformations and variations. Litter loss (in 2 of 20 dams) was observed in the 250 mg/kg bw/day dose group in rats. In addition, there was delayed or retarded development along with fetal body weight reductions in rabbits administered 125 mg CBD/kg bw/day. Moreover, the effects of CBD on pre- and postnatal development were assessed in rats at dose levels of 75, 150, or 250 mg/kg bw/day from gestation day 6 to postnatal day 21. A full battery of assessments was conducted including litter size, body weight, physical and functional development, sexual milestones, auditory startle, motor activity, and learning and memory. Adverse effects of CBD treatment have been observed primarily in the dose groups of 150 or 250 mg/kg bw/day including decreased pup body weights, delays in achieving developmental landmarks (eye opening, pupillary reflex, and sexual maturation in male and female), neurobehavioral changes (decreased locomotor activity), and adverse effects on reproductive system structure (small testis) and possibly function (Center for Drug Evaluation and Research, 2018b).

There are several reports suggesting that CBD may induce chromosome damage and therefore exhibits clastogenicity. An in vivo micronucleus assay conducted in mice showed increased incidence of micronuclei (Zimmerman and Raj, 1980). More recently, the in vitro COMET assay and the micronucleus assay conducted in a human cell line also suggested an increase in chromosomal damage by CBD (Russo et al., 2019). By contrast, several guideline studies evaluating the genotoxicity of CBD concluded that CBD is not genotoxic. A standard battery of genetic toxicology studies was conducted according to FDA guidelines and GLP in support of the Epidiolex® New Drug Application, which included the Ames assay, the in vivo micronucleus assay in the rat, and the in vivo COMET assay (Center for Drug Evaluation and Research, 2018b). CDER summarized the results by stating that “CBD was negative for mutagenicity and clastogenicity in adequately conducted assays” (Center for Drug Evaluation and Research, 2018b). Similarly, a guideline-compliant study evaluating the safety of CBD-containing hemp extracts (CBD: 25%; other cannabinoids: 1%; edible fatty acid: 61%) concluded that no evidence of genotoxicity was found in a bacterial reverse mutation test (Ames test), in vitro mammalian chromosomal aberration test, or in an in vivo mouse micronucleus assay (Marx et al., 2018). In addition, a study conducted in human lymphocytes suggested no increase in chromosome damage after administration of 1200mg CBD/day for 20 days in healthy human volunteers (Matsuyama and Fu, 1981).

4.2. The safety evaluation of CBD in clinical studies

Recently, a substantial number of clinical studies for CBD-based therapeutic Epidiolex® have been conducted including randomized controlled trials and open-label expanded access trials following good clinical practices (Devinsky et al., 2017; Devinsky et al., 2016; Devinsky et al., 2019; Devinsky et al., 2018a; Devinsky et al., 2018b; Devinsky et al., 2018c; Herlopian et al., 2020; Laux et al., 2019; Szaflarski et al., 2018a; Szaflarski et al., 2018b; Thiele et al., 2019; Thiele et al., 2018). A total of 2754 patients were enrolled in these clinical trials and received CBD ranging from 5 to 50 mg/kg bw/day for 2 to 146 weeks. Adverse effects produced by CBD have been evaluated and reported in these clinical trials. As summarized in CDER’s report, the most commonly observed adverse events ascribed to CBD treatment “were in the following categories: central nervous system (e.g., somnolence and sedation), gastrointestinal (e.g., decreased appetite and diarrhea), hepatic (e.g., increased serum transaminase levels), and infections (e.g., pneumonia). These events were generally mild to moderate in severity. Serious and/or severe adverse events were generally related to elevated serum transaminase, somnolence and lethargy, and infections” (Center for Drug Evaluation and Research, 2018a). Overall, CDER concluded based on a risk-benefit analysis that the risks associated with Epidiolex® are acceptable, although the risk of liver injury has the potential to be serious (Center for Drug Evaluation and Research, 2018a). A follow-up meta-analysis of adverse effects of CBD in randomized clinical trials concluded that “associations of CBD with abnormal liver function tests, somnolence, sedation and pneumonia were limited to childhood epilepsy studies, where CBD may have interacted with other medications such as clobazam and/or sodium valproate. After excluding studies in childhood epilepsy, the only adverse outcome associated with CBD treatment was diarrhea” (Chesney et al., 2020). The authors suggested that “additional safety data from clinical trials outside of childhood epilepsy syndromes and from studies of over-the-counter CBD products are needed” (Chesney et al., 2020). Towards this end, a recent study was conducted in healthy adults to evaluate the effect of CBD on liver safety (Watkins et al., 2020). Sixteen healthy adults were enrolled in an open-label trail receiving 1500 mg/day CBD (approx. 20 mg/kg bw/day in a 70 kg person) for 3.5 weeks. It is reported that 7 (44%) participants experienced peak serum ALT values greater than the upper limit of normal. Moreover, the ALT values in 5 (31%) participants exceeded 5 times of the upper limit of normal, which meets the international consensus criteria for drug-induced liver injury. Therefore, the authors concluded “healthy adults consuming CBD may experience elevations in serum ALT consistent with drug-induced liver injury” (Watkins et al., 2020).

4.3. Summary of the safety profile of CBD and data gaps

Overall, the extensive pre-clinical and clinical studies have provided a comprehensive safety profile of CBD for therapeutic use. The risks associated with CBD at therapeutic doses (10–20 mg/kg bw/day) are considered acceptable by CDER, with liver toxicity by CBD being recognized as a potentially serious adverse health outcome. In addition, there are some data gaps pertaining to CBD toxicity. For example, reproductive and developmental toxicity of CBD has been reported in animals but only at high doses (i.e., 150–250 mg/kg bw/day). The immune suppressive effects of CBD in laboratory animals have been extensively reported but few studies have been conducted in humans or human models. Given that an increased incidence of respiratory infections has been observed in Epidiolex® clinical trials, it is important to further evaluate the effects of CBD on the human immune system.

5. Safety of CBD-containing consumer products

Although CBD-containing consumer products are considered relatively safe by the public, are they risk free? Clearly the answer to this question is very much dependent on the amount of CBD contained in the products as well as how many and the amounts of these products a typical consumer uses over time. It is important to keep in mind that approval of CBD as a treatment for Dravet syndrome and Lennox-Gastaut syndrome was determined based, in part, on (a) the benefit of CBD outweighing the potential risks; and (b) how patients respond to the limited therapeutics currently available for the treatment of these disorders. However, the benefit profile of CBD for the average consumer will differ substantially from therapeutic use for Dravet and Lennox-Gastaut syndrome.

Currently there is no regulatory guidance on how much CBD can be safely consumed daily. A risk assessment of CBD should take into consideration a number of factors, including results from dose-response studies that provide no adverse effect levels, the uncertainty pertaining to CBD toxicity due to the aforementioned data gaps, as well as potential variations in sensitivity to adverse health outcomes across individuals in response to CBD. In addition, it has been shown that food can greatly influence CBD bioavailability as evidenced by plasma concentrations of CBD increasing by 4–5-fold when CBD was taken with high-fat meals (Taylor et al., 2018). Moreover, interactions between CBD and other drugs have been suggested based on elevated transaminase levels (indicator of liver injury) in patients taking the antiepileptic drug valproate, concomitantly with Epidiolex® (Gaston et al., 2017). Furthermore, most of the currently available studies were focused on the toxicity of CBD when administered orally. The toxicity profile of CBD administered via other routes of exposure, such as inhalation and dermal application, has not been adequately addressed in the published literature, which is relevant to vaping, smoking, and topically applied products that contain CBD.

Attempts have been made to identify a safe daily intake limit for CBD in consumer products. Recently, a position paper on the potential adverse effects of CBD-containing consumer products was drafted by the United Kingdom’s Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment, which is an independent scientific committee that provides advice to government departments and agencies on matters concerning the toxicity of chemicals. Based on their evaluation, the committee concluded that “1 mg/kg bw/day of CBD represents a pragmatic upper level of intake above which there would be clear concerns about safety, until further data are available” (Committee on Toxicity of Chemicals in Food Consumer Products and the Environment, 2020).

It should also be noted that quality assurance issues have led to safety- and regulatory compliance-related concerns with CBD-containing products placed into the market. First, inaccurate labeling has been reported as a prevalent issue among CBD products sold online (Bonn-Miller et al., 2017; Hazekamp, 2018; Pavlovic et al., 2018). Bonn-Miller and co-workers have analyzed 84 CBD products from 31 companies and found only 31% of products were accurately labeled with respect to CBD content (<10% variability). The other 69% of the products were mislabeled, with 26% containing less CBD and 43% containing more CBD than indicated on the label (Bonn-Miller et al., 2017). In addition to labeling inaccuracies, the lack of consistent and clear guidance on the dose that should be used increases the likelihood for consumers to self-administer amounts of CBD that could result in adverse outcomes. Second, many CBD-containing products may contain other constituents derived from hemp (such as other cannabinoids and terpenes), as well as other substances and contaminants, many of which have not been adequately evaluated for their toxicity. Examples include cases of poisoning from a synthetic cannabinoid found in CBD oil in Utah (Horth et al., 2018) and detection of polycyclic aromatic hydrocarbons exceeding recommended levels in 20 out of 29 CBD products analyzed by the International Cannabis and Cannabinoid Institute in the Czech Republic (White, 2019). The above would suggest that there is a need for more guidance on use and quality controls in the CBD consumer product industry.

6. Regulation of the use of CBD in consumer products

In the U.S., CBD is regulated based on its origin and intended use. As previously noted, CBD occurs naturally in the plant Cannabis sativa. C. sativa is subject to regulation as marijuana or as hemp, depending on its content of THC. The Controlled Substances Act (CSA) defines “marijuana” to include certain parts of C. sativa and derivatives thereof. Marijuana is a controlled substance, such that its possession and distribution are tightly restricted. However, the CSA definition of “marijuana” expressly excludes “hemp” as defined in the Agricultural Marketing Act (AMA). The AMA defines “hemp” to include C. sativa and derivatives thereof that contain less than 0.3% THC by dry weight. Thus, hemp and products derived from hemp can be lawfully marketed without running afoul of federal controlled substances law.

The exclusion of hemp from the definition of marijuana has given rise to a robust market in products derived from hemp, including a wide range of products that contain hemp-derived CBD. Many of those products are subject to regulation by the U.S. FDA under the authority of the Federal Food, Drug, and Cosmetic Act (FFDCA). That law defines and establishes the requirements for lawful distribution of drugs, biological products, medical devices, foods, cosmetics, and tobacco products. The discussion that follows focuses on the use of CBD in drugs, foods (including conventional foods and dietary supplements), and cosmetics.

As previously discussed, FDA has approved a drug that contains CBD as an active ingredient (Epidiolex®). That approval has important implications for the regulatory status of CBD in foods because of provisions in the FFDCA that protect the integrity of the drug approval pathway. Briefly, those provisions prohibit the commercial distribution as a food of any substance that FDA has approved as a drug, unless the substance has a prior history of marketing as a food. Currently, FDA’s position is that those provisions apply to CBD, such that CBD cannot be lawfully used in food. FDA could choose to waive this prohibition through the issuance of a regulation. However, FDA has never pursued that type of rulemaking for any substance, and as yet there have been no concrete indications that the agency has firm plans to do so for CBD.

Notwithstanding FDA’s position that the use of CBD in food is illegal, the market for CBD-containing food products – particularly dietary supplements – has exploded. That explosion appears to have been driven largely by promotion of the many health-related benefits purportedly associated with CBD. As long as those benefits derive from an effect on a structure or function of the body, they can be lawfully promoted in association with dietary supplements through the use of what is referred to as a structure/function claim. Thus, for example, a claim that a CBD-containing dietary supplement enhances mood, promotes relaxation, or supports sleep would be consistent with that product’s status as a dietary supplement because those claims are structure/function claims.

To date, FDA has not acted to curtail the commercial distribution of dietary supplements that are promoted with structure/function claims. However, FDA has acted against dietary supplements that are promoted with any claim to diagnose, treat, cure, prevent, or mitigate a disease. Such a claim renders a dietary supplement an unapproved drug. Thus, for example, a claim that a CBD-containing dietary supplement relieves pain, treats anxiety or depression, or mitigates a sleep disorder is likely to draw an objection from FDA.

Consumers have also shown great interest in cosmetic products that contain CBD. FDA’s approval of Epidiolex® has not hampered the development of a market for CBD-containing cosmetics because the legal provisions that prohibit the use of CBD in food do not apply to cosmetics. That said, the marketing potential for cosmetics is limited by the fact that a cosmetic is legally defined as an article intended to cleanse, beautify, promote attractiveness, or alter the appearance. A cosmetic cannot be lawfully promoted with a structure/function claim, nor can it be promoted with a claim to diagnose, treat, cure, prevent, or mitigate any disease. In either case, FDA would deem the cosmetic to be an unapproved new drug.

FDA is not the only regulatory agency with an interest in policing the market for CBD products. The Federal Trade Commission (FTC) regulates advertising of consumer products generally, including many of the products regulated by FDA. FTC’s principal interest lies in ensuring that advertising claims for consumer products are truthful, accurate, not misleading, and adequately substantiated. In this context, adequate substantiation means that an advertiser must have a reasonable basis for an advertising claim. The quantity and quality of evidence required to substantiate a claim varies according to the nature of the claim. Claims of health-related benefits such as structure/function claims are subject to a relatively high standard of substantiation – namely competent and reliable scientific evidence. The failure to possess adequate substantiation at the time an advertising claim is made can leave a marketer vulnerable to an enforcement action by FTC. That same failure can also leave a marketer vulnerable to civil lawsuits under state laws grounded in consumer fraud. There have already been several such lawsuits targeting CBD products that allegedly overstated product benefits or simply overstated the quantity of CBD on the product label.

Setting aside questions of regulatory status and the use of promotional claims, products containing CBD are subject to all of the same FDA requirements as products that do not contain CBD. Chief among these is the need to establish safety, in accord with the safety standard that applies to the product in question. The safety standard for substances intentionally used in conventional food is reasonable certainty of no harm, which is a very high standard. The safety standard for dietary ingredients used in dietary supplements is no significant or unreasonable risk of illness or injury under the conditions recommended or suggested in labeling, or under ordinary conditions of use. A cosmetic is deemed adulterated if it bears or contains a poisonous or deleterious substance that may render the product injurious to users under the conditions of use prescribed in labeling, or under customary or usual conditions of use. By comparison, the safety standard for drugs is relative because it is viewed through the lens of the drug’s benefits versus its risks.

As additional examples of FDA requirements that could apply to a product containing CBD, conventional foods must be manufactured under applicable good manufacturing practices and preventive controls. These manufacturing requirements are intended to help ensure both safety and quality and have been enhanced as a result of recent amendments to the FFDCA made by the FDA Food Safety Modernization Act of 2011. Similarly, a dietary supplement must be manufactured in compliance with extensive and detailed good manufacturing practice requirements that are specific to dietary supplements. Finally, a product must be labeled in accord with all applicable requirements. Failure to comply with any of these safety, quality, or labeling-related requirements can provide an independent basis for FDA to take regulatory action. In addition to meeting federal legal requirements, products containing CBD must also meet any requirements that apply under state law. Ordinarily, there is not much variance between federal and state requirements for FDA-regulated products. However, FDA’s objection to the use of CBD in food has prompted some states to establish their own regulatory frameworks to permit the marketing of such products under state law. Thus, for example, Colorado law allows the use of CBD in food, provided that all of the requirements specified under Colorado law are met. In addition, a number of other types of CBD-containing products, such as tinctures and vapes, are being marketed under state laws. The emergence of such state-based regulatory schemes could result in conflicting requirements that could impede the development of a national market for CBD products.

In summary, the legal framework for CBD remains complex and murky, notwithstanding the fact that hemp is clearly no longer subject to regulation as a controlled substance under federal law. Clarity might come in the form of additional action by FDA and other regulators, or perhaps through additional legislation by the U.S. Congress. Federal legislation that would create a regulatory path for the use of hemp-derived CBD in dietary supplements has been introduced, but its prospects are uncertain. In the interim, those with an interest in the CBD market will need to closely monitor scientific and regulatory developments on many fronts, and consult with qualified scientific and legal experts as needed to assess the impact of those developments.

7. Conclusion

Given the current state of the science pertaining to the safety and potential benefits of CBD and lingering questions about its regulatory status, a reasonable question is, “What does the future hold for CBD-containing consumer products?” Although CBD products are relatively new, they are rapidly growing in popularity and are predicted to become a multi-billion-dollar industry in the near future.

In the near term, one of the most significant obstacles facing the CBD consumer products industry is the convoluted regulatory landscape. Although hemp-derived CBD is not regulated as a controlled substance under federal law, CBD products must still comport with all applicable provisions of the FFDCA. FDA’s position that the use of CBD in food is illegal is a fundamental barrier to entry for many companies, and many in the industry are working to convince FDA that some modification of that position is in order – or failing that, to convince Congress that a change in law is necessary.

With respect to safety, a major informational gap for inclusion and marketing of CBD in consumer products is the absence of a comprehensive risk assessment providing guidance on a safe daily intake for consumers. Although CBD in the form of Epidiolex® underwent extensive pre-clinical and clinical evaluations prior to approval as a drug, this approval was based on an assessment of risk versus benefit in the context of a specific disease and patient population. The use of CBD in a wide range of products used by the general population every day for long periods of time raises questions that can be resolved through the generation of additional safety data. The highest priority data includes the point of departure of CBD-induced hepatotoxicity, developmental toxicity and immunotoxicity generated in human-relevant models. Moreover, the toxicity profile of CBD administered via other routes of exposure, such as inhalation and dermal application, needs to be established.

Lastly, it is important to continuously address quality-related questions about the identity and composition of some products. Specifically, beyond CBD, what other cannabinoids and cannabis-derived substances are present in hemp-containing products? Cannabis sativa contains over 100 different structurally related cannabinoids, many of which have not been the subject of robust published safety studies. Second, some companies continue to struggle with quality control. Many, if not most, CBD products sold today by larger manufacturers and distributors undergo analytical testing for contaminants including metals and pesticides and are manufactured and labeled under appropriate controls. However, the industry is highly diverse, and a recent study found that only a third of CBD products evaluated were correctly labeled for CBD quantity. Finally, labeling directions regarding the quantity/dose that consumers should use is often unclear, with many CBD-containing products providing limited guidance. As the cannabinoid consumer products sector matures, there is an increasing need for industry-wide standards to ensure quality and safety.

The strong consumer demand for CBD-containing products will drive a rapid expansion of the category. Continued collaboration between FDA, industry, and the scientific community will be important to ensure that consumer safety, regulatory compliance and quality of products is achieved as the industry moves forward.

Highlights:

1. A review of the health effects of CBD in consumer products.

2. Assess the state-of-the-science on the safety of CBD and identify critical knowledge gaps for future studies.

3. Summarize the current regulations that govern CBD use in consumer products.

Abbreviations:

THC

Δ9-tetrahydrocannabinol

CBD

cannabidiol

CB1

cannabinoid receptor type 1

CB2

cannabinoid receptor type 2

TRPV1

transient receptor potential vanilloid type 1

FAAH

fatty acid amide hydrolase

PPAR-γ

peroxisome proliferator-activated receptor gamma

FDA

Food and Drug Administration

CDER

Center for Drug Evaluation and Research

GLP

good laboratory practices

ALT

alanine aminotransferase

CSA

Controlled Substances Act

AMA

Agricultural Marketing Act

FFDCA

Federal Food, Drug, and Cosmetic Act

FTC

Federal Trade Commission